SUO 2024: Adjuvant Chemotherapy after Primary RPLND for Seminoma - When, Who, if Ever?

(UroToday.com) The 2024 Society of Urologic Oncology (SUO) annual meeting held in Dallas, TX between December 3^rd – 6^th, 2024 was host to a session addressing current controversies in the management of seminoma patients. Dr. Samuel Funt discussed the current indications for adjuvant chemotherapy following a primary retroperitoneal lymph node dissection (RPLND) in seminoma patients.

Dr. Funt noted that when counselling testis cancer patients following a primary RPLND, we need to balance the risks of higher recurrence rates with surveillance versus the increased toxicity rates with adjuvant chemotherapy.

It has long been demonstrated that there are no difference in overall survival rates between immediate adjuvant chemotherapy versus observation in testicular cancer patients with completely resected pathologic stage II non-seminomatous germ cell tumors. In the seminal work by Williams et al. published in 1987, 195 patients were randomly assigned to be treated with two cycles of immediate adjuvant cisplatin-based chemotherapy versus monthly observation with treatment at time of relapse. The median follow-up period was four years. Recurrence rates were higher in the observation arm (49% versus 6%); however, there were no significant differences in overall survival (3/97 deaths in adjuvant arm versus 5/98 in surveillance arm). No identifiable factors were strongly associated with the risk of relapse.¹

While the majority of early recurrences appear to be salvageable in this setting, with no differences in survival rates, Dr. Funt noted that we must acknowledge the fear of cancer recurrence in adolescent and young adult cancer survivors. This issue has become better recognized in the medical community, and there are now multiple groups advocating for a personalized approach to the management of such patients, despite high-level evidence suggesting that there are no differences in overall survival rates.

Despite the increased anxiety that these young adult patients often experience due to the fear of disease recurrence, we must counsel these patients about the increased risks of secondary malignancies with systemic therapy. In 2016, Kier et al. demonstrated that BEP chemotherapy increased the 20-year cumulative incidence of a second malignant neoplasm by 1.7-fold, and that there was a 1.6-fold excess morality due to a secondary malignancy following BEP.²

What about cardiovascular disease after chemotherapy? Numerous well-conducted studies have demonstrated that the risk of major adverse cardiovascular events increases by 3–7 fold in testicular cancer patients who receive chemotherapy.

Instead of dichotomizing the treatment choice to either adjuvant full-dose chemotherapy versus observation, can we offer patients an alternative third option such as reduced intensity chemotherapy (e.g., EP x2)? In a study of 150 patients with stage II non-seminomatous germ cell tumors who received EP x2 between 1989 and 2016 and were followed for a median of 9 years, only 2 patients (1.3%; 1 patient each with pN2 and pN3 disease) experienced relapse. Three patients died, all unrelated to NSGCT. The 10-year disease-specific, recurrence-free, and overall survival rates were 100%, 98%, and 99%, respectively.³

What are the advantages of EP x 2 versus BEP x 3 or EP x 4? There are less treatment visits with EP x2 (10 versus 20 and 21 with BEP x3 and EP x4, respectively). The elimination of bleomycin avoids pulmonary and vascular toxicities displayed by Raynaud’s phenomenon and possibly cardiovascular disease. This regimen is also associated with less neurotoxicity, nephrotoxicity, and myelosuppression.^4-6 Two cycles of adjuvant chemotherapy also results in significantly better paternity rates (100%), compared to 3 or 4 cycles (76% to 83%).

Another important consideration in the decision-making process is the fact that non-seminoma patients who do not receive adjuvant chemotherapy will require more frequent visits and cross-sectional imaging.

What lessons can we learn from other cancers regarding nodal involvement and risk of recurrence? In breast, gastric, and rectal cancers, it has been consistently demonstrated that the number of pathologic lymph nodes involved is significantly prognostic of subsequent survival rates. However, discrimination between high and low-risk nodal groups required samples of 30 to 200 cases, which has long been difficult to achieve in series of testicular cancer patients.

What can we learn from the primary RPLND for seminoma datasets? In PRIMETEST, SEMS, and COTRIMS, none of the patients received adjuvant chemotherapy.^8-10 Conversely, in SWENOTECA and the MSKCC series, 29% and 36% of patients received BEP x1 and EP x2, respectively.

The relapse rates are highlighted below. In the three trials without adjuvant chemotherapy (PRIMETEST, SEMS, and COTRIMS), the relapse rates ranged between 10% and 30%, and no pathologic predictors of relapse were identified. Conversely, in SWENOTECA and the MSKCC series, the rates approached the lower bound of 10-11%.

Similar to what was performed in the other sites of malignancy, can we stratify the recurrence rates by the nodal stage? In the SEMS trial, the 2-year recurrence-free survival rates stratified by pathologic nodal stage failed to demonstrate a significant difference by nodal stage (p=0.36). However, on further evaluation, we note meaningful absolute differences in the 2-year rates, and the lack of statistical significance likely reflects an ‘underpowering’ issue, as opposed to reflecting ta true absence of difference.

A similar pattern was observed in the Indiana University series, where no significant differences in recurrence rates were observed when stratified by pathologic nodal stage or number of positive nodes.¹¹

However, it appears that patients with a longer time from orchiectomy to RPLND (>12 months) and longer time on surveillance may have superior recurrence-free survival rates.¹¹

With regards to follow-up for seminoma patients, there are minimal differences in the number of follow-up visits needed, irrespective of whether adjuvant chemotherapy was administered or not (10 versus 11). However, patients treated with adjuvant chemotherapy require half the number of axial scans within a 5-year frame (3 versus 6 CTs or MRIs).

Can we personalize the approach to adjuvant chemotherapy post-RPLND using novel technologies? For example, ctDNA has been demonstrated in the IMvigor-010 trial to be a useful predictive tool to determine which patients benefit from adjuvant atezolizumab post-radical cystectomy for high-risk, muscle-invasive urothelial carcinoma.¹²

In testes cancer, there is emerging evidence recently presented at ASCO GU 2024 that suggests that ctDNA can be used as a prognosticating tool for event-free survival in patients undergoing surveillance following a primary RPLND and/or chemotherapy.

Dr. Funt concluded as follows with regards to adjuvant chemotherapy after primary RPLND for seminoma patients:

• Important considerations are patient preference and quality of life as, well as minimizing the late side effects of chemotherapy.
• The one randomized trial of adjuvant chemotherapy versus surveillance was done for patients with non-seminomatous germ cell tumors approximately 30 years ago and showed no overall survival difference.
• There may be a higher risk of relapse with worse pathologic nodal stage.
• Adjuvant chemotherapy is highly effective and minimizes the burden of surveillance for all patients and the burden of chemotherapy for those destined to relapse.
• We are early in the primary RPLND for seminoma experience, but a discussion of the risks and benefits of adjuvant chemotherapy is appropriate.
• Future studies should incorporate novel biomarkers of minimal residual disease (e.g. ctDNA and/or miRNA).

Presented by: Dr. Samuel Funt, MD, Assistant Attending, Genitourinary Medical Oncologist, Memorial Sloan Kettering Cancer Center, New York, NY

Written by: Rashid K. Sayyid, MD, MSc – Robotic Urologic Oncology Fellow at The University of Southern California, @rksayyid on Twitter  during the 2024 Society of Urologic Oncology (SUO) annual meeting held in Dallas, between the 3^rd and 6^th of December, 2024.

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