Cancer

There is clear evidence of long-term benefits The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) 2000 overview of adjuvant systemic treatment trials for early breast cancer has demonstrated clear evidence of substantial and significant reductions in both recurrence and mortality, with follow-up now to 15 years.1 This is the fourth EBCTCG overview of adjuvant systemic therapies, conducted at 5-year intervals since 1985.2-6 The EBCTCG 2000 analysis, based on individual patient data from 145 000 women diagnosed with early breast cancer, involved 194 trials started by 1995 in which chemotherapy and hormonal therapy were evaluated alone and in combination for their effects on recurrence, breast cancer mortality and total mortality. This overview, with data from more trials than the earlier overviews, more patients and more years of follow-up, provided new and long-term information on adjuvant chemotherapy in women aged 50–69 years, tamoxifen duration, combined modality therapy, and cause-specific mortality (Box). What were the benefits?Chemotherapy regimens included single agents or polychemotherapy, either cyclophosphamide, methotrexate and fluorouracil (CMF), or anthracycline-containing regimens, mostly fluorouracil, adriamycin, and cyclophosphamide or substituting epirubicin for adriamycin. Anthracycline-containing regimens of about 6 months’ duration reduced the annual breast cancer death rate by 38% in women younger than 50 years, and by 20% in women aged 50–69 years. Similar reductions in annual recurrence rates were seen. The benefits were largely independent of the use of tamoxifen, oestrogen receptor status, or nodal status. Anthracycline-containing regimens were significantly better than CMF regimens for recurrence (2P = 0.0001 [2P is a two-sided P value]) and mortality (2P = 0.00001). There were insufficient trials involving women older than 69 years (< 5% of women) to reliably determine treatment effects. Hormonal therapies studied were tamoxifen (in most trials), ovarian ablation or ovarian suppression. The 15-year follow-up provided an opportunity to evaluate both early and late effects on recurrence and breast cancer mortality for each modality, given alone or in combination with chemotherapy. With respect to mortality, in women with oestrogen-receptor-positive tumours, 5 years of tamoxifen use reduced the annual breast cancer death rate by 31% and the annual recurrence rate by 40%, independent of patient age, the use of chemotherapy, progesterone receptor status or tumour characteristics. However, there was no advantage for a higher dose of tamoxifen than 20 mg per day. Tamoxifen given for 5 years was significantly superior to 1–2 years of therapy, but the evidence for any effect of continuing tamoxifen for more than 5 years remained inconclusive. With respect to recurrence, a significant trend was seen with increasing reduction of annual recurrence rates with increasing age (40–49 years, 29%; ≥ 70 years, 51%; age trend 2P = 0.05). The overview did not include any trials in which tamoxifen and chemotherapy given concurrently were compared with one modality followed by the other. However, as the benefits of tamoxifen and of chemotherapy were largely independent of whether treatment included the other modality, a mortality reduction of 57% for women younger than 50 years and 45% for women aged 50–69 years could be expected by using both modalities together. Do benefits occur early or late?Most of the benefit of polychemotherapy on recurrence was seen in the first 5 years (absolute reductions of recurrence of 12.5%, 12.4% and 12.4% at 5, 10 and 15 years follow-up, respectively, for women younger than 50 years), whereas the benefit for mortality continued to increase for 15 years (absolute reductions in breast cancer mortality of 4.7%, 7.9% and 10.0% at 5, 10 and 15 years, respectively). The early effect of chemotherapy on recurrence had been well established in the previous overview,6 but the continuing late mortality benefit has only now been established by the longer follow-up. The late mortality benefit was less apparent for chemotherapy in women aged 50–69 years. The pattern of benefit from 5 years of tamoxifen was similar to that seen with chemotherapy for women aged less than 50 years, but was apparent in all age groups. Again, most of the effect on recurrence occurred in the first 5 years (absolute reductions for recurrence: 10.4%, 13.6% and 11.8% at 5, 10 and 15 years), whereas much of the benefit on breast cancer mortality occurred after the first 5 years (absolute reductions of 3.6%, 7.9% and 9.2% at 5, 10 and 15 years). This extended mortality benefit, seen with both chemotherapy and tamoxifen, is striking and suggests that an important number of patients with residual disease after primary therapy are cured of their original tumour by adjuvant tamoxifen or chemotherapy, although they remain at continuing risk of new contralateral breast cancer in the long term. Given the similar pattern for clinical benefits observed for the two treatment modalities, the biological outcomes of their effects at the cellular level may have more in common than has previously been recognised. Ovarian ablation or suppression also had a significant, beneficial effect on recurrence (2P < 0.00001) and mortality (2P < 0.004). The pattern of benefit — an early effect on recurrence and a later effect on mortality — was similar to tamoxifen. However, in contrast to tamoxifen, the effect of suppression or ablation was less in trials where all women also received chemotherapy, perhaps because the chemotherapy also suppressed ovarian function. This question is being addressed in current trials. What were the harms?There were minimal long-term effects of all of these agents on non-breast cancer mortality. Chemotherapy was associated with a small, non-significant increase in mortality from heart disease, leukaemia and lymphoma (0.2%); tamoxifen was associated with a small excess mortality from uterine cancer and pulmonary embolus (0.2%). However, the small increase in non-cancer deaths (a few per 10 000 patients per year) was very much less than the reduction in breast cancer deaths seen for each treatment modality. What are the implications?The data from the earlier EBCTCG overviews have already contributed to widespread changes in practice and a recent fall in breast cancer mortality of around 20% in several developed countries. The findings of the 2000 overview will encourage an even wider use of systemic therapies and should contribute to further reductions in mortality.7 Overall, the most important finding from the 2000 overview is that important practical and biological information is gained from long periods of follow-up. Not only has this overview produced definitive results relevant to breast cancer management but, importantly, it has clearly demonstrated two important biological principles. First, that an early reduction in recurrence rates is invariably followed by a reduction in mortality. Hence, recurrence rate reduction may be an acceptable basis on which to recommend changes in practice before survival data is obtain-able. Second, despite the substantial benefits of 5 years of tamoxifen, 2% of patients continue to have a breast cancer recurrence each year from years 5 to 15 after diagnosis. This is a several-fold greater risk of new breast cancer events than was required for the “high risk” women to be eligible for the tamoxifen prevention trials.8 New strategies for ongoing management of these women should be considered. Further, other questions will need to be addressed by the overview process, including the value of tamoxifen or other endocrine therapies beyond 5 years and addition of a taxane to chemotherapy regimens.9 What are the limitations?The current overview only encompassed therapies used up to 1995, which — although clearly effective — are not optimal for all patients in 2005. The 2000 overview did not involve taxanes (there are now more than 10 000 patients in several trials) or aromatase inhibitors (about 30 000 patients in seven trials).10,11 Nor did it include trials with trastuzumab (Herceptin) for women with tumours expressing HER2.12 However, answers to other specific questions such as the value of long-term aromatase inhibitors and of targeted therapies will likely be based on a smaller number of larger trials rather than an overview of many smaller trials. Many such trials, including the important “SOFT”, “TEXT”, and “PERCHE” trials of different combinations of chemotherapy, aromatase inhibitor and tamoxifen for younger women, as well as trials for older women, and trials of taxanes and of trastuzumab, are being conducted in Australia by the Australian New Zealand Breast Cancer Trials Group through international collaboration. These trials should be the subject of separate meta-analyses, conducted in a timely manner to facilitate rapid dissemination of the results. However, long-term follow-up is a particularly valuable feature of the EBCTCG overviews, and the EBCTCG investigators are pursuing strategies to ensure that data from the 2005 overview will be made available sooner and more widely. Key findings of the Early Breast Cancer Trialists’ Collaborative Group 2000 overview Overview of 194 randomised trials of systemic therapies for early breast cancer started by 1995, including data at 10 and 15 years follow-up. Anthracycline-containing regimens are superior to cyclophosphamide, methotrexate and fluorouracil (CMF). Anthracycline-based polychemotherapy reduced annual death rates by 38% (standard error [SE], 5) for women younger than 50 years, and by 20% (SE, 4) for women aged 50–69 years. Tamoxifen reduced annual mortality rates for oestrogen-receptor-positive tumours in all age groups (31%; SE, 3). Combination therapy with tamoxifen and chemotherapy may produce a larger mortality reduction (45%–57%). Effects on recurrence occur early; effects on mortality occur later. Long-term benefits maintained to 15 years. Long-term non-breast cancer deaths from treatment are a few per 10 000 per year, and are greatly outweighed by the reduction in breast cancer deaths. More rapid data dissemination from overviews is required.

John F Forbes FRACS, FRCS, MS · Jack Cuzick PhD

Is it time to walk the line between overtreating indolent disease and undertreating aggressive disease? Few other health care issues in Australia have been as contentious as the diagnosis and treatment of early prostate cancer. Debate centres on two hotly contested but important issues: do prostate cancers diagnosed by an elevated serum prostate-specific antigen (PSA) level pose a significant threat to health, and if they do, can intervention alter the natural history of the disease? In this editorial, we consider the contribution that two recently published studies make to this debate, with a focus on survival and the role of surgical management. Study one: In the first study, Albertsen and colleagues presented an update of a retrospective cohort study first published in 1998.1 They estimated 20-year survival after clinically localised prostate cancer was treated without curative intent in 767 men diagnosed with this condition between 1971 and 1984. After a median of 24 years, the men’s current vital status was obtained and the contribution of prostate cancer to any subsequent mortality was determined by examining death certificates. Survival was assessed on a competing risk analysis, and stratified for age and tumour differentiation. The primary finding was that the risk of death from localised prostate cancer did not increase significantly with time from diagnosis — leading the authors to suggest that aggressive management of localised prostate cancer is perhaps unnecessary. The study also found that prostate cancer graded as Gleason sum 7 and above (moderately to poorly differentiated) is lethal. These results can directly inform our current debate only if the population studied is comparable to contemporary patients, and as these men were diagnosed in the pre-PSA era, there are major differences in this regard. Of the men in the cohort, 71% were diagnosed on the basis of surgical intervention for benign prostatic hyperplasia, either by transurethral resection of the gland or open prostatectomy. Both of these procedures sample the transition zone exclusively, where less than 25% of all prostate cancers originate. A relatively high proportion of these T1 tumours are true “transitional zone tumours”, which are well recognised to be smaller in volume and better differentiated, and to run a more indolent biological course. This is reflected in the finding that 33% of the cohort had cancers with Gleason sums of between 2 and 5 — well differentiated tumours. In contrast, significant or lethal prostate cancer with high Gleason sums is found predominantly in the posterolateral part of the prostate, the peripheral zone. Prostate cancer diagnosed after a finding of an elevated PSA level with sampling of the peripheral zone shows cancer with a Gleason sum of less than 6 in less than 5% of cases, with most cancer detected by PSA testing scoring 6 or 7 (moderately differentiated). Thus, this study cohort contained a high number of clinically insignificant prostate tumours that would be less likely to be diagnosed by needle biopsy. Any comparison with contemporary prostate cancer series detected by PSA testing is also confounded by the late age of diagnosis (median, 69 years) and the high rate of significant comorbidity in this cohort. Further, 42% of patients with clinically localised disease received some form of androgen deprivation therapy within 6 months of diagnosis (which was presumably continued until death), despite there being no evidence of disease progression. It is now becoming increasingly appreciated that hormonal therapy creates a disease in itself, which can contribute significantly to mortality from other causes (particularly cardio-vascular mortality from diethylstilboestrol).2 Despite its differences from more contemporary studies, the study by Albertsen and colleagues does offer striking insights into the biology of conservatively treated prostate cancer. Clearly, cancers graded Gleason 7 and above are lethal when managed conservatively, even in a population of sick elderly men. Conversely, at least up to 15 years of follow-up, cancers graded Gleason 2 to 5 run an indolent course, which suggests that in elderly and medically compromised men, a more conservative course can be followed. However, data from another series which is less contaminated with transition zone tumours suggested that low grade tumours can dedifferentiate and metastasise, which has particular relevance to men diagnosed at a younger age.3 Study two: In the second study under consideration, Bill-Axelson and colleagues directly addressed the second point of contention — can intervention alter the natural history of prostate cancer?4 Again, this was an updated analysis of a previously reported study. It was an elegant study premised on a beguilingly simple hypothesis that: by removing prostate cancer that is confined to the gland via radical prostatectomy, metastases can be prevented; by preventing metastases, death from prostate cancer can be reduced; and by reducing death from prostate cancer, overall survival is improved. Radical prostatectomy is the surgical removal of the prostate and seminal vesicles by dividing the prostate at the bladder neck and urethra, and suturing a vesicourethral anastomosis over the catheter. It has been performed by open abdominal surgery and, more recently, by a minimally invasive laparoscopic or robotic approach. In Bill-Axelson and colleagues’ randomised controlled trial, 695 men with clinically localised prostate cancer were allocated to either radical prostatectomy or “watchful waiting”. In both groups, hormonal therapy (medical or surgical castration) could be introduced at the discretion of the treating physician. Mean age at diagnosis was 64 years, and mean serum PSA level at diagnosis was 13 ng/mL. Median follow-up was 8.2 years. Importantly, this study is more representative of the era in which PSA testing is used to detect prostate cancer. Diagnosis was by contemporary sextant, ultrasound-guided needle biopsy of the peripheral zone, and only 11% of diagnoses were at transurethral resection of prostate, although a higher proportion had palpable disease than a modern series might. In this study, 77% of cancers were T2 (organ-confined) prostate cancers. In contrast to the Albertsen study, 77% of tumours were graded Gleason 5 to 7, and only 13% were graded Gleason 2 to 4. Nearly half (48%) of Bill-Axelson and colleagues’ cohort had a PSA level greater than 10 ng/mL at diagnosis. In all, this cohort of patients represents a somewhat more advanced disease group than would be representative in Australia in 2005 (where PSA testing is now more prevalent, and more cancer is being discovered in the 4–10 ng/mL PSA range). Nonetheless, the results presented by Bill-Axelson and colleagues are instructive, underscoring the biological truth of the study hypothesis. In men treated with surgical intervention, the incidence of metastatic disease and risk of death from prostate cancer was significantly reduced compared with those who were managed by watchful waiting. This led to a significant reduction in all-cause mortality, providing evidence for the first time that radical intervention for localised prostate cancer can deliver a real health benefit. This health benefit was highest in men younger than 65 years of age, with 19% of watchful-waiting patients compared with 8% of patients treated with surgery dying from prostate cancer at 10 years. Although the study authors remained cautious, suggesting further research needs to be done before introducing an immediate change in clinical practice, their results were impressive in terms of metastatic rate (14% in the surgery group versus 23% in the watchful-waiting group) and local progression of prostate cancer (64 in the surgery group versus 149 in the watchful-waiting group, showing a 25% risk reduction in local progression in the surgery group at 10 years). Further, 177 of the patients in the watchful-waiting arm versus 110 in the surgery arm received hormone therapy, with a median time to hormone therapy treatment of 4 years. So, now that Bill-Axelson and colleagues have shown in a randomised controlled trial that surgery for prostate cancer saves lives, do we have all the answers? Would that this were so. These data are extremely important in guiding men about the relevance of PSA testing, the risk of death and risk of metastatic and local progression from untreated histologically significant prostate cancer. However, the injudicious application of prostate testing has opened a Pandora’s box. We have seen an explosion in diagnosis of potentially insignificant non-life-threatening prostate cancer. There is now a strong push in the United States to have the PSA cutpoint for prostate cancer biopsy lowered from 4 ng/mL to 2.5 ng/mL or even lower.5 Some suggest all men have a prostate biopsy at the age of 50 years. The PSA test is good, but not great. It doesn’t help us differentiate between the indolent and dangerous prostate cancer. Gleason histology grading does help as a differentiator. But what is the cost–benefit balance of making a diagnosis of indolent microfocal Gleason 6 prostate cancer in a 78-year-old man with a PSA level of 6 ng/mL? We can take comfort in the proven knowledge that surgery is indicated for younger men with at least 15 years of life expectancy. However, a more judicious approach in managing older men with comorbidities will be needed. Countering this, newer technical developments in prostate cancer surgery, including laparoscopic and robotic radical prostatectomy, will further improve outcomes for men by reducing the morbidity of the operation and improving cancer control.6-8 Perhaps the next big question (and answer) in prostate cancer surgery has been articulated by Klotz.9 They are conducting a program of active surveillance with regular PSA testing and repeat biopsy, with surgical intervention with curative intent if there is cancer progression, in men with defined low-risk prostate cancer. This approach may help us to reduce unnecessary treatment in men at low-risk of disease progression. Eventually, an improved molecular understanding of the biology of these cancers will help us to predict precisely long-term outcomes in patients with prostate cancer and, thus, to decide on the most appropriate management for each individual patient.

Anthony J Costello FRACS, MD · Niall M Corcoran MB, AFRCSI · Scott Van Appledorn MD

Objectives: To describe the main media narratives in the reportage of singer Kylie Minogue’s illness with breast cancer; and to assess the impact of this coverage on bookings for screening for breast cancer by mammography in four Australian states.Setting: Government sponsored BreastScreen programs in Queensland, Victoria, Tasmania and Western Australia.Main outcome measures: Narratives on breast cancer in television news programs 17–27 May 2005; initial and re-screening bookings for mammograms.Participants: Women aged ≥ 40 years who booked for mammograms in BreastScreen programs in the 19 weeks before, the 2 weeks during, and the 6 weeks after the publicity.Results: There was a 20-fold increase in news coverage of breast cancer, which emphasised that young women do get breast cancer and that early detection was critical. Overall screening bookings rose 40% in the 2 weeks of the publicity, with a 101% increase in non-screened women in the eligible age-group 40–69 years. Six weeks after the publicity, bookings remained more than a third higher in non-screened women.Conclusions: News coverage of Kylie Minogue’s breast cancer diagnosis caused an unprecedented increase in bookings for mammography. Health advocates should develop anticipatory strategies for responding to news coverage of celebrity illness.

Simon Chapman PhD · Simon Holding BA · Kim McLeod BA(Hons) · Melanie Wakefield PhD

Objective: To investigate attitudes of Australian health professionals working in oncology to health-related information in the media and on the Internet and to patients who search for this information.Design: Questionnaire-based survey.Setting and participants: Questionnaires were mailed in January 2003 to all 333 health professionals belonging to the Victorian Cooperative Oncology Group.Main outcome measures: 27 items about attitudes to information in the media and the Internet, patient information-seeking and its effects on the doctor–patient relationship.Results: 226 surveys (68%) were returned and assessable. Most respondents took notice of medical information reported on television/radio, in newspapers (80% each) and on the Internet (56%), mainly to be informed when patients ask questions (82%) and to check its accuracy (60%). Most were concerned about this accuracy (64% believed it accurate only sometimes, and 23% rarely), and 91% believed information from the Internet had the potential to cause harm to patients. Nevertheless, they generally supported patients’ information-searching, believing it allowed them to be better informed (58%), and did not affect their ability to cope with their illness (49%), or their trust in, and relationship with, their doctor (69% and 67%, respectively).Conclusions: Oncology health professionals are aware of patients’ use of the Internet and other media to obtain medical information. To ensure oncology patients find reliable and relevant information and to minimise the risk of harm, the health professionals treating them should provide guidance in finding information sources, and assistance in interpreting the information obtained.

Genni M Newnham MB BS(Hons) · W Ivon Burns FRACP · Raymond D Snyder FRACP · Anthony J Dowling FRACP · Nadia F Ranieri · Emma L Gray · Sue-Anne McLachlan MSc, FRACP

The discovery of novel mutations in genes encoding succinate dehydrogenase subunits has revealed that familial phaeochromocytomas are much more common than previously thought. Genetic screening should be offered to patients with apparently sporadic phaeochromocytomas and their first-degree relatives. An increasing proportion of phaeochromocytomas present preclinically on genetic testing or as “incidentalomas” on abdominal imaging, rather than with classic symptoms and signs. Clinical suspicion should prompt measurement of plasma levels of free metanephrine or 24-hour urinary catecholamine and metanephrine levels, followed, if positive, by tumour localisation studies. With appropriate perioperative care, surgical management of phaeochromocytomas is safe and effective. Most tumours can be removed laparoscopically.

Yaser Alderazi MB BS · Michael W Yeh MD · Bruce G Robinson MD, FRACP · Diana E Benn PhD · Mark S Sywak FRACS · Diana L Learoyd PhD, FRACP · Leigh W Delbridge MD, FRACS · Stan B Sidhu PhD, FRACS

The aromatase inhibitors deplete oestrogen by inhibiting aromatase, the enzyme that synthesises oestrogen from androgens. They are effective as therapies for breast cancer only in postmenopausal women whose tumours express oestrogen or progesterone receptors. As adjuvant therapy, tamoxifen and the aromatase inhibitors have similar efficacy in the first 5 years of treatment. Aromatase inhibitors can be used as an alternative to tamoxifen in women with symptomatic intolerance or a contraindication to tamoxifen. Early data suggest that switching to an aromatase inhibitor after 2–5 years of tamoxifen therapy is beneficial in women with high-risk disease. Aromatase inhibitors are associated with more hot flushes than placebo, but with fewer hot flushes, less endometrial toxicity and venous thromboembolism, and more arthralgia, myalgia and bone fracture than tamoxifen.

Ilona C Nordman MB BS · Andrew J Spillane BM BS, MD, FRACS · Anne L Hamilton MB BS, FRACP

Objective: To evaluate the frequency and management of anaemia in Australian adults with solid and haematological malignancies.Design: 6-month observational, prospective, multicentre study.Participants: 694 patients recruited from outpatient oncology clinics in 24 hospitals in five Australian states between 9 April 2001 and 31 July 2001.Main outcome measures: Frequency of anaemia (haemoglobin [Hb] level < 120 g/L) at enrolment and over ensuing 6 months, by tumour type, disease status and cancer treatment; anaemia treatment and “trigger” Hb level for this treatment.Results: Participants had median age 60 years, and 61% were women. Prevalence of anaemia at enrolment was 35% (199/562), with 78% of these 199 having mild anaemia (Hb, 100–119 g/L). Frequency of anaemia (either present at enrolment or developing during the study) was 57% overall (323/566), and varied with tumour type, from 49% (lymphoma/myeloma) to 85% (urogenital cancer). Patients who received radiotherapy either in combination or concomitant with chemotherapy were more likely to have anaemia (73%) than those receiving chemotherapy alone (58%) (P = 0.004). Of all chemotherapy patients not anaemic at enrolment, 23% developed anaemia by the second monthly follow-up. Independent predictors for anaemia in chemotherapy patients were low baseline Hb level (odds ratio [OR], 5.4; 95% CI, 2.7–10.9) and use of platinum chemotherapeutic agents (OR, 4.8; 95% CI, 2.1–11.4) (P < 0.001). Anaemia was treated in 41% of patients with anaemia at enrolment — by transfusion (36%), iron (5%) and erythropoietic agents (2%). Frequency of anaemia treatment varied between tumour types, from 19% (breast cancer) to 60% (leukaemia). The mean “trigger Hb” for initiating transfusion was 95 g/L.Conclusions: Anaemia is prevalent among Australian patients with cancer managed in hospital oncology units. Its management varies between tumour types. Many patients do not receive treatment for their anaemia.

Tara Seshadri MB BS · H Miles Prince FRACP, MD · David R Bell FRACP · Paul B Coughlin FRACP, PhD · Philip P B James DM, FRACP · Gary E Richardson FRACP · Boris Chern FRACP, FAChPM · Peter Briggs FRACP · John Norman FRACP · Ian N Olver MD, PhD, FRACP · Chris Karapetis FRACP, MMedSc · John Stewart FRACP

Until definitive evidence of the effectiveness of prostate cancer screening is available, most guidelines advocate that men make their own decisions about testing, after being fully informed. A man’s perception of his personal risk is a key element in the decision-making process. In this decision-making, the current routine use of population risk estimates may be misleading. Risk estimates need to be relevant to the man making the choice. In particular, they should be age-specific and, where possible, include adjustments for known risk factors such as family history. As an example, although the population risk of lung cancer mortality is twice that of prostate cancer, for a non-smoking man with a family history of prostate cancer the direction of this comparison would be reversed. A man aged 50 diagnosed with prostate cancer has a greater likelihood (60%) of dying prematurely (before 80 years) from prostate cancer than a man diagnosed when aged 70 (38%). This can be attributed to the longer time available for the prostate cancer to progress, and the increased effect of competing causes of death among older men. This suggests that the oft-used statement “men are more likely to die with prostate cancer than from prostate cancer” is misleading, particularly for men diagnosed in their 50s or 60s. Decisions need to be made by men based on the best possible understanding of their personal vulnerability, and the individualisation of risk provides a more realistic appraisal of potential threat posed by the disease.

Peter D Baade PhD · Suzanne K Steginga PhD · Joanne F Aitken PhD · Carole B Pinnock PhD

Clinical record A 53-year-old woman with a 10-year history of coeliac disease controlled by a gluten-free diet presented with a 6-month history of dramatic weight loss and pyrexia. Physical examination showed wasting and peripheral oedema. Plasma albumin level was 23 g/L (normal, 34–48 g/L). Computed tomography of head, neck, chest, abdomen and pelvis, gallium and positron emission tomography scans, liver biopsy and bone marrow biopsy were normal. The serum lactate dehydrogenase (LDH) level was 466 U/L (normal, 110–230 U/L), raising the possibility of occult malignancy, especially enteropathy-associated T-cell lymphoma (EATL). Endoscopic duodenal biopsy revealed mild increase in intraepithelial lymphocytes, crypt hyperplasia and villous abnormality in keeping with coeliac disease. Molecular clonality studies of the lymphoid cells in the duodenal biopsy yielded a monoclonal band of T-cell receptor (TCR) γ gene rearrangement in two separate series of biopsies taken 6 weeks apart. Refractory sprue was diagnosed, and the patient received sequential trials of prednisolone, cyclosporin A and infliximab without benefit. High dose cyclophosphamide (2 g/m2) was administered 3 months later for presumed EATL. This resulted in immediate resolution of the fever and improved weight gain. The patient subsequently complained of paraesthesiae in her feet. Neurological examination was normal. Nerve conduction studies suggested an early axonal sensory peripheral neuropathy. Vitamin B12, folate, vitamin A-tocopherol, red blood cell transaminase and transketolase studies, vasculitic screen, glycated haemoglobin, syphilis serology and thyroid function tests were normal. Paraprotein was not detected in serum electrophoresis. Magnetic resonance imaging (MRI) of the brain showed non-specific patchy periventricular areas of high signal not suggestive of the suspected lymphoma. Her systemic symptoms of fever, sweats and weight loss responded to two further doses of cyclophosphamide (1 g/m2), despite worsening neurological symptoms. After 3 months, the patient relapsed with recurrence of pyrexia, and the serum LDH level progressively rose to 838 U/L. Neuropathy progressed to the point where she could not walk. Reflexes were lost, with a glove-and-stocking pattern of sensorimotor disturbance. A repeated nerve conduction study confirmed severe axonal sensorimotor peripheral neuropathy affecting both upper and lower limbs. Cerebrospinal fluid was normal, and there were no malignant cells. Repeated investigations, including brain MRI and upper gastrointestinal endoscopy, did not reveal any further evidence of malignancy. A right sural nerve biopsy showed severe loss of myelinated nerve fibres, and many of the surviving fibres showed varying stages of axonal degeneration (Box 1) associated with a sparse, patchy endoneurial mononuclear cell infiltrate in some fascicles and prominent endoneurial fibrosis on trichrome stain. The CD45RB immunostain showed increased numbers of immunopositive endoneurial lymphoid cells that showed immunopositivity with the T-cell markers CD3 (Box 2) and CD5. The CD68 immunostain showed increased endoneurial macrophages, and ultrastructural assessment confirmed macrophage phagocytosis of degenerate myelinated fibres. CD20 immunostain was negative. The Congo red stain for amyloid was negative. A TCRγ clonality study of the nerve biopsy showed a monoclonal band identical to the previous band detected in the duodenal biopsies, confirming infiltration of the nerve by T-cell lymphoma (Box 3). Subsequent treatment with cyclophosphamide, doxorubicin and dexamethasone was complicated by Enterococcus faecalis septicaemia and florid disseminated intravascular coagulation, leading to the patient’s death. Coeliac disease is associated with an increased risk of malignancy.1 Most of these tumours are T-cell lymphomas, in contrast to the common sporadic B-cell lymphomas that usually occur in the gastrointestinal tract. Enteropathy-associated T-cell lymphoma (EATL) often presents as refractory sprue. The risk of EATL usually decreases to a low level after adhering to a gluten-free diet for 5 years. Common symptoms of presentation include diarrhoea, abdominal pain and weight loss. Patients may also present with acute bleeding, perforation or obstruction.2 Our patient presented with weight loss, pyrexia and, subsequently, neuropathy. Clinical deterioration despite compliance with a gluten-free diet should raise suspicion of EATL. Conversely, as coeliac disease may be undiagnosed at the time of presentation of the intestinal lymphoma, patients with T-cell lymphoma or a gut primary localisation should be tested for coeliac disease. Endoscopy with biopsy is usually the test of choice. Laparotomy is performed in some instances, especially when patients present with an acute abdomen. Our case illustrates a number of interesting features. First, a definitive diagnosis of EATL may be elusive, and persistence in obtaining histological confirmation is warranted. The elevated serum lactate dehydrogenase (LDH) level raised the possibility of an underlying malignancy. Second, in patients with refractory sprue, a clonal TCRγ rearrangement often precedes the onset of overt T-cell lymphoma, which constitutes an early or cryptic form of EATL.3-5 The difficulty is distinguishing antigen-dependent T cells from neoplastic T cells. Management decisions may have to be based on DNA clonality studies alone. Finally, although central nervous system involvement has been reported,6,7 to our knowledge this is the first reported case of peripheral nerve involvement in EATL. Clinical evidence of peripheral neuropathy is observed in 0.1% to 8% of patients with malignant lymphomas,8 and neurotoxic chemotherapeutic agents are frequently presumed to be the cause. Peripheral nerve involvement in T-cell lymphomas is very uncommon.8-10 It is also interesting that the infiltrative neuropathy progressed relentlessly despite an initial good response of systemic symptoms to cyclophosphamide. Both refractory sprue and EATL carry a very poor prognosis, with a 5-year survival rate of 11%. This is related to the unresponsive malabsorption in cryptic EATL, which is often diagnosed late. Associated malabsorption and malnutrition make tolerance of chemotherapy difficult, and treatment-related complications such as gastrointestinal bleeding and perforation also worsen prognosis.2 Favourable outcomes with multi-drug therapy generally occur in patients who have minimal gastrointestinal symptoms before the diagnosis of lymphoma and can tolerate therapy. Chemotherapy should be considered for all patients and should constitute drugs active in intermediate- and high-grade lymphoma. A variety of regimens, including CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone), have been used. The optimal cytotoxic regimen is unclear, as data are limited to uncontrolled retrospective case series. The role of salvage treatments and high-dose chemotherapy at relapse also remains to be investigated.2 Earlier diagnosis and development of more effective treatments are required to improve the outcome for these patients. Lessons from practice Coeliac disease is associated with an increased risk of malignancy, especially intestinal lymphoma or enteropathy-associated T-cell lymphoma (EATL). EATL often presents as refractory sprue, but definitive diagnosis may be difficult and requires T-cell clonality studies. Earlier diagnosis and development of more effective treatments are warranted to improve the poor outcome in these patients. 1 Nerve fibres in varying stages of axonal degeneration Longitudinal section. Transverse section. 2 Positive CD3 immunostaining of lymphocytes 3 Polyacrylamide gel electrophoresis of T-cell receptors Lane 1, positive control; lane 2, negative control; lane 3, normal (polyclonal) control; lanes 4 and 5, duodenal biopsy, 12 Apr 2002; lanes 6 and 7, duodenal biopsy, 19 Jul 2002; lanes 8 and 9, nerve tissue, 9 Oct 2002.

Yoon-Sim Yap MBBS · Adrian Cummins FRACP, MD, PhD · Jennifer Hardingham BSc, PhD · Sunil Dabadghao MD, MBBS · John Norman MBBS, FRACP · Peter Blumbergs MBBS, FRACP, FRCPA

Objective: To investigate whether Indigenous Australians with cancer have more advanced disease at diagnosis than other Australians, and whether late diagnosis explains lower Indigenous cancer survival rates.Design: Retrospective cohort study.Setting and participants: Indigenous and non-Indigenous people diagnosed with cancers of the colon and rectum, lung, breast or cervix and non-Hodgkin lymphoma in the Northern Territory of Australia in 1991–2000.Main outcome measures: SEER summary stage of cancer at diagnosis (local, regional or distant spread), cause-specific cancer survival rates and relative risk of cancer death.Results: Diagnosis with advanced disease (regional or distant spread) was more common for Indigenous people (70%; 95% CI, 62%–78%) than for non-Indigenous people (51%; 95% CI, 53%–59%) with cancers of the colon and rectum, breast, cervix and non-Hodgkin lymphoma, but for lung cancer the opposite was found (Indigenous, 56% [95% CI, 46%–65%] v non-Indigenous, 69% [95% CI, 64%–75%]). Stage-adjusted survival rates were lower for Indigenous people for each cancer site. With few exceptions, the relative risk of cancer death was higher for Indigenous people for each category of stage at diagnosis for each cancer site.Conclusions: Health services apparently could, and should, be performing better for Indigenous people with cancer in the Northern Territory, and probably elsewhere in Australia. This study has demonstrated that data from cancer registers, enhanced with data on stage at diagnosis, can be used to monitor health service performance for Indigenous Australians in the Northern Territory; similar data is available in other States, and could be used to monitor health service performance for Indigenous people throughout Australia.

John R Condon MPH, FAFPHM · Tony Barnes MSc · Bruce K Armstrong DPhil · Sid Selva-Nayagam FRACP · J Mark Elwood MD

Objective: To assess differences in trends for prostate cancer mortality, radical prostatectomy and prostate-specific antigen (PSA) testing for Australian men aged 50–79 years living in capital cities compared with regional and rural areas.Design: Descriptive, population-based study based on data from official sources from 1985 to the 2002/03 financial year (depending on data availability).Main outcome measures: Age-standardised rates per 100 000 men aged 50–79 years of mortality from prostate cancer, incidence of prostate cancer, PSA tests and radical prostatectomy.Results: We found a statistically significant and increasing (age-standardised) mortality excess for prostate cancer in regional and rural areas. In 2000–2002 the excess (compared with capital cities) was 21% (95% CI, 14%–29%). Rates of radical prostatectomy in rural and regional Australia were 29% lower (95% CI, 23% lower to 35% lower) than in capital cities. Although PSA testing is common across the whole of Australia, age-standardised rates in 2002/03 were 16% lower (95% CI, 15% lower to 17% lower) in regional and rural areas than in capital cities.Conclusions: Our results show that the probability of a man having a PSA test and the management of his prostate cancer depend on where he lives. The cause or causes of the prostate cancer mortality excess in regional/rural areas cannot be established in a descriptive study, but fewer radical prostatectomies in regional and rural areas, perhaps associated with less PSA screening, remain among the several competing hypotheses. Other possibilities are related to other differences in management, perhaps associated with access to urologists. Governments and other budget holders need good evidence about the effectiveness of prostate cancer screening and early treatment, but also about the best strategies for providing equitable access to cancer services in both urban and rural areas.

Michael D Coory MB BS, PhD, FAFPHM · Peter D Baade BSc, MMedSc, PhD

We describe a patient with myasthenia gravis and thymoma who developed recurrent severe myasthenic crises associated with the use of combination chemotherapy. Myasthenia gravis (MG) is an uncommon immunological disorder of the neuromuscular junction that is characterised by abnormal weakness and fatigability of some or all striated voluntary muscles. It is the most common autoimmune disorder in patients with thymoma, in whom the incidence is 30%–50%. 1 In patients with MG, up to 90% of their acetylcholine receptors may be destroyed by autoantibodies, predisposing them to disease exacerbation by any agent that impedes neuromuscular transmission.2 Clinical recordIn February, a 49-year-old self-employed builder developed MG and was subsequently found to have invasive thymoma. This was incompletely excised. The surgical procedure was complicated by left phrenic nerve palsy. In May, the patient commenced his first cycle of chemotherapy, which was to comprise doxorubicin 50 mg/m2 Day 1, cisplatin 100 mg/m2 Day 1 and etoposide 120 mg/m2 Days 1, 3 and 5, with dexamethasone 20 mg, ondansetron 8 mg and metoclopramide 10 mg administered before chemotherapy to control nausea. His MG had been well controlled on pyridostigmine 60 mg twice daily. However, within 24 hours of the first dose of chemotherapy, he developed a severe myasthenic crisis with respiratory failure requiring intubation. This was managed with dexamethasone 8 mg daily and plasmapheresis, and was thought to be due to the high-dose dexamethasone given prior to chemotherapy. In addition, he had developed a chest infection a couple of days before starting chemotherapy, which may have contributed to the respiratory failure. A methicillin-sensitive Staphyloccus aureus was isolated from sputum cultures. This was managed upon hospitalisation with intravenous ceftriaxone 1 g daily for 7 days. In June, the patient received his second cycle of chemotherapy, this time without dexamethasone. Within several hours, he developed increasing breathlessness with bulbar dysfunction and generalised weakness. Despite treatment with steroids and intravenous neostigmine, his respiratory state continued to deteriorate, necessitating intubation and subsequent plasmapheresis. No further cycles of chemotherapy were administered. A restaging computed tomography scan at the time revealed minimal residual tumour and mediastinal lymphadenopathy. In August, he completed a course of mediastinal radiotherapy that was complicated by mild radiation pneumonitis. DiscussionA review of the literature revealed no previous report of MG unmasked or aggravated by chemotherapeutic agents. However, several other classes of drugs have been associated with exacerbation of pre-existing MG. Aminoglycosides have been most frequently associated with drug-induced neuromuscular blockade. However, agents most likely to cause aggravation of MG when overused are anticholinesterase drugs, high-dose prednisolone, anaesthetic agents and neuromuscular blockers. Immunosuppressive drugs have also been implicated,3 and transient worsening of MG by high-dose corticosteroids is commonly encountered.4 Miller and colleagues5 found a positive correlation between serum methylprednisolone sodium succinate concentrations and deterioration in neuromuscular transmission. No effect on acetylcholine-receptor antibodies was noted. They speculated that the effects of steroids on MG arise from dissociation of nerve excitation and muscle contraction. Our patient developed recurrent severe myasthenic crises despite the omission of steroids in his second cycle of chemotherapy. It is highly likely that at least one of the three chemotherapeutic agents used had a direct inhibitory effect on neuromuscular transmission, aggravating pre-existing MG. The adverse drug reaction was assessed as “probable” based on a score of 5 on the Naranjo Adverse Drug Reaction Probability Scale.6 The exact mechanism for the neuromuscular blockade is uncertain, but may be due to disrupted calcium entry into the presynaptic nerve terminal, inhibiting presynaptic acetylcholine release. Alternatively, it may be due to postsynaptic blockade, the drugs may bind competitively to the acetylcholine, or may interfere with ionic conductance across the muscle membrane.7 A combination of pre- and post-synaptic blockade may also occur.

Christina V T Ng MB BS,FRACP

Establishing a causal link between HPV and certain head and neck cancers would have implications for prognosis, prevention and therapy More than half a million cases of squamous cell carcinoma (SCC) of head and neck mucosa are diagnosed each year, making it the eighth most common malignancy globally.1 The highest incidence has been observed in developed countries like Australia, where there were 853 new cases in 2001, accounting for 3.8% of all cancers in men and 1.9% of all cancers in women.2 Tobacco and alcohol consumption are accepted as the two major risk factors for head and neck cancer,3 and micronutrient deficiencies, genetic factors and poor oral hygiene are also suspected of playing a role.4 Over recent years, both epidemiological and experimental evidence has implicated oncogenic human papillomavirus (HPV) in the development of a subset of head and neck cancers.5-7 This evidence has been strongly supported by a recent large case–control study coordinated by the International Agency for Research on Cancer (IARC).8 The study, involving centres in nine countries (including the Royal Prince Alfred Hospital in Sydney), concluded that HPV plays an aetiological role in many oropharyngeal cancers and possibly in a small group of cancers of the oral cavity. In all studies, the association has been strongest in the tonsil, where HPV DNA positivity rates frequently exceed 50%. HPV type 16, predominant in cervical cancers, is overwhelmingly the most common type.8-10 The critical issue now is to confirm that the association of HPV with these cancers is causal, as is clearly the case with cervical cancer. This may have implications for prognosis, treatment and prevention. Both the mutagens in tobacco smoke and alcohol and the HPV oncogenes E6 and E7 are known to disrupt the two major pathways controlling the cell cycle — those involving the tumour suppressors p53 and pRb (the retinoblastoma protein). Experimental evidence supporting a causal role has come from reports that the HPV genome is found localised to only the primary tumour cells and their metastases, at similar copy numbers to those reported in other HPV-associated malignancies, including those of the cervix.9,10 Demonstration (by reverse transcription/polymerase chain reaction assays) that E6 and E7 are active in the cancer cell has also been of key importance in establishing an aetiological role.7 Integration of HPV DNA into the host chromosome, which frequently heralds malignant conversion in cervical lesions, has also been observed, although there are indications that the proportion of head and neck cancers carrying the virus in non-integrated form in the cell nucleus may be higher than in the cervix.10 Seroreactivity against the viral capsid proteins and oncogenes has also been associated with an increased risk of cancer.8 Molecular analyses of p53 and of cellular proteins in the pRb pathway (including cyclin D1, a positive regulator, and p16, a negative regulator of the cell cycle) have suggested that HPV-positive head and neck cancers are a biologically distinct group. HPV-positive cancers are generally characterised by loss of expression of pRb and cyclin D1 and overexpression of p16 following inactivation of pRb by the viral E7 oncoprotein.6,11 In contrast, HPV-negative tumours consistently show overexpression of pRb and cyclin D1 and loss of p16. Mutations in the p53 gene appear to be much more common in HPV-negative cancers than in HPV-positive cancers. In HPV-positive cancers, p53 inactivation is achieved by interaction with the viral oncoprotein E6. Nonetheless, HPV and p53 mutations appear to coexist in at least a proportion of head and neck cancers. The recent IARC study,8 like other, smaller surveys, shows that HPV-positive head and neck cancers are more common in patients who do not smoke or chew tobacco,8,12 but HPV infection and tobacco consumption together are associated with an increased risk (whether the effect is additive or synergistic is not known). Several studies have reported a clustering of HPV-positive cancers in younger age groups,13 but the association with age remains controversial. HPV has statistical associations with a history of multiple sexual partners, the practice of giving oral sex and a history of genital warts, suggesting sexual transmission, although conclusive data are lacking.8,12 A lower rate of oral exposure to HPV because of cultural or social attitudes relating to sexual practices (notably orogenital contact) may help explain the lack of HPV DNA in a recent small series of tonsillar cancers from Chinese patients.14 What are the practical implications of an aetiological role for HPV in head and neck cancer in the clinical setting? The prognosis for head and neck cancer has not improved appreciably over the past two decades, despite a better understanding of the biology of invasive tumours, advances in surgery and the increased use of combined-modality treatment. Clinical staging is the primary guide to treatment modality, but provides a limited guide to outcome. There have been general expectations that genetic analysis is “the way of the future” in terms of identifying markers for prevention, therapy and prognosis. Attempts to find prognostic cellular markers in head and neck cancers have been disappointing, but including HPV status as a variable in the data analysis may yield more rewarding results. There are real prospects that HPV itself may provide a new generation of prognostic markers. Surveys have consistently linked HPV-positive cancers with a more favourable clinical outcome than HPV-negative cancers. The risk of recurrence or death from the disease associated with HPV status is independent of established prognostic factors, including tumour stage and lymph-node metastasis.6,10,11 The apparently better prognosis for patients with HPV-positive cancers may reflect the inability of the viral E6 protein to fully inactivate p53 and/or the adverse effect of radiation and other toxic agents on the ability of E6 to interfere with p53 and other host proteins, so that the cancers are more susceptible to therapy. Screening of head and neck cancers for HPV 16 and/or raised p16 as a marker of HPV-related transformation (Box) may identify a new group of patients (those with HPV-negative tumours) who would benefit from closer-than-usual follow-up or additional therapy. However, large-scale prospective studies will be needed to establish the cost-effectiveness of this approach. Internationally, HPV DNA testing is gaining acceptance as an adjunct to cytology in cervical cancer screening programs. Early diagnosis is still the best predictor of good outcome in head and neck cancer. The possible public health benefits of cytological screening and/or detection of HPV DNA in cells collected from the oral cavity by dentists or general practitioners await evaluation. Such studies will need to include details of how and when specimens are taken and cost–benefit analyses. Both in Australia and overseas, clinical trials are under way to test HPV vaccines (developed from viral capsids generated in the laboratory) for prevention of cervical cancer. The demonstrated efficacy of an HPV 16 vaccine in preventing persistent infection in the female genital tract15 has raised expectations that such vaccines may eventually reduce the incidence of head and neck cancer. However, the potential of vaccine programs designed for the genital tract to reduce the incidence of HPV infection in the head and neck is still to be evaluated. Specific randomised controlled trials to address the prevention of persistent oral HPV infections may need to be considered. Therapeutic vaccines based on the viral oncogenes E6 and E7 remain at the experimental stage, but may eventually prove a valuable addition to surgical, radiation and chemotherapeutic approaches to managing advanced disease. Upregulation of p16 as a marker of HPV-mediated transformation in tonsillar cancer cells Strong, diffuse staining for p16 is shown in a high proportion of tumour cells (arrow). A close-up view of tumour cells (inset, x 400) shows staining throughout the nucleus and cytoplasm. Glossary Viral oncogenes. DNA sequences in the viral genome that code for a protein capable of setting the cell on a course to malignant transformation. Tumour suppressors. Classes of proteins that protect the cell against malignant transformation (eg, by monitoring the integrity of the cell or by preventing unscheduled cell cycling).

Barbara R Rose PhD, MASM, BSc · Christopher J O’Brien FRACS · Wei Li MMed, MM

Objectives: To determine the response to colorectal cancer (CRC) screening by colonoscopy, through direct invitation or through invitation by general practitioners.Design and setting: Two-way comparison of randomised population sampling versus cluster sampling of a representative general practice population in the Australian Capital Territory, May 2002 to January 2004.Intervention: Invitation to screen, assessment for eligibility, interview, and colonoscopy.Subjects: 881 subjects aged 55–74 years were invited to screen: 520 from the electoral roll (ER) sample and 361 from the general practice (GP) cluster sample.Main outcome measures: Response rate, participation rate, and rate of adenomatous polyps in the screened group.Results: Participation was similar in the ER arm (35.1%; 95% CI, 30.2%–40.3%) and the GP arm (40.1%; 95% CI, 29.2%–51.0%) after correcting for ineligibility, which was higher in the ER arm. Superior eligibility in the GP arm was offset by the labour of manual record review. Response rates after two invitations were similar for the two groups (ER arm: 78.8%; 95% CI, 75.1%–82.1%; GP arm: 81.7%; 95% CI, 73.8%–89.6%). Overall, 53.4% ineligibility arose from having a colonoscopy in the past 10 years (ER arm, 98/178; GP arm, 42/84). Of 231 colonoscopies performed, 229 were complete, with 32% of subjects screened having adenomatous polyps.Conclusions: Colonoscopy-based CRC screening yields similar response and participation rates with either random population sampling or general practice cluster sampling, with population sampling through the electoral roll providing greater ease of recruitment.

Mike Corbett FRACP · Sharon L Chambers RN, GradDipNurs · Bruce Shadbolt PhD · Doug Taupin PhD · Lybus C Hillman MD, FRACP

Peter J Gilbar,* Christine V Carrington† *† Co-Chair, Committee of Specialty Practice in Oncology, The Society of Hospital Pharmacists of Australia, Suite 3, 27-33 Raglan Street, South Melbourne, VIC 3205. peter_gilbarAThealth.qld.gov.au To the Editor: The national media recently highlighted the tragic consequences of the inadvertent spinal administration of the antineoplastic drug vincristine. The 7.30 Report (ABC Television) detailed the case of a young man erroneously administered vincristine intrathecally instead of, as intended, intravenously, resulting in progressive neurotoxicity, paralysis and death.1 Since the first report in 1968 of unintentional intrathecal administration of vincristine,2 many, invariably fatal, cases have been described. These have involved a combination of human and system errors affecting the medical, nursing and pharmacy professions. On behalf of the Society of Hospital Pharmacists of Australia, we recommend the following strategies to reduce the opportunity for error: Only specifically trained and designated oncology staff should prepare, dispense and administer cytotoxic medication. Intrathecal chemotherapy should only be administered during normal working hours, and in an area where no other cytotoxic drugs are given or stored. Medical staff must use a formal checking procedure, involving an oncology-trained nurse, to ensure the right drug is given at the right dose, by the right route, to the right patient. Intrathecal drugs must be packaged separately and clearly labelled both on the syringe and outer container “For intrathecal use”. Specifically designated containers should be used for transportation of intrathecal drugs from the pharmacy and for storage on the ward. Intrathecal doses should be delivered separately and preferably administered after drugs to be given by other routes have been supplied to the ward and administered. Vincristine should be prepared in a small-volume intravenous bag rather than a syringe.3 For adults, prepare vincristine in an intravenous bag in 50 mL of sodium chloride 0.9% and administer it as a short intravenous bolus over 5–10 minutes. Smaller volumes and a slower administration rate are suggested for children. While this method has been criticised as potentially increasing the risk of extravasation injury, this has not been reported as a problem. Vincristine should be clearly labelled both on the intravenous bag and outer container “For intravenous use only — fatal if given by other routes”. Negative labels, such as “Not for intrathecal use”, must never be used. Many hospitals currently use syringes for vincristine and increase the diluent volume in the syringe as a deterrent to intrathecal administration; however, fatalities have occurred after the administration of vincristine supplied in 10 mL4 and 20 mL5 syringes. The safest method of eliminating the potential for spinal instillation of vincristine remains the abolition of the syringe as a means of administration.

Peter J Gilbar · Christine V Carrington

Objectives: To review changes in patterns of care for women with early invasive breast cancer in Western Australia from 1989 to 1999, and compare management with recommendations in the 1995 National Health and Medical Research Council guidelines.Design and setting: Population-based surveys of all cases listed in the Western Australian Cancer Registry and Western Australian Hospital Morbidity Data System.Main outcome measures: Congruence of care with guidelines.Results: Data were available for 1649 women with early invasive breast cancer (categories pT1or pT2; pN0 or pN1; and M0). In 1999, 96% had a preoperative diagnosis by fine-needle aspiration or core biopsy (compared with 66% in 1989), with a synoptic pathology report on 95%. Breast-conserving surgery was used for 66% of women with mammographically detected tumours (v 35% in 1989) and 46% of those with clinically detected tumours (v 28% in 1989), with radiotherapy to the conserved breast in 90% of these cases (83% in 1989). Adjuvant chemotherapy was given to 92% of premenopausal women with node-positive disease and 63% with poor-prognosis node-negative tumours (v 78% and 14%, respectively, in 1989). Among postmenopausal women with receptor-positive tumours, tamoxifen was prescribed for 91% of those with positive nodes (85% in 1989) and 79% of those with negative nodes (30% in 1989). Among postmenopausal women with receptor-negative tumours, chemotherapy was prescribed for 70% with positive nodes (v 33%) and 58% with negative nodes (v none).Conclusions: Patterns of management of women with early invasive breast cancer in Western Australia during the 1990s changed significantly in all respects toward those recommended in the 1995 guidelines.

Suzanne P McEvoy MAppEpid, FAFPHM · Claire Haworth RN · Jennett M Harvey FRCPA · Lin Fritschi PhD, FAFPHM · David M Ingram MS, FRACS · Michael J Byrne BMedSci, FRACP · Joanna Dewar FRACP · David J Joseph FRANZCR · James Trotter MD, FRACP · Chris Harper FRANZCR · Greg F Sterrett FRCPA, FIAC · Konrad Jamrozik DPhil, FAFHM

A 28-year-old woman presented with a 3-month history of wrist and ankle pain, lethargy and weight loss. She had clubbing of the fingers (Box 1) and toes. A bone scan (Box 2) and chest x-ray (Box 3) revealed periostosis in the wrists and pulmonary metastases, respectively. Two years earlier she had been diagnosed with a malignant phyllodes tumour of the left breast (Box 4), which was treated by mastectomy and axillary dissection. Hypertrophic osteoarthropathy (HOA) secondary to pulmonary metastatic phyllodes tumour was diagnosed. HOA is a paraneoplastic syndrome characterised by digital clubbing, polyarthralgia and periostosis.1 The joint pain, resistant to non-opiate and opiate analgesia, responded to intravenous pamidronate. There was no tumour response to chemotherapy with adriamycin and ifosfamide. Phyllodes tumours are fibroepithelial lesions arising from intralobular breast stroma. They account for less than 1% of breast neoplasms. Treatment is by surgical resection. About 20% of patients with phyllodes tumours develop distant metastases, and long-term survival in these women is rare.2 1 Digital clubbing The distal portions of the fingers show characteristic thickening. 2 Wrist views from whole-body bone scan Note the symmetrical increased radioisotope uptake (arrows) in the periosteum of the distal radius and ulna. 3 Chest x-ray Multiple “cannon ball” pulmonary metastases are present (arrows). 4 Histopathological specimen from mastectomy A malignant phyllodes tumour with a sarcomatous stromal component is present (arrows) (haematoxylin – eosin stain, x 12.5)

Fiona J Collinson MB ChB, MRCP · A Michael Bilous MA, MB ChB, FRCPA · Richard F Kefford MB BS, FRACP, PhD

Objective: To examine whether hospital patients with cancer who were identified as Indigenous were as likely to receive surgery for the cancer as non-Indigenous patients.Design, setting and patients: Epidemiological survey of all Western Australian (WA) patients who had a cancer registration in the state-based WA Record Linkage Project that mentioned cancer of the breast (1982–2000) or cancer of the lung or prostate (1982–2001).Main outcome measures: The likelihoods of receiving breast-conserving surgery or mastectomy for breast cancer, lung surgery for lung cancer, or radical or non-radical prostatectomy for prostate cancer were compared between the Indigenous and non-Indigenous populations using adjusted logistic regression analyses.Results: Indigenous people were less likely to receive surgery for their lung cancer (odds ratio [OR], 0.64; 95% CI, 0.41–0.98). Indigenous men were as likely as non-Indigenous men to receive non-radical prostatectomy (OR, 0.69; 95% CI, 0.40–1.17); only one Indigenous man out of 64 received radical prostatectomy. Indigenous women were as likely as non-Indigenous women to undergo breast-conserving surgery (OR, 0.86; 95% CI, 0.60–1.21).Conclusions: These results indicate a different pattern of surgical care for Indigenous patients in relation to lung and prostate, but not breast, cancer. Reasons for these disparities, such as treatment choice and barriers to care, require further investigation.

Sonja E Hall BA, MPH, RN · Caroline E Bulsara BA(Hons), GradDipEdStudies · Max K Bulsara BSc(Hons), MSc · Delia Hendrie BSc, MA · C D'Arcy J Holman MPH, PhD, FAFPHM · Timothy G Leahy FRACGP, MFM · Margaret R Culbong

Objective: To assess changes in people’s knowledge and beliefs about cancer between 1964 and 2001.Design: Questions in a 1964 survey of beliefs about cancer (randomly selected households) were replicated in a 2001 telephone survey (random-digit dialling).Setting: Perth, Western Australia.Participants: 984 and 491 participants aged 20 years or older in the 1964 and 2001 surveys, respectively (response rates, 86.8% and 47.0%).Main outcome measures: Changes in knowledge and beliefs about cancer.Results: Between 1964 and 2001, there were major improvements in knowledge about the causes of cancer, with several myths dispelled. In 1964, the proportion of Perth residents surveyed who believed that cancer is contagious was 20% (95% CI, 18%–22%), compared with 3% (95% CI, 2%–4%) in 2001. Similarly, the proportion who believed cancer is caused by “a knock” was 25% (95% CI, 22%–28%) in 1964, compared with 1% (95% CI, 0–2%) in 2001. Cancer screening participation rates also greatly improved, from 18% (95% CI, 16%–20%) in 1964 to 77% (95% CI, 73%–81%) in 2001. Changes in participants’ sources of knowledge about cancer were also evident, with family members and television increasing markedly as sources of information.Conclusions: Improved education of the public in health matters over the past four decades appears to have had a major and positive impact on knowledge about cancer.

Robert J Donovan BPsych(Hons), PhD · Owen B J Carter BPsych, DPsych · Geoffrey Jalleh BComm, MPH · Sandra C Jones BA, MPH, PhD

Health policy decisions are based on more than evidence Benjamin Franklin’s 18th-century slice of wisdom that “In this world nothing can be said to be certain except death and taxes” still rings true today. But, in these modern times, adding “and rising health costs” would not be inappropriate. The inexorable increase in public spending on healthcare is a political issue for much of the developed world, and Australia is no exception. Our healthcare expenditure rose from 7.5% of GDP in 1989 to 8.5% in 1999, and it shows no sign of abating.1 Indeed, the federal treasurer recently observed that “When we look across the next forty years we find that the largest area of pressure in relation to Government spending is going to be in the health area.”2 So what are we to do? Commenting on a North American view of the United Kingdom’s National Health Service,3 the President of the Royal College of Physicians recently wrote: To contain the costs of growing needs and expectations for health and care services, there is an increasing emphasis on the clinical and cost effectiveness of health care, with evaluation of procedures and technologies, targeting of resources to services and interventions of proven effectiveness . . .4 This endorsement of evaluation of evidence, effectiveness and efficacy is the stuff of which evidence-based medicine (EBM) is made, and must be a godsend for governments, health ministers and their public servants. For, as noted by a UK social scientist, “EBM offers the vision . . . of solving all health care funding problems by eliminating unnecessary and unproven health care.”5 In short, stringent evidence is required if the public purse is to pay for new drugs, medical technology or other interventions. Policing bodies exist to effect this policy. For decisions regarding government funding support in Australia, the Federal Minister for Health seeks the advice of the Pharmaceutical Benefits Advisory Committee (PBAC) for new drugs and the Medical Services Advisory Committee (MSAC) for emerging medical technologies or procedures. How do these committees arrive at their advice? What are their modi operandi and tensions? Answers to these questions have not been readily forthcoming, as these bodies work behind closed doors, the details of their deliberations are confidential, and participants are bound by a code of silence. In this issue of the Journal (page 627), the door of a bureaucratic conclave is opened slightly as Ware and his colleagues examine the government’s deliberations regarding public funding of positron emission tomography (PET) services.6 Much of their information was obtained through freedom of information requests and, despite its inherent limitations, their account was of sufficient interest to the Journal for us to pursue the long road to publication. Each story has two sides and we also sought the views of the Australian Government Department of Health and Ageing (page 633).7 The “exposé” by Ware and colleagues raises issues about the political pressures that come to bear on potential “big ticket” medical technology roll-outs, the processes involved in technology assessment and the values attending this exercise. As certain as death and taxes is that new technology spawned by research and commercial concerns will increase pressure on the already runaway cost of healthcare. PET is one such technology. It is the latest in a stream of imaging modalities, following computed tomography and magnetic resonance imaging. PET capitalises on the differential metabolism of glucose by malignant cells and is of significant clinical utility in cancer diagnosis and staging, and for following the effects of treatment. But it is expensive, and not readily seen as cost-effective if judged exclusively through standard outcomes such as survival or mortality. PET fell victim to the health bureaucracy doctrine that new technology should not be comprehensively funded by the public purse in the absence of high levels of evidence of both clinical and cost effectiveness. Supposedly because of this, and much to the disappointment of Ware and colleagues, the current Commonwealth government funding arrangements for PET limit the number and location of publicly funded PET services8 and the clinical indications for its use.9 Ware’s qualms about MSAC’s deliberations raise questions about the hype of EBM in health policy. Nobody would disagree with the then Health Minister’s ideal that with the establishment of MSAC “the gap between research knowledge and clinical practice will narrow and patients will benefit earlier from the most advanced procedures drawing on the best scientific medical evidence”10 — in short, EBM. But it appears that the rhetoric surrounding EBM has led to a misunderstanding of policymaking. Indeed, the certainty value of EBM in this setting is more fanciful than real, as other considerations are involved.5,11 These include: competing goals other than clinical effectiveness (social, financial and political); beliefs that some of the research is irrelevant to circumstances in which assessments are taking place; lack of consensus in understanding, interpretation and applicability of the research; other types of competing evidence (personal experience, local information, eminent opinions and evidence provided by advocacy groups); a social or political environment that is not conducive to policy change; and scientific information being poorly presented to the policymakers. Ware et al’s critique of MSAC’s deliberations is not unique. Similar concerns have been raised about Britain’s National Institute of Clinical Excellence in its regulatory role for the introduction of new technology, interventions and pharmaceuticals in the NHS.12 Finally, the experience of Ware et al in extracting information through freedom of information provisions raises the issue of transparency and accountability of health-policy formulation. Most Australians would accept that even healthcare resources are finite. Most would expect our governments to make the tough decisions about how public funds are spent, however unpalatable the decisions may be to sections of the community. But the public is not impressed by the secret milieu in which this occurs. It leads to mistrust and suspicion. Professional disquiet can also arise when expert opinions proferred in committees are not reflected in the final outcome. Onora O’Neill, in the 2002 BBC Reith Lectures, counselled that, to confront society’s burgeoning culture of suspicion, “We need genuine rights, genuine accountability, genuine efforts to reduce deception and genuine communication”.13 More transparency in decision-making that affects the public is not unreasonable. Meanwhile, for the foreseeable future, rising healthcare costs will remain one of life’s certainties. Evidence-based medicine alone will not contain this.

Martin B Van Der Weyden MD, FRACP, FRCPA · Ruth M Armstrong BMed

The Commonwealth Government constituted the Medicare Services Advisory Committee (MSAC) to implement its commitment to entrench the principles of evidence-based medicine in Australian clinical practice. With its recent review of positron emission tomography (PETReview), the Commonwealth intervened in an established MSAC process, and sanctioned the stated objective to restrict expenditure on the technology. In our opinion: The evaluation of evidence by PETReview was fundamentally compromised by a failure to meet the terms of reference, poor science, poor process and unique decision-making benchmarks. By accepting the recommendations of PETReview, the Commonwealth is propagating information which is not of the highest quality. The use of inferior-quality information for decision-making by doctors, patients and policy-makers is likely to harm rather than enhance healthcare outcomes.

Robert E Ware MB BS, FCP · Hilton W Francis MB BS, FRACP, FFPMANZCA · Kenneth E Read LLB(Hons)

To the Editor: We read with interest the article by Mitchell et al and the editorial by Cole on comparatively adverse outcomes in adolescents and young adults with cancer.1,2 The improvements in cancer survival, most remarkably demonstrated in children, have failed to similarly benefit older adolescents and young adults, a population with a higher and increasing incidence of cancer.3 Most authors advocate increasing research, networking resources and information, enhancing support for clinical trials and facilitating participation in them. Recently announced funding for a comprehensive cancer-care program for adolescents and young adults at the Peter MacCallum Cancer Institute in Melbourne is a welcome step towards these goals. The specific emotional and psychosocial needs of this age group are also poorly addressed within traditional models of care.4 Patients in this group express strong preference for peer support, opportunities to be cohorted with each other and access to specific support services.4 The short and long term sequelae of cancer, as well as of its treatment, in adolescents and young adults create particular challenges for both healthcare professionals and the broader community. In December 2003, an entire issue of the European Journal of Cancer was dedicated to adolescent oncology — this science, clinical care and the needs of the patient population.5 An important development in the United Kingdom has been the establishment of eight “teenage cancer units” with a comprehensive approach to all aspects of care.6 Preliminary research in Australia and New Zealand by one of our group (J E) highlights gaps in service and support perceived by consumers, concerns yet to be addressed by appropriate policy and funding.7 The paediatric model of care has provided not only excellent survival but also an exemplary family-centred and comprehensive support system. The recent emphasis on the transition process for adolescents with a variety of chronic illnesses has highlighted systemic differences between the paediatric and adult models. Some paediatric oncologists, especially in the United States, have proposed raising the upper age limit for eligibility to childhood cancer units as a solution. A more realistic approach, particularly in Australia, requires establishing specialist facilities operated in partnership between (preferably collocated) adult and paediatric units, with subspecialisation of the multidisciplinary workforce, an age-appropriate environment and peer support from groups like the Australian Organisation for Young People Living with Cancer (CanTeen). This approach is capable of addressing all of the above issues, from better science through to psychosocial expertise appropriately targeted for age. The ideal number and distribution of such centres/partnerships should be guided by the paediatric track record for balancing centralisation and quality with access and family focus.

Les White · Jane Ewing · Anne M Senner · Madeleine King · Belinda Goodenough

To the Editor: It has been claimed that patients are missing out on the most effective current treatments if they are not given an opportunity to enrol in clinical trials. Such statements are misleading and have the potential both to create concern in those without access to trials and to reduce the likelihood of true informed consent for involvement in trials. Trials are, by definition, just that — trials. Treatment in the “innovative” arm(s) may result in worse outcomes. The finding that those involved in trials have a better outcome (eg, 5-year survival) may have numerous explanations. It is unlikely that the innovation is an adequate explanation for the finding — confounding factors such as selection bias, adherence to best current practice, and intensity of monitoring are more likely explanatory factors. Furthermore, it is important to focus on other outcomes of therapeutic endeavour, such as quality of life, and the impact of the illness on other family members. Patients who live some distance away from tertiary referral centres or trial centres may have a greater adverse effect from involvement in a trial than other patients who live close to such centres. Well designed trials are a crucial part of advancing medical therapeutics. However, the recent editorial by Cole1 and the article by Mitchell and colleagues2 in the Journal have been picked up by the news media as demonstrating that only through involvement in clinical trials can patients get best-quality care. It is not surprising that this is the way that the message has been received. The truth is importantly different. It is only through the conduct of clinical trials that best practice can be defined. However, patients anywhere in the country should be able to access current best-practice treatment even if they do not want to be involved in a clinical trial. Encouragement to participate in clinical trials should be based on arguments about the “greater good” and not about issues of quality of care. To use the latter as the basis for argument must be seen as coercion and as unethical.

Alex N Thomson

In reply: Thomson is correct in stating that patients involved in clinical trials have better 5-year survival rates when compared with patients not recruited into clinical trials. There may, as Thomson points out, be numerous possible explanations for this finding. Nonetheless, this improvement in survival is well documented and has been recognised for some time.1 Although it is becoming increasingly important to focus on other therapeutic outcomes, such as quality of life, it is incorrect to assume that involvement in clinical cancer trials equates to impairment of quality of life and an increase in adverse effects. In fact, the primary end-point of numerous clinical cancer trials is improved quality of life.2 We agree with Thomson when he states that patients anywhere in the country should be able to access current best-practice treatment. We agree that best-practice treatment can only be defined through the conduct of clinical trials. Hence, well designed clinical trials are necessary, and indeed crucial, to the advancement of cancer therapy. In the context of adolescents and young adults with cancer, the lower than expected improvement in survival may be explained, in part, by a low rate of participation in clinical trials.3 There is no doubt that participation in late-phase clinical trials provides a “benchmark” and ensures the provision of quality medical care. Rural and regional settings should not, a priori, be a barrier to trial participation. Adequate infrastructure and support should be available for such centres to participate. Greater cooperation between all adult and paediatric clinicians involved in the care of adolescents and young adults with cancer is essential to ensure that the inequity in survival is corrected.

Anne E Mitchell · Deborah L Scarcella · Gemma L Rigutto · David M Ashley · Vicky J Thursfield · Graham G Giles · Maree Sexton

Although the risk from medical radiation is small, we should not become complacent Ionising radiation is one of the most extensively researched agents in our society. Indeed, more is known about its effects than the effects of most other things in our environment. High doses are known to be harmful, with the main long-term adverse effect being cancer induction. The best evidence for this comes from survivors of the atomic bomb explosions in Japan, where models have been developed relating increased cancer induction to the dose of radiation received. Although the magnitude of the effect is small, the link is well established. When people are exposed to radiation, its use must be justified by ensuring that it does more good than harm. Diagnostic x-rays are the largest man-made source of exposure of the general population to radiation. Even if the risk from radiation to an individual is very small, exposure of a large number of people over time could translate into a considerable number of cancer cases. A recent report in The Lancet attempts to quantify the risk of cancer induction from diagnostic x-ray procedures, averaged over the population.1 From surveys of medical radiation use in a number of countries, the authors obtained information on the average annual frequency of various x-ray procedures and estimated the doses to various organs from those procedures. They then applied a model of radiation-induced cancer cumulative risk to the doses received by the various organs to derive an estimate of the attributable risk of developing cancer. Their analysis suggests that in Australia about 431 cancers per year (1.3% of all cancers) could be attributable to diagnostic x-rays. The corresponding percentages for 14 other countries considered ranged from 0.6% in the United Kingdom and Poland to 3.2% in Japan. Their study does not provide any new evidence that radiation from diagnostic medical procedures causes cancer. Rather, the researchers rigorously applied an existing model to medical diagnostic radiation exposure of the population to derive the best estimate to date of the magnitude of the risk of cancer induction. They acknowledge that there is considerable uncertainty attached to this estimate and that a number of assumptions had to be made in performing the analysis. There is uncertainty about the number and types of radiological procedures, the derivation from these data of doses to individual organs, and the applicability of the cancer induction model at the low doses used in diagnostic radiology. Nevertheless, it is probable that medical radiation procedures do lead to a small increase in cancer incidence in the population. The lowest dose of x-radiation for which there is epidemiological evidence of increased cancer risk is 10–50 mSv for an acute whole-body exposure.2 Some of the higher-dose diagnostic radiological procedures such as computed tomography (CT) produce effective doses at the lower end of this range.3 At lower radiation dose levels, in the absence of epidemiological evidence, there is some uncertainty as to whether there is any effect. However, a linear relationship between risk and dose with no threshold is commonly accepted and is supported by some laboratory data.2 Radiation protection agencies have adopted this linear-no-threshold hypothesis in their approach to risk management.4 The total population dose of radiation from medical diagnostic procedures is increasing worldwide, mainly due to the increase in CT scanning. CT entails the use of higher radiation doses than other common radiological procedures.3 In Australia, Medicare data indicate that CT use has increased 140% over the decade 1992–2002. The reason for the increased use of CT is that it is now able to provide much better and more valuable clinical information, and to do so more easily, than in the past. As the technology has improved, the image quality has improved and scanning times have been reduced to just a few seconds. CT can now image fine detail, even in mobile organs, and hence the indications for its use have expanded. It is easy to overlook the possible side effects of radiation, particularly if the risk is very low and the effect may not become apparent for years. Cancer may not develop until 20 to 30 years after radiation exposure, and so the group most at risk are people with a long life expectancy. Children are also more susceptible to the carcinogenic effects of radiation than adults. When people are exposed to radiation, its use must be justified by ensuring that it does more good than harm. If radiological investigations are done for a specific clinical problem, the potential benefit significantly outweighs the very small risk. However, if there is no valid clinical reason for a procedure, the risk is still present for no tangible benefit. One area in which risk is considered to outweigh benefit is whole-body CT screening of healthy asymptomatic people. The Royal Australian and New Zealand College of Radiologists has produced imaging guidelines on the appropriate use of diagnostic radiological procedures.5 The Australian Radiation Protection and Nuclear Safety Agency is in the process of drafting guidelines on radiation safety in medicine.6 Modern radiological equipment has the potential to reduce the radiation dose compared with older equipment. Radiologists also need to optimise their procedures to obtain the required diagnostic information using the lowest radiation dose.7 The Lancet article serves as a reminder that the potential dangers of radiation need to be respected.

Graeme J Dickie FRANZCR, FRACP, MBA · Robert S Fitchew MSc, MACPSEM, MAIP