Colon Adenocarcinoma Treatment & Management

Systemic chemotherapy

5-Fluorouracil remains the backbone of chemotherapy regimens for colon cancer, both in the adjuvant and metastatic setting. In the past 10 years, it was established that combination regimens provide improved efficacy and prolonged progression-free survival in patients with metastatic colon cancer. In addition to 5-fluorouracil, oral fluoropyrimidines such as capecitabine (Xeloda) and tegafur are increasingly used as monotherapy or in combination with oxaliplatin (Eloxatin) and irinotecan (Camptosar). Some of the standard combination regimens employ prolonged continuous infusion of fluorouracil (FOLFIRI, FOLFOX)^[25] or capecitabine (CAPOX, XELOX, XELIRI). Availability of new classes of active drugs and biologics for colorectal cancer pushed the expected survival for patients with metastatic disease from 12 months 2 decades ago to about 22 months currently.

A meta-analysis of 6 randomized phase II and II trials examined the efficacy of capecitabine with oxaliplatin (CAP/OX) compared with fluorouracil with oxaliplatin (FU/OX) in metastatic colorectal cancer. CAP/OX resulted in a lower response rate but overall progression-free survival and overall survival were not affected and were similar in both treatment regimens. Characteristic toxicity occurred in the FU schedules and thrombocytopenia and hand-foot syndrome were more prominent in the CAP regimens.^[26]

In a study by Sehgal et al, capecitabine administered for a week on/week off schedule in a dose of 3000 mg/m² on days 1-7, combined with oxaliplatin/bevacizumab, for treatment of metastatic colorectal cancer did not appear to have any advantages over current standard first-line metastatic colorectal cancer treatment regimens. Cycles were repeated every 2 weeks.^[27]

In a phase III multicenter trial, Kim et al compared overall survival of second-line therapy for patients with advanced colorectal carcinoma refractory to fluorouracil. Fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) (n=246) versus irinotecan (n=245) was compared (crossover to the other treatment was mandated if disease progression occurred). Overall survival did not significantly differ between FOLFOX4 and irinotecan; 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.^[28]

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.^[29]

Key clinical questions relate to the most advantageous selection of drug combination and the sequence of different treatment options in individual patients with colorectal cancer. This information is to be derived from information on tumor biology, patient performance status, organ function, and pharmacogenomics testing.

A study by Seymour et al found that with appropriate designs, including reduced starting doses of chemotherapy, frail and elderly patients can participate in randomized controlled trials, which is important because they are often under-represented in such trials despite being frequently treated with chemotherapy.^[30]

Adjuvant (postoperative) chemotherapy

The standard therapy for patients with stage III and some patients with stage II colon cancer for the last 2 decades consisted of fluorouracil in combination with adjuncts such as levamisole and leucovorin.^{[31, 32, 33]} This approach has been tested in several large randomized trials and has been shown to reduce individual 5-year risk of cancer recurrence and death by about 30%.

Two recent large randomized trials (MOSAIC and NASBP-C06) investigated the addition of oxaliplatin to fluorouracil (FOLFOX4 and FLOX, respectively) and demonstrated a significant improvement in 3-year disease-free survival for patients with stage III colon cancer. The addition of irinotecan to fluorouracil in the same patient population provided no benefit based on the results from two large randomized trials (CALGB 89803 and PETACC 3). Another randomized study, XACT, demonstrated noninferiority of capecitabine (Xeloda) compared to 5-FU/leucovorin as adjuvant therapy for patients with stage III colon cancer. A large trial comparing capecitabine plus oxaliplatin (XELOX) versus FOLFOX has completed accrual, but survival data have not yet been reported.

Despite its role in the therapy of metastatic colon cancer, bevacizumab (anti-VEGF monoclonal antibody) 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).^[34]

The role of adjuvant chemotherapy for stage II colon cancer is controversial. 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-fluorouracil/leucovorin versus those in the control group. Ongoing adjuvant trials are investigating additional risk stratification of stage II colon cancer based on clinicopathological and molecular markers (ECOG 5202 trial).

Though information on results of adjuvant therapy in stage II and III colon cancer is limited, a data set assembled by the Adjuvant Colon Cancer Endpoints group with fluorouracil-based adjuvant therapy was recently analyzed. The authors concluded that adjuvant chemotherapy provides significant disease-free survival benefit because it reduces the recurrence rate particularly within the first 2 years of adjuvant therapy but with some benefit in years 3-4.^[35]

A study by O’Connor et al found that among Medicare patients with stage II colon cancer, with or without poor prognostic features, overall survival was not substantially improved by adjuvant chemotherapy.^[36]

A study by Ng et al found that statin use during and after adjuvant chemotherapy did not result in improved disease-free survival, recurrence-free survival, or overall survival in patients with stage III colon cancer.^[37]

Biologic agents

Bevacizumab (Avastin) was the first anti-angiogenesis drug to be approved in clinical practice and the first indication was for metastatic colorectal cancer. This is a humanized monoclonal antibody to vascular endothelial growth factor (VEGF) and a pivotal trial demonstrated improved progression-free and overall survival when bevacizumab was added to chemotherapy (IFL, fluorouracil plus irinotecan).

A pooled analysis of cohorts of older patients (aged 65 years or older) from 2 randomized clinical trials examined the benefit of bevacizumab plus fluorouracil-based chemotherapy in first-line treatment of metastatic colorectal cancer. The study concluded that adding bevacizumab to fluorouracil-based chemotherapy improved overall survival and progression-free survival in older patients as it does in younger patients, without increased risks of treatment in the older age group.^[38]

Two other biologic agents approved for colorectal cancer are epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies. Cetuximab (Erbitux) is a chimeric monoclonal antibody approved as monotherapy or in combination with irinotecan (Camptosar) in patients with metastatic colorectal cancer refractory to fluoropyrimidine and oxaliplatin therapy.^[39]

Panitumumab (Vectibix) is fully human monoclonal antibody and the current indication as a monotherapy for patients with colorectal cancer in whom combination chemotherapy failed or was not tolerated. A recent trial by Hecht et al evaluated panitumumab added to bevacizumab and chemotherapy (oxaliplatin- and irinotecan-based) as first-line treatment of metastatic colorectal cancer and concluded that the addition of panitumumab resulted in increased toxicity and decreased progression-free survival.^[40]

Two clinical trials investigated the role of panitumumab (fully human monoclonal antibody against the EGFR) in the first-line^[41] and in second-line^[42] in combination with chemotherapy (FOLFOX and FOLFIRI). The results of both studies suggest clinical benefit of adding panitumumab to chemotherapy for patients with wild-type KRAS colorectal cancer, in terms of improving progression-free survival (PFS) and response rate. Panitumumab becomes an option, or an alternative to cetuximab, for those patients who have tumors without KRAS mutation. No head-to-head comparisons between panitumumab containing combinations versus cetuximab or even bevacizumab (anti-VEGFR monoclonal antibody) chemotherapy combinations in patients with wild-type KRAS tumors have been reported, leaving it up to the oncologist to prioritize the choice or sequence of monoclonals in this patient population.

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.^[43]

Intratumoral KRAS gene mutation can predict sensitivity to anti-EGFR antibodies.^[44] Investigators from a large international trial exploring the benefit of adding cetuximab to first-line chemotherapy with FOLFIRI (CRYSTAL Trial) reported that only patients with wild-type KRAS derived clinical benefit from cetuximab. Patients with mutant KRAS had no clinical benefit from adding cetuximab to chemotherapy and experienced only unnecessary toxicity. KRAS mutations are present in about 40% of colon adenocarcinomas. Based on these results, testing for KRAS mutation has been already added to cetuximab indication by European regulatory agency (EMEA) and is expected to be added to United States indication by the FDA as well.

The addition of anti-EGFR antibody treatment to standard chemotherapy regimens for patients with advanced colorectal cancer improves progression-free survival for those with wild-type (but not mutant) KRAS status.^[45] Testing for KRAS gene mutation has proven to be a fair prediction for nonresponse to anti-EGFR antibody treatment.

Bokemeyer et al examined the overall response rate when combining cetuximab with oxaliplatin, leucovorin, and fluorouracil (FOLFOX-4), as opposed to the regimen without cetuximab, for first-line treatment of metastatic colorectal cancer in a randomized study. They also examined the influence of the KRAS mutation status. They concluded that the overall response rate for cetuximab plus FOLFOX-4 was higher than with FOLFOX-4 alone though a statistically significant increase in odds for a response with the addition of cetuximab could not be established, except in patients with KRAS wild-type tumors, for whom the addition of cetuximab increased chance of response and lowered risk of disease progression.^[46]

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.

Radiation therapy

While radiation therapy remains a standard modality for patients with rectal cancer, the role of radiation therapy is limited in colon cancer. It does not have a role in the adjuvant setting, and in metastatic settings, it is limited to palliative therapy for selected metastatic 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 and may extend indications for radiotherapy in the management of colon cancer in the future.

A prospective, multicenter, randomized phase III study by Hendlisz et al compared the addition of yttrium-90 resin to a treatment regimen of fluorouracil 300 mg/m² IV infusion (days 1-14 q8wk) with fluorouracil IV alone. Yytrium-90 was injected intra-arterially into the hepatic artery. Findings showed that the addition of radioembolization with yytrium-90 significantly improved time to liver progression and median time to tumor progression.^[47]

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.

• 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 where 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 who have been diagnosed with HNPCC, attenuated familial adenomatous polyposis, and metachronous cancers in separate colon segments or at times in acute malignant colon obstructions with unknown status of the proximal bowel.

The advent of laparoscopy has revolutionized the surgical approach of colonic resections for cancers. The same oncologic principles are respected. Large prospective randomized trials have demonstrated that there are no significant differences with regard to intraoperative or postoperative complications, perioperative mortality rates, readmission or reoperation rates, or rate of surgical wound recurrence. At a median follow-up of 7 years, no significant differences existed in the 5-year disease-free survival rate (69% versus 68% in the laparoscopy-assisted colectomy [LAC] and open colectomy groups, respectively) or overall survival (76% versus 75%). Overall laparoscopic colectomy provides comparable oncologic outcomes (cause-specific survival, disease recurrence, number of lymph nodes harvested) to those achieved with an open approach.^{[48, 49, 50, 51, 52, 53]}

Standard management of patients with metastatic disease is systemic chemotherapy. 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. Only randomized prospective data could eventually demonstrate the survival benefit of palliative resection for patients with stage IV colon cancer. Data presented at the American Society of Clinical Oncology 45th Annual Meeting in 2009 indicated that patients with asymptomatic surgically incurable colorectal cancer do not require immediate surgery for primary tumor removal.^[54]

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.^[55]

Curative intent resections of liver metastases have significantly improved long-term survival with acceptable postoperative morbidity. A multivariate analysis of 1001 patients who underwent potentially curative resection of liver metastases identified 5 factors as independent predictors of worse outcome: size greater than 5 cm, disease-free interval of less than a year, more than one tumor, primary lymph-node positivity, and CEA greater than 200 ng/mL.^[56]

A study by Venderbosch et al found that resection of the primary tumor is a prognostic factor for survival in patients with stage IV colorectal cancer; further studies are needed.^[57]

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 have 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 is correlated with tumor size. Hepatic arterial infusion (HAI) of chemotherapeutic agents such as FUDR is a consideration following partial hepatectomy.

Standard colectomies for adenocarcinoma of the colon are depicted in the image below.

• Surgical consultation

  • 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 advanced disease, surgical intervention may be helpful in palliative care of bleeding or obstruction.
• Gastroenterology consultation

  • Gastroenterology consultation is critical for screening of high-risk individuals (ie, people with 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 be necessary in the management of advanced disease. Recent advent of colorectal stents allows a nonsurgical management of impending obstruction in patients who present with unresectable, metastatic disease.
  • A study by Segnan et al found that a single flexible sigmoidoscopy screening in patients age 55-64 years is associated with a substantial reduction of colorectal cancer incidence and mortality.^[58]
  • 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.

Abundant epidemiological literature suggests association of risk for developing colorectal cancer with dietary habits, environmental exposures, and level of physical activity. Less is known about effect of diet and physical activity on the recurrence of colon cancer. A prospective observational study involving patients from the CALGB 89803 adjuvant 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) compared to patients with a "prudent" diet (high intake of fruits and vegetables, poultry, and fish).

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.

Kirkegaarde et al reported that adherence to a "healthy life style" recommendations based on physical activity, waist circumference, smoking, alcohol intake, and diet may significantly reduce colorectal cancer risk, by about 23%.^[59]

These interesting and important observations pave the way for future interventional studies involving diet and physical activity in patients with stage II and III colon cancer.

See Diet.