Cancer

Evidence-based therapies offer hope of prolonged survival for selected patients with this disease There is now a substantial body of published evidence of the survival benefits conferred by cytoreductive surgery (peritonectomy) and perioperative intraperitoneal chemotherapy comprising hyperthermic intraperitoneal chemotherapy and early postoperative intraperitoneal chemotherapy for the treatment of peritoneal carcinomatosis. The technique of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is described in the Box. Here, we, the clinicians at the St George Hospital Peritoneal Surface Malignancy Program, who have had more than 12 years of experience in this treatment, provide a review of this topic. Peritoneal carcinomatosis refers to the dissemination of tumour onto the surfaces of the peritoneum. If left untreated, it is considered a terminal disease with a mean survival time for affected patients of 6 months.1 Over the past decade, the clinical view of peritoneal carcinomatosis has evolved from it being regarded as a terminal and untreatable condition that is palliated with systemic chemotherapy and bypass surgery, to a locoregional disease that is potentially curable in a defined group of patients after aggressive cytoreductive surgery and perioperative intraperitoneal chemotherapy. Unlike liver resection for colorectal liver metastases, for which there is no randomised clinical trial to justify its use, the current literature provides level I evidence to suggest the routine use of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in suitable patients with colorectal cancer peritoneal carcinomatosis. Two randomised controlled trials and a multi-institutional study of 506 patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy have been conducted. The body of these current results, and results from other non-randomised clinical series, as previously summarised,2 have shown a median survival time ranging from 13 to 29 months, and a 5-year survival rate ranging from 11% to 19%. To date, we have treated 60 patients with colorectal peritoneal carcinomatosis at our unit with a median survival time of 33 months and a 3-year survival rate of 38%.3 Pseudomyxoma peritonei or “jelly-belly” is a clinical syndrome characterised by the production and accumulation of mucinous ascites within the peritoneal cavity after the rupture of a mucinous tumour in the appendix. For patients treated in our unit who had favourable findings on histological examination of the tumour (disseminated peritoneal adenomucinosis), the median survival time for 73 patients was 97 months, with a 5-year survival rate of 70%. In patients with unfavourable histological findings (peritoneal mucinous carcinomatosis), the median survival time for 11 patients was 33 months, with a 3-year survival rate of 30%.4 These outcomes are similar to those published for 863 patients, who had median survival times ranging from 51 to 156 months, and a 5-year survival rate ranging from 52% to 96%.5 Long-term survival results, with a 10-year survival rate of 21%, have also been reported in a series of patients treated with debulking surgery.6 However, this treatment is associated with high rates of recurrence. The incidence of malignant mesothelioma is rising in Australia as a consequence of widespread exposure to asbestos in the 1970s. A third of malignant mesothelioma arises from the peritoneum. A recent systematic review of cytoreductive surgery and perioperative intraperitoneal chemotherapy for malignant peritoneal mesothelioma from seven observational studies reported a median survival time ranging from 34 to 92 months, with a 1-year survival rate of 60%–80% and a 3-year survival rate of 43%–65%.7 In a recent report of 20 consecutive patients from our institution, the overall median survival time was 30 months, with a 3-year survival rate of 46%. In patients who had favourable prognostic features (complete cytoreduction and epithelioid tumour), the median survival time was 87 months, with a 1-year survival rate of 90%.8 The 5-year survival rate of patients with advanced ovarian cancer is less than 25%.9 Intraperitoneal chemotherapy is the standard of care following a Gynecologic Oncology Group (GOG) Phase III trial that compared intravenous chemotherapy with intravenous plus intraperitoneal chemotherapy in Stage III ovarian cancer.10 However, the adoption of this therapy into standard practice has been slow, perhaps because of its poor tolerability.11 A systematic review of 15 studies of 512 patients with primary advanced ovarian cancer and recurrent ovarian cancer reported an overall median survival time of 29–64 months. In patients with an optimal cytoreduction, survival time ranged from 29 to 66 months, with a 3-year survival rate of 35%–63% and a 5-year survival rate of 12%–66%.12 In our unit, we have only treated patients with recurrent ovarian cancer who are not responsive to conventional treatment options. In 12 patients with recurrent ovarian cancer and peritoneal carcinomatosis whom we have treated with cytoreductive surgery and early postoperative intraperitoneal chemotherapy, the median survival was 36 months, with a 3-year survival rate of 39%. St George Hospital in Sydney is the only high-volume specialist institution offering cytoreductive surgery and hyperthermic intraperitoneal chemotherapy treatment in Australia. Despite the limited number of randomised trials of these therapies, there is strong evidence from Phase II studies of the survival benefits. The unit’s mortality rate has been 3% in the last 210 patients and we have demonstrated a learning curve effect.13 Our treatments are in accordance with the consensus statements from the Peritoneal Surface Oncology Group International.14-16 We emphasise that, in carefully selected patients, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is able to offer the hope of prolonged survival for cancer patients who are diagnosed with what many still regard as a terminal disease. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) Cytoreductive surgery and HIPEC combines surgery and intraoperative chemotherapy. This combined therapy is an aggressive approach to treating patients with diffuse and widespread intra-abdominal cancers localised to the peritoneal cavity, and is performed with the aims of cure and life prolongation. The surgery involves stripping the diseased peritoneum and performing multiple visceral organ resections to achieve maximal cytoreduction, leaving a minimal residual tumour volume within the abdomen. Following surgery, but intraoperatively, a heated chemotherapy perfusate is administered into the abdomen to cover all raw peritoneal surfaces. Intraperitoneal chemotherapy allows a high local concentration of a cytotoxic drug to be achieved for microscopic cytoreduction to target any microscopic residual tumour volume with minimal adverse systemic effects. Hyperthermia has been shown to act synergistically with the chemotherapy, and can thus enhance the cytotoxicity of the drug.

Terence C Chua BScMed(Hons) · Winston Liauw FRACP · David L Morris MD, PhD, FRACS

A woman with metastatic breast cancer developed diarrhoea, vomiting, and hand and foot discomfort within about 10 days of ceasing therapy with capecitabine and starting docetaxel therapy. The palms of both hands and feet were inflamed and tender, with confluent blanching erythematous areas (Figure). Extensive desquamation occurred from Day 12 to Day 19 after admission, with return to normal skin by Day 30. Hand–foot syndrome has been reported after therapy with various antineoplastic agents, most commonly cytarabine, liposomal doxorubicin, capecitabine, 5-fluorouracil, sorafenib and sunitinib. Increased metabolism of capecitabine in the palms may contribute to the local reaction;1 as may the concentration of docetaxel in eccrine glands in the palms and soles.2 Management involves stopping therapy with the implicated drug, analgesia, and preventing superinfection. Palmar surfaces of the hands showing confluent and erythematous lesions, and the plantar surface of one foot showing a blanching erythematous rash.

Chitra Sivaramamoorthy · Eddy S Thientosapol · Martin H Tattersall

To the Editor: We agree with Smith and Gray that the uptake of telemedicine is slow despite the availability of hardware in many facilities.1 Not every field in medicine is amenable to videoconferencing consultations. Specialties in which the physical examination needs to be performed by the specialist, such as cardiology, are not suitable. However, decisions in medical oncology are based on history, pathology and imaging studies, making the specialty well suited to telemedicine. If physical examination is needed, it can be performed by a proxy examiner. Towns with high patient loads are probably not suited, but towns with fewer patients would be ideal for this method. For the past 2 years, Townsville Hospital’s Department of Medical Oncology has managed cancer patients in Mount Isa (800 km — a 2-hour flight or 10-hour drive — from Townsville, one way) using weekly videolinked clinics. The team comprises a medical oncologist in Townsville, and a senior medical officer (SMO), a chemotherapy nurse, patients and families in Mount Isa. Except for the initial period of familiarisation, running the clinics has been smooth. Forty patients have been managed in Mount Isa in over 200 consultations. Consultations have included new cases, ward consultations and reviews. Four patients were considered for palliation only and were managed in Mount Isa without being transferred to Townsville, which was particularly helpful for those at terminal stages. In 2008, we conducted a survey to assess the level of patient satisfaction and assessed the safety of chemotherapy delivery. We found that all 25 patients who participated in the survey were satisfied with the service, with scores of more than 80% on a five-point Likert scale (ie, “agree” or “strongly agree”).2 Ninety-two per cent of patients would rather “see” the specialist via videoconference than travel to Townsville. All three SMOs and both nurses felt they were able to communicate more effectively with and receive support from the specialists. Thirty-two patients received active chemotherapy between 2006 and 2008. Rate of occurrence of severe side effects among patients in Mount Isa was similar to that of patients treated in Townsville (< 5%). Four patients were admitted for complications, but there were no treatment-related deaths. We believe that this technology is safe and appreciated by patients. The technology can be adopted by medical oncologists to manage patients in rural areas, where travel by specialists and patients is not cost- or time-effective. The major advantages are that the patients have the opportunity to be treated closer to home, and doctors receive specialist support on a weekly basis.

Sabe S Sabesan · Pieter Nel · Suresh C Varma

One of the dilemmas in delaying sex-assignment surgery is the increased risk of gonadal malignancy Few areas of medicine are as controversial as the management of disorders of sex development (DSD). The use of the term DSD to describe patients born with ambiguous genitalia has undergone major change from older terms with negative connotations, such as “intersex”, “testicular feminisation” and “hermaphroditism”.1 Meanwhile, international debate continues about the ethics of performing genital surgery on affected infants and children. In fact, the debate has been raging for more than a decade between the medical profession and patient advocacy groups in Western countries, and has been documented by anthropologist Katrina Karkazis in a recent book.2 A long-term outcome study of 50 patients aged 18–32 years who had been treated in Melbourne when they were children showed that mental and physical health outcomes were as good for most of the DSD patients as for those in two control groups; however, there was a small minority of patients whose gender identity as adults was a source of such profound discomfort that they felt compelled to undergo treatment to change it.3 Clearly, this is unsatisfactory, and management practices have been reviewed internationally by clinicians looking for ways of minimising the risk of making such mistakes about gender assignment. The main problem relates to feminising genitoplasty (Box), which involves the removal of phallic erectile tissues and skin that cannot be replaced. This type of operation is considered appropriate for 46,XX girls with congenital adrenal hyperplasia (Box), who rarely identify as male when they are adults if they are treated with appropriate hormones to maintain androgen suppression from soon after birth and throughout childhood.4 However, feminising genitoplasty is much more of a problem in patients with a Y chromosome. For example, in one study of 14 adult patients with genetically confirmed partial androgen insensitivity who were treated at Johns Hopkins University in the United States as children, 25% experienced gender dysphoria (Box) as adults, and a small number wanted to undergo sex change surgery.5 Although policy changes are still being discussed, it seems likely that fewer and fewer XY patients with frankly ambiguous genitalia due to DSD will have feminising genitoplasty and be raised female. The option to assign a gender but postpone surgery until the child is able to give consent has been strongly advocated in some quarters,6 but has not gained much traction because of concerns that children might suffer psychological harm if left with ambiguous genitalia. In 2008, clinicians from Melbourne’s Royal Children’s Hospital, recognised for their expertise in the management of DSD, were required to meet representatives of the Victorian state Justice Department. They were asked to respond to a proposal — advanced by an advisory committee representing the interests of the gay, lesbian, bisexual, transsexual and intersex communities — that doctors wanting to perform surgery to treat ambiguous genitalia in children too young to consent on their own behalf should have to seek approval from the Family Court of Australia on a case-by-case basis. Also in 2008, the Australian Human Rights Commission decided to initiate a public inquiry into the same question, and circulated a draft discussion paper called Genital surgery for babies born intersex to health professionals for comment. Thus, in Australia as elsewhere, the arm wrestle between medical professionals and patient advocacy groups continues. What has largely been missing from the debate is recognition of the fact that surgery forms a necessary part of the risk management strategy for preventing gonadal malignancy. In any DSD associated with a Y chromosome, there is an increased risk of germ cell cancer,7 especially when the testes are intra-abdominal (the risk of seminoma in partial androgen insensitivity is 50% for an intra-abdominal testis) or when there is gonadal dysgenesis. In this issue of the Journal, a salutary case report by Parker and colleagues8 reminds us of the need to be mindful of this risk, and also to take a long-term view of risk. If the intra-abdominal gonad in the patient described had been removed at the initial surgery, he would never have needed to fear this tumour. It had not been removed because, by today’s standards, he had been inadequately investigated in the past, and therefore the intersex condition was not recognised. The trend for surgeons to recommend male-sex rearing for greater numbers of children with DSD could also mean greater reluctance to remove testes that pose a significant risk of cancer on the grounds that physiologically useful hormone secretion might be retained. It is therefore imperative that a risk management strategy be prepared for each patient. This would mandate: educating parents and patients about risk; removing all intra-abdominal gonads that cannot be brought down into the scrotum; regular clinical and ultrasound surveillance of scrotal gonads with removal of any that contain suspicious lumps; biopsy of testes after the onset of puberty, looking for early signs of malignant change; and effective communication between paediatric and adult care-providers at the time of transition. It is also important for all children identified as having DSD to be referred to a centre of excellence where they will be seen by paediatric endocrinologists, surgeons and other health care professionals with expertise in the field and who recognise the importance of a multidisciplinary team approach.9 Case conferences about patients diagnosed as having a DSD in adult life would be enhanced if paediatric specialists in DSD were asked to comment. Of equally great importance is the need for an accurate aetiological diagnosis wherever possible. At the moment, about 40% of patients with 46,XY forms of DSD are left without a precise diagnosis.10 The application of microarray (gene chip) technology,11 which is available in Australia, is an exciting and promising step forward in identifying genetic mutations. In this technique, samples of very large numbers of genes are arranged in a regular pattern on a solid surface or membrane, which is then incubated with DNA from a patient. Alterations in known (and even unknown) genes are rapidly detected by studying patterns of matches and mismatches. The current challenge for researchers is to develop new tools, such as microarray technology, that will lead to gene discovery and to better methods of screening patients for mutations in all the known genes. Glossary of terms relating to disorders of sex development DSD: Disorders of sex development, previously known as intersex. Congenital conditions in which development of the chromosomal, gonadal or anatomical sex is atypical. Feminising genitoplasty: Surgery carried out to give genitalia that were originally ambiguous a more female appearance. Usually involves clitoral reduction (removal of erectile tissue) and surgery to create a vaginal opening separate from the urethra. Congenital adrenal hyperplasia: A genetic disorder caused by a deficiency of the enzyme 21-hydroxylase in the adrenal cortex, and the commonest adrenal disorder of childhood. Cause of virilisation in an affected female fetus. Partial androgen insensitivity: An X-linked genetic disorder causing ambiguous genitalia in 46,XY individuals. Caused by a lack of androgen receptors in androgen target tissues, such as genital skin. Gender dysphoria: Mental distress caused by unhappiness with one’s own sex and the desire to be identified as the opposite sex.

Garry L Warne MB BS, FRACP · Jacqueline K Hewitt MB BS

Disorders of sex development (DSD), previously termed intersex, are uncommon, and are usually, but not always, diagnosed at birth. Issues of gender assignment, psychosexual development and the potential for malignant change in a dysgenetic gonad need to be considered. Here, we report a rare presentation of advanced malignancy in an abdominal gonad associated with the formation of a uterus in an adult male with a previously undiagnosed DSD. Clinical recordA 59-year-old man presented with haematuria and gynaecomastia, and was subsequently found to have a large pelvic mass. Examination of his left breast identified a 3–4 cm mobile mass. Ultrasonography of the breast confirmed a mass, but could not distinguish between glandular tissue and a breast tumour. Computed tomography (CT) of the abdomen and pelvis showed a 10 cm complex pelvic mass that was thought to extend to the seminal vesicles. A core biopsy showed mixed cytological and immunohistochemical features of a possible granulosa cell tumour, but the precise diagnosis was limited by the small amount of material present for examination. A provisional diagnosis of gonadal malignancy in a dysgenetic gonad was considered. A bone scan was negative and a thoracic CT scan showed three 5–7 mm lesions in the lung fields, suggestive of possible metastases. His prostate-specific antigen (PSA) level was very low (0.01 ng/mL), and tests for testicular tumour markers were negative (alpha-fetoprotein, 3 ng/mL; human chorionic gonadotropin, < 5 U/L). Other biochemical tests showed the following levels: serum oestradiol, 372 pmol/L (male reference range [RR], < 160 pmol/L); testosterone, 1.1 nmol/L (RR, 8–38 nmol/L); follicle-stimulating hormone, < 0.1 U/L (male RR, 1.0–9.2 U/L); luteinising hormone, 2.1 U/L (male RR, 2–8 U/L); prolactin, 385 mU/L (RR, 0–500 mU/L). The patient had a history of penoscrotal hypospadias, cryptorchidism and right inguinal hernia that were surgically repaired in infancy. The hypospadias was corrected at 20 months of age. He had a right inguinal hernia repair at 3 years of age and, at that time, was found to have an undescended right testis that was treated by orchidopexy. The patient’s parents were told that the left testis was removed during this procedure. He was married with no children, and we do not know whether the issue of fertility had ever been questioned. He was noted to have minor obstructive urinary symptoms at 47 years of age that were thought to be caused by a urethral stricture secondary to his previous hypospadias repair. He re-presented 8 years later with a bloody urethral discharge that settled after treatment with antibiotics. On rectal examination at age 55, he had a small prostate and his PSA level was low (0.02 ng/mL). At that time, an intravenous pyelogram showed normal kidneys, ureters and bladder. At cystoscopy, he was found to have a mid-urethral stricture from his previous hypospadias repair, with a number of hairs present in the skin at the stricture site. The hairs were thought to be from graft skin used to repair his hypospadias, and this was felt to be the cause of his bleeding. He re-presented with intermittent urethral blood loss 2 years later, at 57 years of age, and repeat cystoscopy again showed a mid-urethral stricture that was treated by dilatation. At 59 years of age, a laparotomy was performed and the patient was found to have a large left adnexal mass (Box 1, A) and a normally formed uterus. The mass was removed and a subtotal hysterectomy performed as there was no distinct lower margin of the cervix (Box 1, B). The patient was informed of the operative findings and the diagnosis of intersex. Peripheral blood karyotyping showed a 46,XY genotype. The histopathology of the gonadal tumour showed a sex cord-stromal tumour of indeterminate differentiation (Box 2). The histopathology of the uterus showed simple endometrial hyperplasia. The patient was treated with postoperative chemotherapy, but died 18 months later. DiscussionDisorders of sex development (DSD) are rare in the general population, and comprise a wide variety of clinical, anatomical and genetic problems. Most patients with DSD are diagnosed at birth, but diagnosis may not be made until childhood, adolescence or, more rarely, in adulthood, as in our case. This case shows how incomplete initial assessment and treatment of a neonate with abnormal genital development, and failure to recognise this rare disorder in adulthood can have tragic, adverse health consequences. An international consensus statement on intersex disorders and their management proposed the term “disorders of sex development” to describe congenital conditions with atypical development of chromosomal, gonadal and anatomical sex.1 It was considered that previous terminology, such as hermaphroditism, was controversial, pejorative to patients and confusing. DSD are a heterogeneous group of conditions, all of which interfere with normal sex differentiation in the embryo and fetus. The incidence of DSD in the population is estimated to be one in 5500.2 Patients with DSD can present at birth with ambiguous genitalia, apparent female or apparent male genitalia. Patients with apparent female genitalia can have an enlarged clitoris, posterior labial fusion or an inguinal / labial mass. Patients with apparent male genitalia can have non-palpable testes, micropenis, isolated perineal hypospadias or hypospadias with undescended testes. Congenital adrenal hyperplasia is the most common cause of ambiguous genitalia in the newborn period.2 The birth of an infant with ambiguous genitalia requires a strategy of clinical, hormonal, genetic, molecular and radiographic investigations to determine the aetiology and to plan a therapeutic approach.3 Clinical and diagnostic evaluation protocols are available.2 Although most DSD are diagnosed in the neonatal period, a wide variety of clinical presentations have been reported in childhood, adolescence and adulthood. Later presentations include previously unrecognised genital ambiguity, inguinal hernia in a girl, delayed or incomplete puberty, primary amenorrhoea, virilisation in a girl, breast development in a boy and gross haematuria in an adolescent male.1,2 A wide variety of clinical presentations have been reported in adults with undiagnosed DSD. These include psychiatric disturbances,4 short stature, infertility,4,5 lower abdominal pain6 or haematuria. Our patient presented with intermittent haematuria that was initially investigated with cystoscopy and an intravenous pyelogram. A computed tomography urogram with intravenous contrast has now replaced intravenous pyelography as the standard investigation of the urinary tract in patients with haematuria. If this investigation had been performed at the time of his earlier presentations, a pelvic mass may have been identified and further investigated. Recent advances in molecular genetics have increased our understanding of both normal and abnormal sex development. The bipotential gonad develops at the urogenital ridge between 5 and 6 weeks’ gestation and a number of genes involved in testis determination are expressed at this stage.7 The first histological evidence of testis formation occurs at 7 weeks’ gestation. Leydig cell synthesis of testosterone mediates the development of the vas deferens, epididymis and seminal vesicles, and conversion of testosterone to its more potent form, dihydrotestosterone, masculinises the external genitalia to form a penis and scrotum. Sertoli cell synthesis of anti-Müllerian hormone prevents the Müllerian ducts from developing into a uterus and fallopian tubes.7,8 The development of internal reproductive organs is controlled by the ipsilateral gonad, and prenatal male sex development is finally completed at term by descent of the testes into the scrotum.7 Our patient appears to have produced enough testosterone from the small right testis to promote penile development, albeit with hypospadias. The left gonadal dysgenesis appears to have resulted in inadequate anti-Müllerian hormone production, allowing a uterus to develop. The risk of malignancy in dysgenetic gonads is significantly increased in some patients with DSD.8 The presence of the SPY gene on the GBY region of the Y chromosome is a prerequisite for malignant transformation.9 Tumours can arise in any of the gonadal cells or their precursors.8 Precursor lesions for the development of cancers occur as carcinoma-in-situ in testicular tissue and gonadoblastoma in undifferentiated gonadal tissue. A number of malignant tumour types may occur in dysgenetic gonads.8,10 These include germ cell tumours and sex cord-stromal tumours. Patients presenting with abdominal tumours in dysgenetic gonads in adulthood provide histopathologists with complex diagnostic dilemmas. Histopathological examination of the tumour in our case showed mixed elements, with cells resembling ovarian follicles, testicular tunica, granulosa cells, Sertoli cells and Leydig cells. No germ cell components were identified. The final consensus was a diagnosis of malignant sex cord-stromal tumour of indeterminate differentiation. It is likely that the oestrogen-secreting gonadal tumour had been present for some years in our patient, resulting in endometrial hyperplasia. The uterus is likely to have been connected to the urethra, with endometrial bleeding causing the apparent haematuria. Persisting elevated levels of oestrogen would also have caused gynaecomastia, which resolved after surgical removal of the tumour. Serum follicle-stimulating hormone was likely to have been suppressed by the elevated level of oestradiol, and a normal level of serum luteinising hormone and low level of testosterone are consistent with the history of incomplete external genital development and infertility. Clinicians managing neonates with cryptorchidism and proximal hypospadias should have a high index of suspicion of an underlying DSD.11 Once a DSD is identified, a series of investigations should be initiated with the aim of making a specific diagnosis.7,12 Physical examination and imaging studies should be performed to attempt to locate inguinal or abdominal gonads so that surgical removal can be considered in patients thought to be at high risk of subsequent malignancy.2,10 The sequence of events in our case highlights the diagnostic difficulties that can occur in patients who present in adulthood with unsuspected gonadal dysgenesis. 1 Macroscopic photographs of the left adnexal mass A: Macroscopic photograph of malignant sex cord-stromal tumourdisplaying widespread necrosis and haemorrhage. B: Macroscopic photograph of bisected uterus with a thickened endometrium. 2 Histopathology of the gonadal tumour Microscopic photograph of gonadal tumour. The better differentiated areas of the tumour showed nests of cells with peripheral palisadingand small Call–Exner body-like structures (arrows), suggesting granulosa cell differentiation. Microscopic photograph of gonadal tumour. Also present were areas showing primitive sex cord-like structures (white arrow), lumened tubules lined by eosinophilic epithelial cells and adjacent clustered Leydig cells (black arrow).

Jim L Parker BMed, DRACOG, FRANZCOG · Deborah L Ekman BAppSc · Lawrence J Hayden FRCS

To the Editor: A 71-year-old man presented with a firm erythematous painful swelling over the sternoclavicular region. He had undergone coronary artery bypass grafting (CABG) 18 months earlier. A chest x-ray showed the presence of sternal wires and mediastinal clips from the surgery, and pleural thickening in the right costophrenic angle. There were no focal abnormalities seen on the x-ray when compared with pre-CABG radiographs. A computed tomography scan of the chest showed a destructive lesion of the manubrium, with an associated soft tissue mass extending into the pectoralis muscle and anterior mediastinum. A sternal suture was noted within the lesion, and a separate surgical clip was identified in the suprasternal notch region (Box, A). Surgical exploration of the sternotomy wound revealed tumour in the muscle around the proximal sternum, with bone destruction. Histopathological examination of the tumour confirmed the presence of an osteosarcoma (Box, B). (A section of normal trabecular bone [Box, C] is shown for comparison.) There have been few reported cases of primary sternal tumours. To our knowledge, primary osteosarcoma arising contiguous to a surgical suture has never been reported. It is unknown why the osteosarcoma originated in the part of the sternum that contained the sternal suture rather than originating de novo in another part of the bony skeleton. Chronic localised sternal inflammation or mechanical irritation of the proximal sternum by the suture may have been contributory factors in triggering carcinogenesis in this uncharacteristic site.1 However, the effect of trauma and mechanical stimulation on development of primary cancers and their metastases has never been proven. Patients who present with bony tumours frequently have a history of previous trauma to the area where the tumour develops. While there have been numerous reports suggesting some relationship between trauma/chronic inflammation and oncogenesis,1-5 there is no evidence that a single incident of trauma can cause cancer. The combination of trauma, in-situ metal and malignancy after CABG is rare, and there are currently no grounds for suspecting a direct relationship between them. A: Computed tomography scan of the chest showing a destructive lesion in the cortex of the manubrium. A sternal suture, surgical clip and soft tissue mass are visible within the tumour (A = anterior, R = right). B: Histopathological section of osteosarcoma of the sternum. Pleomorphic and hyperchromatic cells are present in a disorganised immature bone matrix (osteoid) (haematoxylin and eosin stain; original magnification, × 20). C: Histopathological section showing normal trabecular bone of the sternum (haematoxylin and eosin stain; original magnification, × 2.5).

Laurence Weinberg · Joseph Mathew

Early detection of breast cancer has been shown to reduce breast cancer deaths in randomised controlled trials (RCTs) of mammography in women aged 50–69 years, with weaker evidence of benefit in those aged 40–49 or 70 years and older. Magnetic resonance imaging (MRI) and ultrasonography have been evaluated in breast cancer screening, relative to, or in addition to, mammography, in selected populations; neither test has been examined in an RCT, and thus evidence of associated screening benefit is uncertain. MRI is more sensitive than mammography in screening women with suspected or proven inherited mutations of the breast cancer genes. The addition of MRI in screening this population detects 8–24 additional cancers per 1000 screens, but also significantly increases a woman’s risk of being recalled for investigation or surgical biopsy for false-positive findings. In Australia, Medicare funding for MRI screening of women in specific risk groups was announced in February 2009. Ultrasonography can detect cancers not identified on mammography in asymptomatic women with dense breast tissue. Incremental ultrasound cancer detection is reported in 0.27%–0.46% of women with mammography-negative dense breasts; evidence varies on its association with false-positive findings. Computer-aided detection (CAD) is a complementary tool to mammography, prompting the reader to consider lesions on the mammogram that may represent cancer. Emerging evidence and improved CAD technology are likely to help define its role in breast screening.

Nehmat Houssami MB BS(Hons), FAFPHM, PhD · Sarah J Lord MB BS, MSc(Epi) · Stefano Ciatto MD, PhD

To the Editor: The timely article by Olver and Haines on industry-led versus investigator-led studies in cancer clearly outlines the importance of appropriate trial design.1 However, perhaps one aspect of this critical issue was underemphasised. In cancer trials, overall survival is typically seen as the primary endpoint. In fact, at time of relapse or disease progression, patients are generally treated in a non-uniform manner. In this scenario, treatment is frequently tailored depending on whether the aim of therapy is curative or palliative. Ad-hoc or experimental approaches are used for some patients with relapsed or refractory cancer. Thus, although survival is undoubtedly the most clinically relevant endpoint, the lack of standardisation of treatment at relapse inevitably confounds assessment of the impact of the study drug on survival. Furthermore, for many tumour types, full evaluation of time-to-event outcomes, such as event-free and overall survival, requires prolonged follow-up, resulting in studies taking many years to be completed. For these reasons, biomarkers that accurately serve as early surrogate endpoints to predict for clinical outcome are urgently needed. Yet a striking feature of much industry-led trial design is the paucity of correlative laboratory studies and tissue banking to identify and validate new biomolecular endpoints. Such studies are frequently seen as unnecessary and burdensome. By contrast, although investigator-led laboratory studies of novel biomarkers generate much interest from the clinical and scientific community, their resource and cost implications (chiefly data manager support) prevent many centres from participating. Lucrative company-sponsored trials will always take precedence unless state and/or federal initiatives to support investigator-led studies are enacted. Funding research nurses and data managers to help oncology units conduct non-industry trials that are well designed and incorporate laboratory-based biomolecular research would be an important beginning.

Maher K Gandhi

In reply: We support Gandhi’s contention about the value that can be added to clinical trials by performing correlative laboratory studies. The investigation of biomarkers as potential surrogate endpoints that may indicate efficacy, or lack thereof, earlier than the prolonged time sometimes required to reach a survival endpoint, is one such example. Such studies are often not funded by industry and the importance of funding these, which yield greater clinical benefit, should be recognised by government and non-government agencies. It is possible, but very unlikely, that a survival endpoint may be compromised by the lack of a standardised approach to second-line therapies. We believe that if a new first-line agent is associated with a clinically significant improvement in survival, this will be evident irrespective of subsequent therapies used, which will usually yield inferior results to first-line therapies and will most likely be distributed randomly across the treatment arms. The need for tissue banks as a resource required across trials in all tumours is something that governments could address by funding them as vital clinical research infrastructure. The same applies to data managers for non-industry sponsored trials that are well designed and incorporate laboratory-based research, as Gandhi suggests.

Ian N Olver · Ian E Haines

A 45-year-old man presented with marked, progressive bulging of the right tonsil (Figure, A) and slight swelling of the right submandibular region. Gadolinium-enhanced magnetic resonance imaging of the head and neck showed a large (5 × 4 × 3 cm) neoplasm, occupying the right parapharyngeal space, extending from the deep parotid lobe to the ipsilateral tonsillar region (Figure, B). The neoplasm was removed via an incision in the neck and identified, by histological examination, as a pleomorphic adenoma. In many cases, the first clinical sign of a deep-lobe parotid neoplasm is enlargement of the tonsillar region. Other differential diagnoses of tonsillar swelling include peritonsillar abscess, tonsillar neoplasm and internal carotid aneurysm.

Matteo Alicandri-Ciufelli · Gabriele Molteni · Domenico Villari · Francesco Mattioli · Livio Presutti

How can we ensure colonoscopy services are available to those who need them most? Bowel (colorectal) cancer is the most common cancer affecting both men and women in Australia, with 13 076 cases diagnosed and 4164 deaths reported in 2005.1 It is the second commonest cause of cancer-related death, behind lung cancer. The incidence of bowel cancer increases exponentially after 50 years of age, with a lifetime risk of about one in 17 among men and one in 26 among women.1 Bowel cancer satisfies most of the World Health Organization criteria for population cancer screening.2 Specifically, it is a common, serious cancer, and its natural history is reasonably well understood. It arises from precursor adenomas, and removal of these prevents cancer development. Importantly, most adenomas and early cancers are asymptomatic. Detection at early stages confers an excellent prognosis, and there are numerous tests for early detection and intervention, with the potential to reduce the incidence, morbidity and mortality of the disease. Cancer screening aims to identify affected individuals who do not suspect they have the disease. This is in contrast to performing diagnostic investigations for symptomatic patients, or targeting individuals with a significant family history of bowel cancer, a history of inflammatory bowel disease, previous adenomatous polyps or previous bowel cancer. However, bowel cancer screening recommendations can be confusing for medical practitioners. Numerous tests of varying performance levels are available, and it is difficult to separate recommendations for the population from those targeted towards individuals. There are also significant differences between the Australian recommendations endorsed by the National Health and Medical Research Council (NHMRC)3 and two recently published American guidelines, from the United States Preventive Services Task Force (USPSTF)4 and from a collaboration of the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer (representing the American Gastroenterological Association, American Society for Gastrointestinal Endoscopy, American College of Gastroenterology and American College of Physicians) and the American College of Radiology.5 Interestingly, these guidelines differ due to differing interpretations of essentially the same evidence. It is important to note that the newer American guidelines are less relevant to the Australian health care environment, and should not usurp the existing NHMRC recommendations in Australia. The NHMRC guidelines strongly recommend screening from the age of 50 years, by performing a faecal occult blood test (FOBT) at least every second year. The strength of this recommendation arises from three large, population-based, prospective randomised controlled trials demonstrating a mortality reduction of 15%–33%.3-5 No other cancer screening strategy is based on such strong evidence. Flexible sigmoidoscopy performed 5-yearly receives an equivocal recommendation, whereas colonoscopy and computed tomographic (CT) colonography are not recommended because of insufficient evidence. In contrast, the American guidelines recommend presenting information to patients, who then choose from the options, including high-sensitivity FOBT, flexible sigmoidoscopy or colonoscopy.4,5 The American recommendations diverge on CT colonography: the USPSTF does not recommend it on the basis of unknown long-term harm,4 while the collaborative joint guidelines endorse 5-yearly examinations.5 Unlike the US, Australia has moved beyond making passive recommendations to become one of a few countries actively implementing a nationwide population-based bowel cancer screening program — the National Bowel Cancer Screening Program (NBCSP) — although, currently, only individuals aged 50, 55 or 65 years are invited to participate (http://www.cancerscreening.gov.au/internet/screening/publishing.nsf/Content/bowel-about). The NBCSP, which uses a high-sensitivity immunochemical FOBT, began in 2006 after a pilot program (2002–2004) found that bowel cancer screening would be acceptable, feasible and cost-effective.6 The age restriction for invitees is part of a phasing-in process designed to enable resources to cope with increased downstream demand, especially for colonoscopy, which is the recommended investigation for participants with a positive FOBT result. About 7.5% of NBCSP participants have a positive FOBT result, and 5% of these are found to have cancer.7 Although the federal government has made no commitment to the NBCSP beyond June 2011, it is inconceivable that the program will simply be terminated, given the strong evidence basis for its function. The problem facing Australian medical practitioners is what to do in the face of the various disparate guidelines. A simple approach is to recommend participation in the NBCSP for all invitees. Increased awareness of bowel cancer will also cause some individuals outside the eligible ages to enquire about screening. In these cases, the NHMRC recommendations are most appropriate: for medical practitioners wishing to encourage opportunistic screening, an immunochemical FOBT can be recommended for patients aged between 50 and 75 years. Patients with positive FOBT results will then require follow-up colonoscopy. However, these recommendations ignore the growing tendency, often driven by patients, for screening with colonoscopy. In the absence of symptoms, about 500 colonoscopies need to be performed on 50–75-year-olds to identify one cancer,7 with an associated one in 1000 risk of serious complications.8 This contrasts with one cancer found for every 20 colonoscopies in the NBCSP.7 Of course, many patients will have premalignant adenomas that would be found with colonoscopy screening, which in turn creates a substantial requirement for long-term surveillance colonoscopies. Yet the vast majority of patients with adenomas will never develop bowel cancer, even without future intervention.9 Finally, the imperfections of colonoscopy are becoming increasingly recognised, reducing the ratio of its potential benefits to high cost.10,11 Thus, “indiscriminate” use of colonoscopy diverts availability of this expensive resource away from those most in need of it, especially in the public health system. As a step towards improving colonoscopy access, the Western Australian Department of Health will introduce a Colonoscopy Services Model of Care, scheduled for implementation over the next 2 years in the public hospital system, that prescribes appropriate use and referral processes. This will be supported by trained clinical staff and computerised referral systems to improve the quality and triaging of referrals in the public sector. Patients will also be informed of the priority level of their case, and the appropriate waiting time. Other states in Australia should strongly consider implementing similar strategies. Bowel cancer is common, serious and largely preventable. Medical practitioners should be encouraged to refer individuals for bowel cancer screening in compliance with the current Australian NHMRC recommendations and the NBCSP. Such practice will ensure that colonoscopy resources are available to those most in need in our community.

Hooi C Ee MB BS, FRACP, PhD · John K Olynyk MB BS, FRACP, MD

Objectives: To assess the prevalence, severity and distress from physical symptoms and the prevalence of anxiety and depression in patients about to undergo chemotherapy for potentially curable cancers; and to explore the presence of symptom clusters and investigate their relationships with anxiety and depression.Design, participants and setting: Cross-sectional survey of 192 patients with breast or gastrointestinal cancers or lymphoma before first ever chemotherapy treatment with curative intent.Main outcome measures: Hospital Anxiety and Depression Scale to assess anxiety and depression and the Chemotherapy Symptom Assessment Scale to measure physical symptom prevalence, severity and distress (“bother”).Results: Prevalence of anxiety was 45% and depression 25%. The most prevalent physical symptoms were pain (48%), feeling unusually tired (45%) and difficulty sleeping (45%). Physical symptoms rated as most severe were pain (28%), difficulty sleeping (26%) and feeling unusually tired (19%). Physical symptoms causing the most distress were pain (39%), constipation (18%) and nausea (16%). Factor analysis of symptom distress scores indicated that five factors explained 36.7% of the variance and included: gastrointestinal (nausea, vomiting, pain), general malaise (tiredness, feeling weak, headaches), emotional (feeling depressed, feeling anxious), nutritional (changes to appetite, weight loss or gain) and general physical (mouth/throat problems, shortness of breath). Regression analysis indicated that symptom distress for the malaise (β = 1.46; P < 0.001), nutritional (β = 0.70; P < 0.05) and gastrointestinal (β = 0.73; P < 0.05) factors were independent predictors of depression.Conclusions: Before commencing chemotherapy, patients are already experiencing distressing symptoms and have high scores for anxiety and depression, partially explained by physical symptom distress. Patients should be routinely screened for both emotional and physical needs and appropriate interventions should be developed.Trial registration: Australian New Zealand Clinical Trials Registry ACTRN012606000178549.

Sibilah J Breen BSc(Hons), PhD · Carl M Baravelli BBSc(Hons) · Penelope E Schofield BSc(Hons), PhD · Michael Jefford MPH, PhD, FRACP · Patsy M Yates RN, MSocSci, PhD · Sanchia K Aranda BApplSci(AdvNurs), MN, PhD

To the Editor: A 60-year-old Hispanic woman, who had lived in the United States for 10 years, presented with a 1-day history of altered mental status. Physical examination revealed ascites and enlarged right axillary lymph nodes. Magnetic resonance imaging (MRI) of the brain showed multiple intracranial lesions (Box, A). Computed tomography of the chest and abdomen showed massive adenopathy in the right axilla, multiple nodules in upper lung fields, ascites and retroperitoneal adenopathy. Her cancer antigen (CA) 125 level was 1469 U/mL (reference range, 0–35 U/mL); CA27.29 and CA19-9 levels were within the upper limit of the normal ranges. She was initially thought to have metastatic cancer of unknown primary site. However, a right axillary node biopsy revealed necrotising granulomas and no malignancy; an acid-fast bacteria (AFB) stain was negative. Ultrasound-guided retroperitoneal lymph node biopsy showed necrotising granulomas and no malignancy; an AFB stain was positive. We began investigations for disseminated tuberculosis (TB). A QuantiFERON-TB Gold test (Cellestis, Valencia, Calif, USA) and sputum and right axillary node cultures were positive for Mycobacterium tuberculosis; peritoneal and cerebrospinal fluid cultures were negative. Polymerase chain reaction (PCR) of samples of peritoneal fluid and from bronchoalveolar lavage was negative for M. tuberculosis DNA, but a sample from the retroperitoneal lymph node tested positive. The patient was started on four-drug therapy for TB and her condition progressively improved. Follow-up MRI of the brain 5 months later showed a decreased size of all intracranial lesions (Box, B), and her CA125 level was 84 U/mL. Peritoneal TB can mimic advanced ovarian cancer because of similarities in clinical signs and symptoms, such as ascites, abdominal pain and elevated CA125 levels.1 The association of peritoneal TB with high CA125 levels was first described in 1987.2 The positive predictive value of CA125 levels to detect malignancy is estimated at 60%, rising to 98% in postmenopausal women.3-4 In most reported cases of peritoneal TB, CA125 levels were below 500 U/mL; rarely, levels up to 1200 U/mL have been seen.1-4 Culture is of limited clinical usefulness, as results take up to 6 weeks. Although microscopy is rapid, cheap and highly specific, its sensitivity has been shown to be as low as 31% for extrapulmonary TB.5 PCR is of limited value in diagnosing peritoneal TB. Detecting M. tuberculosis DNA by PCR in ascitic fluid poses many challenges — differences in technique, contamination with other bacteria, and the variable number of acid-fast bacilli in samples have been shown to influence its reliability.4-5 Negative results from microscopy, culture and PCR should not distract from a diagnosis of TB. In the face of a growing international incidence of TB, it is important to consider this transmissible and treatable disease in the context of abdominal symptomatology, ascites and raised serum CA125 levels — especially in ethnic groups in which TB prevalence is high. Misdiagnosis or delayed diagnosis can lead to infertility, premature menopause and death. Magnetic resonance (MR) imaging of the brain before and after treatment A: B rain MR image showing multiple intracranial lesions involving the left cerebellum, left occipital lobe, left parietal lobe and corpus callosum. B: MR image of the brain 5 months post-treatment, showing a decrease in the size of all intracranial lesions.

Riad O El Fakih · Bassem M Chehab · Rami A Mortada · Maha Assi

Alan Ferrier was born in Lismore, New South Wales, on 23 July 1954. As a child he suffered from severe asthma, and on medical advice his family moved to Sydney for a better climate. He attended Knox Grammar School, where he achieved distinction academically and at cricket. After graduating from the University of Sydney in 1978, Alan undertook specialist training in obstetrics and gynaecology at the Royal North Shore Hospital in Sydney. From 1986, he spent several years in North America training in gynaecological oncology at institutions such as the Memorial Sloan–Kettering Cancer Center in New York and the University of Toronto in Canada. Returning to Sydney in 1991, Alan was appointed Senior Lecturer in Obstetrics and Gynaecology at the University of Sydney. He was largely responsible for establishing the gynaecological oncology service for the Northern Metropolitan Region of Sydney. Alan soon earned a reputation as a cancer surgeon of exceptional ability. Despite an extraordinarily heavy surgical workload, he continued to enjoy practising obstetrics, which he felt brought a happy balance to his professional life. He mastered new laparoscopic techniques and was one of the first surgeons in Australia to apply them in oncology. He became an expert at radical trachelectomy with laparoscopic lymphadenectomy. Many of his specialist colleagues benefited from his advice and help with difficult cases. This assistance was given without hesitation and was often life-saving. Alan loved to teach and shared his knowledge and techniques generously. He had numerous research articles, book chapters and other publications to his credit and was involved in a broad range of research projects at the time of his death. He was an examiner for many years, a convenor of several postgraduate courses, and a member of various committees, including Chairman of the NSW Committee of the Royal Australian College of Obstetricians and Gynaecologists. Alan was absolutely devoted to his family. He strove to achieve excellence in all that he did personally and professionally. He was renowned for his urbane demeanour and sartorial elegance. Because of his asthma, he was also committed to keeping fit. Despite this, he died in his sleep of a cardiac arrhythmia on 23 December 2007, aged 53 years. Alan is farewelled as one who honoured his family and practised medicine with enormous skill and compassion. He is survived by his wife Sarah and daughters Katherine and Charlotte.

Robert M Ford · Keith G Hartman · Jonathan R Stretch

Objective: To document haemopoietic stem cell transplantation (HSCT) activity and trends among paediatric patients in Australia and New Zealand.Design, setting and participants: A retrospective analysis of data reported to the Australasian Bone Marrow Transplant Recipient Registry by the seven paediatric HSCT institutions in Australia and New Zealand over the 9-year period 1998–2006, with particular focus on the most recent years (2002–2006).Main outcome measures: Types of HSCT performed; transplant-related mortality (TRM); stem cell sources; indications for HSCT; causes of death after HSCT.Results: Over the period 1998–2006, 522 autologous HSCT procedures (41%) and 737 allogeneic procedures (59%) were performed. About 60% of allogeneic transplants involved alternative donors (donors other than a human leukocyte antigen-matched sibling). The use of umbilical cord blood as a source of haemopoietic stem cells has doubled since 1998, with 34% of allogeneic transplants in 2006 using cord blood. Over the period 2002–2006, the median age of patients receiving transplants was 7 years (range, 0–19 years). The most common indications for allogeneic HSCT were acute lymphoblastic leukaemia (33%) and acute myeloid leukaemia (24%). The most common indications for autologous HSCT were neuroblastoma (23%), medulloblastoma (21%) and Ewing sarcoma (10%). TRM at 1 year after transplant was 22% for alternative donor transplants, 7% for matched-sibling transplants and 5% for autologous transplants. Relapse or persistence of a child’s underlying condition accounted for 54% of all deaths within 1 year after transplant.Conclusions: HSCT is an important procedure for children with a range of life-threatening illnesses. Local trends in the indications for HSCT, donor selection and TRM reflect contemporary international practice.

Andrew S Moore MB BS · Peter J Shaw MB BS, MRCP, FRACP · Andrew R Hallahan BSc(Med), MB BS(Hons), FRACP · Tina L Carter MB BS, FRACP, PhD · Tatjana Kilo MD · Ian Nivison-Smith BSc, MAppStat · Tracey A O’Brien MB ChB, FRACP, MHL · Heather Tapp MB BS, FRACP, FRCPA · Lochie Teague MB ChB, FRACP, FRCPA · Shaun R Wilson MB ChB, DCH, MRPCH · Karin Tiedemann OAM, MB BS, FRACP

To the Editor: We question the conclusions drawn by Canfell and colleagues1 from their analysis of trends in hormone replacement therapy (HRT) prevalence and breast cancer incidence for Australian women aged 50 years or older. Their ecological analysis lacks individual-level information on HRT use and information on tumour oestrogen receptor (ER) status, and captures only 2 years following the decline in HRT prevalence. This is an inadequate design within which to judge issues of causality; it is at best an hypothesis-generating exercise.2 The examination of only 2 years of breast cancer incidence after the decline in HRT use is unsound because of substantial unexplained annual variability in national breast cancer incidence. This is evidenced, for example, by the graph in Canfell et al’s Box 2, which identifies a fall in 1998–1999 that was not ascribed to changes in HRT prevalence. The lack of data on tumour ER status is another weakness. HRT use increases the risk of ER+ tumours, so any decline in HRT prevalence would be expected specifically to reduce ER+ tumour incidence. We analysed Victorian Cancer Registry data for women aged 50 years or older for the period 2001–2005 — 2 years past the cut-off in Canfell et al’s analysis. Tumour ER status was available for 87% of breast cancer cases in 2001, rising to 90% in 2005. The demographic characteristics of the women for whom these data were available did not change between 2001 and 2005. Over this period, the proportion of all breast cancers that were ER+ increased from 65% to 71%, and the proportion of tumours with known ER status that were ER+ increased from 74% to 79%. Poisson regression analysis of the age-specific incidence rates for both total and ER+ breast cancer for women aged 50 years or older estimated an average annual decline of 1.7% in the total incidence rate (P = 0.0009) and an annual increase of 0.2% in the ER+ incidence rate (P = 0.7). Our findings are illustrated in the Box. Although there was an apparent small decline in total breast cancer incidence in 2001–2003, this trend was reversed in 2004–2005. More importantly, the trend in ER+ tumour incidence was stable across the entire period. Age-standardised incidence* of invasive breast cancer in women in Victoria aged ≥ 50 years, 2000–2005 Vertical bars represent 95% confidence intervals. ER+ = oestrogen receptor-positive. * Standardised to World Standard Population. These Victorian trends, covering a longer time period and including information on the tumour type most likely to be affected by changes in HRT use, provide no support for the hypothesis of Canfell and colleagues.

Graham G Giles · Richard Bell · Helen Farrugia · Vicky Thursfield

In reply: In saying that our work on the effect of hormone replacement therapy (HRT) on the development of breast cancer is “at best an hypothesis-generating exercise”, Giles and colleagues ignore both the preceding literature and the fact that our analysis of Australian data explicitly tested the hypothesis raised by an analysis of United States data. Both the US and Australian analyses showed falling breast cancer incidence from 2001 in women aged ≥ 50 years, but not in younger women, following large reductions in HRT use.1,2 The logic, methodology and statistics presented by Giles et al are unsound. They present data on incident breast cancers for women in Victoria only, a subset of the national data included in our analysis. Not only is it invalid to use a subset of data to retest a hypothesis previously tested on the larger dataset (unless complex statistics are applied3-5), but Giles et al misrepresent Victorian trends. It is clear that in Victorian women aged ≥ 50 years, breast cancer incidence rates fell substantially and significantly by 11.5% between 2001 and 2003 (95% CI, 6.0%–16.6%; P < 0.0001), with no significant change among women aged 20–49 years (P = 0.3) (Box). Giles et al present no data on HRT use. The largest drop in HRT use in Australia occurred between 2001 and 2003, and thereafter use began to plateau.6 It is therefore statistically inappropriate to calculate an “average annual decline” in breast cancer incidence from 2001 to 2005 because changes in HRT use over this time were not linear. In addition, their claim that the “trend was reversed in 2004–2005” is not supported by statistical testing, which shows no significant change in breast cancer incidence in women aged ≥ 50 years in Victoria from 2003 to 2005 (P = 0.4). US data showed that the fall in breast cancer incidence following the drop in HRT use was seen particularly in oestrogen receptor-positive (ER+) tumours.1 As we pointed out,2 the lack of reliable Australian data on ER status means that no conclusions can be drawn about Australian trends in ER+ tumours. Giles et al acknowledge that the Victorian ER data are incomplete and that the completeness has increased over time. This, together with the possibility of differential ascertainment of ER status in women who used HRT over the period of interest, render the trends they present on ER+ breast cancers uninterpretable. Overall, trends in breast cancer incidence in the subgroup of Victorian women cannot be said to differ materially from the national trends. A recent editorial in the Lancet draws attention to the fact that trends in HRT use and breast cancer incidence similar to those we reported have now been observed in many countries.7 The Australian findings add to the accumulating worldwide evidence that, in settings where HRT use was common and breast cancer screening rates relatively stable, a rapid decline in HRT use after 2001 was followed by a fall in breast cancer incidence. Age-standardised incidence* of invasive breast cancer in women in Victoria, 1996–2005 Vertical bars represent 95% confidence intervals. Vertical dotted line indicates commencement of the period over which there was a hypothesised decrease in breast cancer incidence in women aged ≥ 50 years but not in women aged < 50 years. * Standardised to the Australian 2001 population.

Karen Canfell · Emily Banks · Mark Clements · Yoon J Kang · Valerie Beral

In this 21st century, we will need to better analyse the outcomes of our spending on newer and more expensive anticancer drugs, particularly through postmarketing assessment, to ensure that these investments are justified. Evidence-based medicine is only as good as the evidence available, and we advocate for more independently designed and funded trials that concentrate on the minimum effective dose and duration of therapies to reduce toxicity to patients and to control costs. There is a place for governments to provide funding for these studies in the public good. Although improving survival over standard care is the gold standard for proving the efficacy of a new therapy, surrogate endpoints such as early biological marker changes, functional imaging changes or earlier measures such as progression-free survival must be investigated to enable drug therapies to be discontinued earlier if they are ineffective. Studies searching for the presence of biological targets must be funded to exploit the potential advantage of targeted therapies. Treatment guidelines are best written by experts who are independent of the pharmaceutical industry. Existing databases should be linked to better monitor the outcomes of new therapies. Privacy safeguards are important, but privacy legislation may need to be modified to serve the greater public good from the information gained from linking databases.

Ian N Olver MD, PhD, FRACP · Ian E Haines MB BS, FRACP, FAChPM

To the Editor: In addition to its well established link with rickets and osteoporosis, vitamin D deficiency has been associated with increased risk of autoimmune, malignant and cardiovascular disease.1 Marginal deficiency occurs at serum 25-hydroxyvitamin D [25(OH)D] levels of 25–50 nmol/L and frank deficiency at levels < 25 nmol/L,2 but there is some evidence that levels < 80 nmol/L3 or even < 110 nmol/L2 could be suboptimal. In Australia, vitamin D deficiency is most frequent in nursing home residents, dark-skinned veiled women, and residents of southern latitudes.2 However, those who are instructed to habitually minimise sun exposure following a diagnosis of skin cancer may also be at particular risk. We recruited patients with a history of non-melanoma skin cancer, who were not taking vitamin D or calcium supplements, from outpatient dermatology clinics at Royal Prince Alfred Hospital, Sydney (latitude, 33° south). Ethics approval was obtained from the Sydney South West Area Health Service and University of Sydney ethics committees, and all participants provided written informed consent. Serum 25(OH)D levels were measured by radioimmunoassay (DiaSorin, Saluggia, Italy)4 in both late summer (February 2006 or 2007) and late winter (August 2006), with participants completing a 2-week diary detailing daily sun exposure and sunscreen application before each measurement. Twenty-five participants (12 men, 13 women; mean age, 64 years; range, 44–78 years) completed both assessments. We found a significant reduction in mean 25(OH)D levels in winter (summer, 69 ± 3.4 nmol/L; winter, 59 ± 6.2 nmol/L; P < 0.05). In summer, all but one participant had 25(OH)D levels > 50 nmol/L, and eight had levels > 80 nmol/L. In winter, 12 participants had 25(OH)D levels < 50 nmol/L, two had levels < 25 nmol/L, and only three had levels > 80 nmol/L (Box). Hence, using the accepted target value of 50 nmol/L,2 12 participants (48%) were vitamin D-deficient at the end of winter, compared with one (4%) at the end of summer. In summer, the mean reported daily sun exposure was 1 hour (range, 10 min–2.5 h), comprising 40 minutes of off-peak (before 11 am or after 3 pm) and 20 minutes of peak exposure. In winter, the mean daily exposure was also 1 hour (range, 20 min–1.5 h), comprising 30 minutes each of both peak and off-peak sunlight. Volunteers reported wearing sunscreen during about 50% of their summer sun exposure and 27% of their winter sun exposure. Despite mean reported daily sun exposure falling within recommended guidelines, half of our participants were vitamin D-deficient at the end of winter, with almost all demonstrating reductions in winter 25(OH)D levels. Our findings suggest that vitamin D deficiency may be much more prevalent than expected in these patients, and that vitamin D supplementation might be indicated for this group, at least during winter. Vitamin D levels in summer and winter 25(OH)D = 25-hydroxyvitamin D.

Anna-Marie McCombie · Rebecca S Mason · Diona L Damian

Objective: To document general baseline data on the patterns of childhood malignant tumours at a teaching hospital in south-western Nigeria.Design, setting and participants: A retrospective study of childhood malignancy at Olabisi Onabanjo University Teaching Hospital, Sagamu, Nigeria, during an 11-year period, from January 1996 to December 2006.Results: 77 children were diagnosed with malignant tumours (an average of seven diagnoses per year); 46 were boys (60%), giving a male-to-female ratio of 1.5 : 1. The age distribution of patients was 1–18 years. There were 42 diagnoses (55%) in the 1–5-year age group and 68 malignancies (88%) were diagnosed at ages of 12 years or younger. Lymphomas were the most prevalent malignancy identified, accounting for 31 diagnoses (40%). Burkitt’s lymphoma constituted the majority of malignancies (28 cases; 36%), followed by retinoblastoma (16 cases; 21%) and nephroblastoma (11 cases; 14%). Other malignancies included germ cell tumours (6), neuroblastomas (4), osteosarcomas (3), rhabdomyosarcomas (3) and non-Hodgkin’s lymphomas (3). One case each of medullary thyroid carcinoma, adenocarcinoma of the rectum, invasive mucinous carcinoma of the colon were also identified.Conclusion: These data suggest that Burkitt’s lymphoma is the most common childhood malignant tumour in our geographic area of south-western Nigeria. With the rising incidence of childhood malignancy in resource-poor countries, measuring the baseline occurrence of such tumours is imperative to provide much-needed resource allocation.

Ayodeji O J Agboola MB ChB, MSc · Folashade A Adekanmbi MB BS, FWACP · Adewale A Musa MB BS, FWACS · Adetoun S Sotimehin MB BS, FWACP · Anotu M Deji-Agboola BSc, MSc, PhD · Aderibigbe M O Shonubi MB BS, FWACS · Temitope Y Oyebadejo MB BS, FMCPath · Adekunbi A F Banjo MB BS, FMCPath

Objective: To determine what aspects of communicating and consulting with cancer patients are viewed as difficult and stressful by cancer specialists in Australia.Design, participants and setting: Anonymous, cross-sectional, Internet-based survey completed by 134 cancer specialists between June and August 2007. Participants, who were all members of the Clinical Oncological Society of Australia, included oncologists and palliative care specialists.Main outcome measures: Degree of difficulty perceived for various consultation tasks; level of stress reported during various practice-related situations.Results: Doctors had the most difficulty discussing high-cost drugs with patients they knew could not afford them, followed by topics relating to treatment failure. They had the least difficulty telling patients they had cancer or being honest about prognosis. The most stressful practice situations included having incomplete patient information to conduct the consultation and having a long line of patients waiting for a consultation. At least 62% of respondents reported experiencing some degree of stress in all the practice situations presented. There were differences in difficulty and stress experienced as a function of the doctor’s sex, age and clinical experience.Conclusions: Targeted, evidence-based guidelines and communication courses are required to better equip cancer specialists for providing non-directive advice about unsubsidised high-cost drugs and for offering different forms of hope in the context of treatment failure. Implementing small organisational changes — such as reducing interruptions during consultations and informing patients of the duration of their allocated consultation — may also help reduce stressful practice situations.

Aneta Dimoska BPsych(Hons), PhD · Afaf Girgis BSc(Hons), PhD · Vibeke Hansen BA(Hons) · Phyllis N Butow MClinPsych, MPH, PhD · Martin H N Tattersall MD, MSc, FRCP

A 1978 case report in the Journal described a 25-year-old man with disseminated osteogenic sarcoma whose metastases regressed after treatment with diet and intensive meditation. Thirty years later, there has been no recurrence of his cancer, and a recent pneumonectomy for chronic bronchiectasis revealed mature cancellous bone in the resected lung. The man is otherwise well. (MJA 2008; 189: 663-665) Clinical recordA man who is now 58 years old was diagnosed in 1974, at the age of 24, with histologically confirmed high-grade osteogenic sarcoma of the right femur (Figure, A). His right leg was amputated in January 1975. Histopathologically, the tumour was described (in a 1994 review of the case) as follows: “The tissue is replaced by a cellular malignant spindle cell tumour forming osteoid and bone and having a disorganised pattern of proliferation . . . confirming the diagnosis of a high grade endosteal osteosarcoma (osteogenic sarcoma).” In December 1975, widespread bony and pulmonary metastases were diagnosed. Despite being told in March 1976 that he had only 2–3 weeks to live, the man survived until September that year, when he underwent three cycles of palliative chemotherapy with vincristine, adriamycin, cyclophosphamide and dacarbazine, as well as brief palliative radiation therapy. He elected to discontinue these therapies as his condition deteriorated further. The patient then consulted prominent psychiatrist and hypnotherapist Dr Ainslee Meares, who reported his case and his subsequent remarkable recovery in the Medical Journal of Australia in 1978.1 When Meares first saw the patient, he had visible bony tumours protruding from his ribs, sternum (Figure, B) and iliac crest, and was coughing up blood containing small spicules of bone (Figure, C). Meares taught him how to meditate, and both he and the patient felt this was a key component in recovery, although he also adhered faithfully to a vegan diet and tried many alternative therapies, including massage, acupuncture, faith healing and others. The patient recovered and returned to full-time work, founding and running self-help groups for people with cancer, but had persistent reminders of the original illness. Presumably related to immunosuppression from chemotherapy, he developed pulmonary tuberculosis in June 1978, and was treated for this condition for 12 months. This progressed to cavitation and severe bronchiectasis, causing repeated bouts of pneumonia and persistently elevated erythrocyte sedimentation rate (ESR). Chest x-rays in November 1989, 15 years after the patient’s diagnosis and subsequent recovery, showed evidence of previous tuberculosis and ongoing bronchiectasis, with a left hilar mass compressing the left upper lobe bronchus by 50%. Views of the lumbar spine and pelvis, taken at the same time to investigate ongoing back pain, showed abnormalities initially thought to represent progressive metastatic disease. The report noted “progressive metastatic disease with large osteoblastic deposit right ilium, sacrum, and invasion into L5”. That report was amended 4 days later, after comparison with films from 1978, to state “The appearances in the body of L5 . . . are those of metastatic disease but this appearance is essentially unchanged”. A thoracic computed tomography scan performed a few days later showed evidence of previous left lung tuberculosis. With no further treatment, the patient’s condition remained stable. X-ray images of the chest, pelvis and lumbar spine in 1993 were unchanged from 1989. Lung function testing in 1996 and 1999 showed satisfactory function, with an FEV1/FVC (forced expiratory volume in 1 second/forced vital capacity) ratio of 2.56 L/3.40 L. Indeed, the patient was well enough to go trekking in Nepal for three weeks in 1999 to a height of about 16 000 feet above sea level. However, two episodes of left lower lobe pneumonia in 2004 and chronic bronchiectasis resulted in referral to a thoracic surgeon with a view to pneumonectomy. Noting the patient’s chronically elevated ESR, indicating ongoing sepsis, and recurrent chest infections, the surgeon recommended left pneumonectomy while the patient was still young enough to tolerate the surgery. In December 2004, pneumonectomy was performed. As the patient had relied on elbow crutches since the original leg amputation, it was hoped that a minimally invasive approach might preserve chest wall skeletal structure and musculature, but because of widespread adhesions and tuberculous scarring, this was not possible. A complicated 5-hour pleuropneumonectomy was performed, with the pericardium being opened to enable access to the pulmonary veins, precipitating a short period of intraoperative ventricular fibrillation. Macroscopic pathological examination showed a small, collapsed, scarred left lung. The lung parenchyma was abnormal, and bronchiectasis, cavitation and scarring were widespread, but there was no obvious tumour. Microscopic examination showed severe bronchiectasis, but there was no evidence of mycobacterial infection. The report noted that “palpation of lung parenchyma deep to the hilum reveals a rock-hard consistency, impossible to section with a knife. Using a saw, horizontal cuts . . . reveal a centrally located bony mass 35 × 30 mm about, surrounding the bifurcation of the left main bronchus.” Histopathological examination of decalcified sections showed “a bony mass surrounding and incorporating large central bronchi and neurovascular structures. Much of the bone has a mature cancellous appearance with normal appearing osteocytes, and mature fat within the intertrabecular spaces. In addition there are foci of coarse sclerotic and heavily calcified bone which are devoid of viable osteocytes. No viable tumour is present.” After steady postoperative recovery, the patient returned to full-time work and remains well. DiscussionOsteosarcomas are rare malignant tumours of the skeleton characterised by formation of immature bone by tumour cells. At the time of this patient’s diagnosis, osteosarcoma was a devastating disease with very low survival rates.2 Most patients died within a year of diagnosis. Management centred around limb amputation, with palliative chemotherapy and radiation therapy for recurrences. Over the past 30 years, management has improved dramatically. With the use of limb-sparing surgery, induction and adjuvant chemotherapy, and surgical excision of metastases, survival rates of around 60% can now be expected for patients presenting with localised disease.3-5 There are limited data examining long-term outcomes among patients recovering from osteosarcoma. A few articles have reported long-term follow-up, including surveillance for recurrence,6 the development of other cancers,7 and cardiac toxicity from chemotherapy agents.8 Metastases have been known to develop as long as 14 years after diagnosis.6 While there is a report of spontaneous regression of a pulmonary metastasis that developed 5 years after treatment for osteosarcoma,9 the fate of regressed secondaries has not been well documented. Today, pulmonary metastases are often resected, but this is while the tumour is active. In this patient’s case, the lung was resected, for other reasons, 30 years after the original diagnosis, and incidentally, a large piece of mature cancellous bone was found surrounding the left main bronchus. This presumably represented bone formation by a long-since regressed secondary tumour, similar to the bone found in the primary tumour at the time of amputation. It is clear from the 1978 report that large sections of the externally visible osteogenic secondaries were resorbed as the cancer regressed. This was most obvious on the patient’s chest wall (Figure, D). However, some spinal and pelvic bone formed by the secondaries appears to have remained intact after tumour disappearance, as illustrated by the fact that x-rays taken of the spine and pelvis 15 years after diagnosis and recovery were identical with films of 11 years earlier and by the presence of bone in the resected lung. It is interesting to consider the possible factors involved in this man’s remarkable recovery. Spontaneous remission is a possibility, although exceedingly unlikely at such an advanced stage of disease, and its coincident timing with a wide range of self-help measures adopted by the patient makes this explanation even more improbable. Certainly, the patient had widespread disease from which recovery, even today, would be very unlikely. Although the patient received a short course of palliative chemotherapy and radiotherapy to his lumbar spine, it is unlikely that this would have been curative with such widespread metastatic disease. Meares and the patient attributed the remarkable recovery to intensive meditation,1 and it is true that the patient meditated from 3 to 5 hours daily after developing secondaries. He still regularly meditates and teaches others with cancer to do so. His fastidious adoption of the Gerson diet10 for 3 months, followed by adherence to a plant-based wholefood vegan diet may also have played some part. Such a lifestyle approach, incorporating meditation and a vegan diet, has recently been shown to cause significant modulation of gene expression and biological processes associated with tumour growth.11 Apart from illustrating the value of maintaining hope in the face of apparent hopelessness, this case shows that, long after tumour regression, metastatic lesions from osteosarcoma may contain significant amounts of residual bone. Even in the absence of tumour, these bony deposits may cause health problems in their own right, depending on their location. Our understanding of such unlikely survival continues to improve with the recent demonstration that modifiable lifestyle factors affect gene expression in patients with cancer.11

George A Jelinek MD, FACEM, DipDHM · Ruth H Gawler MB BS, MGPPsych, FACPsyMed

Objective: To measure long-term survival following combined chemotherapy and radiotherapy for inoperable non-small cell lung cancer.Design and setting: Two prospective Phase I/II studies in the multidisciplinary Lung Service of a dedicated cancer hospital in Victoria, commencing in 1996 and 1997–1998.Patients: 33 patients referred for treatment of histologically or cytologically proven inoperable non-small cell lung cancer, who had no evidence of distant metastases, Karnofsky performance status > 70%, weight loss < 10%, and no prior treatment for lung cancer. Patients were followed until death or for a minimum of 9 years.Interventions: Patients in both studies were treated concomitantly with chemotherapy and radiotherapy 60 Gy in 30 fractions over 6 weeks. Chemotherapy in the first study (LURTCE) consisted of cisplatin and etoposide; in the second study (LURTCF), chemotherapy consisted of escalating doses of carboplatin and fluorouracil.Main outcome measure: Overall survival.Results: Six of 33 patients were still alive 9 years after commencement of treatment. Median survival for the whole group was 2.1 years (95% CI, 1.3–3.1 years), with 18% (95% CI, 8%–35%) of patients still alive at 5 years (plateau).Conclusion: Long-term survival can be achieved in some patients with inoperable non-small cell lung cancer treated by radical chemoradiation alone, suggesting the possibility of cure.

Nikki M Plumridge FRANZCR · Michael J Millward MBioethics, FRACP · Danny Rischin MD, FRACP · Michael P MacManus MD, FRCR, FRANZCR · Andrew Wirth FRACP, FRANZCR · Michael Michael FRACP · Kally Yuen MSc, AStat · David L Ball MB BS, MD, FRANZCR

Men surviving cancer. Barry Leigh. Sydney: Jane Curry Publications, 2007 (viii + 255 pp). ISBN 978 1 920727 31 4. This account of men’s stories provides a lesson in the power of interaction and how what we say as health professionals can change people’s perceptions. A single “throw away” statement or sentence can be etched into a patient’s mind forever. It can shape the way a person diagnosed with a life-threatening illness views both their prognosis and their future. Most of the accounts in Men surviving cancer are about Australian men who have had above average difficulties. It could be confronting for those who have been recently diagnosed, as the path ahead may seem horrendous. Those in the course of challenging treatment, however, may be encouraged by the ultimate success of such treatment. The accounts in this book, as well as those in numerous other books on the cancer journey, suggest that men experience the same physical, emotional and sociological problems as do women. Men cry too. Men feel isolated too. Men change their priorities too: focusing on the importance of family, of friends and of nature. This account of men’s experiences may help others in a similar situation recognise that emotions are normal in the abnormal situation of having cancer. These individual inspiring stories help us recognise that fear of death is at the heart of much of our day-to-day anxiety when faced with a cancer diagnosis. Perhaps the title will attract men who would not normally consider reading a book about cancer, and the upbeat nature of the accounts will help them cope better. As health providers, we can be inspired to communicate more deeply with our patients and appreciate more keenly their willingness to appreciate the power of the spoken word.

Dawn Hooper · Mark Tweeddale

Objective: To ascertain the current level of understanding among older men about prostate cancer, including treatment options and their potential side effects.Design and setting: Questionnaires administered by general practitioners in five general practices in the Perth metropolitan and regional areas of Western Australia.Participants: Convenience sample of 503 men aged 40–80 years, with or without prostate cancer, presenting for routine consultations between January and August 2006.Main outcome measure: Knowledge and attitudes of men about prostate cancer, and predictors of knowledge.Results: Eighty per cent of men did not know the function of the prostate, and 48% failed to identify prostate cancer as the most common internal cancer in men. Thirty-five per cent had no knowledge of the treatments for prostate cancer and 53% had no knowledge of the side effects of treatments. Asked how they would arrive at a decision about treatment, 70% said they would ask the GP or specialist for information on all their options and then decide themselves.Conclusion: There is a deficit in knowledge about prostate cancer among men in the at-risk age group, encompassing areas that could delay diagnosis and treatment. Overall, the men preferred some GP or specialist involvement in treatment decision making.

Diane E Arnold-Reed BSc(Hons), PhD · Dana A Hince BSc(Hons), PhD · Max K Bulsara MSc · Hanh Ngo BSc(Hons) · Michael Eaton MB BS, FACRRM · Alan R Wright MB BS, MFM, FRACGP · Frank R Jones MB BCh, FACRRM, FRACGP · Walter Kaczmarczyk MB BS, FRACGP · Andreas G Marangou MB BS, FRACGP · Thomas D Brett MD, FRACGP, MRCGP