New Standard of Care in Rhabdomyosarcoma?

Roxanne Nelson, RB, BSN

October 18, 2019

Adding 6 months of maintenance chemotherapy appears to improve survival for patients with high-risk rhabdomyosarcoma (RMS) and will be the new standard of care in future European clinical trials, according to researchers.

The addition of low-dose vinorelbine/cyclophosphamide improved the 5-year overall survival rate from 73.7% to 86.5%, or an absolute 13% increase.

"We now recommend using maintenance therapy in all high-risk patients as the standard of care," lead author Gianni Bisogno, MD, of the University of Padova, Italy, told Medscape Medical News.

The data come from the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) and were initially presented at a plenary session of the American Society of Clinical Oncology (ASCO) 2018 annual meeting and reported by Medscape Medical News at that time.

Study results were published online September 24 in Lancet Oncology.

Although these results may change practice in Europe, that may not be the case in the US.

During the ASCO meeting, Leonard H. Wexler, MD, a pediatric oncologist who treats RMS at Memorial Sloan Kettering Cancer Center in New York City, pointed out that the duration of the initial chemotherapy given in the US is longer than in Europe (45 weeks vs 27 weeks).

"Results without maintenance treatment in the US are similar to what the EpSSG study reported with maintenance therapy. Whether we can further reduce metastatic disease recurrence by adding maintenance therapy is currently not known," he told Medscape Medical News.

Even though RMS is the most common soft tissue sarcoma in children and young adults, it is still quite rare, with an annual incidence of 4 cases per 1 million in infants, children, and teenager aged 0–19 years. It is diagnosed in about 350 children in the US every year and approximately 400 in Europe.

For patients with non-metastatic disease, survival is about 70% when treated with a risk-adapted multimodal treatment strategy that has been refined over the past few decades, as a result of several studies coordinated by international cooperative groups such as the Children’s Oncology Group (COG) in the US and the EpSSG.

Study Details

Over a 10-year period (2006–2016), 371 patients aged 6 months to 21 years — and with N0 alveolar RMS or those who had undergone incomplete resection (group II or III) of embryonal RMS arising in an unfavorable site and/or N1 complete resection — were enrolled and randomly assigned to the two groups: 186 to active treatment only and 185 to receive maintenance chemotherapy.

Maintenance therapy consisted of weekly vinorelbine 25 mg/m2 on day 1, 8, and 15 every 28 days and daily cyclophosphamide 25 mg/m2, for an overall total of six cycles of maintenance therapy.

At a median follow-up of 60 months, the 5-year disease free survival was 77.6% in the maintenance therapy group vs 69.8% in the group receiving standard therapy alone (hazard ratio [HR], 0.68; P = .06).

As noted above, 5-year overall survival was 86.5% vs 73.7% in favor of the maintenance therapy group (HR, 0.52; P = .01).

Toxicity was manageable in patients who received maintenance chemotherapy, according to the authors: 75% had grade 3–4 leukopenia, 82% grade 3–4 neutropenia, 10% anemia, 1% thrombocytopenia, and 31% had an infection. Only one patient experienced a grade 4 nonhematologic toxicity (neurotoxicity).

"Toxicity was nearly exclusively myelosuppression but this was not a problem in comparison with what we see with standard chemotherapy," said Bisogno. "We were very conservative with our guidelines and recommend dose reduction when neutrophils were below 1000."

Flawed Study, but "Cards Well Played"

In an accompanying commentary, William H Meyer, MD, a pediatric oncologist at the University of Oklahoma Health Sciences Center in Oklahoma City, notes that prior to this report, all studies that added other active chemotherapy drugs to standard treatment (such as an alkylator, vincristine, and dactinomycin) did not find that outcomes were improved.

"As suggested in a commentary discussing the previous European rhabdomyosarcoma study, perhaps the issue is not that we do not have enough cards (ie, cytotoxic drugs) in our deck, but that we have not learned to play them well," writes Meyer.

He said the EpSSG study had flaws. One was its very long accrual period of 10 years, which was originally projected to be 6 years. However, this was a relatively long time even by pediatric oncology standards, he points out.

The original statistical design had to be revised to account for a smaller enrollment than initially planned for. The primary outcome of the study, disease free survival, was clinically significant, although it "did not quite meet the statistical parameters defined by the revised design," Meyer writes.

Some questions also remain unanswered. It is unclear which intervention improved outcomes: the addition of vinorelbine; adding metronomic continuous oral cyclophosphamide; using an active chemotherapy drug pair; or extending the total duration of therapy. "Other important questions include whether the results are equally relevant for both fusion-negative and fusion-positive tumors and whether they are relevant for other rhabdomyosarcoma risk groups," he notes. But, given the rarity of RMS, it is unlikely that future studies "will clarify all these uncertainties," he adds.

Overall, the significance of the EpSSG study is that the use of maintenance chemotherapy cured more patients than standard treatment alone and was generally well tolerated. "The results of this EpSSG study now define maintenance chemotherapy as the new standard for this group of children and adolescents with rhabdomyosarcoma — cards well played," Meyer concludes.

The study was funded by the Fondazione Città della Speranza, Association Léon Berard Enfant Cancéreux, Clinical Research Hospital Program (French Ministry of Health), and Cancer Research UK. The study authors and editorialist have disclosed no relevant financial relationships.

Lancet Oncol. Published online September 24, 2019. Abstract, Editorial

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