Subsequent treatment and the continuum-of-care model
After initial systemic therapy for colorectal cancer, the approach to subsequent therapy is variable. It might include maintenance chemotherapy (particularly for patients treated initially with an oxaliplatin-containing regimen to minimise cumulative neurotoxicity) or a switch to a different regimen altogether because of disease progression or intolerance to the initial regimen.
Overview of evidence (non-systematic literature review)[edit source]
No systematic reviews were undertaken for this topic. Practice points were based on selected reviews, primary studies, and other clinical practice guidelines (see Guideline development process).
Continuum-of-care model[edit source]
For patients with metastatic colorectal cancer, a ‘continuum-of-care’ approach is now favoured over the model of distinct ‘lines’ of chemotherapy (in which regimens containing non-cross-resistant drugs are each used in succession until disease progression).
This approach emphasises an individualised treatment strategy that might include periods of maintenance chemotherapy interspersed with more aggressive treatment protocols, rechallenging patients who responded to first-line treatment with the same agents used first-line as well as reutilisation of previously administered chemotherapy agents in combination with other active drugs.
For medically unfit patients with a poor performance status or extensive comorbidity, supportive care without chemotherapy should be considered.
Discontinuation of treatment and maintenance therapy[edit source]
The optimal duration of initial chemotherapy for non-resectable disease in the absence of disease progression is debated. In general, the decision to permit treatment breaks during initial therapy (i.e. intermittent rather than continuous therapy) must be individualised and based upon several factors, including tolerance of and response to chemotherapy, disease bulk and location, quality of life, patient preferences and symptomatology.
In many cases, particularly with oxaliplatin-based regimens, toxicity occurs before progressive disease and thus cumulative toxicity can be problematic. As a result, discontinuation/de-escalation/intermittent combination therapy or maintenance strategies provide an attractive treatment options for patients who have responded or reached stable disease.
For patients who are responding to an oxaliplatin based initial regimen, it is reasonable to discontinue oxaliplatin before the onset of severe neurotoxicity (usually after three to four months of therapy). Continuation of oxaliplatin is an alternative for responding patients who have no clinically significant neuropathy. The administration of intermittent combination chemotherapy has been investigated in a number of studies. The OPTIMOX1 trial randomised patients to receive FOLFOX4 until progression or unacceptable toxicity or FOLFOX7 (using a higher dose of oxlaplatin) for six cycles only, followed by reintroduction of oxaliplatinat the time of progression after 12 cycles of a non-oxaliplatin-containing 5FU/LV maintenance regimen. No difference in progression free survival or overall survival was noted. This was interpreted as an indication that oxaliplatin-free intervals did not shorten survival times. The subsequent randomised OPTIMOX-2 trial and the MRC COIN trials took this concept a step further by addressing whether complete chemotherapy-free intervals (CFIs) instead of maintenance might provide the same overall treatment benefit. In both studies, a detrimental effect of CFIs could not be excluded based on the data. These data mandate caution and both careful patient selection and vigilant patient monitoring so that therapy can be reinstated promptly at progression when considering chemotherapy-free intervals.
The concept of treatment discontinuation after active induction therapy has been further refined by studies assessing the concept of “maintenance” therapy with biologicals with or without chemotherapy and a CFI. The optimal maintenance treatment following induction with oxaliplatin containing regimen in combination with bevacizumab is a combination of a fluoropyrimidine (cacepcitabine) plus bevacizumab has been demonstrated by the CAIRO-3 and AIO 0207 trials.
The Dutch CAIRO3 trial randomly assigned patients with stable disease or better after six cycles of XELOX plus bevacizumab to continued capecitabine plus bevacizumab or observation alone. Maintenance therapy was associated with a significantly longer progression free survival (calculated from the time of randomisation) and there was a trend toward improved overall survival. Similarly, a benefit for continued fluoropyrimidine plus bevacizumab as compared with observation alone was also shown in the German AIO KRK 0207 trial.
For patients who have no disease progression after an initial course of bevacizumab plus oxaliplatin-containing chemotherapy, bevacizumab alone for maintenance therapy is not recommended in consensus-based guidelines for the treatment of metastatic colorectal cancer from NCCN and ESMO The Spanish MACRO trial investigated this concept. Patients received six cycles of first-line XELOX plus bevacizumab followed by a randomization to continued therapy or bevacizumab maintenance therapy alone until progression or treatment intolerance. The trial failed to achieve its primary endpoint of non-inferiority for progression free survival. Similarly, Swiss SAKK 41-06 trial randomly assigned patients to bevacizumab continuation versus no maintenance after four to six months of first-line bevacizumab-containing chemotherapy. Like the MACRO trial, the trial failed to achieve its primary endpoint of non-inferiority for time to progression.
Although data from the OPTIMOX-2, MRC COIN, NO16966, and CAIRO3 trials suggested that a complete stop of chemotherapy (with or without biologics) might be associated with an inferior outcome, these results have been called into question by a more recent meta-analysis that did not find adverse survival with an intermittent as compared with continuous treatment strategy.
This recent meta-analysis of randomised controlled trials (RCTs) of continuous versus intermittent strategies of delivering systemic chemotherapy to previously untreated patients with metastatic colorectal cancer. It included eight trials, four of which did not employ maintenance therapy, one of which used maintenance therapy with a fluoropyrimidine alone, two trials which used biologic therapy alone, and one trial, a fluoropyrimidine plus a biologic agent. Intermittent delivery of chemotherapy did not result in a significantly reduced overall survival compared with continuous delivery, whether or not maintenance treatment was included. Quality of life was the same or better with intermittent therapy.
The advantage of intermittent treatment with irinotecan-based regimens is unclear, given the relative lack of cumulative toxicity. Furthermore, the available data suggest similar overall outcomes (progression-free survival and overall survival) whether or not the regimen is administered continuously until progression or toxicity, or in 2 months on/2 months off intervals. The benefits/risks of intermittent chemotherapy with an irinotecancontaining regimen were addressed in an Italian trial, which demonstrated that patients started on FOLFIRI as first-line therapy had similar overall outcome (progression free survival and overall survival) whether or not the regimen was administered continuously until progression or toxicity or in "two months on/two months off" intervals. There were no demonstrable differences in treatment-related toxicity between the continuous versus intermittent treatment groups.
Benefit from anti-epidermal growth factor receptor (EGFR) therapies is limited to patients whose tumours lack mutations in one of the RAS oncogenes (i.e., wild-type [WT] RAS). Data on maintenance strategies involving EGFR- antibody therapies are inconclusive at this time.
The future challenge is to determine which patients should be deescalated to a maintenance strategy and which can be safely stopped completely.
Individualisation and discussion with the patient is essential when planning treatment breaks and or de-escalation/maintenance schedules.
When the combination of leucovorin calcium (folinic acid), 5-fluorouracil (5FU) and oxaliplatin (FOLFOX), with or without bevacizumab, is used for first-line therapy, the available data suggest that it is reasonable to discontinue oxaliplatin temporarily while maintaining a fluoropyrimidine with or without bevacizumab.
For patients receiving initial therapy with a single-agent fluoropyrimidine (plus bevacizumab), induction therapy should be maintained.
Initial induction therapy or a second-line therapy should be reintroduced at radiological or first signs of symptomatic progression.
If a second-line therapy is chosen, re introduction of the initial induction treatment should be a part of the entire treatment strategy as long as no relevant residual toxicity is present.
- Goldberg RM, Rothenberg ML, Van Cutsem E, Benson AB 3rd, Blanke CD, Diasio RB, et al. The continuum of care: a paradigm for the management of metastatic colorectal cancer. Oncologist 2007 Jan;12(1):38-50 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17227899.
- de Gramont A, Buyse M, Abrahantes JC, Burzykowski T, Quinaux E, Cervantes A, et al. Reintroduction of oxaliplatin is associated with improved survival in advanced colorectal cancer. J Clin Oncol 2007 Aug 1;25(22):3224-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17664470.
- Yeoh C, Chau I, Cunningham D, Norman AR, Hill M, Ross PJ. Impact of 5-fluorouracil rechallenge on subsequent response and survival in advanced colorectal cancer: pooled analysis from three consecutive randomized controlled trials. Clin Colorectal Cancer 2003 Aug;3(2):102-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12952566.
- Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-Go fashion in advanced colorectal cancer--a GERCOR study. J Clin Oncol 2006 Jan 20;24(3):394-400 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16421419.
- Chibaudel B, Maindrault-Goebel F, Lledo G, Mineur L, André T, Bennamoun M, et al. Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study. J Clin Oncol 2009 Dec 1;27(34):5727-33 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19786657.
- Adams RA, Meade AM, Seymour MT, Wilson RH, Madi A, Fisher D, et al. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol 2011 Jul;12(7):642-53 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21641867.
- Simkens LH, van Tinteren H, May A, ten Tije AJ, Creemers GJ, Loosveld OJ, 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 May 9;385(9980):1843-52 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25862517.
- Hegewisch-Becker S, Graeven U, Lerchenmüller CA, Killing B, Depenbusch R, Steffens CC, 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 Oct;16(13):1355-69 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26361971.
- National Comprehensive Cancer Network. NCCN Guidelines: Colon Cancer. National Comprehensive Cancer Network; 2016.
- Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016 Aug;27(8):1386-422 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27380959.
- Díaz-Rubio E, Gómez-España A, Massutí B, Sastre J, Abad A, Valladares M, 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(1):15-25 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22234633.
- Koeberle D, Betticher DC, von Moos R, Dietrich D, Brauchli P, Baertschi D, 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 Apr;26(4):709-14 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25605741.
- Berry SR, Cosby R, Asmis T, Chan K, Hammad N, Krzyzanowska MK, et al. Continuous versus intermittent chemotherapy strategies in metastatic colorectal cancer: a systematic review and meta-analysis. Ann Oncol 2015 Mar;26(3):477-85 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25057174.
- Wasan H, Meade AM, Adams R, Wilson R, Pugh C, Fisher D, et al. Intermittent chemotherapy plus either intermittent or continuous cetuximab for first-line treatment of patients with KRAS wild-type advanced colorectal cancer (COIN-B): a randomised phase 2 trial. Lancet Oncol 2014 May;15(6):631-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24703531.