Search

The TTX-sensitive rat skeletal muscle sodium channel (rSkM1) exhibits two modes of inactivation (fast vs slow) when the alpha subunit is expressed alone in Xenopus oocytes. In this study, two components are found in the voltage dependence of normalized current inactivation, one having a V1/2 in the expected voltage range (approximately -50 mV, I(N)) and the other with a more hyperpolarized V1/2 (approximately -130 mV, IH) at a holding potential of -90 mV. The I(N) component is associated with the gating mode having rapid inactivation and recovery from inactivation of the macroscopic current (N-mode), while IH corresponds to the slow inactivation and recovery mode (H-mode). These two components are interconvertible and their relative contribution to the total current varies with the holding potential: I(N) is favored by hyperpolarization. The interconversion between the two modes is voltage dependent and is well fit to a first-order two-state model with a voltage dependence of e-fold/8.6 mV and a V1/2 of -62 mV. When the rat sodium channel beta 1-subunit is coinjected with rSkM1, IH is essentially eliminated and the inactivation kinetics of macroscopic current becomes rapid. These two current components and their associated gating modes may represent two conformations of the alpha subunit, one of which can be stabilized either by hyperpolarization or by binding of the beta 1 subunit.

Advanced gastric cancer is an aggressive disease, with continued poor clinical outcomes. In the past two decades, many clinical trials have been conducted, testing chemotherapy agents in different combinations. However, many of these trials have employed aggressive regimens, which may be not suitable for some patients with advanced disease and poor performance status seen in clinical settings. In addition, geographic and ethnic differences in disease pathogenesis/biology, treatment strategies and drug metabolism make universal application of these trial results difficult. Here, we summarize the extant data on chemotherapy agents in gastric cancer, and try to deduce the best combination(s) that may be utilized in this disease, or that may be suitable for particular subgroup patient populations. Importantly, we discuss future directions – how we need to move away from testing various cytotoxic agent permutations and combinations, towards smarter trials that employ targeted therapies.

BACKGROUND: Anti-angiogenesis agents have shown effectiveness in treatment of hepatocellular carcinoma (HCC). It is important to investigate more effective and safe systemic treatment options for patients with advanced HCC. This phase 2 study was designed to determine the efficacy and toxicity of the combination of bevacizumab, capecitabine, and oxaliplatin in patients with advanced unresectable and untransplantable HCC. METHODS: Chemotherapy-naive patients with advanced unresectable and untransplantable HCC were treated with bevacizumab 5 mg/kg and oxaliplatin 130 mg/m2 on day 1 of each cycle, and capecitabine 825 mg/m2 orally twice a day from days 1 to 14 of a 21-day cycle. RESULTS: Forty patients were enrolled to the study, in which 40% had Child-Pugh B disease. Forty percent had an Eastern Cooperative Oncology Group performance status (PS) of 0, 55% had PS of 1, and 5% had PS of 2. Forty percent of patients had hepatitis B virus infection. The median progression-free survival was 6.8 months (95% CI, 3.4-9.1 months), and the median overall survival was 9.8 months (95% CI, 5.2-12.1 months). Eight patients (20%) achieved partial response; 23 patients had stable disease with overall 77.5% disease control rate. The combination was tolerable with limited grade 3/4 toxicity, mainly peripheral neurotoxicity and fatigue. CONCLUSIONS: The combination appeared effective and safe, and the results were encouraging. Further investigation should be considered. Cancer 2011. © 2011 American Cancer Society.

Purpose The combination of sorafenib with chemotherapy is well-tolerated and is associated with encouraging response rates in several malignances. Both docetaxel and cisplatin are active in gastric cancer. A phase II study was conducted to determine the efficacy and toxicity of combined sorafenib, docetaxel, and cisplatin in patients with metastatic or advanced adenocarcinoma of stomach or gastroesophageal junction (GEJ). Patients and Methods Forty-four chemotherapy-naïve patients with Eastern Cooperative Oncology Group performance status 0 or 1, of whom 80% had metastatic disease and two thirds had poorly differentiated gastric or GEJ adenocarcinoma, were enrolled. The treatment regimen was sorafenib 400 mg orally twice a day for 21 days, docetaxel 75 mg/m2 intravenously on day 1, and cisplatin 75 mg/m2 intravenously on day 1, repeated every 21 days. The primary end point was response rate to the combination. Toxicity, overall survival, and progression-free survival were assessed as secondary end points. Results Eighteen of the 44 eligible and treated patients showed partial responses (41%; 90% CI, 28% to 54%). The median progression-free survival was 5.8 months (90% CI, 5.4 to 7.4 months). The median overall survival was 13.6 months (90% CI, 8.6 to 16.1 month). The major toxicity of this regimen was neutropenia, which reached grade 3 to 4 in 64% of patients. One patient experienced hemorrhage at the tumor site. Conclusion The combination of sorafenib, docetaxel, and cisplatin has an encouraging efficacy profile with tolerable toxicity. Additional studies of sorafenib with chemotherapy are warranted in gastric cancer.

Background Unresectable intrahepatic cholangiocarcinoma has a poor prognosis, with a median survival of 5 to 8 months without treatment. Response and survival after chemoembolization were evaluated. Methods Lobar or segmental chemoembolization with cisplatinum, doxorubicin, mitomycin-C, ethiodol, and polyvinyl alcohol particles was performed at monthly intervals for 1-4 sessions until the entire intrahepatic tumor burden was treated. Cross-sectional imaging and clinical and laboratory evaluation were performed before treatment, 1 month after treatment, and then every 3 months. A second cycle of treatment was performed for intrahepatic recurrence. Toxicity was assessed using NCI CTC v.3.0. Response was evaluated using RECIST criteria, and survival was estimated with Kaplan-Meier analysis. Results Sixty-two patients were treated. Thirty-seven had pathologically proven cholangiocarcinoma, and 25 had poorly differentiated adenocarcinoma of unknown primary, likely cholangiocarcinoma. One hundred and twenty-two total procedures were performed during the initial cycle of treatment (mean, 2.0 per patient). Twenty patients received a second cycle, for a total of 165 procedures. There were 5 major complications. Thirty-day disease-specific mortality was 0%. Forty-five of 62 patients were evaluable for morphologic response after completion of their initial cycle: 11% (n = 5) partial responses, 64% (n = 29) stable, and 24% (n = 11) progressed. Median time to progression from first chemoembolization was 8 months, with 28% free of progression at 12 months. Median survival from time of diagnosis was 20 months, with 1-, 2-, and 3-year survival of 75%, 39%, and 17%, respectively. Median survival from time of first chemoembolization was 15 months, with 1-, 2-, and 3-year survival of 61%, 27%, and 8%, respectively. There was no statistically significant difference in survival between patients with cholangiocarcinoma and those with poorly differentiated adenocarcinoma. Patients who also received systemic chemotherapy had improved overall survival (median 28 vs 16 months, P = .02; HR, 1.94; 95% CI, 1.13-3.33). Conclusions Chemoembolization provided local disease control (PR + SD) of intrahepatic cholangiocarcinoma and adenocarcinoma of unknown primary in 76%. Overall survival after chemoembolization showed the best outcomes for those receiving multidisciplinary integrated liver-directed and systemic therapies.

BACKGROUND: Unresectable colorectal liver metastases have a 1- and 2-year survival of 55% and 33% with current systemic therapies. The authors evaluated response and survival after transarterial chemoembolization. METHODS: Chemoembolization with cisplatin, doxorubicin, mitomycin C, ethiodized oil, and polyvinyl alcohol particles was performed at monthly intervals for 1 to 4 sessions. Cross-sectional imaging and clinical and laboratory evaluation were performed before treatment, 1 month after treatment, and then every 3 months. A second cycle was performed for intrahepatic recurrence. Toxicity was assessed using National Cancer Institute's Common Toxicity Criteria version 3.0. Response was evaluated using Response Evaluation Criteria in Solid Tumors criteria. Progression and survival were estimated with Kaplan-Meier analysis. RESULTS: A total of 245 treatments were performed over 141 cycles on 121 patients. Ninety-five of 141 treatment cycles were evaluable for response: 2 (2%) partial response, 39 (41%) stable disease, and 54 (57%) progression. Median time to disease progression (TTP) in the treated liver was 5 months, and median TTP anywhere was 3 months. Median survival was 33 months from diagnosis of the primary colon cancer, 27 months from development of liver metastases, and 9 months from chemoembolization. Survival was significantly better when chemoembolization was performed after first- or second-line systemic therapy (11-12 months) than after third- to fifth-line therapies (6 months) (P = .03). Presence of extrahepatic metastases did not adversely affect survival (P = .48). CONCLUSIONS: Chemoembolization provided local disease control of hepatic metastases after 43% of treatment cycles. Median survival was 27 months overall, and 11 months when initiated for salvage after failure of second-line systemic therapy. Cancer 2011. © 2010 American Cancer Society.

Colorectal cancer (CRC) is the third most common malignancy and the second most common cause of cancer-related death in the USA. Prognosis is best when the disease is detected early; however, nearly two-thirds of newly diagnosed cases of CRC have lymph node involvement or metastatic disease. For years, 5-fluorouracil (FU)-based regimens represented the only viable treatment option for patients with metastatic CRC. However, in recent years several newer agents have been added to the treatment arsenal for this disease. These agents include oxaliplatin, irinotecan and newer monoclonal antibodies targeting the epidermal growth factor receptor (cetuximab and panitumumab) and VEGF (bevacizumab). This review aims to discuss current systemic and targeted therapies for metastatic colon cancer with a focus on mechanism of action, indications, toxicity and efficacy.

Pancreatic adenocarcinoma is one of the most lethal malignancies, with an overall 5-yr disease-free survival rate of 1–2% for all patients. Most patients with pancreatic cancer are not diagnosed until they have developed locally advanced or regionally disseminated disease that is not amenable to attempted curative surgical resection. Chemotherapy and radiation therapy have only modest benefit in this stage of the disease and typical survival is 6 mo. Among those patients with apparently resectable disease who undergo surgical exploration, between 20 and 40% are found to be unresectable, dependent on the pre-operative evaluation. Even those pancreatic cancer patients who have a margin-negative resection have a 5-yr disease-free survival of less than 30%, and approximately half of patients surviving 5 yr will relapse between 6 and 10 yr. Thus, the treatment of pancreatic cancer remains a significant challenge to the surgical, radiation, and medical oncologist.

The combination of a fixed dose rate (FDR) infusion of gemcitabine and irinotecan may have a synergistic effect in the treatment of patients with advanced and metastatic pancreatic and biliary cancer. The current study was conducted to determine the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of the combination.There were 32 patients with metastatic pancreatic and advanced unresectable/metastatic biliary adenocarcinoma who were entered into this open-label, phase 1 dose escalation trial. Gemcitabine was administered at an FDR of 10 mg/m(2)/minute intravenously (iv). Irinotecan was administered iv over 60 minutes after gemcitabine. Both gemcitabine and irinotecan were given on Days 1 and 8 of a 21-day cycle.The MTD of the combination was gemcitabine at an FDR of 1200 mg/m(2) and irinotecan at a dose of 100 mg/m(2). The DLTs were neutropenia and neutropenic fever. Other DLTs included diarrhea, dehydration, and fatigue. Two patients developed deep venous thrombosis during the treatment. The efficacy of the combination was encouraging, even at the lower dose levels. Of 30 assessable patients, there was 1 complete response, 6 partial responses, and 16 patients with stable disease, with a response rate of 23%, a disease control rate of 76%, a median progression-free survival of 4.7 months, and a median overall survival of 7.0 months. The average number of treatment cycles received was 11.The recommended doses of the combination for future study are gemcitabine at an FDR of 1200 mg/m(2) and irinotecan at a dose of 100 mg/m(2). The efficacy of the combination is encouraging. Further assessment of the combination with or without biologic agents is suggested.

2563 Background: TAS-102 is composed of trifluridine (FTD) and tipiracil hydrochloride (TPI) in a 2:1 ratio. FTD is a thymidine analog, and is degraded to inactive trifluoromethyluracil (FTY) by th...

TPS498 Background: Biliary tract cancers (including cholangiocarcinomas) are rare but aggressive malignancies with limited options for treatment. Currently, the combination of gemcitabine and cisplatin is considered the upfront systemic chemotherapy for patients with advanced and metastatic diseases. There is no ‘standard’ for second-line treatment. Several signaling pathways have been identified that might play a role in the development of biliary tract cancer and that may represent targets for directed therapies. Overexpression of VEGF and alterations of the Ras/Raf pathway have been identified in the majority of cholangiocarcinoma; some studies have shown these mutations to be associated with metastasis and poorer prognosis. Regorafenib is an oral multikinase inhibitor of multiple angiogenic and oncogenic kinases (VEGFR1-3, TIE2, PDGFR-β, FGFR1, KIT, RET, RAF) which has shown efficacy as a single agent in multiple solid tumors. This study evaluates the efficacy of regorafenib in patients with advanced/metastatic biliary tract cancer following the failure of first-line chemotherapy. Methods: Enrollment in this phase II, single-arm trial is ongoing. Eligible patients have unresectable advanced or metastatic biliary tract adenocarcinoma, and have failed first-line systemic chemotherapy. Patients receive regorafenib 120 mg orally daily in a 21 days on, 7 days off cycle. Tumor measurements take place every 3 cycles by CT or MRI imaging. Patients continue on therapy until disease progression or unacceptable toxicities. The primary end point of this study is median progression-free survival (PFS). To evaluate for evidence of activity, defined as a median PFS of 3.5 months or greater, with 83% power (one-sided test, α=0.10), target enrollment is 37 patients. Secondary endpoints include safety, overall response rate, disease control rate, median overall survival, and changes in biomarker levels. The correlation of these biomarkers and of tumor mutations with response to treatment is built into the study as well. As of September 2014, 9 patients had been enrolled. ClinicalTrials.gov Identifier: NCT02053376. Clinical trial information: NCT02053376.

TPS495 Background: The activin receptor-like kinase (ALK1) pathway is a novel target in angiogenesis that promotes blood vessel maturation and stabilization. ALK1 binds to the ligand bone morphogenetic protein 9 (BMP9) which is overexpressed in hepatocellular carcinoma (HCC) compared to normal hepatocytes. Dalantercept is an ALK1 receptor fusion protein that binds BMP9 and acts as a ligand trap. Sorafenib, a multi-kinase and vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI), is the standard therapy for advanced HCC. In a preclinical model of HCC, simultaneous blockade of ALK1 and VEGF signaling with dalantercept and sorafenib resulted in additive tumor growth inhibition. In a completed Phase 1 study in thirty-seven subjects with solid tumors, dalantercept monotherapy demonstrated preliminary anti-tumor activity and a safety profile that was generally non-overlapping with VEGFR TKIs. Methods: An open label, multi-center, dose escalating, phase 1b study to evaluate dalantercept plus sorafenib in subjects with advanced HCC is ongoing. The primary endpoint includes the evaluation of the safety and tolerability of dalantercept plus sorafenib and determination of the recommended phase 2 dose levels of the combination. Secondary endpoints include assessments of the pharmacokinetic profile of the combination, preliminary activity including response rate using RECIST 1.1 and time to progression, and pharmacodynamic biomarkers in the serum and tissue including ALK1 and BMP9 expression. In the first two cohorts of 3-6 subjects each, the dalantercept dose levels will be 0.6 and 0.9 mg/kg, respectively, administered subcutaneously (SC) every 3 weeks in combination with sorafenib 400 mg PO once daily. In cohort three, 3-6 subjects will receive dalantercept dose level 0.9 mg/kg SC every 3 weeks with sorafenib 400 mg PO twice daily. Patient safety data through day 22 will be evaluated prior to escalation to the next cohort. An expansion cohort will enroll 10-20 subjects at or below the maximum tolerated dose level. Key eligibility criteria: histologically confirmed advanced HCC, Child-Pugh A liver disease, ECOG performance status of 0-1, and no prior systemic therapy in the advanced setting. Clinical trial information: NCT02024087.

Hypersensitivity reactions to cisplatin and carboplatin have been reported in the literature to occur at a rate of 10%-27%. Initial reports of hypersensitivity reactions to oxaliplatin were low; however, more recently, it appears as if the incidence of hypersensitivity reactions to oxaliplatin is similar to that of the earlier generation platinum agents. The degree of the reaction varies from mild flushing to life-threatening anaphylactic responses. After a mild hypersensitivity reaction to oxaliplatin, re-exposing a patient can be considered after administering immunosuppressants (eg, high-dose corticosteroids and histamine antagonists) and/or prolonging the duration of oxaliplatin infusion. In the case of moderate-to-severe reactions to oxaliplatin, re-exposure is usually not considered, and alternative forms of therapy should be explored. However, there are reports of successful desensitization to oxaliplatin, and therefore, re-exposing a patient can be considered after carefully weighing the risks and benefits of additional oxaliplatin therapy.

Purpose Optimal treatments for metastatic carcinoid tumor remain undefined, and the role of chemotherapy for symptomatic patients with progressive disease is uncertain. Patients and Methods Two hundred forty-nine patients with advanced carcinoid tumors were randomized to either doxorubicin with fluorouracil (FU/DOX) or streptozocin with fluorouracil (FU/STZ). Patients crossed over to the dacarbazine (DTIC) treatment after disease progression following first-line treatment (either FU/DOX or FU/STZ), and 73 patients were assigned to one of these three treatments based on their previous treatment or on abnormal baseline cardiac or renal function. Results In the randomized group, there was no difference between FU/DOX and FU/STZ in response rates (15.9% v 16%) and progression-free survival (4.5 v 5.3 months). FU/STZ (24.3 months) was superior to FU/DOX (15.7 months; P = .0267) in median survival. The response rate of crossover DTIC treatment was 8.2%, with a median survival of 11.9 months. Hematologic toxicities were the major treatment-related toxicities for both FU/DOX and FU/STZ, and mild to moderate renal toxicity was reported in 40 (34.8%) of 115 patients in the FU/STZ arm. Conclusion Response to all three treatment regimens were modest. FU/STZ improved survival compared with the doxorubicin-based regimen, suggesting that the combination should be considered to be an active regimen of therapy when chemotherapy is judged to be an option for selected patients with carcinoid tumors.

As there have been advances in the treatment of metastatic colorectal cancer, exciting developments have also been achieved in the adjuvant treatment of colon cancer. At the same time, more questions have been raised, and some controversies remain. The results of the MOSAIC trial demonstrated the benefit of adding oxaliplatin to 5-fluorouracil (5-FU) and leucovorin (FOLFOX) in adjuvant therapy for stage II and III disease, but the optimal duration of therapy and the management of toxicities remain to be resolved. Capecitabine is at least equivalent to the Mayo Clinic bolus 5-FU and leucovorin regimen in the adjuvant treatment of stage III colon cancer with a lower incidence profile of adverse events, allowing additional options for patients and physicians. Routine adjuvant systemic therapy in all patients with stage II colon cancer is still debatable. Although a statistically significant advantage for adjuvant treatment in stage II disease was shown for the first time from a large randomized study (QUASAR), the subsets of patients who truly benefit from therapy need to be identified. The application of pharmacogenetics and pharmacogenomics in adjuvant therapy for colorectal cancer will help to distinguish those patients with risk factors and to guide individualized therapy.

Although surgical resection is still the only curative maneuver in the treatment of colon cancer, efforts of the past decades have proved that systemic chemotherapy in the adjuvant setting definitely improves the curative rate for those patients with localized colon cancer. The combination of the 5-fluorouracil (5-FU) and leucovorin (LV) remains the reference treatment. However, the advantage of infusional 5-FU/LV with oxaliplatin (FOLFOX) as adjuvant treatment may change the paradigm soon. Capecitabine may be considered as an alternative to 5-FU/LV in the adjuvant therapy of stage III colon cancer. The clinical benefit of adjuvant chemotherapy for localized node negative (stage II) disease is definite but small, even though there is yet no universal consensus. Novel molecular and biologic-oriented agents are being studied. Further analysis and definition of prognostic and predictive markers may allow future adjuvant therapy to be individualized.

From the results of recent studies, it is likely that multimodality therapy with chemotherapy and radiation treatment may improve the overall outcome of locally advanced upper gastrointestinal (GI) malignancies, including esophageal, gastric, pancreatic, and biliary tract carcinomas. However, more effective, more optimal, and less toxic chemotherapy regimen(s) with concomitant radiotherapy are needed beyond the concurrent continuous-infusion fluorouracil (5-FU) with radiation that is commonly applied in general practice. Epirubicin (Ellence), cisplatin, and irinotecan (Camptosar) are all active cytotoxic chemotherapy agents in upper GI cancers. Two phase I studies were designed to test the tolerability of the combination of radiotherapy with infusional 5-FU, epirubicin, and cisplatin (ECF) or 5-FU, irinotecan, and epirubicin (EIF) in the treatment of locally advanced upper GI malignancies.

BMS-184476 is a 7-methylthiomethyl ether derivative of paclitaxel that displays potency superior to paclitaxel against tumor cells in culture and human tumor xenografts. It also inhibits the growth of paclitaxel-resistant human tumor cell lines with multidrug resistance mediated by either P-glycoprotein or mutated tubulin. Given the known synergy between taxanes and cisplatin in vitro and their clinical activity in combination, we performed a Phase I trial of BMS-184476 as a 1-h i.v. infusion followed by cisplatin every 21 days. Twenty-seven patients with a variety of solid tumors and good performance status received 116 cycles of therapy at BMS-184476 doses of 40-60 mg/m(2) together with cisplatin at 75 mg/m(2). The early observation of hypersensitivity reactions required prophylactic premedication in all patients. At the planned highest dose of BMS-184476 (60 mg/m(2)) and cisplatin (75 mg/m(2)), we observed dose-limiting toxicity in the form of neutropenia and diarrhea. Also at this level, five patients experienced grade 3 or worse nausea and vomiting. Aggressive prophylactic treatment eliminated the gastrointestinal toxicity. Mild to moderate peripheral neuropathy was infrequent, as was alopecia. Patient benefits included three partial responses in patients with mesothelioma, esophageal cancer, and head and neck cancer, and two additional minor responses. Plasma pharmacokinetic data are available for 23 patients treated at 40-60 mg/m(2). The mean maximum plasma concentrations and areas under the curves increased in a dose-related manner. The pharmacokinetics of BMS-184476 appeared independent of dose. The mean (+/- SE) values for clearance, volume of distribution at steady state, and the apparent terminal half-lives of the three dose groups during cycle 1 were 243 +/- 5 ml/min/m(2), 423 +/- 58 l/m(2), and 32.2 +/- 4.5 h, respectively. BMS-184476 60 at mg/m(2) with cisplatin at 75 mg/m(2) with appropriate supportive therapy is the dose recommended for further evaluation.

It is a continuing challenge for oncologists to effectively treat advanced/metastatic pancreatic and biliary cancer. Both irinotecan (CPT-11, Camptosar) and gemcitabine (Gemzar) have shown activity against these diseases with different mechanisms. Preclinical and clinical data also suggest additive or synergistic effects of the combination of these two agents with few or no overlapping toxicities. Phosphorylation of gemcitabine, a process of intracellular activation of the agent, is dose-rate dependent. It has been suggested that the fixed-dose-rate infusion of gemcitabine increases the concentration of intracellular triphosphate gemcitabine, which in turn may result in more objective responses and longer median survival compared to the standard infusion. This phase I study tests the toxicity of the combination of irinotecan with fixed-dose-rate infusion of gemcitabine, and determines the dose of the combination for phase II investigation.

Colorectal carcinoma is the most common gastrointestinal tract malignancy, and the second most common cause of cancer mortality in the United States. Based on the American Cancer Society's estimates, there will be 138,900 (68,800 in men and 70,100 in women) new cases diagnosed with colorectal cancer in 2001, and 57,200 deaths will be caused by this disease. Of the new cases, nearly 60% present with lymph node involvement or metastatic disease. Overall survival for colorectal cancer has improved over the past several decades. This is probably because of increased screening, resulting in stage migration with more patients being diagnosed with early, localized disease. Better preoperative staging, improved surgical techniques and pathologic evaluation of resected specimens have also contributed to the improvement of the overall outcome for these patients. Survival has also been improved by the use of adjuvant chemotherapy in colon cancer and combined modality therapy with chemotherapy and radiation in rectal cancer. Recent advances in chemotherapeutic approaches include novel cytotoxic chemotherapy agents. Biological and molecular targeting agents may impact survival even further.

CP-461 is a member of a class of novel proapoptotic drugs that specifically inhibit cyclic GMP phosphodiesterases but not cyclooxygenase-1 or -2. CP-461 inhibits the growth of a broad range of human tumor cell lines in vitro at micromolar concentrations and selectively induces apoptosis in cancer cell lines but not normal cells. Preclinical studies revealed good oral bioavailability and no toxicity in dogs and rats at single doses up to 500 mg/kg. In a Phase I trial, 21 patients with a range of solid tumors and good performance status received CP-461 p.o. twice daily for 28 consecutive days. Cycles were repeated without a treatment-free interval. CP-461 doses ranged from 100 to 800 mg/day. Therapy was well tolerated overall, and a maximum tolerated dose was not reached. Grade 3 asymptomatic aspartate aminotransferase/alanine aminotransferase elevation in 1 patient treated at 800 mg/day was the only dose-limiting toxicity. No hematologic toxicity was noted. Peak plasma concentrations occurred between 1 and 2 h after dosing, and doses above 200 mg/day exceeded the known in vitro EC(50) (1-2 micro M) for apoptosis in cancer cells. No drug was detectable after 24 h of administration, and the terminal half-life was 6.7 h. The area under the plasma concentration-time curve was dose-proportional from 200 to 800 mg/day. Four patients exhibited disease stability after two cycles of treatment. CP-461 is minimally toxic at doses up to 800 mg/day when administered p.o. on a twice-daily schedule.

The cryptophycin analogue LY355703 is a potent inhibitor of microtubule polymerization that displays in vitro and in vivo activity in cell lines and tumor xenografts displaying the multidrug-resistant phenotype. In a Phase I trial, 25 patients received LY355703 as a 2-h i.v. infusion on day 1 and day 8 repeated every 3 weeks. Doses were escalated from 0.1 to 2.22 mg/m2 using a modified continual reassessment method. Neurological toxicity was found to be dose-limiting at 1.84 and 2.22 mg/m2. Among four patients treated at these doses, two had grade 4 constipation/ileus, one with severe myalgias, and one had grade 3 motor neuropathy. These findings were reversible. The 1.5 mg/m2 dose level was well tolerated. An amended twice-weekly schedule was pursued in 11 patients in an attempt to improve dose intensity and avoid dose-limiting neurotoxicity. Doses of0.75 mg/m2 on a day 1, 4, 8, and 11 schedule every 21 days were not tolerated as a result of nausea/constipation, suggesting that LY335703 toxicity is not schedule dependent and is related to cumulative dose. LY355703 plasma concentrations measured by liquid chromatography with tandem mass spectrometry were evaluated using a population pharmacokinetic model. LY355703 was eliminated rapidly with a short terminal half-life that ranged from 0.8 to 3.9 h. Interpatient variability with respect to plasma clearance and volume of distribution, including covariates, was moderate at 32% and 39%, respectively. Maximum plasma concentration and area under the plasma concentration-time curve were linear over the dose range studied. A patient with non-small cell lung cancer previously treated with taxanes experienced a partial response lasting 4 months, and five patients had stable disease lastingor =3 months. LY355703 at a dose of 1.5 mg/m2 is recommended for Phase II evaluation on a days 1 and 8 schedule. Twice-weekly dosing did not allow improvement in dose intensity or tolerability.

The overall survival for patients with metastatic melanoma ranges from 4.7 to 11 months, with a median survival of 8.5 months. Standard treatment for patients with metastatic melanoma has not been defined. The range of treatment options includes close observation, surgical resection of isolated metastases, therapy with dacarbazine, combination chemotherapy, and participation in clinical trials. Numerous chemotherapeutic agents have shown activity in the treatment of malignant melanoma. Dacarbazine (DTIC-Dome; Bayer Corporation, West Haven, CT) has a response rate of 15% to 20% and remains the reference agent for the treatment of metastatic disease. Additional agents with single-agent activity include cisplatin, (Platinol-AQ; Bristol-Myers Oncology, Princeton, NJ); carmustine (BiCNU; Bristol-Myers Oncology, Princeton, NJ); paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ); and docetaxel (Taxotere; Rhone-Poulenc Rorer Pharmaceuticals, Collegeville, PA). Temozolomide (Temodar; Schering-Plough, Kenilworth, NJ), which is essentially an oral form of dacarbazine but with greater central nervous system penetrance, is associated with a response rate of 20%. Combination chemotherapy with or without tamoxifen has been extensively evaluated in patients with metastatic melanoma. Although the initial results with the Dartmouth regimen (dacarbazine, cisplatin, carmustine, and tamoxifen) were associated with overall response rates of 50% to 55% in single-institution studies, results from larger multicenter studies reveal responses rates ranging from 10% to 20%. Based on the results of several clinical trials, there is no evidence that the addition of tamoxifen improves the response rate. Another combination regimen is cisplatin, vinblastine, and dacarbazine (CVD), which is associated with a 20% to 25% response rate. There has been widespread interest in developing immunotherapies against metastatic melanoma. Interferon (IFN)-alfa and interleukin (IL)-2 as single agents have produced response rates in the 15% to 20% range. Biochemotherapy, which is a combination of immunotherapy and cytotoxic chemotherapy, has been studied in patients with metastatic melanoma. Multiple phase II studies have demonstrated high response rates but unclear impact on overall survival. Therapy is associated with significant toxicity. Ongoing randomized clinical trials will clarify the role of biochemotherapy in patients with metastatic melanoma. Ongoing new approaches to treatment include the therapeutic use of vaccines alone or in combination with cytokines.

9522 Background: According to the NIH consensus statement, the three most common and debilitating symptoms for cancer patients are depression, pain and fatigue. The aims of this study were to test ...

9649 Background: Sleep problems have been linked to increased mortality in the general population. The prevalence of sleep problems in those diagnosed with cancer is even higher than the general po...

TPS4148 Background: HER2 overexpression occurs in ≤ 20% of GE cancers, and front-line fluoropyrimidine/platinum with TRAS increases survival in HER2+ GE junction/gastric cancer patients. Weekly PTX...

e17681 Background: The landmark ToGA study demonstrated a significant overall survival benefit in HER2-positive gastric cancer patients with the addition of trastuzumab to chemotherapy with cisplat...

4029 Background: TRAIL is a member of the tumor necrosis factor ligand super family that induces programmed cell death primarily in tumor cells (including liver tumors) through TRAIL death receptor...

PURPOSE: Irinotecan and raltitrexed display schedule-dependent synergy in vitro, which supports the clinical investigation of the combination. Functional polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene result in intracellular redistribution of folate derivatives, which may affect raltitrexed-associated cytotoxicity. PATIENTS AND METHODS: Patients with a range of solid cancers and good performance status received irinotecan as a 90-minute infusion on day 1 and raltitrexed as a 15-minute infusion on day 2, repeated every 21 days. Samples were collected for MTHFR C677T genotyping and fasting plasma homocysteine during the first cycle. RESULTS: Thirty-nine assessable patients received 127 cycles of therapy. Irinotecan doses ranged from 100 to 350 mg/m2, and raltitrexed, 1.0 to 4.0 mg/m2. Raltitrexed doses of more than 3.0 mg/m2 were not tolerated and were associated with dose-limiting asthenia, diarrhea, and AST/ALT elevation. Irinotecan/raltitrexed doses of 350/3.0 mg/m2 were well-tolerated; principal toxicities included neutropenia, diarrhea, and fatigue. Two partial responses were observed in patients with pretreated gastroesophageal cancers. Homozygotes with the MTHFR 677 TT polymorphism incurred significantly less raltitrexed-associated toxicity than those with either wild-type or heterozygous genotypes (P = .05). No significant differences were noted in plasma homocysteine values between the genotypic subtypes, and plasma homocysteine levels did not predict the risk of toxicity. CONCLUSION: Irinotecan and raltitrexed doses of 350 and 3.0 mg/m2 are recommended for further study on a day 1, 2 schedule every 21 days. Efficacy results suggest that trials in upper and lower gastrointestinal malignancies are warranted. MTHFR C677T genotypes may be predictive of clinical raltitrexed toxicity.

Gastric cancer is one of the most common cancers in the world. The prognosis of the disease is poor, with only 40% of patients eligible to undergo potentially curative surgery. Even for those patients who undergo a complete resection, the rate of recurrence is very high. Extensive studies of multidisciplinary adjuvant treatment have been conducted seeking to improve the cure rates in the past two decades. The benefit of D2 dissection is still controversial and is undergoing prospective evaluation. Preliminary results from the United States Gastrointestinal Intergroup study, a well designed trial, have shown overall survival benefit of postoperative chemoradiation therapy. Neoadjuvant chemotherapy or chemoradiation is under active study in order to increase the number of patients to undergo potential curative surgery. Although many chemotherapy regimens have been developed recently, only modest clinical efficacy has been demonstrated for advanced metastatic disease. So far, there is no single regimen considered to be standard.

Investigation of the effects of various antiangiogenic agents in the therapy of solid tumors has been a dominant theme in oncology for the past decade. Hepatocellular carcinoma has joined the short list of tumor types for which single-agent antiangiogenic therapy has shown clear clinical benefit. Here we discuss the findings of a multicenter, phase III trial by Llovet et al., which compared overall survival, time to symptomatic progression, and time to radiologic progression in 602 patients with hepatocellular carcinoma who received either sorafenib (n= 299) or placebo (n = 303). This study showed that patients treated with sorafenib had approximately 3 months longer overall survival and time to radiologic progression compared with patients who received placebo. For optimal clinical application, elucidation of the tumor-specific and patient-specific factors that identify the subpopulation of patients with hepatocellular carcinoma who will derive the greatest benefit from antiangiogenic therapies such as sorafenib is of critical importance.

A reporter epitope was inserted at 11 positions in a region encompassing proposed transmembrane segments S1 and S2 in the second repeat domain (D2) of the rat skeletal muscle type 1 sodium channel. All mutations produced full-length membrane-associated protein following transfection into cultured cells, although the level of expression varied with insertion position. Characterization of cognate cRNAs for each mutation in Xenopus oocytes by two-electrode voltage clamp defined a permissive region between the proposed transmembrane regions in which these large insertions did not interfere with channel function. Two of the mutations, in which the point of insertion was within the proposed S1-S2 loop, demonstrated extracellular membrane labeling when studied either by antibody binding in oocytes or by confocal analysis following transfection into primary muscle cells. Our results define the likely boundaries of an extramembrane region linking the S1 and S2 transmembrane segments in D2 and confirm the extracellular location of this S1-S2 loop predicted by current models of channel tertiary structure.

The diverse pathways and molecules involved in angiogenesis, the formation of new blood vessels, have been targeted for the treatment of colorectal and other cancers. Vascular endothelial growth factor (VEGF)-A binding to VEGF receptor (VEGFR)-2 is believed to be the key signaling pathway mediating angiogenesis. Other VEGF pathways involved in angiogenesis include VEGF-A, VEGF-B, and placental growth factor binding to VEGFR-1, and VEGF-C and VEGF-D binding to VEGFR-2 and VEGFR-3. VEGF signaling also intersects with other pathways, including angiopoietin/Tie, Notch, hypoxia-inducible factor, and integrin pathways. The roles of these pathways in tumor angiogenesis and in various human cancers will be explored in this article. In addition, preclinical and clinical data on bevacizumab, aflibercept (known as ziv-aflibercept in the US), and investigational antiangiogenic agents in development for the treatment of colorectal and other cancers will be reviewed.

3522 Background: Studies show significantly improved disease-free and overall survival (DFS, OS) for oxaliplatin (Ox)-based vs. leucovorin/5-fluorouracil (LV/5-FU) adjuvant therapy in CC, with conflicting reports of Ox benefit in patients > 70 years old. The impact of MC on Ox benefit has not been assessed. We assessed the impact of age and MC on adjuvant treatment outcomes for stage III CC. Methods: N = 4,819 patients from NSABP C-08, XELOXA, X-ACT, and AVANT were analyzed by Ox therapy (XELOX/FOLFOX) vs. LV/5-FU, MC, and age; patients treated with bevacizumab were excluded. Endpoints were DFS (primary), OS, and safety. MC was assessed (except NSABP C-08) by adapted Charlson Comorbidity and NCI Combined Indices (CCI, NCI): Low (≤ 1) vs. high (> 1). Hazardratios (HR) were estimated by Cox regression analyses. Multivariate Cox regression analyses (MVA) tested for independent effects of age and MC on Ox benefit, controlling for gender, T, and N stage. Results: Patient demographics, MC, and disease characteristics (except lymph nodes examined) were well balanced across groups. Median follow-up was shorter in NSABP C-08 and AVANT (36 and 50 months) vs. XELOXA and X-ACT (83 and 74 months). MVA-confirmed DFS/OS benefit was consistently shown for XELOX/FOLFOX vs. LV/5-FU, regardless of age or MC. Grade 3/4 serious adverse event (AE) rates were comparable across cohorts and CCI scores, and higher in patients aged ≥ 70. Grade 3/4 AEs of interest, including peripheral sensory neuropathy, were comparable across ages and CCI scores, and higher with XELOX/FOLFOX. Conclusions: Ox benefit is modestly attenuated in patients aged ≥ 70; however, significant benefit is observed regardless of age or MC in this analysis. Our results further support XELOX or FOLFOX as standard options for the adjuvant management of stage III CC in all age groups. [Table: see text]

4111 Background: Cholangiocarcinoma is an aggressive neoplasm. Current chemotherapy approaches achieve modest results. The epidermal growth factor receptor (EGFR) pathway appears to be associated with tumor stage, prognosis and response to therapy. This trial was designed to evaluate the tolerability and efficacy of the combination of panitumumab, a monoclonal anti-EGFR antibody, with gemcitabine and irinotecan, in patients with advanced cholangiocarcinoma. Molecular analysis of EGFR pathway genes was planned as well. Methods: Patients with advanced (unresectable or metastatic) cholangiocarcinoma, ECOG PS 0-2, and adequate liver, kidney and bone marrow function were treated with panitumumab (9 mg/kg) on day 1, and gemcitabine (1000 mg/m2) and irinotecan (100 mg/m2) on days 1 and 8 of a 21-day cycle. Tissue specimens were collected at diagnosis for correlative molecular analyses. Primary objective is to evaluate the 5-month progression-free survival (PFS) rate. Secondary objectives include overall response rate (ORR), overall survival (OS) and toxicity of the combination. Mutational analysis of EGFR (del 19; 858), KRAS (codons 12, 13) and BRAF (V600E) was done on samples with adequate material for testing. Results: There have been 26 (of planned 42) patients recruited to the study. A median of 6 (0-30) cycles were administered. There were no treatment related deaths. The most common gr 3 or higher toxicities were neutropenia (10 pts, 38%), thrombocytopenia (10 pts, 38%), skin rash (10 pts, 38%) and diarrhea (3 pts, 12%). During the study, there were 3 CR, 6 PR, 10 SD (disease control rate of 90%), and 2 PD (by RECIST) in 21 evaluable pts. Two pts went on to have surgical resection. Median OS is 12.7 months. Of 13 testable samples, no EGFR or BRAF mutations were identified; however, there were 7 KRAS mutations. Retrospective analysis showed no difference in OS by KRAS mutation status. Conclusions: Interim evaluation of this ongoing study showed encouraging tolerability and efficacy of this regimen. Several patients have KRAS mutations; there appears to be no association with response, however. The pre-specified efficacy criteria to continue enrollment were met.

3523 Background: Oxaliplatin-based adjuvant therapy is the standard of care for stage III colon cancer; however, its impact on PRS in these patients is unclear. We therefore compared PRS in trials of patients with stage III colon cancer treated with oxaliplatin plus capecitabine (XELOX) or 5-flourouracil (5-FU; FOLFOX) vs. leucovorin/5-FU (LV/5-FU). Methods: Individual patientdata (N = 4,819) from NSABP C-08, XELOXA, X-ACT, and AVANT were pooled and analyzed by XELOX/FOLFOX vs. LV/5-FU; patients treated with bevacizumab were excluded. Hazard ratios (HR) were estimated by Cox regression analyses and multivariate Cox regression analyses controlled for age, gender, T, and N stage. Post-relapse treatment data were collected when available. Results: Patient demographics and disease characteristics (except lymph nodes examined) were well balanced across analytic groups. Median follow-up was shorter in NSABP C-08 and AVANT (36 and 50 months) than in XELOXA and X-ACT (83 and 74 months). PRS was very similar for XELOX/FOLFOX and LV/5-FU (HR 0.94, 95% CI, 0.82–1.07; P = .33). Multivariate analyses supported these findings, but showed that PRS was associated with younger age and lower N stage at diagnosis after controlling for gender and T stage. PRS was also comparable for capecitabine or XELOX vs. LV/5-FU or FOLFOX (N = 5,819, HR 1.07, 95% CI, 0.95–1.20; P = .26). Post-relapse therapies were comparable across the two cohorts. Conclusions: Adjuvant chemotherapy regimen did not impact on PRS in patients with stage III colon cancer; however, both N stage and age demonstrated independent effects on PRS. Studies have demonstrated significantly improved disease-free and overall survival for oxaliplatin-based therapy, and our data show that survival is not compromised by worsened PRS at subsequent relapse. [Table: see text]

3525 Background: A fluoropyrimidine + Ox is the standard of care for stage III CC but a fluoropyrimidine alone is recommended for selected patients in several practice guidelines. We assessed efficacy and safety of adjuvant capecitabine ± Ox vs. LV/5-FU ± Ox across a population of stage III CC patients enrolled in four trials. Methods: N = 5,819 patients from NSABP C-08, XELOXA, X-ACT, and AVANT were pooled and analyzed; bevacizumab-treated patients were excluded. Endpoints were disease-free survival (DFS, primary), relapse-free survival (RFS), overall survival (OS), and safety. Multivariate Cox regression analyses (MVA) controlled for age, gender, T, and N stage. Results: Patient demographics and disease characteristics (except lymph nodes examined) were well balanced across groups. The number of patients receiving capecitabine and LV/5-FU were 1,942 and 3,877, respectively. Median follow-up was shorter in NSABP C-08 and AVANT (36 and 50 months) vs. XELOXA and X-ACT (83 and 74 months). Five-year DFS was 62.8% for capecitabine ± Ox and LV/5-FU ± Ox. The capecitabine by Ox interaction was significant for OS with a trend for DFS and RFS; likely due to improved outcomes with capecitabine alone and similar outcomes for capecitabine or LV/5-FU + Ox. Serious adverse event (AE) rates were similar for LV/5-FU- and capecitabine-based therapy (16% vs. 20%, respectively). Overall, treatment-related grade 3/4 AEs were more common with LV/5-FU (59% vs. 47%). Treatment-related grade 3/4 AEs of interest included peripheral sensory neuropathy (5% vs. < 1%), diarrhea (12% vs. 15%), febrile neutropenia (2% vs. < 1%), and hand–foot syndrome (< 1% vs. 12%). Conclusions: Adjuvant capecitabine ± Ox and LV/5-FU ± Ox show comparableefficacy benefits for the treatment of stage III CC; further supporting capecitabine or LV/5-FU-based regimens as standard options for the adjuvant therapy of stage III CC. [Table: see text]