Metastatic Rhabdomyosarcoma: Still Room for Improvement

Leonard H. Wexler | © 2015 by American Society of Clinical Oncology | See Original Here

Author Affiliations: Memorial Sloan Kettering Cancer Center, New York, NY

Of the approximately 400 children and adolescents diagnosed each year in the United States with rhabdomyosarcoma, between one in five and one in six will be considered high-risk patients by virtue of the presence of one or more sites of distant metastatic disease, most commonly involving lymph nodes, bones, bone marrow, and the lungs. These patients tend to be disproportionately older, of male sex, and have alveolar histology, and most present with bulky tumors (> 5 cm). Typically, though, even in patients with widespread disease, these bulky tumors respond promptly and dramatically to any number of chemotherapy regimens. It is not unusual for patients who present with extensive disease to achieve complete, or near-complete, radiographic responses within 3 to 6 months from the start of systemic therapy. Indeed, in the First Intergroup Rhabdomyosarcoma Study that opened in 1972, fully three quarters of patients with metastatic rhabdomyosarcoma achieved either a complete (50%) or partial (25%) response within 15 weeks of therapy that would, by modern standards, be considered mild.1 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. Curative front-line therapy is administered to no more than one third of newly diagnosed patients with high-risk rhabdomyosarcoma, with most patients experiencing relapses within 24 months of diagnosis, and with few patients surviving more than 3 years after experiencing relapse. Unfortunately, over the past four decades, intensification of therapy through five generations of United States-led cooperative group clinical trials under the auspices of the Intergroup Rhabdomyosarcoma Study Group and its successor, the Soft Tissue Sarcoma Committee of the Children’s Oncology Group (COG), has produced no meaningful improvement in outcome for the vast majority of patients with metastatic rhabdomyosarcoma.2-6

In the article accompanying this editorial, Weigel et al7 report the final results of the most recently completed COG clinical trial, ARST-0431, for patients with high-risk rhabdomyosarcoma. This 54-week treatment regimen builds on the striking activity and relatively favorable toxicity profile of the combination of vincristine and irinotecan in preclinical8 and phase II window testing6 in newly diagnosed patients with metastatic rhabdomyosarcoma. In addition, the regimen uses filgrastim in an attempt to maximize alkylator dose intensity by administering standard doses of the other agents at reduced intervals of 2 weeks. ARST-0431 enrolled 109 patients with stage IV (metastatic) rhabdomyosarcoma during a 23-month period. Of those patients enrolled, 80% received irinotecan once per day for 5 days. Radiation of the primary site was generally delayed until after approximately 6 months of treatment, and selective irradiation of sites of metastatic disease was encouraged. Surgical resection of the primary site was generally not recommended unless it would significantly reduce the radiation field (or for palliation). The primary objective was to improve 3-year event-free survival (EFS) to 55%, representing a 60% reduction in the risk of treatment failure compared with standard multiagent therapy. As expected, more than half of patients were older than 10 years and had large, predominantly alveolar tumors, and more than half also had regional nodal involvement in addition to distant metastatic disease. Fewer than 20% of patients were younger than 10 years with embryonal rhabdomyosarcoma. Furthermore, it was determined, using a prognostic risk-classification schema developed from a pooled international analysis of patient outcomes for metastatic rhabdomyosarcoma,9 that approximately 60% of patients had two or more risk factors—a group for whom long-term outcome has been particularly grim.

Unfortunately, the results of this trial proved to be as disappointing as previous results. With a median follow-up time of more than 3.5 years for surviving patients (minimum, 7.7 months), patients experienced a 3-year EFS of 38% and an overall survival of 56%. For patients with alveolar rhabdomyosarcoma (the majority of the patients enrolled onto the study), 5-year EFS was 16% (range, 8% to 28%), and 5-year EFS was essentially identical, at 19%, for patients with an Oberlin risk score of ≥ 2. The best outcome was seen in the relatively small proportion of children younger than 10 with embryonal rhabdomyosarcoma (< 20% of the total patient population) whose 3-year EFS of 60% is comparable to the outcome of patients with nonmetastatic, intermediate-risk rhabdomyosarcoma.10 Though not unanticipated, toxicity was substantial: with the exception of the first 6 weeks of vincristine and irinotecan window therapy, febrile neutropenia, with or without documented infection, occurred in well over half of patients; treatment delays, rare in the beginning weeks of therapy, became common during the middle portion of therapy concurrent with the administration of radiation therapy. What, then, can we learn from this study? The good news, though limited, is that outcome for the relatively small number of younger children with embryonal rhabdomyosarcoma and limited metastatic disease (generally lung only) is substantially better than that for all other patients with metastatic rhabdomyosarcoma. Whether these children will maintain the same excellent outcome with significant de-escalation in alkylator exposure planned in the next COG trial for other intermediate-risk patients is uncertain. For the majority of other patients—the too-high number of those who will die prematurely—the outcome was not unexpected. For more than 25 years, pediatric oncologists have prayed at the altar of the goddess of dose intensity and have walked away largely empty handed. This lack of benefit is not confined to patients with metastatic rhabdomyosarcoma, however, as the same observation has been made of patients with metastatic Ewing sarcoma, desmoplastic small round-cell tumor, and osteosarcoma.11-13 Because the status quo remains unacceptable, where, then, do we begin to look for answers? First, basic scientists and clinicians must leave their silos and be afforded regular opportunities to meet and collaborate with each other. Such efforts have begun and must intensify.14 Our ability to develop clinically relevant targeted therapies against rhabdomyosarcoma has thus far been outstripped by our insights into its biology,15,16 but our collaborative efforts must continue, and funding to support them cannot depend only on the philanthropic generosity of families that have been scarred eternally by the loss of a loved one to rhabdomyosarcoma. Second, as has already begun, well-designed clinical trials of hypothesis-driven, biologically targeted therapies must continue. Though the earliest of these trials failed to achieve the enormous promise that two decades of preclinical research had suggested,17,18 more recent trials have achieved positive results.19 Finally, we must recognize that metastatic rhabdomyosarcoma is not the same biologic entity as nonmetastatic rhabdomyosarcoma. For the latter group of patients comprising the majority of children with rhabdomyosarcoma, local relapse remains the dominant form of treatment failure, and treatment strategies aimed at optimizing local control rates while minimizing long-term morbidity are considered paramount. Conversely, for patients diagnosed with metastatic rhabdomyosarcoma, the inability to eradicate occult microscopic residual disease remains the overwhelming challenge. Whether by targeting genetically quiescent cells20 with the administration of longer-duration maintenance therapy in patients with minimal residual disease,21 or by focusing on drug-development strategies that specifically target the metastatic process,22,23 newer treatment paradigms are desperately needed if we are to end the well-intentioned but failed efforts of the past four decades.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Metastatic Rhabdomyosarcoma: Still Room for Improvement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.
Leonard H. Wexler - Consulting or Advisory Role: AstraZeneca

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