To investigate the activity of carboplatin and cetuximab in NSCLC. This was a single arm, multice... more To investigate the activity of carboplatin and cetuximab in NSCLC. This was a single arm, multicenter phase II trial, and the primary objective was response rate. The overall response rate observed was 9% (95% confidence interval [CI], 3-19), the progression-free survival was 2.9 months (95% CI, 1.9-3.6), the median overall survival was 8.2 months (95% CI, 4.9-10.5), and 1-year survival rate was 33% (95% CI, 21-45). The combination of carboplatin and cetuximab demonstrated lower activity than double agent platinum-based therapy and does not warrant further development.
A subset of patients with minimal extrathoracic disease may benefit from aggressive primary tumor... more A subset of patients with minimal extrathoracic disease may benefit from aggressive primary tumor treatment. We report comparative outcomes in oligometastatic non-small cell lung cancer (NSCLC) treated with and without definitive, conventionally fractionated thoracic radiation therapy. We identified consecutive patients with stage IV NSCLC who had an Eastern Cooperative Oncology Group performance status ≤2 and ≤4 total sites of metastatic disease and who had been prescribed ≥50 Gy of thoracic radiation. Twenty-nine patients with oligometastatic NSCLC were identified between January 2004 and August 2010. Median survival was 22 months from diagnosis. Four patients (14%) experienced pneumonitis greater than or equal to grade 3; 6 (21%) had esophagitis greater than or equal to grade 3. Local control was associated with improved survival (P = .02). In matched subset analysis, median survival was 9 months (P < .01) in patients who received chemotherapy alone. Median time to local failure was 18 versus 6 months (P = .01). On multivariable analysis, radiation (P < .01; odds ratio [OR], 0.33), fewer metastases (P < .01; OR, 2.14), and female sex (P < .01; OR, 0.41) were associated with improved survival. Definitive dose radiation therapy may improve survival in a select subset of patients with minimal extrathoracic disease in whom local progression is of primary concern. Prospective trials are needed to further evaluate the role of local control in oligometastatic NSCLC.
The phosphotidylinositol-3 kinase/serine-threonine kinase (AKT)/mammalian target of rapamycin sig... more The phosphotidylinositol-3 kinase/serine-threonine kinase (AKT)/mammalian target of rapamycin signaling pathway is frequently altered in non-small-cell lung cancer (NSCLC). PX-866 is an oral, irreversible, pan-isoform inhibitor of phosphotidylinositol-3 kinase. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory NSCLC. Patients with locally advanced, recurrent, or metastatic NSCLC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to a combination of docetaxel (75 mg/m intravenous every 21 days) with or without PX-866 (8 mg orally daily; arms A and B, respectively). The primary end point was progression-free survival (PFS). Secondary end points included objective response rate, overall survival (OS), toxicity, and correlation of biomarker analyses with efficacy outcomes. A total of 95 patients were enrolled. Median PFS was 2 months in arm A and 2.9 months in arm B (p = 0.65). Objective response rates were 6% and 0% in arms A and B, respectively (p = 0.4). There was no difference in OS between the two arms (7.0 versus 9.2 months; p = 0.9). Grade 3 or higher adverse events were infrequent, but more common in the combination arm with respect to diarrhea (7% versus 2%), nausea (4% versus 0%), and vomiting (7% versus 0%). PIK3CA mutations or PTEN loss were infrequently observed. The addition of PX-866 to docetaxel did not improve PFS, response rate, or OS in patients with advanced, refractory NSCLC without molecular preselection.
Elective nodal irradiation (ENI) and involved field radiotherapy (IFRT) are definitive radiothera... more 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.
Although positron emission tomography computed tomography (PET-CT) has been widely used for small... more 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. 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. 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. 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.
Cisplatin and docetaxel (Doc) are commonly used for adjuvant therapy for non-small cell lung canc... more 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.
International Journal of Radiation Oncology*Biology*Physics, 2012
Several surgical series have identified subcarinal, contralateral, and multilevel nodal involveme... more 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.
To investigate the activity of carboplatin and cetuximab in NSCLC. This was a single arm, multice... more To investigate the activity of carboplatin and cetuximab in NSCLC. This was a single arm, multicenter phase II trial, and the primary objective was response rate. The overall response rate observed was 9% (95% confidence interval [CI], 3-19), the progression-free survival was 2.9 months (95% CI, 1.9-3.6), the median overall survival was 8.2 months (95% CI, 4.9-10.5), and 1-year survival rate was 33% (95% CI, 21-45). The combination of carboplatin and cetuximab demonstrated lower activity than double agent platinum-based therapy and does not warrant further development.
A subset of patients with minimal extrathoracic disease may benefit from aggressive primary tumor... more A subset of patients with minimal extrathoracic disease may benefit from aggressive primary tumor treatment. We report comparative outcomes in oligometastatic non-small cell lung cancer (NSCLC) treated with and without definitive, conventionally fractionated thoracic radiation therapy. We identified consecutive patients with stage IV NSCLC who had an Eastern Cooperative Oncology Group performance status ≤2 and ≤4 total sites of metastatic disease and who had been prescribed ≥50 Gy of thoracic radiation. Twenty-nine patients with oligometastatic NSCLC were identified between January 2004 and August 2010. Median survival was 22 months from diagnosis. Four patients (14%) experienced pneumonitis greater than or equal to grade 3; 6 (21%) had esophagitis greater than or equal to grade 3. Local control was associated with improved survival (P = .02). In matched subset analysis, median survival was 9 months (P < .01) in patients who received chemotherapy alone. Median time to local failure was 18 versus 6 months (P = .01). On multivariable analysis, radiation (P < .01; odds ratio [OR], 0.33), fewer metastases (P < .01; OR, 2.14), and female sex (P < .01; OR, 0.41) were associated with improved survival. Definitive dose radiation therapy may improve survival in a select subset of patients with minimal extrathoracic disease in whom local progression is of primary concern. Prospective trials are needed to further evaluate the role of local control in oligometastatic NSCLC.
The phosphotidylinositol-3 kinase/serine-threonine kinase (AKT)/mammalian target of rapamycin sig... more The phosphotidylinositol-3 kinase/serine-threonine kinase (AKT)/mammalian target of rapamycin signaling pathway is frequently altered in non-small-cell lung cancer (NSCLC). PX-866 is an oral, irreversible, pan-isoform inhibitor of phosphotidylinositol-3 kinase. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory NSCLC. Patients with locally advanced, recurrent, or metastatic NSCLC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to a combination of docetaxel (75 mg/m intravenous every 21 days) with or without PX-866 (8 mg orally daily; arms A and B, respectively). The primary end point was progression-free survival (PFS). Secondary end points included objective response rate, overall survival (OS), toxicity, and correlation of biomarker analyses with efficacy outcomes. A total of 95 patients were enrolled. Median PFS was 2 months in arm A and 2.9 months in arm B (p = 0.65). Objective response rates were 6% and 0% in arms A and B, respectively (p = 0.4). There was no difference in OS between the two arms (7.0 versus 9.2 months; p = 0.9). Grade 3 or higher adverse events were infrequent, but more common in the combination arm with respect to diarrhea (7% versus 2%), nausea (4% versus 0%), and vomiting (7% versus 0%). PIK3CA mutations or PTEN loss were infrequently observed. The addition of PX-866 to docetaxel did not improve PFS, response rate, or OS in patients with advanced, refractory NSCLC without molecular preselection.
Elective nodal irradiation (ENI) and involved field radiotherapy (IFRT) are definitive radiothera... more 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.
Although positron emission tomography computed tomography (PET-CT) has been widely used for small... more 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. 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. 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. 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.
Cisplatin and docetaxel (Doc) are commonly used for adjuvant therapy for non-small cell lung canc... more 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.
International Journal of Radiation Oncology*Biology*Physics, 2012
Several surgical series have identified subcarinal, contralateral, and multilevel nodal involveme... more 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.
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Papers by Tracey Evans