Drug development in advanced colorectal cancer: challenges and opportunities.

Despite recent advances in treatment options, advanced colorectal cancer (ACC) remains a leading cause of cancer death worldwide, and new therapies are needed to improve the grim prognosis of this disease. Drug development in ACC faces the challenges of a constrained pipeline, a paucity of patients enrolled in clinical trials, and an outdated "one drug fits all" model of clinical research. This article discusses potential innovations in clinical trial design--including enrichment strategies, novel patient populations, and the use of randomization in the phase 2 setting--to optimize the testing of new therapies.

NCCN Task Force Report: mTOR inhibition in solid tumors.

The mammalian target of rapamycin (mTOR) protein complex functions as an integration center for various intracellular signaling pathways involving cell cycle progression, proliferation, and angiogenesis. These pathways are frequently dysregulated in cancer, and therefore mTOR inhibition is a potentially important antitumor target. Commercially available mTOR inhibitors include rapamycin (i.

Utility of Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein and des-gamma-carboxy prothrombin, alone or in combination, as biomarkers for hepatocellular carcinoma.

Background & Aims: Des-gamma-carboxy prothrombin (DCP) and Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) are surveillance markers used to detect hepatocellular carcinoma (HCC) in Japan. This study evaluated their utility, alone or in combination, in a North American population.

Methods: Patients with hepatitis C virus-related cirrhosis were followed up prospectively for 2 years.

Serum CA19-9 decline compared to radiographic response as a surrogate for clinical outcomes in patients with metastatic pancreatic cancer receiving chemotherapy.

Objective: Serum carbohydrate antigen 19-9 (CA19-9) has never been compared to radiographic objective response as a surrogate for clinical outcomes in patients receiving chemotherapy for metastatic pancreatic cancer.

Methods: We compared CA19-9 decline to objective response as surrogate end points for both time to progression (TTP) and overall survival (OS) in patients with metastatic pancreatic cancer receiving fixed-dose rate gemcitabine.

Results: A total of 75 patients from 2 studies were eligible for analysis.

The impact of new data in the treatment of advanced hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, causing 500,000 deaths yearly. The risk factors mostly responsible for the rising incidence of HCC in the Western hemisphere are hepatitis C, alcoholic cirrhosis, and nonalcoholic steatohepatitis, which most commonly leads to HCC in the setting of cirrhosis. Over the past 30 years, several chemotherapeutic single agents and combinations have been tested in HCC, yet none have demonstrated any improvement in survival.

A phase II study evaluating bevacizumab in combination with fixed-dose rate gemcitabine and low-dose cisplatin for metastatic pancreatic cancer: is an anti-VEGF strategy still applicable?

Background: The role of bevacizumab, a recombinant humanized monoclonal antibody directed against vascular endothelial growth factor, in the treatment of pancreatic cancer remains unclear. The objectives of this study were to determine safety and efficacy in chemotherapy-naive patients with metastatic pancreatic cancer receiving bevacizumab in combination with fixed-dose rate (FDR) gemcitabine and low-dose cisplatin.

Methods: Eligible patients received gemcitabine 1,000 mg/m2 at FDR infusion (10 mg/m(2) per minute), cisplatin 20 mg/m(2), and bevacizumab 10 mg/kg, on days 1 and 15 of a 28-day cycle.

Phase II trial of T138067, a novel microtubule inhibitor, in patients with metastatic, refractory colorectal carcinoma.

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.

Excess toxicity associated with docetaxel and irinotecan in patients with metastatic, gemcitabine-refractory pancreatic cancer: results of a phase II study.

Background: No therapeutic standard of care exists for patients with advanced pancreatic cancer who progress following first-line treatment with a gemcitabine-based regimen. There is evidence of synergistic activity between docetaxel and irinotecan, and the combination of these two agents has shown promising efficacy in the first-line setting for advanced pancreatic cancer. We, therefore, evaluated this regimen in patients with gemcitabine-refractory disease.

Hepatocellular carcinoma: the role of the North American GI Steering Committee Hepatobiliary Task Force and the advent of effective drug therapy.

Hepatocellular carcinoma (HCC) is a disease that requires multidisciplinary management. There has been no widely accepted standard for systemic therapy for this disease until recently. This article briefly discusses the management of earlier stage HCC, then focuses on newer agents with promise, particularly sorafenib, a drug that appears to be the new standard of care for advanced disease.

A phase II prospective multi-institutional trial of adjuvant active specific immunotherapy following curative resection of colorectal cancer hepatic metastases: cancer and leukemia group B study 89903.

Background: Patients with curatively resected colorectal cancer hepatic metastases often harbor occult metastatic disease and are at high risk of experiencing recurrence. This patient cohort is ideally suited to test novel therapies such as immunotherapy. We treated patients-post-hepatic resection-with anti-idiotype monoclonal antibody vaccines to the tumor-associated antigens carcinoembryonic antigen (CeaVac) and human milk fat globule (TriAb), both of which are co-expressed in more than 90% of colorectal cancer patients.

Vaccination of metastatic colorectal cancer patients with matured dendritic cells loaded with multiple major histocompatibility complex class I peptides.

Developing a process to generate dendritic cells (DCs) applicable for multicenter trials would facilitate cancer vaccine development. Moreover, targeting multiple antigens with such a vaccine strategy could enhance the efficacy of such a treatment approach. We performed a phase 1/2 clinical trial administering a DC-based vaccine targeting multiple tumor-associated antigens to patients with advanced colorectal cancer (CRC).

Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer.

Background: The safety and efficacy of the fully human antibody panitumumab was evaluated in patients with metastatic colorectal cancer refractory to available therapies.

Methods: This phase 2 open-label, multicenter study of panitumumab enrolled patients with metastatic colorectal cancer who had progressed on chemotherapy that included a fluoropyrimidine and irinotecan or oxaliplatin, or both. All patients had tumors with > or =10% 1+ epidermal growth factor receptor (EGFr) staining by immunohistochemistry.

Clinical utility of AFP-L3% measurement in North American patients with HCV-related cirrhosis.

Background And Aims: Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3%) has been reported to be useful in the early detection of hepatocellular carcinoma (HCC) in Japan. The aim of this prospective study was to compare the clinical utility of AFP-L3% with that of total AFP in North American patients.

Methods: Patients with chronic hepatitis (CH) C virus-related cirrhosis from 7 clinical sites were prospectively followed every 3-6 months for 2 yr.

Systemic and regional nonsurgical therapy--what is the optimal strategy for metastatic neuroendocrine cancer?

A multidisciplinary team is essential for the optimal management of patients with metastatic neuroendocrine tumors. In this article, the systemic and regional nonsurgical therapeutic options for metastatic neuroendocrine cancers are discussed. In particular, the roles of biotherapy, chemotherapy, and hepatic artery embolization/chemoembolization are reviewed.

A phase II study of fixed-dose rate gemcitabine plus low-dose cisplatin followed by consolidative chemoradiation for locally advanced pancreatic cancer.

Purpose: The optimal strategy for treating locally advanced pancreatic cancer remains controversial, including the respective roles and timing of chemotherapy and radiation. We conducted a Phase II nonrandomized trial to evaluate sequential chemotherapy followed by chemoradiation in this patient population.

Methods And Materials: Chemotherapy naive patients with locally advanced pancreatic adenocarcinoma were treated with fixed-dose rate gemcitabine (1,000 mg/m(2) at 10 mg/m(2)/min) plus cisplatin 20 mg/m(2) on Days 1 and 15 of a 28-day cycle.