Abstract
Background
Irinotecan and temozolmide achieve objective responses in patients with Ewing sarcoma that recurs after initial therapy. Optimal dose schedules have not been defined.
Procedure
We reviewed published series of patients treated with irinotecan and temozolomide for Ewing sarcoma that recurred after initial therapy. We compared objective response rates for patients who received 5-day irinotecan treatment schedules to response rates for patients who achieved 10-day irinotecan treatment schedules.
Results
Among 89 patients treated with a 10-day irinotecan schedule, there were 47 objective responses (53%). Among 180 patients treated with a 5-day irinotecan schedule, there were 52 responses (29%).
Conclusion
In the treatment of recurrent Ewing sarcoma, investigators should consider the use of a 10-day schedule for administration of irinotecan.
The combination of irinotecan and temozolomide has demonstrated activity in the treatment of recurrent Ewing sarcoma. The initial preclinical development of this combination therapy was carried out at the St. Jude Children’s Research Hospital (SJCRH). The investigators examined a variety of doses and dose schedules for the two agents.1 They reported that schedules that called for 10 days of irinotecan demonstrated greater activity than schedules that utilized shorter durations of administration. Investigators from SJCRH reported the results of a phase I evaluation of irinotecan and temozolomide.2 This manuscript included a statement confirming their evaluation of alternative schedules: “Among all the schedules investigated, the schedule of daily administration for 5 consecutive days for 2 consecutive weeks [(qd · 5) · 2] has shown to be the most effective one.”
European investigators have performed a prospective trial of four chemotherapy regimens for the treatment of recurrent and primary refractory Ewing sarcoma (RR-ES).3 The rEECur (International Randomised Controlled Trial of Chemotherapy for the Treatment of Recurrent and Primary Refractory Ewing Sarcoma) trial was designed as a “pick the winner” strategy to compare four systemic therapy regimens: high-dose ifosfamide, cyclophosphamide/topotecan, irinotecan/temozolomide, and gemcitabine/docetaxel. At the time of the second interim analysis, the investigators concluded that the combination of irinotecan and temozolomide was inferior to two of the other regimens. The study design called for the administration of irinotecan for 5 days in each cycle in combination with temozolomide.
There are multiple reports of the clinical efficacy of irinotecan and temozolomide in the treatment of recurrent Ewing sarcoma (Table 1).3–15 The majority of these reports are retrospective analyses of clinical experience. Of the 12 published reports, only four were prospective phase 1 trials. The Salah et al. study is difficult to analyze.15 Total 53 patients participated in the study, but only 43 were evaluable for objective response. Of the 53 patients, 47 received irinotecan in a 5-day schedule and six received irinotecan in a 10-day schedule. The authors did not report the breakdown of responses by treatment regimen. We have excluded this publication from our analysis. The Kurucu study reported an overall objective response rate of 55% (11 of 20 patients) but did not break down responses as CR or PR.12
Table 1.
Published reports of irinotecan/temozolomide for the treatment of recurrent Ewing sarcoma
| Reference | Phase | Pt # | Median Age, (range) | CR/PR | RR | TMZ (mg/m2) | Irinotecan (mg/m2)xdxw | Other agents |
|---|---|---|---|---|---|---|---|---|
| Wagner (PBC,2007)[1] | R | 16 | 18 (7–33) | 1/3 | 25% | 100 × 5 | IV 10–20 × 5 × 2 | None |
| Casey (PBC 2009)[2] | R | 19 | 19.5 (2–40) | 5/7 | 63% | 100 × 5 | IV 20 × 5 × 2 | None |
| Hernandez-Marques (An Ped 2013)[3] | R | 8 | 13 (6–18) | 0/3 | 37% | 80–100 × 5 | IV 10–20 × 5 × 2 | None |
| Raciborska (PBC 2013) [4] | R | 22 | 14.3 | 5/7 | 54% | 125 × 5 | IV 50 × 5 | VCR |
| McNall-Knapp (PBC 2010)[5] | I | 1 | NA | 0/1 | 100% | 100 × 5 | IV 20 × 5 × 2 | VCR |
| Wagner (PBC 2010)[6] | I | 5 | (<21) | 1/1 | 40% | 100–150 × 5 | PO 35–90 × 5 | VCR |
| Wagner (PBC 2013)[7] | I | 2 | 20,22 | 1/1 | 100% | 150 × 5 | PO 90 × 5 | VCR, BEV |
| Bagatell (PBC 2014)[8] | I | 7 | (<21) | 0/1 | 14% | 100–150 × 5 | PO 50–90 × 5 | TMS |
| Kurucu (Ped Hem Onc 2015)[9] | R | 20 | 14 (1–18) | *see text | 55% | 100 × 5 | IV 20 × 5 × 2 | None |
| Anderson (Exp Opin 2008)[10] | R | 25 | 15 | 7/9 | 64% | 100 × 5 | IV 10 × 5 × 2 | None |
| Palmerini (Acta Onc 2018)[11] | R | 51 | 21 (3–65) | 5/12 | 34% | 100 × 5 | IV 40 × 5 | None |
| McCabe (Proceedings ASCO)[13] | II | 88 | 19 (4–49) | 4/14 | 20% | 100 × 5 | IV 50 × 5 | None |
R: retrospective; I: Phase I; II: Phase 2; IV: intravenous; PO: oral; TMZ: temozolomide; VCR: vincristine; BEV: bevacizumab; TMS: temsirolimus; Uk: unknown; NA: not applicable; PBC: Pediatric Blood and Cancer; An Ped: Annals of Pediatrics; Ped Hem Onc: Pediatric Hematology and Oncology; Exp Opin: Expert Opinion Investigational Drugs; Acta Onc: Acta Oncologica; Clin Trans Oncol: Clinical and Translational Oncology
see text
The Children’s Oncology Group performed a prospective randomized trial comparing a 5-day and a 10-day irinotecan schedule and observed no difference between the two treatment regimens.16 This report does not conflict with the present analysis for two reasons. First, that study was limited to patients with rhabdomyosarcoma and cannot be assumed to be relevant to the treatment of Ewing sarcoma. Second, that study utilized vincristine and irinotecan; no temozolomide was administered with the irinotecan in that study.
The majority of patients in these reports were reported in the context of retrospective reviews. In prospective clinical trials, the timing of follow-up evaluations is prespecified. The lack of prespecified follow-up in retrospective reviews makes comparison of event-free or progression-free survival problematic. This is less of a problem for the evaluation of objective responses. All of the reports utilized objective response as the primary study outcome and objective response rate is the basis of the present analysis.
Despite these limitations, the number of reported patients is large. In aggregate there were 269 patients. Among them there were 99 patients with objective responses. The response rates reported with a 10-day irinotecan schedule were higher than those reported with a 5-day irinotecan schedule. Among 89 patients treated with a 10-day irinotecan schedule, there were 47 objective responses (53%) (Table 2). Among 180 patients treated with a 5-day irinotecan schedule, there were 52 responses (29%).
Table 2.
Irinotecan/temozolomide treatment for recurrent Ewing sarcoma: comparison of 5 day and 10 day schedules of administration
| Irinotecan dose schedule | |||
|---|---|---|---|
| Daily x 5 days x 2 weeks (10 doses) | Daily x 5 days x 1 week (5 doses) | ||
| Patients | Objective responses | Patients | Objective responses |
| 89 | 47 (53%) | 180 | 52 (29%) |
Several of the published reports included additional chemotherapy agents administered with irinotecan and temozolomide, potentially complicating our analysis. Two reports included temsirolimus and bevacizumab; these agents have not been shown to have activity in Ewing sarcoma and can be discounted. Four reports included the use of vincristine. This is a potential confounding factor, as vincristine is an agent of proven activity in Ewing sarcoma. Every published report described the use of irinotecan and temozolomide for the treatment of patients with metastatic recurrent disease following front-line therapy that included vincristine. In addition, of the 35 patients who received vincristine, 34 received the 5-day irinotecan treatment schedule; only one was treated with the 10-day schedule. Of 38 patients who received vincristine with a 5-day irinotecan schedule, the authors reported 16 objective responses (47%). Of 146 patients who received the 5-day irinotecan schedule without vincristine, the authors reported 36 objective responses (25%). It is possible that there was some synergy between vincristine and irinotecan and temozolomide. However, only one patient who was treated with the 10-day irinotecan schedule received vincristine. Among the remaining 88 patients treated with the 10-day irinotecan schedule without vincristine, there were 46 responses (52%), so there was no confounding effect of vincristine on the comparison between the 5-day and the 10-day irinotecan schedules.
As the bulk of the published experience was retrospective, there was no prospective plan for imaging. As a result, the determination of time to progression was arbitrary and depended on clinical decision to obtain follow-up imaging. Only six of the published reports include information about time to progression (Table 3). Two studies that used the 5-day irinotecan schedule reported median times to progression of 3.0 and 3.9 months. Four studies that used the 10-day irinotecan schedule reported median times to progression of 4.6, 5.5, 8.3, and 9.5 months.
Table 3.
Median time to progression in published reports of irinotecan for the treatment of recurrent Ewing sarcoma
| Reference | Phase | Pt # | Median Time To Progression (months) | TMZ (mg/m2) | Irinotecan (mg/m2)xdxw | Other agents |
|---|---|---|---|---|---|---|
| Wagner (PBC,2007)[1] | R | 16 | 4.6 | 100 × 5 | IV 10–20 × 5 × 2 | None |
| Casey (PBC 2009)[2] | R | 19 | 8.3 | 100 × 5 | IV 20 × 5 × 2 | None |
| Raciborska (PBC 2013) [4] | R | 22 | 3.0 | 125 × 5 | IV 50 × 5 | VCR |
| Kurucu (Ped Hem Onc 2015)[9] | R | 20 | 9.5 | 100 × 5 | IV 20 × 5 × 2 | None |
| Anderson (Exp Opin 2008)[10] | R | 25 | 5.5 | 100 × 5 | IV 10 × 5 × 2 | None |
| Palmerini (Acta Onc 2018)[11] | R | 51 | 3.9 | 100 × 5 | IV 40 × 5 | None |
R: retrospective; IV: intravenous; PO: oral; TMZ: temozolomide; VCR: vincristine; Uk: unknown; PBC: Pediatric Blood and Cancer; An Ped: Annals of Pediatrics; Ped Hem Onc: Pediatric Hematology and Oncology; Exp Opin: Expert Opinion Investigational Drugs; Acta Onc: Acta Oncologica; Clin Trans Oncol: Clinical and Translational Oncology
see text
Since 2013, we have conducted a prospective phase II clinical trial evaluating the addition of cycles of irinotecan and temozolomide added to cycles of cyclophosphamide, doxorubicin, and vincristine and cycles of ifosfamide and etoposide for the treatment of newly diagnosed Ewing sarcoma (NCI NCT01864109). All cycles administer irinotecan 20 mg/m2/day × 10 days and temozolomide 100 mg/m2/day × 5 days. Protocol guidelines specify the administration of a second-generation cephalosporin beginning 2 days prior to administration of irinotecan and continuing through the cycle.17 Guidelines also specify administration of activated charcoal on each day of administration of irinotecan. Adverse events are recorded by research nurses at the completion of each cycle of therapy. As of May 2022, we have administered 384 cycles of this combination. We have observed the following frequency of adverse events grade 3 or higher: febrile neutropenia 0%, vomiting <1%, diarrhea <1%. This compares favorably to the frequency of adverse events grade 3 or higher reported for the irinotecan temozolomide arm of the rEECur study: febrile neutropenia 8%, vomiting 10%, diarrhea 24%.
These data suggest that when we employ irinotecan in the treatment of Ewing sarcoma, we should consider the longer administration schedule. It suggests that the investigators of the rEECur trial might consider an additional comparison arm utilizing a 10-day irinotecan schedule for patients with RR-ES.
Abbreviations
- rEECur
International Randomised Controlled Trial of Chemotherapy for the Treatment of Recurrent and Primary Refractory Ewing Sarcoma
- RR-ES
recurrent/refractory Ewing sarcoma
- SJCRH
St. Jude Children’s Research Hospita
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Table 1 References
Total experience 269 patients, 99 Objective responses, Objective response rate: 37%
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