A tribute to biologics in advanced colorectal cancer treatment
Authors: A. Sobrero
Journal: Annals of Oncology (2016)

Twelve years ago, a French trial on the sequential use of FOLFOX and FOLFIRI demonstrated for the first time the achievement of 20-month median survival time (MST) in advanced colorectal cancer [1.Tournigand C. André T. Achille E. et al.FOLFIRI Followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study.J Clin Oncol. 2004; 22: 229-237Crossref PubMed Scopus (2717) Google Scholar]. Now, we celebrate approaching, and sometimes breaking, the 30-month barrier [2.Venook A. Niedzwiecki D. Lenz H.J. et al.CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC).J Clin Oncol. 2014; 32 (abstr LBA 3)Google Scholar, 3.Heinemann V. von Weikersthal L.F. Decker T. et al.FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial.Lancet Oncol. 2014; 15: 1065-1075Abstract Full Text Full Text PDF PubMed Scopus (1289) Google Scholar, 4.Schwartzberg L.S. Rivera F. Karthaus M. et al.PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer.J Clin Oncol. 2014; 32: 2240-2247Crossref PubMed Scopus (521) Google Scholar]. These results can certainly be due to a number of factors, including stage migration, better surgery and supportive care [5.Jawed I. Wilkerson J. Prasad V. et al.Colorectal cancer survival gains and novel treatment regimens: a systematic review and analysis.JAMA Oncol. 2015; doi:10.1001/jamaoncol.2015.1790Crossref PubMed Scopus (70) Google Scholar], but it is generally recognized that the new biologic drugs play the most important role in this improvement [6.Sargent D. Improved outcomes in metastatic colon cancer: giving credit where credit is due.JAMA Oncol. 2015; 1: 795-796Crossref PubMed Scopus (3) Google Scholar]. The paper by Yamazaki et al. [7.Yamazaki K. Nagase M. Tamagawa H. et al.Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G).Ann Oncol. 2016; 27: 1539-1546Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar] reports the best survival results obtained so far (31-month MST) on a mixed population of RAS wt and mutated patients using FOLFOX or FOLFIRI plus bevacizumab followed by the appropriate use of anti-EGFR agents in later lines of treatment. This confirms that bevacizumab is an excellent choice for first-line therapy, irrespective of the RAS status, and that all available biologics should be used for optimal outcome. These excellent results are particularly relevant because of the quality of the study. Despite the fairly weak but justifiable primary end point (non-inferiority in progression-free survival), the internal validity of this trial is very strong. The external validity (generalizability) is maximal for patients eligible for the most efficacious regimens available today. In fact, the patients characteristics are slightly better than average, the median time on treatment is among the longest reported, the resection of metastases was carried out in 10% of patients, second-line treatment was given to 80% and anti-EGFR therapy was given to ∼90% of RAS wt patients in the later course of the disease. All these figures reflect excellent trial conduct and overall patient management as well. One could argue that the relevance of these data is limited because these results were obtained on Japanese patients and because the dose of irinotecan used was slightly lower than that used in western countries (150 instead of the classical 180 mg/sqm). However, this concern is attenuated by the consistency of these results with those of several phase II trials reviewed by Yamazaki et al. [7.Yamazaki K. Nagase M. Tamagawa H. et al.Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G).Ann Oncol. 2016; 27: 1539-1546Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar] along with those recently reported in the randomized MAVERICC trial pursuing the same comparison of FOLFOX bevacizumab versus FOLFIRI-bevacizumab on western patients [8.Lenz H.J. Lee F. Yau L. MAVERICC, a phase II study of mFOLFOX6-bevacizumab (BV) vs FOLFIRI-BV as first-line (1L) chemotherapy (CT) in patients (pts) with metastatic colorectal cancer (mCRC): outcomes by tumor location and KRAS status.J Clin Oncol. 2016; 34 (Suppl); abstr 3515PubMed Google Scholar]. This paper does not change clinical practice but has a substantial impact on it in this disease concerning at least three aspects. First, the confirmed efficacy of bevacizumab in first line. A common criticism of the potential benefit of bevacizumab is that a significant difference in overall survival was not observed in any of the randomized large trials of chemotherapy plus or minus bevacizumab, except for the registration trial that used a suboptimal irinotecan-containing regimen which is no longer used in practice [9.Hurwitz H. Fehrenbacher L. Novotny W. et al.Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.N Engl J Med. 2004; 350: 2335-2342Crossref PubMed Scopus (9189) Google Scholar]. This paper does not address that question, but its excellent efficacy results make it harder and harder not to recognize the very substantial contribution of the anti-VEGF agent to the overall improved outcome—especially if we compare these results with those of the similar sequential chemotherapy trial conducted in the pre-biologic era in France [1.Tournigand C. André T. Achille E. et al.FOLFIRI Followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study.J Clin Oncol. 2004; 22: 229-237Crossref PubMed Scopus (2717) Google Scholar]. In that trial, the patient population, the duration of treatment, the reported toxicity and the percent of liver resection were similar to those of the present Japanese trial, although a slightly lower percent of second lines (68%) was given. The significance of breaking the barrier of 30-month MST in this trial lies in the fact that this result has been achieved on a mixed population of RAS wt and RAS mut patients. Even the most toxic FOLFOXIRI bevacizumab combination did not reach this threshold on a similar population of patients [10.Loupakis F. Cremolini C. Masi G. et al.Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer.N Engl J Med. 2014; 371: 1609-1618Crossref PubMed Scopus (741) Google Scholar]. Whenever the population is restricted to the RAS wt cohort, the MST is ∼6 months longer compared with the mixed population and the threshold of 30 months is passed as a result of the additional efficacy of the anti-EGFR agents in this subset of patients [2.Venook A. Niedzwiecki D. Lenz H.J. et al.CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC).J Clin Oncol. 2014; 32 (abstr LBA 3)Google Scholar, 3.Heinemann V. von Weikersthal L.F. Decker T. et al.FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial.Lancet Oncol. 2014; 15: 1065-1075Abstract Full Text Full Text PDF PubMed Scopus (1289) Google Scholar, 4.Schwartzberg L.S. Rivera F. Karthaus M. et al.PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer.J Clin Oncol. 2014; 32: 2240-2247Crossref PubMed Scopus (521) Google Scholar]. Of course, these data do not help to clarify the debated question on the preference of anti-VEGF versus anti-EGFR in first line in patients with RAS wt tumors. However, they do not exclude potential further improvements through a more rational positioning of the biologics in the RAS wt population. The recent correlation between the location of the primary tumor and the efficacy of anti-VEGF and anti-EGFR agents [11.Venook A.P. Niedzwiecki D. Innocenti F. et al.Impact of primary (1°) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance).J Clin Oncol. 2016; 34 (Suppl): abstr 3504Crossref Google Scholar], as well as the side-dependent expression of key molecular predictors of anti-EGFR efficacy [12.Lee S.M. Advani S.M. Morris J. et al.Association of primary (1°) site and molecular features with progression-free survival (PFS) and overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor (αEGFR) therapy.J Clin Oncol. 2016; 34 (Suppl); abstr 3506Google Scholar], may help to simplify the choice of biologics: bevacizumab could be preferred in first line (i) for right-sided tumor, irrespective of the RAS status, and (ii) in RAS mut left-sided tumors; whereas the anti-EGFRs could be the optimal choice for first line in left-sided RAS wt tumors. This is certainly an oversimplification, but the striking concordance of the clinical and preclinical data is extremely appealing. Secondly, the issue of the companion chemotherapy to bevacizumab. The similar efficacy of the two doublets plus bevacizumab reported by Yamazaki et al. confirms the findings of the large CALGB 80405 trial, reported so far only in abstract form [2.Venook A. Niedzwiecki D. Lenz H.J. et al.CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC).J Clin Oncol. 2014; 32 (abstr LBA 3)Google Scholar], and makes the issue of the companion chemotherapy (FOLFOX or FOLFIRI) over: both combinations are equivalent partners. Thirdly, the relevance of patients' reported outcomes. This paper re-vitalizes the old question of the optimal regimen between FOLFOX and FOLFIRI, with the suggestion that FOLFIRI is preferable. An unprecedented care was taken in collecting QOL data with standard validated tools for a period of 18 months, covering the first two lines of treatments, showing a preference for the doublet FOLFIRI-bevacizumab over FOLFOX-bevacizumab. The apparent slight preference for FOLFIRI contrasts with the almost 20 years of common practice that has always privileged FOLFOX over FOLFIRI for first-line treatment. The reason for this choice has never been substantiated, especially in light of the very disturbing and sometimes irreversible peripheral neuropathy. These results suggest that the burden of receiving FOLFIRI is less than that of receiving FOLFOX, as evaluated by patients. This is very clear for the neurotoxicity scale, where differences approaching 10 points in the scale are reported. The clinical interpretation of the meaning of differences in scores derived from QOL assessment instruments is difficult. However, these changes are known to correlate with a pragmatic scale of ‘no-change, little change, moderate and very much change’ derived from a subjective significance questionnaire [13.Osoba D. Rodrigues G. Myles J. et al.Interpreting the significance of changes in health-related quality-of-life scores.J Clin Oncol. 1998; 16: 139-144Crossref PubMed Scopus (2153) Google Scholar]. Under this prospective, the changes reported here favoring FOLFIRI correspond to ‘little change’. Considering the objective efficacy and toxicity results discussed above and the QOL data, the authors' conclusion that FOLFIRI should be preferred for first-line treatment can be accepted. The reliability of QOL results depends on the compliance to the administered questionnaires. Upon request, the authors were kind enough to provide the compliance data. This was excellent: 97.3% of the forms were collected at baseline; 92.8% at 3 months; 88% at 6 months; 85.1% at 9 months; 77.4% at 12 months; 66.2% at 18 months. This corresponds to more than 90% of forms collected from patients alive at each time. This excellent compliance reinforces the relevance of the QOL findings in this study and the feasibility of focusing on patient-reported outcomes in future trials, as recommended by both ASCO [14.Schnipper L.E. Davidson N.E. Wollins D.S. et al.Updating the American Society of Clinical Oncology value framework: revisions and reflections in response to comments received.J Clin Oncol. 2016; doi:10.1200/JCO.2016.68.2518Crossref PubMed Scopus (437) Google Scholar] and ESMO [15.Cherny N.I. Sullivan R. Dafni U. et al.A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS).Ann Oncol. 2015; 26: 1547-1573Abstract Full Text Full Text PDF PubMed Scopus (533) Google Scholar] in their efforts to grade the clinical benefit and value of cancer treatment. In summary, this paper emphasizes the contribution of biologics to the improvement of the overall outcome of advanced colorectal cancer treatment and demonstrates that long-term recording of QOL is feasible and relevant in this disease. None declared.