Seminoma is cancer found typically in young and otherwise healthy individuals. Improved treatment stratification to continue to maximize treatment success while also mitigating the long-term side effects of chemotherapy is an important goal for the field. This is illustrated by epidemiological data from Scandinavia that shows a drop-off in relative survival in patients treated for germ cell tumors 30-years after treatment. This drop-off in part may be explained by treatment, as the rates of secondary cancer decades after treatment increases with the number of cycles of cisplatin-based therapies given.
The two prior abstracts, therefore, were focused on trying to improve the risk stratification of seminoma and explore strategies of treatment de-escalation. Dr. Albers proposed his strategy for evaluating data, specifically: (1) Is it of importance?, (2) Is it accurate?, (3) Will it change practice?, and (4) What do to next?
He first discussed the IGCCCG update presented by Dr. Gillessen, which represents a much larger cohort of seminoma patients as compared to the original 1997 publication. This study showed improvement in 5-year progression-free survival from 81% to 89.2% and improved 5-year overall survival from 85% to 95.5%. One important observation made by Dr. Albers is that the proportion of intermediate-risk patients in the 1997 classification was almost 10%, whereas it was only just above 2% in this update. The update also suggested that elevated LDH > 2.5x the upper limit of normal could uniquely separate classically good-risk patients into the intermediate-risk category. This matches data that has been known for decades, but also makes biological sense as the LDHB gene is expressed from isochromosome 12p, a unique genomic marker generally exclusive to germ cell tumors. However, Dr. Albers notes that if you use this LDH cutoff to re-classify the patients in this updated cohort, now 12% of seminoma patients would be classified as intermediate risk, requiring 4 cycles rather than 3 of platinum-based chemotherapy. He argues that in the setting of a disease that is still quite curable, this may represent over-treatment. Dr. Albers, therefore, noted that this is an accurate and important abstract but may not be enough to change practice given effective salvage treatment strategies. As for what to do next, he argues that the major advances could come from figuring out how to de-escalate therapy in the good risk seminoma patients.
To this end, he next discussed the SEMITEP trial data. FDG-PET has been shown to have a 92% negative predictive value for viable tumor tissue in residual post-chemotherapy lesions > 3 cm in size. Unfortunately, the positive predictive value for this imaging modality is quite low as confirmed by multiple studies. The SEMITEP trial attempted to take this one favorable aspect of FDG-PET in seminoma (low rate of false negatives) and use it to de-escalate. Dr. Albers made several remarks about this trial. First, he was impressed that FDG-PET was a useful test within three weeks after the second cycle of chemotherapy. Second, he did not agree with the administration of one cycle of carboplatin to the FDG-PET negative patients. It is an inferior treatment option, and he posited that if FDG-PET is truly a biomarker of disease negativity, then chemotherapy should be stopped altogether after two cycles. Third, he noted that the patients in SEMITEP were enriched for low-volume disease, with 61% of patients having stage IIA/IIB disease. These findings, therefore, may not be completely generalizable to all metastatic seminoma patients.
After this discussion, Dr. Albers concluded that SEMITEP is an important and accurate trial that may change practice but requires an international phase III trial comparing FDG-PET based de-escalation of therapy versus the standard three cycles of platinum-based chemotherapy before doing this in all patients. He specifically stated that de-escalation of metastatic seminoma therapy from three cycles of platinum therapy should ONLY be done within the context of a clinical trial at the moment.
Presented by: Peter Albers MD, Professor of Urology, University Hospital Dusseldorf
Written by: Alok Tewari, MD, PhD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2020 ASCO Genitourinary Cancers Symposium (#GU20), February 13th-February 15th, San Francisco, CA.