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ABSTRACT: OBJECTIVES:: Positron emission tomography/computed tomography (PET/CT) is increasingly used for disease staging and evaluation of treatment effectiveness in limited-stage small cell lung cancer (LS-SCLC). However, the prognostic value of PET/CT metrics in LS-SCLC is not clear. METHODS:: Subjects in this retrospective study were 50 patients with LS-SCLC who had had PET/CT before definitive chemoradiation therapy in January 2003 to August 2009; 15 (29%) had also had induction chemotherapy. Median radiation dose was 45 Gy (range, 40.5 to 61.8 Gy). All scans were read and scored by 1 radiologist. Kaplan-Meier curves were used to estimate survival outcomes, and Cox regression analysis was used to evaluate the prognostic value of pretreatment standardized uptake values (SUVs) with regard to locoregional control (LRC) and overall survival (OS). RESULTS:: At a median follow-up time of 18.2 months (range, 2.1 to 78 mo), LRC rates were 64% at 2 and 3 years; OS rates were 81% at 2 years and 61% at 3 years. None of the metrics assessed (receipt of induction chemotherapy, pretreatment SUVprimary, SUVnodal, meanSUVmax) was associated with LRC or OS, but patients with residual SUV≤5.5 after treatment had a 3-year OS rate of 69% versus 34% for those with SUV>5.5. CONCLUSIONS:: Pretreatment PET/CT metrics had no prognostic significance for patients with LS-SCLC, perhaps because of the rapid proliferation of SCLC or other confounding factors affecting survival.
American journal of clinical oncology 10/2012; · 2.21 Impact Factor
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Anne S Tsao,
Suyu Liu,
Junya Fujimoto,
Ignacio I Wistuba,
J Jack Lee,
Edith M Marom,
Chusilp Charnsangavej, Frank V Fossella,
Hai T Tran,
George R Blumenschein,
Vassiliki Papadimitrakopoulou,
Merrill S Kies,
Waun K Hong,
David J Stewart
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ABSTRACT: Two phase II clinical trials in the aerodigestive tumors were undertaken to evaluate the efficacy of imatinib mesylate-docetaxel. We hypothesized that imatinib mesylate would inhibit platelet-derived growth factor receptor (PDGFR) on pericytes and increase docetaxel uptake into tumor cells for an additive antitumor effect. Baseline tumor specimens, serum, and perfusion computed tomography (CT) scans were obtained for supportive evaluation.
Eligible patients with metastatic non-small cell lung cancer (NSCLC) treated with 1 prior therapy and chemonaive patients with head and neck squamous cell carcinoma (HNSCC) were enrolled in separate trials, which administered both docetaxel (60 mg/m every 3 weeks) and oral imatinib mesylate (400 mg daily). Both trials used interim analyses for efficacy and safety.
Twenty-two patients with NSCLC and seven patients with HNSCC were enrolled. Both trials were closed early due to lack of efficacy, significant toxicity, and a potential antagonistic effect. In the NSCLC study, the response rate was 4.5%, median progression-free survival (PFS) 7.9 weeks, and overall survival 35.6 weeks. The HNSCC trial yielded a response rate 0%, PFS 8.8 weeks, and overall survival 34.7 weeks. Baseline NSCLC tumor immunohistochemical biomarker analyses indicated that lower expression of stromal PDGFRβ correlated with a better PFS, whereas stromal PDGFRα and tumor cell PDGFRβ were associated with a worse clinical outcome when treated with imatinib mesylate-docetaxel.
We do not recommend further investigation of this regimen in the aerodigestive tumors. Future investigations in PDGFR tyrosine kinase inhibitors should be used with caution in combination with taxanes and validation of the potential predictive or prognostic biomarkers stromal PDGFRα/β, and tumor cell PDGFRβ are needed.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 09/2011; 6(12):2104-11. · 4.55 Impact Factor
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ABSTRACT: Omitting elective nodal irradiation from planning target volumes does not compromise outcomes in patients with non-small-cell lung cancer, but whether the same is true for those with limited-stage small-cell lung cancer (LS-SCLC) is unknown. Therefore, in the present study, we sought to determine the clinical outcomes and the frequency of elective nodal failure in patients with LS-SCLC staged using positron emission tomography/computed tomography and treated with involved-field intensity-modulated radiotherapy.
Between 2005 and 2008, 60 patients with LS-SCLC at our institution underwent disease staging using positron emission tomography/computed tomography before treatment using an intensity-modulated radiotherapy plan in which elective nodal irradiation was intentionally omitted from the planning target volume (mode and median dose, 45 Gy in 30 fractions; range, 40.5 Gy in 27 fractions to 63.8 Gy in 35 fractions). In most cases, concurrent platinum-based chemotherapy was administered. We retrospectively reviewed the clinical outcomes to determine the overall survival, relapse-free survival, and failure patterns. Elective nodal failure was defined as recurrence in initially uninvolved hilar, mediastinal, or supraclavicular nodes. Survival was assessed using the Kaplan-Meier method.
The median age of the study patients at diagnosis was 63 years (range, 39-86). The median follow-up duration was 21 months (range, 4-58) in all patients and 26 months (range, 4-58) in the survivors. The 2-year actuarial overall survival and relapse-free survival rate were 58% and 43%, respectively. Of the 30 patients with recurrence, 23 had metastatic disease and 7 had locoregional failure. We observed only one isolated elective nodal failure.
To our knowledge, this is the first study to examine the outcomes in patients with LS-SCLC staged with positron emission tomography/computed tomography and treated with definitive intensity-modulated radiotherapy. In these patients, elective nodal irradiation can be safely omitted from the planning target volume for the purposes of dose escalation and toxicity reduction.
International journal of radiation oncology, biology, physics 04/2011; 82(1):e91-7. · 4.59 Impact Factor
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ABSTRACT: Bevacizumab has recently been demonstrated to prolong overall survival when added to carboplatin and paclitaxel for chemotherapy-naïve patients with nonsquamous nonsmall-cell lung cancer (NSCLC). However, the effects of combining bevacizumab with other standard, front-line, platinum-based doublets have not been extensively explored. We designed this single treatment arm, phase 2 trial to determine whether the combination of carboplatin, docetaxel, and bevacizumab is tolerable and prolongs progression-free survival of chemotherapy-naïve patients with advanced, nonsquamous NSCLC.
Forty patients were treated with up to 6 cycles of carboplatin (AUC 6), docetaxel (75 mg/m(2)), and bevacizumab (15 mg/kg) on Day 1 every 21 days. Patients with an objective response or stable disease received maintenance bevacizumab (15 mg/kg) every 21 days until disease progression. The primary endpoint was median progression-free survival. Secondary endpoints included safety, response rates, and overall survival.
The median number of chemotherapy and maintenance bevacizumab cycles/patient was 6 and 2, respectively. Grades 3-5 adverse events included febrile granulocytopenia (10%), infections (13%), bleeding (13%), thrombotic events (13%), hypertension (5%), bowel perforation (5%), and proteinuria (3%). Median progression-free survival was 7.9 months and median overall survival was 16.5 months. Partial responses were observed in 21 patients (53%), and stable disease >or=6 weeks occurred in another 17 patients (43%), for a disease control rate of 95%.
Carboplatin, docetaxel, and bevacizumab were feasible and effective for front-line treatment of advanced, nonsquamous NSCLC. These data provide further evidence that bevacizumab may be used in combination with multiple standard, platinum-based doublets in this setting.
Cancer 03/2010; 116(10):2401-8. · 4.77 Impact Factor
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ABSTRACT: Irinotecan has significant activity in small-cell lung cancer (SCLC). The authors' previous phase 1 study of alternating weekly therapy with irinotecan/cisplatin (IP), etoposide/cisplatin (EP), and granulocyte-colony-stimulating factor (G-CSF) support was well tolerated and active in patients with SCLC. A phase 2 trial was conducted to estimate the efficacy of this regimen in previously untreated patients with extensive SCLC.
A total of 33 patients were treated between June 2002 and July 2007. Patients received 12 weeks of therapy with cisplatin (20 mg/m(2)) on Day 1 and irinotecan (100 mg/m(2)) on Day 1 and G-CSF on Days 2 to 5 (Weeks 1, 3, 5, 7, 9, and 11) followed by cisplatin (20 mg/m(2)) on Day 1 and etoposide (60 mg/m(2)) on Days 1 to 3 with G-CSF on Days 4 to 7 (Weeks 2, 4, 6, 8, 10, and 12). The primary endpoint was 1-year survival rate.
Grade 4 neutropenia (toxicities were determined using the National Cancer Institute Common Toxicity Criteria [version 2.0]) was noted in 5 (1.5%) of 343 courses with neutropenic fever in only 5 (1%) of 343 courses. One patient died of neutropenic sepsis. Nonhematologic toxicities grade >or=2 were observed in 15 (4%) of 343 courses and were limited to fatigue, hyponatremia, and diarrhea. The overall objective response rate was 89% in 28 assessable patients (no complete responses and 25 partial responses). The median progression-free and overall survivals were 6.0 months and 10.9 months, respectively. The 1-year survival rate was 33%.
Weekly therapy with IP alternating with EP and G-CSF support was well tolerated in patients with extensive SCLC, but did not demonstrate improved progression-free or overall survival when compared with historical controls at the study institution.
Cancer 03/2010; 116(10):2409-15. · 4.77 Impact Factor
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ABSTRACT: To determine in a Phase I study the maximum tolerated dose of weekly gemcitabine concurrent with radiotherapy in locally advanced non-small-cell lung cancer (NSCLC), as well as the relationship between the volume of the esophagus irradiated and severe esophagitis.
Twenty-one patients with Stage III NSCLC received gemcitabine initially at 150 mg/m(2)/wk over 7 weeks concurrently with chest radiotherapy to 63 Gy in 34 fractions. The first 9 patients underwent treatment with two-dimensional (2D) radiotherapy; the remaining 12 patients, with three-dimensional conformal radiotherapy (3D-CRT) and target volume reduced to clinically apparent disease. Consolidation was 4 cycles of gemcitabine at 1000 mg/m(2)/wk and cisplatin 60 mg/m(2).
In the 2D group, the dose-limiting toxicity, Grade 3 esophagitis, occurred in 3 of 6 patients in the 150-mg/m(2)/wk cohort and 2 of 3 patients in the 125-mg/m(2)/wk cohort. No cases of Grade 3 esophagitis occurred at these doses in the 3D group. At gemcitabine 190 mg/m(2)/wk, 2 of 6 patients in the 3D cohort had Grade 3 esophagitis. The mean percentages of esophagus irradiated to 60 Gy were 68% in the 2D cohort and 18% in the 3D cohort.
We could not escalate the dose of gemcitabine with concurrent radiotherapy when using 2D planning because of severe acute esophagitis. However, we could escalate the dose of gemcitabine to 190 mg/m(2)/wk when using 3D planning. The Phase II dose is 150 mg/m(2)/wk. Three-dimensional CRT permitted the use of higher doses of gemcitabine.
International journal of radiation oncology, biology, physics 07/2008; 73(1):119-27. · 4.59 Impact Factor
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04/2008: pages 283 - 314; , ISBN: 9780470696330
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Andrea Ardizzoni,
Luca Boni,
Marcello Tiseo, Frank V Fossella,
Joan H Schiller,
Marianne Paesmans,
Davorin Radosavljevic,
Adriano Paccagnella,
Petr Zatloukal,
Paola Mazzanti,
Donald Bisset,
Rafael Rosell
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ABSTRACT: Because the efficacy of carboplatin and cisplatin in the treatment of advanced non-small-cell lung cancer (NSCLC) has not been proven to be equivalent, an individual patient data meta-analysis comparing the two treatments was performed.
Randomized trials comparing carboplatin to cisplatin in first-line treatment of advanced NSCLC were identified and their electronic databases obtained. A general variance-based method was used to estimate the summary hazard ratios (HRs), odds ratios (ORs), and their 95% confidence intervals (CIs) for mortality, objective response, and toxicity. Cochran's chi-square test (Q test) was used to test for heterogeneity among trials, and the I2 index, which expresses the proportion of variability of the results due to heterogeneity, was calculated. A random-effects model that takes into account interstudy variation was also applied. All statistical tests were two-sided.
Nine trials that included a total of 2968 patients were analyzed; overall median follow-up was 1021 days. The objective response rate was higher for patients treated with cisplatin than for patients treated with carboplatin (30% versus 24%, respectively; OR = 1.37; 95% CI = 1.16 to 1.61; P<.001). Carboplatin treatment was associated with a non-statistically significant increase in the hazard of mortality relative to treatment with cisplatin (HR = 1.07; 95% CI = 0.99 to 1.15; P = .100). In patients with nonsquamous tumors and those treated with third-generation chemotherapy, carboplatin-based chemotherapy was associated with a statistically significant increase in mortality (HR = 1.12; 95% CI = 1.01 to 1.23 and HR = 1.11; 95% CI = 1.01 to 1.21, respectively). Cisplatin-based chemotherapy was associated with more severe nausea and vomiting and nephrotoxicity; severe thrombocytopenia was more frequent during carboplatin-based chemotherapy.
Our individual patient data meta-analysis suggests that cisplatin-based chemotherapy is slightly superior to carboplatin-based chemotherapy in terms of response rate and, in certain subgroups, in prolonging survival without being associated with an increase in severe toxic effects. Therefore, cisplatin-based third-generation regimens should remain the standard reference for the treatment of selected patients with advanced-stage NSCLC and of those with earlier-stage disease.
CancerSpectrum Knowledge Environment 06/2007; 99(11):847-57. · 14.07 Impact Factor
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ABSTRACT: People 80 years of age and older constitute 17.8% of all lung cancer patients in the United States. Because the life expectancies of 80-year-old men and women are 87.3 years and 89.0 years, respectively, non-small cell lung cancer shortens lives in addition to causing morbidity. In this retrospective study, all patients with chemotherapy-naive advanced non-small cell lung cancer 80 years of age and older treated at the M. D. Anderson Cancer Center with one or more follow-ups were identified from the database for the years 1997 to 2004. A cohort of patients younger than 80 years old was matched based on treatment year, race, histology, and gender in a 2:1 ratio. Of 13,690 thoracic oncology patients, 496 (3.6%) were 80 years of age and older, of whom 46 met the criteria. In older and younger patients, respectively, platinum doublets were given in 43% versus 79% (p < 0.0001), the response rate was 41% versus 47%, the median progression-free survival was 5.55 versus 3.91 months (p = 0.216), and the median overall survival was 10.7 versus 9.8 months (p = 0.43). Hematologic and nonhematologic toxicities were similar. Our data indicate that selected patients 80 years of age and older may tolerate and benefit from chemotherapy, and prospective evaluation of these patients is indicated.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 02/2007; 2(2):141-6. · 4.55 Impact Factor
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Michael P Fanucchi, Frank V Fossella,
Robert Belt,
Ronald Natale,
Panos Fidias,
David P Carbone,
Ramaswamy Govindan,
Luis E Raez,
Francisco Robert,
Maria Ribeiro,
Wallace Akerley,
Karen Kelly,
Steven A Limentani,
Jeffrey Crawford,
Hans-Joachim Reimers,
Rita Axelrod,
Oscar Kashala,
Shihong Sheng,
Joan H Schiller
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ABSTRACT: To evaluate the efficacy and toxicity of bortezomib +/- docetaxel as second-line therapy in patients with relapsed or refractory advanced non-small-cell lung cancer (NSCLC).
Patients were randomly assigned to bortezomib 1.5 mg/m2 (arm A) or bortezomib 1.3 mg/m2 plus docetaxel 75 mg/m2 (arm B). A treatment cycle of 21 days comprised four bortezomib doses on days 1, 4, 8, and 11, plus, in arm B, docetaxel on day 1. Patients could receive unlimited cycles. The primary end point was response rate.
A total of 155 patients were treated, 75 in arm A and 80 in arm B. Baseline characteristics were comparable. Investigator-assessed response rates were 8% in arm A and 9% in arm B. Disease control rates were 29% in arm A and 54% in arm B. Median time to progression was 1.5 months in arm A and 4.0 months in arm B. One-year survival was 39% and 33%, and median survival was 7.4 and 7.8 months in arms A and B, respectively. Adverse effect profiles were as expected in both arms, with no significant additivity. The most common grade > or = 3 adverse events were neutropenia, fatigue, and dyspnea (4% and 53%, 19% and 26%, and 17% and 14% of patients in arms A and B, respectively).
Bortezomib has modest single-agent activity in patients with relapsed or refractory advanced NSCLC using this schedule, with minor enhancement in combination with docetaxel. Additional investigation of bortezomib in NSCLC is warranted in combination with other drugs known to be active, or using different schedules.
Journal of Clinical Oncology 11/2006; 24(31):5025-33. · 18.37 Impact Factor
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05/2006: pages 1-24;
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Sheeba K Thomas, Frank V Fossella,
Diane Liu,
Rainell Schaerer,
Anne S Tsao,
Merrill S Kies,
Katherine M Pisters,
George R Blumenschein,
Bonnie S Glisson,
J Jack Lee,
Roy S Herbst,
Ralph G Zinner
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ABSTRACT: The primary objective of this retrospective study was to investigate the potential role of East Asian ethnicity or origin in predicting response to gefitinib in advanced-stage non-small-cell lung cancer (NSCLC).
A chart review was done of all patients treated with gefitinib at M. D. Anderson Cancer Center on the Expanded Access Program.
There were 223 patients with advanced-stage NSCLC who were enrolled. Of these, 182 received >or= 1 dose, and 160 were evaluable for response. The partial response rate was 8.8%, and the stable disease rate was 26.3%. Median time to progression was 2.5 months, and median survival was 6.8 months. The 1- and 2-year survival rates were 35.3% and 12.4%, respectively. Partial responses were seen in 7 of 12 patients (58.3%) of East Asian origin compared with 7 of 131 patients who were white (5.3%). This difference was statistically significant when controlling for histology, smoking status, hemoglobin, and diarrhea. Never smoking and diarrhea were also independent predictors of response.
For the first time, in a multivariate analysis, we observed a positive relationship between East Asian origin and response to gefitinib. These findings might help determine which patients will likely benefit from gefitinib.
Clinical Lung Cancer 04/2006; 7(5):326-31. · 2.94 Impact Factor
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ABSTRACT: This multicenter, open-label, phase I/IIa study was undertaken to establish the safety/toxicity profile of cetuximab in combination with gemcitabine and carboplatin in patients with chemotherapy-naïve, epidermal growth factor receptor-positive, stage IV non-small-cell lung cancer. Secondary objectives were to gather preliminary evidence of efficacy including tumor response rate, time to progression, and overall survival.
Thirty-five patients received a total of 264 3-week cycles of treatment with cetuximab, carboplatin, and gemcitabine. An initial dose of cetuximab 400 mg/m2 intravenously was administered the first week, followed by weekly doses of 250 mg/m2. Carboplatin (area under the curve = 5, day 1) and gemcitabine 1,000 mg/m2 on days 1 and 8 were administered every 3 weeks. Patients were evaluated for tumor response after every two cycles of therapy.
The most frequently reported adverse events related to cetuximab included an acne-like rash (88.6%), dry skin (34.3%), asthenia and skin disorders (31.4%), mucositis/stomatitis (25.7%), fever/chills (20%), and nausea/vomiting (17.1%). The majority of these toxicities were mild to moderate. One patient withdrew from the study because of a grade 3 allergic reaction. Myelosuppression was the most frequently observed toxicity related to chemotherapy. Responses among 35 assessable patients included 10 partial responses (28.6%). Twenty-one patients had stable disease. The median time to progression was 165 days, and the median overall survival was 310 days.
The combination of cetuximab, carboplatin, and gemcitabine was well tolerated with an acceptable toxicity profile. Most grade 3 adverse events were attributable to chemotherapy. The response rate and median survival are encouraging and warrant additional investigation.
Journal of Clinical Oncology 01/2006; 23(36):9089-96. · 18.37 Impact Factor
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Ralph G Zinner, Frank V Fossella,
Gregory W Gladish,
Bonnie S Glisson,
George R Blumenschein,
Vassiliki A Papadimitrakopoulou,
Katherine M W Pisters,
Edward S Kim,
Yun W Oh,
Beverly O Peeples,
Zhishen Ye,
Rafael E Curiel,
Coleman K Obasaju,
Waun K Hong,
Roy S Herbst
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ABSTRACT: The primary objectives of this study were to determine the efficacy and tolerability of a pemetrexed-carboplatin combination as first-line therapy in patients with advanced nonsmall cell lung cancer.
Eligibility criteria included Zubrod performance status of 0 or 1, Stage IIIB (malignant effusion) or IV disease, and no prior chemotherapy. Treatment was pemetrexed 500 mg/m2 given intravenously and carboplatin area under the serum concentration-time curve = 6 given intravenously on Day 1 every 3 weeks for six cycles; patients could receive additional cycles at the discretion of the treating physician and patient. All patients received folic acid, vitamin B12, and dexamethasone prophylaxis.
Fifty patients (31 men and 19 women) were treated. The median age was 62 years. Ninety-six percent of patients had Stage IV disease, and 88% had a performance status of 1. The median number of cycles was 6; 15 patients received 8 or more cycles. There was Grade 3/4 neutropenia in 11 (22%) and 2 (4%) patients, respectively; Grade 3/4 thrombocytopenia in 1 (2%) and 0 patients, respectively. Three patients (6%) experienced Grade 3 nonhematologic side effects (diarrhea, neutropenic pneumonia, and fatigue). No patients had sensory neuropathy or alopecia >Grade 1. The partial response rate was 24%, median time to progression 5.4 months, 1-year survival 56.0%, and median survival 13.5 months.
This is an active, very well-tolerated regimen. Trials focused on how to integrate this doublet with novel agents are warranted.
Cancer 12/2005; 104(11):2449-56. · 4.77 Impact Factor
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Ralph G. Zinner M.D,
Frank V. Fossella M.D,
Gregory W. Gladish M.D,
Bonnie S. Glisson M.D,
George R. Blumenschein Jr. M.D,
Vassiliki A. Papadimitrakopoulou M.D,
Katherine M.W. Pisters M.D,
Edward S. Kim M.D,
Yun W. Oh M.D,
Beverly O. Peeples M.D, [......],
Vassiliki A. Papadimitrakopoulou,
Katherine M.W. Pisters,
Edward S. Kim,
Yun W. Oh,
Beverly O. Peeples,
Zhishen Ye,
Rafael E. Curiel,
Coleman K. Obasaju,
Waun K. Hong,
Roy S. Herbst
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ABSTRACT: BACKGROUND
The primary objectives of this study were to determine the efficacy and tolerability of a pemetrexed-carboplatin combination as first-line therapy in patients with advanced nonsmall cell lung cancer.METHODS
Eligibility criteria included Zubrod performance status of 0 or 1, Stage IIIB (malignant effusion) or IV disease, and no prior chemotherapy. Treatment was pemetrexed 500 mg/m2 given intravenously and carboplatin area under the serum concentration–time curve = 6 given intravenously on Day 1 every 3 weeks for six cycles; patients could receive additional cycles at the discretion of the treating physician and patient. All patients received folic acid, vitamin B12, and dexamethasone prophylaxis.RESULTSFifty patients (31 men and 19 women) were treated. The median age was 62 years. Ninety-six percent of patients had Stage IV disease, and 88% had a performance status of 1. The median number of cycles was 6; 15 patients received 8 or more cycles. There was Grade 3/4 neutropenia in 11 (22%) and 2 (4%) patients, respectively; Grade 3/4 thrombocytopenia in 1 (2%) and 0 patients, respectively. Three patients (6%) experienced Grade 3 nonhematologic side effects (diarrhea, neutropenic pneumonia, and fatigue). No patients had sensory neuropathy or alopecia >Grade 1. The partial response rate was 24%, median time to progression 5.4 months, 1-year survival 56.0%, and median survival 13.5 months.CONCLUSIONS
This is an active, very well-tolerated regimen. Trials focused on how to integrate this doublet with novel agents are warranted. Cancer 2005. © 2005 American Cancer Society.
Cancer 11/2005; 104(11):2449 - 2456. · 4.77 Impact Factor
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Edward S Kim,
Merrill S Kies, Frank V Fossella,
Bonnie S Glisson,
Sara Zaknoen,
Paul Statkevich,
Reginald F Munden,
Carmen Summey,
Katherine M W Pisters,
Vali Papadimitrakopoulou,
Mourad Tighiouart,
Andre Rogatko,
Fadlo R Khuri
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ABSTRACT: The authors evaluated the safety, tolerability, and efficacy of treatment using lonafarnib, a novel farnesyltransferase inhibitor (FTI), in combination with paclitaxel in patients with metastatic (Stage IIIB/V), taxane-refractory/resistant nonsmall cell lung carcinoma (NSCLC).
Patients with NSCLC who experienced disease progression while receiving previous taxane therapy or who had disease recurrence within 3 months after taxane therapy cessation were treated with continuous lonafarnib 100 mg orally twice per day beginning on Day 1 and paclitaxel 175 mg/m(2) intravenously over 3 hours on Day 8 of each 21-day cycle.
A total of 33 patients were enrolled, 29 of whom were evaluable for response. Partial responses (PR) and stable disease (SD) were observed in 3 (10%) and 11 patients (38%), respectively. Thus, 48% (14 of 29) experienced clinical benefit (PR or SD). The updated and final median overall survival time was 39 weeks and the median disease progression-free survival time was 16 weeks. The combination of lonafarnib and paclitaxel was well tolerated with minimal toxicity. Grade 3 toxicities included fatigue (9%), diarrhea (6%), and dyspnea (6%). Grade 3 neutropenia occurred in only 1 patient (3%). Grade 4 adverse events included respiratory insufficiency in 2 patients (6%) and acute respiratory failure in 1 patient (3%).
Lonafarnib plus paclitaxel demonstrated clinical activity in patients with taxane-refractory/resistant metastatic NSCLC. In addition, the combination of lonafarnib and paclitaxel was well tolerated with minimal toxicity. Evaluation of this combination therapy in additional clinical trials is warranted.
Cancer 09/2005; 104(3):561-9. · 4.77 Impact Factor
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Edward S. Kim M.D,
Merrill S. Kies M.D,
Frank V. Fossella M.D,
Bonnie S. Glisson M.D,
Sara Zaknoen M.D,
Paul Statkevich M.D,
Reginald F. Munden M.D,
Carmen Summey M.D,
Katherine M.W. Pisters M.D,
Vali Papadimitrakopoulou M.D, [......],
Bonnie S. Glisson,
Sara Zaknoen,
Paul Statkevich,
Reginald F. Munden,
Carmen Summey,
Katherine M.W. Pisters,
Vali Papadimitrakopoulou,
Mourad Tighiouart,
Andre Rogatko,
Fadlo R. Khuri
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ABSTRACT: BACKGROUND
The authors evaluated the safety, tolerability, and efficacy of treatment using lonafarnib, a novel farnesyltransferase inhibitor (FTI), in combination with paclitaxel in patients with metastatic (Stage IIIB/V), taxane-refractory/resistant nonsmall cell lung carcinoma (NSCLC).METHODS
Patients with NSCLC who experienced disease progression while receiving previous taxane therapy or who had disease recurrence within 3 months after taxane therapy cessation were treated with continuous lonafarnib 100 mg orally twice per day beginning on Day 1 and paclitaxel 175 mg/m2 intravenously over 3 hours on Day 8 of each 21-day cycle.RESULTSA total of 33 patients were enrolled, 29 of whom were evaluable for response. Partial responses (PR) and stable disease (SD) were observed in 3 (10%) and 11 patients (38%), respectively. Thus, 48% (14 of 29) experienced clinical benefit (PR or SD). The updated and final median overall survival time was 39 weeks and the median disease progression-free survival time was 16 weeks. The combination of lonafarnib and paclitaxel was well tolerated with minimal toxicity. Grade 3 toxicities included fatigue (9%), diarrhea (6%), and dyspnea (6%). Grade 3 neutropenia occurred in only 1 patient (3%). Grade 4 adverse events included respiratory insufficiency in 2 patients (6%) and acute respiratory failure in 1 patient (3%).CONCLUSIONS
Lonafarnib plus paclitaxel demonstrated clinical activity in patients with taxane-refractory/resistant metastatic NSCLC. In addition, the combination of lonafarnib and paclitaxel was well tolerated with minimal toxicity. Evaluation of this combination therapy in additional clinical trials is warranted. Cancer 2005. © 2005 American Cancer Society.
Cancer 07/2005; 104(3):561 - 569. · 4.77 Impact Factor
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ABSTRACT: Amifostine (AMF) has been shown to protect some normal tissues from acute effects of radiation therapy +/- chemotherapy. We enrolled 62 patients in a randomized study investigating the efficacy of AMF: 31 had concurrent chemoradiation for non-small cell lung cancer and 31 had the same treatment + AMF. AMF reduced the frequency and severity of esophagitis, pneumonitis, and neutropenic fever. We have tried to identify patients who get more benefit from AMF by checking their DNA repair capability of normal cells. It was hypothesized that DNA repair capacity from patients' lymphocytes damaged by bleomycin could predict their normal tissue sensitivity to chemoradiation and could be protected by AMF. Forty-six of the 62 patients provided pretreatment blood for assessment of mutagen sensitivity (MS) using a peripheral lymphocyte assay that infers DNA repair capacity from cellular damage remaining after in vitro mutagenic exposure and recovery. Bleomycin-induced chromosome breaks in 50 metaphases were counted and expressed as the mean number of breaks per cell. Patients with an average of more than one break/cell were deemed to exhibit the MS phenotype. Data analysis used Pearson's chi-square and Kaplan-Meier survival function estimates with Strata 8.2 statistical software. The Log-rank test was used to assess the equality of survival function using a P value of .05. Twelve patients (10 AMF, 2 control) exhibited the MS phenotype. The remaining 34 patients (13 AMF, 21 control) were considered to have normal DNA repair. There were no significant differences in overall survival, disease specific survival, or local control by MS. Those with high MS had shorter distant metastasis-free survival compared with low MS patients ( P = .029). There were no differences in severe esophagitis or neutropenic fever by MS. Both high and low MS patients from the control group developed severe lung fibrosis compared with five of 21 who had AMF ( P = .025). The incidence of grade 3/4 lung fibrosis was two of 10 with AMF compared with two of two in the control group ( P = .025) with higher MS. Higher MS was associated with shorter distant metastasis-free survival and more frequent grade 3/4 lung fibrosis. AMF reduced the incidence of grade 3/4 lung fibrosis among higher MS. These data suggest that MS might help identify subgroups of patients who could receive more benefit from AMF with respect to lung damage.
Seminars in Oncology 05/2005; 32(2 Suppl 3):S92-8. · 3.50 Impact Factor
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Joe Y Chang,
Ritsuko Komaki,
Ryohei Sasaki,
Zhongxing Liao,
Craig W Stevens,
Charles Lu, Frank V Fossella,
Pamela K Allen,
James D Cox,
Margaret R Spitz,
Xifeng Wu
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ABSTRACT: To investigate whether the bleomycin sensitivity assay, an in vitro peripheral blood lymphocyte assay, can predict outcome in patients with inoperable stage III non-small-cell lung cancer (NSCLC) treated with definitive radiotherapy and chemotherapy.
We identified 102 patients with inoperable stage III NSCLC cell lung cancer treated with definitive radiotherapy and chemotherapy. The patients' pretreatment peripheral blood lymphocyte cultures were treated with the radiomimetic mutagen bleomycin. An index of bleomycin sensitivity was determined by counting the number of chromatid breaks in 50 metaphases. The correlation between bleomycin sensitivity (expressed as mean breaks per cell) and clinical outcome was analyzed.
High bleomycin sensitivity (defined as a mean of >1.02 chromatid breaks/cell, representing the third quartile of bleomycin sensitivity) predicted poor disease-specific survival and overall survival. The 6-year disease-specific survival was 27% in patients with high bleomycin sensitivity compared with 46% in patients without such sensitivity (P = 0.0094). The association remained statistically significant when adjusted for smoking status, age, and radiation dose. The 6-year overall survival was 19% for patients with high bleomycin sensitivity and 29% for those without (P = 0.0193). There was a trend toward worse local regional control and worse disease-free survival among patients with high bleomycin sensitivity. There was no difference between the two groups in distant metastasis-free survival or radiation treatment-related complications.
High bleomycin sensitivity correlated with poor overall survival and disease-specific survival in these patients with stage III NSCLC treated with radiotherapy and chemotherapy. Bleomycin sensitivity may function as a biomarker for poor clinical outcome for this group of patients.
Clinical Cancer Research 04/2005; 11(8):2894-8. · 7.74 Impact Factor
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Hai T Tran,
George R Blumenschein,
Charles Lu,
Christina A Meyers,
Vali Papadimitrakopoulou, Frank V Fossella,
Ralph Zinner,
Timothy Madden,
Lori G Smythe,
Vinay K Puduvalli,
Reggie Munden,
Mylene Truong,
Roy S Herbst
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ABSTRACT: Preclinical studies have demonstrated a synergistic effect with the angiogenesis inhibitor TNP-470 and several cytotoxic agents. A recent clinical trial with the combination of paclitaxel and TNP-470 has shown promising effects. The present study was designed to determine the toxicity and pharmacokinetics of carboplatin in combination with TNP-470 in comparison with the doublet regimen of paclitaxel and carboplatin in patients with solid tumors.
Enrolled in the study were 17 patients with lung (11), head/neck (3), sarcoma (2) and thymoma (1). The patients received intravenous paclitaxel and carboplatin on day 1 followed by TNP-470 (60 mg/m(2) i.v. over 1 h administered thrice weekly on Monday, Wednesday, and Friday). Each cycle of therapy consisted of 3 weeks. The initial cohort of three patients received carboplatin at AUC 5 mg/ml x min. No dose-limiting toxic effects occurred, thus the subsequent cohort received carboplatin at AUC 6 mg/ml x min. In addition to toxicity, the pharmacokinetics of carboplatin were evaluated, and tumor response and patient survival rates were assessed.
The administered regimen of paclitaxel (225 mg/m(2) i.v. over 3 h) and carboplatin (AUC 6 mg/ml x min i.v. over 1 h) on day 1 followed by TNP-470 (60 mg/m(2) i.v. over 1 h administered thrice weekly on Monday, Wednesday, and Friday) was defined as both the maximum tolerated and optimal dose. Hematological toxic effects were similar to those expected with the chemotherapy doublet. All neurocognitive impairments were graded as mild to moderate and reversed after discontinuation of TNP-470 administration. No alterations in the pharmacokinetic disposition of carboplatin were noted. Overall, the median survival duration was 297 days. Four patients (24%) had a partial response, and eight (47%) had stable disease.
The combination of TNP-470, paclitaxel, and carboplatin is a reasonably well tolerated regimen. Further randomized studies of TNP-470 with this doublet regimen are now warranted for non-small-cell lung carcinoma and other solid tumors.
Cancer Chemotherapy and Pharmacology 11/2004; 54(4):308-14. · 2.83 Impact Factor
