Browsing by Author "Lawrence, Theodore S."

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    Effect of Midtreatment PET/CT-Adapted Radiation Therapy With Concurrent Chemotherapy in Patients With Locally Advanced Non–Small-Cell Lung Cancer
    (American Medical Association, 2017-10-01) Kong, Feng-Ming; Ten Haken, Randall K.; Schipper, Matthew; Frey, Kirk A.; Hayman, James; Gross, Milton; Ramnath, Nithya; Hassan, Khaled A.; Matuszak, Martha; Ritter, Timothy; Bi, Nan; Wang, Weili; Orringer, Mark; Cease, Kemp B.; Lawrence, Theodore S.; Kalemkerian, Gregory P.; Radiation Oncology, School of Medicine
    IMPORTANCE Our previous studies demonstrated that tumors significantly decrease in size and metabolic activity after delivery of 45 Gy of fractionated radiatiotherapy (RT), and that metabolic shrinkage is greater than anatomic shrinkage. This study aimed to determine whether 18F-fludeoxyglucose–positron emission tomography/computed tomography (FDG-PET/CT) acquired during the course of treatment provides an opportunity to deliver higher-dose radiation to the more aggressive areas of the tumor to improve local tumor control without increasing RT-induced lung toxicity (RILT), and possibly improve survival. OBJECTIVE To determine whether adaptive RT can target high-dose radiation to the FDG-avid tumor on midtreatment FDG-PET to improve local tumor control of locally advanced non–small-cell lung cancer (NSCLC). DESIGN, SETTING, AND PARTICIPANTS A phase 2 clinical trial conducted at 2 academic medical centers with 42 patients who had inoperable or unresectable stage II to stage III NSCLC enrolled from November 2008, to May 2012. Patients with poor performance, more than 10% weight loss, poor lung function, and/or oxygen dependence were included, providing that the patients could tolerate the procedures of PET scanning and RT. INTERVENTION Conformal RT was individualized to a fixed risk of RILT (grade >2) and adaptively escalated to the residual tumor defined on midtreatment FDG-PET up to a total dose of 86 Gy in 30 daily fractions. Medically fit patients received concurrent weekly carboplatin plus paclitaxel followed by 3 cycles of consolidation. MAIN OUTCOMES AND MEASURES The primary end point was local tumor control. The trial was designed to achieve a 20% improvement in 2-year control from 34% of our prior clinical trial experience with 63 to 69 Gy in a similar patient population. RESULTS The trial reached its accrual goal of 42 patients: median age, 63 years (range, 45–83 years); male, 28 (67%); smoker or former smoker, 39 (93%); stage III, 38 (90%). Median tumor dose delivered was 83 Gy (range, 63–86 Gy) in 30 daily fractions. Median follow-up for surviving patients was 47 months. The 2-year rates of infield and overall local regional tumor controls (ie, including isolated nodal failure) were 82% (95% CI, 62%–92%) and 62% (95% CI, 43%–77%), respectively. Median overall survival was 25 months (95% CI, 12–32 months). The 2-year and 5-year overall survival rates were 52% (95% CI, 36%–66%) and 30% (95% CI, 16%–45%), respectively. CONCLUSIONS AND RELEVANCE Adapting RT-escalated radiation dose to the FDG-avid tumor detected by midtreatment PET provided a favorable local-regional tumor control. The RTOG 1106 trial is an ongoing clinical trial to validate this finding in a randomized fashion. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01190527
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    Ensuring sample quality for blood biomarker studies in clinical trials: a multicenter international study for plasma and serum sample preparation
    (2017-12) Kong, Feng-Ming (Spring); Zhao, Lujun; Wang, Luhua; Chen, Yuhchyau; Hu, Jie; Fu, Xiaolong; Bai, Chunxue; Wang, Li; Lawrence, Theodore S.; Anscher, Mitchell S.; Dicker, Adam; Okunieff, Paul; Radiation Oncology, School of Medicine
    Background Sample quality is critical for biomarker detection in oncology, and platelet degradation and contamination in plasma have a remarkable impact on the ability to accurately quantify many blood-based biomarkers. Platelet factor 4 (PF4) can be used as an indicator to monitor sample quality. This multicenter study aimed to determine the impact of critical components of the blood sample handling process on platelet degradation/contamination and to establish an optimal method for collecting platelet-poor plasma samples. Methods At each of six participating centers, blood samples were drawn from 12–13 healthy volunteers. Serum and plasma samples were prepared from whole blood samples using nine different methods that have been commonly used in ongoing multicenter trials. PF4 levels in the prepared samples were measured by enzyme-linked immunosorbent assay (ELISA). Paired t-tests were used for statistical analysis. Results Blood samples were collected from 74 subjects enrolled in six centers. PF4 levels were significantly higher in serum samples than in plasma samples (P<0.001), in plasma samples from blood that sat at room temperature for 5 minutes (P=0.021), in plasma samples prepared at an insufficient centrifugal force (P<0.001), and in plasma samples prepared from blood that sat for longer than 4 hours on ice (P=0.001). For each method, the PF4 levels did not differ significantly among the centers or between Chinese and American subjects. The methods that resulted in normal levels of PF4 involved keeping blood samples on ice for 30 minutes to <4 hours and centrifugation at 2,500–3,000 ×g for 30 min. Conclusions This multicenter study evaluated multiple blood sample handling conditions for minimizing platelet degradation during plasma serum preparation and determined an optimal method for preparing platelet-poor plasma. The findings of this study can be applied in future blood biomarker studies.
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    Greater Reduction in Mid-treatment FDG-PET Volume May Be Associated with Worse Survival in Non-Small Cell Lung Cancer
    (Elsevier, 2019-03) Kong, Feng-Ming (Spring); Li, Ling; Wang, Weili; Campbell, Jeff; Waller, Jennifer L.; Piert, Morand; Gross, Milton; Cheng, Monica; Owen, Dawn; Stenmark, Matthew; Huang, Colin; Frey, Kirk A.; Ten Haken, Randall K.; Lawrence, Theodore S.; Radiation Oncology, School of Medicine
    Background and purpose: This study tested the hypotheses that 1) changes in mid-treatment fluorodeoxyglucose (FDG)-positron emission tomography (PET) parameters are predictive of overall survival (OS) and 2) mid-treatment FDG-PET-adapted treatment has the potential to improve survival in patients with non-small cell lung cancer (NSCLC). Material and methods: Patients with stage I-III NSCLC requiring daily fractionated radiation were eligible. FDG-PET-CT scans were obtained prior to and mid-treatment with radiotherapy at 40-50 Gy. The normalized maximum standardized uptake value (NSUVmax), normalized mean SUV (NSUVmean), PET-metabolic tumor volume (MTV), total lesion glycolysis (TLG), and computed tomography-based gross tumor volume (CT-GTV) were consistently measured for all patients. The primary study endpoint was OS. Results: The study is comprised of 102 patients who received 3-dimensional conformal radiotherapy, among whom 30 patients who received mid-treatment PET-adapted dose escalation radiotherapy. All PET-CT parameters decreased significantly (P < 0.001) mid-treatment, with greater reductions in FDG-volumetric parameters compared to FDG-activity factors. Mid-treatment changes in MTV (P = 0.053) and TLG (P = 0.021) were associated with OS, while changes in NSUVmax, NSUVmean, and CT-GTV were not (all Ps>0.1). Patients receiving conventional radiation (60-70 Gy) with MTV reductions greater than the mean had a median survival of 14 months, compared to those with MTV reductions less than the mean who had a median survival of 22 months. By contrast, patients receiving mid-treatment PET-adapted radiation with MTV reductions greater than the mean had a median survival of 33 months, compared to those with MTV reductions less than the mean who had a median survival of 19 months. Overall, PET-adapted treatment resulted in a 19% better 5-year survival than conventional radiation. Conclusion: Changes in mid-treatment PET-volumetric parameters were significantly associated with survival in NSCLC. A greater reduction in the mid-treatment MTV was associated with worse survival in patients treated with standard radiation, but with better survival in patients who received mid-treatment PET-adapted treatment.
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    In Support of a Patient-Driven Initiative and Petition to Lower the High Price of Cancer Drugs
    (Elsevier, 2015-08) Tefferi, Ayalew; Kantarjian, Hagop; Rajkumar, S. Vincent; Baker, Lawrence H.; Abkowitz, Jan L.; Adamson, John W.; Advani, Ranjana Hira; Allison, James; Antman, Karen H.; Bast Jr., Robert C.; Bennett, John M.; Benz Jr., Edward J.; Berliner, Nancy; Bertino, Joseph; Bhatia, Ravi; Bhatia, Smita; Bhojwani, Deepa; Blanke, Charles D.; Bloomfield, Clara D.; Bosserman, Linda; Broxmeyer, Hal E.; Byrd, John C.; Cabanillas, Fernando; Canellos, George Peter; Chabner, Bruce A.; Chanan-Khan, Asher; Cheson, Bruce; Clarkson, Bayard; Cohn, Susan L.; Colon-Otero, Gerardo; Cortese, Jorge; Coutre, Steven; Cristofanilli, Massimo; Curran Jr., Walter J.; Daley, George Q.; DeAngelo, Daniel J.; Deeg, H. Joachim; Einhorn, Lawrence H.; Erba, Harry P.; Esteva, Francisco J.; Estey, Elihu; Fidler, Isaiah J.; Foran, James; Forman, Stephen; Freireich, Emil; Fuchs, Charles; George, James N.; Gertz, Morie A.; Giralt, Sergio; Golomb, Harvey; Greenberg, Peter; Gutterman, Jordan; Handin, Robert I.; Hellman, Samuel; Hoff, Paulo Marcelo; Hoffman, Ronald; Hong, Waun Ki; Horowitz, Mary; Hortobagyi, Gabriel N.; Hudis, Clifford; Issa, Jean Pierre; Johnson, Bruce Evan; Kantoff, Philip W.; Kaushansky, Kenneth; Khayat, David; Khuri, Fadlo R.; Kipps, Thomas J.; Kripke, Margaret; Kyle, Robert A.; Larson, Richard A.; Lawrence, Theodore S.; Levine, Ross; Link, Michael P.; Lippman, Scott M.; Lonial, Sagar; Lyman, Gary H.; Markman, Maurie; Mendelsohn, John; Meropol, Neal J.; Messinger, Yoav; Mulvey, Therese M.; O’Brien, Susan; Perez-Soler, Roman; Pollock, Raphael; Prchal, Josef; Press, Oliver; Radich, Jerald; Rai, Kanti; Rosenberg, Saul A.; Rowe, Jacob M.; Rugo, Hope; Runowicz, Carolyn D.; Sandmaier, Brenda M.; Saven, Alan; Schafer, Andrew I.; Schiffer, Charles; Sekeres, Mikkael A.; Silver, Richard T.; Siu, Lillian L.; Steensma, David P.; Stewart, F. Marc; Stock, Wendy; Stone, Richard; Storb, Rainer; Strong, Louise C.; Tallman, Martin S.; Thompson, Michael; Ueno, Naoto T.; Van Etten, Richard A.; Vose, Julie M.; Wiernik, Peter H.; Winer, Eric P.; Younes, Anas; Zelenetz, Andrew D.; Department of Medicine, IU School of Medicine
    Comment in Lowering the High Cost of Cancer Drugs--III. [Mayo Clin Proc. 2016] Lowering the High Cost of Cancer Drugs--I. [Mayo Clin Proc. 2016] Lowering the High Cost of Cancer Drugs--IV. [Mayo Clin Proc. 2016] In Reply--Lowering the High Cost of Cancer Drugs. [Mayo Clin Proc. 2016] US oncologists call for government regulation to curb drug price rises. [BMJ. 2015]
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    Prediction of Radiation Esophagitis in Non-Small Cell Lung Cancer Using Clinical Factors, Dosimetric Parameters, and Pretreatment Cytokine Levels
    (Elsevier, 2018-02) Hawkins, Peter G.; Boonstra, Philip S.; Hobson, Stephen T.; Hayman, James A.; Ten Haken, Randall K.; Matuszak, Martha M.; Stanton, Paul; Kalemkerian, Gregory P.; Lawrence, Theodore S.; Schipper, Matthew J.; Kong, Feng-Ming (Spring); Jolly, Shruti; Radiation Oncology, School of Medicine
    Radiation esophagitis (RE) is a common adverse event associated with radiotherapy for non-small cell lung cancer (NSCLC). While plasma cytokine levels have been correlated with other forms of radiation-induced toxicity, their association with RE has been less well studied. We analyzed data from 126 patients treated on 4 prospective clinical trials. Logistic regression models based on combinations of dosimetric factors [maximum dose to 2 cubic cm (D2cc) and generalized equivalent uniform dose (gEUD)], clinical variables, and pretreatment plasma levels of 30 cytokines were developed. Cross-validated estimates of area under the receiver operating characteristic curve (AUC) and log likelihood were used to assess prediction accuracy. Dose-only models predicted grade 3 RE with AUC values of 0.750 (D2cc) and 0.727 (gEUD). Combining clinical factors with D2cc increased the AUC to 0.779. Incorporating pretreatment cytokine measurements, modeled as direct associations with RE and as potential interactions with the dose-esophagitis association, produced AUC values of 0.758 and 0.773, respectively. D2cc and gEUD correlated with grade 3 RE with odds ratios (ORs) of 1.094/Gy and 1.096/Gy, respectively. Female gender was associated with a higher risk of RE, with ORs of 1.09 and 1.112 in the D2cc and gEUD models, respectively. Older age was associated with decreased risk of RE, with ORs of 0.992/year and 0.991/year in the D2cc and gEUD models, respectively. Combining clinical with dosimetric factors but not pretreatment cytokine levels yielded improved prediction of grade 3 RE compared to prediction by dose alone. Such multifactorial modeling may prove useful in directing radiation treatment planning.
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    Radiation-induced lung toxicity in non-small-cell lung cancer: Understanding the interactions of clinical factors and cytokines with the dose-toxicity relationship
    (Elsevier, 2017-10) Hawkins, Peter G.; Boonstra, Philip S.; Hobson, Stephen; Hearn, Jason W.D.; Hayman, James A.; Haken, Randall K. Ten; Matuszak, Martha M.; Stanton, Paul; Kalemkerian, Gregory P.; Ramnath, Nithya; Lawrence, Theodore S.; Schipper, Matthew J.; Kong, Feng-Ming (Spring); Jolly, Shruti; Radiation Oncology, School of Medicine
    BACKGROUND AND PURPOSE: Current methods to estimate risk of radiation-induced lung toxicity (RILT) rely on dosimetric parameters. We aimed to improve prognostication by incorporating clinical and cytokine data, and to investigate how these factors may interact with the effect of mean lung dose (MLD) on RILT. MATERIALS AND METHODS: Data from 125 patients treated from 2004 to 2013 with definitive radiotherapy for stages I-III NSCLC on four prospective clinical trials were analyzed. Plasma levels of 30 cytokines were measured pretreatment, and at 2 and 4weeks midtreatment. Penalized logistic regression models based on combinations of MLD, clinical factors, and cytokine levels were developed. Cross-validated estimates of log-likelihood and area under the receiver operating characteristic curve (AUC) were used to assess accuracy. RESULTS: In prognosticating grade 3 or greater RILT by MLD alone, cross-validated log-likelihood and AUC were -28.2 and 0.637, respectively. Incorporating clinical features and baseline cytokine levels increased log-likelihood to -27.6 and AUC to 0.669. Midtreatment cytokine data did not further increase log-likelihood or AUC. Of the 30 cytokines measured, higher levels of 13 decreased the effect of MLD on RILT, corresponding to a lower odds ratio for RILT per Gy MLD, while higher levels of 4 increased the association. CONCLUSIONS: Although the added prognostic benefit from cytokine data in our model was modest, understanding how clinical and biologic factors interact with the MLD-RILT relationship represents a novel framework for understanding and investigating the multiple factors contributing to radiation-induced toxicity.