Kayla Rosati

Paclitaxel poliglumex, temozolomide, and radiation for newly diagnosed high-grade glioma: a Brown University Oncology Group Study.

Objectives:Paclitaxel poliglumex (PPX), a drug conjugate that links paclitaxel to poly-L-glutamic acid, is a potent radiation sensitizer. Prior studies in esophageal cancer have demonstrated that PPX (50 mg/m2/wk) can be administered with concurrent radiation with acceptable toxicity. The primary objective of this study was to determine the safety of the combination of PPX with temozolomide and concurrent radiation for high-grade gliomas. Methods:Eligible patients were required to have WHO grade 3 or 4 gliomas. Patients received weekly PPX (50 mg/m2/wk) combined with standard daily temozolomide (75 mg/m2) for 6 weeks with concomitant radiation (2.0 Gy, 5 d/wk for a total dose of 60 Gy). Results:Twenty-five patients were enrolled, 17 with glioblastoma and 8 with grade 3 gliomas. Seven of 25 patients had grade 4 myelosuppression. Hematologic toxicity lasted up to 5 months suggesting a drug interaction between PPX and temozolomide. For patients with glioblastoma, the median progression-free survival was 11.5 months and the median overall survival was 18 months. Conclusions:PPX could not be safely combined with temozolomide due to grade 4 hematologic toxicity. However, the favorable progression-free and overall survival suggest that PPX may enhance radiation for glioblastoma. A randomized study of single agent PPX/radiation versus temozolomide/radiation for glioblastoma without MGMT methylation is underway.

Complete Neoadjuvant Treatment for Rectal Cancer: The Brown University Oncology Group CONTRE Study.

Purpose: Following preoperative chemoradiation and surgery, many patients with stage II to III rectal cancer are unable to tolerate full-dose adjuvant chemotherapy. BrUOG R-224 was designed to assess the impact of COmplete Neoadjuvant Treatment for REctal cancer (CONTRE), primary chemotherapy followed by chemoradiation and surgery, on treatment delivery, toxicities, and pathologic response at surgery. Methods: Patients with clinical stage II to III (T3 to T4 and/or N1 to N2) rectal cancer received 8 cycles of modified FOLFOX6 followed by capecitabine 825 mg/m2 bid concurrent with 50.4 Gy intensity-modulated radiation therapy. Surgery was performed 6 to 10 weeks after chemoradiation. Results: Thirty-nine patients were enrolled between August 2010 and June 2013. Median age was 61 years (30 to 79 y); 7 patients (18%) were clinical stage II and 32 (82%) stage III. Thirty-six patients (92%) received all 8 cycles of mFOLFOX6, of whom 35 completed subsequent chemoradiation; thus 89% of patients received CONTRE as planned. No unexpected toxicities were reported. All patients had resolution of bleeding and improvement of obstructive symptoms, with no complications requiring surgical intervention. Pathologic complete response (ypT0N0) was demonstrated in 13 patients (33%; 95% CI, 18.24%-47.76%). Conclusions: CONTRE seems to be a well-tolerated alternative to the current standard treatment sequence. Evaluating its impact on long-term outcomes would require a large randomized trial, but using pathologic response as an endpoint, it could serve as a platform for assessing the addition of novel agents to preoperative treatment in stage II to III rectal cancer.

Lenalidomide for second-line treatment of advanced hepatocellular cancer: a Brown University oncology group phase II study.

Purpose:To assess the activity and toxicity of lenalidomide for patients with advanced hepatocellular cancer (HCC) previously treated with sorafenib. Materials and Methods:Patients with advanced HCC who progressed on or were intolerant to sorafenib were eligible. Patients received lenalidomide 25 mg orally for 1 to 21 days in a 28-day cycle until disease progression or unacceptable toxicities. Results:Forty patients were enrolled and were classified according to the Child-Pugh score: 19 were Child-Pugh A, 16 patients were Child-Pugh B, and 5 were Child-Pugh C. Seventeen patients had extrahepatic disease. Grade 4 neutropenia occurred in 1 of 40 patients (2.5%). Grade 3 fatigue (n=3) and rash (n=4) were the most common nonhematologic toxicities attributable to lenalidomide. Six of 40 patients (15%) had a partial response. Two patients (5%) have not progressed at 36 and 32 months. The median progression-free survival was 3.6 months and the median overall survival was 7.6 months. Conclusions:Lenalidomide can be administered to patients with advanced HCC and hepatic dysfunction. Promising, and in a small percentage of patients, durable activity has been demonstrated. Investigations are needed to explore the mechanism of action of lenalidomide in HCC.

FOLFOX+Nab-Paclitaxel (FOLFOX-A) for Advanced Pancreatic Cancer: A Brown University Oncology Research Group Phase I Study.

Background:The Brown University Oncology Research Group performed a phase I study to remove irinotecan from FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, and leucovorin) and substitute nab-paclitaxel. Methods:Patients with newly diagnosed advanced pancreatic adenocarcinoma were eligible. Patients received oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, and 5-fluorouracil 2400 mg/m2 with 3 dose levels of nab-paclitaxel (125, 150, and 175 mg/m2) every 2 weeks. Dose-limiting toxicities were assessed in the first 2 cycles of treatment. The final dose level was expanded to assess cumulative neurotoxicity. Results:Thirty-five patients were entered; 24 with metastatic and 11 with locally advanced pancreatic cancer. The maximum tolerated dose of nab-paclitaxel was 150 mg/m2 every 2 weeks with FOLFOX. Cumulative neuropathy was the most important toxicity. Grade 3 neuropathy developed in 2 of the first 6 patients at 10 and 11 cycles of FOLFOX-A. Following an amendment to reduce oxaliplatin to 65 mg/m2 if grade 2 neuropathy developed, no additional patients developed grade 3 neurotoxicity. Twenty-one of 35 patients (60%) had a partial response. The median survival for patients with metastatic disease was 15 months. Conclusions:The maximum tolerated dose of nab-paclitaxel is 150 mg/m2 every 2 weeks with FOLFOX. The regimen of FOLFOX-A represents a promising treatment for pancreatic cancer.

PPX and Concurrent Radiation for Newly Diagnosed Glioblastoma Without MGMT Methylation: A Randomized Phase II Study: BrUOG 244.

Purpose: Efficacy signals but substantial myelosuppression were demonstrated in a single arm phase II study of paclitaxel poliglumex (PPX) in combination with temozolomide (TMZ) and radiation therapy (RT) for first-line treatment of glioblastoma. The objective of this randomized phase II trial was to assess the efficacy and safety of single-agent PPX with RT (PPX/RT) versus TMZ with RT (TMZ/RT) for glioblastoma without O6-methylguanine-DNA methyltransferase (MGMT) methylation. Materials and Methods: Patients with glioblastoma with unmethylated MGMT without prior chemotherapy or RT were eligible. Patients were randomly assigned 2:1 to PPX, 50 mg/m2/wk for 6 weeks, or standard TMZ, with concurrent 60.0 Gy RT. One month after completion of chemoradiation all patients received standard maintenance TMZ. The primary endpoint was progression-free survival (PFS). Results: Of the 164 patients enrolled, 86 were MGMT unmethylated. Of these, 63 patients were randomized (42 to PPX/RT and 21 to TMZ/RT). Fifty-nine patients could be analyzed. The median PFS was 9 months in the PPX/RT group and 9.5 months in the TMZ/RT group (hazard ratio in the PPX/RT group, 1.10; 95% confidence interval, 0.79-2.08; P=0.75). Median overall survival was 16 versus 14.8 months for PPX/RT and TMZ/RT groups, respectively (hazard ratio, 1.44; 95% confidence interval, 0.75-2.77; P=0.27). In the PPX and TMZ groups 44% versus 22% of patients, respectively, experienced one or more grade 3 or higher toxicities during chemoradiation. Conclusions: PPX/RT did not improve PFS or overall survival. This study provides an effective trial design for screening RT sensitizers in glioblastoma.

Assessment of the effectiveness of a prechemotherapy teaching session: A Brown University Oncology Group study.

260 Background: Pre-chemotherapy teaching sessions, often coordinated by nursing personnel, are an opportunity to educate patients on treatment side effects, schedule, medications for toxicities such as nausea, and how to contact the oncology team if adverse events develop. Our institution provides a structured 60-minute nurse-coordinated pre-chemotherapy teaching session. The aims of this study were to evaluate whether pre-chemotherapy teaching sessions improve patient knowledge, preparedness, and anxiety in relation to chemotherapy. METHODS Patients were offered the opportunity to participate in the study after their medical oncologist had reviewed their treatment regimen. After informed consent was obtained, participants were administered a 10-question survey assessing knowledge of treatment adverse effects, treatment schedule, management of complications, accessing their medical team, and patient anxiety. Subjects then participated in a pre-chemotherapy teaching session with an oncology nurse. The survey was readministered when patients returned on day 1, cycle 1 of treatment and on day 1, cycle 2. The questionnaire used a 1 to 4 rating scale (1=no knowledge, 2= minimally informed, 3= reasonably informed, 4= well informed). A pre-defined mean change of 1 on the rating scale was considered to be clinically significant. Paired one-sided t-tests were performed to evaluate the mean change in groups between each of the three surveys. p values <0.05 were considered statistically significant. RESULTS At the time of analysis, 78 patients had completed a pre-chemotherapy teaching session and all three surveys. After participating in a teaching session, there was an increase in patients perceived knowledge of side effects (mean score 2.3 vs. 3.5, p<0.001), knowledge of the treatment schedule (mean score 2.4 vs. 3.5, p<0.001) and medications to prevent nausea (mean score of 1.4 vs. 3.1, p <0.001). There was also a statistically significant reduction in patient anxiety in relation to treatment, p< 0.001. CONCLUSIONS These results show that a nurse-coordinated, pre-chemotherapy teaching session increases patient knowledge and reduces anxiety regarding their upcoming treatment.

Do patients participating in oncology clinical trials understand the informed consent form? A Brown University Oncology Research Group study.

23 Background: The informed consent process is used to provide research participants information that includes the purpose and procedures of the research study, risks, benefits, potential alternatives and that participation is voluntary. The goal of informed consent to is to provide this information in language that is understandable to the research participant. The aim of this study is to evaluate whether research participants in adult hematology/oncology clinical trials understand the information presented during the informed consent process. METHODS Patients receiving active treatment on an oncology clinical trial that utilizes chemotherapy, radiation, targeted agents, biologic therapy or hormonal therapy were eligible to participate in this study. After informed consent was obtained, research participants are given a 14-question test. The questions evaluate whether patients understand the following elements on the informed consent related to their oncology treatment study: The purpose and procedures of the research study, risks, benefits, potential alternatives, research related injury compensation, study contact information, measures used to protect confidentiality, and that participation is voluntary. The possible answers to each question are disagree, unsure, and agree. RESULTS This study was initiated in June 2012. Eleven patients enrolled on this study within the first month. Participants include those on cooperative group studies, pharmaceutical industry trials and investigator initiated trials. The average length of the informed consent document exceeded 20 pages. An initial analysis of data is planned after the study has been open for six months. CONCLUSIONS Informed consents are becoming increasingly lengthy and complex. Much of the language added is regulatory and legal in nature and used to protect the institutions conducting the research. This study will assess the readability of the informed consent and whether patients participating in oncology research trials understand the essential elements of the informed consent document. The first data analysis will be December 2012.