-
[show abstract]
[hide abstract]
ABSTRACT: : The Eastern Cooperative Oncology Group (ECOG) 4599 study showed a significant survival benefit with the use of bevacizumab (BV) in combination with carboplatin and paclitaxel (CP) in comparison with CP chemotherapy alone in patients with previously untreated advanced, metastatic or recurrent non-small-cell lung cancer (NSCLC). Such results were achieved using BV as maintenance therapy until progressive disease. Because current data on single-agent BV maintenance in non-small-cell lung cancer are limited, we present a retrospective analysis of safety and efficacy outcomes for patients who received maintenance BV after induction treatment and the maintenance-eligible population of the control arm in ECOG 4599.
: Landmark analyses were conducted in patients in both the CP and CP+BV groups who were alive and progression free through the completion of six cycles + 21 days. The BV maintenance population consisted of patients in the CP+BV arm, who were alive without progressive disease before the start of maintenance (maintenance-nonprogressor population). CP nonprogressors were those patients in the CP-alone arm without progressive disease after six cycles of CP + 21 days.
: Two hundred and seventeen patients (51%) were alive, progression free, and eligible for maintenance therapy six cycles + 21 days after induction CP+ BV compared with 134 patients (30%) in the CP-alone arm. Postinduction progression-free survival was significantly longer in the BV maintenance group relative to CP nonprogressors (4.4 versus 2.8 months; hazards ratio [HR] 0.64; p < 0.001). One-year overall survival rates were 75% for the BV maintenance group versus 69% in the CP nonprogressor group. Two-year overall survival rates were 34% for the BV maintenance group versus 25% in the CP nonprogressor group. Median postinduction overall survival (OS) was also significantly longer for the BV-maintenance group compared with CP nonprogressors (12.8 versus 11.4 months; HR 0.75; p = 0.030). Within the subgroup having complete response or partial response after induction, the progression-free survival and OS hazard ratio estimates were 0.59 (95% [confidence interval] CI: 0.41-0.84) and 0.78 (95% CI: 0.53-1.14), respectively. In the maintenance setting, BV was associated with a less-than 1% rate of grade 3 or 4 hematological toxicities, no grade 3 or 4 nausea, vomiting or diarrhea, and no grade 5 toxicities.
: In this retrospective analysis of patients in the ECOG 4599 study, who were alive, progression free, and on-study 21 days after six cycles of induction therapy, significant reductions in HRs for progression (0.64, p < 0.001) and survival (0.75, p = 0.03) were associated with BV treatment during induction and maintenance compared with CP induction therapy alone and suggestive of possible benefit because of bevacizumab maintenance.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 10/2012; 7(11):1707-12. · 4.55 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Vascular endothelial growth factor (VEGF) is a key mediator of angiogenesis. Solid tumors, including non-small cell lung cancer (NSCLC), are dependent on angiogenesis for growth and metastasis. Anti-VEGF therapy has demonstrated clinical benefits in the first-line treatment of NSCLC. Central nervous system (CNS) metastases are a common occurrence among patients with lung cancer and confer significant morbidity and mortality. The risk of CNS hemorrhage in NSCLC patients receiving anti-VEGF therapy is still relatively unexplored because patients with CNS metastases have generally been excluded from trials of anti-VEGF therapy due to a perceived increased risk of cerebral hemorrhage. Recently, large prospective, randomized trials, open-label studies and observational cohort studies in NSCLC have provided data on the incidence of CNS hemorrhage in large patient populations, reflective of community practice.
We conducted a literature review for the available data on the incidence of CNS hemorrhage in NSCLC patients with brain metastases receiving anti-VEGF therapy.
There is no significantly increased risk of CNS hemorrhage in patients with NSCLC and emerging (previously untreated) or pretreated CNS metastases receiving anti-VEGF therapy.
We conclude that clinical trial data indicate that anti-VEGF therapy can be considered for NSCLC patients with emerging or pretreated CNS metastases.
Lung cancer (Amsterdam, Netherlands) 08/2012; 78(1):1-7. · 3.14 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Enrollment of patients with lung cancer into clinical trials is required to accelerate the pace of new therapy development and contribute to a better understanding of the biological characteristics of cancer. METHODS: We conducted a retrospective chart review of all patients seen by the thoracic medical oncology team at the Vanderbilt Ingram Cancer Center (VICC) from November 2005 to November 2008 to determine the barriers associated with patient enrollment in to clinical trials. RESULTS: One thousand forty-three patient charts were audited: 32% of patients were eligible for enrollment, and 14% enrolled in a study. There were no significant differences in protocol availability or eligibility by sex, smoking status, or age. Patients living further from the cancer center were significantly less likely to have a study protocol available (P = .009), but if a protocol was available they were more likely to be eligible for enrollment (P < .001). Significantly more protocols were available for patients with non-small-cell lung cancer (NSCLC) compared with those who had small-cell lung cancer (SCLC) (63% vs. 48%; P < .001). Patients with advanced disease were more likely to have a protocol available (P < .001) and enter a study (P = .031). The most common reasons for patients not being eligible for enrollment were poor performance status (32%) and presence of comorbid disease (27%). The most common reasons for potentially eligible patients not enrolling in a study included preference for treatment closer to home (49%) and patient refusal (43%). CONCLUSION: Additional strategies are required to increase accrual of patients into lung cancer trials, including development of protocols for early-stage disease and modifying eligibility and performance status criteria for this unique patient population.
Clinical Lung Cancer 05/2012; · 2.94 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: S-1 is a rationally designed oral agent that combines the 5-fluorouracil prodrug tegafur with gimeracil and oteracil, which inhibit 5-fluorouracil degradation by dihydropyrimidine dehydronase and phosphorylation within the gastrointestinal tract, respectively, to increase antineoplastic activity while reducing gastrointestinal toxicity. We investigated the activity and toxicity of S-1 in combination with cisplatin in patients with unresectable non-small cell lung cancer (NSCLC).
Cisplatin, 75 mg/m, was administered intravenously on day 1, with S-1, 25 mg/m PO two times a day, days 1 to 14, every 21 days for a maximum of six cycles. Primary end point was overall response.
A total of 58 patients received at least one cycle of protocol-specified therapy. The best overall response rate was 23.2% (95% confidence interval: 13.0-36.4), and the disease control rate was 67.9%. The median progression-free survival was 4.0 months (95% confidence interval: 3.3-5.5). There did not appear to be any relationship between response to therapy and tumor histology. The most frequently reported adverse events of G3 or more (≥10%) were neutropenia (28%), hyponatremia (19%), diarrhea (17%), hypokalemia (12%), fatigue (10%), dehydration (10%), and deep vein thrombosis (10%).
Although the S-1 + cisplatin regimen used in this study appeared to have a similar level of antitumor activity and toxicity to that of established cisplatin-based doublets in NSCLC, the protocol-specified criteria of sufficient efficacy to warrant further study with an objective response rate ≥30% was not achieved. Therefore, while S-1 appears to be a promising agent in NSCLC, further evaluation should be conducted to determine the optimal S-1-based regimen to take forward for additional study.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 06/2011; 6(8):1400-6. · 4.55 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Our study set out to determine the antitumor efficacy of carboplatin and irinotecan as assessed by response rate in persons with chemotherapy-naive extensive-disease, small-cell lung cancer (ED-SCLC). Secondary objectives included progression-free survival (PFS), overall survival, and toxicity findings.
Patients with previously untreated ED-SCLC, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2, life expectancy ≥ 3 months, and adequate organ function were eligible. Patients were treated with carboplatin AUC 5 intravenously over 30-60 minutes on day 1, followed by CPT-11(irinotecan) 50 mg/m(2) intravenously over 30-90 minutes on days 1 and 8 every 3 weeks for 4-6 cycles at the discretion of the treating physician.
Fifty-six patients were enrolled, and 50 patients were eligible. The median age of patients was 60.1 years. The most common toxicities were neutropenia, thrombocytopenia, nausea/vomiting, and dehydration. The overall response rate was 58%. Median PFS was 5.3 months, median overall survival was 9.7 months, and 1-year overall survival was 28.7%.
Carboplatin and irinotecan is a safe and reasonable combination for the treatment of patients with ED-SCLC.
Clinical Lung Cancer 05/2011; 12(3):161-5. · 2.94 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: E4599 compared carboplatin and paclitaxel with (PCB) or without (PC) bevacizumab in patients with advanced-stage non-small cell lung cancer. Bevacizumab improved overall survival. However, an unplanned subset analysis did not show a survival benefit for females treated with bevacizumab.
Known prognostic factors and toxicities were compared by sex. Proportional hazards models of survival with multiple factor combinations were used to adjust for treatment effect.
The analysis includes 850 patients. The median survival was 8.7 months (PC) versus 11.7 months (PCB) for males (p = 0.001) and 13.1 months (PC) versus 13.3 months (PCB) for females (p = 0.87). Progression-free survival and response rate on the PCB arm were 6.3 months and 29% for males and 6.2 months and 41% for females (p > 0.05). Progression-free survival and response rate on the PC arm were 4.3 months and 16% for males and 5.3 months and 14% for females (p > 0.05). No significant demographic differences were seen between the two arms for males, whereas fewer females on the PCB arm had liver metastasis (PCB 11.7% versus PC 23.2%, p = 0.003). Adverse events with a sex difference on the PCB arm included severe hypertension (males: 4.2%, females: 9.9%, p = 0.02), constipation (males: 1.4%, females: 4.7%, p = 0.05), and abdominal pain (males: 0.9%, females: 5.2%, p = 0.01). In the proportional hazards model adjusting for the other factors, the test for a sex by treatment interaction was not significant (p = 0.09).
Multiple factors may contribute to the apparent sex-specific differences in efficacy of bevacizumab noted in this study.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 11/2010; 6(1):103-8. · 4.55 Impact Factor
-
David P Carbone,
J Stuart Salmon,
Dean Billheimer,
Heidi Chen, Alan Sandler,
Heinrich Roder,
Joanna Roder,
Maxim Tsypin,
Roy S Herbst,
Anne S Tsao,
Hai T Tran,
Thao P Dang
[show abstract]
[hide abstract]
ABSTRACT: We applied an established and commercially available serum proteomic classifier for survival after treatment with erlotinib (VeriStrat) in a blinded manner to pretreatment sera obtained from recurrent advanced NSCLC patients before treatment with the combination of erlotinib plus bevacizumab. We found that VeriStrat could classify these patients into two groups with significantly better or worse outcomes and may enable rational selection of patients more likely to benefit from this costly and potentially toxic regimen.
Lung cancer (Amsterdam, Netherlands) 09/2010; 69(3):337-40. · 3.14 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The combination of paclitaxel/carboplatin (PC) and bevacizumab (B) was previously shown to extend overall survival (OS) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). An analysis of survival and safety outcomes based on histology is presented here.
Patients with cytologically or histologically confirmed metastatic NSCLC were treated with PC + B (PCB) or PC. Median OS for all patients was determined using Kaplan-Meier methodology. Hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained using an unstratified Cox proportional hazards model. Histology-by-treatment interaction was tested with an unstratified multivariate Cox regression model.
A total of 444 patients were randomized to PC, and 434 patients were randomized to PCB (the intent-to-treat population). Median OS times were 10.3 and 12.3 months for PC and PCB, respectively, with an HR for PCB of 0.80 (95% CI: 0.69-0.93). A total of 68.8% of patients had adenocarcinoma histology; 18.9% had "not otherwise specified"; 5.5% had large cell undifferentiated; 2.6% had bronchoalveolar carcinoma; and 3.9% "other." For adenocarcinoma, median OS was 10.3 months for PC treatment (n = 302) and 14.2 months for PCB (n = 300), HR 0.69 (95%CI: 0.58-0.83). Sample sizes for other specific histologic subtypes were too small for meaningful comparisons. Safety profiles among histologies were consistent with the overall safety profile, and there were no unexpected adverse event trends.
Addition of B to PC is associated with increased survival in previously untreated patients with nonsquamous NSCLC. Adenocarcinoma was associated with an increased survival benefit of PCB treatment. Data for other histologies are inconclusive, primarily because of small patient sample sizes and large CIs.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 09/2010; 5(9):1416-23. · 4.55 Impact Factor
-
Francisco Robert, Alan Sandler,
Joan H Schiller,
Glenn Liu,
Karen Harper,
Lev Verkh,
Xin Huang,
Jennifer Ilagan,
Lesley Tye,
Richard Chao,
Anne M Traynor
[show abstract]
[hide abstract]
ABSTRACT: Sunitinib in combination with docetaxel enhances antitumor activity in xenograft models of human breast and non-small cell lung cancer. We assessed the maximum tolerated doses (MTDs), safety, pharmacokinetic profiles, and preliminary efficacy of sunitinib plus docetaxel in patients with advanced solid tumors.
In this phase I study, successive patient cohorts received sunitinib 25, 37.5, or 50 mg/day for 4 weeks of a 6-week cycle (Schedule 4/2, 4 weeks on, 2 weeks off) or for 2 weeks of a 3-week cycle (Schedule 2/1, 2 weeks on, 1 week off) with docetaxel 60 or 75 mg/m(2) IV q21d to determine the MTDs of this treatment combination.
Fifty patients enrolled: 10 on Schedule 4/2 and 40 on Schedule 2/1. MTDs were established as sunitinib 25 mg on Schedule 4/2 with docetaxel 60 mg/m(2) q21d, and as sunitinib 37.5 mg on Schedule 2/1 with docetaxel 75 mg/m(2) q21d. On Schedule 2/1, the most frequent dose-limiting toxicity was neutropenia (+/-fever; grade [G]3/4, n = 5) and the most common G3/4 non-hematologic adverse event (AE) was fatigue (G3, n = 8). Hematologic AEs were managed with growth factor support in 11 of 23 (48%) patients treated at Schedule 2/1 MTD. Three patients achieved a partial response at the Schedule 2/1 MTD. There were no pharmacokinetic drug-drug interactions with either schedule.
Oral sunitinib 37.5 mg/day on Schedule 2/1 with docetaxel 75 mg/m(2) IV q21d is a clinically feasible regimen with a manageable safety profile, no pharmacokinetic drug-drug interactions, and shows antitumor activity in patients with advanced solid tumors.
Cancer Chemotherapy and Pharmacology 09/2010; 66(4):669-80. · 2.83 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Lung cancer is the leading cause of cancer-related mortality in the United States with non-small cell lung cancer (NSCLC)
accounting for 80-85% of cases. Regardless of histology, the majority of patients present with advanced disease and have a
median survival of approximately 10 months for patients treated with traditional chemotherapy agents. Therefore, novel therapies
are required. ECOG4599 was the first trial to demonstrate survival beyond 1 year for patients with NSCLC treated with traditional
chemotherapy in combination with an anti-angiogenic agent. Angiogenesis, the growth of new from preexisting vessels, is a
fundamental step in the transition of tumors from dormant to malignant. In the last few years, there has been substantial
interest in developing novel molecular-targeted agents that inhibit the angiogenic pathway. The aim of this chapter is to
summarize the data for agents that have been approved and are in development for the treatment of patients with NSCLC and
small cell lung cancer (SCLC).
KeywordsAngiogenesis-Bevacizumab-Small molecule inhibitors
03/2010: pages 227-252;
-
[show abstract]
[hide abstract]
ABSTRACT: Motesanib is a small-molecule antagonist of vascular endothelial growth factor receptor 1, 2, and 3, platelet-derived growth factor receptor, and Kit. This phase 1b study assessed the safety, maximum tolerated dose (MTD), and pharmacokinetics, and explored the objective response of motesanib plus carboplatin/paclitaxel and/or the fully human anti-epidermal growth factor receptor monoclonal antibody panitumumab in advanced non-small cell lung cancer (NSCLC).
Patients with unresectable NSCLC received sequentially escalating doses of motesanib [50, 125 mg once daily; 75 mg twice daily] orally continuously plus carboplatin/paclitaxel (arm A; first line) or panitumumab (arm B; first and second line) once every 21-day cycle or 125 mg once daily plus carboplatin/paclitaxel and panitumumab (arm C; first line).
Forty-five patients received motesanib. Three dose-limiting toxicities occurred: grade 4 pulmonary embolism (n = 1; arm A, 50 mg once daily) and grade 3 deep vein thrombosis (n = 2; arm A, 125 mg once daily; arm C). The MTD was 125 mg once daily. Common motesanib-related adverse events were fatigue (60% of patients), diarrhea (53%), hypertension, (38%), anorexia (27%), and nausea (22%). Three cases of cholecystitis occurred but only in the 75-mg twice-daily schedule, which was subsequently discontinued. At 125 mg once daily, motesanib pharmacokinetics were not markedly changed with carboplatin/paclitaxel coadministration; however, exposure to paclitaxel was moderately increased. The objective response rates were 17%, 0%, and 17% in arms A, B, and C, respectively.
Treatment with motesanib was tolerable when combined with carboplatin/paclitaxel and/or panitumumab, with little effect on motesanib pharmacokinetics at the 125-mg once daily dose level. This dose is being investigated in an ongoing phase 3 study in NSCLC.
Clinical Cancer Research 12/2009; 16(1):279-90. · 7.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Non-small cell lung cancer (NSCLC) is a major global health problem and represents the leading cause of cancer-related deaths worldwide. The majority of patients with NSCLC are diagnosed with advanced-stage disease, and the prognosis for such patients is poor. The currently approved cytotoxic chemotherapy is associated with substantial limitations in both efficacy and safety. The availability of agents targeted against the epidermal growth factor receptor (EGFR), as well as the antiangiogenic agent bevacizumab, have provided some clinical benefit. Nonetheless, the efficacy of these agents is also inadequate, and resistance has emerged as a clinical problem. Numerous novel targeted therapies are now in clinical development and may have potential for overcoming the limitations associated with currently available agents. In this article we review clinical data for molecular-targeted therapies in NSCLC, with emphasis on EGFR inhibitors and antiangiogenic agents.
Clinical Cancer Research 09/2009; 15(16):5040-8. · 7.74 Impact Factor
-
Joan H Schiller,
Timothy Larson,
S-H Ignatius Ou,
Steven Limentani, Alan Sandler,
Everett Vokes,
Sinil Kim,
Katherine Liau,
Paul Bycott,
Anthony J Olszanski,
Joachim von Pawel
[show abstract]
[hide abstract]
ABSTRACT: This phase II study evaluated efficacy and safety of single-agent axitinib, an oral, potent, selective inhibitor of vascular endothelial growth factor receptors (VEGFR) -1, -2, and -3, in patients with advanced non-small-cell lung cancer (NSCLC).
This was an open-label, single-arm, multicenter, phase II study with a Simon two-stage minimax design. Patients received a starting dose of axitinib 5 mg orally BID. The primary end point was Response Evaluation Criteria in Solid Tumors (RECIST) -defined objective response rate. Secondary end points included safety and tolerability, overall survival (OS), and progression-free survival (PFS).
Thirty-two patients were enrolled, with a median age of 66.5 years. The majority of patients (75%) had adenocarcinoma. Nine patients (28%) had received no prior chemotherapy for metastatic disease, and 23 (72%) had received > or = one regimen. Three patients (9%) had a RECIST investigator-assessed, confirmed partial response (PR); disease control rate (PR + stable disease) was 41%. Median PFS was 4.9 months overall (95% CI, 3.6 to 7.0 months). Median OS was 14.8 months (95% CI, 10.7 months to not estimable) overall and 14.8 months (95% CI, 12.5 months to not estimable) in patients receiving first-line axitinib. One-year survival rates for patients with or without prior therapy for metastatic disease were 57% and 78%, respectively. Grade 3 treatment-related adverse events in > or = 5% of patients comprised fatigue (22%), hypertension (9%), and hyponatremia (9%).
Axitinib demonstrated single-agent activity in patients with advanced NSCLC. Therapy was well tolerated with manageable toxicities. Further investigation of this VEGFR inhibitor in NSCLC is of interest.
Journal of Clinical Oncology 09/2009; 27(23):3836-41. · 18.37 Impact Factor
-
Stuart Salmon,
Heidi Chen,
Shuo Chen,
Roy Herbst,
Anne Tsao,
Hai Tran, Alan Sandler,
Dean Billheimer,
Yu Shyr,
Ju-Whei Lee,
Pierre Massion,
Julie Brahmer,
Joan Schiller,
David Carbone,
Thao P. Dang
[show abstract]
[hide abstract]
ABSTRACT: Purpose: Although many lung cancers express the epidermal growth factor receptor and the vascular endothelial growth factor, only a small fraction of patients will respond to inhibitors of these pathways. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MS) has shown promise in biomarker discovery, potentially allowing the selection of patients who may benefit from such therapies. Here, we use a matrix-assisted laser desorption/ionization MS proteomic algorithm developed from a small dataset of erlotinib-bevacizumab treated patients to predict the clinical outcome of patients treated with erlotinib alone.
Methods: Pretreatment serum collected from patients in a phase I/II study of erlotinib in combination with bevacizumab for recurrent or refractory non-small cell lung cancer was used to develop a proteomic classifier. This classifier was validated using an independent treatment cohort and a control population.
Result: A proteomic profile based on 11 distinct m/z features was developed. This predictive algorithm was associated with outcome using the univariate Cox proportional hazard model in the training set (p = 0.0006 for overall survival; p = 0.0012 for progression-free survival). The signature also predicted overall survival and progression-free survival outcome when applied to a blinded test set of patients treated with erlotinib alone on Eastern Cooperative Oncology Group 3503 (n = 82, p < 0.0001 and p = 0.0018, respectively) but not when applied to a cohort of patients treated with chemotherapy alone (n = 61, p = 0.128).
Conclusion: The independently derived classifier supports the hypothesis that MS can reliably predict the outcome of patients treated with epidermal growth factor receptor kinase inhibitors.
Journal of Thoracic Oncology 05/2009; 4(6):689-696. · 3.66 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The current standard of care for good performance status patients with locally advanced non-small cell lung carcinoma is concurrent chemoradiation, although a clearly superior regimen has not been identified. Docetaxel has been shown to possess good single-agent activity against non-small cell lung cancer (NSCLC) and radiosensitizing properties, both alone and synergistically with carboplatin. We undertook this phase II study to determine the safety and efficacy of weekly docetaxel-carboplatin and concurrent radiation therapy followed by docetaxel-carboplatin consolidation for the treatment of locally advanced NSCLC.
Sixty-seven patients having previously untreated stage IIIA or IIIB unresectable NSCLC were enrolled, with 61 patients evaluated for endpoints. Docetaxel 20 mg/m IV infusion over 30 minutes followed by carboplatin area under the curve = 2 over 30 minutes was administered weekly during concurrent thoracic radiotherapy. After 3 week rest, consolidation docetaxel 75 mg/m(2) IV infusion over 60 minutes and carboplatin area under the curve = 6 over 30 minutes was administered every 3 weeks for two cycles. Concurrent thoracic radiation consisted of 45 Gy (1.8 Gy fractions 5 d/wk for first 5 weeks) followed by 18 Gy boost (2.0 Gy fractions 5 d/wk for 2 weeks) for a total dose of 63 Gy.
One and 2 years overall survival rates were 45 and 20%, respectively. Progression free survival at 1 year was 27%. Median survival time was 12 months. Median time to progression was 8 months. The primary hematologic toxicity was leukopenia. The primary nonhematologic toxicity was esophagitis.
The administered regimen of weekly docetaxel-carboplatin and concurrent radiation therapy followed by docetaxel-carboplatin consolidation has acceptable toxicity profile. However, the overall survivals at 1 and 2 years are somewhat disappointing.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 05/2009; 4(6):722-7. · 4.55 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To determine the 1-year survival, response rate, and toxicity for patients with limited stage small cell lung cancer treated with the combination of cisplatin plus etoposide plus paclitaxel with delayed concurrent (starting with cycle 3) high dose thoracic radiotherapy.
Patients with previously untreated limited stage small cell lung cancer, Easter Cooperative Oncology Group performance status of 0-2 and adequate organ function were eligible. Cycles 1 and 2 of chemotherapy consisted of paclitaxel 170 mg/m intravenous day 1, etoposide 80 mg/m intravenous days 1 to 3, and cisplatin 60 mg/m intravenous day 1 followed by filgrastim 5 microg/kg subcutaneously days 4 to 13. Cycles 3 and 4 of chemotherapy consisted of a reduced dose of paclitaxel 135 mg/m intravenous day 1, and the same dose of etoposide and cisplatin with concurrent thoracic radiation therapy 1.8 Gy in 35 fractions (total 63 Gy) administered over 7 weeks.
Sixty-three patients were entered, 61 patients were eligible. The most common grade 4 toxicity seen was granulocytopenia (62%). Nonhematologic toxicities included febrile neutropenia in 19% of patients, grade 3 and 4 esophagitis in 32% of patients, and grade 3 peripheral neuropathy in 14% of patients. Two patients suffered lethal toxicities. The overall response rate was 79%. The 1-year survival rate was 64%. The median overall survival was 15.7 months, and the median progression-free survival was 8.6 months.
The combination of cisplatin plus etoposide plus paclitaxel chemotherapy and concurrent delayed thoracic radiotherapy as administered in this trial provide no apparent advantage with respect to response, local control, or survival compared with historical controls.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 03/2009; 4(4):527-33. · 4.55 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Biologic agents that target molecules involved in tumor growth, progression, and pathological angiogenesis--such as the human epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF)--have demonstrated efficacy in patients with non-small cell lung cancer (NSCLC). Erlotinib (Tarceva); OSI Pharmaceuticals, Inc., Melville, NY, Genentech, Inc., South San Francisco, CA, and F. Hoffmann-La Roche Ltd, Basel, Switzerland), a highly selective tyrosine kinase inhibitor that inhibits EGFR, and bevacizumab (Avastin); Genentech, Inc., South San Francisco, CA, and F. Hoffmann-La Roche Ltd, Basel, Switzerland), a VEGF-targeted recombinant humanized monoclonal antibody, have displayed very encouraging activity in a randomized phase II trial in patients with previously treated NSCLC. Because erlotinib and bevacizumab act on two different pathways critical to tumor growth and dissemination, administering these drugs concomitantly may confer additional clinical benefits to cancer patients with advanced disease, by virtue of their complementary (or additive) antitumor activity. The combination of bevacizumab plus erlotinib may prove to be a viable second-line alternative to chemotherapy or erlotinib monotherapy in patients with NSCLC. The benefits of the combination may be further enhanced by selecting for patients who are likely to respond to this therapy. While a number of potential predictive markers have been identified for erlotinib, their value remains to be confirmed in prospective trials. In addition, the application of such personalized therapy will also depend on the availability of validated screening methods.
The Oncologist 12/2008; 13(11):1166-76. · 3.91 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Methylthioadenosine phosphorylase (MTAP)-deficient tumors are dependent on the de novo purine synthesis pathway. These cancers are potential targets for selective chemotherapy with inhibitors of de novo adenine synthesis such as L-alanosine [L-2-amino-3-(N-hydroxy-N-nitrosamino) propionic acid]. This phase II study was designed to evaluate the efficacy and safety of L-alanosine in patients with MTAP-deficient solid tumors.
Patients with mesothelioma, non-small cell lung cancer (NSCLC), soft tissue sarcoma, osteosarcoma, or pancreatic cancer whose tumors were MTAP deficient by immunohistochemistry were eligible. Patients received L-alanosine at a starting dose of 80 mg/m(2) by continuous intravenous infusion daily for 5 days every 21 days. Computed tomography scans or magnetic resonance imaging were performed every 3 cycles.
65 patients (16 mesothelioma, 13 NSCLC, 15 soft tissue sarcoma, 7 osteosarcoma, 14 pancreatic cancer) were enrolled at 19 centers; 55 were evaluable for response. There were no objective responses; 24% had s disease, including 2 patients with mesothelioma who had prolonged stable disease lasting 7.5 and 15.2 months, respectively. Grade 3/4 toxicities included mucositis 11%, fatigue 6%, nausea 3%, and renal failure 1.5%.
At this dose and schedule, L-alanosine was ineffective in patients with advanced MTAP-deficient tumors.
Investigational New Drugs 08/2008; 27(1):75-81. · 3.36 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We examine the processes and document the calendar time required to activate phase II and III clinical trials by an oncology group: the Eastern Cooperative Oncology Group (ECOG). Methods: Setup steps were documented by (a) interviewing ECOG headquarters and statistical center staff, and committee chairs, (b) reviewing standard operating procedure manuals, and (c) inspecting study records, documents, and e-mails to identify additional steps. Calendar time was collected for each major process for each study in this set.
Twenty-eight phase III studies were activated by ECOG during the January 2000 to July 2006 study period. We examined a sample from 16 of those studies in detail. More than 481 distinct processes were required for study activation: 420 working steps, 61 major decision points, 26 processing loops, and 13 stopping points. Median calendar days to activate a trial in the phase III subset was 783 days (range, 285-1,542 days) from executive approval and 808 days (range, 435-1,604 days) from initial conception of the study. Data were collected for all phase II and phase III trials activated and completed during this time period (n = 52) for which development time represented 43.9% and 54.1% of the total trial time, respectively.
The steps required to develop and activate a clinical trial may require as much or more time than the actual completion of a trial. The data shows that to improve the activation process, research should to be directed toward streamlining both internal and external groups and processes.
Clinical Cancer Research 06/2008; 14(11):3427-33. · 7.74 Impact Factor
-
Mary J Fidler,
Athanassios Argiris,
Jyoti D Patel,
David H Johnson, Alan Sandler,
Victoria M Villaflor,
John Coon,
Lela Buckingham,
Kelly Kaiser,
Sanjib Basu,
Philip Bonomi
[show abstract]
[hide abstract]
ABSTRACT: Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, potentiates antitumor effects of erlotinib in preclinical studies, and COX-2 is frequently expressed in non-small cell lung cancer (NSCLC). With these observations, we designed a phase II trial to evaluate the efficacy and safety of erlotinib plus celecoxib in advanced NSCLC.
Previously treated stage IIIB/IV NSCLC patients were given celecoxib at 400 mg orally twice daily and erlotinib at 150 mg orally daily until disease progression. Planned accrual was 40 patients. Tissue was collected for epidermal growth factor receptor (EGFR) analysis and COX-2 immunohistochemistry.
Twenty-six patients were enrolled (17 men, 9 women; median age, 66 years). Eighteen and 21 patients had tissue available for EGFR analysis and COX-2 immunohistochemistry, respectively. The median progression-free survival (PFS) and overall survival were 2.0 and 9.2 months, respectively. Eleven of 21 patients tested had increased tumor COX-2 expression, which was strongly associated with prolonged PFS (P=0.048). Four patients on anticoagulation or with a history of peptic ulcer disease had grade 3/grade 4 upper gastrointestinal bleeding (GIB), prompting early study closure. Three patients with GIB had endoscopy that found peptic ulcers.
The combination of erlotinib and celecoxib does not seem superior to erlotinib alone in unselected patients. However, longer PFS with high-tumor COX-2 expression suggests that trials of EGFR and COX-2 inhibitors may be warranted in this patient subset. GIB observed in our trial supports excluding patients with a history of peptic ulcer disease or those requiring therapeutic anticoagulation from future EGFR and COX-2 inhibitor studies.
Clinical Cancer Research 05/2008; 14(7):2088-94. · 7.74 Impact Factor
