<div>Irinotecan dose schedule for the treatment of Ewing sarcoma</div><div>Paul A Meyers, MD Memorial Sloan Kettering Cancer Center</div><div>Emily Slotkin, MD Memorial Sloan Kettering Cancer Center</div><div>Corresponding author:</div><div>Paul A Meyers, MD</div><div>Memorial Sloan Kettering Cancer Center</div><div>1275 York Ave</div><div>New York, NY 10065</div><div>Phone: 1-212-639-5952</div><div>Email: meyersp@mskcc.org</div><div>Abstract:</div><div>Background: Irinotecan and temozolmide achieve objective responses in
patients with Ewing sarcoma which recurrences after initial therapy.
Optional dose schedules have not been defined.</div><div>Procedure: We reviewed published series of patients treated with
irinotecan and temozolomide for Ewing sarcoma which 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.</div><div>Results: Among 94 patients treated with a 10 day irinotecan schedule
there were 48 objective responses (51%). Among 218 patients treated
with a 5 day irinotecan schedule there were 65 responses (30%).</div><div>Conclusion: When we use irinotecan to treat Ewing sarcoma we should
administer 10 days of treatment.</div><div>Abstract word count: 118</div><div>Text word count: 892</div><div>Short running title: Irinotecan dose schedule for Ewing sarcoma</div><div>Keywords: Ewing sarcoma, irinotecan, dose schedule</div><div>Number of tables: 2</div><div>Number of figures: 0</div><div>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 which called for 10 days of irinotecan
demonstrated greater activity than schedules which 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 five consecutive days for two
consecutive weeks [(qd · 5) · 2] has shown to be the most effective
one”.</div><div>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 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 five days in each cycle in combination with temozolomide.</div><div>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 4 were
prospective phase 1 trials. The Salah study is difficult to
analyze.[15] 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 6 received irinotecan in a 10 day
schedule. The authors did not report the breakdown of responses by
treatment regimen. For the purpose of analysis an arbitrary assignment
of responses was made by assigning responses in proportionately to the
use of regimens. Of 12 objective responses observed in 43 evaluable
patients, for the purpose of the analysis one of 5 who received the 10
day schedule was assumed to have achieved an objective response and 11
0f 38 patients who received the 5 days schedule were assumed to have
achieved an objective response. 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]</div><div>The majority of patients in these reports were accrued 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.</div><div>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.</div><div>Despite these limitations, the number of reported patients is large. In
aggregate there were 312 patients. Among them there were 111 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 94 patients treated with a 10 day irinotecan
schedule there were 48 objective responses (51%)(Table 2). Among 218
patients treated with a 5 day irinotecan schedule there were 65
responses (30%).</div><div>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
x 10 days and temozolomide 100 mg/m2/day x 5 days. Protocol guidelines
specify the administration of a second generation cephalosporin
beginning two 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 &lt;1%,
diarrhea &lt;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%.</div><div>These data suggest that, in the absence of definitive evidence that
shorter schedules of irinotecan are as effective as longer schedules,
when we employ irinotecan in the treatment of Ewing sarcoma we should
utilize 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
recurrent/refractory Ewing sarcoma.</div><div>1. Houghton, P.J., et al., <i>Efficacy of topoisomerase I inhibitors,
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