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This study sought to define the role of first-line platinum-based doublet chemotherapy in older patients with non-small cell lung cancer (NSCLC).We analyzed three first-line NSCLC trials: CALGB 9730, CALGB 30203, and CALGB 30801, which tested carboplatin and paclitaxel; carboplatin and gemcitabine; and carboplatin with either pemetrexed or gemcitabine, respectively. Overall survival was the primary endpoint. Age-based comparisons with a cutpoint of 65 years were performed with Cox proportional hazards models with adjustments for sex, tumor histology, cancer stage, chemotherapy, and smoking history and after stratifying by performance score. Secondary endpoints were grade 3-5 adverse events, chemotherapy cycles completed, and whether toxicity prompted chemotherapy discontinuation.730 patients were included; 337 (46%) were 65+ years of age. No statistically significant difference in survival was observed for older (≥65) versus younger patients (HR = 1.096; 95% CI = (0.94, 1.28); p = 0.25). A trend emerged with increased odds of a grade 3-5 adverse event for patients ≥65 years versus65 years (OR = 1.52; 95% CI = (0.99, 2.31); p = 0.05). The proportion of completed chemotherapy cycles was marginally lower in older patients (difference = -5%; 95% CI = (-9, 0.2); p = 0.06) for those ≥65 years versus65 years, but no statistically significant difference occurred in the rate of chemotherapy discontinuation for toxicity (OR = 1.4; 95% CI = (0.85, 2.19); p = 0.21) for patients ≥65 years versus65 years. A cutpoint of 70 years yielded similar results.These findings support carboplatin doublet-based chemotherapy in select older patients with advanced NSCLC.

Purpose: Many US academic centers have acquired community practices to expand their clinical care and research footprint. The objective of this assessment was to determine whether the acquisition and integration of community oncology practices by Yale/Smilow Cancer Hospital improved outcomes in quality of care, disease team integration, clinical trial accrual, and patient satisfaction at network practice sites. Methods: We evaluated quality of care by testing the hypothesis that core Quality Oncology Practice Initiative measures at network sites that were acquired in 2012 were significantly different after their 2016 integration into the network. Clinical and research integration were measured using the number of tumor board case presentations and total accruals in clinical trials. We used Press-Ganey scores to measure patient satisfaction pre- and postintegration. Results: Mean Quality Oncology Practice Initiative scores at Smilow Care Centers were significantly higher in 2016 than in 2012 for core measures related to improvement in tumor staging ( z = 1.33; P < .05), signed consent and documentation plans for antineoplastic treatment ( z = 2.69; P < .01; and z = 2.36; P < .05, respectively), and appropriately quantifying and addressing pain during office visits ( z = 2.95; P < .05; and z = 3.1; P < .01, respectively). A total of 493 cases were presented by care center physicians at the tumor board in 2017 compared with 45 presented in 2013. Compared with 2012, Smilow Care Center clinical trial accrual increased from 25 to 170 patients in 2017. Last, patient satisfaction has remained at greater than the 90th percentile pre- and postintegration. Conclusion: The process of integration facilitates the ability to standardize cancer practice and provides a platform for quality improvement.

The US lung cancer population is aging, the majority of which receive a diagnosis of incurable advanced non-small cell lung cancer (NSCLC). In US clinical oncology practice, elderly is defined as patients older than 70 years. Treatment of elderly patients with advanced NSCLC is complex. Choosing appropriate chemotherapy in this setting is complicated by multiple chronic conditions in addition to geriatric syndromes, challenging the traditional oncology practice. Although promising new options are on the horizon, the standard of care remains either platinum-based doublet or single-agent chemotherapy. Clinical trials have determined doublet therapy is appropriate for elderly patients; however, out of concern for excessive toxicity, many elderly patients do not receive appropriate treatment. Determining which patients are most likely to benefit from doublet chemotherapy versus monotherapy is a difficult challenge. Researchers have started to implement geriatric assessment and predictive chemotherapy toxicity tools in prospective clinical trials; however, knowledge gaps remain on how to appropriately select and treat elderly patients with advanced NSCLC in efforts to improve disease management and symptoms, maintain functional status, and minimize toxicity.

Purpose Survival of patients with completely resected non–small-cell lung cancer (NSCLC) is unsatisfactory, and in 2002, the benefit of adjuvant chemotherapy was not established. This phase III study assessed the impact of postoperative adjuvant gefitinib on overall survival (OS). Patients and Methods Patients with completely resected (stage IB, II, or IIIA) NSCLC stratified by stage, histology, sex, postoperative radiotherapy, and chemotherapy were randomly assigned (1:1) to receive gefitinib 250 mg per day or placebo for 2 years. Study end points were OS, disease-free survival (DFS), and toxicity. Results As a result of early closure, 503 of 1,242 planned patients were randomly assigned (251 to gefitinib and 252 to placebo). Baseline factors were balanced between the arms. With a median of 4.7 years of follow-up (range, 0.1 to 6.3 years), there was no difference in OS (hazard ratio [HR], 1.24; 95% CI, 0.94 to 1.64; P = .14) or DFS (HR, 1.22; 95% CI, 0.93 to 1.61; P = .15) between the arms. Exploratory analyses demonstrated no DFS (HR, 1.28; 95% CI, 0.92 to 1.76; P = .14) or OS benefit (HR, 1.24; 95% CI, 0.90 to 1.71; P = .18) from gefitinib for 344 patients with epidermal growth factor receptor (EGFR) wild-type tumors. Similarly, there was no DFS (HR, 1.84; 95% CI, 0.44 to 7.73; P = .395) or OS benefit (HR, 3.16; 95% CI, 0.61 to 16.45; P = .15) from gefitinib for the 15 patients with EGFR mutation-positive tumors. Adverse events were those expected with an EGFR inhibitor. Serious adverse events occurred in ≤ 5% of patients, except infection, fatigue, and pain. One patient in each arm had fatal pneumonitis. Conclusion Although the trial closed prematurely and definitive statements regarding the efficacy of adjuvant gefitinib cannot be made, these results indicate that it is unlikely to be of benefit.

Purpose To compare single-agent pemetrexed (P) versus the combination of carboplatin and pemetrexed (CP) in first-line therapy for patients with advanced non–small-cell lung cancer (NSCLC) with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2. Patients and Methods In a multicenter phase III randomized trial, patients with advanced NSCLC, ECOG PS of 2, any histology at first and later amended to nonsquamous only, no prior chemotherapy, and adequate organ function were randomly assigned to P alone (500 mg/m2) or CP (area under the curve of 5 and 500 mg/m2, respectively) administered every 3 weeks for a total of four cycles. The primary end point was overall survival (OS). Results A total of 205 eligible patients were enrolled from eight centers in Brazil and one in the United States from April 2008 to July 2011. The response rates were 10.3% for P and 23.8% for CP (P = .032). In the intent-to-treat population, the median PFS was 2.8 months for P and 5.8 months for CP (hazard ratio [HR], 0.46; 95% CI, 0.35 to 0.63; P < .001), and the median OS was 5.3 months for P and 9.3 months for CP (HR, 0.62; 95% CI, 0.46 to 0.83; P = .001). One-year survival rates were 21.9% and 40.1%, respectively. Similar results were seen when patients with squamous disease were excluded from the analysis. Anemia (grade 3, 3.9%; grade 4, 11.7%) and neutropenia (grade 3, 1%; grade 4, 6.8%) were more frequent with CP. There were four treatment-related deaths in the CP arm. Conclusion Combination chemotherapy with CP significantly improves survival in patients with advanced NSCLC and ECOG PS of 2.

Background This study was a retrospective analysis of elderly patients treated with stereotactic body radiotherapy (SBRT) in the setting of a multi-institutional consortium. Patients and Methods Three institutions pooled data on patients aged ≥ 75 years who received SBRT for stage I non–small-cell lung cancer (NSCLC). Forty-seven tumors in 46 patients were analyzed in patients aged 75 to 92 years (median, 82 years). Treatment was delivered during 2007 to 2009, with a median follow-up of 12.4 months. All patients underwent staging positron emission tomography–computed tomography (PET-CT), and 87% of tumors were confirmed by biopsy results. Total doses were 35 to 60 Gy, mainly in 3 to 5 fractions. All tumors were treated using a linear accelerator, with 96% of patients receiving 3-dimensional (3D) conformal RT and 4% undergoing intensity modulated RT (IMRT). Results At the time of analysis, the local failure rate was 2% (1 of 47). The regional failure rate was 9% (4 of 47). The distant failure rate was 6% (3 of 47). The combined failure rate was 15% (7 of 47) because 1 patient experienced both regional and distant failure. Among 20 tumors with any acute toxicity, there were no ≥ grade 3 toxicities. Pneumonitis (n = 10) grades 1 (n = 3) and 2 (n = 2) was seen in 15% and 10% of patients, respectively; these data were missing for 25% of patients. Conclusion SBRT in patients aged ≥ 75 years with stage I NSCLC proved tolerable, with toxicity rates comparable to those in younger patients. Excellent rates of local, regional, and distant control were achieved at a median follow-up of 12.4 months. This patient population represents a rapidly growing segment of the early lung cancer population, and SBRT appears to be a safe and effective treatment option for patients who are not optimal candidates for surgery.

The use of EGF receptor inhibitors has recently been incorporated into the armamentarium of agents available to treat patients with non-small-cell lung cancer. Their use in combination with chemotherapy and radiotherapy has been investigated in Phase II and III trials. The use of EGF receptor tyrosine kinase inhibitors in combination with chemotherapy has been somewhat disappointing, whereas the use of anti-EGF receptor monoclonal cetuximab in combination with chemotherapy has provided mixed results. The use of cetuximab in combination with chemotherapy and radiotherapy in patients with locally advanced disease has generated encouraging results in Phase II trials, and Phase III trials are currently ongoing. The identification of molecular biomarkers to predict benefit is a work in progress.

Purpose IPI-504 is a novel, water-soluble, potent inhibitor of heat-shock protein 90 (Hsp90). Its potential anticancer activity has been validated in preclinical in vitro and in vivo models. We studied the activity of IPI-504 after epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in patients with advanced, molecularly defined non–small-cell lung cancer (NSCLC). Patients and Methods Patients with advanced NSCLC, prior treatment with EGFR TKIs, and tumor tissue available for molecular genotyping were enrolled in this prospective, nonrandomized, multicenter, phase II study of IPI-504 monotherapy. The primary outcome was objective response rate (ORR). Secondary aims included safety, progression-free survival (PFS), and analysis of activity by molecular subtypes. Results Seventy-six patients were enrolled between December 2007 and May 2009 from 10 United States cancer centers. An ORR of 7% (five of 76) was observed in the overall study population, 10% (four of 40) in patients who were EGFR wild-type, and 4% (one of 28) in those with EGFR mutations. Although both EGFR groups were below the target ORR of 20%, among the three patients with an ALK gene rearrangement, two had partial responses and the third had prolonged stable disease (7.2 months, 24% reduction in tumor size). The most common adverse events included grades 1 and 2 fatigue, nausea, and diarrhea. Grade 3 or higher liver function abnormalities were observed in nine patients (11.8%). Conclusion IPI-504 has clinical activity in patients with NSCLC, particularly among patients with ALK rearrangements.

Purpose During the last 25 years, National Cancer Institute (NCI) cooperative trial groups have extended trial networks from academic centers to include certain community and Veterans Health Administration (VHA) centers. We compared trial patients' attributes and outcomes by these enrollment settings. Patients and Methods Studying 2,708 patients on one of 10 cooperative group, randomized lung trials at 272 institutions, we compared patient attributes by enrollment setting (ie, academic, community, and VHA affiliates). We used adjusted Cox regression to evaluate for survival differences by setting. Results Main member institutions enrolled 44% of patients; community affiliates enrolled 44%; and VHAs enrolled 12%. Patient attributes (ie, case-mix) of age, ethnicity, sex, and performance status varied by enrollment setting. After analysis was adjusted for patient case-mix, no mortality differences by enrollment setting were noted. Conclusion Although trial patients with primarily advanced-stage lung cancer from nonacademic centers were older and had worse performance statuses than those from academic centers, survival did not differ by enrollment setting after analysis accounted for patient heterogeneity. An answer for whether long-term outcomes for patients at community and VHA centers affiliated with cooperative trial groups are equivalent to those at academic centers when care is delivered through NCI trials requires additional research among patients with longer survival horizons.

Purpose A randomized phase II trial of two novel treatment strategies in the first-line management of advanced non–small-cell lung cancer patients with performance status (PS) 2. Patients and Methods Patients were assigned to docetaxel 30 mg/m2 on days 1, 8, and 15 every 28 days in combination with either cetuximab 400 mg/m2 loading dose followed by 250 mg/m2 weekly (D + C) or bortezomib 1.6 mg/m2 on days 1, 8, and 15 every 28 days (D + B) for up to 4 cycles. Patients with responding or stable disease continued cetuximab or bortezomib until progression. The primary end point was progression-free survival (PFS) rate at 6 months. Results Sixty-four patients were enrolled and 59 were included in this analysis. Complete or partial response rates were 13.3% and 10.3% for D + C and D + B, respectively. Median PFS was 3.4 months in the D + C arm and 1.9 months in the D + B arm. Corresponding figures for 6-month PFS were 27.8% and 13.8% and 5.0 and 3.9 months for median survival, respectively. Grade 3/4 hematologic toxicity was 16% for D + C and 21% for D + B, whereas nonhematologic toxicities were observed in 63% and 44% of patients, respectively. There was one treatment-related death in each arm. Conclusion These results confirm the poor prognosis associated with a PS of 2 and the difficulty in translating recent advances in targeted therapy to this subset of patients. While the results in the D + C arm are numerically superior, neither combination met the prespecified PFS end point to justify further research in this setting.

Even with the introduction of targeted agents and the establishment of multiple lines of therapy, the median survival for patients with advanced non-small cell lung cancer (NSCLC) does not considerably extend beyond 1 year. Emerging research suggests that clinical characteristics alone are insufficient for selecting patients for therapies that may confer significant survival benefit. The discovery of predictive and prognostic molecular markers such as gene mutations in EGFR and KRAS as well as high tumor expression levels of DNA repair pathway components ribonucleotide reductase subunit 1 and excision repair cross-complementing group 1 has sparked an interest in the development of individualized therapy as a strategy for increasing survival in patients with NSCLC. Techniques to analyze molecular biomarkers, such as immunohistochemistry, fluorescence in situ hybridization, polymerase chain reaction, and, more recently, gene microarray techniques, are being investigated for their potential to accurately predict an individual patient's response to therapy. Many prospective trials are still needed to clarify and confirm the utility of molecular biomarkers for guiding treatment selection, and continued participation in clinical trials is critical for the development of tools to provide customized treatment plans for patients with NSCLC.

Purpose:Data from two randomized phase III trials were analyzed to evaluate prognostic factors and treatment selection in the first-line management of advanced non-small cell lung cancer patients with performance status (PS) 2.Patients and Methods:Patients randomized to combination chemotherapy (carboplatin and paclitaxel) in one trial and single-agent therapy (gemcitabine or vinorelbine) in the second were included in these analyses. Both studies had identical eligibility criteria and were conducted simultaneously. Comparison of efficacy and safety was performed between the two cohorts. A regression analysis identified prognostic factors and subgroups of patients that may benefit from combination or single-agent therapy.Results:Two hundred one patients were treated with combination and 190 with single-agent therapy. Objective responses were 37 and 15%, respectively. Median time to progression was 4.6 months in the combination arm and 3.5 months in the single-agent arm (p < 0.001). Median survival times were 8.0 and 6.6 months, and 1-year survival rates were 31 and 26%, respectively. Albumin

The treatment of advanced non-small cell lung cancer has evolved substantially during the last decade. Chemotherapy with a platinum-based doublet prolongs survival and improves quality of life in patients with good performance status. Recently, the addition of bevacizumab and the use of epidermal growth factor receptor inhibitors in appropriately selected patients have further improved the outcome of patients with advanced non-small cell lung cancer. Newer targeted agents are being developed and tested in the clinical arena at a rapid pace. In addition, the identification by clinical or molecular criteria of patient populations that benefit the most from these agents is under active investigation. In contrast, the development of newer cytotoxic agents, with innovative mechanisms of action, has been comparatively disappointing. Whether standard cytotoxic drugs are required as newer biologic agents are more frequently used or whether a more active and safer chemotherapy can be used as a template for combinations with biologic agents remains an important research topic.

The promise of effective targeted therapy for lung cancer requires rigorous identification of potential targets combined with intensive discovery and development efforts aimed at developing effective “drugs” for these targets. We now recognize that getting the right drug to the right target in the right patient is more complicated than one could have imagined a decade ago. As knowledge of targets and development of agents have proliferated and advanced, so too have data demonstrating the biologic heterogeneity of tumors. The finding that lung cancers are genetically diverse and can exhibit several pathways of resistance in response to targeted agents makes the prospect for curative therapy more daunting. It is becoming increasingly clear that single-agent treatment will be the exception rather than the rule. This information raises important new questions about the development and assessment of novel agents in lung cancer treatment: (1) How do we identify the most important drug targets for tumor initiation and maintenance? (2) What is the best way to assess drug candidates that may only be relevant in a small fraction of patients? (3) What models do we use to predict clinical response and identify effective combinations? And (4) how do we bring combination regimens to the clinic, particularly when the agents are not yet approved individually and may be under development from different companies? The Fifth Cambridge Conference on Novel Agents in the Treatment of Lung Cancer was held in Cambridge, Massachusetts, on October 1–2, 2007, to discuss these questions by reviewing recent progress in the field and advancing recommendations for research and patient care. New information, conclusions, and recommendations considered significant for the field by the program faculty are summarized here and presented at greater length in the individual articles and accompanying discussions that comprise the full conference proceedings. A CME activity based on this summary is also available at www.informedicalcme.com/cme.

Introduction We conducted a multicenter phase II study to evaluate the efficacy and safety of oxaliplatin and gemcitabine with bevacizumab in patients with advanced non-small cell lung cancer (NSCLC). Methods Patients with chemotherapy-naive, nonsquamous, stage IIIB or IV NSCLC received gemcitabine 1000 mg/m 2 on days 1 and 8, oxaliplatin 130 mg/m 2 on day 1, and bevacizumab 15 mg/kg on day 1 every 21 days for 4 cycles. Patients with stable disease or response received maintenance bevacizumab every 3 weeks until progression. Primary end point was median time to progression (TTP). Results Nineteen of 44 eligible patients had partial response in the intent-to-treat analysis for an objective response rate of 43% (95% confidence interval [CI], 26.3–60.1%); 16 patients had stable disease for a disease control rate of 80% (95% CI, 72.0–87.0%). Median TTP was 5.5 months (95% CI, 3.8–6.9 months), which approached that seen in phase III studies. Median survival was 13.7 months (95% CI, 7.3–21.8 months). The most common grade 3 or 4 adverse events were hypertension (11%), neutropenia (9%), diarrhea (7%), dyspnea (7%), and thromboembolic events (7%). Pulmonary hemorrhage was not observed. Conclusions The results of this phase II study suggest that oxaliplatin and gemcitabine with bevacizumab was active and reasonably well tolerated. Median TTP approached that in phase III studies. This combination represents another treatment option for advanced NSCLC.

Purpose A multicenter randomized phase II trial to evaluate two treatment strategies in the first-line management of advanced non–small-cell lung cancer (NSCLC) patients with a performance status (PS) of 2. Patients and Methods Patients were assigned to erlotinib 150 mg orally daily until progression or to carboplatin (area under the curve [AUC] 6) and paclitaxel (200 mg/m2 day 1 every 3 weeks) for up to four cycles. Patients who experienced progression or did not tolerate or refused further chemotherapy were allowed to cross over to erlotinib. The primary end point was progression-free survival (PFS). Secondary end points were response, survival, quality of life (QOL), and a retrospective molecular correlation. Results Fifty-two patients were randomly assigned to erlotinib and 51 to chemotherapy. Partial responses were 2% and 12%, respectively. Median PFS was 1.9 months in the erlotinib arm and 3.5 months in the chemotherapy arm (hazard ratio [HR] = 1.45; 95% CI, 0.98 to 2.15; P = .06). Median survival times were 6.5 and 9.7 months, respectively (HR = 1.73; 95% CI, 1.09 to 2.73; P = .018). Patients who crossed over to erlotinib had a median survival of 14.9 months. Sex, histology, skin rash, and smoking history predicted outcome with erlotinib. Rash and diarrhea were more common with erlotinib; emesis, alopecia, peripheral neuropathy, and fatigue were more common with chemotherapy. QOL was similar between the two arms. Molecular correlation was limited by available samples. Conclusion Unselected patients with advanced NSCLC and PS 2 are best treated with combination chemotherapy as first-line therapy. Erlotinib may be considered in patients selected by clinical or molecular markers.

Background Stage IV non-small cell lung cancer (NSCLC) remains a treatable but incurable disease. Methods A MEDLINE search was performed to identify pertinent peer-reviewed articles that addressed the questions posed for this section. The writing committee developed and graded recommendations, which were subsequently approved by the American College of Chest Physicians. Results Platinum-based doublets remain the standard of care in patients with good performance status (PS); there is no evidence that the addition of a third cytotoxic agent improves survival. Likewise, with only one exception, the addition of a new targeted or biological agent to platinum-based doublets does not improve survival. The one exception is the addition of bevacizumab, an antiangiogenic agent, to carboplatin/paclitaxel in patients with stage IV disease and good PS. Patients for whom bevacizumab is recommended must also be selected on the basis of histology (nonsquamous), absence of brain metastases and hemoptysis, and no indication for therapeutic anticoagulation. In patients with stage IV NSCLC and PS of 2, chemotherapy is recommended, but the optimal approach has not been defined. Elderly patients, defined as ≥ 70 years old, also derive benefit from chemotherapy. Most elderly patients should receive single-agent chemotherapy, but elderly patients with good PS and without significant comorbidities seem to derive a similar benefit from platinum-based doublets compared with their younger counterparts without a prohibitive difference in treatment toxicities. Because stage IV NSCLC is incurable, quality-of-life issues are important, and tools exist to monitor a patient's quality of life during therapy. Last, patients need to be informed of the implication of the diagnosis of stage IV NSCLC and be educated about treatment options that are available to them. Conclusions Advances have been made in stage IV NSCLC, and the appropriate use of chemotherapy continues to evolve on the basis of well-designed clinical trials that address critical issues in this population.

Background:We conducted a multicenter randomized phase II trial to evaluate two schedules of single-agent docetaxel in the first-line treatment of elderly and performance status (PS) 2 patients with advanced non-small cell lung cancer (NSCLC).Methods:Patients 70 years of age and older with a PS 0–1 or patients of any age and PS 2 were randomly assigned to docetaxel 75 mg/m2 on day 1 every 3 weeks or 30 mg/m2 on days 1, 8, and 15 every 28 days. The primary end point was frequency of grade 3/4 toxicities. Health-related quality of life, response, and survival were secondary end points.Results:Fifty-five patients were randomized to received docetaxel every 3 weeks and 56 to receive docetaxel weekly. Hematologic toxicity, primarily grade 3/4 neutropenia, was significantly lower in the weekly schedule (0% versus 44%; p < 0.001). Health-related quality of life was similar between the two arms. Efficacy parameters were not significantly different, with a trend toward better survival in the weekly schedule group (6.7 versus 3.5 months). Patients with PS 0–1 had a significantly longer survival compared with PS 2 patients (7.8 versus 2.9 months; p < 0.001). A subset analysis of 30 octogenarian patients revealed similar outcomes as in 70- to 79-year-old patients.Conclusion:Weekly docetaxel is associated with less neutropenia and a trend toward improved survival in elderly or PS 2 patients. PS rather than age is the primary determinant of outcome in this population. Octogenarians benefited from weekly docetaxel. Future studies should separate elderly patients from PS 2 patients.

The treatment of patients with advanced non-small cell lung cancer has changed considerably in the past decade. This paper reviews the most significant changes seen in chemotherapy and the most promising new agents in development for this disease.Chemotherapy prolongs survival and improves quality of life in patients with a good performance status and appears to alleviate disease-related symptoms in patients with a lower performance status. Platinum-based regimens became standard; none of the third-generation drug combinations seemed to be superior to the others. Nonplatinum combinations are reasonable alternatives now and offer a better toxicity profile in certain populations. Attempts to add molecular-targeted therapy to combination chemotherapy have failed except for bevacizumab. New compounds such as pemetrexed, bortezomib, TLK286, bevacizumab, and the epothilones are currently being evaluated in non-small cell lung cancer.Management of non-small cell lung cancer has improved considerably in the past decade. The overall benefit of chemotherapy over supportive care has been shown, platinum-based doublets have been established, nonplatinum regimens have been developed, chemotherapy has been used more broadly in subgroups of patients who have been previously neglected, and a shorter chemotherapy duration has been shown to be equally effective. After hitting a plateau in the benefit of chemotherapy, new drugs with novel action mechanisms such as the ones described here offer hope to improve therapy for this disease.

The antisense oligonucleotide aprinocarsen specifically inhibits the transcription of protein kinase C-alpha. This study evaluated the response rate of the combination therapy of aprinocarsen, gemcitabine, and carboplatin in previously untreated patients with advanced non-small cell lung cancer (NSCLC). Secondary objectives included the measurement of time-to-event efficacy parameters and toxicity. Patients with stage IV or stage IIIB disease (N(3) and/or pleural/pericardial effusion) were treated with gemcitabine 1,250 mg/m(2) on days 1 and 8 and carboplatin AUC 5 on day 1 every 21 days. Aprinocarsen was administered as 2mg/kg/day continuous iv infusion on the first 14 days of each cycle, following the carboplatin treatment. A total of 36 patients received a median of 3 treatment cycles, with 10 patients completing 6 cycles. No complete response was observed, while partial response was seen in 25% of patients. Stable disease and progressive disease was observed in 36.1% and 22.2% of patients. The median overall survival was 8.3 months, and the median duration of progression-free survival was 5.7 months (95% CI, 3.2-7.1 months). Thrombocytopenia (78%) and neutropenia (50%) were the major grade 3/4 toxicities. Enrollment for this study was stopped and the study was terminated in March 2003 due to the results of a large phase III study, which suggested that aprinocarsen did not improve response or add survival benefit to chemotherapy in advanced NSCLC. The addition of aprinocarsen to gemcitabine+carboplatin therapy in patients with NSCLC showed moderate activity. However, this combination resulted in severe thrombocytopenia in the majority of patients.

Background: The present study was designed to evaluate the efficacy and safety of the regimen of carboplatin plus paclitaxel (investigational arm) versus the reference regimen of cisplatin plus etoposide for the treatment of advanced or metastatic non-small-cell lung cancer. Patients and methods: A total of 369 patients were enrolled, 179 on arm A (cisplatin 75 mg/m 2 and etoposide 100 mg/m 2 ) and 190 on arm B (carboplatin AUC = 6 mg/ml min and paclitaxel 225 mg/m 2 ), with cycles repeated every 3 weeks. The arms were well balanced with respect to age, performance status, weight loss, stage of disease and disease measurability. However, significantly more women were randomized to arm A than to arm B (P = 0.039). Results: The objective response rate (ORR) was 15% on arm A compared with 23% on arm B (P = 0.061). Median survival time, time to progression and 1-year survival rates for arms A and B were 274 days and 233 days (P = 0.086), 111 days and 121 days (P = 0.877), and 37% and 32%, respectively. The most prevalent toxicities were neutropenia and leukopenia and they occurred at a higher rate in arm A than in arm B. Conclusion: There was no statistically significant survival advantage for carboplatin‐ paclitaxel compared with cisplatin ‐ etoposide. However, there was an overall benefit in quality of life with the

Background The purpose of this study was to compare quality of life and overall toxicity in patients with advanced non-small-cell lung cancer (NSCLC) treated with vinorelbine–gemcitabine (VG) or carboplatin–paclitaxel (Taxol) (CP). Patients and methods A total of 165 previously untreated patients were randomized to the two regimens. Quality of life was assessed by the Lung Cancer Symptom Scale (LCSS). Overall toxicity and secondary efficacy end points were evaluated by standard WHO criteria. Results There was no significant difference in overall quality of life between the two treatments. Neutropenia, thrombocytopenia, peripheral neuropathy, and alopecia, were more common in the CP arm, whereas constipation was more frequent in the VG arm. Response rates were 14.6% in the VG arm and 16.9% in the CP arm. Median survival times were 7.8 and 8.6 months, and 1 year survival rates were 38.4% and 31.9%, respectively. Conclusions Patients treated with VG experienced lower toxicity, but overall quality of life was similar in both arms. Efficacy seemed comparable between VG and CP. Our study shows that VG is a viable alternative to platinum-based chemotherapy in patients with advanced NSCLC.

BACKGROUND The authors conducted a Phase II study to evaluate the activity of the combination of gemcitabine and vinorelbine in patients with advanced nonsmall cell lung carcinoma (NSCLC). METHODS Patients were eligible if they had Stage IIIB (malignant pleural effusion) or Stage IV NSCLC, no prior chemotherapy, and Cancer and Leukemia Group B performance status (PS) 0–2. Patients with brain metastases were eligible if they were neurologically stable after brain irradiation. Thirty-three patients from participating institutions were enrolled. One patient was ineligible due to untreated brain metastases. Patients were treated with gemcitabine 1250 mg/m2 over 30 minutes (1000 mg/m2 for the first 6 patients) and vinorelbine 25 mg/m2 over 6 minutes, both administered intravenously on Days 1 and 8 every 21 days. Treatment was planned for a total of six cycles or more if the patient had persistent benefit. Growth factors were not allowed. RESULTS Among all 32 eligible patients, there were 8 partial responses, for an overall response rate of 25% (95% confidence interval [CI], 11.5–43.4%). The median survival time was 8.3 months and the 1-year survival rate was 38% (95% CI, 24–59%). Patients with PS 0–1 had a median survival of 11.7 months and a 1-year survival rate of 48%. Grade 3 and 4 neutropenia was observed in 13% and 25% of the 148 treatment cycles, respectively. One patient died of neutropenic sepsis. Only 2 episodes of Grade 3 and 4 thrombocytopenia were observed. Nonhematologic toxicity was minimal. CONCLUSIONS Gemcitabine and vinorelbine is an active and well-tolerated regimen in patients with advanced NSCLC, with response and survival rates at least comparable to those achieved with standard platinum-based regimens. This combination may be particularly suitable for the elderly or for patients who cannot tolerate more toxic platinum-based regimens. Cancer 2000;88:557–62. © 2000 American Cancer Society.

PURPOSE The objectives of this phase I trial were to determine the dose-limiting toxicities (DLTs) of the novel topoisomerase I inhibitor topotecan combined with cisplatin, to define the maximum-tolerated doses (MTDs) of the combination without and with the use of filgrastim, and to define recommended doses for phase II trials. PATIENTS AND METHODS Patients with advanced solid tumors were eligible if they had normal bone marrow, renal, and hepatic function and had not previously been treated with platinum compounds. Topotecan was administered intravenously on days 1 through 5 and cisplatin was administered intravenously on day 1 of a 21-day cycle. The topotecan dose was fixed at 1.0 mg/m2/d on the first four dose levels, and cisplatin was escalated in 25-mg/m2 increments from 25 to 100 mg/m2 without filgrastim. After encountering DLT, the dose of cisplatin was decreased by one level and topotecan dose escalation was attempted. After defining the MTD without growth factor, the study proceeded with escalating cisplatin doses to define the MTD with filgrastim 5 micrograms/kg subcutaneously (SC) daily starting on day 6 of treatment. Priming with filgrastim 5 micrograms/kg SC on days -6 to -2 before the first course was explored last. RESULTS Of 38 patients entered, 37 were eligible, 35 assessable for toxicity in the first course, and 28 assessable for response. The principal toxicity was grade 4 neutropenia, which had to last more than 7 days to be considered dose-limiting. No DLT was observed at the starting cisplatin dose of 25 mg/m2 (dose level 1). On level 2 (cisplatin 50 mg/m2, one patient had dose-limiting neutropenia and one patient had grade 3 renal toxicity. On level 3 (cisplatin 75 mg/m2), two patients had dose-limiting neutropenia. Therefore, cisplatin dose escalation was stopped. On dose level 5 (cisplatin 50 mg/m2 and topotecan 1.25 mg/m2/d), one patient had grade 4 neutropenia that lasted more than 7 days and one patient died of neutropenic sepsis. The remaining dose levels used topotecan 1.0 mg/m2/d plus cisplatin 75 mg/m2 (level 6) and 100 mg/m2 (levels 7 and 8) with filgrastim. No DLT was observed on level 6. On level 7, two patients had dose-limiting neutropenia and one patient had grade 3 hyperbilirubinemia. Priming with filgrastim on level 8 demonstrated no obvious advantage over level 7, and one patient had grade 4 thrombocytopenia that lasted more than 7 days. Three patients with non-small-cell lung cancer achieved a partial response and one patient with breast cancer had a complete response. CONCLUSION Topotecan and cisplatin in combination cause more neutropenia than expected from either drug given alone at the same dosage. The recommended phase II doses are topotecan 1.0 mg/m2/d for 5 days in combination with cisplatin 50 mg/m2 on day 1 without filgrastim or cisplatin 75 mg/m2 on day 1 with filgrastim support.

Stage IV non-small cell lung cancer (NSCLC) remains a treatable but incurable disease.A MEDLINE search was performed to identify pertinent peer-reviewed articles that addressed the questions posed for this section. The writing committee developed and graded recommendations, which were subsequently approved by the American College of Chest Physicians.Platinum-based doublets remain the standard of care in patients with good performance status (PS); there is no evidence that the addition of a third cytotoxic agent improves survival. Likewise, with only one exception, the addition of a new targeted or biological agent to platinum-based doublets does not improve survival. The one exception is the addition of bevacizumab, an antiangiogenic agent, to carboplatin/paclitaxel in patients with stage IV disease and good PS. Patients for whom bevacizumab is recommended must also be selected on the basis of histology (nonsquamous), absence of brain metastases and hemoptysis, and no indication for therapeutic anticoagulation. In patients with stage IV NSCLC and PS of 2, chemotherapy is recommended, but the optimal approach has not been defined. Elderly patients, defined as/= 70 years old, also derive benefit from chemotherapy. Most elderly patients should receive single-agent chemotherapy, but elderly patients with good PS and without significant comorbidities seem to derive a similar benefit from platinum-based doublets compared with their younger counterparts without a prohibitive difference in treatment toxicities. Because stage IV NSCLC is incurable, quality-of-life issues are important, and tools exist to monitor a patient's quality of life during therapy. Last, patients need to be informed of the implication of the diagnosis of stage IV NSCLC and be educated about treatment options that are available to them.Advances have been made in stage IV NSCLC, and the appropriate use of chemotherapy continues to evolve on the basis of well-designed clinical trials that address critical issues in this population.

6595 Background: Because the elderly are numerically underrepresented in cancer clinical trials, the benefits and toxicities of cancer therapies in the general population of elderly patients is not known. Nevertheless, clinicians need such information. A solution may be found in analyses of observational data. Specific Aim: We performed a criterion validation study to determine the accuracy with which observational Medicare claims data measure clinically significant chemotherapy-related toxicities in elderly Medicare beneficiaries with cancer. Methods: We created a cohort of 175 elderly clinical trial patients treated on two Cancer and Leukemia Group B (CALGB) trials (i.e., 9,344 adjuvant breast and 9,730 advanced lung cancer trials) and merged participants’ CALGB data with their Centers for Medicare and Medicaid Services (CMS) data. From CALGB data, we identified all grade III/IV toxicities with a frequency of ≥3%. We reviewed diagnostic and procedure codes from CMS coding manuals, developed initial algorithms to measure the toxicities and then finalized the algorithms after empiric review of individual patients’ actual CMS codes incurred during the observation period (i.e., date of first trial treatment through 90 days following last trial treatment). We compared results of each of our CMS toxicity algorithms to gold-standard of CALGB grade III/IV toxicity information in order to calculate the CMS algorithms’ test characteristics. Results: The following 15 grade III /IV chemotherapy-related toxicities occurred in ≥3% of the 175 patients: white blood cell, hemoglobin, platelets, anorexia, nausea, vomiting, diarrhea, stomatitis, sensory neuropathy, motor neuropathy, motor or sensory neuropathy, dyspnea, hyperglycemia, infection, and malaise. Of these, only the CMS-based algorithm measuring ‘grade III/IV vomiting‘ had a sensitivity, specificity, and area under the ROC of ≥ 80%. Conclusions: The results of this preliminary study suggest that CMS claims data may be of only limited value in measuring clinically significant chemotherapy- related toxicities in elderly Medicare beneficiaries with cancer. Future research will focus on confirming these findings in a larger and more diverse patient sample. No significant financial relationships to disclose.

7595 Background: There is no standard treatment for patients (pts) with advanced NSCLC and PS 2. Docetaxel (D) is active and well tolerated on a weekly schedule. Cetuximab (C) and Bortezomib (B) are new agents with activity in NSCLC. We explored these two new combinations in PS 2 pts. Methods: In a multi-center randomized phase II trial, untreated pts with advanced NSCLC and PS 2 were randomized to D 30 mg/m2 d1,8,15 q. 28 days in combination with either C 400 mg/m2 week 1 then 250 mg/m2 weekly, or B 1.6 mg/m2 d1,8,15 q. 28 days for 4 cycles. Pts with CR/PR/SD were allowed to continue C or B until PD. The study was non-comparative and the primary endpoint was progression-free survival (PFS) rate at 6 months. The trial had a type I error of 0.0746 and power of 0.9 to differentiate a 6-mo PFS of 42%. Results: 64 pts were enrolled between 7/05 and 9/06. 5 were ineligible and 3 never received protocol treatment. Results are reported for 55 pts (27 D+C; 28 D+B). Most pts had stage IV adenoCa and 13% had brain metastases. Median age was 70 (range, 35–88) and 65% were male. Response: 10.5% for D+C and 13.6% for D+B. Median PFS was 3.1 mo for D+C and 1.8 mo for D+B. PFS rates at 4 mo (data not yet mature for 6-mo): 33% and 28%, respectively. Median survival: 3.8 mo for D+C and 3.3 mo for D+B. Gr 3/4 hematologic toxicity was 17% in both arms. Gr 3/4 non-heme toxicities were 44% in D+C and 36% in D+B arm. 5 pts died of treatment-related toxicities (3 D+C; 2 D+B). Conclusions: These results confirm the poor prognosis associated with a PS of 2. Based on our preliminary analysis, neither combination produced results that justify further research in this subset of patients. The treatment of PS 2 patients with advanced NSCLC remains a vexing problem and new approaches are urgently needed. No significant financial relationships to disclose.

Introduction To evaluate the efficacy and safety of myeloid growth factors in patients with locally advanced non-small cell lung cancer treated with combined modality therapy (CMT). Methods Patients with stage IIIA/B non-small cell lung cancer, performance status 0 to 1, and forced expiratory volume in 1 second ≥1.5, received cisplatin 75 mg/m 2 on day 1 + etoposide 80 mg/m 2 on days 1 to 3 every 3 weeks for 2 cycles concurrent with thoracic radiotherapy to 61 Gy. filgrastim 5 mcg/kg/d was administered for 10 days beginning on day 4 of each chemotherapy cycle. Patients without progression received docetaxel 75 mg/m 2 every 21 days for 3 cycles with peg-filgrastim 6 mg on day 2. The primary end point was a 50% reduction in the incidence of grade ¾ neutropenia compared with historical controls. Results A total of 26 eligible patients were enrolled. Median age was 67, 76% were men, and 58% had stage IIIA. Gr3/4 neutropenia during CMT was 19.2% and 3.8%, respectively. There were no episodes of febrile neutropenia. Gr4 thrombocytopenia was 15.4% with 2 patients requiring transfusions. Gr3 esophagitis was noted in 7.7% and Gr ¾ pneumonitis in 21.6% of patients. No patients died of treatment-related toxicities. Dose reductions/delays occurred in 3.8% of patients during CMT. Median progression-free survival and median survival were 10.7 and 27.6 months, respectively. The 1- and 2-year survival rates were 61.5% and 46.2%, respectively. Conclusions Our data suggest that the addition of filgrastim to CMT is safe and effective. The rate of grade ¾ toxicities, including febrile neutropenia, compares favorably to previous trials using a similar regimen. Dose intensity is maintained. This strategy merits further evaluation.

The insulin growth factor pathway (IGF), a complex one with multiple receptors and ligands, is involved in essential steps of cancer development such as survival, proliferation, and metastases.1 Although expression of IGF signaling seems to have prognostic significance, predictive factors for benefit have not yet been identified. Cross talk between the IGF and other pathways, particularly EFGR, may be important for understanding and mitigating resistance. Several compounds, including monoclonal antibodies and tyrosine kinase inhibitors, are currently under clinical investigation for inhibition of the IGF pathway.