Comment
Adjuvant metronomic chemotherapy for locoregionally
advanced nasopharyngeal carcinoma
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
FatCamera/Getty Images
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
Published Online ever increasing financial burden on health-care systems
June 7, 2021
https://doi.org/10.1016/
and making it virtually impossible for most patients
S0140-6736(21)01240-X with cancer, especially those who live in low-income and
See Articles page 303 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.1–4 Depending
on the drug used, metronomic chemo­ therapy exerts
antitumour effects through different, and sometimes
overlapping, mechanisms, which include targeting
the tumour microenvironment (eg, by inhibiting
angiogenesis1–4), 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
278 www.thelancet.com Vol 398 July 24, 2021
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.
 Comment

This trial7 has the potential to change clinical practice, expert testimony from Genentech, outside the area of work commented on here;
and if so, would be of particular benefit to patients receiving scientific advisory board fees from Nonagen Therapeutics, OncoHost,
Novelty Nobility, and CSTS Healthcare, outside the area of work commented on
receiving intensive definitive chemoradiotherapy and here; receiving experimental drugs for use in mice from Genentech; and receiving
in those living in LMICs. The results are also encouraging travel support from Novelty Nobility in Seoul and from 20 academic institutions or
societies for meetings or lectures in the past 3 years. NA reports receiving grants and
when considered in the context of the successes of drugs for a metronomic immune therapy trial from Bristol Myers Squibb; receiving
other phase 3 trials of metronomic chemotherapy.8,9,12,13 drugs for a metronomic repurposed drug and chemotherapy trial from Pierre Fabre;
receiving drugs and grants for a clinical trial from Bristol Myers Squibb, outside the
However, this prospect has to be balanced with some area of work commented on here; receiving travel support from Bristol Myers
Squibb for an International Society of Paediatric Oncology meeting; and
limitations of the trial, which are shared with other participating as a scientific advisory board member (without receiving personal
similar trials. First, this was an open-label, non-placebo- fees) for Bayer and Bristol Myers Squibb, outside the area of work commented
on here, and Partners Therapeutics related to metronomic chemotherapy.
controlled trial (although the radiologists involved were
masked to group allocation). In addition, the optimal dose *Robert S Kerbel, Nicolas Andre
robert.kerbel@sri.utoronto.ca
and duration of adjuvant metronomic chemotherapy
Department of Medical Biophysics, Biological Sciences Platform, Sunnybrook
are unknown, and there is no known molecular target Research Institute, University of Toronto, Toronto, ON M4N 3M5, Canada (RSK);
that can be exploited as a potential biomarker for Metronomic Global Health Initiative, Children Hospital of La Timone, AP-HM,
Aix Marseille Université, Marseille, France (NA)
metronomic chemotherapy. Exploration of biomarkers,
1 Hanahan D, Bergers G, Bergsland E. Less is more, regularly: metronomic
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5
2 Browder T, Butterfield CE, Kraling BM, et al. Antiangiogenic scheduling of
as dihydropyrimidine dehydrogenase status,14 is needed. chemotherapy improves efficacy against experimental drug-resistant
cancer. Cancer Res 2000; 60: 1878–86.
Despite these problems, and the practicality of the 3 Klement G, Baruchel S, Rak J, et al. Continuous low-dose therapy with
metronomic chemotherapy concept, there have been vinblastine and VEGF receptor-2 antibody induces sustained tumor
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encouraging phase 2 and 3 trials that can be used as 4 Pasquier E, Kavallaris M, Andre N. Metronomic chemotherapy:
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5 Peereboom DM, Alban TJ, Grabowski MM, et al. Metronomic capecitabine
recent phase 3 trials of metronomic chemotherapy done as an immune modulator in glioblastoma patients reduces myeloid-
over the past 2 years that use off-patent medications, derived suppressor cells. JCI Insight 2019; 4: e130748.
6 Andre N, Tsai K, Carre M, et al. Metronomic chemotherapy: direct targeting
this trial was done, for obvious reasons, without major of cancer cells after all? Trends Cancer 2017; 3: 319–25.
pharmaceutical company support, relying instead on 7 in Chen Y-P, Liu X, Zhou Q, et al. Metronomic capecitabine as adjuvant therapy
locoregionally advanced nasopharyngeal carcinoma: a multicentre,
charities and governmental grants. Perhaps these results 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.
will initiate a change in the pharmaceutical industry 8 Wang X, Wang SS, Huang H, et al. Effect of capecitabine maintenance
mindset, especially when considering the potential therapy using lower dosage and higher frequency vs observation on
disease-free survival among patients with early-stage triple-negative
benefits of combining metronomic chemotherapy for breast cancer who had received standard treatment: the SYSUCC-001
randomized clinical trial. JAMA 2021; 325: 50–58.
long-term maintenance with more expensive patented
9 Simkens LHJ, van Tinteren H, May A, et al. Maintenance treatment with
drugs for use in high-income countries. However, for
15
capecitabine and bevacizumab in metastatic colorectal cancer, the phase 3
CAIRO3 study of the Dutch Colorectal Cancer Group (DCCG). Lancet 2015;
now, this trial of metronomic chemotherapy, and other
7
385: 1843–52.
similar trials, paves the way for improving access to 10 Chua DT, Sham JS, Au GK. A phase II study of capecitabine in patients with
recurrent and metastatic nasopharyngeal carcinoma pretreated with
so-called new and affordable cancer therapies in LMICs, platinum-based chemotherapy. Oral Oncol 2003; 39: 361–66.
and will allow adaptation to local constraints beyond 11 Ciuleanu E, Irimie A, Ciuleanu TE, et al. Capecitabine as salvage treatment in
relapsed nasopharyngeal carcinoma: a phase II study. J BUON 2008;
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oncology centres in the absence of public transportation, 12 Bisogno G, De Salvo GL, Bergeron C, et al. Vinorelbine and continuous
low-dose cyclophosphamide as maintenance chemotherapy in patients
the incidence of toxic effects, the treatment of frail with high-risk rhabdomyosarcoma (RMS 2005): a multicentre, open-label,
randomised, phase 3 trial. Lancet Oncol 2019; 20: 1566–75.
patients, advanced disease due to delayed diagnosis, and 13 Patil V, Noronha V, Dhumal SB, et al. Low-cost oral metronomic chemotherapy
the use of central catheters.16 versus intravenous cisplatin in patients with recurrent, metastatic, inoperable
head and neck carcinoma: an open-label, parallel-group, non-inferiority,
RSK reports receiving a grant from the Canadian Institutes for Health Research to randomised, phase 3 trial. Lancet Glob Health 2020; 8: e1213–22.
study the preclinical effect of metronomic chemotherapy on immune checkpoint 14 Chamorey E, Francois E, Etienne MC, et al. DPD status and fluoropyrimidines-
antibody therapy outcomes; owning stock or stock options in OncoHost and based treatment: high activity matters too. BMC Cancer 2020; 20: 436.
Angiocrine Bioscience (neither company is working in the area of metronomic 15 Zsiros E, Lynam S, Attwood KM, et al. Efficacy and safety of pembrolizumab
chemotherapy); receiving consulting fees from PharmAbcine and Novelty Nobility, in combination with bevacizumab and oral metronomic cyclophosphamide
outside the area of work commented on here; receiving speaker’s fees from the in the treatment of recurrent ovarian cancer: a phase 2 nonrandomized
Societe Internationale d’Urologie, National Taiwan University Hospital, International clinical trial. JAMA Oncol 2021; 7: 78–85.
Symposium on Cancer Invasion and Metastasis (Taipei, Taiwan), and the 16 Andre N, Banavali S, Snihur Y, et al. Has the time come for metronomics in
56th Annual Meeting of Japan Society of Clinical Oncology; receiving payment for low-income and middle-income countries? Lancet Oncol 2013; 14: e239–48.

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