Patients with tumors that have high gene expression levels of epiregulin and amphiregulin and patients with wild-type K-ras are more likely to have disease control on cetuximab treatment. The identified markers could be developed further to select patients for cetuximab therapy.

Background-Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the intestinal tract. The standard treatment of localized, primary GIST has been surgical resection alone. Most GISTs have a mutation in the KIT proto-oncogene, or less commonly in platelet-

Background Pancreatic ductal adenocarcinoma utilizes the CCL2/CCR2 chemokine axis to facilitate recruitment of tumor associated macrophages to sculpt an immunosuppressive tumor microenvironment. This pathway has prognostic implications in pancreas cancer, and blockade of CCR2 restores anti-tumor immunity in pre-clinical models. This provided the rationale for a clinical study in pancreatic adenocarcinoma to determine the safety and recommended phase 2 oral dosage of the CCR2 inhibitor PF-04136309 in combination with chemotherapy (FOLFIRINOX). Methods In this single-center, open label, phase Ib clinical trial patients age ≥ 18 years with treatment naïve borderline resectable or locally advanced, biopsy-proven pancreatic ductal adenocarcinoma, Eastern Cooperative Oncology Group performance status <2, measurable disease by Response Evaluation Criteria in Solid Tumors Version 1.1, and normal end organ function were eligible for enrollment. FOLFIRINOX (oxaliplatin, 85 mg/m2; irinotecan, 180 mg/m2; leucovorin, 400 mg/m2, and bolus fluorouracil 400 mg/m2 followed by 2,400 mg/m2 46 hour continuous infusion) was administered every 2 weeks for a total of six treatment cycles. To determine the recommended phase 2 dose, PF-04136309 was orally administered at a starting dose of 500 mg twice daily in a standard 3+3 dose de-escalation design with an expansion phase planned at the recommended phase 2 dose. Both FOLFIRINOX and PF-04136309 were simultaneously initiated with a total treatment duration of 3 months. The primary endpoints were to determine the recommended phase 2 dose and toxicity of PF-04136309 in combination with FOLFIRINOX. All patients in the dose de-escalation and expansion phase received the recommended phase 2 dose of PF-04136309 were combined for assessment of treatment toxicity by an intention to treat analysis. For tissue specimen comparison in corollary studies, a group of patients receiving FOLFIRINOX alone were enrolled and evaluated for treatment related toxicity. This study has been completed and is registered at ClinicalTrials.gov; number NCT01413022. Results From April 19th, 2012 through November 12th, 2014 a total of 47 patients were enrolled. The dose de-escalation group (n=6) received PF-04136309 at 500 mg administered orally twice daily. No dose-limiting toxicities were observed and this was established as the recommended phase 2 dose. The expansion phase cohort (n=33) and patients in the dose de-escalation arm receiving PF-04136309 at the recommended phase 2 dose (n=6) were combined for assessment of treatment related toxicity. No therapy related deaths occurring during the study interval. Early termination as the result of treatment related toxicity occurred in 2 of the 39 patients (5%) in the FOLFIRINOX plus PF-04136309 arm. Grade ≥3 adverse events reported in ≥10% of the patients receiving PF-04136309 included neutropenia in 27 patients (69%), febrile neutropenia in 7 patients (18%), lymphopenia in 4 patients (10%), diarrhea in 6 patients (15%), and hypokalemia in 7 patients (18%). Among...

Multidrug resistance (MDR), whereby tumor cells simultaneously possess intrinsic or acquired cross-resistance to diverse chemotherapeutic agents, hampers the effective treatment of cancer. Molecular investigations in MDR resulted in the isolation and characterization of genes coding for several proteins associated with MDR, including P-glycoprotein (P-gp), the multidrug resistance associated protein (MRP1), the lung resistance protein (LRP), and, more recently, the breast cancer resistance protein (BCRP). These transmembrane proteins cause MDR either by decreasing the total intracellular retention of drugs or redistributing intracellular accumulation of drugs away from target organelles. These proteins are expressed at varying degrees in different neoplasms, including the AIDS-associated non-Hodgkin lymphoma and Kaposi sarcoma and are generally associated with poor prognosis. Several MDR-reversing agents are in various stages of clinical development. First-generation modulators such as verapamil, quinidine, and cyclosporin required high doses of drugs to reverse MDR and were associated with unacceptable toxicities. Second- and third-generation MDR inhibitors include PSC 833, GF120918, VX-710, and LY335979, among others. Limitations to the use of these modulators include multiple and redundant cellular mechanisms of resistance, alterations in pharmacokinetics of cytotoxic agents, and clinical toxicities. Studies to validate the role of MDR reversal in the treatment of various malignancies are underway. A potential use of these agents may be to enhance intestinal drug absorption and increase drug penetration to biologically important protective barriers, such as the blood-brain, blood-cerebrospinal fluid, and the maternal-fetal barriers. The use of MDR modulators with drugs such as the antiviral protease inhibitors and cytotoxics may enhance drug accumulation in sanctuary sites that are traditionally impenetrable to these agents.

cholangiocarcinoma (IHC) carries a poor prognosis, with a median overall survival (OS) of 11 months. Hepatic arterial infusion (HAI) of high-dose chemotherapy may have potential benefit in these patients.OBJECTIVE To evaluate clinical outcomes when HAI chemotherapy is combined with systemic chemotherapy in patients with unresectable IHC. DESIGN, SETTING, AND PARTICIPANTSA single-institution, phase 2 clinical trial including 38 patients was conducted with HAI floxuridine plus systemic gemcitabine and oxaliplatin in patients with unresectable IHC at Memorial Sloan Kettering Cancer Center between May 20, 2013, and June 27, 2019. A confirmatory phase 1/2 study using the same therapy was conducted during the same time period at Washington University in St Louis. Patients with histologically confirmed, unresectable IHC were eligible. Resectable metastatic disease to regional lymph nodes and prior systemic therapy were permitted. Patients with distant metastatic disease were excluded.INTERVENTIONS Hepatic arterial infusion of floxuridine and systemic administration of gemcitabine and oxaliplatin. MAIN OUTCOMES AND MEASURESThe primary outcome was progression-free survival (PFS) of 80% at 6 months. RESULTSFor the phase 2 clinical trial at Memorial Sloan Kettering Cancer Center, 42 patients with unresectable IHC were included and, of these, 38 patients were treated (13 [34%] men; median [range] age at diagnosis, 64 [39-81] years). The median follow-up was 30.5 months. Twenty-two patients (58%) achieved a partial radiographic response, and 32 patients (84%) achieved disease control at 6 months. Four patients had sufficient response to undergo resection, and 1 patient had a complete pathologic response. The median PFS was 11.8 months (1-sided 90% CI, 11.1) with a 6-month PFS rate of 84.1% (90% CI, 74.8%-infinity), thereby meeting the primary end point (6-month PFS rate, 80%). The median OS was 25.0 months (95% CI, 20.6-not reached), and the 1-year OS rate was 89.5% (95% CI, 80.2%-99.8%). Patients with resectable regional lymph nodes (18 [47%]) showed no difference in OS compared with patients with node-negative disease (24-month OS: lymph node negative: 60%; 95% CI, 40%-91% vs lymph node positive: 50%; 95% CI, 30%-83%; P = .66). Four patients (11%) had grade 4 toxic effects requiring removal from the study (1 portal hypertension, 2 gastroduodenal artery aneurysms, 1 infection in the pump pocket). Subgroup analysis showed significant improvement in survival in patients with IDH1/2 mutated tumors (2-year OS, 90%; 95% CI, 73%-99%) vs wild-type (2-year OS, 33%; 95% CI, 18%-63%) (P = .01). In the Washington University in St Louis confirmatory cohort, 9 patients (90%) achieved disease control at 6 months; the most common grade 3 toxic effect was elevated results of liver function tests, and median PFS was 12.8 months (1-sided 90% CI, 6.4). CONCLUSIONS AND RELEVANCEHepatic arterial infusion plus systemic chemotherapy appears to be highly active and tolerable in patients with unresectable IHC; further evaluation is warranted.

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Objectives Our purpose was to determine whether geriatric assessments are associated with completion of a chemotherapy course, grade III/IV toxicity or survival in older adults with cancer. Materials and Methods In this prospective cohort study, patients aged 65 years and older with colorectal, lung, or breast cancer or lymphoma completed a brief geriatric assessment prior to chemotherapy. Endpoints included completion of the planned number of chemotherapy cycles, grade III/IV toxicity and survival. Multivariate logistic regression determined which factors were independently associated with completion of therapy, grade III/IV toxicity or death. Results Sixty-five patients were enrolled in the study. The median age was 73 years (range 65–89). Geriatric syndromes were common, including depression (21.5%), dependence on others to carry out instrumental activities of daily living (38.5%) and activities of daily living (10.8%), and comorbidities (mild 47.7%, moderate 20%, severe 15.4%). Of the 65 participants, 67.6% completed the planned number of chemotherapy cycles. Curative intent therapy [OR 4.97 (95% CI 1.21–18.81)], Eastern Cooperative Oncology Group (ECOG) performance status 2–3 [OR 0.089 (0.015–0.53)] and renal function [OR 1.03 (1.00–1.06) per ml/min] were significantly associated with therapy completion. Furthermore, 31.1% experienced grade III/IV non-hematologic toxicity. Moderate to severe comorbidities significantly increased the risk of grade III/IV non-hematologic toxicity [OR 6.13 (1.65–22.74)]. Patients who received chemotherapy with curative intent had lower mortality [HR 0.15 (0.06–0.42)], while patients who reported a fall in the month prior to chemotherapy had an increased risk of death [HR 3.20 (1.13–9.11)]. Conclusions Geriatric assessment is associated with completion of a planned number of cycles of chemotherapy, grade III/IV non-hematologic toxicity and mortality.

The overall survival time after hepatic artery chemoembolization or HAE among patients with neuroendocrine tumors is approximately 3.5 years. The progression-free survival time approaches 1.5 years. The presence of extrahepatic metastasis or an unresected primary tumor should not limit the use of hepatic artery chemoembolization or HAE.