Prospective Randomized Trial of Docetaxel Versus Best Supportive Care in Patients With Non-Small-Cell Lung Cancer Previously Treated With Platinum-Based Chemotherapy.

PURPOSE: To evaluate whether treatment with single-agent docetaxel would result in longer survival than would best supportive care in patients with non-small-cell lung cancer who had previously been treated with platinum-based chemotherapy. Secondary end points included assessment of response (docetaxel arm only), toxicity, and quality of life.PATIENTS AND METHODS: Patients with performance statuses of 0 to 2 and stage IIIB/IV non-small-cell lung cancer with either measurable or evaluable lesions were eligible for entry onto the study if they had undergone one or more platinum-based chemotherapy regimens and if they had adequate hematology and biochemistry parameters. They were excluded if they had symptomatic brain metastases or if they had previously been treated with paclitaxel. Patients were stratified by performance status and best response to cisplatin chemotherapy and were then randomized to treatment with docetaxel 100 mg/m2 (49 patients) or 75 mg/m2 (55 patients) or best supportive care. Patients in both arms were assessed every 3 weeks. RESULTS: One hundred four patients (103 of whom were eligible for entry onto the study) were well balanced for prognostic factors. Of 84 patients with measurable lesions, six (7.1%) achieved partial responses (three patients at each dose level). Time to progression was longer for docetaxel patients than for best supportive care patients (10.6 v 6.7 weeks, respectively; P < .001), as was median survival (7.0 v 4.6 months; log-rank test, P = .047). The difference was more significant for docetaxel 75 mg/m2 patients, compared with corresponding best supportive care patients (7.5 v 4.6 months; log-rank test, P = .010; 1-year survival, 37% v 11%; χ2 test, P = .003). Febrile neutropenia occurred in 11 patients treated with docetaxel 100 mg/m2, three of whom died, and in one patient treated with docetaxel 75 mg/m2. Grade 3 or 4 nonhematologic toxicity, with the exception of diarrhea, occurred at a similar rate in both the docetaxel and best supportive care groups. CONCLUSION: Treatment with docetaxel is associated with significant prolongation of survival, and at a dose of 75 mg/m2, the benefits of docetaxel therapy outweigh the risks.

Quality and cost outcomes of an integrated supportive care program.

PURPOSE: This article reports findings from a demonstration project funded by the Center for Medicare and Medicaid Innovation (CMMI). The purpose of the project was to test a supportive care program on the outcomes of quality of care and quality of life, and costs in patients with advanced cancer. METHODS: The project was conducted between February 2015 and February 2018, enrolling adult, Medicare or Medicaid beneficiaries with advanced or progressed solid tumor malignancy. A comparative longitudinal comparison of the program with both a concurrent control and an historic control was used to evaluate outcomes. The intervention included routine electronic biopsychosocial screening, early access to specialty palliative care, and nurse care coordination. Quality of life, aggressiveness of care, and healthcare utilization were measured. RESULTS: A total of 1340 people were enrolled, with 71% of the total sample being Caucasian; 41.4% had stage IV cancer, and 20% utilized Medicaid only. Significant differences in the enrolled patients and the comparison group were controlled for through statistical analysis. There were significantly fewer ED visits, unplanned admissions, and fewer total hospitalization days in the intervention group. In the last 30 days of life, hospital and ICU admissions were less and a greater proportion of patients were enrolled in hospice in the intervention group. Quality of life had a marked improvement for enrolled patients. Average cost per member per month was not less in the enrolled group. CONCLUSION: This pragmatic demonstration project confirmed the clinical benefits of an integration of supportive care for patients with advanced cancer, although no reduction in costs was found.

Artificial intelligence in oncology: Path to implementation.

In recent years, the field of artificial intelligence (AI) in oncology has grown exponentially. AI solutions have been developed to tackle a variety of cancer-related challenges. Medical institutions, hospital systems, and technology companies are developing AI tools aimed at supporting clinical decision making, increasing access to cancer care, and improving clinical efficiency while delivering safe, high-value oncology care. AI in oncology has demonstrated accurate technical performance in image analysis, predictive analytics, and precision oncology delivery. Yet, adoption of AI tools is not widespread, and the impact of AI on patient outcomes remains uncertain. Major barriers for AI implementation in oncology include biased and heterogeneous data, data management and collection burdens, a lack of standardized research reporting, insufficient clinical validation, workflow and user-design challenges, outdated regulatory and legal frameworks, and dynamic knowledge and data. Concrete actions that major stakeholders can take to overcome barriers to AI implementation in oncology include training and educating the oncology workforce in AI; standardizing data, model validation methods, and legal and safety regulations; funding and conducting future research; and developing, studying, and deploying AI tools through multidisciplinary collaboration.

A phase II study of paclitaxel + etoposide + cisplatin + concurrent radiation therapy for previously untreated limited stage small cell lung cancer (E2596): a trial of the Eastern Cooperative Oncology Group.

INTRODUCTION: To determine the 1-year survival, response rate, and toxicity for patients with limited stage small cell lung cancer treated with the combination of cisplatin plus etoposide plus paclitaxel with delayed concurrent (starting with cycle 3) high dose thoracic radiotherapy. PATIENTS AND METHODS: Patients with previously untreated limited stage small cell lung cancer, Easter Cooperative Oncology Group performance status of 0-2 and adequate organ function were eligible. Cycles 1 and 2 of chemotherapy consisted of paclitaxel 170 mg/m intravenous day 1, etoposide 80 mg/m intravenous days 1 to 3, and cisplatin 60 mg/m intravenous day 1 followed by filgrastim 5 microg/kg subcutaneously days 4 to 13. Cycles 3 and 4 of chemotherapy consisted of a reduced dose of paclitaxel 135 mg/m intravenous day 1, and the same dose of etoposide and cisplatin with concurrent thoracic radiation therapy 1.8 Gy in 35 fractions (total 63 Gy) administered over 7 weeks. RESULTS: Sixty-three patients were entered, 61 patients were eligible. The most common grade 4 toxicity seen was granulocytopenia (62%). Nonhematologic toxicities included febrile neutropenia in 19% of patients, grade 3 and 4 esophagitis in 32% of patients, and grade 3 peripheral neuropathy in 14% of patients. Two patients suffered lethal toxicities. The overall response rate was 79%. The 1-year survival rate was 64%. The median overall survival was 15.7 months, and the median progression-free survival was 8.6 months. CONCLUSIONS: The combination of cisplatin plus etoposide plus paclitaxel chemotherapy and concurrent delayed thoracic radiotherapy as administered in this trial provide no apparent advantage with respect to response, local control, or survival compared with historical controls.

Program report cards: evaluation across multiple residency programs at one institution.

The designated institution official (DIO) is responsible for monitoring all residency programs within an institution. Although program-evaluation tools have been developed for residency program directors to use, there are currently no such published evaluation tools for DIOs. This manuscript describes the development and implementation of a standardized, dimensional program report card for the more than 60 residency and fellowship programs at our institution. This report card measures the theoretical construct of residency program performance and is divided into four sections: (1) quality of candidates recruited, (2) the resident educational program, (3) graduate success, and (4) overall house officer satisfaction. Each section is measured by objective and subjective metrics that allow the DIO to record programmatic strengths and weaknesses. These results are confidentially shared with the residency program director and encourage a partnership between the DIO and the program director. It is difficult to provide concrete construct validity with this instrument. The process used to develop the report card seems valid. The authors recognize that this report card is a surrogate for each program's RRC's perception of quality. In the future, the authors hope to work closely with the Accreditation Council for Graduate Medical Education and/or the group on resident affairs of the Association of American Medical Colleges to set national benchmark criteria for acceptable residency program performance for each medical discipline. They hope that DIOs and program directors will be able to compare residency programs objectively and identify areas for improvement at a local and national level.

Phase II trial of thalidomide as maintenance therapy for extensive stage small cell lung cancer after response to chemotherapy.

BACKGROUND: Extensive-stage small cell lung cancer (SCLC) is a highly aggressive malignancy for which little therapeutic progress has been made over the past 20 years. SCLC is a highly angiogenic tumor and targeting angiogenesis is being investigated. The putative mechanism of action of thalidomide is through inhibition of new blood vessel formation. This trial was designed to evaluate thalidomide in ES-SCLC. PATIENTS AND METHODS: Patients who had received first-line chemotherapy without disease progression were eligible. Patients received thalidomide 200 mg daily as maintenance therapy starting 3-6 weeks after completion of chemotherapy. RESULTS: Thirty patients were enrolled. Toxicity was minimal with grade 1 neuropathy in 27% of patients and only one case of grade 3 neuropathy. Median survival from time of initiation of induction chemotherapy was 12.8 months (95% CI: 10.1-15.8 months) and 1-year survival of 51.7% (95% CI: 32.5-67.9%). Median duration on thalidomide was 79 days. CONCLUSION: Thalidomide 200mg daily is well tolerated when given as maintenance therapy for ES-SCLC after induction chemotherapy. Further evaluation of anti-angiogenic agents in SCLC is warranted.

Randomized phase II trial of different schedules of administration of rebeccamycin analogue as second line therapy in non-small cell lung cancer.

Rebeccamcyin analogue (RA) is an antitumor antibiotic that results in DNA intercalation and topoisomerase I and II inhibition. Phase I trials of the daily x 5 schedule and once every 3 week schedule have been completed. Antitumor activity was observed during the phase I trials. The purpose of this study is to primarily determine the response rate of 2 different schedules of administration of RA in patients with advanced non-small cell lung cancer (NSCLC) who had progressed on one prior chemotherapy regimen. Secondary endpoints were median and 1-year survival rates. A two-stage Simon design was employed for both arms of the study. Patients were randomly assigned to either of two RA treatment schedules of 500 mg/m(2) as a 1 hr infusion repeated every 3 weeks (Arm A) or 140 mg/m(2)/day x 5 days repeated every 3 weeks (Arm B). Forty-two patients were randomized. No confirmed objective responses were seen. Stable disease was seen in 52% of patients on arm A and 37% on arm B. Median survival and 1 year survival rates were 5.6 months and 33.3% for arm A, 9.7 months and 42.1% for arm B respectively. Cox regression model demonstrated increased risk of death in patients younger than the age of 61 and for patients treated on arm A. RA failed to demonstrate a significant response rate in this disease setting, although the proportion of patients with stable disease and 1-year survival were encouraging and similar to other published studies of approved single agents for second-line therapy of NSCLC.

Docetaxel and cyclooxygenase-2 inhibition with celecoxib for advanced non-small cell lung cancer progressing after platinum-based chemotherapy: a multicenter phase II trial.

PURPOSE: To assess the overall and progression-free survival, response rate, and toxicity of combined docetaxel and celecoxib in the treatment of patients with non-small cell lung cancer progressing after initial chemotherapy for advanced disease. PATIENTS AND METHODS: Patients with non-small cell lung cancer and either measurable or evaluable disease experiencing progression after one or more platinum-based chemotherapy regimens given for advanced or metastatic disease, ECOG performance status 0-2, and adequate hematologic and biochemistry parameters were eligible for study inclusion; exclusion criteria included symptomatic brain metastases and full dose anti-coagulation. Therapy consisted of docetaxel 75 mg/m(2) every 21 days for a maximum of six cycles and celecoxib 400 mg orally twice daily commencing 7 days prior to docetaxel and continuing until disease progression. RESULTS: A total of 41 patients were enrolled of whom 39 were deemed eligible and received at least one course of docetaxel. The mean age of enrolled patients was 60.5 years (range, 44-77); 67% were men and 79% white. All but one patient had an Eastern Clinical Oncology Group (ECOG) performance status of 0 or 1. Most (72%) had been treated with a prior taxane. Overall survival was 11.3 months (95% confidence interval [CI]: 7.9, 15.7) and progression-free survival 19.6 weeks (95% CI: 13.5, 25.0). A response rate of 10.2% (95% CI: 3%, 24%) for all eligible and treated patients was found. Grade 3 or 4 neutropenia occurred in 10/39 patients (25.6%); one death due to neutropenic sepsis occurred. No grade 3 or 4 renal or hepatic toxicities were documented. CONCLUSION: Treatment with combination celecoxib and docetaxel is a safe regimen with a toxicity profile similar to that of docetaxel alone. Survival data are encouraging compared to historical controls and may prolong time to disease progression compared with single-agent docetaxel.

Docetaxel for malignant mesothelioma: phase II study of the Eastern Cooperative Oncology Group.

This Eastern Cooperative Oncology Group phase II trial was conducted to study the effectiveness of docetaxel in patients with malignant mesothelioma. Patients were treated with docetaxel 100 mg/m2 intravenously administered as a 1-hour infusion repeated every 3 weeks. The study accrued a total of 20 patients, 1 of whom was considered ineligible. Of the 19 eligible patients, 1 patient (5%) achieved a partial response, 3 patients (16%) had stable disease, 11 patients (58%) had progressive disease, and 4 patients (21%) were unevaluable. The study was terminated after the first accrual stage because of an insufficient number of complete or partial responses. To date, only 1 patient (with stable disease) has not relapsed. The estimated median survival time is 4 months and the estimated median time to treatment failure is 2.2 months. There were 3 early deaths associated with the treatment regimen: severe gastrointestinal toxicity, hemorrhage, and an acute pulmonary event. Docetaxel as a single agent does not demonstrate evidence of activity in malignant mesothelioma.

Cardiovascular safety profile of combretastatin a4 phosphate in a single-dose phase I study in patients with advanced cancer.

PURPOSE: The purpose of our study was to review and determine the cardiovascular safety profile of combretastatin A4 phosphate (CA4P) in a Phase I study in 25 patients with advanced solid tumors. EXPERIMENTAL DESIGN: CA4P was administered in a dose-escalating fashion starting at 18 mg/m(2) i.v. every 21 days, and the maximal dosage was 90 mg/m(2). Continuous evaluation included bedside blood pressure and pulse monitoring, 12-lead electrocardiogram (ECG) at fixed time points for measured QT interval determination, determination of the corrected QT interval (QTc) using Bazett's formula QTc = QT/(R-R interval)(1/2), and chart review. Pharmacodynamic correlations of CA4P dose, CA4P/CA4 area under the curve, and C(max) versus heart rate (HR), blood pressure, QT, and QTc intervals, over the first 4 h postdosing were analyzed. RESULTS: After CA4P administration, there were significant increases in QTc interval at the 3-h and 4-h time points [27.2 ms (P < 0.0001) and 30.8 ms (P < 0.0001), respectively] and HR at the 3- and 4-h time points [13.2 beats per minute (bpm; P < 0.01) and 15.1 bpm (P < 0.001), respectively]. Three of 25 patients had prolonged QTc intervals at baseline, whereas 15 (60%) of 25 and 18 (75%) of 24 patients had prolonged QTc intervals at 3 and 4 h. The slope of HR and QTc increasing as a function of time during the first 4 h was correlated to dose (in milligrams) of CA4P (P = 0.01 and r = 0.49 for HR, P = 0.005 and r = 0.55 for QTc) and to CA4 area under the curve (P = 0.04 and r = 0.41 for HR, P = 0.02 and r = 0.44 for QTc); blood pressure and uncorrected QTc interval dose-response correlations were not significant. Two patients had ECG changes consistent with an acute coronary syndrome within 24 h of CA4P infusion. CONCLUSIONS: CA4P prolongs the QTc interval. There was a temporal relationship with the CA4P infusion and with ECG changes consistent with an acute coronary syndrome in two patients. It is advisable that future trials with CA4P have eligibility guidelines limiting patients with known coronary artery disease or those with multiple coronary artery disease risk factors until more experience is gained regarding potential cardiovascular toxicity with this agent.

Combination chemotherapy with topotecan for non-small cell lung cancer.

Patients with non-small cell lung cancer (NSCLC) typically receive platinum-based combination chemotherapy. In spite of improvements in symptoms and survival, response rates remain low and newer agents are being investigated. The newer agents may offer increased efficacy and reduced toxicity compared with established agents and regimens. The topoisomerase-I inhibitor, topotecan, achieves single-agent response rates of 4-25% in NSCLC. Topotecan has also been studied in combinations: a combination of topotecan, administered using the standard 5-day schedule, with cisplatin was effective but was associated with myelosuppression. The combination of topotecan plus carboplatin may be better tolerated and warrants further investigation. Topotecan was also combined with newer agents (gemcitabine, vinorelbine, docetaxel, paclitaxel) using a range of different administration schedules of topotecan. Response rates of up to 30% were achieved. A weekly schedule of topotecan was effective and well tolerated and was also convenient for healthcare professionals and patients.

Correlation of EUS measurement with pathologic assessment of neoadjuvant therapy response in esophageal carcinoma.

BACKGROUND: EUS-measured reduction in tumor size after neoadjuvant therapy has previously been correlated with downstaging and improved survival in patients with esophageal cancer. The aim of this study was to determine whether tumor changes measured by EUS correspond to pathologically assessed chemoradiotherapy-induced tumor regression. METHODS: Forty-one patients with esophageal cancer treated with combined modality treatment were studied. After initial EUS, patients completed a cisplatin/carboplatinum, 5-fluorouracil, and radiotherapy regimen and underwent repeat EUS before resection. A positive response on EUS was defined as a 50% reduction in maximal tumor cross-sectional area. Chemoradiotherapy-induced tumor regression was assessed in resection specimens by using a previously defined pathologic scoring system based on the extent of tumor proliferation into adjacent fibrosis. RESULTS: Pathologic tumor regression was present in 23, indeterminate in 5, and minimal or absent in 13 patients. EUS measured a positive response in 20 of 23 (87%) patients with CRT-induced tumor regression and a negative response in 10 of 13 (77%) patients with absent tumor regression (p < 0.001). EUS had a positive predictive value of 80% for pathologic tumor regression. CONCLUSIONS: Measurement of tumor size by EUS is a reliable clinical method for assessing pathologic tumor regression before surgery.