A Phase 2 Clinical Trial of Combination Nivolumab, Ipilimumab, and Paclitaxel in Patients With Untreated Metastatic NSCLC: The OPTIMAL Trial.

Introduction: Most patients with advanced NSCLC will experience disease progression and death within 2 years. Novel approaches are needed to improve outcomes. Methods: We conducted an open-label, nonrandomized, phase 2 trial in patients with treatment-naive, advanced NSCLC to assess the safety and efficacy of nivolumab 360 mg every 3 weeks, ipilimumab 1 mg/kg every 6 weeks, and four to six cycles of paclitaxel 80 mg/m2 on days 1 and 8 of every 21-day treatment. The primary end point of the study was median progression-free survival (PFS), with secondary end points of safety, objective response rate, and median overall survival (OS). Results: A total of 46 patients underwent consent and received treatment. The median age was 66 (range: 48-82) years, most had adenocarcinoma (63%), and 50% (23) had programmed death-ligand 1 greater than or equal to 1%. The median follow-up on the study as of October 2021 was 19 months. The primary end point of median PFS was 9.4 months (95% confidence interval [CI]: 5.9-16.6) in all patients regardless of programmed death-ligand 1 expression. The objective response rate for patients in the study was 47.8% (95% CI: 33.4-62.3). The 12-month OS rate was 69.5% (95% CI: 53%-81%), and median OS was not yet reached. Treatment-related grade greater than or equal to 3 adverse events was found in 54.3% of the patients. Conclusions: The toxicity observed was consistent with other reported chemo-immunotherapeutic combinations and was manageable. The primary end point of exceeding median PFS of 9 months was achieved with nivolumab, ipilimumab, and weekly paclitaxel and should be evaluated further in a randomized trial.

Safety and effectiveness of bevacizumab-containing treatment for non-small-cell lung cancer: final results of the ARIES observational cohort study.

INTRODUCTION: Bevacizumab, a recombinant humanized monoclonal antibody against vascular endothelial growth factor, was approved by the US Food and Drug Administration for the treatment of advanced non-small-cell lung cancer (NSCLC) in combination with carboplatin and paclitaxel. ARIES (Avastin Regimens: Investigation of Effectiveness and Safety), a prospective observational cohort study, evaluated outcomes in a large, community-based population of patients with first-line NSCLC. METHODS: From 2006 to 2009, ARIES enrolled patients with locally advanced or metastatic NSCLC who were eligible for bevacizumab, excluding those with predominantly squamous histology. Patients were required to provide informed consent and to have initiated bevacizumab with chemotherapy within 4 months before enrollment. There were no protocol-defined treatments or assessments. The dosing of bevacizumab and chemotherapy, and the choice of chemotherapy regimen, was at the discretion of the treating physician. RESULTS: ARIES enrolled 1967 patients with first-line NSCLC. At study closure, median follow-up was 12.5 months (range, 0.2-65.5). Median age was 65 years (range, 31-93), and 252 patients (12.8%) identified as never smokers. Median progression-free survival was 6.6 months (95% confidence interval, 6.3-6.9), and median overall survival was 13.0 months (95% confidence interval, 12.2-13.8) with first-line bevacizumab plus chemotherapy. Incidences of bevacizumab-associated adverse events (19.7% overall) were consistent with those in randomized controlled trials of bevacizumab in NSCLC. CONCLUSION: Results from ARIES demonstrate similar outcomes to randomized controlled trials of bevacizumab when added to standard chemotherapy in a real-world patient population with advanced NSCLC.

Assessment of the impact of adjunctive proactive telephone counseling to promote smoking cessation among lung cancer patients' social networks.

PURPOSE: When a patient is diagnosed with lung cancer, members of his/her social network may be more likely to engage in smoking cessation efforts. Proactive telephone counseling combined with a tailored self-directed intervention may be more effective at promoting smoking cessation than a tailored self-directed intervention alone. DESIGN: Randomized controlled trial. SETTING: Four clinical sites. SUBJECTS: Current smokers who are family members and close friends of patients with lung cancer. INTERVENTION: Six counselor-initiated counseling calls using motivational interviewing techniques and focusing on teaching adaptive coping skills based on the transactional model of stress and coping along with tailored self-directed materials (including nicotine patches, if not contraindicated) (n  =  245) vs. tailored self-directed materials (including nicotine patches, if not contraindicated) (n  =  251). MEASURES: Participants were surveyed at baseline and at 2 weeks, 6 months, and 12 months postintervention. The outcome was 7-day point prevalent abstinence. ANALYSIS: The objective of this study was to test for arm differences in smoking cessation rates at 2 weeks and 6 months postintervention (primary) and at 12 months postintervention (secondary). RESULTS: We found no overall effect of the proactive intervention on cessation rates. Among younger participants (age <50), the cessation rate in the intervention group was higher than in the control group at 2 weeks postintervention (16% vs. 4%, p  =  .046). For older participants (age >50), there were no group differences. CONCLUSION: Proactive telephone counseling focusing on adaptive coping skills was difficult to implement among smokers in lung cancer patients' social network. Although this study did not demonstrate any added benefit to cessation rates, this null finding may be a result of an intervention that was weaker than intended, owing to difficulties in completing the counseling phone calls. We discuss lessons learned and areas for future research in this special population.

Attachment styles in patients with lung cancer and their spouses: associations with patient and spouse adjustment.

PURPOSE: This study examined attachment styles in patients with lung cancer and their spouses and associations between attachment styles and patient and spouse adjustment. METHODS: One hundred twenty-seven patients with early stage lung cancer completed measures of attachment style, marital quality, self-efficacy, pain, depression, anxiety, and quality of life. Their spouses completed measures of attachment style, marital quality, self-efficacy, caregiver strain, and mood. RESULTS: Analyses indicated that, among patients, those high in either attachment anxiety or avoidance had significantly higher levels of anxiety and poorer social well-being. Attachment avoidance was also significantly associated with higher levels of depression and poorer marital quality and functional well-being. Spouse avoidant attachment was significantly associated with patient reports of increased pain and poorer functional well-being, and spouse anxious attachment was associated with poorer patient marital quality. Among spouses, those high in attachment avoidance reported significantly higher levels of caregiver strain, anger, depressed mood, and poorer marital quality; those high in attachment anxiety reported higher anxious mood. Dyads in which both partners were insecurely attached had significantly poorer adjustment compared to dyads in which both partners reported secure attachment. CONCLUSIONS: These preliminary findings raise the possibility that attachment styles of cancer patients and their spouses as individuals and as a dyad may be important factors affecting adjustment in multiple domains.

Randomized phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small-cell lung cancer: Cancer and Leukemia Group B trial 30407.

PURPOSE: Cancer and Leukemia Group B conducted a randomized phase II trial to investigate two novel chemotherapy regimens in combination with concurrent thoracic radiation therapy (TRT). PATIENTS AND METHODS: Patients with unresectable stage III non-small-cell lung cancer (NSCLC) were randomly assigned to carboplatin (area under the curve, 5) and pemetrexed (500 mg/m(2)) every 21 days for four cycles and TRT (70 Gy; arm A) or the same treatment with cetuximab administered concurrent only with TRT (arm B). Patients in both arms received up to four cycles of pemetrexed as consolidation therapy. The primary end point was the 18-month overall survival (OS) rate; if the 18-month OS rate was ≥ 55%, the regimen(s) would be considered for further study. RESULTS: Of the 101 eligible patients enrolled (48 in arm A and 53 in arm B), 60% were male; the median age was 66 years (range, 32 to 81 years); 44% and 35% had adenocarcinoma and squamous carcinoma, respectively; and more patients enrolled onto arm A compared with arm B had a performance status of 0 (58% v 34%, respectively; P = .04). The 18-month OS rate was 58% (95% CI, 46% to 74%) in arm A and 54% (95% CI, 42% to 70%) in arm B. No significant difference in OS between patients with squamous and nonsquamous NSCLC was observed (P = .667). The toxicities observed were consistent with toxicities associated with concurrent chemoradiotherapy. CONCLUSION: The combination of pemetrexed, carboplatin, and TRT met the prespecified criteria for further evaluation. This regimen should be studied further in patients with locally advanced unresectable nonsquamous NSCLC.

Proactive recruitment of cancer patients' social networks into a smoking cessation trial.

BACKGROUND: This report describes the characteristics associated with successful enrollment of smokers in the social networks (i.e., family and close friends) of patients with lung cancer into a smoking cessation intervention. METHODS: Lung cancer patients from four clinical sites were asked to complete a survey enumerating their family members and close friends who smoke, and provide permission to contact these potential participants. Family members and close friends identified as smokers were interviewed and offered participation in a smoking cessation intervention. Repeated measures logistic regression model examined characteristics associated with enrollment. RESULTS: A total of 1062 eligible lung cancer patients were identified and 516 patients consented and completed the survey. These patients identified 1325 potentially eligible family and close friends. Of these, 496 consented and enrolled in the smoking cessation program. Network enrollment was highest among patients who were white and had late-stage disease. Social network members enrolled were most likely to be female, a birth family, immediate family, or close friend, and live in close geographic proximity to the patient. CONCLUSIONS: Proactive recruitment of smokers in the social networks of lung cancer patients is challenging. In this study, the majority of family members and friends declined to participate. Enlisting immediate female family members and friends, who live close to the patient as agents to proactively recruit other network members into smoking cessation trials could be used to extend reach of cessation interventions to patients' social networks. Moreover, further consideration should be given to the appropriate timing of approaching network smokers to consider cessation.

Caregiver-assisted coping skills training for lung cancer: results of a randomized clinical trial.

CONTEXT: Lung cancer is one of the most common cancers in the United States and is associated with high levels of symptoms, including pain, fatigue, shortness of breath, and psychological distress. Caregivers and patients are adversely affected. However, previous studies of coping skills training (CST) interventions have not been tested in patients with lung cancer nor have systematically included caregivers. OBJECTIVES: This study tested the efficacy of a caregiver-assisted CST protocol in a sample of patients with lung cancer. METHODS: Two hundred thirty-three lung cancer patients and their caregivers were randomly assigned to receive 14 telephone-based sessions of either caregiver-assisted CST or education/support involving the caregiver. Patients completed measures assessing pain, psychological distress, quality of life (QOL), and self-efficacy for symptom management; caregivers completed measures assessing psychological distress, caregiver strain, and self-efficacy for helping the patient manage symptoms. RESULTS: Patients in both treatment conditions showed improvements in pain, depression, QOL, and self-efficacy, and caregivers in both conditions showed improvements in anxiety and self-efficacy from baseline to four-month follow-up. Results of exploratory analyses suggested that the CST intervention was more beneficial to patients/caregivers with Stage II and III cancers, whereas the education/support intervention was more beneficial to patients/caregivers with Stage I cancer. CONCLUSION: Taken together with the broader literature in this area, results from this study suggest that psychosocial interventions can lead to improvements in a range of outcomes for cancer patients. Suggestions for future studies include the use of three-group designs (e.g., comparing two active interventions with a standard-care control) and examining mechanisms of change.

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.

Randomized phase II multicenter trial of two schedules of lapatinib as first- or second-line monotherapy in patients with advanced or metastatic non-small cell lung cancer.

PURPOSE: This randomized phase II study was initially designed to test the activity of two dose schedules of lapatinib (GW572016H), an oral, reversible, dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2/neu; HER2), in chemotherapy-naive patients with non-small cell lung cancer (NSCLC); it was later amended to target patients with bronchioloalveolar carcinoma or no smoking history. EXPERIMENTAL DESIGN: Patients with good performance status and recurrent or metastatic NSCLC were randomized to lapatinib (orally, 1,500 mg once daily or 500 mg twice daily) until progression or intolerance. Patients could have had a maximum of one prior systemic therapy (chemotherapy or biological therapy) for NSCLC. Safety and activity were assessed every 4 and 8 weeks, respectively. Tumors were analyzed for EGFR and HER2 mutations and/or amplifications. RESULTS: Of 75 patients in the nontargeted population, 1 (1.3%) had partial response and 16 (21%) had stable disease of >or=24 weeks. No complete or partial responses were observed in 56 patients in the targeted population; 14 (25%) had stable disease of >or=24 weeks. No responses were seen in three patients with EGFR mutations and five with EGFR gene amplification. No mutations in HER2 were found. One of two patients with HER2 amplification had a 51% decrease in tumor size; however, this response was unconfirmed. The most common adverse events were grade 1 or 2 diarrhea, rash, fatigue, nausea, and anorexia. Adverse events were similar across dosing regimens. CONCLUSIONS: Lapatinib was well tolerated, with no notable difference in toxicity between treatment groups. Lapatinib monotherapy did not induce a significant number of tumor regressions in NSCLC. Further studies may be warranted to determine whether lapatinib is active in combination with other agents in the treatment of NSCLC.

Persistent smoking after a diagnosis of lung cancer is associated with higher reported pain levels.

UNLABELLED: The purpose of this study was to evaluate the impact of smoking status after a diagnosis of lung cancer on reported pain levels. We conducted a telephone survey of patients with lung cancer identified from 4 participating sites between September 2004 and July 2006. Patients were asked to rate their usual pain level over the past week on a 0 to 10 rating scale on which 0 was "no pain" and 10 "pain as bad as you can imagine." We operationally defined persistent smokers as patients who reported continuing to smoke after their lung cancer diagnosis. A logistic regression analysis was used to test the hypothesis that persistent smokers report higher usual pain levels than nonsmokers. Overall, 893 patients completed the survey. The majority (76%) was found to have advanced cancer (stages IIIb and IV). The mean age was 63 years (SD = 10). Seventeen percent of the patients studied were categorized as persistent smokers. The mean pain score for the study sample was 3.1 (SD = 2.7) and 41% reported moderate (4 to 6) or severe pain (7 to 10). A greater proportion of persistent smokers reported moderate or severe pain than nonsmokers or former smokers (P < .001). Logistic regression analysis revealed that smoking status was associated with the usual pain even after adjusting for age, perceived health status, and other lung cancer symptoms such as dyspnea, fatigue, and trouble eating. In conclusion, patients who continue to smoke after a diagnosis of lung cancer report higher levels of usual pain than nonsmokers or former smokers. More research is needed to understand the mechanisms that relate nicotine intake to pain and disease progression in late-stage lung cancer. PERSPECTIVE: This article examines the relationship between pain and persistent smoking in patients with lung cancer. Although more research is needed to understand the mechanisms that relate nicotine intake to pain and disease progression, physicians can promote smoking cessation in patients with lung cancer to improve health and quality of life.

Safety and feasibility of aerobic training on cardiopulmonary function and quality of life in postsurgical nonsmall cell lung cancer patients: a pilot study.

BACKGROUND: A feasibility study examining the effects of supervised aerobic exercise training on cardiopulmonary and quality of life (QOL) endpoints among postsurgical nonsmall cell lung cancer (NSCLC) patients was conducted. METHODS: Using a single-group design, 20 patients with stage I-IIIB NSCLC performed 3 aerobic cycle ergometry sessions per week at 60% to 100% of peak workload for 14 weeks. Peak oxygen consumption (VO(2peak)) was assessed using an incremental exercise test. QOL and fatigue were assessed using the Functional Assessment of Cancer Therapy-Lung (FACT-L) scale. RESULTS: Nineteen patients completed the study. Intention-to-treat analysis indicated that VO(2peak) increased 1.1 mL/kg(-1)/min(-1) (95% confidence interval [CI], -0.3-2.5; P = .109) and peak workload increased 9 W (95% CI, 3-14; P = .003), whereas FACT-L increased 10 points (95% CI, -1-22; P = .071) and fatigue decreased 7 points (95% CI; -1 to -17; P = .029) from baseline to postintervention. Per protocol analyses indicated greater improvements in cardiopulmonary and QOL endpoints among patients not receiving adjuvant chemotherapy. CONCLUSIONS: This pilot study provided proof of principle that supervised aerobic training is safe and feasible for postsurgical NSCLC patients. Aerobic exercise training is also associated with significant improvements in QOL and select cardiopulmonary endpoints, particularly among patients not receiving chemotherapy. Larger randomized trials are warranted.

Self-efficacy for managing pain, symptoms, and function in patients with lung cancer and their informal caregivers: associations with symptoms and distress.

This study examined self-efficacy for managing pain, symptoms, and function in patients with lung cancer and their caregivers, and associations between self-efficacy and patient and caregiver adjustment. One hundred and fifty-two patients with early stage lung cancer completed measures of self-efficacy, pain, fatigue, quality of life, depression, and anxiety. Their caregivers completed a measure assessing their self-efficacy for helping the patient manage symptoms and measures of psychological distress and caregiver strain. Analyses indicated that, overall, patients and caregivers were relatively low in self-efficacy for managing pain, symptoms, and function, and that there were significant associations between self-efficacy and adjustment. Patients low in self-efficacy reported significantly higher levels of pain, fatigue, lung cancer symptoms, depression, and anxiety, and significantly worse physical and functional well being, as did patients whose caregivers were low in self-efficacy. When patients and caregivers both had low self-efficacy, patients reported higher levels of anxiety and poorer quality of life than when both were high in self-efficacy. There were also significant associations between patient and caregiver self-efficacy and caregiver adjustment, with lower levels of self-efficacy associated with higher levels of caregiver strain and psychological distress. These preliminary findings raise the possibility that patient and caregiver self-efficacy for managing pain, symptoms, and function may be important factors affecting adjustment, and that interventions targeted at increasing self-efficacy may be useful in this population.

A phase II trial of carboplatin/vinorelbine with pegfilgrastim support for the treatment of patients with advanced non-small cell lung cancer.

INTRODUCTION: The impact of chemotherapy dose delivery has not been well studied in patients with non-small cell lung cancer (NSCLC). Overlapping hematologic toxicities commonly limit planned dose intensity of combination chemotherapy regimens. A phase II study investigating carboplatin and vinorelbine, supported by pegfilgrastim, in the treatment of patients with advanced NSCLC was performed. METHODS: Chemotherapy-naïve patients with locally advanced or metastatic NSCLC were treated with carboplatin area under the curve (AUC) 6 mg/ml per minute intravenously on day 1 and vinorelbine 30 mg/m2 intravenously on days 1 and 8 every 3 weeks for four planned cycles. Pegfilgrastim was administered on day 9 of each cycle as a 6-mg subcutaneous injection. The primary endpoint was incidence of cycle 1 febrile neutropenia. Secondary endpoints included incidence of grade 3/4 hematologic and nonhematologic toxicities, delivered dose intensity, and overall survival. RESULTS: Thirty patients (21 men, 9 women) with a median age of 61 years (range, 43-79) were enrolled. Of 120 planned patient cycles, 101 (84%) were completed. There was one episode of cycle 1 febrile neutropenia. Overall response rate was 27%. Median dose delivered for vinorelbine was 17.2 mg/m2 per week, representing a delivered dose intensity of 86%. Median survival was 9.4 months (95% confidence interval: 6.1-18.0) with a 3-year survival rate of 20%. CONCLUSIONS: This regimen of carboplatin and vinorelbine with pegfilgrastim support was associated with a low rate of febrile neutropenia and good maintenance of planned dose intensity. Although response and survival are similar to other chemotherapy regimens in advanced NSCLC, studies optimizing chemotherapy delivery in this setting may help inform treatment approaches in patients with earlier stage disease.

Vaccine therapy in non-small-cell lung cancer.

Lung cancer is the leading cause of death from cancer worldwide. First-line therapy is based on stage at diagnosis and can include chemotherapy, radiation, and surgery. Despite advances, the prognosis for advanced-stage lung cancer is very poor. Vaccines with the capability to activate the host immune system may have a role in second-line therapy. Advances in the understanding of cellular and molecular immunology are forming the basis for improving vaccine therapy. Most trials to date have demonstrated safety but inconsistent efficacy. Further research is needed to enhance this potential.

The impact of induction chemotherapy and the associated tumor response on subsequent radiation-related changes in lung function and tumor response.

PURPOSE: To assess the impact of induction chemotherapy, and associated tumor shrinkage, on the subsequent radiation-related changes in pulmonary function and tumor response. METHODS AND MATERIALS: As part of a prospective institutional review board-approved study, 91 evaluable patients treated definitively with thoracic radiation therapy (RT) for unresectable lung cancer were analyzed. The rates of RT-associated pulmonary toxicity and tumor response were compared in the patients with and without pre-RT chemotherapy. In the patients receiving induction chemotherapy, the rates of RT-associated pulmonary toxicity and tumor response were compared in the patients with and without a response (modified Response Evaluation Criteria in Solid Tumor criteria) to the pre-RT chemotherapy. Comparisons of the rates of improvements in pulmonary function tests (PFTs) post-RT, dyspnea requiring steroids, and percent declines in PFTs post-RT were compared in patient subgroups using Fisher's exact test, analysis of variance, and linear or logistic regression. RESULTS: The use of pre-RT chemotherapy appears to increase the rate of radiation-induced pneumonitis (p = 0.009-0.07), but has no consistent impact on changes in PFTs. The degree of induction chemotherapy-associated tumor shrinkage is not associated with the rate of subsequent RT-associated pulmonary toxicity. The degree of tumor response to chemotherapy is not related to the degree of tumor response to RT. CONCLUSIONS: Additional study is needed to better clarify the impact of chemotherapy on radiation-associated disfunction.

Safety of topotecan in the treatment of recurrent small-cell lung cancer and ovarian cancer.

The topoisomerase I inhibitor, topotecan, is approved for the treatment of recurrent small-cell lung cancer (SCLC) and ovarian cancer (OC). Patients with recurrent SCLC and OC typically experience multiple relapses and receive multiple rounds of chemotherapy. In these settings, disease stabilisation is considered a treatment benefit, and quality-of-life effects and cumulative toxicities of treatments should be considered. Many patients with recurrent cancer may be predisposed to treatment-related adverse events because of advanced age, renal impairment or extensive prior therapy. The standard regimen of topotecan, 1.5 mg/m(2) on days 1-5 of a 21-day cycle, has generally mild nonhaematological toxicity and a well-defined haematological toxicity profile characterised by reversible and noncumulative neutropenia. Alternative regimens may lower the incidence of haematological toxicities and maintain antitumour efficacy. Topotecan may provide physicians with a versatile therapeutic option for the treatment of patients with relapsed SCLC or OC.

Topotecan: An evolving option in the treatment of relapsed small cell lung cancer.

The topoisomerase I inhibitor topotecan is the only single-agent therapy approved for the treatment of recurrent small cell lung cancer (SCLC). Many patients with recurrent SCLC may be predisposed to treatment-related adverse events because of the presence of comorbidities such as advanced age, renal impairment, or extensive prior therapy. In this setting, disease stabilization is considered a treatment benefit, and quality-of-life effects and toxicity profiles of treatments should be considered. The approved regimen of topotecan 1.5 mg/m² on days 1 to 5 of a 21-day cycle is active and has generally mild nonhematologic toxicity and a well-established hematologic toxicity profile characterized by reversible, manageable, and noncumulative neutropenia. Alternative dosing and treatment schedules may lower the incidence of hematologic toxicities while maintaining antitumor efficacy in this patient population. Therefore, topotecan may provide physicians with an effective and versatile therapeutic option for the treatment of patients with relapsed SCLC.

A phase I study of dose-dense topotecan given upfront to standard therapy in patients with small cell lung cancer.

OBJECTIVE: To determine the feasibility and maximum tolerated dose of dose-dense topotecan as induction chemotherapy before standard therapy (carboplatin plus etoposide alone or in combination with radiotherapy) in patients with small cell lung cancer (SCLC). PATIENTS AND METHODS: Chemotherapy-naive patients with SCLC and good performance status were eligible. Three 2-week cycles of dose-dense topotecan administered on days 1-3 with granulocyte colony-stimulating factor support were followed by four cycles of standard carboplatin plus etoposide therapy alone (extensive-stage SCLC) or with radiotherapy (limited-stage SCLC). The dose of topotecan was escalated from 1.5 mg/m2/day to 2.5 mg/m2/day in increments of 0.25 mg/m2/day within cohorts of 3-5 patients each. Dose-limiting toxicity was defined as any grade 3 or 4 toxicity resulting in a treatment reduction or a delay of >3 days. RESULTS: Twenty-two patients with SCLC (5 limited-stage, 17 extensive-stage) were enrolled. Treatment was well tolerated. The dose-limiting toxicities were thrombocytopenia and neutropenia, and the maximum tolerated dose of dose-dense topotecan induction therapy was 2.25 mg/m2/day. Overall, topotecan-related grade 3/4 haematological toxicities included neutropenia (n = 4), thrombocytopenia (n = 3) and febrile neutropenia (n = 1). No grade 4 non-haematological toxicities occurred. Grade 3 adverse events included nausea (n = 2), renal toxicity (n = 1) and anorexia (n = 1). Toxicity during the carboplatin plus etoposide +/- radiotherapy phase of therapy was consistent with that reported in previous trials. The overall response rate was 80% for limited-stage and 76% for extensive-stage SCLC. Median survival was 8 months in patients with limited-stage SCLC and 13.5 months for patients with extensive-stage SCLC. CONCLUSION: The results of this phase I study suggest that a regimen of sequential dose-dense topotecan and carboplatin plus etoposide is feasible, and the preliminary activity observed in patients with SCLC warrants further investigation at a starting dose of topotecan 2.25 mg/m2/day.