Trial Caps 4 Decades of Failure With Pediatric Sarcoma

There is a long legacy of disappointment in the treatment of children and young adults with metastatic rhabdomyosarcoma.

Rhabdomyosarcoma is a rare disease, with about 400 children and young adults diagnosed annually in the United States. And metastatic rhabdomyosarcoma is rarer still, with about 15% to 20% of that group of youngsters having the more advanced disease at diagnosis.

These patients with stage 4 disease, with the exception of a small number of those younger than 10 years who have embryonal rhabdomyosarcoma, have a long-term, event-free survival (EFS) of less than 20%.

In other words, the disease marches grimly onward sooner, rather than later, in the great majority of these young patients with advanced cancer.

During the last 30 years, none of a variety of new treatment approaches has been able to improve that outcome, according a new study in this setting by Brenda J. Weigel, MD, from the University of Minnesota in Minneapolis, and colleagues.

The new study, which started enrolling patients in 2006, sought to reverse that history, and it effectively carried treatment efforts into a fourth decade.

The clinical trial design of the Children's Oncology Group ARST0431 trial had considerable promise, explain the authors in the study, which was published online October 26 in the Journal of Clinical Oncology.

It involved a complex chemotherapy schedule that included multiple weeks of use of vincristine/irinotecan, which previously had demonstrated a complete or partial response rate of 70%, "the highest of any combination tested to date," observe the authors.

Furthermore, irinotecan is a radiation-sensitizing agent and was scheduled with concurrent radiation, a strategy that has proved useful when used in a variety of other malignancies.

In addition, the chemotherapy strategy included dose intensification with interval compression, an approach that had improved the outcome of patients with localized Ewing sarcoma compared with standard dosing.

Some Good News

The investigators enrolled 109 patients with stage IV (metastatic) rhabdomyosarcoma, most aged 20 years or younger (94%).

Coauthor Carola Arndt, MD, from the Mayo Clinic in Rochester, Minnesota, explained to Medscape Medical News that the clinical presentation of rhabdomyosarcoma "depends on where primary tumor site is." She added that the cancer "can present as proptosis or simus complaints if parameningeal, lump/bump on extremity, abdominal mass, or urinary retention."

In the study, patients received 54 weeks of therapy: blocks of therapy with vincristine/irinotecan (weeks 1 - 6, 20 - 25, and 47 - 52), interval compression with vincristine/doxorubicin/cyclophosphamide alternating with etoposide/ifosfamide (weeks 7 - 19 and 26 - 34), and vincristine/dactinomycin/cyclophosphamide (weeks 38 - 46). Radiation therapy occurred at weeks 20 to 25 (primary) but was also permitted at weeks 1 to 6 (for intracranial or paraspinal extension) and weeks 47 to 52 (for extensive metastatic sites).

Radiation of the primary site was generally delayed until after approximately 6 months of treatment, and irradiation of sites of metastatic disease was selectively undertaken. Surgical resection of the primary site was generally not recommended unless it would significantly reduce the radiation field.

The study had a median follow-up for surviving patients of 3.8 years. The 3-year EFS rate was 38%, and the overall survival rate was 56%.

The results, unfortunately, add to the list of failures in the disease because the primary objective was to improve 3-year EFS to 55%, representing a 60% reduction in the risk for treatment failure compared with standard multiagent therapy.

There was, however, some good news.

Patients with 0-1 Oberlin risk factors had better outcomes. The risk factors include age older than 10 years or younger than 1 year, unfavorable primary site of disease, at least three metastatic sites, and bone or bone marrow involvement. Those patients with 0 or 1 of those risk factors had a 3-year EFS rate of 69%, which compared favorably to the 20% for those with two or more such factors. Unfortunately, these favorable-risk patients (who tend to have metastases only in the lung) are a minority. Dr Arndt described who these patients tend to be: a "very small group of patients who have [embryonal rhabdomyosarcoma] and are older than 10 but nevertheless have an Oberlin score of less than 2."

This trial caps off 4 decades of "well-intentioned but failed efforts" to improve outcomes in this setting, comments Leonard Wexler, MD, from the Memorial Sloan Kettering Cancer Center in New York City. He wrote an accompanying editorial that was published online November 16 in the Journal of Clinical Oncology.

The First Intergroup Rhabdomyosarcoma Study opened in 1972, he pointed out.

Dr Wexler explained that the "challenge for this population, generally, is not eradicating macroscopic disease visible at the time of diagnosis but, rather, preventing the recurrence of occult disease that is invariably still present at the completion of therapy."

Furthermore, most patients with newly diagnosed high-risk rhabdomyosarcoma treated with curative frontline therapy experience relapses within 24 months of diagnosis. Few patients survive more than 3 years after relapse, he added.

The new results are another repudiation of the idea that chemotherapy dose intensification can improve outcomes in children. "For more than 25 years, pediatric oncologists have prayed at the altar...of dose intensity and have walked away largely empty handed," writes Dr Wexler.

"[N]ewer treatment paradigms" are needed for metastatic rhabdomyosarcoma, he writes.

On a positive note, Dr Wexler observes that "well-designed clinical trials of hypothesis-driven, biologically targeted therapies" have begun. And he mentions that a recent phase 2 trial, which employs bevacizumab and temsirolimus in combination with vinorelbine and cyclophosphamide, has "achieved positive results" ( J Clin Oncol. 2014;32:Abstract 10003), as reported by Medscape Medical News.

Dr Arndt owns stock in Merck and Pfizer. Other study authors also have financial ties to industry. Dr Wexler is an advisor/consultant to AstraZeneca.

J Clin Oncol. Published online October 26, 2015. Article abstract.

J Clin Oncol. Published online November 16, 2015. Editorial full text

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Cite this: Trial Caps 4 Decades of Failure With Pediatric Sarcoma - Medscape - Dec 31, 2015.