Alberts, Steven R.

Abstract Learning Objectives After completing this course, the reader should be able to: Explain the role of chemotherapy in the treatment of liver metastases from colorectal cancer and the shifting goals of therapy—from palliation to prolongation of life.Select among the evolving treatment options for patients with unresectable, not optimally resectable, and resectable liver metastases.Discuss the unresolved research issues, including the optimal timing of perioperative chemotherapy and the role of biologic agents in the management of liver metastases from colorectal cancer. CME This article is available for continuing medical education credit at CME.TheOncologist.com Colorectal cancer (CRC) is a highly prevalent malignant disease in industrialized nations. The annual incidence of invasive CRC in the U.S. is among the highest in the world, and the liver is the only metastatic site in approximately one third of patients. Without treatment, patients with metastatic disease have a poor prognosis; however, long-term survival benefits and even cure have been reported in patients undergoing surgical resection of metastases. In addition, advances in chemotherapy, imaging, and surgical techniques have increased the proportion of patients who are eligible for resection. Combination therapy with fluorouracil and leucovorin has been the mainstay of treatment for metastatic CRC; however, the introduction of newer agents, such as oxaliplatin and irinotecan, and targeted agents, such as cetuximab and bevacizumab, has yielded improvements in response rates (RRs) and survival. Maximizing the exposure of hepatic metastases to high target concentrations of cytotoxic drugs using hepatic arterial infusion (HAI) increases RRs further than with systemic chemotherapy; however, the impact of HAI on survival is unclear. As the goals of chemotherapeutic treatment for metastatic CRC increasingly shift from palliation to prolongation of survival, improvement in RRs, and downsizing of tumors in order to enable or optimize resection, treatment in a multidisciplinary environment involving a medical oncologist, radiologist, and surgical oncologist with hepatobiliary expertise will become central to deciding the best course of therapy and timing of surgery.

Abstract Purpose: Proapoptotic BH3-only proteins Bad and Bid initiate apoptosis by binding to regulatory sites on prosurvival Bcl-2 proteins to directly neutralize their function. We determined if expression of these proteins in colon cancers may account for differences in patient survival. Experimental Design: Tumor-node-metastasis stages II and III primary colon carcinomas from patients treated in 5-fluorouracil-based adjuvant therapy trials were studied. Immunohistochemical analysis of Bad and Bid proteins was done in tumors (n = 379) and adjacent normal mucosa. Expression was correlated with clinicopathologic variables, disease-free survival rates (DFS), and overall survival (OS) rates. Results: High expression of the Bad protein [hazard ratio (HR), 0.64; 95% confidence interval (95% CI), 0.43-0.96; P = 0.031] in the cytoplasm of tumor cells was significantly associated with more favorable OS in a univariate analysis. The combined Bad and Bid variable was prognostic for DFS (P = 0.027) and OS (P = 0.006). Stage and histologic grade, but not DNA mismatch repair status, were also prognostic for OS. Multivariate Cox analysis showed that high expression of Bad (HR, 0.64; 95% CI, 0.43-0.97; P = 0.027) and Bid (HR, 0.68; 95% CI, 0.49-0.97; P = 0.034) were independent predictors of OS after adjustment for stage, grade, age, treatment, and study. The combined variable of Bad + Bid was independently associated with DFS (P = 0.020) and OS (P = 0.004). Conclusion: Proapoptotic Bad and Bid proteins are independent prognostic variables in colon cancer patients receiving adjuvant treatment. If validated, Bad and Bid expression may assist in risk stratification and selection of patients to receive adjuvant chemotherapy.

Purpose To evaluate clinical characteristics and survival outcomes among patients with locally advanced or metastatic colorectal cancer who achieve a complete response (CR) to systemic treatment either alone or with multimodality approach. Patients and Methods Data were collected retrospectively from CRC patients enrolled onto the phase III trial N9741, a National Cancer Institute–funded and Gastrointestinal Cancer Intergroup–sponsored study coordinated by the North Central Cancer Treatment Group. Patients were randomly assigned to combinations of oxaliplatin, fluorouracil (FU)/leucovorin (LV) and irinotecan. The three treatment arms consist of IFL (irinotecan + FU/LV), FOLFOX4 (oxaliplatin + FU/LV), and IROX (irinotecan + oxaliplatin). Median follow-up was 42.6 months. Results Sixty-two (4%) of 1,508 patients had a CR to chemotherapy alone, and an additional 32 (2%) had a CR after multimodality treatment. Factors associated with achieving CR with systemic chemotherapy alone included FOLFOX4 treatment, patients with assessable disease, or a single site of metastasis. Continuing protocol treatment beyond two cycles after documentation of CR was not associated with improved survival. The rate of curative intent resection was significantly higher for patients treated with oxaliplatin-containing regimens (P = .02). Median survival was similar between patients with CR after chemotherapy alone (44.3 months) or after multimodality approach (47.4 months; P = .81). Conclusion FOLFOX4 was more likely to produce a CR than were IFL or IROX. Oxaliplatin regimens were more likely to result in successful surgical resections. Patients who have CR to systemic chemotherapy alone can achieve impressive survival outcomes similar to those seen among patients who attained a CR status after multimodality treatment.

Purpose A phase II study was conducted to determine the efficacy and toxicity of radiotherapy with concomitant gemcitabine and cisplatin for patients with locally advanced pancreatic adenocarcinoma. Patients and Methods Forty-eight patients with locally advanced pancreatic adenocarcinoma received gemcitabine (30 mg/m2) and cisplatin (10 mg/m2) twice weekly during the first 3 weeks of radiotherapy. The radiation dose to the primary tumor and regional nodes was 45 Gy in 25 fractions, and the gross tumor volume received an additional 5.4 Gy in three fractions. Four weeks after radiotherapy, patients received gemcitabine (1,000 mg/m2) once weekly every 3 of 4 weeks for a 12-week period. The primary end point was survival at 12 months. Secondary end points were time to progression, toxicity, and quality of life. Results Survival at 1 year was 40% for 47 eligible patients. The median survival was 10.2 months. Confirmed responses were observed for 8.5% (two partial, two complete), and median time to progression was 7.3 months. Grade 4 or higher toxicity was observed for 31% and consisted primarily of hematologic and GI toxicity. There was a trend toward improved overall quality of life, measured by the Symptom Distress Scale (P = .06), with significant improvements in domains of insomnia, pain, and outlook. Conclusion The combination of radiotherapy, gemcitabine, and cisplatin was well tolerated. Survival results were similar to those achieved with other treatment regimens for patients with locally advanced pancreatic cancer but did not meet our predefined criteria for additional evaluation of this regimen.

Purpose Colorectal cancer is the second leading cause of cancer mortality in the United States. Antiangiogenic therapy with bevacizumab combined with chemotherapy improves survival in previously untreated metastatic colorectal cancer. This study was conducted to determine the effect of bevacizumab (at 10 mg/kg) on survival duration for oxaliplatin-based chemotherapy in patients with previously treated metastatic colorectal cancer. Patients and Methods Eight hundred twenty-nine metastatic colorectal cancer patients previously treated with a fluoropyrimidine and irinotecan were randomly assigned to one of three treatment groups: oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) with bevacizumab; FOLFOX4 without bevacizumab; or bevacizumab alone. The primary end point was overall survival, with additional determinations of progression-free survival, response, and toxicity. Results The median duration of survival for the group treated with FOLFOX4 and bevacizumab was 12.9 months compared with 10.8 months for the group treated with FOLFOX4 alone (corresponding hazard ratio for death = 0.75; P = .0011), and 10.2 months for those treated with bevacizumab alone. The median progression-free survival for the group treated with FOLFOX4 in combination with bevacizumab was 7.3 months, compared with 4.7 months for the group treated with FOLFOX4 alone (corresponding hazard ratio for progression = 0.61; P < .0001), and 2.7 months for those treated with bevacizumab alone. The corresponding overall response rates were 22.7%, 8.6%, and 3.3%, respectively (P < .0001 for FOLFOX4 with bevacizumab v FOLFOX4 comparison). Bevacizumab was associated with hypertension, bleeding, and vomiting. Conclusion The addition of bevacizumab to oxaliplatin, fluorouracil, and leucovorin improves survival duration for patients with previously treated metastatic colorectal cancer.

Abstract Cancer incidence for American Indians and Alaska Natives is typically reported as a single rate for all U.S. indigenous populations combined. Previously reported combined rates suggest that American Indians and Alaska Natives have lower cancer incidence rates compared with the U.S. population. Alaska Native people comprise three major ethnic groups: Eskimo, Indian, and Aleut people. We examined cancer incidence from only Alaska Indians and compared incidence rates with an American Indian population living in New Mexico. These data indicate striking differences in cancer patterns between two American Indian populations. Cancer data for the years 1993 to 2002 for American Indians of New Mexico and U.S. Whites are from the National Cancer Institute Surveillance, Epidemiology, and End Results Program Public-use data set. Data for Alaska Indians are from the Alaska Native Tumor Registry, which is also a Surveillance Epidemiology and End Results Program participant. Overall, cancer incidence rates for all sites combined in New Mexico Indian men and women were lower than U.S. White rates, whereas Alaska Indian men and women exceeded U.S. rates. In comparing Alaska and New Mexico Indians, we observed a 2.5-fold higher incidence of cancer among Alaska Indians. The largest differences between the two Indian populations were noted primarily in cancers associated with tobacco use, including cancers of the oral cavity/pharynx, esophagus (only in men), colon and rectum, pancreas, larynx (men), lung, prostate, and urinary bladder (men). Lung cancer rates in Alaska Indian men and women were 7 and 10 times those of New Mexico Indian men and women. (Cancer Epidemiol Biomarkers Prev 2006;15(8):1515–9)

Purpose Previously, we reported results of Intergroup N9741, which compared standard bolus fluorouracil (FU), leucovorin, plus irinotecan (IFL) with infused FU, leucovorin, plus oxaliplatin (FOLFOX4) and irinotecan plus oxaliplatin in patients with untreated metastatic colorectal cancer. High rates of grade ≥ 3 toxicity on IFL (resulting in some deaths) led us to reduce the starting doses of both irinotecan and FU by 20% (rIFL). This article compares rIFL with FOLFOX4. Patients and Methods The primary comparison was time to progression, with secondary end points of response rate (RR), overall survival, and toxicity. Results Three hundred five patients were randomly assigned. The North Central Cancer Treatment Group Data Safety Monitoring Committee interrupted enrollment at a planned interim analysis when outcomes crossed predetermined stopping boundaries. The results were significantly superior for FOLFOX4 compared with rIFL for time to progression (9.7 v 5.5 months, respectively; P < .0001), RR (48% v 32%, respectively; P = .006), and overall survival (19.0 v 16.3 months, respectively; P = .026). Toxicity profiles were not significantly different between regimens for nausea, vomiting, diarrhea, febrile neutropenia, dehydration, or 60-day all-cause mortality. Sensory neuropathy and neutropenia were significantly more common with FOLFOX4. Approximately 75% of patients in both arms received second-line therapy; 58% of rIFL patients received oxaliplatin-based second-line therapy, and 55% of FOLFOX4 patients received irinotecan-based regimens as second-line therapy. Conclusion FOLFOX4 led to superior RR, time to progression, and overall survival compared with rIFL. The survival benefit for FOLFOX4 observed in the earlier stage of the study was preserved with equal use of either irinotecan or oxaliplatin as second-line therapy.

Purpose To compare maintenance epoetin alfa administered once every 3 weeks with continued weekly epoetin alfa for patients with cancer-associated anemia. Patients and Methods Eligible patients were randomly assigned at enrollment to receive three weekly doses of epoetin alfa 40,000 U subcutaneously (SC), followed by either standard weekly epoetin alfa (40K arm) or 120,000 U of epoetin alfa (120K arm) SC every 3 weeks for 18 additional weeks. Results Three hundred sixty-five patients were enrolled. One hundred eighty-three patients were assigned to the 40K arm, and 182 were assigned to the 120K arm. There was no difference in the proportion of patients requiring transfusions during the study (23% in 40K arm and 18% in 120K arm, P = .22) or specifically during the maintenance phase (13% in 40K arm v 15% in 120K arm, P = .58). Patients randomly assigned to the 40K arm were more likely to have a ≥ 2 or ≥ 3 g/dL hemoglobin (Hb) increment, were more likely to have a drug dose held because of high Hb, and had higher mean end-of-study Hb levels. Toxicities, including thromboembolism, and overall survival were similar. Patients in the 40K arm had a higher global quality of life (QOL) at baseline for unclear reasons, whereas patients in the 120K arm had a greater global QOL improvement during the study, so end-of-study QOL was equivalent. Conclusion After three weekly doses of epoetin alfa 40,000 U, a dose of 120,000 U can be administered safely once every 3 weeks without increasing transfusion needs or sacrificing QOL. The Hb increment is somewhat greater with continued weekly epoetin alfa. Lack of blinding as a result of different treatment schedules may have confounded results.