Faculty Bibliography

Vascular endothelial growth factor (VEGF) plays a crucial role in the growth and metastatic spread of cancer. Bevacizumab (Avastin) is the first commercially available VEGF inhibitor, earning U.S. Food and Drug Administration (FDA) approval in February 2004. In combination with fluorouracil (5-FU)-based chemotherapy, this agent significantly prolongs overall and progression-free survival of patients with metastatic colorectal cancer. This review details the emerging role of the drug, its unique side effects, and other practical considerations related to bevacizumab therapy. Ongoing trials attempting to define additional indications for bevacizumab as well as the development of other promising angiogenesis inhibitors are also reviewed.

Rituximab, a monoclonal antibody directed against the B cell-specific protein CD20, has revolutionized lymphoma treatment by providing a highly effective form of therapy with relatively mild toxic side effects. Effective as a single agent against some forms of B cell lymphoma, rituximab also has a chemosensitizing effect, enhancing the efficacy of chemotherapy against other forms of the disease. Although the mechanisms whereby rituximab achieves its effects remain incompletely understood, these seem to involve at least three distinct phenomena: (i) antibody-dependent cell-mediated cytotoxicity, (ii) complement-mediated cell lysis, and (iii) stimulation of apoptosis in target cells. The latter occurs through interaction of complexes of rituximab and CD20 in lipid rafts, with elements of a signaling pathway involving Src kinases. Effector molecules trigger various gene expression events, leading to sensitization of malignant cells to proapoptotic stimuli. Lessons learned from the research on rituximab may be applied to the rational development of antibody-based therapies against other forms of cancer.

Gallbladder carcinoma and carcinoma of the bile ducts are relatively rare cancers in the United States. These cancers are often diagnosed in an advanced stage due to their nonspecific symptomatology and until recently have been associated with a dismal prognosis. Recent advances in imaging and surgical techniques along with emerging options in palliative chemotherapy have improved the outlook in these cancers. While complete surgical resection remains the only hope of cure in both these cancers, palliative biliary decompression and chemotherapy result in substantial improvement in quality of life. Part 1 of this review, which appeared in last month's issue, provided a relevant and comprehensive update of molecular pathology, imaging modalities, and surgical care. In part 2, we examine palliative care and systemic therapy in gallbladder and biliary tract carcinomas, as well as the use of liver transplantation in the treatment of cholangiocarcinomas. These strategies are of relevance to internists as well as oncologists caring for these patients.

Gallbladder carcinoma and carcinoma of the bile ducts are relatively rare cancers in the United States. These cancers are often diagnosed in an advanced stage due to their nonspecific symptomatology and until recently have been associated with a dismal prognosis. Recent advances in imaging and surgical techniques along with emerging options in palliative chemotherapy have improved the outlook in these cancers. While complete surgical resection remains the only hope of cure in both these cancers, palliative biliary decompression and chemotherapy result in substantial improvement in quality of life. Part 1 of this review provides a relevant and comprehensive update of molecular pathology, imaging modalities, and surgical care. In part 2, which will appear next month, we will review palliative care and systemic therapy in gallbladder and biliary tract carcinomas, as well as the use of liver transplantation in the treatment of cholangiocarcinomas. These strategies are of relevance to internists as well as oncologists caring for these patients.

The case of a patient developing multiple brain metastases from carcinoma of the exocrine pancreas has been described. A 56-year-old man with stage IV pancreatic cancer attained a clinical and radiographic response while receiving the G-FLIP chemotherapy regimen (biweekly gemcitabine, irinotecan, 5-fluorouracil, leucovorin and cisplatin). After 4 months of therapy, he developed gait imbalance and weakness in the right hand. An MRI of the brain showed multiple 1-2 mm enhancing nodules in the cerebral hemispheres and pons. A subsequent biopsy confirmed that these were pancreatic carcinoma metastases. The patient experienced a rapid deterioration in his neurological status and died 3 days after brain biopsy. Previously reported cases of brain metastases from pancreatic cancer are reviewed.

This phase I trial was initiated based on encouraging clinical data with 5-fluorouracil (5-FU)/leucovorin (LV), gemcitabine and cisplatin (G-FLIP) in the therapy of solid tumors. In this trial, G-FLIP has been modified to facilitate outpatient administration and to optimize sequence-dependent synergistic activity. Treatment consisted of biweekly (once every 14 days) cycles of sequential gemcitabine 500 mg/m, irinotecan per dose escalation schedule, bolus 5-FU 400 mg/m and LV 300 mg on day 1 followed by a 24-h 5-FU infusion 1500 mg/m, followed by cisplatin 35 mg/m on day 2. The irinotecan starting dose was 80 mg/m and escalated by 20 mg/m in cohorts of three patients until the maximum tolerated dose (MTD) was defined. Twenty-three patients were enrolled (13 men/10 women) with the following cancers: 11 pancreatic, five gallbladder, three squamous cell carcinoma of the head and neck, one hepatocellular carcinoma, one melanoma, one gastric, and one breast cancer. Median patient age was 63 years (range 44-78) and median Karnofsky performance status (KPS) was 80. Patients received a median of 8 cycles (range 1-16) over five irinotecan dose levels (80, 100, 120, 140 and 160 mg/m). Dose-limiting toxicity consisting of grade 3 nausea/vomiting despite aggressive anti-emetic therapy occurred in one patient at dose level 1 and three patients at dose level 3. Grade 3-4 hematological toxicities per patient consisted of thrombocytopenia (3%), anemia (6%), thrombosis (23%), neutropenia (16%) and neutropenic fever (10%). Of 18 patients evaluable for response, one complete response (pancreatic) and eight partial responses (three gallbladder, two pancreatic, two head and neck, and one breast) were attained. Seven patients had disease stabilization (five pancreatic, one hepatocellular and one gastric) for a median of 16 weeks (range 10-22). Median time to disease progression among all 23 patients enrolled to the phase I portion of the trial was 20.5 weeks (range 4-37). We conclude that G-FLIP is a novel outpatient chemotherapy regimen with acceptable toxicity at the maximum tolerated irinotecan dose of 120 mg/m. The phase II trial of G-FLIP using an irinotecan dose of 120 mg/m for patients with metastatic pancreatic cancer is ongoing.

This update is devoted to discussion of optimal supportive and palliative care of patients with pancreatic cancer. Approximately 33,000 new cases of pancreatic cancer are predicted for the U.S. in 2002. Because diagnosis and intervention occur late in the course of this disease, the vast majority of patients already have metastatic disease at the time of diagnosis. These tumors are relatively resistant to systemic chemotherapy, making pancreatic cancer the fourth leading cause of cancer-related death in the U.S. and the Western world. For these reasons, efforts at identifying and treating disease-related symptomatology are priorities. This update overviews symptom management, supportive care strategies, and both standard and emerging palliative chemotherapy options. The incorporation of molecularly targeted therapies into treatment of metastatic pancreatic cancer is reviewed as well. These strategies are of relevance to internists, gastroenterologists, oncologists, and other specialists who care for patients with pancreatic cancer.

Phase II studies have suggested an improved response rate and acceptable toxicity profile associated with gemcitabine combinations compared to gemcitabine alone for treatment of metastatic adenocarcinoma of the pancreas. The GFP regimen (gemcitabine, 5-fluorouracil, leucovorin, and cisplatin) is based on laboratory evidence of disease-specific chemotherapy interaction. This retrospective analysis examined the outcome of 49 consecutive patients with histologically confirmed metastatic pancreatic adenocarcinoma treated between July 1998 and September 2000. Day 1 treatment consisted of gemcitabine 500 mg/m2 over 30 minutes and then leucovorin 300 mg bolus, 5-fluorouracil (5-FU) 400 mg/m2 bolus, followed by infusional 5-FU 600 mg/m2 over 8 hours. Day 2 consisted of leucovorin 300 mg bolus, 5-FU 400 mg/m2 bolus, followed by cisplatin 50-75 mg/m2 over 30 minutes and then infusional 5-FU 600 mg/m2 over 8 hours. Treatment was administered every 2 weeks. Median patient age was 61.5 years, 74% were men, and 20 patients had refractory disease (11 patients had disease progression upon gemcitabine-based therapy). Grade 3-4 toxic effects (% patients) consisted of neutropenia (30%), thrombocytopenia (14%), anemia (8%), and neutropenic fever (2%). Grade 3-4 nonhematological toxicities (% patients) consisted of neuropathy (14%), ototoxicity (8%), nephrotoxicity (6%), nausea/vomiting (14%), and mucositis (10%). The majority of dose reductions were made for neuropathy or cytopenias. Filgrastim and erythropoietin were given as needed to promote dose intensity. Eight patients attained a partial response (PR) by RECIST criteria. Fourteen had stable disease (SD). Two patients attaining PR and two attaining SD had progressive disease with prior gemcitabine-based therapy. The median time to disease progression (TTP) from GFP start was 9 weeks. For all 49 patients, the median overall survival (OS) from GFP start was 10.6 months, 12-month survival was 46%, and 24-month survival was 30%. Notably, upon disease progression, 31 patients continued to receive the GFP regimen with irinotecan 80 mg/m2 inserted on day 1 following gemcitabine, the G-FLIP regimen (gemcitabine, 5-fluorouracil, leucovorin, irinotecan, and cisplatin). Measured from G-FLIP initiation, the TTP for the 31 patients treated sequentially was 10 weeks, and for the 14 patients attaining SD or PR the TTP was 25 weeks. The median overall survival measured from GFP initiation was 11.8 months. The response rate, non-cross resistance, TTP, OS, and tolerability warrant prospective development of this novel combination. This experience also demonstrates that adding a single new drug such as irinotecan to the same first-line chemotherapy combination upon disease progression may be an important alternative for the treatment of relapsed/resistant cancer.