Dr. Olderburg debates the pro for the use of carboplatin for patients with stage 1 seminoma. He starts the talk discussing the importance of identifying the risk of treatment burden as with either therapy the expected cure rate is greater than 95%. Dr. Olderburg argues that that recurrences associated with stage 1 seminoma are not trivial and with adjuvant treatment, they can be significantly reduced from 12% to 4%. He reports that a single dose of carboplatin is even more important in patients with high-risk features, tumors > 4 cm and rete testis invasion, where the risk of recurrence can be as high as 40% and be reduced to 5.7% with adjuvant chemotherapy. Most study groups have administered one to two courses of single-agent carboplatin to all stage I patients, with excellent results. Relapse rates are similar to those after adjuvant RT, the most common site being the retroperitoneum, and 5-year cause-specific survival is close to 100%. There seems to exist a dose-response relationship for carboplatin, as the incidence of relapses varies from one course (4.4%) to two courses (1.2%). He acknowledges that patients with no risk factors could be spared from adjuvant chemotherapy as this patient’s risk for recurrence is exceedingly low, and the risk of benefit ratio for these patients can be quite high.
Dr. Oldeburg argues that single dose carboplatin chemotherapy is very well tolerated main side effects are mild emesis and clinically irrelevant thrombocytopenia. Not only is adjuvant carboplatin well tolerated but on long-term follow-up, the cardiovascular risk associated with other chemo-regimens are not seen. In a report by Powel et al., 199 patients treated with single-agent carboplatin were prospectively followed, after a median follow-up of 9.0 years, there was no excess in overall mortality, in deaths from circulatory disease or in the incidence of second cancers in comparison with expected values derived from the UK general population, noting the safety of the single dose agent.
Dr. Hamilton discusses the benefit of using active surveillance in patients with stage 1 seminoma. He reasons that in this patient population any form of adjuvant treatment will overtreat approximately 80% of the patients. He argues that with surveillance there is no trade-off in survival and most patients that recur can be rescued with a variety of salvage treatments (chemotherapy, radiation or surgery). Dr. Hamilton maintains that while the absolute reduction associated with adjuvant chemotherapy appear significant, the absolute risk reduction is only in order of 2-9%. Moreover, the current prediction models for stage 1 seminoma recurrence remain elusive with rete testis invasion found not to be a significant predictor of recurrence in two separate metanalyses. In regard to size, a dichotomize measure, > 4 cm, has been found to be significantly correlated with recurrence but it’s accuracy for predicting recurrence remains low at ~65%.
Dr. Hamilton argues that subjecting patients to adjuvant carboplatin can alter the natural history of the disease. The median time to recurrence in those patients undergoing a surveillance protocol is usually 14 months which is significantly extended in those treated with carboplatin to 19 months. Furthermore, late recurrences are more common in patients treated with carboplatin with ~ 15% of patients recurring at 3 years vs. 8% of those undergoing surveillance. The shift to later recurrences leads to prolonged surveillance times translating to more CT scans increased radiation exposure. Moreover, those recurring following adjuvant chemotherapy tend to recur at higher stages (stage 3: 15% vs. 6.2%) noting a possible selection of more aggressive clones. Lastly, he notes that there appears small but real increase risk of death associated with recurrences in those treated with adjuvant chemotherapy compared to those managed with surveillance (1.6% vs. 0%).
Dr. Hamilton agrees that current evidence does show long-term toxicity associated adjuvant treatment with single dose carboplatin appears to be low. He cautions that 10-year follow-up may not be sufficient to identify possible cardiovascular, metabolic, and cognitive side effects associated with other chemotherapy regimens.
In summary, there is no internationally accepted consensus on the best management approach. The overall burden of treatment needed, therapy-related morbidity, predicted pattern of relapses, relative intensity of follow-up, quality of life issues, patient risk and preferences and economic costs should all be considered. Both debaters agree that treatment selection should be individualized to each patient noting that careful patient education with explanation of all potential risk is crucial as the decision should be a shared one rather than one directed by a treatment algorithm.
Jan Oldenburg MD Ph.D., Lorenskog, Normway -Carboplatin
Robert Hamilton MD, Toronto, Canada - Surveillance
Written by: Shreyas Joshi, MD, Urologic Oncology, Fox Chase Cancer Center, Philadelphia, PA at the 2018 European Association of Urology Meeting EAU18, 16-20 March, 2018 Copenhagen, Denmark.