Gemcitabine and Irinotecan for Patients with Untreated Extensive Stage Small Cell Lung Cancer: SWOG 0119

IntroductionTo evaluate the activity of a nonplatinum-, nonetoposide-containing regimen for patients with extensive stage small cell lung cancer.MethodsPatients with untreated extensive stage small cell lung cancer were treated with gemcitabine 1000 mg/m2 and irinotecan 100 mg/m2 on days 1 and 8 of a 21-day cycle for a maximum of six cycles. Patients with brain metastases were eligible if asymptomatic or controlled after radiation.ResultsEighty-four eligible patients with untreated extensive stage small cell lung cancer with adequate organ function and a performance status of 0–2 were accrued. The median age was 64 years (range, 42–85) and 45 (54%) were women. Six cycles were completed by 28 (33%) patients. Some degree of diarrhea occurred in 57% (grade 3/4, 18%). Other grade 3/4 toxicities were neutropenia (26%), anemia (10%), thrombocytopenia (8%), febrile neutropenia (5%), fatigue (11%), nausea (10%), and vomiting (8%). The response rate was 32% (95% confidence interval: 22%–43%) among the 81 patients with measurable disease. The median survival was 8.5 months (95% confidence interval: 7.0–9.8) with 1- and 2-year survival rates of 26% and 7%, respectively. Salvage therapy data were captured by prospective collection, and only 50% of patients were treated secondarily.ConclusionThe overall response rate with the combination of gemcitabine and irinotecan was disappointing, and the median survival rate was lower than expected. Further development of this combination in small cell lung cancer is not recommended

Phase II Study of Cediranib in Patients with Malignant Pleural Mesothelioma: SWOG S0509

IntroductionMalignant pleural mesothelioma (MPM) tumors express vascular epithelial growth factor (VEGF) and VEGF receptors. We conducted a phase II study of the oral pan-VEGF receptor tyrosine kinase inhibitor, cediranib, in patients with MPM after platinum-based systemic chemotherapy.MethodsPatients with MPM previously treated with a platinum-containing chemotherapy regimen and a performance status 0 to 2 were eligible for enrollment. Cediranib 45 mg/d was administered until progression or unacceptable toxicity. The primary end point was response rate. Tumor measurements were made by RECIST criteria, with a subset analysis conducted using modified RECIST. A two-stage design with an early stopping rule based on response rate was used.ResultsFifty-four patients were enrolled. Of 47 evaluable patients, 4 patients (9%) had objective responses, 16 patients (34%) had stable disease, 20 patients (43%) had disease progression, 2 patients (4%) had symptomatic deterioration, and 1 patient (2%) had early death. The most common toxicities were fatigue (64%), diarrhea (64%), and hypertension (70%); 91% of patients required a dose reduction. Median overall survival was 9.5 months, 1-year survival was 36%, and median progression-free survival was 2.6 months.ConclusionCediranib monotherapy has modest single-agent activity in MPM after platinum-based therapy. However, some patient tumors were highly sensitive to cediranib. This study provides a rationale for further testing of cediranib plus chemotherapy in MPM and highlights the need to identify a predictive biomarker for cediranib

Phase 1b Trial of Proteasome Inhibitor Carfilzomib with Irinotecan in Lung Cancer and Other Irinotecan-Sensitive Malignancies That Have Progressed on Prior Therapy (Onyx IST Reference Number: CAR-IST-553)

Introduction Proteasome inhibition is an established therapy for many malignancies. Carfilzomib, a novel proteasome inhibitor, was combined with irinotecan to provide a synergistic approach in relapsed, irinotecan-sensitive cancers. Materials and Methods Patients with relapsed irinotecan-sensitive cancers received carfilzomib (Day 1, 2, 8, 9, 15, and 16) at three dose levels (20/27 mg/m2, 20/36 mg/m2 and 20/45 mg/m2/day) in combination with irinotecan (Days 1, 8 and 15) at 125 mg/m2/day. Key eligibility criteria included measurable disease, a Zubrod PS of 0 or 1, and acceptable organ function. Patients with stable asymptomatic brain metastases were eligible. Dose escalation utilized a standard 3 + 3 design. Results Overall, 16 patients were enrolled to three dose levels, with four patients replaced. Three patients experienced dose limiting toxicity (DLT) and the maximum tolerated dose (MTD) was exceeded in Cohort 3. The RP2 dose was carfilzomib 20/36 mg/m2 (given on Days 1, 2, 8, 9, 15, and 16) and irinotecan 125 mg/m2 (Days 1, 8 and 15). Common Grade (Gr) 3 and 4 toxicities included fatigue (19%), thrombocytopenia (19%), and diarrhea (13%). Conclusions Irinotecan and carfilzomib were well tolerated, with common toxicities of fatigue, thrombocytopenia and neutropenic fever. Objective clinical response was 19% (one confirmed partial response (PR) in small cell lung cancer (SCLC) and two unconfirmed); stable disease (SD) was 6% for a disease control rate (DCR) of 25%. The recommended phase II dose was carfilzomib 20/36 mg/m2 and irinotecan125 mg/m2. The phase II evaluation is ongoing in relapsed small cell lung cancer

Sequential Vinorelbine and Docetaxel in Advanced Non-small Cell Lung Cancer Patients Age 70 and Older and/or with a Performance Status of 2: A Phase II Trial of the Southwest Oncology Group (S0027)

BackgroundThis phase II study (S0027) evaluated the efficacy and tolerability of planned sequential single-agent chemotherapy with vinorelbine followed by docetaxel in patients with advanced non-small cell lung cancer (NSCLC) age 70 and older and/or a performance status (PS) of 2.MethodsPatients with stage IIIB (pleural effusion) or stage IV NSCLC, age 70 and older with a PS of 0-1 or 2, any age, received three cycles of vinorelbine 25 mg/m2 days 1 and 8 every 21 days followed by three cycles of docetaxel 35 mg/m2 days 1, 8, and 15 every 28 days.ResultsA total of 125 patients entered the study; 117 patients were assessable for response, survival, and toxicity. Seventy-five patients were in stratum1 (age 70 and older, PS 0-1) and 42 patients in stratum 2 (PS 2, any age). Objective response was 19% (95% confidence interval [CI]: 11%–30%) and 11% (95% CI: 3%–25%) in strata 1 and 2, respectively. Median survival was 9.1 months (95% CI: 7.1–12.7) and 5.5 months (95% CI: 3.1–6.5) in strata 1 and 2, respectively. Survival at 12 months was 41% and 13% in strata 1 and 2, respectively. Grade 3/4 neutropenia was seen in 32% and 31% of patients in strata 1 and 2, respectively. Three deaths probably related to treatment were noted: one in stratum 1 and two in stratum 2.ConclusionSequential vinorelbine and docetaxel is a well-tolerated and effective regimen in comparison with reports of other treatments tested in patients with advanced NSCLC age 70 and older and/or with a PS of 2

The IASLC Lung Cancer Staging Project: A Renewed Call to Participation

Over the past two decades, the International Association for the Study of Lung Cancer (IASLC) Staging Project has been a steady source of evidence-based recommendations for the TNM classification for lung cancer published by the Union for International Cancer Control and the American Joint Committee on Cancer. The Staging and Prognostic Factors Committee of the IASLC is now issuing a call for participation in the next phase of the project, which is designed to inform the ninth edition of the TNM classification for lung cancer. Following the case recruitment model for the eighth edition database, volunteer site participants are asked to submit data on patients whose lung cancer was diagnosed between January 1, 2011, and December 31, 2019, to the project by means of a secure, electronic data capture system provided by Cancer Research And Biostatistics in Seattle, Washington. Alternatively, participants may transfer existing data sets. The continued success of the IASLC Staging Project in achieving its objectives will depend on the extent of international participation, the degree to which cases are entered directly into the electronic data capture system, and how closely externally submitted cases conform to the data elements for the project

The IASLC Lung Cancer Staging Project: proposals for revision of the M descriptors in the forthcoming (seventh) edition of the TNM classification of lung cancer.

International audiencePURPOSE: To analyze all nonlymphatic metastatic components (T4 and M1) of the current TNM system of lung cancer, with the objective of providing suggestions for the next edition of the TNM classification for lung cancer. MATERIAL AND METHODS: Data on 100,809 patients were submitted to the International Association for the Study of Lung Cancer International Database. Of these, 5592 selected T4M0 and M1 patients fulfilled the inclusion criteria for the analysis. Specific categories of clinically staged T4 (lesions not continuous with the primary tumor) and M1 cases were compared with respect to overall survival using Kaplan-Meier survival estimates and comparisons via Cox regression analysis. Relevant findings were validated internally by geographic area and type of database and were validated externally by the North American Surveillance, Epidemiology and End Results Registries. RESULTS: Median survival for cT4M0 with malignant pleural effusion was significantly worse than that of other cT4M0 patients (8 months versus 13 months) and was more comparable with M1 cases with metastases to the contralateral lung only (10 months). M1 cases with metastases outside the lung/pleura had a significantly poorer prognosis than those with metastases confined to the lung, with a median survival of 6 months. CONCLUSIONS: Revisions to the TNM classification system for lung cancer should include grouping cases with malignant pleural effusions and cases with nodules in the contralateral lung in the M1a category, and cases with distant metastases should be designated M1b. In addition, cases with nodule(s) in the ipsilateral lung (nonprimary lobe), currently staged M1, should be reclassified as T4M0, in accordance with the recommendations of the T descriptor subcommittee of the IASLC international staging committee

Preoperative supraphysiological testosterone in older men undergoing knee replacement surgery

OBJECTIVES: Older patients undergoing knee replacement surgery can recover more slowly than younger patients and require extended rehabilitation. Because administration of supraphysiological testosterone (T) dramatically increases strength, we hypothesized that preoperative T therapy would improve functional recovery and reduce hospital stay in older men undergoing knee replacement surgery. DESIGN: Double-blinded, placebo-controlled pilot trial. SETTING: A Veterans Affairs orthopedics clinic and inpatient postoperative unit. PARTICIPANTS: Twenty-five men, mean age 70, undergoing elective knee replacement. INTERVENTION: Preoperative, supraphysiological T administration (600 mg T enanthate intramuscularly weekly for 4 weeks) or sesame oil placebo. MEASUREMENTS: Length of hospital stay and functional ability by Functional Independence Measure (FIM) score. RESULTS: Mean length of hospital stay +/- standard deviation was nonsignificantly reduced in the T group (5.9 +/- 2.4 days vs 6.8 +/- 2.5 days; P =.15). At postoperative Day 3, there was a significant improvement in ability to stand (mean FIM score 5.2 +/- 1.0 vs 4.0 +/- 1.1; P =.04) and trends towards improvements in walking and stair climbing in the T group. There were no complications attributable to T therapy. CONCLUSIONS: In older men undergoing knee replacement surgery, preoperative supraphysiological T administration may confer some clinical benefit. Future studies using longer courses of preoperative T administration in larger numbers of older men undergoing knee replacement surgery are warranted