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Therapy for metastatic colorectal cancer in older adult patients and those with a poor performance status

Therapy for metastatic colorectal cancer in older adult patients and those with a poor performance status
Literature review current through: Jan 2024.
This topic last updated: Aug 25, 2023.

INTRODUCTION — Colorectal cancer (CRC) is a leading cause of cancer-related death in the United States and other developed countries. The incidence of CRC steadily increases with age. Nearly 60 percent of cases develop over the age of 65; 30 percent are 75 years or older [1]. The United States Census Bureau projects that by the year 2030, the number of Americans over age 65 make up 21 percent of the population (compared with 15 percent at present) [2]. As a result, the number of patients over the age of 70 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 chemotherapy. Multiple chemotherapy agents (fluorouracil, irinotecan, oxaliplatin, and trifluridine-tipiracil), multiple molecularly targeted agents (bevacizumab, aflibercept, ramucirumab, cetuximab, and panitumumab), and the oral multikinase inhibitor regorafenib are approved for use in advanced CRC. Most recently, immune checkpoint inhibitors have been approved for treatment of advanced microsatellite instability-high or deficient mismatch repair mCRC in the first-line setting.

This topic review will cover issues related to selection of systemic therapy for nonresectable mCRC in older adult patients and those with a poor performance status (PS). General principles of chemotherapy treatment for mCRC, specific treatment recommendations for initial therapy, and the approach to later lines of systemic therapy for non-older adult patients are presented elsewhere, as is adjuvant chemotherapy for older adult patients with colon cancer and the management of potentially resectable CRC liver and lung metastases. (See "Systemic therapy for metastatic colorectal cancer: General principles" and "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach" and "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy" and "Adjuvant therapy for resected colon cancer in older adult patients" and "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy" and "Surgical resection of pulmonary metastases: Outcomes by histology" and "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques".)

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 that are relevant to the treatment of patients with CRC are outlined in the table (table 1). A thorough discussion of the age-related changes that should be considered when assessing the risk of systemic chemotherapy for mCRC is presented elsewhere. (See "Systemic chemotherapy for cancer in older adults".)

Quality of life issues — 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 chemotherapy as their younger counterparts, but less willing to endure severe treatment-related side effects.

There are few data about how chemotherapy affects QOL in older patients with mCRC [3,4]. 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 advanced 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 with or without oxaliplatin, or capecitabine with or without oxaliplatin [4]. 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 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, p = 0.04).

QOL improvement was the primary outcome measure for the comparison of capecitabine versus short-term infusional FU plus leucovorin. 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. Chronological 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 chemotherapy and to assess short-term prognosis. Regardless of age, patients with a poor PS (eg, ECOG PS >2, KPS or PPS <60) usually tolerate chemotherapy 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 chemotherapy toxicity, reduce falls during cancer treatment, increase advance directive completion, and for patients with CRC improve completion of scheduled chemotherapy. (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 older cancer patients. American Society of Clinical Oncology (ASCO) guidelines recommend that a geriatric assessment be undertaken in all patients age 65 and older who are receiving chemotherapy, and we agree with this approach [5]. (See "Comprehensive geriatric assessment for patients with cancer", section on 'Who needs a CGA?'.)

There is no uniform CGA measurement tool. The ASCO guidelines provide a minimum dataset for practical assessment of vulnerabilities in older patients with cancer (table 4) [5]. The guidelines also include recommendations for specific interventions guided by the geriatric assessment (table 5). This subject is discussed in more detail elsewhere. (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 [6]. 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 small number of older patients enrolled in clinical trials [7,8], good quality evidence about safety and efficacy of chemotherapy in older patients with CRC has come mainly from subgroup analyses of pooled data from large phase III clinical 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 (table 7) [6,9-13]. 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 adult patients receiving chemotherapy 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 adult patients who are at risk for severe treatment-related toxicity, which may impact treatment selection [14]. (See "Comprehensive geriatric assessment for patients with cancer", section on 'Domains of a CGA' and "The mental status examination in adults", section on 'Cognitive screening tests'.)

Decision making can be aided by several tools. The information obtained from the CGA has been combined with other information, including the proposed chemotherapy regimen, hematologic and renal function, hearing impairment, and cancer type to derive models used to predict risk for severe and potentially fatal chemotherapy toxicity in the older adult population (table 8 and table 9) [15]. This subject is discussed in detail elsewhere. (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 "Systemic therapy for metastatic colorectal cancer: General principles", 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 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 adult patients. 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 (table 10) [16]. Given the small increased risk of neutropenia, we often omit the FU bolus from both FOLFOX (eg, modified FOLFOX7) (table 11) and FOLFIRI in older patients in order 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 [16].

For most patients 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 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. Whether these results can be extrapolated to the older adult is unclear. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", 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 cytotoxic therapy 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 due to the additional associated risks. (See 'Bevacizumab and biosimilars' below.)

This general approach is consistent with consensus-based guidelines for treatment of mCRC in the older adult from the National Comprehensive Cancer Network [17] and the International Society of Geriatric Oncology [18]. A compilation of commonly used chemotherapy regimens for CRC is available. (See "Treatment protocols for small and large bowel cancer".)

Safety and efficacy of specific regimens in older adults

Goals of chemotherapy and regimen selection — The twin goals of systemic chemotherapy 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 [19]. (See "Systemic therapy for metastatic colorectal cancer: General principles", 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 chemotherapy of mCRC in older adult patients.

Immunotherapy for patients with deficient mismatch repair — Largely based on the progression-free survival (PFS) benefit and more favorable toxicity profile of pembrolizumab in the phase III KEYNOTE-177 trial, first-line immunotherapy has become a preferred approach over cytotoxic chemotherapy for individuals of any age with nonoperable mCRC that is deficient in mismatch repair [20]. 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. These data are presented elsewhere. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Patients with deficient DNA mismatch repair/microsatellite unstable tumors'.)

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 12)) is as effective and well tolerated in fit older patients who are enrolled on clinical trials as in younger individuals [6,11,12,21,22], although rates of side effects may be slightly higher in older patients [11,12]. One analysis of older adult patients 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 [23]. 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 "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", 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 below. (See 'Capecitabine-containing doublets' below.)

Irinotecan/FU combinations — In many [24-28], but not all [28,29] studies, combinations of irinotecan with infusional FU and LV (eg, FOLFIRI, (table 13)) 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 1259 (19 percent ≥70) patients treated with irinotecan with either bolus FU (IFL) or short-term infusional FU (FOLFIRI) for mCRC [25]. There were no age-related differences in response rate, time to progression, or survival (median 17 versus 18 months for older and younger patients, respectively). 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) [28]. Although the overall response rate was higher with FOLFIRI (42 versus 21 percent), this did not translate into significantly better median progression-free (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 below. (See 'Capecitabine-containing doublets' below.)

Capecitabine-containing doublets — Multiple trials that substitute the oral fluoropyrimidine capecitabine for IV FU in combination with oxaliplatin (XELOX/CAPOX) (table 12) or irinotecan (XELIRI/CAPIRI) have been reported in fit older adult patients, 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 elsewhere. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", 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 adult patients 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 adult patients 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 [30]. 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 [31]. 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 progression-free 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 [11] (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 (table 12) 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 "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Capecitabine doublets'.)

In a later subanalysis of older adults (>70 years of age) versus non-older adult patients enrolled in the trial, older adult patients had significantly higher rates of asthenia and dehydration with XELIRI compared with their younger counterparts [13]. Similar high rates of toxicity with XELIRI have been seen by others despite the use of lower starting doses of both drugs [32,33].

Targeted therapies — For fit older patients, the decision to add a biologic agent (ie, bevacizumab or cetuximab/panitumumab, if RAS/BRAF WT) to cytotoxic therapy 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.

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 anti-EGFR agent on RAS/BRAF mutation status, contraindications to bevacizumab, and the sidedness of the primary tumor. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'EGFR inhibitors versus bevacizumab and the influence of tumor sidedness'.)

An algorithmic approach to selecting initial therapy based upon these and other factors is presented in the algorithm (algorithm 1).

Bevacizumab and biosimilars — Bevacizumab is a humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF). 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 "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", 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".)

Biosimilars for bevacizumab have also been approved by the US Food and Drug Administration [34,35].

The comparable efficacy of bevacizumab in older as compared with younger patients with mCRC has been shown in at least two separate pooled analyses [36,37]. However, the benefits are modest and side effects, particularly ATEs, are of concern when treating older adults [38-44]:

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) [37]. For the older age group, the median OS benefit from adding bevacizumab was only 3.3 months (median 17.4 versus 14.1 months, HR 0.79, 95% CI 0.66-0.93). Bleeding, hypertension, proteinuria, ATEs, venous thromboembolic events, wound-healing complications, fistulae, gastrointestinal perforation, and congestive 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) [45].

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) [44]. Combined therapy was associated with significantly longer median PFS (the primary endpoint, 9.1 versus 5.1 months) and a non-significant 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 adult patients. Caution (and informed consent) is warranted when prescribing bevacizumab in combination with chemotherapy for older adult 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. 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 epidermal growth factor receptor (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 recent analyses suggest that exclusion of patients with other mutations in KRAS or NRAS identifies a population that is more likely to benefit from an anti-EGFR agent. (See "Systemic therapy for metastatic colorectal cancer: General principles", section on 'RAS testing'.)

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

Treatments targeting the EGFR seems to be similarly effective and safe in older as compared with younger patients [46-51], although some reports suggest greater toxicity, especially diarrhea and acneiform skin rash [52,53]. The largest experience comes from an analysis of patients with RAS WT mCRC receiving first-line doublet chemotherapy plus an anti-EGFR agent (n = 1191) versus doublet chemotherapy alone (n = 729) from seven prospective controlled clinical trials [51]. In younger patients, the addition of first-line anti-EGFR therapy versus doublet chemotherapy significantly 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 trend towards improvement 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 anti-EGFR agent 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.

Accumulating data from this trial and others suggest an association between location of the primary tumor and efficacy of anti-EGFR agents when administered for first-line therapy of mCRC. If a biologic agent is chosen for initial chemotherapy, the available data support a preference for a bevacizumab-containing rather than an anti-EGFR-containing regimen for initial treatment of right-sided tumors if a biologic agent is chosen in conjunction with cytotoxic chemotherapy, and there are no contraindications to bevacizumab even if they are WT for RAS and BRAF. By contrast, for patients who have a left-sided WT RAS/BRAF primary tumor, cetuximab may provide better outcomes than bevacizumab, if a biologic agent is chosen for initial therapy. Due to the potential for detrimental impacts on survival, for patients with a right-sided tumor and a contraindication to bevacizumab, chemotherapy alone is a reasonable choice for initial therapy. These issues are all addressed elsewhere. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'EGFR inhibitors versus bevacizumab and the influence of tumor sidedness'.)

LESS FIT PATIENTS WITH AN ECOG PS 0 OR 1 — Less fit patients who are not frail and who have a sufficient PS are generally less able to tolerate intensive chemotherapy, although they may tolerate some chemotherapy. Options include dose-reduced FOLFOX (oxaliplatin plus short-term infusional fluorouracil and leucovorin) or CAPOX, monotherapy with a fluoropyrimidine, single-agent irinotecan, or, for patients without a contraindication to bevacizumab, a combination of a bevacizumab with a fluoropyrimidine (fluorouracil [FU]/leucovorin [LV], capecitabine or trifluridine-tipiracil). 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 an 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 [4]. 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 progression-free (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 progression-free survival (PFS; 5.8 versus 4.5 months, 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 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 [54-57]), given the greater efficacy and tolerability, especially hematologic and gastrointestinal [58,59]. The need for central venous access and an ambulatory infusion pump may be a limiting factor.

LV enhances FU cytotoxicity by interacting with thymidylate synthase to form a stable ternary complex, prolonging inhibition of the enzyme by FU [60]. Compared with bolus FU alone, FU/LV is associated with a twofold higher response rate (21 versus 11 percent in two meta-analyses [61,62]), which, in one, translated into a small but statistically significant 10 percent improvement in one-year survival (47 versus 37 percent [61]).

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 12) and is similarly effective as the racemic mixture [63].

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) [9]. 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 adult patients 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 [64-67]. 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 [68,69]. 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 [68].

Capecitabine monotherapy appears to be a similarly effective, albeit potentially more toxic substitute for FU in fit older adult patients with mCRC [4,70-75]. 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) [70]. 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 [4]. (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 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 [71]. 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 [76].

Oral cytotoxics 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 [77].

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 [78].

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 [79]. Response rates are approximately 25 percent with UFT monotherapy and 40 percent in combination with oral LV (150 mg daily) [80]. In phase III studies, UFT plus LV has comparable efficacy and better tolerability as compared with intravenous bolus FU [81,82]. 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 [44,83-88]. 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.

FU/LV plus bevacizumab – The safety and efficacy of bevacizumab plus short-term infusional fluorouracil (FU) with leucovorin (LV) has been shown in several studies [83-86,88,89]. In one of these, JCOG1018, the combination of bevacizumab plus either the de Gramont regimen or capecitabine monotherapy provided similar overall and PFS results to regimens that contained oxaliplatin and bevacizumab with either capecitabine or the de Gramont regimen, although the objective response rates were lower (30 versus 48 percent) [88].

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 [44]. 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 cytotoxic agent 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 wild-type. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", 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 [87,90].

A similar result was found in the much larger phase III SOLSTICE trial, which compared the same combinations 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 [91]. In a preliminary report, there was a trend toward better PFS (median 9.4 versus 9.3 months, HR 0.87) and OS (median 10.6 versus 9.3 months, HR 0.85) that favored TAS-102, and disease control rates were similar. However, patients receiving TAS-102 plus bevacizumab also had much higher rates of ≥grade 3 neutropenia (66 versus 2 percent).

HER2-targeted therapy — 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 conventional chemotherapy. Further details on available agents are discussed separately. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'RAS wild-type, HER2 overexpressors'.)

Some patients with HER2-overexpressing mCRC, such as those who are not candidates for intensive therapy, may be eligible for first-line therapies targeting HER2, and this approach is supported in guidelines from the National Comprehensive Cancer Network [92]. However, this is not our preferred approach; for most patients we reserve this for later lines of therapy. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Not candidates for intensive therapy'.)

Single-agent irinotecan — Irinotecan is active as monotherapy. In some trials, older age is a risk factor for severe (grade 3 or 4) diarrhea [93-95]. As an example, in a phase III comparison of weekly (125 mg/m2) versus every three week (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 [95]. 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 [96]. 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 PS (eg, Eastern Cooperative Oncology Group [ECOG] PS ≥2 (table 2), Karnofsky PS <60 (table 17)) usually tolerate chemotherapy 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 chemotherapy, particularly if their PS decline is cancer related.

The influence of PS on the efficacy and toxicity of first-line chemotherapy was addressed in a pooled analysis of nine trials with over 6200 patients [97]. 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 chemotherapy, 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) [98].

If a trial of chemotherapy 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 [38]. Short-term infusional FU/LV (table 10) 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 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 anti-EGFR agent — As with younger patients, for older individuals who did not receive initial EGFR-targeted therapy (ie, cetuximab or panitumumab), an anti-EGFR agent as monotherapy or in combination with a cytotoxic chemotherapy backbone could be used for later lines of therapy. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'No prior initial therapy with cetuximab/panitumumab'.)

Regorafenib — Regorafenib is an orally active inhibitor of angiogenic (including the VEGF receptors 1 to 3) receptor tyrosine kinases and other kinases that is 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, 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 [99]. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", 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".)

There are no published data on the safety or efficacy of regorafenib in older adults; however, a preliminary report of a preplanned subgroup analysis of the CORRECT trial presented at the 2012 American Society of Clinical Oncology annual meeting suggested similar efficacy in patients 65 and under and those who are older [100].

Treatment of patients ≥70 years of age with regorafenib is feasible and demonstrates similar efficacy to that seen in younger patients [101]. 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 "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'Regorafenib'.)

Trifluridine-tipiracil — Trifluridine-tipiracil is an oral cytotoxic 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) [102]. 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 [103,104].

Further details on trifluridine-tipiracil with or without bevacizumab for the treatment of metastatic colorectal cancer is discussed separately. (See 'Frail, significant functional impairment, poor performance status' above and "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", 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 and short-term infusional fluorouracil) 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 [105]. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", 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 [106]. 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).

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 "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'Multipanel somatic (tumor) and germline genomic testing'.)

As examples:

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, 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 "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'Microsatellite unstable/deficient mismatch repair tumors'.)

RAS wild-type, BRAF mutant disease – For patients with RAS wild-type but BRAF V600E mutant mCRC that has progressed after initial chemotherapy, cetuximab plus encorafenib is an option. 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 [107]. Comparative safety was not addressed. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", 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 "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'RAS wild-type, HER2 overexpressors' and "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", 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 18), 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 adult patients 70 or older [108]. 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 adult patients have been included in trials of neoadjuvant chemotherapy. The safety and efficacy of liver resection and preoperative chemotherapy in older adult patients has been addressed in two series [109,110]:

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]) [109]. 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) [110]. 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 adult patients 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 adult patients 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 [111], 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 no large series 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 [112-116]. (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 5th to 6th 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 10th to 12th 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 topics (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: Colorectal cancer treatment; metastatic 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 adult patients with mCRC generally mirrors that in younger patients and is outlined in the algorithm (algorithm 1) (see "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach"):

Patients with deficient mismatch repair/microsatellite instability-high tumors – Largely based on the progression-free survival benefit and more favorable toxicity profile of pembrolizumab in the phase III KEYNOTE-177 trial, first-line immunotherapy has become a preferred approach over cytotoxic chemotherapy for individuals of any age with nonoperable mCRC that is deficient in mismatch repair (dMMR). This subject is addressed in detail elsewhere. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Patients with deficient DNA mismatch repair/microsatellite unstable tumors'.)

Patients with proficient mismatch repair

-Chemotherapy regimen – For fit older adult patients, we suggest a chemotherapy doublet (FOLFOX, XELOX, or FOLFIRI) (table 12 and table 19 and table 13) 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 in order to diminish treatment-related cytopenias.

-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 cytotoxic therapy 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 due to the additional associated risks.

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 anti-EGFR agent on RAS/BRAF mutation status, contraindications to bevacizumab, and the sidedness of the primary tumor. Specific recommendations are provided separately and outlined in the algorithm (algorithm 1).

Less fit adults with an adequate performance status

For patients with whose tumors have dMMR, pembrolizumab monotherapy is an alternative to first-line systemic chemotherapy. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Patients with deficient DNA mismatch repair/microsatellite unstable tumors'.)

For others, options include reduced dose FOLFOX or XELOX, leucovorin-modulated FU with or without bevacizumab, capecitabine with or without bevacizumab, irinotecan alone, cetuximab/panitumumab monotherapy (for RAS/BRAF WT tumors) 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 chemotherapy and are offered supportive care. (See 'Frail, significant functional impairment, poor performance status' above.)

A trial of chemotherapy 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 outlined in detail elsewhere. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'Options for treatment at progression'.)

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Topic 2512 Version 74.0

References

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