Small cell lung cancer: past, present, and future.

Small cell lung cancer (SCLC) accounts for about 10% to 15% of all lung cancers. It is characterized by its rapid doubling time, high rate of dissemination, and increased sensitivity to chemotherapy and radiation. Although the incidence of SCLC has been steadily decreasing over time, it remains a serious public health problem given its aggressive clinical behavior and the lack of effective therapies. This review looks at the evolution of SCLC treatment and the standard treatments that are currently available, including platinum-based combination chemotherapy, hyperfractionated thoracic radiation, and prophylactic cranial irradiation. The development of novel therapies for SCLC has been lagging behind, but completed clinical trials and ongoing investigations are helping us define what will be the best therapeutic targets for this disease.

New treatment strategies in patients with advanced non-small-cell lung cancer and performance status 2.

Patients with performance status (PS) 2 represent approximately 30%-40% of all patients with advanced non-small-cell lung cancer (NSCLC) seen in clinical practice. Although these patients have been historically excluded from randomized clinical trials, recent studies have suggested a benefit from systemic chemotherapy. The development of biologic agents offers a new promise for the treatment of PS 2 patients as a result of the perceived improved therapeutic index of these agents. However, many of the recent advances in NSCLC have been limited to good PS patients and have not translated into an improvement in the management of the PS 2 population because the studies have excluded this patient population or have failed to demonstrate a survival benefit.

Randomized phase 2 study of tivantinib plus erlotinib versus single-agent chemotherapy in previously treated KRAS mutant advanced non-small cell lung cancer.

BACKGROUND: KRAS mutations are identified in approximately 25% of non-small cell lung cancer (NSCLC) cases and are associated with resistance to currently available targeted therapies. The MET oncogene may be implicated in malignant progression of KRAS-mutant tumors. In a pre-specified subset analysis of KRAS mutant cancers in an earlier phase 2 study of erlotinib plus the oral MET inhibitor tivantinib, combination therapy was associated with substantial clinical benefit compared to erlotinib alone (progression-free survival [PFS] HR 0.18; P < 0.01). The current study was conducted to evaluate this combination further in KRAS mutant non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Previously treated patients with advanced KRAS mutant NSCLC were randomized to receive either oral tivantinib (360 mg twice daily) plus erlotinib (150 mg daily) (ET) or single-agent chemotherapy (investigator's choice of pemetrexed, docetaxel, or gemcitabine) (C). The primary endpoint was PFS. At progression, crossover from C to ET was permitted. RESULTS: Ninety-six patients were randomly assigned to ET (n = 51) or to C (n = 45). Median PFS was 1.7 months (mos) for ET and 4.3 mos for C (HR 1.19; 95% CI, 0.71-1.97; P = 0.50). There was no difference in overall survival (HR 1.20; 95% CI, 0.76-1.88; P = 0.44). There were 4 partial responses in the C arm, and none in the ET arm. Overall, adverse events occurred more frequently in the C arm, with more cytopenias, nausea, fatigue, and alopecia. Dermatologic toxicities were more common in the ET arm. CONCLUSION: In previously treated patients with advanced KRAS mutant NSCLC, the combination of the MET inhibitor tivantinib and erlotinib is not superior to conventional single-agent chemotherapy.

Should health-related quality of life be measured in cancer symptom management clinical trials? Lessons learned using the functional assessment of cancer therapy.

There are several advantages to including comprehensive health-related quality of life (HRQL) in symptom trials in oncology. The most obvious is to test the hypothesis that HRQL will be improved in addition to the symptom benefit. We should not "require," however, that a successful symptom intervention also improve other dimensions of HRQL. On the other hand, we should expect that it will not make other dimensions worse through side effects or exacerbation of disease, even if it improves the symptom. HRQL assessment in the trial helps evaluate the competing risks of any therapy. Furthermore, assessment of HRQL is now accomplished with very brief assessment (usually 30 questions or less), and the knowledge gained is valuable. With HRQL, one can compare cancer patients with those with other conditions and can determine the contribution of symptoms and side effects to the more broadly defined HRQL. Examples using the Functional Assessment of Cancer Therapy measurement system will demonstrate how HRQL assessment has contributed to our understanding of common cancer symptoms and their place in the conceptualization of HRQL. The prevalence of clinically significant symptoms is greatest in poor performance status (PS) patients compared with patients with good PS. Symptom improvement trials specifically designed for these patients should be encouraged, particularly with interventions that can provide symptomatic relief and improve multidimensional HRQL.

The evolving role of cetuximab in non-small cell lung cancer.

Cetuximab is a monoclonal antibody directed against the ligand binding site in the extracellular domain of the epidermal growth factor receptor (EGFR). Cetuximab is currently approved for the treatment of patients with refractory colorectal cancer. In locally advanced head and neck carcinoma, cetuximab in combination with radiotherapy significantly improved survival compared with radiotherapy alone, and this treatment awaits Food and Drug Administration approval. In previously treated non-small cell lung cancer, single-agent cetuximab produced an objective response in 3 of 66 eligible patients and a median survival of 8.1 months. Treatment was well tolerated, with skin rash as the principal toxicity. The vast majority of patients (60 of 66) expressed EGFR by immunohistochemistry but no correlation existed between response and EGFR mutations. Two single-arm phase II trials testing cetuximab in combination with a platinum-based doublet in previously untreated patients showed responses in the range of 26% to 29%, with median survival times of 10 to 11 months. A European phase II randomized trial tested cisplatin/vinorelbine with or without cetuximab as first-line therapy in 86 patients with advanced non-small-cell lung cancer. Overall efficacy was slightly superior in the cetuximab arm and a phase III trial is currently ongoing to definitively determine the role of cetuximab in this setting.

Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the cancer and leukemia group B (study 9730).

PURPOSE: We compared the efficacy of combination chemotherapy versus single-agent therapy in patients with advanced non-small-cell lung cancer. PATIENTS AND METHODS: A total of 561 eligible patients were randomly assigned to receive paclitaxel alone or in combination with carboplatin. RESULTS: The response rate was 17% in the paclitaxel arm and 30% in the carboplatin-paclitaxel arm (P < .0001). Median failure-free survival was 2.5 months in the paclitaxel arm and 4.6 months in the carboplatin-paclitaxel arm (P = .0002). Median survival times were 6.7 months (95% CI, 5.8 to 7.8) and 8.8 months (95% CI, 8.0 to 9.9), and 1-year survival rates were 32% (95% CI, 27% to 38%), and 37% (95% CI, 32% to 43%), respectively. The overall survival distributions were not statistically different: hazard ratio = 0.91 (95% CI, 0.77 to 1.17; P = .25). Hematological toxicity and nausea were more frequent in the combination arm, but febrile neutropenia and toxic deaths were equally low in both arms. There was no significant survival difference in elderly patients. Performance status 2 patients treated with combination chemotherapy had a better survival rate than those treated with single-agent therapy (P = .019). CONCLUSION: Combination chemotherapy improves response rate and failure-free survival compared with single-agent therapy, but there was no statistically significant difference in the primary end point of overall survival. The results in elderly patients were similar to younger patients. Performance status 2 patients had a superior outcome when treated with combination chemotherapy.

Topotecan therapy in patients with relapsed small-cell lung cancer and poor performance status.

PURPOSE: Topotecan is generally well tolerated and active in patients with relapsed small-cell lung cancer (SCLC) and poor performance status (PS). In this study, we investigated whether treatment with topotecan is associated with improvement in PS as measured by the rate of conversion from PS 2 to PS 0/1. PATIENTS AND METHODS: A retrospective analysis of data from 7 clinical trials (N = 795) investigating topotecan in patients with relapsed SCLC was performed. All patients received topotecan 1.25-1.5 mg/m2 daily on days 1-5 of a 21-day cycle. Demographics were similar for patients with PS 2 and PS 0/1. A total of 152 patients with PS 2 at baseline received 502 cycles (median, 2 cycles; range, 1-14 cycles) of therapy, and 32 (21%) experienced PS improvement to PS 0/1 that lasted for > or = 2 cycles. RESULTS: Overall, 50% of patients who experienced PS conversion also exhibited an objective antitumor response, compared with 8% of patients with PS 2 who had no improvement in PS and achieved a response. Similarly, median overall survival was longer for patients with PS improvement (37 weeks; 95% confidence interval, 29.6-49.4 weeks) compared with patients with PS 2 who had a response but no PS improvement (10.4 weeks; 95% confidence interval, 8.7-13.6 weeks). A substantial proportion of patients with PS 2 and relapsed SCLC experienced PS improvement during topotecan treatment. These patients had a substantially longer median survival and a higher response rate compared with the overall trial population. CONCLUSION: Improvement in PS appears to be a good indicator of benefit from topotecan therapy.

Optimizing Treatment Risk and Benefit for Elderly Patients With Advanced Non-Small-Cell Lung Cancer: The Right Treatment for the Right Patient.

The Oncology Grand Rounds series is designed to place original reports published in theJournal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published inJournal of Clinical Oncology, to patients seen in their own clinical practice.A 78-year-old woman with a 40-pack-year smoking history has been referred for treatment of advanced non-small-cell lung cancer. She presented with a persistent cough and worsening dyspnea on exertion. A chest x-ray followed by a chest computed tomography scan revealed a 3-cm right upper lobe mass along with a moderate-size pleural effusion. Pleural fluid cytology was positive for adenocarcinoma. A brain magnetic resonance imaging scan was negative. A reflex molecular profile, includingKRAS,EGFR,ALK,BRAF,HER2,RET,MET, andROS, did not reveal an actionable abnormality. Her past medical history includes diabetes, hypertension, and osteopenia. Her medications include a ß-blocker, angiotensin-converting enzyme inhibitor, oral antidiabetic agent, calcium, and vitamin D. The laboratory evaluation is notable for a hemoglobin of 10.8 g/dL and a creatinine clearance of 36 mL/min. The other laboratories are within normal limits. She is somewhat limited by the shortness of breath but maintains an Eastern Cooperative Oncology Group performance status of 1. She is independent in all of her instrumental and basic activities of daily living and denies falls. She has been referred to discuss treatment options.

Treatment of Elderly Patients With Non-Small-Cell Lung Cancer: Results of an International Expert Panel Meeting of the Italian Association of Thoracic Oncology.

Most patients with non-small-cell lung cancer (NSCLC) are elderly, and age has important implications for their management and treatment. In May 2014, the Italian Association of Thoracic Oncology organized an International Experts Panel Meeting with the intent to review the available evidence regarding the treatment of elderly patients with NSCLC and to discuss the implications for clinical practice and future research in this field; this article summarizes the panelists' conclusions. All patients aged more than 70 years should receive an assessment of physiologic age, including mortality and toxicity prediction. Age itself does not contraindicate adjuvant chemotherapy after resection. Elderly patients with locally advanced NSCLC should be considered for combined chemo-radiotherapy. In the advanced setting, the combination of carboplatin/paclitaxel results in prolonged survival compared with single-agent gemcitabine or vinorelbine, albeit with increased toxicity. In fit selected patients, other carboplatin-based or cisplatin-based regimens are feasible, but randomized trials specifically showing survival prolongation in elderly patients are lacking. The survival benefit for bevacizumab added to chemotherapy seems limited to patients aged less than 75 years. In unfit elderly patients, single agents are recommended. Regardless of age, patients with advanced nonsquamous NSCLC, and those who have never smoked independently of their histologic subtype, should be tested for epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement. In patients with NSCLC harboring EGFR mutation or ALK rearrangement, targeted drugs are feasible and well tolerated.

Role of Chemoradiotherapy in Elderly Patients With Limited-Stage Small-Cell Lung Cancer.

PURPOSE: To investigate outcomes for elderly patients treated with chemotherapy (CT) alone versus chemoradiotherapy (CRT) in the modern era by using a large national database. PATIENTS AND METHODS: Elderly patients (age ≥ 70 years) with limited-stage small-cell lung cancer clinical stage I to III who received CT or CRT were identified in the National Cancer Data Base between 2003 and 2011. Hierarchical mixed-effects logistic regression with clustering by reporting facility was performed to identify factors associated with treatment selection. Overall survival (OS) of patients receiving CT versus CRT was compared by using the log-rank test, Cox proportional hazards regression, and propensity score matching. RESULTS: A total of 8,637 patients were identified, among whom 3,775 (43.7%) received CT and 4,862 (56.3%) received CRT. The odds of receiving CRT decreased with increasing age, clinical stage III disease, female sex, and the presence of medical comorbidities (all P < .01). Use of CRT was associated with increased OS compared with CT on univariable and multivariable analysis (median OS, 15.6 v 9.3 months; 3-year OS, 22.0% v 6.3%; log-rank P < .001; Cox P < .001). Propensity score matching identified a matched cohort of 6,856 patients and confirmed a survival benefit associated with CRT (hazard ratio, 0.52; 95% CI, 0.50 to 0.55; P < .001). Subset analysis of CRT treatment sequence showed that patients alive 4 months after diagnosis derived a survival benefit with concurrent CRT over sequential CRT (median OS, 17.0 v 15.4 months; log-rank P = .01). CONCLUSION: In elderly patients with limited-stage small-cell lung cancer, modern CRT appears to confer an additional OS advantage beyond that achieved with CT alone in a large population-based cohort. Our findings suggest that CRT should be the preferred strategy in elderly patients who are expected to tolerate the toxicities of the combined approach.

Treatment of patients with advanced lung cancer and poor performance status.

Patients with advanced lung cancer and poor performance status (PS) have been underrepresented in clinical trials. As a consequence, the management of these patients in clinical practice is empirical and inconsistent. Recent data in advanced non-small-cell lung cancer (NSCLC) indicate that patients with a PS of 2 tend to benefit from first-line chemotherapy with respect to symptom improvement and perhaps overall survival. Whether single-agent therapy or combination chemotherapy is preferable remains debatable. In previously treated patients with NSCLC, gefitinib produced a substantial rate of clinical benefit, and erlotinib led to an improvement in survival compared with placebo in studies that included a significant percentage of patients with poor PS. In patients with recurrent small-cell lung cancer, who frequently present with a compromised PS, the use of topotecan as a single agent led to an improvement in PS in approximately one third of these patients without excessive toxicities. Patients with advanced lung cancer and a PS of 2 have been the focus of intense clinical investigation in recent years. When more specific data for this special population become available, it will hopefully lead to more consistent management and improved outcomes.

Treatment of advanced non-small-cell lung cancer in special populations.

The benefits of chemotherapy in non-small-cell lung cancer (NSCLC) patients remains, to some extent, restricted to younger patients with a good performance status (PS). It has long been assumed that chemotherapy is too toxic and of marginal benefit for elderly NSCLC patients and those with a PS of 2. Nevertheless, retrospective analyses and more recent prospective trials have suggested that such patients enjoy longer survival and a better quality of life when treated with chemotherapy. This article will review the data and discuss their clinical implications.

Stereotactic body radiotherapy in patients with stage I non-small-cell lung cancer aged 75 years and older: retrospective results from a multicenter consortium.

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.

Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung cancer and Eastern Cooperative Oncology Group performance status of 2.

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/m(2)) or CP (area under the curve of 5 and 500 mg/m(2), 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.

Accrual to National Cancer Institute-sponsored non-small-cell lung cancer trials: insights and contributions from the CCOP program.

BACKGROUND: The Community Clinical Oncology Program (CCOP) has been a success in augmenting accrual to cooperative group research trials from community-based institutions. We analyzed accruals to selected phase II and III cooperative group non-small-lung cancer (NSCLC) trials to determine specific accrual patterns that might guide the implementation of future studies and their application to community settings. PATIENTS AND METHODS: Data from each of the adult multispecialty cooperative group trials that studied treatment interventions in NSCLC and completed accrual from 2000 to 2005 were gathered. We tabulated and analyzed information regarding the percentage of total accrual that derived from CCOPs according to cooperative group, extent of disease, trial phase, and modality of treatment. RESULTS: CCOP contributions did not seem to vary greatly by phase of study or by extent of disease. In general, CCOP accrual to Radiation Therapy Oncology Group trials was lower than for the other cooperative groups. CCOP accrual to multimodality trials, in which systemic treatment was not the primary study question, was poorer. Trials of standard therapy with or without a new therapeutic agent in advanced disease tend to enjoy better accrual. CONCLUSION: Multidisciplinary studies in NSCLC provide challenges for CCOPs and will require more effort and greater incentives. CCOP leaders should participate more actively in the design and implementation of cooperative group NSCLC trials in order to maximize their participation.

New horizons in chemotherapy: platforms for combinations in first-line advanced non-small cell lung cancer.

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.

Prevalence of poor performance status in lung cancer patients: implications for research.

INTRODUCTION: Performance status (PS) is a standard functional classification in oncology research and practice. However, despite its widespread use, little is known about the prevalence of poor PS in lung cancer patients, in relation to other cancers, based on the assessments of health care providers and patients. METHODS: Data from two quality of life studies were pooled for analysis. Analyses were performed on the subset of patients with lung cancer (n = 503) from the entire population of cancer patients (n = 2885). The prevalence of poor PS (defined as PS = 2-4 on a 0-4 scale) was determined for lung cancer patients. RESULTS: Prevalence of poor PS among lung cancer patients was 34% when estimated by providers and 48% when estimated by patients themselves. Agreement between providers and patients was only fair (weighted [kappa] = 0.41). For both advanced and early stage disease, lung cancer patients were at the highest risk for poor PS compared with other common cancers. CONCLUSIONS: The prevalence of poor PS is quite high in lung cancer patients. Providers tend to underestimate poor PS. Specific clinical trials and treatment guidelines for this patient population are urgently needed.

Summary statement novel agents in the treatment of lung cancer: Fifth Cambridge Conference assessing opportunities for combination therapy.

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.