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Neuroendocrine tumors comprise a broad family of tumors, the most common of which are carcinoid and pancreatic neuroendocrine tumors. The NCCN Neuroendocrine Tumors Guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine tumors. Most of the recommendations pertain to well-differentiated, low- to intermediate-grade tumors. This updated version of the NCCN Guidelines includes a new section on pathology for diagnosis and reporting and revised recommendations for the surgical management of neuroendocrine tumors of the pancreas.

Single-agent management of metastatic biliary tract cancers with 5-fluorouracil (5-FU) or gemcitabine has shown limited efficacy, although 5-FU has been shown to be more effective than best supportive care alone. An analysis of phase II trials has suggested that platinums enhanced the efficacy of single-agent fluoropyrimidines. In a phase III randomized trial comparing single-agent gemcitabine with gemcitabine plus cisplatin, the gemcitabine/cisplatin combination significantly improved median overall survival (OS) and progression-free survival (PFS), which established a new option for standard of care. However, the future of cancer medicine lies in newer, targeted agents. In the management of biliary tract cancers, preliminary evidence with epidermal growth factor receptor inhibitors has already demonstrated activity. This article reviews systemic therapies for metastatic biliary tract cancers as they relate to current and emerging standards of care.

Objectives: The epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) pathways play key and often complementary roles in the pathogenesis of colorectal cancer (CRC). This study explores the clinical and biological effects of combined blockade of these pathways., Methods: Cetuximab-naive patients with refractory CRC were treated with cetuximab (400 mg/m loading dose followed by weekly cetuximab at 250 mg/m) and celecoxib (200 mg orally twice daily). Urinary PGE-M, a stable metabolite of PGE2 that correlates with in vivo COX-2 activity, and serum TGF-α, a ligand that binds to EGFR, were measured serially to assess the biological effect of COX-2 and EGFR blockade., Results: Seventeen patients accrued in this study. Of the 13 patients evaluable for response, 2 (15.4%) had confirmed partial responses, 4 (30.8%) had stable disease, and 7 (53.8%) had progressive disease. The median progression-free survival for all evaluable patients was 55 days (95% confidence interval, 45-112; range, 10-295 d). This study was terminated early owing to lack of sufficient clinical activity. There were no statistically significant differences in serum TGF-α or urinary PGE-M between cycles in responders or nonresponders., Conclusions: This regimen resulted in response rates similar to those published for cetuximab monotherapy in patients with recurrent CRC. Apart from a higher than expected rate of infusion reactions, no other unexpected toxicities were observed. No differences in serum TGF-α or urinary PGE-M between cycles were seen, suggesting that the appropriate targets may not have been hit.

Purpose: This phase I study assessed the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of SJG-136, a sequence-specific DNA cross-linking agent, in patients with advanced cancer., Experimental Design: In schedule A, seven patients received escalating doses of SJG-136 (6, 12, 24, and 48 μg/m(2)) daily for 5 of 21 days. Blood samples were collected for PK analysis on days 1 and 5 of cycle 1. In schedule B, SJG-136 was given daily for 3 of 21 days (N = 17; doses 20, 25, 30, and 35 μg/m(2)). Blood samples were collected on days 1 and 3 of cycles 1 and 2 for PK and PD analysis. Patients in schedule B received dexamethasone and early diuretic care., Results: Schedule A-dose-limiting toxicities included grade 3 edema, dyspnea, fatigue, and delayed liver toxicity (grade 3-4). PK analysis revealed dose-dependent increases in AUC and C(max). Substantial changes in volume of distribution at steady-state occurred after repeated dosing in some patients prior to the onset of edema. Schedule B-the same toxicities were manageable with steroid premedication and diuretic support. No significant myelosuppression occurred on either schedule. DNA interstrand cross-links correlated with systemic exposure of SJG-136 following the second dose in cycle 1 and were still detectable immediately before cycle 2., Conclusions: The MTD of SJG-136 in this study was 30 μg/m(2) administered on a daily 3× basis with no myelosuppression effects. Coupled with supportive management, SJG-136 is now advancing to a phase II trial in ovarian cancer., (©2011 AACR.)

Pancreatic cancer is the fourth leading cause of cancer death, and it is estimated that over 43,000 people would be diagnosed with and over 36,000 people would die of pancreatic cancer in the United States in 2010. Surgical resection remains the only chance for possible cure, but only 15% to 20% of patients newly diagnosed with pancreatic cancer are considered for surgical resection. Of these, the median five-year survival rate is still less than 20%, with most resections resulting in recurrent disease. This suggests that even seemingly resectable pancreatic cancer has microscopic systemic spread before operative intervention occurs. Both adjuvant and neoadjuvant therapies have been studied in an effort to improve survival for patients with resectable pancreatic cancer.

Adjuvant therapy for pancreatic cancer remains a controversial topic, with a paucity of randomized controlled trials in this area and various limitations in the trials that have been conducted to date, leaving many questions as to a true "standard of care" for patients with resectable or potentially resectable disease. Several large and well-conducted phase 3 trials have reported results recently and have helped to solidify the role of chemotherapy, with either 5-fluorouracil or gemcitabine, as an effective intervention in the adjuvant setting. The role of radiotherapy remains unclear, but it does seem to be feasible and safe, and there are trials in development that may shed more light on this question. Many small trials have pointed to the potential utility of neoadjuvant strategies in selecting the patients who are most likely to benefit from surgery and in improving outcomes by providing systemic therapy early on. Larger trials are ongoing in hopes that they will give more definitive answers as to when this strategy should be used. It is hoped that trials using novel agents, either alone or in combination with more traditional therapies, will better define the best strategy for improving outcomes in patients with resectable disease.

This article summarizes the expert discussion on the management of hepatocellular carcinoma (HCC), which took place during the 10th World Gastrointestinal Cancer Congress (WGICC) in Barcelona, June 2008. A multidisciplinary approach to a patient with HCC is essential, to guarantee optimal diagnosis and staging, planning of surgical options and selection of embolisation strategies or systemic therapies. In many patients, the underlying cirrhosis represents a challenge and determines therapeutic options. There is now robust evidence in favour of systemic therapy with sorafenib in patients with advanced HCC with preserved liver function. Those involved in the care for patients with HCC should be encouraged to participate in well-designed clinical trials, to increase evidence-based knowledge and to make further progress.

Purpose: To evaluate the safety and describe the pharmacokinetic profile of OSI-7904L, a novel liposomal thymidylate synthase inhibitor, in combination with cisplatin (CDDP) in adults with advanced solid tumors., Experimental Design: CDDP was administered as a 2-h intravenous infusion followed by OSI-7904L intravenously over 30 min, both given every 3 weeks. Doses of each drug were escalated in separate cohorts of patients. Five dose levels of CDDP/OSI-7904L were explored: 60/6, 60/9, 60/12, 60/7.5, and 75/7.5 mg/m2. Pharmacokinetic samples, baseline plasma homocysteine, and genotype polymorphisms were evaluated., Results: Twenty-seven patients were treated with 101 total courses of CDDP/OSI-7904L. Dose-limiting toxicity was observed in 2 patients in the CDDP/OSI-7904L 60/12 mg/m2 cohort. One patient experienced rash, stomatitis, dehydration, renal failure, hyperbilirubinemia, and fatal neutropenic sepsis, whereas the other patient experienced grade 3 nausea, vomiting, and ileus. Therefore, the CDDP/OSI-7904L 60/9 mg/m2 cohort was expanded, with 2 of 6 patients reporting significant fatigue. Other toxicities were mild or moderate. Intermediate dose levels of 60/7.5 and 75/7.5 mg/m2 were evaluated, and the latter was identified as the recommended dose for phase II studies. No major pharmacokinetic interactions between CDDP and OSI-7904L were observed. Three patients had partial responses (gastric adenocarcinoma and heavily pretreated breast cancer). There was no significant relationship between baseline homocysteine and toxicity., Conclusions: The recommended doses for CDDP and OSI-7904L administered once every 3 weeks are 75 and 7.5 mg/m2, respectively. Pharmacokinetic interaction between the agents was not apparent. Preliminary clinical activity was observed in breast and gastric cancer.

Objectives: This phase I study was conducted to evaluate the combination of irinotecan, a topoisomerase I inhibitor, with epirubicin, a topoisomerase II inhibitor, when administered sequentially on a once-every-three week basis., Methods: Irinotecan was administered at doses ranging from 100 to 150 mg/m(2) intravenously over 90 minutes, 24 hours before epirubicin, in doses from 30 to 60 mg/m(2), every 3 weeks. Toxicity assessments were performed weekly. Tumor evaluation by radiographic and physical examination was performed after every 3 cycles using Response Evaluation Criteria in Solid Tumors., Results: Eighteen patients with metastatic solid tumors were enrolled in this study. The maximum tolerated dose and recommended phase II dose was irinotecan 150 mg/m(2) and epirubicin 30 mg/m(2). Dose-limiting toxicities were primarily neutropenia. Other toxicities at this dose level were mild. Three patients with colon cancer, 1 patient with renal cell cancer and 1 patient with adenosquamous cell carcinoma of the ethmoid sinus had stable disease. No objective responses were observed., Conclusions: The maximum tolerated dose and recommended phase II dose for irinotecan and epirubicin administered 24 hours apart every 3 weeks was 150 mg/m(2) and 30 mg/m(2), respectively. Higher doses were limited by significant hematologic toxicity and fatigue.

Purpose: To identify the maximum tolerated dose (MTD) and describe dose-limiting toxicities (DLT) of pemetrexed and oxaliplatin given on a once-every-2-week schedule in patients with metastatic cancer., Patients and Methods: Twenty-five patients were enrolled. Due to toxicities observed at the first dose level in unselected patients, a second MTD was determined in patients who had received zero to two prior chemotherapy regimens., Results: DLT was observed at dose level 1-pemetrexed 400 mg/m(2) and oxaliplatin 85 mg/m(2)-in the form of grade 3 fatigue in two of six patients. Enrollment was then limited to lightly pretreated patients and DLT was observed at dose level 2-pemetrexed 500 mg/m(2) and oxaliplatin 85 mg/m(2)-in the form of neutropenic fever in one of five patients. Complete response was confirmed in one patient (squamous cell carcinoma of the head and neck) and partial response was confirmed in three patients., Conclusions: The combination of pemetrexed and oxaliplatin can be safely administered at doses of 400 to 500 mg/m(2) of pemetrexed and 85 mg/m(2) in patients without extensive prior therapy and 300 and 85 mg/m(2), respectively, every 2 weeks in patients with more extensive prior therapy. Based on promising results observed in this study, a phase II trial in patients with recurrent head and neck cancer has been initiated.

Gastrointestinal stromal tumors (GIST) are tumors most frequently found in adults. They are often related to activating mutations in the CD-117 tyrosine kinase receptor, most commonly at exon 11. Gastrointestinal stromal tumors have been reported in children. However, until recently, there had not been reports of activating mutations in the CD-117 gene, and none have yet documented an exon 11 mutation. We report the case of a 17-year-old found to have an activating mutation in exon 11 of the CD-117 gene. This could play a role in treatment with the targeted therapeutic agent imatinib mesylate.

Background: This study was conducted before the approval of oxaliplatin, cetuximab, and bevacizumab and was designed to evaluate a novel microtubule targeting agent, T138067, in patients with metastatic colorectal cancer (CRC) previously treated with irinotecan and 5-fluorouracil., Patients and Methods: Patients from 3 institutions were enrolled over 4 months and treated with T138067 on days 1, 8, and 15 of a 21-day cycle. Disease evaluation was performed after 9 weeks., Results: Treatment was tolerable with moderate hematologic and gastrointestinal toxicity. Neurotoxicity, an expected side effect, was minimal. Among 23 evaluable patients, there were no responses. Median time to tumor progression was 1.4 months and median survival was 9.3 months., Conclusion: T138067 at this dose and schedule was well tolerated by patients with CRC. However, there was no evidence of clinical activity for T138067 in 5-fluorouracil/irinotecan-refractory CRC. The long median survival likely reflects availability of other agents and/or patient selection.

Purpose: To confirm the anecdotal observation that patients in North Carolina (NC) and Tennessee (TN) treated with cetuximab experience hypersensitivity reactions (HSR) at a much higher rate than are reported nationally and internationally (

Despite attempted curative resection of localized adenocarcinoma of the pancreas, most patients experience a recurrence and die of their disease. The Gastrointestinal Tumor Study Group, European Organisation for Research and Treatment of Cancer, and European Study Group for Pancreatic Cancer trials have suggested the benefit of adjuvant therapy. However, the relatively few randomized trials available have not established a definite standard of care due to study limitations. Although these trials, and the recently published Chariti Onkologie (CONKO)-001 trial, have shown a definite advantage of adjuvant chemotherapy, the most effective chemotherapy and the role of radiation therapy remain unclear. This review will discuss the data available from reported trials of adjuvant and neoadjuvant therapy in pancreatic cancer, address the issues leading to the ongoing controversies, and consider future directions for clinical trials.

Since 1997, when gemcitabine showed superior clinical benefit to single-agent 5-fluorouracil, it has remained the standard of care for the treatment of advanced pancreatic cancer. Numerous new agents, both cytotoxic and targeted, have been tested against this standard. Some trials showed improved response rates or progression free survival, but there was no clear improvement in survival. For the current report, those trial results were reviewed in depth for methodology, endpoints, and study characteristics. More recent studies have shown progress. Studies with combinations of gemcitabine and capecitabine and with the epidermal growth factor receptor antagoinist, erlotinib, have demonstrated survival benefits. Currently, studies of combinations with oxaliplatin, bevacizumab, and cetuximab are ongoing. Other targeted therapies also are considered for future clinical trials. Based on a comprehensive review of past trials, a consensus on endpoints in the treatment of pancreatic cancer and an approach to new trials is presented.

Objectives: Determine the toxicity, tolerability, and pharmacokinetics of SU5416, a vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor, coadministered with bolus 5-fluorouracil (5-FU), leucovorin, and irinotecan (IFL) in untreated patients with metastatic colorectal cancer., Methods: SU5416 (85 or 145 mg/m2) was administered twice weekly throughout a 6-week period along with standard IFL (4 weeks on/2 weeks off). Plasma samples were assayed for SU5416, irinotecan, and SN-38 by reverse-phase HPLC. Contrast enhanced, color Doppler sonography was performed on patients at the MTD to identify changes in tumor perfusion., Results: Eleven patients received treatment with SU5416 85 mg/m2 (n = 5) or 145 mg/m2 (n = 6). At 85 mg/m2, no DLTs were observed. At 145 mg/m2, grade 3 diarrhea and vomiting were observed during cycle 1; other grade 3 toxicities included fatigue, nausea, anorexia, anemia, pain, urinary retention, and hypertension. The pharmacokinetics of irinotecan and SN-38 were not altered by coadministration of SU5416. SU5416 pharmacokinetics were not altered by IFL. Contrast-enhanced, color Doppler sonography was performed on 2 patients and demonstrated reduced tumor perfusion after treatment in a patient who responded to treatment and increased perfusion in a patient who developed progressive disease. Three patients (27%) had confirmed partial responses, 2 patients (18%) had unconfirmed partial responses, and 4 patients (36%) had stable disease., Conclusions: Twice weekly SU5416 can be administered with bolus IFL without unexpected toxicities or altering the pharmacokinetic behavior of the administered drugs. Changes in tumor blood perfusion can be detected by contrast-enhanced, color Doppler sonography. The further development of SU5416 was halted before this study was completed.

Purpose: The clinical objective of this trial was to evaluate gefitinib in patients with metastatic colorectal cancer that had progressed despite prior treatment. Serial tumor biopsies were performed when possible and analyzed for activation of the epidermal growth factor receptor (EGFR) signaling pathway. Serial serum samples were measured for amphiregulin and transforming growth factor-alpha (TGFalpha)., Patients and Methods: One hundred fifteen patients were randomly assigned to receive gefitinib 250 or 500 mg orally once a day. One hundred ten patients were assessable for clinical efficacy. Biologic evaluation was performed on paired tumor samples from 28 patients and correlated with clinical outcome., Results: Median progression-free survival was 1.9 months (95% CI, 1.8 to 2.1 months) and 4-month progression-free survival rate was 13% +/- 5%. One patient achieved a radiographic partial response (RR = 1%; 95% CI, 0.01% to 5%). Median survival was 6.3 months (95% CI, 5.1 to 8.2 months). The most common adverse events were skin rash, diarrhea, and fatigue. In the biopsy cohort, expression of total or activated EGFR, activated Akt, activated MAP-kinase, or Ki67 did not decrease following 1 week of gefitinib. However, a trend toward decreased post-treatment levels of activated Akt and Ki67 was observed in patients with a PFS higher than the median, although these did not reach the .05 level of significance., Conclusion: Gefitinib is inactive as a single agent in patients with previously treated colorectal cancer. In tumor samples, gefitinib did not inhibit activation of its proximal target, EGFR. Trends were observed for inhibition of downstream regulators of cellular survival and proliferation in patients achieving longer progression-free survival.

In the last decade, continued efforts in pancreas cancer research have led to the development of new, more effective therapies. Additionally, progress in understanding the molecular processes underlying the development and progression of this disease provides hope for the development of more effective treatment strategies. Recent clinical trials have provided reason for hope that novel chemotherapy combinations and molecularly targeted agents will lead to improved clinical outcomes for patients with this disease. This article will summarize the data that has led to the current standards of therapy for patients with resectable and advanced pancreatic cancer and review new treatment strategies for this disease.

The epidermal growth factor receptor (EGFR) is the prototypical member of the erbB receptor family. The EGFR axis is activated by a variety of ligands that are crucial in the formation and propagation of many tumors, including colorectal cancer, through their effects on cell signaling pathways, cellular proliferation, control of apoptosis, and angiogenesis. The importance of the EGFR axis in tumorigenesis and tumor progression makes it an attractive target for the development of anticancer therapies. A variety of targeting strategies to exploit the role of EGFR in tumors have been employed. The most highly developed of these anti-EGFR approaches are the monoclonal antibodies and the tyrosine kinase inhibitors (TKIs). Clinical evaluations of these compounds have yielded some promising results. The role of the EGFR axis in colorectal cancer formation and progression is reviewed and the clinical development of these anticancer EGFR-targeted drugs is reviewed and updated.

Background: The aim of this study was to evaluate the overall response rate, toxicity and overall survival in patients with locally advanced or metastatic esophageal cancer treated with gemcitabine, 5-fluorouracil (5-FU) and leucovorin., Patients and Methods: Patients with either adenocarcinoma or squamous cell carcinoma of the esophagus could enroll; however, patients could not have received prior chemotherapy for metastatic disease. Treatment cycles consisted of infusions of all three agents at days 1, 8 and 15, repeated every 28 days. Patients received gemcitabine 1,000, leucovorin 25 and 5-FU 600 mg/m(2). Tumor assessment was performed every 2 cycles. Responses were assessed using the Eastern Cooperative Oncology Group solid tumor response criteria., Results: Thirty-five patients with metastatic or locally advanced esophageal cancer enrolled. One complete response and ten partial responses were observed for an overall response rate of 31.4%. An additional 11 patients had stable disease as their best response. The median survival was 9.8 months with a 1-year survival rate of 37.1%. Toxicity was predominately hematologic, with 58% of patients experiencing grade 3 or 4 neutropenia., Conclusion: The combination of gemcitabine, 5-FU and leucovorin had activity in advanced esophageal cancer. Patients tolerated the regimen well, with myelosuppression occurring most commonly. The combination merits further investigation as a treatment for esophageal cancer.

The epidermal growth factor receptor (EGFR) is a member of the family of transmembrane protein kinase receptors known as the erbB or HER receptor family. When activated, EGFR phosphorylates and activates other intracellular proteins that affect cell signaling pathways, cellular proliferation, control of apoptosis and angiogenesis. EGFR signaling is best thought of as a network of activating and inactivating proteins with EGFR as the entry point into the network. EGFR overexpression occurs in most GI malignancies and while data are not entirely consistent, EGFR overexpression often confers a poor prognosis in those GI malignancies that have been studied. It often correlates with poorly differentiated histology, more advanced stage and other known poor prognostic markers. The EGFR is a tempting target because of its presence and overexpression on so many tumor types. However, downstream of the EGFR are several proteins that may be activated without EGFR thus allowing blockade to be overcome. Therefore, while blocking the activity of the EGFR protein appears to be a promising anticancer strategy, a simplistic strategy of blocking only EGFR is likely to only impact a minority of patients. It is time for the laboratory and clinical researchers to work closely together to develop this treatment strategy, moving back and forth from clinical to laboratory to best understand how to block this network effectively enough to produce a broader antitumor effect. While multiple methods of targeting the EGFR pathway are under development, including the inhibition of downstream proteins, only two modalities have entered clinical trials in GI malignancies: small molecule inhibitors of the intracellular kinase domain of EGFR and antibodies designed to block the extracellular ligand-binding domain of EGFR. EGFR inhibitors are still experimental in every GI malignancy with the notable exception of cetuximab that is approved for second or third-line therapy of metastatic colorectal cancer, used either alone or in combination with irinotecan (Camptosar, Kalamazoo, Mich). Data on clinical applications of these agents in GI malignancies will be the focus of this paper.

Purpose: This study was performed to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetics of brostallicin, a nonalkylating DNA minor groove binder and a synthetic derivative of distamycin A, given as a weekly i.v. infusion., Experimental Design: Using an accelerated dose escalation design, patients with advanced solid tumor malignancies were treated with brostallicin administered as a 10-min i.v. infusion on days 1, 8, and 15 of a 28-day cycle. The starting dose of brostallicin was 0.3 mg/m(2)/week. To study the pharmacokinetic behavior of brostallicin, serial blood samples were obtained before and after the first and last infusions during cycle 1, and in cycles 2 and 4 in a limited number of patients., Results: Fourteen patients received 32 complete cycles of brostallicin. Dose-limiting toxicity was febrile neutropenia and was observed in 3 of 5 patients treated at 4.8 mg/m(2)/week. The maximum tolerated dose and recommended Phase II dose was 2.4 mg/m(2)/week. The mean +/- SD terminal half-life at the maximum tolerated dose was 4.6 +/- 4.1 h. There was moderate distribution of brostallicin into tissues, and the clearance was approximately 20% of the hepatic blood flow. The area under the concentration time curve(0- infinity ) of brostallicin increased in a dose-linear fashion. No significant relationship was observed between any plasma pharmacokinetic parameter and clinical toxicities. There were no objective responses during the trial, but 5 patients had stable disease after two cycles of treatment., Conclusions: The dose-limiting toxicity of weekly brostallicin was neutropenia. Systemic exposure increases linearly with dose. The recommended dose for Phase II studies is 2.4 mg/m(2) on days 1, 8, and 15 of a 28-day cycle.

Background: Responses have been observed in several studies of docetaxel as treatment for advanced pancreatic carcinoma. This trial was designed to determine if the addition of docetaxel to gemcitabine therapy produced responses in >/=25% of patients with chemonaive advanced pancreatic cancer., Patients and Methods: This trial involved patients with biopsy-proven, advanced carcinoma of the pancreas not amenable to surgical resection. Patients received docetaxel 75 mg/m(2) i.v. over 1 h followed by gemcitabine 2,000 mg/m(2) biweekly until progression or intolerable toxicity. The primary endpoint of the trial was to determine the objective response rate with secondary endpoints of progression-free survival and overall survival., Results: Out of the 32 eligible patients, 2 patients had a complete response and 2 patients had a partial response for an observed objective response rate of 12.5% (90% CI: 4.4, 26.4%). Median survival was 4.7 months. Most toxicities were hematologic, with 48% of patients experiencing grade 4 toxicity., Conclusions: The confirmed complete response rate of 6% and partial response rate of 6% is encouraging, but the toxicity of this regimen appears significant. Based upon these results, this combination of gemcitabine and docetaxel is not worthy of further study. Different schedules and dosages may be more promising., (Copyright 2004 S. Karger AG, Basel)

Purpose: In North America, no effective therapy has been available for patients with progressive metastatic colorectal cancer after front-line treatment with irinotecan, bolus fluorouracil (FU), and leucovorin (IFL)., Patients and Methods: Patients with metastatic colorectal cancer who progressed after IFL therapy were randomly assigned to bolus and infusional FU and leucovorin (LV5FU2), single-agent oxaliplatin, or the combination (FOLFOX4). This planned interim analysis evaluated objective response rate (RR), time to tumor progression (TTP), and alleviation of tumor-related symptoms (TRS) in an initial cohort of patients., Results: Between November 2000 and September 2001, 463 patients from 120 sites in North America were randomly assigned to treatment. FOLFOX4 proved superior to LV5FU2 in all measures of clinical efficacy. Objective RRs determined by an independent radiology panel were 9.9% for FOLFOX4 versus 0% for LV5FU2 (Fisher's exact test, P <.0001). Median TTP was 4.6 months for FOLFOX4 versus 2.7 months for LV5FU2 (two-sided, stratified log-rank test, P <.0001). Relief of TRS occurred in 33% of patients treated with FOLFOX4 versus 12% of patients treated with LVFU2 (chi2 test, P <.001). Single-agent oxaliplatin was not superior to LV5FU2 in any measure of efficacy. Patients treated with FOLFOX4 experienced a higher incidence of clinically significant toxicities than patients treated with LV5FU2, but these toxicities were predictable and did not result in a higher rate of treatment discontinuation or 60-day mortality rate., Conclusion: For patients with metastatic colorectal cancer, second-line treatment with FOLFOX4 is superior to treatment with LVFU2 in terms of RR, TTP, and relief of TRS.

Advances in chemotherapy for pancreatic cancer have been limited. In the past decade, the standard therapy for metastatic disease has switched from 5-fluorouracil (5-FU) to gemcitabine. However, several other cytotoxic agents have shown limited but promising efficacy in pancreatic cancer, and many of these appear to be well suited for combination chemotherapy. Although 5-FU and cisplatin have not demonstrated substantial survival benefits when combined with gemcitabine, results of several phase III trials with other agents are still pending. For locally advanced disease, most recent studies have incorporated gemcitabine into combined-modality therapy. Similarly, in surgically resectable disease, current trials are incorporating gemcitabine into adjuvant therapy. Other trials are using neoadjuvant therapy as a possible means to improve upon current surgical results. However, much hope comes from the development of newer "targeted" therapies for this disease. Although matrix metalloproteinase inhibitors and farnesyl transferase inhibitors did not appear to be effective in initial studies, other targeted therapies are beginning to enter clinical trials.

Purpose: The objectives of this trial were to assess the maximal tolerated dose and toxicity of the combination of oral eniluracil and 5-fluorouracil and intravenous gemcitabine., Patients and Methods: Patients with histologically confirmed, incurable malignancy (solid tumor or lymphoma) refractory to standard therapy or for which no standard therapy exists were enrolled. The treatment plan consisted of weekly gemcitabine for three weeks with twice daily dosing of 5-FU and eniluracil for 21 days beginning on day one of gemcitabine. Cycles repeated on an every four week schedule. The initial cohort received gemcitabine 800 mg/m2, oral 5-FU 0.6 mg/m2 and eniluracil 6.0 mg/m2., Results: Twenty-six patients were enrolled. Eight patients received less than 2 cycles of therapy. Hematologic and gastrointestinal toxicity predominated, with 48% of courses resulted in grade one or two neutropenia. Hematologic toxicity was dose limiting. One treatment related death occurred., Conclusions: The combination of eniluracil, 5-fluorouracil and gemcitabine offers an oral alternative for 5-FU administration. The recommended phase II dose is gemcitabine 1000 mg/m2, 5FU 1.2 mg/m2 and eniluracil 12 mg/m2.

Recent trials have established the IFL combination (fluorouracil [5-FU], leucovorin, and irinotecan [CPT-11, Camptosar]) as a new standard first-line therapy for patients with metastatic colorectal cancer. Median survival for such patients treated with IFL still ranges from approximately 14 to 18 months, however, underscoring the need for new agents with novel mechanisms of action. Angiogenesis has become an attractive target for anticancer drug development, based on its important roles in tumor growth, invasion, and metastasis. A potent stimulus of angiogenesis is vascular endothelial growth factor (VEGF); two agents developed to inhibit VEGF activity, bevacizumab (Avastin) and SU5416, are in advanced clinical trials. Based on encouraging results in phase I and II trials with bevacizumab, a randomized trial of IFL with or without this monoclonal antibody is under way. Similarly, a randomized trial of 5-FU and leucovorin with or without the tyrosine kinase inhibitor SU5416 has recently completed accrual and results are pending. SU5416 is also being tested in a phase I/II trial combined with IFL. This article briefly reviews preclinical and clinical data leading to the current trials of these two agents in patients with colorectal cancer.

Purpose: Gemcitabine is generally considered to constitute first-line therapy for pancreatic cancer. To determine whether the addition of fluorouracil (5-FU) improves on the results from single-agent gemcitabine, the Eastern Cooperative Oncology Group (ECOG) compared gemcitabine plus bolus 5-FU with gemcitabine alone for patients with advanced pancreatic carcinoma., Patients and Methods: This trial involved patients with biopsy-proven, advanced carcinoma of the pancreas not amenable to surgical resection. Patients were randomized to receive either gemcitabine alone (1,000 mg/m(2)/wk) weekly for 3 weeks of every 4 or to receive gemcitabine (1,000 mg/m(2)/wk) followed by 5-FU (600 mg/m(2)/wk) weekly on the same schedule. The primary end point of the trial was survival, with secondary end points of time to progression and response rate., Results: Of 327 patients enrolled over 18 months, 322 were eligible. Overall, the median survival was 5.4 months for gemcitabine alone and 6.7 months for gemcitabine plus 5-FU (P =.09). Progression-free survival for gemcitabine alone was 2.2 months, compared with 3.4 months for gemcitabine plus 5-FU (P =.022). Objective responses were uncommon and were observed in only 5.6% of patients treated with gemcitabine and 6.9% of patients treated with gemcitabine plus 5-FU. Most toxicities were hematologic or gastrointestinal; no significant differences were noted between the two treatment arms., Conclusion: 5-FU, administered in conjunction with gemcitabine, did not improve the median survival of patients with advanced pancreatic carcinoma compared with single-agent gemcitabine. Further studies with other combinations of gemcitabine and 5-FU are not compelling, and clinical trial resources should address other combinations and novel agents.

This article will review the pertinent data on the use of chemotherapy for all stages of pancreatic cancer. For patients with metastatic disease, fluorouracil (5-FU) was the standard of care for several decades until a single randomized trial established that gemcitabine (Gemzar) produced a greater clinical benefit response, median survival, and 1-year survival. Among the currently available chemotherapy agents, the taxanes, fluoropyrimidines, and camptothecins are being evaluated in clinical trials alone or in combination with gemcitabine. Newer agents that are not classically cytotoxic are also under investigation and hold promise for the future. In patients with locally advanced unresectable disease, chemotherapy is commonly used to sensitize the cancer to radiation. Current investigations focus on trying to improve chemotherapy as a radiation sensitizer, using, for example, infusional 5-FU and gemcitabine. Early-stage, surgically resectable patients may benefit from the combination of chemotherapy and radiation, although more recent trials conducted in Europe raise some doubt. However, flaws in trial design do not allow firm conclusions to be drawn about the benefits of adjuvant therapy. Both chemotherapy and chemoradiation are under further investigation. Significant improvements in the survival of patients with pancreatic cancer will be achieved as more effective systemic therapies are developed, including agents with novel cellular targets.

Gemcitabine has recently been compared favorably to 5-fluorouracil (5-FU) as the standard chemotherapy for advanced pancreas cancer. Based on phase I data that combining gemcitabine with 5-FU is safe and has evidence for clinical activity, a phase II trial was conducted by the Eastern Cooperative Oncology Group (ECOG). Patients with metastatic disease, good performance status and organ function were eligible and enrolled after providing informed consent. Patients were given gemcitabine (1,000 mg/m(2)) followed by 5-FU (600 mg/m(2)) weekly for 3 weeks of every 4. Of 37 patients enrolled over a 3-month period, 36 were eligible. Partial responses were seen in 5 patients (14%). Median survival was 4.4 months with a 1-year survival rate of 8.6%. A randomized trial of the combination of 5-FU and gemcitabine versus gemcitabine alone is currently accruing patients in ECOG., (Copyright 2000 S. Karger AG, Basel)

Five patients from a single institution received concomitant warfarin and 5-fluorouracil (5-FU) during a 3-year period. The mean weekly warfarin dose before starting chemotherapy was 40.66 mg and during chemotherapy it was 24 mg (p=0.0026). All patients required a warfarin dosage reduction (range 18-74%, mean 44%). Two patients were hospitalized, one with a major retroperitoneal bleed, the other for fresh-frozen plasma administration and observation. Maximum international normalized ratios (INRs) ranged from 3.66-23.7. This series confirms a common, clinically significant interaction between warfarin and 5-FU. An interaction between capecitabine, the orally available prodrug of 5-FU, and warfarin also has been reported. We recommend weekly monitoring of prothrombin time and INR for all patients receiving concomitant warfarin and 5-FU or capecitabine.

This report is a multi-institutional phase II study designed to obtain the response rate, survival, and toxicity profile for patients having hormone-refractory prostate cancer. Patients who had bidimensionally measurable prostate carcinoma in first or second remission after previous hormonal therapy but no history of chemotherapy were eligible. Patients were treated with leucovorin, 20 mg/m2 intravenously, followed by 5-fluorouracil (5-FU), 425 mg/m2 intravenously daily for 5 days, with cycles repeated every 28 days. Of 38 eligible patients, 3 (7.9%) had partial responses to therapy and 20 (52.6%) had stable disease. Median survival was 11.6 months for all 38 patients and median time to progression was 4.4 months. Most of the serious side effects were gastrointestinal or hematologic and overall, 23 of 38 patients (60.5%) experienced at least one grade 3 or 4 treatment-related toxicity of any type, as measured by the National Cancer Institute common toxicity criteria. Five patients (13.2%) withdrew from the study because of adverse reactions from chemotherapy. We conclude that treatment of hormone-refractory prostate cancer patients with 5-FU and leucovorin chemotherapy produced few responses at the cost of significant side effects. Further investigation of this combination is not warranted in this setting.

Introduction: This was a dose escalation phase I trial designed to establish the MTD (maximum tolerated dose) and toxicity profile of the combination of gemcitabine, leucovorin and 5-fluorouracil (5-FU)., Methods: Standard eligibility criteria were required for patients with advanced malignancy to enroll. Gemcitabine was escalated from an initial dose of 800 mg/m2. Gemcitabine was administered prior to leucovorin (25 mg/m2) followed by bolus 5-FU (600 mg/m2) every week for 3 weeks followed by 1 week of rest., Results: Of 21 patients enrolled, 20 were eligible for MTD determination. Patients received a median of three 4-week cycles of chemotherapy (range: 1 to 8 cycles). Toxicity was predominantly hematologic or gastroenterologic. Four dose levels were studied. At a gemcitabine dose of 1,500 mg/m2 systemic symptoms of fatigue accompanied hematologic toxicity and patients refused further therapy. At 1,250 mg/m2, full dose intensity was not delivered during the first cycle in 7 of 8 patients treated. Therefore, 1,000 mg/m2 was established as the recommended phase II dose for gemcitabine in this study. Antitumor activity was seen at all dose levels., Conclusions: The combination of gemcitabine, leucovorin and 5-FU was tolerable at full doses of all 3 drugs with an expected toxicity profile. Recommended phase II dose for gemcitabine was 1,000 mg/m2. Initial evidence of clinical activity was seen in a variety of tumor types.

Electron microscopic cytochemistry was used to determine the localization of five phosphatase enzymes-glucose-6-phosphatase, inosine diphosphatase, thiamine pyrophosphatase, acid phosphatase, and adenosine triphosphatase-in control human testes. Glucose-6-phosphatase occurred in the endoplasmic reticulum and nuclear envelope of Sertoli cells, Leydig cells and primitive spermatogonia, but was not observed in more advanced spermatogenic cells. The presence of glucose-6-phosphatase activity paralleled the presence of glycogen in spermatogenic cells, i.e., both occurred in type AL and AD spermatogonia but not in type AP or B spermatogonia or in more advanced spermatogenic cells. Inosine diphosphatase activity was found in the endoplasmic reticulum, nuclear envelope, and Golgi complex of Sertoli cells and all spermatogenic cells except late spermatids. Additionally, inosine diphosphatase activity was localized at the junctions between Sertoli cells and late spermatids, but was not associated with any other plasma membrane. Thiamine pyrophosphatase reaction product was found in the Golgi bodies of Sertoli cells and in spermatogenic cells through immature spermatids. Neither inosine diphosphatase nor thiamine pyrophosphatase was observed in the Golgi bodies of spermatids during acrosomal formation. Acid phosphatase activity was found in lysosomes of spermatogonia, spermatocytes, and spermatids, in lysosomes of Leydig cells, and in lysosomes, lipofuscin bodies, and Golgi cisternae of Sertoli cells. It is thought that Sertoli lysosomes play a role in the phagocytosis of degenerating germ cells; however, the role of spermatogenic or Leydig lysosomes is unknown. Adenosine triphosphatase activity occurred at the interfaces between two spermatogonia, and between Sertoli cells and spermatogonia, but was not observed in the spaces between two Sertoli cells, two spermatocytes, two spermatids, or between Sertoli cells and spermatocytes, or between Sertoli cells and spermatids.

Bract and leaf samples from growing cotton plants and from cotton textile wastes were examined by scanning electron microscopy to determine if intact capitate hairs are important components fo raw cotton wastes. The density of capitate hairs on bract and leaf fragments in raw cotton was similar to that found on bracts and leaves from greenhouse and field collections. A bale of strict low middling raw cotton contains between 1.23 an 2.54 X 10(8) capitate hairs of bract origin alone. Capitate hairs could be important components of cotton textile wastes because of their abundance and because they contain chemicals that may be involved in the cause of respiratory disease in textile workers.

A permanent human tissue culture cell line (SW-48) has been established from an adenocarcinoma of the transverse colon. Cells in the center of early colonies were cuboidal and loosely bound; cells on the periphery of the same colonies were more columnar, the nuclei were displaced toward the basal region, and the free surface formed stunted microvilli. These columnar cells ofter aligned themselves to resemble normal absorptive tissue. Carcinoembryonic antigen (CEA) was identified by immunofluorescent microscopy on the surface membrane of the tumor cells. Significantly more CEA could be isolated from the culture medium than from the whole cells. On agar gel diffusion analysis with a monospecific anti-CEA serum (G.P. 32), SW-48 CEA and CEA preparations from solid tumors demonstrated complete identity.

Electron microscopic examination of normal human testicular tissue revealed annulate lamellae (AL) in the cytoplasm of primary spermatocytes and spermatids. AL of primary spermatocytes are encountered in the perinuclear region, parallel to the nuclear envelope and form single or multiple membranous profiles containing numerous annuli (500-600 A in diameter) frequently associated with a fibrillar electron dense material. Spermatids contain numerous layers of AL either continuous with the nuclear envelope and caudal to the acrosome or peripherally positioned in the cytoplasm. Individual lamellae possess terminal dilations and display continuities with the endoplasmic reticulum. The interlamellar space in spertmatid AL is entirely filled with a fine granular electron dense material. Additionally, the breakdown of AL in spermatozoan residual bodies is indicated by a dilation of AL cisternae to form vacuoles following the dissolution of pore complexes.