Systemic chemotherapy treatment options for first-line treatment
Chemotherapy combinations commonly used in the treatment of metastatic colorectal cancer include:
- fluorouracil (5FU) and leucovorin (FU/LV)
- leucovorin calcium (folinic acid), 5FU and oxaliplatin (FOLFOX)
- leucovorin calcium (folinic acid), 5FU and irinotecan hydrochloride (FOLFIRI)
- leucovorin calcium (folinic acid), 5FU, oxaliplatin and irinotecan hydrochloride (FOLFOXIRI)
- capecitabine plus oxaliplatin (XELOX) – also called CAPOX
- capecitabine plus irinotecan hydrochloride (XELIRI) (see eviQ protocols: Colorectal Metastatic CAPIRI (XELIRI) (Capecitabine Irinotecan) and Colorectal Metastatic CAPIRI (XELIRI) (Capecitabine Irinotecan) with Bevacizumab).
First line chemotherapy for metastatic colorectal cancer typically contains a fluoropyrimidine (intravenous 5FU or oral capecitabine) in combination with either oxaliplatin or irinotecan in various schedules.
For information on protocols, see eviQ cancer treatments.
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).
The cytotoxic chemotherapy backbone[edit source]
Systemic chemotherapy produces clinically meaningful improvements in median survival and progression-free survival. These benefits are most pronounced with regimens containing irinotecan or oxaliplatin in combination with 5FU.
Therapy should be individualised, based upon biomarker studies (see Molecular pathology and biomarkers), previous treatment, disease extent, organ function, and medical comorbidities. For most patients, treatment will be palliative, not curative. The treatment goals may be to prolong overall survival and maintain quality of life for as long as possible. Although specific regimens may be designated as initial therapy, second line therapy after progression, maintenance and beyond, it is important to clarify that these designations represent a continuum of care and that these lines of therapy are blurred rather than distinct.
Combination chemotherapy with a fluoropyrimidine plus either oxaliplatin or irinotecan (FOLFOX or FOLFIRI) achieves higher response rates and improved progression free survival times than a fluoropyrimidine or 5FU/LV alone. FOLFOX and FOLFIRI are both acceptable choices for first-line therapy. This recommendation is consistent with consensus-based guidelines by the US National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO).
5FU chemotherapy can be delivered in a number of different ways. Continuous infusion 5FU is generally less toxic than some bolus and oral regimens. See eviQ protocol Colorectal Metastatic De Gramont (Modified) (Fluorouracil and Leucovorin). Capecitabine, the oral formulation, can be used as an alternative to 5FU/LV alone (XELOX and XELIRI) or as monotherapy in patients with poor performance status or medical comorbidities precluding the use of combination therapy approaches. The combination of capecitabine and irinotecan (XELIRI) has been shown to be inferior and more toxic (higher rates of severe vomiting, diarrhoea and dehydration) than infusional fluorouracil and irinotecan (FOLFIRI). The preferred regimen of the eviQ reference committee is FOLFIRI or irinotecan monotherapy.
When determining the choice, duration and specific combination of systemic therapies a patient’s performance status, comorbidities and treatment related toxicities need to be taken into consideration. The major dose-limiting side effect of oxaliplatin is a cumulative, late-onset predominantly sensory neuropathy, which may require drug discontinuation despite ongoing tumour response. It occurs with increasing frequency above cumulative doses of 680 mg/m2. Guidelines for dosing modifications for all common toxicities of agents described in this section are available at eviQ Cancer Treatments online.
The following monoclonal antibodies have been shown to improve the clinical outcome of patients with metastatic colorectal cancer when combined with combination chemotherapy in the first-line setting:
- panitumumab. See Role of biological agents in first-line treatment of metastatic colorectal cancer.
Patients who are candidates for intensive chemotherapy[edit source]
For patients who are able to tolerate it, we suggest combination chemotherapy with a doublet (FOLFOX, XELOX, or FOLFIRI) rather than a single-agent sequential therapy for initial treatment of metastatic colorectal cancer, particularly for those who have limited liver metastases that might become potentially resectable. This recommendation is consistent with consensus-based guidelines from NCCN) and ESMO.
The three active conventional chemotherapy agents for metastatic colorectal cancer are fluoropyrimidines, irinotecan, and oxaliplatin. The proportion of patients exposed to all three drug classes at some point in the continuum of care correlates with an increased median survival as evidenced from a combined analysis of data from seven phase III clinical studies.Results from a randomised study to evaluate the efficacy of FOLFIRI and FOLFOX regimens as initial therapy and to evaluate the effect of using sequential therapy with the alternate regimen on progression showed no sequence to be superior with respect to progression free survival or overall survival.
The triplet combination chemotherapy regimen FOLFOXIRI with or without bevacizumab can be considered for first-line therapy in selected patients who are able to tolerate intensive therapy and for whom a more aggressive initial approach is chosen due to patient factors such as excellent performance status, younger age, higher tumour load, conversion therapy for initially non-resectable liver metastases, contraindication to cetuximab/panitumumab (e.g. RAS/BRAF mutation). In an Italian study FOLFOXIRI was shown to be superior to FOLFIRI in terms of response rate (the primary end point, 66% versus 41%) the number of patients able to undergo complete secondary surgical cytoreduction of liver metastases, median progression-free survival, and median overall survival (23 versus 17 months).
Similar high response rates and improved median overall survival were noted with FOLFOXIRI plus bevacizumab as compared to FOLFIRI plus bevacizumab in the TRIBE trial, but it did not confirm higher rates of secondary surgical resection of liver metastases with an initial three-drug chemotherapy backbone. Furthermore, grade 3 to 4 toxic effects that were more common with FOLFOXIRI included diarrhoea, stomatitis, neutropenia, and peripheral neuropathy. Not all studies have concluded a benefit from triplet cytotoxic therapy versus a standard doublet and the contribution bevacizumab makes to the triplet regimen remains uncertain.
For patients in whom either oxaliplatin or irinotecan need to be withheld because of toxicity, it is reasonable to continue the fluoropyrimidine plus bevacizumab. See Discontinuation of treatment and maintenance therapy.
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Patients who are not candidates for intensive chemotherapy[edit source]
For patients who are not candidates for an intensive first-line oxaliplatin or irinotecan-based combination regimen, we suggest fluoropyrimidine therapy alone. This recommendation is consistent with consensus-based guidelines from the NCCN and ESMO.
Capecitabine monotherapy is an effective first-line regimen when fluoropyrimidines alone are indicated. If intravenous 5FU is used, short-term infusional FU/LV rather than bolus 5FU administration is preferable because of its favourable toxicity profile.
The use of FU/LV or capecitabine plus bevacizumab is also appropriate in patients who are not good candidates for oxaliplatin or irinotecan and who do not have contraindications to antiangiogenesis therapy. In two phase II randomised controlled trials (RCTs) in which previously untreated patients were assigned to bolus FU/LV with or without bevacizumab (5 or 10 mg/kg every two weeks), response rates were approximately two fold higher with bevacizumab, and median survival was extended by 7.7 and 3.7 months for the two doses, respectively.
Furthermore, in the multi-centre AVEX trial, 280 patients age 70 or older with previously untreated metastatic colorectal cancer were randomly assigned to capecitabine with or without bevacizumab at standard doses. Combined therapy was associated with significantly longer median progression-free survival (the primary endpoint, 9.1 versus 5.1 months) and a non-significant trend toward longer overall survival (median 21 versus 17 months). However, there were significantly more events leading to treatment discontinuation in the bevacizumab arm (25 versus 15 percent), and higher rates of all-grade haemorrhage (25 versus 7 percent), hypertension (19 versus 5 percent), and venous thromboembolic events (12 versus 5 percent, grade 3 or higher, 8 versus 4 percent). There were six arterial thromboembolic events in the combined therapy group, compared with three with capecitabine monotherapy (4 versus 2 percent). Although rates of grade 5 (fatal) toxicities were not higher with bevacizumab (8.2 versus 11.8 percent with capecitabine alone), they were higher than expected in both groups.
Combination of capecitabine and bevacizumab is therefore an option for elderly patients or those not suitable for more intensive regimens. Caution is warranted when prescribing bevacizumab in combination with chemotherapy for elderly patients with a history of atherosclerotic cardiovascular disease. The risks probably outweigh the benefits in patients with a history of stroke or myocardial infarction within the preceding 6 to 12 months, or a history of thromboembolic disease, and the drug is contraindicated in patients with severe uncontrolled hypertension. See eviQ protocol Colorectal Metastatic Capecitabine with Bevacizumab
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Practice points[edit source]
For patients who are candidates for intensive chemotherapy
For patients who are able to tolerate it, combination chemotherapy with a doublet (FOLFOX, XELOX [CAPOX], or FOLFIRI) rather than a single agent sequential therapy for initial treatment of metastatic colorectal cancer, is preferred.
When the aim is cytoreduction prior to surgical resection
Patients with potentially resectable metastatic disease should be discussed at a multidisciplinary meeting, and treatment plans should consider patient comorbidity and suitability for an aggressive treatment strategy
For those with good performance status and without significant comorbidities intensive triplet chemotherapy with FOLFIRINOX can be considered.
For patients who are not candidates for intensive chemotherapy
Patient comorbidities, ECOG performance status, and location and burden of metastatic disease should be considered in treatment decisions.
For patients who are medically unfit with poor performance status, a supportive care approach may be appropriate.
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