Cancer of the colon is a highly treatable and often curable disease when localized to the bowel. Surgery is the primary form of treatment and results in cure in approximately 50% of patients. Recurrence following surgery is a major problem and often is the ultimate cause of death. The prognosis of colon cancer is clearly related to the degree of penetration of the tumor through the bowel wall and the presence or absence of nodal involvement. These 2 characteristics form the basis for all staging systems developed for this disease. Bowel obstruction and bowel perforation are indicators of poor prognosis. Elevated pretreatment serum levels of carcinoembryonic antigen (CEA) have a negative prognostic significance. Many other prognostic markers have been evaluated retrospectively in the prognosis of patients with colon cancer, although most, including allelic loss of chromosome 18q or thymidylate synthase expression, have not been prospectively validated. Microsatellite instability, also associated with hereditary nonpolyposis colon cancer, has been shown to be associated with improved survival independent of tumor stage in a population-based series of 607 patients less than 50 years of age with colorectal cancer. Age greater than 65 years at presentation is not a contraindication to standard therapies; acceptable morbidity and mortality, as well as long-term survival, are achieved in this patient population. Racial differences in overall survival after adjuvant therapy have been observed, without differences in disease-free survival, suggesting that comorbid conditions play a role in survival outcome in different patient populations.
Because of the frequency of the disease, the identification of high-risk groups, the demonstrated slow growth of primary lesions, the better survival of patients with early-stage lesions, and the relative simplicity and accuracy of screening tests, screening for colon cancer should be a part of routine care for all adults starting at age 50 years, especially for those with first-degree relatives with colorectal cancer. There are groups that have a high incidence of colorectal cancer. These groups include those with hereditary conditions, such as familial polyposis, hereditary nonpolyposis colon cancer (HNPCC), Lynch I Syndrome, Lynch II Syndrome, and ulcerative colitis. Together they account for 10% to 15% of colorectal cancers. Patients with HNPCC reportedly have better prognoses in stage-stratified survival analysis than patients with sporadic colorectal cancer, but the retrospective nature of the studies and possibility of selection factors make this observation difficult to interpret. More common conditions with an increased risk include: a personal history of colorectal cancer or adenomas, first degree family history of colorectal cancer or adenomas, and a personal history of ovarian, endometrial, or breast cancer. These high-risk groups account for only 23% of all colorectal cancers. Limiting screening or early cancer detection to only these high-risk groups would miss the majority of colorectal cancers.
Following treatment of colon cancer, periodic evaluations may lead to the earlier identification and management of recurrent disease. The impact of such monitoring on overall mortality of patients with recurrent colon cancer is limited by the relatively small proportion of patients in whom localized, potentially curable metastases are found. To date, there have been no large-scale randomized trials documenting the efficacy of a standard, postoperative monitoring program. Postoperative monitoring may detect asymptomatic recurrences that can be resected or metachronous tumors. CEA is a serum glycoprotein frequently used in the management of patients with colon cancer. A review of the use of this tumor marker suggests: that CEA is not a valuable screening test for colorectal cancer due to the large numbers of false-positive and false-negative reports; that postoperative CEA testing be restricted to patients who would be candidates for resection of liver or lung metastases; and that routine use of CEA alone for monitoring response to treatment not be recommended. However, the optimal regimen and frequency of follow-up examinations are not well defined, since the impact on patient survival is not clear and the quality of data is poor.
The current generation of large prospective randomized trials has demonstrated consistent evidence of benefit for systemic adjuvant chemotherapy employing fluorouracil (5-FU) plus either levamisole or leucovorin. In 1990, a large intergroup trial of 5-FU/levamisole reported prolonged disease-free and overall survival in patients with stage III colon cancer, compared to patients who received no treatment after surgery. This benefit has persisted with continued follow-up.
The National Surgical Adjuvant Breast and Bowel Project (NSABP) then reported a trial for stage II and III patients comparing the fluorouracil/semustine/ vincristine regimen to a weekly regimen of 5-FU plus high-dose leucovorin. This demonstrated a statistically significant benefit for 5-FU/leucovorin in both overall and disease-free survival. Adjuvant 5-FU plus leucovorin (in different treatment schedules) was also compared to surgery alone in 4 large randomized trials that closed prematurely in the early 1990s when surgery alone control arms were no longer felt to represent standard care for stage III patients. Three of these trials, conducted in Canada, France, and Italy, have had their primary data pooled and analyzed together. The 3-year recurrence- free and overall survival rates were also statistically significantly improved in this analysis. Taken together, about 4,000 patients have participated in the positive randomized trials comparing adjuvant chemotherapy to surgery alone with a reduction in mortality of between 22% and 33%. These results are quite clear in stage III patients but uncertain in stage II patients. Adjuvant treatment of stage III colon cancer appears to be cost- effective when costs of treatment and quality-of-life measures are taken into account.
At this time, patients with stage III (Dukes' C) colon cancer should be considered for adjuvant therapy with 5-FU/leucovorin for 6 to 8 months. Regional adjuvant therapy directed at reducing liver metastasis has been tested using both portal-vein infusion 5-FU and hepatic radiation, and an early trial by Taylor showed promising results. The preliminary results of confirmatory trials from the NSABP, the Mayo Clinic, and the United Kingdom Large Bowel Cancer Project, however, have failed to demonstrate a significant benefit for hepatic-directed adjuvant therapy in the reduction of liver recurrences. The NSABP trial, but not the Mayo Clinic trial, showed a modest benefit in survival but no change in the incidence of liver metastases. Neither prolongation of survival nor reduction of liver recurrences was seen in a Gastrointestinal Tumor Study Group study of adjuvant hepatic radiation with 5-FU.
For locally advanced disease, the role of radiation therapy with chemotherapy in colon cancer is under clinical evaluation. Palliation may be achieved in approximately 10% to 20% of patients with 5-FU. Several studies suggest an advantage when leucovorin is added to 5-FU in terms of response rate and palliation of symptoms, but not always in terms of survival. Irinotecan (CPT-11) has been approved by the Food and Drug Administration for the treatment of patients whose tumors are refractory to 5-FU. Participation in clinical trials is appropriate. A number of other drugs are undergoing evaluation for the treatment of colon cancer. Oxaliplatin, alone or combined with 5-FU and leucovorin, has also shown activity in 5-FU refractory patients.
Some retrospective studies suggest that perioperative blood transfusions impair prognosis of patients with colorectal cancer. A small, single-institution, prospective randomized trial found the need for allogeneic transfusions following resection of colorectal cancer was an independent predictor of tumor recurrence. This finding was not confirmed by a large, multi-institutional, prospective randomized trial which demonstrated no benefit for autologous blood transfusions when compared to allogeneic transfusions. Both studies established that patients who do not require any blood transfusion have a reduced risk of recurrence, but it would be premature to change transfusion procedures based on these results as other studies have not confirmed this finding. There are a large number of studies correlating various clinical, pathological, and molecular parameters with prognosis, but none of these parameters has been demonstrated to be as important as pathologic stage, and none yet has a major impact on choice of, or outcome from, therapy.
adenocarcinoma (majority of cases) mucinous (colloid) adenocarcinoma signet ring adenocarcinoma scirrhous tumorsneuroendocrine: Tumors with neuroendocrine differentiation typically
have a poorer prognosis than pure adenocarcinoma variants.
Treatment decisions should be made with reference to the TNM classification, rather than the older Dukes' or the Modified Astler-Coller (MAC) classification schema.
The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification.
Primary tumor (T)
TX:
Primary tumor cannot be assessed
T0: No evidence of primary tumor
Tis: Carcinoma in situ: intraepithelial or invasion of the lamina propria*
T1: Tumor invades submucosa
T2: Tumor invades muscularis propria
T3: Tumor invades through the muscularis propria into the subserosa, or into
nonperitonealized pericolic or perirectal tissues
T4: Tumor directly invades other organs or structures, and/or perforates
visceral peritoneum **
*Note: Tis includes cancer cells confined within the glandular basement membrane (intraepithelial) or lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa.
**Note: Direct invasion in T4 includes invasion of other segments of the colorectum by way of the serosa; for example, invasion of the sigmoid colon by a carcinoma of the cecum.
Regional lymph nodes (N)
NX:
Regional nodes cannot be assessed N0: No regional lymph node metastasis N1:
Metastasis in 1 to 3 regional lymph nodes N2: Metastasis in 4 or more regional
lymph nodes
A tumor nodule greater than 3 mm in diameter in the perirectal or pericolic fat
without histologic evidence of a residual node in the nodule is classified as
regional perirectal or pericolic lymph node metastasis. A tumor nodule 3 mm or
less in diameter is classified in the T category as a noncontiguous extension,
that is T3.
Distant metastasis (M)
MX:
Distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis
Tis, N0, M0
T1,
N0, M0
T2, N0, M0
T3,
N0, M0
T4, N0, M0
Any
T, N1, M0
Any T, N2, M0
Any T, Any N, M1
Standard treatment of colon cancer has been open surgical resection of the primary and regional lymph nodes for localized disease. The role of laparoscopic techniques in the treatment of colon cancer is under evaluation in a prospective randomized trial comparing laparoscopic colectomy to open colectomy. When resection can be performed with clear margins, patients whose tumors extend through the bowel wall and to adjacent structures have no worse prognosis than similarly staged patients without such invasion. Surgery is also curative in 20% of patients who develop resectable metastases in the liver. Many early trials of adjuvant chemotherapy failed to show a significant improvement in either overall or disease-free survival for patients receiving treatment compared to concurrently randomized control patients receiving no adjuvant therapy. These trials employed fluorouracil (5-FU) alone or 5-FU plus semustine (methyl-CCNU). The North Central Cancer Treatment Group (NCCTG) conducted a randomized trial comparing surgical resection alone with postoperative levamisole or 5-FU/levamisole. A significant improvement in disease-free survival was observed for patients with stage III (Dukes' C) colon cancer who received 5-FU/levamisole, but overall survival benefits were of borderline statistical significance. A survival benefit of approximately 12% (49% versus 37%) was seen in patients with stage III disease treated with 5-FU/levamisole. In a large, confirmatory intergroup trial, 5-FU/levamisole prolonged disease-free and overall survival in patients with stage III colon cancer, compared to patients who received no treatment after surgery. Levamisole alone did not confer these benefits. In 1990, a National Institutes of Health Consensus Panel recommended that adjuvant therapy with 5-FU/levamisole be considered for patients with stage III (Dukes' C) colon cancer.
A study comparing 5-FU and leucovorin with fluorouracil/semustine/vincristine has demonstrated a statistically significant benefit in both survival and disease-free survival for the 5-FU/leucovorin arm. The National Surgical Adjuvant Breast and Bowel Project (NSABP) regimen used 5- FU at 500 milligrams per square meter daily and high-dose leucovorin at 500 milligrams per square meter daily, both administered every seventh day for 6 weeks out of every 8 weeks for 1 year. A controlled trial of postoperative 5- FU plus leucovorin compared to surgery alone has also demonstrated a disease- free and overall survival advantage for the NCCTG regimen of 5-FU at 425 milligrams per square meter daily and low-dose leucovorin at 20 milligrams per square meter daily for 5 days repeated every 4 to 5 weeks for 6 months of chemotherapy. Investigators from the International Multicentre Pooled Analysis of Colon Cancer Trials have combined data from 3 other trials for patients with stages II and III (Dukes' B and C) colon cancer using either no postoperative therapy or 5-FU at 370 to 400 milligrams per square meter plus intermediate-dose leucovorin at 200 milligrams per square meter daily for 5 days every 28 days for 6 cycles. A statistically significant improvement in disease-free and overall survival was demonstrated in all patients receiving adjuvant therapy.
The NCCTG performed a trial comparing 6 months to 12 months of treatment using either 5-FU and levamisole or 5-FU, levamisole, and leucovorin for patients with stages II and III (Dukes' B and C or MAC B2, B3, and C1-3) colon cancer. The trial showed that for equivalent survival benefit, the 5-FU plus levamisole regimen must be given for 12 months, while the 3-drug regimen could be administered over just 6 months. An intergroup trial with 4 treatment arms, including 5-FU plus levamisole, 5-FU plus low-dose leucovorin (the NCCTG regimen), 5-FU plus high-dose leucovorin (the NSABP regimen), or 5-FU plus leucovorin plus levamisole, has been reported in preliminary fashion. This study also demonstrated that 6 months of 5-FU plus leucovorin is at least as effective as 12 months of 5-FU/levamisole. The NSABP C-04 study found equivalent results in overall survival for 1 year of 5-FU plus high-dose leucovorin when compared to 1 year of 5-FU plus levamisole. The addition of levamisole to 5-FU and leucovorin did not improve disease-free or overall survival. Mature data from NSABP C-05 suggest no survival benefit from the addition of interferon alfa-2a to 5-FU and high-dose leucovorin, but did note a substantial increase in grade 3 or higher toxic effects.
Based on the outcomes of all of these trials, a recommendation was made at the 1997 American Society of Clinical Oncology meeting that any 1 of 3 regimens could be considered for postoperative treatment of patients with stage III colon cancer, all of which have resulted in a survival advantage over no postoperative chemotherapy. These include the NCCTG regimens of 5-FU and levamisole for 1 year, or 5-FU and low-dose leucovorin for 6 months, or the NSABP regimen of 5-FU and high-dose leucovorin for 6 months. At this time, there are insufficient data to determine if there is any advantage to the 3- drug combination of 5-FU and leucovorin and levamisole over any of the previously noted 2-drug regimens. There is also insufficient data to distinguish whether high-, intermediate-, or low-dose leucovorin is most advantageous as a modulator of 5-FU.
Based on survival benefits from an early trial of adjuvant portal-vein 5-FU infusion in patients with colon cancer, a number of confirmatory trials were conducted. The preliminary results of these studies have failed to demonstrate a significant benefit for hepatic-directed adjuvant therapy in the reduction of liver recurrences. However, a meta-analysis has shown a modest improvement in overall survival when patients are treated with portal- vein 5-FU infusion as compared to no postoperative therapy. This technique for adjuvant therapy is therefore of some historical interest and should generally not be employed because of more effective systemic adjuvant regimens administered by the more convenient peripheral intravenous route. A randomized trial by the Swiss Group for Clinical Cancer Research revealed no survival difference between systemic 5-FU versus portal-vein 5-FU infusion versus surgery alone in 769 patients with resected colon or rectal cancer. However, the Intergroup currently has an open trial that tests the hypothesis of perioperative systemic delivery of 5-FU chemotherapy.
The potential value of adjuvant therapy for patients with stage II (Dukes' B or MAC B2 or B3) colon cancer also remains a controversial issue. Investigators from the NSABP have indicated that the reduction in the risk of recurrence by adjuvant therapy in patients with stage II disease is of similar magnitude to the benefit seen in patients with stage III disease treated with adjuvant therapy, although an overall survival advantage has not been established. However, a randomized trial of post-operative 5-FU plus levamisole compared to surgery alone showed no survival advantage to postoperative adjuvant chemotherapy. A meta-analysis of 1000 stage II patients whose experience was amalgamated from a series of trials indicates a 2% advantage in disease- free survival at 5 years when adjuvant therapy treated patients treated with 5- FU/leucovorin are compared to untreated controls. Patients with stage II colon cancer remain candidates for clinical trials in which either surgery alone or 5-FU/leucovorin represents standard therapy.
Chemotherapy trials, typically with 5-FU-based regimens, have demonstrated increased numbers of partial responses and prolongation of the time to progression of disease, as well as improved survival and quality of life for patients receiving chemotherapy compared to best supportive care. Several trials have analyzed the activity and toxic effects of various 5-FU plus leucovorin regimens in patients 70 years of age or older as compared to younger patients. Similar quantitative and qualitative toxic effects of therapeutic outcomes have been observed for patients of all ages. Patients should be considered candidates for clinical trials evaluating new approaches to treatment. Irinotecan (CPT-11) is a topoisomerase-I inhibitor with a 10% to 20% partial response rate in patients with metastatic colon cancer, in patients who have received no prior chemotherapy, and in patients progressing on 5-FU therapy. It has been approved by the Food and Drug Administration for the treatment of patients with metastatic disease that is refractory to 5-FU.
The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.
Stage 0 colon cancer is the most superficial of all the lesions and is limited to the mucosa without invasion of the lamina propria. Because of its superficial nature, the surgical procedure may be limited.
Treatment options:
1.
Local excision or simple polypectomy with clear margins.
2. Colon resection for larger lesions not amenable to local excision.
Because of its localized nature, stage I has a high cure rate.
Treatment options:
Wide surgical resection and anastomosis.
Treatment options:
1.
Wide surgical resection and anastomosis.
2. Following surgery, patients should be considered for entry into carefully
controlled
clinical trials evaluating the use of systemic or regional
chemotherapy,1
radiation therapy, or biologic therapy. Information
about ongoing clinical trials is available from the NCI
http://cancernet.nci.nih.gov/trialsrch.shtml
Adjuvant therapy
is not indicated for most patients unless they are entered into a clinical
trial.
Although subgroups of patients with stage II colon cancer may be at higher than average risk for recurrence (including those with anatomic features such as tumor adherence or fixation to adjacent structures (MAC stage B3), perforation, complete obstruction, or with biologic characteristics such as aneuploidy, high S-phase analysis, or deletion of 18q), there is no consistent evidence that adjuvant 5-fluorouracil-based chemotherapy is associated with an overall improved survival compared with surgery alone. In some trials, subset analysis of adjuvant chemotherapy has demonstrated benefits in disease-free and overall survival compared with surgery alone, but such treatment has not been considered standard for all stage II patients. Improved local control with postoperative radiation therapy has been suggested in patients with T3 and T4 tumors; an intergroup clinical trial designed to explore the role of adjuvant combined chemotherapy and radiation therapy compared with postoperative chemotherapy alone for selected patients with this high-risk stage II colon cancer was closed because of low accrual. However, preliminary results, published only in abstract form, have not suggested a survival advantage from routine postoperative adjuvant radiation therapy in this subgroup of patients.
Stage III colon cancer denotes lymph node involvement. Studies have indicated that the number of lymph nodes involved affects prognosis: patients with 1 to 3 involved nodes have a significantly better survival than those with 4 or more involved nodes. Improved local control with postoperative radiation therapy has been suggested in patients with adherence or fixation to adjacent structures. Intraoperative electron beam radiation therapy, to the site of residual microscopic or gross residual disease following surgical extirpation, has also been reported to improve local control when combined with external beam radiation therapy and chemotherapy. However, preliminary results, published only in abstract form, have not suggested a survival advantage from routine postoperative adjuvant radiation therapy in this subgroup of patients. (Refer to the discussion of adjuvant therapy in the treatment option overview section of this summary.)
In the late 1980s, a passive immunotherapy approach to adjuvant treatment of stage III colorectal cancer demonstrated encouraging results in a single randomized trial. This trial compared postoperative administration of a murine monoclonal antibody to 17-1A antigen (MOAB 17-1A), a cell surface glycoprotein of uncertain function expressed on both normal and malignant epithelial cells, to surgery alone. Treated patients appeared to have a survival benefit comparable to that seen in adjuvant chemotherapy trials, with a relative reduction in mortality of 32%.
Treatment options:
1. Wide surgical resection and anastomosis. For patients who are not
candidates
for clinical trials, postoperative chemotherapy with
fluorouracil (5-FU)/leucovorin for 6 months. 5-FU/levamisole for 12
months may also be considered, although at least 1 trial has shown this
to be inferior in survival to 6 months of 5-FU plus high-dose
leucovorin. Levamisole does not appear to be a
mandatory component of adjuvant therapy.
2. Eligible patients should be considered for entry into carefully
controlled
clinical trials comparing various postoperative chemotherapy
regimens, postoperative radiation therapy, or biological therapy, alone or
in combination. Information about ongoing clinical trials is
available from the NCI http://cancernet.nci.nih.gov/trialsrch.shtml
Stage IV colon cancer denotes distant metastatic disease. Local regional approaches to treating liver metastases include hepatic resection and/or intraarterial administration of chemotherapy with implantable infusion ports or pumps. For patients with limited (3 or less) hepatic metastases, resection may be considered with 5-year survival rates of 20% to 40%. For those patients with hepatic metastases deemed unresectable (due to factors such as location, distribution, excessive number), cryosurgical ablation has been associated with long-term tumor control. Prognostic variables that predict a favorable outcome for cryotherapy are similar to those for hepatic resection and include low preoperative carcinoembryonic antigen level, absence of extrahepatic disease, negative margin, and lymph node negative primary. Other local ablative techniques that have been used to manage liver metastases include embolization and interstitial radiation therapy. Limited pulmonary metastases may also be considered for surgical resection, with 5-year survival possible in highly selected patients. The role of additional systemic therapy after potentially curative resection of liver metastases is uncertain. A trial of hepatic arterial floxuridine plus systemic fluorouracil (5-FU) plus leucovorin was shown to result in improved 2-year disease-free and overall survival (86% versus 72%, but did not show a significant statistical difference in median survival, compared to systemic 5-FU therapy alone. Further studies are required to confirm these findings and to determine whether more effective combination chemotherapy alone may provide similar results compared to hepatic intra-arterial therapy plus systemic treatment.
Hepatic intra-arterial chemotherapy with floxuridine for liver metastases has produced higher overall response rates but no consistent improvement in survival when compared to systemic chemotherapy. Controversy regarding the efficacy of regional chemotherapy has led to initiation of a large multicenter phase III trial (CALGB-9481) of hepatic arterial infusion versus systemic chemotherapy. The use of the combination of intraarterial chemotherapy with hepatic irradiation, especially employing focal radiation of metastatic lesions, is under evaluation. Several studies show increased local toxic effects with hepatic infusional therapy, including liver function abnormalities and fatal biliary sclerosis.
In stage IV and recurrent colon cancer, chemotherapy has been used for palliation, with 5-FU-based treatment considered to be standard. 5-FU has been shown to be more cytotoxic, with increased response rates but with variable effects on survival, when modulated by leucovorin or methotrexate. Randomized clinical trials show that interferon alfa appears to add toxic effects but no clinical benefit to 5-FU therapy. Continuous-infusion 5-FU regimens have also resulted in increased response rates in some studies, with a modest benefit in median survival. The benefits of continuous infusion 5-FU compared to bolus regimens have been summarized in a meta-analysis. Oral fluoropyrimidines are also being evaluated in phase II-III trials. Oral regimens using prodrugs of 5-FU or inhibitors of dihydropyrimidine dehydrogenase (DPD) (GW 776C85) pharmacologically simulate continuous infusion and are under clinical evaluation. The choice of a 5-FU-based chemotherapy regimen for an individual patient should be based on known response rates and the toxic effects profile of the chosen regimen, as well as cost and quality-of-life issues. In a meta-analysis of 1219 patients in randomized trials where patients were assigned to receive 5-FU with or without leucovorin via either continuous infusion or bolus, neutropenia was noted in 4% of patients who received continuous infusion versus 31% of patients who received bolus and hand-foot syndrome was found in 34% of patients who received continuous infusion versus 13% of patients who received bolus. All other toxic effects were noted with similar frequency and severity, regardless of continuous- infusion or bolus administration.
DPD is the rate-limiting enzyme in the degradation pathway for 5-FU. While genetic polymorphism commonly results in considerable individual variability in levels of this enzyme, between 0.5% and 3% of the population are severely DPD deficient. Severe mucositis, neutropenia, diarrhea, and cerebellar dysfunction can result in toxic deaths among patients who are DPD deficient. Standard testing for DPD is not widely available, but one study found that patients with a pretreatment ratio of dihydrouracil to uracil of 1.8 or less were at risk of increased 5-FU toxic effects.
Irinotecan (CPT-11) is a topoisomerase-I inhibitor with a 10% to 20% partial response rate in patients with metastatic colon cancer, in patients who have received no prior chemotherapy, and in patients progressing on 5-FU therapy. It is now considered standard therapy for patients with stage IV disease who do not respond to or progress on 5-FU.
CPT-11 has been compared to either retreatment with 5-FU or best supportive care in a pair of randomized European trials of patients with colorectal cancer refractory to 5-FU. In both trials, there was a survival and quality-of-life advantage for patients treated with CPT-11 over 5-FU or supportive care.
Two phase III prospective randomized, controlled trials were designed to evaluate the combination of 5-FU, leucovorin, and CPT-11 to 5-FU and leucovorin alone. The first of these trials compared the bolus 5-FU, leucovorin, and CPT- 11 to bolus 5-FU and leucovorin alone and to CPT-11; the primary endpoint was progression-free survival. The trial demonstrated significant benefit in terms of confirmed response rates, time-to-tumor progression, and overall survival. The combination treatment showed confirmed responses in 39% of patients, compared with 21% in patients treated with 5-FU and leucovorin alone and 18% in patients treated with CPT-11. This benefit was highly significant in favor of the combination. In addition, time- to-tumor progression was significantly prolonged with the combination (7.0 versus 4.3 months. Median survival was also improved with the combination; median survival was 14.8 months for patients on the combination arm and 12.6 months for patients on the 5-FU and leucovorin arm .
The second pivotal trial of combination chemotherapy with CPT-11 compared 2 different regimens of infusional 5-FU and folinic acid. Either weekly or biweekly CPT-11 was administered according to the schedule of the infusional 5-FU. This trial also demonstrated improvements in response rate, time-to-tumor progression, and median survival. For the most important endpoint, median survival, the combination arm was associated with a median survival of 17.4 months, compared with 14.1 months for the 5-FU and folinic acid arm. A combined analysis of the survival advantages seen in these 2 trials was presented at the 2000 American Society of Clinical Oncology meeting. The combined survival for the combination of CPT-11, 5-FU, and leucovorin was 15.9 months, compared to 13.3 months for the non-CPT-11 regimen. This represents a survival hazard ratio of 0.79.
Another drug, Tomudex, is a specific thymidylate synthase inhibitor which has demonstrated activity similar to that of bolus 5-FU and leucovorin. A number of other drugs are undergoing evaluation for the treatment of colon cancer.
Oxaliplatin, alone or combined with 5-FU and leucovorin, has shown promising activity in previously treated and untreated patients with metastatic colorectal cancer and in patients with 5-FU refractory disease. One multicenter trial reported a response rate of 21%, a median progression-free survival of 5 months, and a median survival of 11 months. Overall survival from the start of first-line chemotherapy was 19 months. In this trial, oxaliplatin was given first, followed by 48-hour infusion of 5-FU, with short leucovorin infusion. Clinical trials evaluating oxaliplatin plus 5-FU and leucovorin and oxaliplatin plus CPT-11 as first- and second-line therapy and adjuvant therapy in patients with advanced disease are underway in North America and Europe.
Patients with advanced colon cancer who have relapsed after either adjuvant therapy or treatment for advanced disease with 5-FU and leucovorin may be considered for additional therapy. A number of approaches have been used in the treatment of such patients, including retreatment with 5-FU and treatment with CPT-11. Patients retreated with bolus or infusional 5-FU following adjuvant 5-FU therapy or discontinuation of 5-FU in responding patients with metastatic disease have response rates and response durations similar to previously untreated patients.
Treatment options:
1. Surgical resection/anastomosis or bypass of obstructing primary lesions
in selected cases.
2. Surgical resection of isolated metastases (liver, lung,
ovaries).
3. Chemotherapy.
4. Clinical trials evaluating new drugs and biologic therapy.
5. Radiation therapy.
Treatment of recurrent colon cancer depends on the sites of recurrent disease demonstrable by physical examination and/or radiographic studies. In addition to standard radiographic procedures, radioimmunoscintography may add clinical information which may affect management.1 However, such approaches have not led to improvements in long-term outcome measures such as survival. Unique approaches to treating liver metastases include resection of metastases, cryotherapy, and/or intra-arterial chemotherapy using improved implantable infusion ports and pumps. Hepatic intra-arterial chemotherapy with floxuridine has produced a higher overall response rate but no consistent improvement in survival, even when combined with resection of hepatic metastases. Several studies show increased local toxic effects, including liver function abnormalities and fatal biliary sclerosis. Local ablative techniques for elimination of liver metastases have been used, including cryosurgery, embolization, and ultrasound techniques. However, some evidence suggests that survival may be enhanced in some patients if resection results in no remaining measurable tumor. For those patients with hepatic metastases deemed unresectable (due to factors such as location, distribution, excessive number), cryosurgical ablation has been associated with long term tumor control. Prognostic variables that predict a favorable outcome for cryotherapy are similar to those for hepatic resection and include low preoperative carcinoembryonic antigen level, absence of extrahepatic disease, negative margin, and lymph node (negative primary). Locally recurrent colon cancer, such as a suture line recurrence, may be resectable, particularly if an inadequate prior operation was performed. Limited pulmonary metastases may also be considered for surgical resection, with 5-year survival possible in highly selected patients.
In stage IV and recurrent colon cancer, chemotherapy has been used for palliation, with fluorouracil (5-FU)-based treatment considered to be standard. 5-FU has been shown to be more cytotoxic, with increased response rates but with variable effects on survival, when modulated by leucovorin, methotrexate, or other agents. Interferon alfa appears to add toxic effects but no clinical benefit to 5-FU therapy. Continuous-infusion 5-FU regimens have also resulted in increased response rates in some studies, with a modest benefit in median survival. The benefits of continuous-infusion 5-FU compared to bolus regimens have been summarized in a meta-analysis. Oral regimens using prodrugs of 5-FU or inhibitors of DPD (GW 776C85) pharmacologically simulate continuous infusion and are under clinical evaluation. The choice of a 5-FU-based chemotherapy regimen for an individual patient should be based on known response rates and the toxic effects profile of the chosen regimen, as well as cost and quality- of-life issues. Innovative ways of altering toxic effects patterns, and potentially improving clinical benefit, include chronomodulated therapy, in which drug doses are varied throughout the day to allow for greater dose intensity without increased toxic effects. In a meta-analysis of 1219 patients in randomized trials where patients were assigned to receive 5-FU with or without leucovorin via either continuous infusion or bolus, neutropenia was noted in 4% of patients who received continuous infusion versus 31% of patients who received bolus and hand-foot syndrome was found in 34% of patients who received continuous infusion versus 13% of patients who received bolus. All other toxic effects were noted with similar frequency and severity, regardless of continuous-infusion or bolus administration.
Irinotecan (CPT-11) is a topoisomerase-I inhibitor with a 10% to 20% partial response rate in patients with metastatic colon cancer, in patients who have received no prior chemotherapy, and in patients progressing on 5-FU therapy. It is now considered standard therapy for patients with stage IV disease who do not respond to or progress on 5-FU.
CPT-11 has been compared to either retreatment with 5-FU or best supportive care in a pair of randomized European trials of patients with colorectal cancer refractory to 5-FU. In both trials, there was a survival and quality-of-life advantage for patients treated with CPT-11 over 5-FU or supportive care.
Two phase III prospective randomized, controlled trials were designed to evaluate the combination of 5-FU, leucovorin, and CPT-11 to 5-FU and leucovorin alone. The first of these trials compared the bolus 5-FU, leucovorin, and CPT- 11 to bolus 5-FU and leucovorin alone and to CPT-11; the primary endpoint was progression-free survival. The trial demonstrated significant benefit in terms of confirmed response rates, time-to-tumor progression, and overall survival. The combination treatment showed confirmed responses in 39% of patients, compared with 21% in patients treated with 5-FU and leucovorin alone and 18% in patients treated with CPT-11. This benefit was highly significant in favor of the combination. In addition, time- to-tumor progression was significantly prolonged with the combination (7.0 versus 4.3 months). Median survival was also improved with the combination; median survival was 14.8 months for patients on the combination arm and 12.6 months for patients on the 5-FU and leucovorin arm.
The second pivotal trial of combination chemotherapy with CPT-11 compared 2 different regimens of infusional 5-FU and folinic acid. Either weekly or biweekly CPT-11 was administered according to the schedule of the infusional 5-FU. This trial also demonstrated improvements in response rate, time-to-tumor progression, and median survival. For the most important endpoint, median survival, the combination arm was associated with a median survival of 17.4 months, compared with 14.1 months for the 5-FU and folinic acid arm . A combined analysis of the survival advantages seen in these 2 trials was presented at the 2000 American Society of Clinical Oncology meeting. The combined survival for the combination of CPT-11, 5-FU, and leucovorin was 15.9 months, compared to 13.3 months for the non-CPT-11 regimen. This represents a survival hazard ratio of 0.79.
Another drug, Tomudex, is a specific thymidylate synthase inhibitor which has demonstrated activity similar to that of bolus 5-FU and leucovorin. A number of other drugs are undergoing evaluation for the treatment of colon cancer. Oxaliplatin plus 5-FU and leucovorin has also shown activity in previously untreated and 5-FU refractory patients.
Oxaliplatin, alone or combined with 5-FU and leucovorin, has shown promising activity in previously treated and previously untreated patients with metastatic colorectal cancer and in patients with 5-FU refractory disease. One multicenter trial reported a response rate of 21%, a median progression-free survival of 5 months, and a median survival of 11 months. Overall survival from the start of first-line chemotherapy was 19 months. In this trial, oxaliplatin was given first, followed by 48-hour infusion of 5-FU, with short leucovorin infusion. Clinical trials evaluating oxaliplatin plus 5-FU and leucovorin and oxaliplatin plus CPT-11 as first- and second-line therapy and adjuvant therapy in patients with advanced disease are underway in North America and Europe.
Patients with advanced colon cancer who have relapsed after either adjuvant therapy or treatment for advanced disease with 5-FU and leucovorin may be considered for additional therapy. A number of approaches have been used in the treatment of such patients, including retreatment with 5-FU and treatment with CPT-11. Patients retreated with bolus or infusional 5-FU following adjuvant 5-FU therapy or discontinuation of 5-FU in responding patients with metastatic disease have response rates and response durations similar to previously untreated patients.
Treatment options:
1. Resection of liver metastases in selected patients (5-year cure
rate
for resection of solitary or combination metastases exceeds
20%).
2. Resection of isolated pulmonary or ovarian metastases.
3. Surgical resection of locally recurrent cancer.
4. Palliative radiation therapy.
5. Palliative chemotherapy.
6. Clinical trials evaluating biological therapy.
7. Chemotherapy phase I and II clinical trials, mostly relating
to
biochemical modulation of fluoropyridines and continuous-infusion
schedules, or oral fluoropyrimidine programs simulating continuous
infusion.
Date Last Modified: 12/2000
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