We are very proud to shaer here a comment written by Robert Kerbel from the Department of Medical Biophysics, Biological Sciences Platform, Sunnybrook Research Institute, University of Toronto, Canada & Nicolas André from the Metronomics Global Health Initiative, Children Hospital of La Timone, AP-HM, Aix Marseille Université, Marseille, France taht has been publisehd in the Lancet as a comment for a randomized trial (Chen Y-P Liu X Zhou Q et al.Metronomic capecitabine as adjuvant therapy in locoregionally advanced nasopharyngeal carcinoma: a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial. Lancet. 2021; (published online June 7 https://doi.org/10.1016/S0140-6736(21)01123-5)

It is a golden age for cancer drug development. There are frequent announcements of regulatory approvals of new drugs, or more commonly, an existing but fairly new drug or drug combination for yet another indication. Immune checkpoint inhibitors and antibody drug conjugates are among the most common of such recent approvals. One disadvantage of this otherwise remarkable development is the enormous cost of such drugs, thereby placing an ever increasing financial burden on health-care systems and making it virtually impossible for most patients with cancer, especially those who live in low-income and middle-income countries (LMICs), to benefit from these successes. The lack of access for many patients highlights the need to develop readily accessible, less toxic, and substantially less expensive treatments than currently available on-patent treatments, such as immune checkpoint inhibitors or targeted therapies, for patients without financial means and especially those in LMICs.

One example of such accessible and less expensive treatment relies on the use of continuous, oral, break-free, low-dose chemotherapy with off-patent drugs, currently referred to as metronomic chemotherapy.1, 2, 3, 4 Depending on the drug used, metronomic chemotherapy exerts antitumour effects through different, and sometimes overlapping, mechanisms, which include targeting the tumour microenvironment (eg, by inhibiting angiogenesis1, 2, 3, 4), enhancing tumour immunity,5 and directly targeting cancer cells, including cancer stem cells.6

In The Lancet, Yu-Pei Chen and colleagues7 report the results of a multicentre, open-label, parallel-group, randomised, controlled phase 3 trial evaluating a 1-year adjuvant daily oral low-dose metronomic capecitabine protocol in patients with locoregionally advanced nasopharyngeal carcinoma. The rationale for the trial was based on several considerations. First, locoregionally advanced nasopharyngeal carcinoma is often initially responsive to concurrent radiotherapy and chemotherapy with cisplatin, with complete control and disappearance of disease, but subsequently relapses with metastases in a high proportion of patients.7 Second, metronomic capecitabine has been used successfully in other phase 3 trials (eg, as an adjuvant regimen in triple-negative breast cancer,8 or as maintenance therapy in metastatic colorectal cancer9). Third, previous phase 2 studies in patients with advanced nasopharyngeal carcinoma indicated potential activity and clinical benefit,10, 11 and fourth, there is an unmet medical need for a validated, effective adjuvant therapy in patients with high-risk locoregionally advanced nasopharyngeal carcinoma after successful conventional therapy. Finally, if successful, metronomic chemotherapy would meet the aims of achieving minimal cost and convenience, which are important considerations in LMICs.

The 406 patients included in this trial7 had high-risk locoregionally advanced nasopharyngeal carcinoma (stage III–IVA, excluding T3–4N0 and T3N1 disease) with no locoregional disease or distant metastases after definitive chemoradiotherapy. Patients were randomly assigned (1:1) to receive either oral metronomic capecitabine (650 mg/m2 body surface area twice daily9 for 1 year; metronomic capecitabine group) or observation (standard therapy group). The median age of patients was 45 years (range 18–65), and most patients in both groups were male (161 [79%] of 204 in the metronomic capecitabine group; 150 [74%] of 202 patients in the standard therapy group). Previous induction chemotherapy was administered in most patients (316 [78%] of 406). The primary endpoint was failure-free survival, defined as the time from randomisation to disease recurrence (distant metastasis or locoregional recurrence) or death due to any cause, in the intention-to-treat population. Failure-free survival at 3 years was significantly higher in the metronomic capecitabine group (85·3% [95% CI 80·4–90·6]) than in the standard therapy group (75·7% [69·9–81·9]), with a stratified hazard ratio of 0·50 (95% CI 0·32–0·79; p=0·0023). All subgroups analysed benefited from metronomic capecitabine. Toxicity was manageable, with grade 3 adverse events (mainly hand–foot syndrome) in 35 (17%) of 201 patients in the metronomic capecitabine group and 11 (6%) of 200 patients in the standard therapy group. The authors concluded that adjuvant metronomic capecitabine added after chemoradiotherapy, with or without previous induction chemotherapy, confers a clinical benefit in improving failure-free survival in patients with high-risk locoregionally advanced nasopharyngeal carcinoma.This trial7 has the potential to change clinical practice, and if so, would be of particular benefit to patients receiving intensive definitive chemoradiotherapy and in those living in LMICs. The results are also encouraging when considered in the context of the successes of other phase 3 trials of metronomic chemotherapy.8, 9, 12, 13 However, this prospect has to be balanced with some limitations of the trial, which are shared with other similar trials. First, this was an open-label, non-placebo-controlled trial (although the radiologists involved were masked to group allocation). In addition, the optimal dose and duration of adjuvant metronomic chemotherapy are unknown, and there is no known molecular target that can be exploited as a potential biomarker for metronomic chemotherapy. Exploration of biomarkers, such as circulating immunosuppressive myeloid-derived suppressor cells,5 or pharmacological biomarkers, such as dihydropyrimidine dehydrogenase status,14 is needed. Despite these problems, and the practicality of the metronomic chemotherapy concept, there have been encouraging phase 2 and 3 trials that can be used as foundations for future trials. Finally, similar to most other recent phase 3 trials of metronomic chemotherapy done over the past 2 years that use off-patent medications, this trial was done, for obvious reasons, without major pharmaceutical company support, relying instead on charities and governmental grants. Perhaps these results will initiate a change in the pharmaceutical industry mindset, especially when considering the potential benefits of combining metronomic chemotherapy for long-term maintenance with more expensive patented drugs for use in high-income countries.15 However, for now, this trial of metronomic chemotherapy,7 and other similar trials, paves the way for improving access to so-called new and affordable cancer therapies in LMICs, and will allow adaptation to local constraints beyond cost, such as patients needing to travel long distances to oncology centres in the absence of public transportation, the incidence of toxic effects, the treatment of frail patients, advanced disease due to delayed diagnosis, and the use of central catheters.16

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2 Browder T, Butterfield CE, Kraling BM, et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 2000; 60: 1878–86.

3 Klement G, Baruchel S, Rak J, et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 2000; 105: R15–24.

4 Pasquier E, Kavallaris M, Andre N. Metronomic chemotherapy: new rationale for new directions. Nat Rev Clin Oncol 2010; 7: 455–65.

5 Peereboom DM, Alban TJ, Grabowski MM, et al. Metronomic capecitabine as an immune modulator in glioblastoma patients reduces myeloidderived suppressor cells. JCI Insight 2019; 4: e130748.

6 Andre N, Tsai K, Carre M, et al. Metronomic chemotherapy: direct targeting of cancer cells after all? Trends Cancer 2017; 3: 319–25.

7 Chen Y-P, Liu X, Zhou Q, et al. Metronomic capecitabine as adjuvant therapy in locoregionally advanced nasopharyngeal carcinoma: a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial. Lancet 2021; published online June 7. https://doi.org/10.1016/ S0140-6736(21)01123-5.

8 Wang X, Wang SS, Huang H, et al. Effect of capecitabine maintenance therapy using lower dosage and higher frequency vs observation on disease-free survival among patients with early-stage triple-negative breast cancer who had received standard treatment: the SYSUCC-001 randomized clinical trial. JAMA 2021; 325: 50–58.

9 Simkens LHJ, van Tinteren H, May A, et al. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer, the phase 3 CAIRO3 study of the Dutch Colorectal Cancer Group (DCCG). Lancet 2015; 385: 1843–52.

10 Chua DT, Sham JS, Au GK. A phase II study of capecitabine in patients with recurrent and metastatic nasopharyngeal carcinoma pretreated with platinum-based chemotherapy. Oral Oncol 2003; 39: 361–66.

11 Ciuleanu E, Irimie A, Ciuleanu TE, et al. Capecitabine as salvage treatment in relapsed nasopharyngeal carcinoma: a phase II study. J BUON 2008; 13: 37–42.

12 Bisogno G, De Salvo GL, Bergeron C, 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: 1566–75.

13 Patil V, Noronha V, Dhumal SB, et al. Low-cost oral metronomic chemotherapy versus intravenous cisplatin in patients with recurrent, metastatic, inoperable head and neck carcinoma: an open-label, parallelgroup, non-inferiority, randomised, phase 3 trial. Lancet Glob Health 2020; 8: e1213–22.

14 Chamorey E, Francois E, Etienne MC, et al. DPD status and fluoropyrimidinesbased treatment: high activity matters too. BMC Cancer 2020; 20: 436.

15 Zsiros E, Lynam S, Attwood KM, et al. Efficacy and safety of pembrolizumab in combination with bevacizumab and oral metronomic cyclophosphamide in the treatment of recurrent ovarian cancer: a phase 2 nonrandomized clinical trial. JAMA Oncol 2021; 7: 78–85.

16 Andre N, Banavali S, Snihur Y, et al. Has the time come for metronomics in low-income and middle-income countries? Lancet Oncol 2013; 14: e239–48.