We have just published in Nature Reviews Clinical Oncology a short piece about metronomic chemotherapy and drug repositioning entitled "Metronomics — fulfilling unmet needs beyond level A evidence" The 3 authors are MGHI members : Nicolas André, Shripad Banavali and Eddy Pasquier from the Inserm UMR_S 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, 27 Boulevard Jean Moulin, Faculté de Pharmacie, Aix-Marseille Université; the Service d’Hématologie & Oncologie Pédiatrique, AP-HM; the Metronomics Global Health Initiative, and the Department of Medical Oncology, Tata Memorial Centre, Dr. E Borges Road, 400012, Parel, Mumbai, India

To improve the survival rates globally for paediatric patients with cancer, looking beyond level A evidence to treat children in low and middle-income countries is imperative. Herein, we discuss why metronomic chemotherapy, which is less toxic and more affordable, offers a pragmatic approach to provide new standards for patients with relapsed disease who have no alternatives.

Owing to the success of medical research over the past decades, cancer statistics in high- income countries (HICs) often reflect that 8 out of 10 children with cancer are now cured. Although this figure is accurate in developed countries, this statistic analysis is widely misleading when considering global oncol- ogy. With 80% of children living in low and middle-income countries (LMICs) — in which the survival rate of childhood cancer patients stagnates around 20%1, and can dip below 10% in some African countries — in reality we are saving less than 4 out of 10 patients with childhood cancer, globally. What should we do about it? Do we wait for infrastructures and wealth to develop uniformly across the globe so that every child with cancer can get access to sophisticated, highly effective treatments? Alternatively, do we acknowledge that our gen- eration might never benefit from this prosper- ity and look for another solution? Shouldn’t we consider this a state of emergency2?

In HICs, a general assumption is that these unmet needs will be fulfilled with the devel- opment of new drugs. However, it takes a tre- mendous amount of time and money to set up the studies that will demonstrate the outcomes cancer in low- and middle-income countries — of a new drug with statistical significance that might pave the way for its incorporation in first-line treatment. Patient advocacy groups and physicians have pleaded for expediting both the drug development and approval pro- cesses, for instance through innovative study design3. In paediatric oncology, the treatments used are often based on expected benefits that are yet to be validated in randomized trials. For instance, proton therapy is being gradually implemented in the clinic for chil- dren with brain tumours, as it could poten- tially spare normal brain tissue and decrease long-term adverse effects, such as cognitive impairment. However, good level of evidence for proton therapy is lacking owing to caveats, such as retrospective, non-randomized com- parisons that do not use modern radiotherapy techniques, small patient numbers, or differ- ent neuropsychological test measures, in the published studies4. Furthermore, there are increasing concerns regarding the variations in the relative biological effectiveness of pro- ton therapy, which is considered important both for tumour control and toxicity against healthy tissue. An even greater concern is the fast-growing use of personalized treatments on the basis of tumour-profiling studies, although the recent SHIVA trial concluded that molecularly guided treatments should not be performed outside of registered trials5. The situation is quite different in LMICs, where standards of care from HICs can- not simply be deployed. In this regard, the studies have shown the potential of metro- nomic maintenance in paediatric patients with solid tumours9–11 and results from state-of-the-art randomized trials in osteo- sarcoma (NCT02273583) and rhabdo- myosarcoma (NCT00379457) are expected. No formal demonstration has been provided, but one can speculate that the level of evi- dence is high enough and the potential bene- fits clearly outweigh the limited toxicity and the lack of randomized trial for patients at very high risk of relapse.

Some patients are too frail (owing to late presentation, infection, malnutrition, or organ dysfunction) to receive conventional maxi- mum tolerated dose chemotherapy. In this context, the pre-phase treatment for patients with Burkitt lymphoma with a high burden of disease is based on low-dose chemother- apy. This strategy enables starting treating the disease while managing both the risk of tumour-lysis syndrome and further organ dysfunction. Some studies have reported on the application of this type of approach in a LMIC setting. One trial assessed a low-dose vincristine–cyclophosphamide–methotrexate combination upfront to treat children with advanced-stage cancer in Mali12. A similar approach has been successfully developed in children with AML11.

In the context of precision medicine and heavy regulation, we believe it is important to be fully aware of the unmet needs paedi- atric patients are facing. In an ideal world, randomized trials should be performed, but this is neither realistic nor sometimes appro- priate owing to cost considerations and local constraints. Trying to fulfil unmet needs should not risk low-quality care, and thus, we should not abandon our commitment to state-of-the-art clinical trials. However, these two approaches should be complementary. A learning strategy must be applied to any local initiative in LMIC as well, and we advo- cate for national and international coordina- tion through prospective registries to ensure evaluation of the treatment undertaken in terms of outcome and toxicity, to provide context-adapted standard of care. The time has come for stakeholders (such as academics, charities, governments, pharmaceutical companies, national and international non-governmental organisa- tions) to consider all possible strategies and implement a global programme to systemati- cally study, document and define the place of non-level A evidence-based treatments, such as metronomics10,11, in the armamentarium against cancer. Trials must be designed so that reliable surrogate markers of clinical benefit are investigated to enable oncologists to opti- mize the value of the trials both in the context of personalized medicine and in LMICs. The recent results of the DFMO maintenance trial for children with neuroblastoma performed by the NMTCR represent a unique opportu- nity to develop this kind of collaboration with the constitution of a dedicated international task force to set a state-of-the-art clinical trial for children with neuroblastoma treated with DFMO in LMICs (G. Sholler, personal communication).

In paediatric oncology, some unmet needs should be urgently fulfilled. This is true for patients with relapsed disease in HICs who represent a minority of patients, but this is unfortunately an even bigger emergency for most paediatric patients living in the poorest countries of the world. Do we need to wait for randomized trials to validate constraint- adapted strategies or can we at least try and do the best we can without level A evidence?

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