Maintenance Chemo Improves Pediatric RMS

According to results from a 10-year clinical trial led by the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG), maintenance chemotherapy after standard treatment improves the survival of children with high-risk rhabdomyosarcoma (RMS). The findings were presented by Gianni Bisogno, MD, of the University Hospital of Padova in Italy, during the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL, June 1–5.

RMS, a mesenchymal tumor that occurs when skeletal muscle cells fail to fully differentiate, is “exceptionally rare,” Bisogno noted, with just 350 children diagnosed in the United States each year. Although this cancer is highly aggressive, treatment with an intensive chemotherapy cocktail, along with radiation and surgery, can induce complete remissions—no radiologic evidence of tumor—in most patients, he added. Even so, up to 40% relapse within the first year and most of these children do not survive.

“Our idea was to see if a regimen of low-dose chemotherapy could help eradicate the persistent residual disease that is a major obstacle in terms of increasing the cure rate,” Bisogno said. Data from some breast cancer studies have suggested therapeutic activity with this approach, also known as metronomic chemotherapy, “which is why we applied the concept to our study,” he added.

The EpSSG study involved 371 patients, most 10 years old or younger, with high-risk RMS—characterized by tumors occurring in unfavorable sites, including the head and neck, as well as unfavorable alveolar histology. All were in complete remission after nine cycles of standard therapy with high-dose ifosfamide, vincristine, and actinomycin D, with doxorubicin added in some cases. They were randomly assigned to receive 6 months of low-dose intravenous vinorelbine and oral cyclophosphamide, or no further treatment.

In the trial's experimental arm, the 5-year disease-free survival and overall survival rates increased by 8% and 13%, respectively, Bisogno reported. The maintenance regimen was also largely well tolerated, he said, with mainly hematologic side effects and no cardiac, renal, or hepatic toxicities.

The rarity of RMS notwithstanding, 40% of all cases diagnosed are in adults; as such, the tolerability of this pediatric regimen “is notable and important, because it should be easily applicable to adult patients,” said Robin Jones, MD, of The Institute of Cancer Research in London, UK.

“It always amazes me that the field of pediatric oncology continues to make great strides by using old drugs in new ways,” remarked Richard Schilsky, MD, chief medical officer of ASCO. He observed that metronomic chemotherapy is thought to potentially exert antitumor efficacy by inhibiting angiogenesis, and wondered whether this might help explain the improved outcomes.

Bisogno agreed that it could be one mechanism, along with low-dose cyclophosphamide possibly having immunomodulatory effects. Then, too, the use of vinorelbine—not part of standard therapy—could be another contributing factor, he said.

Douglas Hawkins, MD, of Seattle Children's Hospital in Washington, pointed out that standard RMS treatment regimens used in the EU and by the U.S.-based Children's Oncology Group last for 27 weeks and 42 weeks, respectively. With this EpSSG study, patients in the experimental arm received 51 weeks of treatment. “Perhaps the benefit is not from maintenance per se, but rather the prolonged duration of therapy,” he said.

Meanwhile, these results have established a new standard of care in the EU, Bisogno said, that incorporates low-dose maintenance therapy for high-risk pediatric RMS. He also encouraged further trials investigating this approach in treating other types of pediatric solid tumors. –Alissa Poh