This is a comment by Nicolas ANDRE from the Department of Pediatric Hematology and Oncology, Hôpital de La Timone, AP-HM, the UMR Inserm 1068, CNRS UMR 7258, AixMarseille Université U105, Marseille Cancer Research Center (CRCM) and Metronomics Global Health Initiative,Marseille, France published in Pediatric Blood and Cancer

The special report from Slotkin and Meyer regarding the question of the schedules of administration of irinotecan for the treatment of Ewing sarcoma1 was of great interest by highlighting how the question of “dose & schedule” is still central for chemotherapy and remains largely unanswered in 2022. However, I would like to further address here that the différences in outcome observed with different irinotecan schedules might also be explained by different mechanisms of action of irinotecan. Indeed, for a given cancer chemotherapy drug, changes in doses and/or schedules are logically translated into changes in pharmacokinetics and ultimately in turn potentially in different pharmacodynamics. Thus, for irinotecan, the protracted schedule that has been proposed from the start as the most effective2 may be rooted in different pharmacodynamics and therefore different mechanisms of action. While the term “protracted schedule” has been chosen for irinotecan, it would otherwise have been called a metronomic schedule for many other anti-cancer agents.3 In that perspective, beyond direct effects on cancer cells or cancer stem cells4 protracted/metronomic irinotecan also displays anti-angiogenic properties5 and importantly pro-immune anticancer properties. Indeed, irinotecan has been shown to both reduce Tregs and augment major histocompatibility complex/ class I–mediated tumor antigen presentation.6 Elsewhere, it was shown that irinotecan could also downregulate PD1 expression.7 Lastly,Waxman et al. have reported that an intermittent intermediate metronomic schedule could further re-enforce the pro-immune effect of chemotherapy.8 Therefore, the protracted schedule of irinotecan (5 days on /2 days off for 2 weeks) that has been identified as optimal likely strengthens its potential immunomodulation effect. Rhabdomyosarcoma seems to be a “metronomic-sensitive” disease. For instance, metronomic etoposide is frequently prescribed for palliative care9 and navelbine-cyclophosphamide10 and a more complex multidrug metronomic combination11 are now being used as a maintenance regimen. As mentioned by Slotkin and Meyers,1 irinotecan is used in combination with temozolomide for a growing number of pediatric tumors (medulloblastoma, rhabdomyosarcoma, neuroblastoma), whether the same kind of metronomic schedules are better for each tumor type or not needs to be confirmed. Similarly, one could also question the best schedule for temozolomide. Indeed, temozolomide also has significant multi-target activity, including selective Treg depletion, when used in a metronomic manner.12 It would be interesting to further prospectively study through translational work the impact of different schedules of irinotecan on both immunity and angiogenesis in samples from patients. The example of irinotecan illustrates the influence of wording on how we determine the way a treatmentmight work. More importantly, it paves theway for designing more rational combinations and choosing the optimal settings.

REFERENCES 1. Slotkin EK, Meyers PA. Irinotecan dose schedule for the treatment of Ewing sarcoma. Pediatr Blood Cancer. 2022: e30005.

2. Rodriguez-Galindo C, et al. Phase I study of the combination of topotecan and irinotecan in children with refractory solid tumors. Cancer Chemother Pharmacol. 2006;57:15-24. Pediatr Blood Cancer. 2022;e30124.

3. Pasquier E, Kavallaris M, André N. Metronomic chemotherapy: new rationale for new directions. Nat Rev Clin Oncol. 2010;7:455-465.

4. André N, Orbach D, Pasquier E. Metronomic maintenance for highrisk pediatric malignancies: one size will not fit all. Trends Cancer. 2020;6:819-828.

5. Bocci G, et al. Antiangiogenic and anticolorectal cancer effects of metronomic irinotecan chemotherapy alone and in combination with semaxinib. Br J Cancer. 2008;98: 1619-1629.

6. Iwai T, Sugimoto M, Wakita D, Yorozu K, Kurasawa M, Yamamoto K. Topoisomerase I inhibitor, irinotecan, depletes regulatory T cells and up-regulates MHC class I and PD-L1 expression, resulting in a supraadditive antitumor effect when combined with anti-PD-L1 antibodies. Oncotarget. 2018;9:31411-31421.

7. Jabbari N, et al.Modulation of immune checkpoints by chemotherapy in human colorectal liver metastases. Cell Rep Med. 2020;1:100160.

8. Wu J, Waxman DJ. Immunogenic chemotherapy: dose and Schedule dependence and combination with immunotherapy. Cancer Lett. 2018;419:210-221.

9. Devadas SK, Banavali S. Retrospective analysis of outcomes of patients with relapsed, refractory and metastatic sarcomas who have received metronomic chemotherapy. Gulf J Oncol. 2019;1:22-28.

10. Bisogno G, et al. Vinorelbine and continuous low-dose cyclophosphamide as maintenance chemotherapy in patients with high-risk rhabdomyosarcoma (RMS 2005): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20:1566- 1575.

11. Klingebiel T, al. Treatment of children with metastatic soft tissue sarcoma with oral maintenance compared to high-dose chemotherapy: report of theHDCWS-96 trial. Pediatr Blood Cancer. 2008;50:739-745.

12. André N, Carré M, Pasquier E. Metronomics: towards personalized chemotherapy? Nat Rev Clin Oncol. 2014;11:413-431.