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1.  Thymidylate Synthase and Folyl-polyglutamate synthase (FPGS) Are Not Clinically Useful Markers of Response to Pemetrexed [Pem] in Patients with Malignant Pleural Mesothelioma [MPM] 
Purpose
Thymidylate synthase (TS) is a potential predictor of outcome after pemetrexed (Pem) in patients with malignant pleural mesothelioma (MPM), and assays measuring TS levels are commercially marketed. The goal of this study was to further evaluate the value of TS and to study another potential biomarker of response, the enzyme, folyl-polyglutamate synthase (FPGS), which activates Pem intracellularly.
Patients and Methods
Levels of TS and FPGS were semi-quantitatively determined immunohistochemically using H-scores on tissue samples from 85 MPM patients receiving Pem as primary therapy. H-score was correlated with radiographic disease control rate (DCR), time to progression (TTP) and overall survival (OS). In addition, expression levels of TS and FPGS in MPM cell lines were determined using immunoblotting and correlated with their sensitivity to Pem-induced cell death.
Results
H-scores from patients with disease control versus progressive disease showed extensive overlap. There were no significant correlations of DCR, TTP, or OS to either TS levels (p = 0.73, 0.93, and 0.59, respectively), FPGS levels (p = 0.95, 0.77 and 0.43 respectively) or the ratio of FPGS/TS using the median scores of each test as cutoffs. There was no correlation between TS or FPGS expression and chemosensitivity of mesothelioma cells to Pem in vitro.
Conclusions
Although previous retrospective data suggest that TS and FPGS expression might be potential markers of Pem efficacy in MPM, our data indicate these markers lack sufficient predictive value in individual patients and should not be used to guide therapeutic decisions in the absence of prospective studies.
doi:10.1097/JTO.0b013e318283da3e
PMCID: PMC3601580  PMID: 23486267
2.  Penetration of Recommended Procedures for Lung Cancer Staging and Management in the United States over 10 Years: A Quality Research in Radiation Oncology Survey 
Purpose
To document the penetration of clinical trial results, practice guidelines, and appropriateness criteria into national practice, we compared the use of components of staging and treatment for lung cancer among patients treated in 2006–2007 versus in 1998–1999.
Methods
Patient, staging work-up, and treatment characteristics were extracted from the process survey database of the Quality Research in Radiation Oncology (QRRO), comprising records from 340 patients with locally advanced non-small cell lung cancer (LA-NSCLC) at 44 institutions and 144 patients with limited-stage small cell lung cancer (LS-SCLC) at 39 institutions. Data were compared for patients treated in 2006–2007 versus patients treated in 1998–1999.
Results
Use of all recommended procedures for staging and treatment was more common in 2006–2007. Specifically, disease was staged with brain imaging (magnetic resonance imaging or computed tomography) and whole-body imaging (positron emission tomography or bone scanning) in 66% of patients with LA-NSCLC in 2006–2007 (vs. 42% in 1998–1999, p=0.0001) and in 84% of patients with LS-SCLC in 2006–2007 (vs. 58.3% in 1998–1999, p=0.0011). Concurrent chemoradiation was used for 77% of LA-NSCLC patients (vs. 45% in 1998–1999, p<0.0001) and for 90% of LS-SCLC patients (vs. 62.5% in 1998–1999, p<0.0001). Use of the recommended radiation dose (59–74 Gy for NSCLC and 60–70 Gy as once-daily therapy for SCLC) did not change appreciably, being 88% for NSCLC in both periods and 51% (2006–2007) vs. 43% (1998–1999) for SCLC. Twice-daily radiation for SCLC was used for 21% of patients in 2006–2007 vs. 8% in 1998–1999. Finally, 49% of patients with LS-SCLC received prophylactic cranial irradiation (PCI) in 2006–2007 (vs. 21% in 1998–1999).
Conclusion
Although adherence to all quality indicators improved over time, brain imaging and recommended radiation doses for stage III NSCLC were used in <90% of cases. Use of full thoracic doses and PCI for LS-SCLC also require improvement.
doi:10.1016/j.ijrobp.2012.10.016
PMCID: PMC3897271  PMID: 23273996
lung cancer; QRRO; quality indicators; clinical performance measures; healthcare management; standard of care; patterns of care
3.  Immunological effects of the TGFβ-blocking antibody GC1008 in malignant pleural mesothelioma patients 
Oncoimmunology  2013;2(8):e26218.
We evaluated a neutralizing anti-TGFβ antibody (GC1008) in cancer patients with malignant pleura mesothelioma (MPM). The goal of this study was to assess immunoregulatory effects in relation to clinical safety and clinical response. Patients with progressive MPM and 1–2 prior systemic therapies received GC1008 at 3mg/kg IV over 90 min every 21 d as part of an open-label, two-center Phase II trial. Following TGFβ blockade therapy, clinical safety and patient survival were monitored along with the effects of anti-TGFβ antibodies on serum biomarkers and peripheral blood mononuclear cells (PBMC). Although designed as a larger trial, only 13 patients were enrolled when the manufacturer discontinued further development of the antibody for oncology indications. All participants tolerated therapy. Although partial or complete radiographic responses were not observed, three patients showed stable disease at 3 mo. GC1008 had no effect in the expression of NK, CD4+, or CD8+ T cell activating and inhibitory markers, other than a decrease in the expression of 2B4 and DNAM-1 on NK cells. However, serum from 5 patients showed new or enhanced levels of antibodies against MPM tumor lysates as measured by immunoblotting. Patients who produced anti-tumor antibodies had increased median overall survival (OS) (15 vs 7.5 mo, p < 0.03) compared with those who did not. To our knowledge, these data represent the first immune analysis of TGFβ- blockade in human cancer patients.
doi:10.4161/onci.26218
PMCID: PMC3812201  PMID: 24179709
GC1008; anti-TGFβ antibody; antibody therapy; clinical trial; immunotherapy; malignant mesothelioma
4.  Utilization of Supportive and Palliative Care Services among Oncology Outpatients at One Academic Cancer Center: Determinants of Use and Barriers to Access 
Journal of Palliative Medicine  2012;15(8):923-930.
Abstract
Background
Cancer causes significant symptom burden and diminished quality of life. Despite the expansion of supportive and palliative care services (SPCS), little is known about rates of utilization and barriers to access to these services among oncology outpatients.
Methods
We performed a cross-sectional survey in three outpatient medical oncology clinics. Patients with a diagnosis of breast, lung, or gastrointestinal (GI) cancer and a Karnofsky score of ≥60 were included. Patients reported their use of SPCS and any perceived barriers. Multivariable logistic regression was used to identify factors associated with SPCS use.
Results
Among 313 participants, (50.5%) had not used SPCS since cancer diagnosis. The most common services used were nutrition (26.5%), psychiatric/psychological counseling (29.7%), and physical therapy (15.1%). Pain/palliative care and cancer rehabilitation consultations were used by 8.5% and 4.1% of participants, respectively. In multivariate analysis, graduate education was associated with greater SPCS use (adjusted odds ratio [AOR] 2.14, 95% confidence interval [CI] 1.08-4.26) compared with those with high school or less, whereas having lung cancer was associated with less SPCS use (AOR 0.48, 95% CI 0.24-0.96) when compared with those having breast cancer. The biggest reported barriers to using SPCS were a lack of awareness (22.4%) and lack of physician referral (23%).
Conclusions
Approximately half of these patients had not accessed SPCS since cancer diagnosis and cite lack of awareness and physician nonreferral as barriers. Further research is needed to understand patients' needs and beliefs regarding SPCS, and how to integrate SPCS into conventional treatments to improve cancer care.
doi:10.1089/jpm.2011.0217
PMCID: PMC3396135  PMID: 22731514
5.  Phase II Study of Accelerated High-Dose Radiation Therapy with Concurrent Chemotherapy for Patients With Limited Small-Cell Lung Cancer: RTOG 0239 
Purpose
To investigate whether high-dose thoracic radiation given twice daily during cisplatin–etoposide chemotherapy for limited small cell lung cancer (LSCLC) improves survival, acute esophagitis, and local control rates relative to findings from Intergroup trial 0096 (47%, 27%, and 64%)..
Patients and Methods
Patients were accrued over a 3-year period from 22 U.S. and Canadian institutions. Patients with LSCLC and good performance status were given thoracic radiation to 61.2 Gy over 5 weeks (daily 1.8-Gy fractions on days 1-22, then twice-daily 1.8-Gy fractions on days 23-33). Cisplatin (60 mg/m2 IV) was given on day 1 and etoposide (120 mg/m2 IV) on days 1-3 and days 22-24, followed by 2 cycles of cisplatin+etoposide alone. Patients who achieved complete response were offered prophylactic cranial irradiation. Endpoints included overall and progression-free survival; severe esophagitis (CTC v 2.0) and treatment-related fatalities; response (RECIST); and local control.
Results
Seventy-two patients were accrued from June 2003 through May 2006; 71 were evaluable (median age 63; 52% female; 58% Zubrod 0). Median survival time was 19 months; at 2 years, overall survival rate was 36.6% (95% CI 25.6%-47.7%), and progression-free survival 19.7% (95% CI 11.4%-29.6%). Thirteen patients (18%) experienced severe acute esophagitis and 2 (3%) died of treatment-related causes; 41% achieved complete response, 39% partial response, 10% stable disease, and 6% progressive disease. The local control rate was 73%. Forty-three patients (61%) received prophylactic cranial irradiation.
Conclusions
The overall survival rate did not reach the projected goal; however, rates of esophagitis were lower, and local control higher, than projected. This treatment strategy is now one of three arms of a prospective trial of chemoradiation for LSCLC (RTOG 0538/CALGB 30610).
doi:10.1016/j.ijrobp.2012.01.075
PMCID: PMC3377848  PMID: 22560543
concomitant boost thoracic radiation; limited stage small cell lung cancer; cisplatin, etoposide
6.  Induction chemotherapy with cetuximab, carboplatin and paclitaxel for the treatment of locally advanced squamous cell carcinoma of the head and neck 
Although controversy exists in the management of locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN), clinicians often use induction chemotherapy for treatment of the most advanced cases. One promising regimen combines weekly cetuximab (400 mg/m2 loading dose followed by 250 mg/m2) with carboplatin (AUC of 2) and paclitaxel (90 mg/m2). We retrospectively evaluated patients treated with this regimen prior to definitive chemoradiation or surgery between May 2008 and December 2011. The primary endpoint used for this retrospective analysis was feasibility. Thirty consecutive, unselected patients were included. Median follow-up was 13.7 months (range, 5.0–38.7 months). All but one patient had stage IV SCCHN. Dose intensity was high for carboplatin (92%), paclitaxel (93%) and cetuximab (85%). Grade 3–4 toxicities occurred in <7% of the study population and were limited to rash, neutropenia and infusion reactions. Response rate (RR) to induction chemotherapy was 97% (30% complete response, 67% partial response). All patients completed subsequent chemoradiotherapy or surgery. Nineteen patients (63%) demonstrated a complete response and 11 patients (37%) demonstrated a partial response. Median overall survival and progression-free survival data are not yet mature. The RR to therapy in our off-protocol experience is at least comparable to that observed in the two phase II studies of this regimen and appears superior to that observed with docetaxel, cisplatin and fluorouracil (TPF).
doi:10.3892/etm.2013.948
PMCID: PMC3628719  PMID: 23599744
locally advanced squamous cell carcinoma of the head and neck; head and neck cancer; induction chemotherapy; chemoradiotherapy
7.  Cost Effectiveness of Personalized Therapy for First-Line Treatment of Stage IV and Recurrent Incurable Adenocarcinoma of the Lung 
Journal of Oncology Practice  2012;8(5):267-274.
Cost-effectiveness analysis supports EGFR mutation testing in patients with stage IV or recurrent lung adenocarcinoma, rebiopsying if insufficient tissue is available, and first-line erlotinib treatment for those with EGFR mutations.
Purpose:
Patients with epidermal growth factor receptor (EGFR) mutation–positive stage IV adenocarcinoma have improved survival with tyrosine kinase inhibitor (TKI) treatments, but the cost effectiveness of personalized first-line therapy using EGFR mutation testing is unknown.
Methods:
We created a decision analytic model comparing the costs and effects of platinum combination chemotherapy with personalized therapy in which patients with EGFR mutation–positive tumors were treated with erlotinib. We used two testing strategies: testing only those with tissue available and performing a repeat biopsy if tissue was not available versus three nontargeted chemotherapy regimens (ie, carboplatin and paclitaxel; carboplatin and pemetrexed; and carboplatin, pemetrexed, and bevacizumab).
Results:
Compared with a carboplatin plus paclitaxel regimen, targeted therapy based on testing available tissue yielded an incremental cost-effectiveness ratio (ICER) of $110,644 per quality-adjusted life year (QALY), and the rebiopsy strategy yielded an ICER of $122,219 per QALY. Probabilistic sensitivity analysis revealed substantial uncertainty around these point estimates. With a willingness to pay of $100,000 per QALY, the testing strategy was cost effective 58% of the time, and the rebiopsy strategy was cost effective 54% of the time. Personalized therapy with an EGFR TKI was more favorable when the nontargeted chemotherapy regimen was more expensive. Compared with carboplatin, pemetrexed, and bevacizumab, ICERs were $25,547 per QALY for the testing strategy and $44,036 per QALY for the rebiopsy strategy.
Conclusion:
Although specific clinical circumstances should guide therapy, our cost-effectiveness analysis supports the strategy of testing for EGFR mutations in patients with stage IV or recurrent adenocarcinoma of the lung, rebiopsying patients if insufficient tissue is available for testing, and treating patients with EGFR mutations with erlotinib as first-line therapy.
doi:10.1200/JOP.2011.000502
PMCID: PMC3439225  PMID: 23277762
8.  Sequential vs Concurrent Chemoradiation for Stage III Non–Small Cell Lung Cancer: Randomized Phase III Trial RTOG 9410 
Background
The combination of chemotherapy with thoracic radiotherapy (TRT) compared with TRT alone has been shown to confer a survival advantage for good performance status patients with stage III non–small cell lung cancer. However, it is not known whether sequential or concurrent delivery of these therapies is the optimal combination strategy.
Methods
A total of 610 patients were randomly assigned to two concurrent regimens and one sequential chemotherapy and TRT regimen in a three-arm phase III trial. The sequential arm included cisplatin at 100 mg/m2 on days 1 and 29 and vinblastine at 5 mg/m2 per week for 5 weeks with 60 Gy TRT beginning on day 50. Arm 2 used the same chemotherapy regimen as arm 1 with 60 Gy TRT once daily beginning on day 1. Arm 3 used cisplatin at 50 mg/m2 on days 1, 8, 29, and 36 with oral etoposide at 50 mg twice daily for 10 weeks on days 1, 2, 5, and 6 with 69.6 Gy delivered as 1.2 Gy twice-daily fractions beginning on day 1. The primary endpoint was overall survival, and secondary endpoints included tumor response and time to tumor progression. Kaplan–Meier analyses were used to assess survival, and toxic effects were examined using the Wilcoxon rank sum test. All statistical tests were two-sided.
Results
Median survival times were 14.6, 17.0, and 15.6 months for arms 1–3, respectively. Five-year survival was statistically significantly higher for patients treated with the concurrent regimen with once-daily TRT compared with the sequential treatment (5-year survival: sequential, arm 1, 10% [20 patients], 95% confidence interval [CI] = 7% to 15%; concurrent, arm 2, 16% [31 patients], 95% CI = 11% to 22%, P = .046; concurrent, arm 3, 13% [22 patients], 95% CI = 9% to 18%). With a median follow-up time of 11 years, the rates of acute grade 3–5 nonhematologic toxic effects were higher with concurrent than sequential therapy, but late toxic effects were similar.
Conclusion
Concurrent delivery of cisplatin-based chemotherapy with TRT confers a long-term survival benefit compared with the sequential delivery of these therapies.
doi:10.1093/jnci/djr325
PMCID: PMC3186782  PMID: 21903745
9.  Phase II Study of Carboplatin and Paclitaxel in Advanced Thymoma and Thymic Carcinoma 
Journal of Clinical Oncology  2011;29(15):2060-2065.
Purpose
The purpose of this study was to evaluate the impact of carboplatin and paclitaxel in patients with advanced previously untreated thymoma and thymic carcinoma.
Patients and Methods
We conducted a prospective multicenter study in patients with unresectable thymoma (n = 21) or thymic carcinoma (n = 23). Patients were treated with carboplatin (area under the curve, 6) plus paclitaxel (225 mg/m2) every 3 weeks for a maximum of six cycles. The primary end point of this trial was to evaluate the objective response rate.
Results
From February 2001 through January 2008, 46 patients were enrolled. Thirteen patients had grade 4 or greater toxicity, mostly neutropenia. Using RECIST (Response Evaluation Criteria in Solid Tumors) 1.0 criteria, three complete responses (CRs) and six partial responses (PRs; objective response rate [ORR], 42.9%; 90% CI, 24.5% to 62.8%) were observed in the thymoma cohort; 10 patients had stable disease. For patients with thymic carcinoma, no CRs and five PRs (ORR, 21.7%; 90% CI, 9.0% to 40.4%) were observed; 12 patients had stable disease. Progression-free survival (PFS) was 16.7 (95% CI, 7.2 to 19.8) and 5.0 (95% CI, 3.0 to 8.3) months for thymoma and thymic carcinoma cohorts, respectively. To date, only seven patients (33.3%) with thymoma have died, compared with 16 patients (69.6%) with thymic carcinoma. Median survival time was 20.0 months (95% CI, 5.0 to 43.6 months) for patients with thymic carcinoma, but it has not been reached for patients with thymoma.
Conclusion
Carboplatin plus paclitaxel has moderate clinical activity for patients with thymic malignancies, but this seems less than expected with anthracycline-based therapy. Patients with thymic carcinoma have poorer PFS and overall survival than patients with thymoma.
doi:10.1200/JCO.2010.32.9607
PMCID: PMC3107762  PMID: 21502559
10.  Molecular Analysis of Non-Small Cell Lung Cancer (NSCLC) Identifies Subsets with Different Sensitivity to Insulin like Growth Factor I Receptor (IGF-IR) Inhibition 
Purpose
Identify molecular determinants of sensitivity of NSCLC to anti-insulin like growth factor receptor (IGF-IR) therapy.
Experimental Design
216 tumor samples were investigated. 165 consisted of retrospective analyses of banked tissue and an additional 51 were from patients enrolled in a phase 2 study of figitumumab (F), a monoclonal antibody against the IGF-IR, in stage IIIb/IV NSCLC. Biomarkers assessed included IGF-IR, EGFR, IGF-2, IGF-2R, IRS-1, IRS-2, vimentin and E-cadherin. Sub-cellular localization of IRS-1 and phosphorylation levels of MAPK and Akt1 were also analyzed.
Results
IGF-IR was differentially expressed across histological subtypes (P=0.04), with highest levels observed in squamous cell tumors. Elevated IGF-IR expression was also observed in a small number of squamous cell tumors responding to chemotherapy combined with F (p=0.008). Since no other biomarker/response interaction was observed using classical histological sub-typing, a molecular approach was undertaken to segment NSCLC into mechanism-based subpopulations. Principal component analysis and unsupervised Bayesian clustering identified 3 NSCLC subsets that resembled the steps of the epithelial-to-mesenchymal transition: E-cadherin high/IRS-1 low (Epithelial-like), E-cadherin intermediate/IRS-1 high (Transitional) and E-cadherin low/IRS-1 low (Mesenchymal-like). Several markers of the IGF-IR pathway were over-expressed in the Transitional subset. Furthermore, a higher response rate to the combination of chemotherapy and F was observed in Transitional tumors (71%) compared to those in the Mesenchymal-like subset (32%, p=0.03). Only one Epithelial-like tumor was identified in the phase 2 study, suggesting that advanced NSCLC has undergone significant de-differentiation at diagnosis.
Conclusion
NSCLC comprises molecular subsets with differential sensitivity to IGF-IR inhibition.
doi:10.1158/1078-0432.CCR-10-0089
PMCID: PMC2952544  PMID: 20670944
IGF-IR; Figitumumab; NSCLC
11.  Roles of EGFR and KRAS Mutations in the Treatment Of Patients With Non–Small-Cell Lung Cancer 
Pharmacy and Therapeutics  2011;36(5):263-279.
After decades of empirical treatment, molecular subtypes of non–small-cell lung cancer (NSCLC) are now emerging that may enable us to target treatment for patients and increase the likelihood of response. Of the biomarkers under evaluation, gene mutations are gaining recognition as predictive markers for anti–epidermal-growth factor receptor (EGFR) therapy. To date, unlike the situation in colorectal cancer, mutation of the v-Ki-Ras-2 Kirsten rat sarcoma viral oncogene homolog (KRAS) has an inconclusive role in NSCLC and should not be used to exclude patients from anti-EGFR therapy. For first-line NSCLC therapy, EGFR mutation status constitutes a prudent test to identify patients who are most likely to benefit from EGFR–tyrosine kinase inhibitor therapy rather than from chemotherapy. In first-line maintenance and relapsed (second-line or third-line) settings, clinical data support the use of erlotinib (Tarceva), as currently indicated, without regard to evaluation of EGFR mutation status. All patient subsets have been shown to benefit with prolonged progression-free and overall survival.
PMCID: PMC3138369  PMID: 21785539
NSCLC; EGFR mutation; KRAS; erlotinib
12.  Palliative thoracic radiotherapy in lung cancer: An American Society for Radiation Oncology evidence-based clinical practice guideline 
Practical Radiation Oncology  2011;1(2):60-71.
Purpose
To provide guidance to physicians and patients with regard to the use of external beam radiotherapy, endobronchial brachytherapy, and concurrent chemotherapy in the setting of palliative thoracic treatment for lung cancer, based on available evidence complemented by expert opinion.
Methods and Materials
A Task Force authorized by the American Society for Radiation Oncology (ASTRO) Board of Directors synthesized and assessed evidence from 3 systematic reviews on the following topics: (1) dose fractionation in thoracic external beam radiotherapy (EBRT); (2) clinical utility of initial and salvage endobronchial brachytherapy (EBB); and (3) use of concurrent chemotherapy (CC) with palliative thoracic radiotherapy. Practice guideline recommendations were produced and are contained herein.
Results
Studies suggest that higher dose/fractionation palliative EBRT regimens (eg, 30 Gy/10 fraction equivalent or greater) are associated with modest improvements in survival and total symptom score, particularly in patients with good performance status. As these improvements are associated with an increase in esophageal toxicity, various shorter EBRT dose/fractionation schedules (eg, 20 Gy in 5 fractions, 17 Gy in 2 weekly fractions, 10 Gy in 1 fraction), which provide good symptomatic relief with fewer side effects, can be used for patients requesting a shorter treatment course and/or in those with a poor performance status. No defined role for EBB in the routine initial palliative treatment of chest disease has been demonstrated; however, EBB can be a reasonable option for the palliation of endobronchial lesions causing obstructive symptomatology including lung collapse, or for hemoptysis after EBRT failure. The integration of concurrent chemotherapy with palliative intent/fractionated radiotherapy is not currently supported by the medical literature.
Conclusion
This Guideline is intended to serve as a guide for the use of EBRT, EBB, and CC in thoracic palliation of lung cancer outside the clinical trial setting. Further prospective clinical investigations with relevant palliative endpoints into the respective roles of EBB and CC/targeted therapy in the thoracic palliation of lung cancer are warranted, given the current state of the medical literature in these areas.
doi:10.1016/j.prro.2011.01.005
PMCID: PMC3808743  PMID: 24174996
13.  Quality of Life Supersedes the Classic Prognosticators for Long-Term Survival in Locally Advanced Non–Small-Cell Lung Cancer: An Analysis of RTOG 9801 
Journal of Clinical Oncology  2009;27(34):5816-5822.
Purpose
To determine the added value of quality of life (QOL) as a prognostic factor for overall survival (OS) in patients with locally advanced non–small-cell lung cancer (NSCLC) treated on Radiation Therapy Oncology Group RTOG-9801.
Patients and Methods
Two hundred forty-three patients with stage II/IIIAB NSCLC received induction paclitaxel and carboplatin (PC) and then concurrent weekly PC and hyperfractionated radiation (to 69.6 Gy). Patients were randomly assigned to amifostine (AM) or no AM during chemoradiotherapy. The following pretreatment factors were analyzed as prognostic factors for OS: Karnofsky performance status, stage, sex, age, race, marital status, histology, tumor location, hemoglobin, tobacco use, treatment arm (AM v no AM) and QOL scores (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 [QLQ-C30] and Lung Cancer 13 [LC-13]). A multivariate (MVA) Cox proportional hazards model was performed using a backwards selection process.
Results
Of the 239 analyzable patients, 91% had a baseline global QOL score. Median follow-up time was 59 months for patients still alive and 17 months for all patients. Median baseline QLQ-C30 global QOL score was 66.7 on both treatment arms. Whether the global QOL score was treated as a dichotomized variable (based on the median score) or a continuous variable, all other variables fell out of the MVA for OS. Patients with a global QOL score less than 66.7 had an approximately 70% higher rate of death than patients with scores ≥ 66.7 (P = .004). A 10-point higher baseline global QOL score corresponded to a decrease in the hazard of death by approximately 10% (P = .004). The other independent QOL predictors for OS were the QLQ-C30 physical functioning (P = .011) and LC-13 dyspnea scores (P = .012).
Conclusion
In this analysis, baseline global QOL score replaced known prognostic factors as the sole predictor of long-term OS for patients with locally advanced NSCLC.
doi:10.1200/JCO.2009.23.7420
PMCID: PMC2793002  PMID: 19858383
14.  Safety, Pharmacokinetics, and Pharmacodynamics of the Insulin-Like Growth Factor Type 1 Receptor Inhibitor Figitumumab (CP-751,871) in Combination with Paclitaxel and Carboplatin 
Introduction
This phase 1 study was conducted to determine the recommended phase 2 dose of the selective insulin-like growth factor type 1 receptor (IGF-IR) inhibitor figitumumab (F, CP-751,871) given in combination with paclitaxel and carboplatin in patients with advanced solid tumors.
Methods
Patients received paclitaxel 200 mg/m2, carboplatin (area under the curve of 6), and F (0.05–20 mg/kg) q3 weeks for up to six cycles. Patients with objective response or stable disease were eligible to receive additional cycles of single agent F until disease progression. Safety, efficacy, pharmacokinetic, and pharmacodynamic endpoints were investigated.
Results
Forty-two patients, including 35 with stages IIIB and IV non-small cell lung cancer (NSCLC), were enrolled in eight dose escalation cohorts. A maximum tolerated dose was not identified. Severe adverse events possibly related to F included fatigue, diarrhea, hyperglycemia, gamma glutamyl transpeptidase elevation, and thrombocytopenia (one case each). F plasma exposure parameters increased with dose. Fifteen objective responses (RECIST) were reported, including two complete responses in NSCLC and ovarian carcinoma. Notably, levels of bioactive IGF-1 seemed to influence response to treatment with objective responses in patients with a high baseline-free IGF-1 to IGF binding protein-3 ratio seen only in the 10 and 20 mg/kg dosing cohorts.
Conclusions
F was well tolerated in combination with paclitaxel and carboplatin. Based on its favorable safety, pharmacokinetic, and pharmacodynamic properties, the maximal feasible dose of 20 mg/kg has been selected for further investigation.
doi:10.1097/JTO.0b013e3181ba2f1d
PMCID: PMC2941876  PMID: 19745765
IGF-1R; Figitumumab; CP-751,871; NSCLC
15.  Phase I Dose Escalation, Pharmacokinetic and Pharmacodynamic Study of Naptumomab Estafenatox Alone in Patients With Advanced Cancer and With Docetaxel in Patients With Advanced Non–Small-Cell Lung Cancer 
Journal of Clinical Oncology  2009;27(25):4116-4123.
Purpose
Two phase I studies were conducted of ABR-217620 alone or in combination with docetaxel. This is a recombinant fusion protein consisting of a mutated variant of the superantigen staphylococcal enterotoxin E (SEA/E-120) linked to fragment antigen binding moiety of a monoclonal antibody recognizing the tumor-associated antigen 5T4.
Patients and Methods
Patients with non–small-cell lung cancer (NSCLC), pancreatic cancer (PC), and renal cell cancer (RCC) received 5 daily boluses of ABR-217620 (3-month cycles) in escalating doses to determine the maximum-tolerated dose (MTD; ABR-217620 dose escalation monotherapy [MONO] study). Doses were selected based on individual patient anti–SEA/E-120 titers pretreatment. Patients with NSCLC received 4 daily, escalating doses of ABR-217620 followed by docetaxel in 21-day cycles (ABR-217620 dose escalation combination with docetaxel [COMBO] study).
Results
Thirty-nine patients were enrolled in the MONO study and 13 were enrolled in the COMBO study. The monotherapy MTD was 26 μg/kg (NSCLC and PC) and 15 μg/kg (RCC). Dose-limiting toxicities (DLTs) in the MONO study were fever, hypotension, acute liver toxicity, and vascular leak syndrome. In the COMBO study, the MTD was 22 μg/kg (neutropenic sepsis). Adverse events included grade 1 to 2 fever, hypotension, nausea, and chills. Treatment caused a systemic increase of inflammatory cytokines and selective expansion of SEA/E-120 reactive T-cells. Tumor biopsies demonstrated T-cell infiltration after therapy. Fourteen patients (36%) had stable disease (SD) on day 56 of the MONO study. Two patients (15%) in the COMBO study had partial responses, one in a patient with progressive disease on prior docetaxel, and five patients (38%) had SD on day 56.
Conclusion
ABR-217620 was well tolerated with evidence of immunological activity and antitumor activity.
doi:10.1200/JCO.2008.20.2515
PMCID: PMC2734423  PMID: 19636016
16.  Phase III Trial of Irinotecan/Cisplatin Compared With Etoposide/Cisplatin in Extensive-Stage Small-Cell Lung Cancer: Clinical and Pharmacogenomic Results From SWOG S0124 
Journal of Clinical Oncology  2009;27(15):2530-2535.
Purpose
Irinotecan plus cisplatin (IP) improved survival over etoposide plus cisplatin (EP) in Japanese patients with extensive-stage small-cell lung cancer (E-SCLC). To confirm those results and discern the potential role of population-related pharmacogenomics (PG) in outcomes, we conducted a large randomized trial of identical design to the Japanese trial in North American patients with E-SCLC.
Patients and Methods
Patients were randomly assigned to IP (irinotecan 60 mg/m2 on days 1, 8, and 15; cisplatin 60 mg/m2 day 1, every 4 weeks) or EP (etoposide 100 mg/m2 on days 1 through 3; cisplatin 80 mg/m2 day 1, every 3 weeks). Blood specimens for genomic DNA analysis were collected before random assignment in 169 patients.
Results
Of 671 patients, 651 were eligible (324 and 327 patients in the IP and EP arms, respectively). Response rates with IP and EP were 60% and 57%, respectively (P = .56). Median progression-free survival for IP and EP was 5.8 and 5.2 months, respectively (P = .07). Median overall survival for IP and EP was 9.9 and 9.1 months, respectively (P = .71). Severe diarrhea was more common with IP (19% v 3%); severe neutropenia and thrombocytopenia were higher with EP versus IP (68% v 33% and 15% v 4%, respectively). PG analysis showed that ABCB1 (C3435T)T/T (membrane transport) was associated with IP-related diarrhea; UGT1A1 (G-3156A)A/A (drug metabolism) was associated with IP-related neutropenia.
Conclusion
This large North American trial failed to confirm the previously reported survival benefit observed with IP in Japanese patients. Both regimens produced comparable efficacy, with less hematologic and greater gastrointestinal toxicity with IP. These results emphasize the potential importance of PG in interpreting trials of cancer therapy.
doi:10.1200/JCO.2008.20.1061
PMCID: PMC2684855  PMID: 19349543
17.  Issues Related to Implementing a Smoking Cessation Clinical Trial for Cancer Patients1 
Cancer causes & control : CCC  2008;20(1):97-104.
Given high rates of smoking among cancer patients, smoking cessation treatment is crucial, yet limited data exist to guide integration of such trials into the oncologic context. To determine the feasibility of conducting smoking cessation clinical trials with cancer patients, screening and baseline data from a large randomized placebo-controlled pharmacotherapy trial were analyzed. Descriptive statistics and regression analyses were used to compare enrollees to decliners, describe program enrollees, and assess correlates of confidence in quitting smoking. Of 14,514 screened patients, 263 (<2%) were eligible; 43 (16%) refused enrollment. Among eligible patients, 220 (84%) enrolled. Enrollment barriers included: smoking rate, medical history/contraindicated medication, lack of interest, and language. Compared to enrollees, decliners were more likely to have advanced cancer. The trial enrolled a sample of 67 (>30%) African Americans; participants had extensive smoking histories; many were highly nicotine dependent; and participants consumed about 7 alcoholic beverages/week on average. Head and neck and breast cancer were the most common tumors. Fifty-two (25%) reported depressive symptoms. A higher level of confidence to quit smoking was related to lower depression and lower tumor stage. Integrating a smoking cessation clinical trial into the oncologic setting is challenging, yet feasible. Recruitment strategies are needed for patients with advanced disease and specific cancers. Once enrolled, addressing participant’s depressive symptoms is critical for promoting cessation.
doi:10.1007/s10552-008-9222-x
PMCID: PMC2628415  PMID: 18758971
cancer patients; smoking cessation; confidence; feasibility data

Results 1-17 (17)