After 30 Years, a 'Home Run' for Treating Rhabdomyosarcoma?

Alexander M. Castellino, PhD

June 04, 2018

CHICAGO — After 30 years, a significant advancement has been reported on how outcomes can be improved for patients with rhabdomyosarcoma (RMS).

Dr Gianni Bisogno

In this rare childhood disease, which is diagnosed in 350 children in the United States every year, 6 months of low-dose maintenance therapy after standard treatment increased 5-year disease-free survival (DFS) by ~8% and improved overall survival by 13%.

The new data come from the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) and were presented here at a plenary session of the American Society of Clinical Oncology (ASCO) 2018 annual meeting.

"This study establishes the new standard of treatment for patients with high-risk rhabdomyosarcoma, at least in Europe," said lead author Gianni Bisogno, MD, of the University Hospital of Padova, Italy.

ASCO Expert Warren Chow, MD, clinical professor at City of Hope, Duarte, California, agreed. "The study established maintenance chemotherapy after standard chemotherapy as the standard of care in the European consortium," he said.

"By keeping the pressure on this cancer longer with maintenance therapy, we are giving patients two wins — we are boosting cure rates by preventing relapses, and doing so with few side effects," Chow said.

Chow pointed out that this trial was limited to patients younger than 21 years. It is yet to be determined whether this approach can be applied to patients older than 21 years, who are considered to be at high risk because of their age, he noted.

This is the first significant advance in this cancer in more than 30 years. Dr Warren Chow

"Even with the caveats, this is the first significant advance in this cancer in more than 30 years. No doubt, this trial was a home run," Chow said.

However, another expert not involved in the study questioned whether these new results would change clinical practice in the United States. The duration of the initial chemotherapy given in the United States is longer (45 weeks vs 27 weeks in Europe), noted Leonard H. Wexler, MD, pediatric oncologist who treats RMS at Memorial Sloan Kettering Cancer Center, New York City. "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.

Study Details

Because of the rarity of this cancer, the EpSSG study (called RMS2005 Maintenance study) took 11 years to complete. The first patient was enrolled in April 2006, and the study was completed in December 2016.

The trial enrolled patients with pathologically proven high-risk RMS from 108 centers across 14 countries. Enrollment required that patients have no evidence of metastasis and that they had received no treatment for their disease.

Patients were aged 6 months to 21 years and had N0 alveolar RMS or had undergone incomplete resection (group II or III) of embryonal RMS arising in an unfavorable site (eg, the head) and/or N1 complete resection.

All patients received standard intensive therapy, which consisted of nine cycles of high-dose chemotherapy (a combination of ifosfamide, vincristine, and actinomycin D with or without doxorubicin), followed by radiotherapy and surgery.

"Ninety percent of patients achieve complete remission with this approach. Of the others, about a third relapse and will die," Bisogno said. "Some persistent residual disease is a major obstacle to increase cure rates in these patients," he added.

The purpose of the trial was to see whether low-dose chemotherapy given as maintenance therapy was effective against minimal residual disease that was still present after the conclusion of standard chemotherapy, he explained. That is why patients with no evidence of tumor were randomly assigned to receive no treatment (n = 186) or 6 months of maintenance treatment (n = 185).

Maintenance therapy consisted of weekly vinorelbine 25 mg/m2 given intravenously on day 1, 8, and 15 every 28 days; daily cyclophosphamide 25 mg/m2 was given orally daily. Patients received a total of six cycles of maintenance therapy.

Median follow-up was 5 years.

Study Results

The 5-year DFS was 77.6% for patients who received maintenance therapy; it was 69.8% for those who received standard therapy alone (azard ratio [HR], 0.68; P = .06)

Five-year overall survival was 86.5% for the patients who received maintenance therapy vs 73.7% for the those who received standard therapy (HR, 0.52; P = .01).

Compared with standard therapy, maintenance therapy was associated with less anemia, neutropenia, and thrombocytopenia, less infection episodes, and no cardiac, hepatic, gastrointestinal, or renal toxicity.

Bisogno pointed out that future EpSSG trials will study alternate maintenance regimens and different durations of maintenance therapy. He also indicated that, given these data, this approach merits consideration in other solid childhood malignancies.

Team Should Be Congratulated

The discussant for the study, Douglas S. Hawkins, MD, chief of the Division of Hematology/Oncology at Seattle Children's Hospital, Washington, provided context to the EpSSG trial and speculated on why this intervention improved outcomes. He also discussed who should receive maintenance chemotherapy in the future.

"The EpSSG should be congratulated. They conceived, conducted, and completed a randomized study in an exceptionally rare population of patients — pediatric rhabdomyosarcomas," he said. The EpSSG study is only the third positive study of pediatric RMS to be reported in the past 40 years.

He suggested that improvement in outcomes in the EpSSG study may be due to the activity of vinorelbine (Navelbine, Pierre Fabre), which has yielded response rates of 36% and 50% as single agent in relapsed/refractory RMS. Similar responses have been seen with the combination of cyclophosphamide and vinorelbine. In the maintenance phase, patients received 18 doses of vinorelbine, which perhaps accounts for the outcomes reported, he noted.

Hawkins also weighed in on the duration of therapy. He pointed out that, compared with the total of 51 weeks of treatment that patients in the maintenance arm received in this study, the duration of standard therapy in the US Children's Oncology Group (US COG) study is 42 weeks, and it does not include maintenance therapy.

As to who should receive treatment, he noted that low-risk patients, who constitute a third of patients, were excluded from the study. Hawkins pointed out that, of the high-risk patients, only those who demonstrated radiographic remission at week 27 were eligible for maintenance therapy. "Patients with the highest risk were not studied in this study," he said. In particular, treatment outcomes for patients who did not achieve complete remission and were excluded from the study were not reported.

Also, patients with alveolar RMS with regional lymph node involvement (N1) and those with distant metastases — the highest-risk group — were not included in the study.

Hawkins identified reasons why extrapolation of these data to those from the US COG can be challenging. He noted that the standard treatment in the US COG is 42 weeks, which is longer than the 27 weeks in the EpSSG trial. "It is not certain that adding maintenance treatment will improve the outcome," he said. Secondly, he noted that the backbone chemotherapy differs in significant ways in the first 27 weeks. He also indicated that strategies for local control are not identical.

He also indicated that US COG and EpSSG risk stratification do not overlap. Comparisons cannot be made without some adjustments, he said.

Limited Impact in the United States

A press statement from ASCO indicated that findings from this trial have been shared by investigators with soft tissue study group institutions in 14 countries and that the protocol used in this trial is now standard in Europe.

Asked at the press conference about the study's impact on clinical practice in the United States, Chow indicated that it is unusual to use maintenance chemotherapy for pediatric sarcomas. "So this is a paradigm shift," he said.

Dr Warren Chow

However, Chow also noted that this approach needs to be tested with US protocols before it can be standard of care in the United States.

He explained that in the United States, US COG uses irinotecan (Camptosar, Pfizer) on the backbone of vincristine, actinomycin D, and cyclophosphamide, but no maintenance therapy.

Medscape Medical News approached sarcoma experts in the United States who were not associated with the study. All experts acknowledged that the results of this study are not likely to change practice in the United States.

Dr Wexler explained that there is a population of children with newly diagnosed RMS whose tumors have not spread visibly; for these patients, the risk for recurrence is between 30% and 40%. Treatment failure occurs because the tumor is not eradicated at the primary site, appears at other sites, or both.

He also noted that that treatment approach is common in the United States. "There is a near uniform treatment for this disease," he said. Wexler explained that patients are given 3 months of preradiation chemotherapy, followed by concurrent chemotherapy and radiotherapy. Some patients may undergo surgery prior to or after radiotherapy. This approach is designed to achieve local control, he pointed out.

After radiotherapy, patients receive 20 to 22 weeks of chemotherapy, which is expected to achieve systemic control and kill any tumor cells in parts of the body secondary to the primary site. "The entire process takes from 40 to 45 weeks," he noted.

When recurrence occurs, it is either at the primary site or at other sites. The pattern of recurrence indicates whether the tumor is resistant to radiotherapy or chemotherapy. Recurrence at the primary site indicates resistance to radiotherapy; in such cases, providing additional chemotherapy will not benefit the patient. If the tumor recurs at secondary sites, the disease is resistant to chemotherapy, which means that not enough chemotherapy was given initially.

"The purpose of maintenance therapy is to get rid of tumors that are chemoresistant, ie, occur at secondary sites," Wexler said.

In the EpSSG study, all patients were randomly assigned to receive maintenance therapy or no treatment after complete response at week 27, he further explained. Although it is helpful to know that risk for recurrence was reduced, it would be better to know the pattern of recurrence. "What was not shared in the presentation was whether maintenance treatment reduced metastatic recurrence or local recurrence," Wexler said. One would expect all benefit would be at secondary sites, since the purpose of systemic therapy is to reduce the development of metastatic disease.

Margaret von Mehren, MD, chief of the Division of Sarcoma Medical Oncology at Fox Chase Cancer Center in Philadelphia, Pennsylvania, treats adults with RMS in her practice.

"Overall, it is a chemosensitive disease, and we can cure a lot of patients by giving the right-intensity regimen for the right patient," she said.

"This study group [EpSSG] has done a tremendous amount of work in getting meaningful data and getting it right. The results of this study are intriguing and look like maintenance therapy can have a meaningful impact on the disease," von Mehren told Medscape Medical News.

"Chemotherapy is better tolerated in children. Could we give this to adults, and is it feasible in high-risk adults?" von Mehren questioned.

"In the US, pediatric oncologists are a more disciplined group and look for clear guidance from trial data before changing practice. These results will have to be replicated in clinical trials before maintenance chemotherapy can be the standard of care in the US," von Mehren told Medscape Medical News.

Alberto Pappo, MD, director of the Solid Tumor Division at St. Jude's Children's Research Hospital in Memphis, Tennessee, said the new results are exciting, but he needed to see more. "We do not have all the data," he said.

In particular, he noted a discrepancy between the event-free survival, which was the primary endpoint and was not significant, and OS. "As standard treatment, we also do not know how many patients got surgery and how many got radiation or both," he said.

Pappo concluded that, from the abstract, patients who received standard chemotherapy were also randomly assigned to receive doxorubicin or not to receive it. "We do not know whether the patients who received doxorubicin did better," he said.

Given these uncertainties, Pappo indicated that he would not adopt maintenance therapy for his patients in the United States.

Dr Bisogno reports consulting with Clinigen Group and that his travel, accommodations, and expenses are paid by Jazz Pharmaceuticals. Dr Hawkins has received travel expenses from Bayer, Bristol-Myers Squibb, Celgene, and Loxo.

American Society of Clinical Oncology (ASCO) 2018. Abstract LBA2, presented June 3, 2018.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: