Adjuvant therapy for resected colon cancer in older adults

INTRODUCTION — 

Colorectal cancer (CRC) is one of the most common cancers worldwide. Age is a major risk factor for sporadic CRC. The number of patients over the age of 65 who present with CRC care is expected to rise over time. (See "Epidemiology and risk factors for colorectal cancer", section on 'Age'.)

Surgical resection is the only curative treatment for locoregional colon cancer. Outcomes are most closely related to the extent of disease at presentation (table 1 and figure 1) [1]. (See "Clinical presentation, diagnosis, and staging of colorectal cancer", section on 'TNM staging system'.)

This topic review will discuss adjuvant (ie, postoperative) therapy for older adult patients with resected colon cancer. Other topics related to the management of colon cancer are discussed separately.

●(See "Adjuvant therapy for resected stage III (node-positive) colon cancer".)

●(See "Adjuvant therapy for resected stage II colon cancer".)

●(See "Adjunctive therapy for non-metastatic treated colorectal cancer: Aspirin, NSAIDs, and vitamin D".)

●(See "Management of metastatic colorectal cancer in older adults and those with a poor performance status".)

●(See "Post-treatment surveillance for colorectal cancer".)

CHALLENGES SPECIFIC TO OLDER ADULTS — 

The essential principles of treating colon cancer in older adults are the same as in younger patients. However, for older patients, who may have age-related organ function decline and comorbid conditions that may limit life expectancy, special attention must be paid to the risks of systemic therapy, including both treatment-related toxicity and quality of life issues.

Age-related organ function decline — Aging is commonly accompanied by a decline in the function of critical organ system [2,3]. (See "Systemic chemotherapy for cancer in older adults", section on 'Challenges specific to older-adult patients'.)

This has several implications for older adult patients undergoing adjuvant systemic therapy for colon cancer (table 2). As examples:

●Liver/kidney function – Declining liver and kidney function with age can alter cancer drug metabolism and elimination. Of the drugs commonly used in the adjuvant setting to treat colon cancer, only capecitabine is predominantly cleared by the kidney. A 25 percent dose reduction is recommended for patients who have an estimated glomerular filtration rate (GFR) of 30 to 50 mL/min, and the drug should be avoided if the estimated GFR is <30 mL/min. (See "Nephrotoxicity of chemotherapy and other cytotoxic agents", section on 'Dosing considerations for nephrotoxicity'.)

In addition, liver and/or kidney disease places patients at an increased risk for a non-colon cancer-related death [4]. (See 'Comorbid conditions' below.)

●Cardiovascular conditions – Normal aging is associated with an increased risk of coronary artery disease. Among patients undergoing adjuvant systemic therapy for colon cancer, the possibility of fluorouracil or capecitabine-induced vasospasm is in the differential diagnosis for patients who develop chest pain or otherwise unexplained decompensated heart failure during treatment. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines", section on 'Antimetabolites'.)

●Bone marrow reserve – Bone marrow reserve diminishes as a part of normal aging, placing older patients at greater risk for severe and prolonged chemotherapy-related cytopenias. Chemotherapy dose reduction and/or delay may be necessary.

Another alternative is the use of hematopoietic growth factor support during treatment. However, there is no role for primary prophylaxis with myeloid growth factors. Guidelines from the American Society of Clinical Oncology (ASCO) support primary prophylaxis with myeloid growth factors only for chemotherapy regimens that have a risk of febrile neutropenia ≥20 percent [5]. None of the commonly used systemic therapy regimens for adjuvant treatment of colon cancer meets this criterion. (See "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation", section on 'Primary prophylaxis' and "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation".)

Comorbid conditions — Patients over the age of 75 have an average of five other medical conditions at the time of diagnosis of colorectal cancer (CRC) [4,6]. The most common are anemia (often from occult blood loss related to a primary colon cancer), hypertension, other gastrointestinal diagnoses, and heart disease [4]. Of these, liver and kidney disease place patients at greatest risk of non-cancer-related death [4].

Among patients undergoing surgery for colon cancer, severe comorbidity increases the complexity of cancer management, and it decreases both overall and cancer-specific survival (table 3) [7].

For seriously ill patients with severe comorbid illness that diminishes life expectancy (particularly to one year or less), the risks of adjuvant systemic therapy for colon cancer may outweigh its benefits. On the other hand, for patients who have multiple but not life-threatening comorbid conditions, the benefits of adjuvant therapy appear to be preserved without an increased risk of severe systemic therapy toxicity or hospitalization during adjuvant therapy [7].

Several comorbidity indices are available, and all appear useful for predicting which patients are likely to have lower levels of overall and cancer-specific survival after colon cancer surgery [8]. One such tool is the Charlson comorbidity index (CCI) (table 4). In one series, patients with a CCI of ≥3 had a significant twofold higher risk of colon cancer-specific mortality, and a CCI of 2 or higher was associated with a significant 1.49-fold higher rate of overall mortality [8]. (See "Comprehensive geriatric assessment for patients with cancer", section on 'Comorbidity'.)

Quality of life issues — Quality of life is a crucial component of decision-making when treating older cancer patients. The available data suggest that older patients are just as willing to try systemic therapy as their younger counterparts, but less willing to endure severe treatment-related side effects. (See "Systemic chemotherapy for cancer in older adults", section on 'Quality of life issues'.)

Measures of physical function and reserve — Chronological age is a poor marker of a patient's functional status. Several methods of functional assessment are available, but there is no single valid measure that is both feasible in routine clinical practice, and can reliably predict and/or improve outcomes of older patients. (See "Systemic chemotherapy for cancer in older adults", section on 'Assessments of physical function and reserve'.)

●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 two widely used scales, the Eastern Cooperative Oncology Group (ECOG) scale (table 5) and Karnofsky Performance Status (KPS) (table 6).

PS tends to underestimate the degree of functional impairment in the older patient. However, both the ECOG PS and KPS are useful to assess a patient's ability to tolerate systemic therapy. Regardless of age, patients with a poor PS (eg, ECOG PS >2, KPS <60) usually tolerate systemic therapy poorly.

●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 includes 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.

●Comprehensive geriatric assessment – Assessment of functional status with the ADL and IADL scales is a component of the comprehensive geriatric assessment (CGA) that is used by geriatricians to identify frail older patients at high risk of adverse outcomes such as falls, hospitalization, and death. Incorporating a more thorough geriatric assessment of function using the CGA can aid treatment decision-making in older cancer patients. (See "Comprehensive geriatric assessment for patients with cancer".)

ASCO guidelines recommend that a geriatric assessment be undertaken in all patients age 65 and older who are receiving systemic therapy [9]. 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 7) [9]. The guidelines also include recommendations for specific interventions guided by the geriatric assessment (table 8). This subject is discussed in more detail separately. (See "Comprehensive geriatric assessment for patients with cancer".)

Use of physical function to guide treatment decisions — There is general agreement that frail older adults, those with significant functional impairment or an ECOG PS of 3 to 4 (table 5), are not appropriate candidates for adjuvant systemic therapy. There is also general agreement that adjuvant systemic therapy should be offered to active, fit, older patients without comorbidity although which regimen should be used is unclear (table 9). (See 'Choice of regimen' below.)

It is the patients who are neither frail nor fit for whom treatment decision making is most complex.

Validated models have been developed that can be useful in predicting which patients are at increased risk of developing severe or fatal toxicity from systemic therapy [10]. Parameters included within this model include age, type of cancer, the proposed systemic therapy regimen, kidney and hematologic function, hearing, and activity levels from the comprehensive geriatric assessment (ability to take medications, physical activity, social activity). These parameters have been combined into a model that can be useful in predicting which patients are at increased risk of developing severe or fatal toxicity from systemic therapy (table 10 and table 11) [10]. This subject is discussed in detail separately. (See "Systemic chemotherapy for cancer in older adults", section on 'Models predicting chemotherapy toxicity and early death'.)

OVERVIEW OF ADJUVANT SYSTEMIC THERAPY

Rationale — For patients who have undergone potentially curative resection for colon cancer, disease recurrence is thought to arise from clinically occult micrometastases that are present at the time of surgery. The goal of adjuvant (postoperative) systemic therapy is to eradicate these micrometastases, thereby increasing the cure rate.

The benefits of adjuvant systemic therapy have been most clearly demonstrated in stage III (node-positive) disease (table 1), where adjuvant fluoropyrimidine (FU)-based systemic therapy reduces the risks of disease recurrence and mortality. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Rationale and endpoints to define benefit'.)

The benefit of adjuvant systemic therapy in stage II disease is more controversial. In patients with resected stage II disease, data suggest that the use of adjuvant fluorouracil (FU)-based systemic therapy does not exceed an absolute improvement in five-year overall survival (OS) of 5 percent. Because of the higher risk of recurrence, adjuvant systemic therapy is often offered to patients with higher-risk stage II disease (a T4 primary (table 1), or two or more of the following high-risk features: fewer than 12 nodes in the surgical specimen, perforation, obstruction, lymphovascular or perineural invasion, poorly differentiated histology, high tumor budding score). However, there are no data to support that these features identify those patients with stage II disease who might derive relatively greater benefit from adjuvant systemic therapy. In fact, observational data indicate that adjuvant systemic therapy is not associated with substantial improvements in OS in patients with stage II colon cancer over the age of 65, with or without any of these poor prognostic features [11]. Nevertheless, the use of adjuvant therapy in the setting of resected stage II disease is similar for younger and older individuals who are deemed able to tolerate it. These and other data addressing the benefit of adjuvant systemic therapy for stage II disease are addressed in detail separately. (See "Adjuvant therapy for resected stage II colon cancer", section on 'Selection of adjuvant therapy (pMMR tumors)'.)

Molecular testing

DNA mismatch repair/microsatellite stability testing — All patients with colon cancer should have their tumors tested for deoxyribonucleic acid (DNA) mismatch repair status, which influences management. Colon cancers are either mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) or mismatch repair proficient (pMMR)/microsatellite stable (MSS). DNA mismatch repair status can be obtained using by molecular testing such as next-generation sequencing (NGS) for MSI-H signatures, or immunohistochemistry for loss of mismatch repair protein expression. (See "Adjuvant therapy for resected stage II colon cancer", section on 'Testing for Lynch syndrome'.)

Approximately 5 to 15 percent of colorectal cancers (CRCs) have deficient mismatch repair proteins, most commonly MutL homolog 1 (MLH1) or MutS homolog 2 (MSH2). MSI-H is the biologic footprint of tumors that are dMMR. (See "Molecular genetics of colorectal cancer", section on 'Mismatch repair genes'.)

A dMMR/MSI-H mutation is either sporadic or inherited due to Lynch syndrome (hereditary nonpolyposis CRC), and it is necessary to distinguish between the two situations. Over 90 percent of Lynch-syndrome-related CRCs will be MSI-H, whereas 15 percent of sporadic CRCs are MSI-H. For patients with dMMR/MSI-H CRC, the approach to screening for Lynch syndrome is discussed separately (algorithm 1). (See "Adjuvant therapy for resected stage II colon cancer", section on 'Testing for Lynch syndrome' and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis".)

PIK3CA mutations — All patients with resected colon cancer should be assessed for somatic (ie, tumoral) PIK3CA mutations using NGS to evaluate for the use of adjunctive aspirin. Further details are discussed separately. (See "Adjunctive therapy for non-metastatic treated colorectal cancer: Aspirin, NSAIDs, and vitamin D", section on 'PIK3CA mutations'.)

Choice of regimen — Regimen choice is influenced by disease stage.

Stage III — The randomized MOSAIC trial established the superiority of oxaliplatin plus leucovorin (LV) and short-term infusional FU (FOLFOX) as compared with FU and LV alone for adjuvant therapy of patients with stage III resected colon cancer. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'FOLFOX and the MOSAIC trial'.)

While an oxaliplatin-containing regimen such as modified FOLFOX6 (table 12) is preferred for most patients, if there is a contraindication to oxaliplatin (eg, preexisting neuropathy), FU plus LV is an option. Short-term infusional regimens of FU/LV (eg, the de Gramont regimen (table 13)) are associated with a more favorable toxicity profile than are bolus monthly or weekly regimens, but they also require central venous access and an ambulatory infusion pump. (See "Treatment protocols for small and large bowel cancer".)

Issues regarding the benefit of adjuvant oxaliplatin in older individuals are discussed below. (See 'Oxaliplatin-based regimens' below.)

An alternative to FU/LV is oral capecitabine or, outside of the United States, oral UFT. In randomized trials, both fluoropyrimidines have been shown to be at least as effective as bolus FU and LV for adjuvant treatment of colon cancer. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Oral fluoropyrimidines'.)

Stage II — For patients who choose adjuvant systemic therapy, the optimal regimen for stage II disease is controversial. As noted above, the FOLFOX regimen was superior to short-term infusional FU/LV in the MOSAIC trial, which was conducted in patients with both stage II and III disease. However, the survival and disease-free survival (DFS) benefit was limited to stage III disease. In an exploratory analysis, there was an absolute difference in five-year DFS that favored FOLFOX in the subgroup of stage II patients with high-risk tumors, but it was not statistically significant (82 versus 75 percent, hazard ratio 0.72) [12]. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Oxaliplatin-based therapy'.)

In both Europe and the United States, the FOLFOX regimen is approved for adjuvant therapy only for patients with stage III disease. Many oncologists routinely use FU/LV in this setting and discuss FOLFOX with patients who have very high-risk stage II disease, which is defined variably by expert groups (table 14).

An oxaliplatin-based regimen is also preferred over a fluoropyrimidine-alone regimen in patients with stage II tumors with mismatch repair enzyme deficiency (dMMR), the biologic footprint of which is a high level of microsatellite instability (MSI-H). These tumors are relatively refractory to fluoropyrimidines alone.

While there are no data addressing the benefit of capecitabine in patients with stage II disease (the randomized X-ACT trial of capecitabine versus bolus intravenous FU/LV was conducted exclusively in stage III disease), capecitabine monotherapy is a reasonable alternative to FU/LV in this setting, as long as the tumor is not dMMR. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Oral fluoropyrimidines'.)

Duration — If a fluoropyrimidine alone is administered, the standard duration of therapy is six months.

If an oxaliplatin-based regimen is chosen, there is only a marginal improvement in outcomes for continuing therapy for six months. In our view, both three and six months of systemic therapy are reasonable options, and the decision should be individualized based on patient values regarding potential small improvement in DFS balanced with excess neurotoxicity rates with longer treatment. This subject is discussed in detail separately. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Duration of therapy' and "Adjuvant therapy for resected stage II colon cancer", section on 'Duration of chemotherapy'.)

SAFETY AND EFFICACY OF ADJUVANT SYSTEMIC THERAPY — 

Despite the significant reduction in recurrence and death associated with adjuvant systemic therapy in high-risk resected colon cancer in all populations, including older adults, it has been used less commonly in eligible patients over age 65, particularly those over 80 [13-24].

Individual adjuvant systemic therapy trials provide little information on efficacy in older adults because they excluded older adults or pooled their results with those of younger patients. Yet, initial pooled subanalyses of older adult patients enrolled in clinical trials suggested that older adult patients derive as much benefit from adjuvant therapy as do younger individuals. The similar magnitude of benefit from adjuvant systemic therapy in older as compared with younger patients is supported by a pooled analysis of randomized clinical trials, a systematic review of data from both observational studies and trials in which outcomes in older adult patients were compared with those in non-older adult patients, and several population-based retrospective analyses [15,18,25-30].

Whether rates of toxic effects are higher in older adults is less well established. While many of available studies do not indicate a clinically relevant increase in severe complications in older adult as compared with non-older adult patients, a systematic review of 25 studies of adjuvant therapy in older adults (both oxaliplatin and fluoropyrimidine-based) concluded that grade 3 or 4 adverse events were higher among older adult patients for cardiac disorders (two of five studies), neutropenia (4 of 16 studies), infection (2 of 10 studies), dehydration (two of six studies), diarrhea (6 of 20 studies), and fatigue (6 of 13 studies) [30]. Furthermore, an analysis of 37,568 patients enrolled in 25 randomized trials of adjuvant systemic therapy derived from the ACCENT database noted that early mortality (within one to six months of starting adjuvant systemic therapy) was significantly more prevalent in older patients, particularly those over the age of 70 [31]. These data underscore the need to carefully evaluate the risk-to-benefit ratio when making treatment decisions in this age group. If systemic therapy is employed in this setting, a single-agent fluoropyrimidine is the regimen of choice. (See 'Choice of regimen' below.)

Fluorouracil plus leucovorin

Efficacy — The best evidence to support the similar magnitude of benefit from adjuvant fluorouracil (FU)-based systemic therapy in older as compared with younger patients comes from a pooled analysis of individual data from 3351 patients in seven randomized trials comparing adjuvant systemic therapy versus surgery alone for stage II or III colon cancer [25]. When patients were grouped into four age categories (≤50, 51 to 60, 61 to 70, and >70 years old), adjuvant treatment was associated with significant 24 percent reduction in mortality (overall survival [OS] 71 versus 64 percent) and a 32 percent reduction in disease recurrence, both of which were similar in all age groups.

The rate of toxic effects was not higher in older adult patients, with the exception of a higher rate of grade 3 or 4 neutropenia (8 versus 4 percent) in a single study. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Bolus fluorouracil plus leucovorin' and "Clinical presentation and risk factors for chemotherapy-associated diarrhea, constipation, and intestinal perforation".)

A constraint of the pooled data is selection bias, in that presumably more fit older adults were enrolled on the individual clinical trials, and the fact that fewer than 1 percent of the trial participants were in their 80s. However, analysis of several population-based databases, including those of the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute (NCI), Medicare, and the National Cancer Database (NCDB), provides corroborating evidence of the benefits of adjuvant FU-based systemic therapy in older adults with stage III colon cancer [15,16,18,32-34].

Fewer data are available for older patients with stage II disease. However, a survival benefit for fluoropyrimidine-based adjuvant systemic therapy could not be shown in an analysis from the linked SEER/Medicare database of 24,847 patients aged 65 and older who underwent colectomy for stage II colon cancer [11].

Toxicity — As noted above, the pooled analysis of data from randomized trials concluded that older patients do not necessarily have more side effects from FU/leucovorin (LV), with the possible exception of myelosuppression [25]. However, toxicity with FU/LV is very schedule dependent. More frequent and severe gastrointestinal toxicity (diarrhea, mucositis) is reported in older adult patients receiving bolus FU/LV, particularly the monthly bolus Mayo regimen [27,35,36]. By contrast, short-term infusional regimens of FU/LV (the so-called de Gramont regimen) seem to be well tolerated, even in those with marginal fitness. (See "Management of metastatic colorectal cancer in older adults and those with a poor performance status", section on 'Fluoropyrimidine monotherapy'.)

Oral fluoropyrimidines

Capecitabine — Capecitabine is routinely used as adjuvant therapy in older patients and is reasonably well tolerated, although some studies suggest modestly higher rates of adverse effects in older as compared with younger individuals:

●A study of patients receiving capecitabine plus oxaliplatin (CAPOX), or FU/LV in the adjuvant setting suggested an increase in selected adverse events, such as diarrhea and dehydration, in patients aged 65 and older compared with younger patients [37]. The rate of all grade 3 or 4 adverse events (65 versus 57 percent), serious adverse events (30 versus 17 percent), and withdrawals because of adverse effects (30 versus 16 percent) were also higher in the older patients, although the effect of kidney function was not addressed in this study.

●In a subgroup analysis of patients over 70 treated on the X-ACT trial, capecitabine and bolus FU/LV were similarly effective in older and younger patients [38]. Dose reduction for treatment-related toxicity was required in a higher percentage of older patients (51 versus 39 percent of those under age 70).

Capecitabine should be used with caution in the very old, particularly those with diminished kidney function. 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) [39]. The specific dose of capecitabine was not given. (See "Management of metastatic colorectal cancer in older adults and those with a poor performance status", section on 'Orally active fluoropyrimidines'.)

The approved dose is 1250 mg/m² twice daily for 14 of every 21 days. However, this is often poorly tolerated in American patients. Most American oncologists start with 1000 mg/m² twice daily, rounding down to accommodate pill size, and titrate the dose upward as indicated by drug tolerability.

UFT — 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). There are few older adult-specific data on the tolerability of UFT. In one trial in which the control arm was 39 patients over the age of 70 with resected colon cancer who received UFT alone, adverse drug reactions were rarely observed, and all were grade 2 or lower [40]. Although UFT is widely available in Europe and Asia, it is not available in the United States.

Oxaliplatin-based regimens — Studies have evaluated whether adjuvant oxaliplatin-based systemic therapy is as safe and effective in older patients as it is in younger patients with colon cancer. Most data suggest that older patients who are fit enough to enroll on clinical trials tolerate oxaliplatin-based systemic therapy nearly as well as younger patients. Oxaliplatin also seems to result in a similar time to recurrence. However, the disease-free and overall survival benefits of adjuvant oxaliplatin-based systemic therapy are attenuated in patients over the age of 70 years [12,41-48]. Observational data also generally support that treatment as tolerable as well as the attenuation of survival benefit in older adults [29,49]. However, older adult patients with resected node-positive colon cancer are less likely to receive an oxaliplatin-based regimen as compared with their younger counterparts [13,23].

As an example, in a pooled analysis of 12 trials from the ACCENT and IDEA database that included 17,909 patients with stage III colon cancer treated with three or six months of adjuvant systemic therapy with either FOLFOX or CAPOX, time to recurrence was similar between patients <70 years old and those ≥70 years [47]. However, DFS and OS were shorter in those ≥70 years old, possibly related to shorter survival after recurrence in this population. Grade ≥3 toxicity rates were similar between older and younger adults except for diarrhea and neutropenia, which were more frequent in older adults treated with CAPOX.

In our view, for fit older adults with stage III disease (and those with high-risk stage II tumors with mismatch repair enzyme deficiency), the risks and potential benefits of an oxaliplatin-based systemic therapy regimen should be discussed. (See "Adjuvant therapy for resected stage II colon cancer", section on 'Prevalence of MMR enzyme deficiency'.)

Clinicians should evaluate carefully whether older patients are sufficiently robust to tolerate treatment-related toxicity and have an estimated life expectancy of at least five years before recommending the use of oxaliplatin. For patients who are reasonable candidates for oxaliplatin and who have an estimated life expectancy of at least five years, we suggest oxaliplatin-based systemic therapy rather than FU/LV or capecitabine monotherapy. The use of FU plus LV remains a reasonable alternative to an oxaliplatin-based regimen for adjuvant treatment in older adult patients with stage III disease, or stage II tumors without mismatch repair enzyme deficiency. These recommendations are consistent with consensus-based guidelines for treatment of colorectal cancer (CRC) in older patients from the International Society of Geriatric Oncology [50].

Irinotecan-based regimens, bevacizumab, and cetuximab — Irinotecan, bevacizumab, and cetuximab have not proven beneficial in the adjuvant setting in randomized trials, and their use is not recommended. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Irinotecan' and "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Bevacizumab' and "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Cetuximab'.)

Choice of regimen — The optimal regimen for older adult patients who require adjuvant systemic therapy for high-risk colon cancer is uncertain. For fit older patients with stage III disease, or stage II tumors with deficient mismatch repair enzymes, we discuss the benefits and risks of an oxaliplatin-based regimen versus FU/LV alone. Clinicians should evaluate carefully whether older patients are sufficiently robust to tolerate treatment-related toxicity and have an estimated life expectancy of at least five years before recommending the use of oxaliplatin. (See 'Oxaliplatin-based regimens' above.)

If an oxaliplatin-based regimen is chosen, we prefer modified oxaliplatin plus LV and short-term infusional FU (FOLFOX) 6 (table 12). Omission of the FU bolus (ie, modified FOLFOX7 (table 15)) may be necessary because of neutropenia and/or thrombocytopenia persisting until the subsequent cycle. If ambulatory infusion pump therapy is not feasible, CAPOX (table 16) is a reasonable alternative, but appropriate dosing for older adult patients remains an area of uncertainty. (See "Treatment protocols for small and large bowel cancer".)

In less fit older patients with stage III disease and for those with high-risk stage II disease (table 14) without deficient mismatch repair enzymes who choose adjuvant therapy, we use FU/LV rather than an oxaliplatin-based regimen. We prefer a modified short-term infusional schedule (table 13) which is well tolerated, even in those of marginal fitness. If well tolerated, oxaliplatin could be added to later cycles for patients with stage III disease. (See "Treatment protocols for small and large bowel cancer".)

Single-agent capecitabine is a reasonable alternative to FU/LV for older patients who are unlikely to tolerate combination therapy and who clearly understand how to take the medicine and what to do in the event of an adverse reaction. The appropriate capecitabine dose is unclear. Most American oncologists start at 1000 mg/m² twice daily and titrate the dose upward as tolerated.

Chemotherapy dosing in obese patients — For cancer patients with a large body surface area (BSA), chemotherapy drug doses are often reduced, because of concern for excess toxicity. However, there is no evidence that fully dosed obese patients experience greater toxicity from chemotherapy for CRC; furthermore, at least in the setting of advanced disease, obese patients who are given reduced doses may have inferior outcomes [51]. Guidelines from the American Society of Clinical Oncology (ASCO) recommend that full weight-based chemotherapy doses be used to treat obese patients with cancer, particularly when the goal of treatment is cure [52]. (See "Dosing of anticancer agents in adults", section on 'Dosing for patients with obesity and who are overweight'.)

Use of web-based tools for assessing prognosis and benefit from adjuvant therapy — The decision to select a patient for adjuvant therapy can be challenging, particularly for older adult patients who are neither frail nor fit.

For individual patients, a postoperative nomogram has been developed that permits a prediction of the risk of a colon cancer recurrence based on clinicopathologic factors and whether adjuvant systemic therapy was administered or not (but not the type of systemic therapy) [53]. The nomogram, which has not yet been independently validated, is available online. It is approved for use in patients with colon cancer by the American Joint Committee on Cancer (AJCC), meeting all quality criteria [54]. However, besides age, it does not estimate the burden of comorbid disease.

While tools such as these can provide a useful adjunct to aid in the discussion of the risks and benefits of adjuvant systemic therapy for individual patients, they need to be interpreted in the context of physiologic age and comorbidity. Furthermore, they are not a substitute for sound physician judgment. The decision to pursue treatment requires careful evaluation of all aspects of the individual patient by the clinician, including those that are not contained in any of the web-based calculators (eg, the presence of perforation).

POST-TREATMENT SURVEILLANCE AND SECONDARY PREVENTION — 

Post-treatment surveillance is warranted only if the patient is a candidate for aggressive therapy, including a potentially curative surgery. Post-treatment surveillance for colorectal cancer (CRC) discussed in detail separately. (See "Post-treatment surveillance for colorectal cancer".)

Recommendations for secondary prevention (changes in diet, physical activity, and the use of aspirin and other nonsteroidal anti-inflammatory drugs [NSAIDs]) are also discussed separately. (See "The roles of diet, physical activity, and body weight in cancer survivors" and "Adjunctive therapy for non-metastatic treated colorectal cancer: Aspirin, NSAIDs, and vitamin D", section on 'Aspirin and other NSAIDs'.)

SOCIETY GUIDELINE LINKS — 

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

INFORMATION FOR PATIENTS — 

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

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

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

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

SUMMARY AND RECOMMENDATIONS

●Who can receive adjuvant therapy? – Older patients derive as much benefit from fluorouracil (FU)-based adjuvant systemic therapy as do younger patients, although the incremental benefit from oxaliplatin may be less. (See 'Overview of adjuvant systemic therapy' above.)

•We routinely offer adjuvant systemic therapy for fit older patients with stage III and high-risk stage II colon cancer (table 14), and we discuss the risks and benefits of adjuvant systemic therapy with non-fit but non-frail older adult patients.

•Frail older adults, those with significant functional impairment or an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 3 to 4 (table 5), are not appropriate candidates for adjuvant systemic therapy. (See 'Use of physical function to guide treatment decisions' above.)

A comprehensive geriatric assessment (CGA) may be useful to determine candidacy for adjuvant therapy and to formulate an appropriate, individualized treatment plan. (See "Comprehensive geriatric assessment for patients with cancer".)

The use of web-based tools to calculate prognosis and the benefits of adjuvant therapy can serve as an adjunct to aid discussions on the risks and potential benefits of adjuvant systemic therapy with individual patients, but tools such as these cannot replace a CGA, sound clinician judgment, or patient preference. (See 'Use of web-based tools for assessing prognosis and benefit from adjuvant therapy' above.)

●Choice of regimen

•Fit patients with stage III disease – For fit patients with stage III disease, who are reasonable candidates for oxaliplatin and who have an estimated life expectancy of at least five years, we suggest oxaliplatin-based systemic therapy rather than FU/leucovorin (LV) or capecitabine monotherapy (Grade 2B). However, given the uncertainty as to the overall survival (OS) benefit for oxaliplatin-based regimens in older adults, a reasonable alternative is a fluoropyrimidine alone. (See 'Oxaliplatin-based regimens' above.)

•Fit patients with stage II dMMR disease – For fit patients with a stage II colon cancer that is deficient in mismatch repair (dMMR), who are reasonable candidates for oxaliplatin and who have an estimated life expectancy of at least five years, we suggest oxaliplatin-based systemic therapy rather than fluoropyrimidine monotherapy (Grade 2B).

If an oxaliplatin regimen is chosen, we prefer the modified oxaliplatin plus LV and short-term infusional FU (FOLFOX) 6 regimen in this population (table 12). Given the added risk of significant myelosuppression in older adults, an alternative is FOLFOX with omission of the FU bolus (ie, modified FOLFOX7 (table 15)). (See 'Choice of regimen' above.)

If ambulatory infusion pump is not feasible, capecitabine plus oxaliplatin (CAPOX (table 16)) is a reasonable alternative. If CAPOX is chosen, we begin therapy at 825 mg/m² twice daily, and escalate to 1000 mg/m² twice daily only as tolerated. Capecitabine also requires dose reduction in patients with kidney function impairment. (See 'Capecitabine' above.)

•Less fit individuals with stage III or high-risk pMMR stage II disease – For less fit individuals with stage III disease who are deemed less likely to tolerate oxaliplatin or who have comorbid conditions that are likely to limit their five-year survival, and for those with high-risk stage II tumors that are proficient in mismatch repair (pMMR), we suggest a fluoropyrimidine alone rather than FOLFOX (Grade 2B). (See 'Fluorouracil plus leucovorin' above.)

If leucovorin-modulated fluorouracil (LV/FU) is chosen, we prefer a modified short-term infusional schedule of FU/LV (table 13). (See 'Fluorouracil plus leucovorin' above and "Treatment protocols for small and large bowel cancer".)

Single-agent capecitabine is a reasonable alternative, particularly if ambulatory infusion therapy is not feasible. We suggest starting with 1000 mg/m² twice daily for 14 of every 21 days and titrating the dose upward as indicated by treatment tolerability. Capecitabine requires dose reduction in patients with kidney function impairment. (See 'Capecitabine' above.)

•Agents not used – We do not use bevacizumab, cetuximab, or an irinotecan-based regimen (Grade 1A) in the adjuvant setting for any age group.

●Duration of therapy

•If a fluoropyrimidine alone is administered, the standard duration of therapy is six months.

•If an oxaliplatin-based regimen is chosen, both three and six months of systemic therapy are reasonable options. The potential for small improvements in disease-free survival (DFS), particularly for high-risk stage III cancer, must be weighed against the higher neurotoxicity rates seen with longer treatment and the decision must be individualized. (See 'Duration' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Richard M Goldberg, MD, who contributed to earlier versions of this topic review.