Node-positive Colon Cancer Research Articles

Preoperative carcinoembryonic antigen predicts outcomes in node-negative colon cancer patients: a multivariate analysis of 572 patients

Background: Although prospective trials have demonstrated that postoperative chemotherapy for nodepositive colon cancer patients provides survival benefit, no improvement in survival has been documented for node-negative colon cancer patients. There are, however, a subset of node-negative patients that go on to die of their disease. We hypothesize that this subset of node-negative patients may benefit from postoperative chemotherapy. We analyzed a large cohort of nodenegative colon cancer patients from a single institution to determine prognostic factors that predict which patients with node-negative colon cancer might experience recurrence and can benefit from postoperative chemotherapy. Study Design: A review of the prospective database for colorectal cancer at Memorial Sloan-Kettering Cancer Center (MSKCC) between 1985 and 1993 identified 572 patients who underwent curative resection for nodenegative colon cancer (T 1,2,3,4N 0M 0). Demographic, serum, and pathologic factors were analyzed for prognostic significance. Survival was calculated by the method of Kaplan-Meier and compared by log rank test. Multivariate analysis was calculated by the Cox proportional hazard model. Results: Median follow-up was 35 months. Factors predictive of survival by univariate analysis include tumor stage, overall stage, and preoperative serum carcinoembryonic antigen (CEA) elevation. By multivariate analysis, overall stage and preoperative serum CEA level predicted survival. Conclusions: Routine histologic and demographic factors do not predict outcome in node-negative colon cancer patients. Preoperative CEA and overall stage predict survival by multivariate analysis. Preoperative CEA elevation in node-negative patients identifies a group of patients that has a poor prognosis and defines a subset of patients who may benefit from postoperative chemotherapy.

Preoperative carcinoembryonic antigen predicts outcomes in node-negative colon cancer patients: a multivariate analysis of 572 patients.

Although prospective trials have demonstrated that postoperative chemotherapy for node-positive colon cancer patients provides survival benefit, no improvement in survival has been documented for node-negative colon cancer patients. There are, however, a subset of node-negative patients that go on to die of their disease. We hypothesize that this subset of node-negative patients may benefit from postoperative chemotherapy. We analyzed a large cohort of node-negative colon cancer patients from a single institution to determine prognostic factors that predict which patients with node-negative colon cancer might experience recurrence and can benefit from postoperative chemotherapy. A review of the prospective database for colorectal cancer at Memorial Sloan-Kettering Cancer Center (MSKCC) between 1985 and 1993 identified 572 patients who underwent curative resection for node-negative colon cancer (T(1,2,3,4)N0M0). Demographic, serum, and pathologic factors were analyzed for prognostic significance. Survival was calculated by the method of Kaplan-Meier and compared by log rank test. Multivariate analysis was calculated by the Cox proportional hazard model. Median follow-up was 35 months. Factors predictive of survival by univariate analysis include tumor stage, overall stage, and preoperative serum carcinoembryonic antigen (CEA) elevation. By multivariate analysis, overall stage and preoperative serum CEA level predicted survival. Routine histologic and demographic factors do not predict outcome in node-negative colon cancer patients. Preoperative CEA and overall stage predict survival by multivariate analysis. Preoperative CEA elevation in node-negative patients identifies a group of patients that has a poor prognosis and defines a subset of patients who may benefit from postoperative chemotherapy.

Tumor Angiogenesis as a Predictor of Recurrence and Survival in Patients with Node-Negative Colon Cancer

The authors' objective was to quantitatively assess angiogenesis or neovascularity within node-negative colon cancers and to determine if increased angiogenesis correlated with higher recurrence and lower survival rates. Neovascularization promotes rapid tumor growth by facilitating nutrient and metabolite exchange. Recent work with breast and nonsmall cell lung cancers has shown that low angiogenic activity imparts a lower risk of recurrence and metastasis. Although adjuvant therapy is beneficial for patients with node-positive colon cancers, no such benefit has been demonstrated for patients with node-negative lesions. Nevertheless, up to 30% of this latter group will experience recurrence. We sought to identify a subset of patients with node-negative colon cancers at high risk for recurrence who might benefit from such therapy. One hundred five node-negative colon cancers were immunostained for endothelial cell factor VIII-related antigen. Blood vessels within three microscopic fields at 100X magnification were counted, the mean calculated, and an angiogenesis score assigned. A subjective angiogenesis grade (1-4) was assigned after each slide was surveyed in its entirety. Score and grade were then assessed with respect to cancer recurrence and patient survival. Mean patient age was 71 years (range, 41-90 years) and mean tumor size, 5.6 cm (range, 2-12 cm). Mean follow-up was 6.5 years; mean angiogenesis score, 27.9 (range, 4-50); and mean grade, 2.0 (range, 1-4). Patients living 5 years had significantly lower angiogenesis scores than did nonsurvivors (22.8 vs. 43.2, p = 0.0004). Each 10-vessel increase in score imparted a 2.0-fold greater hazard of death and a 2.7-fold greater hazard of recurrence. The probability of surviving 5 years is estimated by: [formula: see text] and the probability of recurrence is estimated by: [formula: see text] Angiogenesis within colon cancer is an important predictor of tumor behavior and may identify patients at higher risk for recurrence and early death.

Prospective phase I evaluation of radiation therapy, 5-fluorouracil, and levamisole in locally advanced gastrointestinal cancer

Purpose : A recent clinical trial in patients with resected node-positive colon cancer demonstrated a clear survival advantage for patients treated with adjuvant 5-fluorouracil and levamisole. This finding led to interest in development of a Phase III trial comparing 5-fluorouracil and levamisole with 5-fluorouracil, levamisole, and radiation therapy in colon cancer patients at high risk for local recurrence. A prospective evaluation of 5-fluorouracil, levamisole, and radiation therapy was undertaken with the goal of establishing a satisfactorily tolerated regimen. Methods and Materials : Fifteen patients were studied who had locally advanced or locally recurrent upper abdominal gastrointestinal cancer (11 patients) or large bowel cancer confined to the pelvis (4 patients). The tumor and regional lymph nodes received 45 Gy in 25 fractions. Patients with pelvic tumors subsequently were treated with a radiation boost of 5.4–9 Gy in 3–5 fractions. Systemic therapy consisted of 5-fluorouracil, 450 mg/m 2, given intravenously for 3 consecutive days during the first and last weeks of radiation therapy. Levamisole, 50 mg, given orally 3 times daily was used for 3 consecutive days concurrent with initiation of radiation therapy and 5-fluorouracil, at the beginning of the third week of radiation therapy, and concurrent with the final 3-day course of 5-fluorouracil. Results : Therapy was generally well tolerated. In two patients, ≥ grade 3 nonhematologic toxicity developed and consisted of transient small bowel obstruction in one and severe nausea and vomiting related to levamisole administration in another. One patient experienced grade 3 hematologic toxicity with a leukocyte count nadir of 1,600 cells/μL. Conclusions : These results are similar to the toxicity profile reported elsewhere for radiation therapy and 5-fluorouracil. The addition of levamisole to radiation therapy and 5-fluorouracil does not appear to increase toxicity significantly.

Adjuvant treatment of colorectal adenocarcinoma

Colorectal adenocarcinoma is diagnosed in 150,000 Americans yearly, and more than 50,000 die of this disease each year. Recently, as a result of well-controlled, randomized, cooperative group trials, it has been demonstrated that adjuvant therapy of node-positive colon cancer (stage III) and node-positive or negative rectal cancer (stage II or stage III) can reduce recurrence and mortality and significantly improve overall survival. It is now the standard of care to provide adjuvant chemotherapy with 5-fluorouracil and levamisole for patients with node-positive colon cancer and provide adjuvant chemoradiotherapy with both 5-fluorouracil and high-dose radiotherapy for patients with stage II or stage III rectal cancer. It is estimated that these interventions, which are readily tolerated, will reduce the incidence of recurrence by more than 30% in both patient groups at a reasonable economic and health cost. Although the ideal method of therapy for this type of disease is not yet firmly established, it appears that adjuvant therapy for node-negative stage III colon cancer may be effective as well. Recently completed and ongoing cooperative group trials are investigating different combinations of chemotherapy and radiotherapy, including 5-fluorouracil with the biomodulator leucovorin or continuous-infusion 5-fluorouracil with radiotherapy, and comparing different durations of therapy. Other trials are investigating combined modality therapy for the neoadjuvant treatment of locally advanced rectal cancer. New findings in the genetics of colon cancer are being studied as prognostic information or markers to determine whether there are subsets of patients who might benefit from more or less therapy. Randomized placebo-controlled trials have been initiated to study the use of aspirin as a means of colon cancer prevention in high-risk populations. Taken together, the recent advances in our treatment and understanding of colorectal adenocarcinoma have resulted in a major-albeit silent-revolution in therapy and give firm promise for further progress.

Adjuvant therapy with hepatic irradiation plus fluorouracil in colon carcinoma

In an attempt to reduce disease recurrence after curative resection of transmural or node positive colon cancer, the Gastrointestinal Tumor Study Group performed a randomized trial of observation versus 5-FU plus 2100 cGy to the liver. A total of 300 eligible trial participants form the basis of this report. Significant toxicity after the combination caused major dose reduction from the original course of 500 mg/m2 to 350 mg/m 2 No therapeutic benefits were noted in either survival or recurrence endpoints; the liver recurrence rate was not decreased by the therapy. Analysis of patients with transmural colonic involvement and negative nodes, one to four positive, and greater than four positive nodes indicates that not all patients are alike with respect to disease outcome or overall survival, and that node number is an important determinant of patient selection for adjuvant trials.

Prognosis of node-positive colon cancer

The most recent American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) staging system subgroups patients into one to three and four or more positive nodes. However, the Gastrointestinal Study Group and the National Surgical Adjuvant Breast and Bowel Project divides node-positive patients into one to four and five or greater. A Cox multi-variate retrospective analysis was done of the overall survival of node-positive colon cancer patients with the specific objective of determining the most appropriate subcategorization. Data on 306 patients with node-positive colon cancer who underwent potentially curative surgery from 1970 to 1984 were analyzed retrospectively. No patient received adjuvant chemotherapy. Also excluded were patients with synchronous resected metastatic disease or those with rectal primaries. The median follow-up was 6 years, and the median survival for the entire group was 8.6 years. By univariate analysis, the following were significant prognostic features: number of positive nodes (P less than 0.0001), degree of differentiation (P less than 0.0001), colon primary site (P = 0.009), tumor stage (P = 0.001), and tumor size (P less than 0.0001). Lymphatic/blood vessel invasion and a mucinous histology were not significant. By Cox multivariate analysis the number of positive lymph nodes remained the best discriminant of survival (P = 0.0001). The number of positive nodes was related inversely to prognosis with the optimal dichotomization between one to three (66% 5-year survival) and four or greater nodes (37% 5-year survival).

Levamisole Toxicity

To the Editor: Levamisole use will no doubt increase following the recent report by Laurie et al and the National Cancer Institute (NCI) Clinical Alert both related to the use of levamisole/fluorouracil (5-FU) as adjuvant treatment for colon cancer. Toxicity of levamisole is generally described as mild with nausea, diarrhea, and leukopenia being the most significant adverse effects with fatigue, dermatitis, and stomatitis also seen. Depsite the generally mild nature of the toxicity, occasional patients experience enough side effects to cause discontinuation of therapy. We report a patient with an unusual levamisole toxicity that resulted in discontinuation of the drug. A 47-year-old woman with node-positive colon cancer agreed to randomization in a clinical trial (EST 2284, Intergroup-0035) evaluating levamisole versus levamisole with 5-FU. She received levamisole 50 mg orally three times a day every 2 weeks and 5-FU 450 mg/m2 weekly. In the fifth month of treatment, she experienced the onset of bilateral arm pain occurring late in the first day of levamisole and resolving by 24 hours after the last dose. These symptoms also occurred with the next course of levamisole. Clinical examination showed upper arm pain with aching and stiffness in the wrists and fingers. Forearm muscles were tender, but there was no joint inflammation. There was no fever, rash, mucositis, leukopenia, or eosinophilia. The erythrocyte sedimentation rate was 8 mm/hr, creatine kinase 31 U/L, and antinuclear antibodies less than 1:20. The next course of levamisole resulted in similar but more severe pain with significant disruption of the patient's work as a florist. 5-FU alone was continued with no recurrence of these symptoms. Three years later the patient is well without pain or evidence for recurrent tumor. This symptom complex is clearly related to the levamisole treatment and might be considered a variant of the "flu-like" symptoms reported in other levamisole trials. We suggest that clinicians using levamisole in randomized trials or without the NCI Group C mechanism be aware of the wide spectrum of toxicities that may be seen with this interesting drug for the purpose of pretreatment discussion with patients and for the monitoring of therapy. The last sentence of the letter-to-the-editor entitled "Levamisole Toxicity" by Drs Leonard DeLorenza and James A. Stewart, published in the February 1990 issue (J Clin Oncol 8:365, 1990) contained an error. The sentence should have read: "We suggest that clinicians using levamisole in randomized trials or within the NCI Group C mechanism be aware of the wide spectrum of toxicities that may be seen with this interesting drug for the purpose of pretreatment discussion with patients and for the monitoring of therapy."