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 [1]. Nearly 60 percent of cases develop over the age of 65; 30 percent are 75 years or older [2]. The United States Census Bureau projects that by the year 2030, the number of Americans over age 65 will double [3]. 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 [FU], irinotecan, oxaliplatin, and trifluridine-tipiracil [TAS-102]), multiple molecularly targeted agents (bevacizumab, aflibercept, ramucirumab, cetuximab, and panitumumab), and the oral multikinase inhibitor regorafenib are approved for use in advanced colorectal cancer. Most recently, immune checkpoint inhibitors have been approved for treatment of advanced microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) 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. 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 chemotherapy 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 "Management of potentially resectable colorectal cancer liver metastases" 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 metastatic colorectal cancer (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 — 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 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 [4,5]. 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 [5]. 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 performance status 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 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 'Oxaliplatin/FU combinations' below and 'Capecitabine' 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.

●Performance status – The most common method to measure physiologic reserve and functional status in cancer patients is the clinician estimated performance status (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 overall survival. 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 performance status (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 comprehensive geriatric assessment (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 colorectal cancer 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 [6]. (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) [6]. 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 [7]. 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).

The patients who are neither frail nor fit are the patients in whom treatment decision-making is most complex. Their treatment requires excellent communication and individualized care.

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 7 and table 8) [8]. This subject is discussed in detail elsewhere. (See "Systemic chemotherapy for cancer in older adults", section on 'Models predicting chemotherapy toxicity and early death'.)

OVERVIEW OF TREATMENT SELECTION — The FOLFOX and FOLFIRI regimens 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 preexisting neuropathy.

●Grade 3 or 4 neutropenia and thrombocytopenia are more common with FOLFOX than with FOLFIRI (table 9) [9]. Given the small increased risk of neutropenia, we often omit the fluorouracil (FU) bolus from both FOLFOX (eg, modified FOLFOX7) (table 10) and FOLFIRI 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) tend to be more common with FOLFIRI than with FOLFOX [9]

The triplet chemotherapy regimen FOLFOXIRI (oxaliplatin plus irinotecan, leucovorin, and infusional FU) improves progression-free and overall survival in metastatic colorectal cancer [10-13]. However, randomized trials to date have been restricted to patients younger than 70 years, therefore, caution should be used in extrapolating these data to the older adult. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Three- versus two-drug combinations'.)

Bevacizumab can be added to first-line chemotherapy in older patients unless the risk of a serious adverse event (particularly arterial thromboemboli) supersedes potential benefit. For patients with wild-type RAS/BRAF V600E tumors, choosing to add cetuximab or panitumumab rather than bevacizumab to the first-line chemotherapy backbone is reasonable, particularly in patients with left-sided primary cancers. However, acneiform skin rash and diarrhea may be prominent. (See 'Cetuximab and panitumumab' below and "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Anti-EGFR agent versus bevacizumab and the influence of tumor sidedness'.)

FU/leucovorin alone or capecitabine with or without bevacizumab or cetuximab/panitumumab (for RAS/BRAF wild-type tumors) can be considered for older adult patients who are not suitable for an irinotecan or oxaliplatin-based regimen. Short-term infusional FU/leucovorin (table 11) is well tolerated but requires central venous access and an ambulatory infusion pump. While potentially more convenient than infusional FU/leucovorin, capecitabine monotherapy is probably more toxic than the de Gramont regimen. (See 'Capecitabine' below.)

This general approach is consistent with consensus-based guidelines for treatment of mCRC in the older adult and those not appropriate for intensive therapy from the National Comprehensive Cancer Network (NCCN) [14] and the International Society of Geriatric Oncology [15]. A compilation of commonly used chemotherapy regimens for CRC is available. (See "Treatment protocols for small and large bowel cancer".)

Regardless of age, individuals with a poor performance status (PS) (eg, Eastern Cooperative Oncology Group [ECOG] PS ≥2 (table 2), Karnofsky PS <60 (table 12)) usually tolerate chemotherapy poorly and have a poor short-term prognosis. However, patients with mCRC who have a PS of 2 should be considered for chemotherapy, particularly if their PS decline is cancer related. Although such patients have a median survival that is approximately half that seen for patients with a PS of 0 or 1, they benefit to an equal extent from combination chemotherapy.

SAFETY AND EFFICACY OF CHEMOTHERAPY FOR METASTATIC DISEASE — Chemotherapy for metastatic colorectal cancer (mCRC) markedly improves outcomes over supportive cancer alone [16]. (See "Systemic chemotherapy for metastatic colorectal cancer: General principles", section on 'Chemotherapy versus supportive care'.) Phase III trials conducted in patients of all ages now commonly report median survivals of well over two years, and nearly 10 percent of patients are still alive at five years [17]. (See "Systemic chemotherapy for metastatic colorectal cancer: General principles".)

Despite the demonstrated benefit of systemic therapy for advanced colorectal cancer, the available evidence suggests that fewer older adult patients receive irinotecan, oxaliplatin, or bevacizumab as a component of initial therapy as compared with younger individuals, presumably because of toxicity concerns [18]. In some trials, older adult patients receiving chemotherapy for mCRC have been more susceptible to toxicity, particularly diarrhea and neutropenia [19-22], although this is not a universal finding [23-26].

Because of the small number of older patients enrolled in clinical trials [27,28], 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 performed both in the adjuvant and metastatic disease settings. 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 13) [7,29-33]. However, in general, patients in these trials have been fit and uniformly of good performance status (PS).

Phase II and III trials of chemotherapy for mCRC are beginning to be conducted in older adult patients, but the patients enrolled in these trials are usually fit and have a good PS. It is unclear that any of these data can be extrapolated to less fit older patients. Nevertheless, these are the best data that are available.

Very few of these trials have attempted to use geriatric factors (such as a comprehensive geriatric assessment [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 impaired cognition (as assessed by the Mini Mental Status Examination [MMSE]) and impaired autonomy (as assessed by Instrumental Activities of Daily Living [IADL]) can be used to identify those older adult patients who are at risk for severe treatment-related toxicity [34]. (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'.)

The following sections will review the available data from both pooled analyses and clinical trials that specifically address the benefits and side effects of different options for chemotherapy of mCRC in older adult patients.

Single agent fluorouracil — Fluorouracil (FU) alone or when given with leucovorin modulation 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 (leucovorin, interferon, or methotrexate) [29]. 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 [20,35-37]. 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:

●A subgroup analysis of one study that used FU and leucovorin administered by bolus dose daily for five days once per month (the so-called Mayo regimen) found that patients over age 70 were significantly more likely to experience severe treatment-related toxicity including diarrhea (24 versus 14 percent), leukopenia (24 versus 10 percent), and treatment-related death (9 versus 2 percent) [19].

●In contrast, short-term infusional FU with leucovorin (the de Gramont schedule) is particularly well tolerated in older adults, and is preferred over bolus administration, where feasible [38]. The need for central venous access and an ambulatory infusion pump may be a limiting factor.

Capecitabine — Capecitabine is routinely used for treatment of advanced CRC in older patients; however, it appears to be associated with more treatment-related side effects than is short-term infusional FU plus leucovorin. A number of small, older adult-specific trials in mCRC have found capecitabine monotherapy to be fairly well tolerated in fit older adult patients with a similar or slightly better efficacy than expected with FU given in bolus regimens [39-43]. As an example, a Spanish trial of 51 patients aged 70 or older with mCRC who were considered ineligible for combination chemotherapy used capecitabine 1250 mg/m² twice daily for 14 of every 21 days [43]. The overall response rate was 24 percent, and grade 3 or 4 adverse events were noted only in six patients (12 percent).

Treatment-related toxicity may be more prominent in the oldest old, and in less fit older adult patients, as illustrated by the following:

●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 compared with the overall population (60 versus 40 percent), particularly diarrhea (31 versus 13 percent) [44]. 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 leucovorin with or without oxaliplatin, or capecitabine with or without oxaliplatin [5]. (See 'Quality of life issues' 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.

The following findings were noted in the factorial comparison of capecitabine versus short-term infusional FU plus leucovorin:

•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).

•There was no evidence that substitution of fluorouracil with capecitabine had an effect on response rates (23 versus 24 percent with capecitabine and FU-based regimens, respectively), response duration, or overall survival.

•Compared with fluorouracil, 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.

Thus, capecitabine monotherapy appears to be an equally effective, albeit more toxic substitute for FU in fit older adult patients with mCRC, at least for those under the age of 80.

The appropriate dose of capecitabine is not well defined, at least for American patients. At least some data suggest that patients over the age of 70 (especially women) have reduced capecitabine clearance and a notable increase in the capecitabine area under the concentration x time curve (AUC) than do younger patients, leading to increased drug exposure [45].

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. (See 'Bevacizumab and biosimilars' below.)

Additional data on the use of capecitabine as a substitute for short-term infusional FU in combination regimens in older adults are discussed below. (See 'Substituting capecitabine for FU in combinations' below.)

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 [46].

Oxaliplatin/FU combinations — The results of pooled and subgroup analyses of phase III trials and phase II trials conducted exclusively in older patients suggest that oxaliplatin plus short-term infusional FU and leucovorin (FOLFOX (table 14)) is just as effective and well tolerated in fit older patients who are enrolled on clinical trials as in younger individuals [7,31,32,47,48], although rates of side effects may be slightly higher in older patients [31,32]. 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 [49].

The benefit of an oxaliplatin as compared with a non-oxaliplatin-containing regimen in less fit patients was directly addressed in the MRC FOCUS2 trial, described above [5] (see 'Quality of life issues' above). 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 leucovorin 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. In the comparison of FOLFOX versus short-term infusional FU and leucovorin alone (the de Gramont regimen), the following were noted:

●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 (10.7 versus 10.1 months) with FOLFOX, 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 significantly higher rates of grade 3 or worse diarrhea, neurosensory toxicity, nausea, vomiting, and neutropenia compared with no use of oxaliplatin.

Thus, the available data suggest that oxaliplatin combination regimens with short-term FU and leucovorin are as effective in older as compared to younger individuals and relatively well tolerated in fit older adults. The benefits of an oxaliplatin-containing regimen may not outweigh the risks in less fit older adult patients who are considered poor candidates for full-dose chemotherapy. Additional data on combination regimens substituting capecitabine for short-term infusional FU are discussed below. (See 'Substituting capecitabine for FU in combinations' below and "Treatment protocols for small and large bowel cancer".)

Irinotecan/FU combinations — In most [26,50-53] but not all [54] studies, combinations of irinotecan with infusional FU and leucovorin (eg, FOLFIRI, (table 15)) have been well tolerated in older patients:

●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 [50]. 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.

●The benefit and toxicity of adding irinotecan to FU/leucovorin 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 leucovorin with or without irinotecan (150 mg/m² for cycles 1 and 2, with the dose increased to 180 mg/m² thereafter if tolerated) [55]. 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 overall survival (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.

Regimens combining irinotecan with bolus FU and leucovorin (eg, IFL) are even more toxic. An investigation into early deaths in patients treated on North Central Cancer Treatment Group (NCCTG) N9741 and Cancer and Leukemia Group B (CALGB) 89803 trials suggested that age was a potential risk factor for early treatment-related death in patients receiving IFL [56].

Results from the randomized phase III BICC-C study also support the use of infusional as compared to bolus FU/leucovorin in combination with irinotecan. In period 2 of that trial, 117 patients with mCRC received either FOLFIRI or a modified IFL bolus regimen, both with bevacizumab. In a subset analysis of older (≥ age 70) versus younger patients, median progression-free and overall survival were both longer in the FOLFIRI group [33]. Rates of grade 3 or higher toxicity did not differ significantly by age group. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'FOLFOX versus FOLFIRI'.)

Taken together, these studies suggest that irinotecan/FU regimens are relatively safe for older adults, but administration with infusional rather than bolus FU is preferred. Combinations of irinotecan with capecitabine are discussed below. (See 'XELIRI' below.)

Single agent irinotecan — Irinotecan is active as monotherapy. In some trials, older age is a risk factor for severe (grade 3 or 4) diarrhea [57-59]. 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 [59]. 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 [60]. Older patients had comparable efficacy, and toxicity (including diarrhea) was not worse as compared with younger individuals.

Substituting capecitabine for FU in combinations — 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'.)

Multiple trials that substitute the oral fluoropyrimidine capecitabine for IV FU in combination with oxaliplatin (XELOX/CAPOX) (table 14) or irinotecan (XELIRI/CAPIRI) have been reported in fit older adult patients, and most indicate the safety and efficacy of this approach [31,61-66]. 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 — The efficacy and safety of XELOX in fit older adult patients has been addressed in several 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 [63]. The response rate was 36 percent, and median time to tumor progression (TTP) and overall survival 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 [62]. 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 overall survival 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 [31] (see 'Oxaliplatin/FU combinations' above). The objective response rates for XELOX in older and younger patients were 35 and 45 percent, respectively, and median overall survival 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).

●The efficacy and risks of XELOX in less fit older adult patients were also addressed in the previously described MRC FOCUS2 trial, described above [5]. (See 'Quality of life issues' above.)

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 leucovorin 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 patients randomly assigned to XELOX started with capecitabine 800 mg/m² twice daily on days 1 to 15, and oxaliplatin 104 mg/m² on day 1, with cycles repeated every 21 days.

The following findings were noted:

•Compared with FOLFOX, the use of 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), identical progression-free survival (5.8 months in each group), and a trend toward longer median overall survival that was not statistically significant (12.4 versus 10.7 months).

•From the standpoint of toxicity, 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.

Taken together, these data suggest that for fit older adult patients, XELOX is an effective alternative, albeit with somewhat higher rates of grade 3 or 4 toxicities, as compared with regimens that combine oxaliplatin with short-term infusional FU. For less fit individuals, it is unclear whether the risks of substituting capecitabine for short-term infusional FU in combination with oxaliplatin outweigh the benefits.

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 800 mg/m² twice daily in less fit or very old patients. (See "Treatment protocols for small and large bowel cancer".)

XELIRI — XELIRI (capecitabine in combination with irinotecan) produced inferior outcomes compared to FOLFIRI (table 14) 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 progression-free survival 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 [33]. Similar high rates of toxicity with XELIRI have been seen by others despite the use of lower starting doses of both drugs [65,67].

Thus, because of concerns as to efficacy and safety, our preference remains delivering irinotecan with infusional FU in older patients.

Targeted therapies — In contrast to the growing evidence about the safety and efficacy of combination cytotoxic chemotherapy in fit older patients, few data are available in such patients concerning the use of the currently approved biologic agents: bevacizumab, aflibercept, cetuximab, panitumumab, and regorafenib. Although fit older patients included in clinical trials of these agents appear to derive similar benefit to younger patients in terms of response rate and progression-free survival, data are lacking as to whether this leads to significant patient-relevant gains such as improved survival with an acceptable quality of life [15]. Anticipated benefits must be balanced against the potential for serious treatment-related toxicity.

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, progression-free survival, and survival. However, these advances have come with a cost of treatment-related side effects, including bleeding, hypertension, proteinuria, bowel perforation, arterial thromboembolic events, 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 "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects" and "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects".)

Biosimilars for bevacizumab have also been approved by the US Food and Drug Administration (FDA) [68,69].

The comparable efficacy of bevacizumab in older as compared with younger patients with mCRC has been shown in at least two separate pooled analyses [70,71]. However, side effects, particularly arterial thromboembolic events (ATEs), have been of greatest concern for treatment of older adults [72-81]. The following additional studies address issues of toxicity and efficacy of adding bevacizumab to chemotherapy for older adult patients with mCRC:

●An analysis of 2526 patients over age 65 with stage IV colorectal cancer derived from the linked Surveillance, Epidemiology, and End Results (SEER)/Medicare database found a modest improvement in outcomes when bevacizumab was added to chemotherapy (hazard ratio [HR] for death 0.85, 95% CI 0.78-0.93); the addition of bevacizumab significantly increased the risk of stroke (4.9 versus 2.5 percent with chemotherapy alone) but not venous thrombotic events [81].

A later analysis of a larger data set from the linked SEER/Medicare database found a lower three-year incidence of ATEs in older adult patients treated with bevacizumab (165 cases out of 6370 mCRC patients with no history of a prior ATE, 2.6 percent) [82]. Although use of bevacizumab was associated with a significantly higher risk of an ATE compared to no bevacizumab use (HR 1.82, 95% CI 1.20-2.76), the absolute incidence rates of ATE were 15.9 versus 12.4 per 1000 person-years follow-up, thus reflecting an excess risk of only 3.5 additional cases per 1000 person-years.

●In the randomized phase II PRODIGE 20 study of chemotherapy (short-term infusional FU plus leucovorin alone or with oxaliplatin or irinotecan) with or without bevacizumab in individuals aged 75 or older, the addition of bevacizumab was associated with a significantly higher rate of grade 3 or 4 arterial hypertension (14 versus 6 percent), but the rates of other severe adverse effects, including ATE (9.8 versus 6.1 percent), were not significantly different [83].

●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) [84]. Combined therapy was associated with significantly longer median progression-free survival (the primary endpoint, 9.1 versus 5.1 months) and a non-significant trend toward longer overall survival (median 21 versus 17 months). However, there were significantly more events leading to treatment discontinuation in the bevacizumab arm (25 versus 15 percent), and higher rates of all-grade 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 arterial thromboembolic events in the combined therapy group, compared with three with capecitabine monotherapy (4 versus 2 percent). Although rates of grade 5 (fatal) toxicities were not higher with bevacizumab (8.2 versus 11.8 percent with capecitabine alone), they were higher than expected in both groups.

The combination of capecitabine and bevacizumab is a good treatment option for older adult patients. Caution (and informed consent) is warranted when prescribing bevacizumab in combination with chemotherapy for older adult patients, particularly those 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 16 and table 17). (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Arterial thromboembolic events' and "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Hypertension'.)

Aflibercept — Aflibercept (VEGF Trap, Zaltrap) is a recombinant fusion protein consisting of VEGF binding portions from key domains of human VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G1. It acts as a soluble "decoy" receptor that binds to human VEGF-A, VEGF-B, and placental growth factor (PIGF), thereby inhibiting the binding of these ligands and activation of their respective receptors.

Aflibercept is approved in the United States for use in combination with FOLFIRI for the treatment of patients with mCRC that is resistant to or has progressed following an oxaliplatin-containing regimen. Approval was based on the placebo-controlled VELOUR trial, in which 1226 patients with oxaliplatin-refractory mCRC were randomly assigned to aflibercept (4 mg/kg IV) or placebo, plus FOLFIRI, every two weeks until progression. Median overall survival was significantly longer in patients treated with aflibercept (13.5 versus 12.1 months) [85]. Benefit and safety were similar regardless of prior bevacizumab exposure. While the side effect profile of aflibercept was consistent with other agents targeting VEGF (bleeding, hypertension, proteinuria, wound infection, arterial thromboembolic events), rates of diarrhea, mucositis, complicated neutropenia, infection, and fatigue associated with aflibercept in this trial were higher than usually seen with bevacizumab, as were rates of treatment discontinuation for toxicity or refusal (30 versus 12 percent). The VELOUR trial enrolled patients over the age of 65, and in a preplanned subgroup analysis, the survival benefit was similar in older as compared to younger individuals; a breakdown of toxicities according to age was not provided [86]. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'Aflibercept'.)

The optimal way to integrate aflibercept into treatment of older adult patients with mCRC is unclear. Particularly given the data on benefit from bevacizumab after progression on a first-line bevacizumab-containing regimen, whether aflibercept plus second-line FOLFORI is the preferred approach after progression on first-line FOLFOX plus bevacizumab is unclear. In our view, FOLFORI plus aflibercept is an alternative to FOLFIRI alone or FOLFIRI with bevacizumab in this setting. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'Continuation of bevacizumab (or biosimilars) beyond progression'.)

As with bevacizumab, because of the risk of impaired wound healing, bowel perforation, and fistula formation, at least 28 days should elapse between major surgery and administration of aflibercept, except in emergency situations. This recommendation does not apply to minor procedures such as implantation of a venous access device. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Delayed wound healing' and "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Intestinal perforation/fistula formation'.)

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 improved overall survival compared with placebo plus FOLFIRI for second line-treatment of mCRC in patients previously treated with first-line bevacizumab plus oxaliplatin and a fluoropyrimidine [87]. (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 [88]. 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).

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 (wild-type [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 nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Extended RAS testing'.)

Furthermore, response to EGFR-targeted agents is highly unlikely in patients whose tumors harbor a BRAF V600E mutation. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'BRAF'.)

Emerging data also suggest that the location of the primary tumor is another factor that influences the efficacy of anti-EGFR agents, at least when administered for first-line therapy. 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, even if they are WT for RAS and BRAF. However, anti-EGFR agents could be used for later lines of therapy in patients with a right-sided primary. For patients with a right-sided tumor and a contraindication to bevacizumab, chemotherapy alone is a reasonable choice for initial therapy. In contrast, for patients who have a left-sided primary tumor, cetuximab may be preferred over bevacizumab if a biologic agent is chosen for initial therapy. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Anti-EGFR agent 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).

Few clinical trials have addressed the safety and efficacy of these drugs in older patients; however, there are no readily apparent safety concerns about their use:

●A retrospective series of 56 patients over the age of 70 (median age 76) who received cetuximab with or without irinotecan for heavily pretreated KRAS WT mCRC found no unexpected toxicities [89]. Skin rash occurred in 75 percent of treated patients (11 percent grade 3), and diarrhea in 80 percent (20 percent grade 3 or 4). The authors concluded that efficacy was similar to that expected in younger individuals and that tolerability of cetuximab was acceptable in older adult patients.

●Similar conclusions were reached in an analysis of 657 patients (305 ≥65 years old) receiving cetuximab plus chemotherapy for treatment of mCRC and were registered into an observational database in Germany [90]. Efficacy was comparable in older as compared to younger individuals, and the prevalence of side effects was similar, although there was a trend toward higher grade and duration of both dermatologic and non-dermatologic toxicity in older individuals.

●In contrast, a higher rate of acneiform rash was noted in a phase II trial of cetuximab plus capecitabine in 66 older adult patients with previously untreated mCRC (30 percent grade 3 or 4) [91]. (See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".)

●Panitumumab seems also to be effective and reasonably well tolerated:

•In the registration trial of panitumumab compared with best supportive care, a stratified analysis by age found those over 65 received a similar degree of progression-free survival benefit as did those younger than 65 (HR >65, 0.60; HR <65, 0.51) [92]. Toxicity information was not reported.

•In a subsequent retrospective series of 40 "frail" older adult patients receiving panitumumab as first-line or second-line therapy for mCRC, toxicity-related dose reductions were required in about one-fourth of patients, but no one discontinued treatment permanently as a result of adverse effects [93].

•Monotherapy with panitumumab may be a well-tolerated first-line option for frail older adult patients with WT RAS tumors. In a phase II trial of 33 patients with previously untreated mCRC and an Eastern Cooperative Oncology Group (ECOG) PS ≤3, median PFS was 7.9 months in the RAS WT subgroup, and there were no deaths or grade 4 or 5 toxicities attributed to panitumumab [94].

•Leucovorin-modulated FU (FU/LV) plus panitumumab for up to six months followed by panitumumab alone for maintenance therapy is another reasonable alternative to FOLFOX plus panitumumab for older patients [95]. In the randomized PANDA trial, patients who received FU/LV/panitumumab had a similar median PFS (9.1 versus 9.6 months) and objective response rate (57 versus 65 percent), but marked lower rates of grade 3 or 4 treatment-related toxicity (including neutropenia, diarrhea, stomatitis, and neurotoxicity).

For selected older individuals (eg, those with WT RAS tumors and a contraindication to bevacizumab), adding cetuximab or panitumumab to first-line chemotherapy is a reasonable option.

Testing for RAS and the benefits of adding an anti-EGFR agent to first-line irinotecan or oxaliplatin-based chemotherapy for patients with RAS WT mCRC are addressed in detail elsewhere. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'RAS mutations'.)

Immunotherapy — Approximately 3.5 to 6.5 percent of stage IV CRCs are characterized as having high levels of microsatellite instability (MSI-H), which is the biologic footprint of deficiency in DNA mismatch repair enzymes (deficient mismatch repair [dMMR]). Cancers with dMMR/MSI-H appear to be uniquely susceptible to drugs that inhibit immune checkpoints. (See "Molecular genetics of colorectal cancer", section on 'Mismatch repair genes' and "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Clinical efficacy of anti-PD-1 therapy'.)

An option for treatment at progression for patients who have advanced MSI-H/dMMR tumors and who did not receive first-line immunotherapy is immunotherapy with an immune checkpoint inhibitor that targets programmed death receptor-1 (PD-1; ie, nivolumab, pembrolizumab, or combination therapy with nivolumab plus ipilimumab). In clinical trials, objective response rates are 30 to 50 percent, and some responses are durable. The subject of immunotherapy with immune checkpoint inhibitors for recurrent MSI-H/dMMR mCRC is discussed in detail elsewhere.

First-line pembrolizumab — Most of the data on benefits of immune checkpoint inhibitor immunotherapy are in previously treated patients, after failure of conventional cytotoxic chemotherapy. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'Microsatellite unstable/deficient mismatch repair tumors'.)

However, results from the KEYNOTE-177 trial suggest that front-line pembrolizumab offers better outcomes than first-line oxaliplatin or irinotecan-containing chemotherapy in patients with dMMR/MSI-H tumors [96]. Compared with upfront chemotherapy, pembrolizumab doubled median PFS (16.5 versus 8.2 months), and it improved objective response rate, duration of response, and tolerability (grade 3 to 5 adverse reaction rates 22 versus 66 percent). Largely based on these data, pembrolizumab is now approved for first-line therapy of metastatic dMMR/MSI-H colorectal cancer. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Patients with deficient DNA mismatch repair/microsatellite unstable tumors'.)

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 WT, an anti-EGFR therapy. Approval 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 demonstrated a significant survival benefit for regorafenib (median 6.4 versus 5 months), albeit with little objective antitumor response [97].

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 "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects" and "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects".)

Other reported side effects in the CORRECT trial were fatigue, diarrhea, hand-foot skin reaction, and liver failure. 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 (ASCO) annual meeting suggested similar efficacy in patients 65 and under and those who are older [98].

Treatment of patients ≥70 years of age with regorafenib is feasible and demonstrates similar efficacy to that seen in younger patients [99]. However, the risk of severe (grade 3 or 4) adverse events is >80 percent (especially fatigue and hand-foot syndrome). Treatment should be initiated at a dose of 80 mg per day, and only escalate if the lower dose is well tolerated.

The approved starting dose of 160 mg daily is probably too high for most patients. In the randomized phase II regorafenib dose optimization study (ReDOS) trial, 123 patients with refractory colorectal cancer were randomized to receive regorafenib at the standard starting dose of 160 mg/day, or to an incremental dose-escalation strategy beginning with 80 mg/day and escalating 40 mg a week to the goal dose of 160 mg. More patients in the dose-escalation arm stayed on the drug long enough to initiate cycle three than patients in the standard dosing arm, 43 versus 26 percent. Patients in the dose-escalation arm also experienced a lower incidence of adverse effects [100]. This trial was conducted in patients aged 29 to 81 with good performance status, so while it is not specific to older patients, such a strategy may be particularly important in patients with borderline functional status who wish to try regorafenib for refractory disease. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'Regorafenib'.)

Trifluridine-tipiracil — Trifluridine-tipiracil (TAS-102) 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. Benefit in refractory mCRC was shown in the phase III trial (RECOURSE) in which 800 patients who were refractory to or intolerant of fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab, and anti-EGFR agents (if WT KRAS) were randomly assigned to trifluridine-tipiracil (35 mg/m² orally twice daily on days 1 through 5, and 8 to 12 of each 28-day cycle) or placebo [101]. Trifluridine-tipiracil was associated with a significant prolongation in median overall survival, the primary endpoint (7.1 versus 5.3 months), and this benefit was irrespective of prior regorafenib use. 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 the treatment of patients with longstanding treatment-refractory disease who are often battling gastrointestinal distress as a consequence of their disease and are not tolerant of high-grade gastrointestinal toxicity. There are no published data on the safety or efficacy of trifluridine-tipiracil in older adults. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'Trifluridine-tipiracil'.)

ROLE OF METASTASECTOMY

Liver metastases — Despite advances in chemotherapy for metastatic colorectal cancer (mCRC), resection offers the only 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 "Management of potentially resectable colorectal cancer liver metastases", section on 'Overview of surgical resection'.)

Similar findings were noted in a report from the LiverMetSurvey registry of 999 well-selected older adult patients 70 or older [102]. 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 "Management of potentially resectable colorectal cancer liver 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 [103,104]:

●A retrospective review included 181 liver resections that were performed in 178 consecutive patients over age 70, 19 percent of whom received neoadjuvant FOLFOX [103]. 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 fluorouracil (FU)/leucovorin (n = 10) [104]. In older adults, use of XELOX was associated with a significantly higher response rate than bolus FU/leucovorin (68 versus 0 percent), and responding patients had significantly better overall and recurrence-free survival (RFS). Five-year overall survival 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 [105], clinicians should exercise caution when giving oxaliplatin and irinotecan to an older patient pre-resection. (See 'Challenges specific to older adults' above and "Management of potentially resectable colorectal cancer liver metastases".)

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 "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", 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 [106-110]. (See "Surgical resection of pulmonary metastases: Outcomes by histology", section on 'Colorectal cancer'.)

MANAGEMENT OF PATIENTS WITH A POOR PERFORMANCE STATUS — As with older adults, physicians may be reluctant to administer aggressive combination chemotherapy to patients with a poor performance status (PS) for fear that they will derive more toxicity and less benefit than those with a better PS. Regardless of age, individuals with a poor PS (eg, Eastern Cooperative Oncology Group [ECOG] PS ≥2 (table 2), Karnofsky PS <60 (table 12)) usually tolerate chemotherapy poorly and have a poor short-term prognosis [111].

However, patients with mCRC who have a PS of 2 should be considered for chemotherapy, particularly if their PS decline is cancer related. Although such patients have a median survival that is approximately half that seen for patients with a PS of 0 or 1, they benefit to an equal extent from combination chemotherapy.

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 [112]. Patients with 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 selected patients with PS 3 to 4 may benefit from chemotherapy, with upfront dose reduction and close monitoring for toxicity to minimize the risk for serious adverse events. 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) [111].

The choice of regimen is unclear. In the MRC trial of fluorouracil (FU) or capecitabine with or without oxaliplatin in older adult and frail patients discussed above (in which 29 percent of the 460 enrollees had a PS of 2), the addition of oxaliplatin to a fluoropyrimidine significantly improved outcomes without worsening toxicity [113]. In contrast, the substitution of capecitabine for infusional FU/leucovorin did not improve outcomes and significantly worsened toxicity. (See 'XELOX' above.)

For patients who are not considered appropriate candidates for intensive first-line therapy with an oxaliplatin or irinotecan-based combination regimen, leucovorin-modulated FU is an appropriate option [72]. Short-term infusional FU/leucovorin (table 9) is preferred because of its more favorable toxicity profile compared with other schedules. The addition of bevacizumab is reasonable, but the modest survival benefit from adding bevacizumab to first-line therapy must be balanced against the potential for serious treatment-related toxicity. An equally effective but potentially more toxic alternative first-line regimen, when fluoropyrimidines alone are indicated, is capecitabine with or without bevacizumab. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Not candidates for intensive therapy' and "Treatment protocols for small and large bowel cancer".)

At the time of progression, patients initially treated with a fluoropyrimidine alone whose PS has improved could be treated either with an irinotecan-based or an oxaliplatin-based regimen [114]. In contrast, supportive care alone is an option for those whose PS declines or does not improve.

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The COVID-19 pandemic has increased the complexity of cancer care. Important issues include balancing the risk from delaying cancer treatment versus harm from COVID-19, minimizing the number of clinic and hospital visits to reduce exposure whenever possible, mitigating the negative impacts of social distancing on delivery of care, and appropriately and fairly allocating limited healthcare resources. Specific considerations for patients undergoing palliative chemotherapy for stage IV colorectal cancer include establishing goals of care and discussing advance care planning, utilizing oral rather than intravenous therapy, where appropriate, transitioning outpatient care (eg, pump disconnection) to home whenever possible, using upfront chemotherapy or nonsurgical embolic or ablative methods to delay metastasectomy, and using intermittent rather than continuous therapy (with or without maintenance therapy), where feasible. (See 'Capecitabine' above and 'Role of metastasectomy' above and "Systemic chemotherapy for metastatic colorectal cancer: General principles", section on 'Continuous versus intermittent therapy'.)

These and other recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with 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 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

Older adults — The principles of treating metastatic colorectal cancer (mCRC) in older adults are similar to those that guide treatment of 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 chemotherapy (treatment-related toxicity and quality of life [QOL] issues), particularly in the context of estimated life expectancy. Serious comorbidity negatively impacts survival and increases the complexity of cancer management in this population. (See 'Challenges specific to older adults' above.)

Treatment decisions should not be based upon age alone, but upon functional status, the presence of comorbidities, and consideration of drug-specific toxicities that can be worse in older individuals because of their diminished reserve:

●In general, fit older adult patients with mCRC derive as much benefit from chemotherapy as do younger patients, with only a minor increase in expected toxicity. We recommend that these patients be offered combination chemotherapy, including a biologic agent, if appropriate.

●Combination chemotherapy should be used cautiously, given in attenuated doses initially, or be avoided altogether in frail older patients (particularly those with severe comorbidity, poor physical function). In this population, sequential single agent therapy is a probably preferable.

However, if the decline in physical function is entirely related to cancer, treatment should be considered, as patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 (table 2) appear to benefit from chemotherapy. (See 'Management of patients with a poor performance status' above.)

●The majority of older adult patients are neither fit nor frail. Individualized treatment decision-making is paramount in this group as presently there is no evidence to support or refute the benefit and safety of therapy. However, we strongly encourage physicians to at least discuss treatment with these patients and to tailor it (particularly for patients with cognitive or functional impairment) by starting with attenuated doses in combination regimens or single agents, escalating intensity as tolerated. The default of simply omitting chemotherapy is no longer acceptable. (See 'Safety and efficacy of chemotherapy for metastatic disease' above.)

Choice of regimen — The following represents our general approach to initial treatment for fit older adult patients with mCRC, which mirrors our approach to younger patients and is outlined in the algorithm (algorithm 1) (see "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach"):

●For fit, relatively healthy older adult patients, we suggest a chemotherapy doublet (FOLFOX, XELOX, or FOLFIRI) (table 14) rather than a fluoropyrimidine alone (Grade 2B). The choice among these regimens may be driven by toxicity concerns. Given the small increased risk of neutropenia, we often omit the fluorouracil (FU) bolus from both FOLFOX (eg, modified FOLFOX7) (table 17) and FOLFIRI in order to diminish treatment-related cytopenias. (See 'Overview of treatment selection' above and "Treatment protocols for small and large bowel cancer".)

The triplet chemotherapy regimen FOLFOXIRI (oxaliplatin plus irinotecan, leucovorin, and infusional FU (table 19)) improves progression-free and overall survival in mCRC compared to doublet chemotherapy regimens. However, randomized trials to date have been restricted to patients younger than 70 years; therefore, caution should be used in extrapolating these data to older adults. (See 'Overview of treatment selection' above.)

●Although some experts disagree, regardless of whether an oxaliplatin-based or an irinotecan-based chemotherapy backbone is selected, it is reasonable to add a biologic agent to the first-line regimen for patients who can tolerate an intensive regimen. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Role of biologics'.)

Among fit patients, the individual clinical and molecular profile of each patient's cancer should be used to select which biologic to administer with the selected oxaliplatin-based or irinotecan-based chemotherapy regimen.

For patients with RAS or BRAF V600E mutated cancers, we suggest adding bevacizumab to first-line chemotherapy (table 12 and table 20) (Grade 2B). However, the potential for improved outcomes from the addition of bevacizumab to first-line therapy must be balanced against the potential for serious treatment-related toxicity. Because patients over age 65 may be at increased risk of a bevacizumab-induced arterial thromboembolic event, bevacizumab should only be used with informed consent regarding these risks. In patients with a personal history of stroke or active coronary heart disease, the benefit offered by bevacizumab is likely outweighed by the risk of an arterial thrombotic event. (See 'Bevacizumab and biosimilars' above and "Treatment protocols for small and large bowel cancer".)

Treatments targeting the epidermal growth factor receptor (EGFR) appear to be less effective in subgroups of patients with right-sided cancers, even if they are wild type for both RAS and BRAF V600E, and we suggest adding bevacizumab rather than an anti-EGFR agent to first-line therapy for these patients. For patients with left-sided wild-type RAS and BRAF tumors, a regimen that includes a fluoropyrimidine plus anti-EGFR agent (eg, leucovorin-modulated fluorouracil plus panitumumab for up to six months followed by panitumumab maintenance) may be preferred particularly if a patient is not a candidate for bevacizumab. (See 'Cetuximab and panitumumab' above and "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Anti-EGFR agent versus bevacizumab and the influence of tumor sidedness'.)

●For patients who are not considered appropriate candidates for intensive first-line therapy with an oxaliplatin or irinotecan-based regimen, we suggest leucovorin-modulated FU (Grade 2B). We prefer short-term infusional FU/leucovorin (table 9) because of its more favorable toxicity profile compared with other schedules. The survival benefit of adding bevacizumab to first-line FU plus leucovorin must be balanced against the potential for serious treatment-related toxicity. (See 'Single agent fluorouracil' above and 'Bevacizumab and biosimilars' above and "Treatment protocols for small and large bowel cancer".)

An equally effective but potentially more toxic alternative first-line regimen, when fluoropyrimidines alone are indicated, is capecitabine with or without bevacizumab. (See 'Capecitabine' above and 'Bevacizumab and biosimilars' above.)

As noted above, the potential for improved outcomes from the addition of bevacizumab to first-line therapy must be balanced against the potential for serious treatment-related toxicity. Because patients over age 65 may be at increased risk of a bevacizumab-induced arterial thromboembolic event, bevacizumab should only be used with informed consent regarding these risks. In patients with a personal history of stroke or active coronary heart disease, the benefit offered by bevacizumab is likely outweighed by the risk of an arterial thrombotic event. (See 'Bevacizumab and biosimilars' above.)

●We routinely incorporate drug holidays into the treatment plan for many patients with mCRC, regardless of age. This allows recovery from cumulative toxicity that will often permit later resumption of chemotherapy. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Duration of initial chemotherapy'.)

●Data from the randomized KEYNOTE-177 trial provide support for first-line pembrolizumab monotherapy as an alternative to cytotoxic chemotherapy for patients with mismatch repair-deficient/microsatellite unstable mCRC, although this is indication is not yet FDA approved. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Patients with deficient DNA mismatch repair/microsatellite unstable tumors'.)

●Several options are available for treatment at progression. 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'.)

Poor performance status — Supportive care alone is a reasonable option for medically unfit patients, for those with an ECOG PS 3 or 4 (table 2), and for individuals with extensive comorbidity. For patients with mCRC who have an ECOG PS of 2 (table 2), we suggest chemotherapy rather than supportive care alone, particularly if their PS decline is cancer related (Grade 2B). (See 'Management of patients with a poor performance status' above.)

●For patients who are not considered appropriate candidates for intensive first-line therapy with an oxaliplatin or irinotecan-based regimen based on their PS, leucovorin-modulated FU (eg, with the de Gramont regimen (table 11)), capecitabine monotherapy, or single-agent cetuximab or panitumumab (if RAS wild type) are appropriate options. (See "Treatment protocols for small and large bowel cancer".)

●As with older adult patients, the survival benefit from adding bevacizumab or cetuximab/panitumumab to first-line therapy must be balanced against the potential for serious treatment-related toxicity. At the time of progression, patients whose PS has improved could be treated either with an irinotecan-based or an oxaliplatin-based regimen, including the addition of the appropriate biologic (eg, based on RAS, BRAF, and tumor location) in those who have markedly improved. For those whose PS declines or does not improve, supportive care alone is an option.