Cancer

Exposure of the thyroid gland to any irradiation requires lifelong follow-up supervision One of the questions most frequently asked by patients about to receive radioactive iodine as therapy for non-malignant conditions is whether it will result in bodily cancer. This question has been satisfactorily answered in the negative,1,2 so strong reassurance can be given. No such reassurance can be given for the malignant effects of therapeutic external beam irradiation on the thyroid gland. In childhood, the sensitive thyroid gland can be exposed to therapeutic irradiation directly, as in the treatment of localised neck tumours such as lymphoma or sarcoma and in total-body irradiation before bone marrow transplantation. Where the thyroid gland is not directly the target of therapy, it can be affected by scatter irradiation, as occurs during prophylactic cranial irradiation of the central nervous system in haematological malignancies. Thus far, no measures have been found to protect the thyroid gland from external irradiation in these settings. In this issue of the Journal (page 584), Somerville and her colleagues report the first Australian experience in a study encompassing a large number of children recruited to the Late Effects Oncology Clinic of the Children's Hospital at Westmead.3 The period of study covers 10 years. The sample population was divided into a group who received direct irradiation and another, designated as "scatter", in which there was exposure to the upper half of the body as external beam irradiation but no direct irradiation of the thyroid gland. The study was designed to emulate the approach that would commonly be used by a clinician seeking evidence of change in the thyroid gland. Palpation was used to delineate size and other characteristics. The customary thyroid function tests were carried out. These findings were supplemented by high-resolution ultrasound examination of the neck, and, if the findings warranted, fine-needle aspiration biopsy was undertaken. Suspicious findings from any of these evaluations led usually to surgery, but an abnormal ultrasound result was the chief indication for surgery. Some surprising and important revelations have come to light: Palpation of the thyroid gland was unreliable and misleading in a significant proportion of patients, with a preponderance of non-discovery. Ultrasound examination was almost always abnormal when the thyroid gland was palpable, and abnormal in more than 50% of patients in which the gland could not be felt. Thyroid function tests gave little warning of malignancy, and the elevation of thyroid-stimulating hormone in inadequately supplemented patients, although noted, gave no pointer to the status of the thyroid gland as a whole or the underlying presence of malignancy. Fine-needle aspiration biopsy was carried out in a few patients, but did not materially influence their management. The authors advocate total thyroidectomy for multiple nodules on ultrasound examination or where new nodules appear after partial thyroidectomy. Twenty-five patients from the direct-irradiation group had abnormal ultrasound results and underwent surgery, whether or not the thyroid gland was palpable; six of them harboured malignancy. On the other hand, in the scatter group, of 24 patients with similarly abnormal ultrasound results 12 were affected. Not only were localised recurrences frequent, but additional cancers in other areas of the body were noted by the authors, so vigilance in this respect is required. When surgery was carried out, the histological appearance of glands exposed to both types of irradiation indicated widespread damage and evidence of increased endothelial activity ranging from scarring through to nuclear atypia. There are important lessons to be learned. Exposure of the thyroid gland to any irradiation requires lifelong supervision and introspection. This should include high-resolution ultrasound. The extent of thyroid exposure to radiation may be arcane and not recalled when the highlight of the history is focused on areas away from the gland. Most radiation oncology units in Australia have follow-up facilities, but the duration of follow-up is not uniform. Moreover, patients travel and disperse, so their supervision will be most likely carried out by doctors with less experience of such patients. In this regard the American Thyroid Association publishes an excellent information sheet for patients.4 The article concludes with a series of pertinent recommendations which emanate from the study. Although false positive results can occur, the risks demonstrated in this study indicate that the management regimen recommended by Somerville et al far outweighs a sanguine approach to the problem. Implicit in this is the importance of providing patients with information about the potential risks and the need for regular assessment. Somerville et al observe that the Australian experience has disclosed a greater incidence of thyroid abnormality than seen in some other countries. This may derive from differing methods in the extent and depth of the studies, together with the sophistication of the ultrasound. The magnitude of the dose in the reported series did not seem to influence the emergence of malignancy. Only time from the administration of the radiation therapy was important. It will be interesting to learn of the further evolving experience. In this regard, results of fluorodeoxyglucose positron emission tomography, in association with rising thyroglobulin levels, seem to give a clearer delineation of recurrent malignancy than can be obtained by other methods.5 There may come a time when it will be possible to protect patients from scatter irradiation involving the head, neck or upper-body region in the treatment of more generalised cancer such as leukaemia. However, such protection does not appear to be imminent and, even if attained, there will still be a group of potential thyroid cancer subjects as a legacy of the current therapeutic era.

Alex K Cohen AO, MD, FRACP · Agatha A van der Schaaf FRACP

Objectives: To describe a cohort of survivors of childhood malignancy at risk of developing thyroid abnormality, and propose guidelines for management of such patients.Design: Retrospective case series.Setting: Late-effects oncology clinic at a large children's hospital in Sydney.Subjects: 142 patients who had received irradiation to the thyroid from the 1970s onwards, who attended the late-effects clinic from May 1989 to December 1998.Interventions: Thyroid palpation by an endocrinologist or surgeon, serum thyroid-stimulating hormone assay and thyroid ultrasound examination were performed on all subjects and, depending on findings, some subjects proceeded to fine-needle biopsy or surgery (total thyroidectomy). A few patients required adjuvant 131I administration.Outcome measures: Radiation dose received; results of thyroid palpation; thyroid function tests; ultrasound findings; diagnosis of the abnormalities; and outcomes of surgical interventions.Results: 49 subjects (24 of 65 patients who received scatter irradiation to the thyroid and 25 of 78 patients who received direct irradiation) had thyroid surgery. Of these, 12 in the scatter and six in the direct irradiation group were found to have thyroid malignancy. Fifty subjects with abnormal ultrasound results remain under surveillance. Having a palpable thyroid was predictive of malignancy, but age at original diagnosis, sex, current age, time since irradiation, radiation dose, nodule type and nodal involvement were not.Conclusion: There is a significant risk of cancer in thyroid glands exposed to radiation as part of therapy for childhood cancer. This risk is greater for patients who received scatter (versus direct) irradiation. Nodular change is usually not apparent for many years, so lifelong surveillance is necessary. Palpation alone is not sufficient to detect thyroid cancer and thyroid ultrasound examination is recommended.

Helen M Somerville MB BS, MPaed · Albert H Lam MD, FRACR · Michael M Stevens MB BS, FRACP · Kate S Steinbeck PhD, FRACP · Graham Stevens MD, FRANZCR · Leigh W Delbridge MB BS, FRACS

To the Editor: I agree with the assessment by Del Mar and colleagues of available data according to evidence-based guidelines on hormone replacement therapy (HRT) after mastectomy.1 As they note, these data are not definitive. Standard practice has been to avoid oestrogen use in women with a history of breast cancer. Ours is an increasingly litigious society and courts make decisions according to different criteria than do scientists. In particular, precedent is very important to the law of tort, even if the scientific basis for the precedent is unproven. For some years now, I have seen 100 or more new patients per year with recently diagnosed early breast carcinoma. By the time I see them, every single one already knows that: anti-oestrogens are used in treatment of breast cancer; and women are at least 30% more likely to develop breast cancer after five years of HRT. Further, these women fear recurrence of breast cancer more than any other health problem. Hence, I am concerned that the sound evidence-based conclusions reached by Del Mar and colleagues could be successfully challenged in court by a woman who developed recurrence of breast cancer while receiving HRT. In addition to the costs and stress for the individual practitioner involved and other members of his medical indemnity organisation, such action would set back scientific enquiry into this important subject, possibly forever. There is a wealth of well conducted research into non-oestrogenic management for menopausal symptoms. Lifestyle measures (clothing and activity) and dietary modifications (avoiding spicy foods, alcohol) have a role in well-being. Oral progestogens, clonidine, venlafaxine, black cohosh, and probably tibilone, all produce better outcomes than placebo.2 Evening primrose oil, pyridoxine, dong quai, Chinese herbs, progestogen and yam creams, and phytoestrogens do not work better than placebo.3 The last may actually be harmful. Advisory statements for general practitioners about oestrogen replacement therapy for managing menopausal symptoms after breast cancer should be prefaced with this information, as should any discussion with patients. I do prescribe oestrogens for distressing menopausal symptoms after breast cancer treatment, but only after several consultations to allow time for women to appreciate the uncertainties involved.

Robert N Hitchins

To the Editor: I was pleased to see the issue of hormone replacement therapy (HRT) after breast cancer raised by Del Mar and colleagues in a recent issue of the Journal.1 However, I was a little disappointed to see that Australian research in this area had been "missed" by their search.2,3 There are a number of other studies that I am aware of which would suggest to me that perhaps their search technique was not particularly thorough.4-7 Nonetheless, I should add that I do agree with their conclusions. In fact, I am not aware of any clinical trials that have shown an adverse effect of HRT after a diagnosis of breast cancer. However, the studies examined by Del Mar and colleagues are all population studies and not randomised controlled trials. I also think it's important that the readers of the Journal understand that there are other strategies for controlling menopause symptoms after breast cancer, such as the use of progestins, antidepressants and stress-reduction techniques. Even though the evidence we have suggests that HRT after breast cancer is "safe", we do not have even one published randomised trial on this question, so caution should be the rule. HRT after breast cancer should always be viewed as a last resort.

Robert N Hitchins MB BS, FRACP, FAChPM · Christopher M Pyke MB BS, FRACS, FACS

To the Editor: While I have little concern with the conclusion of the article by Del Mar and colleagues,1 I have some concerns about its use to portray a mode of healthcare delivery where any given health practitioner, armed only with what can be gleaned from the Internet, can issue advice. For example, in such a circumstance, should not the general practitioner also refer to the National Health and Medical Research Council clinical practice guidelines on the management of early breast cancer,2 which suggests that the "safety of oestrogen replacement therapy in women with breast cancer has not yet been established", and, further, that "HRT [hormone replacement therapy] and women with breast cancer" is an area where research is needed? Should the doctor also point out to the patient that she is eligible to enter a prospective randomised trial looking at the use of HRT following breast cancer treatment versus the best non-hormonal treatment of menopausal symptoms, currently being administered by the Australian and New Zealand Breast Cancer Trials Group (as part of International Breast Cancer Study Group trial 17-98)? How should practitioners protect themselves when they find the management they are recommending is outside that recommended in the evidence-based guidelines published by specialty groups? A few other minor points: the content of the article refers to women with breast cancer, whereas the title refers only to women who have had mastectomy, and the imaginary patient asked about loss of libido, which was not addressed at any subsequent point in the article.

Christopher B Del Mar MD FRACGP FAFPHM · Paul P Glasziou PhD FRACGP FAFPHM

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