Adjuvant Treatment Of Colorectal Cancer
Lisa S. Poritz, M.D.
Adjuvant chemotherapy: Post resection treatment. The purpose is to destroy microscopic residual disease thereby preventing later development of metastatic disease. Therapy for known macroscopic metastatic cancer is not considered adjuvant therapy. Most new chemotherapeutic agents are tested in randomized trials with patients with known metastatic disease. If they are beneficial in this patient population with acceptable side effects they are then used in clinical trials in patients with nonmetastatic disease.
Neoadjuvant therapy: Pre-operative treatment. Neoadjuvant therapy will not be addressed.
COLON CANCER
Adjuvant chemotherapy is usually offered to patients with Stage III (any T, N1 or N2, Dukes’ C) as a statistically significantly increase in survival has been shown. Stage II patients (T3 or T4, N0, Dukes’ B2) are often offered adjuvant therapy although studies do not consistently show a statistically significant benefit.
5-FU
Mode of action: 5-FU is activated to 5-fluoro-2’deoxyuridylate which combines with methylenetetrahydrofolate to form a ternary complex with thymidylate synthesis. This interferes with DNA synthesis by inhibiting the conversion of deoxyuridylate to thymidylate. 5-FU is also directly incorporated into DNA and RNA.
Effectiveness as a single agent: No survival advantage has been shown with 5-FU as a single agent. Buyse et al randomized 4700 patients (all stages) to 5-FU and surgery alone. A survival advantage of 2.3-5.7% which was not statistically significant was seen.
CAPECITABINE (XELODA)
Mode of action: 5-FU prodrug for oral administration. It is absorbed in the GI tract and undergoes a 3-step conversion to 5-FU.
This drug is used primarily in advanced/metastatic colon cancer
LEVAMISOLE
Mode of action: Levamisole is an antihelminthic agent that positively modulates the immune system.
Effectiveness as a single agent: Not effective alone in stage II or stage III disease.
LEUCOVORIN
Mode of action: Increases the half life of the 5-fluoro-2’deoxyuridylate-thymidylate synthase-methylenetetrahydrofolate complex.
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Studies using the following two agents have been conducted in patients with metastatic disease and they have shown a survival benefit alone and in combination with 5-FU and leucovorin in these patients. Studies in the adjuvant setting in patients with Stage II or III colon cancer are not completely matured, but show an improvement in disease free survival and a trend towards an increase in overall survival. The trials have not had enough time to show a benefit in overall survival but oncologists are optimistic that the survival benefit in patients with metastatic disease will carry over to those with stage II and stage III disease. Patients with stage II and III disease are now routinely treated with these agents in combination with 5-FU and leucovorin (see below). The survival data presented below is for patients with metastatic disease.
IRINOTECAN (CPT-11)
Mode of action: semi-synthetic derivative of camptothecin which targets Topoisomerase I. Irinotecan is converted to its active metabolite SN-38. SN-38 stabilizes the DNA-topoisomerase complex leading to replication arrest and apoptosis.
Side effects: diarrhea, acute cholinergic syndrome
Effectiveness as a single agent: The survival advantage with monotherapy with CPT-11 in advanced colon cancer is similar to FU/leucovorin
OXALIPLATIN
Mode of action: third generation platinum with a 1,2-diaminocylohexane carrier ligand which forms DNA adducts and resultant strand breaks. Only platinum with activity in colorectal cancer.
Side effects: neurotoxicity (2 types): acute cold induced sensory neuropathy and a dose dependent neuropathy (10-15% of patients after 780-850 mg/m2)
Effectiveness as a single agent: activity in 18-20% of chemotherapy-naïve with patients metastatic disease and 10% of patients who have failed 5-FU based therapy.
COMBINATION REGIMENS
5-FU and Levaminsole: Significantly increased disease free survival in Stage III patients (60% vs 46%). No effect in Stage II patients. Must be given for 12 months. 6 months is not adequate therapy.
Side effects: occasional myelosuppression, neurotoxicity, arthralgia, mild elevation of transaminases
5-FU and Leucovorin:
Mayo Regimen: 5-FU 425 mg/m2 daily with LV 20 mg/m2 daily for 5 consecutive days every 4 weeks for two cycles then every 5 weeks.
Roswell Park Regimen: 5-FU 500 mg/m2 and LV 500mg/m2 weekly for 6 weeks then every 8 weeks.
Both regimens improved survival in stage III patients compared to surgery alone. No significant difference in survival between the 2 regimens. No significant difference in survival with 6 months of 5-FU/leucovorin vs 12 months of 5-FU/levaminsole. Therefore most patients are treated with 5-FU/leucovorin because they only need to be treated for 6 months. Results in patients with stage II colon cancer are variable with some studies (NSABP-CO-1) showing a benefit and others (INT-0035) showing no benefit.
Bolus vs continuous infusion therapy: meta-analysis of 6 randomized trials showed no survival benefit. There was an improved response rate for continuous infusion compared to bolus.
Side effects: diarrhea, stomatitis, leukopenia, neutropenia
5-FU/CPT-11/Leucovorin (Saltz regimen, IFL): Improved response rate (39% vs. 21%) and survival (14.8 vs 12.6 months) compared to 5-FU and Leucovorin alone in metastatic disease. A phase III intergroup study randomized stage III patients to 5-FU/leucovorin vs IFL. The study was halted because of an unexpected number of deaths (2.5% in IFL vs 0.8% in 5-FU/leucovorin). Another study, V-307 comparing the same groups is in process. Early results from phase III trials using IFL have shown a significant improvement in disease free survival for patients treated with the regimen over 5-FU/leucovorin. Survival data is not yet available.
5-FU/Oxaloplatin/Leucovorin (FOLFOX): Survival advantage over IFL with a response rate of 45% vs 31% and a median survival of 19.5 months vs. 14.8 months in metastatic disease. A randomized trial (MOSIAC) comparing 5-FU/leucovorin and Oxaloplatin/5-FU/leucovorin as adjuvant therapy in Stage II and III colon cancer has completed accrual. There is a significant improvement in disease free survival for patients treated with this regimen over 5-FU/leucovorin and also those treated with IFL. Survival data is not yet available.
RECTAL CANCER
The chemotherapeutic agents are the same as those used for colon cancer. The difference is that multimodality therapy in the form of chemotherapy and radiation is the standard of care for stage II or stage III disease. The review will address only adjuvant (post-operative) radiation in combination with chemotherapy.
Stage I Rectal Cancer: T1 lesions with favorable characteristics (well differentiated, lack of blood vessel or lymphatic invasion) have a recurrence free survival of >90% after local excision and do not need adjuvant therapy. T1 lesions with unfavorable characteristics and T2 lesions have a failure rate of 20% or greater after local excision and should be treated with adjuvant therapy. Post-operative chemoradiation improves local control ( 5 year) to 85% in single institutional studies. Two Multi-Institutional studies have shown lower 6 year failure free survival at 78-83%.
Stage II-III Rectal Cancer: Surgery alone (LAR/APR) leads to 25-40% locoregional failure. Significantly improved survival, local control and distant metastasis in combined postoperative chemotherapy and radiation (40-48Gy) compared to surgery alone, chemotherapy alone, or radiation therapy alone. Acute toxicity was higher in combined therapy.
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