Single-dose carboplatin followed by involved-node radiotherapy for stage IIA and stage IIB seminoma (SAKK 01/10): a single-arm, multicentre, phase 2 trial.

BACKGROUND

Standard treatment options for patients with stage IIA or stage IIB seminoma include either para-aortic and pelvic radiotherapy or three to four cycles of cisplatin-based combination chemotherapy. These options result in 3-year progression free survival rates of at least 90%, but bear risks for acute and late toxic effects, including secondary malignancies. We tested a novel approach combining de-escalated chemotherapy with de-escalated involved node radiotherapy, with the aim of reducing toxicity while preserving efficacy.

METHODS

In the single-arm, multicentre, phase 2 SAKK 01/10 trial, patients with stage IIA or IIB classic seminoma (either at primary diagnosis or at relapse during active surveillance for stage I) were enrolled at ten centres of the Swiss Group for Clinical Cancer Research and ten centres of the German Testicular Cancer Study Group. WHO performance status 0-2, age 18 years or older, and adequate bone marrow and kidney function were required for eligibility. Treatment comprised one cycle of carboplatin (area under the curve 7) followed by involved-node radiotherapy (30 Gy in 15 fractions for stage IIA disease and 36 Gy in 18 fractions for stage IIB disease). The primary endpoint was 3-year progression-free survival. Efficacy analyses were done on the full analysis set, which comprised all patients who signed the informed consent, were registered in the trial, initiated trial treatment, and met all medically relevant inclusion or exclusion criteria. Safety was assessed in all patients who were treated at least once with one of the trial treatments. The study is ongoing but no longer recruiting, and is registered with Clinicaltrials.gov, NCT01593241.

FINDINGS

Between Oct 18, 2012, and June 22, 2018, 120 patients were registered in the study. 116 patients were eligible and started treatment according to the study protocol (46 patients with stage IIA disease and 70 with stage IIB disease). After a median follow-up of 4·5 years (IQR 3·9-6·0), 3-year progression-free survival was 93·7% (90% CI 88·5-96·6). With a target progression-free survival of 95% at 3 years, the primary endpoint was not met. Acute treatment-related adverse events of any grade were noted in 58 (48%) of 116 patients, and grade 3 or 4 treatment-related adverse events occurred in the form of neutropenia in five (4%) patients, thrombocytopenia in three (3%) patients, and vomiting in one (1%) patient. No treatment-related deaths and no late treatment-related adverse events were reported. Serious adverse events were reported in five (4%) of 116 patients (one transient creatinine increase and four second primary tumours).

INTERPRETATION

Despite the fact that the primary endpoint was not met, we observed favourable 3-year progression-free survival with single-dose carboplatin area under the curve 7 and involved-node radiotherapy, with minimal toxic effects. Our findings might warrant discussion with patients about the SAKK 01/10 regimen as an alternative to standard-of-care treatment, but more research on this strategy is needed.

FUNDING

Swiss State Secretariat for Education, Research and Innovation and Rising Tide Foundation for Clinical Cancer Research.

Informations de copyright

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Déclaration de conflit d'intérêts

Declaration of interests AP has received honoraria from Astellas, Debiopharm, Janssen, Merck Serono, and Sanofi; and travel support from Astellas, AstraZeneca, and Bayer. MP has received consulting fees from Abbvie, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eisei, Merck Serono, Merck Sharpe & Dohme, Novartis, Pfizer, Roche, and Takeda; honoraria from Amgen, Bayer, Janssen, Nestle, and Sanofi; and travel support from AstraZeneca, Boehringer Ingelheim, BMS, Daiichi Sankyo, Roche, Takeda, and Vifor. MH has received consulting fees from EusaPharma, Janssen, and Sanofi; honoraria from AstraZeneca, Amgen, Celgene, Janssen, Jazz Pharma, Sanofi, and Takeda; and travel support from Janssen. D-RB has received consulting fees from Astellas, Bayer, BMS, Ipsen, Janssen, MSD, and Novartis; and travel support from Ipsen and Janssen. DZ has received honoraria from BMS and travel support from Janssen; and has participated in advisory boards for BMS, Janssen, Merck-Serono, MSD, Pierre-Fabre, and Sanofi. RC has received consulting fees from Astellas, BMS, Bayer, Janssen, Sanofi, Roche, Novartis, MSD, Pfizer, Merck, Debiopharm, and AstraZeneca; and honoraria from Astellas, Roche, and Pfizer. AP, JB, MH, SK, AL, FZ, AD, A-CM, SG, and RC are members of the German Testicular Cancer Study Group. AP, SH, MP, AL, D-MA, PMP, D-RB, DZ, CS, CB, SG, and RC are members of the Swiss Group for Clinical Cancer Research. All other authors declare no competing interests.