Adjuvant therapy for resected colon cancer in older adult patients

INTRODUCTION — Colorectal cancer is a common malignancy. Age is a major risk factor for colorectal cancer (figure 1) [1]. The median age at diagnosis is 67 [2]. Approximately 57 percent of cases develop over the age of 65; 32 percent are 75 years or older. The United States Census Bureau projects that by the year 2035, there will be 78 million Americans aged 65 or older, and older people are expected to outnumber children for the first time in United States history [3]. As a result, the number of patients over the age of 70 presenting for colorectal cancer care is expected to rise.

Surgical resection is the only curative treatment for locoregional colon cancer, and outcome is most closely related to the extent of disease at presentation (table 1 and figure 2) [4]. For patients who have undergone potentially curative resection, disease recurrence is thought to arise from clinically occult micrometastases that are present at the time of surgery. Postoperative (adjuvant) systemic chemotherapy is recommended for high-risk patients to eradicate these micrometastases, thereby increasing the cure rate.

This topic review will cover the benefits, risks, and choice of adjuvant chemotherapy for older adult patients with resected colon cancer. A general discussion of the benefits of adjuvant chemotherapy for resected colon and rectal cancer, surgical management and prognosis of colon cancer, benefits of adjunctive therapy with diet, exercise, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), vitamin D, and coffee consumption in patients with early stage colorectal cancer, chemotherapy considerations in older individuals with advanced colorectal cancer, a compilation of chemotherapy protocols for colorectal cancer, and recommendations for post-treatment follow-up are discussed separately. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer" and "Adjuvant therapy for resected rectal adenocarcinoma in patients not receiving neoadjuvant therapy" and "Overview of the management of primary colon cancer" and "Adjunctive therapy for patients with resected early stage colorectal cancer: Diet, exercise, NSAIDs, and vitamin D" and "Therapy for metastatic colorectal cancer in older adult patients and those with a poor performance status" and "Treatment protocols for small and large bowel cancer" and "Post-treatment surveillance after colorectal cancer treatment".)

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 chemotherapy, 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 [5,6]. (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 chemotherapy for colon cancer (table 2). As examples:

●Liver/renal 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 predominately 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.

In addition, liver and/or kidney disease places patients at an increased risk for a non-colon cancer-related death [7]. (See 'Comorbid conditions' below.)

●Cardiovascular – Normal aging is associated with an increased risk of coronary artery disease. Among patients undergoing adjuvant chemotherapy for colon cancer, the possibility of fluorouracil or capecitabine-induced vasospasm should be considered in 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 [8]. None of the commonly used chemotherapy regimens used for adjuvant treatment of colon cancer meet 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 [7,9]. The most common are anemia (often from occult blood loss related to a primary colon cancer), hypertension, other gastrointestinal diagnoses, and heart disease [7]. Of these, liver and kidney disease place patients at greatest risk of non-cancer-related death [7].

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) [10].

For seriously ill patients with severe comorbid illness that diminishes life expectancy (particularly to one year or less), the risks of adjuvant chemotherapy 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 chemotherapy toxicity or hospitalization during adjuvant therapy [10].

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 [11]. One such tool, the Charlson comorbidity index (CCI), is outlined in the table (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 [11]. (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 chemotherapy 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 chemotherapy. Regardless of age, patients with a poor PS (eg, ECOG PS >2, KPS <60) usually tolerate chemotherapy 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 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.

●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 chemotherapy [12]. 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) [12]. The guidelines also include recommendations for specific interventions guided by the geriatric assessment (table 8). This subject is discussed in more detail elsewhere. (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 chemotherapy. There is also general agreement that adjuvant chemotherapy 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 chemotherapy [13]. Parameters included within this model include age, type of cancer, the proposed chemotherapy regimen, renal 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 chemotherapy (table 10 and table 11) [13]. 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 STANDARD ADJUVANT CHEMOTHERAPY FOR COLON CANCER — The benefits of adjuvant chemotherapy have been most clearly demonstrated in stage III (node-positive) disease, where there is an approximately 30 percent reduction in the risk of disease recurrence and a 22 to 32 percent reduction in death compared with observation alone.

The benefit of adjuvant chemotherapy in stage II disease is more controversial. Data from randomized trials and meta-analyses indicate that if there is benefit for adjuvant fluorouracil (FU)-based chemotherapy in patients with resected stage II disease, it does not exceed an absolute improvement in five-year survival of 5 percent. Because of the higher risk of recurrence, adjuvant chemotherapy 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 13 nodes in the surgical specimen, perforation, obstruction, lymphovascular or perineural invasion, poorly differentiated histology, high tumor budding score), although there are no data that support the view that these features identify those patients with stage II disease who might derive relatively greater benefit from adjuvant chemotherapy. In fact, at least some data from the linked Surveillance, Epidemiology and End Results (SEER)/Medicare database indicate that adjuvant chemotherapy does not substantially improve overall survival in patients over the age of 65 with stage II colon cancer, with or without any of these poor prognostic features [14]. Nevertheless, guidelines for use of adjuvant therapy in the setting of resected stage II disease are similar for younger and older individuals who are deemed able to tolerate it. These and other data addressing the benefit of chemotherapy for stage II disease are addressed in detail elsewhere. (See "Adjuvant therapy for resected stage II colon cancer", section on 'Is there benefit for fluoropyrimidine-based chemotherapy?'.)

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 (table 12)) 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 13) is preferred for most patients [15], 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 14)) 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 chemotherapy, 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 [HR] 0.72) [16]. (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 15).

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, six months of therapy is considered standard. If an oxaliplatin-based regimen is chosen, the optimal duration is unclear. In our view, both three and six months of chemotherapy are reasonable options, although neurotoxicity rates are clearly higher with longer treatment, and the decision must be individualized. If three months of therapy is chosen, CAPOX may be a better choice than FOLFOX, and it avoids the need for an ambulatory infusion pump. This subject is discussed in detail elsewhere. (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 CHEMOTHERAPY IN OLDER ADULTS — Despite the significant reduction in recurrence and death associated with adjuvant chemotherapy 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 [17-28].

Individual adjuvant chemotherapy trials provide little information on chemotherapy effectiveness 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 chemotherapy 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 [19,22,29-34].

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) [34]. 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 chemotherapy) was significantly more prevalent in older patients, particularly those over the age of 70 [35]. These data underscore the need to carefully consider the risk to benefit ratio when making treatment decisions in this age group. If chemotherapy is employed in this setting, a single-agent fluoropyrimidine is the regimen of choice. (See 'Choice of regimen' below.)

Fluorouracil plus leucovorin — The best evidence to support the similar magnitude of benefit from adjuvant fluorouracil (FU)-based chemotherapy in older as compared with younger patients comes from a pooled analysis of individual data from 3351 patients in seven randomized trials comparing adjuvant chemotherapy versus surgery alone for stage II or III colon cancer [29]. 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 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 "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation".)

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 chemotherapy in older adults with stage III colon cancer [19,20,22,36]:

●A survival benefit for adjuvant chemotherapy was supported by data from a population-based series of 4768 Medicare patients aged ≥65 with stage III colon cancer [19]. Although it was received by only 52 percent of eligible patients, the use of FU-based chemotherapy was associated with a significant 34 percent reduction in mortality.

●Likewise, data reported to the NCDB in 2001 to 2002 suggest that although adjuvant chemotherapy was used less often in the older adult population (82, 77, 69, and 39 percent of patients younger than 60, 60 to 69, 70 to 79, and over age 80, respectively), the magnitude of benefit in patients with stage III disease was similar to that achieved in younger individuals [22].

●An analysis derived from the linked SEER/Medicare database concluded that while older adult patients of all ages had a significant survival benefit associated with the receipt of adjuvant chemotherapy for stage III colon cancer, the magnitude of benefit declined with advancing age [36].

●Finally, data from two registry-based series suggest that up to one-third of older patients do not complete the full six-month course of adjuvant chemotherapy, and that early treatment discontinuation is associated with a decline in survival [37,38].

Fewer data are available for older patients with stage II disease. However, a survival benefit for fluoropyrimidine-based adjuvant chemotherapy 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 [14].

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 [29]. 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 [31,39,40]. 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 "Therapy for metastatic colorectal cancer in older adult patients 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 [41]. 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 renal 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 [42]. Dose reduction for treatment-related toxicity was required in a higher percentage of older patients (51 versus 39 percent of those under age 70).

●A number of small older adult-specific trials in metastatic colorectal cancer have also found capecitabine monotherapy to be fairly well tolerated. As an example, a Spanish trial of 51 patients aged 70 or older treated with capecitabine (1250 mg/m² twice daily for 14 of every 21 days) for metastatic colorectal cancer reported grade 3 or 4 adverse events in only six patients (12 percent) [43].

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) [44]. The specific dose of capecitabine was not given. (See "Therapy for metastatic colorectal cancer in older adult patients 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, although Europeans and Asians seem to be better able to tolerate this dose. 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 [45]. Although UFT is widely available in Europe and Asia, it is not available in the United States.

Oxaliplatin-based regimens — Older adult patients with resected node-positive colon cancer are less likely to receive an oxaliplatin-based regimen as compared with their younger counterparts [17,27]. However, whether oxaliplatin-based chemotherapy is as effective and safe in older patients as it is in younger individuals is uncertain. The available data are conflicting. Analysis of data from several [16,46-48] (although not all [49]) randomized trials suggest that adding oxaliplatin to a fluoropyrimidine-based adjuvant regimen does not yield significant benefit among older patients. However, most of these trials enrolled younger healthier patients, with few over the age of 65.

The following data are available regarding the benefit for oxaliplatin in addition to adjuvant fluoropyrimidine-based chemotherapy in older patients:

●A survival benefit for oxaliplatin in older patients and those with higher levels of comorbidity is supported by an analysis of five observational database cohorts (the largest of which was the linked SEER/Medicare database), altogether totaling 4060 patients who were treated for stage III colon cancer at the community level in diverse practice settings between 2004 and 2009 [50]. Compared with the survival benefit seen with the use of oxaliplatin in five randomized controlled trials with a fluoropyrimidine-alone control arm (hazard ratio [HR] for death at three years 0.80, 95% CI 0.70-0.92; three-year overall survival 86 versus 82 percent), three-year survival of the oxaliplatin-treated patients was remarkably similar in the database cohorts. Furthermore, after adjusting for differences in patient and tumor characteristics between treatment arms, the survival HR point estimates of all of the retrospective cohorts showed at least as much reduction in death rates with the addition of oxaliplatin as did the randomized trial analysis although the effect was statistically significant in only two of the cohorts, including SEER/Medicare.

The benefit of oxaliplatin was maintained across all clinically relevant patient subgroups although small sample size limited the precision of the HR estimates. As an example, oxaliplatin-treated patients aged 70 to 74 had significantly improved survival in the SEER/Medicare database (HR for death 0.66, 95% CI 0.52-0.84) but not in others. Benefit for oxaliplatin was also evident in patients with a Carlson Comorbidity Index of 2, although in four of the five cohorts, the benefit was not statistically significant. (See 'Comorbid conditions' above.)

In a later similar analysis of data from four of the observational cohorts (including SEER/Medicare) that was limited to patients over the age of 75, the incremental benefit of oxaliplatin over non-oxaliplatin-based regimens was even less clear, with a nonstatistically significant difference in outcomes (HR for death 0.84, 95% CI 0.69-1.04) [33].

●A benefit for oxaliplatin in individuals aged 70 and over was also suggested in a pooled analysis of individual patient data from four randomized trials comparing an oxaliplatin-containing versus non-oxaliplatin containing adjuvant chemotherapy regimen for stage III colon cancer [51]. Overall survival was significantly improved in all age groups, although the benefits of oxaliplatin were attenuated in those aged 70 and older (HR 0.78, 95% CI 0.61-0.99, versus HR 0.62, 95% CI 0.54-0.72).

●On the other hand, results from the MOSAIC trial (short-term-infusional FU/LV with and without oxaliplatin) and NSABP C-07 (bolus weekly FU and LV with and without oxaliplatin) cast doubt as to the benefit of oxaliplatin in older adults [52,53]. In subgroup analyses of both trials, the significant disease-free survival benefit of adding oxaliplatin was present only in patients under age 70.

●The benefit of oxaliplatin in patients aged 70 and older was further called into question by an analysis of data from the ACCENT database [54]. Of the 14,528 patients enrolled in randomized trials comparing intravenous FU versus combinations that contained irinotecan, oxaliplatin, or oral fluoropyrimidines, 2575 were 70 years of age or older. Although statistically significant interactions between treatment arm and age were not observed, overall survival, DFS, and time to tumor recurrence were significantly better for oxaliplatin-based therapy in individuals under the age of 70 (HR for overall survival 0.83 in favor of oxaliplatin versus intravenous FU) but not in older patients (HR 1.04).

It is difficult to know how to interpret these data. The analysis did not consider issues related to toxicity or competing risk of death from non-colon cancer causes. The finding of a trend toward a higher risk of death within six months of starting therapy in older compared with younger individuals receiving oxaliplatin (3.12 versus 0.88 percent) suggests that patient selection is a key factor. Death from non-colorectal causes, and dose reductions and/or delays may largely explain the observed differences between older and younger patients.

●The relative toxicity of oxaliplatin versus non-oxaliplatin-containing adjuvant chemotherapy in older adult patients was addressed in a separate retrospective analysis of data from the linked SEER/Medicare, New York State Cancer Registry (NYSCR)/Medicare, and NYSCR/Medicaid databases [55]. There was evidence of a trend toward more adverse events with oxaliplatin as compared with fluoropyrimidine use with advancing age (odds ratios [ORs] for age 65 to 69, 70 to 74, 75 to 79, 80 to 84, and ≥85 years were 1.67, 3.18, 1.8, 3.37, and 3.18, respectively). However, the incremental harms were modest and limited to outpatient adverse events. Among patients 75 and older, rates of neutropenia (OR 17.3, 95% CI 9.80-30.42) and nausea and vomiting (OR 2.14, 95% CI 1.73-2.65), but not diarrhea and dehydration, were significantly higher with treatment with oxaliplatin versus a fluoropyrimidine alone. Rates of emergency department use, hospitalization, or early death were not higher in those who received oxaliplatin as compared with a fluoropyrimidine alone.

In summary, questions remain as to the survival benefit of adding oxaliplatin to a FU-based adjuvant chemotherapy regimen in older adults. Data from systematic reviews and meta-analyses suggest little benefit for the addition of oxaliplatin in individuals older than 70 years [56,57]. Nevertheless, 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 chemotherapy regimen should be discussed. (See "Adjuvant therapy for resected stage II colon cancer", section on 'Prevalence of MMR enzyme deficiency'.)

Clinicians should consider 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 chemotherapy 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 in older patients from the International Society of Geriatric Oncology [58].

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 chemotherapy 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 consider 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 13). Omission of the FU bolus (ie, modified FOLFOX7 (table 16)) may be necessary because of neutropenia and/or thrombocytopenia persisting until the subsequent cycle. If ambulatory infusion pump therapy is not feasible, CAPOX (table 17) 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 15) without deficient mismatch repair enzymes who choose adjuvant therapy, we use FU/LV rather than an oxaliplatin-based regimen. Rather than the original de Gramont regimen [59], we prefer a modified short-term infusional schedule (table 14) that eliminates the day 2 bolus doses of FU and LV as it is very 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. Out-of-pocket expense issues may influence the use of capecitabine.

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 colorectal cancer; furthermore, at least in the setting of advanced disease, obese patients who are given reduced doses may have inferior outcomes [60]. Guidelines from the American Society of Clinical Oncology (ASCO) recommend that full weight-based cytotoxic chemotherapy doses be used to treat obese patients with cancer, particularly when the goal of treatment is cure [61]. (See "Dosing of anticancer agents in adults", section on 'Dosing for overweight/obese patients'.)

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 chemotherapy was administered or not (but not the type of chemotherapy) [62]. 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 [63]. 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 chemotherapy 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 consideration 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 would be considered a candidate for aggressive therapy, including a potentially curative surgery. Specific elements of the surveillance strategy, and the frequency and duration of testing, including guidelines from several expert groups, are discussed in detail elsewhere. (See "Post-treatment surveillance after colorectal cancer treatment".)

Recommendations for secondary prevention (changes in diet, physical activity, and the use of aspirin and other nonsteroidal anti-inflammatory drugs [NSAIDs]) are also discussed elsewhere. (See "The roles of diet, physical activity, and body weight in cancer survivors" and "Adjunctive therapy for patients with resected early stage colorectal cancer: Diet, exercise, 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: Colorectal cancer treatment; metastatic cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Indications for adjuvant therapy – Older patients derive as much benefit from fluorouracil (FU)-based adjuvant chemotherapy as do younger patients, although the incremental benefit from oxaliplatin may be less. We routinely recommend adjuvant chemotherapy for fit older patients with stage III and high-risk stage II colon cancer (table 15), and we discuss the risks and benefits of chemotherapy 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 chemotherapy. (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 chemotherapy 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

•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 chemotherapy rather than FU/leucovorin (LV) or capecitabine monotherapy (Grade 2B). However, given the uncertainty as to the overall survival benefit for oxaliplatin-based regimens in older adults, a reasonable alternative is a fluoropyrimidine alone. (See 'Oxaliplatin-based regimens' above.)

•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 chemotherapy 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 13). Given the added risk of significant myelosuppression in older adults, an alternative is FOLFOX with omission of the FU bolus (ie, modified FOLFOX7 (table 16)). (See 'Choice of regimen' above and "Treatment protocols for small and large bowel cancer".)

If ambulatory infusion pump is not feasible, capecitabine plus oxaliplatin (CAPOX (table 17)) 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 renal function impairment. (See 'Capecitabine' above.)

•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 MMR, 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 14), rather than the original de Gramont schedule. (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 renal function impairment. (See 'Capecitabine' above.)

•We recommend not using bevacizumab (Grade 1A), cetuximab (Grade 1A), or an irinotecan-based regimen (Grade 1A) in the adjuvant setting for any age group. (See 'Irinotecan-based regimens, bevacizumab, and cetuximab' above.)

●Duration of therapy

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

•If an oxaliplatin-based regimen is chosen, the optimal duration is unclear. In our view, both three and six months of chemotherapy are reasonable options, although neurotoxicity rates are clearly higher with longer treatment and the decision must be individualized. (See 'Duration' above.)