Colon Cancer Treatment & Management

Surgery is the only curative modality for localized colon cancer (stage I-III). Surgical resection potentially provides the only curative option for patients with limited metastatic disease in liver and/or lung (stage IV disease), but the proper use of elective colon resections in nonobstructed patients with stage IV disease is a source of continuing debate.

Adjuvant chemotherapy is standard for patients with stage III disease. Its use in stage II disease is controversial, but current guidelines recommend its use in selected patients with risk factors for recurrence. ^{[1, 77]} At present, the role of radiation therapy is limited to palliative therapy for selected metastatic sites such as bone or brain metastases.

Chemotherapy rather than surgery has been the standard management for patients with metastatic colorectal cancer. Biologic agents have assumed a major role in the treatment of metastatic cases, with selection increasingly guided by genetic analysis of the tumor. The proper use of elective colon/rectal resections in nonobstructed patients with stage IV disease is a source of continuing debate.

For more information, see Colon Cancer Treatment Protocols.

Surgery is the only curative modality for localized colon cancer (stage I-III) and potentially provides the only curative option for patients with limited metastatic disease in liver and/or lung (stage IV disease). The general principles for all operations include removal of the primary tumor with adequate margins including areas of lymphatic drainage. Standard colectomies for adenocarcinoma of the colon are depicted in the image below.

For lesions in the cecum and right colon, a right hemicolectomy is indicated. During a right hemicolectomy, the ileocolic, right colic, and right branch of the middle colic vessels are divided and removed. Care must be taken to identify the right ureter, the ovarian or testicular vessels, and the duodenum. If the omentum is attached to the tumor, it should be removed en bloc with the specimen.

For lesions in the proximal or middle transverse colon, an extended right hemicolectomy can be performed. In this procedure, the ileocolic, right colic, and middle colic vessels are divided and the specimen is removed with its mesentery.

For lesions in the splenic flexure and left colon, a left hemicolectomy is indicated. The left branch of the middle colic vessels, the inferior mesenteric vein, and the left colic vessels along with their mesenteries are included with the specimen.

For sigmoid colon lesions, a sigmoid colectomy is appropriate. The inferior mesenteric artery is divided at its origin, and dissection proceeds toward the pelvis until adequate margins are obtained. Care must be taken during dissection to identify the left ureter and the left ovarian or testicular vessels.

Total abdominal colectomy with ileorectal anastomosis may be required for patients with any of the following:

• Hereditary nonpolyposis colon cancer syndrome (HNPCC; Lynch syndrome)
• Attenuated familial adenomatous polyposis (FAP)
• Metachronous cancers in separate colon segments

Total abdominal colectomy may also be indicated for some patients with acute malignant colon obstructions in whom the status of the proximal bowel is unknown.

Laparoscopic surgery

The advent of laparoscopy has revolutionized the surgical approach to colonic resections for cancers. Large prospective randomized trials have found no significant differences between open and laparoscopic colectomy with regard to intraoperative or postoperative complications, perioperative mortality rates, readmission or reoperation rates, or rate of surgical wound recurrence. Oncologic outcomes (cause-specific survival, disease recurrence, number of lymph nodes harvested) are likewise comparable. ^{[78, 79, 80, 81, 82, 83]}

For example, the Clinical Outcomes of Surgical Therapy Study Group trial found no significant differences between laparoscopic-assisted colectomy (LAC) or open colectomy in terms of 5-year disease-free survival rate (69% versus 68% in the LAC and open colectomy groups, respectively) or overall survival (76% versus 75%). ^[79] In a study by Lacy et al with median followup of 95 months, LAC was more effective than open colectomy, although the tendency toward higher cancer-related and overall survival did not reach statistical significance. ^[82]

Metastatic colorectal cancer

Chemotherapy rather than surgery has been the standard management for patients with metastatic colorectal cancer. The proper use of elective colon/rectal resections in nonobstructed patients with stage IV disease is a source of continuing debate.

Medical oncologists properly note the major drawbacks to palliative resection, such as loss of performance status and risks of surgical complications that potentially lead to delay in chemotherapy. However, surgeons understand that elective operations have lower morbidity than emergent operations on patients who are receiving chemotherapy.

There is a trend toward nonsurgical management of patients with asymptomatic, surgically incurable colorectal cancer, with studies showing that fewer than 10% of these patients subsequently require surgery for obstruction or perforation. ^{[84, 85]} A review by Venderbosch et al found that resection of the primary tumor appears to improve survival in patients with stage IV colorectal cancer, but these researchers concluded that prospective studies are warranted, given the potential bias of those results. ^[86]

Curative-intent resections of liver metastases have significantly improved long-term survival, with acceptable postoperative morbidity, including in older patients. ^[87] A study by Brouquet et al found that resection of colorectal liver metastases after a second-line chemotherapy regimen was safe and provided a modest hope for definitive cure, making this approach viable in patients with advanced colorectal liver metastases. ^[88]

Hepatic arterial infusion (HAI) of chemotherapeutic agents such as floxuridine (FUDR) is a consideration following partial hepatectomy. A study by House et al found that adjuvant HAI-FUDR combined with modern systemic chemotherapy resulted in improved survival compared with adjuvant chemotherapy alone. ^[89]

During the past decade, colonic stents have introduced an effective method of palliation for obstruction in patients with unresectable liver metastasis. However, a study by van Hooft et al found that colonic stenting has no decisive clinical advantages compared with emergency surgery. Although it may be used as an alternative treatment in undefined sets of patients, concerns about tumor spread caused by perforations remains. ^[90]

Although resection is the only potentially curative treatment for patients with colon metastases, other therapeutic options for those who are not surgical candidates include thermal ablation techniques. Cryotherapy uses probes to freeze tumors and surrounding hepatic parenchyma. It requires laparotomy and can potentially results in significant morbidity, including liver cracking, thrombocytopenia, and disseminated intravascular coagulation (DIC).

Radiofrequency ablation (RFA) uses probes that heat liver tumors and the surrounding margin of tissue to create coagulation necrosis. RFA can be performed percutaneously, laparoscopically, or through an open approach. Although RFA has minimal morbidity, local recurrence is a significant problem and correlates with tumor size.

Analysis of a data set assembled by the Adjuvant Colon Cancer Endpoints group showed that adjuvant chemotherapy provides a significant disease-free survival benefit in stage II and III colon cancer because it reduces the recurrence rate. The benefit was particularly evident within the first 2 years of adjuvant therapy but some benefit extended to years 3-4. ^[91]

The standard chemotherapy for patients with stage III and some patients with stage II colon cancer for the last two decades consisted of 5-fluorouracil (5-FU) in combination with adjuncts such as levamisole and leucovorin. ^{[1, 2, 3, 4]} This approach was tested in several large randomized trials and was shown to reduce individual 5-year risk of cancer recurrence and death by about 30%.

Capecitabine (Xeloda) has also become a standard option. Like 5-FU, capecitabine is a fluoropyrimidine, but is given orally rather than intravenously; it undergoes a three-step enzymatic conversion to 5-FU, with the last step occurring in the tumor cell. ^[1] The randomized X-ACT study demonstrated the noninferiority of capecitabine compared with 5-FU/leucovorin as adjuvant therapy for patients with stage III colon cancer, with efficacy benefits maintained at 5 years and in older patients. ^[92]

The addition of oxaliplatin to fluoropyrimidine-based therapy has also become standard. A phase III trial in 1886 patients with resected stage III colon cancer reported superior overall survival with capecitabine plus oxaliplatin (XELOX, or CapeOx) versus 5-FU/leucovorin (73% vs 67%, respectively; P = 0.04) after a median follow-up of almost 7 years. The results of that study suggested that low tumor expression of dihydropyrimidine dehydrogenase may be predictive for XELOX efficacy. ^[93] Similarly, the large MOSAIC trial demonstrated significant improvement in 5-year disease-free survival and 6-year disease-free survival for patients with stage III colon cancer when oxaliplatin was added to 5-FU/leucovorin (ie, FOLFOX4).

Elderly patients

In an observational study of 1291 patients with stage III colon cancer, 56% of whom received adjuvant chemotherapy, van Erning et al concluded that adjuvant chemotherapy should be considered in elderly patients with stage III disease. Adjuvant chemotherapy reduced the risk of distant recurrence after surgery by about half in both elderly patients and younger ones. With adjuvant chemotherapy, hazard ratios for distant recurrence were 0.50 in patients < 75 years of age and 0.57 in those 75 years and older. ^[94]

Therapy duration

In the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) trial (n=12,834), which compared 3 versus 6 months of FOLFOX or XELOX, 3-year disease-free survival in the FOLFOX 3-month arm was lower than that in the 6-month arm by 0.9% (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.00 - 1.15). To meet the prespecified noninferiority threshold, the upper limit of the 95% CI had to be 1.12 or less, so noninferiority was not established. However, shorter therapy was associated with significantly less neurotoxicity. Rates of neurotoxicity were 17% versus 48% with 3 versus 6 months, respectively, of FOLFOX; comparable figures with XELOX were 15% and 45%, respectively; P < 0.0001). ^[95]

An American Society of Clinical Oncology (ASCO) guideline on adjuvant chemotherapy with oxaliplatin and a fluoropyrimidine for patients with resected stage III colon cancer recommends offering adjuvant chemotherapy for a duration of 6 months for patients at a high risk of recurrence (T4 and/or N2). For patients at a low risk of recurrence (T1, T2, or T3 and N1), either 6 months or 3 months of chemotherapy may be offered. ^[96]

For patients with stage III colon cancer, National Comprehensive Cancer Network (NCCN) guidelines also recommend basing adjuvant treatment duration on risk status, as follows ^[97] :

• Low-risk stage III: CapeOx for 3 mo or FOLFOX for 3-6 mo
• High risk stage III: CapeOx for 3-6 mo or FOLFOX for 6 mo

Adjuvant therapy in stage II colon cancer

The role of adjuvant chemotherapy for stage II colon cancer is controversial. ^[1] Surgery alone is usually curative for stage II colon cancer, but approximately 20-30% of these patients develop tumor recurrence and ultimately die of metastatic disease.

A large European trial (QUASAR) demonstrated small but significant benefit (3.6%) in terms of absolute 5-year survival rate for those patients who received 5-FU/leucovorin versus those in the control group. ^[98] In contrast, a study by O’Connor et al found that in Medicare patients with stage II colon cancer, with or without poor prognostic features, overall survival was not substantially improved by adjuvant chemotherapy. ^[99]

ASCO recommends against the routine use of adjuvant chemotherapy in patients with stage II colon cancer who are at low risk of recurrence, including in younger patients. ^[77] However, ASCO recommends offering adjuvant chemotherapy to patients with stage IIB colon cancer (ie, T4) and stage IIC colon cancer (ie, lesions either penetrating visceral peritoneum or invasive of surrounding organ), with a discussion of the potential benefits and risks of harm. In addition, ASCO suggests offering adjuvant therapy to patients with stage IIA colon cancer who have any of the following high-risk factors (with consideration of the number of risk factors as part of the shared decision-making process, since the presence of more than one risk factor may increase the risk of recurrence):

• Sampling of fewer than 12 lymph nodes in the surgical specimen
• Perineural or lymphovascular invasion
• Poorly differentiated or undifferentiated tumor grade
• Intestinal obstruction
• Tumor perforation
• Grade BD3 tumor budding (≥ 10 buds)

ASCO guidelines do not routinely recommend the addition of oxaliplatin to fluoropyrimidine-based adjuvant therapy, but consider that it may be offered as a result of shared decision making. ASCO recommends against routinely offering adjuvant therapy to patients with mismatch repair deficiency/microsatellite instability (dMMR/MSI) tumors, but if the combination of dMMR/MSI and high-risk factors results in a decision to offer adjuvant therapy, ASCO recommends including oxaliplatin in the chemotherapy regimen.

A comparison of 3 vs 6 months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOx adjuvant chemotherapy in 1254 patients with high-risk stage II resected colorectal cancer found that neurotoxicity was approximately 5 times lower in the 3-month arm than the 6-month arm. Noninferiority of 3 months of therapy was not shown for 5-year relapse-free survival. However, a possible regimen effect was observed, suggesting that either 3 months of CapeOx or 6 months of FOLFOX therapy can be used when an oxaliplatin doublet is indicated for treatment of patients with stage II colorectal cancer. ^[100]

Ongoing adjuvant trials are investigating additional risk stratification of stage II colon cancer based on clinicopathological and molecular markers. For example, the ECOG 5202 trial is studying the addition of bevacizumab to adjuvant therapy with 5-FU, leucovorin, and oxaliplatin in high-risk patients, with low-risk patients undergoing observation only. In this trial, high-risk patients are defined as those with microsatellite stability (MSS) or low-frequency microsatellite instability (MSI-L) and loss of heterozygosity at 18q. Low-risk patients are those with MSS or MSI-L and retention of 18q, or high-frequency MSI with or without loss of heterozygosity at 18q.

Therapy for metastatic disease

Combination regimens provide improved efficacy and prolonged progression-free survival (PFS) in patients with metastatic colon cancer. The advent of new classes of active drugs and biologics for colorectal cancer has improved the expected survival for patients with metastatic disease.

In a phase III multicenter trial in patients with advanced colorectal carcinoma refractory to fluorouracil, overall survival did not significantly differ between patients treated with FOLFOX4 (n=246) compared with irinotecan (n=245); however, FOLFOX 4 improved response rate (RR) and time to progression (TTP) compared with irinotecan (P=0.0009 for each RR and TTP). FOLFOX4 was associated with more neutropenia and paresthesias. ^[101]

Although many patients with colorectal cancer are elderly, exclusion of these patients from randomized controlled trials has impeded the creation of evidence-based guidelines for this population. A study by Seymour et al demonstrated that elderly and frail patients with untreated metastatic colorectal cancer can participate in a randomized controlled trial. Study patients, who were considered unfit for full-dose chemotherapy, underwent a comprehensive health assessment and were started on chemotherapy at 80% of standard doses. ^[102]

In 2015, the US Food and Drug Administration (FDA) approved trifluridine/tipiracil (Lonsurf) for metastatic colorectal cancer. Trifluridine is a nucleoside analog that inhibits cell proliferation by incorporating into DNA and interering with DNA synthesis; tipiracil inhibits the metabolism of trifluridine. The efficacy and safety of trifluridine/tipiracil were evaluated in the phase III RECOURSE trial, an international, randomized, double-blind study involving 800 patients with previously treated metastatic colorectal cancer. Patients had received chemotherapy with a fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and—for patients with KRAS wild-type tumors—cetuximab or panitumumab. The primary efficacy end point of the study was median overall survival, which was 7.1 months with trifluridine/tipiracil vs 5.3 months with placebo (P <  0.001). The secondary end point was PFS, which was 2 months with trifluridine/tipiracil vs 1.7 months with placebo. ^[103]

In August 2023, the FDA approved trifluridine/tipiracil in combination with bevacizumab for metastatic colorectal cancer in adults previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti–vascular endothelial growth factor (VEGF) biologic therapy, and if RAS wild-type, anti–epidermal growth factor receptor (EGFR) therapy.

Approval was based on the results from the phase III SUNLIGHT trial, in which 246 patients received either trifluridine/tipiracil plus bevacizumab (combination group) or trifluridine–tipiracil alone (FTD–TPI group). The median overall survival was 10.8 months in the combination group and 7.5 months in the FTD–TPI group (P < 0.001). The median PFS was 5.6 months in the combination group and 2.4 months in the FTD–TPI group (P < 0.001). ^[104]

Biologic agents

Targeted therapy with biologic agents, based on molecular characteristics of the tumor, have become a standard part of treatment for metastatic colon cancer. Biologic agents used for targeted therapy include monoclonal antibodies against VEGF and EGFR, as well as a kinase inhibitor and a decoy receptor for VEGF. Such agents include the following:

• Bevacizumab (Avastin, Mvasi)
• Cetuximab (Erbitux)
• Nivolumab (Opdivo)
• Panitumumab (Vectibix)
• Pembrolizumab (Keytruda)
• Tucatinib (Tukysa)
• Fruquintinib (Fruzaqla)

Detection of microsatellite instability (MSI) has also become important for treatment for metastatic colorectal cancers. Tumors with MSI tend to respond favorably to biologic therapy with immune checkpoint inhibitors (eg, pembrolizumab, nivolumab). These tumors typically have high expression of checkpoint proteins, including programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1), which interfere with the body’s antitumor T-cell response. By disabling these proteins, checkpoint inhibitors enable T cells to kill tumor cells. ^[105]

Bevacizumab

Bevacizumab is a humanized monoclonal antibody to VEGF. It was the first anti-angiogenesis drug to be approved in clinical practice and its first indication was for metastatic colorectal cancer. Approval was based on a pivotal trial that demonstrated improved PFS and overall survival when bevacizumab was added to chemotherapy with irinotecan, 5-FU, and leucovorin (IFL).

Bevacizumab, in combination with fluorouracil-based chemotherapy, is indicated for first- and second-line treatment of metastatic colorectal carcinoma. Bevacizumab is also approved for second-line treatment in patients who have progressed on a first-line bevacizumab-containing regimen.

Approval for continuation treatment was based on a study that showed maintenance of VEGF inhibition with bevacizumab plus standard second-line chemotherapy. The risk of death was reduced by 19% for those who received bevacizumab in combination with standard chemotherapy in both the first- and second-line compared with those who received chemotherapy alone (hazard ratio [HR]=0.81, P=0.0057). PFS improved by 32% (HR=0.68, P < 0.0001). ^[106]

A pooled analysis of cohorts of older patients (aged 65 years or older) from two randomized clinical trials concluded that adding bevacizumab to fluorouracil-based chemotherapy for first-line treatment of metastatic colorectal cancer improved overall survival and PFS in older patients as it does in younger patients, without increased risks of treatment in the older age group. Median overall survival improved from 14.3 months to 19.3 months with the addition of bevacizumab, while median PFS improved from 6.2 months to 9.2 months. ^[107]

Results from the randomized CAIRO3 trial appear to show that, compared with observation, maintenance therapy with capecitabine and bevacizumab significantly delayed disease progression in 558 previously untreated patients with stable (or better) metastatic colorectal cancer after six cycles of induction therapy with capecitabine, oxaliplatin, and bevacizumab (CAPOX-B). ^[108] Patients in both groups were treated with CAPOX-B at first progression until second progression.

At a median follow-up of 48 months, CAPOX-B was restarted in 48% of those in the maintenance treatment group and 61% of patients in the observation group. ^[108] Median second progression after randomization occurred at 11.7 months in the maintenance group and 8.5 months in the observation group, and median first progression after randomization occurred at 8.5 months in the maintenance group compared with 4.1 months in the observation group. The most pronounced benefit of maintenance therapy was in patients with RAS/BRAF wild-type and BRAF V600E–mutant tumors. ^[108]

In a study by Tebbutt et al, bevacizumab was found to be associated with a modestly increased risk of arterial thromboembolism (ATE). However, safety was not significantly worse in older patients or those with a history of ATE or other vascular risk factors. ^[109]

Despite its role in the therapy of metastatic colon cancer, bevacizumab did not significantly prolong disease-free survival in patients with stage II and III colon cancer, when added to adjuvant chemotherapy (mFOLFOX6) in a randomized trial (NASBP C-08). ^[110]

In 2017, the FDA approved Mvasi (bevacizumab-awwb) as a biosimilar to Avastin (bevacizumab), to be used in combination with fluoropyrimidine-irinotecan–based or fluoropyrimidine-oxaliplatin–based chemotherapy for the second-line treatment of patients with metastatic colorectal cancer that has progressed on a first-line bevacizumab-product–containing regimen. The approval was based on evidence from animal study data, human pharmacokinetic and pharmacodynamics data, and clinical immunogenicity data that supported Mvasi as a biosimilar to Avastin. ^[111]

Cetuximab

Cetuximab is a chimeric monoclonal antibody against EGFR that is approved for treatment of KRAS mutation–negative (wild-type), EGFR-expressing, metastatic colorectal cancer. Cetuximab may be used as monotherapy or in combination with irinotecan (Camptosar) in patients with metastatic colorectal cancer refractory to fluoropyrimidine and oxaliplatin therapy. ^[112] Additionally, cetuximab is approved as combination therapy with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin). ^{[113, 114]}

KRAS mutations, which are present in about 40% of colon adenocarcinomas, affect sensitivity to anti-EGFR treatment. ^[69] The addition of anti-EGFR antibody treatment to standard chemotherapy regimens for patients with advanced colorectal cancer improves PFS for those with wild-type KRAS status, but not those with mutant KRAS. ^[115]

The CRYSTAL trial, a large international trial exploring the benefit of adding cetuximab to first-line chemotherapy with FOLFIRI, documented that only patients with wild-type KRAS derived clinical benefit from cetuximab. In patients with mutant KRAS, adding cetuximab to chemotherapy provided no clinical benefit and resulted only in unnecessary toxicity. ^[114]

Based on these results, testing for KRAS mutation was added to the cetuximab indication by the European Medicines Agency (EMA). The FDA approved the use of cetuximab in combination with FOLFIRI for first-line treatment of patients with wild-type KRAS metastatic colorectal cancer, as determined by FDA-approved tests, in 2012.

Panitumumab

Panitumumab is a fully human monoclonal antibody against EGFR. This agent was originally approved as monotherapy for patients with EGFR-expressing metastatic colorectal cancer in whom combination chemotherapy with regimens containing fluoropyrimidine, oxaliplatin, and irinotecan had failed or was not tolerated.

In 2014, the FDA approved panitumumab for first-line treatment of patients with wild-type KRAS (exon 2) metastatic colorectal carcinoma in combination with fluorouracil, leucovorin, and oxaliplatin (FOLFOX4). ^[116] Approval was based on results from the PRIME trial. ^[117]

The PRIME trial, a phase III study, showed that patients with wild-type KRAS tumors achieved statistically significant improvement in PFS with panitumumab and FOLFOX4 versus FOLFOX4 alone (9.6 versus 8.0 months, P=0.02) and a nonsignificant improvement in OS versus FOLFOX4 alone (23.9 versus 19.7 months, P =0.07). In contrast, patients with mutant KRAS had significantly reduced PFS with panitumumab-FOLFOX4. ^[117]

Thus, panitumumab becomes an option, or an alternative to cetuximab, for patients who have tumors with wild-type KRAS. ^{[118, 119]} However, Hecht et al reported that adding panitumumab to bevacizumab and chemotherapy (oxaliplatin- and irinotecan-based) as first-line treatment of metastatic colorectal cancer resulted in increased toxicity and decreased PFS. ^[120]

In a randomized study of first-line treatment of metastatic colorectal cancer, Bokemeyer et al concluded that the overall response rate for cetuximab plus FOLFOX-4 was higher than with FOLFOX-4 alone. However, a statistically significant increase was seen only in patients with KRAS wild-type tumors, for whom the addition of cetuximab increased chance of response and lowered the risk of disease progression. ^[121]

Douillard and colleagues reported that in addition to KRAS mutations in exon 2, additional RAS mutations (KRAS exon 3 or 4; NRAS exon 2, 3, or 4; or BRAF exon 15) are associated with inferior PFS and OS with panitumumab-FOLFOX4 treatment. ^[122] Other mutations that involve some of the kinases downstream from KRAS (such as BRAF and PI3K) are being investigated and may result in even more selective methods to identify patients that may benefit from EGFR inhibition.

In 2017, the FDA extended approval for panitumumab for use in wild-type RAS (both KRAS and NRAS) metastatic colorectal cancer. Approval was based on a retrospective analysis from the PRIME trial and prospective, pre-defined analyses from the phase 3 '0007 study. The '0007 study evaluated the efficacy of panitumumab plus best supportive care (BSC) versus BSC alone in patients with chemorefractory, wild-type KRAS metastatic colorectal cancer. ^[123] Key secondary endpoint data showed significant improvement in overall survival (OS) of 10 months in BSC with panitumumab compared to 6.9 months with BSC alone.

Ramucirumab

The FDA approved ramucirumab for use in combination with FOLFIRI for the treatment of patients with metastatic colorectal cancer that has progressed on a first-line bevacizumab-, oxaliplatin- and fluoropyrimidine-containing regimen. The approval was based on the phase III RAISE trial, in which the ramucirumab-FOLFIRI combination improved overall survival and progression-free survival (13.3 months, 5.7 months) compared with placebo-FOLFIRI (11.7 months, 4.5 months) (P = 0.023 and < 0.001, respectively). ^[124]

Nivolumab

In the CheckMate 142 phase II study, nivolumab, with or without ipilimumab, appeared tolerable and demonstrated clinical activity in patients with microsatellite instability-high metastatic colorectal cancer. The study enrolled dMMR and MSI-H colorectal cancer patients whose disease had progressed on, or who were intolerant to, at least one prior line of therapy. Patients were dosed with nivolumab every two weeks. ^[125]

The primary endpoint was investigator-assessed objective response rate (ORR), defined as the percentage of patients whose tumor shrank or disappeared. Secondary endpoint was independent review committee-assessed ORR. Other measures, including safety, PFS, overall survival, and effectiveness in specific subsets were also assessed.

Data revealed patients receiving nivolumab had the investigator-assessed ORR and disease control rate were 31% and 69%. One year after entering the trial, 48.4% of patients were still alive and disease-free. One-year overall survival was 73.8%. Treatment was well tolerated, with no safety signals. ^[126]

Nivolumab monotherapy demonstrated encouraging activity in patients with MSI-H tumor. The study brought an accelerated approval to nivolumab in 2017 for the treatment of patients 12 years or older with dMMR and MSI-H metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Continued approval of nivolumab for this indication may be contingent upon the outcomes of confirmatory trials. ^[127]

Pembrolizumab

Pembrolizumab, which is a monoclonal antibody to PD-1, is approved for treatment of unresectable or metastatic colon cancer that has tested positive for microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) and has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. It is also approved for any solid tumor that has tested positive for MSI-H or dMMR in patients who have had prior treatment and have no satisfactory alternative treatment options. ^[128] The multicenter, randomized KEYNOTE-177 trial found that treatment with pembrolizumab monotherapy significantly reduced the risk of disease progression or death by 40% (HR, 0.60; 95% CI, 0.45 - 0.80; P = 0.0004), with a median PFS of 16.5 months versus 8.2 months for chemotherapy, in patients with dMMR colorectal cancers. ^[128]

Targeted Therapy

For patients with dMMR/MSI-H tumors who are not eligible for cytotoxic combinations, National Comprehensive Cancer Network (NCCN) guidelines recommend the following as first-line immunotherapy options ^[97] :

• Nivolumab
• Pembrolizumab
• Nivolumab plus ipilimumab

The NCCN recommends nivolumab with or without ipilimumab or pembrolizumab for the second- and third-line treatment of patients with dMMR/MSI-H colorectal cancer.

Besides determining the status of MMR and/or MSI, the NCCN has expanded its recommendation for biomarker testing to include KRAS/RAS or BRAF mutations, HER2 amplifications, and NTRK fusions in patients with metastatic colorectal cancer. The determination of these tumor markers provides more treatment options for these patients. ^[97]

Regorafenib

Regorafenib, a kinase inhibitor, is approved for patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; anti-VEGF therapy (eg, bevacizumab, ziv-aflibercept); and, if KRAS wild type, anti-EGFR therapy (eg, cetuximab, panitumumab). ^[129]

Approval was based on a multicenter trial (n=760) that randomized patients at a 2:1 ratio to receive regorafenib in addition to best supportive care or placebo plus best supportive care. Statistically significant benefit in OS and PFS was observed for regorafenib over placebo in patients with metastatic colon cancer in whom all approved standard therapies had failed. ^[130]

Fruquintinib

Fruquintinib (Fruzaqla), a selective and potent oral inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3, was approved by the FDA in November 2023 for adults with metastatic colorectal cancer who received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type and medically appropriate, an anti-EGFR therapy.

Approval was based on results of the FRESCO and FRESCO-2 trials. ^{[131, 132]} OS was the major efficacy outcome in both trials. In FRESCO-2, median OS was 7.4 months in the fruquintinib group versus 4.8 months in the placebo group (hazard ratio [HR] 0.66, P < 0.0001). ^[132] In FRESCO, median OS was 9.3 months and 6.6 months (HR 0.65, P < 0.001). ^[131]

Ziv-aflibercept

Ziv-aflibercept is a fusion protein that acts as a decoy receptor for VEGF-A, VEGF-B, and placental growth factor (PlGF). This agent was approved for use in combination with FOLFIRI for the treatment of patients with metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing fluoropyrimidine-based regimen. ^[133]

Approval was based on the Aflibercept Versus Placebo in Metastatic Colorectal Cancer (mCRC) After Failure of an Oxaliplatin-Based Regimen (VELOUR) trial that included 1226 patients. Results showed that when ziv-aflibercept was used in combination with FOLFIRI, overall survival and progression-free survival improved in patients with mCRC previously treated with an oxaliplatin containing regimen. ^[134]

A phase III trial by Van Cutsem and colleagues in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen found that the addition of ziv-aflibercept to fluorouracil, leucovorin, and irinotecan (FOLFIRI) improves survival. Median survival time was 13.5 months with ziv-aflibercept plus FOLFIRI versus 12.06 months with FOLFIRI alone (P = 0.0032); PFS was 6.90 versus 4.67 months, respectively (P < 0.0001). ^[135]

Larotrectinib

Larotrectinib is a highly selective inhibitor of tropomyosin receptor kinases A, B, and C (TRKA, TRKB, TRKC), which are encoded by NTRK genes. In 2018, the FDA granted tissue-agnostic approval for larotrectinib for adult and pediatric patients who meet the following criteria ^[136] :

• Have solid tumors that harbor an  NTRK gene fusion without a known acquired resistance mutation (note that  NTRK fusions can be hard to detect and are found in only about 1% of colorectal cancers)
• Have metastatic disease or disease that has progressed after treatment
• Are likely to experience severe morbidity as a result of surgery
• Lack alternative satisfactory treatments

Therapy for BRAF V600E–positive disease

For advanced or metastatic colon cancer that is BRAF V600E mutation positive, NCCN guidelines include the following as second-line therapy options ^[97] :

• Dabrafenib plus trametinib plus either cetuximab or panitumumab 
• Encorafenib plus either cetuximab or panitumumab, with or without binimetinib

In the open-label, phase III BEACON trial, therapy with the BRAF inhibitor encorafenib and the EGFR inhibitor monoclonal antibody cetuximab, with or without the MEK inhibitor binimetinib (ie, triplet or doublet therapy) provided an overall survival benefit for patients with metastatic colorectal cancer who had the BRAF V600E mutation. The BEACON trial enrolled 665 patients with BRAF V600E–mutated metastatic colorectal cancer who had disease progression after one or two previous regimens. ^[137]  

Updated analysis of BEACON showed that median overall survival was 9.3 months in the triplet- and doublet-therapy groups, compared with 5.9 months for patients in the control group, who received standard-of-care therapy with cetuximab plus irinotecan or cetuximab plus FOLFIRI. The confirmed objective response rate (ORR) was 26.8% for triplet therapy, 19.5% for doublet therapy, and 1.8% for control. Thus, the increased toxicity from the addition of binimetinib can be avoided, while maintaing good outcomes. ^[138]

HER2-positive disease

HER2 is overexpressed in approximately 3% of colorectal cancers overall and in 5-14% of RAS/BRAF–wild type colorectal tumors. Experimental therapeutic approaches for tumors that have HER2 overexpression have included trastuzumab plus lapatinib and trastuzumab plus pertuzumab. ^[95]

In a phase II proof-of-concept study, 27 heavily pretreated patients with HER2-positive metastatic colon cancer showed good response to a therapy regimen that is commonly used to treat HER2-positive breast cancer and does not include a chemotherapy backbone. The 27 patients in the study were identified through screening of 914 patients with KRAS exon 2 (codons 12 & 13) wild-type metastatic colorectal cancer. ^[139]

Most of the patients had extensive metastatic disease and distal colon tumors. Almost 75% had received at least four prior treatment regimens and had spent a median total time of 20 months on previous treatments.

Patients were treated with a combination of trastuzumab and lapatinib. At 1 year, 12 of the 27 patients (45%) were still alive. At a median follow-up of 94 weeks, one patient (4%) had achieved a complete response, seven (26%) had achieved a partial response, and disease had stabilized in 12 patients (44%). ^[139]

Another regimen, tucatinib in combination with trastuzumab, was granted accelerated approval by the FDA in 2023 for RAS wild-type HER2-positive unresectable or metastatic colorectal cancer that has progressed after treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. Approval was based on results from the open-label, multicenter MOUNTAINEER study in 84 patients, in which treatment with tucatinib in combination with trastuzumab yielded an overall response rate of 35% (3.6% complete response; 35% partial response), with a median duration of response of 12.4 months. ^[140]

Although radiation therapy remains a standard modality for patients with rectal cancer, it has only a limited role in colon cancer. Radiation therapy is not used in the adjuvant setting, and in metastatic settings it is used only for palliative care in selected sites such as bone or brain metastases.

Newer, more selective ways of administering radiation therapy, such as stereotactic radiotherapy (CyberKnife) and tomotherapy, are currently being investigated. In the future, these techniques may extend the indications for radiotherapy in the management of colon cancer.

A prospective, multicenter, randomized phase III study by Hendlisz et al showed that the addition of radioembolization with yttrium-90 significantly improved time to liver progression and median time to tumor progression in patients with unresectable, chemotherapy-refractory, liver-limited metastatic colorectal cancer. The study compared treatment with fluorouracil alone with fluorouracil plus yttrium-90 resin, which was injected into the hepatic artery. ^[141]  The US Food and Drug Administration (FDA) has approved yttrium-90 resin microspheres (SIR-Spheres) for the treatment of unresectable metastatic liver tumors from primary colorectal cancer in combination with adjuvant intra–hepatic artery chemotherapy with floxuridine.

In a prospective cohort study that included 1575 healthcare professionals with stage I to III colorectal cancer, Song et al found that rates of colorectal cancer (CRC)–specific mortality and overall mortality were lower in patients who had higher intake of dietary fiber, especially from cereals. Survival rates were higher in patients who increased their fiber intake after diagnosis from levels before diagnosis, and in patients reporting higher intake of whole grains. ^[142]

After multivariable adjustment, each 5 g increment in daily fiber intake was associated with a 22% decrease in CRC-specific mortality and a 14% decrease in all-cause mortality. In patients who increased their fiber intake after diagnosis, each 5 g increase in daily fiber intake was associated with 18% lower CRC-specific mortality. The relationship between fiber intake after diagnosis and CRC-specific mortality  reached a maximum at approximately 24 g/d, beyond which no further mortality reduction was found. ^[142]

Evaluation of the source of fiber showed that cereal fiber was associated with lower CRC-specific mortality (33% per 5-g/d increment) and all-cause mortality (22%); vegetable fiber was associated with 17% lower all-cause mortality but not with significantly lower CRC-specific; no association was found for fruit fiber. Whole grain intake was associated with lower CRC-specific mortality (28% decrease in risk per 20-g/day increment), although this beneficial association fell to 23% after adjusting for fiber intake. ^[142]

A prospective cohort study in 1011 patients with stage III colon cancer found that postdiagnosis intake of unprocessed red meat or processed meat was not associated with risk of recurrence or death. Van Blarigan et al reported that multivariable hazard ratios comparing the highest versus the lowest quartiles for cancer recurrence or death were 0.84 (95% CI, 0.58-1.23) for unprocessed red meat and 1.05 (95% CI, 0.75-1.47) for processed meat. ^[143]

Colorectal cancer, especially early stage disease, can be cured surgically. Following diagnosis and staging, obtaining surgical consultation for the possibility of resection may be appropriate. After surgery, the stage of the tumor may be advanced depending on the operative findings (eg, lymph node involvement, palpable liver masses, peritoneal spread).

In the care of patients with colorectal cancer and isolated liver metastases, consider surgical consultation for possible resection. In some cases, resection of previously unresectable liver metastases may become feasible after cytoreduction with neoadjuvant chemotherapy. Therefore, ongoing involvement of the surgical oncologist is very important in patient care, even if the tumor is not considered resectable at the time of diagnosis. In patients with advanced disease, palliative surgery may be helpful in cases of bleeding or obstruction.

Gastroenterology (GI) consultation is critical for screening of high-risk individuals (ie, patients with a family history of colorectal cancer or polyposis syndromes) and those individuals who are found to be inappropriately iron deficient or to have occult blood on screening fecal examination. A colonoscopy or sigmoidoscopy is necessary to visualize the colon endoscopically, to obtain biopsies, or to resect polyps.

GI consultation may also be necessary in the management of advanced disease. The advent of colorectal stents allows a nonsurgical management of impending obstruction in patients who present with unresectable, metastatic disease.

GI consultation is necessary in the follow-up of patients after surgical resection and adjuvant chemotherapy. Patients must be screened for recurrent disease in the colon by colonoscopic examination at 1 year after surgery and then every 3 years.

Pooled analysis from several large adjuvant trials showed that 85% of colon cancer recurrences occur within 3 years after resection of primary tumor, with 95% occurring within 5 years. Therefore, patients with resected colon cancer (stage II and III) should undergo regular surveillance for at least 5 years following resection. ^[144] Recommendations for post-treatment surveillance, from the European Society for Medical Oncology (ESMO), ^[145] the American Society for Clinical Oncology (ASCO), ^[144] and the National Comprehensive Cancer Network (NCCN) ^[97] are compared in Table 2, below.

Table 2. Surveillance recommendations for stage II and III colon cancer (Open Table in a new window)

Followup should be guided by the patient’s presumed risk of recurrence and functional status. Testing at the more frequent end of the range should be considered for patients at high risk. Patients with severe comorbid conditions that make them ineligible for surgery or systemic therapy should not undergo surveillance testing. ^[144]

Cancer Care Ontario published guidelines for the follow-up care of survivors of stages II and III colorectal cancer, and these were endorsed by the American Society of Clinical Oncology. The recommendations include the following ^[144] :

• Surveillance is especially important in the initial 2-4 years following treatment, when most recurrences occur

• Patients should be followed for 5 years, and regular reviews of medical history, physical examination, and carcinoembryonic antigen testing should be performed every 3-6 months

• Annual computed tomography (CT) scanning of the abdomen and chest should be performed for 3 years

• Pelvic CT scanning should be performed in patients with rectal cancer annually for 3-5 years

• In patients who have not received pelvic radiation, a rectosigmoidoscopy should be performed every 6 months for 2-5 years

• A surveillance colonoscopy should be performed approximately 1 year after initial surgery

• Patients should be counseled to maintain a healthy body weight, be physically active, and follow a healthy diet

Colorectal cancer prevention strategies fall into three categories:

• Screening (see Workup)
• Lifestyle measures
• Pharmacologic prevention

Lifestyle measures

Abundant epidemiologic literature suggests an association of risk for developing colorectal cancer with dietary habits, environmental exposures, and level of physical activity. For example, a prospective cohort study in the general population of two Danish cities concluded that 23% of colorectal cancer cases might have been prevented if all participants had followed recommendations for the following five lifestyle factors ^[146] :

• Physical activity
• Waist circumference
• Smoking
• Alcohol intake
• Diet

A study of 79,952 men and 93,475 women who participated in the Multiethnic Cohort Study found that greater adherence to plant-based diets rich in healthy plant foods and low in less-healthy plant foods is associated with a reduced risk of colorectal cancer in men, but not in women. Plant foods designated as healthy were whole grains, fruits, vegetables, vegetable oils, nuts, legumes, and tea and coffee; those designated as less healthy were refined grains, fruit juices, potatoes, and added sugars. Benefits of a plant-based diet were greater in Japanese American, Native Hawaiian, and White groups than in African-American or Latino groups and for left colon and rectal tumors than right tumors. ^[147]  

There is also evidence that diet and physical activity affect the risk for recurrence of colon cancer. A prospective observational study involving patients with stage III colon cancer from the CALGB 89803 adjuvant chemotherapy trial demonstrated adverse effect with regards to risk for recurrence and increased mortality for patients following a "Western" diet (high intake of red meat, refined grains, fat, and sweets) versus a "prudent" diet (high intake of fruits and vegetables, poultry, and fish). ^[10]

In another observational study from the same cohort of patients, patients were prospectively monitored and physical activity was recorded. The study concluded that physical activity reduces the risk of recurrence and mortality in patients with resected stage III colon cancer. ^[148]

Calcium and vitamin D supplementation

Although earlier data had strongly indicated that calcium supplementation can help prevent colorectal cancer, and had suggested a preventive effect of vitamin D supplementation, a randomized trial by Baron et al found that daily supplementation with vitamin D3 (1000 IU), calcium (1200 mg), or both after removal of colorectal adenomas did not significantly reduce the risk of recurrent colorectal adenomas over a period of 3 to 5 years. ^[149]

However, a randomized trial by Barry et al suggested that vitamin D receptor genotype may affect the benefits of vitamin D3 supplementation. In their analysis of 41 single-nucleotide polymorphisms (SNPs) in vitamin D and calcium pathway genes in 1702 patients with colorectal adenomas, vitamin D3 supplementation decreased risk for advanced adenomas (but not adenomas overall) by 64% in study subjects with the AA genotype at the rs7968585 SNP, but increased risk by 41% in those with one or two G alleles. The benefits of calcium supplementation were not significantly linked to genotype. ^[150]

Circulating levels of 25 hydroxyvitamin D (25[OH]D) that are optimal for preventing colorectal cancer may be significantly higher than levels necessary for bone health, according to an international collaborative meta-analysis that pooled 17 cohorts. Although levels of 50 to < 62.5 nmol/L are considered adequate for bone health by the Institute of Medicine, the study found that levels of 75–< 87.5 were associated with 19% lower risk and levels of 87.5–< 100 nmol/L were associated with 27% lower risk. ^[151]

For each 25 nmol/L increment in circulating 25(OH)D, colorectal cancer risk was 19% lower in women and 7% lower in men. In addition, the study confirmed that vitamin D deficiency increases colorectal cancer risk: 25(OH)D levels of less than 30 nmol/L were associated with a 31% greater risk compared with adequate levels. ^[151]

Pharmacologic prevention

Pharmacologic prevention is based on the understanding of colorectal carcinogenesis and the availability of pharmacologic agents that are effective yet minimally toxic. The efficacy of these agents is usually first tested in high-risk populations.

Celecoxib (Celebrex), a selective cyclooxygenase-2 inhibitor, was first tested in patients with familial adenomatous polyposis (FAP). Celecoxib was effective in decreasing the number and size of polyps on serial colonoscopies, which was the primary surrogate endpoint for this trial. ^[152] The drug was approved for FAP patients, although it remains to be seen whether this intervention translates to reduced cancer incidence and prolonged survival.

Enthusiasm for cyclooxygenase-2 inhibitors as chemopreventive agents has dampened because of a high incidence of cardiovascular toxicity in trial patients, which led to the removal of rofecoxib from the market. Other nonsteroidal anti-inflammatory drugs (NSAIDs), such as sulindac and nonselective cyclooxygenase inhibitors, have been tested in lower-risk populations.

Aspirin use has been shown to be effective in both primary prevention of colorectal cancer (at doses of 300 mg or more daily for about 5 years ^[153] ) and secondary prevention (at doses ranging from 81 to 325 mg daily ^[154] ) of colorectal adenomas. The decrease in colon cancer risk with aspirin use may vary among population subgroups. However, body mass index, physical activity, and plasma C-peptide levels were shown to not have a significant impact on aspirin’s effect on colon cancer risk. ^[155]

Examination of questionnaire data collected from the Nurses’ Health Study and the Health Professionals Follow-up Study showed regular aspirin use was associated with lower risk of BRAF –wild-type colorectal cancer (multivariable hazard ratio [HR], 0.73) but not with BRAF -mutated cancer risk (multivariable HR, 1.03). Status of tumor PTGS2 expression or PIK3CA or KRAS mutation had no effect on this association. ^[156]

A 2013 study showed that low-dose aspirin taken every other day lowers the risk for colorectal cancer in middle-aged women. Nearly 40,000 women aged 45 and older were randomized to low-dose aspirin (100 mg) or placebo every other day for roughly 10 years; 84% were followed for an additional 7 years after treatment ended. At followup, colorectal cancer risk was lower in the aspirin group, mostly owing to a reduction in proximal colon cancer; this reduction in risk emerged after 10 years. ^[157]

American College of Gastroenterology (ACG) guidelines suggest the use of low-dose aspirin to reduce risk of colorectal cancer in individuals aged 50–69 years with a cardiovascular disease risk of 10% or higher over the next 10 years, who are not an increased risk for bleeding and are willing to take aspirin for at least 10 years. The ACG recommends against the use of aspirin as a substitute for colorectal cancer screening. ^[47]

Some trials focused on combined inhibition of polyamine production and cyclooxygenase inhibition. A report from a large randomized trial of a combination of sulindac and dimethylformamine (DMFO), an inhibitor of ornithine decarboxylase (ODC), described a dramatic effect of this combination in reducing polyp recurrence in patients with prior history of colon polyps. Confirmatory trials are ongoing. ^[158]