The epidemiology of herpes zoster and its complications in Medicare cancer patients.

BACKGROUND: Literature on the epidemiology of herpes zoster (HZ) in cancer patients is sparse and does not include the elderly. The objectives of this study were to determine the incidence of HZ and related complications in elderly cancer patients and assess risk factors associated with HZ. METHODS: Patients ≥65 years diagnosed with cancer in 1991-2007 were identified from the Surveillance, Epidemiology, and End Results (SEER) cancer registry-Medicare linked database in this retrospective, longitudinal, open cohort study. The observation period spanned from first cancer diagnosis until the end of data availability. A random group of non-cancer Medicare patients served as the comparison group. Cases of HZ and related complications were ascertained from medical claims. Incidence rates (IR) and adjusted IR ratios were reported. RESULTS: The study population consisted of 82,832 hematologic (HEM) and 944,777 solid cancer patients (SOLID). During follow-up, 9.2% of HEM and 6.3% of SOLID were diagnosed with HZ. The IR of HZ was significantly higher in HEM than SOLID (31.0 vs. 14.9 per 1,000 patient-years, p <0.01). The adjusted IR ratio vs. non-cancer elderly patients was 2.4 in HEM and 1.2 in SOLID. The proportion of patients with complications was higher in HEM than SOLID (17.8% vs. 15.8%, p <0.01). Age, gender, race, certain cancer therapies, and immunosuppression were HZ risk factors. CONCLUSIONS: Elderly cancer patients run a 1.2-2.4 times higher risk of developing HZ than those without cancer. The rates of HZ and HZ-related complications are significantly higher for hematologic than solid cancer patients.

Phase I study of the c-raf-1 antisense oligonucleotide ISIS 5132 in combination with carboplatin and paclitaxel in patients with previously untreated, advanced non-small cell lung cancer.

BACKGROUND: A phase I trial was performed to evaluate the administration of carboplatin/paclitaxel in combination with ISIS-5132, a phosphorothioate antisense oligodeoxynucleotide inhibitor of c-raf-1 kinase expression, in patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Previously untreated patients with stage IIIB/IV NSCLC received ISIS 5132 by continuous intravenous infusion at 2.0 mg/kg/d for 14 days. Starting doses were paclitaxel 175 mg/m(2) and carboplatin targeting an area under the free platinum plasma concentration-time curve (AUC(fp)) of 5 mg . min/ml (dose level 1). The carboplatin dose was then increased to AUC(fp) 6 mg . min/ml (dose level 2) after which the paclitaxel dose was increased to 200 mg/m(2) (dose level 3). The maximum tolerated dose was established by toxicity during the first two 21-day cycles of therapy. The pharmacokinetics of all three agents was determined before and during the ISIS 5132 infusion. RESULTS: Thirteen patients were treated with the carboplatin/paclitaxel/ISIS 5132 combination. Dose-limiting neutropenia occurred in two patients at dose level 3. Grade 3 and 4 nonhematologic toxicities were infrequent and limited to nausea and constipation. The maximum tolerated doses were carboplatin AUC(fp) 6 mg . min/ml, paclitaxel 175 mg/m(2), and ISIS 5132 2.0 mg/kg/d for 14 days. There were no objective responses and the concurrent infusion of ISIS 5132 did not alter the plasma pharmacokinetics of paclitaxel or total platinum. CONCLUSION: ISIS 5132 can be safely combined with standard doses of carboplatin and paclitaxel. Combining cytotoxic chemotherapeutic agents with inhibitors of aberrant signal transduction mediated by Raf proteins produced no objective responses in the dose and schedule administered in this study.

Costs associated with intravenous chemotherapy administration in patients with small cell lung cancer: a retrospective claims database analysis.

OBJECTIVES: With new oral chemotherapy drugs emerging, it is useful to understand the costs associated with traditional intravenous (IV) therapy. This study aims to assess costs associated with IV chemotherapy in patients with small cell lung cancer (SCLC) from the perspective of large employer-payers. STUDY DESIGN: Descriptive retrospective claims database analysis. METHODS: Using medical claims data from 5.5 million beneficiaries between 01/01/1998 and 01/31/2006, we identified patients with lung cancer (ICD-9 codes 162.3-162.9, 176.4, or 197.0) who received IV chemotherapy. A case-finding SCLC algorithm was then applied which selected patients who were treated with chemotherapies commonly used in SCLC (cisplatin/etoposide, cisplatin/irinotecan, carboplatin/etoposide, topotecan, or cyclophosphamide/doxorubicin/vincristine) and then excluded those who had treatments or procedures indicative of non-small cell lung cancer (NSCLC) (positron emission tomography [PET] scan imaging, lung surgery, common NSCLC chemotherapies). Average total costs paid per day of IV chemotherapy administration were computed, along with separate costs for IV chemotherapy drugs, IV chemotherapy administration procedures, and other drugs and services received on IV visit days. Costs were also estimated per course of treatment based on the assumption of four chemotherapy cycles per course with three visits per cycle. RESULTS: Among 8010 patients with a lung cancer diagnosis, 802 were identified as SCLC. In the SCLC subset, the average total daily cost was $787 ($9449/course), with $395 ($4742/course; 50.2%) attributable to IV chemotherapy drugs, $93 ($1112/course; 11.8%) to IV chemotherapy administration, and $300 ($3595/course; 38.0%) to other drugs and services. CONCLUSIONS: The proposed algorithm identified about 10% of patients with lung cancer receiving IV chemotherapy as likely SCLC cases. Future studies should validate this algorithm with medical records data. IV chemotherapy administration and other visit-related drugs and services represented about half of the total cost per IV visit day, with the remainder attributable to direct costs for IV chemotherapy drugs.

Phase II clinical trial of chemotherapy-naive patients > or = 70 years of age treated with erlotinib for advanced non-small-cell lung cancer.

PURPOSE: This is a phase II, multicenter, open-label study of chemotherapy-naïve patients with non-small-cell lung cancer (NSCLC) and age > or = 70 years who were treated with erlotinib and evaluated to determine the median, 1-year, and 2-year survival. The secondary end points include radiographic response rate, time to progression (TTP), toxicity, and symptom improvement. PATIENTS AND METHODS: Eligible patients with NSCLC were treated with erlotinib 150 mg/d until disease progression or significant toxicity. Tumor response was assessed every 8 weeks by computed tomography scan using Response Evaluation Criteria in Solid Tumors. Tumor samples were analyzed for the presence of somatic mutations in EGFR and KRAS. RESULTS: Eighty eligible patients initiated erlotinib therapy between March 2003 and May 2005. There were eight partial responses (10%), and an additional 33 patients (41%) had stable disease for 2 months or longer. The median TTP was 3.5 months (95% CI, 2.0 to 5.5 months). The median survival time was 10.9 months (95% CI, 7.8 to 14.6 months). The 1- and 2- year survival rates were 46% and 19%, respectively. The most common toxicities were acneiform rash (79%) and diarrhea (69%). Four patients developed interstitial lung disease of grade 3 or higher, with one treatment-related death. EGFR mutations were detected in nine of 43 patients studied. The presence of an EGFR mutation was strongly correlated with disease control, prolonged TTP, and survival. CONCLUSION: Erlotinib monotherapy is active and relatively well tolerated in chemotherapy-naïve elderly patients with advanced NSCLC. Erlotinib merits consideration for further investigation as a first-line therapeutic option in elderly patients.

Phase I trial of the matrix metalloproteinase inhibitor marimastat combined with carboplatin and paclitaxel in patients with advanced non-small cell lung cancer.

PURPOSE: Marimastat is an orally bioavailable inhibitor of matrix metalloproteinases. A phase I study was initiated to determine whether conventional doses of carboplatin and paclitaxel are tolerated when combined with marimastat and to assess the influence of marimastat on paclitaxel pharmacokinetics. EXPERIMENTAL DESIGN: Three dose levels were evaluated. Marimastat (10 or 20 mg oral administration b.i.d.) was administered continuously with paclitaxel (175 or 200 mg/m(2) as a 3-hour i.v. infusion) and carboplatin (at a dose providing an area under the free drug plasma concentration-time curve of 7 mg min/mL) administered each 3 weeks. Toxicity and response were evaluated throughout the intended four cycles of combined therapy. The plasma pharmacokinetics of paclitaxel was determined in each patient both without concurrent marimastat and after receiving marimastat for 1 week. RESULTS: Twenty-two chemotherapy-naive patients with stage IIIb (27%) or stage IV (73%) non-small cell lung cancer were enrolled. Their median age was 56 years (range, 39-73 years), 50% were female, and their performance status (Eastern Cooperative Oncology Group) ranged from 0 to 2. Treatment was well tolerated, as 18 (82%) of the patients completed all four cycles of chemotherapy without dose-limiting toxicity. Grade 2 musculoskeletal toxicities were reported in 3 of 12 patients receiving marimastat (20 mg b.i.d.). Nine patients required dose reductions, predominantly related to low-grade myelosuppression. Partial responses occurred in 12 of 21 (57%) evaluable patients with disease stabilization in another 5 (19%). Marimastat had no effect on paclitaxel pharmacokinetics. CONCLUSIONS: The administration of marimastat (10 mg b.i.d.) with paclitaxel (200 mg/m(2)) and carboplatin at an area under the free drug plasma concentration-time curve of 7 mg min/mL was well tolerated with no apparent pharmacokinetic interaction. Study of this drug combination in the adjuvant setting should be considered if tissue inhibition of matrix metalloproteinase activity can first be shown.

Radiofrequency ablation of thoracic lesions: part 2, initial clinical experience--technical and multidisciplinary considerations in 30 patients.

OBJECTIVE: The purpose of our study was to report our initial experience with patients who underwent percutaneous imaging-guided radiofrequency ablation of thoracic lesions, and to emphasize technical and multidisciplinary issues and adjunctive procedures specific to thoracic tumor ablation. MATERIALS AND METHODS: Our cohort consisted of 30 patients with a spectrum of primary (n=18) and secondary (n=11) lung tumors, mesothelioma (n=1), and five secondarily eroded, painful ribs who underwent ablation of 36 total lesions (one patient had two ablations). Patients either were nonsurgical candidates because of medical comorbidities or extent of disease, or had exhausted chemotherapy and radiation therapy options, or had refused surgery or undergone unsuccessful surgery. Patients were treated with radiofrequency ablation after agreement among oncologists, thoracic surgeons, and interventional radiologists. An array-style electrode under impedance control was used to treat 29 thoracic tumors and the adjacent rib metastases (n=5). A cool-tip radiofrequency probe was used for two patients. CT guidance and general anesthetic were used for all but one patient. Sonographic guidance and IV conscious sedation were used in one patient. Pain (n=11) and tumor cure or control (n=19) were the primary indications for the procedures. Adjunctive procedures to the radiofrequency ablations included the creation of saline or water windows (n=3); establishment of transosseous and transchondral routes (n=4); use of intercostal and paravertebral nerve blocks (n=15); and use of an intraprocedural catheter (n=1), needle (n=1), or sheath (n=3) for treatment of pneumothoraces. Follow-up was from 2 to 26 months. RESULTS: All ablations were technically successful. No periprocedural mortality occurred. Necrosis of tumor was greater than 90% in 26 of 30 lesions based on short-term follow-up imaging (CT, PET, MRI). In the 11 patients who underwent ablation for pain, relief was complete in four and partial in the other seven. One patient developed a local skin burn, four patients had self-limited hemoptysis up to 4 days after ablation, one had transient atrial fibrillation, one developed hoarseness, and two patients were transiently reintubated after extubation. Eight pneumothoraces developed; one patient underwent placement of a chest tube. Four patients died within 1 year of ablation from extrathoracic spread of tumor. CONCLUSION: Radiofrequency ablation for a variety of thoracic tumors can be performed safely and with a high degree of efficacy for pain control and tumor killing. The effect of ablation can be assessed with CT, MRI, or PET. Various technical issues differentiate thoracic tumor ablation from standard abdominal ablations. Numerous other thoracic interventional radiology procedures are beneficial to assist the radiofrequency ablation. A multidisciplinary approach offers valuable expertise for patient care.

Clinical mimics of lymphoma.

Lymphadenopathy is a common clinical finding and is frequently benign. Warning signs suggestive of a malignant etiology include lymph nodes >2 cm in size, supraclavicular location, and generalized lymphadenopathy associated with hepatosplenomegaly or systemic symptoms. A metastatic solid tumor is always in the differential diagnosis of localized lymphadenopathy, particularly in older individuals. In the case of more generalized lymphadenopathy, in addition to the more common lymphomas, benign etiologies as well as benign and atypical lymphoproliferative disorders need to be considered. Benign etiologies of lymphadenopathy can include infections, autoimmune disorders, drug hypersensitivity reactions, sarcoidosis, and amyloidosis. Rare but benign lymphoproliferative disorders include Kikuchi's disease, Rosai-Dorfman disease, and progressive transformation of germinal centers. Atypical lymphoproliferative disorders that bear close surveillance for evolution to a more aggressive malignancy include Castleman's disease, lymphomatoid granulomatosis, and lymphomatoid papulosis. Previously considered in this category but now classified as a true lymphoma is angioimmunoblastic lymphadenopathy with dysproteinemia. Physicians need to be aware of all of these disorders when evaluating suspicious lymphadenopathy, while also considering the more common lymphomas and leukemias.

Haptoglobin alpha-subunit and hepatocyte growth factor can potentially serve as serum tumor biomarkers in small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) frequently presents as metastatic disease. It would be useful to detect serum tumor biomarkers at an earlier stage in order to improve the overall survival. MATERIALS AND METHODS: Serum samples from SCLC patients (6 limited disease, 7 extensive disease, 4 relapsed disease, 4 no evidence of disease post-treatment) and 5 normal controls were used to identify tumor biomarkers utilizing proteomics. Serum hepatocyte growth factor was also studied using standard ELISA. RESULTS: Utilizing MALDI-TOF-Mass Spectrometry (MS) based protein identification techniques, a SCLC specific overexpressed protein was identified to be haptoglobin alpha-subunit, with its serum level correlating with the disease stage. The mean level of alpha-haptoglobin was increased in SCLC serum as compared to the normal controls. Serum HGF was also studied as potential tumor biomarker and was found to correlate with the disease status. Either serum alpha-haptoglobin relative level (above 1.9 U), or HGF level (above 500 pg/ml) was associated with a trend towards worse survival. CONCLUSION: Our current findings suggest that serum levels of alpha-haptoglobin and HGF may serve as useful serum tumor biomarkers in SCLC. It would now also be useful to determine if these serum biomarkers are altered in response to therapy for this disease.

Outcomes of patients with advanced non-small cell lung cancer treated with gefitinib (ZD1839, "Iressa") on an expanded access study.

PURPOSE: To investigate the anti-tumor activity and toxicity of the epidermal growth factor receptor (EGFR) inhibitor gefitinib (ZD1839 or Iressa; AstraZeneca Pharmaceuticals, Wilmington, DE), in patients with advanced non-small cell lung cancer (NSCLC). METHODS: This was an open label, expanded access program (EAP) of oral gefitinib administered at 250 mg per day continuously until evidence of undue toxicity or disease progression. RESULTS: Two hundred consecutive patients with advanced NSCLC were enrolled in this study. The median number of prior chemotherapy regimens was 2 (range 0-6). One hundred seventy-two patients were treated with gefitinib; 23 expired from disease progression prior to treatment and 5 withdrew their consent. One hundred fifty-four patients are evaluable for toxicity; 8 (5.2%) experienced grade 3/4 toxicity; 2 patients discontinued therapy for grade 3 rash and one for grade 3 nausea. Of 172 patients evaluable for efficacy, 7 (4.1%; 95% CI; 1.7-8.2%) experienced a partial response (PR); 60 patients (34.9%) had stable disease (SD) as their best response. Median survival for all patients was 4.5 months (95% CI; 4.1-4.9 months). One-year survival was 29%. Significant independent prognostic factors associated with improved survival were female gender, good performance status (0/1), and adenocarcinoma histology. CONCLUSION: Gefitinib has anti-tumor activity, in a heterogeneous population of NSCLC patients treated on the EAP study. Treatment with gefitinib in this population is associated with a longer survival in women, those with good performance status and in patients with adenocarcinomas. These findings need to be further validated in additional clinical studies.

Recent advances in the molecular biology, diagnosis and novel therapies for various small blue cell tumors.

Small blue cell tumors are a group of tumors that share a common histologic characteristic with H&E staining. This makes differentiation from one another difficult as they all appear small, blue and round. Even though they all appear the same, they are vastly different from each other. Several different techniques have been developed to help further delineate and classify these tumors which include: small cell lung cancer (SCLC); non-Hodgkin's lymphoma (NHL); Ewing's sarcoma; rhabdomyosarcoma; Merkel carcinoma; neuroblastoma; carcinoid tumors; and intra-abdominal desmpolastic small round cell tumor. Using immunoperoxidase staining, reverse transcriptase polymerase chain reaction and fluorescence in situ hybridization techniques, these tumors have been successfully differentiated from one another. This separation makes staging and treatment of these tumors more effective, as not all of these tumors respond to the same modality of treatment. The following review summarizes some of the recent findings in the various small blue cell tumors and with the potential of novel therapies.

Induction docetaxel and carboplatin followed by weekly docetaxel and carboplatin with concurrent radiotherapy, then surgery in stage III non-small cell lung cancer: a Phase I study.

PURPOSE: To determine the maximum-tolerated dose of docetaxel (DOC) in combination with carboplatin (CAR) and thoracic radiotherapy (RT), in the setting of trimodality treatment of patients with stage III non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Thirty-two patients with biopsy-proven stage IIIA (n = 20) or IIIB (n = 12) NSCLC were given two initial cycles of CAR (area under the curve = 6) and DOC (75 mg/m(2)), subsequent RT (54 Gy) with concurrent weekly CAR (area under the curve = 2), and DOC at six dose levels from 10 to 40 mg/m(2), then surgery if the patient's disease was resectable. RESULTS: Three patients did not complete induction computed tomography (CT). Twenty-nine patients received concurrent CT/RT. Fifteen patients were eligible for surgery. Dose-limiting toxicities occurred in 2 patients, at dose levels two (atrial fibrillation) and three (transaminitis). The maximum-tolerated dose, as defined by the protocol, was not reached, although grade 3 and 4 toxicities were encountered at all dose levels. The most common more than or equal to grades 3 toxicities were neutropenia, nausea, vomiting, and fatigue. Four patients (13.3%) responded to induction CT. Ten patients (38.5%) responded to CT/RT. Eight surgical patients (57.1%) were downstaged, including 3 pathologic complete responses. Median relapse free and overall survivals are 8.5 and 12 months. One-year and estimated 2-year survival rates are 56.3 and 34.3%. CONCLUSION: This new regimen for stage III NSCLC of induction CAR/DOC, then weekly CAR/DOC with concurrent RT followed by surgery, can be safely administered and offers encouraging results. DOC at 30 mg/m(2) in combination with CAR and RT is recommended for Phase II study.

Circulating tumor cells and serum tumor biomarkers in small cell lung cancer.

Lung cancer accounts for approximately 30% of all cancer mortalities in the United States. Small cell lung cancer (SCLC), which is an aggressive malignancy with frequent and early metastases, accounts for about 15% of all of the lung cancer cases with a dismal 5-year survival rate of < 5% with current standard therapies. Early detection of SCLC is challenging, in part due to the lack of adequate serum tumor markers. The goal of this review is to summarize the current knowledge of circulating tumor cells and serum biomarkers in small cell lung cancer. The role of circulating tumor cells in prognostication is controversial, but may be better defined with advancing technologies of detection of such cells with higher precision, and improved clinico-pathological correlations. The current knowledge on the known serum cytokines and tumor biomarkers of SCLC, such as CEA, chromogranin-A and neuron-specific enolase will be presented. Serum cytokines, such as vascular endothelial growth factor (VEGF), stem cell factor (SCF) and hepatocyte growth factor/scatter factor (HGF/SF) are also discussed. New findings in the search for novel diagnostic and therapeutic molecular markers using the emerging genomics and proteomics technologies are emphasized. It is our hope that validation of these new research platforms and technologies will result in improved early detection, prognostication and finally treatment of SCLC with potential novel molecularly-targeted therapeutics.

Dose-intensive therapy for extensive-stage small cell lung cancer and extrapulmonary small cell carcinoma: long-term outcome.

Treatment for extensive-stage small cell lung cancer (ES SCLC) or extrapulmonary small cell carcinoma (EPSC) is typically palliative. We set out to determine progression-free survival (PFS) and overall long-term survival of ES SCLC and EPSC patients, physiologically aged < or = 60 years, responding to first-line chemotherapy followed by high-dose combination alkylating agents with hematologic stem cell support. Patients in first-line chemotherapy response underwent stem cell collection (marrow, peripheral blood progenitor cells, or both) followed by high-dose therapy with 1 of 2 regimens: CBP (cyclophosphamide, cisplatin, and carmustine) or ICE (ifosfamide, carboplatin, and etoposide) with or without etanidazole. Involved-field radiotherapy was given to selected patients with oligometastatic disease distributed in sites allowing for reasonable radiation ports, and prophylactic cranial radiotherapy was given upon recovery to patients in complete response (CR) or near-CR. A total of 36 patients were treated. Of 29 patients with ES SCLC, 6 (21%) had achieved CR, 18 near-CR, and 5 partial response prior to high-dose therapy. Of 7 patients with EPSC, 3 (43%) had achieved CR, 3 had achieved near-CR, and 1 had progression of disease prior to high-dose therapy. Thirteen ES SCLC patients received high-dose CBP. Of the remaining 23 patients with SCLC or EPSC, 17 were treated with ICE and 6 with ICE plus etanidazole, a hypoxic cell sensitizer. Treatment-related mortality was 11% (4 of 36 patients). For all patients, the median event-free survival (EFS) was 5 months. The 2- and 5-year survivals after intensification were 12% (95% confidence interval [CI], 5%-31%) and 9% (95% CI, 3%-27%), respectively. Of the 30 patients in or near CR prior to high-dose therapy, 5 remain continuously progression-free (2 ES SCLC, 3 EPSC) for a median of 55 months (range, 1-96 months) after high-dose therapy. By multivariate analysis, factors associated with more favorable EFS were the use of a more aggressive induction regimen (ICE), and the EPSC histology. These factors were also associated with more favorable overall survival. Other factors associated with more favorable overall survival were the use of short induction therapy (< or = 4 cycles) and younger age (<50 years). Except for high-dose ICE with etanidazole, the use of high-dose systemic therapy in ES SCLC and EPSC was associated with low treatment-related morbidity and mortality over the past 5 years. Late complications were infrequent, and most patients returned to full-time work and activity, barring disease recurrence. Nonetheless, few patients with ES SCLC have progression-free long-term survival. We conclude that high-dose therapy is not indicated as an approach for ES SCLC, except as part of an investigative trial. Conversely, 3 of the 7 patients with EPSC remain relapse-free (range, 1-96 months), warranting further phase II evaluation of this approach in this population.

Concurrent docetaxel and thoracic radiation in non-small-cell lung cancer.

Locally advanced (stages IIIA and IIIB) non-small-cell lung cancer (NSCLC) represents approximately 25% of new cases of NSCLC diagnosed annually. The treatment strategy for these patients involves combined-modality therapy with chemotherapy and thoracic radiation. Furthermore, a subset of patients with stage IIIA disease undergo surgical resection. Docetaxel is a chemotherapy agent with activity in both first- and second-line treatment of patients with advanced NSCLC. Several recent studies have also incorporated docetaxel in the treatment of patients with stage III NSCLC as neoadjuvant therapy, alone or in combination with cisplatin or carboplatin and thoracic radiation. Docetaxel has also been used as consolidation therapy. This review will summarize the data to date on the use of docetaxel and thoracic radiation in the treatment of patients with stage III NSCLC.

Radiotherapy versus chemotherapy plus radiotherapy in surgically treated IIIA N2 non-small-cell lung cancer.

Preoperative chemotherapy in patients with stage III non-small-cell lung cancer (NSCLC) remains controversial. Phase II trials utilizing preoperative chemotherapy in selected patients have achieved complete resection rates of 50%-70% with 3-5 year failure-free survival rates of 15%-33%. Between October 1992 and November 1994, 57 adults (50 of whom were evaluable) with surgically staged IIIA NSCLC and pathologically documented ipsilateral mediastinal nodal involvement (N2) were enrolled in a Cancer and Leukemia Group B randomized trial. Preoperative therapy was thought to be critical to facilitating surgical resectability. For patients randomized to the radiotherapy/surgery/radiotherapy (RSR) arm (n = 24), treatment consisted of preoperative radiation therapy (RT) at 40 Gy, surgery, and then additional RT at 14-20 Gy. For patients randomized to the chemotherapy/surgery/chemotherapy/radiotherapy (CSCR) arm (n = 26), treatment consisted of 2 cycles of cisplatin/etoposide with filgrastim support (PE) followed by surgery, 2 more cycles of PE, then RT 54-60 Gy. The total dose of RT on either arm was 54 Gy if completely resected or 60 Gy if incompletely resected or unresected. Clinical characteristics were well balanced between the two arms. Thoracotomy was performed in 42 patients (84%), 28 (67%) of whom had complete resection. The median failure-free and overall survival rates were 12 months (95% confidence interval [CI], 9-23 months) and 23 months (95% CI, 19 months-infinity) for the RSR arm and 11 months (95% CI, 5-20 months) and 18 months (95% CI, 12-32 months) for the CSCR arm. The rates of overall and complete surgical resection, downstaging of nodal involvement, and failure-free (P = 0.92) and overall survival (P = 0.41) did not differ between the two treatment arms. Moreover, in this trial, the chemotherapy regimen was sufficiently toxic to have had a lower completion rate of prescribed therapy in the CSCR arm than in the RSR arm.