The results of recent clinical trials and the design of ongoing trials in the management of patients with metastatic colorectal cancer are reviewed.
J. J. Mahany, Jr. Sunset, 2002. Photograph. Healy, Alaska.
Metastatic Colorectal Cancer: Systemic Treatment in the New Millennium Anelisa K. Coutinho, MD, and Caio Max S. Rocha Lima, MD Background: Colorectal cancer (CRC) is common in North America. Metastatic disease is present at diagnosis in 30% of the patients, and approximately half of early-stage patients will eventually present with metastatic disease. Until recently, few chemotherapy options were available to treat metastatic CRC. Methods: The authors review the results of recent clinical trials and the design of ongoing trials in the management of patients with metastatic colorectal cancer. Results: Fluorouracil (5-FU) with leucovorin (LV) modulation has a marginal but positive effect on survival in those patients. The recent incorporation of irinotecan (CPT-11) and oxaliplatin for the management of advanced CRC has generated further improvement in survival. The development of oral fluoropyrimidines, mimicking continuous infusion 5-FU, is convenient. In randomized trials, capecitabine was equally effective to bolus 5-FU and LV in the management of metastatic CRC. Conclusions: Recently completed or ongoing clinical trials to study novel targeting agents have initiated a new era of drug development. Anti-angiogenesis drugs, tyrosine kinase inhibitors, and epidermal growth factor blockers are among this new generation of agents with encouraging preliminary data. Randomized trials will determine the impact of these newer agents on survival and quality of life of patients with metastatic CRC.
Introduction Colorectal cancer (CRC) is the most common gastrointestinal cancer in the United States.1 Among all sites, CRC is the third most commonly diagnosed malignancy in both genders in North America. Projections From the Clinica AMO-Assistencia Muldiciplinar em Oncologia, Salvador-Bahia, Brazil (AKC), and the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida (CMRL). Submitted January 16, 2003; accepted March 31, 2003. Address reprint requests to Caio Max S. Rocha Lima, MD, Gastrointestinal Tumor Program, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL 33612-9497. E-mail:
[email protected] 224 Cancer Control
for 2003 estimate that 147,500 new cases of CRC will be diagnosed and 57,100 patients will die of this disease.1 Approximately 30% of all patients with CRC have metastatic disease at diagnosis, and 50% of earlystage patients will eventually develop metastatic or advanced disease.2 Chemotherapy is effective in proNo significant relationship exists between Dr Coutinho and the companies/organizations whose products or services are referenced in this article. Dr Rocha Lima receives grants/research support from Pfizer Inc, Aventis Pharmaceuticals Inc, and Eli Lilly and Co. He also receives honorarium from and is a consultant for these companies and GlaxoSmithKline.
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longing survival and time to disease progression in patients with metastatic CRC.3-5 The paucity of active agents in the treatment of CRC in the past resulted in extensive investigation of 5-fluorouracil (5-FU) and 5-FU–based combinations. This agent has been developed in many different schedules of administration. Modulation of 5-FU anticancer effects with leucovorin (LV) became one of the standard treatment regimens for metastatic colon cancer.
Additional pharmacologic strategies to enhance the effectiveness of 5-FU included combination with methotrexate, cisplatin, N-(phosphonacetyl)-L-aspartic acid (PALA), and interferon. Despite these attempts, no survival advantage was established until the advent of the newer cytotoxic drugs irinotecan and oxaliplatin.6,7 Additionally, improvement in convenience of drug administration has been achieved with the development of oral fluoropyrimidines for the treatment of metastatic CRC.
Table 1. — Phase III Trials of Second-Line Irinotecan (CPT-11) for Metastatic Colorectal Cancer Author Cunningham
11
Rougier12
No. of Patients
Design
1-Yr Survival
Median Survival
279
CPT-11 + best supportive care vs Best supportive care
36%
N/A
CPT-11 vs 5-FU (de Gramont regimen)
45%
10.8 mos
32%
8.5 mos
267
13%
Table 2. — Phase III Treatment Trials for First-Line Irinotecan (CPT-11) for Metastatic Colorectal Cancer Author
No. of Patients
Saltz14
683
Douillard15
387
Design
Progression-Free Survival (mos)
Response Rate (%)
Median Survival (mos)
Arm 1 I 125 mg/m2 IV F 500 mg/m2 IV bolus L- 20 mg/m2 IV bolus Schedule: weekly for 4 wks every 6 wks
7.0
39
14.8
Arm 2 F 425 mg/m2 IV bolus L 20 mg/m2 IV bolus Schedule: d1-5 every 4 wks
4.3
21
12.6
Arm 3 I 125 mg/m2 IV Schedule: weekly for 4 wks every 6 wks
4.2
21
12.0
(P=.004)
(P=.001)
(P=.04)
6.7
49
17.4
4.4
31
14.1
(P=.001)
(P90% of the O dose)
27
5.3 mos/10.8 mos
Neuropathy: 16 Neutropenia: 24 Diarrhea: 7 Global: 46
Maindrault-Goebel27 (2001)
48
FOLFOX 7 (second-line treatment)
O 130 mg/m2 plus L 400 mg/m2 in 2 hrs d1 followed by F 400 mg/m2 bolus and 2.4 g/m2 in 46 hrs Schedule: every 2 wks (64% received 90% of the O dose)
42
6 mos/16.1 mos
Neuropathy: 15 Neutropenia: 9 Diarrhea: 11 Global: 38
O = oxaliplatin L = leucovorin F = fluorouracil FOLFOX = oxaliplatin, fluorouracil, and leucovorin
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lated IV-infusion 5-FU 700 mg/m2 per day and LV 300 mg/m2 per day, with half of these patients also receiving oxaliplatin.31 The objective RR was 16% and 53%, respectively, favoring the oxaliplatin arm (P
