High-risk Colon Cancer Research Articles

Weekly 5-fluorouracil and leucovorin: achieving lower toxicity with higher dose-intensity in adjuvant chemotherapy after colorectal cancer resection

BackgroundCurrent standard therapy following resection of high-risk colon cancer is intravenous bolus5-fluorouracil (5-FU) with leucovorin (LV), but there is no consensus on the optimum regimen of these drugs: practice ranges from the high toxicity Mayo Clinic schedule to the very low toxicity weekly QUASAR schedule. We present data for a weekly schedule that aims to provide moderately dose-intense treatment with low toxicity. Patients and methodsOne hundred and sixty-two patients were studied: 60% male; median age 65 years (36% over 70 years); 94% colorectal primary. Treatment was intravenous bolus (5 min) 5-FU 425 mg/m2 plus d,l-LV 45 mg flat rate once weekly, for a planned 24 weeks. Data for toxicity, dose-reductions, delays and stoppages were collected. ResultsOverall, 20% of patients experienced any grade ≥3 toxicity, most commonly diarrhoea (14% patients). Dose reductions were made in 35% of patients (although only 21% required 20% or more reduction); toxicity contributed to a decision to stop treatment before 24 weeks in 16% of patients. Median delivered dose intensity (DI) was 96% of planned (407 mg/m2/week) during treatment, and 91% of planned (385 mg/m2/week) over the full 24 week treatment plan. Female sex and age >70 years were significantly associated with higher rates of toxicity and dose adjustment, and lower delivered DI. ConclusionsWeekly treatment at these doses is convenient and well-tolerated for the large majority of patients, and achieves DI comparable with the 5 days a month QUASAR schedule and other more toxic standard regimens.

Genetic testing for high-risk colon cancer patients

Colorectal cancer is the third leading cause of cancer-related deaths in both men and women in the United States and is estimated to have affected 148,000 people in 2002. The cumulative lifetime risk for colon cancer is approximately 5%–6%, and this risk is influenced by hereditary and lifestyle factors. In fact, 20%–30% of all colon cancer cases have a potentially definable inherited cause, and 3%–5% of colon cancers occur in genetically defined high-risk colon cancer family syndromes. Although the genes responsible for the cases of moderate-risk colon cancer remain to be characterized, many of the genes responsible for the high-risk colon cancer cases have already been determined. These genetic discoveries have been translated into clinical practice and have led to improved risk assessment through the use of genetic testing. The introduction into clinical practice of genetic testing for the assessment of colon cancer risk has led to more effective management strategies for patients with potentially high-risk colon cancer and has presented new challenges to the clinician because of the unique issues involved with genetic testing. In this review, an overview of the colon cancer high-risk syndromes, with a focus on the availability and indications for genetic testing, is presented.

Role of Radiotherapy in High-Risk Colon Cancer

Role of Radiotherapy in High-Risk Colon Cancer

North Central Cancer Treatment Group--Mayo Clinic trials in colon cancer.

The adjuvant treatment of colon cancer is now accepted as an effective therapy following surgical resection of the primary tumor in patients at high risk for relapse. Results of studies conducted in the last 10 years have confirmed the benefits of using various 5-fluorouracil (5-FU)-based chemotherapy regimens to decrease recurrence rates and improve patient survival. The North Central Cancer Treatment Group-Mayo Clinic studies have made a significant contribution to establishing the role of adjuvant therapy in colon cancer. Our first study to suggest the effectiveness of adjuvant chemotherapy in patients with stage III disease was reported in 1989. The study used a combination of 5-FU and the anthelminthic agent levamisole, tested because of its ability to positively modulate the human cellular immune system. The results of this study were confirmed by a larger Intergroup study (0035) showing significant decreases in relapse and death rates in stage III colon cancer patients treated with 5-FU plus levamisole compared with surgery alone. Clinical trials conducted throughout the 1990s tested various 5-FU based regimens against the standard 5-FU and levamisole combination. From these trials, the combination of 5-FU plus leucovorin emerged as the standard surgical adjuvant treatment of colon cancer. The efficacy of treatment with this regimen for 6 months was similar to that of a 1-year 5-FU plus levamisole regimen. These findings led to the design of trials in which 5-FU was combined with both leucovorin and levamisole. No differences in efficacy were found in any of the various combinations tested. Current clinical trials are investigating the use of newer agents such as CPT-II in the adjuvant setting. The results of these trials may further improve the efficacy of adjuvant therapy in patients with high-risk colon cancer.

North Central Cancer Treatment Group-Mayo Clinic trials in colon cancer

The adjuvant treatment of colon cancer is now accepted as an effective therapy following surgical resection of the primary tumor in patients at high risk for relapse. Results of studies conducted in the last 10 years have confirmed the benefits of using various 5-fluorouracil (5-FU)-based chemotherapy regimens to decrease recurrence rates and improve patient survival. The North Central Cancer Treatment Group-Mayo Clinic studies have made a significant contribution to establishing the role of adjuvant therapy in colon cancer. Our first study to suggest the effectiveness of adjuvant chemotherapy in patients with stage III disease was reported in 1989. The study used a combination of 5-FU and the anthelminthic agent levamisole, tested because of its ability to positively modulate the human cellular immune system. The results of this study were confirmed by a larger Intergroup study (0035) showing significant decreases in relapse and death rates in stage III colon cancer patients treated with 5-FU plus levamisole compared with surgery alone. Clinical trials conducted throughout the 1990s tested various 5-FU based regimens against the standard 5-FU and levamisole combination. From these trials, the combination of 5-FU plus leucovorin emerged as the standard surgical adjuvant treatment of colon cancer. The efficacy of treatment with this regimen for 6 months was similar to that of a 1-year 5-FU plus levamisole regimen. These findings led to the design of trials in which 5-FU was combined with both leucovorin and levamisoie. No differences in efficacy were found in any of the various combinations tested. Current clinical trials are investigating the use of newer agents such as CPT-II in the adjuvant setting. The results of these trials may further improve the efficacy of adjuvant therapy in patients with high-risk colon cancer.

Fluorouracil and Leucovorin with or without Interferon Alfa-2a as Adjuvant Treatment, in Patients with High-Risk Colon Cancer

Background: It has been shown in randomized studies that adjuvant treatment with the combination of fluorouracil (FU) and levamisole reduced the risk of recurrence and deaths of patients with stage III colon cancer. Pharmacological studies of FU led to its use in combination with a number of modulating agents including interferon-α and leucovorin (LV) that appear to enhance its activity in vitro. Furthermore, a meta-analysis suggested that the combination of FU with LV increased the response rate as compared to FU monotherapy in patients with advanced colorectal cancer. Purpose: To evaluate the impact of adjuvant treatment with the combination of FU and LV with or without interferon alfa-2a (IFN) on disease-free survival (DFS) and overall survival (OS) for patients with stage II or III colon cancer. Patients and Methods: From August 1989 to July 1997, 280 patients with stage II and III colon cancer entered the study and were randomly assigned to receive either the combination of FU (600 mg/m²/week × 6, followed by a 2-week rest) and LV (500 mg/m²/week × 6 as a 2-hour infusion, followed by a 2-week rest) for 4 cycles (group A, 139 patients), or the same chemotherapy plus recombinant IFN (3 MU subcutaneously 3 times a week) for 1 year (group B, 141 patients). Results: A total of 109 patients (78.9%) of group A and 119 (84.4%) of group B completed four cycles of chemotherapy. Also, 51.4% of patients of group A and 53.9% of group B received ≥80% of the planned dose of FU. One patient (group A) was found to be ineligible and was not included in the analysis. The median relative dose intensity of FU in the two groups was 0.90 and 0.85, respectively. As of August 1998, after a median follow up of 4 years, there was no significant difference in either 3-year DFS (group A, 83.1%; group B, 75.9%, p = 0.14) or OS (group A, 84.5%; group B, 80.0%, p = 0.27). In the Cox model, stage of disease, number of infiltrated nodes, tumor grade and presence of regional implants were identified as significant prognostic factors for OS. Grade 3–4 toxicities, mainly diarrhea, were observed in 26.1% of patients of group A and in 24.8% of group B. There were no treatment-related deaths. Conclusions: The addition of IFN to the combination of FU with LV postoperatively does not improve DFS and OS of patients with stage II or III colon cancer.

Expression of cripto and amphiregulin in colon mucosa from high risk colon cancer families.

We assessed the expression of the epidermal growth factor (EGF)-related peptides, cripto-I (CR-I) and amphiregulin (AR), in a small panel of human colon adenomas and carcinomas. CR-I immunoreactivity was found in 17/31 (55%) of colon adenomas, and in 33/39 (84%) colon carcinomas. AR immunostaining was observed in 16/26 adenomas (61%) and in 20/26 carcinomas (77%). CR-I and AR staining were also assessed in 29 specimens from 24 individuals that belong to families with high incidence of colorectal carcinoma, and in 5 non-high risk individuals. Expression of CR-I was detected in 18/29 (62%) of high risk colon mucosa specimens, but only in 1/5 (20%) specimens from non-high risk individuals, while AR staining was found in 20/29 (69%) and in 4/5 (80%) of colon mucosa samples from high and low risk individuals, respectively. A majority (21/29; 72%) of the specimens from the high risk individuals had a high proliferative rate, as measured by Ki-67 staining. A statistically significant correlation was found between high proliferative rate, increased expression of CR-I and reduced expression of AR in the mucosa specimens from high risk individuals, suggesting that these might represent early events in colon tumorigenesis.

Phase I Trial ofU racil-Tegafur (UFT) plus Oral Leucovorin: 28-Day Schedule

UFT [Taiho Pharmaceutical Co. Ltd., Tokyo, Japan; (BMS-200604), Bristol-Myers Squibb, Princeton, NJ], a fluorouracil prodrug, is an oral 4:1 molar concentration of uracil plus tegafur. This study examined the dose-limiting toxic effects and maximum tolerated dose of UFT plus leucovorin administered for 28 consecutive days followed by a 7-day rest period. A course of therapy was repeated every 35 days. UFT dose levels examined were 200 mg/m2/day, with planned escalations to 250, 300, 350, and 400 mg/m2/day; the leucovorin dose remained at 150 mg/day. Three patients were initially enrolled at each UFT dose level. The total daily doses of both UFT and leucovorin were divided into three doses administered every 8 hr. Diarrhea became the dose-limiting toxicity at 400 mg/m2/day UFT, with grade 3 diarrhea noted in 2 of the 3 patients receiving that dose. To further define a phase II UFT starting dose, 3 additional patients were entered at the 350 mg/m2 level; 3 of the 6 patients treated at this level developed grade 3 nonhematological toxic effects. No partial or complete responses were observed. The recommended phase II UFT starting dose is 300 mg/m2/day plus 150 mg/day leucovorin. Since neutropenia, significant mucositis, and “hand-foot syndrome“ were not observed with UFT plus leucovorin, the toxicity profile of this regimen appears favorable compared with that of intravenous regimens of fluorouracil plus leucovorin. This phase I trial of UFT served as the basis for a phase II trial, current phase III trials, and a national adjuvant therapy trial of UFT for high-risk colon cancer patients.

Adjuvant therapy for colon cancer.

Adjuvant therapy for colon cancer is now a mature and widely accepted standard of care for patients with resected large bowel tumors: adjuvant therapy for stage III colon cancer has also been shown to be highly cost-effective. The cost of 5-FU/levamisole therapy for stage III colon cancer per year of life saved is less than $ 5,000, which represents a favorable cost-benefit relationship for a medical intervention. The clinician managing a patient with colon cancer at the present time has several options for therapy. In patients with stage III colon cancer, therapy with 5-FU-based regimens clearly increases overall and disease-free survival. It is also clear that the results that have been obtained are not perfect; therefore, the first option of therapy should always be an ongoing clinical trial. Many such trials are available, and Table 7 lists currently active studies in the United States. The clinician managing a patient with stage III colon cancer who is not in a clinical trial may choose a variety of regimens administered for durations of 6 to 12 months (Table 8). The preponderance of evidence suggests that 5-FU plus levamisole for 12 months is equal in efficacy to 5-FU plus leucovorin-based regimens given for a shorter period of time. A clinician may still choose the 5-FU plus levamisole regimen because of the decreased oral, myelosuppressive, and diarrheal toxicities associated with that regimen as opposed to the 5-FU/leucovorin regimens. Portal vein infusion of fluorinated pyrimidines still must be considered investigational. Finally, although we cannot be absolutely sure about the benefit of adjuvant therapy in patients with resected node-negative colon cancer, the NSABP data suggest that some benefit may be seen in these patients. It is known that patients with stage II cancers demonstrating high-grade bowel obstruction or bowel perforation have poor prognoses with surgery alone. Such patients may be good candidates for adjuvant therapy. Also, a major effort to define high risk and low risk for recurrence in patients with stage II colon cancer by analyzing molecular genetic factors (tumor ploidy and alternations in tumor suppressor genes) may lead to a selection of Dukes B patients definitely requiring adjuvant therapy.

Colonic retinoblastoma protein and proliferation in cancer and non-cancer patients.

Both suppressor oncogene and proliferative activity are believed to indicate colon cancer risk. The retinoblastoma (Rb) gene is a suppressor oncogene affecting cell differentiation. Retinoblastoma gene inactivation is associated with tumour development. However, the relation of the Rb protein to cell proliferation and colon tumour formation is unknown. Retinoblastoma protein quantity was correlated with proliferative activity in flat, unaffected mucosa specimens from 36 cancer patients, 21 non-cancer control subjects and in 29 tumour tissue samples from cancer patients. Nuclear Rb protein was measured by using automated CAS-200 image analysis of monoclonal antibody labelled frozen sections from fresh, surgically removed tissue. All colon cells within 15 whole crypts were imaged. Proliferative activity was also measured by using analysis with Ki-67 monoclonal antibody. Retinoblastoma protein content correlated directly with proliferative activity in flat mucosa of non-cancer control subjects (r = 0.63; P < 0.001; n = 21). A significant correlation was also found in flat mucosa specimens of non-metastatic (Duke's stages A and B) cancer patients (r = 0.52; P < 0.01; n = 22). However, Rb protein did not correlate with proliferation in flat mucosa from metastatic (Duke's stages C and D) cancer patients (r = 0.03; NS; n = 14) or in cancer tissue (r = 0.068; NS; n = 29). Mucosal Rb protein in the colon normally increases as proliferation increases. Dissociation between Rb protein and colon proliferation may occur in flat mucosa in patients with a higher risk of metastatic tumour growth. Future studies comparing Rb protein quantity and proliferative activity may help identify high-risk colon cancer patients.

Recent advances in adjuvant chemotherapy in colonic cancers

Carcinoma of the large bowel is one of the most common malignant disease. In France, 15,000 died each year from the metastatic or locoregional progression of this cancer. In the past, effective surgical adjuvant therapy has been an elusive goal with no evidence of benefit from chemotherapy or immunotherapy. However, a meta-analysis published in 1988 showed that one-year adjuvant chemotherapy using 5-fluorouracil (5-FU) containing regimens may slightly improve survival. Accelerated progress has been made since 1990: in colon cancer with regional nodal metastasis (stage C tumor), therapy with combined 5-FU and levamisole has resulted in a 33% reduction in the death rate. Controlled clinical trials demonstrated improved tumor response rates when the combination of 5-FU and leucovorin was compared with single-agent 5-FU in patients with metastatic colorectal cancer. Recent results indicate that this combination is effective in preventing tumor relapse and improving survival in patients with high risk colon cancer (especially stage C tumor). The comparison of 5-FU and leucovorin to 5-FU and levamisole is ongoing; the preliminary results of these controlled trials showed that 6 months of adjuvant therapy with 5-FU and leucovorin is as effective as the standard 12 months 5-FU and levamisole regimen and less toxic. No clear adjuvant benefit has been established in patients with Dukes' stage B2 colon cancer. The lack of statistical power of the trials and the 80% overall survival rate of these patients may explain these negative results. Almost all the specialists of these tumors considered that it is possible to select patients who are at sufficiently high risk of recurrence so that treatment can be justified. These patients are those who presented initially with tumor perforation or obstruction, adherence to or invasion of adjacent organs, young patients. Clinical trials suggest a survival benefit from the direct portal administration of the 5-FU in the immediate post-operative period, although the magnitude of the effect is less than that seen in the systemic therapy trials.

Whole abdominal radiotherapy and concomitant 5-fluorouracil as adjuvant therapy in advanced colon cancer

This analysis was undertaken to assess whole abdomen radiation therapy and concurrent 5-fluorouracil for toxicity and patterns of failure in high-risk colon cancer patients after curative surgical resection. Eighteen patients were treated adjuvantly after curative resection. Four patients (22 percent) had Stage B and 14 (78 percent) had Stage C disease. Histology was poorly differentiated in 4 (22 percent) and moderately differentiated in 14 (78 percent) patients. Four patients received whole abdominal radiation only, 30 Gy at 1 Gy/day. Fourteen patients had an additional locoregional boost of 9.6 to 16 Gy at 1.6 Gy/day. The liver received 19.8 Gy at 0.67 Gy/day. 5-Fluorouracil was given as a continuous infusion during therapy. With a median follow-up of three years, 6 of 18 (33 percent) patients have relapsed. Failure occurred locally in 3 of 18 (17 percent) and distantly in 4 of 18 patients (22 percent). Four of six (67 percent) failures occurred in the liver. The five-year actuarial survival and disease-free survival were 78 percent and 66 percent, respectively. Median elapsed time on radiotherapy was 73 days, with 5 of 18 patients (28 percent) requiring two or more weeks of unplanned treatment breaks. Acute Grade 3 to 4 toxicity (diarrhea, leukopenia) occurred in 3 of 18 patients (17 percent), with late complications (bowel obstruction) occurring in 2 of 18 patients (11 percent). Whole abdominal radiotherapy with concomitant 5-fluorouracil appears to improve local control but not to prevent liver metastases. Significant toxicity resulted in frequent interruption of therapy and protracted its course. Whether this adjuvant regimen impacts on survival or offers an advantage over locoregional irradiation remains to be studied.

Adjuvant radiation therapy for colon cancer

Post-operative radiation therapy has been used in selected patients with colon cancer. In contrast with rectal cancer, the primary failure pattern in colon cancer is abdominal. Local failure does occur, but is less frequent and more difficult to detect. Retrospective data suggest a benefit from local/regional radiation therapy on local control and disease-free survival in subsets of patients compared to historical controls. An ongoing phase III intergroup trial (INT 0130) will determine if local/ regional radiation therapy improves the results of chemotherapy in subsets of patients with high-risk colon cancer. In general, the results of whole abdominal radiation plus 5-fluorouracil (5-FU) have been disappointing. However, the more recent data from the Southwest Oncology Group pilot trial are encouraging. In contrast to rectal cancer, where adjuvant chemotherapy plus radiation therapy is standard treatment in high-risk patients, the use of radiation therapy (either local/regional or whole abdomen) in colon cancer remains investigational.

Fluorouracil plus Levamisole as Effective Adjuvant Therapy after Resection of Stage III Colon Carcinoma: A Final Report

To determine the effectiveness of two adjuvant therapy regimens in improving surgical cure rates in stage III (Dukes stage C) colon cancer. Randomized, concurrently controlled clinical trial. Major cancer centers, universities, and community clinics affiliated with the North Cancer Treatment Group, the Southwest Oncology Group, and the Eastern Cooperative Oncology Group. Those who had had curative-intent resections of stage III colon cancer in the previous 1 to 5 weeks. Patients were assigned to observation only, to levamisole alone (50 mg orally three times/d for 3 days, repeated every 2 weeks for 1 year), or to this regimen of levamisole plus fluorouracil (450 mg/m2 body surface area intravenously daily for 5 days and then, beginning at 28 days, weekly for 48 weeks). Rates of cancer recurrence and death. Early- and late-treatment side effects. With all 929 eligible patients able to be followed for 5 years or more (median follow-up, 6.5 years), fluorouracil plus levamisole reduced the recurrence rate by 40% (P < 0.0001) and the death rate by 33% (P = 0.0007). Levamisole reduced the recurrence rate by only 2% and the death rate by only 6%. With few exceptions, toxicity was mild and patient compliance was excellent. No evidence of late side effects was seen. Fluorouracil plus levamisole is tolerable adjuvant therapy to surgery; it has been confirmed to substantially increase cure rates for patients with high-risk (stage III) colon cancer. It should be considered standard treatment for all such patients not entered into clinical trials.

Adjuvant treatment of colon cancer. A plea for a large-scale European trial

The is now compelling evidence that systemic adjuvant 5-fluorouracil (5-FU) based chemotherapy can delay or reduce recurrence after resection of high-risk (Dukes' C or TNM stage III) colon cancer. A meta-analysis of performed adjuvant studies with intraportal 5-FU suggests that an equal advantage can be obtained with this treatment modality. This might be related to the timing of chemotherapy rather than to the route. In the US large-scale cooperative studies are ongoing or completed that will answer important additional questions such as the more optimal systemic chemotherapy and the duration of treatment. The European Organization for Research and Treatment of Cancer (EORTC) Gastrointestinal Tract Cooperative Group has initiated a large-scale study that compares the combination of 'early' postoperative locoregional directed chemotherapy plus 'late' systemic chemotherapy with systemic chemotherapy only. A plea is made for participation in this European trial that requires 2000 patients.

ADJUVANT TREATMENT OF COLON-CANCER - A PLEA FOR A LARGE-SCALE EUROPEAN TRIAL

The is now compelling evidence that systemic adjuvant 5-fluorouracil (5-FU) based chemotherapy can delay or reduce recurrence after resection of high-risk (Dukes' C or TNM stage III) colon cancer. A meta-analysis of performed adjuvant studies with intraportal 5-FU suggests that an equal advantage can be obtained with this treatment modality. This might be related to the timing of chemotherapy rather than to the route. In the US large-scale cooperative studies are ongoing or completed that will answer important additional questions such as the more optimal systemic chemotherapy and the duration of treatment. The European Organization for Research and Treatment of Cancer (EORTC) Gastrointestinal Tract Cooperative Group has initiated a large-scale study that compares the combination of 'early' postoperative locoregional directed chemotherapy plus 'late' systemic chemotherapy with systemic chemotherapy only. A plea is made for participation in this European trial that requires 2000 patients.

Adjuvant therapy for adenocarcinoma of the rectum

Surgical resection continues to be the primary curative modality for patients with adenocarcinoma of the rectum. However, local tumor recurrence in the pelvis and/or distant metastasis may occur in spite of complete excision of grossly visible malignant disease. Surgical and pathologic staging can identify a subset of surgically treated rectal cancer patients at high risk for tumor relapse and death. Irradiation and chemotherapy have been used as adjuvant therapy in conjunction with surgery as single modalities and in combination for patients with high risk rectal cancer. Evidence from controlled clinical trials indicates a significant decrease in local tumor recurrence, and a significant improvement in disease-free and overall survival with the use of combined postoperative irradiation and chemotherapy in this setting. A current national clinical trial in the United States of America is studying whether irradiation can be combined with new chemotherapy regimens which have shown significant therapeutic benefit as surgical adjuvant therapy for patients with high risk colon cancer (5FU + levamisole) and for patients with metastatic colorectal cancer (5FU + leucovorin) to further improve the efficacy of surgical adjuvant therapy for adenocarcinoma of the rectum.

Improved outcome with postoperative radiation therapy in high risk colon cancer

Improved outcome with postoperative radiation therapy in high risk colon cancer

Enzymes used in predicting high risk to colon cancer

Attempts have been made to use enzyme assays primarily in tissue, to predict risk of colon cancer in high risk colon cancer families, and in patients with polyposis. Efforts have also been made to predict recurrence in surgically "cured" cancer patients. The use of thymidine kinase, ornithine decarboxylase, LDH isoenzymes, and other enzymes for these purposes will be reviewed.

Total abdominal irradiation for cancer of the colon

A retrospective analysis of 55 patients treated with whole abdominal irradiation following surgical excision for cancer of the colon is presented. Three groups of patients were given whole abdominal irradiation, eight with gross residual tumor following surgery, 17 with peritoneal seeding, and 30 who had complete surgical excision of the tumor but were felt to be at high risk for relapse. Only one of the eight patients with gross residual tumor, and one of the 17 with peritoneal metastases, are currently alive and well, with the majority dying from local or peritoneal metastases. The 5 year actuarial survival for the 30 patients irradiated following complete surgical excision is 55%. The treatment was well tolerated and few complications were observed. It is concluded that whole abdominal irradiation is ineffective for the treatment of colon cancer if peritoneal metastases are present, or if gross residual tumor is left behind following surgery. A randomized controlled clinical trial is being organized to test whether total abdominal irradiation is of benefit in terms of survival in high risk colon cancer patients following complete surgical removal.