The aim of adjuvant chemotherapy is to eliminate micrometastatic disease, thereby reducing the risk of cancer recurrence and improving recurrence-free and overall survival.
Many studies that had reported benefit for adjuvant chemotherapy in this setting occurred in the era preceding neoadjuvant chemoradiation, before surgical advances became part of standard treatment. Pathological complete response to neoadjuvant therapy occurs in 10–20% of patients and is associated with a good prognosis. As such, the role of postoperative therapy has now been brought into question.
Postoperative adjuvant therapy for cancers above the peritoneal reflection should be decided as per colon cancer recommendations (see Adjuvant treatment for colon cancer).
Oxaliplatin in combination with a fluoropyrimidine has now become standard therapy for stage III colon cancer, based on several trials including the MOSAIC and NSABP C-07 studies (see Adjuvant treatment for colon cancer). It has since been investigated for rectal cancer.
Overview of evidence (non-systematic literature review)[edit source]
No systematic reviews were undertaken for this topic. Practice points were based on selected published evidence. See Guidelines development process.
Post-operative adjuvant chemotherapy for rectal cancer following preoperative neoadjuvant therapy[edit source]
Two recent systematic reviews and meta-analyses were published in 2015 addressing this issue specifically in patients who had received prior neoadjuvant therapy:
- A 2015 systematic review and meta-analysis included four eligible phase III randomised controlled trials (RCTs) in patients with stage II or III rectal cancer with R0 resection (n = 1196). It found no significant differences in overall survival between those patients who received adjuvant chemotherapy compared with observation alone (hazard ratio [HR] 0.97, p=0.775). Disease-free survival and distant recurrences were also similar between arms. Subgroup analysis indicated that those patients with upper rectal tumour (10–15 cm from the anal verge) benefited from chemotherapy, with improved disease-free survival and less distant recurrence. This was based on an individual patient data meta-analysis. However, there was no difference in survival outcomes with or without chemotherapy for patients with pathological stage III (node positive) versus stage II disease, or based on pathological nodal status (N0 vs N1 vs N2).
- A 2015 systematic review and meta-analysis included two RCTs, one pooled analysis of five additional RCTs, and 10 retrospective studies, including 5457 patients in total. This analysis found improved 5 year overall survival (OR 0.64, p = 0.0006) and 5-year disease-free survival (odds ratio [OR] 0.71, p < 0.0001) but noted most of this benefit was limited to the retrospective studies. Subgroup analysis of those with node positive disease was not undertaken.
A 2012 Cochrane meta-analysis of adjuvant chemotherapy for rectal cancer, including literature published between 1975 and 2011, included 21 RCTs and nearly 10,000 patients with rectal cancer. Only adjuvant 5FU was used in these trials (i.e. no oxaliplatin or other agents). The Cochrane review found that adjuvant chemotherapy significantly reduced the risk of death and disease recurrence. However, only one of these trials included neoadjuvant chemoradiation for all patients, so the data are hard to interpret in the context of today’s conventional neoadjuvant treatment. In the three trials that reported data separately for stage III (node positive) rectal cancer, there were no differences in overall survival for patients with stage III disease who did and did not receive adjuvant chemotherapy.
Overall, the benefit of fluoropyrimidine-based adjuvant chemotherapy for patients is somewhat uncertain in the modern management of rectal cancer, which includes neoadjuvant treatment and more anatomically appropriate surgery (such as total mesorectal excision) than previously. International guidelines vary. The US National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines recommends adjuvant chemotherapy, preferably doublet therapy including oxaliplatin, for any T3-4 or node positive rectal cancer. European Society for Medical Oncology (ESMO) Guidelines note that adjuvant chemotherapy ‘can be given’ for high risk stage II and stage III rectal cancer but acknowledge that the level of scientific evidence for benefit is much lower than for colon cancer. The St Gallen European Organisation for Research and Treatment of Cancer (EORTC) Consensus Panel agreed that for tumours staged clinically and pathologically as N0, adjuvant chemotherapy was not recommended. However, for cN+ downstaged to pN0 there was no consensus, and most participants preferred to deliver adjuvant therapy for pN+ disease.
Strong evidence for benefit of adjuvant chemotherapy for rectal cancer is lacking, even in patients with node positive disease. In disease regarded as high risk, the uncertain benefits of adjuvant chemotherapy should be acknowledged.
Patients with upper third rectal tumours (10–15cm from the anal verge) with either cN+ or pN+ findings, are possibly those who may derive any/most benefit from adjuvant chemotherapy.
The role for oxaliplatin as adjuvant therapy in rectal cancer[edit source]
Several trials have investigated the role of oxaliplatin in the adjuvant setting for rectal cancer:
- The ADORE phase II RCT conducted in Korea, randomised 321 patients with resected stage II/III rectal cancer who had received neoadjuvant CRT, to four cycles of adjuvant bolus 5FU/LV or eight cycles of FOLFOX chemotherapy. At 3-year follow-up, disease-free survival was improved favouring the FOLFOX arm (71.6% versus 62.9%, HR 0.657, p = 0.047). The benefit appeared limited to patients with pathological stage III disease with no benefit observed for those with stage II cancer. Overall survival was also improved for the FOLFOX arm (3-year overall survival 95% versus 85.7%; HR 0.456, p = 0.036). Higher rates of toxicities were observed in the FOLFOX arm, including myelosuppression and neuropathy.
- The CHRONICLE phase III RCT compared either observation alone or six cycles of XELOX (capecitabine and oxaliplatin) therapy in 113 patients with resected rectal cancer following chemoradiation. This study closed prematurely and did not meet its target recruitment of 780 patients so interpretation is limited due to low statistical power. Only 48% of patients assigned to postoperative chemotherapy completed all six cycles, with 39% of these patients having dose reductions and 40% experiencing grade 3–4 toxicities. The 3-year disease-free survival was not significantly different: 78% (chemotherapy) versus 71%, HR 0.8, p = 0.56, and 3-year overall survival was also similar.
A 2016 systematic review and meta-analysis included four RCTs (n = 2793) including both the above trials and also the PETACC-6 and CAO/ARO/AIO-04 studies, both of which included postoperative oxaliplatin in their randomisations. It reported that adjuvant oxaliplatin-based chemotherapy was associated with improved disease-free survival (HR 0.85, p = 0.03) but no difference in overall survival, compared with fluoropyrimidine-based chemotherapy alone. Comparison between stage II and stage III disease was not made. Similar compliance levels, but higher toxicities were noted for oxaliplatin-containing arms. Notably there was significant heterogeneity; in particular regimens differed considerably across the trials and follow up to date is relatively short.
A second review and meta-analysis of five randomized trials (either fluoropyrimidine-only or fluoropyrimidine plus oxaliplatin-based adjuvant chemotherapy) did not find an overall survival or disease-free survival benefit, when comparing adjuvant oxaliplatin-based chemotherapy with fluoropyrimidine alone.
For patients with pathological stage II/III rectal cancer, adjuvant oxaliplatin-based chemotherapy is associated with increased toxicities. Benefits, if any, may be confined to those with stage III disease; but not all data concur.
The uncertain benefits of oxaliplatin as adjuvant therapy in rectal cancer should be acknowledged.
The role of adjuvant chemotherapy after pathological complete response[edit source]
A 2012 systematic review and meta-analysis of patient outcomes following pathological complete response, which included 16 studies, demonstrated that those patients with a pathological complete response had fewer local recurrences (OR 0.25, p = 0.002) and lower rates of distant failure (OR 0.23, p < 0.001). It was noted that 61.4% of patients in the pathological complete response cohort received adjuvant chemotherapy.
A 2015 pooled analysis of individual patient data from 13 separate datasets, included 3313 patients, 898 (27%) of whom achieved pathological complete response after neoadjuvant chemoradiation and surgery. These patients had good prognosis, with statistically improved recurrence-free, disease-free and overall survival compared with patients who did not achieve pathological complete response. Of these patients, 290 (32%) subsequently had adjuvant chemotherapy whilst 608 (68%) did not. For those patients with pathological complete response, adjuvant chemotherapy made no impact on rates of recurrence-free survival, disease-free survival, or overall survival.
One prospective Spanish single-institution study included 176 patients with cT3-4 rectal cancer who received neoadjuvant chemoradiation then surgery. Those who had pathological complete response did not receive adjuvant chemotherapy. For 26 patients (15%) who achieved pathological complete response, 5-year disease-free survival was 95% and overall survival was 100%. Follow-up of 210 patients from a single-institution database in China identified 40 patients with pathological complete response following neoadjuvant chemoradiation and surgery, of whom 19 received post-operative chemotherapy and 21 did not (non-randomised). Five-year disease free survival was 90% and 76% (p = 0.142). Retrospective studies are however limited by selection bias among other biases.
Data for the role of adjuvant chemotherapy following pathological complete response are otherwise largely limited to retrospective studies. A 2006 retrospective study of 95 patients who had received chemoradiation followed by surgery observed that chemotherapy added no additional 3-year disease-free survival benefit for patients with pathological node-negative disease.
With large studies of adjuvant chemotherapy in rectal cancer (regardless of pathological response) not showing clear benefit for adjuvant chemotherapy, it would seem intuitive that those with pathological complete response, who inherently have better prognosis, could avoid its potential toxicities. Given that a RCT comparing observation with adjuvant therapy in patients with pathological complete response is unlikely, decisions need to be made on the basis of available prospective and retrospective cohort studies. The St Gallen EORTC consensus panel was divided as to whether or not adjuvant chemotherapy should be given in this context.
- Maas M, Nelemans PJ, Valentini V, Das P, Rödel C, Kuo LJ, et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol 2010 Sep;11(9):835-44 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20692872.
- Yothers G, O'Connell MJ, Allegra CJ, Kuebler JP, Colangelo LH, Petrelli NJ, 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 Oct 1;29(28):3768-74 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21859995.
- Breugom AJ, Swets M, Bosset JF, Collette L, Sainato A, Cionini L, et al. Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-analysis of individual patient data. Lancet Oncol 2015 Feb;16(2):200-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25589192.
- Petrelli F, Coinu A, Lonati V, Barni S. A systematic review and meta-analysis of adjuvant chemotherapy after neoadjuvant treatment and surgery for rectal cancer. Int J Colorectal Dis 2015 Apr;30(4):447-57 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25433820.
- Petersen SH, Harling H, Kirkeby LT, Wille-Jørgensen P, Mocellin S. Postoperative adjuvant chemotherapy in rectal cancer operated for cure. Cochrane Database Syst Rev 2012 Mar 14;(3):CD004078 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22419291.
- National Comprehensive Cancer Network. NCCN Guidelines for Rectal Cancer Version 2.; 2016 Available from: https://www.tri-kobe.org/nccn/guideline/colorectal/english/rectal.pdf.
- Glimelius B, Tiret E, Cervantes A, Arnold D, ESMO Guidelines Working Group.. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013 Oct;24 Suppl 6:vi81-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24078665.
- Lutz MP, Zalcberg JR, Glynne-Jones R, Ruers T, Ducreux M, Arnold D, et al. Second St. Gallen European Organisation for Research and Treatment of Cancer Gastrointestinal Cancer Conference: consensus recommendations on controversial issues in the primary treatment of rectal cancer. Eur J Cancer 2016 May 30;63:11-24 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27254838.
- Hong YS, Nam BH, Kim KP, Kim JE, Park SJ, Park YS, 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 Oct;15(11):1245-53 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25201358.
- Glynne-Jones R, Counsell N, Quirke P, Mortensen N, Maraveyas A, Meadows HM, et al. Chronicle: results of a randomised phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin (XELOX) versus control. Ann Oncol 2014 Jul;25(7):1356-62 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24718885.
- Zhao L, Liu R, Zhang Z, Li T, Li F, Liu H, et al. Oxaliplatin/fluorouracil-based adjuvant chemotherapy for locally advanced rectal cancer after neoadjuvant chemoradiotherapy and surgery: a systematic review and meta-analysis of randomized controlled trials. Colorectal Dis 2016 Aug;18(8):763-72 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27169752.
- Boustani J, Caubet M, Bosset JF. Adjuvant Chemotherapy in Rectal Cancer after Chemoradiotherapy. Clin Oncol (R Coll Radiol) 2016 Feb;28(2):140-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26698026.
- Martin ST, Heneghan HM, Winter DC. Systematic review and meta-analysis of outcomes following pathological complete response to neoadjuvant chemoradiotherapy for rectal cancer. Br J Surg 2012 Jul;99(7):918-28 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22362002.
- Maas M, Nelemans PJ, Valentini V, Crane CH, Capirci C, Rödel C, et al. Adjuvant chemotherapy in rectal cancer: defining subgroups who may benefit after neoadjuvant chemoradiation and resection: a pooled analysis of 3,313 patients. Int J Cancer 2015 Jul 1;137(1):212-20 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25418551.
- García-Albéniz X, Gallego R, Hofheinz RD, Fernández-Esparrach G, Ayuso-Colella JR, Bombí JA, et al. Adjuvant therapy sparing in rectal cancer achieving complete response after chemoradiation. World J Gastroenterol 2014 Nov 14;20(42):15820-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25400468.
- Fietkau R, Barten M, Klautke G, Klar E, Ludwig K, Thomas H, et al. Postoperative chemotherapy may not be necessary for patients with ypN0-category after neoadjuvant chemoradiotherapy of rectal cancer. Dis Colon Rectum 2006 Sep;49(9):1284-92 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16758130.