Management of metastatic colorectal cancer in older adults and those with a poor performance status

INTRODUCTION — 

Colorectal cancer (CRC) is a leading cause of cancer-related death in the United States and other resource-abundant countries. The incidence of CRC steadily increases with age. As a result, the number of older adults (patients over the age of 65) presenting for CRC care is expected to rise. Although some patients with metastatic CRC (mCRC) are potentially resectable for cure (particularly those with isolated liver metastases), treatment for most patients is palliative and generally consists of systemic therapy.

This topic review will discuss systemic therapy for nonresectable mCRC in older adults and those with a poor performance status (PS). Adjuvant therapy for older adult patients with colon cancer and other topics relevant to the treatment of mCRC are presented separately.

●(See "Adjuvant therapy for resected colon cancer in older adult patients".)

●(See "Initial systemic therapy for metastatic colorectal cancer".)

●(See "Second- and later-line systemic therapy for metastatic colorectal cancer".)

●(See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy".)

CHALLENGES SPECIFIC TO OLDER ADULTS — 

The essential principles of treating mCRC in older adults are the same as in younger patients. However, in older patients, who may have age-related organ function decline and medical comorbidity, special attention must be paid to the risks of systemic therapy (both treatment-related toxicity and quality of life [QOL] issues), particularly in the context of estimated life expectancy. Age-related organ function changes are relevant to the treatment of patients with CRC (table 1). A thorough discussion of the age-related changes that should be considered when assessing the risk of systemic therapy for mCRC is presented separately. (See "Systemic chemotherapy for cancer in older adults".)

Quality of life issues — Quality of life (QOL) is a crucial component of decision-making when treating older patients. The available data suggest that older patients are just as willing to try systemic therapy as their younger counterparts but less willing to endure severe treatment-related side effects.

There are few data about how systemic therapy affects QOL in older patients with mCRC [1,2]. A major issue is whether the higher response rates and generally longer survival seen with modern combination regimens (as compared with a strategy of sequential single agents) are outweighed by the greater likelihood of side effects and adverse impact on QOL. In one of the only trials to address this issue, the MRC FOCUS2 trial, 459 patients who were considered unfit for full-dose chemotherapy because of older age alone (29 percent), frailty (32 percent), or both (38 percent) were randomly assigned, using a 2x2 factorial design, to short-term infusional fluorouracil (FU) plus leucovorin (LV) with or without oxaliplatin, or capecitabine with or without oxaliplatin [2]. The median age was 74, with 43 percent of patients older than 75, and 13 percent older than 80 years of age; 29 percent had a PS of 2 (table 2).

The following findings were noted:

●In the factorial comparison, the addition of oxaliplatin to either fluoropyrimidine was associated with significantly higher response rates and a trend toward better progression-free survival (PFS) and overall survival (OS) that was not statistically significant. However, the use of oxaliplatin had a detrimental impact on QOL, with significantly fewer patients reporting improved global QOL at week 12 to 14 (49 versus 62 percent).

●QOL improvement was the primary outcome measure for the comparison of capecitabine versus short-term infusional FU plus LV. Rates of improved global QOL at 12 to 14 weeks were the same in both groups (56 percent), despite more treatment-related side effects with capecitabine.

This study is described in more detail below. (See 'Reduced dose FOLFOX or XELOX' below.)

Measures of physical function and reserve — Age-related changes in physical health vary widely among individuals. Chronologic age is a poor marker of a patient's functional status. Several methods of functional assessment are available, several of which are used in the comprehensive geriatric assessment (CGA).

●Performance status – The most common method to measure physiologic reserve and functional status in cancer patients is the clinician estimated PS. There are three widely used scales, the Eastern Cooperative Oncology Group (ECOG) scale (table 2), the Karnofsky Performance Status (KPS) (table 3), and the Palliative Prognostic Scale (PPS), which includes information about self-care, oral intake, physical activity, disease extent, and level of consciousness and has been found to have similar predictive accuracy for survival as the KPS. (See "Survival estimates in advanced terminal cancer", section on 'Performance status'.)

These performance scales are useful to assess a patient's ability to tolerate systemic therapy and to assess short-term prognosis. Regardless of age, patients with a poor PS (eg, ECOG PS >2, KPS or PPS <60) usually tolerate systemic therapy poorly and have a short median OS. However, PS tends to underrepresent the degree of functional impairment in the older patient. (See "Systemic chemotherapy for cancer in older adults", section on 'Assessments of physical function and reserve'.)

Studies addressing management of patients with mCRC and a poor PS (who may not necessarily be older adults) are presented below.

●ADL and IADL scales – A more comprehensive understanding of an older patient's functional state can be obtained by use of Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scales. ADL refers to the skills that are necessary for basic living, and include feeding, grooming, transferring, and toileting. IADL refers to the skills required to live independently in the community, including shopping, managing finances, housekeeping, preparing meals, and the ability to take medications.

The comprehensive geriatric assessment — Assessment of functional status the ADL and IADL scales is a component of the CGA. Randomized trials have shown that CGA-driven interventions can improve patient and caregiver satisfaction with communication about aging-related concerns and satisfaction with overall care, reduce systemic therapy toxicity, reduce falls during cancer treatment, increase advance directive completion, and for patients with CRC, improve completion of scheduled systemic therapy. (See "Comprehensive geriatric assessment for patients with cancer", section on 'Potential benefits'.)

Incorporating a more thorough geriatric assessment of function using the CGA can aid treatment decision-making in cancer patients age 65 and older. (See "Comprehensive geriatric assessment for patients with cancer", section on 'Who needs a CGA?'.)

There is no uniform CGA measurement tool. However, practical assessment of vulnerabilities in older patients with cancer (table 4) and specific interventions guided by the geriatric assessment (table 5) are available. These and other CGA measurement tools are discussed separately. (See "Comprehensive geriatric assessment for patients with cancer", section on 'Domains of a CGA' and "Comprehensive geriatric assessment for patients with cancer", section on 'Obtaining patient data'.)

Guiding treatment decisions by assessment of physical function — There is general agreement that frail older adults, those with significant functional impairment, or an ECOG PS of 3 to 4 (table 2), should be supported with palliative measures aimed at maintaining QOL [3,4]. There is also general agreement that active, fit, older patients without comorbidity should be treated in the same fashion as younger patients with mCRC (table 6). (See 'Frail, significant functional impairment, poor performance status' below and 'Relatively fit patients with a good performance status' below.)

For patients who are neither frail nor fit (the majority of older adults) treatment decision-making is the most complex. Their treatment requires excellent communication and individualized care. (See 'Less fit patients with an ECOG PS 0 or 1' below.)

Because of the limited number of older patients enrolled in clinical trials [5,6], good quality evidence about safety and efficacy of systemic therapy in older patients with CRC has come mainly from subgroup analyses of pooled data from phase III trials. These pooled analyses and other trials of various chemotherapy regimens in combined populations suggest that older patients have similar efficacy from chemotherapy for CRC as do younger patients, usually with only minor differences in rates of severe toxicity [3,7-11]. However, in general, patients in these trials have been fit with a good to excellent PS.

Very few of these trials have attempted to use geriatric factors (such as a CGA or specific domains of the CGA such as functional status or cognitive function) to predict for severe toxicity in older adults receiving systemic therapy for mCRC. At least one prospective trial of different chemotherapy strategies in patients over the age of 75 suggests that baseline impaired cognition (as assessed by the Mini Mental Status Examination) and impaired autonomy (as assessed by IADL) can identify those older adults who are at risk for severe treatment-related toxicity, which may impact treatment selection [12]. (See "Comprehensive geriatric assessment for patients with cancer", section on 'Domains of a CGA' and "The mental status examination in adults", section on 'Mental status scales or inventories'.)

Decision making can be aided by several tools. The information obtained from the CGA has been combined with other information, including the proposed systemic therapy regimen, hematologic and kidney function, limited hearing, and cancer type to derive models used to predict risk for severe and potentially fatal systemic therapy toxicity in the older adult population (table 7 and table 8) [13]. This is discussed in detail separately. (See "Systemic chemotherapy for cancer in older adults", section on 'Models predicting chemotherapy toxicity and early death'.)

The importance of molecular profiling — Increasingly, biomarker expression is driving therapeutic decision-making in treatment of advanced cancer. Gene profiling of tumor tissue should be undertaken as quickly as possible after diagnosis of mCRC because of the significant treatment implications, both for initial systemic therapy as well as subsequent treatments. However, biomarkers that identify patients who are candidates for most of the approved agents that are active against mCRC are unknown, with several notable exceptions. (See "General principles of systemic therapy for metastatic colorectal cancer", section on 'Predictive biomarkers'.)

RELATIVELY FIT PATIENTS WITH A GOOD PERFORMANCE STATUS

Overview of treatment selection — In general, we follow a similar algorithm for treatment selection in fit older patients with a good performance status (PS; Eastern Cooperative Oncology Group [ECOG] 0 to 1 (table 2)) as we do in younger individuals (algorithm 1), with some exceptions. Specific issues that pertain to regimen selection in older adults are as follows:

●The doublet regimens FOLFOX (oxaliplatin plus short-term infusional fluorouracil [FU] and leucovorin [LV]) and FOLFIRI (irinotecan plus LV and short-term infusional FU) are among the most effective for treatment of mCRC, and both are appropriate choices for first-line therapy in fit, older adults. The available evidence suggests that the benefits of these regimens are similar to those in younger patients, with some variations in toxicity patterns that may affect the choice of therapy:

•Sensory neuropathy is the most important dose-limiting toxicity of oxaliplatin; it tends to occur once cumulative drug doses ≥700 mg/m² are reached. Initiation of FOLFIRI rather than FOLFOX may be prudent in patients with a pre-existing neuropathy.

•Grade 3 or 4 neutropenia and thrombocytopenia are more common with FOLFOX than with FOLFIRI [14]. Given the small increased risk of neutropenia, we often omit the FU bolus from both FOLFOX (eg, modified FOLFOX7) (table 9) and FOLFIRI in older patients to diminish treatment-related cytopenias.

•Nausea (13 versus 3 percent), vomiting (10 versus 3 percent), stomatitis (10 versus 1 percent), and alopecia (24 versus 9 percent) all tend to be more common with FOLFIRI than with FOLFOX [14].

●For most patients over 70 years old, we do not use a triplet chemotherapy regimen containing both oxaliplatin and irinotecan (eg, FOLFOXIRI, oxaliplatin plus irinotecan, LV, and infusional FU) over a doublet regimen containing either oxaliplatin or irinotecan. Although the triplet regimen may improve progression-free survival (PFS) and overall survival (OS) compared with either FOLFOX or FOLFIRI in mCRC, it is also a more toxic regimen and randomized trials to date have been restricted to patients younger than 70 years. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'Three- versus two-drug combinations'.)

●The decision to add a biologic agent (ie, bevacizumab or cetuximab/panitumumab, if RAS/BRAF wild-type [WT]) to chemotherapy for first-line treatment must be individualized. Although fit older patients may derive similar benefits as do younger patients, these are potentially offset by the risks of serious treatment-related toxicity. In particular, we generally do not use bevacizumab in patients with stroke or myocardial infarction within the last six months or other thromboembolic disease, with the exception of treated deep vein thrombosis (DVT) or pulmonary embolism (PE), due to the additional associated risks. (See 'Bevacizumab and biosimilars' below.)

Safety and efficacy of specific regimens in older adults

Goals of systemic therapy and regimen selection — The twin goals of systemic therapy for mCRC in older individuals is the same as in younger individuals: improved symptoms and prolongation of survival. Phase III trials conducted in patients of all ages unselected for biomarkers such as RAS now commonly report median survivals of well over two years, and nearly 10 percent of patients are still alive at five years [15]. (See "General principles of systemic therapy for metastatic colorectal cancer", section on 'Systemic therapy versus supportive care'.)

The following sections will review the available published data that specifically address the benefits and side effects of different options for systemic therapy of mCRC in older adults.

dMMR/MSI-H tumors — For individuals of any age with nonoperable mCRC that is mismatch repair deficient (dMMR) or microsatellite-instability high (MSI-H), initial treatment with immunotherapy has become the preferred approach over chemotherapy. For fit, older adults, treatment options are the same as younger individuals and include pembrolizumab (table 10), dostarlimab, and nivolumab plus ipilimumab. These data are presented separately. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'DNA mismatch repair deficient/microsatellite unstable tumors'.)

Specific data on these agents in older adults are described below.

●Pembrolizumab – In a phase III trial (KEYNOTE-177) trial of patients with treatment-naïve dMMR/MSI-H mCRC, pembrolizumab improved PFS over chemotherapy [16]. The trial enrolled patients up to age 93, and approximately one-half were ≥65 years of age. In unplanned subgroup analysis, the PFS benefit was significant only in those ≤70, but a test for interaction was not provided and the confidence intervals for those >70 years of age significantly overlapped those of the younger cohort. Further details of this trial are presented separately. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'Pembrolizumab'.)

●Dostarlimab – Dostarlimab is another option for initial therapy in fit older adults with dMMR/MSI-H mCRC, extrapolating from studies in relapsed/refractory disease. These data are discussed separately. (See "Overview of advanced unresectable and metastatic solid tumors with DNA mismatch repair deficiency or high tumor mutational burden", section on 'Dostarlimab'.)

●Nivolumab plus ipilimumab – Nivolumab plus ipilimumab is an option that may also be discussed with fit older patients with dMMR/MSI-H mCRC. However, patients must be cautioned that the risk of immune-mediated adverse events is generally higher with such combination immunotherapy relative to single-agent immunotherapy. (See "Overview of toxicities associated with immune checkpoint inhibitors".)

In a phase III trial (CheckMate 8HW) of patients with treatment-naïve dMMR/MSI-H mCRC, nivolumab plus ipilimumab improved PFS compared with single-agent nivolumab and compared with chemotherapy [17,18]. Grade 3 to 4 treatment-related adverse events were lower with nivolumab plus ipilimumab when compared with chemotherapy but higher when compared with single-agent nivolumab. No data are available on whether efficacy with nivolumab plus ipilimumab is retained in older patients. Further details of this study are discussed separately. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'Nivolumab plus ipilimumab'.)

Tumor with proficient mismatch repair

Chemotherapy doublets

Oxaliplatin/FU combinations — The results of pooled and subgroup analyses of phase III trials, as well as phase II trials conducted exclusively in older patients suggest that standard oxaliplatin plus short-term infusional fluorouracil (FU) and LV (FOLFOX (table 11)) is as effective and well tolerated in fit older patients who are enrolled on clinical trials as in younger individuals [3,9,10,19,20], although rates of side effects may be slightly higher in older patients [9,10]. One analysis of older adults with CRC who were treated in the community concluded that individuals age 70 and older had higher rates of nausea, neutropenia, and neuropathy with an oxaliplatin-containing regimen as compared with those treated with a fluoropyrimidine alone [21]. In general, efficacy rates with FOLFOX appear similar to those of irinotecan combined with FU and LV (FOLFIRI), but the side effect profile differs. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'FOLFOX versus FOLFIRI' and "Treatment protocols for small and large bowel cancer".)

Additional data on combination regimens substituting capecitabine for short-term infusional FU in combination with oxaliplatin are discussed separately. (See 'Capecitabine-containing doublets' below.)

Irinotecan/FU combinations — In many [22-25], but not all [24,26] studies, combinations of irinotecan with infusional fluorouracil (FU) and LV (eg, FOLFIRI (table 12)) have been well tolerated in older patients. As examples:

●The safety and efficacy in older adults as compared with younger patients was addressed in a pooled analysis of 2691(29 percent ≥70) patients treated with irinotecan with either bolus FU (IFL) or short-term infusional FU (FOLFIRI) for mCRC [25]. These regimens conferred PFS benefits for both older and younger patients. There were no age-related increases in diarrhea, infection, or other severe adverse events. Bolus IFL regimens have fallen out of favor because of greater toxicity (especially diarrhea) compared with infusional regimens like FOLFIRI.

●The benefit and toxicity of adding irinotecan to FU/LV for first-line treatment of mCRC in older adults was directly addressed in a trial in which 166 patients ≥75 years of age were randomly assigned to short-term infusional FU and LV with or without irinotecan (150 mg/m² for cycles 1 and 2, with the dose increased to 180 mg/m² thereafter if tolerated) [24]. Although the overall response rate was higher with FOLFIRI (42 versus 21 percent), this did not translate into significantly better median PFS (7.3 versus 5.2 months) or OS (13.3 versus 14.2 months). Furthermore, rates of grade 3 or 4 toxicity were also significantly higher with irinotecan (76 versus 52 percent), with higher rates of neutropenia, febrile neutropenia, and diarrhea.

Taken together, these studies suggest that irinotecan/infusional FU regimens are relatively safe for older adults. Combinations of irinotecan with capecitabine are discussed separately. (See 'Capecitabine-containing doublets' below.)

Capecitabine-containing doublets — Multiple trials that substitute the oral fluoropyrimidine capecitabine for intravenous (IV) FU in combination with oxaliplatin (XELOX/CAPOX) (table 13) or irinotecan (XELIRI/CAPIRI) have been reported in fit older adults, and most indicate the safety and efficacy of this approach. However, because of concerns as to both efficacy and safety, our preference remains to deliver irinotecan with infusional FU rather than capecitabine in older patients.

●XELOX – XELOX is a reasonable substitute for FOLFOX in fit older adults. However, XELOX is not necessarily less toxic, more convenient, or less expensive than FOLFOX for the following reasons:

•The appropriate dose of capecitabine is not well defined, at least for American patients.

•A central venous access line is often needed for reasons other than infusional FU in patients with mCRC. Because a significant number of patients report local pain when oxaliplatin is infused via peripheral vein, many centers routinely infuse the drug centrally.

These issues are discussed in detail separately. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'Capecitabine doublets'.)

A major issue is that the appropriate dose of capecitabine to use in the XELOX regimen is not established. While the two European trials described above used 1000 mg/m² twice daily for 14 days, this dose is higher than most American patients can tolerate. We generally start with 850 mg/m² twice daily in fit older adults and start with even lower doses (750 to 800 mg/m² twice daily) in less fit individuals and in those with moderately decreased kidney function. (See "Treatment protocols for small and large bowel cancer".)

The efficacy and safety of XELOX in fit older adults has been addressed in the following trials:

•A Spanish trial administered oxaliplatin (130 mg/m² on day 1) followed by capecitabine (1000 mg/m² twice daily for 14 of every 21 days) for first-line therapy of mCRC in 50 patients age 70 or older [27]. The response rate was 36 percent, and median time to tumor progression and OS were 6 and 13 months, respectively. Treatment was relatively well tolerated. Grade 3 or 4 adverse events included diarrhea (22 percent), asthenia (16 percent), nausea and vomiting (14 percent), neutropenia or thrombocytopenia (6 percent), and hand-foot syndrome (4 percent). There was one treatment-related death. Comparable results were reported in an Italian study of a similar regimen in 76 patients age ≥70 [28]. The starting dose of capecitabine was 1000 mg/m² twice daily with dose escalation permitted to 1250 mg/m² twice daily in the absence of toxicity; the initial oxaliplatin dose was 85 mg/m², with escalation to 110 mg/m², or even 130 mg/m² if tolerated.

The overall response rate was 41 percent, and median PFS and OS were 9 and 14 months, respectively. Only 5 percent of patients developed grade 3 or 4 hematologic toxicity during treatment, 8 percent developed grade 3 neuropathy, and 13 percent had severe hand-foot syndrome.

•The previously described randomized phase III trial of first-line oxaliplatin plus either short-term weekly infusional FU or capecitabine included 109 patients 70 years of age or older and 233 younger individuals [9] (see 'Oxaliplatin/FU combinations' above). The objective response rates for XELOX in older and younger patients were 35 and 45 percent, respectively, and median OS was 17 versus 21 months; neither difference was statistically significant. Within the XELOX group, the only statistically significant toxicity difference between older and younger patients was a higher rate of grade 3 or 4 diarrhea (25 versus 8 percent).

●XELIRI – Because of concerns as to efficacy and safety, our preference remains delivering irinotecan with infusional FU rather than capecitabine in older patients.

XELIRI (capecitabine in combination with irinotecan) produced inferior outcomes compared with FOLFIRI as first-line therapy in the randomized BICC-C trial. In the original report, compared with FOLFIRI alone, capecitabine/irinotecan was associated with significantly higher rates of nausea, vomiting, diarrhea, febrile neutropenia, and dehydration as well as significantly worse PFS and a trend towards inferior median survival. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'Capecitabine doublets'.)

In a later subanalysis of older adults (>70 years of age) versus non-older adults enrolled in the trial, older adults had significantly higher rates of asthenia and dehydration with XELIRI compared with their younger counterparts [11]. Similar high rates of toxicity with XELIRI have been seen by others despite the use of lower starting doses of both drugs [29].

Addition of targeted therapies — For fit older patients, the decision to add a biologic agent (ie, bevacizumab or cetuximab/panitumumab, if RAS/BRAF WT) to chemotherapy for first-line treatment must be individualized (algorithm 1). Although fit older patients may derive similar benefits as do younger patients, these are potentially offset by the risks of serious treatment-related toxicity.

If the decision is made to add a biologic agent, we follow the same principles as with younger patients, basing the choice of bevacizumab or an epidermal growth factor receptor (EGFR) inhibitor on RAS/BRAF mutation status, contraindications to bevacizumab, and the sidedness of the primary tumor. (See 'Impact of tumor-sidedness on selection of targeted agent' below and "Initial systemic therapy for metastatic colorectal cancer", section on 'EGFR inhibitors versus bevacizumab and the influence of tumor sidedness' and "Initial systemic therapy for metastatic colorectal cancer", section on 'RAS mutant tumors'.)

Bevacizumab and biosimilars — Bevacizumab is a humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF). Biosimilars for bevacizumab have also been approved by the US Food and Drug Administration [30]. Adding bevacizumab to regimens containing a fluoropyrimidine, irinotecan, or oxaliplatin improves response rates, PFS, and survival. However, these advances have come with a cost of treatment-related side effects, including bleeding, hypertension, proteinuria, bowel perforation, arterial thromboembolic events (ATEs), and wound healing complications. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'Efficacy and toxicity of bevacizumab and biosimilars' and "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents" and "Cardiovascular toxicities of molecularly targeted antiangiogenic agents".)

The comparable efficacy of bevacizumab in older as compared with younger patients with mCRC has been shown in at least two separate pooled analyses [31,32]. However, the benefits are modest and side effects, particularly ATEs, are of concern when treating older adults [33-39]:

●In a pooled analysis of data from four randomized trials, the magnitude of benefit for the addition of bevacizumab to fluoropyrimidine-containing chemotherapy was similar albeit modest across all age groups (<65, ≥65, ≥70) [32]. For patients age ≥70 years, the median OS benefit from adding bevacizumab was only 3.3 months (median 17.4 versus 14.1 months, hazard ratio [HR] 0.79, 95% CI 0.66-0.93). Bleeding, hypertension, proteinuria, ATEs, venous thromboembolic events, wound-healing complications, fistulae, gastrointestinal perforation, and heart failure were all more common in bevacizumab-treated patients. Among individuals 70 and older, the risk an arterial thrombotic event was twofold higher in the bevacizumab group (6.7 versus 3.2 percent).

●The randomized phase II PRODIGE 20 study of chemotherapy (short-term infusional FU plus LV alone or with oxaliplatin or irinotecan) with or without bevacizumab in individuals aged 75 or older, the addition of bevacizumab was associated with only a trend toward improved PFS (9.7 versus 7.8 months, HR 0.79, 95% CI 0.53-1.17) and OS (median 21.7 versus 19.8 months, HR 0.73, 95% CI 0.48-1.11) but significantly higher rate of grade 3 or 4 arterial hypertension (14 versus 6 percent) [40].

●Similarly, in the multi-center AVEX trial, 280 patients age 70 or older with previously untreated mCRC were randomly assigned to capecitabine (1000 mg/m² twice daily on days 1 to 14 every 21 days) with or without bevacizumab (7.5 mg/kg on day 1 every 21 days) [38]. Combined therapy was associated with significantly longer median PFS (the primary endpoint, 9.1 versus 5.1 months) and a nonsignificant trend toward longer OS (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 hemorrhage (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 ATEs 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.

The combination of capecitabine and bevacizumab is a good option for older adults. Caution is warranted when prescribing bevacizumab in combination with chemotherapy for older adults 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 (with the exception of DVT or PE), and the drug is contraindicated in patients with severe uncontrolled hypertension. Guidelines for pretreatment risk assessment, surveillance, and treatment of hypertension in patients receiving VEGF pathway signaling inhibitors are available (table 14 and table 15). (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Arterial thromboembolic events' and "Cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Hypertension'.)

The relationship between tumor sidedness and benefit from bevacizumab versus cetuximab in first-line therapy of patients with RAS/BRAF WT tumors is addressed below.

Cetuximab and panitumumab — Two monoclonal antibodies targeting the EGFR (cetuximab and panitumumab) are active in the treatment of mCRC that lacks mutations in the RAS genes (WT RAS). Although WT RAS was initially defined as the absence of mutations in codons 12 and 13 of exon 2 of the KRAS gene, more contemporary analyses suggest that exclusion of patients with other mutations in KRAS or NRAS identifies a population that is more likely to benefit from an EGFR inhibitor. (See "General principles of systemic therapy for metastatic colorectal cancer", section on 'RAS testing'.)

Furthermore, response to EGFR-targeted agents is highly unlikely in patients whose tumors harbor a BRAF V600E mutation. (See "General principles of systemic therapy for metastatic colorectal cancer", section on 'BRAF mutations'.)

Treatments targeting the EGFR seems to be similarly effective and safe in older as compared with younger patients [41-46], although some reports suggest greater toxicity, especially diarrhea and acneiform skin rash [47,48]. In one analysis, patients with RAS WT mCRC receiving first-line doublet chemotherapy plus an EGFR inhibitor (n = 1191) versus doublet chemotherapy alone (n = 729) from seven prospective controlled clinical trials [45]. In younger patients, the addition of first-line anti-EGFR therapy versus doublet chemotherapy improved median PFS (11.2 versus 8.9, HR 0.70, 95% CI 0.60-0.82) and median OS (23.9 versus 20.3 months, HR 0.82, 95% CI 0.70-0.95), but there was only a nonstatistically significant trend towards improved PFS and OS in older individuals (PFS 9.1 versus 8.7 months, HR 0.85, 95% CI 0.63-1.15; OS 24.7 versus 17.6 months, HR 0.77, 95% CI 0.58-1.04). When the analysis was limited to left-side only tumors, the addition of an EGFR inhibitor significantly improved outcomes in older individuals (PFS 13.1 versus 8.5 months, HR 0.51, 95% CI 0.28-0.93; OS 26.3 versus 16.5 months, HR 0.49, 95% CI 0.28-0.85). There were no significant differences in toxicity among different age groups.

Impact of tumor-sidedness on selection of targeted agent — Data suggest an association between location of the primary tumor and efficacy of EGFR inhibitors when administered for first-line therapy of mCRC. For older adults with mCRC who are receiving a biologic agent in addition to chemotherapy, we follow the same principles as with younger patients, basing the choice of bevacizumab or an EGFR inhibitor on RAS/BRAF mutation status, contraindications to bevacizumab, and the sidedness of the primary tumor.

●RAS/BRAF wild-type right-sided tumors – Those with a RAS/BRAF WT right-sided primary tumor are treated with the addition of bevacizumab rather than an EGFR-inhibitor to chemotherapy for initial treatment. Those with a contraindication to bevacizumab are treated with chemotherapy alone rather than adding an EGFR inhibitor to chemotherapy. Further details are discussed separately. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'EGFR inhibitors versus bevacizumab and the influence of tumor sidedness'.)

●RAS/BRAF wild-type left-sided tumors – Those with a RAS/BRAF WT left-sided primary tumor are treated with the addition of an EGFR inhibitor (eg, cetuximab or panitumumab) rather than bevacizumab to chemotherapy as initial treatment. Further details are discussed separately. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'EGFR inhibitors versus bevacizumab and the influence of tumor sidedness'.)

●RAS mutant tumor – Those with RAS mutant tumor and any primary tumor site location are treated with the addition of bevacizumab rather than EGFR inhibitor chemotherapy. Patients who are ineligible for bevacizumab may be offered chemotherapy alone. EGFR inhibitors are not used as part of initial therapy to treat RAS-mutated mCRC since such tumors are resistant to these agents. Further details are discussed separately. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'RAS mutant tumors' and "General principles of systemic therapy for metastatic colorectal cancer", section on 'RAS'.)

●RAS wild-type, BRAF V600E mutant tumors – The initial management of RAS WT, BRAF V600E mutant tumors is discussed separately. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'RAS wild-type, BRAF V600E-mutant tumors'.)

LESS FIT PATIENTS WITH AN ECOG PS 0 OR 1 — 

Less fit patients who are not frail and who have a sufficient performance status (PS) are generally less able to tolerate intensive systemic therapy, although they may tolerate some carefully selected regimens.

dMMR/MSI-H tumors — For less fit patients with a good performance state, we offer single-agent immunotherapy with either pembrolizumab (table 10) or dostarlimab which may offer progression-free survival (PFS) benefit with acceptable toxicity. Combination immunotherapy with nivolumab plus ipilimumab is less preferred given the higher rate of immune-related adverse events seen with such combination immunotherapy compared with single-agent immunotherapy. (See 'dMMR/MSI-H tumors' above.)

Patients with a contraindication to immunotherapy may be offered chemotherapy using the same approach as those with mismatch repair proficient tumors. (See 'Tumors with proficient mismatch repair' below.)

Tumors with proficient mismatch repair — For patients with mismatch repair proficient mCRC, options include dose-reduced FOLFOX (oxaliplatin plus short-term infusional fluorouracil [FU] and leucovorin [LV]) or CAPOX, LV-modulated FU with or without bevacizumab, capecitabine with or without bevacizumab, irinotecan alone, cetuximab/panitumumab either as monotherapy or in combination with FU plus LV (for RAS/BRAF wild-type [WT] tumors only), or trifluridine-tipiracil plus bevacizumab. For patients without a contraindication to bevacizumab, the survival benefit of adding bevacizumab to a first-line fluoropyrimidine must be balanced against the potential for serious treatment-related toxicity.

If fluoropyrimidine monotherapy is chosen, we prefer short-term infusional LV/FU (the de Gramont regimen) (table 16) because it is usually very well tolerated but requires central venous access and an ambulatory infusion pump. While potentially more convenient than infusional LV/FU, capecitabine monotherapy is probably more toxic.

Reduced dose FOLFOX or XELOX — The benefit of a reduced-dose oxaliplatin-containing regimen as compared with a non-oxaliplatin-containing regimen in less fit patients was directly addressed in the MRC FOCUS2 trial, described above [2]. Briefly, 459 patients who were considered unfit for full-dose chemotherapy because of age, frailty, or both were randomly assigned, using a 2x2 factorial design, to short-term infusional FU plus LV with or without oxaliplatin, or capecitabine with or without oxaliplatin. Starting doses were reduced by 20 percent in all groups, with dose escalation to 100 percent of standard dose allowed at six weeks provided no grade 2 or worse toxic effects.

The following were noted:

●In the comparison of FOLFOX versus short-term infusional FU and LV alone (the de Gramont regimen) FOLFOX was associated with a significantly higher objective response rate (38 versus 11 percent) and disease control rate (objective response plus stable disease, 71 versus 46 percent). There was a trend toward longer median PFS (5.8 versus 3.5 months) and overall survival (OS; 10.7 versus 10.1 months) with oxaliplatin, which was not statistically significant. The overall risk of having a grade 3 or worse toxic effect during the first 12 weeks of treatment was slightly higher for FOLFOX (33 versus 27 percent).

●In the factorial comparison of oxaliplatin-containing versus non-oxaliplatin-containing chemotherapy, use of oxaliplatin was associated with a nonsignificant trend towards better median PFS (5.8 versus 4.5 months, hazard ratio [HR] 0.84, 95% CI 0.69-1.01) but significantly higher rates of grade 3 or worse diarrhea, neurosensory toxicity, nausea, vomiting, and neutropenia compared with no use of oxaliplatin.

●Compared with FOLFOX, the use of capecitabine plus FU (XELOX) was associated with a slightly lower objective response rate (32 versus 38 percent) and overall disease control rate (objective response plus stable disease, 65 versus 71 percent), but identical PFS (5.8 months in each group), and a trend toward longer median OS that was not statistically significant (12.4 versus 10.7 months). The overall risk of having a grade 3 or worse event was higher with XELOX than FOLFOX (43 versus 33 percent). In the factorial comparison of capecitabine versus FU-containing chemotherapy, capecitabine was specifically associated with higher rates of nausea, vomiting, diarrhea, anorexia, and hand-foot syndrome.

Fluoropyrimidine monotherapy

Leucovorin-modulated FU — Where fluoropyrimidine monotherapy is indicated, short-term infusional LV plus fluorouracil (FU; LV/FU) regimens, such as the de Gramont regimen (table 16), are preferred over bolus regimens (which include the Mayo and Roswell park regimens [49-52]), given the greater efficacy and tolerability, especially hematologic and gastrointestinal [53,54]. The need for central venous access and an ambulatory infusion pump may be a limiting factor.

In regimens containing LV, most American patients receive a racemic mixture of d,l-leucovorin. However, the l-isomer is the biologically active moiety, and a preparation of l-leucovorin is now commercially available in the United States (LEVOleucovorin, Fusilev). It is dosed at one-half that of d,l-leucovorin (table 17) and is similarly effective as the racemic mixture [55].

●Efficacy in older as compared with younger patients – FU monotherapy is consistently tolerable in older patients, and efficacy is similar to that in younger patients.

•Efficacy was addressed in a retrospective analysis of 629 patients over the age of 70 who were treated on 22 phase II or III trials of FU with or without modulators (including LV, interferon, or methotrexate) [7]. There were 484 patients aged 70 and 75, 125 aged 75 to 80, and 20 older than 80. Response rates and survival durations among older adults were similar to those of younger individuals, with infusional FU regimens having a higher response rate than bolus regimens.

•The results of this pooled analysis have been replicated by a number of other investigators in population-based studies, other pooled analyses, and a few phase II studies conducted exclusively in the older adult with mCRC [56-59]. In general, older patients derive as much benefit as younger individuals, the incidence of severe neutropenia is only slightly higher in older patients, and there is no increase in other severe complications with age.

The schedule of administration impacts on toxicity.

Orally active fluoropyrimidines

●Capecitabine – Two identically designed randomized trials (602 and 605 patients, respectively) have shown similar efficacy for capecitabine monotherapy (1250 mg/m² twice daily for 14 of every 21 days) compared with intravenous FU/LV (the bolus Mayo regimen) for the first-line treatment of mCRC [60,61]. However, toxicity profiles differ. In one of the trials, the incidence of grade 3 or 4 diarrhea, stomatitis, nausea, and neutropenic sepsis were significantly less in the capecitabine group; only hyperbilirubinemia and hand-foot syndrome were more common compared with FU/LV [60].

Capecitabine monotherapy appears to be a similarly effective, albeit potentially more toxic substitute for FU in fit older adults with mCRC [2,62-67]. As examples:

•In a combined analysis of data from phase III trials, a higher incidence of grade 3 or 4 adverse effects (largely diarrhea, but also hand-foot syndrome) was seen in patients ≥80 years compared with the overall population (60 versus 40 percent), particularly diarrhea (31 versus 13 percent) [62]. The specific dose of capecitabine was not given.

•In the MRC FOCUS2 trial described above, 459 patients who were considered unfit for full-dose chemotherapy because of age, frailty, or both were randomly assigned, using a 2x2 factorial design, to short-term infusional FU plus LV with or without oxaliplatin, or capecitabine with or without oxaliplatin [2]. (See 'Reduced dose FOLFOX or XELOX' above.)

Starting doses were reduced by 20 percent in all groups, with dose escalation to 100 percent of standard dose allowed at six weeks provided no grade 2 or worse toxic effects. The patients in the capecitabine alone arm began treatment at 1000 mg/m² twice daily on days 1 to 15 every 21 days. In the factorial comparison of capecitabine versus short-term infusional FU plus LV, rates of improved global quality of life (QOL) at 12 to 14 weeks were the same in both groups (56 percent). There was no evidence that substitution of FU with capecitabine had an effect on response rates (23 versus 24 percent with capecitabine- and FU-based regimens, respectively), response duration, or OS. However, compared with FU, capecitabine significantly increased the risk of a grade 3 or worse toxicity and was specifically associated with higher rates of nausea, vomiting, diarrhea, anorexia, and hand-foot syndrome.

Capecitabine is approved in the United States for first-line treatment of mCRC, when fluoropyrimidines alone are indicated. The approved dose is 1250 mg/m² twice daily for 14 of every 21 days, and this dose may be tolerated in older individuals [63]. However, the appropriate dose of capecitabine is not well defined, especially for American patients. As was done in the MRC FOCUS2 trial described above (and in the AVEX trial of capecitabine with or without bevacizumab described below), many clinicians start with 1000 mg/m² rather than 1250 mg/m² twice daily, and dose-escalate to tolerance. Capecitabine also requires dose reduction in individuals with kidney impairment and in those being crossed over from infusional FU/LV [68].

Oral chemotherapy agents such as capecitabine require patients to make decisions regarding the safety of taking a dose in light of ongoing adverse effects such as diarrhea and hand-foot syndrome. This shifts the burden of treatment decisions from provider to the patient, which may be difficult for some older patients [69].

●S-1 – S-1 is an oral fluoropyrimidine that includes three different agents: ftorafur (tegafur), gimeracil (5-chloro-2,4 dihydropyridine, a potent inhibitor of dihydropyrimidine dehydrogenase [DPD]), and oteracil (potassium oxonate, which inhibits phosphorylation of intestinal FU, thought responsible for treatment-related diarrhea). It is available in some countries outside of the United States.

Although data are limited, S-1 appears to have a lower incidence of hand-foot syndrome than does capecitabine [70].

●UFT – Tegafur plus uracil (UFT) is a 1:4 molar combination of ftorafur (tegafur) with uracil, which competitively inhibits the degradation of FU, resulting in sustained plasma and intratumoral concentrations [71]. Response rates are approximately 25 percent with UFT monotherapy and 40 percent in combination with oral LV (150 mg daily) [72]. In phase III studies, UFT plus LV has comparable efficacy and better tolerability as compared with intravenous (IV) bolus FU [73,74]. The dose limiting toxicity is diarrhea. Myelosuppression and hand-foot syndrome are infrequent.

Bevacizumab-containing regimens — For patients with mCRC who are not good candidates for oxaliplatin or irinotecan, and who have no contraindications to use of bevacizumab, another option is bevacizumab plus a fluoropyrimidine [38,75-80]. If this approach is chosen, for most patient we suggest capecitabine plus bevacizumab rather than trifluridine-tipiracil (TAS-102) plus bevacizumab, given the more favorable side effect profile. Short-term infusional FU plus LV plus bevacizumab is another alternative.

When adding a targeted agent to initial backbone chemotherapy, tumor sidedness impacts the selection between bevacizumab and an epidermal growth factor receptor (EGFR) inhibitor. Further details are discussed separately. (See 'Impact of tumor-sidedness on selection of targeted agent' above.)

●FU/LV plus bevacizumab – Studies have shown that bevacizumab plus short-term infusional FU with LV is safe and effective in older adults [75-78,80,81]. As an example, in an open-label phase III trial (JCOG1018), the combination of bevacizumab plus either the de Gramont regimen or capecitabine monotherapy demonstrated similar OS (median 21 versus 20 months) and PFS (median 9 versus 10 months) compared with regimens that contained oxaliplatin and bevacizumab with either capecitabine or the de Gramont regimen, although the objective response rates were lower (33 versus 52 percent) [80].

●Capecitabine plus bevacizumab – The benefit of adding bevacizumab to capecitabine was shown in the phase III AVEX trial, conducted in patients 70 years of age or older [38]. Treatment consisted of capecitabine 1000 mg/m² twice daily on days 1 to 14 of every 21-day cycles, with or without bevacizumab (7.5 mg/kg IV on day 1 of each treatment cycle). Median PFS was significantly longer with combination therapy (9.1 versus 5.1 months), although the rate of ≥grade 3 toxicity was also worse (40 versus 22 percent), especially hand-foot syndrome (16 versus 7 percent) and venous thromboembolic events (8 versus 4 percent).

●Trifluridine-tipiracil plus bevacizumab – TAS-102 is an oral chemotherapy that consists of the nucleoside analog trifluridine (trifluorothymidine, a cytotoxic antimetabolite that, after modification within tumor cells, is incorporated into deoxyribonucleic acid (DNA) causing strand breaks) and tipiracil (a potent thymidine phosphorylase inhibitor, which inhibits trifluridine metabolism and has antiangiogenic properties as well). It is approved in the United States for treatment of mCRC previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an antiangiogenic biologic product, and a monoclonal antibody targeting the EGFR, if RAS WT. (See "Second- and later-line systemic therapy for metastatic colorectal cancer", section on 'Trifluridine-tipiracil with or without bevacizumab'.)

Two trials have directly compared the combination of TAS-102 plus bevacizumab versus capecitabine plus bevacizumab for first-line therapy, with similar outcomes:

•In the TASCO1 trial, which included 153 patients with previously untreated mCRC who were ineligible for intensive therapy median PFS (the primary endpoint) was modestly but nonstatistically higher with TAS-102 (9.2 versus 7.8 months), as was median OS (22 versus 18 months, HR 0.78, 95% CI 0.55-1.10); both therapies were well tolerated, but patients receiving TAS-102 had more ≥grade 3 neutropenia and those receiving capecitabine had more ≥grade 3 hand-foot syndrome and diarrhea [79,82].

•A similar result was found in another phase III trial (SOLSTICE), which compared TAS-102 to capecitabine in 856 previously untreated patients with mCRC who were older (42 percent), had a poor Eastern Cooperative Oncology Group (ECOG) PS or extensive comorbidity, a low tumor burden, or a preference for less intensive initial therapy [83]. At a median follow-up of 16 months, TAS-102 demonstrated similar PFS to capecitabine (median 9.4 versus 9.3 months, HR 0.87, 95% CI 0.75-1·02) but had more toxicities including higher rates of ≥grade 3 neutropenia (52 versus 1 percent) and anemia (14 versus 4 percent). However, capecitabine caused more grade 3 hand-foot syndrome (15 versus 0 percent).

Cetuximab and panitumumab-containing regimens — For older adults with KRAS/BRAF WT mCRC and a good PS who are unable to tolerate oxaliplatin- and irinotecan-containing doublet regimens, options include an EGFR inhibitor (cetuximab or panitumumab) either as monotherapy or in combination with a fluoropyrimidine (FU plus LV). When adding a targeted agent to initial backbone chemotherapy, tumor sidedness impacts the selection between bevacizumab and an EGFR inhibitor. Further details are discussed separately. (See 'Impact of tumor-sidedness on selection of targeted agent' above.)

In a randomized phase II trial (PANDA) of 91 older adults with previously untreated RAS/BRAF WT mCRC, FOLFOX plus panitumumab was compared with FU plus LV plus panitumumab [46]. At a median follow-up of 50 months, compared with FU plus LV plus panitumumab, FOLFOX plus panitumumab improved objective response rates (69 versus 52 percent) but had similar PFS (median 9.6 versus 9 months) and was more toxic (grade >2 toxicity rate 60 versus 37 percent).

Other regimens

Single-agent irinotecan — Irinotecan is active as monotherapy. In some trials, older age is a risk factor for severe (grade 3 or 4) diarrhea [84-86]. As an example, in a phase III comparison of weekly (125 mg/m²) versus every three weeks (300 mg/m² for those over the age of 70, otherwise 350 mg/m²) dosing of single-agent irinotecan, patients over age 70 had 1.8 times the odds of severe diarrhea than younger patients [86]. They were also twice as likely to have severe neutropenia. The authors did not comment on rates of infection or hospitalization by age, or what proportion of the patients with grade 5 (fatal) chemotherapy toxicity were older adults.

On the other hand, excessive toxicity was not seen in a trial of second-line irinotecan (350 mg/m² once every three weeks) in 339 patients with mCRC (72 age 70 or older) who were progressing on a fluoropyrimidine [87]. Older patients had comparable efficacy, and toxicity (including diarrhea) was not worse as compared with younger individuals.

FRAIL, SIGNIFICANT FUNCTIONAL IMPAIRMENT, POOR PERFORMANCE STATUS — 

Individuals who are frail, who have a poor functional status or a poor performance status (PS; eg, Eastern Cooperative Oncology Group [ECOG] PS ≥2 (table 2), Karnofsky PS <60 (table 18)) usually tolerate systemic therapy poorly and have a poor short-term prognosis. For most patients, supportive care should be emphasized. However, some selected patients with mCRC who have a PS of ≥2 can be considered for trial of systemic therapy, particularly if their PS decline is cancer related.

The influence of PS on the efficacy and toxicity of first-line systemic therapy was addressed in a pooled analysis of nine trials with over 6200 patients [88]. Patients with a PS of 2 derived similar advantages with regard to efficacy from superior (ie, combination versus single agent) chemotherapy as did those with a PS of 0 to 1, but with a significantly higher risk of ≥grade 3 nausea and vomiting. The median survival for patients with a PS of 2 was less than nine months, and 12 percent died within 60 days of the start of treatment.

Even some selected patients with a PS of 3 to 4 may benefit from systemic therapy, with upfront dose reduction and close monitoring for toxicity to minimize the risk for serious adverse events. As an example, in an analysis of 65 patients with mCRC and an ECOG PS 3 or 4, chemotherapy use led to a survival gain (median 6.8 versus 2.3 months for best supportive care) [89].

If a trial of systemic therapy is chosen, the choice of regimen must be individualized. For patients who are not considered appropriate candidates for intensive first-line therapy with an oxaliplatin or irinotecan-based combination regimen, leucovorin (LV)-modulated fluorouracil (FU) is an appropriate option [33]. Short-term infusional FU/LV (table 16) is preferred because of its more favorable toxicity profile compared with other fluoropyrimidine monotherapy schedules. (See 'Fluoropyrimidine monotherapy' above.)

The addition of bevacizumab may be reasonable if there are no contraindications, but the modest survival benefit from adding bevacizumab to first-line therapy must be balanced against the potential for serious treatment-related toxicity. (See 'Bevacizumab-containing regimens' above.)

If PS improves, patients initially treated with a fluoropyrimidine alone or with bevacizumab whose PS has improved could be switched to either with an irinotecan-based or an oxaliplatin-based regimen. By contrast, supportive care alone is an option for those whose PS declines or does not improve with therapy.

OPTIONS FOR LATER LINES OF THERAPY — 

Patients who retain a reasonable performance status (PS) and who have disease progression on the first line regimen could be considered for second-line therapy. The safety and efficacy of some of these regimens in older adults is outlined in the sections below.

RAS/BRAF wild-type tumors not treated initially with an EGFR inhibitor — As with younger patients, for older individuals who did not receive initial epidermal growth factor receptor (EGFR)-targeted therapy (ie, cetuximab or panitumumab), an EGFR inhibitor as monotherapy or in combination with a chemotherapy backbone could be used for later lines of therapy. (See "Second- and later-line systemic therapy for metastatic colorectal cancer", section on 'No prior initial therapy with cetuximab/panitumumab'.)

Regorafenib — Regorafenib is an orally active inhibitor of angiogenic (including the vascular endothelial growth factor [VEGF] receptors 1 to 3) receptor tyrosine kinases and other kinases that are approved in the United States for the treatment of patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF agent, and, if KRAS wild-type (WT), an anti-EGFR therapy. Approval for mCRC was based upon the results of the CORRECT trial, which compared best supportive care plus regorafenib (160 mg orally once daily for three of every four weeks) or placebo in 760 patients with chemotherapy refractory disease, and showed a significant survival benefit for regorafenib over best supportive care alone (median 6.4 versus 5 months), albeit with little objective antitumor response [90]. (See "Second- and later-line systemic therapy for metastatic colorectal cancer", section on 'Regorafenib'.)

While regorafenib shares many of the same side effects as bevacizumab and aflibercept, including hemorrhage, bowel perforation, and hypertension, it is not yet clear whether there is an increased incidence of blood clots with this agent. (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents" and "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents".)

In a subgroup analysis of a placebo-controlled phase III trial (CORRECT), regorafenib was similarly effective in patients 65 and under and those who are older [90].

Treatment of patients ≥70 years of age with regorafenib is feasible and demonstrates similar efficacy to that seen in younger patients [91]. However, the risk of severe (grade 3 or 4) adverse events is >80 percent (especially fatigue and hand-foot syndrome).

The approved starting dose of 160 mg daily is probably too high for most patients, including older individuals. Treatment should be initiated at a dose of 80 mg per day (one-half the usual dose), and only escalate if the lower dose is well tolerated. Such a strategy may be particularly important in patients with borderline functional status who wish to try regorafenib for refractory disease while minimizing treatment-related significant side effects. (See "Second- and later-line systemic therapy for metastatic colorectal cancer", section on 'Regorafenib'.)

Trifluridine-tipiracil — Trifluridine-tipiracil is an oral chemotherapy agent that consists of the nucleoside analog trifluridine (trifluorothymidine, a cytotoxic antimetabolite that inhibits thymidylate synthetase and induces DNA strand breaks) and the potent thymidine phosphorylase inhibitor tipiracil, which inhibits the metabolism of trifluridine and has antiangiogenic properties as well.

In the placebo-controlled RECOURSE trial, trifluridine-tipiracil improved overall survival (OS) irrespective of age (>65 versus ≤65 years) [92]. The most frequently observed toxicities were gastrointestinal and hematologic, but the gastrointestinal toxicities with trifluridine-tipiracil were almost all grade 1 and 2 with few grade ≥3 events recorded. That is relevant to older patients with longstanding treatment-refractory disease who are often not tolerant of high-grade gastrointestinal toxicity.

Studies also suggest that trifluridine-tipiracil in combination with bevacizumab is also reasonably well tolerated in older adults [83,93].

Further details on trifluridine-tipiracil with or without bevacizumab for the treatment of metastatic colorectal cancer are discussed separately. (See 'Frail, significant functional impairment, poor performance status' above and "Second- and later-line systemic therapy for metastatic colorectal cancer", section on 'Trifluridine-tipiracil with or without bevacizumab'.)

Ramucirumab — Ramucirumab is a monoclonal antibody that binds to the VEGFR-2 extracellular domain and prevents binding of all VEGF ligands. The RAISE phase III clinical trial demonstrated that the addition of ramucirumab to FOLFIRI (irinotecan plus leucovorin [LV] and short-term infusional fluorouracil [FU]) improved OS compared with placebo plus FOLFIRI for second-line treatment of mCRC in patients previously treated with first-line bevacizumab plus oxaliplatin and a fluoropyrimidine [94]. (See "Second- and later-line systemic therapy for metastatic colorectal cancer", section on 'Ramucirumab'.)

The survival benefit appears to extend to individuals 65 years of age and older, according to a subgroups analysis of this trial [95]. Furthermore, the incidence of treatment-emergent adverse reactions associated with anti-VEGF therapy were not elevated in either the ≥65 or the ≥75 age groups (although only 51 patients receiving ramucirumab were 75 or older).

Fruquintinib — Fruquintinib, a multitargeted antiangiogenic agent, is an option for older adults with mCRC previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; a VEGF inhibitor such as bevacizumab; and an EGFR inhibitor (for RAS WT tumors). Fruquintinib may also be offered to those who progress on trifluridine-tipiracil with or without bevacizumab. In phase III trials of patients with treatment-refractory mCRC (which included those of age 65 years or older) fruquintinib, improved OS and progression-free survival (PFS) over placebo and was well-tolerated [96,97]. Further details are discussed separately. (See "Second- and later-line systemic therapy for metastatic colorectal cancer", section on 'Fruquintinib'.)

Targeted therapies — For patients who retain a sufficient PS and adequate levels of comorbidity, targeted therapies may be an appropriate choice for second-line therapy and beyond, if there is a potentially therapeutically actionable target, as detected by germline genomic or tumoral molecular profiling. (See "Second- and later-line systemic therapy for metastatic colorectal cancer", section on 'Multipanel somatic (tumor) and germline genomic testing'.)

As examples:

●HER2-positive tumors – Approximately 3 to 5 percent of CRCs have amplification of the human epidermal growth factor receptor 2 (HER2) oncogene or overexpress its protein product, HER2. HER2-targeted therapies are used to treat patients with HER2-overexpressing mCRC who progress on systemic therapy. For older adults with HER2-overexpressing mCRC who are ineligible for intensive therapy, we offer therapies targeting HER2 as later lines of therapy. Further details on available agents are discussed separately. (See "Second- and later-line systemic therapy for metastatic colorectal cancer", section on 'RAS wild-type, HER2 overexpressors'.)

●Immunotherapy – For patients whose tumors have deficient mismatch repair/microsatellite instability-high or high levels of tumor mutational burden and who did not receive immunotherapy as a first-line option, immunotherapy with an immune checkpoint inhibitor that targets programmed death receptor-1 (ie, nivolumab, pembrolizumab, dostarlimab, or combination therapy with nivolumab plus ipilimumab) is also an option for treatment at the time of disease progression on the first-line regimen. In clinical trials, objective response rates are 30 to 50 percent, and some responses are durable. (See "Second- and later-line systemic therapy for metastatic colorectal cancer", section on 'dMMR/MSI-H tumors'.)

●RAS wild-type, BRAF mutant disease – For patients with RAS WT but BRAF V600E mutant mCRC that has progressed after initial systemic therapy, cetuximab plus encorafenib is an option, if not previously received. In an unplanned subgroup analysis of the phase III BEACON trial, efficacy of encorafenib plus cetuximab was similar in those <65 and ≥65 years of age [98]. Comparative safety was not addressed. (See "Second- and later-line systemic therapy for metastatic colorectal cancer", section on 'RAS wild-type, BRAF mutated tumors'.)

●Other actionable alterations – Other potentially therapeutically actionable tumoral molecular alterations include human epidermal growth factor receptor 2 overexpression, tropomyosin receptor kinase (TRK) fusions, and RAS G12C mutations. (See "Second- and later-line systemic therapy for metastatic colorectal cancer", section on 'RAS wild-type, HER2 overexpressors' and "Second- and later-line systemic therapy for metastatic colorectal cancer", section on 'TRK fusion-positive tumors'.)

ROLE OF METASTASECTOMY

Liver metastases — Despite advances in chemotherapy and immunotherapy for mCRC, resection offers the best chance of long-term survival for patients with metastatic disease. The likelihood of cure is greatest in patients with liver-isolated mCRC. In surgical case series including both younger and older patients, five-year survival rates after resection range from 24 to 58 percent, averaging 40 percent (table 11), and perioperative mortality rates are generally less than 5 percent. (See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy".)

Similar findings were noted in a report from the LiverMetSurvey registry of 999 well-selected older adults 70 or older [99]. The three-year survival rate after hepatic metastasectomy was 57 percent (similar to that of younger patients), and the 60-day perioperative mortality rate was 4 percent.

Preoperative chemotherapy may facilitate the downstaging of liver metastases and render initially unresectable disease potentially resectable. (See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy", section on 'Patients with initially unresectable metastases'.)

However, few older adults have been included in trials of neoadjuvant chemotherapy. The safety and efficacy of liver resection and preoperative chemotherapy in older adults has been addressed in two series [100,101]:

●A retrospective review included 181 liver resections that were performed in 178 consecutive patients over age 70, 19 percent of whom received neoadjuvant FOLFOX (oxaliplatin plus short-term infusional fluorouracil [FU] and leucovorin [LV]) [100]. Resection involved more than two liver segments (figure 1) in 58 percent of patients and was complete in 92 percent. Perioperative mortality was 5 percent. At a median follow-up of 18 months, the actuarial rates of three-year overall and disease-free survival were 43 and 32 percent, respectively.

●The second series included 70 patients aged 70 or older who underwent hepatic metastasectomy; 41 percent received neoadjuvant chemotherapy with XELOX (n = 19) or bolus FU/LV (n = 10) [101]. In older adults, use of XELOX was associated with a significantly higher response rate than bolus FU/LV (68 versus 0 percent), and responding patients had significantly better overall and recurrence-free survival. Five-year overall survival (OS) in older adults was comparable to that of younger individuals treated at the same institution over the same time period (38 versus 43 percent, respectively).

Based upon these observations, the principles of management of potentially resectable liver metastases in fit older adults are the same as in younger patients. However, treatment choices for neoadjuvant chemotherapy, if needed to downstage liver metastases to the point of resectability, are likely to be more critical for older patients. As noted above, whether the decreased volume of normal hepatic parenchyma seen as a consequence of normal aging predisposes older patients to chemotherapy-induced liver injury and the attendant increase in perioperative complications is unknown. However, as both irinotecan and oxaliplatin can induce liver injury, with steatohepatitis being associated with an increased risk of perioperative complications [102], clinicians should exercise caution when giving oxaliplatin and irinotecan to an older patient preresection. (See 'Challenges specific to older adults' above and "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy", section on 'Post-treatment assessment and duration of neoadjuvant therapy'.)

Bevacizumab inhibits wound healing. In view of this fact, and the long half-life of this agent (20 days), at least 28 days (and preferably six to eight weeks) should elapse between the last dose of bevacizumab and major surgery, including hepatectomy, if bevacizumab is included in the preoperative regimen. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Bevacizumab'.)

Pulmonary metastases — Metastasectomy may also be considered for fit older patients with isolated pulmonary metastases. There are limited high-quality data that examine the feasibility and outcomes in older adults. However, older age has not been an independent predictor of adverse outcomes in series in which it has been examined in multivariate analysis [103-107]. (See "Surgical resection of pulmonary metastases: Outcomes by histology", section on 'Colorectal cancer'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Colorectal cancer".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Colon and rectal cancer (The Basics)")

●Beyond the Basics topics (see "Patient education: Colon and rectal cancer (Beyond the Basics)" and "Patient education: Treatment of metastatic colorectal cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Pretreatment assessments

•Treatment decisions in older adults with metastatic colorectal cancer (mCRC) include considerations of functional status, comorbidities, and drug-specific toxicities. (See 'Challenges specific to older adults' above.)

•Gene profiling of tumor tissue should be undertaken as quickly as possible after diagnosis of mCRC because of the significant treatment implications, both for initial systemic therapy as well as subsequent treatments. (See 'The importance of molecular profiling' above.)

●First-line regimen for fit adults – Our approach to initial treatment for fit older adults with mCRC generally mirrors that in younger patients (algorithm 1) (see "Initial systemic therapy for metastatic colorectal cancer"):

•Patients with deficient mismatch repair/microsatellite instability-high tumors – For individuals of any age with nonoperable mCRC that is mismatch repair deficient (dMMR) or microsatellite-instability high (MSI-H), initial treatment with immunotherapy has become the preferred approach over chemotherapy. For fit, older adults, treatment options are the same as younger individuals and include pembrolizumab (table 10), dostarlimab, and nivolumab plus ipilimumab. These data are presented separately. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'DNA mismatch repair deficient/microsatellite unstable tumors'.)

•Patients with proficient mismatch repair

-Chemotherapy regimen – For fit older adults, we suggest a chemotherapy doublet (FOLFOX, CAPOX/XELOX, or FOLFIRI) (table 11 and table 13 and table 12) rather than fluoropyrimidine monotherapy or a triplet regimen containing both oxaliplatin and irinotecan (Grade 2C). Given the small increased risk of neutropenia, we often omit the fluorouracil (FU) bolus from both FOLFOX (eg, modified FOLFOX7) (table 15) and FOLFIRI to diminish treatment-related cytopenias. (See 'Overview of treatment selection' above and 'Tumor with proficient mismatch repair' above.)

-Addition of biologic agent – For fit older patients, the decision to add a biologic agent (ie, bevacizumab or cetuximab/panitumumab, if RAS/BRAF wild-type [WT]) to chemotherapy for first-line treatment must be individualized. Although fit older patients may derive similar benefits as do younger patients, these are potentially offset by the risks of serious treatment-related toxicity. We do not use bevacizumab in patients with a history of stroke, myocardial infarction, or other thromboembolic disease within the preceding 6 to 12 months (with the exception of deep vein thrombosis [DVT] or pulmonary embolism [PE]) due to the additional associated risks. (See 'Addition of targeted therapies' above.)

If the decision is made to add a biologic agent to first-line chemotherapy, we follow the same principles as with younger patients, basing the choice of bevacizumab or an epidermal growth factor receptor (EGFR) inhibitor on RAS/BRAF mutation status, contraindications to bevacizumab, and the sidedness of the primary tumor. Specific recommendations are provided separately (algorithm 1). (See "Initial systemic therapy for metastatic colorectal cancer", section on 'EGFR inhibitors versus bevacizumab and the influence of tumor sidedness'.)

●Less fit adults with an adequate performance status

•For patients whose tumors have dMMR, we offer initial therapy with single-agent immunotherapy (pembrolizumab or dostarlimab). Nivolumab plus ipilimumab is less preferred due to higher rates of immune-related adverse events. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'DNA mismatch repair deficient/microsatellite unstable tumors'.)

•For others, options include reduced dose FOLFOX or CAPOX, leucovorin (LV)-modulated FU with or without bevacizumab, capecitabine with or without bevacizumab, irinotecan alone, cetuximab/panitumumab either as monotherapy or in combination with FU plus LV (for RAS/BRAF WT tumors only), or trifluridine-tipiracil plus bevacizumab. For patients without a contraindication to bevacizumab, the survival benefit of adding bevacizumab to a first-line fluoropyrimidine must be balanced against the potential for serious treatment-related toxicity. (See 'Less fit patients with an ECOG PS 0 or 1' above and "Treatment protocols for small and large bowel cancer".)

●Frail or poor performance status

•Most individuals with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 3 or 4 (table 2) cannot tolerate systemic therapy and are offered supportive care. (See 'Frail, significant functional impairment, poor performance status' above.)

•A trial of systemic therapy is reasonable for highly selected patients with mCRC who have an ECOG PS of ≥2 (table 2), particularly if their PS decline is cancer related.

●Treatment at progression – Several options are available for treatment at progression in individuals who maintain an adequate PS; limited data support efficacy and safety in older individuals. (See 'Options for later lines of therapy' above.)

Our approach in older, fit individuals mirrors that for younger patients and is discussed separately. (See "Second- and later-line systemic therapy for metastatic colorectal cancer", section on 'Options for treatment at progression'.)