Cancer

In reply: Eden, Pyke and Hitchins are happy with the findings of the rapid literature search that we performed for the general practitioner who wanted to know about the safety of HRT in a woman treated for breast cancer. However, they have concerns with the process. Eden is worried that we missed two Australian publications on the issue. In fact, they misunderstand our intentions. Firstly, we did not raise the issue, nor deliver an "advisory statement". It was the general practitioner who asked the question. We were trying to provide a rapid (few days) and responsive service to provide credible information to help a doctor manage a patient. Secondly, we were not able to undertake a full systematic review (which would take a full-time researcher as long as six months and would cost accordingly).1 Instead, our best strategy was to use a cascade process of searching, looking first for the most rigorous study types that would answer the clinical question. If not available we go to the next most rigorous, and so on, stopping when we find the relevant evidence.2 For this question, the ideal study type would be a meta-analysis of randomised controlled trials (RCTs). However, no RCTs were available (as Eden, and the guidelines to which Pyke refers, note), and we had to content ourselves with observational studies. We should remember that no evidence for safety is not the same as evidence for danger. What is important is that we did not miss any trials. Legal issues worry many doctors, even when decisions are supported by best research evidence,3 but, rather than pose a medicolegal threat, we believe that this evidence-based approach is more likely to protect doctors. Why? Failures in communication are the most common preventable cause for doctors being sued by patients.4 Yet, taking the trouble to find empirical information such as this and then discussing it with the patient is surely the most effective way of communicating the pros and cons of different treatment strategies (including, we agree, alternatives such as those mentioned by Hitchins). In the end the patient has to decide on the basis of the risks and benefits, and the choice can often be extremely difficult. It is likely to be more dangerous to assume the patient has abdicated this responsibility to the doctor without checking first. Can doctors be sued for a "safe" decision that leaves a patient exposed to unnecessary symptoms? It may be dangerous to assume that doctors can play "safe" in any one direction. Why do experts take exception when non-experts delve in their areas for the best evidence to manage patients? After all, a cat may look at a king.5 Experts seem to welcome the attention, but seem to think they should be dispensing the information. However, until the information can be delivered more effectively, this sort of stopgap system will have to do.

Robert N Hitchins

Objective: To determine the prevalence of colorectal neoplasia detected by rescreening people with average risk five years after initial screening by flexible sigmoidoscopy.Design: Prospective survey of results of a colorectal cancer screening program.Participants: People aged 55–64 years with no symptoms or family history of colorectal cancer who were recruited from the community for flexible sigmoidoscopy screening five years previously (July 1995 to December 1996) and had no colorectal neoplasms detected.Setting: Fremantle Hospital, Western Australia, a community-based teaching hospital, December 2000 to June 2001.Main outcome measures: Number and size of colorectal neoplasms (adenomas or cancer) compared between rescreened patients and initial screening population (all 982 people screened between July 1995 and December 1996).Results: 803 people were eligible for rescreening; 138 were no longer at the recorded address, and 361 of the remaining 665 (54%) were rescreened. Rescreening found a significantly lower prevalence of colorectal adenomas than initial screening (8% [95% CI, 5%–11%] versus 14% [95% CI, 13%–15%]; P < 0.05) and also a lower percentage of adenomatous polyps over 5 mm in diameter (32% [95% CI, 15%–49%] versus 51% [95% CI, 46%–56%]; no significant difference).Conclusion: Average-risk people who have been screened for colorectal neoplasms, with none found, have a low prevalence of neoplastic lesions five years later. Longer rescreening intervals need to be considered.

Cameron F E Platell PhD, FRACS · Gillian Philpott EN · John K Olynyk MD, FRACP

To the Editor: We conducted a joinpoint analysis of death certificate data on prostate cancer from the Australian Bureau of Statistics. Between 1979 and 1994, mortality rates increased by 2.1% per year (95% CI, 1.6% to 2.5%). However, between 1994 and 1999, mortality decreased by 4.2% per year (95% CI, – 5.8% to – 2.4%). The total decrease in mortality rates for the five years to 1999 (the most recent year for which data were available) was 22.6% (95% CI, – 32.9% to – 12.7%). Joinpoint analysis is a statistical method that measures changing trends over time. It chooses the best-fitting points (called joinpoints) at which the rate of increase or decrease changes significantly.1 We did not look at the data and then choose 1994 as the start of the decreasing trend in prostate cancer mortality. The significant decrease since 1994 (and the consistent increase between 1979 and 1994) were identified by the joinpoint analysis. Whether early diagnosis and treatment of prostate cancer subsequent to screening with prostate-specific antigen (PSA) tests can save lives is still an open question that is best answered by randomised-controlled, long term trials. Nevertheless, it is important that we try to understand the recent decrease in population-based mortality. The mortality decline started in 1995, about five years after PSA testing became widely available in Australia. The use of PSA testing increased dramatically, reaching a peak in most States in 1994 and 1995.2 In 1996, the Australian Health Technology Advisory Committee reviewed the evidence and recommended against screening.3 Since then, the number of PSA tests has decreased.2 Recent mortality declines have also been observed in the United States and the United Kingdom following increases in the use of PSA testing. The mortality decline in the US has been greater than that in the UK, coinciding with more PSA testing in the US than the UK.4 At least three questions arise from these observations: Is it plausible that the decrease could be due to some factor other than PSA testing, such as better treatment? How do we explain these results to men who want to make an informed choice about whether to be tested? Is this type of evidence strong enough to warrant a change in the current recommendations on PSA testing?

Michael Coory MB BS, PhD · Peter Baade BSc, PhD

Comment: Using joinpoint analysis, Coory and Bade have identified a significant trend towards lower mortality rates from prostate cancer since 1994, and relate this chronologically to the increased use of prostate-specific antigen (PSA) testing in Australia. The authors raise three reasonable questions regarding this finding: Is it plausible that the decrease could be due to some factor other than PSA testing, such as better treatment? Ecological data such as those presented by Coory and Baade are subject to the pitfalls of ecological fallacy and confounding.1 Ecological fallacy exists when there is an apparent association (eg, more men in the population screened, fewer men in the population dying), but there is no association at an individual level. Confounding would occur when there are other factors that account for the outcome, or distort the relationship between PSA testing and mortality. Treatment is one such factor, but changes in diet and other factors could also play a role (eg, lycopene from tomato-based foods2). How do we explain these results to men who want to make an informed choice about whether to be tested? If these data were presented to men, then it would have to be explained that the data do not provide evidence of the benefits of screening and that many other factors could explain the relationship. Further, men need to be informed of the risks of false negative and false positive results associated with screening, and the risks of complications associated with treatment. It is important to assist men to make a balanced decision. Interestingly, studies in which men have been involved in such informed decisions show that information can reduce the probability that men will choose to be screened.3,4 Is this type of evidence strong enough to warrant a change in the current recommendations on PSA testing? Ecological associations generate hypotheses that are worthy of further investigation. Randomised controlled trial evidence at best, or case–control studies at least, would be required to provide evidence of the benefit of screening using PSA. Some such studies are currently in progress, including the prostate, lung, colorectal and ovarian cancer screening trial of the National Cancer Institute,5 and the European Screening Study for prostate cancer.6 Those in favour of PSA testing argue that it is the only means of diagnosing prostate cancer at an early and potentially curable stage.7 Against this is the argument that many prostate cancers are not clinically significant, as they are slow growing and will not spread, and there is a danger of diagnosis and treatment adding substantially to men's psychological and physical morbidity without benefits in terms of survival or quality of life.8 In the absence of evidence from randomised controlled trials or case–control studies, screening for prostate cancer using PSA testing remains controversial.9

Julie B Byles

Clinical questionAfter mastectomy, chemotherapy and radiotherapy for high-grade ductal carcinoma with nodal involvement and lymphatic infiltration, a 48-year-old woman had premature menopause, with symptoms of loss of libido. Her general practitioner wanted to know how safe and effective hormone replacement therapy (HRT) would be for this patient. Search questionThe revised question was: "Does HRT increase the likelihood of recurrence in a patient previously diagnosed with breast cancer?". The ideal study to answer this question would be a randomised controlled trial of HRT versus placebo comparing outcomes of mortality and recurrence in women previously treated for breast cancer or high-grade ductal carcinoma of the breast. SearchWe searched two online databases: PubMed Clinical Queries <http://www.ncbi.nlm.nih.gov/entrez/query/static/clinical.html> and the Cochrane Library, using the search terms "hormone replacement therapy", "breast cancer", "breast neoplasm", "mastectomy" and "libido". Summary of findingsNo ideal studies have been published. However, five observational studies (three cohort and two case–control) were identified that reported the occurrence of adverse events after administration of HRT in women previously treated for breast cancer. Two of the cohort studies were prospective studies of 24 and 25 women who had received HRT after treatment for breast cancer.1,2 No recurrences were reported in the 24 women observed over a period of 24–44 months;1 and three recurrences occurred in the 25 women after a mean follow-up of 30.4 months (survival rate, 96%).2 In the retrospective cohort study, seven recurrences occurred in 77 women;3 the average interval from diagnosis to relapse was 45.3 months. A case–control study was conducted in a subset of the 77 patients in the cohort study mentioned above. Forty-one patients who received HRT were matched with 82 controls not receiving HRT. There were no significant differences in disease-free times and survival times between the two groups.4 The second case–control study of women after primary surgical treatment, in which 21 women received HRT and 42 matched controls did not, reported relapse in four patients in the treatment group (19%) and five in the control group (11%). The authors estimated the risk of relapse of breast cancer among women who had received HRT for a mean of 28 months compared with the control group (odds ratio [OR], 1.74; 95% CI, 0.34–8.88), and among those who had received HRT for less than 24 months (OR, 0.65; 95% CI, 0.02–7.85).5 CommentIn the studies identified in this search, there was little evidence of increased recurrence of breast cancer with the use of HRT in patients previously diagnosed with breast cancer. However, these studies involved small numbers of patients, the duration of follow-up was not long, and there was potential for bias. Caution should prevail until appropriate clinical trials are conducted. OutcomeAfter weighing up the evidence against the benefits of menopause symptom control, the general practitioner continued to prescribe HRT for this patient.

Christopher B Del Mar · Paul P Glasziou · Anneliese B Spinks · Sharon L Sanders · Deborah J Hilton

A New South Wales Supreme Court jury has decided that environmental tobacco smoke (ETS) can cause or materially contribute to the development of laryngeal cancer. Evidence presented that ETS may cause or materially contribute to laryngeal cancer included the molecular genetics of tobacco-smoke-induced carcinogenesis, and two relevant epidemiological studies. The plaintiff's exposure to ETS was established indirectly, on the basis of occupational history involving work as a bar attendant in licensed premises. The jury's decision seems likely to encourage other "passive smoking" cases, and may result in measures to reduce occupational exposure to ETS.

Bernard W Stewart PhD, FRACP · Peter C B Semmler MA, QC

To the Editor: We have recently noticed changes in the incidence of invasive cervical carcinoma in the Gippsland Health Region and would like to know whether other regions have noticed similar demographic changes. During 24 months in 1999–2000, 19 women (median age, 59 years; range, 33–88 years) with squamous carcinoma were registered in our pathology practice. Based on information from the Victorian Cervical Cytology Register, almost half (10 women) had no previous cervical smear history whatsoever, while three had had smears, but at irregular intervals up to 14 years apart. The remaining six women had had regular Pap smears, with 1–3 negative smears preceding the diagnosis of cancer. Sixteen of the women had consulted their general practitioner for some other ailment before the cervical cancer was discovered (median interval, 14 months), but no cervical smear had been obtained. Of particular interest is the fact that six of the 19 patients are in their seventh decade or older, with a median age of 80 years (range, 79–88 years). The Victorian Department of Human Services reports that the cervical-smear participation rate for eligible women in the Gippsland region is 68%, a rate not much different from the other regions.1 The two-yearly participation rate for the 60–69-years age group is 56%, and, although no official figure is available for women in their seventh or eighth decades, it is likely to be considerably lower. The Cancer Epidemiology Centre has recorded that, over a 16-year period, the incidence of cervical carcinoma in Victorian women aged over 70 years fell by 50%, and simultaneously there has been a shift in the peak incidence from the 70–74-years age group to one a decade older (Vicky Thursfield, Information Manager, personal communication). Accordingly, we suspect that women over 70 years of age still have a significant incidence of invasive cervical carcinoma, but are not being offered cervical smears, even when the National Health and Medical Research Council guidelines indicate the necessity.

Nicholas J Mulvany · Norman R Sonenberg

Progress in new diagnostic tools and therapeutic strategies has been rapid in gastroenterology and hepatology, and pending advances include the use of magnification endoscopy with dye spraying to detect early cancers, and endoscopic sewing procedures for reflux oesophagitis. Prevention. Genetic tests have recently been developed for the hereditary colon cancer syndromes (< 3% of all colon cancers). This major advance helps to identify at-risk family members, so that premalignant lesions and early cancers can be removed, and those who are not carrying the gene can be reassured. Accuracy in both familial adenomatous polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC) approaches 100%, as long as the index case is positive for the mutation tested. The rate of carriage of an easily identifiable mutation is about 80% in FAP, but presently substantially less in HNPCC.1 Pilot testing of population screening for common (sporadic) colorectal cancer is about to begin in Australia. More specific immunochemical tests for occult gastrointestinal bleeding are now available. Diagnosis. First described in 1991, magnetic resonance cholangiopancreatography (MRCP) continues to evolve. It produces diagnostic-quality images of normal and diseased biliary ducts, is non-invasive, and does not require contrast media or ionising radiation. MRCP is gradually replacing invasive techniques, such as endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography, for purely diagnostic imaging, leaving these procedures for interventional or problem cases. MRCP is indicated for detecting biliary stenosis and level of obstruction, and depicting the biliary tree on both sides of the stricture. It is also useful in identifying cases of choledocholithiasis likely to benefit from ERCP calculus removal. Avoiding intubation of the biliary tree decreases the risk of bacterial colonisation in cases of biliary stricture (including primary sclerosing cholangitis [PSC]) and choledocholithiasis. MRCP is not particularly good for detecting ampullary calculi, or assessing chronic pancreatitis or the very early changes of PSC. Availability is the main limiting factor to its widespread use.2 Intervention. Localised hepatocellular carcinoma (HCC) in patients with non-cirrhotic livers is best managed by surgical resection. Liver transplantation has been associated with excellent long term survival in highly selected cases of cirrhosis, but is limited in Australia by a small donor pool. Effective local control of small HCCs has been achieved with percutaneous ethanol injection (PEI), and radiofrequency ablation (RFA). The main determinant of outcome is the size of the tumour. PEI, under ultrasound or computed tomography guidance, is simple, inexpensive and safe in patients with advanced cirrhosis. It is suitable for HCCs less than 3 cm in size, with fewer than three nodules, but multiple treatments may be required. There is minimal discomfort, so it can be performed as an outpatient procedure. RFA involves placing the needle electrode percutaneously with laparoscopic control or ultrasound guidance under local anaesthesia. However, heavy sedation or anaesthesia may be required as significant pain may occur. Both PEI and RFA have very low complication rates, and treatment can be repeated for recurrence or new lesions. Long-term survival rates have been reported at over 70% (three years) and over 40% (five years), but unfortunately no randomised controlled trials have been performed.3 The management of chronic hepatitis B infection has changed recently with approval of lamivudine, a nucleoside analogue and potent inhibitor of viral DNA replication. Sustained viral inhibition is seen within four weeks in over 95% of cases, with 15%–20% becoming e-antigen negative at 12 months. There is also evidence that liver fibrosis and inflammation decrease during therapy, even without seroconversion. A high proportion of patients with hepatitis B e-antigen seroconversion (73%) have a sustained virological remission for up to 19 months (median). As with other therapies, loss of surface antigen is relatively uncommon. The development of a drug-resistant mutant form of the virus (YMDD) emerges with prolonged therapy (about 50% at three years), and can be associated with significant flares of hepatitis.4 Infliximab, a cytokine-directed biological therapy, represents a significant advance in the understanding of Crohn's disease. This chimeric monoclonal antibody blocks tumour necrosis factor α (ΤΝF-α), a key cytokine in bowel inflammation. Therapy results in rapid reduction in the signs and symptoms of Crohn's disease in two-thirds of cases, with a decrease in bowel inflammation, and improved mucosal healing and quality of life. Three infusions are given for fistulous disease and rapid closure occurs usually within two weeks, with a median benefit exceeding three months. Serious adverse events are infrequent and have been successfully managed with medications. However, the cost of this therapy currently restricts widespread use. Allergic reactions are also a serious consideration, but may be addressed in the future with modified molecules already in trial.5

Amanda J Nicoll PhD, FRACP · Ian J Kronborg FRACP · Neville D Yeomans MD, FRACP

With our increased understanding of the molecular mechanisms of haematological disorders, it has become possible to target therapy precisely to the underlying defect. Targeted therapy can increase safety and potency, while causing fewer side effects than standard treatment. "Smart" drugs and gene therapy have recently shown great promise in a wide range of malignant haematological and coagulation disorders. Figure: Cytogenetic analysis showing ABL probe (red) on chromosome 9, BCR probe (green) on chromosome 22, and both probes on the Philadelphia chromosome, indicating the abnormal hybrid BCR-ABL gene. Chronic myeloid leukaemia.1 Since the Philadelphia chromosome was recognised over 40 years ago, the genetic changes that lead to chronic myeloid leukaemia (CML) have been progressively unravelled. A reciprocal translocation between chromosomes 9 and 22 creates a unique hybrid gene, BCR-ABL, which encodes a protein with tyrosine kinase activity. The abnormal gene is found in almost all patients with CML and can be detected routinely on cytogenetic analysis using fluorescent markers (Figure). The BCR-ABL protein confers on its host cell extended life span, disregard for marrow inhibitory signals and inevitable progression to a more malignant phenotype, clinically recognised as blast crisis. Imatinib is a specifically designed, highly targeted drug that blocks BCR-ABL tyrosine kinase action. At well tolerated oral doses, it eliminates the abnormal Philadelphia clone and dramatically normalises blood counts in almost all chronic-phase patients, as well as in most of those with advanced disease (accelerated phase and blast crisis). Remissions appear durable, although long term data are unavailable. While imatinib is not yet believed to cure CML, it could become initial therapy for all patients, including those who would otherwise have proceeded immediately to allogeneic stem-cell transplantation. Gene therapy in haemophilia.2 Much is already known about the genetic abnormalities, laboratory measurement and clinical course of haemophilia. This condition is an excellent model to demonstrate the feasibility of human gene transfer, as large clinical benefits can follow even small improvements in the level of clotting factors (eg, from less than 1% to 5% of factor VIII or IX). Factor VIII or IX genes have been successfully transferred in at least 29 people with haemophilia, using either skin, blood, muscle or liver cells transformed by various carrier vectors. All studies have demonstrated some clinical efficacy, with sustained improvement in factor level over a period, and reductions in bleeding symptoms and use of clotting-factor concentrate. However, concerns remain about the potential of the technique to alter the individual's genetic code, leading to cancer and transmission of changed genes to the next generation. "Magic bullet" therapy in non-Hodgkin's lymphoma.3 The CD20 antigen is a specific protein expressed in virtually all malignant B-cell lymphomas, but not non-lymphoid cells, normal early B lymphocytes or plasma cells. This antigen is the target for the monoclonal antibody rituximab, which has shown great clinical benefit in patients with non-Hodgkin's lymphoma. Around half of patients with relapsed or refractory low-grade, non-Hodgkin's lymphoma have a response to rituximab, which can last for over a year (median, 12 months). Because of its specificity, rituximab has side effects that are milder than and differ from those of other forms of chemotherapy. The main, but uncommon, problem is infusion-related fever, chills or wheeze. When rituximab is used in conjunction with standard chemotherapy as initial treatment for lymphoma, it improves response with virtually no added toxicity. Further benefit is seen in patients with refractory lymphoma, when radioactively tagged anti-CD20 antibody can be used to deliver targeted local radiation treatment. New anticoagulants.4,5 Anticoagulants have been designed that are more specific than standard and low molecular weight heparin. Most focus has been on factor X and thrombin, but there are new anticoagulants for almost every coagulant factor. Three direct thrombin inhibitors (hirudin, bivalirudin, and argatroban) are approved for clinical use in the United States. Four other anticoagulants (activated protein C, tissue factor pathway inhibitor, synthetic pentasaccharide, and the oral thrombin inhibitor H376/95) are undergoing or have completed phase III evaluation studies. Each drug must show a positive benefit-to-risk profile, and particularly cost effectiveness, in the face of the marginal therapeutic advantage over established agents. The new drugs are likely to avoid the serious non-anticoagulant side effects of heparin, such as thrombocytopenia, and perhaps osteoporosis. With the trend for reduced hospital stay and evidence suggesting that the risk of venous thrombosis remains high for several months after orthopaedic surgery, oral agents are likely candidates for improving care. The oral thrombin inhibitor H376/95 is arousing most interest, as it produces predictable anticoagulant response without laboratory monitoring. It is currently being evaluated in phase III trials as a possible substitute for warfarin in venous disease and atrial fibrillation. The early completion of the Human Genome Project and advances in biotechnology will inevitably increase the number of new therapies specifically designed for the individual patient and disease.

Ross I Baker FRACP, FRCPA · Alison M Street FRACP, FRCPA · Kerry M Taylor FRACP, FRCPA

Our knowledge of the biology of cancer has increased exponentially in the past 30 years. Although application of this knowledge to patient care has been modest, some important improvements in healthcare delivery are available now or expected in the near future. Prevention. The prevention of cancer through dietary or drug interventions is a critical but largely unmet challenge. Recent clinical trials have shown that drugs such as the non-steroidal anti-inflammatory agent sulindac can reduce the size and number of adenomas in individuals with familial adenomatous polyposis.1 Tamoxifen and the newer selective oestrogen- receptor modulators have similar benefits in breast cancer.1 Yet, cancer chemoprevention is in its infancy, and issues regarding dosage and long-term treatment risk are unresolved. Finally, control of Helicobacter pylori infection may lead to lower rates of gastric cancer. Diagnosis. Advances in cancer knowledge and genomics allow predictions of familial predisposition to several tumours, including breast, ovarian and colon cancer. The accurate diagnosis of familial cancer involves input from various medical practitioners, and increasingly involves recognition by pathologists of distinctive cancer phenotypes, such as breast cancer with BRCA1 mutations or colorectal cancers seen in hereditary non-polyposis colorectal cancer. The identification of germline mutations that cause colorectal or breast/ovarian cancer is both labour- and time-intensive. However, identification of these mutations facilitates screening of family members and the targeting of strategies for prevention or early detection of cancer, and allows reassurance of unaffected individuals within a cancer-prone family. Intervention. Incremental advances in treatment modalities, including cytotoxics, hormonal agents and anti-emetics, have yielded modest improvements during the past five years. Sadly, of the more than 480 cancer therapeutics currently in clinical development,2 few novel cancer treatments will reach the oncology clinic, and even fewer will have significant effects on cancer care. For decades, we have been promised drugs that will target cancer cells without damaging normal cells, be they "magic bullets" based on monoclonal antibodies, or, more recently, "silver bullets" — small molecules that target genetic events central to carcinogenesis. In the past year, the clinical utility of some of these new therapies has been realised. Two genetically engineered antibodies, trastuzumab and rituximab, are now available for treating breast cancer and non-Hodgkin's lymphoma, respectively. Their effectiveness results from targeting molecules important for tumour growth rather than from immune-mediated cell killing. Trastuzumab targets the erbB-2 (HER-2/neu) receptor, which is overexpressed in about 20% of breast cancers, and antibody binding culminates in cell-cycle arrest.3 Trastuzumab is well tolerated, although it must be administered regularly to control tumour growth. One study has shown that the combination of trastuzumab and paclitaxel modestly improves the survival of women with advanced breast cancer. However, trastuzumab cannot be used safely with all chemotherapy, as illustrated by the high incidence of cardiac dysfunction (27% of patients) when the drug was combined with anthracyclines. The "silver bullets" target fundamental genetic changes in tumour cells. One example is ST1571, a small molecule that inhibits the tyrosine kinase activity of the BCR-ABL fusion protein.4 This oral drug shows great promise for treating chronic myeloid leukaemia, reversing the haematological and cytogenetic features of the disease.5 It may also be effective against gastrointestinal stromal tumours owing to its activity against the tyrosine kinase KIT. This is particularly encouraging, as these tumours rarely respond to chemotherapy and radiotherapy. As drugs can now be tailored to specific molecular targets, there is a demand for complex molecular assessments of each tumour. For example, suitability for trastuzumab therapy is predicated on accurate identification of erbB-2 overexpression. This requires specialised, expensive techniques such as immunostaining and FISH analysis. This trend is likely to continue. Up to 200 new anticancer drugs will be launched by 2005. These drugs will increasingly utilise our knowledge of the molecular basis of cancer. It is hoped that many of these drugs will act against malignancies of the lung and colorectum, for which there remains a large unmet clinical need.2

Robyn L Ward MB BS, PhD · Nicholas J Hawkins MB BS, PhD

Radiotherapy is one of the cornerstones of cancer treatment, being a component of management in at least half of all cancer patients. Increasingly, radiotherapy is used in multimodal treatment protocols in combination with surgery and chemotherapy. The best outcomes are achieved when specialists in each of these disciplines work in a multidisciplinary way, understanding the benefits and limitations that each brings to the patient's management. The aim is to individualise treatment using the best evidence available while continually advancing our knowledge through clinical trials. The Trans-Tasman Radiation Oncology Group has taken a leadership role in this regard. Advances in radiation oncology have historically been linked to developments in technology and biology. Never has this been more evident than in the present era. Technology. The power of ionising radiation as a therapeutic tool lies in its ability to penetrate non-invasively to any part of the body. The challenge is to target tumour tissue and minimise normal tissue toxicity. This requires sophisticated techniques for disease localisation, treatment planning, delivery and verification. Excellence in oncological imaging is at the heart of modern radiation oncology. The advent of fast, multislice CT scanners, new MRI techniques, metabolic imaging with PET and the advent of machines producing fused CT and PET scans has revolutionised radiation oncology. Patients can now be more accurately staged, their disease can be precisely localised, and treatment can be planned accordingly.1 Modern planning for radical radiotherapy involves the delineation on cross-sectional scans of the target volumes to be irradiated and the normal tissues to be excluded from the high dose volume. The ability to achieve three-dimensional conformal dose distributions allows critical normal tissues to be spared from injury and tumour doses to be increased safely. In the case of prostate cancer this has been shown to translate into improved outcomes.2 The ability to sculpt the high dose radiation volume to match tumour localisation is maximised by intensity-modulated radiation therapy. This technique uses a computer-controlled beam-shaping device in the head of the linear accelerator, which changes the beam shape continually during radiation exposure to produce any desired dose distribution. This is a far cry from the situation only a few years ago, when the only method of protecting normal tissues was to insert a lead block in the radiation beam, external to the treatment machine. For treatment verification and quality assurance, electronic portal imaging systems that provide a real-time digital image of each treatment field are now available. These allow detection of variations from the intended treatment set-up. Unfortunately, these technologies are available at only a few Australian centres, and use is severely restricted because of the under-resourcing of radiation oncology departments. A balance has to be struck between offering sophisticated treatment to some patients and forcing longer waiting times for treatment on others. Our goal for the next five years must be to redress the shortfalls in infrastructure so the advantages of existing technology will become more widely available.3 Biology. In the past five years, many of the seeds of earlier research have come to fruition with proven clinical benefit in randomised trials. Perhaps the best example is the development of integrated protocols combining radiotherapy with chemotherapy4 or hormonal therapy for many cancers, including lung, cervix, rectum, larynx/pharynx, breast and prostate cancer. The explosion of knowledge in molecular biology and genetics has led to new understanding of how ionising radiation causes cell death and has provided the rationale for trials combining radiation with designer-made inhibitors of molecular pathways, such as those mediated by EGFR and Ras oncogenes. Intensive research into the molecular determinants of radiation-induced apoptosis has created the possibility of selectively manipulating these mechanisms to improve the therapeutic ratio. Another major research focus is to identify predictively patients who are genetically predisposed to radiation injury and who, if treated with radiotherapy, are at risk of severe complications. Excluding this small group of patients would allow dose escalation for others, resulting in increased local cure rates. The next five years will see a revolution in the molecular phenotyping of tumour and normal tissues, using gene-array microchip technology. Within each anatomical/histological subtype, tumours will be characterised at the molecular level in a way that will permit rational application of the most effective treatment modalities, including radiation. The ultimate aim is to combine molecular characterisation with the technological sophistication of radiation treatment to use this powerful anti-cancer weapon to maximum benefit.5

Lester J Peters MD, FRANZCR · Lizbeth M Kenny MB BS, FRANZCR

The practice of urology continues to be affected by the compulsory wearing of seatbelts, resulting in less trauma, and antismoking initiatives. Bladder cancer is an occupationally related tumour, but cigarette smoke is by far the most significant environmental carcinogen, so a recent report suggesting that smoking rates may be declining1 is heartening. Prostate cancer. The trend to earlier diagnosis of prostate cancer continues. Detection of an elevated serum prostate specific antigen (PSA) level is usually followed by biopsies guided by transrectal ultrasound (TRUS). PSA analysis has been expanded to give more information; rate of change of total PSA (PSA velocity) and the percentage of free PSA (unbound) are most often used (lower percentages of free enzyme being associated with a higher likelihood of malignancy, especially for total PSA levels 4–10 g/L). TRUS-guided sextant prostatic biopsies are not new, but, particularly with larger prostates, repeat biopsies after negative findings have increased detection rates up to 30%.2 Consequently, eight or more biopsy samples are now often obtained. As well as pre-TRUS–PSA, Gleason score and number of tumour-containing cores (with percentage involvement) serve to predict the likelihood of cancer being localised. Thus, the PSA–transrectal ultrasound approach appears to have reached maturity and a change in direction, such as molecular characterisation of ejaculate, is now required to advance early diagnosis and natural history prediction. The focus on PSA by patients has contributed to androgen suppression starting earlier, despite unwanted side effects with all forms of hormonal treatment and a lack of convincing evidence that earlier intervention improves survival. Intermittent androgen blockade does not adequately compensate for early commencement of androgen suppression, as, certainly in the short-term, many unwanted effects, including testosterone suppression, are not always reversible. The popularity of maximal androgen blockade has waned since the publication of unsupportive meta-analysis data.3 Notwithstanding its major advantage of avoiding contrast media, spiral computed tomography (CT) serves as an adjunct to, rather than a replacement for, intravenous urography, which remains the first-line investigation for most ureteric colic patients. Non-contrast CT does not provide functional information, but may detect other abnormalities. Female urinary incontinence. This is one of the conditions managed by both urologists and gynaecologists. The mainstay of treatment for patients with overactive bladders (frequency and urgency with or without urgency incontinence in the absence of attributable local, pathological or metabolic factors4) is anticholinergic drugs, with doses limited by dry mouth and constipation especially. Recently evaluated uroselective agents have shown a considerable reduction in unwanted effects without loss of efficacy. The tension-free vaginal tape (TVT) procedure was recently introduced for stress incontinence. Its low rate of short-term complications has been attributed to its wide-mesh monofilament polypropylene composition, reputed to retain flexibility and admit macrophages, fibroblasts, blood vessels and collagen into its pores to permit elimination of infiltrating bacteria. Whether such attributes translate into lower complication rates and continued success in the longer term (more than two years) remains to be seen. Concerns about an uncritical adoption of the TVT procedure, paralleling initial enthusiasm for needle suspension operations in the 1980s, are justifiable. TVT operations are often performed as day procedures — a not insignificant attraction given the current shortage of hospital beds. Lower urinary tract symptoms (LUTS). LUTS, even when categorised as storage or emptying, are poor indicators of underlying LUT dysfunction. A third of men with LUTS do not have bladder outflow obstruction (BOO), accurate diagnosis of which is problematical. Consequently, there is a tendency to treat LUTS with medications and to identify BOO only when considering more invasive therapies. This approach relates particularly to the commonly used saw palmetto berry (Serenoa repens) extract, which affords LUTS relief for many men. Treatment by α1-blockade (doxazosin, prazosin, terazosin) is well established for benign prostatic hyperplasia (BPH) causing BOO. BPH is predominantly a stromal condition and these drugs target prostatic and bladder-neck smooth muscle. Improvements in symptom scores and flow rates often persist long-term. Seventy per cent of prostatic adrenoreceptors are of the α1A receptor subtype. Tamsulosin, a selective α1A antagonist, has a safety profile superior to non-selective α1 antagonists, with comparable effects on LUTS. However, dizziness and abnormal ejaculation may still occur. Male sexual dysfunction. The adverse impact of sexual dysfunction on quality of life has only recently been acknowledged. Papaverine and prostaglandin E1 intracavernosal injections were a significant advance. However, a dramatic change came with the serendipitous discovery of sildenafil, which prolongs nitric oxide-induced cavernosal muscle relaxation. While sildenafil therapy represents a revolution in impotence treatment, it does not address underlying pathogeneses.5 Infertility. One of the most remarkable milestones of the 1990s was intracytoplasmic sperm injection (ICSI). Despite the possibility that sperm with suboptimal genetic characteristics may be selected for this process, ICSI has become established as a valuable option in infertility management. Conclusion. Urology is continuing to evolve at a rapid rate. Consequently, urologists are tending to subspecialise rather than practise in the broad range of conditions which constitute this fascinating yet practical specialty.

Robert A Gardiner MB BS, MD, FRCS, FRACS

Editorial Tumour banks: providing human tissue for cancer research Providing there are safeguards to protect the rights of patients, the supply of human tissue for research can benefit the community as a whole MJA 2001; 175: 293-294 Unprecedented insights into the biology of cancer cells are coming from research using recently developed methods such as global gene expression analysis.1 In clinical oncology, the benefits of these advances are likely to be significant in the diagnostic classification of tumours and informed design of novel anticancer agents. However, for this potential to be realised, the molecular analysis of large numbers of tumours is required, which in turn is dependent on the availability of collections of well-preserved and well-characterised tumour tissue for research. Coincident with increased need for human tissue specimens in cancer research is the increased complexity of the attending ethical issues. Ironically, it is the power of modern genetic analysis that creates the most difficult ethical dilemmas. The potential for discovering inherited genetic lesions that confer an increased risk of developing cancer (eg, a mutation in the breast cancer susceptibility gene BRCA1) has led to concern that "genetic research" may uncover information that is unwanted by the patient, has implications for family members and could potentially lead to discrimination.2 Serious ethical questions are also raised by the involvement of commercial interests in human-tissue-based research, in particular relating to potential conflicts of interest and the distribution of financial benefits.2,3 Moreover, these ethical issues must be negotiated in the current climate of public concern following recent media reporting on the retention of human organs following autopsy.4,5 Cancer remains a leading cause of morbidity and mortality in our community and the continued need for research into its nature and treatment is undisputed. It is also clear that society's view on involvement of individuals in all aspects of their healthcare has changed, resulting in the expectation of a more stringent regulatory environment for the conduct of research. This is reflected in a number of initiatives relevant to the collection and use of human tissue. In 1999, the National Health and Medical Research Council (NHMRC) issued updated guidelines for the conduct of ethical research involving humans.6 The guidelines incorporate the internationally accepted principles of integrity, respect for persons, beneficence and justice in the conduct of research, and reaffirm the crucial role of independent human research ethics committees (HRECs) to review and regulate research in specific institutions. Recently, the necessity for legislation on these issues has been considered, with a proposed review of the Human Tissue Act 1983 (NSW)7 and a joint inquiry into protection of human genetic information by the Australian Law Reform Commission and the Australian Health Ethics Committee of the NHMRC.8 The supply of human tissue for cancer research requires an integrated system of safeguards to protect the rights of patients, allow research that may benefit the wider community to continue, and offer a workable framework for hospitals, and, in particular, pathology departments, to support the process. Increasingly, tumour banks are emerging as an appropriate response to the concerns of involved parties. A tumour bank is an independent facility that collects samples of surgical specimens removed in the course of usual treatment from cancer patients who have given informed consent for their removal and use in research. The tissue taken is in excess of requirements for histopathological assessment and may include both cancer and normal tissue. The tumour bank also includes a database of relevant demographic, clinical and follow-up information.9 Researchers may apply to the tumour bank for samples to use in projects that have appropriate HREC approval. The decision to supply samples is generally made by a committee, comprised of clinicians and scientists, on the basis of scientific merit, available resources and the extent of collaboration with groups involved in collection of tumour bank specimens. The key safeguard in the conduct of ethical research is the involvement of an HREC, and the most important issues for the HREC to oversee in relation to a tumour bank pertain to donor consent and privacy protection.6 The informed consent process relating to tumour banks does not involve supply of the specific details of research projects, as these may not be known at the time of sample collection. The non-specific nature of this consent needs to be taken into account by the HREC when researchers proposing to use tumour bank specimens submit projects for review.6 The extent to which research participants are identifiable is an important factor. Tumour banks maintain links between donor identity and tissue samples, but supply samples to researchers without identifying information.9 The benefits of this system are that the privacy of donors is protected while maintaining the capacity to collect valuable follow-up information and to recontact donors if necessary. In the event that research studies uncovered information that might be relevant to the wellbeing of a donor, the HREC would play a pivotal role in consideration of the issues. Establishment and management of a tumour bank is a long-term commitment requiring substantial resources and secure funding. However, these costs must be met to ensure that progress in cancer research continues, ethical challenges posed by new investigative technology are met and public confidence in the conduct of research is maintained. Rosemary L Balleine Staff Specialist Karen E Humphrey Senior Tumour Bank Officer Christine L Clarke NHMRC Senior Research Fellow, and Department Head Department of Translational Oncology, Westmead and Nepean Hospitals Westmead, NSW rosemary_balleineATwmi.usyd.edu.au Marx J. DNA arrays reveal cancer in its many forms. Science 2000; 289: 1670-1672. Reilly PR, Boshar MF, Holtzman SH. Ethical issues in genetic research: disclosure and informed consent. Nat Genet 1997; 15: 16-20. Magnusson RS. The use of human tissue samples in medical research: legal issues for human research ethics committees. J Law Med 2000; 7: 390-403. Jacobsen G. Morgue chief removed over "sickening" tests. Sydney Morning Herald 2001; 19 March; 3. Retention of organs after necropsy. Lancet 2001; 357: 157. National Health and Medical Research Council. National statement on ethical conduct in research involving humans. Commonwealth of Australia, 1999. Available at: <http://www.nhmrc.gov.au/publications/pdf/e35.pdf>. Accessed 14 August 2001. Review of the Human Tissue Act 1983 (NSW). Discussion paper. Organ and tissue donation and use and post mortem examination. October 1999. Available at <http://www.health.nsw.gov.au/csd/llsb/organ/issuespaper.pdf>. Accessed 7 August 2001. Protection of human genetic information. A joint inquiry of the Australian Law Reform Commission and Australian Health Ethics Committee of the National Health and Medical Research Council. Commonwealth of Australia, February 2001. Available at: <http//:www.alrc.gov.au/current/genetic/overview.htm>. Accessed 14 August 2001. Grizzle WE, Aamodt R, Clausen K, et al. Providing human tissues for research: how to establish a program. Arch Pathol Lab Med 1998; 122: 1065-1076. Make a comment

Rosemary L Balleine · Karen E Humphrey · Christine L Clarke

Editorial Testicular cancer management We have to keep our eye on the ball MJA 2001; 174: 320-321 Almost 600 young Australian men are diagnosed with testicular cancer each year. It is the second most common malignancy in men aged 18-35 years, behind melanoma, and its incidence has more than doubled over the past 30 years.1 Fortunately, this disease is one of the major successes of modern oncology, and almost all of these men can now expect to be cured. With the advances in the management of the disease over the past 25 years, most men with metastatic testicular cancer are now curable with combination chemotherapy. During the same time, patients with earlier stages of the disease have benefited from changes that reduce the toxicity of treatment. These changes include: a reduction in the number of cycles of chemotherapy required for treatment of good-prognosis metastatic disease, a reduction in the radiation dose and field size for the treatment of early-stage seminoma, and the introduction of active surveillance (close, structured follow-up to detect and treat relapse) for Stage I non-seminomatous tumours. ... there is much variability in the care of these men, and this may affect the extent and toxicity of their treatment These advances are the outcomes of oncologists' long term commitment to high quality clinical trials, and Australian research has contributed substantially to this evidence base.1-3In this issue of the Journal, Toner et al provide, for the first time, Australian population-based data on the management of testicular cancer.4 They retrospectively surveyed doctors who were involved in the management of more than 600 patients in Victoria with testicular cancer between 1988 and 1993. Their survey included information on the location of care, investigations performed, treatment and survival. The men were treated at a large number of hospitals, most of which treated fewer than two patients with testicular cancer each year. How did this dispersion of care and expertise affect management and outcomes? Staging and surveillance were often inadequate. There was a low rate of completion of staging and follow-up investigations in the first year for patients with early-stage disease undergoing active surveillance, and no patients underwent primary retroperitoneal lymph node dissection. Furthermore, more than 10% of patients with Stage I seminoma were managed with surveillance (often poorly implemented), which at the time (and arguably even today) was not a proven treatment. There are no data about the delivery or adverse effects of treatment. Despite some of the shortcomings in management, there was an excellent overall relative five-year survival of 95%, a figure that is similar to those obtained elsewhere in Australia,5,6 and internationally.7 However, these findings offer only partial reassurance, since differences in outcomes between groups may be hard to establish with so few adverse events. This has been noted previously in similar studies. For example, no differences in outcome based on location of care were identified for Scandinavian men with testicular cancer when all patients were considered. However, when the patients with the earliest stage of disease (and hence the best prognosis) were excluded, differences became apparent, with better survival for patients cared for in centres that treated large numbers of patients.8 This is reinforced by better outcomes for patients managed in centres treating large numbers of patients in reports from the United States9 and the United Kingdom.10 The data also suggest better outcomes for men treated in centres recruiting the largest numbers of patients to randomised clinical trials.11 Indeed, management of patients in small centres without the necessary expertise may limit access to some treatments. The failure by Toner et al to demonstrate differences in outcome between the centres treating many patients and those treating few may also reflect imbalances in prognostic factors. For example, patients with the worst prognostic features seen at smaller centres are likely to be referred to larger centres, making outcomes appear to be better at the former and worse at the latter. Furthermore, in a disease with such effective salvage treatment, the main disadvantage of inadequate surveillance may be the need for more intensive therapy, with the associated problems of increased toxicity and cost, rather than worse overall survival. These aspects were not assessed in the Victorian study. The apparent shortcomings in care must also be considered in the light of the study's limitations. The data are based on a questionnaire completed three to eight years after the patients were treated. Although the response rate was high (with information obtained for 95% of cases), there was no independent verification of the data provided by the respondents. The answers reflect both the quality of the practitioners' medical records and their knowledge of the purpose and expectations of the investigators. In addition, although many hospitals each treated a small number of patients, it is not clear how many individual doctors were involved — potentially more important in terms of clinical experience and expertise. Outcomes for men with testicular cancer in Victoria are excellent. However, there is much variability in the care of these men, and this may affect the extent and toxicity of their treatment. Optimal management is demanding on patients, doctors and support staff. Men with testicular cancer should be treated in centres with multidisciplinary expertise, experience and access to all treatment options — there is too much at stake for it not to be done right. Michael J Boyer Head, Department of Medical Oncology Martin R Stockler Senior Lecturer in Cancer Medicine and Clinical Epidemiology Sydney Cancer Centre, Royal Prince Alfred Hospital and University of Sydney, Sydney, NSW Levi JA, Thomson D, Sandeman T, et al. A prospective study of cisplatin-based combination chemotherapy in advanced germ cell malignancy: role of maintenance and long-term follow-up. J Clin Oncol 1988; 6: 1154-1160. Levi JA, Raghavan D, Harvey V, et al. The importance of bleomycin in combination chemotherapy for good-prognosis germ cell carcinoma. Australasian Germ Cell Trial Group. J Clin Oncol 1993; 11: 1300-1305. Boyer MJ, Cox K, Tattersall MH, et al. Active surveillance after orchiectomy for nonseminomatous testicular germ cell tumors: late relapse may occur. Urology 1997; 50: 588-592. Toner GC, Neerhut GJ, Schwarz MA, et al. The management of testicular cancer in Victoria, 1988-1993. Med J Aust 2001; 174: 328-331. Supramanian R, Smith D, Coates M, Armstrong B. Survival from cancer in New South Wales in 1980 to 1995. Sydney: NSW Cancer Council, 1999. South Australian Cancer Registry. Epidemiology of cancer in South Australia. Adelaide: South Australian Cancer Registry, 2000. Ries LAG, Kosary CL, Hankey BF, et al. SEER cancer statistics review, 1973-1996. Bethesda: National Cancer Institute, 1999. Aass N, Klepp O, Cavallin-Stahl E, et al. Prognostic factors in unselected patients with nonseminomatous metastatic testicular cancer: a multicenter experience. J Clin Oncol 1991; 9: 818-826. Feuer EJ, Frey CM, Brawley OW, et al. After a treatment breakthrough: a comparison of trial and population-based data for advanced testicular cancer. J Clin Oncol 1994; 12: 368-377. Harding MJ, Paul J, Gillis CR, Kaye SB. Management of malignant teratoma: does referral to a specialist unit matter? Lancet 1993; 341: 999-1002. Collette L, Sylvester RJ, Stenning SP, et al. Impact of the treating institution on survival of patients with "poor-prognosis" metastatic nonseminoma. European Organization for Research and Treatment of Cancer Genito-Urinary Tract Cancer Collaborative Group and the Medical Research Council Testicular Cancer Working Party. J Natl Cancer Inst 1999; 91: 839-846. Make a comment

Michael J Boyer · Martin R Stockler

Healthcare The management of testicular cancer in Victoria, 1988-1993 Guy C Toner, Greg J Neerhut, Max A Schwarz, Vicky J Thursfield, Thomas F Sandeman, Graham G Giles and Ross M Snow, for the Urology Study Committee of the Victorian Co-operative Oncology Group MJA 2001; 174: 328-331 For editorial comment, see Boyer & Stockler Abstract - Methods - Results - Discussion - Acknowledgements - References - Authors' details - - More articles on Oncology Abstract Objectives: To evaluate the patterns of care and management of testicular cancer in Victoria. Design and setting: Retrospective analysis of all cases of testicular cancer in Victoria from 1988 to 1993 identified through the Victorian Cancer Registry. Main outcome measures: Description of patient characteristics, staging investigations, initial management, and outcome. Results: 667 eligible cases of testicular cancer were identified and questionnaires were returned for 633 of these patients (94.9% response rate). There were 357 (56.4%) patients with pure seminoma; 271 (42.8%) with non-seminomatous germ cell tumours, 3 (0.5%) with stromal tumours, and 2 (0.3%) with other tumours. The median age was 32 years (range, 0-80 years). Preoperative marker levels were not available for 8% of patients, and initial staging was considered inadequate in 6%. Surveillance programs used for patients with Stage I disease were considered inadequate in most. Relative survival at five years was 99% for patients with seminoma and 91% for non-seminoma. Conclusions: There was considerable variation in the investigation, treatment, and follow-up of these patients, which is likely to have resulted in unnecessary morbidity. Clinical practice guidelines should be developed and implemented to promote optimal management. Testicular cancer is uncommon but has a significant effect on the community, as it typically develops in young men. The median age of incidence is approximately 30 years.1 Excellent survival rates are expected with the use of surgery, radiation therapy, and chemotherapy.2 Cure is expected in about 80% of patients with metastatic and relapsed disease.2There is a strong evidence base available to guide management, with relatively uniform practice at major centres internationally. Some aspects of management are peculiar to this malignancy. These include: the strong reliance on serum tumour markers for management,3,4 the use of surveillance in patients with Stage I disease, with anticipated cure by salvage therapy in those who relapse,5 the expectation of cure of metastatic disease with a brief, intensive course of chemotherapy,6 and the use of surgery to resect residual masses at metastatic sites after chemotherapy.7 Because of the potential for cure, the multidisciplinary nature of management and the availability of high quality evidence to guide practice, the management of testicular cancer is expected to provide an excellent assessment of the quality of cancer management in a community. However, there are no comprehensive data on the management of testicular cancer in the community in Australia. Methods The Urology Study Committee of the Victorian Co-operative Oncology Group undertook a survey of the management of testicular cancer in Victoria. A population-based sample was identified from the cancer registry. The period 1988 to 1993 was chosen to allow an adequate sample size and follow-up for the survey. A questionnaire was developed covering aspects of presentation, diagnosis, staging investigations, therapy, and follow-up. In January 1996, after approval by the Ethics Committee of the Anti-Cancer Council of Victoria, the questionnaire was sent to the treating doctors of all patients with testicular cancer in 1988-1993 identified in the cancer registry. Questionnaires were subsequently sent to other doctors identified as participants in the patients' care. Neither the doctors' nor the patients' names were identified to third parties. At the end of the survey, the data were entered into a database and a de-identified file was used for analysis. Classification of testicular cancer Germ cell tumours were classified as seminoma or non-seminoma. Seminoma included only those cases with pure seminoma in the histological specimens and a normal serum α-fetoprotein level. Cases where any other histological component (such as embryonal carcinoma, yolk sac or endodermal sinus tumour, choriocarcinoma, or teratoma) was identified, or in which the serum α-fetoprotein level was elevated, were classified as non-seminoma. Analysis Analysis was conducted using the SPSS statistical package8 for descriptive statistics and χ2 tests for significance of associations for categorical data. Survival analysis was performed using the RelSurv Version 2.09 software package. First, relative survival proportions were computed separately for each prognostic indicator. This method adjusts the survival proportions for the other causes of mortality associated with age using Victorian life-tables. Second, a multivariate analysis (proportional hazards regression) was performed, with variables entered stepwise into the regression model in descending order of significance in the univariate analyses. Improvement to the model was tested after each addition and the variable was removed if the improvement was not significant (P < 0.05). Quality of care In an attempt to assess the quality of care provided, a number of performance measures were developed retrospectively by the working group after review of the initial data analysis. All patients were expected to have had preoperative measurement of serum α-fetoprotein and human chorionic gonadotropin levels. Adequate staging investigations were considered to be computed tomography (CT) scans of the abdomen and chest (or chest x-ray) for non-seminoma and Stage II and III seminoma. Staging of Stage I seminoma was expected to include the above or a lymphangiogram instead of the CT scan. Adequate surveillance for Stage I non-seminoma was deemed to be at least six measurements of tumour marker levels and four CT scans of the abdomen in the first 12 months of follow-up. We arbitrarily defined these performance measures, but we believe they represent reasonable standards of care at the time of the study. Results There were 689 patients with testicular cancer identified in the Victorian Cancer Registry for the six-year period 1988 to 1993. There was a trend of increasing incidence, with the age-standardised incidence per 100 000 men for the six consecutive years increasing from 3.7 to 5.3, with an average annual rate of increase of 7.5%. Twenty-two patients were excluded for reasons including residence outside Victoria, diagnosis outside the study period, and incorrect diagnosis. Questionnaires were sent to the treating doctor for all 667 eligible patients, and replies were received for 633 (94.9% response rate). Patient characteristics Patient characteristics are shown in Box 1. There was a slight predominance of seminoma. In most patients, disease was confined to the testis at diagnosis; non-seminomas were more likely to present at an advanced stage. There were 64 (10%) patients with cryptorchidism and 2 (0.3%) with bilateral tumours at presentation. Location of care The 633 patients were treated at 93 hospitals. Eighty-six of these hospitals treated fewer than five patients with testicular cancer per year, and 71 treated fewer than two per year. One hundred and seventeen (19.4%) patients were managed exclusively at centres that treated fewer than five patients with testicular cancer per year, and 111 patients (17.5%) were treated exclusively in private practice. Initial investigation Staging investigations at diagnosis included abdominal CT scan in 591 men (93.4%), thoracic CT in 270 (42.7%), chest x-ray in 496 (78.4%), and lymphangiography in 234 (37.0%). There was a time trend for less use of lymphangiography (P = 0.02) and greater use of CT scanning of the chest (P = 0.005) during the period of the survey. An abdominal CT scan or lymphangiogram was not performed in 26 patients (4.1%), and a chest CT scan or chest x-ray was not performed in 33 (5.2%). Serum tumour markers were not measured at diagnosis in 16 patients (2.5%) and were recorded as "don't know" in 44 (7.0%). Management Initial management of the patients is shown in Box 2. Thirty-four patients with seminoma and 103 patients with non-seminoma were managed with surveillance. No patients were managed with primary retroperitoneal lymph node dissection for Stage I or II non-seminoma. Thirty-one (4.9%) patients did not receive initial chemotherapy or radiation therapy and did not appear to enter an active surveillance program. There was considerable variation in the follow-up of patients on surveillance, which was inadequate for many patients according to our criteria. For patients with seminoma, investigations during the first year of surveillance did not include an abdominal CT scan in 12 (36%), did not include a chest x-ray or chest CT scan in 17 (55%), and included fewer than four serum tumour marker measurements in 25 (76%). Similarly, for patients with non-seminoma, no abdominal CT scan was performed in the first year in 6 (6%), no chest imaging in 31 (30%), and fewer than four measurements of serum marker levels in 26 (26%). Three of the 33 patients with seminoma managed with surveillance relapsed, and one of these patients died. Twenty-seven of 102 patients with Stage I non-seminoma managed with surveillance relapsed (one of whom died), with a median time to relapse of nine months. Overall relative survival for these 102 patients was 99%. Survival Median follow-up was 87 months. The five-year relative survival proportion for all men was 95% (95% CI, 94%-97%). There were significant differences in survival according to histology, age, and stage. These factors remained significant in multivariate analysis (Box 3). There was no significant difference in survival by date of diagnosis (1988-1990 v 1991-1993) or location of treatment (categorised according to number of patients seen). The relative survival according to tumour type and stage is shown in Box 4. The relative survival at five years for patients with seminoma (all stages) was 99% (95% CI, 98%-100%). For patients with non-seminoma, relative survival at five years was Stage I, 98% (95% CI, 97%-100%); Stage II, 92% (95% CI, 84%-100%); Stage III, 69% (95% CI, 56%-82%). The overall relative survival for Stage II and III patients was 84% (95% CI, 76%-91%). Quality of care Only 68% of patients completed all the quality-of-care measures that we considered appropriate (Box 5). There was a correlation between the successful completion of all measures and the number of cases treated at an institution (P < 0.001; data not shown). Discussion Many published series from major cancer treatment centres internationally have demonstrated that excellent outcomes are now the expected result of testicular cancer management. However, less detailed information is available in population-based series. Our survey was designed to assess management patterns and results in the population of Victoria. The 94.9% response rate to the questionnaire ensured that the results are representative of the entire community. Studies in Scotland,10 Norway11 and New York12 have indicated higher survival proportions for patients treated in centres treating a greater number of cases of testicular cancer compared with patients treated in a "community" setting. A recently published clinical trial performed in 49 European centres found the relative risk of death was 1.85 (95% CI, 1.16-3.03) for patients with metastatic poor-prognosis non-seminoma treated at centres entering fewer than five patients on the study compared with those treated at centres entering a greater number.13 We found that management in Australia has been dispersed increasingly to many individual clinicians and hospitals. In this series, testicular cancer was managed in 93 centres; 71 of these centres treated fewer than two patients per year, and 86 fewer than five per year. Yet, we did not find a significant difference in survival between these centres and ones that treated more patients. Our results show a pleasing 95% relative survival of testicular cancer patients when compared with a matched cohort from the same population. Survival in other reported series includes a 95.7% relative survival in the United States Surveillance, Epidemiology and End Results (SEER) review for a similar time period,14 and a 99% cancer-related survival in a community survey in southern Norway.11 The stage at diagnosis and survival outcomes in the SEER review are very similar to ours. The 69% relative survival at five years for Stage III non-seminoma is lower than expected. However, it is difficult to compare this figure with published results, as not all details of prognostic factors4 are available. The 7.5% per year increase in incidence over the six-year period of the survey is consistent with a continuation of the threefold increase in Victoria between 1950 and 1980.15 Similar dramatic increases in incidence have been reported in other Western countries,1 but the cause remains uncertain.16 Survival figures alone are an inadequate assessment of treatment. The aim of management is to achieve cure with the least morbidity. Patients who are initially managed poorly may be cured by salvage therapy, but at the price of greater toxicity. The resulting morbidity may be severe and potentially includes infertility, sexual dysfunction, and an increased risk of secondary malignancy. Our survey identified a number of problems. There was a wide variation in patterns of practice, particularly in patients with early-stage disease and those undergoing surveillance. Thirty-two per cent of patients failed to complete five simple measures of quality of care. More complex measures of quality of care, such as the extent of disease at relapse after initial surveillance or the quality and type of radiation therapy and chemotherapy, were not assessed in this survey. Surveillance after orchidectomy of Stage I seminoma, as an alternative to radiation therapy, was initially described in 1988,17 but we did not consider it to be accepted management during the period of the survey. Thus, we were surprised by the number of Stage I seminoma patients managed by surveillance. These patients were managed at multiple centres and there is no evidence that they were entered into a clinical trial. We were particularly concerned about inappropriate schedules for follow-up when surveillance was initiated. Published results of surveillance programs have emphasised the need for strict and frequent follow-up and investigation to ensure that any relapse is detected at an early stage.18 There are no published data to indicate less rigorous programs of surveillance maintain the same proportion of cure. Many patients with Stage I disease were also lost to follow-up or refused therapy. Young men are often not well motivated to continue regular and extensive follow-up. Therefore, it is essential to ensure such patients are fully informed about the options for therapy and the potential risk of unnecessary morbidity and mortality if an appropriate program of management is not followed. We believe the development and implementation of management guidelines for testicular cancer in our community may help to reduce the problems we identified. Acknowledgements We gratefully acknowledge the support of the Anti-Cancer Council of Victoria, the Urological Study Committee of the Victorian Co-operative Oncology Group, the Victorian Cancer Registry, and the urologists and oncologists who participated in the survey and completed the questionnaires. References McKiernan JM, Goluboff ET, Liberson GL, et al. Rising risk of testicular cancer by birth cohort in the United States from 1973 to 1995. J Urol 1999; 162: 361-363. Bosl GJ, Motzer RJ. Testicular germ-cell cancer. N Engl J Med 1997; 337: 242-253. Bosl GJ, Geller NL, Cirrincione C, et al. Serum tumor markers in patients with metastatic germ cell tumors of the testis. A 10-year experience. Am J Med 1983; 75: 29-35. International Germ Cell Cancer Collaborative Group. International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol 1997; 15: 594-603. Read G, Stenning SP, Cullen MH, et al. Medical Research Council prospective study of surveillance for stage I testicular teratoma. Medical Research Council Testicular Tumors Working Party. J Clin Oncol 1992; 10: 1762-1768. Einhorn LH. Testicular cancer as a model for a curable neoplasm: the Richard and Hinda Rosenthal Foundation Award Lecture. Cancer Res 1981; 41: 3275-3280. Toner GC, Panicek DM, Heelan RT, et al. Adjunctive surgery after chemotherapy for nonseminomatous germ cell tumors: recommendations for patient selection. J Clin Oncol 1990; 8: 1683-1694. SPSS Inc. SPSS-X user's guide. 3rd ed. New York: McGraw-Hill; 1988. Hedelin G. RELSURV: a program for relative survival. Technical report of the Department of Epidemiology and Public Health, Faculty of Medicine. Strasbourg, France: Louis Pasteur University, 1995. Harding MJ, Paul J, Gillis CR, Kaye SB. Management of malignant teratoma: does referral to a specialist unit matter. Lancet 1993; 341: 999-1002. Hernes EH, Harstad K, Fossa SD. Changing incidence and delay of testicular cancer in southern Norway (1981-1992). Eur Urol 1996; 30: 349-357. Feuer EJ, Frey CM, Brawley OW, et al. After a treatment breakthrough: a comparison of trial and population-based data for advanced testicular cancer. J Clin Oncol 1994; 12: 368-377. Collette L, Sylvester RJ, Stenning SP, et al. Impact of the treating institution on survival of patients with "poor-prognosis" metastatic nonseminoma. European Organization for Research and Treatment of Cancer Genito-Urinary Tract Cancer Collaborative Group and the Medical Research Council Testicular Cancer Working Party. J Natl Cancer Inst 1999; 91: 839-846. Ries LAG, Kosary CL, Hankey BF, et al. SEER cancer statistics review, 1973-1996. Bethesda, MD: National Cancer Institute, 1999. Stone JM, Cruickshank DG, Sandeman TF, Matthews JP. Trebling of the incidence of testicular cancer in Victoria, Australia (1950-1985). Cancer 1991; 68: 211-219. Bergstrom R, Adami HO, Mohner M, et al. Increase in testicular cancer incidence in six European countries: a birth cohort phenomenon. J Natl Cancer Inst 1996; 88: 727-733. Horwich A, Peckham MJ. Surveillance after orchidectomy for clinical stage I germ-cell tumours of the testis. Prog Clin Biol Res 1988; 269: 471-479. Boyer MJ, Cox K, Tattersall MH, et al. Active surveillance after orchidectomy for nonseminomatous testicular germ cell tumors: late relapse may occur. Urology 1997; 50: 588-592. (Received 28 Jun, accepted 7 Nov, 2000) Authors' details Peter MacCallum Cancer Institute, Melbourne, VIC. Guy C Toner, MD, FRACP, Head, Medical Oncology; Thomas F Sandeman, MD ChB, FRACR, Radiation Oncologist. Geelong Hospital, Geelong, VIC. Greg J Neerhut, MB BS, FRACS(Urol), Urologist. Alfred Hospital, Melbourne, VIC. Max A Schwarz, MB BS(Hons), FRACP, Head, Medical Oncology Unit; Ross M Snow, MB BS, FRACS(Urol), Head, Urology Unit. Anti-Cancer Council of Victoria, Melbourne, VIC. Vicky J Thursfield, BSc, GradDip(Applied Stats), Information Manager, Cancer Epidemiology Centre; Graham G Giles, PhD, Director, Victorian Cancer Registry. Reprints will not be available from the authors. Correspondence: Associate Professor G C Toner, Head, Medical Oncology, Peter MacCallum Cancer Institute, St Andrew's Place, East Melbourne, VIC 3002. gtonerATpetermac.unimelb.edu.au Make a comment 1: Patient characteristics Seminoma Non-seminoma Total* Number of patients 357 271 633 Stage I (confined to testis) 295 (83%) 158 (58%) 457 (72%) II (retroperitoneal nodes) 50 (14%) 61 (23%) 112 (18%) III (more extensive) 12 (3%) 52 (19%) 64 (10%) Median age (range)† 35 (17-80) 27 (0-76) 32 (0-80) * Includes three patients with stromal tumours and two with "other" histology. † The difference in age between men with seminoma and non-seminoma was significant (P<0.001). Back to text 2: Principal initial management after orchidectomy Surveillance Radiation therapy Chemotherapy Other Seminoma (Stage) I (confined to testis) 33 239 6 17 IIa,b (RP nodes 1 25 6 1 IIc,d (RP nodes >5cm) 0 2 15 0 III (more extensive) 0 2 9 1 Non-seminoma (Stage) I (confined to testis) 102 5 39 12 II (RP nodes) 1 0 60 0 III (more extensive) 0 0 52 0 Patients who received more than one form of therapy (eg, radiation and chemotherapy) were classified to the most significant form of treatment. Patients in the "other" category were reported as lost to follow up, 7 (22.6%); refused therapy, 16 (51.6%); received other therapy, 6 (19.4%); and not stated, 3 (9.7%). RP nodes=retroperitoneal nodes. Back to text 3: Multivariate analyses of prognostic factors for survival Non-seminoma (n=266) All patients (n=633) 5-year survival RR (95% CI) P 5-year survival RR (95% CI) P Morphology Seminoma 99% 1.0 Non-seminoma 91% 6.2 (1.9-20.0) Other 65% 51.9 (8.5-319) Age 93% 1.0 96% 1.0 30-49 years 92% 1.4 (0.5-3.6) 0.039 98% 1.5 (0.6-3.7) 0.002 ≥50 years 61% 6.0 (1.9-19.3) 78% 9.8 (4.4-32.0) Stage I 98% 1.0 99% 1.0 II 92% 3.6 (0.8-17.0) 96% 2.4 (0.7-8.6) III 69% 15.3 (4.4-52.8) 73% 11.9 (4.4-32.0) Multivariate analysis of survival for seminoma was not appropriate given the small number of deaths in this group. RR=relative risk. Back to text Back to text 5: Measures of quality of care Measure Eligible Completed Preoperative measurement of tumour markers 633 584 (92%) Adequate staging investigations 633 595 (94%) Radiation therapy for Stage I seminoma 295 239 (81%) Appropriate surveillance for Stage I non-seminoma 102 22 (22%) Chemotherapy for Stage IId, III seminoma and Stage II, III non-seminoma 132 127 (96%) All of the appropriate measures completed in each case 633 430 (68%) Back to text

Guy C Toner · Greg J Neerhut · Max A Schwarz · Vicky J Thursfield · Thomas Sandeman

Research Use of fake tanning lotions in the South Australian population Kerri R Beckmann, Barbara A Kirke, Kieran A McCaul and David M Roder MJA 2001; 174: 75-78 Abstract - Methods - Results - Discussion - Conclusions - References - Authors' Details - - More articles on Public and environmental health Abstract Objective: To explore the relationship between the use of fake tanning lotions and repeated sunburn among South Australian adults, with a view to informing the Anti-Cancer Foundation of South Australia's (ACFSA) policy on fake tanning products. Study design: Population survey. Participants: 2005 South Australians aged 18 years or older, selected randomly from the electronic White Pages. Main outcome measures: Self-reported use of fake tanning lotions in the past 12 months; frequency of sunburn over summer; and various sun-protective behaviours. Results: 2005 of the 2536 eligible participants (79%) were surveyed by telephone. Fake tan use was most prevalent among women (15.9%), people aged 18-24 years (15.4%), and people with household incomes above $40 000 per year (11.9%). Fake tan users were more likely than non-users to use sunscreens (81.3% v 56.5%; P < 0.001), but less likely to take other precautions such as wearing hats (40.9% v 51.0%; P = 0.04) and protective clothing (22.3% v 34.1%; P = 0.005). They were also more likely to report having been burnt more than once over summer (26.2% v 16.5%; P = 0.025). Multivariate analysis indicates a statistically significant association between fake tan use and repeated sunburn (odds ratio, 2.07; 95% confidence interval, 1.17-3.69), which was independent of age, sex, skin type and sun-protection practices. Conclusion: Users of fake tanning products may be at greater risk of repeated sunburn. The ACFSA sees no justification at this stage for altering its present policy position of not actively promoting the use of fake tanning lotions as a means of reducing sunburn. Anticancer organisations in Australia have been conducting programs aimed at reducing Australia's high rate of skin cancer for over two decades.1 The main objective of these programs is to encourage people to reduce their exposure to solar ultraviolet radiation, the major contributing factor to the development of skin cancer.2In Australia public awareness about the dangers of overexposure to the sun is generally high. In spite of this, a suntan is still desired by some sectors of the community -- in particular, young, fashion-conscious people.3,4 Skin cancer prevention programs have attempted to change attitudes that value tanned skin as attractive and healthy with such messages as "there is no such thing as a safe tan" and "a tan is a sign of skin damage". Last year, Chapman challenged anticancer organisations to consider the role that fake tanning lotions might play in reducing sun exposure, suggesting that they should be assessed as a potential harm-reduction strategy.5 The Anti-Cancer Foundation of South Australia (ACFSA) has, for a number of years, provided information on fake tanning lotions. While not actively encouraging their use, the information suggests that, for those desiring a tan, using fake tanning lotions is preferable to exposure to artificial or solar ultraviolet radiation. In October 1999, the ACFSA included a question on the use of fake tanning lotions in a Health Monitor Survey along with questions on skin type, experience of sunburn and frequency of wearing hats, cover-up clothing, applying sunscreen and seeking shade. This article reports the findings of that survey and discusses them in relation to the position taken by the ACFSA regarding fake tanning lotions. Methods Questions relating to sun exposure and ultraviolet radiation protective behaviours, including one relating to the use of fake tanning lotions, were asked of a random sample of South Australians, by computer-assisted telephone interviewing. These questions (Box 1) were part of a larger health-related survey organised and conducted by the Department of Human Services, South Australia, in October 1999. Except for the question relating to fake tan use, these questions have been used routinely in monitoring sun-protection behaviours in South Australia and were originally validated as written questions in a national Secondary School Children's Survey conducted triennially since 1990.6 The question on fake tan use is a slightly modified version of a question asked in Victorian surveys in 1993 and 1995.7,8Ethical approval for the survey that incorporated the questions used in this study was obtained through the Department of Human Services, with legal authorisation under section 64d of the South Australian Health Commission Act (1976). A sample of 3400 residences from rural and metropolitan areas within South Australia was drawn from the electronic White Pages. One adult from each household (the person whose birthday was the most recent) was invited to participate. Two thousand and five interviews were conducted from the 2536 households that could be contacted after six callback attempts, giving a participation rate of 79.1%. All data were weighted by age, sex and region, and on the probability of selection within the household. The population profile for weighting was obtained from the Australian Bureau of Statistics' estimated population for South Australia, 1997. Geographical region was defined as either metropolitan or country region. Both descriptive analysis of the survey data and logistic regression modelling were undertaken using STATA version 6,9 as this software allows calculation of robust estimates of standard error using methods devised by Huber10 and White.11 Consequently, variance estimates are adjusted for the data weighting. The relationship between fake tan use and reported sunburn over summer was examined using logistic regression modelling, allowing adjustment for age, sex, skin type and sun-protective behaviours. We first constructed a model containing known risk factors for sunburn and then added fake tan use to this model to establish if this improved the fit of the model. "Having been burnt two or more times during the previous summer" was the dependent (outcome) variable. For each of the sun protective behaviour questions, respondents were coded as regular users if they indicated that they "usually, almost always, or always" took such precautions when out in the sun for an hour or more, and were coded as irregular users if they indicated that they "never, rarely or sometimes" took these measures. Results Based on results from this survey, the estimated prevalence of fake tanning lotion use during the past 12 months among South Australians aged 18 years or more was 8.7% (95% confidence interval [CI], 7.3%-10.5%). The prevalence of fake tan use among various subgroups of the population is shown in Box 2. The use of fake tanning lotions is most common among younger people, particularly women, with the peak prevalence being 28% among young women aged 18-24 years. Fake tan use is also more common among those who report that their skin burns before tanning, compared with those whose skin just tans or just burns. Fake tan use also appears to be related to household income, with those with relatively high household incomes (above $40 000 per year) more likely to use fake tanning lotions. Individuals who had used fake tanning lotions in the past year were more likely to report regularly using sunscreen with a sun protection factor (SPF) of 15+ or higher when in the sun than non-users (81% v 57%; P < 0.001). However, they were less likely to report regularly wearing hats (41% v 51%; P = 0.04) or protective clothing (22% v 34%; P = 0.005). They reported seeking shade at levels similar to those who had not used fake tanning lotions (80% v 76%, P = 0.4). Those who had used fake tanning lotions were also more likely to report having been burnt two or more times during the previous summer (26% v 17%; P = 0.025) (Box 3). Factors such as age, skin type, sex and regular sun-protective behaviours are likely to confound the association between fake tan use and risk of burning. Results of logistic regression modelling, which takes into account the effects of these potential confounders, indicate an increased risk among fake tan users of having been sunburnt more than once (odds ratio [OR], 2.07; 95% CI, 1.17-3.69), as shown in Box 4. As the use of fake tanning lotions was much more prevalent among women than men, we also undertook regression analyses for women and men separately. No association between fake tan use and sunburn was found among men (OR, 0.90; 95% CI, 0.14-5.97). This was most probably owing to the fact that only 12 men reported using fake tanning lotions. There was, however, a strong association between using fake tanning lotions and repeated sunburn among women (OR, 2.47; 95% CI, 1.38-4.42). Discussion While the overall prevalence of fake tan use among adult South Australians is low (8.7%; 95% CI, 7.3%-10.5%), the use of fake tanning lotions is fairly common in younger women, with more than one in four women aged 18-24 years reporting having used fake tanning lotions in the past year. These findings are consistent with the reported prevalence of use in Victoria.7,8Respondents who reported using fake tanning lotions were more likely to report regularly using SPF 15+ or higher sunscreen when out in the sun during summer, but were less likely to report wearing hats or protective clothing. Fake tan users were more likely to report being sunburnt two or more times over the past summer. When other known risk factors were taken into account, fake tan users had twice the risk of repeated sunburn over summer compared with non-users. The only previously reported findings in relation to the association between fake tan use and sunburn are from two surveys conducted in Victoria, one in 19937 and one in 1995.8 The first of these surveys found a higher prevalence of sunburn among fake tan users (66% v 46%), while the latter survey found no difference (39% v 40%). The inconsistency of these two reports may have been owing to the relatively small sample size of each survey (n < 700). Owing to the limited nature of the questions in this survey, we were unable to determine whether fake tanning lotions were used just at the start of the season to give a tanned look before a sun-induced tan could be achieved, or throughout the summer as a substitute for sunbathing. Given the timing of the survey (ie, spring), there may be some inaccuracy in people's recall of sunburn in the previous summer. However, it seems unlikely to us that one group would have been more or less likely to under-report having been sunburnt, so any recall effect would have been equivalent in both groups. Another limitation in relation to the timing and cross-sectional nature of the survey is the inability to establish a temporal relationship. In some cases, sunburn may have preceded the use of fake tanning lotions. We can not conclude that fake tan use contributes directly to an increased risk of sunburn. We can only suggest that the behaviours of fake tan use and sun exposure may be linked. A further limitation of this study is that we did not ask about the reason for or frequency of use. We do not know whether there are differences in the risk of sunburn among those who use fake tanning lotions only on special occasions (eg, theatrical performances) compared with those who use such products regularly to maintain a tanned appearance. This lack of detail does not negate the finding that, as a whole, those who use fake tanning lotions are at greater risk of sunburn. Regardless of when and why people use fake tanning lotions, the results of this survey do not offer any evidence that use of fake tanning lotions, as currently practised, protects against sunburn. However, since this is an observational study, we can not rule out the possibility that the use of fake tanning lotions may actually offer some protection. It is conceivable that, had users not been applying fake tanning lotions, sunburn levels could have been even higher in this group. Further clarification of this issue would require a longitudinal (experimental) study design. Our results suggest that, rather than reducing their sun exposure, fake tan users are more likely to be exposing their skin to damaging levels of ultraviolet radiation than non-users. The evidence also suggests that, in general, fake tan users take fewer precautions to protect their skin from the sun. While fake tan users are more likely to report using sunscreens, they appear to rely on sunscreens alone for sun protection rather than using multiple strategies, as recommended by the Anti-Cancer Foundation. Some fake tan users may believe that the tanned effect provided by fake tanning lotions offers protection against the sun. Further confusion may arise in cases where their chosen brand of tanning lotion contains sunscreen. An inspection of fake tanning lotions currently available in South Australia showed that most brands do not include a sunscreen, and many state on the label that the fake tan does not provide protection against solar ultraviolet radiation. Some brands also include the advice to use a regular SPF 30+ sunscreen when going into the sun. However, a few brands of fake tanning lotions do contain sunscreen, varying in their sun protection factor from 4 to 15. One commonly available product with an SPF 4 rating states on its label, "UV Protection: Protects you in the sun, providing 4 times your natural sunburn protection". While technically correct, the protection would apply only to the period immediately after application and not for the time that the tan remains visible on the skin. Such claims are obviously very misleading. Anticancer organisations advise that sunscreens need to be reapplied regularly, ideally two-hourly, to maintain adequate protection. If such advice was followed when using a fake tanning lotion containing a sunscreen, the colour of the tan would deepen with each application. Also, it may take up to four hours for the tan colour to fully develop. Most products recommend removal of dry or flaky skin before applying the fake tanning lotion. The need to do this and the effect of repeated applications on tan colour are likely to preclude regular reapplication of fake tanning lotions, thereby increasing the likelihood of users risking sunburn if they rely on the protection offered by one application. In our view, including a sunscreen in a fake tanning lotion offers no obvious benefit. On the contrary, it has the potential to generate a false sense of protection which may lead to sunburn in fake tan users. Conclusions In response to the discussion posed by Chapman5 in relation to the use of fake tanning lotions as a "harm minimisation" approach, the ACFSA was prompted to review its policy in relation to the promotion and sale of fake tanning lotions. The results of this study do not point to a reduced risk of harmful sun exposure among fake tan users. Rather, they suggest an elevated risk of sunburn. In the light of these findings, the ACFSA sees no justification for altering its current position on the use of fake tanning lotions. The use of fake tanners is not actively promoted by the ACFSA. However, where there is a strong desire for a tan, people are advised that the use of fake tanning lotions is a better alternative than sunbathing or using a solarium. They are also advised that a fake tan does not provide protection against the sun and are warned about the limited protection offered by products that contain a sunscreen. More in-depth investigation of why and when fake tanning lotions are used, and the extent to which fake tan users believe they are protected from the harmful effects of the sun while using such products, is needed to inform education strategies and guide any policy change by organisations such as the ACFSA. The potential of the labelling of fake tan products containing sunscreens to be misleading needs to be brought to the attention of the relevant authorities. References Gray N. Report of the Chairman of the Education Committee. Australian Cancer Society Annual Report, 1979. Sydney: ACS, 1979: 9. Armstrong BK. Stratospheric ozone and health. Int J Epidemiol 1994; 23: 873-885. Arthey S, Clarke V. Suntanning and Sun protection: A review of the psychological literature. Soc Sci Med 1995; 40 (2): 265-274. Clarke V, Williams T, Arthey S. Skin type and optimistic bias in relation to the sun protection and suntanning behaviors of young adults. J Behav Med 1997; 20: 207-222. Chapman S. Faking it: should cancer control agencies promote fake tanning lotions? Med J Aust 1999; 170: 603-604. Broadstock M, Borland R, Hill D. Knowledge, attitudes and reported behaviours relevant to sun protection and suntanning in adolescents. Psychol Health 1996; 11: 527-539. Purchase M, Borland R. Public reaction to the 1992/93 SunSmart campaign: results from a representative survey of Victorians. SunSmart Evaluation Studies 3. Melbourne: Anti-Cancer Council of Victoria, 1994: 93. Dixon H, Cappiello M, Borland R. Reaction to the 1994/95 SunSmart campaign: results from a representative household survey of Victorians. SunSmart Evaluation Studies 5. Melbourne: Anti-Cancer Council of Victoria, 1997: 64. Stata version 6 [computer program]. College Station, TX: Stata Corporation, 1999. Huber PJ. The behavior of maximum likelihood estimates under non-standard conditions. Proceedings of the Fifth Berkeley Symposium on Mathematical Statistics and Probability 1967; 1: 221-233. White H. A heteroskedasticity-consistent covariance matrix estimator and direct test for heteroskedasticity. Econometrica 1980; 48: 817-830. (Received 21 Mar, accepted 31 Jul, 2000) Authors' Details Anti-Cancer Foundation of South Australia, Adelaide, SA. Kerri R Beckmann, BSc(Hons), MPH, Program Evaluation Officer; Barbara A Kirke, DipN, MPHC, Skin Cancer Prevention Project Officer. Collaborative Research Centre for Asthma, University Department of Medicine, Sir Charles Gairdner Hospital, Perth, WA. Kieran A McCaul, BSc, MPH, Biostatistician. Epidemiology Branch, South Australian Department of Human Services, Adelaide, SA. David M Roder, AM, MPH, DDSc, Director. Reprints will not be available from the authors. Correspondence: Ms K R Beckmann, Anti-Cancer Foundation of South Australia, PO Box 929, Unley, SA 5061. kbeckmannATcancersa.org.au Make a comment Back to text Back to text Back to text 4: Factors associated with being burnt more than once over summer All respondents Women only Adjusted Adjusted odds ratio 95% CI P odds ratio 95% CI P Fake tan use Non-users Users 1.00 2.07 - 1.17-3.69 0.013 2.47 1.38-4.42 0.002 Sex Female Male 1.00 2.99 - 2.09-4.29 - - - Age (group years) 65+ 18-24 25-34 35-44 45-54 55-64 1.00 13.70 5.83 4.72 2.46 1.27 - 7.00-26.78 3.19-10.65 2.66-8.38 1.34-4.53 0.61-2.66 0.004 0.529 15.46 4.40 5.12 3.56 0.40 5.34-44.77 1.71-11.34 2.04-12.86 1.37-9.23 0.09-1.65 0.002 0.001 0.009 0.203 Skin type Just tan Burn then tan Just burn 1.00 2.07 2.47 - 1.20-3.56 1.47-4.16 0.009 0.001 1.86 2.12 0.69-5.01 0.83-5.39 0.222 0.117 Sunscreen use Irregular Regular 1.00 1.03 - 0.72-1.48 0.876 0.82 0.44-1.49 0.509 Hat wearing Irregular Regular 1.00 0.69 0.48-0.98 0.038 0.91 0.52-1.59 0.746 Protective clothing Irregular Regular 1.00 0.63 - | 0.44-0.91 0.014 0.95 0.56-1.61 0.856 Shade seeking Irregular Regular 1.00 0.91 - 0.62-1.32 0.604 0.55 0.30-1.01 0.056 *Logistic regression modelling using forced entry of all variables. Separate models for all respondents and women only. Back to text

Kerri R Beckmann · Barbara A Kirke · Kieran A McCaul · David M Roder

Research A randomised crossover trial of chemotherapy in the home: patient preferences and cost analysis Danny Rischin, Michelle A White, Jane P Matthews, Guy C Toner, Kathryn Watty, Anthony J Sulkowski, Jan L Clarke and Lois Buchanan MJA 2000; 173: 125-127 Abstract - Methods - Results - Discussion - References - Authors' details - - More articles on Oncology Abstract Objectives: To determine patient preferences and cost differences between home-based and hospital-based chemotherapy. Design: Randomised crossover trial. Setting: A tertiary cancer hospital in Melbourne, Victoria. Participants: 20 patients who required chemotherapy suitable for administration at home. Interventions: Patients were assigned at random to receive their first chemotherapy treatment in either the home or the hospital and the second treatment in the alternative setting. Main outcome measures: Patient preference, costs. Results: There was universal agreement by the 20 patients in the randomised trial that home-based chemotherapy was the preferred option (P < 0.0001). No problems were nominated by the patients as being associated with home-based chemotherapy. Home-based treatment was estimated to result in an increased cost of $83 (P = 0.0002) for each chemotherapy treatment compared with hospital-based treatment. Reported advantages for chemotherapy in the home included the elimination of travel, reduction in treatment-associated anxiety, reduction in the burden on carers and family, and the ability to continue other duties. There were no significant complications associated with administration of chemotherapy in the home. Conclusions: Patients prefer home-based chemotherapy to hospital-based treatment. The future of chemotherapy-in-the-home programs in Australia will depend on whether patient preferences are deemed to offset any potential increase in costs. Patients with cancer who require treatment with chemotherapy will experience major changes in lifestyle and overall well-being. Some intravenous chemotherapy regimens require frequent visits to hospital to receive treatment. This may be time-consuming and inconvenient for a patient, and may also disrupt the lives of other family members and carers. The concept of home-based therapy is not new,1-3 but there have been few reports on chemotherapy-in-the-home programs, and these have had a different emphasis from our study (eg, costs [in a US paediatric population];4 costs and safety [in a retrospective review of an Australian adult population]5). We performed a randomised crossover trial, the aim of which was to compare (i) patient preference for hospital-based versus home-based chemotherapy; and (ii) the cost of therapy administered in hospital versus that in the home. Methods Patient eligibility Patients were considered eligible if they met the following criteria: they were to receive chemotherapy that was suitable to be given at home; their first two treatments were planned to be identical; they had not received chemotherapy in the preceding 12 months; they lived in an area that was geographically suitable for treatment at home; and they were aged 18 years or over. Patients gave written informed consent and the study was approved by the ethics committee of the Peter MacCallum Cancer Institute. Study design At enrolment, patients were randomly assigned to receive their first chemotherapy treatment in hospital and the second at home, or their first treatment at home and the second in hospital. They were assigned according to a computer-generated randomisation chart, using an allocation scheme based on a biased coin design.6Chemotherapy treatment refers to the first two administrations of chemotherapy. Following completion of the first two treatments, patients filled out a questionnaire regarding the two different locations of therapy. Questions focused on (i) patients' preference for where to receive their remaining chemotherapy after completing their two study treatments; and (ii) any perceived difficulties or advantages of treatment in hospital or in the home. Chemotherapy nurse specialists who also worked in the chemotherapy day ward at the hospital administered all home chemotherapy treatments. Patients were reviewed by a doctor before each chemotherapy cycle. Cost assessment Cost comparisons for hospital-based versus home-based therapy were made specifically from the perspective of the treating hospital, not the patient or society in general. Costs were estimated using Transition software (Eclipsys Transition Systems, Boston, MA), which distributes direct and indirect costs for an entire financial year between patient episodes on the basis of the services received. It was decided to compare only those components of the cost for which there could be a genuine difference to the hospital attributable to the site of delivery of the chemotherapy. Thus, costs related to patient records, allied health, medical staff and pharmacy were excluded. All overheads associated with the chemotherapy-in-the-home program, including vehicle costs and travelling time, were apportioned by Transition to nursing costs on the basis of time spent with each patient. Similarly, hospital overheads were apportioned on the basis of nursing times. The cost of providing a single meal was included in the hospital costs. Statistical methods A target sample size of 20 eligible patients with identical chemotherapy for their first two treatments was chosen, to provide 84% power to test the null hypothesis that no one setting is preferred versus the alternative hypothesis that at least 85% of patients prefer one setting over the other, using a two-sided test of significance at a significance level of 0.05. To determine if significantly more patients preferred treatment at home rather than in hospital, or vice versa, the proportion of patients preferring to have their third treatment in the same location as their first treatment was compared between the two randomisation arms using Fisher's exact test for 2 x 2 contingency tables. This test is valid even if there are "period" effects -- that is, if patients tolerate their second chemotherapy treatment better than their first, or vice versa.7 Standard methods for a 2 x 2 crossover trial7 were used to compare costs of chemotherapy in hospital with costs in the home, and costs between the first and second chemotherapy given ("period" effects), after ensuring there were no significant carryover effects. (Carryover effects were tested by comparing the sum of the costs in the home and hospital for patients in the "hospital first" arm with patients in the "home first" arm.) Statistical significance and 95% confidence intervals (CIs) were estimated from the means and standard errors assuming a Student's t-distribution. Two-sided P-values have been given throughout. All statistical tests were carried out using Stat Xact 4 (CYTEL Software Corporation, Cambridge, MA, 1998) and Microsoft Excel (Microsoft Corporation, Redmond, WA, 1996) software. Results Patient selection and profile The trial accrued the target 20 patients, out of a total of 64 registered on the chemotherapy-in-the-home program, between February 1996 and March 1997 (see Box 1). Patient demographics are shown in Box 2. Patient preferences When asked where they would have preferred to receive their first two treatments if they had had their time again, 70% of patients expressed a preference for having both treatments at home, while none said they would have preferred to have both treatments in hospital (Box 3). Patients were then asked to nominate their preferred site for the remaining treatments (the primary endpoint of the trial). All 20 patients (100%; 95% CI, 83%-100%) preferred to have their remaining therapy given at home (P < 0.0001). None of the patients in the trial reported concerns with chemotherapy being given in their home; however, four (20%) reported concerns with treatment in hospital, relating to transport difficulties and waiting times. Eighteen (90%) of the patients felt there were advantages with treatment in the home. The reasons given included convenience; avoidance of travel and parking problems (particularly not having to travel while feeling unwell); reduction in treatment-associated anxiety; not burdening their carers and family; and being able to continue other duties, such as caring for their dependants. Only one patient felt there were specific advantages to chemotherapy in the hospital. This patient felt it was good to see other people who were worse off. No major complications of chemotherapy administration (eg, hypersensitivity reactions or extravasation) were reported. Costing Overall, chemotherapy in the home was associated with an estimated average increased cost of $83 (95% CI, $46-$120; P = 0.0002) relative to the cost of chemotherapy in the hospital. The average cost of the first treatment was estimated to be $57 more than the cost of the second (95% CI, $20-$94; P = 0.0044). There was no carryover effect (P = 0.16). Discussion This study has demonstrated that patients have an overwhelming preference for home-based therapy. Clearly, home-based therapy is not possible, or indeed appropriate, for all patients. Patients living outside designated geographical areas or having special needs that can be met in the hospital setting (eg, need for an interpreter) would be more easily treated at the hospital.8 Complex or prolonged chemotherapy regimens or those associated with a risk of an immediate serious complication are more appropriately administered in the hospital day ward setting. Nevertheless, many commonly administered chemotherapy regimens are suitable for administration in the home, and this study clearly demonstrates that, given the choice, patients prefer to have such treatments at home. While in our study the cost of home-based treatment was on average $83 higher than the cost of hospital-based therapy, this estimate did not include costs to the patient (such as travelling costs, lost time for the patient or carers, and childcare costs). These could all have made the hospital episode more costly relative to the home episode. Furthermore, given that the cost per visit for any chemotherapy-in-the-home program is dependent on the throughput of patients and the geographical spread of the patients, an increase in the frequency of home visits or a more limited geographical spread of patients might further reduce the difference between home and hospital costs. Unlike some other hospital-in-the-home programs, chemotherapy in the home does not necessarily result in cost savings to the administering hospital, as treatment in the hospital does not require overnight admission. The future of chemotherapy-in-the-home programs in Australia will depend on how governments, hospital administrators, oncologists and nurses balance the overwhelming patient preference for treatment at home with any potential increase in costs. References Grayson ML, Silvers J, Turnidge J. Home intravenous antibiotic therapy. A safe and cost effective alternative to inpatient care. Med J Aust 1995; 162: 249-253. Koopman MMW, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low molecular weight heparin administered at home. N Engl J Med 1996; 334: 682-687. Bielory L, Long GC. Home health care costs: intravenous immunoglobulin home infusion therapy. Ann Allergy Asthma Immunol 1995; 74(3): 265-268. Close P, Burkey E, Kazak A, et al. A prospective, controlled evaluation of home chemotherapy for children with cancer. Pediatrics 1995; 95: 896-900. Lowenthal RM, Piaszczyk A, Arthur GE, et al. Home chemotherapy for cancer patients: cost analysis and safety. Med J Aust 1996; 165: 184-187. Wei LJ, Lachin JM. Properties of the urn randomization in clinical trials. Control Clin Trials 1988; 9: 345-364. Jones B, Kenward MG. Design and analysis of cross-over trials. London: Chapman and Hall Ltd, 1989. Zalcberg JR, Siderov J, Petty M. Outpatient chemotherapy: there's no place like home - sometimes. Med J Aust 1996; 165: 182. (Received 11 Oct 1999, accepted 24 May, 2000) Authors' details Peter MacCallum Cancer Institute, Melbourne, VIC. Danny Rischin, MB BS(Hons), FRACP, Consultant Medical Oncologist, Division of Haematology and Medical Oncology; Michelle A White, MB BS(Hons), FRACP, Clinical Fellow, Division of Haematology and Medical Oncology; Jane P Matthews, BSc(Hons), PhD, AStat, Director, Statistical Centre; Guy C Toner, MD, BS, FRACP, Head of Medical Oncology, Division of Haematology and Medical Oncology; Kathryn Watty, RN, RM, Clinical Nurse Consultant, Division of Nursing; Anthony J Sulkowski, RN, BEd, Clinical Nurse Consultant, Division of Nursing; Jan L Clarke, RN, Clinical Nurse Consultant, Division of Nursing; Lois Buchanan, RN, RM, Clinical Nurse Consultant, Division of Nursing. Reprints will not be available from the authors. Correspondence: Dr D Rischin, Division of Hematology and Medical Oncology, Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett Street, Melbourne, VIC 8006. drischinATpetermac.unimelb.edu.au Make a comment Click in box for larger version Back to text 2: Patient demographics, by randomisation arm (first chemotherapy treatment given at hospital vs first treatment at home). Values are number of patients unless otherwise stated Hospital first Home first Total (%) Sex Male Female 1 8 4 7 25% 75% Age Median (years) Range (years) 40-49 50-59 60-69 70 61 47-71 0 2 1 5 1 59 26-69 1 4 1 5 0 -- -- 5% 30% 10% 50% 5% Diagnosis Breast cancer Colon cancer Non-Hodgkin's lymphoma Pancreatic cancer 5 3 0 1 5 5 1 0 50% 40% 5% 5% Chemotherapy CMF(P)* 5-FU† ± folinic acid or levamisole CHOP‡ 5 4 0 5 5 1 50% 45% 5% Support at home Spouse/parent Parent Son/daughter Other Not specified 4 1 3 0 1 7 0 1 3 0 55% 5% 20% 15% 5% * Cyclophosphamide, methotrexate, 5-fluorouracil ±prednisolone. † 5-Fluorouracil. ‡Cyclophosphamide, doxorubicin, vincristine and prednisolone. Back to text 3: Preferred location for chemotherapy treatments, by randomisation arm (first chemotherapy treatment given at hospital vs first treatment at home). Values are number of patients Hospital first Home first Total (%) For first 2 treatments Both at home First at home, second at hospital No preference First at hospital, second at home Both at hospital 7 0 1 1 0 7 2 1 1 0 14 (70%) 2 (10%) 2 (10%) 2 (10%) 0 For subsequent treatments Home Hospital 9 0 11 0 20 (100%) 0 Back to text

Danny Rischin · Michelle A White · Jane P Matthews · Guy C Toner · Kathryn Watty · Anthony J Sulkowski · Jan L Clarke · Lois Buchanan

Editorial Cancer in the family: risks and management A recent NHMRC publication addresses the clinical implications of cancer genetics for Australian families MJA 2000; 172: 529-530 A family history of cancer is widely recognised as an important risk factor for common cancers, with 5%-10% of cancers considered attributable to genetic predisposition. A recent National Health and Medical Research Council (NHMRC) publication for health professionals, Familial aspects of cancer: a guide to clinical practice,1 addresses the clinical implications of cancer genetics. Why do we need such a guide, and what does it cover? Cancer genetics Knowledge of the genetic basis of cancer has increased dramatically in the past decade. It is now clear that cancers evolve in Darwinian fashion, exploiting mutations in genes that regulate cellular growth, death and differentiation. The cumulative acquisition of defects in a number of these genes facilitates the progressive selection of cells towards a highly malignant and uncontrolled state of cellular proliferation and immortality. In the majority of cancers, these mutations are acquired in particular cells over a lifetime (somatic mutations). There are, however, families displaying clear inherited predisposition to certain common cancers, including breast, ovarian, colorectal and prostate cancer and melanoma. The affected members of these families carry an inherited (germline) mutation in one of their "cellular fitness" genes. Germline mutations affect all body cells, but give certain tissues a genetic head start down the cascade of genetic errors that results in cancer. Genes prone to such inherited abnormalities are called "cancer susceptibility" genes. The individuals carrying mutations in these genes often carry a very high lifetime chance (> 50%) of developing cancer. Implications for clinical practice The improved ability to detect individuals at high risk of cancer through analysis of family history and/or genetic testing has fortunately been accompanied by major advances in screening, surveillance and prevention. The clinical usefulness of such advances is exemplified in the management of familial adenomatous polyposis (FAP), a condition caused by a dominantly inherited mutation in the adenomatous polyposis coli (APC) gene. Individuals with FAP develop hundreds of adenomatous polyps, of which one or more may, if untreated, become malignant, often at an early age. Until recently, all at-risk individuals required regular screening sigmoidoscopy from the early teenage years. Now, after being genetically tested, only those family members found to carry the mutation need to undergo intensive cancer screening and eventually prophylactic colectomy.2 Similarly, genetic testing for hereditary non-polyposis colorectal cancer has proved to be acceptable to families, and may reduce the cost of unnecessary screening colonoscopy in those family members found not to carry a mutation.3Familial cancer clinics have now been set up in response to the growing public and professional awareness of family history as a risk factor for cancer. These clinics provide pedigree analysis, risk assessment and advice to those at high risk of cancer, and may also carry out genetic testing (if appropriate) in association with genetic counselling. The NHMRC document1 stratifies risk categories for people with a family history of diseases such as breast and colorectal cancer. It identifies those who may benefit from referral to familial cancer clinics and the role of general practitioners and specialists in managing high risk families. In the context of a detailed ethical discussion, an attempt is made to designate those who may benefit from genetic testing (see Box). Why national guidelines? A coordinated national policy on cancer genetics has arisen in response to a number of factors: In recent years there has been heightened public awareness of the problem and increased demand for access to familial cancer services from those at perceived risk of cancer. (At the Familial Cancer Service at Westmead Hospital, for example, referrals, carefully screened for adherence to eligibility criteria, increased from 120 new families in 1996 to almost 300 in 1999); Health authorities have understandable concerns about the potential for proliferation of unregulated, unevaluated genetic testing facilities for cancer, as has occurred in the United States, and the need for public education and guidance in this area; Scientists face considerable challenges in assuring quality for complex, new and constantly evolving diagnostic tests, overcoming difficulties in resource management, and ensuring the timely and appropriate translation of relevant technologies from a research to a diagnostic environment. While similar documents have been produced by other international groups,4-7 these issues need to be addressed in a manner relevant to the Australian population. Guidelines based on US data for breast cancer, for example, may be quite inappropriate for Australia, and specific mutations in melanoma susceptibility genes may be more highly penetrant under the influence of Australian sunlight.8,9 In 1995 the Australian Cancer Network (ACN), in joint sponsorship with the NHMRC National Breast Cancer Centre (NBCC) and the Human Genetics Society of Australasia, convened the ACN Cancer Genetics Working Party to draft national guidelines for clinical practice. The current guidelines are the culmination of an extensive consultation and collaboration process. The future In such a rapidly changing field, future refinements of the guidelines will depend on the availability of high quality Australian data from national epidemiological studies. These studies will provide information on the frequency and penetrance of mutations in cancer susceptibility genes in the Australian population and the effect of local environmental factors on those mutations. A welcome spin-off of the endeavour to compile this guide has been the unification of diverse research interests throughout Australia in well organised, comprehensive consortia investigating the cancer genetics of breast cancer, melanoma and colorectal cancer.* In parallel with these exciting developments in research, we need to improve the accessibility of such information to general practitioners.10 The NBCC and the ACN have already moved toward the provision of more succinct information for GPs with their publications Current best advice about familial aspects of breast cancer11 (under current revision to incorporate familial ovarian cancer) and Advice about familial aspects of bowel cancer: a guide for general practitioners (ACN, in preparation). Consumer information has been developed to accompany these documents. The National Cancer Control Institute is also fostering a national approach to education and data management for families with a genetic predisposition to malignancy. The energy, goodwill and collaborative spirit associated with the preparation of these new guidelines provide a strong basis for the ongoing care of cancer families in Australia. Judy Kirk Senior Staff Specialist Familial Cancer Service and Westmead Institute for Cancer Research Westmead Hospital, Westmead, NSW Richard Kefford Professor of Medicine, Westmead Institute for Cancer Research Westmead Hospital, Westmead, NSW *Breast cancer: The Kathleen Cuningham Consortium for Research on Familial Breast Cancer (kConFab) research project (see <http://www.pmci.unimelb. edu.au/kconfab>), led by Joseph Sambrook, and the Australian Breast Cancer Family Study, led by John Hopper (j.hopperATgpph.unimelb.edu.au). Colorectal cancer: The Australasian Colorectal Cancer Study, led by Jeremy Jass (j.jassATmailbox.uq.edu.au). Melanoma: The Australian Melanoma Family Study, led by Graham Mann (gmannATmail.usyd.edu.au) National Health and Medical Research Council. Familial aspects of cancer: a guide to clinical practice. Endorsed Nov 1999. Available at: <http://www.nhmrc.health.gov.au/publicat/cp-home.htm>. Accessed 2 May 2000. (Catalogue No. 993839X.) Gardner M, St John J. Gene testing and genetic counselling in familial polyposis. Med J Aust 1995; 162: 457. Stanley AJ, Gaff CL, Attomaki AK, et al. Value of predictive genetic testing in management of hereditary non-polyposis colorectal cancer (HNPCC). Med J Aust 2000; 172: 313-316. Burke W, Daly M, Garber J, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. Cancer Genetics Studies Consortium. JAMA 1997; 277: 997-1003. Burke W, Petersen G, Lynch P, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium. JAMA 1997; 277: 915-919. Eisinger F, Alby N, Bremond A, et al. Recommendations for medical management of hereditary breast and ovarian cancer: the French National Ad Hoc Committee. Ann Oncol 1998; 9: 939-950. Kefford RF, Newton Bishop JA, Bergman W, Tucker MA. Counseling and DNA testing for individuals perceived to be genetically predisposed to melanoma: a consensus statement of the Melanoma Genetics Consortium. J Clin Oncol 1999; 17: 3245-3251. Cannon-Albright LA, Meyer LJ, Goldgar DE, et al. Penetrance and expressivity of the chromosome 9p melanoma susceptibility locus (MLM). Cancer Res 1994; 54: 6041-6044. Bishop JA, Wachsmuth RC, Harland M, et al. Genotype/phenotype and penetrance studies in melanoma families with germline CDKN2A mutations. J Invest Dermatol 2000; 114: 28-33. Gupta L, Ward JE, Hayward RS. Clinical practice guidelines in general practice: a national survey of recall, attitudes and impact. Med J Aust 1997; 166: 69-72. National Breast Cancer Centre. Current best advice about familial aspects of breast cancer. Sydney: NBCC, 1997. Available at: <http://www.nbcc.org.au/ pages/info/resource/nbccpubs/advice.htm>. Accessed 2 May 2000. Make a comment Familial aspects of cancer: a guide to clinical practice New NHMRC guidelines1 address the following key issues: Importance of an accurate, extended family history in assessing cancer risk Identification of rare families with a genetic predisposition to one of the common malignancies (eg, breast, ovarian, colorectal or prostate cancer, or melanoma) Role of familial cancer clinics in the management of families at risk Evolving role of genetic testing in risk assessment Requirement for genetic counselling in association with genetic testing Ethical issues relating to genetic counselling and testing for cancer predisposition Management, screening and cancer prevention for individuals found to be at high risk or potentially high risk of developing cancer Continued need for national collaborative research in this field Back to text

Judy Kirk · Richard Kefford

Viewpoint Active and passive cigarette smoking and breast cancer: is a real risk emerging? Recent studies may explain the apparent inconsistencies between earlier results Robert C Burton and Nabil Sulaiman MJA 2000; 172: 550-552 Conflicting results on smoking and breast cancer - Postulated mechanisms - Resolving the conflicts - Where to from here? - References - Authors' details - - More articles on Public and environmental health Cigarette smoking has been suggested as a cause of breast cancer, but many studies addressing the relationship have yielded inconsistent results. A possible explanation is that many of these studies have overlooked the potential effects of passive exposure to cigarette smoke when assessing the effects of active smoking. A further source of confusion is the hypothesised existence of a window of vulnerability to tobacco smoke carcinogens during childhood and adolescence.1 We summarise the epidemiological evidence for a causal association between smoking and breast cancer and consider recent studies on the effects of active and passive exposure to cigarette smoke in the context of this hypothesised window of vulnerability. Conflicting results on smoking and breast cancer A review of publications on the relationship between smoking and breast cancer to 1984 found more evidence for a protective than for a harmful effect of cigarette smoking.2 In contrast, a 1990 review reported that the summary odds ratio (OR) for breast cancer in smokers compared with non-smokers was 1.12 for case-control studies (95% CI, 1.06-1.19) and 1.14 for cohort studies (95% CI, 1.02-1.27).3 A large case-control study of about 7000 case and 9000 control participants, published in 1996, found no relationship between cigarette smoking and breast cancer.4Conflicting results have also emerged from large, well designed cohort studies. A 1989 analysis of the United States Nurses' Cohort Study (about 120 000 women) found no relationship between cigarette smoking and breast cancer.5 In contrast, the American Cancer Society Cohort Study (about 600 000 women) reported in 1994 that women who were current smokers at the time of death had a higher breast cancer mortality than non-smokers (relative risk [RR], 1.26; 95% CI, 1.05-1.50).6 Furthermore, mortality tended to increase with the amount and duration of smoking; for example, RR was 1.74 (95% CI, 1.15-2.62) for women who smoked 40 or more cigarettes per day. Postulated mechanisms A range of biological and epidemiological explanations have been proposed for these varying results. On the one hand, cigarette smoking may have a protective effect, as women who smoke have an earlier menopause, with fewer total years of menstruation,7,8 and weigh less than non-smokers,7,9 and also cigarette smoking alters oestrogen metabolism.10,11 That is, the negative effect of cigarette smoking on oestrogen production may reduce the risk of oestrogen-dependent diseases.2On the other hand, cigarette smokers may have increased risk of breast cancer, as carcinogens from tobacco smoke absorbed into the bloodstream may produce carcinogenesis of breast ductal epithelium.12 Several polycyclic aromatic hydrocarbons are produced by tobacco combustion, including the carcinogens benzo[a]pyrene, which is mutagenic for the p53 tumour suppressor gene in humans,13 and 7,12-dimethylbenz[a]anthracene, which is used to induce mammary tumours in animals.14 Data reported recently from the Carolina breast cancer study showed that archival breast cancer tissue from current cigarette smokers had a higher prevalence of p53 mutations than breast cancer tissue from never smokers: 40.4% versus 24.8%.15 Of particular interest was the finding that p53 mutations of the type found in lung cancers from smokers were detected in breast cancer tissues from 21% of current smokers but only 5% of never smokers. In addition, Palmer and colleagues hypothesised that women's risk of breast cancer is increased by exposure to cigarette smoke during childhood and adolescence, as these are times of rapid breast growth.1 They reported two case-control studies of breast cancer risk among women who smoked 25 or more cigarettes per day compared with never active smokers. These studies found that ORs for smokers who began smoking before the age of 14 years, compared with never active smokers, were 2.6 (95% CI, 1.0-6.8) and 1.9 (95% CI, 0.9-4.1), respectively. In contrast, ORs were lower for those who began smoking later, at ages 18-21 years, compared with never active smokers: 1.1 (95% CI, 0.7-1.7) and 1.2 (95% CI, 0.7-1.8), respectively.15 Resolving the conflicts The explanation for much of the discrepancy between the above results on active smoking and breast cancer may be that the studies did not consider passive exposure to tobacco smoke.16 This issue has been addressed by three recent case-control studies which compared smokers with women who had no exposure to tobacco smoke, either active or passive.12,17,18 They found ORs ≥ 2.0 for the overall risk of breast cancer in ever smokers (two studies12,18) or ever smokers with premenopausal breast cancer (one study17) compared with women with no active or passive exposure to tobacco smoke. Selected data from these three studies are shown in the Box. These three studies also examined the association between breast cancer and passive exposure to cigarette smoke, as did two other case-control studies19,20 and two cohort studies.16,21 Data from the Hirayama cohort, reported in 1998 (91 540 women), showed that spouses who were passively exposed had an RR of 1.32 (95% CI, 0.83-2.09).16 A recent Korean cohort study on spouses' passive exposure to smoke and lung cancer (160 130 women) also found an increased risk of breast cancer (RR, 1.7; 95% CI, 1.0-2.8).21 Selected data from the five case-control studies on the effects of passive exposure to cigarette smoke, including effects of age of exposure, are shown in the Box. Two studies found a significant exposure-response effect in terms of the number of smokers and smoker-years to which women were passively exposed. The age of passive exposure also appeared important, as Palmer et al observed for active exposure in two previous case-control studies.1 Smith et al found childhood exposure to be almost as important as adult exposure,19 and Lash and Aschengrau found that the risk of breast cancer in females passively exposed to cigarette smoke was highest when exposure occurred before the age of 12 years, less when it occurred at 12-20 years, and least when it occurred after the age of 20.18 Furthermore, they found an OR of 7.5 (95% CI, 1.6-36) for the occurrence of breast cancer in girls exposed to passive smoking who were also active smokers before the age of 12 years. It should be noted that, as there were few case and control participants, 95% confidence intervals were wide, and the estimates should be viewed with caution. The ORs shown in the Box suggest a causal association between active and passive exposure to cigarette smoke and breast cancer (ORs > 2.0 are considered to indicate a strong association22). Interestingly, a recent review of established and possible aetiological factors in breast cancer found that only age, strong family history, mutations in BRCA-1 or BRCA-2 genes, country of birth and atypical cells in nipple aspirates were associated with ORs over 4.0.23 Lash and Aschengrau based their study on a model of susceptibility of breast tissue to tobacco smoke which was derived from new knowledge on breast tissue development and susceptibility to chemical carcinogens.18 The physiological development of the mammary gland involves four different lobule types, representing sequential developmental stages.24 During sexual maturation (puberty), breast tissues evolve from lobule type 1 (highest doubling rate and greatest susceptibility to carcinogens) to type 2 (intermediate doubling rate and susceptibility to carcinogens). During pregnancy, or gradually with premenopausal ageing, breast tissues evolve to type 3 (low doubling rate and susceptibility to carcinogens). Type 4 lobules (maximal expression of development and differentiation) develop during lactation. Therefore, the window of maximum vulnerability of girls to tobacco-smoke-induced breast cancer should be from birth through puberty. Where to from here? Clearly, further studies are needed to investigate and better measure the effects of active and passive exposure to cigarette smoke in various phases of childhood, adolescence and adult life. Furthermore, the recent studies reviewed here involved women in Europe and the United States who presented with breast cancer in the 1980s and 1990s. Their exposure to cigarette smoke during the hypothesised window of vulnerability would have occurred mainly in the 1930s to 1950s, and would reflect the smoking habits of teenage and young women and their parents at that time. Therefore, Australian data are urgently needed, as exposures may have differed in this country. Finally, if active and passive exposure to cigarette smoke in childhood and adolescence proves to cause breast cancer, then the current smoking habits of Australian teenage girls are of even greater concern. The 1996 survey on use of tobacco and alcohol among Australian secondary students revealed that 14%-20% of girls aged 12-15 years were current smokers in the period 1984-1996, and that they smoked an average of 18.7-21.2 cigarettes per week.25 By the age of 12 years, 32% of girls had experimented with cigarette smoking.25 A proportion of Australia's future burden of breast cancer may already have been initiated. References Palmer JR, Rosenberg L, Clarke EA, et al. Breast cancer and cigarette smoking: a hypothesis. Am J Epidemiol 1991; 134: 1-13. Baron JA. Smoking and estrogen-related disease. Am J Epidemiol 1984; 119: 9-22. MacMahon B. Cigarette smoking and cancer of the breast. In: Wald N, Baron J, editors. Smoking and hormone-related disorders. Oxford: Oxford University Press, 1990: 154-166. Baron JA, Newcomb PA, Longnecker MP, et al. Cigarette smoking and breast cancer. Cancer Epidemiol Biomarkers Prev 1996; 5: 399-403. London SJ, Colditz GA, Stampfer MJ, et al. Prospective study of smoking and the risk of breast cancer. J Natl Cancer Inst 1989; 81: 1625-1631. Calle EE, Miracle-McMahill HL, Thun MJ, et al. Cigarette smoking and risk of fatal breast cancer. Am J Epidemiol 1994; 139: 1001-1007. Willett WC, Stampfer MJ, Brian C, et al. Cigarette smoking, relative weight and menopause. Am J Epidemiol 1983; 117: 651-658. Kaufman DW, Slone D, Rosenberg L, et al. Cigarette smoking and age at natural menopause. Am J Public Health 1980; 70: 420-422. Istvan JA, Cunningham TW, Garfinkel L. Cigarette smoking and body weight in the cancer prevention study I. Int J Epidemiol 1992; 21: 849-853. MacMahon B, Trichpoulos D, Cole P, et al. Cigarette smoking and urinary estrogens. N Engl J Med 1982; 307: 1062-1065. Michnovicz JJ, Hershcope RJ, Naganuma H, et al. Increased 2-hydroxylation of estradiol as a possible mechanism for the anti-estrogenic effect of cigarette smoking. N Engl J Med 1986; 315: 1305-1309. Morabia A, Bernstein M, HŽritier S, et al. Relation of breast cancer with passive and active exposure to tobacco smoke. Am J Epidemiol 1996; 143: 918-928. Denissenko MF, Pao A, Tang M, Pfeifer GP. Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hot spots in P53. Science 1996; 274: 430-432. Huggins CB. Selective induction of hormone-dependent mammary adenocarcinoma in the rat. J Lab Clin Med 1987; 109: 262-266. Conway K, Edmiston SN, Cui L, et al. The prevalence and spectrum of p53 mutations in the Carolina breast cancer study suggests a role for cigarette smoking in breast cancer development. Proc Amer Assoc Cancer Res 2000; 41: 222. Wells AJ. Breast cancer, cigarette smoking and passive smoking. Am J Epidemiol 1998; 147: 991-992. Johnson KC, Hu J, Mao Y, et al. Passive and active smoking and breast cancer risk in Canada, 1994-1997. Canadian Cancer Registries Epidemiology Research Group. Cancer Causes Control 2000; II: 211-221. Lash TJ, Aschengrau A. Active and passive cigarette smoking and the occurrence of breast cancer. Am J Epidemiol 1999; 149: 5-12. Smith SJ, Deacon JM, Chilvers CE. Alcohol, smoking, passive smoking and caffeine in relation to breast cancer risk in young women. UK National Case-Control Study Group. Br J Cancer 1994; 70: 112-119. Sandler DP, Wilcox AJ, Evesan RB. Cumulative effects of lifetime passive smoking on cancer risk. Lancet 1985; 1: 312-315. Jee SH, Ohrr H, Kin IS. Effect of husbands smoking on the incidence of lung cancer in Korean women. Int J Epidemiol 1999; 28: 824-828. Beaglehole R, Bonita R, Kjellstršm T. Basic epidemiology. Geneva: World Health Organization, 1993. Kelsey JL, Bernstein L. Epidemiology and prevention of breast cancer. Annu Rev Public Health 1996; 17: 47-67. Russo J, Russo I. Toward a physiological approach to breast cancer prevention. Cancer Epidemiol Biomarkers Prev 1994; 3: 353-364. Hill D, White V, Letcher W. Tobacco use among Australian secondary students in 1996. Aust N Z J Public Health 1999; 23: 252-259. Authors' details Anti-Cancer Council of Victoria, Melbourne, VIC. Robert C Burton, MD, PhD, Director; Nabil Sulaiman, MD, PhD, Epidemiologist. Reprints will not be available from the authors. Correspondence: Dr R C Burton, Anti-Cancer Council of Victoria, 1 Rathdowne Street, Carlton, VIC 3053. directorATaccv.org.au Make a comment &copy 2000 Medical Journal of Australia. Smoking and risk of breast cancer in case-control studies that controlled for, or investigated the effects of, passive exposure to tobacco smoke* Smoking exposure Adjusted odds ratio for breast cancer† (95% CI) Reference Active smoking (Referent group never exposed, actively or passively) 1.0 Current smoker, cigarettes per day 1-9 10-19 ≥20 1.5 (0.9-3.9) 2.1 (0.9-4.8) 5.1 (2.1-12.6) Morabia et al12 Ever smoker, average lifetime cigarettes per day 1-9 10-19 ≥20 2.2 (1.0-4.4) 2.7 (1.4-5.4) 4.6 (2.2-9.7) Morabia et al12 Ever smoker, cigarettes per day while active smoker 1-9 10-19 ≥20 2.5 (1.2-5.2) 2.3 (1.1-4.6) 2.0 (1.0-4.0) Johnson et al17 Smoking relative to first full-term pregnancy Only before Only after Before and after 5.6 (1.5-21) 2.1 (1.1-4.0) 1.1 (0.6-2.0) Lash and Aschengrau18 Passive exposure (Referent group never exposed, actively or passively, unless shown otherwise) 1.0 Duration of exposure 1-50 hours/day-years‡ >50 hours/day-years 3.1 (1.5-6.2) 3.2 (1.6-6.3) Morabia et al12 Total smoker-years (residential plus occupational) 1-13 14-32 33-70 >70 1.5 (0.5-4.4) 2.0 (0.9-4.5) 2.9 (1.3-6.6) 3.0 (1.3-6.6) Johnson et al17 Timing of passive exposure Before age 12 years Age 12-20 years After age 20 years 4.5 (1.2-16) 3.8 (1.1-13) 2.4 (0.9-6.1) Lash and Aschengrau18 Never§ Childhood only Adulthood only Both 1.00 1.98 (0.35-11.36) 2.65 (0.80-8.83) 3.13 (1.05-9.38) Smith et al19 Number of household smokers§ 0 1 2 3 or more 1.0 2.0 2.4 3.3 Sandler et al20 *Selected data are shown, with 95% CIs when given in the cited article. †Adjusted for multiple risk factors, including alcohol intake, except in Sandler et al.20 ‡Hours/day-years=hours/day x duration for all episodes of passive exposure. For example, 50 hours/day-years could represent 1 hour per day for 50 years, 2 hours per day for 25 years, or 12.5 hours per day for 4 years, and so on. § Some members of both referent and exposed groups were active smokers. Back to text

Robert C Burton · Nabil Sulaiman

Editorial Virtually viewing the large bowel: the future of colorectal cancer screening? New technologies add to the debate over how best to screen for colorectal cancer MJA 2000; 172: 416-417 Colorectal cancer is a disease ideal for screening: it is common; prognosis is poor if it is detected late but excellent if it is treated early; and there is a premalignant phase (the adenoma) which has a relatively long dwell time during which it can be detected and treated relatively safely. In addition, higher-than-average-risk groups can be identified and targeted. It has been recommended that a colorectal cancer screening program be established in Australia, but, because of uncertainties about the program's feasibility, that this be implemented through a series of pilot studies.1 Nonetheless, for asymptomatic individuals aged over 50 years without a family history of colorectal cancer, the National Health and Medical Research Council favours screening by annual faecal occult blood testing (FOBT), complemented by flexible sigmoidoscopy every five years.2The problem is that all current screening tools are imperfect. FOBT is most widely advocated as the only test shown to reduce mortality from colorectal cancer (by 15%-33%) when used for mass population screening.1 It is also cheap, safe and can be administered by the general practitioner. Accuracy depends on the type of FOBT used and the frequency of testing, but, on an individual basis, FOBT misses between 21% and 63% of cancers and most adenomas, and has a false-positive rate of 2%-13%.3 Flexible sigmoidoscopy is under trial both in Australia and overseas as a tool for population screening. The rationale is that most neoplasms occur within reach of the flexible sigmoidoscope, and that distal adenomas may be predictors of proximal lesions. In this issue of the Journal, Nicholson and colleagues4 show, as have others,5 that, among screened subjects with adenomas, 25% have proximal adenomas only (defined by Nicholson et al as proximal to the splenic flexure). These are beyond the reach of flexible sigmoidoscopy. This study illustrates one of the problems of flexible sigmoidoscopy screening -- accuracy for cancer and polyp detection. However, other important issues must be considered in assessing a screening test, such as acceptability, compliance, availability, safety and cost. Indeed, in the Australian context, initial participation rates in flexible sigmoidoscopy screening have been disappointing (12%),6 although recent data indicate that these rates have increased to around 40% (Associate Professor John Olynyk, Department of Gastroenterology, Fremantle Hospital, Fremantle, WA, personal communication). The findings of Nicholson and colleagues support the need for imaging the whole colon in colorectal neoplasm screening. Methods advocated for this include double-contrast barium enema and colonoscopy. Both have their supporters. However, data on use of these methods for population screening of average-risk individuals are limited, and both have drawbacks that make them unlikely to be widely accepted for mass screening. Setting aside considerations of compliance, double-contrast barium enema is probably not sufficiently accurate without concomitant flexible sigmoidoscopy (which would increase costs and almost certainly decrease compliance), and imposes a significant radiation dose. Total colonoscopy has the advantages of accuracy and ability to combine screening with therapy (polypectomy) but carries a small but significant risk.7 A certain level of competence is required to achieve adequate rates of caecal intubation, and, although it is difficult to determine exact completion rates, outside specialist centres they may be only 80%-90%8,9 or less. Taking into account the need for sedation, consequent bed fees and cost of time off work, colonoscopy is relatively expensive. A recent contender for screening is virtual colonoscopy (computed tomography [CT] colography). After bowel preparation, the colon is insufflated with air or carbon dioxide, and a spiral CT scan performed, preferably in supine and prone positions. Because of the volumetric nature of data acquisition, sagittal and coronal reformatted images can be viewed, as well as the source axial images, and endoluminal images can be reconstructed, simulating an endoscopic view. Navigation using these images can be achieved by manual manoeuvres or "fly-through" techniques that automatically centre on the bowel lumen. While not yet as accurate as colonoscopy for polyp detection, virtual colonoscopy is likely to become significantly more accurate with expected developments in hardware and software. Currently, virtual colonoscopy is more accurate than FOBT and can probably compete with flexible sigmoidoscopy with regard to larger polyps. A study from Boston has reported sensitivities of 91%, 82% and 55% for polyps of diameter 10 mm or more, 6-9 mm, and 5 mm or less, respectively.10 Virtual colonoscopy also has several potential advantages as a screening tool: it is minimally invasive and quick for the patient (the scan takes only a few minutes); no sedation is required; and initial studies have shown that it is highly acceptable to patients.11 Its "high-tech", virtual reality profile makes it potentially attractive to the lay public. While using ionising radiation, dosages are considerably less than for double-contrast barium enema when low-dosage protocols are used. Using the current scanning protocol in our institution, total effective radiation dose has been calculated to be less than 5 mSv, even when supine and prone scans are performed (compared with about 8 mSv for conventional double-contrast barium enema). In addition, early studies hold out the possibility that magnetic-resonance (MR) virtual colonoscopy may eventually supersede CT virtual colonoscopy, eliminating ionising radiation.12 Lastly, there is the potential to detect incidental extracolonic disease, such as asymptomatic aortic aneurysms and renal carcinoma. Problems currently limiting the application of virtual colonoscopy as a screening tool include its lack of sensitivity for small polyps, particularly those 5 mm or less in diameter.10 Does this matter in the context of a screening program? Probably not: the chances of a 5 mm lesion being malignant are negligible; if screening takes place every five years the dwell time for such a small lesion allows an enlarging lesion to be picked up on subsequent examinations. A further limitation is the need for bowel preparation, which is likely to be a significant factor in reducing participation rates. However, the use of faecal tagging to allow software to differentiate faeces and polyps may eventually minimise, or even eliminate, the need for bowel preparation. In addition, other factors, such as availability, operator experience and cost, need to be evaluated in assessing the potential role of virtual colonoscopy as a screening tool for colorectal cancer. Much of the present cost is related to the time required for image processing and reading of the images by the radiologist, which is as long as 30-45 minutes with current commercially available technology. However, this time will inevitably be reduced significantly by further technological advances, such as faster computer processing and automated polyp detection software. Finally, it would be preferable that images are read promptly so that individuals with abnormalities have the opportunity of proceeding to same-day colonoscopy to avoid the need for a second bowel preparation. So, is virtual colonoscopy a viable option as a screening tool for colorectal cancer in the average-risk individual? There is little doubt that, in its current state of development, it is not ready for widespread use. In addition to the limitations already discussed, the excellent sensitivity data reported by some centres10,13 have not been widely replicated.14 Equally, there is a high probability that, at its rate of evolution, in the not-too-distant future CT (or MR) virtual colonoscopy will become an accepted (or even the accepted) modality for colorectal cancer screening. In the meantime, while waiting for the technology to catch up, feasibility studies of virtual colonoscopy are needed to examine issues such as participation rates, factors affecting recruitment into screening programs, acceptability and cost. Richard M Mendelson Radiologist Geoffrey M Forbes Gastroenterologist, and Clinical Senior Lecturer University of Western Australia, Royal Perth Hospital, WA Disclosure statement: The authors are active in clinical research into virtual colonoscopy and are planning a feasibility study of the technique in colorectal cancer screening. Australian Health Technology Advisory Committee. Colorectal cancer screening. Canberra: AGPS, 1997. National Health and Medical Research Council. Guidelines for the prevention, early detection and management of colorectal cancer. Canberra: NHMRC, 1999. Allison JE, Tekawa IS, Ransom LJ, Adrain AL. A comparison of fecal occult blood tests for colorectal-cancer screening. N Engl J Med 1996; 334: 155-159. Nicholson FB, Korman MG, Stern AI, Hansky J. Distribution of colorectal adenomas: implications for bowel cancer screening. Med J Aust 2000; 172: 428-430. Kadakia SC, Wrobleski CS, Kadakia AS, Meier NJ. Prevalence of proximal colonic polyps in average-risk asymptomatic patients with negative fecal occult blood tests and flexible sigmoidoscopy. Gastrointest Endosc 1996; 44: 112-117. Olynyk JK, Aquilia S, Fletcher DR, Dickinson JA. Flexible sigmoidoscopy screening for colorectal cancer in average-risk subjects: a community-based pilot project. Med J Aust 1996; 165: 74-76. Waye J, Kahn O, Auerbach M. Complications of colonoscopy and flexible sigmoidoscopy. Gastrointest Endosc Clin N Am 1996; 6: 343-377. Thiis-Evensen E, Hoff GS, Sauar J, et al. Flexible sigmoidoscopy or colonoscopy as a screening modality for colorectal adenomas in older age groups? Findings in a cohort of normal population aged 63 to 72 years. Gut 1999; 45: 834-839. Freeman B, Engel JJ, Fine MS, DiVita DP. Colonoscopy to the cecum: How often do we get there? Experience in a community hospital. Am J Gastroenterol 1993; 88: 789. Fenlon HM, Nunes DP, Schroy P, et al. A comparison of virtual and conventional colonoscopy for the detection of colorectal polyps. N Engl J Med 1999; 341: 1496-1503. Forbes GM, Mendelson RM. Patient acceptance of virtual colonoscopy [letter]. Endoscopy 2000; 32: 274. Debatin JF, Luboldt W, Bauerfeind P. Virtual colonoscopy in 1999: computed tomography or magnetic resonance imaging? Endoscopy 1999; 31: 174-179. Kay CL, Kulling D, Hawes RH, et al. Virtual endoscopy -- comparison with colonoscopy in the detection of space-occupying lesions of the colon. Endoscopy 2000; 32: 226-232. Rex DK, Vining D, Kopecky KK. An initial experience with screening for colon polyps using spiral CT with and without CT colography (virtual colonoscopy). Gastrointest Endosc 1999; 50: 309-313. Make a comment

Richard M Mendelson · Geoffrey M Forbes

Healthcare Distribution of colorectal adenomas: implications for bowel cancer screening Fiona B Nicholson, Melvyn G Korman, Anthony I Stern and Jack Hansky MJA 2000; 172: 428-430 For editorial comment, see Mendelson & Forbes Abstract - Methods - Results - Discussion - References - Authors' details - - More articles on Oncology Abstract Objective: To determine the distribution of colorectal adenomas relative to the splenic flexure in an asymptomatic population undergoing colonoscopy, as an indicator of the number of patients with adenomas who would be missed by screening with flexible sigmoidoscopy. Design: Retrospective survey of medical records. Setting: Private endoscopy centres in Melbourne, Victoria. Subjects: All 1131 asymptomatic individuals who underwent full colonoscopy between 1 January 1995 and 31 December 1997 after referral from a bowel cancer prevention program organised by the endoscopy centres. People referred were aged either 40 years or over with a first-degree relative with bowel cancer, or 50 years or over with marked anxiety about bowel cancer. Main outcome measures: Presence and distribution of colorectal adenomas. Results: Polyps were found in 270 individuals (24%) and were confirmed to be adenomas in 138 (12%). These 138 comprised 106 men and 32 women, with mean age 54 years (range, 40-78 years). Most (86%) had a single adenoma. Position of adenomas in relation to the splenic flexure was: distal only in 85 of the 138 people (62%), proximal only in 34 (25%), and both distal and proximal in 19 (14%). Conclusions: In 25% of asymptomatic people found to have adenomas by this bowel cancer prevention program, the adenomas were found only in the proximal colon, well beyond the reach of the flexible sigmoidoscope. This distribution of adenomas suggests that screening programs cannot rely solely on flexible sigmoidoscopy. Colorectal cancer is the most common internal malignancy in Australia and the second most common cancer overall.1 One in 18 men and one in 27 women will develop this cancer during their lifetime.2 As most colorectal cancers are diagnosed at an advanced stage after symptoms develop, significant improvements in colorectal cancer mortality depend on prevention and early diagnosis. Most colorectal cancers develop from adenomatous polyps.3 If adenomas can be identified and removed, the adenoma-carcinoma sequence is broken, and colorectal cancer may be prevented.4 As adenomas usually cause few, if any, symptoms, they can be detected only by searching for them in asymptomatic individuals. While colonoscopic surveillance programs for detecting adenomas are accepted for those at higher risk of developing colorectal cancer (eg, with a family history),5 screening for the average-risk population remains controversial. In Australia, there are no population-based colorectal cancer screening programs, but the recent report from the Australian Health Technology Advisory Committee suggested pilot programs of faecal occult blood testing (FOBT) alone or in combination with flexible sigmoidoscopy.6 This combination is probably the most accepted method of screening for average-risk colorectal cancer. However, as adenomas and cancers may occur on the right side of the colon, and as not all of these bleed, they could be missed by this combination of tests. In 1991, some private endoscopy centres in Melbourne, Victoria, developed a Bowel Cancer Prevention Program. We aimed to determine how many asymptomatic people who underwent colonosocopy as part of this program had adenomas in the proximal colon only. This would indicate the number of patients with adenomas who would be missed by flexible sigmoidoscopy screening in an Australian population. Methods The study was a retrospective review of patient medical records. Data collection was approved by the Victorian Southern Health Care Network Ethics Committee. Subjects We examined the records of all asymptomatic individuals who underwent full colonoscopy between 1 January 1995 and 31 December 1997 after referral from the Bowel Cancer Prevention Program. Individuals with any symptoms that could be referable to colorectal cancer, such as rectal bleeding, anaemia, change in bowel habit or weight loss, were excluded from the study. The Bowel Cancer Prevention Program targets interested employees of major employer groups or members of participating unions and organisations. Each participant receives educational material about colorectal cancer and is asked to return a simple questionnaire. This assists an expert panel to assess and advise on individual risk of developing colorectal cancer, based on Gut Foundation7 and international guidelines.8 Asymptomatic individuals are referred for colonoscopy if: They are aged 40 years or over and have a self-reported family history of at least one first-degree relative with bowel cancer; or They are aged 50 years or over, and a doctor has requested a colonoscopy for bowel cancer screening because of the patient's marked anxiety. Procedures Informed consent was obtained, and a full colonoscopy was performed with visualisation of the caecum. Adenomas were confirmed by histological examination by private pathology services. Locations of adenomas were noted on the procedure report by the endoscopist at the time of colonoscopy. The position of the splenic flexure, as recognised at colonoscopy, was used to classify adenoma locations as: distal to the splenic flexure only; both distal and proximal to the splenic flexure; and proximal to the splenic flexure only. Data recorded The number of individuals with adenomas and the site of each adenoma within the colon and rectum were recorded, as were complications of sedation or the procedure. Results The records of 1131 asymptomatic individuals who underwent full colonoscopy were examined. The 1131 comprised 715 men and 416 women, with mean age 54 years (range, 40-78 years); 907 (80%) had a family history of colorectal cancer. None of the patients died or required hospitalisation for complications of sedation or the procedure. Colorectal polyps were found in 270 people (24%) and were confirmed to be adenomas in 138 (12%). These 138 comprised 106 men and 32 women, with mean age 54 years (range, 40-78 years). Adenomas were found in 118 of the 907 people with a first-degree relative with bowel cancer (13%) and in 20 of the 224 people whose only risk factor was age 50 years or more (9%). This difference in adenoma rates was statistically significant (P < 0.05). Most of the 138 patients (86%) had a single adenoma, while 14% had two or more. The adenomas ranged from 5 mm to 2 cm in diameter. Distribution of adenomas relative to the splenic flexure is shown in the Box. The distribution did not differ significantly between people who had a family history of colorectal cancer and those who did not: in both groups, 25% had adenomas proximal to the splenic flexure only. Discussion Different regimens are proposed for screening programs to prevent colorectal cancer. These include FOBT, periodic flexible sigmoidoscopy, FOBT combined with flexible sigmoidoscopy, or full colonoscopy. The rationale for a screening sigmoidoscopy is that it would detect most adenomas, as they are most common in the left colon. Further, in those with adenomas (or cancer) proximal to the splenic flexure, the theory is that adenomas would also be found in the distal colon by flexible sigmoidoscopy, thus signalling the need for full colonoscopy -- the concept of the "sentinel" polyp [adenoma].8This theory is not supported by the results of our study. We found that in 25% of asymptomatic individuals with adenomas, the adenomas were found only in the proximal colon, beyond the reach of the flexible sigmoidoscope. This figure is consistent with other studies.9 A sentinel adenoma on the left side signalling proximal adenomas was found in only 14% of people; 62% of subjects had only left-sided adenomas. In our study the distribution of adenomas was assessed from the endoscopists' reports. Experienced endoscopists are correct in determining scope-tip position 83% of the time.10 One cannot assume that a 60 cm flexible sigmoidoscope will reach the splenic flexure. Indeed, a recent report suggests that it reaches 60 cm in only 34% of cases, and far less often in women than in men, with the problem worsening with increasing patient age.11 There are no other Australian data on the incidence or distribution of adenomatous polyps in the colon and rectum. Collett et al showed that distal colorectal cancer or adenomas predicted proximal neoplasia in 30% of subjects, but their study was based on colonoscopy only after a positive result from flexible sigmoidoscopy.12 Their study design did not allow them to accurately determine the distribution of adenomas in the colon and rectum. Colonoscopy remains the final diagnostic pathway for any positive result for a bowel cancer screening test. Some international experts recommend use of colonoscopy as the optimum screening tool to prevent the development of colorectal cancer.13 However, it has not been embraced as the primary screening modality because of concerns about cost, compliance and risk. The risks of colonoscopy include those related to sedation, as well as the procedure, such as perforation (reported at 1 in 200014) and bleeding complicating polypectomy. Complication rates are usually derived from hospital populations, which include many ill patients who have significant comorbidity, and it may be that the risk is considerably less in the far healthier "screening" population. No significant sedation- or procedure-related complications or deaths occurred in our comparatively small series of colonoscopies. The proportion of men to women in the group with the adenomas was about 2:1. This probably reflects our target population rather than a true difference in the incidence of adenomas. However, men are significantly more likely to develop colorectal cancer than women.15 Unfortunately, most reported case series of adenomas have studied populations heavily biased with men. Larger studies examining the influence of sex on adenoma frequency and distribution within the colon and rectum are needed. Well-designed overseas studies have confirmed that programs based on annual FOBT followed by colonoscopy for those with positive FOBT results significantly reduce anticipated mortality from colorectal cancer.16,17 Adding flexible sigmoidoscopy to FOBT to detect proximal adenomas seems sensible but adds significantly to cost. Indeed, a recent Australian economic study using computer modelling clearly showed that only FOBT or five- or 10-yearly colonoscopy are cost-effective bowel-cancer screening methods; flexible sigmoidoscopy alone or in combination with FOBT was not cost-effective.18 The distribution of adenomas found in our study adds weight to the recent suggestion that it is time to consider adding full colonoscopy to the menu of options available to general practitioners when discussing bowel cancer screening and prevention with their patients.19 References Coates M, Day P, McCredie M. Cancer in New South Wales: incidence and mortality 1992. Sydney: NSW Cancer Council, 1995. Australian Institute of Health and Welfare and the Australasian Association of Cancer Registries. Cancer in Australia 1991-1994 (with projections to 1999). Canberra: AIHW, 1998. Muto T, Bussey H, Morson B. The evolution of cancer in the colon and rectum. Cancer 1975; 36: 2251-2270. Winawer S. The National Polyp Study. Design, methods, and characteristics of patients with newly diagnosed polyps. The National Polyp Study Workgroup. Cancer 1992; 70: 1236-1245. National Health and Medical Research Council. Clinical practice guidelines. The prevention, early detection and management of colorectal cancer. Canberra: NHMRC, 1999. Australian Health Technology Advisory Committee. Colorectal cancer screening. Canberra: AGPS, 1997. Gut Foundation of Australia. Colorectal cancer prevention, diagnosis and treatment (public information booklet). Sydney: The Foundation, 1999. Winawer S, Fletcher R, Miller L, et al. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 1997; 112: 594-642. Kadakia S, Wrobleski C, Kadakia A. Prevalence of proximal colonic polyps in average-risk asymptomatic patients with negative fecal occult blood tests and flexible sigmoidoscopy. Gastrointest Endosc 1996; 44: 112-117. Shah S, Saunders B, Brooker J, Williams C. What happens during routine colonoscopy? An audit using magnetic positional imaging (MPI). Gut 1999; 44 Suppl 1: A105. Jacobs J, Burke C, Larive B. 60 cm flexible sigmoidoscopy, how far do we really get? [abstract] Gastroenterology 1999; 116 (4 Pt 2): A428. Collett J, Platell C, Fletcher D, et al. Distal colonic neoplasms predict proximal neoplasia in average-risk, asymptomatic subjects. J Gastroenterol Hepatol 1999; 14: 67-71. Rex D, Amitabh C, Vasudeva R. Prospective determination of distal colon findings in average-risk patients with proximal colon cancer. Gastrointest Endosc 1999; 49: 727-730. Basson M, Etter L, Panzini L. Rates of colonoscopic perforation in current practice. Gastroenterology 1998; 114: 1115. Rex D, Lehman G, Ulbright T, et al. Colonic neoplasia in asymptomatic persons with negative fecal occult blood tests: influence of age, gender and family history. Am J Gastroenterol 1993; 88: 825-831. Mandel J, Bond J, Church T. Reducing mortality from colorectal cancer by screening for fecal occult blood. N Engl J Med 1993; 328: 1365-1371. Hardcastle J, Chamberlain J, Robinson M, et al. Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet 1996; 348: 1472-1477. Bolin T, Korman M, Stanton R. Positive cost effectiveness of early diagnosis of colorectal cancer. Colorectal Dis 1999; 1: 113-122. Bolin T, Korman M. How can we reduce the incidence and mortality of colorectal cancer? Med J Aust 1997; 166: 175-176. (Received 5 Nov 1999, accepted 24 Jan 2000) Authors' details Gastroenterology Unit and Department of Medicine, Monash Medical Centre, Melbourne, VIC. Fiona B Nicholson, FRACP, Fellow; Melvyn G Korman, PhD, FRACP, Director; Anthony I Stern, PhD, FRACP, Visiting Physician; Jack Hansky, FRACP, Visiting Physician. Reprints: Dr M G Korman, Department of Gastroenterology, Monash Medical Centre, 246 Clayton Road, Clayton, VIC 3168. m.kormanATshcn.com.au Make a comment Back to text

Fiona B Nicholson · Melvyn G Korman · Anthony I Stern · Jack Hansky

Editorial Breast cancer guidelines in action The challenge is to develop and sustain audit programs on an ongoing basis MJA 2000; 172: 196-197 In 1995, when the National Health and Medical Research Council (NHMRC) released Clinical practice guidelines for the management of early breast cancer,1 the first of their evidence-based recommendations, the initial response by clinicians was very positive: 97% regarded them as a good summary of recent evidence and 85% believed they would be useful in improving management.2This was encouraging, but the more important question was whether the guidelines would result in evidence-based care for women with breast cancer. Until recently, there has been little national information about breast cancer management in Australia, a lack noted by the House of Representatives in 1995, whose response was to recommend a comprehensive national monitoring system.3 However, it was not until 1999 that an accurate national picture of breast cancer management emerged. A report by the NHMRC National Breast Cancer Centre,4 analysing the surgical management of 4237 women with breast cancer in 1995 (ie, 88% of all women in Australia diagnosed with breast cancer in the six months before release of the guidelines), showed that, at that time, most women were receiving care in accord with most of the recommendations. However, some aspects of care were not in line with the guidelines: for example, the report highlighted the need to encourage the use of tamoxifen in women with oestrogen receptor positive tumours (particularly in women less than 50 years); to decrease rates of testing for distant metastases at the time of diagnosis of early breast cancer; and to increase participation in clinical trials. Progress will occur only if other local groups also see value in promoting evidence as their mast-head and recognising the fundamental role of audit in evidence-based treatment Information about current practice plays a key role in supporting evidence-based care. It enables the best use of scarce resources, as costly implementation strategies can be targeted at aspects of care not in accord with the recommendations. The process of audit itself is also effective in changing practice, particularly if individual clinicians can compare their own practice with evidence-based recommendations or with the practice of their peers.5,6 In this context, the article in this issue of the Journal by Craft et al 7 is of considerable significance, as it demonstrates the feasibility of a community-based audit of breast cancer management by a multidisciplinary team (the Australian Capital Territory and South Eastern New South Wales [ACT and SE NSW] Breast Cancer Treatment Group). The Group is to be commended both for its meticulous approach to encouraging evidence-based care through local audit and for the high standards of care provided. The results presented by Craft et al7 suggest that more women than in the national survey were managed in accordance with the NHMRC guidelines. For example, in the national data, 85% of women with breast-conserving therapy received radiotherapy, compared with 98% of the sample studied by Craft et al, and all women in the sample aged under 50 with axillary node involvement received adjuvant chemotherapy. We do not know, of course, to what extent these results can be generalised to the 21% of cases occurring in the region and not included in the audit. Although these differences may show an embracing of the guidelines since their release, it is unclear whether these changes would be apparent across Australia or whether they are due to intensive efforts within the ACT and SE NSW region. However, an audit conducted in a surgical practice in Echuca, a rural town in Victoria, also demonstrated patterns of care generally in accordance with the guidelines.8 The report by Craft et al also shows the role of local ownership of guidelines and a multidisciplinary team approach to management. The ACT and SE NSW Breast Cancer Treatment Group was formed to consider priorities within the region and to select indicators of local significance for inclusion in their audit. Consumer input was included. Further, the audit was not limited to one institution, but attempted to include all clinicians, including potentially more isolated clinicians in the region, making it more likely to have an impact on outcomes. The strategies used by the Group appear to have been successful, with 23 of 24 clinicians participating and the identification of an estimated 79% of all cases of breast cancer occurring in the region. There is some evidence that a multidisciplinary team approach is more likely to result in evidence-based care and better patient outcomes than clinicians working in isolation.9,10 Recent initiatives within Australia are designed to foster multidisciplinary care, including Victoria's Breast Care Enhancement Program and the federally funded National Multidisciplinary Care Demonstration Project coordinated by the National Breast Cancer Centre. After Craft et al's conclusive demonstration of the value of local audit, the challenge now is to develop and sustain other audit programs on a continuing basis. There is a real danger that the evidence-based approach will founder from a lack of resources for guideline implementation at the local level and for support of audit programs. A commitment from State and local health services to resourcing these programs is vital. The recent initiative by the Royal Australasian College of Surgeons in developing an audit system for breast cancer should prove particularly valuable in future assessment of guideline adherence. The audit is national and provides contributing surgeons with feedback about their practice compared with that of their peers. There are also benefits to daily clinical practice: the audit provides a standardised record, which can be used in patient notes or to inform general practitioners or patients. Apart from surgery, other disciplines are also considering developing similar approaches to audit in breast cancer, notably the Royal Australian and New Zealand College of Radiologists (Faculty of Radiation Oncology) and the Medical Oncology Group, all in association with the National Breast Cancer Centre. Progress will occur only if other local groups also see value in promoting evidence as their masthead and recognising the fundamental role of audit in evidence-based treatment. In demonstrating the feasibility of this approach, the achievement of the ACT and SE NSW Breast Cancer Treatment Group could serve as a model for other regions. Sally Redman Director, NHMRC National Breast Cancer Centre, Sydney, NSW Tom S Reeve Executive Officer, Australian Cancer Network, Sydney, NSW National Health and Medical Research Council. The management of early breast cancer. Clinical Practice Guidelines. Canberra: NHMRC/AGPS, 1995. Carrick S, Bonevski B, Redman S, et al. Surgeons' opinion about the NHMRC clinical practice guidelines for the management of early breast cancer. Med J Aust 1998; 169: 300-305. House of Representatives Standing Committee on Community Affairs. Report on the management and treatment of breast cancer in Australia. Canberra: AGPS, 1995. Hill D, Jamrozik K, White V, et al. Surgical management of breast cancer in Australia in 1995. Sydney: NHMRC National Breast Cancer Centre; 1999. Thomson MA, Oxman AD, Davis DA, et al. Audit and feedback to improve health professional practice and health care outcomes (Parts I and II) (Cochrane Review). Oxford: The Cochrane Library 1999: Issue 1. NHS Centre for Reviews and Dissemination, University of York. Getting evidence into practice. Effective Health Care 1999; 5(1). Craft PS, Zhang Y, Brogan J, et al, and the Australian Capital Territory and South Eastern New South Wales Breast Cancer Treatment Group. Implementing clinical practice guidelines: a community-based audit of breast cancer treatment. Med J Aust 1999; 172: 213-216. Tulloh BR, Goldworthy ME. Breast cancer management: a rural perspective. Med J Aust 1997; 166: 26-29. Sainsbury R, Haward B, Rider L, et al. Influence of clinician workload and patterns of treatment on survival from breast cancer. Lancet 1995; 345: 1251-1252. Gillis CR, Hole DJ. Survival outcome of care by specialist surgeons in breast cancer: a study of 3786 patients in the west of Scotland. BMJ 1996; 312: 145-148. Make a comment

Healthcare Implementing clinical practice guidelines: a community-based audit of breast cancer treatment Paul S Craft, Yanping Zhang, Jennifer Brogan, Noel Tait, John M Buckingham, and the Australian Capital Territory and South Eastern New South Wales Breast Cancer Treatment Group MJA 2000; 172: 213-216 For editorial comment, see Redman & Reeve Abstract - Methods - Results - Discussion - Acknowledgement - References - Authors' details - - More articles on Oncology Abstract Objective: To improve breast cancer management by facilitating implementation of treatment guidelines. Design: A prospective, longitudinal study (developed by clinicians and consumers) of all patients with newly diagnosed breast cancer. Four locally agreed breast cancer management guidelines were established (based on 1995 National Health and Medical Research Council guidelines) as practice indicators. Setting: Breast cancer treatment facilities and medical practices in the Australian Capital Territory and South Eastern New South Wales, May 1997 to July 1998. Main outcome measures: Actual treatment received by patients for primary breast cancer during the study period. Results: During the 14 months of the study, 19 clinicians registered 221 new patients with a proven diagnosis of breast cancer. Of 191 women with localised invasive breast cancer, 112 (59%) had tumours 2 cm or less in diameter. Axillary surgery in 173 (91%) of these women showed 107 (56%) had no axillary lymph node involvement. Of 87 women treated with breast-conserving surgery for locally invasive cancer, 85 (98%) also received postoperative radiotherapy. Some form of systemic adjuvant therapy was indicated in 99 women (axillary nodes positive or tumours > 2 cm diameter) and this treatment was received by 95 (96%). All 27 women aged under 50 years with node-positive disease received adjuvant chemotherapy. Conclusions: Enhancing uptake of breast cancer management guidelines is feasible at a regional level with an audit program and broad support among clinicians and consumers. Breast cancer is a major health problem in Australia, with 9800 new cases diagnosed each year.1 Management guidelines for early breast cancer were developed in 1995 by the National Health and Medical Research Council (NHMRC) to assist clinicians and consumers make decisions about treatment and thus to improve health outcomes.2 Observed differences in treatment outcome between populations suggest that opportunities for improvement are available.3 Moreover, potentially important variations in clinical practice are well documented in Australia and elsewhere.4-6 Treatment practice which appears to be informed by evidence, for example greater use of breast-conserving surgery, has been observed more frequently among clinicians who regularly treat patients with breast cancer.7 Furthermore, congruence of treatment practice with published guidelines has been directly associated with improved patient survival;8 improved treatment practice has the potential to improve survival by up to 10%.8,9 Therefore, enhanced implementation of soundly developed, evidence-based treatment guidelines is an appropriate goal for health services and individual clinicians. In 1996, clinicians and consumers involved in breast cancer diagnosis and treatment in the Australian Capital Territory (ACT) and South Eastern New South Wales (SE NSW) formed a cooperative group aimed at improving breast cancer management and facilitating implementation of treatment guidelines. A prospective, longitudinal, community-based study of breast cancer treatment was established to assist with guidelines implementation. Our report describes the results of the first 14 months of this ongoing project. Methods Breast Cancer Treatment Group All surgeons, radiation oncologists, medical oncologists, radiologists, pathologists, nurses and other health professionals who were known by the ACT Breast Screen Program to be involved in the treatment of breast cancer in the ACT and SE NSW were invited by mail to participate in a multidisciplinary breast cancer treatment group. Consumer representatives from "The Bosom Buddies", a community organisation of women with a history of breast cancer, were also invited to join the group. Fifty consumers and clinicians expressed interest and continue to receive all correspondence, with meetings every two months attracting between 15 and 30 attendees. A general practitioner representative from the ACT Division of General Practice also participated. The Breast Cancer Treatment Group adopted treatment guidelines based on the NHMRC Clinical Practice Guidelines, commenced a community-based audit, and later developed a set of agreed practice indicators against which treatment decisions could be compared. The 1998 estimated populations of the ACT and South Eastern NSW were 311 000 and 118 000 respectively (source: Australian Bureau of Statistics, Estimated Residential Populations, 30 June 1998). Practice indicators The group adopted four indicators for which unanimous local agreement about the relevant guideline was available: Women with operable invasive breast cancer should undergo some form of axillary surgery sufficient to develop a prognosis based on axillary node status; Women undergoing less than total mastectomy for operable invasive breast cancer should receive postoperative adjuvant radiotherapy; Women with a completely resected invasive breast cancer tumour greater than two centimetres in diameter or with involved axillary lymph nodes should receive adjuvant systemic therapy (either chemotherapy, endocrine therapy or both); and Women under the age of 50 years with completely resected axillary lymph node positive breast cancer should receive adjuvant chemotherapy. Audit A prospective study of breast cancer treatment was commenced in May 1997. The study was designed as a quality assurance project and notified as such under Section 7 of the Health Act 1993 (ACT) in June 1997. The study was approved by the Ethics Committee of the ACT Department of Health and Community Care. All clinicians involved specifically with the care of patients with breast cancer were invited to participate in the study. Participating clinicians agreed to approach all of their patients presenting with newly diagnosed breast cancer requesting permission to include them in the study. Eligible patients were women or men with newly diagnosed invasive or in-situ breast cancer. For each eligible patient a brief notification form was completed and submitted by mail to the study centre at the Women's Health Program of ACT Community Care. Written informed consent was obtained from the patient by the notifying clinician, and subsequently a detailed data form was completed giving details of presentation, clinical and pathological staging, and treatment. The dataset was based on a prior survey conducted by the Provincial Surgeons of Australia (Dr David Adamthwaite, President of the Provincial Surgeons of Australia, personal communication). Additional data relating to enrolled patients were obtained from treatment units in the region. Information from the audit forms, supplemented where necessary from pathology reports and treatment facility records, was entered into a secure database developed by the project officer. As well as facilitating project management, the database allows individualised, confidential reports to be produced for each participating clinician, providing detailed feedback about each clinician's practice, with comparisons across the group and against the agreed criteria. Aggregated data across the whole clinician group are presented at regular meetings of the treatment group. Data collected during the first 14 months of the project, and analysed to provide an initial report to contributing clinicians, form the basis of our report. Accrual of patients to the project is ongoing. Results Specialist participation Since commencement of the project, 23 of 24 medical specialists known to treat breast cancer within the region have registered as participants, with 19 specialists contributing data to the study to date (13 surgeons, three radiation oncologists and three medical oncologists). All of the radiation and medical oncologists were based in Canberra, while the principal practices of six surgeons were based in SE NSW. Patient accrual During 14 months from May 1997 to July 1998, 221 patients, including four men, with a diagnosis of primary breast cancer were registered for the study (Box 1). Some 123 new cases of invasive breast cancer (excluding male patients and patients with in-situ disease only) were registered with ACT addresses. In comparison, the observed mean annual incidence of breast cancer in the ACT during 1993-1996 was 134.1 Thus, during the 14-month study period, about 156 incident cases would be expected. The project therefore detected 79% of predicted ACT incident cases during the study period. Of the 221 registered patients, there were 10 with distant metastases, 16 with carcinoma-in-situ only and four men, leaving 191 women with primary, localised, invasive breast cancer. It is to these women that the treatment guidelines apply. In five women with bilateral synchronous tumours, details are given of the tumour judged by the treating clinician to have the worse prognosis. Eighty-one per cent of tumours were oestrogen receptor (ER) positive or progesterone receptor (PgR) positive by immunohistochemical analysis done in routine diagnostic histopathology laboratories. The pathological characteristics of the tumours in these 191 women are presented in Box 2. Comparisons with practice indicators (Box 3) Axillary surgery was undertaken in 173 women. One elderly patient declined to have any surgery. Thus, 17 of 190 patients did not undergo any form of axillary surgery, at variance with the guideline. Of these women, six were aged 80 years or older. Seven of the remaining 11 patients had tumours less than 1 cm in diameter. Among women having axillary surgery, five (3%) had four or fewer nodes resected. Only two of 87 women who underwent breast-conserving surgery did not also receive postoperative radiotherapy. Of the 191 patients with invasive breast cancer, 103 (54%; 95% CI, 47-61) underwent mastectomy. The overall concordance of treatment with the practice indicators relating to systemic adjuvant therapy was strong. Of 33 women with tumours greater than 2 cm in diameter and negative or unknown axillary lymph node status, 32 (97%) received either tamoxifen (18), chemotherapy (4), or both (10). Of 66 women with axillary lymph node involvement, 63 (95%) received systemic adjuvant therapy with either tamoxifen (14), chemotherapy (19) or both (30). Thus, only four of 99 women for whom adjuvant systemic therapy was considered appropriate under the guidelines did not receive such therapy. All 27 women under 50 years of age with axillary lymph node involvement received adjuvant chemotherapy. Data quality The project officer actively sought clarification of ambiguous or missing data items. Initial notification forms required clarification for 192 of 221 registrations. Of these queries, one follow-up data request was required for 91 patients, two requests for 60 patients and three requests for 41 patients. After these data requests, 3.6% of records remained incomplete in some way. Initial under-reporting of adjuvant treatments received was noted, particularly in regard to postoperative radiotherapy. Discussion Our report demonstrates the feasibility of regionally based multidisciplinary groups adopting treatment guidelines and then assessing their implementation. Strong concordance of practice with the four practice indicators was observed. Despite a third of our patients living in rural areas, there were high rates of postoperative radiotherapy after breast-conserving surgery. The rate of axillary surgery was lower than recommended, but in almost all of these women a partial explanation was available (advanced age or very small primary tumour). Whether the decision not to perform axillary surgery in these patients was appropriate is the subject of debate and ongoing clinical trials. Given the degree of involvement of clinicians in establishing the data collection and practice indicators, the strong concordance with actual practice observed is not surprising. The practice indicators chosen were not particularly controversial, enabling rapid consensus among the group members. Indicators relating to the use of breast-conserving surgery for early breast cancer and to the use of adjuvant chemotherapy for node-negative disease, although more contentious, are appropriate further areas for local consensus and audit. Observed concordance with guidelines for adjuvant chemotherapy in node-negative breast cancer has been relatively low, presumably because of the more modest benefits of treatment (in absolute terms) in this group.11 Implementing guidelines successfully can be difficult. Just producing and publishing guidelines for breast cancer treatment does not ensure their uptake into clinical practice.12 Over time clinical practice may adhere more closely to published guidelines, although a causal relationship cannot be easily proven.13 In a survey of clinicians in Sydney, most respondents supported the NHMRC Clinical Practice Guidelines, but only 20% believed the guidelines had influenced clinical practice.14 The introduction of guidelines has been a stimulus for institutionally focused audits of surgical practice.15 Audits incorporating structured feedback to clinicians may be a critical strategy in implementing guidelines. Organisations such as the Royal Australasian College of Surgeons have recognised audit as an important tool in the treatment of breast cancer, and Clinical Indicator 7.1 of the Australian Council of Healthcare Standards Internal Medicine Indicators, version 2, measures the proportion of premenopausal women with node-positive early breast cancer receiving chemotherapy.16 Many factors affect treatment decisions in primary breast cancer. Women bring to the process their own preferences and needs. Many of the treatment decisions require trade-offs between long term gain and unpleasant treatments, such as chemotherapy. We did not examine the decision-making processes followed by these patients and their attending health professionals. Entry of any individual patient into the audit was voluntary, both for the clinician and for the patient. Participating clinicians undertook to offer enrolment to all of their patients, and every effort was made to enhance compliance. Nevertheless, complete enrolment was not achieved and this may have introduced bias, with patients receiving multimodality care possibly being more likely to be enrolled. An advantage of our audit was that it was community based and prospective. Surgical audits have generally been based on retrospective casenote review and, as such, have sometimes been hampered by missing data.17 Some community-based studies assessing the process of treatment have relied on the secondary analysis of administrative data with linkage to population-based cancer registries.18 In Canada, a population-based cancer registry has been linked to clinical records to obtain treatment details and allow comparisons with treatment guidelines.19 Successful collection of community-based audit data requires both enthusiasm and trust on the part of the treating clinicians voluntarily submitting information about their own practice. We believe this may be best achieved within a framework of agreed treatment guidelines and indicators. An enthusiastic project officer and involvement of practice staff and institutional data managers is crucial. As new ways of managing breast cancer (and other diseases) become available, an ongoing implementation process with agreed, clinically relevant indicators and guidelines, and a regionally based audit, can be an effective tool. Members of the Australian Capital Territory and South Eastern New South Wales Breast Cancer Treatment Group contributing to the study Chairperson Dr Doris Zonta. Surgeons Bega, NSW: Dr Andrew Thomson. Canberra, ACT: Dr Guan Chong, Dr Ian Davis, Dr Dennis Dyason, Dr Diarmid McKeown, Dr John Stuchbery Goulburn, NSW: Dr Margaret Beevors, Dr John Hayman. Moruya, NSW: Dr Peter Gough, Dr John Groome, Dr David Thomson. Medical Oncologists Canberra, ACT: Associate Professor Robin Stuart-Harris, Dr William Coupland. Radiation Oncologists Canberra, ACT: Dr Deborah Thornton, Dr George Jacob, Dr Kenneth Sunderland. Epidemiologist Canberra, ACT: Dr Bruce Shadbolt. Pathologists Canberra, ACT: Dr Jane Dahlstrom, Dr Sanjiv Jain. Acknowledgement Initial funding was provided by the Commonwealth Department of Health and Aged Care Cancer Screening Unit. References Australian Institute of Health and Welfare. Breast and cervical cancer screening in Australia 1996-1997. Canberra: AIHW, 1998: 33. (Cancer Series no. 8.) National Health and Medical Research Council. Clinical practice guidelines. The management of early breast cancer. Canberra: NHMRC, 1995. Richards M, Sainsbury R, Kerr D. Inequalities in breast cancer care and outcome. Br J Cancer 1997; 76: 634-638. Craft PS, Primrose JG, Lindner JA, McManus PR. Surgical management of breast cancer in Australian women in 1993: analysis of Medicare statistics. Med J Aust 1997; 166: 626-629. Nattinger AB, Goottlieb MS, Veum J, et al. Geographic variation in the use of breast-conserving treatment for breast cancer. N Engl J Med 1992; 326: 1102-1107. Samet JM, Hunt WC, Farrow DC. Determinants of receiving breast-conserving surgery. The surveillance, epidemiology and end results program 1983-1986. Cancer 1994; 73: 2344-2351. Hill DJ, White VM, Giles GG, et al. Changes in the investigation and management of primary operable breast cancer in Victoria. Med J Aust 1994; 161: 110-122. Sainsbury R, Haward B, Rider L, et al. Influence of clinician workload and patterns of treatment on survival from breast cancer. Lancet 1995; 345: 1265-1270. Gillis CR, Dole D. Survival outcome of care by specialist surgeons in breast cancer: a study of 3786 patients in the west of Scotland. BMJ 1996; 312: 145-148. Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 1991; 19: 403-410. Sawaka C, Olivotto I, Coldman A, et al. The association between population-based treatment guidelines and adjuvant therapy for node-negative breast cancer. Br J Cancer 1997; 75: 1534-1542. Chouillet AM, Bell CM, Hiscox JG. Management of breast cancer in southeast England. BMJ 1994; 308: 168-171. Ray-Coquard I, Philip T, Lehmann M, et al. Impact of a clinical guidelines program for breast and colon cancer in a French cancer center. JAMA 1997; 278: 1591-1595. Ward JE, Boyages J, Gupta L. Local impact of the NHMRC early breast cancer guidelines: where to from here? Med J Aust 1997; 167: 362-365. McCarthy DO, Blamey RW, Robertson JF, Mitchell AK. A one-year audit of 255 operable breast cancers. Eur J Surg Oncol 1997; 23: 399-402. Australian Council on Healthcare Standards. Clinical indicators in summary. Revised edition. Sydney: ACHS, 1998. Clamp SE. Management of breast cancer. Incomplete case notes hamper research. BMJ 1994; 308: 715. Hillner BE, McDonald MK, Penberthy L, et al. Measuring standards of care for early breast cancer in an insured population. J Clin Oncol 1997; 15: 1401-1408. Olivotto IA, Coldman AJ, Hislop TG, et al. Compliance with practice guidelines for node-negative breast cancer. J Clin Oncol 1997; 15: 216-222. (Received 29 Jul, accepted 4 Dec, 1999) Authors' details Medical Oncology Unit, The Canberra Hospital, Canberra, ACT. Paul S Craft, MPH, FRACP, Director. Women's Health Program, ACT Community Care, Canberra, ACT. Yanping Zhang, Project Officer; Jennifer Brogan, Director. The Calvary Clinic, Canberra, ACT. Noel Tait, FRACS, Consultant Surgeon; John M Buckingham, FRACS, Consultant Surgeon. Reprints: Dr P S Craft, Medical Oncology Unit, The Canberra Hospital, PO Box 11, Woden, ACT 2606. Paul_CraftATact.gov.au Make a comment 1: Patient and tumour characteristics for all registered breast cancer patients (n=221)nPercentage (95% CI)Median age, 57 years (range, 25-88)SexMale42% (1%-5%)Menopausal statusPremenopausal63 29% (23%-35%)Postmenopausal12557% (50%-63%)Perimenopausal2712% (8%-17%)Unknown or male63% (1%-6%)Place of residenceAustralian Capital Territory14767% (61%-73%)DiagnosisIn-situ disease only167% (4%-11%)Invasive carcinoma20593% (89%-96%)Tumour extentDistant metastases at diagnosis105% (3%-9%)Synchronous bilateral tumours52% (1%-5%) Back to text 2: Pathological characteristics of the tumour in 191 women with invasive breast cancer and no distant metastases CharacteristicnPercentage (95% CI)Tumour size (mm)0-103016% (11%-22%)11-208243% (36%-50%)21-506233% (27%-40%)>50147% (4%-12%)Unknown32% (1%-5%) Axillary lymph node statusNegative107 56% (49%-63%)Positive66 35% (29%-42%)No axillary surgery168% (5%-13%)Unknown21% (1%-5%) CharacteristicnPercentage (95% CI)Tumour type and grade*Invasive ductalGrade 12915% (11%-21%)Grade 26635% (29%-42%)Grade 35328% (22%-35%)Invasive lobular2010% (7%-15%)Special types†2312% (8%-17%)Receptor statusER positive or PgR positive15581% (75%-86%)ER negative and PgR negative3016% (11%-22%)Unknown63% (1%-6%) *See Elston and Ellis.10 †Includes seven tubular, four mucinous, six cribriform, one papillary, one medullary, one squamous cell, and one metaplastic carcinoma. There was also one spindle cell tumour and one cystosarcoma phylloides tumour reported. ER=Oestrogen receptor. PgR=Progesterone receptor. Back to text 3: Women with breast cancer - comparison of treatment received with practice indicators Indicatorn Percentage (95% CI)Breast-conserving surgeryRadiotherapy8598% (92%-99%)No radiotherapy22% (1%-8%)Total87 100%Surgery for invasive cancerAxillary surgery17391% (86%-94%)No axillary surgery179% (6%-14%)Total190 100%Axillary nodes positive or tumours >2 cmSome form of adjuvant systemic therapy95 96% (90%-98%)No adjuvant systemic therapy44% (2%-10%)Total99100%Women aged less than 50 years with positive axillary nodesAdjuvant chemotherapy27100%No adjuvant chemotherapy00Back to text

Paul S Craft · Yanping Zhang · Jennifer Brogan · Noel Tait · John M Buckingham

Abstract Objective: To assess Australian radiation and medical oncologists' self-reported knowledge about and attitudes towards a range of non-traditional therapies used by people with cancer. Design: Postal survey during May and June 1997 of all 265 radiation and medical oncologists practising in Australia. Participants: 161 oncologists returned surveys (61% response rate). Main outcome measures: Oncologists' own level of knowledge, and, for each known therapy, their perceptions of its likely harm or benefit in patients being treated curatively and palliatively, and of the prevalence of use among their patients. Results: Oncologists reported knowing most about acupuncture, antioxidant therapy and meditation and least about cellular therapy, magnetotherapy and psychic surgery. The therapies most likely to be considered helpful were meditation, acupuncture and hypnotherapy. Those most likely to be considered harmful were coffee enemas, psychic surgery, Iscador therapy and diet therapies. Perceptions of patients' use of most therapies varied widely, with herbal therapies, antioxidant therapy and meditation considered the most commonly used. Conclusions: These results indicate self-identified gaps in oncologists' knowledge about non-traditional therapies their patients may use; they suggest a need to consider including education about these therapies in oncologists' training. Introduction Recent studies have confirmed the popularity of non-traditional therapies among Australian cancer patients: 22%-52% of medical oncology patients,1,2 40% of those being treated palliatively3 and 46% of children with cancer4 report using at least one non-traditional therapy. Many of the most popular non-traditional therapies are psychosocial (eg, relaxation, meditation and visual imagery) and are unlikely to pose threats to patients' health.1-4 However, other popular therapies include dietary therapies, antioxidants, high dose vitamins and herbal therapies,1-4 many of which are poorly evaluated and could pose physical threats to patients, either directly, or by interfering with traditional therapies. Despite the lack of scientific evidence, 25%-73% of patients using non-traditional therapies expect them to cure their cancer or to prolong their lives,1-4 and 74%-86% expect them to assist their traditional therapies.2 Despite fairly high reported levels of satisfaction and perceived benefit with non-traditional therapies,1,2 17% of patients in one study reported negative side effects,4 10%-36% of patients reported no perceived benefit or feeling worse,1,2 and around 20% reported they would not take the therapy again or recommend it to other patients.2 Even if not harmful, many non-traditional therapies are expensive,1,2 and only 64% of patients felt the non-traditional therapies provided value for money.1 Recent guidelines highlight the need for oncologists to be aware of non-traditional therapies being used or considered by their patients, and to encourage patients to discuss them.5 This would require oncologists having at least a basic understanding of these therapies. We were able to identify only two relevant studies in this area -- a quantitative survey of 106 Italian oncologists6 and a qualitative study of 18 Canadian oncologists.7 They found limited knowledge about non-traditional therapies,6,7 relatively positive attitudes towards psychological therapies,6,7 more negative attitudes towards more invasive therapies,7 negative attitudes towards non-traditional therapy practitioners6 and more positive attitudes towards the use of non-traditional therapies by palliative patients.7 As there is a lack of data in this field, we explored Australian medical and radiation oncologists' knowledge of and attitudes to non-traditional therapies, and their perceptions of the frequency with which their patients used them. Given the increased tolerance among overseas oncologists of palliative patients using non-traditional therapies,7 we assessed attitudes to palliative and curative patients separately. We use the term "non-traditional therapies" to describe all therapies other than surgery, radiotherapy, chemotherapy and hormone therapy. Methods In May and June 1997, 273 questionnaires about 19 non-traditional therapies covering a wide range of psychosocial and physical therapies commonly discussed in the literature and media were mailed to all oncologists who practise in Australia. Non-responders received a written reminder after four weeks and a telephone reminder after six weeks. Ethical approval for this study was granted by the University of Newcastle's Human Research Ethics Committee. Sample identification We identified all medical and radiation oncologists practising in Australia through the Clinical Oncological Society of Australasia (COSA) and the Royal Australasian College of Radiologists' (RACR) Faculty of Radiation Oncology. The list of all the individuals registered with the Medical and Radiation Oncology Groups of COSA in late April 1997 comprised 155 Australian-based medical oncologists and 62 radiation oncologists. As the Medical Oncology Group of Australia advised they were aware of only 165 practising Australian-based medical oncologists, we considered the COSA list comprehensive for medical oncologists. However, the RACR advised they had 123 members currently practising in Australia, and, in line with its policy of not releasing members' contact details, they agreed to mail surveys to any of their members not on the COSA list -- an additional 56 radiation oncologists. The final sample of 273 thus comprised 155 medical and 118 radiation oncologists. The survey We designed a brief survey whereby oncologists rated, on a four-point scale ("none/never heard of it", "very little", "some" or "lots"), their own levels of knowledge about each of 19 non-traditional therapies; we provided no additional information about these therapies. Oncologists were also asked to rate each therapy they knew (also on a four-point scale: "very", "fairly", "neither" or "don't know"), according to how harmful or helpful they considered it for patients being treated palliatively and curatively. Finally, they were asked to estimate the proportion of their palliative and curative patients they believed were using, or had used, each known therapy. Copies of the survey may be obtained from the authors. Statistical analysis We report descriptive statistics on oncologists' knowledge and attitudes, including 95% confidence intervals around the proportion of oncologists knowing "lots" about each therapy. All analyses were conducted with the SAS statistical package;10 95% confidence intervals were calculated using Microsft Excel,11 based on the standard binomial approximation formula.12Results Of the 273 oncologists identified, four medical and two radiation oncologists were no longer practising and two radiation oncologists received surveys through both the COSA and RACR lists, leaving 265 eligible oncologists. Completed surveys were returned by 161 (61%) -- 60 radiation oncologists, 64 medical oncologists and 37 who could not be classified because they had destroyed the identifying number that allowed us to make this differentiation. Knowledge about non-traditional therapies Box 1 shows that meditation, relaxation and visual imagery were the therapies that most oncologists (about a quarter) reported knowing a lot about. Approximately a fifth of the oncologists surveyed also reported knowing a lot about antioxidant therapy and microwave, or Tronado, therapy. The least-known therapies were cellular therapy, magnetotherapy and psychic surgery. Perceptions of each therapy's potential harmfulness or helpfulness Box 2 shows that oncologists tended to consider the psychosocial therapies helpful for patients being treated both palliatively and curatively. Acupuncture was also considered helpful, especially for palliative patients. Many therapies were considered more likely to help palliative patients and, conversely, more harmful for curative patients. Not surprisingly, the less familiar, more physical or invasive therapies dominated those considered likely to be harmful. Perceptions of their patients' use of each therapy Box 3 compares the median proportion of their curative and palliative patients that oncologists believed were using or had used each non-traditional therapy with levels of use reported by Australian cancer patients.1-4 The oncologists showed a consistent trend to estimate higher use among palliative patients. The oncologists' estimates were within the ranges reported by Australian cancer patients for acupuncture, antioxidants, faith healing, hypnotherapy, iridology and meditation, relaxation and visual imagery. However, the oncologists overestimated patients' use of aromatherapy, coffee enemas, herbal therapies, naturopathy, homoeopathy, magnetotherapy and shark cartilage therapy. No patient data were available to compare cellular, mistletoe, microwave and ozone therapies or psychic surgery, and estimates for diet therapy were difficult to compare because of variation in the definitions used. Discussion As in the overseas studies,6,7 we found that oncologists identified gaps in their knowledge about many non-traditional therapies. It is interesting to note, however, that the therapies most patients reported using (meditation, relaxation and visual imagery and antioxidants) were also the therapies that most oncologists -- although still only up to a quarter -- reported knowing a lot about. Also consistent with the overseas studies,6,7 psychosocial therapies were viewed positively, and non-traditional therapies were considered more likely to be potentially helpful to patients being treated palliatively and potentially harmful to those being treated curatively. The more positive attitudes towards psychosocial therapies may reflect oncologists' awareness of some evidence of proven benefits from these therapies.8,9 Although our respondents tended to accurately estimate their patients' use of more commonly used non-traditional therapies, they tended to overestimate patients' use of more radical therapies, especially those with higher media profiles, such as coffee enemas and shark cartilage therapy. While the oncologists' and patients' estimates come from different surveys of different populations collected at different points in time, making some degree of variation inevitable, such variation is unlikely to explain the reasonably large differences for many of the lesser-used therapies. The trend for oncologists to estimate higher use of non-traditional therapies among palliative than curative patients is consistent with Australian and international data suggesting that patients with more advanced cancers are more likely to use non-traditional therapies.2,13-15 Our study has some other limitations. Firstly, for brevity, we sought no demographic information, thus prohibiting any assessment of the respondents' representativeness of Australian oncologists. However, as we targeted all Australian oncologists, and received responses from over 60% of the population, covering the full range of responses, we are confident that our data provide the first quantitative, reasonably representative overview of Australian oncologists' knowledge of and attitudes to non-traditional therapies. Secondly, we used self-report rather than an objective assessment of oncologists' actual knowledge about non-traditional therapies. As the oncologists are unlikely to have deliberately underestimated their knowledge levels, these estimates of how much they know should probably be interpreted as best-case scenarios. Also, we provided no definitions of "helpful" or "harmful", leaving individual oncologists to decide what constituted a harm or a help. This was done intentionally, as patients seek a range of benefits from non-traditional therapies, including physical, psychosocial and spiritual ones. Finally, while our results represent the first quantitative data on oncologists' knowledge and attitudes in this area, they cannot be generalised to other clinicians who treat people with cancer, such as surgeons, haematologists and general practitioners. Sceptics may question the need for oncologists to increase their knowledge about non-traditional therapies when the benefit of most remains unproven. However, without some basic knowledge of what is involved in each therapy, and of any demonstrated benefits or adverse reactions, oncologists may be unable to give adequate advice to patients. As outlined in the National Health and Medical Research Council guidelines, overly heavy-handed and dismissive attitudes are less likely to succeed in discouraging patients from using potentially harmful non-traditional therapies than more rational and considered discussions.5 Conclusions Research is needed to facilitate the production of evidence-based information summaries for oncologists in the area of non-traditional therapies, to compare oncologists' perceptions of use with their own patients' reported use of such therapies, and to establish the knowledge and attitudes of other clinicians treating cancer patients. Acknowledgements This research was funded by the NSW Cancer Council's Cancer Education Research Program. The views expressed are not necessarily those of the Cancer Council, which had no direct role in the design and/or analyses of this study or in the decision about publication of the results. We gratefully acknowledge the assistance of the Clinical Oncological Society of Australasia and the Royal Australasian College of Radiologists' (RACR) Faculty of Radiation Oncology for their assistance with identifying eligible oncologists, and the oncologists who completed the surveys. References Begbie SD, Kerestes ZL, Bell DR. Patterns of alternative medicine use by cancer patients. Med J Aust 1996; 165: 545-548. Miller M, Boyer MJ, Butow PN, et al. The use of unproven methods of treatment by cancer patients: frequency, expectations and cost. Supportive Care Cancer 1998; 6: 337-347. Yates PM, Beadle G, Clavarino A, et al. Patients with terminal cancer who use alternative therapies: their beliefs and practices. Sociol Health Illness 1993; 15: 199-216. Sawyer MG, Gannoni AF, Toogood IR, et al. The use of alternative therapies by children with cancer. Med J Aust 1994; 160: 320-322. National Health and Medical Research Council. Clinical practice guidelines: the management of early breast cancer. Sydney: The Stone Press; 1995. Crocetti E, Crotti N, Montella M, Musso M. Complementary medicine and oncologists' attitudes: A survey in Italy. Tumori 1996; 82: 539-542. Bourgeault IL. Physicians attitudes toward patients' use of alternative cancer therapies. Can Med Assoc J 1996; 155: 1679-1685. Meyer TJ, Mark MM. Effects of psychosocial interventions with adult cancer patients: a meta-analysis of randomized experiments. Health Psychol 1995; 14: 101-108. Devine EC, Westlake SK. The effects of psychoeducational care provided to adults with cancer: meta-analysis of 116 studies. Oncol Nurs Forum 1995; 22: 1369-1381. SAS [computer program], version 6.12. Cary, NC: SAS Institute Inc, 1998. Microsoft Excel [computer program], version 97. Seattle: Microsoft Corporation, 1997. Dobson AJ. Calculating sample size. Trans Menzies Found 1984; 7: 75-79. Risberg T, Lund E, Wist E. Use of non-proven therapies. Differences in attitudes between Norwegian patients with non-malignant disease and patients suffering from cancer. Acta Oncologica 1995; 34: 893-898. Sollner W, Zingg-Schir M, Rumpold G, Fritsch P. Attitude toward alternative therapy, compliance with standard treatment, and need for emotional support in patients with melanoma. Arch Dermatol 1997; 133: 316-321. Risberg T, Lund E, Wist E, et al. The use of non-proven therapy among patients treated in Norwegian oncological departments. A cross-sectional national multicentre study. Eur J Cancer 1995; 31A: 1785-1789. (Received 5 Jul, accepted 5 Nov, 1999) Authors' details NSW Cancer Council Cancer Education Research Program (CERP). Sallie Newell, PhD Research Academic (also Conjoint Lecturer, Discipline of Behavioural Science in Medicine, Faculty of Medicine and Health Sciences, University of Newcastle; currently Epidemiologist (Health Promotion Evaluation, Northern Rivers Institute for Health and Research, Lismore, NSW). Rob W Sanson-Fisher, PhD, Director (also Professor, Discipline of Behavioural Science in Medicine, Faculty of Medicine and Health Sciences, University of Newcastle; currently Dean of Faculty). Reprints will not be available from the authors. Correspondence: The Secretary, NSW Cancer Council Cancer Education Research Program, Locked Bag 10, Wallsend, NSW 2287. cherylmATmail.newcastle.edu.au Make a comment Back to text 2: Percentage of the 161 oncologists believing non-traditional therapies about which they reported at least some knowledge ("very little" or more) to be helpful or harmful Curative patients Palliative patients TherapyNo. reporting some knowledge of therapy*HelpfulHarmfulHelpfulHarmfulAcupuncture16025%1% 58%1%Antioxidants/high-dose vitamin C1605% 30%5%23%Aromatherapy1569%2% 21%1%Cellular therapy57029% 026%Coffee enemas1511%71% 1%70%Diet therapy (Gerson/macrobiotic)1422% 49%4%48%Faith healing/spiritualism15212%24% 23%15%Herbal therapies/naturopathy1598% 22%13%15%Homoeopathy1504%12% 8%6%Hypnotherapy15631%4% 46%3%Immune-enhancing therapy1313%27% 5%22%Iridology144 1%15%1%8%Iscador/mistletoe therapy1032%55% 2%45%Magnetotherapy695%8% 8%6%Meditation/relaxation/visual imagery15969% 3%82%2%Microwave/Tronado therapy1207%45% 7%37%Ozone therapy961%46% 2%37%Psychic surgery872%57% 2%56%Shark cartilage therapy1501%23% 1%17% *The remaining response options were "neither helpful nor harmful" and "don't know" - the balance of the oncologists with some knowledge of the therapy selected one of these options. Back to text 3: Perceptions among the 161 oncologists of their patients' use of non-traditional therapies compared with that reported by Australian cancer patients Oncologists' perceptions TherapyNo. reporting some knowledge of therapyMedian curative patientsMedian palliative patientsAcupuncture1606%10%Antioxidants/high-dose vitamin C16015%20%Aromatherapy1565%10%Cellular therapy573%3%Coffee enemas1513%5%Diet therapy (Gerson/macrobiotic)*14210%10%Faith healing/spiritualism1525%10%Herbal therapies/naturopathy15920%25%Homoeopathy15010%15%Hypnotherapy1565%5%Immune-enhancing therapy1315%8%Iridology1443%5%Iscador/mistletoe therapy1032%3%Magnetotherapy692%3%Meditation/relaxation/visual imagery15920%20%Microwave/Tronado therapy1201%1%Ozone therapy963%5%Psychic surgery871%1%Shark cartilage therapy1505%10% Reported use Therapy% Paediatric patients (n=48)4% Palliative patients (n=151)3% Medical oncology patients (n=319) 1% Medical oncology patients (n=156)2Acupuncture- 7%3%5%Antioxidants/high-dose vitamin C8%24%12%12%-16%Aromatherapy- --0.5%Cellular therapy----Coffee enemas---1%Diet therapy (Gerson/macrobiotic)*8%18%13%30%(diet therapy)(special foods)(diet therapy)(changed diet) 0.5% (Gerson)Faith healing/spiritualism6%9%7%3%Herbal therapies/naturopathy8%3%-8%6%5%-10%Homoeopathy2% 5%3%2%Hypnotherapy15%--3%Immune-enhancing therapy-3%4% -Iridology- --3%Iscador/mistletoe therapy----Magnetotherapy--- 0.5%Meditation/relaxtion/visual imagery4%-17%19%10%-13%12%-28%Microwave/Tornado therapy----Ozone therapy----Psychic surgery----Shark cartlilage therapy---4% *As diet therapies included those ranging from basic dietary changes through to very restricted diets (eg, Gerson diet), the actual wording used in each of the studies is included. Back to text

Sallie Newell · Rob W Sanson-Fisher

The Centenary Institute of Cancer Medicine and Cell Biology The institute with the long name, short history, and tall goalposts Antony Basten Introduction - The first decade: - The second decade: - The future: the next decade - References - Authors' details - - More articles on Immunology and allergy Introduction As the joint centenaries of the University of Sydney's Medical School and its campus teaching hospital, Royal Prince Alfred Hospital (RPAH), crept closer in the early 1980s, a small group of clinical academics from medical, surgical, and obstetric specialties could be seen huddled together in corridors. What were they meeting about? asked their colleagues, exuding, as always, the paranoia and suspicion so common in academia. The answer soon became clear. Having trained and then exported, to other States and overseas, some of Australia's most talented researchers and clinical department heads, the time was ripe for the medical school and the hospital to reverse the New South Wales brain drain. The proposed mechanism was to be the creation on campus of a centre of excellence in medical research, akin to the successful Victorian institutes (the Walter and Eliza Hall, Baker and Howard Florey institutes) and the Garvan Institute in Sydney. The first decade: 1981-1989 The idea of a centre of excellence in medical research was warmly endorsed, not just by the university and hospital, but by the then Federal Liberal Government and the New South Wales State Labor Government, which jointly funded a feasibility study for construction of a research building, to accommodate 300 staff, adjacent to the medical school and hospital campus. In recognition of the need for a single major centre specialising in all aspects of cancer research and cell biology, the proposed institute received the name it still bears under an Act of the NSW Parliament: the Centenary Institute of Cancer Medicine and Cell Biology.1 Although failing to fit on any conference registration form, the name was intended to cover "all bases" -- in particular, to embody the concept that, to understand the abnormalities responsible for disease, the biology of normal cells must be studied first. In 1984, an Australian Science and Technology Council (ASTEC) Working Party2 reviewed the proposal and concluded that it was far too ambitious. The Working Party's verdict was that it was better to start small and build up slowly around a competitive research group. As a result, the wind was taken out of the Centenary Institute's sails and the project was becalmed for four long years. In retrospect, it is clear that this delay worked to the Institute's disadvantage in the long term. Instead of being established before the value of the specialised research centre was fully appreciated in NSW, its creation as a functional entity coincided with the rush to institute status by multiple groups on our own campus and elsewhere, leading ultimately to the current situation, with too many "institutes" competing for limited resources. In 1989, I was invited to be the inaugural Director of the Centenary Institute. At the time, as head of the Clinical Immunology Research Centre, one of the original 10 Commonwealth Centres of Excellence, I was trying to juggle exciting new research based on transgenic technology with the task of advising the Federal Government on medical and scientific aspects of HIV/AIDS. Little did I suspect, back then, that I would be jumping out of the frying pan into the fire. The second decade: 1989-1999 Early days The challenge in 1989 was to create an independent institute at a time of dwindling resources, both in the tertiary education sector and in the healthcare system. The Clinical Immunology Research Centre, operating from its crowded quarters in the 1880 building shared with other hospital and university staff, became the core unit of the Institute. We were faced with three formidable tasks. The first was to cope with the loss of our Centre of Excellence grant from the Australian Research Council, as funding for medical research centres was now deemed to be the responsibility of the National Health and Medical Research Council (NHMRC). Despite negotiating an increase in our NHMRC program grant, we were faced with an immediate loss of around $250 000 in research funding -- not the most auspicious start for a new institute. The second task was to appoint a new Board and Chairperson. A vigorous search, itself an experience for a naive academic like me, enabled us to secure the former Chairman of the Stock Exchange, Jim Bain, to chair the new Board. Under his stewardship, the Institute was steered through the next three difficult years and the Board established a Foundation, chaired by Tim Besley (Chairman of the Commonwealth Bank). The "Kick a Goal for Life" fundraising campaign, the brainchild of Ken Cowley (Chief Executive of News Ltd), a Foundation Trustee, gave us, for the first time, a public profile and much-needed funds. The campaign was launched to coincide with the final of the Commonwealth Bank Cup, awarded to the winners of the schoolboy rugby league competition. Alas, the number of on-field brawls reached such a pitch that the Commonwealth Bank promptly withdrew its support and our initial foray into the community came to an abrupt halt! The third vital task in 1989 was to obtain funding for a new building. Two further feasibility studies and six years later, four and a half floors of the Institute's new six-storey research facility were completed and fitted out at a cost of $17.24 million. This was funded largely from Federal and State capital works grants, with additional assistance from the NSW State Cancer Council and our two parent organisations, the University of Sydney and the Central Sydney Area Health Service. The Institute building is strategically located in the grounds of RPAH, adjacent to the university medical school, and was officially opened by the Prime Minister in 1997. The new team As the new edifice took shape, it was time to begin assembling a team of researchers with the skills to create a "critical mass" in immunology. My group, with its interest in self-tolerance in the B cell lineage, and that of Warwick Britton, head of a research program in mycobacterial infection, were already in place. Jon Sedgwick, well known for his work on autoimmunity in the central nervous system, was the first recruit from overseas. Described by the late Alan Williams of Oxford University as the best "postdoc" he had ever had, Jon was instrumental in grafting "knockout" (gene ablation) technology onto the Institute's existing expertise in transgenesis. Jon was followed by four other immunologists. Barbara Fazekas de St Groth, who, as a medical undergraduate, had done a BSc(Med) under my supervision a decade earlier, was the first. Returning to Sydney from postdoctoral study with Mark Davis at Stanford Medical School, Barbara is now recognised internationally for her work on tolerance and autoimmunity in T cell receptor transgenic models. Together with Patrick Bertolino, who joined us from Lyons in France two years ago, they make a formidable CD4+/CD8+ T cell team. Roland Scollay, known at the time as one of Australia's two leading exponents on thymus biology, was recruited from the Walter and Eliza Hall Institute, along with Phil Hodgkin from the John Curtin School of Medical Research in Canberra. Phil's recent studies on immune regulation and the relationship between division number and lymphocyte behaviour are among the most original contributions to immunology in the past five years. The final member of the quintet was Alan Baxter, who joined us from Cambridge (UK). Alan is rapidly acquiring an excellent international reputation in the field of insulin-dependent diabetes and the genetics of autoimmune diseases, including systemic lupus erythematosus and autoimmune gastritis (see Box). Achievements: the upside During the past decade, the staff has risen from 20 to 95; two NHMRC program grants have been held by research group heads; and the Institute, by virtue of its independent status, has brought to the campus more than $30 million in capital works and infrastructure funds, in addition to over $20 million in peer-reviewed grants. We were particularly delighted that Nobel laureate and immunologist, Peter Doherty, saw fit on the occasion of the official opening of the new building in 1997 to designate us as "Australia's major immunology research centre". A significant amount of the credit for these achievements must go to the Board and to Ken Tribe, its Chairman from 1994 to 1999. Ken brought to the Institute a wealth of knowledge and experience and gave us stable governance during this crucial period in our development. At the same time the work of the research staff has been underpinned by a dedicated research support and management team who have become past masters at maintaining an effective enterprise on the very shortest of shoestrings. Their loyalty and strength of purpose have been most gratifying to me personally. It has also been encouraging to work closely with the other four established independent institutes in NSW (the Garvan, Children's Medical Research, Prince of Wales Medical Research and Heart Research institutes) when negotiating with government and other bodies over issues such as infrastructure funding. The downside If one is honest there is inevitably a downside to any enterprise during its formative years and this has certainly applied to the Centenary Institute. Due to the delay already alluded to in "getting out of the blocks", the Institute has found itself competing for a dwindling pool of resources in the era of what cynics describe as the "epidemic of institutes". Some of them strive to be "independent" like us, while others are "motels" for existing academic and clinical staff or simply single departments renamed for the purpose of raising their profile and respectability. The end-result has been ongoing confusion among funding bodies, government, and even the community at large about who is most deserving of support. The consequence for the well intentioned Director and staff of the Centenary Institute was that when the new building opened they faced a hostile reception on campus, particularly from colleagues who were short of funds and research space. They saw our hard-earned new building as the answer to their prayers, while failing to appreciate our statutory charter and independent status. If only the building had not resembled a casino! Like all of the fledgling independent research centres which have emerged during the recent "epidemic", the Centenary Institute has had to deal with three major issues: inadequate infrastructure, limited funds for developing new groups of merit, and insufficient job security (not to mention salaries) for our full-time career scientists. Perhaps of greatest concern is the fact that the days when one can offer "fame and poverty" to the very best researchers, as Fiona Stanley so aptly put it, are dwindling fast.3 This was driven home to me when two of our most senior group heads were lured to the United States by the offer, not just of much higher salaries, but of far better resources. "If only I did not have to write so many grants for such pathetic amounts of money I would actually have time to do some research", Jon Sedgwick said to me before his departure. The future: the next decade Medical research in Australia Do institutes, independent or otherwise, have a future, or are they likely to acquire the same mortality rate as the biotechnology companies of yesteryear? I believe that some institutes like ours must survive and flourish if Australian medicine is to retain its place at the international table. We have clearly moved into the era of specialisation, in which it is quite acceptable to be recognised as a superb teacher or clinician or researcher, but what is no longer feasible is to be good at every aspect of medicine. The role of institutes, with their critical mass of full-time research staff, is to serve as a focus for collaborative research on the campuses of teaching hospitals and universities with which they are usually affiliated. It is timely that the Wills Review4 has just been published, coinciding as it does with the Federal Government's most welcome commitment to doubling NHMRC funding over the next five to six years. Not only does the Review promote competitive research by extending the concept of partnerships to both Government itself and industry, but it contains a series of innovative recipes which acknowledge the value of the independent institute as a research entity in Australia and of the full-time career scientist. Its implementation is therefore eagerly awaited, particularly by the 30-odd members of the Association of Australian Medical Research Institutes, which between them employ over 2500 research staff. In response to the Wills Review, the challenge for all of us in the medical research community is to secure sufficient ongoing funds to ensure that its recommendations bear fruit. In the case of an institute like ours, this means adding to the existing infrastructural support from the NSW State Government and the Central Sydney Area Health Service by raising funds in the non-Government sector, including from industry and the corporate and wider communities. While creating a public profile and exploiting research are anathema to the purists of the research world, the reality is that the rest of society expects to know about us if they are going to provide the financial support we urgently need. Medical research at the Centenary Institute Having commissioned a new building and recruited high-quality staff, the Institute is now poised to complete the final stage of its 10-year strategic plan. The goal is to create a second critical mass of career researchers in molecular and cellular oncology. A major step forward occurred earlier this year when a $6 million funding package was approved by the Prime Minister. The package is designed to support a strategic alliance with the Sydney Cancer Centre, whereby the Institute would develop a basic cancer research program in the remaining one and a half floors of our building to dovetail with translational and clinical research studies at the Sydney Cancer Centre, located on the adjacent RPAH campus. The first move towards this collaboration has now been made, with the conjoint appointment of John Rasko, a haematologist, who has returned to his old alma mater from the Fred Hutchinson Cancer Research Center in Seattle to head up the Institute's gene therapy laboratory (see Box). The combination of our brand of cellular immunology (traditionally one of Australia's strongest disciplines) with molecular biology targeted at cancer is designed to give the Institute a discrete niche in the postgenomic era now upon us. Edward Jenner as the role model On reading an article recently about the famous country general practitioner, Edward Jenner,5 I rapidly perceived that he was the ideal role model for the institute director of the future. Jenner, famous for his discovery of smallpox vaccination, had other admirable but lesser-known attributes, including an entrepreneurial flair for raising funds, a fascination with diverse areas of science, and proficiency as a poet and musician. When the veracity of his findings on smallpox was being disputed by the inevitable envious colleagues in the United Kingdom and the United States, he raised funds from the public to extend his work (in the absence of any NHMRC equivalent). Later in his life he demanded and received special grants, the first of no less than £10 000, from the government of the day in Great Britain to compensate for the expenses incurred by his research and to set up free vaccination clinics for the public. In 1789 he was elected to the Royal Society, not for his work on vaccination, but rather for his authoritative studies on the habits of the cuckoo nestling. He also found time to classify the botanical specimens brought back by Joseph Banks from James Cook's second voyage to Australia. Despite working full-time on his research, Jenner managed to raise funds and remain a civilised human being. How wonderful it would be for those of us who are institute directors to aspire to just one or two of his many attributes. References Centenary Institute of Cancer Medicine and Cell Biology Act 1985 (NSW). Australian Science and Technology Council. Annual Report 1983-1984. Appendix C. Canberra: AGPS, 1984: 30-36. Stanley FJ. The TVW Telethon Institute for Child Health Research: the birth and growth of a research institute. Med J Aust 1998; 169: 630-633. Wills PJ (Chairman). Health and Medical Strategic Review. The virtuous cycle: working together for health and medical research. Canberra: Department of Health and Aged Care, 1999. Friedman M, Friedland GW. Edward Jenner and vaccination. In: Medicine's 10 greatest discoveries. New Haven: Yale University Press, 1998: 65-93. Authors' details Centenary Institute of Cancer Medicine and Cell Biology, Sydney, NSW. Antony Basten, AO, FAA, FTSE, Executive Director. Reprints: Professor A Basten, Centenary Institute of Cancer Medicine and Cell Biology, Locked Bag 6, Newtown, NSW 2042. a.bastenATcentenary.usyd.edu.au Prime Minister John Howard (center) with Professor Peter Doherty (right) and Professor Antony Basten (left) at the offical opening of the Institute's new building in 1997. The original headquarters of the Centenary Institute located in multipurpose building 94 at the Royal Prince Alfred Hospital. The new Institute building commissioned in 1994. The Centenary Institute of Cancer Medicine and Cell Biology at a glance YearCorporate milestonesResearch milestones 1985Established under an Act of the NSW Parliament as an independent institute with its own Board of Governors and affiliated with the University of Sydney and RPAH 1989Became a functional entity with appointment of Professor Tony Basten as Director and Mr Jim Bain as Chairman of the Board Staff of 20. Director's Clinical Immunology Research Centre became core unit of Institute, comprising his B cell Biology Group and Mycobacterial Research Group (Associate Professor Warwick Britton, University of Sydney) 1991Creation of Foundation with Mr Tim Besley (Chairman), Mr Ken Cowley and Mr Tony Berg as trustees Became a Member Institute of AMRAD Immunopathology Group (Dr Jon Sedgwick, Wellcome Trust SRF)† NHMRC Program Grant to Director renewed 1992Devolved from management of University Appointment of General Manager (Denyse Bartimote) Capital works funding of $17.24 million obtained for new building T cell Biology Group (Dr Barbara Fazekas de St Groth, Wellcome Trust SRF) Thymus Biology Group (Dr Roland Scollay, NHMRC SPRF)† 1994Mr Ken Tribe appointed Chairman of the Board 1995Four and a half floors of new six-storey building commissionedImmune Regulation Group (Dr Phil Hodgkin, Medical Foundation SRF) Liver Immunobiology Group (Professor Geoff McCaughan, RPAH) 1997New building officially opened by Prime Minister New research and development infrastructure funding scheme introduced by State Health Department, providing Institute with $800000 per annumAutoimmunity Research Group (Dr Alan Baxter, NHMRC R Douglas Wright Research Fellow) 1998NHMRC Program Grant in diabetes (Alan Baxter co-chief investigator) 1999$6 million package announced by Prime Minister for joint cancer research program with Sydney Cancer Centre, RPAH Mr Malcolm Noad appointed Chairman of the Board Total staff of 95 Gene Therapy Research Group (Dr John Rasko) Total funding brought to the campus by the Institute was in excess of $50 million *For further details on research programs refer to web site <http://www.centenary.usyd.edu.au> †Left Institute to take up position in United States NHMRC = National Health and Medical Research Council. RPAH = Royal Prince Alfred Hospital. SPRF = Senior Principal Research Fellow. SRF = Senior Research Fellow.

Antony Basten