Cancer

In reply: We feel that Hayes and colleagues repeat the editorial comments of Dixon1 that accompanied our article.2 Our investigation, being retrospective, had biases and limitations normally associated with that type of study. In the third and fourth paragraphs of the discussion section of our article, we examined further the sources of bias and their impact. Hayes and colleagues state that the omission of tumour grade and receptor status from our analysis is a flaw. We agree that including these variables would have made our study more complete, even if we doubt that this would have altered the conclusions. So many of these data were missing that statistical analysis would have been unreliable. As was stated in the methods section, the analysis was adjusted for the covariate HRT use before diagnosis. Tamoxifen use was very similar among HRT users and non-users (58% and 60%, respectively), and any bias introduced by this difference would be insignificant. The scope of our article, as suggested by its title, was limited to the issue of cancer recurrence and mortality. We did not specifically investigate the impact of HRT on cardiovascular and thromboembolic events. Nonetheless, if car-diovascular disease had increased mortality, this would have been apparent as an increase in all-cause mortality. We agree with Hayes and colleagues that it is vital that the media interpret studies correctly for the general public. We are disappointed that Hayes and colleagues have misinterpreted our conclusion. Our article does not advocate HRT use by women with breast cancer. We explicitly stated that "These results need to be confirmed in a randomised trial before HRT can be advocated for all women who have had breast cancer." Furthermore, ". . . the observed association between HRT use and [reduced] risks of breast cancer recurrence and death cannot be inferred to be causal". We believe that we are justified in our conclusion that HRT use in women diagnosed with breast cancer is not associated with an increased risk of recurrence of breast cancer or a shortened life span. It is our clinical practice to use HRT only when alternative therapy fails.

Eva M Durna · Barry G Wren · Gillian Z Heller · Leo R Leader · Peter Sjoblom · John A Eden

To the Editor: McBride reports that there were four deaths from cancer before the age of 40 years in a group of 480 thalidomide-affected people in the United Kingdom, an approximate cumulative mortality rate of 0.83%.1 He compares this with the annual death rate in the under-40-years age group, and concludes that the rate is increased almost 100 times in those affected by thalidomide. The correct comparison is with the cumulative mortality rate in the general population from birth to age 40. From 1999 UK statistics,2 this is about 0.31% — that is, we would expect 1.48 deaths among 480 people. While the observed number of four is greater than this, it is only slightly greater, and the difference is not statistically significant (the mortality ratio is 2.7, with exact 95% confidence limits of 0.7 to 6.9, based on a Poisson distribution). McBride's conclusion is based on an inappropriate comparison. A full analysis would use population death rates over the 40-year period and take account of censoring, but that is unlikely to affect the result substantially.

J Mark Elwood

A 71-year-old man with a past history of right-sided, renal cell carcinoma presented with a recurrent, right upper eyelid lesion (Box, Figure A). The initial biopsy showed Bowen's disease, but review after Mohs micrographic surgery revealed focal sebaceous differentiation suggestive of in-situ sebaceous carcinoma. A diagnosis of Muir–Torre syndrome was suspected, and the patient was referred for genetic counselling and targeted cancer surveillance. This led to the discovery of multiple dysplastic colonic adenomas and a left renal cell carcinoma (Box, Figure B). Muir–Torre syndrome is an autosomal-dominant genodermatosis characterised by cutaneous sebaceous neoplasia and one or more visceral malignancies. Diagnostic criteria include at least one sebaceous gland adenoma, epithelioma, or carcinoma, and at least one internal malignancy. The diagnosis of sebaceous carcinoma can be difficult, particularly in the periocular region, where it often masquerades clinically as blepharoconjunctivitis or recurrent chalazia. Furthermore, sebaceous carcinoma often displays only focal differentiation and, as seen in our patient, may be histologically misdiagnosed as squamous-cell or basal-cell carcinoma. A history of internal malignancy in patients presenting with sebaceous gland carcinoma should raise the possibility of Muir–Torre syndrome. Correct diagnosis in this case enabled early detection of dysplastic colonic polyps and renal cell carcinoma. A: Clinical photograph showing induration and ulceration of the central right upper eyelid margin. B: Computerised tomography scan showing a left renal mass (arrow) confined to the capsule.

Celia S Chen MB BS · Lindy Loweinstein · Shyamala C Huilgol FACD · Dinesh Selva FRANZCO · Craig James FACPA

Re: "Lymphoedema in breast cancer patients", the letter to the editor by Graeme N Brodie in the 3 March issue of the Journal (Med J Aust 2003; 178: 244), in which washing soda, used in a simple dialysis treatment for lymphoedema, was mistakenly called crystalline calcium carbonate. Washing soda is, in fact, sodium carbonate. The web version of the article was corrected on 4 March 2003.

Graeme N Brodie

Objective: To compare the cancer knowledge and skills of interns in 2001 who graduated from graduate medical program (GMP) courses with those from non-GMP courses, and to compare the cancer knowledge and skills of interns in 2001 with those who completed a similar survey in 1990.Design: Questionnaire survey of recently graduated interns in a random sample of Australian and New Zealand hospitals. The questionnaire was designed to allow direct comparison with the 1990 survey, and was guided by the Australian Cancer Society's Ideal Oncology Curriculum for Medical Schools.Results: 443 interns completed the survey (response rate, 62%; 42 were excluded, leaving 401 surveys for analysis: 118 from GMP courses and 283 from non-GMP courses). Interns from GMP courses felt more competent than those from non-GMP courses at discussing death (P = 0.02), breaking bad news (P = 0.04) and advising on smoking cessation (P = 0.02), but less competent at preparing a patient for a hazardous procedure (P = 0.02). More GMP interns would refer a breast cancer patient to a multidisciplinary clinic (83% versus 70%; P = 0.03). Knowledge about cancer risks and prognosis was significantly less in GMP interns, but GMP interns rated their clinical skills, such as taking a Pap smear, higher than non-GMP interns. The GMP and non-GMP groups did not differ in their exposure to cancer patients, but compared with 1990 interns recent graduates had less exposure to patients with cancer.Conclusions: GMP curricula appear to have successfully introduced new course material and new methods of teaching, but have not always succeeded in producing doctors with better knowledge about cancer. Recent graduates have less exposure to cancer patients than those who trained 10 years ago.

Michael B Barton MB BS, FRANZCR · Sharon E Miles BAppSc(HIM) · Martin H Tattersall MD, FRACP · Phyllis N Butow PhD, MClinPsych · Sally Crossing BEc · Konrad Jamrozik DPhil, FAFPHM · Bin Jalaludin PhD, FAFPHM · Christopher H Atkinson MB ChB, FRANZCR

To the Editor: It was estimated in 1989 that cervical screening in Australia was preventing only 46% of squamous malignancies, against a theoretical capacity of 90%.1 This suboptimal achievement after almost 25 years of cervical screening led to a major reorganisation of the program. The 1989 analysis has been repeated, using the most recent year (1998) for which incidence rates have been published (Box). The more recent figures suggest that cervical screening in Australia is now preventing 70% of squamous carcinoma of the cervix. This remarkable improvement can probably be attributed to the improved participation by women in regular screening, improved standards within laboratories, and better follow-up of cytological abnormalities. While there is still scope for improvement, there is clear evidence of a substantially better gain from cervical screening. Continued efforts to increase the participation rate among women aged 60–69 years is appropriate given that the prevented proportion appears to be lower in this age range. Percentage of squamous carcinoma of the cervix prevented, by age group, Australia 1998 Age group Number of women (estimated number with a cervix*) in Australia2 Expected rate (per 100 000 women) of squamous carcinoma without screening† Expected number of squamous carcinomas‡ Estimated number of squamous carcinomas observed in 1998§ Percentage prevented 20–24 665 691 (665 025) 5 33.3 9.6 71.1% 25–29 733 145 (732 412) 15 109.9 34.8 68.3% 30–34 706 925 (687 838) 25 172.0 62.9 63.4% 35–39 748 913 (728 692) 45 327.9 74.7 77.2% 40–44 702 629 (608 477) 45 273.8 76.2 72.2% 45–49 649 539 (562 501) 45 253.1 81.4 67.8% 50–54 570 287 (410 607) 45 184.8 48.1 74.0% 55–59 431 183 (310 452) 45 139.7 40.7 70.9% 60–64 370 123 (251 314) 45 113.1 40.7 64.0% 65–69 348 707 (236 772) 45 106.6 44.4 58.3% Total 5 927 142 (5 194 090) 1714 514 70.0% * Calculated by multiplying the number of women in Australia by the estimated age-specific hysterectomy fractions.3 † Methodology as for the study by the International Agency for Research on Cancer,4 using incidence in Norway at a time when the rates would have been little affected by screening. ‡ Calculated by multiplying the estimated number of women in Australia with a cervix by the expected rate of squamous carcinoma of the cervix in the absence of screening.4 § Calculated by multiplying the number of cases of cervical cancer observed in 1998 by 0.74, which was the proportion of all cervical cancers that were squamous.5

Heather S Mitchell

To the Editor: It has been known for a long time that washing soda (crystalline sodium carbonate) is effective for removing fluid from joint effusions. The crystals are simply wrapped in a tea towel, crushed with a rolling pin and wrapped around the joint overnight. In the morning the sodium carbonate is rock solid and the joint effusion has markedly improved. I was discussing with one my patients her problem of gross upper-limb lymphoedema after surgery and radiotherapy for breast cancer to the axilla. She went home and made an appropriate pack of sodium carbonate, which she wears overnight. She can now use her arm throughout the day. Obviously, the lymph fluid reaccumulates because her lymphatic system is well and truly obstructed. This patient spoke to several other patients in the Day Centre at the Monash Medical Centre, who tried this in addition to other exercises for lymphoedema, and they have found it to be extraordinarily effective. One woman had gross oedema of her hand, which rendered it useless: she simply immersed her hand in a solution of sodium carbonate and thus dialysed the fluid from her hand. Thereafter she could use her hand for 12 hours before significant amounts of fluid reaccumulated. While this is obviously not the perfect solution to lymphoedema in patients with breast cancer, anything that may help them is worth noting. Perhaps a suitable linen device could be made which would cover the whole arm at night. Evidence for the use of this simple dialysis treatment is currently anecdotal. It might be appropriate to design a clinical trial to determine whether this method has potential in treating this extremely troublesome form of lymphoedema.

Graeme N Brodie

In reply: In his letter, Gøtzsche is clearly under the misapprehension that, in using the figure of speech "gives the lie to", I am accusing him of lying. Nothing could be further from the truth. As he quotes, I applied that phrase to his conclusions. In my Australian Oxford Dictionary1 to "give the lie to" can mean — and it is this meaning that I was applying — "serve to show the falsity of a supposition". I was replying to Gough's response2 to my editorial3 on breast screening. He clearly showed that breast screening was unlikely to reduce overall mortality. I agree. I believe, therefore, that Olsen and Gøtzsche are wrong in supposing that analysis on the basis of breast cancer mortality is inappropriate, and that only overall mortality should be considered. Gough argues for this better than I can. Being an editor of the Cochrane Breast Cancer Group does not require me to accept every supposition or conclusion in a Cochrane review. The whole point in publishing a scientific paper — as part of the Cochrane Library or in a peer-reviewed journal — is to open it, after appropriate review, to public scrutiny, scientific comment and even criticism. Their Cochrane review4 has succeeded in achieving all of this.5 Lastly, I reiterate my comments in the editorial3 that mammographic breast screening detects breast cancers that are "smaller, less likely to involve nodes and, if node positive, more likely to involve fewer nodes." In other words, if the TNM (tumour–node–metastasis) system means anything, there is a better prognosis with such breast cancers than with those detected clinically. Perhaps Gøtzsche needs to add a clinical oncology perspective to his undoubted expertise in the finer details of trial methodology analysis.

Alan Rodger

Objectives: To conduct a systematic review of the effects of genetic counselling and testing for familial breast cancer on women's perception of risk and psychological morbidity.Data sources: MEDLINE, PsychLIT and EMBASE were searched for the period 1980–2001.Study selection: Studies were eligible if published in a peer-reviewed journal in English, included women with a family history of breast cancer who underwent genetic counselling or testing and had either a randomised controlled trial or prospective design, with a pre- and at least one post-counselling assessment.Data synthesis: As there was considerable heterogeneity in populations and measures, results were summarised rather than subjected to meta-analysis.Results: Overall, genetic counselling and testing appear to produce psychological benefits and to improve accuracy of risk perception. Carriers of mutations in cancer predisposition genes did not experience significant increases in depression and anxiety after disclosure of their mutation status, while non-carriers experienced significant relief. Women who were tested but declined to learn their results seemed to be at greater risk of a worse psychological outcome.Conclusions: To date, the data on psychological outcomes after genetic counselling and testing are reassuring. However, few studies used a randomised trial design, limiting the strength of the conclusions. Follow-up to date has been short, and we know little about the long-term impact of testing on patient behaviours, perceptions and psychological state.

Phyllis N Butow PhD, MPH, MClinPsych · Elizabeth A Lobb PhD, MAppSci, BAdEd · Alexandra Barratt PhD, MB BS(Hons) · Bettina Meiser PhD, BAppSci · Katherine M Tucker FRACP

To the Editor: Colorectal cancer is, after skin cancer, the most common cancer in Australia, with 11 245 new cases diagnosed in 1997, and over 4600 deaths.1 In clinical trials, screening programs using faecal occult blood testing (FOBT) have been shown to reduce mortality. The Commonwealth Department of Health and Ageing estimates that implementation of effective FOBT screening programs would save around 400 lives per year.1 However, such screening programs have not been widely implemented because of perceived difficulties with patient acceptance, funding, and the complexity of support structures. General practitioners are in the front line of healthcare, and well placed to institute FOBT screening. Thus, we established an opportunistic screening program whereby patients over the age of 50 years attending surgery are asked by reception staff to complete a short questionnaire while in the waiting room. This questionnaire, developed locally to quickly establish whether a patient has symptoms or a family history of bowel cancer, is given to the GP by the patient during the consultation. If the questionnaire indicates colorectal symptoms, appropriate clinical assessment is undertaken. If a family history of colorectal cancer is elicited, the GP further defines the patient's risk by using the established National Health and Medical Research Council guidelines.2 If there are neither symptoms nor a family history, the patient is offered annual FOBT screening. From 17 June to 30 September 2002, 731 patients under the care of 29 GPs completed the questionnaire. Our findings are summarised in the Box. GP-based opportunistic screening can reach significant numbers of people. Moreover, unlike other strategies (eg, distribution of test kits by pharmacies), review by GPs of patients' questionnaires ensures that cases unsuitable for FOBT screening (such as those with previously undeclared symptoms or family history) are appropriately assessed. Data reported so far on patients who completed general practice questionnaires for eliciting family history or symptoms of bowel cancer FOBT = faecal occult blood testing.

Susan J Harnett · SK Cyril Wong · Gavin W Lackey

To the Editor: Optimising the management of cancer patients requires objective decisions about "best treatment" strategies, based on high quality data collected systematically from all treated patients (or at least a representative sample of them). Relating treatment and stage at diagnosis to individual outcome can allow monitoring of whether treatment is consistent with best practice, and can provide a systematic foundation for evidence-based care. Clinical cancer data collection also allows treatment services to be evaluated, as institutions can monitor throughput and endpoints. However, institution-based data collections may not be representative of all cancer patients, and aggregation of data from several institutions is needed to obtain a comprehensive picture. Population-based cancer registries, which operate in all Australian States and Territories, include data on the site and morphology of cancers. Notification of cases to the registries is mandatory for hospitals and pathology providers, and survival of patients is assessed by linkage to mortality data. The registers do not routinely record stage or treatment data. Until recently, there have been no nationally agreed data items or standard data definitions to facilitate the collation of clinical cancer data across institutions. In 1999, the National Cancer Control Initiative (NCCI) commissioned a nationwide consultation process to seek expert advice on developing a core clinical cancer data set. Representatives from the State and Territory population-based cancer registries, the Australian Institute of Health and Welfare and many large cancer treatment centres were consulted.1 A workshop was held in Melbourne in July 2000 to identify key items for inclusion in the data set, and a group was established to work on data definitions. These are now available on the NCCI's website (<http://www.ncci.org.au/projects/data/dat01.htm>). The data set is designed to be compatible with, and expand on, data currently collected by State cancer registries. Definitions are consistent with the New South Wales clinical cancer data set,2 and we acknowledge the input from this source. Items would be collected by treatment centres. Some institutions would need to standardise information already collected for ongoing patient management, while others would need to establish and maintain new collections. The Faculty of Radiation Oncology of the Royal Australian and New Zealand College of Radiologists has recommended incorporation of the NCCI data set into its proposed quality assurance program. Collation of data across institutions requires careful attention to patient identification issues in order to protect privacy and avoid duplication of data from multiple sources. Use of the data set by clinicians and health planners and evaluators at a national level is the ultimate aim. This would require funding and commitment, and attention to issues of privacy, confidentiality, and data ownership. At present, adoption of the data set on a voluntary basis by treatment centres is the best way forward.

Margaret P Staples · J Mark Elwood · Alan S Coates · Lizbeth M Kenny

QuestionShould patients with resectable rectal cancer receive preoperative pelvic radiotherapy? Trial details Design: Multicentre international randomised controlled trial. Setting: 108 hospitals, with a predominance of hospitals in Holland. Patients: 1805 eligible patients with histologically proven adenocarcinoma of the rectum. Patients with fixed tumours were excluded. All patients had either a low anterior resection or an abdominoperineal resection using the standardised surgical approach of total mesorectal excision (TME). Intervention: After stratification for treatment centre and anticipated type of operation, 897 patients were assigned to receive, or not receive, preoperative short course pelvic radiotherapy (25 Gy in five daily fractions). Main outcome measures: Overall survival and local recurrence at 2 years; overall and distant recurrence at 2 years; and postoperative mortality and morbidity (operative blood loss and perineal complications). Overall survival was analysed on an intention-to-treat basis and included all eligible patients. The rate of local recurrence was calculated for patients in whom macroscopically complete resection had been achieved. The rate of distant recurrence was calculated for patients who did not have distant disease at the time of surgery. Main results: Median follow-up in surviving eligible patients without local recurrence was 24.9 months (range, 1.1–56 months). There was no difference in overall survival between the two groups (82.0% radiotherapy and surgery v 81.8% surgery alone; P = 0.84). However, local recurrence was significantly lower in patients who had received radiotherapy compared with those who had not (2.4% v 8.2%; P < 0.001). There was no difference in the rate of distant recurrence (P = 0.87). Median operative blood loss was marginally increased in the combined arm (1000 v 900 mL; P < 0.001), as were perineal complications after abdominoperineal resection (26% v 18%; P = 0.05). Conclusion: A short course of preoperative pelvic radiotherapy reduces pelvic recurrence after total mesorectal excision. Despite this, overall survival was not improved. CommentaryRationale for the trialThe primary treatment for rectal cancer is surgery. The rationale for also irradiating the pelvis is to prevent the suffering associated with local recurrence, even if survival is not improved. Pelvic recurrence after surgery occurs in 20%–50% of patients with poor pathological features, such as transmural spread and nodal involvement.1 Adjuvant treatment may be delivered either before or after surgery and may also include chemotherapy. The risk of serious late bowel complications after postoperative adjuvant treatment is reported to be higher when compared with preoperative treatment.2 It is this finding that has, in part, prompted interest in delivering radiotherapy before surgery. The optimal scheduling for preoperative radiotherapy remains unclear. Radiation oncologists in Europe favour a short preoperative approach (25 Gy in five daily fractions), while those in North America and Australia favour a more protracted preoperative regimen (45–50.4 Gy in 25–28 daily fractions, with infusional chemotherapy) given to a more select subgroup of patients with unfavourable clinical features such as tethering and fixation,3 with the aim of "downstaging" the cancer and enhancing operability. While the approach to pelvic radiotherapy may differ, many surgeons advocate that surgery alone, using a total mesorectal excision (TME) technique, could negate the need for pelvic radiotherapy as a result of relatively low pelvic recurrence rates (< 10%).4 Trial methodsThis was a large and well-constructed multicentre trial with an adequate sample size and an equal balance of important variables, especially disease stage. The random allocation was simple, and the surgery was standardised by training and supervision of surgeons. Pathological findings were independently reviewed. Importantly, the authors detailed all patients deemed ineligible after randomisation with an acceptable figure of 3% in both arms. All protocol violations were listed. A limited subgroup analysis failed to show a differing treatment effect based on TNM stage or tumour location. The results (overall survival and recurrence) are presented at two years, which is appropriate considering the median follow-up time was only 24.9 months and the number of patients reaching three and four years of follow-up limited at the time of analysis. Short-term toxicity data are presented without any significant difference between the two groups, except for perineal complications. In a subsequent report, the authors showed no difference in postoperative mortality (4% v 3.3%; P = 0.49).5 This is an important finding, as previous studies in which a suboptimal radiotherapy technique was used showed an increased mortality rate. New informationThis is one of the largest studies examining the potential benefits of a short course of preoperative pelvic radiotherapy. Unlike a previous Swedish study,6 this trial failed to show any overall survival benefit (at least at two years), despite a significant reduction in local recurrence from 8.2% to 2.4%. This reduction was seen despite standardised TME. The question remains whether the morbidity (acute and late) of radiotherapy justifies the reduction in local recurrence and its associated morbidity (intractable pain, bleeding, discharge). Longer-term toxicity data are not yet available from this trial. Nor are data on the late effect of bowel function and quality of life from the addition of radiotherapy. Despite what many would consider an excellent pelvic control rate with TME alone, the local recurrence rate after surgery only in those diagnosed with tumour–node–metastases (TNM) stage III disease was 15%. Pelvic radiotherapy reduced this to 4.3% (P < 0.001). Those with TNM stage II disease also benefited from radiotherapy, although not as much in absolute terms (5.7% v 1%; P = 0.01). Notably, this study included over 500 patients with TNM stage I disease, so it is not surprising that the local recurrence rate in both arms was less than 1%. Patients with TNM stage I disease are not routinely given adjuvant treatment (see TNM classification of malignant tumours7). Implications for clinical practiceThe optimal approach to adjuvant treatment in rectal cancer remains unclear. The National Health and Medical Research Council (NHMRC) guidelines on the prevention, early detection and management of colorectal cancer currently recommend that any adjuvant treatment should include both chemotherapy and radiotherapy,8 as this combination has been consistently shown to give a survival advantage.9 To date, there are insufficient data to recommend preoperative radiotherapy alone as the standard approach. The NHMRC guidelines recommend combined treatment be given to patients with high-risk rectal cancer (transmural spread and/or nodal involvement). The Trans Tasman Radiation Oncology Group (TROG) is currently comparing long-course preoperative radiotherapy (50.4 Gy in 28 daily fractions) and chemotherapy (infusional fluorouracil) with short-course radiotherapy (25 Gy in five daily fractions), and early surgery in patients with T3 resectable rectal cancer. TROG is also comparing combination preoperative treatment (50.4 Gy and infusional fluorouracil) with surgery plus optional combined adjuvant treatment. The results from this trial will be important in clarifying many unanswered questions. The Dutch Colorectal Cancer Trial raises the not uncommon scenario of a small but potentially clinically meaningful benefit (ie, in this case, decreased pelvic recurrence after total mesorectal excision) from a treatment. But who should benefit? Those at higher risk will obviously benefit the most in absolute terms and perhaps be more willing to accept the toxicity associated with treatment. Ultimately, it is the patient who must decide if the benefits outweigh the inconvenience and potential toxicities of treatment.

Michael J Veness MB BS, MMed(ClinEpi),FRANZCR

To the Editor: Bolin et al,1 in their editorial accompanying articles by Yusoff et al2 and Bampton et al,3 took the opportunity to make their case for endoscopic screening for colorectal cancer. We believe that their editorial is seriously misleading. 1: It is misleading to suggest that the 27 case–control and cohort studies in the meta-analysis by Johns and Houston4 stratified the index case by age at diagnosis. The 2.25 risk quoted by Bolin et al refers to the overall risk of first-degree relatives in families with one affected relative. In those studies in which age was stratified in the meta-analysis, there is a spectrum of risk, with families with onset of bowel cancer at an older age having lifetime relative risks much less than the average. A subanalysis of seven studies with age stratification showed the risk to be 1.82 (95% CI, 1.47–2.25), where the index case was over 59 years at diagnosis. Whether a 1.8-fold risk elevation warrants colonoscopic surveillance could be debated. "First do no harm" is an important axiom in well-patient screening, so one should aim for an order of magnitude of benefit over risk, which in this situation is not secured until the patient being screened is older than the suggested 40 years of age. 2: The recommendation that colonoscopic follow-up of patients with only small, tubular, distal adenomas can be at less frequent intervals is not based on the US National Polyp Study,5 as suggested in the editorial. It is based on the large cohort study of Atkin et al,6 who reported that patients with this finding were actually at below-average risk (relative risk, 0.5) for subsequent colorectal cancer after prolonged follow-up. This occurred despite the inevitable "miss rates". The editorial by Bolin et al handles this issue unconvincingly. The main message of the US National Polyp Study5 was that follow-up (except in exceptional circumstances of numerous polyps, or incomplete removal of malignant polyps) is not needed at 12 months — after 3 years is adequate. The National Health and Medical Research Council guidelines extend this to 4–6 years in the low risk groups, as defined by Atkin et al.6 The Atkin et al data, however, are only Level 3 evidence. 3: Bolin et al1 completely miss the point about pilot programs of screening with faecal occult blood testing (FOBT). There is no intention to confirm evidence of mortality reduction. The pilot studies are neither designed to, nor capable of, doing this. Mortality reduction from FOBT is well established on Level 1 evidence. The pilot studies are in place to answer the very practical questions of how to implement large-scale screening programs in Australia; what logistic and resource issues are involved; how compliance and acceptance will best be secured; and how to approach difficult-to-access populations (perhaps with low health insurance rates as distinct from populations well supplied by colonoscopy services). The central issue in advocating a menu of options to individuals versus more prescriptive screening (based on FOBT) is whether the height of the scientific bar should be at Level 1 evidence or modestly robust Level 3 evidence (flexible sigmoidoscopy) or the less robust Level 3 evidence (colonoscopy), complemented by certain appeals to logic (carefully crafted in the editorial). Medical initiatives based on less than Level 1 evidence have a history of being shown to be wrong, and the concept of colonoscopic surveillance is not immune from this outcome. Where a significant outlay from the public purse is involved, the Federal Government is being appropriately prudent in acting on Level 1 evidence.

Finlay A Macrae · Geoffrey S Hebbard

In reply: Macrae and Hebbard fail to grasp the concept that colorectal cancer is the only potentially preventable cancer in men and one of the two preventable cancers in women. In any discussion about screening options, this fact must be kept clearly in focus. In terms of surveillance of first-degree relatives, we doubt the available evidence is of sufficient quality to be certain whether the absolute risk is 1.82 or 2.25. In either event, we would advocate colonoscopic surveillance. We would, however, agree with Macrae and Hebbard on the importance of safety issues. Elsewhere we have advocated confining the performance of colonoscopies to endoscopists with Conjoint Committee Accreditation, and ensuring that the procedures are undertaken in accredited, suitably equipped facilities.1 We find it difficult to understand why Macrae and Hebbard believe that "the main message of the US National Polyp Study2 was that follow-up . . . is not needed at 12 months". Showing a reduction in expected cancers of 90% seems to us a far more important finding. We would, however, point out that our editorial does not advocate routine colonoscopic follow-up at 12 months. In relation to the pilot faecal occult blood testing (FOBT) studies, we believe that Macrae and Hebbard have missed the point. They advocate delaying colorectal cancer screening for a further five years to await the results of studies which, many believe, will be both outdated and probably inconclusive. Their continued inflexible stand is one that is being rejected by a rapidly increasing number of countries, including the United States, Germany, Italy and the recently formed Global Alliance for the Prevention of Digestive Cancer. Colorectal cancer is the commonest cause of mortality in both non-smoking men and women, with a death from this disease every two hours in Australia. We suggest that introducing screening is far more urgent than Macrae and Hebbard advocate. We re-emphasise the point that individuals should, if they wish, be provided with the opportunity of selecting a screening program from a menu of options chosen after discussion with their primary medical carer.

Terry Bolin · Alistair E Cowen · Melvyn G Korman

Probably in the short term, but results of ongoing trials are needed to determine longer-term safety Oestrogens play an important role in the development of breast cancer. This is most evident in postmenopausal women: circulating levels of endogenous oestradiol are higher in those who develop breast cancer,1 while use of hormone replacement therapy (HRT) increases breast cancer risk.2 Recent results from the Women's Health Initiative randomised trial showed a 26% excess rate of breast cancer development in women who took combined continuous equine oestrogens and medroxyprogesterone acetate for a mean of 5.2 years compared with placebo.3 This finding is consistent with results of earlier epidemiological studies that suggest breast cancer incidence is increased more by combined preparations than by oestrogen alone.2 Further evidence that oestrogen is important in breast cancer development comes from a study of over 9300 postmenopausal women with early breast cancer.4 This found that anastrozole (an aromatase inhibitor that dramatically reduces oestrogen production) significantly reduced the rate of new contralateral breast cancers compared with tamoxifen (hazard ratio, 0.42; 95% CI, 0.22–0.79; P = 0.005).4 Despite the increased incidence of breast cancer in women who use HRT, most studies have shown either no effect on mortality or a decrease.5 The reason appears to be that breast cancers that develop in HRT users are smaller and clinically less advanced, with a lower rate of node positivity, better differentiation and more favourable histological type, than cancers that develop in women not using HRT.2 Menopausal symptoms are reported by two-thirds of postmenopausal women with breast cancer.6 Can HRT be safely used by these women, or does it have the same impact on breast cancer recurrence as it appears to have on breast cancer development? A number of publications have addressed this issue. One systematic review documented 11 studies involving 214 women who took HRT after a diagnosis of breast cancer, and found that the risk of breast cancer recurrence was lower in HRT users (relative risk [RR], 0.64 (95% CI, 0.36–1.15) than in control women who did not use HRT.5 Durna and colleagues report similar findings in this issue of the Journal (page 347).7 They found significantly lower rates of recurrence (RR, 0.62; 95% CI, 0.43–0.87) and death from breast cancer (RR, 0.40; 95% CI, 0.22–0.72) in women who used HRT compared with non-users.7 These are important data and are also consistent with those of a recently published United States case–control study of 174 women who chose to use HRT after breast cancer diagnosis and matched non-users.8 These three studies reported a consistent reduction in recurrence and death from breast cancer in breast-cancer survivors who used HRT to treat menopausal symptoms, but all had potential confounding factors.5,7,8 All studies to date have been observational and are thus subject to a variety of biases. In the Australian study, women who used HRT after treatment of breast cancer had smaller tumours and fewer involved nodes compared with non-users, and were more likely to have used HRT before diagnosis.7 Although the final model adjusted for a number of prognostic factors, these did not include tumour grade, concurrent use of tamoxifen or oestrogen-receptor status. Concurrent tamoxifen is a particular confounding factor, as it was prescribed for almost 60% of women who used HRT, and would have limited the effects of oestrogen on normal and malignant breast epithelium.9 Duration of HRT use after a diagnosis of breast cancer was short in all three studies — a median of only 1.75 years in the Australian study. Surprisingly, in both the Australian7 and American8 studies there appeared to be a lower rate of breast cancer recurrence in patients taking progestogen alone, vaginal oestrogen alone, or a combination of the two. It is difficult to believe that the small amounts of oestrogen absorbed from vaginal preparations could have a positive influence on breast cancer recurrence and survival. This suggests that other characteristics of women who use HRT, whether vaginal or oral, may influence outcome. Socioeconomic status is an independent predictor of breast cancer recurrence and survival: women with more education and higher socioeconomic class have a lower recurrence rate and better survival.10 Hot flushes are more commonly reported by educated women,6 and these women are more likely to take HRT. Thus, socioeconomic factors could conceivably be part of the reason for the better outcome of women with breast cancer who take HRT. What other possible reasons are there to explain why HRT use by women with breast cancer might improve survival? Most of the oestrogens used in HRT preparations are conjugated, a form that does not occur naturally in humans. They are termed "impeded oestrogens", as they interfere with the effect of more powerful, naturally occurring oestrogens, such as oestradiol, and their biological effect on breast cancer cells is unclear. In the pharmacological doses used, they are likely to have direct anti-oestrogenic effects and may also downregulate the oestrogen receptor. The progestogens used in combined HRT preparations may also have anti-oestrogenic effects and are weak aromatase inhibitors. This may be relevant in postmenopausal women, as much of the oestrogen present within their breast cancers is produced locally from androgens by aromatase.11 How should women with breast cancer who develop menopausal symptoms be treated? For vaginal dryness, water-based lubricating gels and vaginal moisturisers significantly improve symptoms. If these measures fail, then locally delivered oestrogens are effective.12 For systemic symptoms, such as hot flushes, evening primrose oil, soya and black cohosh are rarely effective, but low-dose megestrol acetate and the antidepressants venlafaxine and fluoxetine were shown to have benefits in randomised trials in breast-cancer survivors.12,13 More recently, isoflavones from red clover were shown to reduce hot flush symptoms in postmenopausal women,14 although there have been no studies in breast-cancer survivors. When these remedies fail, then HRT can be given in the knowledge that current data do not show any detriment in terms of recurrence or survival. Effective agents for osteoporosis in women with breast cancer include bisphosphonates, tamoxifen, raloxifene, diet and exercise.12 Ongoing randomised trials of HRT in breast-cancer survivors will determine whether longer-term HRT is safe. These trials will evaluate whether the increased incidence of breast cancer and reduced sensitivity of mammography in women using HRT2 are important issues in women with breast cancer. Even if these trials show HRT to be safe, the problem in future will be how to treat menopausal symptoms in women taking one of the new aromatase inhibitors, which are already replacing tamoxifen in postmenopausal women with hormone-responsive breast cancer.4 It makes no sense to give these women oestrogen. Ongoing studies are investigating the role of a variety of agents, including tibolone (a synthetic corticosteroid with oestrogenic, androgenic and progestational activity).

J Michael Dixon

Objective: To determine whether hormone replacement therapy (HRT) after treatment for breast cancer is associated with increased risk of recurrence and mortality.Design: Retrospective observational study.Participants and setting: Postmenopausal women diagnosed with breast cancer and treated by five Sydney doctors between 1964 and 1999.Outcome measures: Times from diagnosis to cancer recurrence or new breast cancer, to death from all causes and to death from primary tumour were compared between women who used HRT for menopausal symptoms after diagnosis and those who did not. Relative risks (RRs) were determined from Cox regression analyses, adjusted for patient and tumour characteristics.Results: 1122 women were followed up for 0–36 years (median, 6.08 years); 154 were lost to follow-up. 286 women used HRT for menopausal symptoms for up to 26 years (median, 1.75 years). Compared with non-users, HRT users had reduced risk of cancer recurrence (adjusted relative risk [RR], 0.62; 95% CI, 0.43–0.87), all-cause mortality (RR, 0.34; 95% CI, 0.19–0.59) and death from primary tumour (RR, 0.40; 95% CI, 0.22–0.72). Continuous combined HRT was associated with a reduced risk of death from primary tumour (RR, 0.32; 95% CI, 0.12–0.88) and all-cause mortality (RR, 0.27; 95% CI, 0.10–0.73).Conclusion: HRT use for menopausal symptoms by women treated for primary invasive breast cancer is not associated with an increased risk of breast cancer recurrence or shortened life expectancy.

Eva M Durna MBioeth · Leo R Leader MD, FRANZCOG · Peter Sjoblom PhD · John A Eden MD, FRANZCOG · Barry G Wren MD, FRANZCOG · Gillian Z Heller PhD

Clinical question"What treatments are available for hot flushes in women receiving tamoxifen?" A 62-year-old woman asked her radiation oncologist this question. She was taking tamoxifen as adjuvant treatment for node-positive breast cancer, but was experiencing persistent and frequent hot flushes. Search questionThe search question was refined to "What treatments can be added to tamoxifen to reduce the frequency or severity of hot flushes? What are the benefits and risks?" The ideal study to answer these questions is a randomised controlled trial that compares various treatments in women taking adjuvant tamoxifen for breast cancer and prospectively assesses changes in flushing. SearchWe used a comprehensive strategy to search electronic databases, including MEDLINE, the Cochrane Library and SUMSearch <http://sumsearch.uthscsa.edu/searchform45.htm>. The search terms "hot flashes" / "hot flushes" and "tamoxifen" were combined to identify the relevant trials. Summary of findingsSeven agents have been tested in randomised, placebo-controlled trials. Appropriate randomisation procedures included stratification for tamoxifen use where applicable. Sample sizes ranged from 85 to 194 women, and the duration of baseline and evaluation periods ranged from 4 to 7 days and 28 to 84 days, respectively. Concurrent tamoxifen was an eligibility requirement in two studies, but otherwise between 59% and 81% of women were taking tamoxifen. Each study used frequency of hot flushes, as well as "activity scores" (which incorporate frequency and severity of flush episodes), to evaluate the medications. These were assessed using daily patient diaries, with a similar format in each study. Megestrol acetate (40 mg/day),1 venlafaxine (37.5–150 mg/day),2 transdermal clonidine (at a dose eqivalent to 0.1 mg/day orally)3 and oral clonidine (0.1 mg/day)4 were all significantly more effective than placebo at reducing the frequency of flushes after four weeks (P < 0.05). They resulted in reductions in the median number of flushes by 73%, 30%–58%, 44%, and 34% from baseline levels, respectively (ie, 4.5–2.7 fewer flushes daily from baselines of 6.1–8.0). The activity scores showed greater percentage reductions. Oral clonidine was also effective at eight weeks, but long-term effectiveness was not examined in any study. The three other agents examined — soy phytoestrogens,5 vitamin E6 and a "herbal remedy" black cohosh (Cimicifuga sp.)7 — were found not to be useful. Hormone replacement therapy is an established treatment for postmenopausal flushing. However, no randomised trials assessing its value in patients receiving tamoxifen for breast cancer were identified. Its safety in women with a history of breast cancer is controversial and it cannot be routinely recommended.8 Adverse reactions greater than those with placebo1-4 were, for megestrol acetate — withdrawal menstrual bleeding (31%); for venlafaxine — dry mouth, anorexia, nausea, and constipation; for oral clonidine — difficulty sleeping (41%); and for transdermal clonidine — itchiness under the patch, drowsiness, dry mouth and constipation. Each side effect may be dose-dependent. Each medication also has a number of recognised contraindications and precautions. OutcomeEach of the medications assessed in randomised trials is a reasonable option for treatment. However, venlafaxine's sole indication on the Pharmaceutical Benefits Scheme is major depression, while transdermal clonidine is not available in Australia. The radiation oncologist discussed the available choices with his patient. She declined venlafaxine on the basis of cost, and both megestrol acetate and clonidine on the basis of potential side effects, but continued to take tamoxifen.

Sean A Bydder MB ChB, FRANZCR · Nigel A Spry MB BS, FRANZCR

The NCCI is supporting many projects for improvement Many countries place great importance on their strategy for cancer control. The precedent was set by former US President Nixon's "war on cancer", declared in 1971, with the goal of reducing cancer incidence by 50% by the year 2000.1 This optimistic aim occasioned an unprecedented expansion of the US National Cancer Institute, its budget reaching $3.5 billion in 2001.2 More recently, the UK National Health Service embarked on a comprehensive reform of cancer services.3 The high profile of cancer in Western countries relates to its associated high morbidity, the high level of public awareness of the disease and the rapidity of research advances. In 1997, Dr Michael Wooldridge, the then Federal Minister for Health and Family Services, contracted the Australian Cancer Society (now the Cancer Council Australia) to establish the National Cancer Control Initiative (NCCI). The formation of the NCCI was based on a conviction that a better return for expenditure on cancer could be obtained, and that the time had come to introduce new evidence-based cancer-control measures.4 Although an array of cancer-control activities was already in place, it was envisaged that the NCCI could make these processes less capricious by applying a national focus, establishing agreed priorities and forming strategic partnerships across government and non-government sectors.5 The NCCI sees cancer control as comprising "all actions that reduce the burden of cancer in the community [including] every aspect of care, from prevention and early diagnosis to curative treatment and palliative care, all underpinned by the best scientific evidence available".6 The NCCI is concerned with assessing both existing programs and potential new developments for their clinical effectiveness, cost–benefit and equity. Its brief extends to managing strategic projects concerned with translating new findings into public health and clinical practice. The NCCI's activities have mainly revolved around cancer care, early diagnosis, and information needs. To provide good-quality clinical care, we need to know what good care is, what care is currently being provided, what gaps exist, and what opportunities there are for improvement. Defining good-quality care requires evidence-based clinical guidelines. The NCCI has been involved in various projects in this area, including production of guidelines on colorectal cancer for specialists, general practitioners and consumers; production of consumer guidelines on prostate cancer; development of guidelines for psychosocial care of patients with cancer; and development of an evidence-based model of optimum utilisation of radiotherapy. The assessment of current care requires management surveys, ideally involving all relevant specialties and representative groups of patients. One of the NCCI's initiatives has been the funding, through a Commonwealth grant, of a national survey of over 2000 patients with colorectal cancer. Improving clinical care requires a range of information-dissemination and learning strategies, with incentives to apply best care. In financial and practical ways, the NCCI is supporting many projects for improvement, including a consultative project, sponsored by the NCCI in collaboration with the Cancer Council Australia and the Clinical Oncological Society of Australia (COSA), to assess the limitations of cancer care provision; development of a national consumers' cancer organisation to increase the scope and effectiveness of consumer involvement; a review, in conjunction with COSA and state and federal governments, of the infrastructure needs for cooperative group clinical trials; initiatives to achieve earlier diagnosis, such as (i) federally funded pilot studies of colorectal cancer screening;7 (ii) assessment of new screening methods for cervical cancer, ovarian cancer, lung cancer and melanoma; and (iii) a project to improve GPs' expertise in managing prostate cancer and using prostate-specific antigen screening. collaboration with State and Territory cancer registries to improve the documentation of cancer and its outcomes, particularly with regard to staging. (The NCCI has developed a core clinical cancer data set for hospitals,8 which includes information on stage of disease and primary treatment, and is designed to be compatible with data collected by population-based cancer registries.); development of ways to assess the frequency of non-melanoma skin cancer, Australia's commonest cancer, using survey methods similar to those used previously,9 but also considering any new methods that become available. In the future, the NCCI will continue to take a leadership role by consensus through an inclusive, consultative approach in dealing with nationally identified priorities. The organisation's core purpose is to be an expert reference body providing timely advice, identifying appropriate initiatives and making specific recommendations to the federal government and other groups regarding the prevention, detection, treatment and palliation of cancer for all Australians.

J Mark Elwood MD DSc FFPHM · Paul D Ireland PhD

A good screening tool seems to offer the best hope, but meanwhile best possible care includes definitive staging and surgery by experienced specialist teams Ovarian cancer is the leading cause of death from gynaecological cancer in Australia, and indeed most Western countries. In the absence of effective primary prevention strategies and screening for early disease, the best possible management of patients with suspected or established ovarian cancer assumes critical importance if inroads are to be made in reducing morbidity and mortality from this disease. In this issue of the Journal (page 11), Grossi et al have reviewed the management of women with ovarian cancer diagnosed in Victoria during the period 1993 to 1995.1 Despite methodological difficulties with research of this type in terms of accurately defining variables such as stage and residual disease, the study is valuable for reflecting what actually happens in everyday clinical life. It shows that more than one in five patients did not undergo a laparotomy, which is required both to make a definitive diagnosis and to adequately stage the disease. Furthermore, a large proportion of patients with this disease are treated by specialists who are not specifically trained in gynaecological oncology, or are treated outside major teaching institutions. This problem is by no means confined to Victoria or indeed Australia. In a recent review of patterns of care of patients with ovarian cancer in the United States, Carney et al found that, of 848 patients with epithelial ovarian cancer, only 333 (39.3%) were seen (not necessarily treated) by a gynaecological oncologist "at some time during their cancer diagnosis and/or treatment".2 The situation in Victoria, as reported by Grossi et al, compares favourably with the US experience. However, both studies clearly demonstrate that significant change is required if women with this kind of gynaecological cancer are to receive the best possible treatment. The Victorian survey suggests that triage of patients to appropriately staffed and equipped gynaecological cancer centres is inadequate. In some measure this may be the result of the relatively low number of patients who had imaging (such as ultrasound) and tumour marker studies (such as carcinoma antigen [CA] 125). These investigations are important in patients who present with a pelvic mass, as, if they suggest a significant risk of malignancy, appropriate referrals can be arranged. This issue is especially important, as Grossi et al have shown that less adequate surgery adversely affects outcomes. Somewhat disturbing is the finding that, even in the hands of trained subspecialist gynaecological oncologists, fewer than half of the patients with apparently early disease had adequate staging performed. For women with early-stage disease the outlook is excellent, and every effort should be made to perform adequate surgery so as to avoid overtreating those whose outcome is not improved by adjuvant chemotherapy and to select those who might benefit from additional therapy. Epithelial ovarian cancers may occur in young women, and in many cases it is possible to both adequately treat the cancer and preserve reproductive function.3 Also revealed by the Victorian survey is the apparent inadequacy of cytoreductive surgery, even when performed by subspecialist gynaecological oncologists. Although residual disease did not appear to be significant in the Victorian survey, other studies have shown that the amount of residual disease at the end of cytoreductive surgery has a major influence on survival,4 and it is accepted that every effort should be made to "debulk" the tumour to the minimum size possible. This can require major resection of bowel or other organs and it can be a formidable undertaking for both the patient and the treating team. Such extensive surgery should only be performed by appropriately trained teams in major centres. Many gynaecological oncology centres both in Australia and overseas report rates of "optimal debulking" of over 70%.5,6 The article by Grossi and colleagues demonstrates that it is a major challenge to ensure that patients with ovarian cancer have timely access to these facilities. What else can be done to improve the outcome for women with ovarian cancer? Ultimately, prevention would be the ideal solution. For women with familial forms of ovarian cancer appropriately timed oophorectomy may offer a high degree of protection. However, for most women, the development of a reliable and acceptable screening method to detect early-stage disease offers the best hope. Currently, there is no acceptable screening method available, but some studies using CA125 and transvaginal ultrasound as screening tools have shown promise.7 A number of large international trials are currently under way to determine if screening will have a significant impact on the mortality of this disease.

Anthony M Proietto BSc(Med), MB BS, FRANZCOG, CGO

Objective: To describe the management of and outcomes in patients with newly diagnosed ovarian cancer during 1993, 1994 and 1995 in Victoria.Design and setting: Retrospective cohort study conducted by surveying doctors involved in managing incident ovarian cancer cases identified from the population-based Victorian Cancer Registry. The survey was conducted in 1997 and the cohort was followed up until the end of 1999 to obtain at least four years of follow-up data on all patients.Patients: All women with invasive epithelial ovarian cancer diagnosed during 1993, 1994 and 1995.Main outcome measures: Reported management in terms of staging, treatment and survival.Results: Management details were obtained for 84.5% (562/665) of eligible patients. Median age at diagnosis was 66 years (range, 22–98 years). Surgery was the primary therapy in 77.2% of women (434/562). Only one in three women had adequate surgery, which was less likely to be performed by general gynaecologists and general surgeons than gynaecological oncologists (21.3% [35/164] v 13.3% [8/60] v 52% [105/202]). After surgery 78.6% of women (341/434) received chemotherapy, usually with platinum-based regimens. The overall five-year relative survival was 46% for women treated surgically; poor survival was related to increasing age, later tumour stage, presence of ascites, residual disease > 2 cm and poorer histological differentiation of the tumour.Conclusions: For optimal care a preoperative carcinoma antigen (CA)-125 assay, chest x-ray and pelvic ultrasound should be performed, and early referral to a multi-disciplinary unit for definitive surgery is advised. Every effort should be made to adequately stage or debulk the tumour. Women with high-risk early-stage and advanced disease should be considered for platinum-based chemotherapy.

Marisa Grossi MB BS, FRACP · Prudence A Francis MB BS, FRACP · Michael A Quinn MB ChB, MGO · Robert M Rome FRCS(Edin), FRANZCOG · Robert S Planner MB BS, FRANZCOG · Vicky J Thursfield BSc, GradDipApplStat · Graham G Giles MSc, PhD

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