Validity of the FACT Hepatobiliary (FACT-Hep) questionnaire for assessing disease-related symptoms and health-related quality of life in patients with metastatic pancreatic cancer.

PURPOSE: Evaluate reliability and validity of the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire and its derivative FACT Hepatobiliary Symptom Indexes (FHSI-18 and FHSI-8) in people with metastatic pancreatic cancer. METHODS: Self-reported questionnaire data from a randomized controlled Phase II study evaluating the efficacy and safety of conatumumab (AMG 655), ganitumab (AMG 479) or placebo combined with gemcitabine were evaluated. The following were assessed: internal consistency, using Cronbach's α; discriminant validity, comparing baseline patient-reported outcomes (PRO) scores across Eastern Cooperative Oncology Group (ECOG) performance status (PS) levels; and ability to detect change, comparing change from baseline PRO score at each cycle across PS and tumour response groups. RESULTS: The analysis included 96 patients. All scale scores demonstrated good internal consistency (Cronbach's α > 0.7) and discriminant validity. Baseline scores were significantly poorer among patients with PS = 1 versus patients with PS = 0 (e.g. difference in FACT-Hep total score -17.27; p < 0.001). Ability to detect change was established for Cycles 2/3 versus baseline; PRO scores reduced in the PS-worsened group versus the PS-stable group (e.g. difference in FACT-Hep total score -24.29; p < 0.001). All PRO scale scores showed significant decline for progressive disease versus stable disease (e.g. difference in FACT-Hep total score -12.58; p = 0.004). Changes on the FHSI-18 and FHSI-8 scales were similar in magnitude whether ECOG improved or worsened. CONCLUSIONS: FACT-Hep detects change and is a reliable and valid instrument for measuring health-related quality of life in patients with metastatic pancreatic cancer.

A phase II study of bevacizumab and temsirolimus in advanced extra-pancreatic neuroendocrine tumors.

We assessed the efficacy and safety of combining bevacizumab with temsirolimus in patients with advanced extra-pancreatic neuroendocrine tumors. This NCI-sponsored multicenter, open-label, phase II study (NCT01010126) enrolled patients with advanced, recurrent, or metastatic extra-pancreatic neuroendocrine tumors. All patients were treated with temsirolimus and bevacizumab until disease progression or unacceptable toxicity. Temsirolimus 25 mg was administered i.v. on days 1, 8, 15, and 22 and bevacizumab 10 mg/kg i.v. on days 1 and 15 of a 4-week cycle. Discontinuation of temsirolimus or bevacizumab did not require discontinuation of the other agent. The primary endpoints were objective response rate and 6-month progression-free survival rate. Fifty-nine patients were enrolled in this study, and 54 were evaluated for efficacy and adverse events. While median progression-free survival was 7.1 months, the median duration of treatment with temsirolimus was 3.9 months and that with bevacizumab was 3.5 months. The objective response rate of combination therapy was 2%, and 6-month progression-free survival was 48%. The most frequently reported grade 3-4 adverse events included fatigue (13%), hypertension (13%), and bleeding (13%). Close to 54% of the patients discontinued treatment due to adverse events, refusal of further treatment, or treatment delays. Three deaths occurred in the study, of which two were due to treatment-related bowel perforations. Given the minimal efficacy and increased toxicity seen with the combination of bevacizumab and temsirolimus, we do not recommend the use of this regimen in patients with advanced extra-pancreatic neuroendocrine tumors.

Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II Consortium.

BACKGROUND: Sorafenib, an inhibitor of B-raf, VEGFR2, and PDGFR-ß, has activity against pancreatic cancer in preclinical models. In a phase I trial of gemcitabine plus sorafenib, 57% of pancreatic cancer patients achieved stable disease. PATIENTS AND METHODS: We conducted a multi-center phase II trial of sorafenib plus gemcitabine in chemo-naïve patients with histologically-confirmed, advanced pancreatic cancer. Patients received sorafenib 400 mg twice daily and gemcitabine 1,000 mg/m(2) on days 1, 8 and 15 of a 28 day cycle. RESULTS: Seventeen patients enrolled at 4 centers; 13 were evaluable for response. There were no objective responses; 18% had stable disease. Median overall survival was 4.0 months (95% CI: 3.4, 5.9); median progression-free survival was 3.2 months (95% CI: 1.6, 3.6). Grade 3/4 toxicities included thrombosis in 18% of patients, dehydration or hand-foot syndrome in 12%, and hypertension or gastrointestinal bleeding in 6%. CONCLUSION: Gemcitabine plus sorafenib is inactive in advanced pancreatic cancer.

Update on malignant pleural mesothelioma.

Malignant pleural mesothelioma is an aggressive cancer principally attributable to asbestos. Although the incidence is now declining in the United States, it will continue to increase worldwide until all nations institute regulations limiting asbestos use and exposure. This is a heterogeneous disease, with three pathological subtypes that yield very different outcomes. Stage is less important than histology in determining prognosis. The biomarkers serum mesothelin-related peptide and osteopontin are being evaluated for screening asbestos-exposed individuals and monitoring disease response. The optimal surgical procedure remains controversial because extrapleural pneumonectomy and pleurectomy/decortication can achieve similar results. The reference chemotherapy regimen, pemetrexed-cisplatin, improves survival and quality of life. Key questions about maintenance therapy and the optimal regimens for elderly and frail patients remain to be answered. Although few other cytotoxic drugs have activity, a surprising number of novel agents are being investigated.

Systemic treatments for mesothelioma: standard and novel.

OPINION STATEMENT: Systemic therapy is the only treatment option for the majority of mesothelioma patients, for whom age, co-morbid medical illnesses, non-epithelial histology, and locally advanced disease often preclude surgery. For many years, chemotherapy had a minimal impact on the natural history of this cancer, engendering considerable nihilism. Countless drugs were evaluated, most of which achieved response rates below 20% and median survival of <1 year. Several factors have hampered the evaluation of systemic regimens in patients with mesothelioma. The disease is uncommon, affecting only about 2500 Americans annually. Thus, most clinical trials are small, and randomized studies are challenging to accrue. There is significant heterogeneity within the patient populations of these small trials, for several reasons. Since all of the staging systems for mesothelioma are surgically based, it is almost impossible to accurately determine the stage of a patient who has not been resected. Patients with very early stage disease may be lumped together with far more advanced patients in the same study. The disease itself is heterogenous, with many different prognostic factors, most notably three pathologic subtypes--epithelial, sarcomatoid, and biphasic--that have different natural histories, and varying responses to treatment. Finally, response assessment is problematic, since pleural-based lesions are difficult to measure accurately and reproducibly. Assessment criteria often vary between trials, making some cross-trial comparisons difficult to interpret. Despite these limitations, in recent years, there has been a surge of optimism regarding systemic treatment of this disease. Several cytotoxic agents have been shown to generate reproducible responses, improve quality of life, or prolong survival in mesothelioma. Drugs with single-agent activity include pemetrexed, raltitrexed, vinorelbine, and vinflunine. The addition of pemetrexed or raltitrexed to cisplatin prolongs survival. The addition of cisplatin to pemetrexed, raltitrexed, gemcitabine, irinotecan, or vinorelbine improves response rate. The combination of pemetrexed plus cisplatin is considered the benchmark front-line regimen for this disease, based on a phase III trial in 456 patients that yielded a response rate of 41% and a median survival of 12.1 months. Vitamin supplementation with folic acid is essential to decrease toxicity, though recent data suggests that there may be an optimum dose of folic acid that should be administered; higher doses may diminish the effectiveness of pemetrexed. There are also several unresolved questions about the duration and timing of treatment with pemetrexed that are the subject of planned clinical trials. It is essential to recognize that the improvements observed with the pemetrexed/cisplatin combination, though real, are still modest. Other active drugs or drug combinations may be more appropriate for specific individuals, and further research is still needed to improve upon these results. Since the majority of mesotheliomas in the United States occur in the elderly, non-cisplatin-containing pemetrexed combinations may be more appropriate for some patients. Now that effective agents have been developed for initial treatment, several classical cytotoxic drugs and many novel agents are being evaluated in the second-line setting. These include drugs targeted against the epidermal growth factor, platelet-derived growth factor, vascular endothelial growth factor, src kinase, histone deacetylase, the proteasome, and mesothelin. Given the progress made in recent years, there is reason to believe that more effective treatments will continue to be developed.

A review of resistance patterns and phenotypic changes in gastrointestinal stromal tumors following imatinib mesylate therapy.

Gastrointestinal stromal tumors are neoplastic lesions that arise from the interstitial cells of Cajal and are associated with somatic mutations in the tyrosine kinase receptor, KIT. The only known curative therapy is complete surgical resection. Unfortunately, postsurgical recurrence rates exceed 50% and most tumors are resistant to standard chemotherapy and radiation. Imatinib mesylate, a novel tyrosine kinase inhibitor, holds promise as a potential adjuvant therapy to prevent recurrence and improve long-term survival. However, as resistance data emerge, it appears that a potential "escape pathway" may originate from secondary mutations in the KIT receptor. This paper reviews the historical clinical experience with imatinib mesylate and discusses resistance patterns following targeted therapy. We highlight this review with an interesting case report that illustrates unique phenotypic tumoral changes associated with imatinib mesylate resistance.

Front-line therapy of advanced pancreatic cancer.

Pancreatic cancer is a devastating illness that has the briefest survival of any solid tumor. Gemcitabine, the standard chemotherapy, improves quality of life and modestly improves response rates and survival compared with 5-fluorouracil. Several single agents have been compared with gemcitabine in phase III trials; none have proven superior to gemcitabine. Similarly, no statistically significant improvement in survival has been observed in multiple phase III trials when doublets of gemcitabine plus a cytotoxic drug have been compared with single-agent gemcitabine. Fixed-dose rate administration has also been evaluated to improve the efficacy of gemcitabine. It appears unlikely that cytotoxic chemotherapy will substantially alter the natural history of this chemo-refractory disease. New agents targeted against specific molecular events involved in pancreatic carcinogenesis, invasion, and metastasis may be more worthy of evaluation than additional gemcitabine doublets. Agents that target vascular endothelial growth factor and the epidermal growth factor receptor are currently being evaluated in phase III trials.

Antiangiogenic therapies for mesothelioma.

A large body of preclinical evidence suggests that angiogenesis plays a key role in the pathogenesis of malignant mesothelioma. Several mediators of angiogenesis seem to be autocrine growth factors in mesothelioma, and in preclinical models, agents that target angiogenesis produce tumor regression. Several clinical trials are currently evaluating the efficacy of inhibitors of angiogenesis in mesothelioma. This article details the preliminary results of these trials and future directions.

Multicenter Phase II Trial of Temsirolimus and Bevacizumab in Pancreatic Neuroendocrine Tumors.

PURPOSE: There are few effective therapies for pancreatic neuroendocrine tumors (PNETs). Recent placebo-controlled phase III trials of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the vascular endothelial growth factor (VEGF)/platelet-derived growth factor receptor inhibitor sunitinib have noted improved progression-free survival (PFS). Preclinical studies have suggested enhanced antitumor effects with combined mTOR and VEGF pathway-targeted therapy. We conducted a clinical trial to evaluate combination therapy against these targets in PNETs. PATIENTS AND METHODS: We conducted a two-stage single-arm phase II trial of the mTOR inhibitor temsirolimus 25 mg intravenously (IV) once per week and the VEGF-A monoclonal antibody bevacizumab 10 mg/kg IV once every 2 weeks in patients with well or moderately differentiated PNETs and progressive disease by RECIST within 7 months of study entry. Coprimary end points were tumor response rate and 6-month PFS. RESULTS: A total of 58 patients were enrolled, and 56 patients were eligible for response assessment. Confirmed response rate (RR) was 41% (23 of 56 patients). PFS at 6 months was 79% (44 of 56). Median PFS was 13.2 months (95% CI, 11.2 to 16.6). Median overall survival was 34 months (95% CI, 27.1 to not reached). For evaluable patients, the most common grade 3 to 4 adverse events attributed to therapy were hypertension (21%), fatigue (16%), lymphopenia (14%), and hyperglycemia (14%). CONCLUSION: The combination of temsirolimus and bevacizumab had substantial activity and reasonable tolerability in a multicenter phase II trial, with RR of 41%, well in excess of single targeted agents in patients with progressive PNETs. Six-month PFS was a notable 79% in a population of patients with disease progression by RECIST criteria within 7 months of study entry. On the basis of this trial, continued evaluation of combination mTOR and VEGF pathway inhibitors is warranted.

Pemetrexed in pancreatic cancer.

New drugs are clearly needed for the treatment of advanced pancreatic cancer, a disease refractory to most chemotherapy. Pemetrexed, a novel antifolate, inhibits thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, and aminoimidazole carboxamide ribonucleotide formyltransferase. Pemetrexed is active against pancreatic cancer cell lines in vitro. Two partial responses in pancreatic cancer patients were observed in a phase I trial of pemetrexed. This led to a phase II trial of pemetrexed in patients with advanced pancreatic cancer. The objective response rate was 6%, 1-year survival rate was 28%, and the toxicities of therapy were mild. Pemetrexed is synergistic with gemcitabine in vitro. In a phase I trial, the pemetrexed/gemcitabine combination was broadly active and well tolerated. A phase II trial of this combination in 42 patients with advanced pancreatic cancer showed promising activity. A 520-patient international randomized phase III trial that compares the pemetrexed/gemcitabine combination with single-agent gemcitabine is currently accruing patients.

The role of gemcitabine in the treatment of malignant mesothelioma.

Gemcitabine is broadly active in a variety of solid tumors, including malignant mesothelioma. In vitro, gemcitabine demonstrates activity against mesothelioma cell lines. The role of single-agent gemcitabine in patients with mesothelioma is unclear, since three phase II trials treated a total of 60 patients and achieved response rates of 0%, 7%, and 31%. The combination of gemcitabine and cisplatin is synergistic against mesothelioma cell lines in vitro. Gemcitabine in combination with cisplatin or carboplatin shows definite activity in phase II trials. The trial by Byrne and colleagues that demonstrated a response rate of 48% established the combination of gemcitabine plus cisplatin as a standard therapy for this disease in the United States. Subsequent multicenter trials have achieved lower response rates of 26% and 16% for this combination. Gemcitabine plus carboplatin also has activity. Future roles for gemcitabine in malignant mesothelioma patients include incorporating a gemcitabine/platinum regimen for neoadjuvant or adjuvant therapy, combining it with other cytotoxic chemotherapy agents such as pemetrexed or vinorelbine, or adding novel cytostatic agents such as the vascular endothelial growth factor (VEGF) inhibitor, bevacizumab, to the gemcitabine and platinating agent combination.

New approaches for mesothelioma: biologics, vaccines, gene therapy, and other novel agents.

Although malignant mesothelioma is not a classically immunogenic cancer, there is abundant evidence for immune recognition. The relative ease of obtaining tumor tissue makes mesothelioma ideal for studying surrogate biomarkers such as lymphocytic infiltration or expression of transduced genes. There is evidence that malignant mesothelioma patients as well as asbestos-exposed persons without mesothelioma have impaired immune responsiveness. Substantial progress has been made in animal models using several biological and immunological techniques, but clinical application has been problematic. Systems studied have included lysis by interleukin-2 (IL-2)-activated lymphokine-activated killer (LAK) cells, tumor necrosis factor-alpha (TNF-alpha), a p16-expressing adenovirus vector, suicide gene therapy using the herpes simplex virus-tyrosine kinase (HSV-tk) followed by ganciclovir, and immunomodulatory gene therapy with IL-2, IL-4, interferon-gamma (IFN-gamma), IFN-alpha, TNF-alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, and IL-1beta transfected into tumors. Vaccinia virus has been studied as a vector for cytokine gene transfer. Suicide gene therapy has been combined with a tumor vaccine. The University of Western Australia is initiating a pilot study of autologous vaccination in malignant mesothelioma. Novel agents under study include the angiogenesis inhibitors SU5416, bevacizumab, and thalidomide. ZD1839, an orally administered, highly selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, is being tested in a phase II trial. Since platelet-derived growth factor (PDGF) is thought to be an autocrine growth factor for mesothelioma STI-571 (Gleevec; Novartis, Basel, Switzerland), a highly selective inhibitor of the PDGF receptor tyrosine kinase, is being tested in a phase II trial. The development of more active cytotoxic combinations in this disease should facilitate further studies of chemoimmunotherapy. It seems likely that no single treatment modality will be effective by itself.

The emerging role of pemetrexed for the treatment of malignant mesothelioma.

Malignant mesothelioma is a devastating disease with an onset 20 to 60 years after exposure to asbestos. Although most cytotoxic agents have been evaluated for the treatment of mesothelioma, few single agents have consistently yielded response rates above 20%. Antimetabolites are the most active drugs against mesothelioma, and of these, the antifolate group is the most widely studied and effective. Pemetrexed (Alimta), a new antifolate, may be more active because of its different mechanism of action. Several clinical trials have evaluated pemetrexed alone and in combination with a platinum agent for patients with malignant mesothelioma. A pivotal phase III trial has demonstrated that combination chemotherapy with pemetrexed and cisplatin improves survival, response rate, pulmonary function, and quality of life compared with single-agent cisplatin. Additional trials are evaluating pemetrexed in the neoadjuvant setting and in combination with other cytotoxic and targeted agents.

Current controversies in the stage-specific multidisciplinary management of pancreatic cancer.

Encouraging therapeutic approaches and treatment regimens for patients with both localized and metastatic pancreatic cancer have emerged over the last 5 years. However, these new strategies have brought important challenges and controversy. Clinical staging criteria are constantly evolving. No system has been uniformly adopted, limiting our understanding of the role of both pancreatectomy and neoadjuvant therapies for localized disease. The role of radiation therapy for the treatment of both resectable and unresectable pancreatic cancer remains unclear despite multiple prospective studies. Although two new systemic chemotherapy regimens have essentially transformed the care of many patients with metastatic cancer, criteria to guide their use in the general population have yet to be clearly established. Herein we provide an overview of these important controversies in the context of a broad update on the stage-specific management of patients with newly diagnosed pancreatic cancer.

Peritoneal mesothelioma: the site of origin matters.

The etiology, gender distribution, pathology, natural history, and treatment options for mesothelioma (MM) differ substantially depending on the site of origin. Peritoneal mesothelioma (MPeM) is a rare disease, comprising only approximately 10% to 15% of the 2,500 cases of MM diagnosed in the United States each year. Patients with MPeM are younger than patients with pleural MM, and a higher proportion, mostly women, are long-term survivors. Most MPeM is caused by asbestos exposure. Germ-line mutations of BAP1 (BRCA associated protein 1) can predispose to MM, uveal melanoma, and potentially other cancers. MPeM can be challenging to diagnose, and cytology is rarely helpful. Review by an experienced pathologist using a panel of at least two positive and two negative immunohistochemical stains is essential. The three major pathologic subtypes are epithelial, sarcomatoid, and biphasic. Most cases are epithelial; the others have a dismal prognosis. Two indolent subtypes of borderline malignant potential-well-differentiated papillary mesothelioma and benign multicystic mesothelioma-are more common in the peritoneum and are treated surgically. In highly selected patients receiving treatment at experienced referral centers, an aggressive locoregional strategy that combines cytoreductive surgery to remove all gross disease and hyperthermic intraperitoneal chemotherapy to treat residual microscopic tumors yields a 3-year survival of 60% and a median survival approaching 5 years, far better than expected from historic controls. This approach also provides durable palliation of malignant ascites in nearly all patients. Pemetrexed is the only U.S. Food and Drug Administration (FDA)-approved systemic chemotherapy for pleural MM. Largely on the basis of data from pharmaceutical registry studies, the activity of pemetrexed-based chemotherapy appears to be similar in pleural MM and MPeM.

A New Direction for Pancreatic Cancer Treatment: FOLFIRINOX in Context.

Since 1996, the cornerstone of chemotherapy for advanced pancreatic cancer has been gemcitabine, which has a genuine, but modest effect on survival and quality of life. It has been remarkably difficult to improve on these outcomes. Many phase III studies of gemcitabine doublets have been uniformly negative, with the exception of a trial of gemctabine plus erlotinib, which provided only marginal benefit. In 2010, the FOLFIRINOX regimen (bolus and infusional 5-fluorouracil, irinotecan, and oxaliplatin) emerged as a major treatment advance for patients with metastatic pancreatic cancer. In a trial with 342 patients, FOLFIRINOX yielded a longer median overall survival (11.1 vs. 6.8 months, hazard ratio [HR] 0.57, p < 0.001), a superior progression-free survival (6.4 vs. 3.3 months, HR 0.47, p < 0.001), a higher objective response rate (31.6% vs. 9.4%, p < 0.001), and a significant increase in time until definitive deterioration in quality of life, compared with gemcitabine. FOLFIRINOX is also more cost-effective than gemcitabine. Because of higher rates of grade 3 to 4 neutropenia (46% vs. 21%), febrile neutropenia (5% vs. 1%), and diarrhea (13% vs. 2%) with FOLFIRINOX, vigilant patient selection, education, and monitoring are essential. Retrospective single-institution series confirm the substantial activity of FOLFIRINOX in metastatic, locally advanced, and previously-treated patients; demonstrate its safety in individuals with biliary stents; and elucidate how physicians routinely modify drug doses without clear evidence or guidelines. Ongoing and planned studies will prospectively evaluate FOLFIRINOX in the adjuvant, locally advanced, and borderline resectable settings, will add targeted agents to FOLFIRINOX, and will evaluate how to adjust doses to ameliorate toxicity.

Vatalanib in malignant mesothelioma: a phase II trial by the Cancer and Leukemia Group B (CALGB 30107).

INTRODUCTION: The Cancer and Leukemia Group B (CALGB) conducted a multi-center phase II trial to evaluate the efficacy and safety of vatalanib in previously untreated patients with malignant mesothelioma and to evaluate potential biomarkers of disease response (CALGB 30107). METHODS: Treatment consisted of vatalanib 1250 mg given orally once daily. CT scans were obtained at baseline and every 6 weeks thereafter. Baseline serum levels of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), thrombospondin-1 (TSP-1), and mesothelin were obtained. The primary endpoint was 3-month progression-free survival (PFS). RESULTS: Forty-seven patients enrolled at 19 centers. The median age was 75 years, and the majority of patients (79%) had an ECOG performance status of 1. Tumors were classified as epithelial (77%), sarcomatoid (10%), or mixed (9%) histology. Toxicity was mild; the most common grade 3/4 adverse events were neutropenia (2%), nausea (15%), elevated alanine aminotransferase (11%), hypertension (2%), and gastrointestinal bleeding (2%). Partial responses were observed in 6% of patients and stable disease in 72% of patients. The 3-month PFS rate was 55% (95% CI: 40%, 68%). The median PFS was 4.1 months. Median overall survival was 10.0 months. There was no correlation between serum levels of VEGF, PDGF, TSP-1, or mesothelin and treatment response, PFS, or survival. CONCLUSIONS: Vatalanib as a single agent with this dose and schedule does not warrant further study in this disease.