Identifying patients who may benefit from oxaliplatin-containing perioperative chemo(radio)therapy for rectal cancer
Authors: D. Papamichael, R. Glynne-Jones
Journal: Annals of Oncology (2018)

Advances in each of the components of multimodality treatment of rectal cancer—surgery, radiation, and chemotherapy—have significantly improved patient outcomes over the past two decades. Patients are less likely to recur locally and more likely to maintain sphincter function and have a reasonably good quality of life, although the risks of distant recurrence remain substantial. In the era before preoperative chemoradiation and total mesorectal excision, postoperative 5-fluorouracil was associated with an improvement in overall survival (OS) in patients with Dukes' B and C rectal cancer [1.Fisher B. Wolmark N. Rockette H. et al.Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01.J Natl Cancer Inst. 1988; 80: 21-29Crossref PubMed Scopus (918) Google Scholar]. While neo-adjuvant (chemo)radiation is now considered standard of care, adjuvant (postoperative) chemotherapy has been generally accepted as a component of multimodality therapy for locally advanced rectal cancer with the aim of reducing distant metastases [2.Glynne-Jones R. Wyrwicz L. Tiret E. ESMO Guidelines Committee et al.Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2017; 28: iv22-iv40Abstract Full Text Full Text PDF PubMed Scopus (844) Google Scholar, 3.National Clinical Practice Guidelines in Oncology (NCCN Guidelines): Rectal Cancer Version 1.2018, 14 March 2018. www.ncrn.org (5 April 2018, date last accessed).Google Scholar]. This acceptance is founded mostly on the basis of extrapolation from adjuvant colon cancer trials and meta-analyses in rectal cancer [4.Petersen S.H. Harling H. Kirkeby L.T. et al.Postoperative adjuvant chemotherapy in rectal cancer operated for cure.Cochrane Database Syst Rev. 2012; 3: CD004078PubMed Google Scholar]—despite the lack of any individual trial phase III evidence for benefit in disease-related outcomes. Recently, this strategy has moved chemotherapy earlier up-front based on clinical and pathological response outcomes. Many now endorse a 'total neoadjuvant therapy' (TNT) approach, in which all planned RT and chemotherapy are delivered in the preoperative setting. The CAO/ARO/AIO-04 phase III trial [5.Rödel C. Graeven U. Fietkau R. et al.Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial.Lancet Oncol. 2015; 16: 979-989Abstract Full Text Full Text PDF PubMed Scopus (485) Google Scholar] is one of a series of randomized trials, which investigated the addition of oxaliplatin to neoadjuvant CRT [6.Aschele C. Cionini L. Lonardi S. et al.Primary tumor response to pre op-erative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial.J Clin Oncol. 2011; 29: 2773-2780Crossref PubMed Scopus (599) Google Scholar, 7.Gerard J.P. Azria D. Gourgou-Bourgade S. et al.Comparison of two Neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD12/0405-Prodige2.J Clin Oncol. 2010; 28: 1638-1644Crossref PubMed Scopus (639) Google Scholar, 8.Schmoll H.J. Haustermans K. Price T. et al.Preoperative chemoradio-therapy and postoperative chemotherapy with capecitabine and oxaliplatin versus capecitabine alone in locally advanced rectal cancer: first results of the PETACC-6 randomized phase III trial.J Clin Oncol. 2018; 36Crossref Google Scholar, 9.Allegra C.J. Yothers G. O'Connell M.J. et al.Neoadjuvant 5-FU or capecitabine plus radiation with or without oxaliplatin in rectal cancer patients: a phase III randomized clinical trial.J Natl Cancer Inst. 2015; 107: djv248Crossref PubMed Scopus (205) Google Scholar, 10.Deng Y. Chi P. Lan P. et al.A multi-center randomized controlled trial of mFOLFOX6 with or without radiation in neoadjuvant treatment of local advanced rectal cancer (FOWARCstudy): Preliminary results.J Clin Oncol. 2015; 33Crossref Google Scholar]. The results showed a small but significant 3-year disease-free survival (DFS) benefit of adding oxaliplatin to 5-FU-based perioperative CRT [5.Rödel C. Graeven U. Fietkau R. et al.Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial.Lancet Oncol. 2015; 16: 979-989Abstract Full Text Full Text PDF PubMed Scopus (485) Google Scholar]. This post hoc subset analysis of the effect of age in the CAO/ARO/AIO-04 phase III trial [11.Hofheinz R.-D. Arnold D. Fokas E. et al.German Rectal Cancer Study Group. Impact of age on the efficacy of oxaliplatin in the preoperative chemoradiotherapy and adjuvant chemotherapy of rectal cancer: a post hoc analysis of the CAO/ARO/AIO-04 phase III trial.Ann Oncol. 2018; 29: 1793-1799Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar], reported in the current issue of Annals of Oncology, concluded 'The addition of oxaliplatin significantly improved DFS and OS in younger patients aged <60 years with advanced rectal cancer. Patients aged ≥70 years had no benefit'. At first sight, this conclusion seems entirely credible and would be in line with a number of publications in colon cancer trials using fluoropyrimidines alone [12.Gray R. Barnwell J. McConkey C. Quasar Collaborative Group et al.Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study.Lancet. 2007; 370: 2020-2029Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar] or with the addition of oxaliplatin [13.Yothers G. O'Connell M.J. Allegra C.J. et al.Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses.J Clin Oncol. 2011; 29: 3768-3774Crossref PubMed Scopus (468) Google Scholar, 14.Tournigand C. Andre T. Bonnetain F. et al.Adjuvant therapy with fluorouracil and oxaliplatin in stage II and elderly patients (between ages 70 and 75 years) with colon cancer: subgroup analyses of the Multicenter International Study of oxaliplatin, fluorouracil, and leucovorin in the adjuvant treatment of colon cancer trial.J Clin Oncol. 2012; 30: 3353-3360Crossref PubMed Scopus (257) Google Scholar] as well as a combined analysis from the Adjuvant Colon Cancer End Points (ACCENT) database [15.McCleary N.J. Meyerhardt J.A. Green E. et al.Impact of age on the efficacy of newer adjuvant therapies in patients with stage II/III colon cancer: findings from the ACCENT database.J Clin Oncol. 2013; 31: 2600-2606Crossref PubMed Scopus (174) Google Scholar]. These publications consistently suggest that oxaliplatin does not have the same efficacy in patients over 70 as it does in younger ones. Human aging is characterized by both physical and physiological frailty, and an increased susceptibility to infection and cancer. There is a loss of adaptive immunity—specifically with impairment of function and altered distribution of T cells [16.Whiting C.C. Siebert J. Newman A.M. et al.Large-scale and comprehensive immune profiling and functional analysis of normal human aging.PLoS One. 2015; 10: e0133627.Crossref PubMed Scopus (62) Google Scholar], and dendritic cells activation and migration [17.Gupta S. Agrawal A. Inflammation & autoimmunity in human ageing: dendritic cells take a center stage.Indian J Med Res. 2013; 138: 711-716PubMed Google Scholar]. From the age of ∼60 years, this decline progressively leads to a state of immuno-senescence, which is considered the main cause of diminished vaccine efficacy in older adults. Better outcomes in advanced CRC patients have been reported for oxaliplatin chemotherapy or chemo-immunotherapy if the primary tumour showed marked T-regulatory cell (Treg) infiltration [18.Correale P. Rotundo M.S. Del Vecchio M.T. et al.Regulatory (FoxP3+) T-cell tumor infiltration is a favorable prognostic factor in advanced colon cancer patients undergoing chemo or chemoimmunotherapy.J Immunother. 2010; 33: 435-441Crossref PubMed Scopus (178) Google Scholar]. Oxaliplatin and irradiation induce a similar form of immunogenic cell death [19.Obeid M. Tesniere A. Ghiringhelli F. et al.Calreticulin exposure dictates the immunogenicity of cancer cell death.Nat Med. 2007; 13: 54-61Crossref PubMed Scopus (2181) Google Scholar]. Hence it is not fanciful to imagine that adjuvant chemotherapy drugs such as oxaliplatin with additional immune effects [20.Tesniere A. Schlemmer F. Boige V. et al.Immunogenic death of colon cancer cells treated with oxaliplatin.Oncogene. 2010; 29: 482Crossref PubMed Scopus (769) Google Scholar] may not be so effective in older adults. However, a number of issues need to be addressed before accepting the CAO/ARO/AIO-04 present conclusions. Firstly, in a post hoc analysis the hypothesis being tested does not have to be specified before the examination of data. This omission can potentially give rise to substantial limitations if used to try and answer comparative questions of efficacy. Patients are not randomized, and sources of bias are therefore not controlled for. Secondly, the inherent design of the trial does not allow us to distinguish if any benefit in DFS from the addition of oxaliplatin in younger patients <70 years (which is lacking in older patients) derives from the preoperative concurrent CRT component or the use of postoperative oxaliplatin, or both. Thirdly, it is just possible that the real outlier here is the 240 patients in the control group under 60, who fare badly despite a significantly better performance status (P = 0.001) than the older two groups. The results show 3 year DFS (67%) in the under 60 control versus 78% in those who received oxaliplatin P=0.011). In addition, both the local recurrence (7%) as well as metastatic rate (26%) for the under 60s control group is higher than in any of the other groups (see Table 1). Compliance to treatment with both radiotherapy and chemotherapy appear similar.Table 1Comparison of efficacy for the 3 age groups<60 years old60–69.9 years old ≥70 years old5FU control5FU oxaliplatin5FU control5FU oxaliplatin5FU control5FU oxaliplatin3 year DFS67%78%78%79%67%68%Cumulative incidence of local failure (3-year)7%3%4%3%3%4%Cumulative incidence of distant metastases (3-year)26%19%18%17%23%20%pCR (ypT0N0)16%16%14%21%8%16% Open table in a new tab Demonstrating a benefit from adjuvant chemotherapy in older patients is thought to be harder mostly due to a higher rate of deaths from other causes. This observation is reflected in the DFS and OS figures for the over 70s which are lower numerically than in the younger groups both in the control as well as in the experimental arms. The potential benefit of adding oxaliplatin to CRT and its use in the adjuvant setting remain controversial. None of the randomized trials conducted so far demonstrated any OS benefit from the addition of oxaliplatin to standard CRT [6.Aschele C. Cionini L. Lonardi S. et al.Primary tumor response to pre op-erative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial.J Clin Oncol. 2011; 29: 2773-2780Crossref PubMed Scopus (599) Google Scholar, 7.Gerard J.P. Azria D. Gourgou-Bourgade S. et al.Comparison of two Neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD12/0405-Prodige2.J Clin Oncol. 2010; 28: 1638-1644Crossref PubMed Scopus (639) Google Scholar, 8.Schmoll H.J. Haustermans K. Price T. et al.Preoperative chemoradio-therapy and postoperative chemotherapy with capecitabine and oxaliplatin versus capecitabine alone in locally advanced rectal cancer: first results of the PETACC-6 randomized phase III trial.J Clin Oncol. 2018; 36Crossref Google Scholar, 9.Allegra C.J. Yothers G. O'Connell M.J. et al.Neoadjuvant 5-FU or capecitabine plus radiation with or without oxaliplatin in rectal cancer patients: a phase III randomized clinical trial.J Natl Cancer Inst. 2015; 107: djv248Crossref PubMed Scopus (205) Google Scholar, 10.Deng Y. Chi P. Lan P. et al.A multi-center randomized controlled trial of mFOLFOX6 with or without radiation in neoadjuvant treatment of local advanced rectal cancer (FOWARCstudy): Preliminary results.J Clin Oncol. 2015; 33Crossref Google Scholar]. Systematic reviews of randomized trials evaluating the addition of oxaliplatin have also been reported, with different conclusions. Yang et al. [21.Yang Y.-J. Cao L. Li Z.-W. et al.Fluorouracil-based neoadjuvant chemora-diotherapy with or without oxaliplatin for treatment of locally advanced rectal cancer: an updated systematic review and meta-analysis.Oncotarget. 2016; 7: 45513-45524Crossref PubMed Scopus (38) Google Scholar] conducted a systematic review of all seven trials; the DFS analysis excluded the NSABPR-04 trial and showed an HR ratio of 0.89 (95% CI 0.78–1.00; P = 0.05) in favour of oxaliplatin-CRT. This DFS analysis included two of the trials in which adjuvant treatment with oxaliplatin was added in the investigational arm. Another meta-analysis included eight trials and did not show a significant benefit in terms of 5-year DFS or OS. This publication reported significant differences in terms of higher grade 3–4 toxicity and pCR rates with oxaliplatin-CRT [22.Fu X.-L. Fang Z. Shu L.-H. et al.Meta-analysis of oxaliplatin-based versus fluorouracil-based neo-adjuvant chemoradiotherapy and adjuvant chemotherapy for locally advanced rectal cancer.Oncotarget. 2017; 8: 34340-34351Crossref PubMed Scopus (17) Google Scholar]. It also included the so-called ADORE trial, a multicentre randomized phase II trial examining the use of FOLFOX versus a 5FU/LV regimen, in the setting of 321 patients who received prior chemoradiation and surgery with pathologic stage II/III disease [23.Hong Y.S. Nam B.H. Kim K.P. et al.Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial.Lancet Oncol. 2014; 15: 1245-1253Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar]. With a median follow-up of just over 3 years there was a statistically significant improvement in DFS in favour of FOLFOX (71.6% versus 62.9%, HR 0.657, P = 0.047). When the benefit was evaluated by post-CRT pathologic stage, only yp stage III patients had a DFS benefit. Apart from different trial inclusion, these two systematic reviews used different methodologies to analyse the data and therefore interpretation is challenging. So why is it so difficult to demonstrate a DFS or OS advantage in adjuvant rectal cancer trials? The impact of adjuvant chemotherapy may be over-estimated in the 'modern' era due to stage migration, better surgery [24.Pahlman L.A. Hohenberger W.M. Matzel K. et al.Should the benefit of adjuvant chemotherapy in colon cancer be re-evaluated?.J Clin Oncol. 2016; 34: 1297-1299Crossref PubMed Scopus (56) Google Scholar] better compliance and earlier use of chemotherapy [25.Biagi J.J. Raphael M.J. Mackillop W.J. et al.Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer. A systematic review and meta-analysis.JAMA. 2011; 305: 2335Crossref PubMed Scopus (450) Google Scholar] and other mitigating factors. In addition, it is not unreasonable to consider that a sizeable proportion of patients in these studies will have had stage II disease where the benefit of adjuvant therapy is more difficult to achieve. As the landscape of treatment of rectal cancer continues to evolve, the role and benefit of adjuvant chemotherapy (distinct from chemoradiation) may become increasingly difficult to answer. Newer trials investigating TNT such as RAPIDO (NCT01558921) or eliminating the need for radiotherapy altogether (PROSPECT) (NCT01515787) will be reported over the next few years. Such trials may have an impact on the way we manage rectal cancer in the future. None declared.