Management of Gastrointestinal Cancers
Management of Gastrointestinal Cancers
Colorectal Cancer
Advances in the management of colorectal cancer (CRC) were a prominent feature of the recent European Society of Medical Oncology Congress 2004.
Adjuvant Treatment
Adjuvant chemotherapy has become well established in stage III colon cancer, as there is still a 50% risk of relapse with surgery alone and a 30% risk reduction with 5-fluorouracil (5-FU)-based adjuvant treatment. The benefit of adjuvant treatment is less clear in stage II disease and is, therefore, the subject of ongoing debate. Stage II patients have an 80% five-year survival with surgery alone, and large numbers of patients would be required to demonstrate a statistically significant benefit from the addition of adjuvant chemotherapy. Within the last year, an American Society of Clinical Oncology (ASCO) panel, in collaboration with the Cancer Care Ontario Practice Guidelines Initiative, concluded that based on available evidence, routine adjuvant chemotherapy could not be recommended for stage II colon cancer but should be considered for patients with high-risk features.
Adjuvant treatment has previously been 5-FU-based. The X-ACT study was a randomized phase 3 trial comparing capecitabine with Mayo Clinic bolus 5-FU as adjuvant treatment for Dukes C colon cancer. Powered to show equivalency, the results showed a strong trend toward improved disease-free survival (DFS) and improved overall survival (OS) in favor of capecitabine, with less toxicity except for non-life-threatening hand-foot syndrome. A pharmacoeconomic analysis based on the UK National Health Service was also presented, projecting a cost savings for use of capecitabine compared with 5-FU despite the higher acquisition cost of capecitabine. These results suggest that capecitabine should replace 5-FU as adjuvant monotherapy and should be studied as part of combination regimens.
Earlier this year, the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) study reported a benefit with adjuvant FOLFOX (oxaliplatin with infusional 5-FU) compared with infusional 5-FU for stage II and III patients using 3-year DFS as the primary objective. Updated data after 44.2 months reported a 3-year DFS of 78.7% for FOLFOX compared with 73.3% for 5-FU, with a 24% risk reduction of death. Grade 3 sensory neuropathy was present in 0.5%, whereas it was previously reported in 12.4% during treatment, decreasing to 1.1% after 1 year of follow-up. A subset analysis of the high-risk stage II patients reported a relative risk reduction of relapse similar to stage III patients. Although these results need to be confirmed with 5-year OS data, FOLFOX should be recommended as adjuvant treatment for stage III patients and should be considered for high-risk stage II patients.
Adding to the data on adjuvant treatment in stage II patients are the results of the Quick and Simple and Reliable (QUASAR) study, presented initially at ASCO 2004, and reiterated at the ESMO Oncology Highlights after a median follow-up of 4.6 years reported an absolute survival improvement of 3% with adjuvant treatment.
Advanced Disease
Survival in advanced CRC was initially improved by using infusional regimens instead of bolus 5-FU. More recently, oxaliplatin and irinotecan have demonstrated significant survival benefits in the first- and second-line settings. Combinations of a fluoropyrimidine with either drug have become the standard against which newer treatments are assessed.
Combination chemotherapy. Irinotecan and oxaliplatin (IROX) have been evaluated as an arm in protocol N9741. The final results of protocol EFC4585 were presented at ESMO, where IROX was found to be more active than irinotecan monotherapy in patients who had failed single-agent fluoropyrimidine treatment. A significant improvement in median survival of 13.4 months compared with 11.1 months for irinotecan was reported with no significant difference in toxicity between arms.
Sequencing of palliative chemotherapy. The preliminary results of the UK MRC FOCUS study, designed to explore the optimal sequencing of 5-FU, oxaliplatin, and irinotecan, were presented at the ESMO Presidential Symposium. Patients were treated with one of the following:
Patients (N = 2135) were entered from May 2000 to December 2003, and crossover between treatment combinations was discouraged until December 2002, after which patients could receive salvage capecitabine with whichever other drug they had not previously received. Median survivals for arms A, B (irinotecan/oxaliplatin), and C (irinotecan/oxaliplatin) were 13.7, 14.8/15.5, and 16.2/15.0 months, respectively. Neither arms B nor C were found to be significantly better than arm A in terms of OS. Furthermore, comparison of arms B and C favored arm B, although the difference in survival was again not statistically significant.
These results are somewhat unexpected, as the arms with combination treatment did not perform as well as anticipated. For example, both arms of the study of FOLFIRI (folinic acid, 5-FU, and irinotecan) followed by FOLFOX6, or the reverse sequence reported by Tournigand and colleagues. earlier this year, both achieved survivals in excess of 20 months. The FOCUS study excluded patients with potentially operable liver metastasis, and so may have been a poorer prognosis group. The majority of patients would not have received exposure to all 3 active drugs since the option for salvage treatment was not introduced until the last year of the study. This is noteworthy because the analysis by Grothey and associates of 7 recently published phase 3 trials concluded that OS is maximized by exposure to 3 active drugs. Thus, the implications of the FOCUS study on management are still unclear, but may be elucidated when more advanced results are available.
Oxaliplatin neurotoxicity. The long-term use of oxaliplatin is limited by sensory neurotoxicity. A detailed analysis of oxaliplatin toxicity in the FOLFOX4 arm of protocol N9741 found that the time to response was 2.2 months, whereas the time to grade 3 sensory neuropathy was 6 months in patients who developed toxicity. The incidence of grade 2/3 toxicity was markedly increased above a cumulative oxaliplatin dose of 800 mg/m. The impact of neurotoxicity is apparent from the finding that 74% and 43% of patients who developed grade 3 and 2 neurotoxicity stopped treatment because of it.
Targeted Therapies
The evidence for the additive benefit of the newer targeted therapies when used with chemotherapy is increasing. The 2 most successful targets for inhibitors so far have been the epidermal growth factor receptor (EGFR; also known as HER1 or erbB1) and the vascular endothelial growth factor receptor (VEGFR).
EGFR. EGFR and its associated downstream signaling pathways regulate cell proliferation, differentiation, migration, adhesion, protection from apoptosis and transformation, and may thus have a role in oncogenesis. The efficacy of the chimeric anti-EGFR monoclonal antibody cetuximab has been demonstrated as a single agent and in combination with irinotecan (in irinotecan-refractory patients) with response rates of about 10% and 20%, and median survivals up to 6.9 months and 8.6 months, respectively.
Preliminary results of a phase 2 study where cetuximab was combined with FOLFOX4 as first-line treatment reported a high overall response rate of 81% and a disease control rate of 98%. Other phase 2 studies of interest include a study of humanized anti-EGFR monoclonal antibody panitumumab (ABX-EGF), in combination with leucovorin (IFL), and a study of the oral tyrosine kinase inhibitor gefitinib in combination with simplified FOLFOX6.
VEGF. VEGF has a role in regulating angiogenesis and may be involved in regulating the tumor microenvironment and tumor metastasis. The efficacy of humanized anti-VEGF monoclonal antibody bevacizumab was established in a pivotal study comparing IFL with bevacizumab or placebo in the first-line setting. The bevacizumab arm showed a remarkable OS of 20.3 months compared with 15.6 months in the placebo arm, corresponding to a hazard ratio for death of 0.66 (P < .001). The corresponding rates of response were 44.8% and 34.8% (P = .004).
Patients who were not optimal candidates for treatment with irinotecan were treated instead with Roswell Park 5-FU with bevacizumab or placebo. There was a statistically significant improvement in progression-free survival (PFS) of 9.2 months vs 5.5 months, but not in median survival. When these results were analyzed together with data from an earlier phase 2 study reported by Kabbinavar and colleagues, the survival difference became significant in favor of bevacizumab. The most significant adverse event in the bevacizumab arm was gastrointestinal perforation, which occurred in 2% of patients. The main bevacizumab toxicity was grade 3 hypertension (16%), which was manageable with oral antihypertensives. Pharmacokinetic data on bevacizumab confirmed that 2- or 3-week dosing produces similar steady-state concentrations and overall exposure to drug. There was no significant increase in bleeding complications in patients who received bevacizumab 28-60 days after surgery. Bevacizumab administration before major surgery may, however, modestly increase the risk of wound healing complications. It is recommended, therefore, that elective surgery occurs at least 60 days after last the dose of bevacizumab.
Phase 1/2 studies of PTK787/ZK222584 (PTK/ZK), an oral angiogenesis inhibitor that blocks all known VEGF tyrosine kinases, has shown promising results in combination with FOLFOX4 and FOLFIRI. The benefit includes partial response or stabilization of disease in all of the patients treated thus far, and a median PFS of 11.2 months in the FOLFOX4 combination.
The current evidence is adequate to support the increasingly widespread use of cetuximab and bevacizumab with combination chemotherapy; in particular, bevacizumab with IFL in the first-line setting. The optimal way to incorporate these agents into patient management is the subject of ongoing study. The results from trials of other targeted agents are eagerly anticipated.
Upper Gastrointestinal Cancers Esophageal Cancer
Combined modality treatment with chemoradiotherapy can be used with curative intent in squamous cell carcinoma of the esophagus, although the morbidity associated with treatment can sometimes be significant. A study that attempted to correlate the presence of molecular markers with response to treatment has found that positive EGFR staining by immunohistochemistry may predict for responsiveness to chemoradiotherapy. However, the prevalence of EGFR positivity in this study was only 35% -- well below the high prevalence reported in this disease subtype by other studies. Hence, these results may need to be evaluated prospectively with a larger study population.
At present, there is no standard second-line treatment for esophageal cancer. Two phase 2 studies found that the oral tyrosine kinase inhibitor gefitinib had some activity in esophageal cancer and was well tolerated. Most of the patients included had received prior treatment and most had adenocarcinomas, although van Groeningen and colleagues did include a small number of patients with squamous cell carcinoma who appeared to have a higher response rate than the rest of the group. Gefitinib probably warrants further prospective evaluation in this disease.
Gastric Cancer
A randomized multicenter phase 2 study comparing 5-FU and leucovorin with irinotecan or etoposide (ELF) as first-line treatment in metastatic gastric adenocarcinoma has found the irinotecan-containing arm to be much more effective than ELF. The tumor control rate for the study arm of 58% and the PFS of 129 days is comparable to another recently reported single-arm second-line study. However, no P values were reported and ELF is not an optimal control regimen. The treatment combination is nevertheless promising and should be compared prospectively against more standard regimens such as cisplatin and 5-FU, or the same with epirubicin.
As the risk of relapse in curatively resected localized gastric adenocarcinoma is high, there is a potential role for neoadjuvant and adjuvant strategies in this disease. An extended phase 2 study that treated high-risk patients with adjuvant 5-FU, leucovorin, cisplatin, and radiotherapy found that this regimen was feasible and had acceptable toxicity. Some patients also received paclitaxel as part of the chemotherapy combination. Another study randomized patients with resectable gastric cancer to surgery with or without adjuvant chemotherapy with cisplatin, epirubicin, leucovorin, and 5-FU. A benefit of 4% in survival, which was not statistically significant, was demonstrated for the study arm, although the study was designed to detect a 20% difference.
Treatment in the Elderly
A significant proportion of patients presenting with esophagogastric cancers are over the age of 70 years. Despite this preponderance, patients in this age group are often underrepresented in clinical trials. A retrospective analysis of 3 randomized trials of palliative chemotherapy for esophagogastric cancer found that response rates, survival, and symptomatic benefit were similar between patients above the age of 70 years compared with those who were younger, without increased toxicity. There may have been a bias toward only including elderly patients with poor performance status or significant comorbidity in these studies. However, this is consistent with the increasing body of evidence for considering the overall condition of patients when selecting patients for treatment, and not excluding them from treatment based on calendar age alone.
References
Advances in the management of colorectal cancer (CRC) were a prominent feature of the recent European Society of Medical Oncology Congress 2004.
Adjuvant Treatment
Adjuvant chemotherapy has become well established in stage III colon cancer, as there is still a 50% risk of relapse with surgery alone and a 30% risk reduction with 5-fluorouracil (5-FU)-based adjuvant treatment. The benefit of adjuvant treatment is less clear in stage II disease and is, therefore, the subject of ongoing debate. Stage II patients have an 80% five-year survival with surgery alone, and large numbers of patients would be required to demonstrate a statistically significant benefit from the addition of adjuvant chemotherapy. Within the last year, an American Society of Clinical Oncology (ASCO) panel, in collaboration with the Cancer Care Ontario Practice Guidelines Initiative, concluded that based on available evidence, routine adjuvant chemotherapy could not be recommended for stage II colon cancer but should be considered for patients with high-risk features.
Adjuvant treatment has previously been 5-FU-based. The X-ACT study was a randomized phase 3 trial comparing capecitabine with Mayo Clinic bolus 5-FU as adjuvant treatment for Dukes C colon cancer. Powered to show equivalency, the results showed a strong trend toward improved disease-free survival (DFS) and improved overall survival (OS) in favor of capecitabine, with less toxicity except for non-life-threatening hand-foot syndrome. A pharmacoeconomic analysis based on the UK National Health Service was also presented, projecting a cost savings for use of capecitabine compared with 5-FU despite the higher acquisition cost of capecitabine. These results suggest that capecitabine should replace 5-FU as adjuvant monotherapy and should be studied as part of combination regimens.
Earlier this year, the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) study reported a benefit with adjuvant FOLFOX (oxaliplatin with infusional 5-FU) compared with infusional 5-FU for stage II and III patients using 3-year DFS as the primary objective. Updated data after 44.2 months reported a 3-year DFS of 78.7% for FOLFOX compared with 73.3% for 5-FU, with a 24% risk reduction of death. Grade 3 sensory neuropathy was present in 0.5%, whereas it was previously reported in 12.4% during treatment, decreasing to 1.1% after 1 year of follow-up. A subset analysis of the high-risk stage II patients reported a relative risk reduction of relapse similar to stage III patients. Although these results need to be confirmed with 5-year OS data, FOLFOX should be recommended as adjuvant treatment for stage III patients and should be considered for high-risk stage II patients.
Adding to the data on adjuvant treatment in stage II patients are the results of the Quick and Simple and Reliable (QUASAR) study, presented initially at ASCO 2004, and reiterated at the ESMO Oncology Highlights after a median follow-up of 4.6 years reported an absolute survival improvement of 3% with adjuvant treatment.
Advanced Disease
Survival in advanced CRC was initially improved by using infusional regimens instead of bolus 5-FU. More recently, oxaliplatin and irinotecan have demonstrated significant survival benefits in the first- and second-line settings. Combinations of a fluoropyrimidine with either drug have become the standard against which newer treatments are assessed.
Combination chemotherapy. Irinotecan and oxaliplatin (IROX) have been evaluated as an arm in protocol N9741. The final results of protocol EFC4585 were presented at ESMO, where IROX was found to be more active than irinotecan monotherapy in patients who had failed single-agent fluoropyrimidine treatment. A significant improvement in median survival of 13.4 months compared with 11.1 months for irinotecan was reported with no significant difference in toxicity between arms.
Sequencing of palliative chemotherapy. The preliminary results of the UK MRC FOCUS study, designed to explore the optimal sequencing of 5-FU, oxaliplatin, and irinotecan, were presented at the ESMO Presidential Symposium. Patients were treated with one of the following:
Modified de Gramont 5-FU (MdG) until treatment failure followed by irinotecan monotherapy;
MdG followed by MdG with irinotecan or oxaliplatin; or
First-line MdG with irinotecan or oxaliplatin.
Patients (N = 2135) were entered from May 2000 to December 2003, and crossover between treatment combinations was discouraged until December 2002, after which patients could receive salvage capecitabine with whichever other drug they had not previously received. Median survivals for arms A, B (irinotecan/oxaliplatin), and C (irinotecan/oxaliplatin) were 13.7, 14.8/15.5, and 16.2/15.0 months, respectively. Neither arms B nor C were found to be significantly better than arm A in terms of OS. Furthermore, comparison of arms B and C favored arm B, although the difference in survival was again not statistically significant.
These results are somewhat unexpected, as the arms with combination treatment did not perform as well as anticipated. For example, both arms of the study of FOLFIRI (folinic acid, 5-FU, and irinotecan) followed by FOLFOX6, or the reverse sequence reported by Tournigand and colleagues. earlier this year, both achieved survivals in excess of 20 months. The FOCUS study excluded patients with potentially operable liver metastasis, and so may have been a poorer prognosis group. The majority of patients would not have received exposure to all 3 active drugs since the option for salvage treatment was not introduced until the last year of the study. This is noteworthy because the analysis by Grothey and associates of 7 recently published phase 3 trials concluded that OS is maximized by exposure to 3 active drugs. Thus, the implications of the FOCUS study on management are still unclear, but may be elucidated when more advanced results are available.
Oxaliplatin neurotoxicity. The long-term use of oxaliplatin is limited by sensory neurotoxicity. A detailed analysis of oxaliplatin toxicity in the FOLFOX4 arm of protocol N9741 found that the time to response was 2.2 months, whereas the time to grade 3 sensory neuropathy was 6 months in patients who developed toxicity. The incidence of grade 2/3 toxicity was markedly increased above a cumulative oxaliplatin dose of 800 mg/m. The impact of neurotoxicity is apparent from the finding that 74% and 43% of patients who developed grade 3 and 2 neurotoxicity stopped treatment because of it.
Targeted Therapies
The evidence for the additive benefit of the newer targeted therapies when used with chemotherapy is increasing. The 2 most successful targets for inhibitors so far have been the epidermal growth factor receptor (EGFR; also known as HER1 or erbB1) and the vascular endothelial growth factor receptor (VEGFR).
EGFR. EGFR and its associated downstream signaling pathways regulate cell proliferation, differentiation, migration, adhesion, protection from apoptosis and transformation, and may thus have a role in oncogenesis. The efficacy of the chimeric anti-EGFR monoclonal antibody cetuximab has been demonstrated as a single agent and in combination with irinotecan (in irinotecan-refractory patients) with response rates of about 10% and 20%, and median survivals up to 6.9 months and 8.6 months, respectively.
Preliminary results of a phase 2 study where cetuximab was combined with FOLFOX4 as first-line treatment reported a high overall response rate of 81% and a disease control rate of 98%. Other phase 2 studies of interest include a study of humanized anti-EGFR monoclonal antibody panitumumab (ABX-EGF), in combination with leucovorin (IFL), and a study of the oral tyrosine kinase inhibitor gefitinib in combination with simplified FOLFOX6.
VEGF. VEGF has a role in regulating angiogenesis and may be involved in regulating the tumor microenvironment and tumor metastasis. The efficacy of humanized anti-VEGF monoclonal antibody bevacizumab was established in a pivotal study comparing IFL with bevacizumab or placebo in the first-line setting. The bevacizumab arm showed a remarkable OS of 20.3 months compared with 15.6 months in the placebo arm, corresponding to a hazard ratio for death of 0.66 (P < .001). The corresponding rates of response were 44.8% and 34.8% (P = .004).
Patients who were not optimal candidates for treatment with irinotecan were treated instead with Roswell Park 5-FU with bevacizumab or placebo. There was a statistically significant improvement in progression-free survival (PFS) of 9.2 months vs 5.5 months, but not in median survival. When these results were analyzed together with data from an earlier phase 2 study reported by Kabbinavar and colleagues, the survival difference became significant in favor of bevacizumab. The most significant adverse event in the bevacizumab arm was gastrointestinal perforation, which occurred in 2% of patients. The main bevacizumab toxicity was grade 3 hypertension (16%), which was manageable with oral antihypertensives. Pharmacokinetic data on bevacizumab confirmed that 2- or 3-week dosing produces similar steady-state concentrations and overall exposure to drug. There was no significant increase in bleeding complications in patients who received bevacizumab 28-60 days after surgery. Bevacizumab administration before major surgery may, however, modestly increase the risk of wound healing complications. It is recommended, therefore, that elective surgery occurs at least 60 days after last the dose of bevacizumab.
Phase 1/2 studies of PTK787/ZK222584 (PTK/ZK), an oral angiogenesis inhibitor that blocks all known VEGF tyrosine kinases, has shown promising results in combination with FOLFOX4 and FOLFIRI. The benefit includes partial response or stabilization of disease in all of the patients treated thus far, and a median PFS of 11.2 months in the FOLFOX4 combination.
The current evidence is adequate to support the increasingly widespread use of cetuximab and bevacizumab with combination chemotherapy; in particular, bevacizumab with IFL in the first-line setting. The optimal way to incorporate these agents into patient management is the subject of ongoing study. The results from trials of other targeted agents are eagerly anticipated.
Upper Gastrointestinal Cancers Esophageal Cancer
Combined modality treatment with chemoradiotherapy can be used with curative intent in squamous cell carcinoma of the esophagus, although the morbidity associated with treatment can sometimes be significant. A study that attempted to correlate the presence of molecular markers with response to treatment has found that positive EGFR staining by immunohistochemistry may predict for responsiveness to chemoradiotherapy. However, the prevalence of EGFR positivity in this study was only 35% -- well below the high prevalence reported in this disease subtype by other studies. Hence, these results may need to be evaluated prospectively with a larger study population.
At present, there is no standard second-line treatment for esophageal cancer. Two phase 2 studies found that the oral tyrosine kinase inhibitor gefitinib had some activity in esophageal cancer and was well tolerated. Most of the patients included had received prior treatment and most had adenocarcinomas, although van Groeningen and colleagues did include a small number of patients with squamous cell carcinoma who appeared to have a higher response rate than the rest of the group. Gefitinib probably warrants further prospective evaluation in this disease.
Gastric Cancer
A randomized multicenter phase 2 study comparing 5-FU and leucovorin with irinotecan or etoposide (ELF) as first-line treatment in metastatic gastric adenocarcinoma has found the irinotecan-containing arm to be much more effective than ELF. The tumor control rate for the study arm of 58% and the PFS of 129 days is comparable to another recently reported single-arm second-line study. However, no P values were reported and ELF is not an optimal control regimen. The treatment combination is nevertheless promising and should be compared prospectively against more standard regimens such as cisplatin and 5-FU, or the same with epirubicin.
As the risk of relapse in curatively resected localized gastric adenocarcinoma is high, there is a potential role for neoadjuvant and adjuvant strategies in this disease. An extended phase 2 study that treated high-risk patients with adjuvant 5-FU, leucovorin, cisplatin, and radiotherapy found that this regimen was feasible and had acceptable toxicity. Some patients also received paclitaxel as part of the chemotherapy combination. Another study randomized patients with resectable gastric cancer to surgery with or without adjuvant chemotherapy with cisplatin, epirubicin, leucovorin, and 5-FU. A benefit of 4% in survival, which was not statistically significant, was demonstrated for the study arm, although the study was designed to detect a 20% difference.
Treatment in the Elderly
A significant proportion of patients presenting with esophagogastric cancers are over the age of 70 years. Despite this preponderance, patients in this age group are often underrepresented in clinical trials. A retrospective analysis of 3 randomized trials of palliative chemotherapy for esophagogastric cancer found that response rates, survival, and symptomatic benefit were similar between patients above the age of 70 years compared with those who were younger, without increased toxicity. There may have been a bias toward only including elderly patients with poor performance status or significant comorbidity in these studies. However, this is consistent with the increasing body of evidence for considering the overall condition of patients when selecting patients for treatment, and not excluding them from treatment based on calendar age alone.
References
Benson AB 3rd, Schrag D, Somerfield MR, et al. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol. 2004;22:3408-3419. Abstract
Figueredo A, Charette ML, Maroun J, Brouwers MC, Zuraw L. Adjuvant therapy for stage II colon cancer: a systematic review from the Cancer Care Ontario Program in evidence-based care's gastrointestinal cancer disease site group. J Clin Oncol. 2004;22:3395-3407. Abstract
McKendrick J, Cassidy J, Van Hazel G, et al. Positive efficacy results of the X-ACT phase III trial of capecitabine (X) vs. bolus 5-FU/LV as adjuvant therapy for patients (pts) with Dukes' C colon cancer. Ann Oncol. 2004;15(suppl 3):abstract 276PD.
Douillard JY, Twelves C, McKendrick J, et al. Pharmacoeconomic analysis of capecitabine in the adjuvant setting. Results from the X-ACT trial comparing capecitabine with 5-FU/LV in patients with Dukes' C colon cancer. Ann Oncol. 2004;15(suppl 3):abstract 274PD.
Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343-2351. Abstract
Sargent DJ, Wieand S, Benedetti J, et al. Disease-free survival (DFS) vs. overall survival (OS) as a primary endpoint for adjuvant colon cancer studies: individual patient data from 12,915 patients on 15 randomized trials. Proc Am Soc Clin Oncol. 2004;23:abstract 3502.
de Gramont A, Boni C, Navarro M, et al. Oxaliplatin/5FU/LV in stage II and III colon cancer: updated results (as of January 04) for efficacy and neurotoxicity of the MOSAIC trial. Ann Oncol. 2004;15(suppl 3):abstract 275PD.
Hickish T, Boni C, Navarro M, et al. Stage II patients in the "MOSAIC" trial evaluating oxaliplatin/5FU/LV as adjuvant treatment of colon cancer: a subpopulation analysis. Ann Oncol. 2004;15(suppl 3):abstract 284P.
Gray RG, Barnwell J, Hills R, McConkey C, Williams N, Kerr D. QUASAR: a randomised study of adjuvant chemotherapy (CT) vs observation including 3238 colorectal cancer patients. Proc Am Soc Clin Oncol. 2004;23:abstract 3501.
Kerr DJ, Barnwell J, Hills R, et al. QUASAR Collaborative Group: a randomised study of adjuvant chemotherapy (CT) vs observation in predominantly stage II colorectal cancer (ASCO 2004, Abstr. 3501). Ann Oncol. 2004;15(suppl 3):abstract 43IN.
de Gramont A, Bosset JF, Milan C, et al. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol. 1997;15:808-815. Abstract
de Gramont A, Louvet C, Andre T, et al. A simplified bimonthly regimen with leucovorin (LV) and 5-fluorouracil (5-FU) for metastatic colorectal cancer (MCRC). Feasibility study. Proc Am Soc Clin Oncol. 1997;16:abstract 1019.
Cunningham D, Pyrhonen S, James RD, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998;352:1413-1418. Abstract
Rougier P, Van Cutsem E, Bajetta E, et al. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet. 1998;352:1407-1412. Abstract
Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. 2000;343:905-914. Abstract
Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000;355:1041-1047. Abstract
de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000;18:2938-2947. Abstract
Goldberg RM, Morton RF, Sargent DJ, et al. N9741: oxaliplatin (Oxal) + CPT-11or 5-fluorouracil (5FU)/leucovorin (LV) in advanced colorectal cancer (CRC): final efficacy data from an intergroup study. Proc Am Soc Clin Oncol. 2004;23:abstract 215.
Haller DG, Rothenberg ML, Wong AO, et al. Final results of a randomized phase III trial comparing irinotecan+oxaliplatin (IROX) to irinotecan monotherapy in patients with metastatic colorectal cancer (MCRC) previously treated with fluoropyrimidines. Ann Oncol. 2004;15(suppl 3):abstract 263O.
Seymour M. Optimizing the use and sequencing of fluorouracil, irinotecan and oxaliplatin in advanced colorectal cancer (ACRC): The UK MRC FOCUS (CR08) trial. Ann Oncol. 2004;15(suppl 3):abstract 5IN.
Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22:229-237. Abstract
Grothey A, Sargent D, Goldberg RM, Schmoll HJ. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol. 2004;22:1209-1214. Abstract
Green EM, Sargent DJ, Goldberg RM, Morton RF, Grothey A. Detailed analysis of oxaliplatin-associated neurotoxicity in Intergroup trial N9741. Ann Oncol. 2004;15(suppl 3):abstract 264O.
Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337-345. Abstract
Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol. 2004;22:1201-1208. Abstract
Lenz HJ, Mayer RJ, Gold P, et al. Activity of cetuximab in patients with colorectal cancer refractory to both irinotecan and oxaliplatin. Proc Am Soc Clin Oncol. 2004;23:abstract 3510.
Van Cutsem EJD, Tabernero J, Diaz-Rubio E, et al. An international phase II study of cetuximab in combination with oxaliplatin/5-fluorouracil (5-FU)/folinic acid (FA) (FOLFOX-4) in the first-line treatment of patients with metastatic colorectal cancer (CRC) expressing epidermal growth factor receptor (EGFR). Ann Oncol. 2004;15(suppl 3):abstract 339P.
Berlin J, Malik I, Picus J, et al. Panitumumab therapy with irinotecan, 5-fluorouracil, and leucovorin (IFL) in patients (pts) with metastatic colorectal cancer (mCRC). Ann Oncol. 2004;15(suppl 3):abstract 265PD.
Zampino MG, Lorizzo K, Massacesi C, et al. Gefitinib combined with simplified FOLFOX-6 as first-line treatment in epidermal growth factor receptor (EGFR)-positive advanced colorectal cancer. Ann Oncol. 2004;15(suppl 3):abstract 266PD.
Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335-2342. Abstract
Kabbinavar F, Schulz J, McCleod M, et al. First-line bevacizumab (Avastin) with 5-fluorouracil/leucovorin prolongs progression-free survival in metastatic colorectal cancer (mCRC) patients who are not optimal candidates for irinotecan therapy. Ann Oncol. 2004;15(suppl 3):abstract 261O.
Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003;21:60-65. Abstract
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