Median durations of response in the overall population were 5.7 months in the combination arm and 4.2 months in the monotherapy arm. Compared with patients receiving cetuximab alone, the cetuximab/irinotecan patients experienced a significantly longer median time to disease progression.
Cetuximab plus irinotecan was evaluated in a single-arm, multicenter, open-label clinical trial of 138 patients with EGF-R-expressing metastatic colorectal cancer. Disease had progressed following an irinotecan-containing regimen using the same dose and schedule of cetuximab as in the randomized trial discussed earlier. Patients received the same irino-tecan dose and schedule that they had not responded to previously. Of 138 patients enrolled, 74 patients had documented progression with irinotecan, as determined by an independent review committee. Overall response rates were 15% for the overall population and 12% for the patients not responding to irinotecan. Median durations of response were 6.5 months for the overall population of treated patients (cetuximab/irino-tecan) and 6.7 months for the irinotecan-failure population receivin g cetux imab/irinotecan.
Cetuximab was also studied as a single agent in a multi-center, open-label, single-arm clinical trial in patients with EGF-R-expressing metastatic colorectal cancer whose disease progressed following an irinotecan-containing regimen. Of 57 patients enrolled, 28 patients had documented disease progression with irinotecan. The overall response rates were 9% for all treated patients (with cetuximab and with cetuximab/irinotecan) and 14% for the irinotecan-failure patients. The median duration of response was 4.2 months for both groups.
Panitumumab. Panitumumab (Vectibix, Amgen) is a human monoclonal antibody that targets the EGF-R, a protein that plays an important role in cancer cell signaling. As an IgG2 monoclonal antibody, panitumumab binds with high affinity to the EGF-R. suhagra
Although EGF-R normally regulates the growth of many different cells in the body, it can stimulate cancer cells to grow. In fact, many cancer cells actually require signals mediated by EGF-R for their survival. Residing on the surface of these tumor cells, EGF-R is activated when naturally occurring proteins in the body, such as EGF or transforming growth factor-alpha (TGF-a), bind to it. This binding changes the shape of EGF-R, which, in turn, triggers internal cellular signals that stimulate tumor cell growth. Panitumumab binds to EGF-R, preventing the natural ligands such as EGF and TGF-a from binding to the receptor and interfering with the signals that would otherwise stimulate growth of the cancer cell and allow it to survive.
Panitumumab is indicated for EGF-R metastatic colorectal cancer with disease progression during or following regimens of fluoropyrimidine, oxaliplatin, and irinotecan. The effectiveness of panitumumab for EGF-R metastatic colorectal carcinoma is based on progression-free survival. No available data have demonstrated an improvement in disease-related symptoms or increased survival with panitumumab.
A multinational, open-label phase 3 study enrolled 463 patients with metastatic colorectal cancer who did not respond to standard chemotherapy, including oxaliplatin and irinotecan. The patients were randomly assigned to receive 6 mg/kg of panitumumab plus best supportive care (n = 231) every two weeks or best supportive care alone (n = 232). An independent, central radiology review board assessed disease progression and tumor shrinkage.
Patients who received panitumumab every two weeks showed a 46% decrease in tumor progression rate, compared with the rate for those receiving best supportive care alone
(P < 0.000 000 001). A significantly higher proportion of patients were alive and free of disease progression with panitumumab at all scheduled time points through week 32.
After six months, almost four times as many panitumumab-treated patients were alive and free of disease progression (18%), compared with those receiving best supportive care alone (5%). At week 32, more than twice as many panitumumab patients were alive and free of disease progression (10%), compared with those receiving best supportive care alone (4%).
Panitumumab improved disease control, compared with best supportive care alone (36% vs. 10%, respectively), as measured by response rate and stable disease. Objective, independently evaluated response rates were 8% with panitumumab and zero with best supportive care alone. The median duration of response was 17 weeks. Stable disease rates were 28% with panitumumab and 10% with best supportive care alone.
Approximately 75% of the patients receiving best supportive care entered a crossover arm to receive panitumumab after disease progression (n = 174). Panitumumab also showed a clinical benefit after this switch even with disease progression. For these patients, panitumumab resulted in a 9% partial response, in a rate of stable disease in 32%, and in one complete response.
An interim analysis of overall survival was similar for the two groups. The rate (75%) and timing (median, seven weeks) of crossing over from best supportive care alone to receiving panitumumab, as well as the anti-tumor activity observed after the crossover, probably confounded the ability to show a treatment effect on overall survival (hazard ratio, 0.93).
Panitumumab improved progression-free survival and response rate regardless of the measured level or intensity of EGF-R staining. (EGF-R following immunohistochemical [IHC] staining correlates with patient survival. IHC is used to examine EGF-R expression or overexpression in colon tumor tissue.) Improvements in progression-free survival and disease control also occurred regardless of age, sex, location of the primary tumor (colon or rectum), or performance status.
As per the protocol, patients receiving panitumumab did not require premedication or a loading dose, and the incidence of infusion reactions of any severity was low (1%). There were no grade 3 or 4 infusion reactions. More of the panitumumab patients reported skin toxicities, fatigue, abdominal pain, nausea, and diarrhea. Hypomagnesemia was observed in 38% of the panitumumab patients (3% grade 3 and 4). No formation of de novo human anti-human antibody (HAHA) or anti-panitu-mumab antibody was observed.
Adjuvant Chemotherapy in Stage II Disease. Although the benefit of adjuvant chemotherapy has been confirmed in stage III colon cancer, efficacy in patients with stage II disease is not as well established.
The International Multicentre Pooled Analysis of Colon Cancer Trials Investigators (IMPACT) project pooled adjuvant data from trials conducted by Italian, Canadian, French, and U.S. trial researchers among Dukes stage B2 and C colon cancer patients. Patients were randomly assigned to a control arm or to receive 5-FU/LV for six months in four trials and for one year in one trial.55,56 The median follow-up period ranged from five to 8.5 years.
For the population as a whole, 5-FU/LV was associated with a clear improvementin disease-free survival and overall survival. However, when analyzed according to stage, Dukes B patients show no benefit from treatment in either event-free or overall survival. In contrast, 5-FU/LV appeared to improve both outcomes for stage C patients.
A pooled analysis of stage II patients from four sequen-tialNSABP trials (C-01, C-02, C-03, and C-04) compared adjuvant chemotherapy regimens with each other and with no adjuvant treatment. The trial compared the following:
• C-01: semustine (methyl-CCNYU)/vincristine (Onco-vin)/5-FU (fluorouracil) (MOF) with surgeryalone
• C-02: perioperative 5-FU with surgery alone
• C-03:5-FU/LV with MOF
• C-04: 5-FU/LV versus 5-FU/levamisole versus 5-FU/ LV/levamisole
In all four studies, improvementin disease-free and recurrence-free survival was observed in both Dukes B and C patients. The researchers concluded that patients with Dukes B colon cancer benefited from adjuvant chemotherapy and should be offered this option. Whether or not other clinical prognostic factors were present, Dukes B patients improved after chemotherapy.
A panel convened by the American Society of Clinical Oncology, in partnership with the Cancer Care Ontario Program in Evidence-Based Care’s Gastrointestinal Cancer Disease Site Group, made recommendations on adjuvant therapy for stage II colon cancer. Recommendations were based on a literature review that included 37 trials, 11 meta-analyses, and 20,317 patients. Although disease-free survival improved by 5% to 10% with adjuvant treatment, there was no significant improvement in overall survival. Thus, the panel did not recommend routine adjuvant chemotherapy for stage II colon cancer.
In terms of prognostic information, it is appropriate to convey that the overall survival rate in stage II disease is 75% to 80% and that any improvement in survival with the addition of chemotherapy is less than 5%. Adjuvant chemotherapy improves survival among patients with stage III colon cancer, but no reliable molecular predictors of outcome have been identified.
A study was conducted to analyze tumor tissue from 460 patients with stage III and high-risk stage II colon cancer who had received various combinations of adjuvant 5-FU/LV, and 5-FU/levamisole to determine the ability of certain marker chromosomes (18q, 17p, 8p) and cellular levels of p53 and p21WAF1/CIP1 proteins to predict survival. Loss of heterozygosity at 18q was present in 155 of 319 cancers (49%).
High concentrations of microsatellite instabilitywere found in 62 of 298 tumors (21%); 38 of these 62 tumors (61°%) had a mutation of the gene for the type II receptor for transforming growth factor [51 (TGF-P1). Among patients with microsatellite-stable stage III cancer, five-year overall survival rates after 5-FU-based chemotherapy were 74% if cancer retained 18q alleles and 50% with a loss of 18q alleles (a relative risk of death, 2.75) (95% CI, 1.34-5.65; P = 0.006).
Five-year survival rates for cancer with high levels of micro-satellite instability were 74%with a mutated gene for the type II receptor for TGF-| 1 and 46% without this mutation (a relative risk of death, 2.90) (95% CI, 1.14-7.35;
P = 0.03). Therefore, retention of 18q alleles in microsatellite-stable cancers and mutation of the gene for the type II receptor for TGF-| 1 in cancers with high concentrations of micro-satellite instability suggest a favorable outcome after adjuvant chemotherapy with 5-FU-based regimens for stage III colon cancer.
BIOLOGIC AGENTS IN CLINICAL DEVELOPMENT
Table 1 summarizes some promising agents for treating colorectal cancer.
Small-molecule tyrosine kinase inhibitors of VEGF-R. These potent inhibitors of VEGF-R-1, -2, -3 and platelet-derived growth factor receptor (PDGF-R) tyrosine kinase activity have shown significant antitumor activity.
Combined inhibitors of VEGF, tyrosine kinase, and others. These agents (e.g., sorafenib and semaxanib) inhibit endo-thelial cell proliferation by blocking VEGF-induced signaling and inhibit cancer cell growth by blocking EGFR autocrine signaling. The knowledge that tumors depend on new vessel formation for growth beyond a few millimeters has led to a new field of anticancer drug investigation. Angio-genic inhibitors reduce the ability of tumors to develop new blood vessels, slowing or stopping its growth, not necessarily by targeting tumor cells but by interacting with tumor-related endothelial cells.
VEGF is one of the most important angiogenic factors in patients with colorectal cancer, and its circulating level is associated with the aggressiveness, stage, and prognosis. Thus, drugs targeting either VEGF or its cell surface receptor have attracted major interest.
SU-5416, like other tyrosine kinase inhibitors, is a potent and selective synthetic inhibitor of the Flk-1/kdr VEGF receptor tyrosine kinase. It targets the VEGF pathway, and in vivo and in vitro studies have highlighted its antiangiogenic potential. It inhibits VEGF-dependent mitogenesis of human endothelial cells but does not affect the growth of various tumor cells in vitro, confirming the VEGF receptor (VEGF-R) on endothelial cells as its main target.
Insulin growth factor receptor (IGF-1-R) inhibitors. Increased expression of type I IGF-1-R is associated with cancer, and inhibitors of IGF-1-R are now a target of intensive research. The IGF ligand-receptor system is important in multiple mechanisms that mediate human colon cancer growth, including regulation of VEGF and angiogenesis.
Src oncogene kinase inhibitors. Elevated levels of Src kinase expression are found in human epithelial cancers. Most notably in colon cancer, elevated Src expression correlates with malignant potential and is associated with metastatic disease. Src expression is often elevated in epithelial tumors (colon, breast, pancreas, lung, ovarian), compared with the adjacent normal tissues. In colon cancer, increased Src expression is linked to malignant potential, with increases seen in premalignant lesions and adenomas but with highest levels seen in malignant polyps.
Colorectal cancer is the second most common cause of death from cancer in much of the developed world. Intense research has led to the introduction of three novel cytotoxic agents (capecitabine, irinotecan, oxaliplatin) and the recent approval of three antibodies (bevacizumab, cetuximab, panitumumab). Several novel biologic agents and targets are also in phase 2 clinical studies, and their contribution to future therapy for colorectal cancer remains to be seen.
Colorectal cancer has become an excellent tumor model for evaluating new therapeutic strategies. Understanding how this cancer develops and grows allows a tailored approach to all stages of treatment: prevention, adjuvant therapy, and therapy for advanced disease. Thus, specific molecular processes have been targeted for therapeutic intervention, including growth factor receptors, proliferation signaling, cell cycling, apoptosis, angiogenesis, and the immune system. buy tadacip
Survival rates for patients with metastatic colorectal cancer have nearly doubled. With the incorporation of biologic agents that target angiogenesis (bevacizumab) and tumor growth pathways (cetuximab), researchers have noted additional improvements in these patients. The benefit of these newer drugs is also realized in the adjuvant setting (e.g., adding oxaliplatin to 5-FU/LV, which has led to improved three-year disease-free survival). Future adjuvant studies are needed to determine whether adding new biologic agents to cytotoxic chemotherapy regimens will result in increased overall survival.