INTRODUCTION
Sarcomas represent a heterogeneous group of rare tumors with a variety of histological and biological characteristics and different prognosis. In pediatric age, rhabdomyosarcoma (RMS) is the most common histotype. Like Ewing sarcoma (ES) and desmoplastic small round cell tumors (DSRCT), RMS is a high-grade tumor with a strong tendency for local invasiveness and metastatic spread. These tumors are currently treated using a multidisciplinary approach that includes surgery, radiotherapy, and intensive multi-agent chemotherapy. While the outcome of treatment for patients with localized RMS and ES is generally a 70-80% survival rate, the outcome remains unsatisfactory for patients with distant metastases and those who relapse (1) (2). Patients with DSRCT still carry a poor prognosis in most cases (3) and, together with those who have metastatic or relapsed RMS and ES, form a high-risk group for whom new treatment approaches need to be investigated.
The use of new drugs to target specific molecular alterations is an attractive approach for poor prognosis sarcomas. However, at this time, the activity data of these new agents is still limited (4) (5). An improvement in the outcome of children with high-risk sarcomas may also be pursued by optimizing the use of already-available drugs known to be active against this disease. The treatment of pediatric sarcomas is currently based on administering chemotherapy cycles containing multiple drugs every three weeks. It may be that cancer cells start growing again during the interval between chemotherapy cycles and develop a resistance to the drugs administered.
Reducing the time between chemotherapy cycles to intensify the treatment has proved feasible and effective in the treatment of ES (6) and, to some degree, for metastatic RMS (7). Higher treatment intensity can also be achieved by increasing the dosage of drugs per unit of time, according to the so-called dose-density approach.
Irinotecan is active against various pediatric tumors, including RMS and other sarcomas (8). As it is relatively non-myelotoxic, we hypothesized that it might be associated with other more myelotoxic drugs.
In this study, we explored the feasibility of a dose-density strategy for patients with high-risk soft-tissue sarcomas that involved a novel combination of irinotecan with a more standard regimen based on alkylating agents. This represents a proof of concept that will be further investigated in the next multicenter trial coordinated by the European pediatric Soft tissue sarcoma Study Group (EpSSG).
METHOD
This study included patients with a histologically confirmed diagnosis of RMS, ES, or DSRCT with metastasis at diagnosis or with relapsed/refractory disease. To be eligible, patients had to be >6 months and ≤ 21 years old, and have: a Karnofsky performance status of 70-100% (for patients >12 years old) or a Lansky Play Score of 70-100% (for patients ≤12 years of age); an adequate bone marrow function (absolute neutrophil count ≥1000/mm3, platelet count ≥100,000/mm3); adequate renal and liver function; and no active grade >2 diarrhea or uncontrolled infection.
The study was approved by the local ethical committee, and informed consent was obtained from patients or parents, as appropriate.
The diagnostic workup consisted of CT and/or MRI scans of the primary tumor, chest CT scan, radionuclide bone scan, bone marrow aspirate, and biopsy. 18F-fluorodeoxyglucose PET was optional.
TREATMENT
As detailed in Figure 1, the first part of the regimen investigated consisted of IVA ( ifosfamide at a dose of 3g/m2 on Days 1 and 2 as a 3-hour intravenous infusion (iv) (with sodium mercaptoethanesulfonate at a dose of 3 g/m2 per day and hyperhydration); vincristine at a dose of 1.5 mg/m2 ( maximum, 2 mg) on Day 1 given as a single bolus dose by intravenous injection; actinomycin at a dose of 1.5 mg/m2 (maximum, 2mg) on Day 1 given as a single bolus by intravenous injection, VAC (vincristine 1.5 mg/m2 iv, actinomycin D 1.5 mg/m2 iv, and cyclophosphamide 1.5 mg/m2, all on day 1) currently used respectively by the EpSSG in Europe, and by the Children’s Oncology Group (COG) in the USA. VAC was administered to patients that received ifosfamide in the first line. Irinotecan was started on day 8 and given for 5 days (preferably Monday to Friday to enable its administration in the outpatient setting), irrespective of blood cell counts, providing the patient was in good clinical conditions. Since this was the first attempt to include irinotecan in a dose-density multidrug combination, a fixed, reduced dose of irinotecan was used (20 mg/m2/day for 5 consecutive days) to gather information and ascertain whether a subsequent formal phase I trial would be possible. Diarrhea prophylaxis included the administration of cefixime 8 mg/kg per os once a day for 9 consecutive days starting on day 6.
Cycles were administered every 21 days, with neutrophils >1.0 x 109/l and platelets to >100 x 109/l and following resolution of non-hematopoietic toxicity. The preventive use of colony-stimulating factors was not allowed. Tumor response was scheduled to be assessed after 3 and 9 cycles at the site of both the primary tumor and any metastases, and more assessments were possible if clinically indicated. The response was classified as: complete response (CR) = complete disappearance of all visible disease; partial response (PR) = a tumor volume reduction of more than two-thirds; minor response (MR) = a tumor volume reduction of more than one-third, but less than two-thirds. A reduction in volume of less than one-third was recorded as stable disease (SD), while an increase in tumor size or the detection of new lesions was classified as progression of disease (PD)
Local treatment with radiotherapy and/or surgery had to be considered after the 4th cycle of chemotherapy, but only general recommendations were given because of the heterogeneity of the study population. Resection was recommended for primary tumors with/without metastases, if feasible. Radiotherapy also had to be considered for primary and metastatic sites in newly-diagnosed metastatic sarcomas. If possible, re-irradiation was recommended in relapsed patients.