Irinotecan for rhabdomyosarcoma – pro

Rhabdomyosarcoma arising from skeletal muscle is the most common soft tissue sarcoma of childhood. Approximately 20% of patients present with disseminated disease and have a poor prognosis with combined modality therapy. The remaining 80% of patients present with localized disease and cure rates with combined modality therapy range from 50% to 90% depending on histology, site of disease and the ability of surgery to completely remove all gross and microscopic disease. Patients with recurrent rhabdomyosarcoma have a very poor prognosis and are usually treated with chemotherapy. Active agents for the treatment of recurrent or refractory rhabdomyosarcoma include Cytoxan® (cyclophosphamide), Ifex® (ifosfamide), Adriamycin® (doxorubicin), Actinomycin D® (dactinomycin), Vepesid® (etoposide), Platinol® (cisplatin) and Paraplatin® (carboplatin). A previous study showed a complete or partial response to Camptosar and Cytoxan in 10 of 15 patients with recurrent rhabdomyosarcoma.

Researchers affiliated with the U.S. Children’s Oncology Group reported the outcome of two consecutive trials. In the first trial, patients were initially treated with Camptosar alone. Patients who experienced a partial or complete disappearance of cancer after two cycles of Camptosar then received additional treatment with Camptosar and Oncovin® (vincristine) alternating with the commonly used VAC chemotherapy regimen (Oncovin, Actinomycin D and Cytoxan. Patients who did not respond to treatment with Camptosar received additional treatment with VAC alone. The first trial was closed early due to a high rate of progressive disease (32%) among children who were initially treated with Camptosar alone. The researchers noted, “The unexpectedly high rate of progression seen with Camptosar alone precludes us from recommending the use of this single agent for the treatment of rhabdomyosarcoma.”

The second trial had a similar design, but evaluated the combination of Camptosar and Oncovin, rather than Camptosar alone. Patients who responded to Camptosar and Oncovin received additional treatment with these two drugs alternating with VAC. Patients who did not respond to Camptosar and Oncovin received additional treatment with VAC alone. In the combination trial, 70% of children experienced a partial or complete disappearance of detectable cancer, and only 8% experienced progressive disease. In spite of the promising response rate, survival among children initially treated with Camptosar and Oncovin was similar to that among children treated with VAC alone.

Gastrointestinal problems (abdominal pain, diarrhea, and dehydration) were the most common side effects among children treated with Camptosar and Oncovin. These researchers concluded that the combination of Camptosar and Oncovin is highly active against metastatic rhabdomyosarcoma, and that this combination warrants further testing in intermediate-risk patients with rhabdomyosarcoma.

In the second report researchers affiliated with the French Society of Pediatric Oncology and the United Kingdom Children’s Cancer Study Group reported that Camptosar alone resulted in an overall response rate of 11.4% with one complete response in 35 heavily pretreated patients with rhabdomyosarcoma.The time to disease progression was 1.4 months and the median survival was 5.8 months.

Dacarbazine (DTIC) and temozolomide are similar imidazotetrazine alkylators that methylate DNA at nucleophilic sites. Dacarbazine requires hepatic P450 biotransformation to monomethyl triazenoimidazole carboxamide (MTIC). Temozolomide is orally bioavailable, more lipophilic, and spontaneously converted to MTIC, and it also seems to generate less nausea. Except for phase I studies in patients with solid tumors that included rhabdomyosarcoma, there are no prospective trials for irinotecan and Tmodar, to my knowledge in rhabdomyosarcoma, although there is some evidence of activity in neuroblastoma and Ewings. There are ongoing trials with this combination and cetuximab.

Comments: These data suggest that Camptosar could be a useful agent for the treatment of rhabdomyosarcoma. However, its utility in far advanced patients is not remarkable as a single agent. Adding Camptosar to other drugs earlier in the disease course would be of interest.

Pappo AS, Lyden E, Breitfeld P et al. Two consecutive Phase II window trials of irinotecan alone or in combination with vincristine for the treatment of metastatic rhabdomyosarcoma: the children’s oncology group. Journal of Clinical Oncology 2007;25:362-369.

Vassal G, Couanet D, Stockdale E, et al. Phase III trial of irinotecan in children with relapsed or refractory rhabdomyosarcoma: A joint study of the French Society of Pediatric Oncology and the United Kingdom Children’s Cancer Study Group. Journal of Clinical Oncology 2007:356-361.

Wagner, et al. Temozolomide and intavenous irinotecan for treatment of advanced Ewing Sarcoma. Pediatr Blood Cancer 2007; 48:132-139.

UpToDate, Rhabdomyosarcoma and undifferentiated sarcoma in childhood and adolescence: Treatment

Casey, et al. Irinotecan and temozolomide for Ewing sarcoma: The Memorial Sloan-Kettering experience. Pediatr Blood Cancer 2009; 53:1029-1034.


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