[Show abstract][Hide abstract] ABSTRACT: We evaluated a neutralizing anti-TGFβ antibody (GC1008) in cancer patients with malignant pleura mesothelioma (MPM). The goal of this study was to assess immunoregulatory effects in relation to clinical safety and clinical response. Patients with progressive MPM and 1-2 prior systemic therapies received GC1008 at 3mg/kg IV over 90 min every 21 d as part of an open-label, two-center Phase II trial. Following TGFβ blockade therapy, clinical safety and patient survival were monitored along with the effects of anti-TGFβ antibodies on serum biomarkers and peripheral blood mononuclear cells (PBMC). Although designed as a larger trial, only 13 patients were enrolled when the manufacturer discontinued further development of the antibody for oncology indications. All participants tolerated therapy. Although partial or complete radiographic responses were not observed, three patients showed stable disease at 3 mo. GC1008 had no effect in the expression of NK, CD4(+), or CD8(+) T cell activating and inhibitory markers, other than a decrease in the expression of 2B4 and DNAM-1 on NK cells. However, serum from 5 patients showed new or enhanced levels of antibodies against MPM tumor lysates as measured by immunoblotting. Patients who produced anti-tumor antibodies had increased median overall survival (OS) (15 vs 7.5 mo, p < 0.03) compared with those who did not. To our knowledge, these data represent the first immune analysis of TGFβ- blockade in human cancer patients.
[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION:: Although positron emission tomography computed tomography (PET-CT) has been widely used for small-cell lung cancer (SCLC) staging, no study has examined the clinical impact of PET staging in limited-stage (LS) SCLC. METHODS:: We identified patients with LS-SCLC treated definitively with concurrent chemoradiation. Outcomes were assessed using the Kaplan-Meier approach, Cox regression, and competing risks method. RESULTS:: We treated 54 consecutive LS-SCLC patients with concurrent chemoradiation from January 2002 to August 2010. Forty underwent PET, 14 did not, and all underwent thoracoabdominopelvic CT and magnetic resonance imaging neuroimaging. Most patient characteristics were balanced between the comparison groups, including age, race, sex, bone scanning, median dosage, and performance status. More number of PET-staged patients presented with nodal metastases (p = 0.05). Median follow-up was similar for PET-staged and non-PET-staged patients (p = 0.59). Median overall survival from diagnosis in PET-staged patients was 32 versus 17 months in patients staged without PET (p = 0.03), and 3-year survival was 47% versus 19%. Median time-to-distant failure was 29 versus 12 months (p = 0.04); median time-to-local failure was not reached versus 16 months (p = 0.04). On multivariable analysis, PET staging (odds ratio [OR] = 0.24; p = 0.04), performance status (OR = 1.89; p = 0.05), and N-stage (OR = 4.94; p < 0.01) were associated with survival. CONCLUSION:: LS-SCLC patients staged with PET exhibited improved disease control and survival when compared with non-PET-staged LS-SCLC patients. Improved staging accuracy and better identification of intrathoracic disease may explain these findings, underscoring the value of PET-CT in these patients.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 04/2013; · 4.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Gemcitabine plus cisplatin is active in malignant mesothelioma (MM), although single-arm phase II trials have reported variable outcomes. Vascular endothelial growth factor (VEGF) inhibitors have activity against MM in preclinical models. We added the anti-VEGF antibody bevacizumab to gemcitabine/cisplatin in a multicenter, double-blind, placebo-controlled randomized phase II trial in patients with previously untreated, unresectable MM.
Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 and no thrombosis, bleeding, or major blood vessel invasion. The primary end point was progression-free survival (PFS). Patients were stratified by ECOG performance status (0 v 1) and histologic subtype (epithelial v other). Patients received gemcitabine 1,250 mg/m(2) on days 1 and 8 every 21 days, cisplatin 75 mg/m(2) every 21 days, and bevacizumab 15 mg/kg or placebo every 21 days for six cycles, and then bevacizumab or placebo every 21 days until progression.
One hundred fifteen patients were enrolled at 11 sites; 108 patients were evaluable. Median PFS time was 6.9 months for the bevacizumab arm and 6.0 months for the placebo arm (P = .88). Median overall survival (OS) times were 15.6 and 14.7 months in the bevacizumab and placebo arms, respectively (P = .91). Partial response rates were similar (24.5% for bevacizumab v 21.8% for placebo; P = .74). A higher pretreatment plasma VEGF concentration (n = 56) was associated with shorter PFS (P = .02) and OS (P = .0066), independent of treatment arm. There were no statistically significant differences in toxicity of grade 3 or greater.
The addition of bevacizumab to gemcitabine/cisplatin in this trial did not significantly improve PFS or OS in patients with advanced MM.
Journal of Clinical Oncology 06/2012; 30(20):2509-15. · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: Data are limited on the clinical significance of brachial plexopathy in patients with apical non-small cell lung cancers (NSCLC) treated with definitive radiation therapy. We report the rates of radiation-induced brachial plexopathy (RIBP) and tumor-related brachial plexopathy (TRBP) and associated dosimetric parameters in apical NSCLC patients. METHODS AND MATERIALS: Charts of NSCLC patients with primary upper lobe or superiorly located nodal disease who received ≥50 Gy of definitive conventionally fractionated radiation or chemoradiation were retrospectively reviewed for evidence of brachial plexopathy and categorized as RIBP, TRBP, or trauma-related. Dosimetric data were gathered on ipsilateral brachial plexuses (IBP) contoured according to Radiation Therapy Oncology Group atlas guidelines. RESULTS: Eighty patients were identified with a median follow-up and survival time of 17.2 and 17.7 months, respectively. The median prescribed dose was 66.6 Gy (range, 50.4-84.0), and 71% of patients received concurrent chemotherapy. RIBP occurred in 5 patients with an estimated 3-year rate of 12% when accounting for competing risk of death. Seven patients developed TRBP (estimated 3-year rate of 13%), comprising 24% of patients who developed locoregional failures. Grade 3 brachial plexopathy was more common in patients who experienced TRBP than RIBP (57% vs 20%). No patient who received ≤78 Gy to the IBP developed RIBP. On multivariable competing risk analysis, IBP V76 receiving ≥1 cc, and primary tumor failure had the highest hazard ratios for developing RIBP and TRBP, respectively. CONCLUSIONS: RIBP is a relatively uncommon complication in patients with apical NSCLC tumors receiving definitive doses of radiation, while patients who develop primary tumor failures are at high risk for developing morbid TRBP. These findings suggest that the importance of primary tumor control with adequate doses of radiation outweigh the risk of RIBP in this population of patients.
International journal of radiation oncology, biology, physics 06/2012; · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Radical pleurectomy (RP) for mesothelioma is often considered either technically unfeasible or an operation limited to patients who would not tolerate a pneumonectomy. The purpose of this study was to review our experience using RP and intraoperative photodynamic therapy (PDT) for mesothelioma.
Thirty-eight patients (42-81 years) underwent RP-PDT. Thirty five of 38 (92%) patients also received systemic therapy. Standard statistical techniques were used for analysis.
Thirty seven of 38 (97%) patients had stage III/IV cancer (according to the American Joint Committee on Cancer [AJCC manual 7th Edition, 2010]) and 7/38 (18%) patients had nonepithelial subtypes. Macroscopic complete resection was achieved in 37/38 (97%) patients. There was 1 postoperative mortality (stroke). At a median follow-up of 34.4 months, the median survival was 31.7 months for all 38 patients, 41.2 months for the 31/38 (82%) patients with epithelial subtypes, and 6.8 months for the 7/38 (18%) patients with nonepithelial subtypes. Median progression-free survival (PFS) was 9.6, 15.1, and 4.8 months, respectively. The median survival and PFS for the 20/31 (64%) patients with N2 epithelial disease were 31.7 and 15.1 months, respectively.
It was possible to achieve a macroscopic complete resection using lung-sparing surgery in 97% of these patients with stage III/IV disease. The survival we observed with this approach was unusually long for the patients with the epithelial subtype but, interestingly, the PFS was not. The reason for this prolonged survival despite recurrence is not clear but is potentially related to preservation of the lung or some PDT-induced effect, or both. We conclude that the results of this lung-sparing approach are safe, encouraging, and warrant further investigation.
The Annals of thoracic surgery 05/2012; 93(5):1658-65; discussion 1665-7. · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The objective of this phase I trial was to determine dose-limiting toxicities (DLT) and the maximally tolerated dose of the radiosensitizer Nelfinavir in combination with concurrent chemoradiotherapy in locally advanced non-small cell lung cancer (NSCLC).
Nelfinavir (dose level 1: 625 mg orally [PO] twice a day; dose level 2: 1250 mg PO twice a day) was administered for 7 to 14 days before and concurrently with concurrent chemoradiotherapy to patients with biopsy confirmed IIIA or IIIB unresectable NSCLC. Five patients were treated at dose level 1; eight patients were treated at dose level 2. Patients were treated with concurrent chemoradiotherapy to a dose of 66.6 Gy. DLTs were defined as any treatment-related grade 4 hematologic toxicity requiring a break in therapy or nonhematologic grade 3 or higher toxicity except esophagitis and pneumonitis.
Sixteen patients were enrolled and 13 patients received at least one dose of nelfinavir. Twelve patients were treated with nelfinavir and concurrent chemoradiotherapy. No DLTs have been observed at either dose level. The maximum tolerated dose of nelfinavir was therefore 1250 mg PO twice a day. Six patients experienced grade 4 leukopenia. One patient experienced grade 4 thromobcytopenia. Median follow-up for all 12 response-evaluable patients was 31.6 months and for survivors is 23.5 months. Nine of the 12 patients had evaluable posttreatment positron emission tomography/computed tomography with metabolic response as follows: overall response: 9/9 (100%); complete response: 5/9 (56%); and partial response: 4/9 (44%).
Nelfinavir administered with concurrent chemoradiotherapy is associated with acceptable toxicity in stage IIIA/IIIB NSCLC. The metabolic response and tumor response data suggest that nelfinavir has promising activity in this disease.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 04/2012; 7(4):709-15. · 4.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Photodynamic therapy is increasingly being utilized to treat thoracic malignancies. For patients with early-stage non-small cell lung cancer, photodynamic therapy is primarily employed as an endobronchial therapy to definitely treat endobronchial, roentgenographically occult, or synchronous primary carcinomas. As definitive monotherapy, photodynamic therapy is most effective in treating bronchoscopically visible lung cancers ≤1 cm with no extracartilaginous invasion. For patients with advanced-stage non-small cell lung cancer, photodynamic therapy can be used to palliate obstructing endobronchial lesions, as a component of definitive multi-modality therapy, or to increase operability or reduce the extent of operation required. A review of the available medical literature detailing all published studies utilizing photodynamic therapy to treat at least 10 patients with non-small cell lung cancer is performed, and treatment recommendations and summaries for photodynamic therapy applications are described.
[Show abstract][Hide abstract] ABSTRACT: Several surgical series have identified subcarinal, contralateral, and multilevel nodal involvement as predictors of poor overall survival in patients with Stage III non-small-cell lung cancer (NSCLC) treated with definitive resection. This retrospective study evaluates the impact of extent and location of mediastinal lymph node (LN) involvement on survival in patients with Stage III NSCLC treated with definitive radiotherapy.
We analyzed 106 consecutive patients with T1-4 N2-3 Stage III NSCLC treated with definitive radiotherapy at the University of Pennsylvania between January 2003 and February 2009. For this analysis, mediastinal LN stations were divided into four mutually exclusive groups: supraclavicular, ipsilateral mediastinum, contralateral mediastinum, and subcarinal. Patients' conditions were then analyzed according to the extent of involvement and location of mediastinal LN stations.
The majority (88%) of patients received sequential or concurrent chemotherapy. The median follow-up time for survivors was 32.6 months. By multivariable Cox modeling, chemotherapy use (hazard ratio [HR]: 0.21 [95% confidence interval (CI): 0.07-0.63]) was associated with improved overall survival. Increasing primary tumor [18F]-fluoro-2-deoxy-glucose avidity (HR: 1.11 [CI: 1.06-1.19]), and subcarinal involvement (HR: 2.29 [CI: 1.11-4.73]) were significant negative predictors of overall survival. On univariate analysis, contralateral nodal involvement (HR: 0.70 [CI: 0.33-1.47]), supraclavicular nodal involvement (HR: 0.78 [CI: 0.38-1.67]), multilevel nodal involvement (HR: 0.97 [CI: 0.58-1.61]), and tumor size (HR: 1.04 [CI: 0.94-1.14]) did not predict for overall survival. Patients with subcarinal involvement also had lower rates of 2-year nodal control (51.2% vs. 74.9%, p = 0.047) and 2-year distant control (28.4% vs. 61.2%, p = 0.043).
These data suggest that the factors that determine oncologic outcome in Stage III NSCLC patients treated with definitive radiotherapy are distinct from those observed in patients who undergo surgical resection. The ultimate efficacy of radiation in locally advanced NSCLC is dependent on the intrinsic biology of the tumor.
International journal of radiation oncology, biology, physics 11/2011; 83(1):340-7. · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Photodynamic therapy (PDT) is a light-based cancer treatment that acts to a depth of several millimeters into tissue. This study reviewed the results of patients who underwent a macroscopic complete resection, by two different surgical techniques, and intraoperative PDT as a treatment for malignant pleural mesothelioma.
From 2004 to 2008, 28 patients with malignant pleural mesothelioma underwent macroscopic complete resection, 14 by modified extrapleural pneumonectomy (MEPP) and 14 by radical pleurectomy (RP) and intraoperative PDT. The surgical technique evolved over this period such that 13 of the last 16 patients underwent lung-sparing procedures, even in the setting of large-bulk tumors.
Demographics in the MEPP and RP cohorts were similar in age, sex, stage, nodal status, histology, and adjuvant treatments. Stage III/IV disease was present in 12 of 14 patients (86%), with 50% or more with +N2 disease. The median overall survival for the MEPP group was 8.4 months, but has not yet been reached for the RP group at a median follow-up of 2.1 years.
In addition to the inherent advantages of sparing the lung, RP plus PDT yielded a superior overall survival than MEPP plus PDT in this series. The overall survival for the RP plus PDT group was, for unclear reasons, superior to results reported in many surgical series, especially for a cohort with such advanced disease. Given these results, we believe RP plus PDT is a reasonable option for appropriate patients pursuing a surgical treatment for malignant pleural mesothelioma and that this procedure can serve as the backbone of surgically based multimodal treatments.
The Annals of thoracic surgery 06/2011; 91(6):1738-45. · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The past decade has seen significant breakthroughs in our knowledge of the tumor biology of non-small cell lung cancer (NSCLC). Signaling pathways that are vital for tumor growth have been identified and have been effectively targeted for pharmacologic intervention. Furthermore, advances in imaging and treatment delivery have allowed radiation oncologists to deliver therapy more precisely to mobile tumors, while minimizing the dose to surrounding critical structures. This article summarizes the implications of these advances for the patient with unresectable locally advanced NSCLC and highlights ongoing work to improve clinical outcomes in this disease.
Clinical Cancer Research 05/2011; 17(13):4192-9. · 7.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The clinical benefit of postoperative mediastinal radiation for completely resected Masaoka stage 2 thymoma remains controversial. Due to its indolent nature and infrequent recurrences, no study has definitively determined the optimal approach.
We retrospectively reviewed 175 consecutive patients who underwent thymic resection from January 1990 to July 2008 at the University of Pennsylvania. The primary endpoint was local recurrence, defined as recurrence within the surgical bed, treated by resection alone versus resection plus radiation. Patients with high recurrence risk were referred for adjuvant radiotherapy.
Seventy-four Masaoka stage 2 patients were resected; 62 underwent complete resections with adequate postsurgical follow-up. Thirty-seven patients received adjuvant radiotherapy and 25 patients were observed. The median radiation dose was 5040 cGy. The median follow-up for all patients was 52 months. The local recurrence rate was 3.2%. The proportion of recurrences in patients observed after surgery was 8% versus 0% in those who received adjuvant radiotherapy (P = .15). Size was not an independent predictor of recurrence (P = .81). The tumor-related death rate was 0%, and overall death rate was 3.2%. One death occurred in each group, observation, and radiation. There were no grade 3 or 4 complications with radiation.
Recurrence rates were low following resection of stage 2 thymoma either with or without adjuvant radiotherapy. Adjuvant radiotherapy, although well-tolerated, did not significantly decrease the local relapse rate. Differences may be observed in future studies of patients who are at higher risk for local recurrence, based on completeness of resection, World Health Organization histology, and tumor size.
Cancer 02/2011; 117(15):3502-8. · 5.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Elective nodal irradiation (ENI) and involved field radiotherapy (IFRT) are definitive radiotherapeutic approaches used to treat patients with locally advanced non-small cell lung cancer (NSCLC). ENI delivers prophylactic radiation to clinically uninvolved lymph nodes, while IFRT only targets identifiable gross nodal disease. Because clinically uninvolved nodal stations may harbor microscopic disease, IFRT raises concerns for increased nodal failures. This retrospective cohort analysis evaluates failure rates and treatment-related toxicities in patients treated at a single institution with ENI and IFRT.
We assessed all patients with stage III locally advanced or stage IV oligometastatic NSCLC treated with definitive radiotherapy from 2003 to 2008. Each physician consistently treated with either ENI or IFRT, based on their treatment philosophy.
Of the 108 consecutive patients assessed (60 ENI vs. 48 IFRT), 10 patients had stage IV disease and 95 patients received chemotherapy. The median follow-up time for survivors was 18.9 months. On multivariable logistic regression analysis, patients treated with IFRT demonstrated a significantly lower risk of high grade esophagitis (Odds ratio: 0.31, p = 0.036). The differences in 2-year local control (39.2% vs. 59.6%), elective nodal control (84.3% vs. 84.3%), distant control (47.7% vs. 52.7%) and overall survival (40.1% vs. 43.7%) rates were not statistically significant between ENI vs. IFRT.
Nodal failure rates in clinically uninvolved nodal stations were not increased with IFRT when compared to ENI. IFRT also resulted in significantly decreased esophageal toxicity, suggesting that IFRT may allow for integration of concurrent systemic chemotherapy in a greater proportion of patients.
Radiotherapy and Oncology 03/2010; 95(2):178-84. · 4.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cisplatin and docetaxel (Doc) are commonly used for adjuvant therapy for non-small cell lung cancer based on extrapolation from the metastatic setting. Nevertheless, essentially no data have been published on this regimen in the adjuvant context, leading to controversy, particularly surrounding feasibility.
Using a tumor database augmented with chart reviews, we retrospectively evaluated treatment outcomes of all patients receiving postoperative cisplatin (75 mg/m) and Doc (75 mg/m) between August 2003 and November 2008. During this period, this regimen was considered to be the first choice regimen for sufficiently fit patients at the University of Pennsylvania.
The database captured 54 patients. Overall, 85.2% received all four planned cycles (83.3% at full dose). Chart review allowed definitive assessment of toxicity in 47 patients. A single patient (2%) died of grade 5 febrile neutropenia. There was no grade 4 toxicity, and 8.5% experienced grade 3 febrile neutropenia. No febrile neutropenia was observed in 26 patients given prophylactic peg-filgrastim. The incidence was 23.8% in the 21 patients not given peg-filgrastim during the first cycle; 6.4% each experienced grade 3 gastritis, anorexia, nausea, and fatigue, and 2.1% experienced grade 3 diarrhea. Median progression-free survival was 17.9 months, and median overall survival has not been reached.
Cisplatin and Doc are feasible in the adjuvant setting with superior dose delivery and convenience compared with historic data with cisplatin and vinorelbine.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 03/2010; 5(5):667-72. · 4.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study determined the optimally tolerated regimen (OTR) of oral lapatinib administered in combination with infusional 5-fluorouracil (5-FU), leucovorin and irinotecan (FOLFIRI) and assessed the safety, tolerability and pharmacokinetics of the combination.
Twenty-five patients were enrolled; 12 patients were treated at three dose levels to determine OTR; then 13 patients were treated at OTR to evaluate the pharmacokinetics of the combination.
The 2-weekly OTR comprised lapatinib 1250 mg/day with irinotecan 108 mg/m(2) (day 1) and leucovorin 200 mg/m(2), 5-FU bolus 240 mg/m(2) and 5-FU infusion 360 mg/m(2) (days 1 and 2); doses of 5-FU and irinotecan represent a 40% reduction in dose compared to conventional FOLFIRI. Dose-limiting toxicities were grade 3 diarrhoea and grade 4 neutropenia. Co-administration of lapatinib increased the area under the plasma concentration-time curve of SN-38, the active metabolite of irinotecan, by an average of 41%; no other pharmacokinetic interactions were observed. Of 19 patients evaluable for disease response assessment, four patients had partial response and nine patients had stable disease.
The combination of lapatinib and FOLFIRI is safe and demonstrates clinical activity; the documented PK interaction can effectively be compensated by lowering the doses of 5-FU and irinotecan. This regime may be further tested in a phase II trial.
Annals of Oncology 01/2008; 18(12):2025-9. · 7.38 Impact Factor