Comment
Modified XELIRI (capecitabine plus irinotecan) for metastatic
colorectal cancer
The treatment of metastatic colorectal cancer has
changed substantially in the past two decades with the
development of more effective chemotherapy protocols
and molecular-based strategies. Despite these changes,
intravenous fluorouracil chemotherapy remains an
important component of treatment for metastatic
colorectal cancer, generally combined with leucovorin
plus oxaliplatin (FOLFOX) or leucovorin plus irinotecan
(FOLFIRI). However, changes to the method of delivery
with oral alternatives, such as capecitabine, are being
developed to simplify drug delivery. In gastrointestinal
cancer, oral capecitabine is now considered equivalent to
intravenous forms of fluorouracil. This development has
led to the combination with oxaliplatin (CAPOX) being
accepted as an alternative to FOLFOX. However, because
oral capecitabine has a somewhat different toxicity profile
compared with intravenous fluorouracil, development of
an alternative schedule to FOLFIRI has been complicated
by crossover toxicity when capecitabine is combined
with irinotecan (XELIRI or CAPIRI), with diarrhoea often
limiting dose, and subsequent reported outcomes being
inferior to FOLFIRI.1
In The Lancet Oncology, Rui-Hua Xu and colleagues2
report the findings of their phase 3 trial comparing
modified XELIRI (mXELIRI) to standard intravenous
FOLFIRI, both either with or without bevacizumab, as
second-line therapy for metastatic colorectal cancer. On
the basis of previous concerns about toxicity, the XELIRI
regimen chosen for the trial contained reduced doses
of both capecitabine and irinotecan. Previous groups
have explored dose modifications in phase 2 trials. The
importance of Xu and colleagues’ study is that it is the
first randomised phase 3 trial with the primary goal of
confirming non-inferiority of this modified schedule.
The results between mXELIRI and FOLFIRI, with or
without bevacizumab in both groups, are clear: non-
inferiority is shown with the predefined non-inferiority
margin of 1·30 despite the reduced doses of the drugs
(hazard ratio 0·85, 95% CI 0·71–1·02; pnon-inferiority<0·0001),
and toxicity is similar (46 [15%] of 310 patients in the
mXELIRI group and 63 [20%] of 310 in the FOLFIRI
group reported serious adverse events). Furthermore,
the survival outcomes (ie, the overall survival and
www.thelancet.com/oncology Published online March 16, 2018 http://dx.doi.org/10.1016/S1470-2045(18)30194-3 1
progression-free survival data) are similar or potentially
better than those reported in previous second-line
irinotecan-based trials.1
Biophoto Associates/ Science Photo Library
However, one important question arises: how would
this schedule be incorporated into standard practice?
Although Xu and colleagues’ trial of mXELIRI versus
FOLFIRI was done in a second-line setting, mXELIRI
might also be considered as a first-line treatment;
however, clinicians will need to take into account a
patient’s molecular profile. This mXELIRI schedule
Lancet Oncol 2018
has previously been assessed in two randomised
Published Online
phase 2 first-line trials. The first trial used the same March 16, 2018
doses as Xu and colleagues’ study for mXELIRI compared http://dx.doi.org/10.1016/
S1470-2045(18)30194-3
with CAPOX,3 and the second trial used a higher dose See Online/Articles
of capecitabine (1000 mg/m² twice daily on days 1–14) http://dx.doi.org/10.1016/
S1470-2045(18)30140-2
compared with FOLFIRI.4 The biological agent for both
trials was bevacizumab. Reported survival outcomes
were similar. Since these trials were reported, we now
understand that the side of the primary cancer could
guide the selection of biological drugs. Today, patients
with left-sided, RAS wild-type metastatic colorectal
cancer would be considered for an anti-EGFR agent in
their first-line treatment rather than bevacizumab.5
mXELIRI is unlikely to be appropriate in this setting,
given the potential negative interaction when anti-
EGFR therapy is combined with capecitabine.1 It is also
important to note that the existing data regarding a
negative interaction are based on combining cetuximab
with oxaliplatin and not irinotecan. However, some
insight is provided by the AIO KRK-0104 trial,6 in which
cetuximab was assessed in combination with CAPOX
or CAPIRI. No differences in survival outcomes were
reported between the two groups. Acknowledging
the limitations of a randomised phase 2 trial, one
could postulate that the AIO KRK-0104 trial gives no
evidence to consider these two combinations differently
when considering an anti-EGFR combination. Thus for
patients with the RAS wild-type gene, if irinotecan is
preferred in the first-line setting then FOLFIRI would
be the suggested regimen with an anti-EGFR antibody.
If anti-EGFR therapy were used first line with FOLFOX,
then second-line mXELIRI with bevacizumab would be
an option as reported by Xu and colleagues. However,
 Comment
for patients with the RAS mutation, the decision is
less complex when a schedule of mXELIRI or CAPOX
plus bevacizumab could be considered as the first-
line treatment, especially when considering patients’
quality of life, because these schedules overcome the
need for infusion pumps and possibly port insertion.
Furthermore in some settings, the economic benefit
of a schedule that does not require pumps, pump
disconnection, and additional time spent in the infusion
or chemotherapy suite will be very attractive.7
If irinotecan is used second line, one uncertainty is the
role of continuing a fluoropyrimidine in combination
beyond first-line therapy and therefore the true benefit
of mXELIRI over single-agent irinotecan (with or
without the addition of a biological agent) remains
unclear. A recent Cochrane review did suggest that a
progression-free survival benefit can be derived from
combined irinotecan and fluorouracil compared with
single agent irinotecan; however, no overall survival
advantage was reported.8 This question therefore
remains controversial, although most guidelines
continue to suggest the option of ongoing doublet
chemotherapy, hence meaning that mXELIRI remains a
relevant option for some patients.1
Ultimately, a key question will be whether or not
these results are transferable to non-Asian patient
populations. Debate is ongoing as to difference in
pharmacogenomics between white and Asian patients
for capecitabine,9 and a recent extensive review of
irinotecan did not conclusively answer this same
question, with the authors of the review highlighting
the wide variability between analyses published so far.10
However, despite these unanswered questions, the
results of Xu and colleagues’ study do have the potential
2 www.thelancet.com/oncology Published online March 16, 2018 http://dx.doi.org/10.1016/S1470-2045(18)30194-3
to change practice by giving an alternative option when
using an irinotecan-based schedule in selected patients.
Timothy J Price
Department of Medical Oncology, The Queen Elizabeth Hospital,
University of Adelaide, Adelaide, SA, Australia
timothy.price@sa.gov.au
I declare no competing interests.
1 Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for
the management of patients with metastatic colorectal cancer. Ann Oncol
2016; 27: 1386–422.
2 Xu R, Muro K, Morita S, et al. Modified XELIRI (capecitabine plus irinotecan)
versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with
or without bevacizumab, as second-line therapy for metastatic colorectal
cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority,
phase 3 trial. Lancet Oncol 2018; published online March 16. http://dx.doi.
org/10.1016/S1470-2045(18)30140-2.
3 Schmiegel W, Reinacher-Schick A, Arnold D, et al. Capecitabine/irinotecan
or capecitabine/oxaliplatin in combination with bevacizumab is effective
and safe as first-line therapy for metastatic colorectal cancer: a randomized
phase II study of the AIO colorectal study group. Ann Oncol 2013;
24: 1580–87.
4 Ducreux M, Adenis A, Pignon JP, et al. Efficacy and safety of
bevacizumab-based combination regimens in patients with previously
untreated metastatic colorectal cancer: final results from a randomised
phase II study of bevacizumab plus 5-fluorouracil, leucovorin plus
irinotecan versus bevacizumab plus capecitabine plus irinotecan (FNCLCC
ACCORD 13/0503 study). Eur J Cancer 2013; 49: 1236–45.
5 Arnold D, Lueza B, Douillard JY, et al. Prognostic and predictive value of
primary tumour side in patients with RAS wild-type metastatic colorectal
cancer treated with chemotherapy and EGFR directed antibodies in six
randomized trials. Ann Oncol 2017; 28: 1713–29.
6 Moosmann N, von Weikersthal LF, Vehling-Kaiser U, et al. Cetuximab plus
capecitabine and irinotecan compared with cetuximab plus capecitabine
and oxaliplatin as first-line treatment for patients with metastatic
colorectal cancer: AIO KRK-0104—a randomized trial of the German
AIO CRC Study Group. J Clin Oncol 2011; 29: 1050–58.
7 Tse VC, Ng WT, Lee V, et al. Cost-analysis of XELOX and FOLFOX4 for
treatment of colorectal cancer to assist decision-making on
reimbursement. BMC Cancer 2011; 11: 288.
8 Wulaningsih W, Wardhana A, Watkins J, Yoshuantari N, Repana D,
Van Hemelrijck M. Irinotecan chemotherapy combined with
fluoropyrimidines versus irinotecan alone for overall survival and
progression-free survival in patients with advanced and/or metastatic
colorectal cancer. Cochrane Database Syst Rev 2016; 2: CD008593.
9 Haller DG, Cassidy J, Clarke SJ, et al. Potential regional differences for the
tolerability profiles of fluoropyrimidines. J Clin Oncol 2008; 26: 2118–23.
10 Chen S, Sutiman N, Zhang CZ, et al. Pharmacogenetics of irinotecan,
doxorubicin and docetaxel transporters in Asian and Caucasian cancer
patients: a comparative review. Drug Metab Rev 2016; 48: 502–40.