Capecitabine. An alternative strategy to modulating 5-FU-based chemotherapy has been established through the development of oral fluoropyrimidine analogues. Capecit-abine (Xeloda, Roche), a fluoropyrimidine carbamate with antineoplastic activity, is an orally administered systemic prodrug of 5′-deoxy-5-fluorouridine, which is converted in the body to 5-FU.

Capecitabine is indicated as a single-agent adjuvant therapy for Dukes stage C (stage III) colon cancer patients who have undergone complete resection of the primary tumor when fluoropyrimidine therapy alone would be preferred. Dukes stage C colon cancer refers to the spreading of the cancer outside the colon to one or more lymph nodes. canadian pharmacy cialis

The Food and Drug Administration (FDA) approved cap-ecitabine based on its non-inferiority in disease-free survival to a bolus of 5-FU/LV. Oxaliplatin for injection was approved in combination with infusional 5-FU/LV for adjuvant stage III colon cancer. Although neither capecitabine nor the combination of oxaliplatin plus 5-FU/LV prolonged overall survival in the adjuvant setting, the combination chemotherapy regimen was associated with improved disease-free survival, compared with 5-FU/LV in stage III colon cancer. Physicians should consider these results when prescribing single-agent capecitabine in the adjuvant treatment of Dukes C colon cancer.

Chemotherapy for Metastasis

Capecitabine. Capecitabine (Xeloda) is indicated as first-line treatment of patients with metastatic colorectal carcinoma when fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown a survival benefit compared with 5-FU/LV alone. A survival benefit better than 5-FU/LV has not been demonstrated with capecitabine monotherapy. The use of capecitabine instead of 5-FU/LV in combinations has not been adequately studied to ensure safety or preservation of the survival advantage.

A multicenter randomized, controlled phase 3 clinical trial in patients with Dukes C colon cancer provided data on capecitabine. A total of 1,207 patients with previously untreated metastasized colon cancer were randomly assigned to receive either oral capecitabine (1,250 mg/m2 twice daily on days one to 14 every 21 days; n = 603) or an IV bolus of 5-FU/LV, a Mayo Clinic regimen (n = 604).

Capecitabine was associated with a statistically significant superior response rate (26%), when compared with 5-FU/LV (17%) (P < 0.0002). In a subgroup analysis, capecitabine resulted in consistently superior response rates (P < 0.05), even in patient subgroups with poor prognostic indicators. The median time to response and the duration of response were similar, and the time to progression was equivalent in the two arms (hazard ratio, 0.997; 95% confidence interval [CI] 0.8851.123; P = 0.95). The median survival rates were 4.6 months with capecitabine and 4.7 months with 5-FU/LV. kamagra oral jelly 100mg

A multivariate Cox regression analysis was performed to identify younger age, liver metastases, multiple metastases, and poor Karnofsky Performance Status as independent prognostic indicators for rapid time to progression.

Overall survival was equivalent in the two arms (hazard ratio, 0.95; 95% CI, 0.84-1.06; P = 0.48). Median survival rates were 12.9 months with capecitabine and 12.8 months with 5-FU/LV. Capecitabine resulted in superior response rates, an equivalent time to progression and overall survival, an improved safety profile, and improved convenience, compared with IV 5-FU/LV as a first-line treatment for metastatic colorectal cancer.

When fluoropyrimidine monotherapy is indicated, capecitabine should be considered. It is a suitable replacement for IV 5-FU as the backbone of colorectal cancer therapy.

Bevacizumab. Bevacizumab (BV) (Avastin, Genentech), combined with IV 5-FU-based chemotherapy, is indicated for the first-line or second-line treatment of patients with metastatic carcinoma of the colon or rectum. This recombinant humanized monoclonal IgG1 antibody binds to and inhibits the biological activity of human vascular endothelial growth factor (VEGF) assay systems in vitro and in vivo. BV prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation in models of angiogenesis.

In a phase 3 trial, combining bevacizumab plus IFL increased survival, compared with IFL alone, in the first-line treatment of metastatic colorectalcancer. Median overall survival rates were 18.3 months with 5-FU/LV/BV (n = 110) and 15.1 months with IFL/placebo (n = 100). Median progression-free survival rates were 8.8 months with 5-FU/LV/BV and 6.8 months with IFL/placebo; overall response rates were 40% with 5-FU/ LV/BV and 37% with IFL/placebo; and median response durations were 8.5 months with FU/LV/BV and 7.2 months with IFL/placebo.

Adverse events were consistent with those expected from 5-FU/LV-based or IFL-based regimens, as were modest increases in hypertension and bleeding in the BV arm; these were generally easily managed. The 5-FU/LV/BV regimen seems as effective as IFL and has an acceptable safety profile; it is an active alternative regimen for patients with previously untreated metastatic colorectal cancer.

Another phase 3 open-label, randomized, three-arm, active-controlled, multicenter clinical trial evaluated BV alone, BV with 5-FU/LV and oxaliplatin (FOLFOX4), and FOLFOX4 alone in the second-line treatment of metastatic colon or rectal carcinoma. Patients had previously received IFL and 5-FU for initial therapy for metastatic disease or as adjuvant therapy. Patients were assigned to receive FOLFOX4 as follows:

  • Day one: oxaliplatin 85 mg/m2 and LV 200 mg/m2 concurrently IV, then 5-FU 400 mg/m2 IV bolus, followed by 600 mg/m2 continuously IV
  • Day two: LV 200 mg/m2 IV, then 5-FU 400 mg/m2 IV bolus, followed by 600 mg/m2 continuously IV, repeated every two weeks; FOLFOX4 plus BV, or bevacizumab monotherapy.

BV was administered to all patients at a dose of 10 mg/kg every two weeks. Before receiving FOLFOX4 chemotherapy, the patients in the FOLFOX4/BV arm received BV on the first day.

Overall survival was significantly longer with BV/FOL-FOX4, compared with FOLFOX4 alone. Median overall survival rates were 13 months with BV/FOLFOX4 and 10.8 months with FOLFOX4 alone (hazard ratio, 0.75; 95% CI, 0.63, 0.89; P = 0.001, stratified log rank test).

Patients receiving BV/FOLFOX4 achieved a significantly longer progression-free survival rate and a higher overall respons e rate.

Cetuximab. Cetuximab (Erbitux, Bristol-Myers Squibb) is a recombinant, human/mouse chimeric monoclonal antibody that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGF-R). It is composed of the Fv regions of a murine anti-EGF-R antibody with human

IgG1 heavy-chain and kappa light-chain constant regions. Cetuximab is approved as a second-line agent for metastatic colon or rectal cancer; it is also is indicated as an IV agent to be given in combination with irinotecan or to be used alone if patients cannot tolerate irinotecan.

The efficacy and safety of cetuximab, alone or combined with irinotecan, were studied in a randomized, controlled trial of 329 patients and combined with irinotecan in an open-label, single-arm trial of 138 patients. Cetuximab was further evaluated as a single agent in a third clinical trial of 57 patients. The study also evaluated safety data from 111 patients receiving single-agent cetuximab. All trials studied patients with EGF-R-expressing metastatic colorectal cancer whose disease progressed after receiving an irinotecan-containing regimen. Although positive EGF-R status was required for enrollment in the trials, in practice it is not necessary, because positive EGF-R status does not necessarily correspond to response.

The randomized trial of monotherapy versus combined therapy was conducted in 329 patients who were randomly assigned to receive either cetuximab plus irinotecan (218 patients) or cetuximab monotherapy (111 patients). In both arms, cetuximab was administered as an initial dose of 400 mg/m2, followed by 250 mg/m2 weekly until disease progression or unacceptable toxicity. All patients received a 20-mg test dose on the first day.

In the cetuximab/irinotecan arm, irinotecan was added to cetuximab using the same irinotecan dose and schedule that the patients had not responded to earlier. Acceptable irinotecan schedules were 350 mg/m2 every three weeks, 180 mg/m2 every two weeks, or 125 mg/m2 weekly for four doses every six weeks. An independent radiographic review committee, blinded to the treatment arms, assessed progression with prior irinotecan and the response to the protocol for all patients.

Of the 329 patients, 206 (63%) were male. Their median age was 59 years (range, 26-84 years), and the majority (98%) were Caucasian (323 patients). Eighty-eight percent of patients had baseline Karnofsky Performance Status of 80 or above. Fifty-eight percent of patients had colon cancer, and 40% had rectal cancer. Approximately two-thirds (63%) of the patients had not responded to irinotecan.

The efficacy of cetuximab plus irinotecan or cetuximab monotherapy was evaluated in all of these patients. Analyses were also performed in two prespecified subpopulations: those with cancer refractory to irinotecan and those not responding to oxaliplatin. The irinotecan-refractory population was defined as randomized patients who had received at least two cycles of irinotecan-based chemotherapy before treatment with cetuximab and with disease progression within 30 days of completion of the last cycle of irinotecan-based chemotherapy.
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The irinotecan- and oxaliplatin-failure population was defined as irinotecan-refractory patients who had been treated with, but had not responded to, an oxaliplatin-containing regimen.

Category: Cancer / Tags: Colorectal Cancer, treatment Cancer

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