First-Line Treatment with Bevacizumab and Platinum Doublet Combination in Non-Squamous Non-Small Cell Lung Cancer: A Retrospective Cohort Study in US Oncology Community Practices.

BACKGROUND: Real-world evidence is lacking on the impact of bevacizumab added to carboplatin/paclitaxel (Bev + CP) therapy versus CP alone for patients with non-squamous non-small cell lung cancer (NS-NSCLC), particularly in those excluded from clinical trials. METHODS: This is a retrospective electronic medical record analysis of patients who received first-line therapy with Bev + CP or CP between 1 October 2006 and 30 June 2013. We identified four subsets: elderly patients (≥65 years), patients with brain/central nervous system (CNS) metastases, patients with Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, and patients receiving anticoagulation. We used descriptive statistics to describe patient characteristics and treatment patterns and evaluated progression-free survival (PFS) and overall survival (OS) using survival analyses. RESULTS: The study included 431 patients (Bev + CP: 231; CP: 200). The Bev + CP cohort was more likely to receive four or more cycles of induction therapy (72 vs. 50 %) and was more likely to receive maintenance therapy (45 vs. 21 %) than patients receiving CP. In the overall population, median PFS and OS were significantly longer in the Bev + CP cohort than in the CP cohort: 6.7 vs. 5.1 months (hazard ratio [HR] 0.74; 95 % confidence interval [CI] 0.59-0.92; p = 0.008) and 11.9 vs. 9.0 months (HR 0.57; 95 % CI 0.44-0.73; p < 0.001), respectively. Treatment with Bev + CP in patients aged ≥65 years and in those with brain/CNS metastases was also associated with a significant risk reduction in PFS (35 and 51 %, respectively; p < 0.05 for both) and OS (46 and 62 %, respectively; p < 0.05 for both) compared with CP alone. CONCLUSION: Bev + CP is associated with a significant improvement in PFS and OS in patients with NS-NSCLC and in subsets with brain/CNS metastases and those aged ≥65 years.

Surgical Resection Preferences and Perceptions among Medical Oncologists Treating Liver Metastases from Colorectal Cancer.

BACKGROUND: Liver resection is a key therapeutic strategy to improve survival in patients with colorectal cancer liver metastases. Underutilization may negatively affect outcomes. Using a Web-based survey and standardized imaging scenarios, this study assessed medical oncologists' (MOs) perceptions of resectability, preferences for chemotherapy sequencing, and referral for surgical consultation in a static patient profile of good performance status and no extrahepatic spread but varying bulk and distribution of disease. METHODS: A total of 190 US-based MOs were surveyed. A single patient profile was created and combined with 10 different sets of liver computed tomographic images displaying a broad spectrum of metastases. Assessments of resectability and ranking were compared with the results obtained from an expert panel of 3 hepatic surgeons. RESULTS: The expert hepatic surgeons designated 8 scans resectable, 1 borderline resectable/convertible, and 1 unresectable. In the 8 resectable cases, 34.4 % of MOS perceived the case to be initially resectable, 41.7 % potentially resectable after chemotherapy response, and 23.9 % unresectable. Increasing number of lesions, larger tumor diameter, and bilateral disease were associated with lower resectability perception (P < 0.01). Among those cases considered resectable by MOs, they preferred initial resection (54.2 %) over neoadjuvant chemotherapy (38.4 %). Initial referral for surgical consultation was generally favored only for cases considered initially resectable by MOs. CONCLUSIONS: This study confirms both potential discrepancies between MOs' and hepatic surgeons' perception of resectability and underutilization of early surgical consultation for patients with potentially resectable colorectal cancer liver metastases and underscores the importance of an evaluation that includes an experienced hepatic surgeon.

A phase II study of capecitabine plus docetaxel in gemcitabine-pretreated metastatic pancreatic cancer patients: CapTere.

PURPOSE: Docetaxel and capecitabine combination is synergistic in preclinical models. We investigated the efficacy and toxicity of this combination as second-line chemotherapy in patients with metastatic pancreatic adenocarcinoma (mPC), pretreated with gemcitabine-based chemotherapy. METHODS: Eligible patients were treated with capecitabine 800 mg/m(2) orally PO bid on days 1-14 in combination with intravenous docetaxel 30 mg/m(2) on days 1 and 8 of each 21-day cycle. The primary end point was overall response rate. Using a three-stage sequential design, two interim analyses for early stopping due to lack of efficacy were planned and conducted after 13 and 26 patients were accrued. Secondary end points included time to treatment failure, progression-free survival (PFS), overall survival (OS) and 50 % drop in CA19-9 levels. RESULTS: Forty-three patients were evaluable for toxicity and 42 evaluable for response, at a median age of 64 years. The majority of patients (74 %) had ECOG PS 0-1. Six patients (14 %) achieved a partial tumor response, and stable disease for ≥2 cycles was observed in 59 % of patients (n = 25). Thirty-five percent (n = 11/31) of patients had a ≥50 % decrease in CA19-9 levels. The median PFS was 3.7 months (95 % CI 2.1-4.3 months), and the median OS was 5.3 months (95 % CI 4.3-8.6 months). Treatment was generally well tolerated. Grade 3 toxicity and grade 4 toxicity were seen in 45 and 5 % of patients, respectively. One patient had a potential treatment-related mortality. CONCLUSIONS: The combination of capecitabine and docetaxel is active and well tolerated in mPC patients pretreated with gemcitabine-based therapy.

Cost effectiveness of first-line pemetrexed plus platinum compared with other regimens in the treatment of patients with nonsquamous non-small cell lung cancer in the US outpatient setting.

This retrospective observational study evaluated cost effectiveness of first-line treatment of advanced nonsquamous non-small cell lung cancer (NSCLC) with pemetrexed/platinum (Pem/Plat) relative to paclitaxel/carboplatin (Pac/Carbo) and paclitaxel/carboplatin/bevacizumab (Pac/Carbo/Bev). Patients initiating first-line treatment from 2006 to 2009 were identified in electronic medical records of 20 US oncology practices. Pem/Plat patients were matched 1:1 on important characteristics with Pac/Carbo and Pac/Carbo/Bev patients and followed for 1 year to assess progression, survival, and costs. Bootstrapping was used to calculate the probability of falling within quadrants of the incremental cost-effectiveness plane. Kaplan-Meier analysis and Cox proportional hazards regression modeling were also performed. Three hundred Pem/Plat patients (mean age, 67.6 years; male, 56.0%; PS 0/1, 71.0%) were matched with 300 patients in the other cohorts. Median PFS was 134 days (Pem/Plat) versus 106 days (Pac/Carbo) (hazard ratio [HR]: 0.67, P < 0.001) and 126 days (Pac/Carbo/Bev) (HR: 0.68, P < 0.001). Median OS was 298 days (Pem/Plat) versus 218 days (Pac/Carbo) (HR: 0.88, P = 0.08) and 271 days (Pac/Carbo/Bev) (HR: 0.93, P = 0.31). Pem/Plat therapy costs were higher versus Pac/Carbo ($21,841 higher PFS; $19,137 higher OS; P ≤ 0.05) and lower versus Pac/Carbo/Bev ($15,160 lower PFS; $19,946 lower OS; P ≤ 0.05). Pem/Plat had a greater probability of higher costs/higher effectiveness versus Pac/Carbo (PFS, 90.1%; OS, 96.3%) and lower costs/higher effectiveness versus Pac/Carbo/Bev (PFS, 69.5%; OS, 85.0%). Pem/Plat had higher cost and effectiveness than Pac/Carbo; depending on a payer's or society's willingness to pay, Pem/Plat may be considered cost effective compared with Pac/Carbo. Pem/Plat yielded greater effectiveness with lower costs than Pac/Carbo/Bev.

Phase II study of induction cisplatin and irinotecan followed by concurrent carboplatin, etoposide, and thoracic radiotherapy for limited-stage small-cell lung cancer, CALGB 30206.

INTRODUCTION: We sought to determine the efficacy of using both irinotecan- and etoposide-containing regimens sequentially for patients with untreated limited-stage small-cell lung cancer. METHODS: Patients with untreated, measurable, limited-stage small-cell lung cancer with performance status 0 to 2, and adequate organ function were eligible. Treatment consisted of induction with cisplatin 30 mg/m and irinotecan 65 mg/m intravenously on day 1 and 8, every 21 days for two cycles. Beginning day 43, daily chest irradiation to 70 Gy was administered concurrently with carboplatin area under curve 5 on day 1, and etoposide 100 mg/m on days 1 to 3, every 21 days for three cycles. The primary objective was to differentiate between 45% and 60% 2-year survival. RESULTS: Two induction cycles were delivered to 72 of 75 eligible patients (96%) and all planned treatment was delivered to 59 patients (79%). Cisplatin and irinotecan induction chemotherapy resulted in complete responses in 7% and partial responses in 64% (response rate 71%, 95% confidence interval [CI], 59%-81%). The best response to all therapy included 88% complete or partial responses (95% CI, 78%-94%). With median follow-up of 57 months, the median progression-free survival and overall survival are 12.6 (95% CI, 9.4-14.7) and 18.1 months (15.8-22.9), respectively. The 1- and 2-year survival was 69% and 31%, respectively. Frequent (>20%) grade 3 and 4 toxicities were neutropenia in 84%, hemoglobin in 36%, platelets in 51%, esophagitis in 22%, and dehydration in 24%. There were no fatal toxicities. CONCLUSIONS: This treatment regimen of irinotecan-cisplatin induction chemotherapy followed by 70 Gy concurrent radiation and etoposide-carboplatin had tolerable toxicity but did not meet the preplanned 2-year survival target for further development.

Physician preferences for management of patients with stage IIIA NSCLC: impact of bulk of nodal disease on therapy selection.

INTRODUCTION: Stage IIIA non-small cell lung cancer (NSCLC) constitutes a heterogeneous group of patients with predominant ipsilateral mediastinal (N2) disease. The spectrum of lymph node presentation has lead to a host of trials involving various therapeutic combinations, and optimal management has been unclear. METHODS: In 2007 and 2008, 10 live research events surveyed the practice preferences of American medical oncologists using two hypothetical scenarios. The first scenario was of a stage IIIA NSCLC in the right upper lobe with a single enlarged (>1 cm) 4R lymph node found to be malignant by mediastinoscopy. The second was of a bulky stage IIIA NSCLC with multistation N2 pathologically positive nodes. RESULTS: In the first scenario, 373 (92%) of the oncologists incorporated surgery into their treatment plan. Only 34 (8%) offered chemoradiotherapy alone. Neoadjuvant chemotherapy, followed by surgery and then additional chemoradiotherapy (32%), was the most commonly offered treatment strategy. In the second scenario, 209 (52%) medical oncologists chose definitive chemoradiation. A total of 193 (48%) included surgery as part of the treatment plan. CONCLUSIONS: The current standard of care for IIIA N2 NSCLC recognized before treatment is concurrent chemoradiotherapy. This study demonstrated that a significant proportion of oncologists treating locally advanced lung cancer include surgery as part of the treatment plan more so in single versus multinodal station disease. Since node positive locally advanced disease is such a common presentation for patients with lung cancer, well-designed clinical trials are needed to define the most advantageous treatment strategy for individual subsets of patients with stage IIIA disease.

Cisplatin, irinotecan, and bevacizumab for untreated extensive-stage small-cell lung cancer: CALGB 30306, a phase II study.

PURPOSE: The efficacy of cisplatin, irinotecan, and bevacizumab was evaluated in patients with extensive-stage small-cell lung cancer (ES-SCLC). PATIENTS AND METHODS: Patients with ES-SCLC received cisplatin 30 mg/m(2) and irinotecan 65 mg/m(2) on days 1 and 8 plus bevacizumab 15 mg/kg on day 1 every 21 days for six cycles on this phase II study. The primary end point was to differentiate between 50% and 65% 12-month survival rates. RESULTS: Seventy-two patients were enrolled between March 2005 and April 2006; four patients canceled, and four were ineligible. Grade 3 or 4 toxicities included neutropenia (25%), all electrolyte (23%), diarrhea (16%), thrombocytopenia (10%), fatigue (10%), nausea (10%), hypertension (9%), anemia (9%), infection (7%), vascular access thrombosis (2%), stroke (2%), and bowel perforation (1%). Three deaths (5%) occurred on therapy as a result of pneumonitis (n = 1), stroke (n =1), and heart failure (n = 1). Complete response, partial response, and stable disease occurred in three (5%), 45 (70%), and 11 patients (17%), respectively. Progressive disease occurred in one patient (2%). Overall response rate was 75%. Median progression-free survival (PFS) was 7.0 months (95% CI, 6.4 to 8.4 months). Median overall survival (OS) was 11.6 months (95% CI, 10.5 to 15.1 months). Hypertension ≥ grade 1 was associated with improved OS after adjusting for performance status (PS) and age (hazard ratio [HR], 0.55; 95% CI, 0.31 to 0.97; P = .04). Lower vascular endothelial growth factor levels correlated with worse PFS after adjusting for age and PS (HR, 0.90; 95% CI, 0.83 to 0.99; P = .03). CONCLUSION: PFS and OS times were higher compared with US trials in ES-SCLC with the same chemotherapy. However, the primary end point of the trial was not met. Hypertension was associated with improved survival after adjusting for age and PS.

Chemoradiotherapy and gefitinib in stage III non-small cell lung cancer with epidermal growth factor receptor and KRAS mutation analysis: cancer and leukemia group B (CALEB) 30106, a CALGB-stratified phase II trial.

INTRODUCTION: This study evaluated the addition of gefitinib to sequential or concurrent chemoradiotherapy (CRT) in unresectable stage III non-small cell lung cancer. METHODS: Between May 2002 and April 2005, 63 patients were entered before the study closing early. All received two cycles paclitaxel 200 mg/m and carboplatin area under the curve 6 intravenous plus gefitinib 250 mg daily. Poor risk stratum 1 (> or =5% weight loss and/or performance status 2) received radiotherapy 200 cGy for 33 fractions (6600 cGy) and gefitinib 250 mg daily. Good-risk stratum 2 (performance status: 0-1 weight loss and <5%) received the same RT with gefitinib 250 mg daily and weekly paclitaxel 50 mg/m plus carboplatin AUC 2. Consolidation gefitinib until progression was started after all toxicities were grade < or =2. RESULTS: Acute high-grade infield toxicities were not clearly increased compared with historical CRT data. Poor-risk (N = 21) median progression-free survival was 13.4 months (95% confidence interval [CI]: 6.4-25.2) and median overall survival 19.0 months (95% CI: 9.9-28.4). Good-risk (N = 39) median progression-free survival was 9.2 months (95% CI: 6.7-12.2), and median overall survival was 13 months (95% CI: 8.5-17.2). Thirteen of 45 tumors analyzed had activating epidermal growth factor receptor (EGFR) mutations, and 2 of 13 also had T790M mutations. Seven tumors of 45 had KRAS mutations. There was no apparent survival difference with EGFR-activating mutations versus wild type or KRAS mutation versus wild type. CONCLUSIONS: Survival of poor-risk patients with wild type or mutated EGFR receiving sequential CRT with gefitinib was promising. Survival for good-risk patients receiving concurrent CRT plus gefitinib was disappointing even for tumors with activating EGFR mutations.

Prognostic significance of mucin and p53 expression in stage IB non-small cell lung cancer: a laboratory companion study to CALGB 9633.

INTRODUCTION: Cancer and Leukemia Group B 9633 was a phase III trial that randomized patients with stage IB non-small cell lung cancer to observation or four cycles of carboplatin and paclitaxel. A statistically significant effect in favor of adjuvant chemotherapy was seen for disease-free survival (DFS) and overall survival (OS) in the subgroup of patients with tumors > or =4 cm. A laboratory companion study was conducted to see whether molecular and clinical factors could provide additional prognostic information. METHODS: Formalin-fixed, paraffin-embedded blocks were obtained for 250 of the 344 patients enrolled. Immunohistochemical staining for bcl-2, p53, blood group antigen A, and mucin was correlated with DFS and OS. RESULTS: The prevalence of the markers was bcl-2, 17%; p53, 47%; blood group antigen A, 25%; and mucin, 45%. Univariate analysis for DFS showed a statistically significant effect for the presence of mucin (p = 0.0005) and p53 (p = 0.05) and for OS showed a significant effect for mucin (p = 0.0005). In the multivariate Cox model, there was a statistically significant association between shorter DFS and presence of mucin (p = 0.002; hazard ratio [HR] 2.05) and p53 (p = 0.003; HR 1.95) and between shorter OS and presence of mucin (p = 0.004; HR 2.03) and p53 (p = 0.0005; HR 2.30). Of the clinical factors, male gender and larger tumor volume were also significant adverse prognostic factors (p 0.05). CONCLUSIONS: A statistically significant association between shorter DFS and OS was seen for the patients with p53 protein expression, mucin expression, male gender, and larger tumors in this cohort of patients with stage IB non-small cell lung cancer treated on Cancer and Leukemia Group B 9633.

Phase I study of accelerated conformal radiotherapy for stage I non-small-cell lung cancer in patients with pulmonary dysfunction: CALGB 39904.

PURPOSE: The optimal treatment for medically inoperable stage I non-small-cell lung cancer (NSCLC) has not been defined. PATIENTS AND METHODS: Cancer and Leukemia Group B trial 39904 prospectively assessed accelerated, once-daily, three-dimensional radiotherapy for early-stage NSCLC. The primary objectives were to define the maximally accelerated course of conformal radiotherapy and to describe the short-term and long-term toxicity of therapy. Entry was limited to patients with clinical stage T1N0 or T2N0 NSCLC (< 4 cm) and pulmonary dysfunction. The nominal total radiotherapy dose remained at 70 Gy, while the number of daily fractions in each successive cohort was reduced. RESULTS: Thirty-nine eligible patients were accrued (eight patients each on cohorts 1 to 4 and seven patients on cohort 5) between January 2001 and July 2005. One grade 3 nonhematologic toxicity was observed in both cohort 3 (dyspnea) and cohort 4 (pain). The major response rate was 77%. After a median follow-up time of 53 months, the actuarial median survival time of all eligible patients was 38.5 months. Local relapse was observed in three patients. CONCLUSION: Accelerated conformal radiotherapy was well tolerated in a high-risk population with clinical stage I NSCLC. Outcomes are comparable to prospective reports of alternative therapies, including stereotactic body radiation therapy and limited resection, with less apparent severe toxicity. Further investigation of this approach is warranted.

Treatment outcomes of different prognostic groups of patients on cancer and leukemia group B trial 39801: induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for unresectable stage III non-small cell lung cancer.

BACKGROUND: In Cancer and Leukemia Group B 39801, we evaluated whether induction chemotherapy before concurrent chemoradiotherapy would result in improved survival and demonstrated no significant benefit from the addition of induction chemotherapy. The primary objective of this analysis was to dichotomize patients into prognostic groups using factors predictive of survival and to investigate whether induction chemotherapy was beneficial in either prognostic group. PATIENTS AND METHODS: A Cox proportional hazard model was used to assess the impact on survival of the following factors: (>or=70 versus <70 years), gender, race, stage (IIIB versus IIIA), hemoglobin (hgb) (<13 versus >or=13 g/dl), performance status (PS) (1 versus 0), weight loss (>or=5% versus <5%), treatment arm, and the interaction between weight loss and hgb. RESULTS: Factors predictive of decreased survival were weight loss >or=5%, age >or=70 years, PS of 1, and hgb <13 g/dl (p < 0.05). Patients were classified as having >or=2 poor prognostic factors (n = 165) or or=2 versus patients with or=2 factors (HR = 0.86, 95% CI, 0.63-1.17; p = 0.34) or

Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial.

BACKGROUND: Results from phase II studies in patients with stage IIIA non-small-cell lung cancer with ipsilateral mediastinal nodal metastases (N2) have shown the feasibility of resection after concurrent chemotherapy and radiotherapy with promising rates of survival. We therefore did this phase III trial to compare concurrent chemotherapy and radiotherapy followed by resection with standard concurrent chemotherapy and definitive radiotherapy without resection. METHODS: Patients with stage T1-3pN2M0 non-small-cell lung cancer were randomly assigned in a 1:1 ratio to concurrent induction chemotherapy (two cycles of cisplatin [50 mg/m(2) on days 1, 8, 29, and 36] and etoposide [50 mg/m(2) on days 1-5 and 29-33]) plus radiotherapy (45 Gy) in multiple academic and community hospitals. If no progression, patients in group 1 underwent resection and those in group 2 continued radiotherapy uninterrupted up to 61 Gy. Two additional cycles of cisplatin and etoposide were given in both groups. The primary endpoint was overall survival (OS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00002550. FINDINGS: 202 patients (median age 59 years, range 31-77) were assigned to group 1 and 194 (61 years, 32-78) to group 2. Median OS was 23.6 months (IQR 9.0-not reached) in group 1 versus 22.2 months (9.4-52.7) in group 2 (hazard ratio [HR] 0.87 [0.70-1.10]; p=0.24). Number of patients alive at 5 years was 37 (point estimate 27%) in group 1 and 24 (point estimate 20%) in group 2 (odds ratio 0.63 [0.36-1.10]; p=0.10). With N0 status at thoracotomy, the median OS was 34.4 months (IQR 15.7-not reached; 19 [point estimate 41%] patients alive at 5 years). Progression-free survival (PFS) was better in group 1 than in group 2, median 12.8 months (5.3-42.2) vs 10.5 months (4.8-20.6), HR 0.77 [0.62-0.96]; p=0.017); the number of patients without disease progression at 5 years was 32 (point estimate 22%) versus 13 (point estimate 11%), respectively. Neutropenia and oesophagitis were the main grade 3 or 4 toxicities associated with chemotherapy plus radiotherapy in group 1 (77 [38%] and 20 [10%], respectively) and group 2 (80 [41%] and 44 [23%], respectively). In group 1, 16 (8%) deaths were treatment related versus four (2%) in group 2. In an exploratory analysis, OS was improved for patients who underwent lobectomy, but not pneumonectomy, versus chemotherapy plus radiotherapy. INTERPRETATION: Chemotherapy plus radiotherapy with or without resection (preferably lobectomy) are options for patients with stage IIIA(N2) non-small-cell lung cancer. FUNDING: National Cancer Institute, Canadian Cancer Society, and National Cancer Institute of Canada.

Impact of the ASCO 2007 presentation of HOG Lun 01-24/USO-023 on the prescribing plans of American medical oncologists for patients with stage IIIB non-small cell lung cancer.

INTRODUCTION: Nonoperative treatment of stage III non-small cell lung cancer has evolved over the past 30 years. The current approach in the Unites States most often includes concurrent chemoradiotherapy. METHODS: We have used live, case-based research events to document prescribing plans among American medical oncologists for first-line therapy in patients with N3 stage IIIB non-small cell lung cancer. Changes in prescribing plans documented before and after the 2007 American Society of Clinical Oncology (ASCO) presentation of a Hoosier Oncology Group trial testing the role of consolidation docetaxel chemotherapy in this setting are presented. RESULTS: Data from 2007 show a post-ASCO shift away from plans for docetaxel consolidation, increased use of concurrent chemoradiotherapy alone, and stable to increased plans for concurrent chemoradiation followed by additional cycles of the chemotherapy used during concurrent management (20%). Preliminary data from 2008 confirm the durability of these changes. CONCLUSIONS: The findings of the Hoosier Oncology Group trial support a transition away from docetaxel consolidation. A trend in this direction among American medical oncologists is clear from our data. However, nearly 20% of oncologists studied in 2008 still plan to use docetaxel consolidation. Furthermore, a majority of those studied after ASCO 2007 continue to report plans to use more than two cycles of chemotherapy as part of their preferred treatment recommendation despite no level I evidence to support this approach.

A phase II study of carboplatin, etoposide, and exisulind in patients with extensive small cell lung cancer: CALGB 30104.

PURPOSE: To assess the efficacy and toxicity of carboplatin, etoposide, and exisulind as initial therapy for extensive stage small cell lung cancer. PATIENTS AND METHODS: The Cancer and Leukemia Group B conducted a phase II study of carboplatin (area under the curve 6) day 1 and etoposide 80 mg/m(2) days 1-3 administered intravenously every 21 days with exisulind 250 mg orally twice daily in 44 evaluable patients with previously untreated extensive stage small cell lung cancer. The hypothesis was the addition of a novel cytostatic agent to standard therapy may increase survival time. The primary end point of the study was to evaluate overall survival. The secondary end points were to characterize response rates and toxicity. RESULTS: The majority of the patients were male (64%), Caucasian (95%), and had performance status 0 or 1 (77%). The median age was 61 (range 44-82) years. The percentage of patients alive at 1 year was 36.4% (95% [confidence interval] CI: 24.6-53.8%). The median overall survival was 10.6 months (95% CI: 9.1-14.7). The best overall response rate was 77% (95% CI: 62-89%) with 16% of the patients achieving complete response. The most frequent grade 3 or grade 4 hematological toxicities were neutropenia (64%), thrombocytopenia (36%), and febrile neutropenia (16%). The most common grade 3 or grade 4 nonhematological toxicities were gastrointestinal (30%) and electrolyte changes (23%). CONCLUSIONS: The addition of exisulind to a standard regimen of carboplatin and etoposide did not improve outcomes compared with historic controls treated with chemotherapy alone. Further evaluation of this regimen in small cell lung cancer is not warranted.

Phase II trial of paclitaxel and cisplatin in patients with extensive stage small cell lung cancer: Cancer and Leukemia Group B Trial 9430.

BACKGROUND: Cancer and Leukemia Group B trial 9430 was a randomized phase II trial which investigated the safety and activity of four novel doublets in untreated extensive stage small cell lung cancer. The results of the paclitaxel and cisplatin arm have not been reported. PATIENTS AND METHODS: Patients received paclitaxel 230 mg/m followed by cisplatin 75 mg/m on day 1 every 21 days. All patients received granulocyte colony stimulating factor 5 microg/kg/d beginning on day 3 of each cycle. RESULTS: The patient characteristics of the 34 patients assigned to this treatment arm were: median age 61.5 years (range 41-82), male (76%), performance status 0 (41%), 1 (32%), and 2 (26%). An objective response was observed in 23 patients (68%; 95% confidence interval (CI): 49-83%); 2 complete responses (6%) and 21 partial responses (62%). Median progression-free survival time was 5.6 months (95% CI: 4.8-7.1 month), and median overall survival time was 7.7 months (95% CI: 7.2-12.6 months). The 1-year survival rate observed was 29% (95% CI: 15-45%). Grade 3/4 neutropenia and thrombocytopenia was observed in 5 (15%) and 4 (12%) patients, respectively. Two patients developed febrile neutropenia including one patient who died of neutropenic sepsis. Grade 3/4 nonhematologic observed were: sensory neuropathy in eight patients (24%); and hyperglycemia, malaise and nausea were all observed in four patients (12%). CONCLUSIONS: Cancer and Leukemia Group B will not pursue further investigation of paclitaxel and cisplatin due to the modest activity and the toxicity observed on this trial.

Tomorrow's cancer treatments today: the first 50 years of the Cancer and Leukemia Group B.

Members of the Cancer and Leukemia Group B (CALGB) have been striving to improve cancer therapies for more than 50 years. The organization began in the mid 1950s as a multi-institutional collaboration between investigators at the National Cancer Institute, Roswell Park Memorial Institute, and the Children's Hospital in Buffalo New York. In 1956 the group was officially designated as the Acute Leukemia Group B (ALGB) and for most of its first decade focused largely on leukemia research. Reflecting an expansion of its research portfolio during the 1960s and 70s, the name was changed in 1976 to Cancer and Leukemia Group B. Currently, the organization has hundreds of members, including nurses, clinical research associates, statisticians, physicians, translational scientists, and an administrative staff from a nationwide network of academic and community based organizations and medical practices. Disease areas within the scope of CALGB research include hematologic malignancies, as well as breast, gastrointestinal, genitourinary, and respiratory cancers. Modality expertise includes quality of life, medical oncology, surgery, radiation oncology, pathology, imaging, oncology nursing, health outcomes, geriatrics, biostatistics, data management, and an extensive array of correlative sciences. Some of the major accomplishments of CALGB investigators and the patients participating in CALGB research as critical and committed partners will be reviewed here.

Phase II randomized study of dose-dense docetaxel and cisplatin every 2 weeks with pegfilgrastim and darbepoetin alfa with and without the chemoprotector BNP7787 in patients with advanced non-small cell lung cancer (CALGB 30303).

INTRODUCTION: We investigated dose-dense docetaxel and cisplatin in patients with measurable non-small cell lung cancer in a randomized phase II study without [A] or with [B] a putative chemoprotective agent, BNP7787. PATIENTS AND METHODS: Chemotherapy-naive patients with stage IIIB (effusion) or IV, performance status 0 to 1, and adequate organ function were eligible. Treatment with docetaxel 75 mg/m followed by cisplatin 75 mg/m over 1 hour day 1 with darbepoetin 200 mug day 1 and pegfilgrastim 6 mg day 2 without/with BNP7787 before cisplatin was repeated every other week for up to 6 cycles. The primary end point was to differentiate between grade >/=2 neurotoxicity rates of 30% on [A] and 10% on [B]. Feasibility was prospectively defined as febrile neutropenia in <10% of patients and /=2 occurred in 32% on [A] and 29% on [B]. The incidence of febrile neutropenia was 4% on [A] and 3% on [B]. Treatment delays occurred in 13% and 20% of patients on [A] and [B], respectively. Completion rates for 3/6 cycles were 84%/51% on [A] and 84%/53% on [B]. Objective response rates were 55% on [A] and 51% on [B]. Median progression-free/overall survival times were 5.5/10.7 on [A] and 6.5/14.1 month on [B]. CONCLUSIONS: This dose-dense treatment regimen is active, feasible, and tolerable. Its further investigation in the curative setting in non-small cell lung cancer should be considered. BNP7787 did not result in significant protection from neurotoxicity.

Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups.

PURPOSE: Adjuvant chemotherapy for resected non-small-cell lung cancer (NSCLC) is now accepted on the basis of several randomized clinical trials (RCTs) that demonstrated improved survival. Although there is strong evidence that adjuvant chemotherapy is effective in stages II and IIIA NSCLC, its utility in stage IB disease is unclear. This report provides a mature analysis of Cancer and Leukemia Group B (CALGB) 9633, the only RCT designed specifically for stage IB NSCLC. PATIENTS AND METHODS: Within 4 to 8 weeks of resection, patients were randomly assigned to adjuvant chemotherapy or observation. Eligible patients had pathologically confirmed T2N0 NSCLC and had undergone lobectomy or pneumonectomy. Chemotherapy consisted of paclitaxel 200 mg/m(2) intravenously over 3 hours and carboplatin at an area under the curve dose of 6 mg/mL per minute intravenously over 45 to 60 minutes every 3 weeks for four cycles. The primary end point was overall survival. RESULTS: Three hundred-forty-four patients were randomly assigned. Median follow-up was 74 months. Groups were well-balanced with regard to demographics, histology, and extent of surgery. Grades 3 to 4 neutropenia were the predominant toxicity; there were no treatment-related deaths. Survival was not significantly different (hazard ratio [HR], 0.83; CI, 0.64 to 1.08; P = .12). However, exploratory analysis demonstrated a significant survival difference in favor of adjuvant chemotherapy for patients who had tumors > or = 4 cm in diameter (HR, 0.69; CI, 0.48 to 0.99; P = .043). CONCLUSION: Because a significant survival advantage was not observed across the entire cohort, adjuvant chemotherapy should not be considered standard care in stage IB NSCLC. Given the magnitude of observed survival differences, CALGB 9633 was underpowered to detect small but clinically meaningful improvements. A statistically significant survival advantage for patients who had tumors > or = 4 cm supports consideration of adjuvant paclitaxel/carboplatin for stage IB patients who have large tumors.

Response to the methylation inhibitor dihydro-5-azacytidine in mesothelioma is not associated with methylation of p16INK4a: results of cancer and leukemia group B 159904.

INTRODUCTION: The molecular mechanisms of oncogenesis in mesothelioma involve the loss of negative regulators of cell growth including p16INK4a. Absence of expression of the p16INK4a gene product is exhibited in virtually all mesothelioma tumors and cell lines examined to date. Loss of p16INK4a expression has also been frequently observed in more common neoplasms such as lung cancer as well. In a wide variety of these malignancies, including lung cancer, p16INK4a expression is known to be inactivated by hypermethylation of the first exon. This project (CALGB 159904) intended to test the hypothesis that in mesothelioma loss of p16INK4a via methylation would correlate with response to the cytidine analog and methylation inhibitor dihydro-5-azacytidine (DHAC). METHODS: Using tissue samples from CALGB 8833 and 9031, two clinical studies which used DHAC based therapy in mesothelioma, this study tested the hypothesis that tumors possessing methylation of p16INK4a would have a better response and survival following DHAC treatment than their nonmethylated counterparts. RESULTS: Methylation of p16INK4a was identified in 4 of the 20 specimens. Although there was a trend towards improved survival the result was not statistically significant. CONCLUSIONS: There was no significant correlation between the presence of p16INK4a methylation and response to DHAC therapy or overall survival.