Surgery for Colon Cancer
Surgical removal of the involved segment of colon (colec-tomy), along with its blood supply and regional lymph nodes, is the primary therapy for colon cancer. The conventional and accepted treatment for curative resection of colon cancer is laparotomy with hemicolectomy for right-sided or left-sided lesions .
The technique of colon resection through an open laparotomy incision is well known. Over the past several years, laparoscopy-assisted colectomy has been developed. Laparoscopic surgery can be used for safe and radical resection of cancer in the right, left, and sigmoid colon.
Usually, partial colectomies can be performed in the right, left, transverse, or sigmoid sections, according to the blood supply. The removal of the blood supply at its origin, along with the regional lymph nodes that accompany it, ensures an adequate margin of normal colonic tissue on either side of the primary tumor. When the cancer lies in a position such that the blood supply and lymph drainage are between two of the major vessels, both vessels are removed to ensure complete radical resection (an extended radical right-sided or left-sided colec-tomy).
If the primary tumor penetrates through the bowel wall, any tissue adjacent to the tumor extension is also removed if feasible.
The right, left, or sigmoid colon can be mobilized, and regional lymphadenectomy is performed with laparoscopic instruments and video-imaging equipment. The advantage of laparoscopic colectomy is the abdominal port site and the wound incisions can be small, resulting in less postoperative pain and analgesia, an earlier return of bowel function and normal physical activity, and a shorter hospital stay without increased health care costs.
Surgery is the primary therapy for stages I through III colon cancer unless signs indicate that local invasion would not permit complete removal of the tumor. Although this situation sometimes occurs in advanced stage III tumors, this circumstance is rare, occurring in fewer than 2% of all colon cancer cases.
Radiation Therapy for Rectal Cancer
Published randomized trials suggest that radiation, before or after surgery, appears to have a significant impact on local recurrence, although it does not increase survival rates. Physicians recommend radiation therapy as an adjunct to surgery if there is a concern about the potential for local recurrence postoperatively and if the area of concern can tolerate the radiation. For instance, if the tumor has invaded muscle of the abdominal wall but was not completely removed, this area would be considered for radiation. There are significant dose limits when residual bowel is exposed to radiation, because the small and large intestines do not tolerate this modality well. canadian discount pharmacy
Potential benefits have been reported for radiation therapy before surgery in the treatment of rectal cancer:
- Downstaging of the tumor is possible.
- Resectability of the tumor is increased, possibly with a sphincter-sparing procedure.
- The tumor is less viable, and this may decrease the risk of local recurrence.
- Less radiation is needed for small-bowel loops, which result from pelvic adhesions postoperatively.
- Radiation before surgery works better in well-oxygenated tissues; after surgery, tissues are relatively hypoxic and may be more resistant to radiotherapy.
- Adjuvant therapy may be delayed in patients with postoperative complications.
However, preoperative radiation therapy is associated with some disadvantages, such as (1) a delay in definitive resection, (2) the possible loss of accurate staging, (3) possible over treatment of early-stage (I and II) rectal cancer, (4) increased postoperative complications, and (5) higher morbidity and mortality rates secondary to radiation injury.
Although preoperative radiation decreases the risk of tumor recurrence in patients with stage II or III disease, this practice does not lead to a decrease in distant metastases or in a higher survival rate. Some reports cite an increase in survival, but this is still the minority opinion. The study authors recommend preoperative chemoradiation therapy in patients with large bulky cancers and with obvious nodal involvement.
Advantages of postoperative radiation therapy include (1) immediate, definitive resection and (2) the ability to obtain accurate information on staging of pathology before ionizing radiation is begun. However, this technique is associated with several disadvantages:
- Adjuvant radiation therapy may be delayed if postoperative complications follow.
- There is no effect on tumor cell spread at the time of surgery.
- The effect of radiation is decreased in surgically induced tissue hypoxia.
Adjuvant Chemotherapy for Colorectal Cancer
5-Fluorouracil. It has been 50 years since the introduction of 5-fluorouracil (5-FU) in the treatment of colorectal cancer. The fluoropyrimidine 5-FU was synthesized in 1957 and remains the most widely used agent in treating both early and advanced colorectal cancer. Women receiving 5-FU-based chemotherapy in a five-day bolus schedule experience toxicity more frequently and with greater severity than men. This finding raises the question of whether the recommended initial dose of 5-FU-based chemotherapy should be lower for women.
The largest adjuvant colon cancer trial in the U.S., Inter-group Study 0089, which accrued 3,759 high-risk stage II or III patients for 3.5 years, studied the effect of adding biochemical modulation to 5-FU in the adjuvant setting. This study compared 5-FU plus low-dose leucovorin (LV) versus 5-FU plus high-dose LV versus 5-FU/levamisole versus 5-FU/ levamisole plus low-dose LV.
Combining high-risk stage II and III patients, five-year overall survival rates were 64% with 5-FU/levamisole alone, 66% with either high- or low-dose LV added to 5-FU, and 68% with 5-FU plus low-dose LV plus levamisole.
Toxicities were related to sex and age. The risks of stomatitis and leukopenia were higher in women than in men and in patients older than 70 years of age compared with younger patients. The incidence of diarrhea was higher in women than in men.
In Intergroup Study 0153, patients who had undergone surgery with curative intent were randomly assigned to receive 5-FU/levamisole, given either by bolus or by continuous infusion. The bolus group also received LV. Overall, infusional 5-FU was as effective as six months’ treatment with bolus 5-FU/LV. The infusional regimen was associated with lower toxicity and with less impairment of quality of life. eriacta tablets
A randomized trial of 801 eligible patients compared 12 weeks of infusional 5-FU with a six-month bolus regimen of 5-FU/LV in the adjuvant treatment of colorectal cancer. Five-year overall survival rates were comparable between the two arms (71.5% with bolus 5-FU/LV, 75.7% with infusional 5-FU; P = 0.083), as was the five-year relapse-free survival (66.7% for bolus 5-FU/LV, 73.3% for infusional 5-FU; P = 0.10).
A retrospective subgroup analysis of patients with rectal cancer showed that the infusional 5-FU regimen significantly reduced risk of recurrence, compared with the bolus regimen (P = 0.0246); there was also a trend toward better survival (P = 0.0697).
The National Surgical Adjuvant Breast and Bowel Project (NSABP) assessed the benefit of the addition of interferon alfa-2a (IFN). Patients with Dukes stage B or C cancer (n = 2,176 patients) were entered into this NSABP C-05 study; they were randomly assigned to receive either 5-FU/LV or 5-FU/LV/IFN.
No statistically significant differences were observed in either disease-free survival (69% with 5-FU/LV, 70% with 5-FU/LV/IFN) or in overall survival (80% with 5-FU/LV, 81% with 5-FU/LV/IFN). The addition of interferon to 5-FU/LV had no effect on overall survival at four years (P = 0.41). There was also a higher incidence of grade 3 or greater adverse events in the 5-FU/LV/IFN arm than in the 5-FU/LV arm (72.1% vs. 61.8%).
The combination of 5-FU, LV, and oxaliplatin (FOL-FOX)-based chemotherapy is now the standard of care for patients with advanced colorectal cancer and gastrointestinal cancers. The rationale for this combination was that the folate-dependent enzyme thymidylate synthase (TS) is one of the main targets of 5-FU-based chemotherapy and that the presence of LV provides the requisite substrates to allow for maximal inhibition of TS by the 5-FU metabolite FdUMP.
Irinotecan. Irinotecan HCl (Camptosar, Pfizer) is an anti-neoplastic agent of the topoisomerase I inhibitor class. The Cancer and Leukemia Group B (CALGB) 89803 trial addressed the addition of irinotecan to the adjuvant treatment (5-FU/LV) of stage III colon cancer (This three-drug combination is known as IFL.) The study involved 1,264 patients who were randomly assigned to receive a postoperative bolus regimen of 5-FU/LV or bolus IFL. IFL was associated with a 2.5% mortality rate and no disease-free survival benefit. It was not recommended for stage III colon cancer patients.
Van Cutsem et al. further addressed the role of irinotecan as adjuvant therapy in colon cancer in the Pan-European Trials in Adjuvant Colorectal Cancer-3 (PETACC-3) study. This randomized phase 3 trial compared the following regimens in patients with stage II/III colon cancer:
- Group A1: irinotecan 80 mg/m2 plus LV 500 mg/m2 plus an infusional 5-FU bolus, followed by 2,000 mg/m2 over 24 hours
- Group A2: irinotecan 180 mg/m2 plus LV 200 mg/m2 plus a 5-FU bolus, followed by 600 mg/m2 5-FU IV over 22 hours
- The study included 3,278 patients (stage II/III: 945/2,333 patients). Of these stage III patients, 2,094 received 5-FU/LV with or without irinotecan. Three-year disease-free survival rates were 62.9% for
IFL and 59.9% for 5-FU/LV. Even though the IFL patients experienced slightly more toxicity, the safety profilewas acceptable. For the stage III patients, irinotecan did not significantly increase the efficacy of 5-FU/LV; however, in the pooled population of stage II/III patients, IFLdid increase the efficacy of 5-FU/LV. Overall survival results are not available. erectalis 20 mg
In the French ACCORD adjuvant trial, 400 patients with high-risk disease (N2 or N1 with obstruction) were assigned to receive 5-FU/LV with or without irinotecan. Adjuvant IFL was associated with significantlymore grade 3 and 4 neu-tropenia and diarrhea, compared with 5-FU/LV alone. Furthermore, preliminary results showed no significant improvement in disease-free survival between the two arms. This might be explained in part by the low-dose intensity of IFL in the triple-combination arm, with more dose reductions and cycle delays caused by neutropenia. Thus, three adjuvant trials have not shown a significant disease-free survival advantage when irinotecan was added to either bolus or infusional 5-FU regimen s.
Oxaliplatin. Oxaliplatin (Eloxatin, Sanofi-Aventis) is an antineoplastic agent constituted as an organoplatinum complex; the platinum atom is complexed with 1,2-diaminocyclo-hexane (DACH) and with an oxalate ligand as a “leaving” group (an atom or a group of atoms that is displaced as a stable species).
Used in combination with infusional 5-FU/LV, oxaliplatin is indicated for the adjuvant treatment of stage III colon cancer patients who have undergone complete resection of the primary tumor. The indication is based on an improvement in disease-free survival, with no demonstrated benefit in overall survival after a median follow-up of four years. When combined with infusional 5-FU/LV, oxaliplatin is indicated for advanced colonic or rectal carcinoma.
In NSABP protocol C-07, the same population of patients (i.e., with stage II and III colon cancer) after stratification was assigned to receive either 5-FU/LV or 5-FU/LV plus oxali-platin. The study arm receiving oxaliplatin plus a weekly bolus of 5-FU/LV showed significantly improved three-year disease-free survival (76.5%, n = 1,200 patients), compared withthe 5-FU/LV arm (71.6%, n = 1,207 patients) (P = 0.004). A higher incidence of neurosensory toxicity and diarrhea was observed with the oxaliplatin-containing regimen. The relative treatment benefit in stage II disease was at least equal to the benefit in stage III colon cancers. kamagra tablets
A pooled analysis of four studies with adjuvant chemotherapy indicated that the relative treatment benefit in stage II disease was at least equal to the benefit in stage III colon cancers. The study authors concluded that adjuvant chemotherapy should also be considered the standard of care for stage II colon cancer.
In the Multicenter International Studyof Oxaliplatin/5-FU/ Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC), treatment consisted of infusional 5-FU2/LV with or withoutoxaliplatin (FOLFOX4). (FU2 is the term applied in this study.) At four years, an analysis of the entire cohort of 2,246 stage II and III patients indicated that those who had received FOLFOX4 were significantly more likely to be disease-free (75.9% vs. 69.1%, for an absolute difference of 6.8%) (hazard ratio, 0.76; P = 0.0008). This difference was also statistically significant when stage III patients were considered alone (disease-free survival, 69.7% withFOLFOX4 vs. 61% with 5-FU/LV alone). However, the difference was not significant for stage II patients (disease-free survival, 85.1% vs. 81.3%).
In the FOLFOX4 arm, 176 patients (15.7%) died; in the control arm, 194 patients (17.3%) died. The probabilities of surviving to four years were 84% for patients treated with FOL-FOX4 and 82.4% for patients treated with 5-FU/LV. These results confirm the benefit of the FOLFOX 4 regimen, which significantly outperformed the 5-FU/LV regimen in survivability of patients with advanced colorectal cancer. The principal toxicity associated with the addition of oxaliplatin was grade 3 neuropathy, experienced by 137 patients. However, this condition had resolved in more than 60% of cases by one month and in 95% of patients, by one year. kamagra soft tablets
The NSABP Protocol C-07 study and the MOSAICtrial both demonstrated that adding oxaliplatin to either the infusion or the weekly 5-FU/LV bolus significantly improved three-year disease-free survival. Therefore, it has been suggested that adding oxaliplatin to a regimen of 5-FU/LV may improve the adjuvant treatment of colon cancer.