Annals of Oncology Advance Access originally published online on January 27, 2008
Annals of Oncology 2008 19(3):407-408; doi:10.1093/annonc/mdm594
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editorial |
Stage I seminoma and carboplatin risks
Department of Clinical Oncology, Royal Marsden NHS Foundation Trust and Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5PT, UK
(E-mail: alan.horwich{at}icr.ac.uk)
Should the report of carboplatin morbidity by Powles et al. [1] in this issue influence the management of patients with stage I seminoma post-orchidectomy? In a study of 199 patients treated with one or two cycles of adjuvant carboplatin as a single agent, and followed for between 0.1 and 20.1 years (median 9), the analysis showed no excess mortality compared with the age and sex-matched UK population with 95% confidence intervals (CIs) on their standardised mortality ratio (SMR) from 0.36 to 1.83. They also reported no significant increase in death from circulatory disease (SMR 1.44; 95% CI 0.39–3.69) or in incidence of second cancers [standardised incidence ratio (SIR) 0.96; 95% CI 0.26–2.45).
The safety of carboplatin in testicular cancers is a topical issue [2, 3]. Its relevance to testicular cancer is heightened by the evidence for improving prognosis [4–6] and by concerns over the long-term toxic effects of radiotherapy [7] or combination chemotherapy [8, 9]. Increased risks to testicular cancer survivors of either cardiovascular events or second cancers have been indicated by both population-based and institution-based analyses, but neither were apparent in early years after treatment nor large enough to detect in small cohorts. For example, Travis et al. [10] defined second cancer risk in 28 843 testicular cancer survivors within 16 population-based tumour registries, of whom 3300 had been followed for >20 years. They found an SIR of 1.43 (95% CI 1.36–1.51), with risk increasing with time from treatment. Zagars et al. [11] reported excess mortality in 453 men treated with radiotherapy at the MD Anderson Cancer Center for early seminoma, finding an SMR of 1.59 emerging after 15 years. Similarly, Huddart et al. [12] analysed cardiovascular events in 992 testicular cancer survivors who followed a median of 10 years and found increased risks following either radiotherapy or chemotherapy compared with surveillance but also noted that the incidence increased mainly at >10 years after treatment. The study of 2512 testicular cancer survivors followed for a median of 18.4 years in The Netherlands [13] and found an increased risk of ischaemic heart disease with an SIR of 1.17 (95% CI 1.04–1.31), but again with most risk appearing >10 years after chemotherapy.
So how reassuring is the safety data on carboplatin from Powles et al., given that it is on the basis of just 199 patients with only 89 followed for >10 years? The answer ‘too little too soon’ is illustrated by the wide CIs on the estimated risks, which in fact include within them the risk levels seen for either radiotherapy or cisplatin combinations.
Is it reasonable to recommend the option of adjuvant carboplatin in stage I seminoma without waiting for a 20-year follow-up data on larger patient numbers? American editorials have been averse [2, 3], citing cardiovascular risks identified following full course cisplatin-based combination chemotherapy as well as a lack of long-term efficacy data among other reasons, whereas European Society of Medical Oncology [14] and European Germ Cell Cancer Concensus Group [15] consensus guidelines are generally supportive of discussing this option with patients. The European view is on the basis of the low total dose of carboplatin, its apparent low toxicity profile, the desirability of reducing recurrence rates compared with surveillance and the more clearly defined toxic effects seen with the alternative of adjuvant radiotherapy, albeit on the basis of larger fields and higher doses than are current. Though surveillance appears to present fewest treatment risks, the equation must include an estimate of the radiation carcinogenesis from computed tomography scanning [16] as well as the consequences of the burden of treatment for those who relapse. Survivorship studies on patients treated with multiple cycles of carboplatin for metastatic seminoma [17–20] may be a more sensitive indicator of the risks of this drug in view of the higher dose received by each patient. Cardiovascular risks of chemotherapy may be presaged by ‘the metabolic syndrome’ [21] and it would be useful to survey these risk factors in the carboplatin cohorts.
To some oncologists, it may appear that the energy put into clinical research and editorial reviews of management strategy in stage I seminoma may create more heat than light! After all, the survival rate is extremely high whether patients are managed post-orchidectomy by surveillance or by adjuvant treatments such as carboplatin or radiotherapy. However, as Einhorn has argued in a different context [22], testicular cancer is a model of a curable malignancy from which important oncological principles may be deduced and applied to other cancers, with relevance increasing as we improve the long-term survival rates for these other cancers. Powles et al., together with their patients should be congratulated for ensuring that we have the benefit of follow-up data long after the risk of recurrent seminoma has receded, so that when larger cohorts with longer follow-up have been analysed we can offer patients accurate information on options for adjuvant therapy.
Acknowledgements
My thanks to Anthony Swerdlow for his helpful comments.
References
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