Chris O’Brien Lifehouse and University of Sydney, Camperdown, New South Wales, Australia.
Rare urogenital tumours likely to be encountered by oncologists include testicular cancer, non-urothelial tumours of the bladder and urethral and penile cancers. Testicular cancer is a rare but highly curable urogenital tumour that typically occurs in men aged between 15 and 40 years. Factors responsible for the current success of treatment for testicular cancer include identification of reliable prognostic criteria to define risk and guide choice of therapy, multi-disciplinary management in expert centres, sustained research including international collaboration on practice-changing randomised controlled trials, and implementation of evidence-based guidelines. Unmet needs in testicular cancer include: improving the effectiveness and reducing the complications of treatment; addressing short and long-term survivorship issues; reducing exposure to radiation from repeat imaging; and better understanding the epidemiology and tumour biology. There is also a need to identify sustainable, targeted support for ongoing collaborative testicular cancer research. Australia is at the forefront of research into testicular cancer and recent achievements are outlined. Other rare urogenital tumours have significantly worse outcomes than testicular cancer and lack high-level evidence to guide therapy. Strategies to improve outcomes are discussed.
Rare urogenital tumours likely to be encountered by oncologists during their career include testicular cancer, non-urothelial tumours of the bladder and urethral and penile cancers. This review will outline factors responsible for the current success of treatment for testicular cancer, as well as unmet needs worthy of ongoing collaborative research. Other rare urogenital tumours have significantly worse outcomes than testicular cancer and lack high-level evidence to guide therapy. Strategies to improve outcomes that have been successful in testicular cancer are discussed.
Germ cell tumour of the testis, commonly referred to as testicular cancer, is the most common malignancy in men aged between 15 and 40 years in Australia and many Western countries.1,2 Although highly curable and only comprising about one in 100 cases of male cancer, each year there is a disproportionally high number of years of healthy life lost due to young age at diagnosis. In 2012, there were an estimated 740 cases in Australia, resulting in 20 deaths and almost 1000 years of healthy life lost.1
The incidence of testicular cancer has increased dramatically in populations of European ancestry since the 1970s for unknown reasons.2 Testicular cancer incidence is highest (>5 per 100,000 individuals) in Northern and Western Europe, followed by Australasia and North America and lowest (<1 per 100,000 individuals) in Africa and Asia. Incidence is higher by a factor of five in whites compared to blacks in the United States. In contrast to incidence rates, mortality rates have declined significantly in Western countries since the 1970s to very low levels (0.2 per 100,000 individuals), such that it is one of the most highly curable solid malignancies.2
About 80% of patients are diagnosed with early stage disease that is curable with surgery, followed in some cases by chemotherapy or radiotherapy, whereas the remaining 20% have advanced disease at diagnosis, typically requiring primary chemotherapy.3,4 More than 95% of patients are cured, however over a third with advanced disease and the worst prognostic features will relapse and die despite best available chemotherapy.
The dramatic improvement in survival of patients with testicular cancer over the last 50 years relates to landmark advances, such as the identification of reliable tumour markers to detect metastatic disease, refinements in radiotherapy to cure seminoma, the introduction of cisplatin-based combination chemotherapy to cure metastatic disease and refinements of post-chemotherapy retroperitoneal lymph node dissection.5
Such advances in this rare malignancy have occurred following sustained and methodological research, including: a series of practice-changing randomised controlled trials requiring international collaboration; identification of reliable prognostic criteria to define risk and guide choice of therapy; strong multi-disciplinary collaboration between the fields of medical and radiation and surgical oncology, pathology and radiology; and implementation of evidence-based guidelines by the oncology community.
Testicular cancer makes up a significant proportion of cancer survivors, due to the typically young age at diagnosis and the successes in its management. Unmet needs in testicular cancer requiring further study include improving the effectiveness and reducing the complications of treatment, long-term and short-term survivorship issues, reducing exposure to radiation from computed topography (CT) scans, and a better understanding of the epidemiology and tumour biology of subsets of testicular cancer. There is also a need to identify sustainable, targeted support for ongoing collaborative testicular cancer research.
There is a need for more effective treatment for patients who present with advanced disease and/or poor prognostic features, or who relapse after initial therapy, as well as a need to reduce the acute side-effects and long-term complications of treatment for those who are likely to be cured. Outcomes are better for patients with advanced disease who are treated in high-volume centres,6-8 perhaps due to better compliance with, and quality of, chemotherapy and post-chemotherapy surgery. Outcomes could be improved for patients from remote rural areas by referral to high-volume centres, shared care models, and virtual multi-disciplinary meetings.
The biology of testicular cancer remains poorly understood. A better understanding of the genetics and molecular signatures of testicular cancer could better select patients who require more aggressive or tailored treatment, and avoid over-treatment in other patients. The most pressing clinical questions in stage I testicular cancer are to identify genetic variants within a tumour that identify a group of patients at sufficiently high risk of relapse to justify the short and long-term toxicity of adjuvant therapy, and a group of patients at sufficiently low risk of relapse to avoid both the toxicity of adjuvant therapy, and the inconvenience and radiologic exposure of intense surveillance. The most pressing clinical questions in relapsed testicular cancer are to identify genetic variants within an individual that alter how a person’s body processes chemotherapy, and genetic variants within testicular cancer that make it inherently resistant to standard chemotherapy. Results could lead to the design of tailored treatments for such individuals that could incorporate a higher dose of or an alternative form of chemotherapy. Clinical trials targeting subgroups of men with testicular cancer would pose challenges due to low patient numbers, which would be best addressed via national and international clinical trial group collaboration, as discussed below.
Two-thirds of testicular cancer survivors had significant unmet needs between six months and five years after treatment, according to a recent cross-sectional study led by Ben Smith et al and conducted by the Psycho-oncology Cooperative Research Group (PoCoG) and Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP).12 The most common unmet needs related to life stress, fear of cancer recurrence, need for help for problems with relationships and sex life, and financial concerns. Many of these concerns are similar to those for survivors of breast and other more common cancers, but survivors of testicular cancer, often young men, may not accept interventions which have been designed for a much older person or for women. There is a need for the design and testing of custom-designed psychological interventions and support tailored to the needs of this young age group.
The majority of men with testicular cancer will be cured and live for over 50 years following completion of treatment. There is currently a paucity of information about the long-term physical and psychological complications of testicular cancer and its treatment, and how these complications can be prevented or best managed.
The risk of second cancers is increased in testicular cancer survivors who receive chemotherapy by 2.1-fold, and radiotherapy by 2.6-fold, compared with surgery alone. The risk of cardiovascular disease, such as heart disease or stroke, is also increased in testicular cancer survivors who receive chemotherapy by 1.7-fold, and radiotherapy by 1.2-fold.9 The absolute incidence of second cancer or cardiovascular disease due to chemotherapy or radiotherapy for testicular cancer is likely to be quite significant. There is an opportunity to reduce long-term morbidity and mortality through minimising use of unnecessary adjuvant therapy for stage I disease.
A recent observational study reported by O’Carrigan et al and conducted by the ANZUP found that up to one third of testicular cancer survivors had some degree of hypogonadism.10 This is likely to relate to abnormal development of the remaining testis, sometimes compounded by chemotherapy. This is an under-recognised problem and may result in long-term health issues, including cardiovascular disease, osteoporosis, altered sexual function and poor quality of life.11
A patterns of care survey conducted by ANZUP found that the typical patient with early stage testicular cancer underwent eight or nine CT scans over a five year period in order to screen for recurrence.13 The radiation exposure from these CT scans could lead to secondary cancers.14 There is a need for further research that could reduce radiation exposure by determining the optimal number of CT scans required during follow-up, and investigation of other imaging such as low-dose CT scans and magnetic resonance imaging. There is also a need for Australian clinicians to adopt a standardised evidence-based surveillance schedule.
A vibrant research community supporting innovation in testicular cancer research remains vital for future improvement of care in this group. Trials in this disease are now almost exclusively possible only through cooperative trials groups. Because testicular cancer is uncommon, the pharmaceutical industry and non-commercial granting bodies assign low priority to funding such research despite its importance. Furthermore, many proposed clinical trials to refine treatment, need to be performed with international collaboration in order to recruit sufficient numbers of patients in a timely fashion. Recent Australian funding initiatives from Cancer Australia, Cancer Councils, Cancer Institute NSW, Sydney Catalyst, and the Movember GAP5 initiative are welcomed. Sustainable ongoing funding models for research will need to be identified to continue this work.
Current Australian research activities in testicular cancer
Australia is at the forefront of clinical research to improve outcomes for testicular cancer and other germ cell tumours. Groups including ANZUP and PoCoG, in collaboration with the National Health and Medical Research Council Clinical Trials Centre at the University of Sydney, have conducted eight phase II and III clinical trials and pilot and observational studies over the last 10 years in testicular cancer across multiple centres in Australia and New Zealand. Studies relate to: optimising the efficacy of chemotherapy for metastatic disease;15-17 reducing the toxicity of chemotherapy;18,19 identifying survivorship issues relating to chemotherapy-induced cognitive dysfunction,20 hypogonadism,10 and psychosocial unmet needs;12 and addressing patterns of care in stage I disease.13 Ongoing Australian research includes a current phase III trial of accelerated bleomycin etoposide and cisplatin BEP chemotherapy in intermediate and poor prognosis metastatic disease, led by ANZUP and funded by Cancer Australia, incorporating collection and biobanking of 150 blood and tissue samples for planned translational studies funded by Sydney Catalyst, as well as a pilot study to develop a custom-designed online psychological intervention to address unmet needs in testicular cancer survivors led by PoCoG and funded by Cancer Council NSW.
Other rare urogenital tumours likely to be encountered by oncologists during their career are listed in table 1. Each tumour type is notable for its relative five-year survival being significantly lower than that of germ cell tumours and apart from testicular and penile cancer, being lower than that of all cancers combined, which in Australia is 66%.1 As to be expected, outcomes are best for patients with localised disease amenable to complete surgical resection.
Management of penile cancer has evolved to reduce the morbidity of treatment for localised disease by organ-preserving resection, definitive radiotherapy and laser therapy, with weak to moderate levels of evidence for lymph node dissection and combination chemotherapy to improve outcomes for locally advanced and metastatic disease.21,22 Progress in other rare urogenital tumours has been slower. The role of extended lymph node dissection and radiotherapy for locally advanced disease has not been clearly established. Conventional chemotherapy for metastatic sex cord stromal tumours of the testis, non-urothelial tumours of the bladder and urethral cancer is generally not effective, with recommended regimens based on low levels of evidence, and minimal or no evidence for adjuvant chemotherapy following complete resection of localised or locally advanced disease.
There are a number of strategies to improve outcomes for such rare urogenital tumours that can be drawn from the success in testicular cancer: