A Phase II Study of Pazopanib in Patients with Malignant Pleural Mesothelioma: NCCTG N0623 (Alliance).

PURPOSE: Preclinical and clinical data have shown promise in using antiangiogenic agents to treat malignant pleural mesothelioma (MPM). We conducted this phase II study to evaluate the efficacy and toxicity of single-agent pazopanib in patients with MPM. MATERIALS AND METHODS: Patients with MPM who had received 0-1 prior chemotherapy regimens were eligible to receive pazopanib at a dose of 800 mg daily. The primary endpoint was progression-free survival rate at 6 months (PFS6), with a preplanned interim analysis for futility. Secondary endpoints included overall survival (OS), PFS, adverse events assessment and clinical benefit (complete response, partial response [PR], and stable disease [SD]). RESULTS: Thirty-four evaluable patients were enrolled, with a median age of 73 years (49-84). The trial was closed early because of lack of efficacy at the preplanned interim analysis. Only 8 patients (28.6%; 95% confidence interval [CI], 13.2-48.7%) in the first 28 evaluable were progression-free at 6 months. PFS6 was 32.4% (95% CI, 17.4-50.5). There were 2 PR (5.9%) and 16 SD (47.1%). The overall median PFS and OS were 4.2 months (95% CI, 2.0-6.0) and 11.5 months (95% CI: 5.3-18.2), respectively. The median PFS and OS for the previously untreated patients was 5.4 months (95% CI, 2.7-8.5) and 16.6 months (95% CI, 6.6-30.6), respectively; and 2.0 months (95% CI, 1.3-4.2) and 5.0 months (95% CI: 3.0-11.9), respectively, for the previously treated patients. Grade 3 or higher adverse events were observed in 23 patients (67.6%). CONCLUSION: Single-agent pazopanib was poorly tolerated in patients with MPM. The primary endpoint of PFS6 was not achieved in the current study. ClinicalTrials.gov identification number. NCT00459862. IMPLICATIONS FOR PRACTICE: Single-agent pazopanib did not meet its endpoint in this phase II trial in malignant mesothelioma. Pazopanib is well tolerated in mesothelioma patients with a manageable toxicity profile. There is a need to better identify signals of angiogenesis that can be targeted in mesothelioma. Encouraging findings in frontline treatment warrant further investigations in combination with chemotherapy or immunotherapy.

A phase I study of the VEGFR kinase inhibitor vatalanib in combination with the mTOR inhibitor, everolimus, in patients with advanced solid tumors.

Purpose Combining small-molecule inhibitors of different targets was shown to be synergistic in preclinical studies. Testing this concept in clinical trials is, however, daunting due to challenges in toxicity management and efficacy assessment. This study attempted to evaluate the safety and efficacy of vatalanib plus everolimus in patients with advanced solid tumors and explore the utility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies as a predictive biomarker. Patients and Methods This single-center, phase I trial containing 70 evaluable patients consisted of a dose escalation proportion based on the traditional "3 + 3" design (cohort IA and IB) and a dose expansion proportion (cohort IIA and IIB). Toxicity was evaluated using the Common Terminology Criteria of Adverse Events. Antitumor activity was assessed using the Modified Response Evaluation Criteria in Solid Tumors. Results The maximum tolerated doses were determined to be vatalanib 1250 mg once daily or 750 mg twice daily in combination with everolimus 10 mg once daily. No treatment-related death occurred. The most common toxicities were hypertriglyceridemia, hypercholesterolemia, fatigue, vomiting, nausea and diarrhea. There was no complete response. Nine patients (12.9%) had partial response (PR) and 41 (58.6%) had stable disease (SD). Significant antitumor activity was observed in neuroendocrine tumors with a disease-control rate (PR + SD) of 66.7% and other tumor types including renal cancer, melanoma, and non-small-cell lung cancer. Conclusions The combination of vatalanib and everolimus demonstrated reasonable toxicity and clinical activity. Future studies combining targeted therapies and incorporating biomarker analysis are warranted based on this phase I trial.

A Case Management System for Integrating Patient-reported Outcome Assessment in Clinical Practice: The Beacon Tool.

INTRODUCTION: What if you could only ask one question of the patient during a clinic visit? Further, suppose the patient's biggest concern can pragmatically be incorporated into routine clinical care and clinical pathways that can address the patient's single biggest concern can be identified. If the principal concern can be dealt with efficiently at each visit through key stakeholder case management, positive outcomes should result. Therefore, motivated by the need for patient-centered health care visits, the Beacon electronic patient-reported outcomes (PRO) quality of life (QOL) tool was developed. METHODS: Central to the tool is that at each health care visit, the patient's biggest concern is electronically communicated to the health care team. Therefore, the tool can help catalyze important discussions between the health care team and the patient, perhaps on topics that would not have been discussed otherwise at a routine visit. In recognition of the community of resources needed to provide comprehensive care, the tool generates clinical pathways or actions that can be pursued to address the patient's biggest concern. The concern is efficiently triaged such that members of the health care community with appropriate expertise and resources are identified to address and manage that single biggest concern signaled by the patient. A report, which can be uploaded into the patient's medical chart, is created and provides a list of resources for a case manager to assist the patient and contains graphical presentations of the patient's QOL and a history of prior concerns. The report also labels potentially significant changes in QOL. DISCUSSION: The tool, which has been applied successfully in several health conditions, acts as a beacon to health care providers so that a patient's self-reported concern can be consistently and effectively integrated into their care. KEY POINTS: It is impractical to try to deal with every patient concern in every visit. The key to the Beacon tool is that at each visit the patient's biggest concern is identified, clinical pathways indicated, and resources efficiently matched to address the patient's biggest concern.

Effect of Doxepin Mouthwash or Diphenhydramine-Lidocaine-Antacid Mouthwash vs Placebo on Radiotherapy-Related Oral Mucositis Pain: The Alliance A221304 Randomized Clinical Trial.

Importance: Oral mucositis causes substantial morbidity during head and neck radiotherapy. In a randomized study, doxepin mouthwash was shown to reduce oral mucositis-related pain. A common mouthwash comprising diphenhydramine-lidocaine-antacid is also widely used. Objective: To evaluate the effect of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash for the treatment of oral mucositis-related pain. Design, Setting, and Participants: A phase 3 randomized trial was conducted from November 1, 2014, to May 16, 2016, at 30 US institutions and included 275 patients who underwent definitive head and neck radiotherapy, had an oral mucositis pain score of 4 points or greater (scale, 0-10), and were followed up for a maximum of 28 days. Interventions: Ninety-two patients were randomized to doxepin mouthwash (25 mg/5 mL water); 91 patients to diphenhydramine-lidocaine-antacid; and 92 patients to placebo. Main Outcome and Measures: The primary end point was total oral mucositis pain reduction (defined by the area under the curve and adjusted for baseline pain score) during the 4 hours after a single dose of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash compared with a single dose of placebo. The minimal clinically important difference was a 3.5-point change. The secondary end points included drowsiness, unpleasant taste, and stinging or burning. All scales ranged from 0 (best) to 10 (worst). Results: Among the 275 patients randomized (median age, 61 years; 58 [21%] women), 227 (83%) completed treatment per protocol. Mucositis pain during the first 4 hours decreased by 11.6 points in the doxepin mouthwash group, by 11.7 points in the diphenhydramine-lidocaine-antacid mouthwash group, and by 8.7 points in the placebo group. The between-group difference was 2.9 points (95% CI, 0.2-6.0; P = .02) for doxepin mouthwash vs placebo and 3.0 points (95% CI, 0.1-5.9; P = .004) for diphenhydramine-lidocaine-antacid mouthwash vs placebo. More drowsiness was reported with doxepin mouthwash vs placebo (by 1.5 points [95% CI, 0-4.0]; P = .03), unpleasant taste (by 1.5 points [95% CI, 0-3.0]; P = .002), and stinging or burning (by 4.0 points [95% CI, 2.5-5.0]; P < .001). Maximum grade 3 adverse events for the doxepin mouthwash occurred in 3 patients (4%); diphenhydramine-lidocaine-antacid mouthwash, 3 (4%); and placebo, 2 (2%). Fatigue was reported by 5 patients (6%) in the doxepin mouthwash group and no patients in the diphenhydramine-lidocaine-antacid mouthwash group. Conclusions and Relevance: Among patients undergoing head and neck radiotherapy, the use of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash vs placebo significantly reduced oral mucositis pain during the first 4 hours after administration; however, the effect size was less than the minimal clinically important difference. Further research is needed to assess longer-term efficacy and safety for both mouthwashes. Trial Registration: ClinicalTrials.gov Identifier: NCT02229539.

Electronic patient-reported outcomes and toxicities during radiotherapy for head-and-neck cancer.

PURPOSE: To characterize quality of life (QOL) using real-time, electronic patient-reported outcomes (ePROs) and to evaluate adverse events (AEs) and supportive care during head-and-neck radiotherapy (RT) and concurrent chemoradiotherapy (CCRT). METHODS: Sixty-five patients undergoing head-and-neck RT completed electronic, real-time, 12-item linear analog self-assessments (LASA) at baseline, before biweekly appointments, and at the last week of RT. Changes in QOL domains between time points were calculated. Clinical data were collected from the institutional medical record. AEs were recorded at the same time points as the LASA and graded. RESULTS: During head-and-neck RT, most patients had clinically meaningful decreases in all QOL domains except level of support, financial concerns, and legal concerns. QOL domains with the most prevalent, clinically meaningful decreases were fatigue (75.4% of patients; 95% CI, 62.9-84.9%), social activity (70.8%; 95% CI, 58.0-81.1%), and overall QOL (70.8%; 95% CI, 58.0-81.1%). All patients had grade 2 AEs; 35.4% had grade 3 (50.0%, CCRT; 12.0%, RT; P = .002). Weight loss averaged 5.5 kg (6.9 kg, CCRT; 2.8 kg, RT; P < .001). Intravenous hydration was needed in 52.3% (77.5%, CCRT; 12.0%, RT; P < .001); feeding tube placement 40.0% (57.5%, CCRT; 12.0%, RT; P = .001); emergency department visits without hospitalization, 10.8%; and emergent hospitalization, 27.7% (37.5%, CCRT; 12.0%, RT; P = .04). CONCLUSIONS: Head-and-neck RT, particularly CCRT, negatively impacts patients' overall QOL, social activity, and fatigue, with frequent grade 3 AEs, weight loss, intravenous hydration, feeding tube placement, ED visits, and hospitalization. Real-time ePROs allow providers to monitor QOL at multiple time points during RT, potentially allowing early intervention to improve QOL and mitigate AEs.

Radiofrequency ablation of stage IA non-small cell lung cancer in medically inoperable patients: Results from the American College of Surgeons Oncology Group Z4033 (Alliance) trial.

BACKGROUND: This study evaluated the 2-year overall survival rate, adverse event rate, local control rate, and impact on pulmonary function tests for medically inoperable patients with stage IA non-small cell lung cancer (NSCLC) undergoing computed tomography (CT)-guided radiofrequency ablation (RFA) in a prospective, multicenter trial. METHODS: Fifty-four patients (25 men and 29 women) with a median age of 76 years (range, 60-89 years) were enrolled from 16 US centers; 51 patients were eligible for evaluation (they had biopsy-proven stage IA NSCLC and were deemed medically inoperable by a board-certified thoracic surgeon). Pulmonary function tests were performed within the 60 days before RFA and 3 and 24 months after RFA. Adverse events were recorded and categorized. Patients were followed with CT and fludeoxyglucose positron emission tomography. Local control rate and recurrence patterns were analyzed. RESULTS: The overall survival rate was 86.3% at 1 year and 69.8% at 2 years. The local tumor recurrence-free rate was 68.9% at 1 year and 59.8% at 2 years and was worse for tumors > 2 cm. In the 19 patients with local recurrence, 11 were re-treated with RFA, 9 underwent radiation, and 3 underwent chemotherapy. There were 21 grade 3 adverse events, 2 grade 4 adverse events, and 1 grade 5 adverse event in 12 patients within the first 90 days after RFA. None of the grade 4 or 5 adverse events were attributable to RFA. There was no significant change in the forced expiratory volume in the first second of expiration or the diffusing capacity of lung for carbon monoxide after RFA. A tumor size less than 2.0 cm and a performance status of 0 or 1 were associated with statistically significant improved survival of 83% and 78%, respectively, at 2 years. CONCLUSIONS: RFA is a single, minimally invasive procedure that is well tolerated in medically inoperable patients, does not adversely affect pulmonary function tests, and provides a 2-year overall survival rate that is comparable to the rate reported after stereotactic body radiotherapy in similar patients.

A brief Patient-Reported Outcomes Quality of Life (PROQOL) instrument to improve patient care.

Jeff Sloan and colleagues describe the development of the Patient-Reported Outcomes Quality of Life (PROQOL) instrument, which captures and stores patient-recorded outcomes in the medical record for patients with diabetes. Please see later in the article for the Editors' Summary.

UGT1A1 genotype-guided phase I study of irinotecan, oxaliplatin, and capecitabine.

PURPOSE: We performed a UGT1A1 genotype-guided study to determine the maximum tolerated dose (MTD) and evaluate the toxicities and pharmacokinetics of the combination of capecitabine (CAP), oxaliplatin (OX), and irinotecan (IRIN). EXPERIMENTAL DESIGN: Patients were screened for UGT1A1 *28 genotype prior to treatment. The starting dose (mg/m(2)) was IRIN (150), OX (85) and CAP (400), days 2-15. Doses were escalated or de-escalated within each genotype group (*28/*28, *1/*28 and *1/*1). IRIN pharmacokinetics was performed at the MTD. RESULTS: 50 patients were evaluable for toxicity [11 (*28/*28); 18 (*1/*28); 21 (*1/*1)]. UGT1A1 *28/*28 patients experienced hematologic dose limiting toxicity (DLT), requiring dose-de-escalation. The UGT1A1 *28/*28 recommended phase 2 dose (RP2D) was IRIN (75), OX (85), and CAP (400). In contrast, both UGT1A1 *1/*28 and *1/*1 tolerated higher doses of IRIN and non-hematologic toxicity was dose limiting for UGT1A1 *1/*1. The RP2D was IRIN (150), OX (85), and CAP (400) for UGT1A1*1/*28 and IRIN (150), OX (100), and CAP (1600) for UGT1A1 *1/*1. UGT1A1 *1/*28 and *1/*1 patients treated with IRIN (150) had similar AUCs for the active irinotecan metabolite, SN38 (366 +/- 278 and 350 +/- 159 ng/ml*hr, respectively). UGT1A1 *28/*28 patients (n = 3) treated with a lower IRIN dose (100) had non-significantly higher mean SN38 exposures (604 +/- 289 ng/ml*hr, p = 0.14). Antitumor activity was observed in all genotype groups. CONCLUSIONS: UGT1A1 genotype affects the dose and pharmacokinetics of the CAPIRINOX regimen and UGT1A1 genotype-guided dosing of CAPIRINOX is ongoing in a phase II study of small bowel cancer (NCT00433550).

Rates of Guideline-Concordant Surgery and Adjuvant Chemotherapy Among Patients With Early-Stage Lung Cancer in the US ALCHEMIST Study (Alliance A151216).

Importance: Standard treatment for resectable non-small cell lung cancer (NSCLC) includes anatomic resection with adequate lymph node dissection and adjuvant chemotherapy for appropriate patients. Historically, many patients with early-stage NSCLC have not received such treatment, which may affect the interpretation of the results of adjuvant therapy trials. Objective: To ascertain patterns of guideline-concordant treatment among patients enrolled in a US-wide screening protocol for adjuvant treatment trials for resected NSCLC. Design, Setting, and Participants: This retrospective cohort study included 2833 patients with stage IB to IIIA NSCLC (per American Joint Committee on Cancer 7th edition criteria) who enrolled in the Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) screening study (Alliance for Clinical Trials in Oncology A151216) from August 18, 2014, to April 1, 2019, and who did not enroll in a therapeutic adjuvant clinical trial; patients had tumors of at least 4 cm and/or with positive lymph nodes. Statistical analysis was conducted from June 1, 2020, through October 1, 2021. Exposures: Care patterns were ascertained overall and by sociodemographic and clinical factors, including age, sex, race and ethnicity, educational level, marital status, geography, histologic characteristics, stage, genomic variant status, smoking history, and comorbidities. Main Outcomes and Measures: Five outcomes are reported: whether patients (1) had anatomic surgical resection, (2) had adequate lymph node dissection (≥1 N1 nodal station plus ≥3 N2 nodal stations), (3) received any adjuvant chemotherapy, (4) received any cisplatin-based adjuvant chemotherapy, and (5) received at least 4 cycles of adjuvant chemotherapy. Results: Of the 2833 patients (1505 women [53%]; mean [SD] age, 66.5 [9.2] years) included in this analysis, 2697 (95%) had anatomic surgical resection, 1513 (53%) had adequate lymph node dissection, 1617 (57%) received any adjuvant chemotherapy, 1237 (44%) received at least 4 cycles of adjuvant platinum-based chemotherapy, and 965 (34%) received any cisplatin-based adjuvant chemotherapy. Rates were similar across race and ethnicity. Conclusions and Relevance: This cohort study found that among participants in a screening protocol for adjuvant clinical trials for resected early-stage NSCLC, just 53% underwent adequate lymph node dissection, and 57% received adjuvant chemotherapy, despite indications for such treatment. These results may affect the interpretation of adjuvant trials. Efforts are needed to optimize the use of proven therapies for early-stage NSCLC. Trial Registration: ClinicalTrials.gov Identifier: NCT02194738.

Successes and lessons learned in database development for national multi-site cancer care delivery research trials: the Alliance for Clinical Trials in Oncology experience.

INTRODUCTION: Alliance for Clinical Trials in Oncology (Alliance) coordinated trials utilize Medidata Rave® (Rave) as the primary clinical data capture system. A growing number of innovative and complex cancer care delivery research (CCDR) trials are being conducted within the Alliance with the aims of studying and improving cancer-related care. Because these trials encompass patients, providers, practices, and their interactions, a defining characteristic of CCDR trials is multilevel data collection in pragmatic settings. Consequently, CCDR trials necessitated innovative strategies for database development, centralized data management, and data monitoring in the presence of these real-world multilevel relationships. Having real trial experience in working with community and academic centers, and having recently implemented five CCDR trials in Rave, we are committed to sharing our strategies and lessons learned in implementing such pragmatic trials in oncology. METHODS: Five Alliance CCDR trials are used to describe our approach to analyzing the database development needs and the novel strategies applied to overcome the unanticipated challenges we encountered. The strategies applied are organized into 3 categories: multilevel (clinic, clinic stakeholder, patient) enrollment, multilevel quantitative and qualitative data capture, including nontraditional data capture mechanisms being applied, and multilevel data monitoring. RESULTS: A notable lesson learned in each category was (1) to seek long-term solutions when developing the functionality to push patient and non-patient enrollments to their respective Rave study database that affords flexibility if new participant types are later added; (2) to be open to different data collection modalities, particularly if such modalities remove barriers to participation, recognizing that additional resources are needed to develop the infrastructure to exchange data between that modality and Rave; and (3) to facilitate multilevel data monitoring, orient site coordinators to the their trial's multiple study databases, each corresponding to a level in the hierarchy, and remind them to establish the link between patient and non-patient participants in the site-facing NCI web-based enrollment system. CONCLUSION: Although the challenges due to multilevel data collection in pragmatic settings were surmountable, our shared experience can inform and foster collaborations to collectively build on our past successes and improve on our past failures to address the gaps.

Patient-reported quality-of-life outcomes in relation to provider-assessed adverse events during head and neck radiotherapy.

PURPOSE: To assess the relationship between patient-reported quality-of-life (QOL) outcomes and provider-assessed adverse events (AEs) during head-and-neck (H&N) radiotherapy (RT). METHODS: Sixty-five patients undergoing H&N RT prospectively completed 12-domain linear analogue self-assessments (LASA) at baseline, before biweekly appointments, and at last week of RT. At the same time points, provider-assessed AEs were graded using Common Terminology Criteria for Adverse Events v4.0. LASA scores were stratified by maximum-grade AE and analyzed using Kruskal-Wallis methodology. Agreement between LASA scores and maximum-grade AE was assessed using Bland-Altman analysis. RESULTS: Patient-reported QOL outcomes showed clinically meaningful decreases in most domains, predominantly fatigue (77.8% of patients), social activity (75.4%), and overall QOL (74.2%). Provider-assessed AEs showed 100% grade 2 AE, 35.4% grade 3 AE, and 3.1% grade 4 AE. At baseline, patients with higher grade AEs reported worse physical well-being (WB) (P = .04). At week 1, the following QOL domains were worse for patients with higher grade AEs: overall QOL (P = .03), mental WB (P = .02), and physical WB (P = .03). Bland-Altman analysis showed that QOL scores were relatively worse than AE burden at baseline and relatively better at RT completion. CONCLUSIONS: Worse QOL was associated with higher-grade AEs at baseline and early in RT. The impact of AEs on QOL appears to lessen with time. Patient-reported QOL outcomes and provider-assessed AEs provide complementary information.

A Randomized Double-Blind Phase II Study of the Seneca Valley Virus (NTX-010) versus Placebo for Patients with Extensive-Stage SCLC (ES SCLC) Who Were Stable or Responding after at Least Four Cycles of Platinum-Based Chemotherapy: North Central Cancer Treatment Group (Alliance) N0923 Study.

INTRODUCTION: The Seneca Valley virus (NTX-010) is an oncolytic picornavirus with tropism for SCLC. This phase II double-blind, placebo-controlled trial evaluated NTX-010 in patients with extensive-stage (ES) SCLC after completion of first-line chemotherapy. METHODS: Patients with ES SCLC who did not progress after four or more cycles of platinum-based chemotherapy were randomized 1:1 to a single dose of NTX-010 or placebo within 12 weeks of chemotherapy. The primary end point was progression-free survival (PFS). A prespecified interim analysis for futility was performed after 40 events. Viral clearance and the development of neutralizing antibodies were followed. RESULTS: From January 15, 2010, to January 10, 2013, a total of 50 patients were randomized and received therapy on study (26 received NTX-010 and 24 received placebo). At the specified interim analysis, the median PFS was 1.7 months (95% confidence interval [CI]: 1.4-3.1 months) for the NTX-010 group versus 1.7 months (95% CI: 1.4-4.3 months) for the placebo group (hazard ratio = 1.03, p = 0.92), and the trial was terminated owing to futility. In the NTX-010 group, PFS was shorter in patients with detectable virus at days 7 and 14 versus in those in whom it was not detected after treatment (1.0 month [95% CI: 0.4-1.5 months] versus 1.8 months [95% CI: 1.3-5.5 months, p = 0.008] and 0.9 months [95% CI: 0.4-2.6 months] versus 1.3 months [95% CI: 1.0-5.3 months], respectively [p = 0.04]). CONCLUSIONS: Patients with ES SCLC did not benefit from NTX-010 treatment after chemotherapy with a platinum doublet. Persistence of NTX-010 in the blood 1 or 2 weeks after treatment was associated with a shorter PFS.

Association of resident fatigue and distress with perceived medical errors.

CONTEXT: Fatigue and distress have been separately shown to be associated with medical errors. The contribution of each factor when assessed simultaneously is unknown. OBJECTIVE: To determine the association of fatigue and distress with self-perceived major medical errors among resident physicians using validated metrics. DESIGN, SETTING, AND PARTICIPANTS: Prospective longitudinal cohort study of categorical and preliminary internal medicine residents at Mayo Clinic, Rochester, Minnesota. Data were provided by 380 of 430 eligible residents (88.3%). Participants began training from 2003 to 2008 and completed surveys quarterly through February 2009. Surveys included self-assessment of medical errors, linear analog self-assessment of overall quality of life (QOL) and fatigue, the Maslach Burnout Inventory, the PRIME-MD depression screening instrument, and the Epworth Sleepiness Scale. MAIN OUTCOME MEASURES: Frequency of self-perceived, self-defined major medical errors was recorded. Associations of fatigue, QOL, burnout, and symptoms of depression with a subsequently reported major medical error were determined using generalized estimating equations for repeated measures. RESULTS: The mean response rate to individual surveys was 67.5%. Of the 356 participants providing error data (93.7%), 139 (39%) reported making at least 1 major medical error during the study period. In univariate analyses, there was an association of subsequent self-reported error with the Epworth Sleepiness Scale score (odds ratio [OR], 1.10 per unit increase; 95% confidence interval [CI], 1.03-1.16; P = .002) and fatigue score (OR, 1.14 per unit increase; 95% CI, 1.08-1.21; P < .001). Subsequent error was also associated with burnout (ORs per 1-unit change: depersonalization OR, 1.09; 95% CI, 1.05-1.12; P < .001; emotional exhaustion OR, 1.06; 95% CI, 1.04-1.08; P < .001; lower personal accomplishment OR, 0.94; 95% CI, 0.92-0.97; P < .001), a positive depression screen (OR, 2.56; 95% CI, 1.76-3.72; P < .001), and overall QOL (OR, 0.84 per unit increase; 95% CI, 0.79-0.91; P < .001). Fatigue and distress variables remained statistically significant when modeled together with little change in the point estimates of effect. Sleepiness and distress, when modeled together, showed little change in point estimates of effect, but sleepiness no longer had a statistically significant association with errors when adjusted for burnout or depression. CONCLUSION: Among internal medicine residents, higher levels of fatigue and distress are independently associated with self-perceived medical errors.

Impact of hospital hospitality house programs on quality of life and mood of patients and caregivers after hematopoietic stem cell transplant.

OBJECTIVE/BACKGROUND: The quality of life (QOL) of hematopoietic stem cell transplant (HSCT) patients and their caregivers decreases during the first 8 days after HSCT. METHODS: This prospective pilot study collected preliminary data on the impact of posttransplant living arrangements (hospital hospitality house [HHH] vs. hotel, apartment, or house ["hotel"]) and other factors on the QOL of HSCT patients and their caregivers. The predefined primary end point was QOL of patients and their caregivers on Day 30 (QOL30) as measured by the linear analog self-assessment (LASA). RESULTS: Forty-four HSCT patients participated (HHH 23, hotel 21; allogeneic 18, autologous 26). No significant differences in QOL30 (mean LASA score) were noted between patient groups (55.6 [HHH] vs. 72.2 [hotel], p = .06) or between caregiver groups (77.8 [HHH] vs. 88.9 [hotel], p = .20). Multivariate analysis for QOL30 showed that baseline QOL (p = .006) and age (p = .049) were significant predictors of QOL30 after adjustment for sex, post-HSCT living place, and transplant type. Older patients (≥60 years) had a significantly lower QOL30 than younger patients (mean score, 51.6 vs. 75.3; p = .02). CONCLUSION: Efforts to improve QOL30 of HSCT patients and caregivers in the confined environment of an HHH should focus on patients with low baseline QOL and older patients.

Randomized controlled trial of cryotherapy to prevent paclitaxel-induced peripheral neuropathy (RU221511I); an ACCRU trial.

PURPOSE: This pilot trial aimed to assess if cooling hands and feet with crushed ice during receipt of paclitaxel helps prevent peripheral neuropathy. METHODS: This prospective, randomized trial compared cryotherapy to standard care in patients initiating paclitaxel weekly x 12. For those on cryotherapy, hands and feet were cooled starting 15 min prior to and ending 15 min after each paclitaxel dose. EORTC QLQ-CIPN20 was completed at baseline, weekly x12, then monthly x6. Area under the curve (AUC) was calculated for subscale scores, adjusting for baseline, and compared between arms (Wilcoxon rank-sum test). Cross-study comparisons used data from 2 prior similarly-conducted neuropathy trials. RESULTS: Forty-six patients were accrued. Three withdrew and one was ineligible. Of the remaining 42 (21 cryotherapy, 21 control), 39 (19 cryotherapy, 20 control) were analyzable for AUC. Cryotherapy was well tolerated, but the AUC of the CIPN20 sensory scores over 12 weeks of paclitaxel was not found to differ between the study arms (mean difference 3.45, 95% CI -3.13 to 10.02, p = 0.26). However, the control arm of the current trial experienced less neuropathy than did the placebo arms of two previous similar trials. When our cryotherapy arm was compared to the combined control arms from all three trials, the cryotherapy arm had less neuropathy (Wilcoxon Rank-Sum p = 0.01). CONCLUSION: While there was no difference in CIPN20 scores identified between the 2 study arms in the current phase II trial, further investigation is needed given that the control arm experienced less neuropathy than was expected.

A limited sample model to predict area under the drug concentration curve for 17-(allylamino)-17-demethoxygeldanamycin and its active metabolite 17-(amino)-17-demethoxygeldanomycin.

PURPOSE: The Hsp90-directed anticancer agent 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) is currently undergoing phase I and phase II clinical investigation. Our goal was to develop a simple limited sampling model (LSM) for AUC of 17-AAG and its active metabolite, 17-(amino)-17-demethoxygeldanomycin (17-AG) using drug concentrations from a few time points. METHODS: Pharmacokinetic data from 34 patients treated at 11 dose levels on a Mayo Clinic Cancer Center phase I clinical trial of 17-AAG was utilized. Blood samples were collected at 11 different time points, spanning 25 h. Graphical methods and correlations were used to assess functional forms and univariate relationships. Multivariate linear regression and bootstrap resampling were used to develop the LSM. RESULTS: Using log-transformed data, the two and three time point 17-AAG LSMs are log-AUC (17-AAG) = 0.869 + 0.653*(C(55min)) +0.469*(C(5h)) and log-AUC (17-AAG) = 2.449 + 0.400*(C(55min)) +0.441*(C(5h)) +0.142*(C(9h)). The two and three time point LSMs for 17-AG are log-AUC (17-AG) = 3.590 + 0.747*(C(5h)) +0.169*(C(17h)), and log-AUC (17-AG) = 3.797 + 0.650*(C(5h)) +0.111*(C(9h)) +0.122*(C(17h)). Ninety-seven percent and 94% of the predicted log-AUC values were within 5% of the observed log-AUC for the two and three time point models for 17-AAG and 17-AG respectively. CONCLUSIONS: The precise calculation of AUC is cumbersome and expensive in terms of patient and clinical resources. The LSM developed using a multivariate regression approach is clinically and statistically meaningful. Prospective validation is underway.

A phase I and pharmacologic study of sequences of the proteasome inhibitor, bortezomib (PS-341, Velcade), in combination with paclitaxel and carboplatin in patients with advanced malignancies.

PURPOSE: Bortezomib, a selective inhibitor of the 20S proteasome with activity in a variety of cancers, exhibits sequence-dependent synergistic cytotoxicity with taxanes and platinum agents. Two different treatment schedules of bortezomib in combination with paclitaxel and carboplatin were tested in this phase I study to evaluate the effects of scheduling on toxicities, pharmacodynamics and clinical activity. METHODS: Patients with advanced malignancies were alternately assigned to receive (schedule A) paclitaxel and carboplatin (IV d1) followed by bortezomib (IV d2, d5, d8) or (schedule B) bortezomib (IV d1, d4, d8) followed by paclitaxel and carboplatin (IV d2) on a 21-day cycle. RESULTS: Fifty-three patients (A 25, B 28) were treated with a median of 3 cycles (range 1-8) for schedule A and 3.5 cycles (range 1-10) for schedule B. Grade 3 or higher treatment related hematologic adverse events in all cycles of treatment included neutropenia (A 52%, B 50%), anemia (A 12%, B 7.1%) and thrombocytopenia (A 16%, B 17.9%). Non-hematologic treatment related adverse events were fairly mild (primarily grades 1 and 2). The maximum tolerated dose and the recommended doses for future phase II trials are bortezomib 1.2 mg/m2, paclitaxel 135 mg/m2 and carboplatin AUC = 6 for schedule A and bortezomib 1.2 mg/m2, paclitaxel 175 mg/m2 and carboplatin AUC = 6 for schedule B. Six (21.4%) partial responses (PR) were seen with schedule B. In contrast, only 1 (4%) PR was achieved with schedule A. Similar proteasome inhibition was achieved at MTD for both schedules. CONCLUSION: Administration of sequential bortezomib followed by chemotherapy (schedule B) was well tolerated and associated with an encouraging number of objective responses in this small group of patients. Further studies with this administration schedule are warranted.

Long-Term Results of a Trial of Concurrent Chemotherapy and Escalating Doses of Radiation for Unresectable Non-Small Cell Lung Cancer: NCCTG N0028 (Alliance).

INTRODUCTION: This phase I/II trial was designed to determine the maximally tolerated dose of thoracic radiotherapy as part of a combined modality approach. This report includes the long-term outcomes of patients treated on this study. The phase II portion was never completed, as RTOG-0617 opened before it was concluded. METHODS: In this study, the maximally tolerated dose was defined as 74 Gy of radiation in 37 fractions. Twenty-five patients with unresectable NSCLC were treated with 2-Gy daily fractions and concurrent weekly carboplatin and paclitaxel. Of these patients, 20 had stage III disease and five had stage I or II disease. RESULTS: Patients were followed until death or for a minimum of 5 years in the case of survivors. The median and 5-year survivals were 42.5 months and 20% for all patients, 52.9 months and 40% in patients with stages I or II disease, and 39.8 months and 15% in patients with stage III disease. CONCLUSIONS: The median survival of the stage III patients was quite favorable. We believe that this may have been due to a robust central review program of radiotherapy plans before treatment, ensuring compliance with protocol guidelines along with very low exposure of the heart to radiotherapy. Further improvements in 5-year survival will likely require research on both systemic therapy and thoracic radiotherapy. Potential therapeutic modalities that may aid in these efforts include immunotherapy, targeted therapy, improved imaging, adaptive radiotherapy, simultaneous integrated boost techniques, novel dose fractionation regimens, and charged particle therapy.

Analyzing the "correct" endpoint.

The choice of QOL endpoints for a study should be based on which score will most likely change if the treatment is favorable. How the QOL change is calculated should be based on the expected amount of missing data, how many time points data will be collected, and whether extreme outliers in the scores impact results. The study should have sufficient power to detect a meaningful difference between arms (typically 10 points on a 0-100 point scale) in the chosen QOL endpoint. At the conclusion of a study, several secondary endpoints can be analyzed which can provide additional information and confirm primary endpoint results.

Impact of Sublobar Resection on Pulmonary Function: Long-Term Results from American College of Surgeons Oncology Group Z4032 (Alliance).

BACKGROUND: Sublobar resection (SR) in high-risk operable patients may result in a long-term decrease in pulmonary function. We previously reported 3-month pulmonary function outcomes from a randomized phase III study of SR alone compared with SR with brachytherapy in patients with non-small cell lung cancer. We now report long-term pulmonary function after SR. METHODS: Pulmonary function was measured at baseline and at 3, 12, and 24 months. A decline of 10% or more from baseline in the percentage predicted forced expiratory volume of 1 percentage or in the diffusion capacity of the lung for carbon monoxide was considered clinically meaningful. The effect of study arm, tumor location, size, approach (video-assisted thoracoscopic surgery vs thoracotomy), and SR type (wedge vs segmentectomy) on pulmonary function was assessed using a Wilcoxon rank sum test. A generalized estimating equation model was used to assess the effect of each factor on longitudinal data, including all four time points. RESULTS: Complete pulmonary function data at all time points was available in 69 patients. No significant differences were observed in pulmonary function between SR and SR with brachytherapy, thus the study arms were combined for all analyses. A decline of 10% or more (p = 0.02) in the percentage predicted forced expiratory volume in 1 second was demonstrated for lower-lobe resections at 3 months but was not at 12 or 24 months. A decline of 10% or more (p = 0.05) in the percentage predicted diffusion capacity of the lung for carbon monoxide was seen for thoracotomy at 3 months but was not at 12 or 24 months. CONCLUSIONS: Clinically meaningful declines in pulmonary function occurred after lower lobe resection and after thoracotomy at 3 months but subsequently recovered. This study suggests that SR does not result in sustained decreased pulmonary function in high-risk operable patients.