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De-escalation Strategy in Seminoma: An Alternative Option?

Seminoma, the commonest type of testicular cancer, has a great treatment success rate, with 3-year progression-free survival (PFS) rates of at least 90%. However, the treatment regimen is intense, comprising combination chemotherapy and large-volume radiation therapy, with their associated toxicities.

A new trial (SAKK 01/10) that tested a de-escalated treatment strategy, with lower chemotherapy doses and reduced radiation therapy, has shown a favorable 3-year PFS — similar to that seen with standard-of-care approaches, but with minimal toxic effects.

Even though the study did not meet the primary endpoint of progression-free survival of 95% at 3 years, the authors note that a favorable efficacy and toxicity profile was observed in the trial, and they conclude that “de-escalated combined modality treatment warrants further study in this setting.”

The study was published online October 10 in The Lancet Oncology.

The efficacy of the de-escalation strategy used in this trial suggests that it “could be a valid alternative for some patients,” Patrizia Giannatempo, MD, and Nicola Nicolai, MD, from the Foundation IRCCS National Cancer Institute, Milan, Italy, in an accompanying editorial.

However, they add that “the potential advantage of reducing treatment sequelae cannot be answered by the SAK 01/10 trial yet, since a longer follow-up is needed.”

The editorialists note that this is one of several trials that have explored reductions in treatment.

“De-escalation strategies in stage IIA and IIB seminoma are a current unmet clinical need and could be implemented in the coming years,” they editorialists comment, adding that “patient preference has arisen as a fundamental criterion in the discussion of treatment options.”

Effective, With Lower Toxicity

The single-arm SAKK 01/10 trial was led by Alexandros Papachristofilou, MD, of the Department of Radiation Oncology, University Hospital Basel, Switzerland, and involved 116 patients with seminoma (46 patients with stage IIA disease and 70 with stage IIB disease) with a median age of 40 years. A median of two lymph were affected, and the median lymph node size was 2.5 cm.

All patients received a de-escalated treatment regimen, comprising one cycle of carboplatin (AUC, 7) at a median dose of 989 mg, followed by involved-node radiation therapy (30 Gy in 15 fractions for stage IIA disease and 36 Gy in 18 fractions for stage IIB disease).

This is quite a reduction from the standard treatment approach, which involves three to four cycles of cisplatin-based combination chemotherapy and large-volume pelvic radiation therapy. The authors commented that they were able to reduce the volume of radiation therapy by about three quarters.

After a median follow-up of 4.5 years, the 3-year progression-free survival was 95.2% in patients with stage IIA disease and 92.6% in patients with stage IIB disease.

A total of seven patients had relapse, at a median of 16.7 months after treatment initiation, and all of these patients were successfully treated with salvage standard-dose cisplatin-based combination chemotherapy, the authors note. There was one patient death due to a second primary cancer 2.5 years after entering the trial.

The 3-year overall survival was 99.3% and the seminoma-specific survival was 100% at the time the analysis was conducted, the authors note.

Treatment-related acute adverse events of any grade were observed in 48% (n = 56) of the cohort and were primarily mild (grade 1) in 30 patients (21%) and moderate (grade 2) in 22 patients (19%). Grade 3 or higher events were primarily chemotherapy-associated cytopenias and occurred in eight patients (7%) (neutropenia in 4% and thrombocytopenia in 3%), and vomiting in one patient (1%). There were no treatment-related deaths and no late treatment-related adverse events reported.

“The acute toxicity profile in our trial differs from standard-of-care radiotherapy and cisplatin-based combination chemotherapy, which commonly lead to substantial acute toxic effects in around 50% of patients, ” the authors commented.

“Although no late treatment-related adverse were noted in the study, we did record high rates of metabolic syndrome, in line with previous observations, highlighting the need of long-term follow-up and survivorship programs,” they added. They also noted that hypogonadism affected more than one third of patients, but “we did not gather any data on testosterone replacement therapy, and thus are unable to quantify the possible burden to patients.”

The editorialists emphasize that the long-term effects of full-dose radiation therapy and chemotherapy that are current standard of care are cause for concern. “Population data have shown how clinical hypogonadism, cardiovascular events, metabolic syndrome, and second cancers might occur within the first 10 years after completion of therapy, but the occurrence of these events might further increase after the first decade and could shorten the overall survival of patients by around 7-8 years,” they noted.

The study was funded by the Swiss State Secretariat for Education, Research and Innovation and Rising Tide Foundation for Clinical Cancer Research.

Several of the co-authors have disclosed relationships with industry as noted in the paper. The editorialists have no competing interests.

Lancet Oncol. Published online October 10, 2022. Abstract; Editorial

Roxanne Nelson is a registered nurse and an award-winning medical writer who has written for many major news outlets and is a regular contributor to Medscape.

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