ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Adjuvant therapy for resected stage III (node-positive) colon cancer

Adjuvant therapy for resected stage III (node-positive) colon cancer
Literature review current through: Jan 2024.
This topic last updated: Jan 23, 2023.

INTRODUCTION — For patients with locoregional colon cancer, including stage III (node-positive) disease, surgical resection is the only curative treatment. Outcome is 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 cover adjuvant therapy for patients with resected stage III colon cancer. Adjuvant therapy for stage II (node-negative) colon cancer; adjuvant therapy for colon cancer in older adult patients; the 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; surgical management and prognosis of colon cancer; chemotherapy after resection of colorectal cancer liver metastases; a compilation of protocols for treatment of colon cancer; and recommendations for post-treatment follow-up are discussed separately. (See "Adjuvant therapy for resected stage II colon cancer" and "Adjuvant therapy for resected colon cancer in older adult patients" and "Adjunctive therapy for patients with resected early stage colorectal cancer: Diet, exercise, NSAIDs, and vitamin D" and "Overview of the management of primary colon cancer" and "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy" and "Treatment protocols for small and large bowel cancer" and "Post-treatment surveillance after colorectal cancer treatment".)

RATIONALE AND ENDPOINTS TO DEFINE BENEFIT — 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. The goal of postoperative (adjuvant) therapy is to eradicate these micrometastases, thereby increasing the cure rate.

The benefits of adjuvant chemotherapy have been most clearly demonstrated in stage III (node-positive (table 1)) disease, in which fluoropyrimidine-based adjuvant chemotherapy provides an approximately 30 percent reduction in the risk of disease recurrence and a 22 to 32 percent reduction in mortality [2]; the added benefit from oxaliplatin, while likely to be significant, has not been quantified, since there are no trials directly comparing an oxaliplatin-containing adjuvant therapy regimen versus resection alone. By contrast, the benefit of adjuvant chemotherapy in stage II disease remains controversial.

Historically, the gold standard to define benefit from adjuvant therapy has been improvement in overall survival. However, disease-free survival (DFS; defined as the time from randomization to any event, irrespective of cause [3]) at three years appears to be an acceptable surrogate for five-year overall survival, especially for stage III disease [4-6]. Thus, three-year DFS is a widely accepted endpoint to define benefit from adjuvant therapy in colon cancer.

However, the duration of follow-up that is required to see DFS benefits translating into prolonged overall survival may be longer because of the prolongation in median survival that is associated with newer treatments for metastatic disease. (See "Systemic therapy for metastatic colorectal cancer: General principles", section on 'Available agents' and "Systemic therapy for metastatic colorectal cancer: General principles", section on 'Treatment goals'.)

Nonetheless, two- or three-year DFS is now accepted as a legitimate endpoint for treatment benefit, at least for stage III disease [7]. Significant improvements in three-year DFS formed the basis for the approval of adjuvant FOLFOX (oxaliplatin plus leucovorin and short-term infusional fluorouracil) in the United States. (See 'FOLFOX and the MOSAIC trial' below.)

TIMING OF ADJUVANT THERAPY — Adjuvant chemotherapy is typically started only after recovery from surgery. There is no agreement as to the optimal time to initiate adjuvant chemotherapy. Guidelines from the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) [8] do not explicitly state a time interval within which chemotherapy should commence, while updated guidelines from the European Society of Medical Oncology suggest that adjuvant therapy be initiated as soon as possible after surgery, and ideally no later than eight weeks [9]. Adjuvant colon cancer trials typically mandate initiation of chemotherapy within six to eight weeks of resection, and this has become an accepted approach.

In clinical practice, the interval between surgery and initiation of chemotherapy is often longer than eight weeks; the reasons are often multifactorial, but the dominant reason is delayed recovery from surgery [10-14]. A major advantage of laparoscopic as compared with open resection is its association with earlier initiation of adjuvant chemotherapy [15]. (See "Surgical resection of primary colon cancer", section on 'Open versus laparoscopic colectomy'.)

Other factors that may delay initiation of adjuvant therapy include inefficiencies in the health care system or shortages of resources to deliver care [16,17], and patient-related issues such as greater levels of comorbidity, lack of social support, and lower socioeconomic status [15].

Whether a delay in the administration of adjuvant therapy compromises outcomes is controversial. There are no randomized trials addressing this issue in patients with resected colon cancer. Several retrospective studies are available, most of which consist predominantly or exclusively of patients with stage III disease, and only one of which included patients receiving an oxaliplatin-based regimen [18]. In general, the data are conflicting. While several reports suggest worse overall and event-free survival with a delay beyond eight weeks [14,18-21], one suggests worse overall survival with a delay beyond 12 weeks [16], another suggests worse overall survival but no impact on event-free survival with a delay beyond 60 days [22], and two others suggest no significant impact on either disease-free or overall survival with a delay beyond 45 or 56 days [23,24]. In adjuvant therapy trials in which time between surgery and initiation of chemotherapy has been examined as a prognostic factor for outcome, delay beyond six to eight weeks has not been associated with inferior outcomes [25-27].

The adverse impact of delaying chemotherapy beyond eight weeks has been addressed in two meta-analyses:

One meta-analysis consisted of eight studies that compared outcomes among patients with colon or rectal cancer who had delayed chemotherapy and those who started within eight weeks of surgery [28]. A delay of chemotherapy beyond eight weeks was associated with a significantly higher risk of death (relative risk 1.20, 95% CI 1.15-1.26), although relapse-free survival was not significantly affected. This suggests that most of the mortality was from surgery-related complications and was not cancer related.

The second meta-analysis included 10 studies (one randomized trial and nine cohort/population-based studies), totaling over 15,000 patients [29]. Delaying adjuvant chemotherapy beyond 12 weeks after surgery was associated with a significant increase in mortality (hazard ratio [HR] for death 1.14, 95% CI 1.10-1.17) and disease relapse (HR 1.14, 95% CI 1.10-1.18).

These data support the conclusion that adjuvant chemotherapy should be started within eight weeks of surgery if at all possible. A delay beyond two months may compromise the effectiveness of chemotherapy, but it is not clear whether there is any cutoff point beyond which the benefits of adjuvant chemotherapy are lost. At least some data point toward a persistent benefit of adjuvant chemotherapy even if treatment is delayed beyond 24 weeks postresection, although the magnitude is less than if treatment had been administered within eight weeks of resection [24].

Importantly, both of the meta-analyses included only trials of adjuvant fluoropyrimidine-based chemotherapy. Whether this recommendation applies to oxaliplatin-based regimens (which are preferred for most patients with stage III tumors) is unclear. (See 'Oxaliplatin-based therapy' below.)

This issue was addressed in a population-based analysis of 635 patients with stage III colon cancer, derived from the database of the British Columbia Cancer Agency, who initiated adjuvant chemotherapy with fluorouracil or capecitabine plus oxaliplatin between 2006 and 2011 [30]. The median time from surgery to initiation of adjuvant chemotherapy was 8.3 weeks. At a median follow-up of 57.9 months, five-year relapse-free survival was 70.9 percent for those patients who initiated adjuvant chemotherapy within eight weeks and 72.1 percent for those who started after eight weeks.

Despite these data, we still suggest that adjuvant chemotherapy be started within eight weeks of surgery if at all possible.

SYSTEMIC CHEMOTHERAPY

Oxaliplatin-based therapy — We recommend an oxaliplatin-based regimen, rather than a fluoropyrimidine-based regimen alone, for fit patients with resected stage III disease who are younger than age 70 and likely to tolerate oxaliplatin, and for those whose tumors are mismatch repair enzyme deficient (dMMR) or microsatellite unstable. The survival benefit of adding oxaliplatin to adjuvant fluoropyrimidines in patients with resected stage III colon cancer has been shown in multiple randomized trials, and benefit appears to be evident across diverse practice settings and patient subgroups. However, the benefits of an oxaliplatin- over a non-oxaliplatin-containing regimen are less well established in individuals 70 and over. In the setting of a dMMR colon cancer, fluoropyrimidines alone are ineffective for adjuvant therapy. (See "Adjuvant therapy for resected colon cancer in older adult patients", section on 'Oxaliplatin-based regimens' and 'Patients with deficient mismatch repair' below.)

Choice of regimen — FOLFOX (oxaliplatin plus leucovorin [LV] and short-term infusional fluorouracil [FU] (table 2)) is a widely accepted standard regimen for resected stage III colon cancer, and it represents our preferred regimen when six months of adjuvant therapy is chosen. Oxaliplatin plus oral capecitabine (CAPOX, also known as XELOX (table 3)) may be more toxic, but it may be selected over FOLFOX if a shorter course of adjuvant therapy (eg, three months) is chosen or if an ambulatory infusion pump is not feasible. An important point is that the decision to use CAPOX may not eliminate the need for a central line. A significant number of patients report local pain when oxaliplatin is infused via a peripheral vein, and many centers routinely infuse the drug via a central line. (See 'Duration of therapy' below and "Treatment protocols for small and large bowel cancer".)

Benefits — Oxaliplatin is the only platinum-type drug with activity in colorectal cancer; it is used only in combination with a fluoropyrimidine. The survival benefit of adding oxaliplatin to adjuvant fluoropyrimidine-based therapy after resection of node-positive colon cancer has been demonstrated in randomized trials (which have typically enrolled younger, healthier, and less racially diverse patients) and is supported by a combined analysis of data from five randomized trials [31] and a large analysis of five observational cohorts of patients treated at the community level in diverse practice settings, including older and minority patients and those with higher levels of comorbidity [32]. (See "Adjuvant therapy for resected colon cancer in older adult patients", section on 'Oxaliplatin-based regimens'.)

FOLFOX and the MOSAIC trial — Benefit for adding oxaliplatin to FU/LV was first suggested in the MOSAIC trial, which randomly assigned 2246 patients with resected stage II (40 percent) or III colon cancer to a six-month course of one of the following [33,34]:

The original de Gramont regimen (LV 200 mg/m2 as a two-hour infusion, followed by bolus FU 400 mg/m2 and then a 22-hour infusion of FU 600 mg/m2 on days 1 and 2 every two weeks).

The same regimen of FU/LV plus oxaliplatin (85 mg/m2 on day 1 every 14 days, a regimen termed FOLFOX4).

At a median follow-up of 82 months, five-year disease-free survival (DFS; the primary endpoint) was significantly higher with FOLFOX (73 versus 67 percent, HR 0.80) [34]. Six-year overall survival rates were significantly higher, both in the entire group (79 versus 76 percent, HR 0.84, p = 0.046) and in those with stage III (73 versus 69 percent, HR 0.80, p = 0.023), but not stage II, disease. The survival benefit of oxaliplatin was maintained with long-term follow-up in those with stage III disease (10-year overall survival 67 versus 59 percent, HR 0.80, p = 0.016) [35].

Febrile neutropenia (1.8 versus 0.2 percent) and grade 3 or 4 diarrhea (10.8 versus 6.6 percent) were more common with FOLFOX [33]. Although some form of peripheral neuropathy developed in 92 percent of patients receiving FOLFOX, it was severe (grade 3) in only 13 percent and generally reversible. By 48 months, grade 1, 2, or 3 neuropathy was observed in 12, 3, and 0.7 percent of patients, respectively [34]. (See "Overview of neurologic complications of platinum-based chemotherapy", section on 'Oxaliplatin'.)

Based largely on the MOSAIC trial results, oxaliplatin was approved, in combination with infusional FU/LV, for adjuvant therapy of completely resected stage III colon cancer in the United States. While FOLFOX4 was the regimen used in the adjuvant registration trial, many American oncologists use modified FOLFOX6 (table 2) because it does not require a day 2 bolus of LV. Modified FOLFOX7 (table 4) eliminates bolus FU completely and is less myelosuppressive. (See "Treatment protocols for small and large bowel cancer".)

FLOX and NSABP C-07 — Bolus weekly FU/LV plus oxaliplatin (FLOX) is a more toxic regimen than FOLFOX and is not preferred for most patients. However, based on a small retrospective review, FLOX may be an appropriate alternative for patients who develop fluoropyrimidine-related cardiotoxicity while receiving an infusional regimen such as FOLFOX.

Better outcomes with oxaliplatin compared with fluoropyrimidines alone were also reported in National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07, which randomly assigned 2407 patients with stage II (29 percent) or III colon cancer to three cycles of bolus weekly FU/LV (the Roswell Park Memorial Institute [RPMI] regimen) with or without oxaliplatin (85 mg/m2 on weeks 1, 3, and 5 of every eight-week cycle) [36]. With a median follow-up of eight years, five-year DFS significantly favored FLOX (69 versus 64 percent, HR 0.82) [37], but the difference in overall survival was not statistically significant (five-year survival 80 versus 78 percent, HR 0.88).

Toxicity was prominent in both groups. Hospitalization for diarrhea or dehydration was required in 51 patients receiving FLOX and in 28 patients in the control group (5.5 versus 3 percent, p = 0.08) [37]. While the risk of death within 60 days of starting treatment was 1.2 percent overall and similar in both groups, five deaths in the FLOX group were directly attributed to chemotherapy-induced enteropathy, versus one in the control group. Grade 3 or 4 vomiting (13 versus 9 percent) and grade 3 neurosensory toxicity (8.2 versus 0.2 percent) were also significantly more common with FLOX.

In our view, FLOX appears to be more toxic than combinations of oxaliplatin with infusional FU/LV (eg, FOLFOX), and it is not a preferred regimen. Furthermore, in the setting of metastatic disease, bolus regimens that are similar to FLOX have proven to be inferior to FOLFOX (eg, in the Three Regimens of Eloxatin Evaluation [TREE] trials [38]). (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'FOLFOX versus FOLFIRI'.)

For these reasons, we prefer FOLFOX over FLOX as long as ambulatory infusional therapy is feasible. Guidelines for adjuvant treatment of stage III colon cancer from the National Comprehensive Cancer Network (NCCN) [8] also state a preference for FOLFOX (or CAPOX) when an oxaliplatin-containing regimen is chosen. However, one potential setting in which FLOX may be an appropriate alternative is for patients who develop fluoropyrimidine-related cardiotoxicity while receiving an infusional regimen (such as FOLFOX or CAPOX). Limited data suggest that some patients may be able to safely resume therapy using a bolus FU-containing regimen (such as FLOX, (table 5)) if there are no other viable options [39]. (See "Fluoropyrimidine-associated cardiotoxicity: Incidence, clinical manifestations, mechanisms, and management", section on 'Adjuvant therapy colorectal cancer'.)

Capecitabine plus oxaliplatin — Orally active fluoropyrimidines, such as capecitabine, offer increased convenience. CAPOX (table 3) may be more toxic than FOLFOX, but it is the preferred regimen if a shorter course of adjuvant therapy (eg, three months) is chosen or if an ambulatory infusion pump is not feasible.

The combination of capecitabine (1000 mg/m2 twice daily for 14 days of every 21-day cycle) plus oxaliplatin (130 mg/m2 intravenously on day 1), a regimen termed XELOX, was directly compared with standard intravenous bolus FU/LV in a phase III trial involving 1886 patients with stage III colon cancer [40]. The control arm of FU/LV was either the Mayo (425 mg/m2 FU and 20 mg/m2 LV daily on days 1 to 5 once per month) or the RPMI regimen (FU and LV, each 500 mg/m2, weekly for six of every eight weeks) at the discretion of each center.

In the latest report, after a median follow-up of 74 months, DFS was significantly superior with XELOX than with bolus FU/LV (HR for DFS 0.80, 95% CI 0.69-0.93, seven-year DFS 63 versus 56 percent), as was overall survival (HR 0.83, 95% CI 0.70-0.99, seven-year overall survival 73 versus 67 percent) [41].

Overall, XELOX was associated with less grade 3 or 4 neutropenia (9 versus 16 percent), febrile neutropenia (<1 versus 4 percent), stomatitis (<1 versus 9 percent), and alopecia (4 versus 20 percent) but more neurotoxicity (78 percent [11 percent grade 3 or 4] versus 8 percent [<1 percent grade 3 or 4]), grade 3 hand-foot syndrome (5 versus <1 percent), and grade 3 or 4 thrombocytopenia (5 versus <1 percent) than bolus FU/LV [40,42]. Rates of grade 3 or 4 diarrhea and dehydration with XELOX were significantly higher in patients over the age of 65.

Additional support for the substitution of capecitabine for LV-modulated FU when used in combination with oxaliplatin comes from a pooled analysis of four randomized trials examining a variety of adjuvant strategies in patients with stage III colon cancer [43]. Combination therapy with oxaliplatin provided consistently improved outcomes irrespective of whether the fluoropyrimidine backbone was capecitabine or FU/LV.

Patients who are receiving a capecitabine-containing regimen for adjuvant treatment should probably not take proton pump inhibitors concurrently. Concerns have been raised that higher gastric pH levels may inhibit dissolution and absorption of capecitabine, adversely impacting efficacy [44,45].

Duration of therapy — The optimal duration of adjuvant oxaliplatin chemotherapy for patients with stage III colon cancer is evolving, and the following issues inform the decision:

Based on the MOSAIC and NSABP C-07 trials and an analysis of the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration (six separate randomized trials of six versus three months of adjuvant oxaliplatin-based therapy), we continue to suggest six months of therapy for individuals with high-risk cancers (T4N2 (table 1)). However, patients with high-risk cancers should be counseled about the small magnitude of improvement in five-year overall survival offered by an additional three months of therapy in the most recent analysis of the IDEA collaboration (74.1 versus 72 percent, absolute difference 2.1 percent, HR 1.08, 95% CI 0.95-1.19), which must be counterbalanced by the attendant increase in neuropathy. On the other hand, given the similar five-year overall survival for three versus six months of therapy (89.6 versus 88.9 percent, absolute difference 0.7 percent) and the significantly lower rates of oxaliplatin neuropathy seen in the IDEA analysis, we suggest limiting adjuvant therapy to three months in patients with low-risk disease (T1-3N1).

For patients who opt to continue treatment for six months in order to maximize benefit, clinicians should pay strict attention to the development of neuropathy symptoms. For patients who develop ≥grade 2 neuropathy, oxaliplatin can be eliminated after three months with continuation of the FU/LV or capecitabine alone to complete six months of treatment.

If three months of adjuvant oxaliplatin-based therapy is chosen, a subset analysis of the IDEA collaboration suggests that CAPOX/XELOX may be a better choice than FOLFOX (although this was not a randomized comparison in any of the six trials), and it avoids the need for an ambulatory infusion pump. Another option is three months of oxaliplatin plus a fluoropyrimidine followed by a fluoropyrimidine only to complete six months of therapy. (See 'Capecitabine plus oxaliplatin' above.)

These recommendations are consistent with a year 2019 Clinical Practice Guideline from the American Society of Clinical Oncology (ASCO), which states that six months of adjuvant oxaliplatin-based chemotherapy should be offered to patients with stage III colon cancer who are at a higher risk of recurrence (T4 and/or N2), but that for lower risk patients, either three or six months of therapy may be offered [46]. The ASCO expert panel recommended a shared decision-making approach, taking into account patient characteristics, values, and preferences, and the potential for benefit and risks of harm associated with treatment duration. The guideline did not recommend one oxaliplatin-containing regimen over another for patients who choose three months of adjuvant therapy, but they noted that three months of treatment was inferior to six months among patients receiving FOLFOX but not CAPOX.

Our recommendations are also consistent with updated guidelines from the NCCN, which suggest three months of CAPOX or three to six months of FOLFOX for low-risk stage III disease, and three to six months of CAPOX or six months of FOLFOX for high-risk stage III disease [8].

Three versus six months — Six months of oxaliplatin-based chemotherapy has been the standard of care for adjuvant treatment of stage III colon cancer. However, given the cumulative and dose-limiting peripheral neuropathy associated with oxaliplatin (13 percent grade 3 neuropathy with six months of FOLFOX in the MOSAIC trial [34]), a shorter duration of therapy might be advantageous if equally effective. (See 'FOLFOX and the MOSAIC trial' above.)

IDEA analysis – Three versus six months of oxaliplatin-based adjuvant therapy was compared in six international concurrently conducted randomized trials, outlined in the table (table 6); five of the individual trials have been published [47-52]. All of the trials and the pooled analysis were powered for noninferiority of three as compared with six months of chemotherapy, with the choice of CAPOX or FOLFOX chosen by the individual clinicians. In the pooled analysis, the upper limit of the noninferiority margin was arbitrarily set to no more than a 12 percent relative risk increase in disease recurrence (ie, HR for the upper 95% CI less than 1.12), corresponding to a worsening of three-year DFS of 2.7 percentage points.

In the initial combined analysis of 12,834 patients with resected stage III colon cancer enrolled in all six trials, there was a marginal 0.9 percent decrease on three-year DFS with three versus six months of CAPOX or FOLFOX (HR 1.07, 95% CI 1.00-1.15). However, the upper limit of the HR CI exceeded the predefined margin of 1.12, and the trial failed to meet statistical assumptions for inferiority of three months of treatment [53].

Other findings included the following:

Among individuals with high-risk cancers (T4N2 (table 1)), six months of therapy was superior, with an absolute increase in three-year DFS of 1.7 percent (HR 1.12, 95% CI 1.03-1.23). By contrast, for patients with low-risk cancers (T1-3N1), three-year DFS was 83.1 and 83.3 percent for three and six months of treatment, respectively, and this met the criteria for noninferiority (HR 1.01, 95% CI 0.90-1.12).

In a preplanned subgroup analysis, noninferiority of three versus six months of therapy was supported for patients receiving the CAPOX regimen but not FOLFOX.

The risk of grade 2 or higher neuropathy was markedly diminished in the three-month group (16.6 percent FOLFOX, 14.2 percent CAPOX) compared with the six-month group (47.7 percent FOLFOX, 44.9 percent CAPOX).

A final analysis of these data with median follow-up of 72 months focused on overall survival [54]. The following were noted:

In the entire group, five-year overall survival was similar with three versus six months of therapy (82.4 versus 82.8 percent, absolute difference -0.4, HR 1.02, 95% CI 0.95-1.11), and the upper end of the 95% CI was exactly at the predefined overall survival margin of 1.11. Therefore, it could not be concluded that three months of oxaliplatin therapy was not noninferior to six months. For low-risk patients, the difference in five-year overall survival with three versus six months of treatment was 89.6 versus 88.9 percent (absolute difference +0.7 percent, HR 1.07, 95% CI 0.97-1.18), while for high-risk disease, five-year overall survival was 72 versus 74.1 percent, absolute difference -2.1 percent, HR 1.08, 95% CI 0.98-1.19). The authors concluded that while noninferiority could not be shown for three versus six months of treatment, the very small absolute difference in five-year overall survival supports the use of three months of adjuvant CAPOX for most patients with stage III colon cancer, given the substantial reduction of toxicities, inconveniences, and cost associated with a shorter treatment duration.

As was seen in the earlier analysis, there was a continued interaction between regimen and treatment duration:

-For patients treated with CAPOX, the results for both five-year overall survival and disease-free survival with three versus six months of therapy fell within the prespecified margins of noninferiority. However, further analysis of CAPOX-treated patients with low-risk versus high-risk disease revealed that these noninferiority margins were met only for the low-risk group and not for the high-risk group. Despite this, the absolute magnitude of difference for three versus six months of CAPOX in the high-risk group was only 1 percent in favor of six months of therapy (five-year overall survival 71.4 versus 72.4 percent).

-The results with FOLFOX were somewhat different, with a favorable five-year overall survival outcome for six versus three months of therapy both in the low-risk and high-risk groups. Although the overall survival benefit for longer therapy in the low-risk subgroups was not clinically relevant (five-year survival 89.1 versus 89.4 percent, absolute difference 0.3 percent), there was a more pronounced difference in the high-risk group favoring six months of therapy (five-year overall survival 72.5 versus 75.3 percent, absolute difference 2.8 percent).

Three months of oxaliplatin plus six months of fluoropyrimidine – Another option to mitigate treatment-related neurotoxicity is three months of oxaliplatin plus a fluoropyrimidine followed by three additional months of fluoropyrimidine alone. The benefit of this strategy over six months of oxaliplatin-containing therapy was addressed in a randomized trial in which 1788 patients (78 percent stage III, the remainder high-risk stage II) were assigned to oxaliplatin (three versus six months) with six months of fluoropyrimidine [55]. Among those with stage III disease, the choice of FOLFOX versus CAPOX was left to the clinician discretion; all patients with high-risk stage II disease received FOLFOX.

The trial was discontinued prematurely due to slow accrual. At a median follow-up of 78.7 months, three months of oxaliplatin was noninferior to six months (five-year DFS for six versus three months of oxaliplatin were 81.6 and 82.2 percent [HR 0.953, 95% CI 0.769-1.180, which was within the upper limit of the noninferiority limit, which was set at 1.25]). Neuropathy rates (any grade) were 69.5 versus 58.3 percent (p = 0.0001), though there were no significant differences in rate of ≥grade 3 neuropathy between the arms. Unpreplanned subgroup analysis suggested noninferiority for three versus six months of oxaliplatin among those receiving CAPOX (HR 0.713, 95% CI 0.530-0.959) but not FOLFOX (HR 1.102, 95% CI 0.847-1.435).

Patients who develop neuropathy during treatment — As noted above, if six months of oxaliplatin is chosen, clinicians should carefully monitor for neuropathy during treatment. For patients who develop ≥grade 2 neuropathy, oxaliplatin can be eliminated after three months with continuation of the FU/LV or capecitabine alone to complete six months of treatment. This approach does not appear to compromise oncologic outcomes. In a combined analysis of 10,444 patients participating in one of 11 adjuvant chemotherapy trials, early oxaliplatin discontinuation after three months did not impair disease-free or overall survival compared with those who received the full six months of therapy, but there was a detrimental impact on disease-free survival for administration of <50 percent of planned oxaliplatin doses [56].

Influence of tumor deposits — Extramural tumor deposits that are outside of lymph nodes appear to influence prognosis adversely, both in patients with and without lymph node metastases. (See "Pathology and prognostic determinants of colorectal cancer", section on 'Extramural non-nodal tumor deposits'.)

The possibility that these tumor deposits might influence decision-making on the duration of adjuvant chemotherapy in patients with stage III colon cancer was addressed in the phase III IDEA France trial (PRODIGE-ACCORD), which tested three versus six months of adjuvant oxaliplatin-containing chemotherapy [57]. In a posthoc analysis, 184 (9.5 percent) of the 1942 patients had tumor deposits, including approximately 8 percent of those with otherwise low-risk stage III tumors (ie, pT1-3 and pN1). In multivariate analysis, the presence of tumor deposits was associated with a significantly higher risk of both disease recurrence and death. Of 1454 pN1-staged patients, 35 (2.4 percent) were restaged to pN2 by the addition of tumor deposits to the lymph node metastasis count, and these patients had a lower three-year DFS rate than did those whose tumors remained pN1 despite the addition of tumor deposits to the positive node count (61 versus 79 percent), and the pN2-restaged patients had a similar DFS as did those whose tumors were initially staged pN2. These findings could potentially modify the optimal duration of chemotherapy in patients who are restaged to pN2 disease.

These data are derived from posthoc analysis, and as such, should be considered hypothesis generating. They need to be confirmed in prospective studies before it can be concluded that extramural tumor deposits should influence the duration of chemotherapy. However, given the growing data on the adverse prognostic influence of tumor deposits, we counsel patients on considering six rather than three months of adjuvant chemotherapy if there are >3 extramural non-nodal tumor deposits, but emphasize the uncertainty of benefit from three additional months of chemotherapy in this setting.

Less fit patients or a contraindication to oxaliplatin

Patients without deficient mismatch repair

Fluoropyrimidines alone — For patients under the age of 70 whose tumors lack high levels of microsatellite instability (MSI-H) or dMMR and who have a contraindication to oxaliplatin (eg, preexisting neuropathy) or are not considered fit enough to tolerate an oxaliplatin-containing regimen, treatment with a fluoropyrimidine alone is an acceptable option. However, outcomes may not be as favorable as with an oxaliplatin-based regimen. (See "Adjuvant therapy for resected colon cancer in older adult patients", section on 'Oxaliplatin-based regimens'.)

Choice of regimen — If a fluoropyrimidine alone is chosen, our preferred regimen is six months of short-term infusional FU/LV (the de Gramont regimen), capecitabine alone, or where available, uracil plus tegafur (UFT).

For patients with resected colon cancer who are going to receive FU-based adjuvant chemotherapy (ie, without oxaliplatin), the best adjuvant regimen is not conclusively established. Protracted infusional FU alone (three courses of 250 mg/m2 per day for 56 of every 63 days) and short-term infusional FU/LV (a modified de Gramont regimen is depicted in the table (table 7)) both provide oncologic outcomes that are at least as good and less toxic compared with bolus FU/LV regimens. However, it is unclear whether the added inconvenience and cost of a central venous line and ambulatory infusion pump are justified in patients who are to receive a non-oxaliplatin-based regimen. (See 'Infusional versus bolus fluorouracil' below.)

The oral fluoropyrimidines capecitabine and UFT are at least as effective as bolus FU plus LV, and these are acceptable options for fluoropyrimidine monotherapy. In Japanese patients, S-1 is at least as effective as UFT plus LV; however, it appears to be inferior to capecitabine monotherapy. (See 'Oral fluoropyrimidines' below.)

Importantly, reimbursement policies for oral cytotoxic agents, such as capecitabine, vary greatly between countries and even regionally within the United States. The higher out-of-pocket costs for capecitabine (particularly among patients covered by the United States Medicare program [58]) compared with intravenous FU-based regimens (which are typically covered by the third-party payer) must often be considered in choosing the best treatment for individual patients. (See 'Oral fluoropyrimidines' below.)

Bolus fluorouracil plus leucovorin — Preclinical data indicating a synergistic interaction between LV and FU prompted several trials of adjuvant FU/LV [59-65]. Both drugs together form a stable ternary complex with thymidylate synthetase, and this permits prolonged inhibition of the enzyme by FU [66].

Most American patients receive a racemic mixture of d,l-leucovorin (LV calcium), and this is the version that has been used in most reported clinical trials. However, the l isomer is the biologically active moiety, and an intravenous preparation of l-leucovorin is now commercially available in the United States (levoleucovorin, Fusilev). It is dosed at one-half that of LV calcium.

Three seminal trials established bolus FU/LV as a standard adjuvant regimen for resected stage III colon cancer [60-62,64].

The largest of these, the International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT), consisted of pooled data from 1526 patients with resected Dukes' B (node-negative) or C (node-positive) colon cancer who were enrolled in three independent trials in Italy, Canada, and France [61,62]. In all cases, patients were randomly assigned to observation or six cycles of monthly FU (375 to 400 mg/m2 daily) plus high-dose LV (200 mg daily), both administered on days 1 to 5. Treatment was associated with a significant 22 percent reduction in death (three-year overall survival 83 versus 78 percent) [62]. In subgroup analysis, benefit was almost entirely limited to node-positive disease.

The equivalence of low-dose and high-dose LV in combination with FU has been shown in multiple studies [65,67-69]. Subsequent studies have focused on infusional versus bolus FU schedules.

Infusional versus bolus fluorouracil — A lack of superiority but a more favorable side effect profile for continuous infusion FU over bolus FU plus LV has been shown in at least four trials [25,70-72]. As an example, the Pan-European Trials in Adjuvant Colon Cancer (PETACC) 02 trial directly compared 24 weeks of the Mayo regimen (low-dose bolus FU plus LV daily for five days) versus 24 weeks of high-dose infusional FU (given three different ways depending on geographic region) with or without LV [72]. At a median follow-up of 42 months, there were no differences in relapse-free or overall survival for the high-dose infusional versus bolus arms. Compared with bolus FU/LV, treatment with high-dose infusional FU caused less mucositis and neutropenia, similar rates of diarrhea, and more hand-foot syndrome. However, treatment-related toxicity differed according to the high-dose infusional FU schedule, and it was lowest with short-term infusional FU plus LV (the so-called de Gramont schedule, see below).

No trial has compared infusional FU with the better-tolerated RPMI regimen of weekly bolus FU/LV.

Short-term infusional fluorouracil/leucovorin – In the setting of metastatic disease, short-term infusional regimens of FU plus LV (the so-called de Gramont schedule) are associated with superior outcomes when compared with monthly bolus schedules of FU/LV. These are the FU/LV schedules that have been used in combination with oxaliplatin. (See 'FOLFOX and the MOSAIC trial' above.)

The better tolerability of the de Gramont schedule (the original protocol included LV 200 mg/m2 over two hours, followed by FU 400 mg/m2 bolus and then 600 mg/m2 over 22 hours, on two consecutive days every two weeks) versus monthly bolus FU plus high-dose LV (LV 200 mg/m2, followed by a 15-minute bolus injection of FU 400 mg/m2, both on days 1 to 5 every four weeks) was shown in a randomized trial of 905 patients with resected stage II (43 percent) or III colon cancer [26]. At a median follow-up of six years, there was no statistically significant difference in either DFS or overall survival, but neutropenia, diarrhea, and mucositis were all significantly less with the de Gramont schedule [73].

As with protracted infusional FU, these regimens require central venous access, and it is unclear whether the added inconvenience and cost are justified in patients who are to receive FU/LV alone (without oxaliplatin). Nevertheless, the more favorable toxicity profile of the de Gramont schedule over bolus FU plus LV makes it an attractive option, particularly for individuals with significant comorbidity.

Oral fluoropyrimidines — Orally active fluoropyrimidines, such as capecitabine and UFT, offer increased convenience and the possibility of an improved therapeutic ratio (at least with capecitabine) [74].

Capecitabine is absorbed intact through the intestinal wall and then converted into FU in three sequential enzymatic reactions. The final requisite enzyme, thymidine phosphorylase, is present at consistently higher levels in tumor compared with normal tissue, forming the basis for enhanced selectivity for tumor cells and better tolerability.

UFT is a 1:4 molar combination of tegafur (Ftorafur) with uracil. Uracil competitively inhibits the degradation of FU, resulting in sustained concentrations in both plasma and the tumor.

The benefit of oral fluoropyrimidines was addressed in a meta-analysis of individual data from five Japanese trials involving 5232 patients with resected stage I, II, or III colon cancer who were randomly assigned to adjuvant oral fluoropyrimidines (FU, UFT, or hexacarbamoyl FU) or observation [75]. In the aggregate, oral therapy reduced the risk of recurrence and death by 11 and 15 percent, respectively. However, the absolute survival benefit for patients with stage III disease was only 2.5 percent, a value that seems inferior to that achievable with modern parenteral FU-based regimens.

More recent trials suggest that the magnitude of benefit with either capecitabine or UFT is at least equivalent to that of intravenous bolus FU/LV.

Capecitabine – Two randomized trials have shown equivalence in DFS for six months of oral capecitabine compared with intravenous fluoropyrimidines [76,77]. The earlier trial, the European/Canadian Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) study, randomly assigned 1987 patients with resected stage III colon cancer to six months of capecitabine alone (1250 mg/m2 twice daily for 14 of every 21 days) or monthly bolus FU/LV (the Mayo regimen) [76]. The trial was statistically powered to demonstrate therapeutic equivalence, with DFS as the primary endpoint.

At a median follow-up of 3.8 years, capecitabine was at least as effective as FU/LV, and there was some suggestion of superiority in terms of three-year DFS (64 versus 61 percent, p = 0.05) and overall survival (81 versus 78 percent, p = 0.07) [76]. Despite the fact that one-half of all patients receiving capecitabine required dose reduction, the incidence of adverse effects was lower than with FU/LV, with the exception of hand-foot syndrome. (See "Toxic erythema of chemotherapy (hand-foot syndrome)", section on 'Hand-foot syndrome'.)

Largely based on these data, capecitabine was approved for adjuvant therapy of colon cancer in the United States. However, capecitabine should be used cautiously in older adult patients, particularly those with diminished creatinine clearance. Furthermore, a dose of 1250 mg/m2 twice daily is often poorly tolerated in American patients, although Europeans and Asians seem to be better able to tolerate this dose [78]. (See "Adjuvant therapy for resected colon cancer in older adult patients" and "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Capecitabine'.)

In some cases, patients may be considered for crossover from an FU/LV-based adjuvant regimen to capecitabine. However, at least some data suggest that both the incidence and severity of capecitabine-associated toxicity are substantially higher when it is given after FU/LV [79]. The mechanism underlying this sequence-specific exacerbation of toxicity is unclear.

Whether longer duration of capecitabine is associated with better outcomes is uncertain. A Japanese phase III trial in which 1306 patients with curatively resected stage III colon cancer were randomly assigned to 6 versus 12 months of capecitabine monotherapy (2500 mg/m2 per day for 14 of every 21 days) failed to show a significant benefit for longer therapy in the primary endpoint (DFS, defined as survival without the occurrence of a secondary cancer, recurrence, or death due to any cause). Five-year DFS for 12 versus 6 months of treatment was 69 versus 65 percent (HR 0.858, 95% CI 0.732-1.004). However, 12 months of treatment was associated with modestly better five-year relapse-free survival (74 versus 69 percent, HR 0.796, 95% CI 0.670-0.945) and overall survival (88 versus 83 percent, HR 0.727, 95% CI 0.575-0.919). The optimal duration of adjuvant oral capecitabine requires further investigation.

Patients who are receiving a capecitabine-containing regimen for adjuvant treatment should probably not take proton pump inhibitors concurrently. Concerns have been raised that higher gastric pH levels may inhibit dissolution and absorption of capecitabine, adversely impacting efficacy [44,45].

UFT and S-1 – Six months of UFT plus LV is a standard approach for adjuvant chemotherapy of stage III colon cancer in Japan [80-82]. The comparative efficacy of UFT plus LV compared with parenteral FU/LV was shown in non-Asian populations in the NSABP C-06 trial, in which 1608 patients with resected stage II or III colon cancer were randomly assigned to bolus weekly FU with high-dose LV (for 24 weeks rather than the usual 32 weeks) or UFT plus oral LV (five 35-day cycles) [83]. There were no significant differences in the five-year rates of DFS (68 versus 67 percent for UFT and FU/LV, respectively) or overall survival (79 percent in both groups). A similar conclusion was reached in a smaller Japanese phase III trial conducted only in patients with stage III disease [81].

Although UFT is widely available in Europe and Asia, it is not available in the United States.

S-1 is an oral fluoropyrimidine that includes three different agents: tegafur (Ftorafur), gimeracil (5-chloro-2,4-dihydropyridine, a potent inhibitor of DPD [dihydropyrimidine dehydrogenase]), and oteracil (potassium oxonate, which inhibits phosphorylation of intestinal FU, thought responsible for treatment-related diarrhea). It is approved in Japan for adjuvant treatment of gastric cancer and in Europe for treatment of advanced gastric cancer; it is not available in the United States.

The data on utility of S-1 for adjuvant treatment of stage III colon cancer are mixed:

S-1 (80, 100, or 120 mg daily, depending on body surface area [BSA], for 28 of every 42 days) was directly compared with UFT plus LV (UFT 300 to 600 mg per day according to BSA plus LV 75 mg per day, both daily for 28 of every 35 days) in a Japanese trial of 1535 patients with resected stage III colon cancer [84]. S-1 was found to be noninferior to UFT/LV (HR for DFS 0.85, 95% CI 0.70-1.03), and adverse event rates were comparable.

On the other hand, S-1 was inferior to capecitabine monotherapy in the noninferiority multicenter randomized Japan Clinical Oncology Group (JCOG) 0910 trial [85]. With a median follow-up of 24 months, three-year DFS was 82 percent with capecitabine compared with 77.9 percent with S-1 (HR 1.23, 95% CI 0.89-1.70), and the upper limit of the 95% CI was greater than the set inferiority margin (1.24).

Until further data are available, S-1 should not be considered an acceptable option for adjuvant treatment of stage III colon cancer when a fluoropyrimidine alone is indicated.

Duration of therapy — For patients receiving adjuvant therapy with a fluoropyrimidine alone, a six-month duration remains the standard approach.

The following studies inform the optimal duration of adjuvant chemotherapy when fluoropyrimidines alone are used:

At least three randomized trials have shown no added benefit from 12 as compared with 6 to 8 months of FU/LV-containing adjuvant chemotherapy [65,67,69].

A Cochrane review of studies evaluating shorter (three to six months) versus longer (9 to 12 months) duration of adjuvant chemotherapy concluded that a shorter duration of FU/LV chemotherapy was not associated with inferior relapse-free or overall survival [86], and that adjuvant chemotherapy should not last longer than six months.

No trial has directly compared three versus six months of adjuvant fluoropyrimidines alone. A meta-analysis of four nonrandomized trials totaling 2290 patients concluded that the standard six-month regimen was associated with significantly better survival (HR 0.59, 95% CI 0.52-0.68) [87]. Notably, in these reports, patients who received a shorter duration of adjuvant chemotherapy were probably sicker, and this could have accounted for the apparent better outcomes with a full six months of therapy.

Patients with deficient mismatch repair — For patients who have tumors with MSI-H or dMMR, we suggest not using fluoropyrimidines alone. If adjuvant chemotherapy is needed, an oxaliplatin-based regimen should be at least attempted.

Approximately 5 to 15 percent of colorectal cancers have sporadic or inherited (Lynch syndrome) deficiency of a mismatch repair protein, 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' and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis".)

Most studies support the view that dMMR colon cancers are resistant to fluoropyrimidine chemotherapy [76,88-95]. Despite the lack of data from prospective randomized trials, data from nonrandomized trials as well as the ACCENT pooled analysis of data from a subset of patients enrolled in 12 colon cancer adjuvant therapy trials are fairly compelling as to the retained efficacy of oxaliplatin-based chemotherapy in these patients, particularly for stage III colon cancer [94-96]. However, given that fluoropyrimidines alone are often considered in those with stage III disease who are deemed unlikely to tolerate an oxaliplatin-based regimen, the decision to pursue oxaliplatin must be carefully considered. One option is to start with half-dose oxaliplatin (as was done in the FOCUS2 trial conducted in patients with metastatic disease [97]) and dose escalate as tolerated.

The impact of mismatch repair status on adjuvant therapy decision making for stage II disease is discussed in detail elsewhere. (See "Adjuvant therapy for resected stage II colon cancer".)

MSI-H/dMMR may also indicate the presence of Lynch syndrome, an inherited condition that predisposes to several cancers in addition to colorectal cancer. Although over 90 percent of Lynch syndrome-related colorectal cancers will demonstrate microsatellite instability, 15 percent of sporadic colorectal cancers also are MSI-H. Thus, the finding of MSI-H in a colorectal cancer is not specific for Lynch syndrome. An algorithm to guide the need to refer for germline genetic assessment for Lynch syndrome in the setting of an MSI-H/dMMR colorectal cancer is provided (algorithm 1), and this subject is discussed in detail elsewhere. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Tumor characteristics'.)

Regimens that are not recommended — Adjuvant irinotecan-, bevacizumab-, and cetuximab-containing regimens cannot be considered a standard approach for patients requiring adjuvant chemotherapy for colon cancer.

Irinotecan — Adjuvant irinotecan-containing chemotherapy has been studied in three separate trials, all of which demonstrate no benefit for either bolus or infusional irinotecan-containing chemotherapy compared with a fluoropyrimidine alone [98-100].

Bevacizumab — Bevacizumab (Avastin) is a humanized monoclonal antibody targeting the vascular endothelial growth factor (VEGF), which is a dominant factor controlling tumor-associated angiogenesis. Adding bevacizumab to regimens containing FU/LV plus irinotecan or oxaliplatin improves outcomes among patients with metastatic colorectal cancer, albeit at the cost of treatment-related side effects (bleeding, hypertension, bowel perforation, and thromboembolic events). (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Efficacy and toxicity of bevacizumab and biosimilars' and "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Adverse effects'.)

Two trials failed to demonstrate benefit from the addition of bevacizumab to FOLFOX compared with FOLFOX alone [101,102], one of which suggested there might even be a detrimental impact of adding bevacizumab [102]. A third trial, the QUASAR2 trial, also reported no benefit for bevacizumab when added to capecitabine for adjuvant treatment of patients with high-risk stage II and III colorectal cancer [103].

Cetuximab — Cetuximab is a mouse/human chimeric monoclonal antibody that targets the epidermal growth factor receptor (EGFR); the benefit of this drug in metastatic colorectal cancer is limited to patients whose tumors do not have a mutation in one of the RAS or BRAF genes (ie, wild-type RAS/BRAF). (See "Systemic therapy for metastatic colorectal cancer: General principles", section on 'RAS'.)

A lack of benefit from cetuximab in the adjuvant setting was shown in the N0147 trial, in which patients with resected stage III colon cancer (1760 of whom had wild-type KRAS and 658 of whom had KRAS mutant tumors) were randomly assigned to FOLFOX with or without cetuximab [104]. The trial was closed prematurely after it was determined in an interim analysis that no group of patients benefited from cetuximab. A lack of benefit from adjuvant cetuximab added to FOLFOX in patients selected for wild-type RAS and BRAF stage III colon cancer was also noted in the European PETACC8 trial [105].

Celecoxib — A benefit for adding the COX-2 inhibitor celecoxib to standard adjuvant FOLFOX chemotherapy in patients with stage III colon cancer could not be shown in the CALGB/SWOG 80702 trial [106].

Chemotherapy dosing in obese patients — Full weight-based doses of chemotherapy should be used to treat obese patients in the setting of adjuvant chemotherapy.

For cancer patients with a large 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, obese patients who are given reduced doses may have inferior outcomes [107,108]. Thus, although limited, the available data do not support the policy of routine dose reduction (or capping the maximal BSA to 2 m2) for obese patients with colon cancer. Guidelines from 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 [109]. (See "Dosing of anticancer agents in adults", section on 'Dosing for overweight/obese patients'.)

Tools to aid in decision making for adjuvant therapy

Web-based tools — Web-based tools have been developed to assist in risk stratification and counseling about adjuvant therapy by permitting the clinician to calculate the relative risk of disease recurrence and mortality based on clinicopathologic and other features, and the relative benefit to be gained by adjuvant chemotherapy. While some of these tools can assist in estimating the potential benefit of FU-based versus oxaliplatin-containing adjuvant therapy, in our opinion, these tools are best used as a rough guide to explain the degree of absolute benefit that may be achieved by receipt of adjuvant chemotherapy rather than as a tool to estimate the potential benefit of specific regimens. Unfortunately, many (including Adjuvant! Online and the Mayo Clinic Adjuvant Colon Cancer End Points [ACCENT] database calculator) are no longer available online.

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) [110]. The nomogram, which was revised in 2019 [111], and has been independently validated [112-114], 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 [115].

Other web-based nomograms are available to assist in estimating prognosis based on clinicopathologic variables, but they do not incorporate use of different adjuvant chemotherapy regimens. These are discussed elsewhere. (See "Overview of the management of primary colon cancer", section on 'Prognosis'.)

Molecular markers and genomic profiling — Efforts are underway to improve prognostication in stage III colon cancer beyond that achieved by the tumor, node, metastasis (TNM) staging system. As examples:

Early data suggest that analysis of molecular and clinical prognostic factors might permit the identification of patients with stage III disease whose outcomes are more similar to those of patients with stage II disease [116]. Whether such patients can safely forego adjuvant chemotherapy, however, is a hypothesis that has not been tested. Until further data are available, we consider adjuvant therapy appropriate for all patients with resected stage III colon cancer.

Investigators at Memorial Sloan Kettering Cancer Center have revised their published prognostic nomogram for determining the likelihood of postoperative recurrence in resected stage I to III colon cancer that includes molecular (microsatellite instability) and unique clinicopathologic features, such as the presence of tumor infiltrating lymphocytes [117]. Validation in independent datasets is needed.

A report based on data from NSABP C-07 suggests that genomic profiling through use of the Oncotype DX colon cancer assay may improve risk prognostication in stage III disease and better pinpoint the absolute level of benefit achieved by the addition of oxaliplatin in these patients [118]. There was a higher absolute oxaliplatin benefit obtained at high Recurrence Score values (figure 2). However, even among the patients with the highest risk, stage IIIC (table 1) disease, the absolute difference in recurrence risk at five years from the addition of oxaliplatin with a low Recurrence Score (FU treated 41 percent, 95% CI 28-57 percent, versus oxaliplatin treated 38 percent, 95% CI 23-58 percent) versus a high Recurrence Score (FU treated 67 percent, 95% CI 52-82 percent, versus oxaliplatin treated 59 percent, 95% CI 42-76 percent) was small. Furthermore, the estimates are rather imprecise and may not be clinically meaningful.

Newer data suggest that analysis of circulating tumor DNA (ctDNA) after surgery might be a promising prognostic marker for stage III colon cancer, and that its persistence following adjuvant chemotherapy might identify a patient subset at high risk for disease recurrence despite completing standard adjuvant therapy [119,120]. These data require independent validation and prospective study evaluating whether ctDNA provides for earlier diagnosis of recurrence than conventional components of the post-treatment surveillance strategy (the phase III DYNAMIC III study is underway), as well as whether and how the persistence of ctDNA after adjuvant therapy might inform decisions about additional therapy. (See "Post-treatment surveillance after colorectal cancer treatment".)

REGIONAL CHEMOTHERAPY — The benefit of regional treatment approaches is not yet established in the adjuvant setting, and none of these approaches can be considered a standard treatment option for resected colon cancer outside of a clinical trial.

Liver-directed therapy – The liver is the dominant site of recurrence in one-half of patients undergoing potentially curative colon cancer resection. Several trials have studied prophylactic portal vein infusion (PVI) therapy or hepatic intraarterial infusion of fluoropyrimidines following resection of localized colon cancer, with most showing no benefit from this approach [121-125]. A meta-analysis concluded that, compared with no adjuvant treatment, the absolute survival benefit associated with PVI chemotherapy was 5 percent and not statistically significant [121].

Regional intraportal therapy – Others have explored the benefit of adding a single dose of intraportal chemotherapy (fluorodeoxyuridine and oxaliplatin, administered intraoperatively into a regional vein based on the location of the colonic tumor) to systemic oxaliplatin-based chemotherapy for patients with resected stage II or III colon cancer [126]. Although the group receiving intraportal therapy had significantly better three-year disease-free survival (85 versus 76 percent, p = 0.03) and a significantly lower rate of distant metastasis (13 versus 23 percent), this did not translate into significantly better three-year overall survival (hazard ratio [HR] for death 0.33, 95% CI 0.182-1.231). The wide CI from this small study allows for the possibility that the rate of death may in fact be higher with intraportal chemotherapy.

Intraperitoneal therapy – Others have explored administration of heated (hyperthermic) intraperitoneal chemotherapy (HIPEC) following resection of a locally advanced high-risk colonic cancer without overt peritoneal metastases in an effort to forestall the development of peritoneal metastases. In the randomized phase III HIPECT4 trial, 184 patients with resected T4NxM0 colon cancer were randomly assigned to surgery or surgery plus HIPEC, both followed by systemic adjuvant chemotherapy [127]. In a preliminary report presented at the 2022 ESMO Annual Congress, at a median follow-up duration of 36 months, the addition of HIPEC improved local control (three-year 97 versus 87 percent, p = 0.025), but no differences were observed in disease-free or overall survival.

Studies exploring the use of cytoreductive surgery and heated (hyperthermic) intraperitoneal chemotherapy (HIPEC) after resection of isolated peritoneal or ovarian metastases are addressed elsewhere. (See "Locoregional methods for management and palliation in patients who present with stage IV colorectal cancer", section on 'High-risk patients'.)

ADJUVANT RADIATION THERAPY — The role of adjuvant radiation therapy (RT) in patients with resected colon cancer is poorly defined. Despite the absence of data from randomized trials proving benefit, we offer adjuvant RT to the following subgroups of patients who have an estimated risk of local recurrence ≥30 percent: ascending or descending colon primary with either T4b disease or a positive resection margin.

Postoperative RT is not usually considered a routine component of care for completely resected colon cancer. This is in contrast to patients with rectal cancer, in whom effective adjuvant therapy for both transmural and node-positive disease includes RT. Local recurrence is more frequent with rectal cancer due to the local anatomy and the difficulty in obtaining adequate resection margins. (See "Adjuvant therapy for resected rectal adenocarcinoma in patients not receiving neoadjuvant therapy".)

However, in colon cancer, increasing tumor, node, metastasis (TNM) stage (table 1) predicts for local failure [128-130], as does anatomic location:

The ascending and descending colon are considered anatomically "immobile" structures. The anatomic constraints caused by the close proximity of these bowel segments to retroperitoneal tissues may preclude wide resection, increasing the risk of residual disease and local failure.

The midsigmoid and midtransverse colon are not fixed structures, and a wide margin in the mesentery is usually achievable. In the absence of adherence to local organs, local failure at these sites is uncommon.

Local failure rates for tumors arising in the cecum, hepatic and splenic flexure, or proximal and distal sigmoid vary depending on the amount of mesentery present, the extent of primary disease, and the adequacy of the radial margins.

Selected patients with colon cancer who are at high risk for local recurrence (ie, ascending or descending colon primary, positive resection margins, or T4b disease (table 1)) might potentially benefit from adjuvant RT; however, most of the supporting data come from uncontrolled reports.

Uncontrolled series — Retrospective single-institution series suggest that failure rates within the operative bed for high-risk patients after resection alone are at least 30 percent and that this risk can be reduced substantially by RT [129,131-134].

In the largest report, 171 patients underwent RT for completely resected high-risk colon cancer (T4 tumors; T3N+ disease at sites other than the midsigmoid colon, midtransverse colon, and cecum; and selected patients with high-risk T3N0 disease and a <1 cm radial margin) [132]. Concurrent chemoradiotherapy (mostly fluorouracil [FU] on days 1 to 3 during the first and last week of RT) was administered to 68 patients. The outcomes of this irradiated group were compared with those of a historical cohort of 395 patients of similar T and N stage who underwent surgery alone at the same institution.

Local failure rates in patients treated with RT for T4N0 and T4N+ disease were 7 and 28 percent, respectively; the corresponding values for patients undergoing surgery alone were 31 and 53 percent. Disease-free survival rates for T4N0 and T4N+ tumors in the irradiated group were 79 and 53 percent, compared with 63 and 38 percent, respectively, with surgery alone.

No significant outcome differences could be shown with RT in patients with T3N0 or T3N+ disease without perforation or fistula formation. However, many of these patients were referred for RT because of concerns about adequacy of resection, raising the possibility of selection bias. Nevertheless, the authors concluded that patients with T4 tumors, perforation/abscess formation, a fistula at the tumor site, or positive resection margins all benefited from postoperative RT.

On the other hand, a retrospective analysis of data from the National Cancer Database (NCDB) on over 23,000 patients with pathologic T4 or margin-positive colon cancer who were treated between 2004 and 2016 and who received multiagent adjuvant chemotherapy concluded that, while adjuvant RT was used infrequently (7 percent of the total), it was associated with improved survival in patients with both pathologic T4 disease and positive margins [135].

Intergroup trial — The only available trial, United States Intergroup 0130, randomly assigned 222 patients with adherence to or invasion of adjacent structures or T3N1-2 tumors of the ascending or descending colon (table 1) to FU/levamisole with or without adjuvant RT [136]. The trial was closed prior to the planned goal of 700 patients because of poor accrual.

There was no significant difference in five-year overall survival (62 versus 58 percent for chemotherapy versus chemoradiotherapy) between the two groups. There were 18 local recurrences in each arm. Because of the limited statistical power, no definitive conclusions can be drawn regarding the efficacy of postoperative RT from this trial.

ADJUNCTIVE THERAPY — The benefits of diet and exercise, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDS), vitamin D, and coffee consumption on cancer outcomes are discussed separately. (See "Adjunctive therapy for patients with resected early stage colorectal cancer: Diet, exercise, NSAIDs, and vitamin D".)

ISSUES FOR SURVIVORS — Recommendations for post-treatment cancer surveillance and issues of long-term survivors of colon cancer are discussed in detail elsewhere. (See "Post-treatment surveillance after colorectal cancer treatment" and "Approach to the long-term survivor of colorectal cancer".)

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

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

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

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

Beyond the Basics topics (see "Patient education: Colon and rectal cancer (Beyond the Basics)" and "Patient education: Colorectal cancer treatment; metastatic cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Goals and benefits

Following potentially curative resection of colon cancer, the goal of postoperative (adjuvant) therapy is to eradicate micrometastases, increasing the cure rate. (See 'Rationale and endpoints to define benefit' above.)

We recommend adjuvant systemic therapy after resection of stage III colon cancer (Grade 1A). If possible, chemotherapy should be initiated within six to eight weeks of surgery. (See 'Timing of adjuvant therapy' above.)

Full weight-based doses of chemotherapy should be used to treat obese patients in the adjuvant, potentially curative setting. (See 'Chemotherapy dosing in obese patients' above.)

Choice of regimen

Fit patients likely to tolerate oxaliplatin

-For fit patients younger than 70 who are likely to tolerate oxaliplatin, we recommend an oxaliplatin-based regimen rather than a regimen containing only fluorouracil (FU) plus leucovorin (LV) (Grade 1A). We also suggest an oxaliplatin-based regimen over capecitabine alone (Grade 2C). (See 'Oxaliplatin-based therapy' above.)

-When an oxaliplatin regimen is chosen, we prefer FOLFOX (oxaliplatin plus LV and short-term infusional FU) for most patients who choose six months of therapy. Most American oncologists use modified FOLFOX6 because it does not require the day 2 bolus of FU and LV (table 2). Another option is modified FOLFOX7 (table 4), which eliminates bolus FU completely and is less myelosuppressive. Bolus weekly FU/LV plus oxaliplatin (FLOX) is a more toxic regimen, and not preferred. (See 'Choice of regimen' above.)

Oxaliplatin plus oral capecitabine (CAPOX, also known as XELOX (table 3)) is a potentially more toxic alternative to FOLFOX but preferred if an ambulatory infusion pump is not feasible. In addition, if three months of adjuvant oxaliplatin-based therapy is chosen, we suggest CAPOX rather than FOLFOX for most patients (Grade 2C). Another option if three months of therapy is chosen, is three months of oxaliplatin plus a fluoropyrimidine followed by three additional months of a fluoropyrimidine alone. (See 'Duration of therapy' above.)

Patients receiving adjuvant capecitabine should avoid concomitant use of a proton pump inhibitor. (See 'Capecitabine plus oxaliplatin' above and 'Duration of therapy' above and "Treatment protocols for small and large bowel cancer".)

-For individuals with high-risk cancers (T4N2 (table 1)) we suggest six months of adjuvant therapy (Grade 2B). For most patients with lower risk disease, (T1-3, N1) we suggest limiting adjuvant therapy to three months (Grade 2B). (See 'Duration of therapy' above.)

However, for a patient with N1 disease, if there are >3 extramural non-nodal tumor deposits, we discuss the option of six rather than three months of adjuvant chemotherapy, emphasizing the uncertainty of benefit from three additional months of chemotherapy in this setting. (See 'Influence of tumor deposits' above.)

If six months of therapy is chosen, clinicians should closely monitor for neuropathy. Treatment can be stopped (particularly for low-risk patients) if neuropathy persists, or the oxaliplatin can be eliminated with continuation of the FU/LV or capecitabine alone to complete six months of treatment.

Patients who are not good oxaliplatin candidates

-For patients with preexisting neuropathy or who are considered unlikely to tolerate oxaliplatin who do not have deficient mismatch repair (dMMR), a fluoropyrimidine alone is an acceptable option, although outcomes may not be as favorable. (See 'Patients without deficient mismatch repair' above.)

If a fluoropyrimidine alone is chosen, our preferred regimens are six months of short-term infusional FU/LV (table 7), capecitabine, or where available, oral uracil plus tegafur (UFT) with or without LV. Until further data are available, S-1 should not be considered an acceptable option for adjuvant treatment of stage III colon cancer when a fluoropyrimidine alone is indicated. (See 'Fluoropyrimidines alone' above and "Treatment protocols for small and large bowel cancer".)

-For patients who have dMMR tumors, we suggest not using fluoropyrimidines alone (Grade 2C). However, given that many of these patients are deemed unlikely to tolerate an oxaliplatin-based regimen, decision making must be individualized. One option is to start with half-dose oxaliplatin and escalate as permitted by treatment-related toxicity. (See 'Patients with deficient mismatch repair' above.)

Role of other agents – We recommend against the use of a bevacizumab- (Grade 1A), cetuximab- (Grade 1B), or irinotecan-based regimen (Grade 1A) in the adjuvant setting. (See 'Regimens that are not recommended' above.)

Regional therapies

The benefit of regional treatment approaches is not yet established in the adjuvant setting, and none of these approaches can be considered a standard treatment option for resected colon cancer outside of a clinical trial. (See 'Regional chemotherapy' above.)

The evidence is inconclusive as to the benefit of adding radiation therapy (RT) to chemotherapy for patients at high risk for a local recurrence. We discuss the risks and benefits of adjuvant RT with patients with ascending or descending colon tumors and either T4b disease or a positive resection margins. (See 'Adjuvant radiation therapy' above.)

  1. AJCC Cancer Staging Manual, 7th ed, Edge SB, Byrd DR, Compton CC, et al (Eds), Springer, New York 2010. p.143.
  2. Sargent D, Sobrero A, Grothey A, et al. Evidence for cure by adjuvant therapy in colon cancer: observations based on individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol 2009; 27:872.
  3. Punt CJ, Buyse M, Köhne CH, et al. Endpoints in adjuvant treatment trials: a systematic review of the literature in colon cancer and proposed definitions for future trials. J Natl Cancer Inst 2007; 99:998.
  4. Sargent DJ, Patiyil S, Yothers G, et al. End points for colon cancer adjuvant trials: observations and recommendations based on individual patient data from 20,898 patients enrolled onto 18 randomized trials from the ACCENT Group. J Clin Oncol 2007; 25:4569.
  5. Shi Q, De Gramont A, Dixon JG, et al. Re-evaluating disease-free survival (DFS) as an endpoint versus overall survival (OS) in adjuvant colon cancer (CC) trials with chemotherapy +/- biologics: An updated surrogacy analysis based on 18,886 patients (pts) from the Accent database. J Clin Oncol 2019; 37S: ASCO #3502.
  6. Yin J, Salem ME, Dixon JG, et al. Reevaluating Disease-Free Survival as an Endpoint vs Overall Survival in Stage III Adjuvant Colon Cancer Trials. J Natl Cancer Inst 2022; 114:60.
  7. Sargent D, Shi Q, Yothers G, et al. Two or three year disease-free survival (DFS) as a primary end-point in stage III adjuvant colon cancer trials with fluoropyrimidines with or without oxaliplatin or irinotecan: data from 12,676 patients from MOSAIC, X-ACT, PETACC-3, C-06, C-07 and C89803. Eur J Cancer 2011; 47:990.
  8. NCCN Clinical Practice Guidelines in Oncology. Available at: https://www.nccn.org/professionals/physician_gls/default.aspx (Accessed on September 21, 2021).
  9. Argilés G, Tabernero J, Labianca R, et al. Localised colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2020; 31:1291.
  10. Bayraktar S, Bayraktar UD, Rocha-Lima CM. Timing of adjuvant and neoadjuvant therapy in colorectal cancers. Clin Colorectal Cancer 2010; 9:144.
  11. Gibbs P, Handolias D, McLaughlin S, et al. Single-institution experience of adjuvant 5-fluorouracil-based chemotherapy for stage III colon cancer. Intern Med J 2008; 38:265.
  12. Hendren S, Birkmeyer JD, Yin H, et al. Surgical complications are associated with omission of chemotherapy for stage III colorectal cancer. Dis Colon Rectum 2010; 53:1587.
  13. Merkow RP, Bentrem DJ, Mulcahy MF, et al. Effect of postoperative complications on adjuvant chemotherapy use for stage III colon cancer. Ann Surg 2013; 258:847.
  14. Bos AC, van Erning FN, van Gestel YR, et al. Timing of adjuvant chemotherapy and its relation to survival among patients with stage III colon cancer. Eur J Cancer 2015; 51:2553.
  15. Malietzis G, Mughal A, Currie AC, et al. Factors Implicated for Delay of Adjuvant Chemotherapy in Colorectal Cancer: A Meta-analysis of Observational Studies. Ann Surg Oncol 2015; 22:3793.
  16. Lima IS, Yasui Y, Scarfe A, Winget M. Association between receipt and timing of adjuvant chemotherapy and survival for patients with stage III colon cancer in Alberta, Canada. Cancer 2011; 117:3833.
  17. Wasserman DW, Boulos M, Hopman WM, et al. Reasons for Delay in Time to Initiation of Adjuvant Chemotherapy for Colon Cancer. J Oncol Pract 2015; 11:e28.
  18. Klein M, Azaquoun N, Jensen BV, Gögenur I. Improved survival with early adjuvant chemotherapy after colonic resection for stage III colonic cancer: A nationwide study. J Surg Oncol 2015; 112:538.
  19. Dahl O, Fluge Ø, Carlsen E, et al. Final results of a randomised phase III study on adjuvant chemotherapy with 5 FU and levamisol in colon and rectum cancer stage II and III by the Norwegian Gastrointestinal Cancer Group. Acta Oncol 2009; 48:368.
  20. Czaykowski PM, Gill S, Kennecke HF, et al. Adjuvant chemotherapy for stage III colon cancer: does timing matter? Dis Colon Rectum 2011; 54:1082.
  21. Kim YW, Choi EH, Kim BR, et al. The impact of delayed commencement of adjuvant chemotherapy (eight or more weeks) on survival in stage II and III colon cancer: a national population-based cohort study. Oncotarget 2017; 8:80061.
  22. Bayraktar UD, Chen E, Bayraktar S, et al. Does delay of adjuvant chemotherapy impact survival in patients with resected stage II and III colon adenocarcinoma? Cancer 2011; 117:2364.
  23. Ahmed S, Ahmad I, Zhu T, et al. Early discontinuation but not the timing of adjuvant therapy affects survival of patients with high-risk colorectal cancer: a population-based study. Dis Colon Rectum 2010; 53:1432.
  24. Turner MC, Farrow NE, Rhodin KE, et al. Delay in Adjuvant Chemotherapy and Survival Advantage in Stage III Colon Cancer. J Am Coll Surg 2018; 226:670.
  25. Chau I, Norman AR, Cunningham D, et al. A randomised comparison between 6 months of bolus fluorouracil/leucovorin and 12 weeks of protracted venous infusion fluorouracil as adjuvant treatment in colorectal cancer. Ann Oncol 2005; 16:549.
  26. André T, Quinaux E, Louvet C, et al. Phase III study comparing a semimonthly with a monthly regimen of fluorouracil and leucovorin as adjuvant treatment for stage II and III colon cancer patients: final results of GERCOR C96.1. J Clin Oncol 2007; 25:3732.
  27. Quasar Collaborative Group, Gray R, Barnwell J, et al. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet 2007; 370:2020.
  28. Des Guetz G, Nicolas P, Perret GY, et al. Does delaying adjuvant chemotherapy after curative surgery for colorectal cancer impair survival? A meta-analysis. Eur J Cancer 2010; 46:1049.
  29. Biagi JJ, Raphael MJ, Mackillop WJ, et al. Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer: a systematic review and meta-analysis. JAMA 2011; 305:2335.
  30. Peixoto RD, Kumar A, Speers C, et al. Effect of delay in adjuvant oxaliplatin-based chemotherapy for stage III colon cancer. Clin Colorectal Cancer 2015; 14:25.
  31. Shah MA, Renfro LA, Allegra CJ, et al. Impact of Patient Factors on Recurrence Risk and Time Dependency of Oxaliplatin Benefit in Patients With Colon Cancer: Analysis From Modern-Era Adjuvant Studies in the Adjuvant Colon Cancer End Points (ACCENT) Database. J Clin Oncol 2016; 34:843.
  32. Sanoff HK, Carpenter WR, Martin CF, et al. Comparative effectiveness of oxaliplatin vs non-oxaliplatin-containing adjuvant chemotherapy for stage III colon cancer. J Natl Cancer Inst 2012; 104:211.
  33. André T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004; 350:2343.
  34. André T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 2009; 27:3109.
  35. André T, de Gramont A, Vernerey D, et al. Adjuvant Fluorouracil, Leucovorin, and Oxaliplatin in Stage II to III Colon Cancer: Updated 10-Year Survival and Outcomes According to BRAF Mutation and Mismatch Repair Status of the MOSAIC Study. J Clin Oncol 2015; 33:4176.
  36. Yothers G, O'Connell MJ, Allegra CJ, et al. Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses. J Clin Oncol 2011; 29:3768.
  37. Kuebler JP, Wieand HS, O'Connell MJ, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol 2007; 25:2198.
  38. Hochster HS, Hart LL, Ramanathan RK, et al. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol 2008; 26:3523.
  39. Chakrabarti S, Sara J, Lobo R, et al. Bolus 5-fluorouracil (5-FU) In Combination With Oxaliplatin Is Safe and Well Tolerated in Patients Who Experienced Coronary Vasospasm With Infusional 5-FU or Capecitabine. Clin Colorectal Cancer 2019; 18:52.
  40. Haller DG, Tabernero J, Maroun J, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol 2011; 29:1465.
  41. Schmoll HJ, Tabernero J, Maroun J, et al. Capecitabine Plus Oxaliplatin Compared With Fluorouracil/Folinic Acid As Adjuvant Therapy for Stage III Colon Cancer: Final Results of the NO16968 Randomized Controlled Phase III Trial. J Clin Oncol 2015; 33:3733.
  42. Schmoll HJ, Cartwright T, Tabernero J, et al. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol 2007; 25:102.
  43. Schmoll HJ, Twelves C, Sun W, et al. Effect of adjuvant capecitabine or fluorouracil, with or without oxaliplatin, on survival outcomes in stage III colon cancer and the effect of oxaliplatin on post-relapse survival: a pooled analysis of individual patient data from four randomised controlled trials. Lancet Oncol 2014; 15:1481.
  44. Chu MP, Hecht JR, Slamon D, et al. Association of Proton Pump Inhibitors and Capecitabine Efficacy in Advanced Gastroesophageal Cancer: Secondary Analysis of the TRIO-013/LOGiC Randomized Clinical Trial. JAMA Oncol 2017; 3:767.
  45. Sun J, Ilich AI, Kim CA, et al. Concomitant Administration of Proton Pump Inhibitors and Capecitabine is Associated With Increased Recurrence Risk in Early Stage Colorectal Cancer Patients. Clin Colorectal Cancer 2016; 15:257.
  46. Lieu C, Kennedy EB, Bergsland E, et al. Duration of Oxaliplatin-Containing Adjuvant Therapy for Stage III Colon Cancer: ASCO Clinical Practice Guideline. J Clin Oncol 2019; 37:1436.
  47. Iveson TJ, Kerr RS, Saunders MP, et al. 3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial. Lancet Oncol 2018; 19:562.
  48. Sobrero A, Lonardi S, Rosati G, et al. FOLFOX or CAPOX in Stage II to III Colon Cancer: Efficacy Results of the Italian Three or Six Colon Adjuvant Trial. J Clin Oncol 2018; 36:1478.
  49. André T, Vernerey D, Mineur L, et al. Three Versus 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Patients With Stage III Colon Cancer: Disease-Free Survival Results From a Randomized, Open-Label, International Duration Evaluation of Adjuvant (IDEA) France, Phase III Trial. J Clin Oncol 2018; 36:1469.
  50. Yoshino T, Yamanaka T, Oki E, et al. Efficacy and Long-term Peripheral Sensory Neuropathy of 3 vs 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Colon Cancer: The ACHIEVE Phase 3 Randomized Clinical Trial. JAMA Oncol 2019; 5:1574.
  51. Souglakos J, Boukovinas I, Kakolyris S, et al. Three- versus six-month adjuvant FOLFOX or CAPOX for high-risk stage II and stage III colon cancer patients: the efficacy results of Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) project. Ann Oncol 2019; 30:1304.
  52. Yoshino T, Oki E, Misumi T, et al. Final Analysis of 3 Versus 6 Months of Adjuvant Oxaliplatin and Fluoropyrimidine-Based Therapy in Patients With Stage III Colon Cancer: The Randomized Phase III ACHIEVE Trial. J Clin Oncol 2022; 40:3419.
  53. Grothey A, Sobrero AF, Shields AF, et al. Duration of Adjuvant Chemotherapy for Stage III Colon Cancer. N Engl J Med 2018; 378:1177.
  54. André T, Meyerhardt J, Iveson T, et al. Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials. Lancet Oncol 2020; 21:1620.
  55. Kim ST, Kim SY, Lee J, et al. Oxaliplatin (3 months v 6 months) With 6 Months of Fluoropyrimidine as Adjuvant Therapy in Patients With Stage II/III Colon Cancer: KCSG CO09-07. J Clin Oncol 2022; 40:3868.
  56. Gallois C, Shi Q, Meyers JP, et al. Prognostic Impact of Early Treatment and Oxaliplatin Discontinuation in Patients With Stage III Colon Cancer: An ACCENT/IDEA Pooled Analysis of 11 Adjuvant Trials. J Clin Oncol 2023; 41:803.
  57. Delattre JF, Cohen R, Henriques J, et al. Prognostic Value of Tumor Deposits for Disease-Free Survival in Patients With Stage III Colon Cancer: A Post Hoc Analysis of the IDEA France Phase III Trial (PRODIGE-GERCOR). J Clin Oncol 2020; 38:1702.
  58. Weingart SN, Brown E, Bach PB, et al. NCCN Task Force Report: Oral chemotherapy. J Natl Compr Canc Netw 2008; 6 Suppl 3:S1.
  59. Wolmark N, Fisher B, Rockette H, et al. Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP protocol C-01. J Natl Cancer Inst 1988; 80:30.
  60. Wolmark N, Rockette H, Fisher B, et al. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol 1993; 11:1879.
  61. Zaniboni A, Labianca R, Marsoni S, et al. GIVIO-SITAC 01: A randomized trial of adjuvant 5-fluorouracil and folinic acid administered to patients with colon carcinoma--long term results and evaluation of the indicators of health-related quality of life. Gruppo Italiano Valutazione Interventi in Oncologia. Studio Italiano Terapia Adiuvante Colon. Cancer 1998; 82:2135.
  62. Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators. Lancet 1995; 345:939.
  63. Francini G, Petrioli R, Lorenzini L, et al. Folinic acid and 5-fluorouracil as adjuvant chemotherapy in colon cancer. Gastroenterology 1994; 106:899.
  64. O'Connell MJ, Mailliard JA, Kahn MJ, et al. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol 1997; 15:246.
  65. O'Connell MJ, Laurie JA, Kahn M, et al. Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer. J Clin Oncol 1998; 16:295.
  66. Pinedo HM, Peters GF. Fluorouracil: biochemistry and pharmacology. J Clin Oncol 1988; 6:1653.
  67. Haller DG, Catalano PJ, Macdonald JS, et al. Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol 2005; 23:8671.
  68. Comparison of fluorouracil with additional levamisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for colorectal cancer: a randomised trial. QUASAR Collaborative Group. Lancet 2000; 355:1588.
  69. Dencausse Y, Hartung G, Sturm J, et al. Adjuvant chemotherapy in stage III colon cancer with 5-fluorouracil and levamisole versus 5-fluorouracil and leucovorin. Onkologie 2002; 25:426.
  70. Poplin EA, Benedetti JK, Estes NC, et al. Phase III Southwest Oncology Group 9415/Intergroup 0153 randomized trial of fluorouracil, leucovorin, and levamisole versus fluorouracil continuous infusion and levamisole for adjuvant treatment of stage III and high-risk stage II colon cancer. J Clin Oncol 2005; 23:1819.
  71. Carrato A, Kohne C, Bedenne L, et al. Folinic acid modulated bolus 5-FU or infusional 5-FU for adjuvant treatment of patients of UICC stage III colon cancer: Preliminary analysis of the PETACC-2-study. J Clin Oncol 2006; 24S: ASCO #3563.
  72. Köhne CH, Bedenne L, Carrato A, et al. A randomised phase III intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III colon cancer: the Pan-European Trial in Adjuvant Colon Cancer 2 study. Eur J Cancer 2013; 49:1868.
  73. Andre T, Colin P, Louvet C, et al. Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial. J Clin Oncol 2003; 21:2896.
  74. Cassidy J, Douillard JY, Twelves C, et al. Pharmacoeconomic analysis of adjuvant oral capecitabine vs intravenous 5-FU/LV in Dukes' C colon cancer: the X-ACT trial. Br J Cancer 2006; 94:1122.
  75. Sakamoto J, Ohashi Y, Hamada C, et al. Efficacy of oral adjuvant therapy after resection of colorectal cancer: 5-year results from three randomized trials. J Clin Oncol 2004; 22:484.
  76. Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 2005; 352:2696.
  77. Pectasides D, Karavasilis V, Papaxoinis G, et al. Randomized phase III clinical trial comparing the combination of capecitabine and oxaliplatin (CAPOX) with the combination of 5-fluorouracil, leucovorin and oxaliplatin (modified FOLFOX6) as adjuvant therapy in patients with operated high-risk stage II or stage III colorectal cancer. BMC Cancer 2015; 15:384.
  78. Haller DG, Cassidy J, Clarke SJ, et al. Potential regional differences for the tolerability profiles of fluoropyrimidines. J Clin Oncol 2008; 26:2118.
  79. Hennig IM, Naik JD, Brown S, et al. Severe sequence-specific toxicity when capecitabine is given after Fluorouracil and leucovorin. J Clin Oncol 2008; 26:3411.
  80. Kim DJ, Kim TI, Suh JH, et al. Oral tegafur-uracil plus folinic acid versus intravenous 5-fluorouracil plus folinic acid as adjuvant chemotherapy of colon cancer. Yonsei Med J 2003; 44:665.
  81. Shimada Y, Hamaguchi T, Mizusawa J, et al. Randomised phase III trial of adjuvant chemotherapy with oral uracil and tegafur plus leucovorin versus intravenous fluorouracil and levofolinate in patients with stage III colorectal cancer who have undergone Japanese D2/D3 lymph node dissection: final results of JCOG0205. Eur J Cancer 2014; 50:2231.
  82. Sadahiro S, Tsuchiya T, Sasaki K, et al. Randomized phase III trial of treatment duration for oral uracil and tegafur plus leucovorin as adjuvant chemotherapy for patients with stage IIB/III colon cancer: final results of JFMC33-0502. Ann Oncol 2015; 26:2274.
  83. Lembersky BC, Wieand HS, Petrelli NJ, et al. Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06. J Clin Oncol 2006; 24:2059.
  84. Yoshida M, Ishiguro M, Ikejiri K, et al. S-1 as adjuvant chemotherapy for stage III colon cancer: a randomized phase III study (ACTS-CC trial). Ann Oncol 2014; 25:1743.
  85. Hamaguchi T, Shimada Y, Mizusawa J, et al. Capecitabine versus S-1 as adjuvant chemotherapy for patients with stage III colorectal cancer (JCOG0910): an open-label, non-inferiority, randomised, phase 3, multicentre trial. Lancet Gastroenterol Hepatol 2018; 3:47.
  86. Des Guetz G, Uzzan B, Morere JF, et al. Duration of adjuvant chemotherapy for patients with non-metastatic colorectal cancer. Cochrane Database Syst Rev 2010; :CD007046.
  87. Boyne DJ, Cuthbert CA, O'Sullivan DE, et al. Association Between Adjuvant Chemotherapy Duration and Survival Among Patients With Stage II and III Colon Cancer: A Systematic Review and Meta-analysis. JAMA Netw Open 2019; 2:e194154.
  88. Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 2003; 349:247.
  89. Carethers JM, Smith EJ, Behling CA, et al. Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer. Gastroenterology 2004; 126:394.
  90. Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 2005; 23:609.
  91. de Vos tot Nederveen Cappel WH, Meulenbeld HJ, Kleibeuker JH, et al. Survival after adjuvant 5-FU treatment for stage III colon cancer in hereditary nonpolyposis colorectal cancer. Int J Cancer 2004; 109:468.
  92. Lanza G, Gafà R, Santini A, et al. Immunohistochemical test for MLH1 and MSH2 expression predicts clinical outcome in stage II and III colorectal cancer patients. J Clin Oncol 2006; 24:2359.
  93. Jover R, Zapater P, Castells A, et al. Mismatch repair status in the prediction of benefit from adjuvant fluorouracil chemotherapy in colorectal cancer. Gut 2006; 55:848.
  94. Sargent DJ, Marsoni S, Monges G, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 2010; 28:3219.
  95. Tougeron D, Mouillet G, Trouilloud I, et al. Efficacy of Adjuvant Chemotherapy in Colon Cancer With Microsatellite Instability: A Large Multicenter AGEO Study. J Natl Cancer Inst 2016; 108.
  96. Cohen R, Taieb J, Fiskum J, et al. Microsatellite Instability in Patients With Stage III Colon Cancer Receiving Fluoropyrimidine With or Without Oxaliplatin: An ACCENT Pooled Analysis of 12 Adjuvant Trials. J Clin Oncol 2021; 39:642.
  97. Seymour MT, Thompson LC, Wasan HS, et al. Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial. Lancet 2011; 377:1749.
  98. Saltz LB, Niedzwiecki D, Hollis D, et al. Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803. J Clin Oncol 2007; 25:3456.
  99. Van Cutsem E, Labianca R, Bodoky G, et al. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol 2009; 27:3117.
  100. Ychou M, Raoul JL, Douillard JY, et al. A phase III randomised trial of LV5FU2 + irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802). Ann Oncol 2009; 20:674.
  101. Allegra CJ, Yothers G, O'Connell MJ, et al. Bevacizumab in stage II-III colon cancer: 5-year update of the National Surgical Adjuvant Breast and Bowel Project C-08 trial. J Clin Oncol 2013; 31:359.
  102. André T, Vernerey D, Im SA, et al. Bevacizumab as adjuvant treatment of colon cancer: updated results from the S-AVANT phase III study by the GERCOR Group. Ann Oncol 2020; 31:246.
  103. Kerr RS, Love S, Segelov E, et al. Adjuvant capecitabine plus bevacizumab versus capecitabine alone in patients with colorectal cancer (QUASAR 2): an open-label, randomised phase 3 trial. Lancet Oncol 2016; 17:1543.
  104. Alberts SR, Sargent DJ, Nair S, et al. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. JAMA 2012; 307:1383.
  105. Taieb J, Balogoun R, Le Malicot K, et al. Adjuvant FOLFOX +/- cetuximab in full RAS and BRAF wildtype stage III colon cancer patients. Ann Oncol 2017; 28:824.
  106. Meyerhardt JA, Shi Q, Fuchs CS, et al. Effect of Celecoxib vs Placebo Added to Standard Adjuvant Therapy on Disease-Free Survival Among Patients With Stage III Colon Cancer: The CALGB/SWOG 80702 (Alliance) Randomized Clinical Trial. JAMA 2021; 325:1277.
  107. Chambers P, Daniels SH, Thompson LC, Stephens RJ. Chemotherapy dose reductions in obese patients with colorectal cancer. Ann Oncol 2012; 23:748.
  108. Stocker G, Hacker UT, Fiteni F, et al. Clinical consequences of chemotherapy dose reduction in obese patients with stage III colon cancer: A retrospective analysis from the PETACC 3 study. Eur J Cancer 2018; 99:49.
  109. Griggs JJ, Bohlke K, Balaban EP, et al. Appropriate Systemic Therapy Dosing for Obese Adult Patients With Cancer: ASCO Guideline Update. J Clin Oncol 2021; 39:2037.
  110. Weiser MR, Landmann RG, Kattan MW, et al. Individualized prediction of colon cancer recurrence using a nomogram. J Clin Oncol 2008; 26:380.
  111. Konishi T, Shimada Y, Hsu M, et al. Contemporary Validation of a Nomogram Predicting Colon Cancer Recurrence, Revealing All-Stage Improved Outcomes. JNCI Cancer Spectr 2019; 3:pkz015.
  112. Collins IM, Kelleher F, Stuart C, et al. Clinical decision aids in colon cancer: a comparison of two predictive nomograms. Clin Colorectal Cancer 2012; 11:138.
  113. Kazem MA, Khan AU, Selvasekar CR. Validation of nomogram for disease free survival for colon cancer in UK population: A prospective cohort study. Int J Surg 2016; 27:58.
  114. Liu M, Qu H, Bu Z, et al. Validation of the Memorial Sloan-Kettering Cancer Center Nomogram to Predict Overall Survival After Curative Colectomy in a Chinese Colon Cancer Population. Ann Surg Oncol 2015; 22:3881.
  115. Jessup JM, Goldberg RM, Asare EA, et al. Colon and Rectum. In: AJCC Cancer Staging Manual, 8th ed, Amin MB (Ed), AJCC, Chicago 2017. p.251.
  116. Roth AD, Delorenzi M, Tejpar S, et al. Integrated analysis of molecular and clinical prognostic factors in stage II/III colon cancer. J Natl Cancer Inst 2012; 104:1635.
  117. Weiser MR, Hsu M, Bauer PS, et al. Clinical Calculator Based on Molecular and Clinicopathologic Characteristics Predicts Recurrence Following Resection of Stage I-III Colon Cancer. J Clin Oncol 2021; 39:911.
  118. Yothers G, O'Connell MJ, Lee M, et al. Validation of the 12-gene colon cancer recurrence score in NSABP C-07 as a predictor of recurrence in patients with stage II and III colon cancer treated with fluorouracil and leucovorin (FU/LV) and FU/LV plus oxaliplatin. J Clin Oncol 2013; 31:4512.
  119. Tie J, Cohen JD, Wang Y, et al. Circulating Tumor DNA Analyses as Markers of Recurrence Risk and Benefit of Adjuvant Therapy for Stage III Colon Cancer. JAMA Oncol 2019; 5:1710.
  120. Reinert T, Henriksen TV, Christensen E, et al. Analysis of Plasma Cell-Free DNA by Ultradeep Sequencing in Patients With Stages I to III Colorectal Cancer. JAMA Oncol 2019; 5:1124.
  121. Portal vein chemotherapy for colorectal cancer: a meta-analysis of 4000 patients in 10 studies. Liver Infusion Meta-analysis Group. J Natl Cancer Inst 1997; 89:497.
  122. Sadahiro S, Suzuki T, Ishikawa K, et al. Prophylactic hepatic arterial infusion chemotherapy for the prevention of liver metastasis in patients with colon carcinoma: a randomized control trial. Cancer 2004; 100:590.
  123. Wolmark N, Rockette H, Wickerham DL, et al. Adjuvant therapy of Dukes' A, B, and C adenocarcinoma of the colon with portal-vein fluorouracil hepatic infusion: preliminary results of National Surgical Adjuvant Breast and Bowel Project Protocol C-02. J Clin Oncol 1990; 8:1466.
  124. James RD, Donaldson D, Gray R, et al. Randomized clinical trial of adjuvant radiotherapy and 5-fluorouracil infusion in colorectal cancer (AXIS). Br J Surg 2003; 90:1200.
  125. Labianca R, Fossati R, Zaniboni A, et al. Randomized trial of intraportal and/or systemic adjuvant chemotherapy in patients with colon carcinoma. J Natl Cancer Inst 2004; 96:750.
  126. Chang W, Wei Y, Ren L, et al. Randomized Controlled Trial of Intraportal Chemotherapy Combined With Adjuvant Chemotherapy (mFOLFOX6) for Stage II and III Colon Cancer. Ann Surg 2016; 263:434.
  127. Arjona-Sanchez A, Cano-Osuna MT, Gutierrez A, et al. Adjuvant hyperthermic intraperitoneal chemotherapy in locally advanced colon cancer (HIPECT4): A randomized phase III study (abstracat 314O). Annals of Oncology (2022) 33 (suppl_7): S136-S196. 10.1016/annonc/annonc1048. Abstract available online at https://oncologypro.esmo.org/meeting-resources/esmo-congress/adjuvant-hyperthermic-intraperitoneal-chemotherapy-in-locally-advanced-colon-cancer-hipect4-a-randomized-phase-iii-study (Accessed on October 04, 2022).
  128. Mendenhall WM, Amos EH, Rout WR, et al. Adjuvant postoperative radiotherapy for colon carcinoma. Cancer 2004; 101:1338.
  129. Czito BG, Bendell J, Willett CG. Radiation therapy for resectable colon cancer. Is there a role in the modern chemotherapy era? Oncology (Williston Park) 2006; 20:179.
  130. Gunderson LL, Sosin H, Levitt S. Extrapelvic colon--areas of failure in a reoperation series: implications for adjuvant therapy. Int J Radiat Oncol Biol Phys 1985; 11:731.
  131. Willett CG, Goldberg S, Shellito PC, et al. Does postoperative irradiation play a role in the adjuvant therapy of stage T4 colon cancer? Cancer J Sci Am 1999; 5:242.
  132. Willett CG, Fung CY, Kaufman DS, et al. Postoperative radiation therapy for high-risk colon carcinoma. J Clin Oncol 1993; 11:1112.
  133. Amos EH, Mendenhall WM, McCarty PJ, et al. Postoperative radiotherapy for locally advanced colon cancer. Ann Surg Oncol 1996; 3:431.
  134. Ludmir EB, Arya R, Wu Y, et al. Role of Adjuvant Radiotherapy in Locally Advanced Colonic Carcinoma in the Modern Chemotherapy Era. Ann Surg Oncol 2016; 23:856.
  135. Wegner RE, Abel S, Monga D, et al. Utilization of Adjuvant Radiotherapy for Resected Colon Cancer and Its Effect on Outcome. Ann Surg Oncol 2020; 27:825.
  136. Martenson JA Jr, Willett CG, Sargent DJ, et al. Phase III study of adjuvant chemotherapy and radiation therapy compared with chemotherapy alone in the surgical adjuvant treatment of colon cancer: results of intergroup protocol 0130. J Clin Oncol 2004; 22:3277.
Topic 2471 Version 131.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟