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Maintenance therapy in advanced colorectal cancer, yes or no? Ask the laboratory

2017; Elsevier BV; Volume: 28; Issue: 9 Linguagem: Inglês

10.1093/annonc/mdx395

1569-8041

Alberto Sobrero, Azzurra Damiani,

Genetic factors in colorectal cancer

In oncology, the concept of maintenance therapy is dependent upon two conditions: the availability of an effective induction treatment preventing a rapid progression and a certain degree of toxicity that does not allow indefinite continuation of therapy. When FU was the only active agent against advanced colorectal cancer we knew that continuing FU chemotherapy beyond 3–5 months (the time to response and maximum response to this agent) was not efficacious [1.Maughan T.S. James R.D. Kerr D.J. et al.Comparison of intermittent and continuous palliative chemotherapy for advanced colorectal cancer: a multicenter randomised trial.Lancet. 2003; 361: 457-464Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar]. When FOLFOX and FOLFIRI became standard practice (prolongation of median OS beyond 18 months, but added toxicity), investigating less intense ways of prolonging the first line treatment became necessary. Consequently, the on–off FOLFIRI strategy [2.Labianca R. Sobrero A. Isa L. et al.Intermittent versus continuous chemotherapy in advanced colorectal cancer: a randomised ‘GISCAD’ trial.Ann Oncol. 2011; 22: 1236-1242Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar] and the intermittent use of oxaliplatin [3.Grothey A. Hart L.L. Rowland K.M. et al.Intermittent oxaliplatin (oxali) administration and time-to-treatment failure (TTF) in metastatic colorectal cancer (mCRC): final results of the Phase III CONcePT trial.J Clin Oncol. 2008; 26: 4010Crossref Google Scholar] were demonstrated to be equivalent or better than continuing the doublet until progression. This produced the new concept of ‘first line strategy’ as opposed to the ‘first line treatment’ concept. With the advent of biologics, conditions became more favorable for investigating maintenance treatment after an initial period of induction. In fact, both bevacizumab and the anti-EGFR compounds produced further prolongation of survival, and their long-term toxicities were less severe than those of chemotherapy. Bevacizumab appeared to be a better candidate than anti-EGFRs due to the lack of skin and nails toxicity, its effects in delaying tumor progression and because the rare, but severe, side-effects tend to occur in the first 4–5 months of treatment and are rare thereafter, when usually maintenance treatment would be applicable. Nevertheless, both agents were studied, either alone or in combination with fluoropyrimidines as maintenance treatment in a series of randomized trials. Of these trials, four have used bevacizumab [4.Hegewisch-Becker S. Graeven U. Lerchenmüller C.A. et al.Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial.Lancet Oncol. 2015; 16: 1355-1369Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 5.Diaz-Rubio E. Gomez-Espana A. Massuti B. et al.First-line XELOX plus bevacizumab followed by XELOX plus bevacizumab or single-agent bevacizumab as maintenance therapy in patients with metastatic colorectal cancer: the phase III MACRO TTD study.Oncologist. 2012; 17: 15-25Crossref PubMed Scopus (172) Google Scholar, 6.Koeberle D. Betticher D.C. von Moos R. et al.Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06).Ann Oncol. 2015; 26: 709-714Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 7.Simkens L.H.J. van Tinteren H. May A. et al.Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group.Lancet. 2015; 385: 1843-1852Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar] and three have used anti-EGFR drugs [8.Wasan H. Meade A.M. Adams R. et al.Intermittent chemotherapy plus either intermittent or continuous cetuximab for fi rst-line treatment of patients with KRAS wild-type advanced colorectal cancer (COIN-B): a randomised phase 2 trial.Lancet Oncol. 2014; 15: 631-639Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 9.Tveit K.M. Guren T. Glimelius B. et al.Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII Study.J Clin Oncol. 2012; 30: 1755-1762Crossref PubMed Scopus (425) Google Scholar, 10.Alfonso P. et al.The MACRO-2 trial: maintenance therapy with single-agent cetuximab plus chemotherapy after cetuximab-based induction for patients with metastatic colorectal cancer.Ann Oncol. 2014; 25: 168Abstract Full Text PDF Google Scholar]. Taken together, these studies have demonstrated the following:•These types of studies are difficult to conduct, as evidenced by the overall low adherence to the trial protocols.•All of them have shown a remarkable prolongation of the PFS1, but none have shown a relevant, convincing, cost-effective benefit in OS.•Since bevacizumab is not efficacious by itself and must be given along with a fluoropyrimidine, and the anti-EGFRs are associated with extra skin toxicity, either maintenance regimens do not represent the ‘light touch’ approach that is necessary for ideal maintenance therapy. In this context, the CAIRO 3 study by the DCC group [11.Goey K.K.H. Elias S.G. van Tinteren H. et al.Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroups analyses of the phase 3 CAIRO3 study.Ann Oncol. 2017; 28: 2128-2134Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar] has a special value because of the relevant implications for clinical practice: it identifies the subgroup of patients who benefit most from maintenance therapy based on molecularly defined criteria. Two reports on this study have already been published [7.Simkens L.H.J. van Tinteren H. May A. et al.Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group.Lancet. 2015; 385: 1843-1852Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar, 12.Franken M.D. van Rooijen E.M. May A.M. et al.Cost-effectiveness of capecitabine and bevacizumab maintenance treatment after first-line induction treatment in metastatic colorectal cancer.Eur J Cancer. 2017; 75: 204-212Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar], and this is the third [11.Goey K.K.H. Elias S.G. van Tinteren H. et al.Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroups analyses of the phase 3 CAIRO3 study.Ann Oncol. 2017; 28: 2128-2134Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar]. However, this redundancy does not affect the value of this work but actually enhances the relevance of this three-chapter story, making it stand out among other trials of this kind. The first publication showed a non-convincing marginal OS benefit of the maintenance arm [7.Simkens L.H.J. van Tinteren H. May A. et al.Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group.Lancet. 2015; 385: 1843-1852Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar]. The second addressed the public health-related issue of whether maintenance therapy is cost-effective or not—to which the answer was no [12.Franken M.D. van Rooijen E.M. May A.M. et al.Cost-effectiveness of capecitabine and bevacizumab maintenance treatment after first-line induction treatment in metastatic colorectal cancer.Eur J Cancer. 2017; 75: 204-212Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar]. The present third report [11.Goey K.K.H. Elias S.G. van Tinteren H. et al.Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroups analyses of the phase 3 CAIRO3 study.Ann Oncol. 2017; 28: 2128-2134Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar] identifies those patients who benefit most from the bevacizumab-based maintenance therapy. These are patients with RAS wild-type (wt) or BRAF-mutated tumors, not those with RAS-mutated tumors. Since this latter group of patients represents 58% of the entire patient population in this study, it is not surprising that the effect of maintenance on the overall efficacy on the unselected patient population was not cost-effective, as described in the previous report [12.Franken M.D. van Rooijen E.M. May A.M. et al.Cost-effectiveness of capecitabine and bevacizumab maintenance treatment after first-line induction treatment in metastatic colorectal cancer.Eur J Cancer. 2017; 75: 204-212Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar]. The relevance of this work may be limited by the patient number. In fact, when we pursue subgroup analyses, the confidence intervals of the point estimate values for gains in median OS or HR become very wide, making variability a major factor affecting the search for the real truth. With these words of caution, the data altogether make a plausible story that supports the successful identification of the best candidate for maintenance therapy. In summary:1.Bevacizumab-based maintenance therapy appears to be very effective as measured by prolongation of PFS1 in all groups. It actually works as a PFS1 ‘equalizer’. In fact, PFS1 among those receiving maintenance therapies is very similar in the three molecularly distinct populations, despite very different PFS1 values in the respective control arms.2.This prolongation effect extends to PFS2 in all subgroups, but to a much lower extent in the RAS-mutated group.3.The time from second progression to death continues to be prolonged for RAS wt patients in the maintenance group compared with the control (3.9 months gain), whereas it is reduced compared with the control in the RAS-mutated patients and it collapses in the BRAF-mutated patients. Therefore, the net result is a very substantial prolongation of OS in the RAS wt group and a very substantial prolongation of PFS1 and 2 in the BRAF-mutated patients who maintain a much longer stabilization of the disease before dying very rapidly. As the use of second and third lines in the whole study is well balanced between the maintenance and the control groups, the difference in OS is likely attributable to the first line strategy including maintenance. The plausibility of these data is strengthened by the concordance with results from other trials. For example, the fact that the antiangiogenics are more efficacious in RAS wt patients as compared with RAS-mutated patients has been suggested both in first line for bevacizumab [13.Hurwitz H.I. Yi J. Ince W. et al.The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer.Oncologist. 2009; 14: 22-28Crossref PubMed Scopus (219) Google Scholar] and in second line for aflibercept [14.Wirapati P. Pomella V. Vandenbosch B. et al.Velour trial biomarkers update: Impact of RAS, BRAF, and sidedness on aflibercept activity. [ESMO WGI Abstract LBA-005].J Clin Oncol. 2017; suppl_15 (3538–3538)Google Scholar] and ramucirumab [15.Obermannová R. Van Cutsem E. Yoshino T. et al.Subgroup analysis in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression.Ann Oncol. 2016; 27: 2082-2090Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar]. The lack of an effect of sidedness on efficacy of antiangiogenics has been reported for both bevacizumab [16.Arnold D. Lueza B. Douillard J.Y. et al.Prognostic and predictive value of primary tumour side in patients with RAS Wild-type metastatic colorectal cancer treated with chemotherapy and EGFR direct antibodies in six randomized trials.Ann Oncol. 2017; 28: 1713-1729Abstract Full Text Full Text PDF PubMed Scopus (526) Google Scholar] and aflibercept [14.Wirapati P. Pomella V. Vandenbosch B. et al.Velour trial biomarkers update: Impact of RAS, BRAF, and sidedness on aflibercept activity. [ESMO WGI Abstract LBA-005].J Clin Oncol. 2017; suppl_15 (3538–3538)Google Scholar]. The median OS in the CAIRO 3 study is not inferior to that of the most recent first line randomized trials [17.Heinemann V. Ludwig Fischer 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 (1278) Google Scholar, 18.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 (736) Google Scholar, 19.Venook A.P. Niedzwiecki D. Lenz H.J. et al.Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer.A randomized clinical trial. JAMA. 2017; 317: 2392-2401Crossref PubMed Scopus (523) Google Scholar]. In fact, it must be remembered that randomization here started after the induction treatment period; therefore ∼5 months should be added to the reported median OS in this trial. This brings the median OS value of RAS wt patients >30 months. By the same reasoning, the median OS of BRAF-mutated patients appears extraordinarily long. This is again plausible due to the fact that this patient population has been selected among responding/stable patients and this may be the reason for (or the effect of) the relatively high prevalence of the non-V600e BRAF mutations. Statisticians have always discouraged subgroup analysis of efficacy in responders versus non responders for obvious reasons. However, what counts most for patients is not the average benefit, but the benefit of a certain treatment of their peculiar conditions, including whether they respond to therapy or not. Taking into account the limitation of the relatively small number of patients, we can say that the latest report of the CAIRO 3 study helps clinical practice in this respect. Indeed, the possibility to identify a priori those patients who benefit from bevacizumab-based maintenance therapy from those who do not is exactly what patients want to know before starting treatment. The sine qua non for good clinical science is thoughtful planning in the design phase of a trial, accurate and meticulous conduct, in depth data analyses, honest reporting and rational data interpretation. The Dutch group has gone further. The very accurate translational work, along with the complete clinical data collection of subsequent therapies beyond the planned treatment phase, has allowed the generation of a new principle of molecularly based benefit of maintenance. This will help to guide our choices on this controversial issue in the management of advanced colorectal cancer. None declared.