Faculty Bibliography

BACKGROUND: This Simon 2-stage phase II trial was designed to document antitumor activity of capecitabine in combination with erlotinib in patients with previously untreated metastatic colorectal cancer (CRC). PATIENTS AND METHODS: Time to tumor progression, objective response rate, and time to treatment failure were to be assessed. Secondary objectives included determination of toxicity. This trial was closed prematurely because of slower-than-expected accrual. Thirteen patients were enrolled, and all are off protocol treatment at the time of this report. RESULTS: Notably, 4 subjects discontinued therapy because of adverse events. Of 10 evaluable patients, 1 attained a complete response, 1 attained a partial response, 3 had stable disease, and 5 had progressive disease. Median time to disease progression was 21 weeks, with a range of 8-85 weeks. Overall survival ranged from 12 weeks to 182 weeks, with a median of 76 weeks. CONCLUSION: The toxicities and challenge to complete accrual observed in this trial are consistent with the experience of others attempting to develop erlotinib as part of combination treatment for advanced CRC.

Pancreatic cancer is the fourth most common cause of adult cancer death in the U.S. The high mortality rate from pancreatic cancer is a result of the high incidence of metastatic disease at the time of diagnosis, an often fulminant clinical course, and the lack of adequate systemic therapies. Unfortunately, only 5%-25% of patients present with tumors amenable to resection. The median disease-free survival interval following resection for operable pancreatic cancer is 13.4 months for patients treated with adjuvant gemcitabine and 6.9 months for untreated patients. A much higher percentage of patients present with metastatic disease (40%-45%) or locally advanced disease (40%), and have median survival times of 3-6 months or 8-12 months, respectively. The frustrating lack of significant clinical advancements in the treatment of metastatic pancreatic cancer remains one of medical oncology's biggest disappointments. The past decade-long frustration has resulted in regulators, investigators, and practicing oncologists gradually lowering their standards/expectations with regard to interpreting clinical trials. Two of the more important examples of this include the approval of gemcitabine plus erlotinib and the use of a progression-free survival advantage to defend the use of gemcitabine plus oxaliplatin. Given the marginal benefit of systemic antineoplastics, a scholarly review inclusive of other palliative strategies will help oncologists optimize the care of pancreatic cancer patients. This article examines the existing evidence in support of a role for palliative therapy in metastatic pancreatic cancer, describes recent developments with newer chemotherapeutic and molecular-targeted agents, and explores future study designs.

Development of treatments to improve the outcomes achieved with single-agent gemcitabine therapy for metastatic pancreatic cancer remains a research priority. G-FLIP (gemcitabine, 5-fluorouracil, leucovorin and cisplatin) is a four-drug regimen designed to maximize sequence-dependent synergy, while attempting to minimize toxicity among the four drugs. The dose-limiting toxicities and maximum tolerated dose of irinotecan as part of the G-FLIP regimen have been published. For phase II testing, G-FLIP consisted of sequential gemcitabine 500 mg/m2 at a fixed rate of 10 mg/m2/min, irinotecan 120 mg/m2, bolus 5-fluorouracil 400 mg/m2 and leucovorin 300 mg, followed by a 24-h 5-fluorouracil infusion of 1500 mg/m2 on day 1 and cisplatin 35 mg/m2 on day 2. Cycles were repeated every 14 days. Thirty-three patients with metastatic pancreatic cancer (22 men and 11 women) were treated and 31 were evaluable. Median patient age was 63 years (range 44-78 years) and median Karnofsky performance status score was 70-80. Estimated median time to disease progression was 171 days (6.1 months) and Kaplan-Meir-estimated median overall survival was 229 days (8.1 months). Twelve- and 18-month survivals were 33 and 21%, respectively. As per Response Evaluation Criteria in Solid Tumors criteria, 13 patients had stable disease, seven (22%) attained a partial response, and 10 (32%) had disease progression. One patient attained a complete response and two were not evaluable (one withdrew consent and one died suddenly, each after cycle 1). Treatment generally was well tolerated. Grade 3-4 toxicities/patient were thrombocytopenia (3.1%), leukopenia (15%), neutropenia (21%), neutropenic fever (3%), fatigue (18%) and thrombosis (12.5%). Common grade 1-2 toxicities per patient included nausea/vomiting (69%), diarrhea (45%), constipation (21%) and fatigue (39%). In conclusion, G-FLIP is a feasible outpatient regimen with acceptable toxicity for metastatic pancreatic cancer patients. Disease control rate (stable disease rate plus partial or complete responses) and 1-year survival outcomes are encouraging.

The concept of mucosa-associated lymphoid tissue (MALT) lymphomas was introduced by Isaacson and Wright [Cancer 1983; 52:1410-1416] in 1983. After more than 20 years of clinical research MALT lymphomas are now recognized as a distinct subtype of non-Hodgkin's lymphoma (NHL) with unique pathogenic, histological, and clinical features. Although this subtype of NHL occurs frequently, optimal management remains elusive. This manuscript reviews features of the clinical presentation, diagnosis, pathology, molecular characteristics, and management of both gastric and non-gastric MALT lymphoma.

BACKGROUND: In the past 25 years, clinical trials have demonstrated the benefits of chemotherapy for patients with aggressive non-Hodgkin lymphoma. The authors analyzed the predictors and outcomes of chemotherapy among elderly patients with lymphoma. METHODS: Patients age >/=65 years who were diagnosed with Stage III and IV diffuse large B-cell lymphoma [according to the SEER Summary Staging Manual, 2000] between 1991 and 1999 in the Surveillance, Epidemiology, and End Results-Medicare data base were categorized by treatment: no chemotherapy, a doxorubicin-containing regimen, a regimen without doxorubicin, or chemotherapy not otherwise specified. Among the patients who survived for >6 weeks after diagnosis and who had a chemotherapy regimen specified, logistic regression analysis was used to identify predictors of doxorubicin-based treatment, and Cox proportional-hazards regression was used to analyze outcomes. RESULTS: Less than 66% of patients received any chemotherapy in the 6 months after diagnosis, and 42% of untreated patients died within 6 weeks. Older age, congestive heart failure, and other comorbidities were strong predictors of treatment without doxorubicin. From 1991 to 1999, the proportion of patients who received doxorubicin increased from <20% to >50%. Patients who received doxorubicin survived more than twice as long (24.4 months) as patients who did not receive doxorubicin (11.2 months). Survival was no better among patients who received chemotherapy without doxorubicin than among patients who received no chemotherapy. CONCLUSIONS: By 1999, doxorubicin-based chemotherapy had gained general acceptance for use among the elderly, although nearly 50% of elderly patients still were not receiving it. Given the clinical trial-based evidence of its benefits, in the absence of specific contraindications, most patients, including the elderly, should be treated with regimens that include doxorubicin.

Cancer of the urothelium is the fourth most common malignancy in men in the U.S. and the ninth most common in women. More than 63,000 Americans will be diagnosed with bladder cancer this year (47,010 men and 16,200 women), and more than 13,000 (8,970 men and 4,210 women) can expect to die of their disease. The approximate 5:1 ratio of incidence to mortality roughly parallels the frequency of superficial to invasive disease. Efforts to improve this ratio have generated a potential paradigm shift in the treatment of urothelial cancer, incorporating increasingly active chemotherapy into treatment regimens for high-risk tumors in both the pre-and postoperative settings. This review summarizes the evolution of chemotherapeutic treatment of urothelial cancer and the rationale for its perioperative administration and addresses the future directions of clinical research in this field.

The present study aimed to determine the long-term safety and efficacy of chimeric anti-CD 20 antibody rituxan (rituximab, Biogen IDEC, San Diego, CA, USA; Genentech, South San Francisco, CA, USA) in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy in previously untreated patients with aggressive non-Hodgkin's lymphoma (NHL). Thirty-three patients with previously untreated aggressive B-cell NHL received six infusions of rituximab (375 mg/m(2) per dose) on day 1 of each cycle of CHOP chemotherapy, given on day 3 of each cycle of therapy. Currently, the patients now have a median follow-up of 63 months (range 34 - 82 months). The overall response (OR) rate was 94% and the complete response (CR) rate was 61% at the end of therapy. Of the 33 patients, 2 patients experienced disease progression and subsequently died of their disease, 2 patients experienced disease progression but were alive at last follow-up following additional therapy, and 2 patients died without experiencing disease progression: one due to a cerebral vascular accident at 9 months after therapy and a second patient due to small cell lung carcinoma at 55 months. The 5-year survival rate was 88% (95% confidence interval (CI) 72 - 97) and the 5-year progression-free survival was 82% (95% CI 64 - 93). There were no long-term adverse events noted directly related to the rituximab. The long-term follow-up of patients in this phase II trial of rituximab with CHOP chemotherapy for previously untreated aggressive NHL demonstrates a high response rate, which remains very durable with high 5-year overall and progression-free survivals.

Clinically detected extra-cranial metastases from glioblastoma multiforme (GBM) are quite rare, with an incidence of <2% reported in the published literature. Among the various reported sites of systemic metastases from GBM, there are few cases of clinically symptomatic bone marrow metastasis. The case of a patient developing systemic dissemination of a GBM is described. A 60-year-old man with GBM who developed back pain, thrombocytopenia and subsequently neurological deficits was found to have extensive bony and bone marrow metastases. Previously reported cases of extra-cranial systemic spread of GBM and attempts made in the literature to explain the possible routes of extra-neural dissemination are reviewed.

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.