Risk‐based treatment for patients with first relapse or progression of rhabdomyosarcoma: A report from the Children's Oncology Group

Abstract

Background The purpose of this study was to evaluate risk and response–based multi‐agent therapy for patients with rhabdomyosarcoma (RMS) at first relapse. Methods Patients with RMS and measurable disease at first relapse with unfavorable‐risk (UR) features were randomized to a 6‐week phase 2 window with 1 of 2 treatment schedules of irinotecan with vincristine (VI) (previously reported). Those with at least a partial response to VI continued to receive 44 weeks of multi‐agent chemotherapy including the assigned VI regimen. UR patients who did not have measurable disease at study entry, did not have a radiographic response after the VI window, or declined VI window therapy received 31 weeks of multi‐agent chemotherapy including tirapazamine (TPZ) at weeks 1, 4, 10, 19, and 28. Favorable‐risk (FR) patients received 31 weeks of the same multi‐agent chemotherapy without VI and TPZ. Results One hundred thirty‐six eligible patients were enrolled. For 61 patients not responding to VI, the 3‐year failure‐free survival (FFS) and overall survival (OS) rates were 17% (95% confidence interval [CI], 8%‐29%) and 24% (13%‐37%), respectively. For 30 UR patients not treated with VI, the 3‐year FFS and OS rates were 21% (8%‐37%) and 39% (20%‐57%), respectively. FR patients had 3‐year FFS and OS rates of 79% (47%‐93%) and 84% (50%‐96%), respectively. There were no unexpected toxicities. Conclusions Patients with UR RMS at first relapse or disease progression have a poor prognosis when they are treated with this multi‐agent therapy, whereas FR patients have a higher chance of being cured with second‐line therapy.

Recent advances in understanding and managing pediatric rhabdomyosarcoma

“…Alternatively, those with “favorable risk” disease (botryoid histology, or stage 1, or locally or regionally recurring clinical group I eRMS at initial diagnosis not treated with cyclophosphamide) received the chemotherapy regimen without window therapy, irinotecan, or TPZ. While patients with unfavorable risk continued to have poor outcomes (FFS 14% and 15% with window therapy regimens, 21% with TPZ), the study confirmed that those with favorable risk had good outcomes (FFS 79%, OS 84%) 40 .…”

Defining the impact of prognostic factors at the time of relapse for nonmetastatic rhabdomyosarcoma

“…For instance, the Children's Oncology Group's ARST0121 trial enrolled patients whose RMS progressed or recurred. Those with favorable prognostic features received standard multiagent chemotherapy containing doxorubicin, cyclophosphamide, etoposide, and ifosfamide; those with unfavorable features were included in a randomized trial exploring two different schedules of irinotecan followed by multiagent chemotherapy and, failing any response, these patients were switched to receive tirapazamine (a novel agent under investigation) together with the multiagent chemotherapy 5 …”

“…Prognostic factors are used to decide how to treat a relapse, and children with unfavorable risk factors are often included in experimental trials 5 . All published studies analyzing prognostic factors in patients with relapsed RMS considered tumor characteristics at the time of their initial diagnosis, however, not at the time of recurrence.…”

Relapsed Rhabdomyosarcoma

“…In the IRS studies, patients with stage 4 disease at diagnosis were most likely to develop recurrent disease and for patients with non-metastatic ERMS at diagnosis, higher stage was associated with worse post-relapse survival [ 7 , 8 ]. A more recent prospective study for patients with relapsed RMS conducted by the Children’s Oncology Group (COG) similarly found that patients with lower stage ERMS upfront had superior post-relapse outcomes, compared to those with higher stages of upfront disease [ 26 ]. Data from the SIOP-MMT studies support these findings.…”