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.

N064A (Alliance): Phase II Study of Panitumumab, Chemotherapy, and External Beam Radiation in Patients with Locally Advanced Pancreatic Adenocarcinoma.

BACKGROUND: This North Central Cancer Treatment Group (NCCTG) N064A (Alliance) phase II trial evaluated upfront chemoradiotherapy incorporating the EGFR inhibitor panitumumab, followed by gemcitabine and panitumumab for unresectable, non-metastatic pancreatic cancer. METHODS: The treatment consisted of fluoropyrimidine and panitumumab given concurrently with radiotherapy followed by gemcitabine and panitumumab for 3 cycles followed by maintenance panitumumab. The primary endpoint was the 12-month overall survival (OS) rate and secondary endpoints included confirmed response rate (RR), OS, progression-free survival (PFS), and adverse events. Enrollment of 50 patients was planned and the study fully accrued. RESULTS: Fifty-two patients were enrolled, but only 51 were treated and included in the analysis. The median age of patients was 65 years and 54.9% were women. Twenty-two patients received at least 1 cycle of systemic therapy following radiotherapy, but 29 patients received chemoradiotherapy only without receiving subsequent chemotherapy after completion of chemoradiotherapy. The overall RR was 5.9% (95% CI: 1.2%-16.2%). The 12-month OS rate was 50% (95% CI: 38%-67%) which fell short of the per-protocol goal for success (51.1%). The median PFS was 7.4 months (95% CI: 4.5-8.6) and the median OS was 12.1 months (95% CI 7.9-15.9). Grade 3 or higher adverse events were reported by 88%. CONCLUSION: The combination of panitumumab, chemotherapy, and external beam radiation therapy was associated with very high rates of grades 3-4 toxicities and survival results did not meet the trial's goal for success. This regimen is not recommended for further study (ClinicalTrials.gov Identifier NCT00601627).

Induction versus no induction chemotherapy before neoadjuvant chemoradiotherapy and surgery in oesophageal adenocarcinoma: a multicentre randomised phase II trial (NCCTG N0849 [Alliance]).

AIM: report primary results from the first multicentre randomised trial evaluating induction chemotherapy prior to trimodality therapy in patients with oesophageal or gastro-oesophageal junction adenocarcinoma. Notably, recent data from a single-institution randomised trial reported that induction chemotherapy prolonged overall survival (OS) in patients with well/moderately differentiated tumours. METHODS: In this phase 2 trial (28 centres in the U.S. NCI-sponsored North Central Cancer Treatment Group [Alliance]), trimodality-eligible patients (T3-4N0, TanyN+) were randomised to receive induction (docetaxel, oxaliplatin, capecitabine; Arm A) or no induction chemotherapy (Arm B) followed by oxaliplatin/5-fluorouracil/radiation and subsequent surgery. The primary endpoint was the rate of pathologic complete response (pathCR). Secondary/exploratory endpoints were OS and disease-free survival (DFS). RESULTS: Of 55 patients evaluable for the primary endpoint, the pathCR rate was 28.6% (8/28) in A versus 40.7% (11/27) in B (P = .34). Given interim results indicating futility, accrual was terminated, but patients were followed. After a median follow-up of 60.4 months, a longer median OS in Arm A versus B was unexpectedly observed (3-year rates 57.1% versus 41.7%, respectively) driven by longer DFS after margin-free surgery. In posthoc analysis, induction (versus no induction) chemotherapy was associated with significantly longer OS and DFS among patients with well/moderately differentiated tumours, but not among patients with poorly/undifferentiated tumours (Pinteraction = 0.037). CONCLUSIONS: Adding induction chemotherapy prior to trimodality therapy did not improve the primary endpoint, pathCR. However, induction chemotherapy was associated with longer median OS, particularly among patients with well/moderately differentiated tumours. These findings may inform further development of curative-intent trials in this disease.

Real-world outcomes associated with liposomal irinotecan dose reductions in metastatic pancreatic ductal adenocarcinoma.

Aim: This study sought to understand the association between liposomal irinotecan dose reductions (DRs) and clinical outcomes among patients with metastatic pancreatic ductal adenocarcinoma. Materials & methods: A retrospective study of adult patients with metastatic pancreatic ductal adenocarcinoma treated with liposomal irinotecan in the Flatiron Health database was conducted to assess treatment and clinical outcomes. Results: DRs occurred in 28.4% of the 320 patients in the study. Patients with DRs had longer overall survival (7.7 [95% CI: 6.2-10.2]) vs 3.6 [3.2-4.1] months) and time to discontinuation (4.2 [3.0-4.9] vs 1.4 [1.0-1.5] months) than patients without DRs. Results were consistent in a validation analysis requiring three cycles of treatment. Conclusion: Liposomal irinotecan DRs were associated with improved clinical outcomes compared with patients without DRs.

A comparison of teaching opportunities for rural and urban family medicine residents.

CONTEXT: Medical schools of geographically large nations have expanded into rural areas to facilitate the development of a sustainable rural pipeline of physicians. Preceptor, or clinical teacher, recruitment at these sites has been an ongoing challenge. However, residents-as-teachers (RaT) curricula have not been modified to support the development of rural teachers. This study aimed to compare teaching opportunities between rural and urban family medicine residents and to identify mechanisms underlying potential differences. METHODS: Year-1 and Year-2 family medicine residents at seven Canadian institutions participated in a mixed-methods study utilising a quantitative survey and a qualitative interview. Rural and urban residents rated the quantity and types of teaching opportunities available during their training, from which a chi-squared analysis was completed. Volunteer respondents participated in a structured interview, from which a thematic analysis was performed. RESULTS: Rural family medicine residents had fewer opportunities to teach compared to their urban colleagues. This discrepancy was seen across multiple domains, including informal opportunities when on family medicine rotations, χ2 (4, n = 242) = 45.26, P < .000, Bonferroni's adjusted P < .000. Thematic analysis centred around determining factors influencing teaching opportunities and identified that the academic context, personal factors and programme factors were key dimensions. Within these dimensions, the number of medical students, a desire to be an educator and administrative support were cited as influences on teaching opportunities. CONCLUSIONS: The lack of teaching opportunities for rural trainees is attributable to a combination of practical and organisational factors revealed through thematic analysis. If rural graduates are not comfortable balancing the demands of service and teaching, this could compound the already prevalent issue of rural preceptor recruitment. It is essential to develop a rural-focused RaT curriculum to close this gap and produce competent educators who are ready to inspire generations of rural physicians.

Phase 1 trial of Vismodegib and Erlotinib combination in metastatic pancreatic cancer.

BACKGROUND/OBJECTIVES: Interplay between the Hedgehog (HH) and epidermal growth factor receptor (EGFR) pathways modulating the outcome of their signaling activity have been reported in various cancers including pancreatic ductal adenocarcinoma (PDAC). Therefore, simultaneous targeting of these pathways may be clinically beneficial. This Phase I study combined HH and EGFR inhibition in metastatic PDAC patients. METHODS: Combined effects of HH and EGFR inhibition using Vismodegib and Erlotinib with or without gemcitabine in metastatic solid tumors were assessed by CT. Another cohort of patients with metastatic PDAC was evaluated by FDG-PET and tumor biopsies-derived biomarkers. RESULTS: Treatment was well tolerated with the maximum tolerated dose cohort experiencing no grade 4 toxicities though 25% experienced grade 3 adverse effects. Recommended phase II dose of Vismodegib and Erlotinib were each 150 mg daily. No tumor responses were observed although 16 patients achieved stable disease for 2-7 cycles. Paired biopsy analysis before and after first cycle of therapy in PDAC patients showed reduced GLI1 mRNA, phospho-GLI1 and associated HH target genes in all cases. However, only half of the cases showed reduced levels of desmoplasia or changes in fibroblast markers. Most patients had decreased phospho-EGFR levels. CONCLUSIONS: Vismodegib and Erlotinib combination was well-tolerated although overall outcome in patients with metastatic PDAC was not significantly impacted by combination treatment. Biomarker analysis suggests direct targets inhibition without significantly affecting the stromal compartment. These findings conflict with pre-clinical mouse models, and thus warrant further investigation into how upstream inhibition of these pathways is circumvented in PDAC.

A Phase II Randomized Trial of Panitumumab, Erlotinib, and Gemcitabine Versus Erlotinib and Gemcitabine in Patients with Untreated, Metastatic Pancreatic Adenocarcinoma: North Central Cancer Treatment Group Trial N064B (Alliance).

LESSONS LEARNED: Dual epidermal growth factor receptor (EGFR)-directed therapy with erlotinib and panitumumab in combination with gemcitabine was superior to gemcitabine and erlotinib, but the clinical relevance is uncertain given the limited role of gemcitabine monotherapy.A significantly longer overall survival was observed in patients receiving the dual EGFR-directed therapy.The dual EGFR-directed therapy resulted in increased toxicity. BACKGROUND: Gemcitabine is active in patients with advanced pancreatic adenocarcinoma. The combination of erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, and gemcitabine was shown to modestly prolong overall survival when compared with gemcitabine alone. The North Central Cancer Treatment Group (now part of Alliance for Clinical Trials in Oncology) trial N064B compared gemcitabine plus erlotinib versus gemcitabine plus combined EGFR inhibition with erlotinib and panitumumab. METHODS: Eligible patients with metastatic adenocarcinoma of the pancreas were randomized to either gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle with erlotinib 100 mg p.o. daily (Arm A) or the same combination with the addition of panitumumab 4 mg/kg on days 1 and 15 of a 28-day cycle (Arm B). The primary endpoint of the trial was overall survival. Secondary endpoints included progression-free survival, the confirmed response rate, and toxicity. Comparison between arms for the primary endpoint was done with a one-sided log-rank test, and a p value less than .20 was considered statistically significant. Response rate comparison was done with Fisher's exact test. All other reported p values are two-sided. RESULTS: A total of 92 patients were randomized, 46 to each arm. The median overall survival was 4.2 months in Arm A and 8.3 months in Arm B (hazard ratio, 0.817; 95% confidence interval [CI], 0.530-1.260; p = .1792). The progression-free survival was 2.0 months in Arm A and 3.6 months in Arm B (hazard ratio, 0.843; 95% CI, 0.555-1.280; p = .4190). A partial confirmed response was seen in 8.7% of patients on Arm A and 6.5% on Arm B (p = .9999). No patients had a complete response. Grade 3 and higher nonhematologic toxicities were more common in patients on Arm B compared with those on Arm A (82.6% vs. 52.2%; p = .0018). CONCLUSION: Dual EGFR-directed therapy resulted in a significant prolongation of overall survival in patients with advanced adenocarcinoma of the pancreas but was associated with substantially increased toxicities. Dual EGFR-directed therapy in combination with gemcitabine alone cannot be recommended for further study, as single-agent gemcitabine is no longer considered an appropriate therapy for otherwise fit patients with metastatic pancreatic cancer.

A Randomized, Double-Blind, Placebo-Controlled Phase II Study of the Efficacy and Safety of Monotherapy Ontuxizumab (MORAb-004) Plus Best Supportive Care in Patients with Chemorefractory Metastatic Colorectal Cancer.

Purpose: The purpose of this study was to evaluate the safety and efficacy of ontuxizumab (MORAb-004), a monoclonal antibody that interferes with endosialin (tumor endothelial marker-1) function, in patients with chemorefractory metastatic colorectal cancer and to identify a responsive patient population based on biomarkers.Experimental Design: This was a randomized, double-blind, placebo-controlled, phase II study. Patients were randomly assigned in a 2:1 ratio to receive weekly intravenous ontuxizumab (8 mg/kg) or placebo plus best supportive care until progression or unacceptable toxicity. Tissue and blood biomarkers were evaluated for their ability to identify a patient population that was responsive to ontuxizumab.Results: A total of 126 patients were enrolled. No significant difference between the ontuxizumab and placebo groups was evident for the primary endpoint of progression-free survival (PFS), with a median PFS of 8.1 weeks in each group (HR, 1.13; 95% confidence interval, 0.76-1.67; P = 0.53). There were no significant differences between groups for overall survival (OS) or overall response rate (ORR). The most common treatment-emergent adverse events (TEAEs) in the ontuxizumab group (vs. the placebo group, respectively) were fatigue (53.7% vs. 47.5%), nausea (39.0% vs. 35.0%), decreased appetite (34.1% vs. 27.5%), and constipation (28.0% vs. 32.5%). The most common grade 3/4 TEAE in the ontuxizumab group versus placebo was back pain (11.0% vs. 0%). No single biomarker clearly identified patients responsive to ontuxizumab.Conclusions: No benefit with ontuxizumab monotherapy compared with placebo for clinical response parameters of PFS, OS, or ORR was demonstrated. Ontuxizumab was well tolerated. Clin Cancer Res; 24(2); 316-25. ©2017 AACR.

Comparison of treatment patterns, resource utilization, and cost of care in patients with metastatic pancreatic cancer treated with first-line nab-paclitaxel plus gemcitabine or FOLFIRINOX.

BACKGROUND: We compared real-world treatment patterns, resource utilization, and cost of care for patients with metastatic pancreatic cancer treated with first-line nab-paclitaxel + gemcitabine or FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin). METHODS: This was a retrospective study of inpatient and hospital-based outpatient data in the United States. Primary endpoints included median time to treatment discontinuation (TTD) and total cost of care per patient per month. Secondary endpoints included supportive care costs and hospitalization rate and length. RESULTS: Overall, 345 patients were included (nab-paclitaxel + gemcitabine, n = 182; FOLFIRINOX, n = 163). Median TTD was significantly longer with nab-paclitaxel + gemcitabine vs FOLFIRINOX (4.3 vs 2.8 months; P = .0009). Mean acquisition cost was higher with nab-paclitaxel + gemcitabine ($10,643 vs $6549; P = .0043), but mean total cost of care was lower ($16,628 vs $19,936; P = .1740). Supportive care cost was significantly lower with nab-paclitaxel + gemcitabine ($1995 vs $6456; P < .0001). Hospitalization rate and length were both significantly lower with nab-paclitaxel + gemcitabine. CONCLUSIONS: Despite higher acquisition costs with nab-paclitaxel + gemcitabine, FOLFIRINOX-treated patients had higher total costs driven by supportive care. Toxicity-related costs and drug acquisition costs should be considered when evaluating total cost of care.

Phase I Study of DMOT4039A, an Antibody-Drug Conjugate Targeting Mesothelin, in Patients with Unresectable Pancreatic or Platinum-Resistant Ovarian Cancer.

DMOT4039A, a humanized anti-mesothelin mAb conjugated to the antimitotic agent monomethyl auristatin E (MMAE), was given to patients with pancreatic and ovarian cancer every 3 weeks (0.2-2.8 mg/kg; q3w) or weekly (0.8-1.2 mg/kg). A 3+3 design was used for dose escalation followed by expansion at the recommended phase II dose (RP2D) to evaluate safety and pharmacokinetics. Antitumor response was evaluated per RECIST 1.1 and serum CA19-9 or CA125 declines. Tumor mesothelin expression was determined by IHC. Seventy-one patients (40 pancreatic cancer; 31 ovarian cancer) were treated with DMOT4039A. For the q3w schedule (n = 54), the MTD and RP2D was 2.4 mg/kg, with dose-limiting toxicities of grade 3 hyperglycemia and grade 3 hypophosphatemia at 2.8 mg/kg. For the weekly schedule (n = 17), the maximum assessed dose was 1.2 mg/kg, with further dose escalations deferred because of toxicities limiting scheduled retreatment in later cycles, and therefore the RP2D level for the weekly regimen was determined to be 1 mg/kg. Across both schedules, the most common toxicities were gastrointestinal and constitutional. Treatment-related serious adverse events occurred in 6 patients; 4 patients continued treatment following dose reductions. Drug exposure as measured by antibody-conjugated MMAE and total antibody was generally dose proportional over all dose levels on both schedules. A total of 6 patients had confirmed partial responses (4 ovarian; 2 pancreatic) with DMOT4039A at 2.4 to 2.8 mg/kg i.v. q3w. DMOT4039A administered at doses up to 2.4 mg/kg q3w and 1.0 mg/kg weekly has a tolerable safety profile and antitumor activity in both pancreatic and ovarian cancer.

Phase II trial of gemcitabine and tanespimycin (17AAG) in metastatic pancreatic cancer: a Mayo Clinic Phase II Consortium study.

OBJECTIVES: Heat Shock Protein 90 (HSP90) is a molecular chaperone that stabilizes many oncogenic proteins. HSP90 inhibitors may sensitize tumors to cytotoxic agents by causing client protein degradation. Gemcitabine, which has modest activity in pancreas cancer, activates Chk1, a client protein of HSP90. This phase II trial was designed to determine whether 17AAG could enhance the clinical activity of gemcitabine through degradation of Chk1 in patients with stage IV pancreatic cancer. METHODS: A multicenter, prospective study combining gemcitabine and 17AAG enrolled patients with stage IV pancreatic adenocarcinoma, adequate liver and kidney function, ECOG performance status 0-2, and no prior chemotherapy for metastatic disease. The primary goal was to achieve a 60 % overall survival at 6 months. Sixty-six patients were planned for accrual, with an interim analysis after 25 patients enrolled. RESULTS: After a futility analysis to achieve the endpoint, accrual was halted with 21 patients enrolled. No complete or partial responses were seen. Forty percent of patients were alive at 6 months. Median overall survival was 5.4 months. Tolerability was moderate, with 65 % of patients having ≥ grade 3 adverse events (AE), and 15 % having grade 4 events. CONCLUSIONS: The lack of clinical activity suggests that targeting Chk1 by inhibiting HSP90 is not important in pancreatic cancer sensitivity to gemcitabine alone. Further studies of HSP90 targeted agents with gemcitabine alone are not warranted.

Use of Adjuvant Cisplatin-Based Versus Carboplatin-Based Chemotherapy in Non-Small-Cell Lung Cancer: Findings From the Florida Initiative for Quality Cancer Care.

PURPOSE: For patients with resected non-small-cell lung cancer, national guidelines recommend cisplatin-based doublet chemotherapy as the preferred treatment. However, many patients receive a carboplatin-based regimen instead. We aimed to identify factors associated with use of a cisplatin-based regimen and explore its association with other quality-of-care measures. METHODS: This analysis was part of the Florida Initiative for Quality Cancer Care, an audit and feedback project among 11 medical oncology practices. Feedback-sharing sessions based on findings of year 2006 took place in 2008. Eligible patients were random samples of those with resected stage I to III non-small-cell lung cancer treated in 2006 and 2009. RESULTS: In both years combined, 81 patients received adjuvant platinum-based doublets: 33 patients (41%) received cisplatin, and 48 patients (59%) received carboplatin. Use of a cisplatin-based doublet significantly increased in 2009 compared with 2006, from 24% to 56% (P = .006). Multivariable analysis determined that academic practices used cisplatin more frequently than nonacademic practices (odds ratios, 3.26; 95% CI, 1.19 to 8.91; P = .02). Moreover, patients treated in 2009 were more likely to receive cisplatin than those treated in 2006 (odds ratio, 4.89; 95% CI, 1.75 to 13.67; P = .002). No significant association between use of cisplatin and other quality-of-care measures was found. CONCLUSION: In this study, academic practice status and treatment year predicted use of adjuvant cisplatin-based chemotherapy. The increase in use of cisplatin in 2009, as compared with 2006, suggests that audit and feedback may be effective ways to promote such use.

KRAS as a predictor of poor prognosis and benefit from postoperative FOLFOX chemotherapy in patients with stage II and III colorectal cancer.

PURPOSE: The KRAS gene frequently mutates in colorectal cancer (CRC). Here we investigated the prognostic and predictive role of KRAS mutation in patients with stage II or III CRC. EXPERIMENTAL DESIGN: A consecutive cohort of patients with stage II or III CRC from a single center database was studied. The association between KRAS status, adjuvant FOLFOX therapy, and 3-year disease-free survival (3-y DFS) was analyzed. RESULTS: Of our 433 patients, 166 (38.3%) exhibited the KRAS mutation. Among the 190 patients who did not receive adjuvant therapy, those with KRAS mutation tumors had a worse 3-y DFS (hazard ratio [HR], 1.924; 95% confidence interval [CI], 1.078-3.435; P = 0.027). Among patients who received adjuvant chemotherapy, KRAS mutation was not correlated with worse 3-y DFS (HR, 1.083; 95% CI, 0.618-1.899; P = 0.781). Adjuvant chemotherapy improved 3-y DFS only among patients with KRAS mutant tumors (78.0% vs 69.2%) on multivariate analysis adjusted for age, stage, grade, site, vessel invasion, and carcinoembryonic antigen level (HR, 0.454; 95% CI, 0.229-0.901; P = 0.024). In contrast, there was no benefit of adjuvant chemotherapy in the KRAS wild-type group (84.3% vs 82.0%). CONCLUSIONS: KRAS mutation indicates poor prognosis. FOLFOX adjuvant chemotherapy benefits patients with stage II or III colorectal cancer with KRAS mutant tumors and is worth further investigation.

Comparative economics of a 12-gene assay for predicting risk of recurrence in stage II colon cancer.

BACKGROUND: Prior economic analysis that compared the 12-gene assay to published patterns of care predicted the assay would improve outcomes while lowering medical costs for stage II, T3, mismatch-repair-proficient (MMR-P) colon cancer patients. This study assessed the validity of those findings with real-world adjuvant chemotherapy (aCT) recommendations from the US third-party payer perspective. METHODS: Costs and quality-adjusted life-years (QALYs) were estimated for stage II, T3, MMR-P colon cancer patients using guideline-compliant, state-transition probability estimation methods in a Markov model. A study of 141 patients from 17 sites in the Mayo Clinic Cancer Research Consortium provided aCT recommendations before and after knowledge of the 12-gene assay results. Progression and adverse events data with aCT regimens were based on published literature. Drug and administration costs for aCT were obtained from 2014 Medicare Fee Schedule. Sensitivity analyses evaluated the drivers and robustness of the primary outcomes. RESULTS: After receiving the 12-gene assay results, physician recommendations in favor of aCT decreased 22 %; fluoropyrimidine monotherapy and FOLFOX recommendations each declined 11 %. Average per-patient drugs, administration, and adverse events costs decreased $US2,339, $US733, and $US3,211, respectively. Average total direct medical costs decreased $US991. Average patient well-being improved by 0.114 QALYs. Savings are expected to persist even if the cost of oxaliplatin drops by >75 % due to generic substitution. CONCLUSIONS: This study provides evidence that real-world changes in aCT recommendations due to the 12-gene assay are likely to reduce direct medical costs and improve well-being for stage II, T3, MMR-P colon cancer patients.

Changes in the care of non-small-cell lung cancer after audit and feedback: the Florida initiative for quality cancer care.

PURPOSE: Audit and feedback have been widely used to enhance the performance of various medical practices. Non-small-cell lung cancer (NSCLC) is one of the most common diseases encountered in medical oncology practice. We investigated the use of audit and feedback to improve the care of NSCLC. METHODS: Medical records were reviewed for patients with NSCLC first seen by a medical oncologist in 2006 (n = 518) and 2009 (n = 573) at 10 oncology practices participating in the Florida Initiative for Quality Cancer Care. In 2008, feedback from 2006 audit results was provided to practices, which then independently undertook steps to improve their performance. Sixteen quality-of-care indicators (QCIs) were evaluated on both time points and were examined for changes in adherence over time. RESULTS: A statistically significant increase in adherence was observed for five of 16 QCIs. Adherence to brain staging using magnetic resonance imaging or computed tomography scan for stage III NSCLC (57.8% in 2006 v 82.8% in 2009; P = .001), availability of chemotherapy flow sheet (89.2% v 97.0%; P < .001), documentation of performance status for stage III and IV disease (43.4% v 51.3%; P < .001), availability of pathology report for patients undergoing surgery (95.2% v 99.2%; P = .02), and availability of signed chemotherapy consent (69.5% v 76.3%; P = .04). There were no statistically significant decreases in adherence on any QCIs. CONCLUSION: Audit with feedback was associated with a modest but important improvement in the treatment of NSCLC. Whether these changes are durable will require long-term follow-up.

Phase I trial of everolimus, gemcitabine and cisplatin in patients with solid tumors.

BACKGROUND: A Phase I trial of the 2-drug regimen of everolimus plus gemcitabine (Cohort I) and the 3-drug regimen of everolimus plus gemcitabine and cisplatin (Cohort II) was performed to determine the maximally tolerated dose (MTD) of both combinations. An expansion cohort (Cohort III) of patients with cholangiocarcinoma or gallbladder carcinoma was treated at the MTD. METHODS: A standard 3 + 3 design dose escalation was used. Everolimus was given on Monday/Wednesday/Friday or daily depending upon the dose level. Gemcitabine and cisplatin were administered on days 1 and 8 of each 21 day cycle. RESULTS: Twelve patients were entered in Cohort I and 15 in Cohort II. The MTD for Cohort I was everolimus 5 mg on Monday/Wednesday/Friday and gemcitabine 800 mg/m(2). For Cohort II, it was everolimus 5 mg on Monday/Wednesday/Friday, gemcitabine 600 mg/m(2), and cisplatin 12.5 mg/m(2). All DLTs in this study were hematologic. Complete responses (CR) were seen in a patient with primary peritoneal carcinoma and another with recurrent pancreatic cancer. Partial responses (PR) were seen in 3 patients: breast, ampullary carcinoma and pheochromocytoma. Of 10 patients enrolled in Cohort III, six patients had stable disease and 4 had progressive disease. CONCLUSIONS: This Phase I clinical trial has demonstrated that these 2-drug and 3-drug combinations are generally well tolerated and safely administered. The main DLTs in both regimens were hematologic, specifically thrombocytopenia. The 3-drug combination can be considered as a platform for future studies in specific tumor types.

Should combination chemotherapy serve as the backbone in clinical trials of advanced pancreatic cancer? A pooled analysis of phase II trials of gemcitabine-containing doublets plus bevacizumab.

OBJECTIVE: The objective of this study was to evaluate whether building upon multidrug chemotherapy regimens represents a viable strategy in pancreatic cancer clinical trial design. METHODS: We performed a pooled analysis of all single-arm phase II studies in which a specific targeted agent (the anti-vascular endothelial growth factor monoclonal antibody bevacizumab) was added to gemcitabine-based cytotoxic doublets. The primary end point was overall survival (OS). Secondary end points included objective response rate, CA-19-9 biomarker response rate, and adverse event frequencies. Kaplan-Meier methods estimated time-to-event end points, whereas the Cox proportional hazard model estimated univariate hazard ratios of death. RESULTS: For the 300 patients included in the pooled analysis, median OS was 9.1 months (95% confidence interval, 8.3-10.2). Differences in OS were observed according to patients' baseline performance status (median OS, 10.4 vs 8.6 months for Eastern Cooperative Oncology Group 0 vs 1, respectively). Moreover, bevacizumab-related adverse events were not observed at increased frequency with gemcitabine-based doublets compared with historic data. CONCLUSIONS: Recognizing the limitations of cross-study comparisons, these results compare favorably to those from Cancer and Leukemia Group B 80303, a phase III trial testing bevacizumab in combination with gemcitabine alone. This is the largest data set available to demonstrate the feasibility of building upon more intensive chemotherapy backbones in clinical trials of novel targeted agents in pancreatic cancer.

Complications after 90Y microsphere radioembolization for unresectable hepatic tumors: An evaluation of 112 patients.

PURPOSE: The aim of this study was to estimate the incidence of complications after (90)Y microsphere radioembolization for unresectable hepatic tumors and evaluate risk factors for late complications. METHODS AND MATERIALS: A cohort of 112 consecutive patients from two institutions underwent (90)Y microsphere radioembolization for unresectable hepatic tumors. Complications were graded according to the Common Terminology Criteria for Adverse Events, version 3.0. Symptoms secondary to postradioembolization syndrome occurring within 30 days were recorded as early complications, and all other complications were considered late complications. RESULTS: Seventy-eight patients (70%) experienced postradioembolization syndrome, including fatigue, abdominal pain, nausea, vomiting, anorexia, or fever. Three patients (3%) experienced a Grade 3 early complication; no Grade 4 or 5 early toxicity occurred. Two patients (2%) experienced clinically significant liver dysfunction; 13 patients (12%), 27 patients (24%), and 9 patients (8%) had an elevation of bilirubin, aspartate aminotransferase, and alanine aminotransferase, respectively. Eleven patients (10%) experienced gastrointestinal ulceration, including two Grade 3 complications and one Grade 4 complication. Cholecystitis occurred in 7 patients (6%), including two Grade 3 complications. Grade 2 pancreatitis occurred in 1 patient (1%). No radiation pneumonitis was observed. The cumulative incidence of late Grade 3 or 4 complications at 12 months after radioembolization was 8%. No Grade 5 toxicity occurred. CONCLUSIONS: (90)Y microsphere radioembolization is a well-tolerated treatment for unresectable hepatic tumors with a low risk of Grade 3 or higher early or late toxicity.

A phase 2 trial of ixabepilone plus cetuximab in first-line treatment of metastatic pancreatic cancer.

BACKGROUND: The aim of this phase 2 study was to evaluate the safety and efficacy of ixabepilone plus cetuximab in patients with advanced pancreatic cancer. METHODS: Eligible patients had advanced pancreatic adenocarcinoma that was metastatic or not amenable to resection, a Karnofsky performance status ≥70%, and no prior therapy for advanced disease. Patients received ixabepilone 32 mg/m(2) (3-hour IV infusion) every 3 weeks and cetuximab 250 mg/m(2) (1-hour IV infusion) weekly. The primary efficacy end point was the 6-month survival rate. Secondary end points included tumor response rate, overall survival, progression-free survival, and tolerability. RESULTS: A total of 54 patients were enrolled on this study. The 6-month survival rate was 57% (31/54: 95% CI: 43-71%) with a median overall survival of 7.6 months (95% CI: 5.5-12.2 months). Patients who developed acneiform rash (n = 36) had a median survival of 8.8 months, compared with 2.6 months for those without rash (n = 18). Of 31 patients with measurable disease (defined as response-evaluable), 4 had confirmed partial responses and an additional 24 had stable disease. The combination was generally well-tolerated with the most common grade 3/4 hematological toxicities being leucopenia (39%) and neutropenia (33%). The most common grade 3/4 nonhematologic toxicity was fatigue (17%). CONCLUSIONS: The combination of ixabepilone and cetuximab was active and had acceptable toxicity. The efficacy results are similar to single-agent ixabepilone and gemcitabine-based combination therapies in patients with advanced pancreatic cancer. Exploratory analyses suggest a trend toward improved survival for patients who experienced rash.