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Background and purpose Little is known about complementary and integrative health intervention usage in the primary brain tumor population. We aimed to identify the percentage of patients using these practices and explore the impact on quality of life. Materials and methods Clinical records from patients seen in clinic between December 16, 2013 and February 28, 2014 were reviewed retrospectively. The questionnaires used were a modified version of the International Complementary and Alternative Medicine Questionnaire, the Functional Assessment of Cancer Therapy- Brain Cancer and the Functional Assessment of Chronic Illness Therapy- Fatigue. Results 76% of patients utilized a complementary and integrative health modality. The most frequently reported modalities used were vitamins, massage, and spiritual healing, prayer, diet and meditation. Conclusion These results confirm the usage of complementary and integrative health practices within the primary brain tumor population; however, there was no evidence of association between use and quality of life.

Purpose: Atypical (World Health Organization [WHO] grade 2) and malignant (WHO grade 3) meningiomas have high rates of local recurrence, and questions remain about the role of adjuvant radiation therapy (RT) for patients with WHO grade 2 disease. These patients frequently require salvage therapy, and optimal management is uncertain given limited prospective data. We report on the long-term outcomes for patients with atypical and malignant meningiomas treated with surgery and/or RT at our institution. Methods and Materials: Data were collected through a retrospective chart review for all patients with WHO grade 2 or 3 meningiomas treated with surgery and/or RT at our institution between January 1992 and March 2017. Progression-free survival (PFS) and overall survival (OS) were described using the KaplanMeier estimator. The outcomes in the subgroups were compared with a log-rank test. A Cox proportional hazards model was used for the univariable and multivariable analyses of predictors of PFS. Results: A total of 66 patients were included in this analysis. The median follow-up was 12.4 years overall and 8.6 years among surviving patients. Fifty-two patients (78.8%) had WHO grade 2 meningiomas, and 14 patients (21.2%) had WHO grade 3 disease. Thirty-six patients (54.5%) were treated with surgery alone, 28 patients (42.4%) with surgery and adjuvant RT, and 2 patients (3%) with RT alone. Median PFS and OS were 3.2 years and 8.8 years, respectively. PFS was significantly improved with adjuvant RT compared with surgery alone (hazard ratio, 0.36; 95% confidence interval, 0.18-0.70). Patients with Ki-67 index >10% showed a trend toward worse PFS compared with patients with Ki-67 ≤10% (hazard ratio, 0.51; 95% confidence interval, 0.25-1.04). No significant differences in PFS or OS were observed with respect to Simpson or WHO grade. Conclusions: For patients with atypical or malignant meningiomas, adjuvant RT was associated with significantly improved PFS, and Ki-67 index >10% was associated with a trend toward worse PFS. Given the long-term survival, high recurrence rates, and efficacy of salvage therapy, patients with atypical and malignant meningiomas should be monitored systematically long after initial treatment.

Introduction: Due to the neurocognitive side effects of whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS) is being used with increasing frequency. The use of SRS is expanding for patients with multiple (>4) brain metastases (BM). This study summarizes our institutional experience with single-fraction, linear-accelerator-based SRS for multiple BM. Methods and materials: All patients who were treated between January 1, 2013, and September 30, 2015, with single-fraction SRS for ≥4 BM were included in this institutional review board–approved, retrospective, single-institution study. Patients were treated with linear accelerator–based image guided SRS. Results: A total of 59 patients with ≥4 BM were treated with single-fraction SRS. The median follow-up was 15.2 months, and the median overall survival for the entire cohort was 5.8 months. The median number of treated lesions per patient was 5 (range, 4-23). Per patient, the median planning target volume (PTV) was 4.8 cc (range, 0.7-28.8 cc). The prescribed dose across all 380 BM for the 59 patients ranged from 7 to 20 Gy. The median of the mean dose to the total PTV was 19.5 Gy. Although the number of treated lesions (4-5 vs ≥6) did not influence survival, better survival was noted for a total PTV 12 Gy to ≥10 cc of normal brain had worse survival (5.1 vs 8.6 months, respectively; P = .0028). Conclusion: In single-fraction SRS for patients with multiple BM, smaller total tumor volume, higher total dose, and lower volume of normal brain receiving >12 Gy were associated with increased survival. These data suggest that using SRS for the treatment of multiple BM is efficacious and that outcomes may be affected more by total tumor volume than by the number of lesions.

Virtually all patients with malignant glioma (MG) eventually recur. This study evaluates the safety of concurrent stereotactic radiosurgery (SRS) and bevacizumab (BVZ), an antiangiogenic agent, in treatment of recurrent MG.Fifteen patients with recurrent MG, treated at initial diagnosis with surgery and adjuvant radiation therapy/temozolomide and then at least 1 salvage chemotherapy regimen, were enrolled in this prospective trial. Lesions3 cm in diameter were treated in a single fraction, whereas those 3 to 5 cm in diameter received 5 5-Gy fractions. BVZ was administered immediately before SRS and 2 weeks later. Neurocognitive testing (Mini-Mental Status Exam, Trail Making Test A/B), Functional Assessment of Cancer Therapy-Brain (FACT-Br) quality-of-life assessment, physical exam, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were performed immediately before SRS and 1 week and 2 months following completion of SRS. The primary endpoint was central nervous system (CNS) toxicity. Secondary endpoints included survival, quality of life, microvascular properties as measured by DCE-MRI, steroid usage, and performance status.One grade 3 (severe headache) and 2 grade 2 CNS toxicities were observed. No patients experienced grade 4 to 5 toxicity or intracranial hemorrhage. Neurocognition, quality of life, and Karnofsky performance status did not change significantly with treatment. DCE-MRI results suggest a significant decline in tumor perfusion and permeability 1 week after SRS and further decline by 2 months.Treatment of recurrent MG with concurrent SRS and BVZ was not associated with excessive toxicity in this prospective trial. A randomized trial of concurrent SRS/BVZ versus conventional salvage therapy is needed to establish the efficacy of this approach.

Background Melanoma of the female genitalia has poor overall prognosis. Objective and methods To examine prognostic factors influencing survival, the Duke Melanoma and Tumor Registry Databases were queried for patients who had received their clinical care at Duke University Medical Center, with a diagnosis of melanoma of the female genitalia, including vulva, vagina, and cervix, between 1970 and 2009. From this group, any available histopathologic specimens were procured for further review. Results Eighty-five patients were identified. The median follow-up time was 8.8 years with 60% of the patients experiencing melanoma-related mortality at last follow-up. Survival rates at 1, 5, and 10 years were 85%, 51%, and 30%, respectively. The available histopathologic specimens from 36 cases were reviewed by a dermatopathologist (M.A.S.). Fifteen of 36 cases were notable for the presence of atypical melanocytic hyperplasia adjacent to the primary melanoma. Breslow depth, lymph node status, systemic therapy, and surgery were also examined for differences in survival distributions using the log-rank test. In general, survival was inversely correlated with Breslow depth, extent of nodal involvement, and provision of systemic therapy. A higher survival rate was observed among those who received wide local excision. Log-rank test demonstrated that survival between different decades of diagnosis was not significantly different. Limitations Because of its small sample size, this study may be underpowered. Conclusion Despite new treatments developed and attempted, there is no evidence that survival has improved over the past 40 years. In summary, patients with thinner melanomas amenable to surgical resection had a better prognosis than those with more extensive, metastatic disease at presentation.

The Patient Care Monitor (PCM) is a review of systems survey delivered by means of an electronic patient-reported outcomes (ePRO) data capture system that uses wireless tablet computers. Although the PCM 1.0 is validated, the updated PCM 2.0 has not been validated nor tested in the academic setting.To validate and test the PCM 2.0 in three cancer populations.Two hundred seventy-five individuals participated in three clinical trials enrolling breast (n=65), gastrointestinal (n=113), and lung (n=97) cancer patients. Internal consistency was evaluated using Cronbach's alpha coefficients calculated for six PCM subscales (general physical symptoms, treatment side effects, distress, despair, impaired performance, and impaired ambulation) and a Quality-of-Life Index. Construct validity was evaluated through Pearson's correlation between PCM subscales and subscales of the Functional Assessment of Cancer Therapy--General (FACT-G), the M.D. Anderson Symptom Inventory (MDASI), and the Functional Assessment of Chronic Illness Therapy--Fatigue (FACIT-F). The participants had the following characteristics: mean age was 58 years (standard deviation: 11), 52% were females, 79% were whites, 17% were blacks, 62% had no college degree, and 78% had metastatic or recurrent disease.Raw and normalized scores for PCM 2.0 subscales were internally consistent across study cohorts. PCM 2.0 subscales correlated significantly (P0.05) with the corresponding subscales on FACT-G, MDASI, and FACIT-F, with the exception of FACT-G social well-being, particularly for the lung cancer population. These correlations demonstrated construct validity. PCM 2.0 results followed expected patterns by cancer etiology. Prior reports demonstrate patient satisfaction with PCM 2.0.Within three unique academic oncology populations, PCM 2.0 is a valid ePRO instrument for assessing symptoms with seven patient-centered subscale or index domains.

Summary Background Palliative oxygen therapy is widely used for treatment of dyspnoea in individuals with life-limiting illness who are ineligible for long-term oxygen therapy. We assessed the effectiveness of oxygen compared with room air delivered by nasal cannula for relief of breathlessness in this population of patients. Methods Adults from outpatient clinics at nine sites in Australia, the USA, and the UK were eligible for enrolment in this double-blind, randomised controlled trial if they had life-limiting illness, refractory dyspnoea, and partial pressure of oxygen in arterial blood (PaO 2 ) more than 7·3 kPa. Participants were randomly assigned in a 1:1 ratio by a central computer-generated system to receive oxygen or room air via a concentrator through a nasal cannula at 2 L per min for 7 days. Participants were instructed to use the concentrator for at least 15 h per day. The randomisation sequence was stratified by baseline PaO 2 with balanced blocks of four patients. The primary outcome measure was breathlessness (0–10 numerical rating scale [NRS]), measured twice a day (morning and evening). All randomised patients who completed an assessment were included in the primary analysis for that data point (no data were imputed). This study is registered, numbers NCT00327873 and ISRCTN67448752. Findings 239 participants were randomly assigned to treatment (oxygen, n=120; room air, n=119). 112 (93%) patients assigned to receive oxygen and 99 (83%) assigned to receive room air completed all 7 days of assessments. From baseline to day 6, mean morning breathlessness changed by −0·9 points (95% CI −1·3 to −0·5) in patients assigned to receive oxygen and by −0·7 points (−1·2 to −0·2) in patients assigned to receive room air (p=0·504). Mean evening breathlessness changed by −0·3 points (−0·7 to 0·1) in the oxygen group and by −0·5 (−0·9 to −0·1) in the room air group (p=0·554). The frequency of side-effects did not differ between groups. Extreme drowsiness was reported by 12 (10%) of 116 patients assigned to receive oxygen compared with 14 (13%) of 108 patients assigned to receive room air. Two (2%) patients in the oxygen group reported extreme symptoms of nasal irritation compared with seven (6%) in the room air group. One patient reported an extremely troublesome nose bleed (oxygen group). Interpretation Since oxygen delivered by a nasal cannula provides no additional symptomatic benefit for relief of refractory dyspnoea in patients with life-limiting illness compared with room air, less burdensome strategies should be considered after brief assessment of the effect of oxygen therapy on the individual patient. Funding US National Institutes of Health, Australian National Health and Medical Research Council, Duke Institute for Care at the End of Life, and Doris Duke Charitable Foundation.

BackgroundIn Cancer and Leukemia Group B 39801, we evaluated whether induction chemotherapy before concurrent chemoradiotherapy would result in improved survival and demonstrated no significant benefit from the addition of induction chemotherapy. The primary objective of this analysis was to dichotomize patients into prognostic groups using factors predictive of survival and to investigate whether induction chemotherapy was beneficial in either prognostic group.Patients and MethodsA Cox proportional hazard model was used to assess the impact on survival of the following factors: (≥70 versus

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

Retrospective data suggests prolonging the time to complete thoracic radiotherapy (TRT) may negatively impact tumor control and survival in limited stage small cell lung cancer (LSCLC). We examined the association between TRT duration and outcomes on a prospective phase III study.This review included 267 patients who received protocol TRT on a phase III CALGB LSCLC study assessing the addition of tamoxifen to standard chemo-radiotherapy. TRT, to a planned dose of 50Gy in 2Gy daily fractions, was initiated with the fourth chemotherapy cycle. TRT interruptions were mandated for hematologic toxicity (granulocytes1000/mm3 or platelets75,000/mm3) and esophageal toxicity (dysphagia necessitating intravenous hydration).TRT interruptionsor =3 days occurred in 115 patients (43%), most frequently during the 4th week of TRT, and did not differ between treatment arms. Hematologic toxicity and esophageal toxicity were the most frequent indications for interrupting TRT. Variables including advanced age (70 years), gender, race, or radiotherapy treatment volume did not predict for TRT interruptions. Overall survival (OS) and local tumor control did not correlate with the administration of TRT interruptions or with TRT duration.Toxicity mandated interruptions of conventional dose, once-daily, TRT may not adversely affect outcomes for patients receiving TRT concurrent with chemotherapy (cycle 4) for LSCLC. The implications for accelerated or high dose TRT regimens are not clear.

IntroductionA stepwise approach to the functional assessment of lung resection candidates is widely accepted, and this approach incorporates the measurement of exercise peak Vo2 when spirometry and radionuclear studies suggest medical inoperability. A new functional operability (FO) algorithm incorporates peak exercise Vo2 earlier in the preoperative assessment to determine which patients require preoperative radionuclear studies. This algorithm has not been studied in a multicenter study.MethodsThe CALGB (Cancer and Leukemia Group B) performed a prospective multi-institutional study to investigate the use of primary exercise Vo2 measurement for the prediction of surgical risk. Patients with known or suspected resectable non-small cell lung cancer (NSCLC) were eligible. Exercise testing including measurement of peak oxygen uptake (Vo2), spirometry, and single breath diffusion capacity (DLCO) was performed on each patient. Nuclear perfusion scans were obtained on selected high-risk patients. After surgery, morbidity and mortality data were collected and correlated with preoperative data. Mortality and morbidity were retrospectively compared by algorithm-based risk groups.ResultsThree hundred forty-six patients with suspected lung cancer from nine institutions underwent thoracotomy with or without resection; 57 study patients did not undergo thoracotomy. Patients who underwent surgery had a median survival time of 30.9 months, whereas patients who did not undergo surgery had a median survival time of 15.6 months. Among the 346 patients who underwent thoracotomy, 15 patients died postoperatively (4%), and 138 patients (39%) exhibited at least one cardiorespiratory complication postoperatively. We found that patients who had a peak exercise Vo2 of

Background Patients with early stage nonsmall-cell lung cancer who have undergone complete resection have a recurrence rate of approximately 50%, predominately due to the development of systemic metastases. This study is a prospective analysis of the expression of seven serum protein markers of invasion and metastasis, collected preoperatively (baseline) and serially after resection, to determine the relationship between marker expression and recurrence. Methods Serum was collected from 196 patients with clinical stage I nonsmall-cell lung cancer who underwent resection over a 5-year period (1996 to 2000). Samples were drawn before resection and 1, 4, 6, 12, 18, and 24 months postoperatively. All patients were followed for at least 24 months or until death. Serum protein levels of vascular endothelial growth factor, hepatocyte growth factor), E-selectin, CD44, basic fibroblast growth factor, urokinase plasminogen activator, and urokinase plasminogen activator receptor were determined using enzyme-linked immunosorbent assay. Results To date, 73 patients (37%) have demonstrated recurrence. Baseline levels of only 1 marker (CD44) correlated with pathologic stage ( p = 0.02). Analysis of the serial samples demonstrated that recurrence was predicted (before clinical or radiographic determination) by decreasing levels of E-selectin ( p = 0.002), increasing levels of CD44 ( p = 0.001), and increasing levels of urokinase plasminogen activator receptor ( p = 0.03). Conclusions This study demonstrates the potential to predict recurrence after resection in patients with early-stage nonsmall-cell lung cancer using a panel of serum protein markers. Early identification of patients with recurrence may improve the efficacy of systemic therapy.

Background Little prospective, multiinstitutional data exist regarding the morbidity and mortality after major pulmonary resections for lung cancer or whether a mediastinal lymph node dissection increases morbidity and mortality. Methods Prospectively collected 30-day postoperative data was analyzed from 1,111 patients undergoing pulmonary resection who were enrolled from July 1999 to February 2004 in a randomized trial comparing lymph node sampling versus mediastinal lymph node dissection for early stage lung cancer. Results Of the 1,111 patients randomized, 1,023 were included in the analysis. Median age was 68 years (range, 23 to 89 years); 52% were men. Lobectomy was performed in 766 (75%) and pneumonectomy in 42 (4%). Pathologic stage was IA in 424 (42%), IB in 418 (41%), IIA in 37 (4%), IIB in 97 (9%), and III in 45 (5%). Lymph node sampling was performed in 498 patients and lymph node dissection in 525. Operative mortality was 2.0% (10 of 498) for lymph node sampling and 0.76% (4 of 525) for lymph node dissection. Complications occurred in 38% of patients in each group. Lymph node dissection had a longer median operative time and greater total chest tube drainage (15 minutes, 121 mL, respectively). There was no difference in the median hospitalization, which was 6 days in each group (p = 0.404). Conclusions Complete mediastinal lymphadenectomy adds little morbidity to a pulmonary resection for lung cancer. These data from a current, multiinstitutional cohort of patients who underwent a major pulmonary resection constitute a new baseline with which to compare results in the future.

Summary Purpose: The Cancer and Leukemia Group B (CALGB) conducted a multi-center phase II trial to evaluate the activity of irinotecan in malignant mesothelioma (CALGB protocol 9733). Patients and methods: Twenty-eight patients accrued between January 1998 and January 1999 received irinotecan 125 mg/m 2 by intravenous infusion over 90 min weekly for 4 weeks, every 6 weeks. Eligibility included a performance status of 0–2 by CALGB criteria, and no prior chemotherapy. Twenty-five patients had pleural mesothelioma; two patients had peritoneal mesothelioma, and one patient had pericardial mesothelioma. Sixty-one percent of patients had epithelial histology. Results: There were no complete or partial responders. Thirty-three percent of patients had stable disease and 52% were shown to have progressive disease at the first reassessment. One patient was not evaluable for response. Median survival from study entry was 9.3 months (95% CI 4.5–13.2 months); 1-year survival was estimated at 46% (95% CI 28–65%). Toxicity was moderately severe. Grade 3 or 4 toxicities included neutropenia in 28% of patients, lymphopenia in 43%, and diarrhea in 18%. Three patients died of treatment-related toxicities. All three experienced grade 4 diarrhea, two also had neutropenic sepsis. Conclusion: Single-agent irinotecan in this dose and schedule has considerable toxicity in patients with malignant mesothelioma and has no anti-tumor activity. The relatively long median survival seen in this study principally reflects the prognostic features of the accrued patients.

Summary Purpose: A major problem with the staging system for non-small cell lung cancer (NSCLC) is clinical underestimation of the extent of disease. Many patients with clinical stage 1 disease do not retain that designation following surgical resection. Herein, we present data from Cancer and Leukemia Group B (CALGB) protocol 9761 evaluating the correspondence between clinical and pathologic analysis in early stage NSCLC. Methods: Five hundred and two patients with suspected or biopsy-proven NSCLC classified as clinical stage 1 (T1–2, N0) by computed tomography (CT) scan or cervical mediastinoscopy were prospectively enrolled in CALGB 9761. The purpose of CALGB 9761 was to prospectively evaluate molecular markers of micrometastatic disease in stage 1 NSCLC. Enrollment occurred at 11 selected institutions within the CALGB. Patients with clinically suspected resectable early stage lung cancer were eligible for enrollment if they had no evidence of mediastinal or hilar adenopathy on CT scan or if they had CT evidence of potential N2 or N3 disease (lymph node ≥1.0 cm) but with negative mediastinoscopy. No prior chemotherapy or radiotherapy was permitted. Results: Of the 502 patients felt to have clinical stage 1 NSCLC enrolled in CALGB 9761, 489 underwent resection with complete surgical staging and routine histopathologic analysis. From these 489 patients, only 422 (86.3%) turned out to have pathologically documented NSCLC. Of these 422 patients, 302 (71.6%) had pathologic stage 1 disease (173 stage 1A and 129 stage 1B). Despite clinical assessment of stage 1 disease, 59 (14%) patients had pathologic stage 2 disease, 57 (13.5%) had stage 3 disease, and four (0.9%) patients had stage 4 disease. Of the patients undergoing resection for clinical stage 1 NSCLC, 65 patients did not have NSCLC (44 had benign disease and 21 had malignancies other than NSCLC) and two additional patients had dual synchronous primary NSCLC tumors and were not eligible for the study. Overall, only 61.7% (302 of 489) of patients with suspected stage 1 NSCLC disease retained that stage and diagnosis after complete surgical staging, while 38.3% had an inaccurate pre-operative clinical stage or diagnosis. Conclusions: The results from this prospective trial demonstrate the poor predictive value of current clinical staging techniques in early stage NSCLC. These findings will serve as a benchmark for comparison of future clinical imaging modalities and other tests evaluating early stage NSCLC.

Objectives This study examined the feasibility of thoracoscopic wedge resection and radiotherapy for clinical T1 lesions in patients with compromised cardiopulmonary status. Methods In this phase II, prospective, multicenter, cooperative group trial, high-risk patients had one or more of the following risk factors: forced expiratory volume in 1 second less than 40%, carbon monoxide diffusing capacity in lung less than 50%, and maximum oxygen consumption less than 45 mm Hg. Patients underwent video-assisted wedge resection followed by local (56 Gy) radiotherapy. The primary end point was the proportion of patients whose disease could be completely resected and who received radiotherapy without treatment complications. Results Between September 1995 and September 1999, a total of 65 patients were accrued, of which 58 were eligible (52% male, median age 69 years). Pathologic staging resulted in upgrading to T2 or greater in 16 of 58 cases (28%) and in reassessment as benign in 10 of 58 cases (17%). Conversion to thoracotomy was required in 10 cases (17%), including 1 of 10 benign T1-size lesion (10%), 4 of 35 non-small cell lung cancer T1 lesions (13%), and 5 of 14 non-small cell lung cancer T2 lesions (31%). Resection margins were positive in 5 patients: 6% of T1 and 23% of T2. Surgery was aborted in 2 cases (3.5%), and operative mortality was 4%. Overall operative failure rates of video-assisted wedge resection were 20% for benign T1-size lesions, 22% for T1 non-small cell lung cancer, 21% for all T1 lesions, 50% for T2 non-small cell lung cancer, and 29% for all lesions in this study (clinical T1). Prolonged air leaks occurred in 10%, pneumonia in 6%, and respiratory failure in 4%. Thirty-one patients were eligible for radiotherapy; 3 of them refused, and 1 died before treatment. Among the 28 patients who received radiotherapy, severe dyspnea was noted in 3 patients (11%) and moderate pneumonitis in 4 (14%). Conclusions Clinical staging in high-risk patients is often inaccurate (45% difference from pathologic staging). Intention to treat clinically staged T1 disease by video-assisted wedge resection is associated with a high failure rate. Pathologically staged T1 lesions can be successfully resected in 75% of cases; however, narrow resection margins remain a concern.

Study objective To demonstrate the efficacy, safety, and appropriate mode of instillation of talc for sclerosis in treatment of malignant pleural effusions (MPEs) Design A prospective, randomized trial was designed to compare thoracoscopy with talc insufflation (TTI) to thoracostomy and talc slurry (TS) for patients with documented MPE Measurements The primary end point was 30-day freedom from radiographic MPE recurrence among surviving patients whose lungs initially re-expanded ≥ 90%. Morbidity, mortality, and quality of life were also assessed Results Of 501 patients registered, those eligible were randomized to TTI (n = 242) or TS (n = 240). Patient demographics and primary malignancies were similar between study arms. Overall, there was no difference between study arms in the percentage of patients with successful 30-day outcomes (TTI, 78%; TS, 71%). However, the subgroup of patients with primary lung or breast cancer had higher success with TTI than with TS (82% vs 67%). Common morbidity included fever, dyspnea, and pain. Treatment-related mortality occurred in nine TTI patients and seven TS patients. Respiratory complications were more common following TTI than TS (14% vs 6%). Respiratory failure was observed in 4% of TS patients and 8% of TTI patients, accounting for five toxic deaths and six toxic deaths, respectively. Quality-of-life measurement demonstrated less fatigue with TTI than TS. Patient ratings of comfort and safety were also higher for TTI, but there were no differences on perceived value or convenience of the procedures Conclusions Both methods of talc delivery are similar in efficacy; TTI may be better for patients with either a lung or breast primary. The etiology and incidence of respiratory complications from talc need further exploration

Astrocytoma is comprised of a group of common intracranial neoplasms that are classified into four grades based on the World Health Organization histological criteria and patient survival. To date, histological grade, patient age, and clinical performance, as reflected in the Karnofsky score, are the most reliable prognostic predictors. Recently, there has been a significant effort to identify additional prognostic markers using objective molecular genetic techniques. We believe that the identification of such markers will characterize new chromosomal loci important in astrocytoma progression and aid clinical diagnosis and prognosis. To this end, our laboratory used comparative genomic hybridization to identify DNA sequence copy number changes in 102 astrocytomas. Novel losses of 19p loci were detected in low-grade pilocytic astrocytomas and losses of loci on 9p, 10, and 22 along with gains on 7, 19, and 20 were detected in a significant proportion of high-grade astrocytomas. The Cox proportional hazards statistical modeling showed that the presence of +7q and −10q comparative genomic hybridization alterations significantly increased a patient's risk of dying, independent of histological grade. This investigation demonstrates the efficacy of comparative genomic hybridization for identifying tumor suppressor and oncogene loci in different astrocytic grades. The cumulative effect of these loci is an important consideration in their diagnostic and prognostic implications.

Purpose: The CALGB performed a phase II multicenter study to evaluate the activity of oral capecitabine in patients with malignant mesothelioma (CALGB 39807). Patients and Methods: Between November 15, 2000 and August 31, 2001, 27 patients with mesothelioma were enrolled in this study. Capecitabine was administered at 2500 mg/m2 per day divided in two doses for 14 days followed by a seven-day break. Cycles were repeated every 21 days with restaging performed every two cycles and therapy continuing for up to six cycles. One patient withdrew from the study prior to receiving therapy and is removed from further analysis. Eligibility criteria included no prior treatment, PS 0–1 by CALGB criteria and histologically documented mesothelioma. Patient characteristics: gender; male 19 (73%), female seven; median age 70 (range 40–81); histology: epithelial 15 (58%), mixed eight (31%), unclassified three; site of origin pleura, 25 (96%); weight loss in previous six months of more than 10% in seven (27%), symptoms longer than six months in five (19%). Results: One patient (4%) had a confirmed PR while 10 (38%) achieved SD for 2–6 cycles. Ten patients (38%) had PD as their best response. There were three patients unevaluable for response and two early deaths. Median survival and failure free survival were 4.9 (95% CI 4–10.8) and 2.4 (95% CI 1.5–4.2) months respectively with a one-year survival of 23% (95% CI 11–49%). Grade three or greater toxicities encountered by at least 10% of patients included lymphopenia (12%), fatigue (12%), dehydration (12%) and diarrhea (15%). Three patients (12%) had grade three skin toxicity or hand–foot syndrome. One patient died of treatment related toxicity during cycle one. Conclusion: The antitumor activity of capecitabine is insufficient to warrant further exploration in patients with malignant mesothelioma.

Background To evaluate the activity and tolerability of gemcitabine plus irinotecan or docetaxel as first-line chemotherapy for advanced non-small cell lung cancer (NSCLC). Patients and methods Eligible patients with chemotherapy-naive stage IIIB or IV NSCLC were randomized to receive gemcitabine 1000 mg/m2 on days 1 and 8, plus either irinotecan 100 mg/m2 or docetaxel40 mg/m2 on days 1 and 8. Treatment was administered every 3 weeks. Results Of the 80 enrolled patients with stage IIIB or IV NSCLC, 78 were evaluable for activity and safety. Overall response rates, consisting of partial responses, were 12.8% [95% confidence interval (CI) 4% to 35%] for gemcitabine–irinotecan and 23.1% (95% CI 10% to 42%) for gemcitabine–docetaxel. Median overall survival was 7.95 months (95% CI 5.2–10.2) and 12.8 months (95% CI 7.9–17.1) for gemcitabine–irinotecan and gemcitabine–docetaxel, respectively. The corresponding estimated 1-year survivals were 23% and 51%, respectively. The 2-year survival rate in arm A (gemcitabine–irinotecan) is not currently estimable. The 2-year survival rate for arm B (gemcitabine–docetaxel) is 22% (95% CI 6% to 37%). Both combinations were well tolerated; the most common hematological toxicity was neutropenia, which occurred in 26% of patients in each treatment arm. Conclusions These results suggest that gemcitabine plus docetaxel or irinotecan is well tolerated in patients with chemotherapy-naive advanced NSCLC. The survival data with the combination gemcitabine–docetaxel are promising. Gemcitabine–docetaxel combination therapy may be particularly useful for patients who have experienced toxicities with a platinum regimen or in patients who may be more susceptible to platinum-related toxicity.

Positive control materials for clinical molecular genetic testing applications are currently in critically short supply or non-existent for many genetically based diseases of public health importance. Here we demonstrate that anonymous, residual, clinical blood samples are potential sources of viable lymphocytes for establishing Epstein-Barr virus (EBV)-transformed blood lymphocyte cell lines. We attempted to transform 34 residual blood samples, and analyzed transformation success with respect to sample age, anticoagulant, storage temperature, volume, hemolysis, and patient age and sex. In univariate analysis, sample age was significantly associated with transformation success (P = 0.002). The success rate was 67% (6 of 9) for samples 1 to 7 days old, 38% (3 of 8) for samples 8 to 14 days old and 0% for samples 15 to 21 (0 of 11) days old. When we controlled for sample age in multivariate logistic regression, anticoagulant and storage temperature approached significance (P = 0.070 and 0.087, respectively; samples in acid citrate dextrose (ACD) and refrigerated samples were more likely to transform). Based on these findings, we suggest that samples collected in either ACD or ethylene diamine tetraacetic acid, and up to 14 days old (refrigerated) or 7 days old (stored ambient), are reasonable candidates for EBV transformation. The transformation rate for samples that met these criteria was 63% (10 of 16). Implementation of this process could help alleviate the shortage of positive control materials for clinical molecular genetic testing.

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.

Objective: The 5-year survival for patients with surgically resected stage I non-small cell lung cancer is only 60% to 70%, probably because of undetected systemic occult micrometastases. Detection of occult micrometastases in lymph nodes by reverse-transcriptase polymerase chain reaction for carcinoembryonic antigen messenger RNA in non-small cell lung cancer has not been reported. Detection of occult micrometastases by standard reverse-transcriptase polymerase chain reaction provides only yes or no answers about their presence, whereas quantitative real-time reverse-transcriptase polymerase chain reaction permits reproducible quantitation of target molecules. This study evaluated the ability of quantitative reverse-transcriptase polymerase chain reaction to quantitate lymph node occult metastases with carcinoembryonic antigen messenger RNA as a tumor marker. Methods: Standard reverse-transcriptase polymerase chain reaction and quantitative reverse-transcriptase polymerase chain reaction for carcinoembryonic antigen messenger RNA were performed on 232 lymph nodes from 53 patients with stage I disease (node negative according to histologic examination). Quantitative reverse-transcriptase polymerase chain reaction determined carcinoembryonic antigen messenger RNA quantity by detecting fluorescence increase at a threshold polymerase chain reaction cycle. Threshold polymerase chain reaction cycle values were correlated with standard curves created from serially diluted carcinoembryonic antigen-positive HTB-174 tumor cells to estimate the number of micrometastatic tumor cells in a lymph node. Results: Detection rates of occult metastases were similar for standard reverse-transcriptase polymerase chain reaction and quantitative reverse-transcriptase polymerase chain reaction at 38 of 232 (16.4 %) and 59 of 232 (25.4 %), respectively. Upstaging rates among 53 cases of stage I non-small cell lung cancer were also similar for standard reverse-transcriptase polymerase chain reaction and quantitative reverse-transcriptase polymerase chain reaction at 23 of 53 (43.4 %) and 30 of 53 (56.6%), respectively. Comparison of positive lymph node stations according to quantitative reverse-transcriptase polymerase chain reaction (threshold polymerase chain reaction cycle

Chemotherapy for extensive-stage small-cell lung cancer (E-SCLC) produces high response rates and improved survival but few cures. We tested three new regimens for E-SCLC that might merit further investigation in a subsequent phase III trial. Cancer and Leukemia Group B 9430 was a randomized phase II study evaluating 4 treatment arms in 57 evaluable, previously untreated E-SCLC patients. Each arm consisted of the following: Arm 1: cisplatin plus topotecan; Arm 2: cisplatin plus paclitaxel; Arm 3: paclitaxel 230 mg/m2 plus topotecan; and Arm 4: paclitaxel 175 mg/m2 plus topotecan. Because of an accrual time difference, Arm 2 will not be discussed in this manuscript. Arm 1 (12 patients) produced 1 complete response (CR, 8%) and an overall response rate (ORR) of 42%. Toxicity was excessive, with 3 deaths (25%). Arm 3 (13 patients) produced no CRs, 7 partial responses (PRs, 54%), median survival of 13.8 months, and failure-free survival (FFS) of 7.41 months, with 3 toxic deaths (25%). Among 32 evaluable patients on Arm 4, there were 2 CRs (6%) and 20 PRs (63%) for an ORR of 69%, median survival of 9.9 months, FFS of 5.21 months, and 1-year survival of 40%. There was 1 possible treatment-related death (3%). Topotecan plus cisplatin, in the doses and schedule employed, produced excessive toxicity and modest efficacy in E-SCLC patients. Paclitaxel (230 mg/m2 on day 1) plus topotecan (1 mg/m2 on days 1-5) produced excessive toxicity that was ameliorated with an attenuated paclitaxel dose (175 mg/m2). With the latter regimen (Arm 4) in patients with a performance status of 0/1, CR rates, FFS, overall survival, and 1-year survival were similar to standard etoposide plus cisplatin chemotherapy. Further exploration of topoisomerase inhibitors and taxanes in SCLC patients is warranted.

Doxorubicin is the most widely studied agent for the treatment of malignant mesothelioma. In conventional doses, the response rate is approximately 17%. Higher dose doxorubicin has been successfully employed in other tumor types. Dexrazoxane has been demonstrated to reduce the cardiac toxicity associated with long term, chronic use of doxorubicin. Based upon phase I data generated by the Cancer and Leukemia Group B (CALGB) indicating that doxorubicin at a dose of 120 mg/m(2) when combined with dexrazoxane and GM-CSF could be safely administered, the CALGB undertook a phase II study of high-dose doxorubicin in patients with malignant mesothelioma. Toxicity was excessive, necessitating protocol modification and ultimately protocol termination. There were no objective responses observed. We conclude that high-dose doxorubicin administered with dexrazoxane is unacceptably toxic in this patient population.

Background . This study was designed to determine the prognostic value of immunohistochemical tumor marker expression in a population of patients with node-negative esophageal cancer treated with complete resection alone. Methods . Resection specimens were collected from 61 patients with node-negative T1 (n = 31), T2 (n = 14), and T3 (n = 16) esophageal cancer. A panel of 10 tumor markers was chosen for immunohistochemical analysis, based on associations with differing oncologic mechanisms: apoptosis (p53), growth regulation (transforming growth factor-α, epidermal growth factor receptor, and Her2-neu), angiogenesis (factor VIII), metastatic potential (CD44), platinum resistance (p-glycoprotein and metallothionein), 5-fluorouracil resistance (thymidylate synthetase), and carcinogenic detoxification (glutathione S -transferase-π). Results . Complete resection was performed in all patients (44 adenocarcinoma, 17 squamous cell carcinoma), with no operative deaths. Multivariable analysis demonstrated a significant relationship between cancer-specific death and the following variables: low-level P-gp expression ( p = 0.004), high-level expression of p53 ( p = 0.04), and low-level expression of transforming growth factor-α ( p = 0.03). In addition, the number of involved tumor markers present was strongly predictive of negative outcome ( p = 0.0001). Conclusions . This study supports the prognostic value of immunohistochemical tumor markers, specifically the expression pattern of P-gp, p53, and transforming growth factor-α, in patients with esophageal carcinoma treated with complete resection alone.

The purpose of this study was to examine the safety and efficacy of carboplatin/etoposide/paclitaxel in patients with untreated stage IV non–small-cell lung cancer (NSCLC) and extensive small-cell lung cancer (SCLC). Carboplatin was administered intravenously (I.V.) at an area under the curve (AUC) of 6 with etoposide at either 80 or 100 mg/m 2 I.V. days 1-3 and paclitaxel at 175 or 200 mg/m 2 I.V. over 3 hours along with 5 μg/kg of granulocyte colony-stimulating factor subcutaneously on days 4-18, repeated every 3 weeks for 6 courses. Thirty-one patients (five NSCLC and 26 SCLC) entered into this phase I study. The median age was 63 (range, 42 to 74 years), with 24 males and seven females. The recommended dose level for phase II testing was carboplatin AUC=6, etoposide 80 mg/m 2 days 1-3, and paclitaxel 175 mg/m 2 over 3 hours. With seven patients at this level, 14% had grade 4 neutropenia, 14% had grade 4 thrombocytopenia, none had grade 2/3 neurotoxicity, and no toxic deaths occurred. One of five (20%) patients with NSCLC responded, and 19 of 22 (86%) evaluable SCLC patients experienced a response to therapy. SCLC patients had a median survival of 10 months. The combination of carboplatin/etoposide/paclitaxel has significant activity with acceptable toxicity in patients with extensive SCLC.

Objective The purpose of this study was to determine the relationship between tumor size and survival in patients with stage IA non-small cell lung cancer (non-small cell lung cancer; ie, lesions Method Five hundred ten patients with pathologic stage IA (T1N0M0) non-small cell lung cancer were identified from our tumor registry over an 18-year period (from 1981 to 1999). There were 285 men and 225 women, with a mean age of 63 years (range, 31 to 90 years). The Cox proportional model was used to examine the effect on survival. Tumor size was incorporated into the model as a linear effect and as categorical variables. The Kaplan-Meier product limit estimator was used to graphically display the relationship between the tumor size and survival. Results The Cox proportional hazards model did not show a statistically significant relationship between tumor size and survival (p = 0.701) as a linear effect. Tumor size was then categorized into quartiles, and again there was no statistically significant difference in survival between groups (p = 0.597). Tumor size was also categorized into deciles, and there was no statistical relationship between tumor size and survival (p = 0.674). Conclusions This study confirms stratifying patients with stage IA non-small cell lung cancer in the same TNM classification, given no apparent difference in survival. Unfortunately, these data caution that improved small nodule detection with screening CT may not significantly improve lung cancer mortality. The appropriate prospective randomized trial appears warranted.

In order to explore non-cisplatin containing regimens for advanced non-small cell lung cancer, Cancer and Leukemia Group B conducted a randomized Phase-II study of two novel combinations, paclitaxel/ifosfamide and vinorelbine/ifosfamide. Both regimens were active with a 38% response rate (95% CI: 24%, 53%) and 31% (95% CI: 18%, 47%), respectively. Median survivals were 8.5 and 7.4 months. Toxicity, mostly neutropenia, was acceptable. These two combinations establish a 'proof of principle' that non-cisplatin containing regimens also have activity in this setting.

Purpose: To evaluate the incidence, severity, and clinical/dosimetric predictors of acute and chronic esophageal toxicities in patients with non-small cell lung cancer (NSCLC) treated with high-dose conformal thoracic radiation. Methods and Materials: Ninety-one patients with localized NSCLC treated definitively with high-dose conformal radiation therapy (RT) at Duke University Medical Center (DUMC) were reviewed. Patient characteristics were as follows: 53 males and 38 females; median age 64 yr (range 46–82); stage I—16, II—3, IIIa—40, IIIb—30, X—2; dysphagia pre-RT—6 (7%). Treatment parameters included: median corrected dose—78.8 Gy (range 64.2–85.6); BID fractionation—58 (64%); chemotherapy—43 (47%). Acute and late esophageal toxicities were graded by RTOG criteria. Using 3D treatment planning tools, the esophagus was contoured in a uniform fashion, the 3D dose distribution calculated (with lung density correction), and the dose–volume (DVH) and dose–surface histograms (DSH) generated. At each axial level, the percentage of the esophageal circumference at each dose level was calculated. The length of circumferential esophagus and the maximum circumference treated to doses >50 Gy were assessed. Patient and treatment factors were correlated with acute and chronic esophageal dysfunction using univariate and multivariate logistic regression analyses. Results: There were no acute or late grade 4 or 5 esophageal toxicities. Ten of 91 patients (11%) developed grade 3 acute toxicity. On univariate analysis of clinical parameters, both dysphagia pre-RT ( p = 0.10) and BID fractionation ( p = 0.11) tended toward significantly predicting grade 3 acute esophagitis. None of the dosimetric parameters analyzed significantly predicted for grade 3 acute esophagitis. Twelve of 66 assessable patients (18%) developed late esophageal toxicity. Of the clinical parameters analyzed, only dysphagia pre-RT ( p = 0.06) tended toward significantly predicting late esophageal toxicity. On univariate analyses, the effects of percent organ volume treated >50 Gy ( p = 0.05), percent surface area treated >50 Gy ( p = 0.05), length of 100% circumference treated >50 Gy ( p = 0.04), and maximum percent of circumference treated >80 Gy ( p = 0.01) significantly predicted for late toxicity of all grades. On multivariate analysis, percent organ volume treated >50 Gy ( p = 0.02) and maximum percent of circumference treated >80 Gy ( p = 0.02) predicted for late toxicity. Conclusions: Late esophageal toxicity following aggressive, high-dose conformal radiotherapy is common but rarely severe. Dosimetric variables addressing the longitudinal and circumferential character of the esophagus have biologic rationale and are predictive of late toxicity. Further studies are needed to assess whether these parameters are better predictors than those derived from traditional DVHs.

Summary Background: New agents with activity in mesothelioma are sorely needed. The Cancer and Leukemia Group B (CALGB) therefore performed a phase II study of high-dose paclitaxel in patients with malignant mesothelioma who had no prior chemotherapy. Patients and methods: Thirty-five patients accrued to this multi-institutional phase II study of paclitaxel given as a 24hour infusion at 250 mg/m 2 every three weeks plus filgrastim (G-CSF) 300 meg subcutaneously days 3-18. Results: There were three (9%) regressions of evaluable disease. The median survival was five months (95% confidence interval (95% CI): 1.9-9.6 months), the one-year survival rate was 14% and the two-year survival rate was 6%. Toxicity was tolerable with one death from pneumonia (without neutropenia) on day 18 and a 23% rate of grade 4 granulocytopenia. Conclusions: The level of activity seen with paclitaxel is similar to that seen in other CALGB trials of the single agents carboplatin, trimetrexate and 5-azacytidine. Future studies of of paclitaxel (at lower doses) in combination with synergistic agents could be considered.

Objective: The standard treatment of patients with stage I non–small cell lung cancer is resection of the primary tumor; however, the recurrence rate is 28% to 45%. This study evaluates a panel of molecular markers in a large population of patients with stage I non–small cell lung cancer to determine the prognostic value of each marker and to create a biologic risk model. Methods : Pathologic specimens were collected from 408 consecutive patients after complete resection for stage I non–small cell lung cancer at a single institution, with follow-up of at least 5 years. A panel of 10 molecular markers was chosen for immunohistochemical analysis of the primary tumor on the basis of differing oncogenic mechanisms. Local tumor expansion requires growth regulating proteins (epidermal growth factor receptor, the protooncogene erb -b2); apoptosis proteins (p53, bcl-2); and cell cycle regulating proteins (retinoblastoma recessive oncogene, KI-67). Local tumor invasion requires angiogenesis (factor viii). The development of distant metastases involves the expression of adhesion proteins (CD-44, sialyl-Tn, blood group A). Cox proportional hazards regression analysis was used to construct an independent risk model for cancer recurrence and death. Results: Multivariable analysis demonstrated significantly elevated risk for the following molecular markers: p53 (hazard ratio, 1.68; P = .004); factor viii (hazard ratio, 1.47 P = .033); erb -b2 (hazard ratio, 1.43; P = .044); CD-44 (hazard ratio, 1.40; P = .050); and retinoblastoma recessive oncogene (hazard ratio, 0.747; P = .084). Conclusions: Five molecular markers were associated with the risk of recurrence and death, representing independent metastatic pathways: apoptosis (p53), angiogenesis (factor viii), growth regulation ( erb -b2), adhesion (CD-44), and cell cycle regulation (retinoblastoma recessive oncogene). This study demonstrates the validity of this molecular biologic risk model in patients with stage I non– small cell lung cancer. (J Thorac Cardiovasc Surg 1999;117:736-43)

Background Malignant pleural effusions are a common problem for patients with metastatic disease. Most patients are treated with tube thoracostomy and sclerotherapy, although there remains no standard approach. The purpose of this study was to compare the efficacy of bleomycin with doxycycline sclerotherapy for the treatment of malignant pleural effusions using small-bore catheters. Methods All patients with a symptomatic malignant pleural effusion referred for chest tube drainage and sclerotherapy over a 2-year period were considered eligible. Using image guidance, a 14F self-retaining catheter was inserted into the pleural space and connected to continuous wall suction. When drainage fell below 200 mL/d, patients were randomized to 60 U of bleomycin or 500 mg of doxycycline sclerotherapy. Response at 30 days was determined. Results One hundred six patients were enrolled in the study. Fifteen men (29%) and 37 women (71%) with a mean age of 57 years received bleomycin sclerotherapy. Twenty-one of the 29 patients (72%) alive and evaluable at 30 days had successful sclerotherapy. Twenty-three men (43%) and 31 women (57%) with a mean age of 61 years received doxycycline sclerotherapy. Twenty-three of the 29 patients (79%) alive and evaluable at 30 days had successful sclerotherapy. There was no significant difference in response rates between doxycycline and bleomycin (p=0.760). Conclusions These data continue to support a role for small-bore chest drainage and sclerotherapy, although there was no significant difference in 30-day response rates between doxycycline and bleomycin.

Background: The purpose of this study was to compare the long-term psychosocial adaptation of Hodgkin's disease and adult acute leukemia survivors. Patients and methods: Two hundred seventy-three Hodgkin's disease (HD) and 206 adult acute leukemia (AL) survivors were interviewed by telephone concerning their psychosocial adjustment and problems they attributed to having been treated for cancer, using identical research procedures and a common set of instruments. The following measures were used: Psychosocial Adjustment to Illness Scale (PAIS); Brief Symptom Inventory (BSI); current Conditioned Nausea and Vomiting triggered by treatment-related stimuli (CNVI); Indices of Employment, Insurance and Sexual Problems Attributed to Cancer; Negative Socioeconomic Impact of Cancer Index (NSI). All participants had been treated on one of nine Hodgkin's disease or 13 acute leukemia Cancer and Leukemia Group B (CALGB) clinical trials from 1966-1988, and had been off treatment for one year or more (mean years: HD = 5.9; AL = 5.6). Results: HD survivors' risk of having a high distress score on the BSI was almost twice that found for AL survivors (odds ratio = 1.90), with 21% of HD vs. 14% of AL survivors (P < 0.05) having scores that were 1.5 standard deviations above the norm, suggestive of a possible psychiatric disorder. HD survivors reported greater fatigue (POMS Fatigue, P = 0.01; Vigor Subscales, P = 0.001). greater conditioned nausea (CNVI, P < 0.05), greater impact of cancer on their family life (PAIS Domestic Environment, P = 0.004) and poorer sexual functioning (PAIS Sexual Relationships. P = 0.0001), than AL survivors. Conclusions: Treatment-related issues may have placed HD survivors at a greater risk for problems in long-term adaptation than AL survivors.

Purpose To examine the individual and joint effect of various pretreatment clinical characteristics on the survival of patients with mesothelioma treated by the Cancer and Leukemia Group B (CALGB). Patients and methods Between June 1984 and September 1994, 337 patients with malignant mesothelioma and no prior chemotherapy were accrued to seven phase II studies conducted by the CALGB which screened the efficacy of 10 treatment regimens or dose levels. The eligibility criteria for all studies were virtually identical. Patient characteristics include the following: age older than 60 years (63%); male (83%); performance status (PS) of 0 or 1 (81%); chest pain (60%); definite asbestos exposure (62%); >5% weight loss (41%); and pleural involvement (94%). Median survival time (MST) for the 10 treatment regimens ranged from 3.9 to 9.8 months (overall=7.2; 95% confidence interval [CI], 6.5 to 8.3), with 1-year survival between 14% and 50% (overall=27%; 95% CI, 23 to 33%). Results Cox survival models and exponential regression trees were used to examine the prognostic importance of pretreatment patient characteristics. Univariate analyses show that patients with poor Eastern Cooperative Oncology Group PS, chest pain, dyspnea, platelet count (PLT) >400, 000/μL, weight loss, serum lactate dehydrogenase (LDH) level >500 IU/L, pleural involvement, low hemoglobin (HGB) level, high WBC count, and increasing age over 75 years have a worse prognosis. With decreasing risk ratio, multivariate Cox analyses showed that pleural involvement, LDH >500 IU/L, poor PS, chest pain, PLT >400, 000/μL, nonepithelial histology, and increasing age older than 75 years jointly predict poor survival. PS was the most important prognostic split in the regression tree. Terminal nodes were amalgamated to form six distinct prognostic subgroups with MST (2-year survival) of 13.9 (38%) in 36 patients, 9.5 (21%) in 36 patients, 9.2 (10%) in 146 patients, 6.5 (3%) in 33 patients, 4.4 (0%) in 73 patients, and 1.4 (0%) in 13 patients (p Conclusions The subgroup with the best survival (MST=13.9 months) included patients with PS=0 and age younger than 49 years, and patients with PS=0, age of 49 years or older, and HGB ≧14.6. The worst survival (MST=1.4 months) occurred for patients with PS=1/2 and WBC ≧15.6/μL.

In a prior Cancer and Leukemia Group B (CALGB), 16% of a small cohort of patients with extensive small call lung cancer who had failed to obtain a complete remission with chemotherapy did obtain a complete remission after therapy with interleukin-2 (IL-2). In this current trial, 10 patients with extensive small cell lung cancer who had had no prior therapy were treated with subcutaneous IL-2 as induction therapy and then standard chemotherapy with etoposide/cisplatin. Only one patient experienced an objective response to the IL-2 administered prior to chemotherapy. The factors governing response to IL-2 in the first trial but not in this trial are discussed.

A quality of life (QOL) endpoint supplemented standard clinical endpoints of survival, tumor response, and toxicity in a double-blind study conducted by the Cancer and Leukemia Group B (CALGB) where 291 patients with advanced non-small cell lung cancer (NSCLC) were randomly assigned to receive cisplatin/vinblastine with either hydrazine sulfate (HS) or placebo. The difficulties associated with the analysis of the longitudinal QOL data, and the contributions that the QOL endpoint made to the understanding of treatment differences, will be the focus of this paper.

This Phase II study was designed to determine the efficacy of two chemotherapy regimens with G-CSF support for patients with advanced non-small cell lung cancer (NSCLC). One-hundred and one patients with Stage IIIB or IV NSCLC and performance status 0-1 were randomized to receive ifosfamide 2.0 g/m2 days 1-3, mesna 400 mg/m2 at 0, 4, 6 h days 1-3, cisplatin 33 mg/m2 days 1-3 or etoposide 200 mg/m2 days 1-3, cisplatin 35 mg/m2 days 1-3. Both groups received G-CSF 5 micrograms/kg SQ day 4 to the post day 11 absolute neutrophil count10 000. For the 47 eligible patients receiving ifosfamide/mesna/cisplatin, the response rate was 26% (95% confidence interval: 14-40%) and the median survival 7.5 months (95% confidence interval: 5.8-11.0 months). Grade 3 or worse toxicities were: neutropenia 75%, thrombocytopenia 70%, infection 21%. There were two treatment-related deaths due to infection. For course 1, the median absolute neutrophil count nadir was 1.3, platelet nadir 96 000 and incidence of febrile neutropenia 16%. For the 48 eligible patients receiving etoposide/cisplatin, the response rate was 21% (95% confidence interval: 11-35%) and median survival 5.8 months (95% confidence interval: 4.5-9.7 months). Grade 3 or worse toxicities were: neutropenia 90%, thrombocytopenia 58%, infection 29%. There were three treatment-related deaths due to infection. For course 1, the median absolute neutrophil count was 0.2, platelet nadir 80 000 and incidence of febrile neutropenia 33%. For both ifosfamide/mesna/cisplatin and etoposide/cisplatin, median duration of Grade IV neutropenia was short (or = 4 days), time to subsequent courses 21 days and dose delivered95% of planned dose. Although G-CSF allowed full doses of drugs to be delivered on schedule, both ifosfamide/mesna/cisplatin and etoposide/cisplatin produced response rates and survival similar to other cisplatin-based regimens. In view of the significant cost of G-CSF and no obvious improvement in response rate, survival or toxicity profile, G-CSF cannot be recommended with these chemotherapy regimens for patients with advanced NSCLC.

Background. Although complete surgical resection remains the primary treatment for localized stage I non—small cell lung cancer, the cancer recurrence rate is 25% to 40%. If one could identify a subset of patients using molecular factors that contribute to tumor aggressiveness, one might improve prognosis in this group with additional treatment. High expression of angiogenesis factor viii has been associated with the presence of nodal metastases in breast cancer; here we examined its relation to survival with non—small cell lung cancer. Methods. We examined angiogenesis using immunohistochemistry on paraffin blocks of tumor from 275 consecutive patients with stage I non—small cell lung cancer, more than 68 months of follow-up, and a 64% 5-year survival. Angiogenesis was calculated from the microvessel number per ten 200 × microscope fields measured at the tumor periphery, in the center, and in the area of highest concentration. Results. Measurements in the central area were inconsistent due to prominent necrosis. However, microvessel number recorded at the periphery and at the "hottest" area correlated well ( r 2 = 0.952; p = 0.001), and a significant survival advantage was noted for low-level expression at both areas (peripheral, p = 0.046; "hottest", p = 0.006). Multivariate survival analysis using angiogenesis, protooncogene erb B-2, tumor suppressor gene p53, and the proliferation marker KI-67 defined angiogenesis as the most significant prognostic factor in stage I lung cancer. Conclusions. This molecular biologic substaging system including angiogenesis for stage I non—small cell lung cancer is independent of routine histopathologic factors and revealed an additive adverse effect with expression of several biologic markers (5-year survival: no marker [n = 51] 81%, 1 marker [n = 82] 71%, 2 markers [n = 84] 54%, and 3 to 4 markers [n = 58] 49%; p = 0.0001).

PURPOSE This study was designed to evaluate strategies to overcome the resistance of anaplastic gliomas of the brain to external beam radiotherapy (ERT) plus carmustine (BCNU). Patients were > or = 15 years of age, had a histologic diagnosis of malignant glioma, and a Karnofsky performance status (KPS) > or = 60%. METHODS AND MATERIALS In Randomization 1, patients were assigned to receive either ERT alone (61.2 Gy) or ERT plus mitomycin C (Mito, IV 12.5 mg/m(2)) during the first and fourth week of ERT. After this treatment, patients went on to Randomization 2, where they were assigned to receive either BCNU (i.v. 200 mg/m(2)) given at 6-week intervals or 6-mercaptopurine (6- MP, 750 mg/m(2) IV daily for 3 days every six weeks), with BCNU given on the third day of the 6-MP treatment. Three hundred twenty-seven patients underwent Randomization 1. One hundred sixty-four received ERT alone, and 163 received ERT + Mito [average 52.7 years; 63% male; 69% glioblastoma multiforme (GBM); 66% had a resection; 56% KPS > or = 90%]. Step-wise analysis of survival from Randomization 1 or 2 indicates that survival was significantly diminished by: (a) age > or = 45 years (b) KPS < 90%; (c) GBM/gliosarcoma histology; (d) stereotactic biopsy as opposed to open biopsy or resection. Median survival from Randomization 1 in both arms (ERT + Mito) was 10.8 months. Median survival from Randomization 2 was 9.3 months for BCNU/6MP vs. 11.4 months for the BCNU group (p = 0.35). Carmustine/6-MP showed a possible survival benefit for histologies other than GBM/GS. Two hundred and thirty-three patients underwent Randomization 2. The proportion of patients in the ERT group who terminated study prior to Randomization 2 was significantly less in the ERT group than in the ERT + Mito group (20 vs. 37%, p < 0.001). CONCLUSIONS (a) The addition of Mito to ERT had no impact on survival; (b) patients treated with ERT + Mito were at greater risk of terminating therapy prior to Randomization 2; (c) there was not a significant survival benefit to the addition of 6-MP to BCNU.

Purpose To assess the role of positron emission tomographic (PET) imaging with 18-fluoro-2-deoxyglucose ( 18 FDG) in detecting thoracic lymph node metastases in patients with bronchogenic carcinoma. Materials and methods Over a 2-year period, any patient presenting to our institution with newly diagnosed bronchogenic carcinoma who was to have thoracic nodes sampled was considered eligible. All PET studies were performed prior to nodal sampling and areas of increased uptake were mapped according to the American Thoracic Society classification. Studies were correlated with CT and pathology. Sensitivity and specificity for predicting nodal metastases was calculated. Results Forty-two patients had 62 nodal stations (40 hilar/lobar, 22 mediastinal) sampled. The sensitivity and specificity for hilar/lobar lymph node station metastases using PET imaging was 73% and 76%, respectively. With CT, the sensitivity and specificity were 27% and 86%. The sensitivity and specificity using PET imaging for mediastinal node station metastases was 92% and 100%, respectively, while with CT the figures were 58% and 80%. The sensitivity and specificity for combined thoracic nodal station metastases using PET imaging was 83% and 82%, respectively, while with CT it was 43% and 85%. There was a strong statistical relationship between positive PET imaging and lymph node abnormalities. Conclusions 18 FDG-PET imaging is accurate in detecting thoracic lymph node metastases in patients with bronchogenic carcinoma. Normal results of PET studies virtually preclude the need for mediastinal nodal sampling prior to surgery, whereas abnormal results of studies most likely represent mediastinal metastases. Treatment can be based on the extent of disease suggested by PET imaging.

From October 1989 to February 1992, 74 patients with mediastinoscopically staged IIIA (N2) non-small-cell lung cancer from 30 CALGB-affiliated hospitals received two cycles of preresectional cisplatin and vinblastine chemotherapy. Patients with responsive or stable disease underwent standardized surgical resection and radical lymphadenectomy. Patients who underwent resection received sequential adjuvant therapy with two cycles of cisplatin and vinblastine, followed by thoracic irradiation (54 Gy after complete resection and 59.4 Gy after incomplete resection or no resection at 1.8 Gy per fraction). There were no radiographic complete responses to the neoadjuvant chemotherapy, although 65 (88%) patients had either a response or no disease progression. During induction chemotherapy, disease progressed in seven patients (9%). Sixty-three patients (86%) had exploratory thoracotomy, and 46 of those (75%) had resectable lesions. A complete surgical resection was accomplished in 23 patients, and 23 patients had an incomplete resection with either a diseased margin or diseased highest node resected. Operative mortality was 3.2% (2/63). In 10 patients (22% of the 46 having resection) the disease was pathologically downstaged. There was no correlation between radiographic response to the induction chemotherapy and downstaging at surgical resection. The full protocol was completed by 33 patients (45% of original cohort). Overall survival at 3 years was 23%. Patients undergoing resection had significantly improved survival at 3 years compared with patients not having resection: 46% for complete resection (median 20.9 months), 25% for incomplete resection (median 17.8 months), and 0% for no resection (median 8.5 months). Five deaths occurred during the treatment period. A total of 18 of the 46 (39%) patients who underwent resection are either alive and disease-free or have died without recurrence. (J THORAC CARDIOVASC SURG 1995; 109: 473-85)

Purpose: A pilot trial testing the feasibility of chemotherapy and radiotherapy was done in Stage III A and B non-small cell lung cancer. The schedule was designed to be consistent with the laboratory model of Looney and Hopkins. Methods and Materials: Treatment began with thrice-per-day radiotherapy for 3 days (16.2 Gy/nine fractions), followed by chemotherapy (cis-platinum 100 mg/m2 day 10, and vinblastine 4 mg/m2 days 10 and 12). A second cycle started on day 22, a third on day 43, and a fourth on day 64. We treated three cohorts. The first cohort received three cycles of radiotherapy alone, (48.6 Gy). The second cohort received three completed cycles, and the third received three completed cycles and a fourth radiotherapy course (64.8 Gy). Patients were evaluated for toxicity, protocol compliance, response, and survival. Results: The patients in the first cohort experienced no toxicity. Fifty-six percent (56%) of the patients treated in cohort 2 experienced severe or life-threatening myelosuppression as did 82% of those in cohort 3. Nonhematologic toxicity was not severe; one case of Grade 3 esophagitis, one of reversible adult respiratory distress syndrome, and one radiation pneunomitis. We closed the trial after accrual to the third cohort because of significant myelosuppression. Conclusion: This schedule is too myelosuppressive to be used without modification.