Ramesh Rengan

University of Washington Seattle, Seattle, Washington, United States

Are you Ramesh Rengan?

Claim your profile

Publications (85)390.74 Total impact

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Immune checkpoint inhibitors result in impressive clinical responses, but optimal results will require combination with each other and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here we report major tumour regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation, and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumours, resistance was common. Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T-cell exhaustion. Accordingly, optimal response in melanoma and other cancer types requires radiation, anti-CTLA4 and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T-regulatory cells (Treg cells), thereby increasing the CD8 T-cell to Treg (CD8/Treg) ratio. Radiation enhances the diversity of the T-cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while radiation shapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T-cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligoclonal T-cell expansion. Similarly to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to radiation plus anti-CTLA4, demonstrated persistent T-cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumours to escape anti-CTLA4-based therapy, and the combination of radiation, anti-CTLA4 and anti-PD-L1 promotes response and immunity through distinct mechanisms.
    Nature 03/2015; DOI:10.1038/nature14292 · 42.35 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A subset of patients with minimal extrathoracic disease may benefit from aggressive primary tumor treatment. We report comparative outcomes in oligometastatic non-small cell lung cancer (NSCLC) treated with and without definitive, conventionally fractionated thoracic radiation therapy. We identified consecutive patients with stage IV NSCLC who had an Eastern Cooperative Oncology Group performance status ≤2 and ≤4 total sites of metastatic disease and who had been prescribed ≥50 Gy of thoracic radiation. Twenty-nine patients with oligometastatic NSCLC were identified between January 2004 and August 2010. Median survival was 22 months from diagnosis. Four patients (14%) experienced pneumonitis greater than or equal to grade 3; 6 (21%) had esophagitis greater than or equal to grade 3. Local control was associated with improved survival (P = .02). In matched subset analysis, median survival was 9 months (P < .01) in patients who received chemotherapy alone. Median time to local failure was 18 versus 6 months (P = .01). On multivariable analysis, radiation (P < .01; odds ratio [OR], 0.33), fewer metastases (P < .01; OR, 2.14), and female sex (P < .01; OR, 0.41) were associated with improved survival. Definitive dose radiation therapy may improve survival in a select subset of patients with minimal extrathoracic disease in whom local progression is of primary concern. Prospective trials are needed to further evaluate the role of local control in oligometastatic NSCLC. Copyright © 2014 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
  • [Show abstract] [Hide abstract]
    ABSTRACT: The clinical benefits and risks of dose escalation (DE) for stage III non-small-cell lung cancer (NSCLC) remain uncertain despite the results from Radiation Therapy Oncology Group (RTOG) protocol 0617. There is significant heterogeneity of practice, with many clinicians prescribing intermediate dose levels between the 0617 study arms of 60 and 74 Gy. This study investigated whether this strategy is associated with any survival benefits/risks by analyzing a large multi-institutional database. An individual patient database of stage III NSCLC patients treated with radical intent concurrent chemoradiation therapy was created (13 institutions, n=1274 patients). Patients were divided into 2 groups based on tumor Biological Effective Dose at 10 Gy (BED 10): those receiving standard dose (SD; n=552), consisting of 72Gy ≤ BED 10 ≤ 76.8 Gy (eg 60-64 Gy/30-32 fractions [fr]), and those receiving intermediate dose (ID; n=497), consisting of 76.8Gy < BED 10 < 100.8 Gy (eg >64 Gy/32 fr and <74 Gy/37 fr), with lower-dose patients (n=225) excluded from consideration. Patients were then matched using propensity scores, leading to 2 matched groups of 196 patients. Outcomes were compared using various statistics including interquartile range (IQR), Kaplan-Meier curves, and adjusted Cox regression analysis. Matched groups were found to be balanced except for N stage (more N3 disease in SD), median treatment year (SD in 2003; ID in 2007), platinum and taxane chemotherapy (SD in 28%; ID in 39%), and median follow-up (SD were 89 months; ID were 40 months). Median dose fractionation was 60 Gy/30 fr in SD (BED 10 IQR: 72.0-75.5 Gy) and 66 Gy/33 fr (BED 10 IQR: 78.6-79.2 Gy) in ID. Survival curves for SD and ID matched cohorts were statistically similar (P=.27); however, a nonstatistically significant trend toward better survival for ID was observed after 15 months (median survival SD: 19.3 months; ID: 21.0 months). There was an increase in grades III to V lung toxicity associated with ID (13.0% vs 4.9%, respectively). No significant overall survival benefits were found with intermediate DE; however, more grade III or greater lung toxicity was observed. The separation of survival curves after 15 months of follow-up suggests that a small overall survival improvement associated with intermediate DE cannot be excluded. Copyright © 2015 Elsevier Inc. All rights reserved.
    International journal of radiation oncology, biology, physics 01/2015; 91(1):133-9. DOI:10.1016/j.ijrobp.2014.09.033 · 4.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Photon involved-field (IF) radiation therapy (IFRT), the standard for locally advanced (LA) non-small cell lung cancer (NSCLC), results in favorable outcomes without increased isolated nodal failures, perhaps from scattered dose to elective nodal stations. Because of the high conformality of intensity-modulated proton therapy (IMPT), proton IFRT could increase nodal failures. We investigated the feasibility of IMPT for elective nodal irradiation (ENI) in LA-NSCLC. IMPT IFRT plans were generated to the same total dose of 66.6-72 Gy received by 20 LA-NSCLC patients treated with photon IFRT. IMPT ENI plans were generated to 46 cobalt Gray equivalent (CGE) to elective nodal planning treatment volumes (PTV) plus 24 CGE to IF-PTVs. Proton IFRT and ENI improved the IF-PTV percentage of volume receiving 95% of the prescribed dose (D95) by 4% (P < .01) compared with photon IFRT. All evaluated dosimetric parameters improved significantly with both proton plans. The lung percentage of volume receiving 20 Gy/CGE (V20) and mean lung dose decreased 18% (P < .01) and 36% (P < .01), respectively, with proton IFRT, and 11% (P = .03) and 26% (P < .01) with ENI. The mean esophagus dose decreased 16% with IFRT and 12% with ENI; heart V25 decreased 63% with both (all P < .01). This study demonstrates the feasibility of IMPT for LA-NSCLC ENI. Potential decreased toxicity indicates that IMPT could allow ENI while maintaining a favorable therapeutic ratio compared with photon IFRT. Copyright © 2015 Elsevier Inc. All rights reserved.
    Clinical Lung Cancer 12/2014; DOI:10.1016/j.cllc.2014.12.001 · 3.22 Impact Factor
  • Laura Kollar, Ramesh Rengan
    [Show abstract] [Hide abstract]
    ABSTRACT: Extracranial stereotactic body radiotherapy (SBRT) has been developed and refined over the last 25 years as a means to deliver precisely ablative doses of hypofractionated radiotherapy to small targets located outside of the cranial vault. SBRT has armed the radiation oncologist with a therapeutic approach that allows for intensification of both dose delivered and fractionation regimen employed. As a consequence, tumor control rates have improved to rates that have previously only been associated with surgical resection. Several prospective phase I and II studies have evaluated the use of SBRT for non-small-cell lung cancer, liver tumors, and spinal metastases. This article will give an overview of SBRT and evidence for its use in the most common sites of disease for which it is employed today.
    Seminars in Oncology 12/2014; 41(6). DOI:10.1053/j.seminoncol.2014.09.022 · 3.94 Impact Factor
  • International journal of radiation oncology, biology, physics 11/2014; 90(5). DOI:10.1016/j.ijrobp.2014.08.157 · 4.18 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Intensity modulated arc therapy (IMAT) has been widely adopted for Stereotactic Body Radiotherapy (SBRT) for lung cancer. While treatment dose is optimized and calculated on a static Computed Tomography (CT) image, the effect of the interplay between the target and linac multi-leaf collimator (MLC) motion is not well described and may result in deviations between delivered and planned dose. In this study, we investigated the dosimetric consequences of the inter-play effect on target and organs at risk (OAR) by simulating dynamic dose delivery using dynamic CT datasets.Methods Fifteen stage I non-small cell lung cancer (NSCLC) patients with greater than 10 mm tumor motion treated with SBRT in 4 fractions to a dose of 50 Gy were retrospectively analyzed for this study. Each IMAT plan was initially optimized using two arcs. Simulated dynamic delivery was performed by associating the MLC leaf position, gantry angle and delivered beam monitor units (MUs) for each control point with different respiratory phases of the 4D-CT using machine delivery log files containing time stamps of the control points. Dose maps associated with each phase of the 4D-CT dose were calculated in the treatment planning system and accumulated using deformable image registration onto the exhale phase of the 4D-CT. The original IMAT plans were recalculated on the exhale phase of the CT for comparison with the dynamic simulation.ResultsThe dose coverage of the PTV showed negligible variation between the static and dynamic simulation. There was less than 1.5% difference in PTV V95% and V90%. The average inter-fraction and cumulative dosimetric effects among all the patients were less than 0.5% for PTV V95% and V90% coverage and 0.8 Gy for the OARs. However, in patients where target is close to the organs, large variations were observed on great vessels and bronchus for as much as 4.9 Gy and 7.8 Gy.Conclusions Limited variation in target dose coverage and OAR constraints were seen for each SBRT fraction as well as over all four fractions. Large dose variations were observed on critical organs in patients where these organs were closer to the target.
    Radiation Oncology 11/2014; 9(1):225. DOI:10.1186/s13014-014-0225-3 · 2.36 Impact Factor
  • Charles B Simone, Ramesh Rengan
    [Show abstract] [Hide abstract]
    ABSTRACT: Lung cancer is the leading cause of death from cancer in the United States and worldwide. Radiation therapy plays a prominent role in the treatment of patients with nonmetastatic disease. Radiation therapy alone can be curative for patients with stage I non-small cell lung cancer (NSCLC). Radiation therapy is also used as part of multimodality therapy to treat patients with locally advanced NSCLC. Current treatment delivery is often limited by radiation doses received by normal structures and treatment-related toxicities. Proton therapy for lung cancer can reduce the dose received by normal tissues, including the lungs, esophagus, and spinal cord, and may allow for reduced treatment toxicities. Proton therapy may also more safely allow for reirradiation and for radiation therapy to be combined with chemotherapy and surgery. This review discusses the rationales for and current uses of proton therapy to treat lung cancer, and it highlights key studies of proton therapy to treat early-stage and locally advanced NSCLC.
    The Cancer Journal 11/2014; 20(6):427-32. DOI:10.1097/PPO.0000000000000080 · 3.61 Impact Factor
  • International Journal of Radiation OncologyBiologyPhysics 09/2014; 90(1, Supplement):S639-S640. DOI:10.1016/j.ijrobp.2014.05.1896 · 4.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Recent advances allow safe and effective delivery of ablative doses of radiation with stereotactic precision to tumours, resulting in very high levels of tumour control. Parallel advances in the understanding of tumour biology enable delivery of systemic drugs that selectively antagonise biological pathways in the tumour and surrounding microenvironment. Data is emerging that these treatments have synergistic effects that might further increase therapeutic efficacy, and they are therefore being increasingly used in combination, primarily in metastatic or recurrent disease. In this Review we summarise the biological rationale and clinical data for both sterotactic ablative radiotherapy (SABR) and targeted therapies, and the emerging experience with combination of these treatments. We describe potential pathways of cooperation in both tumour and normal tissue between SABR and targeted drugs, and, because fatal toxicities have been reported, we outline clinical precautions.
    The Lancet Oncology 09/2014; 15(10):e426-e434. DOI:10.1016/S1470-2045(14)70026-9 · 24.73 Impact Factor
  • International Journal of Radiation OncologyBiologyPhysics 09/2014; 90(1, Supplement):S660-S661. DOI:10.1016/j.ijrobp.2014.05.1949 · 4.18 Impact Factor
  • International Journal of Radiation OncologyBiologyPhysics 09/2014; 90(1, Supplement):S628-S629. DOI:10.1016/j.ijrobp.2014.05.1869 · 4.18 Impact Factor
  • International Journal of Radiation OncologyBiologyPhysics 09/2014; 90(1, Supplement):S659. DOI:10.1016/j.ijrobp.2014.05.1946 · 4.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In this era of globalization and rapid advances in radiation oncology worldwide, the American Society for Radiation Oncology (ASTRO) is committed to help decrease profound regional disparities through the work of the International Education Subcommittee (IES). The IES has expanded its base, reach, and activities to foster educational advances through a variety of educational methods with broad scope, in addition to committing to the advancement of radiation oncology care for cancer patients around the world, through close collaboration with our sister radiation oncology societies and other educational, governmental, and organizational groups.
    International journal of radiation oncology, biology, physics 07/2014; 89(3):481-484. DOI:10.1016/j.ijrobp.2013.12.052 · 4.18 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In previously performed animal studies and Phase I-II human trials, Bowman-Birk inhibitor concentrate (BBIC) appeared to be a promising cancer chemopreventive agent. The present study describes the results of two phase I randomized double-blind placebo-controlled trials performed in male subjects to assess the safety and toxicity of the original and new formulations of BBIC administered in a single dose as a suspension in orange juice. The dose of BBIC varied from 800-2,000 chymotrypsin inhibitor (CI) units. The BBI concentration in the serum samples collected from the subjects was analyzed by a dot-blot analysis procedure using the 5G2 monoclonal antibody, which is specific for reduced BBI. A total of 41 subjects were enrolled, 20 in the initial BBIC study and 21 in the second BBIC study. In these human trials, no clinically relevant changes in hematological or biochemical parameters were observed. Overall, BBIC was found to be well-tolerated. For these BBIC single-dose phase I trials, there was no dose-limiting toxicity for BBIC, even at the highest dose evaluated, and there were no apparent differences between the clinical trial results for the two formulations of BBIC. The bioavailability of BBI in the second clinical trial, which used the new BBIC formulation, was approximately 40 to 43% of the BBI bioavailability reached in the first clinical trial, which used the original BBIC formulation. The observed bioavailability difference was attributed to the different BBIC formulations used in these two clinical trials. These trials demonstrated that BBIC is safe when administered in a single dose of up to 2,000 CI units. Therefore, the results from the two trials indicate that a multi-dose trial of BBIC may be safely performed with doses of up to 2,000 CI units per day.
    Oncology letters 04/2014; 7(4):1151-1158. DOI:10.3892/ol.2014.1855 · 0.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Whole brain radiation therapy (WBRT) may cause cognitive and neuropsychological impairment and hence objective assessment of adverse effects of radiation may be valuable to plan therapy. The purpose of our study was to determine the potential of echo planar spectroscopic imaging (EPSI) and diffusion tensor imaging (DTI) in detecting subacute radiation induced injury to the normal brain. Four patients with brain metastases and three patients with lung cancer underwent cranial irradiation. These patients were subjected to 3D-EPSI and DTI at two time points (pre-radiation, and 1 month post-irradiation). Parametric maps of N-acetyl aspartate (NAA), creatine (Cr), choline (Cho), mean diffusivity (MD), and fractional anisotropy (FA) were generated and co-registered to post-contrast T1-weighted images. Normal appearing gray-matter and white-matter regions were compared between the two time points to assess sub-acute effects of radiation using independent sample t-tests. Significantly increased MD (P = .02), Cho/Cr (P = .02) and a trend towards a decrease in NAA/Cr (P = .06) was observed from the hippocampus. Significant decrease in FA (P = .02) from the centrum-semiovale and a significant increase in MD (P = .04) and Cho/Cr (P = .02) from genu of corpus-callosum was also observed. Our preliminary findings suggest that 3D-EPSI and DTI may provide quantitative measures of radiation induced injury to the normal brain.
    Journal of neuroimaging: official journal of the American Society of Neuroimaging 11/2013; 25(1). DOI:10.1111/jon.12070 · 1.82 Impact Factor
  • 11/2013; 1(Suppl 1):P118. DOI:10.1186/2051-1426-1-S1-P118
  • [Show abstract] [Hide abstract]
    ABSTRACT: This study examined rates of tumor progression in treatment-naive patients with non-small-cell lung cancer (NSCLC) as determined by repeat treatment-planning fluorine-18 ((18)F) fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT). This study assessed patients who underwent PET/CT simulation for NSCLC stage II/III, radiation-naive, nonmetastatic NSCLC. It compared planning PET/CT with previous PET/CT images. Patients were analyzed for change in stage, treatment intent, or both. Progression was defined as a change in TNM status leading to upstaging, and standardized uptake value (SUV) velocity was defined as [(SUVscan2 - SUVscan1)/interscan interval in days]. Of 149 consecutive patients examined between April 2009 and April 2011, 47 had prior PET/CT scans and were included. The median age was 68 years. New nodal disease or metastatic disease was identified in 24 (51%) of 47 patients. Fourteen (30%) had evidence of extrathoracic metastatic disease; the remaining 10 (21%) had new nodal disease that required substantial alteration of treatment fields. At a scan interval of 20 days, the rate of upstaging was 17%. SUV velocity was analyzed in the subset of patients who had their studies on the identical PET/CT scanner (n = 14). Nonupstaged patients had a mean SUV velocity of 0.074 units per day, compared with 0.11 units per day in patients that were upstaged by their second PET/CT scan (P = .020). Radiation treatment planning with hybrid PET/CT scans repeated within 120 days of an initial staging PET/CT scan identified significant upstaging in more than half of patients. For a subset of patients who underwent both scans on the same instrument, SUV velocity predicts upstaging, and the difference between those upstaged and those not was statistically significant.
    Clinical Lung Cancer 10/2013; 15(1). DOI:10.1016/j.cllc.2013.08.004 · 3.22 Impact Factor
  • International Journal of Radiation OncologyBiologyPhysics 10/2013; 87(2):S522-S523. DOI:10.1016/j.ijrobp.2013.06.1382 · 4.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Precise patient positioning is critical due to the large fractional doses and small treatment margins employed for thoracic stereotactic body radiation therapy (SBRT). The goals of this study were to evaluate the following: (1) the accuracy of kilovoltage x-ray (kV x-ray) matching to bony anatomy for pretreatment positioning; (2) the magnitude of intrafraction tumor motion; and (3) whether treatment or patient characteristics correlate with intrafraction motion. Eighty-seven patients with lung cancer were treated with SBRT. Patients were positioned with orthogonal kV x-rays matched to bony anatomy followed by cone-beam computed tomography (CBCT), with matching of the CBCT-visualized tumor to the internal gross target volume obtained from a 4-dimensional CT simulation data set. Patients underwent a posttreatment CBCT to assess the magnitude of intrafraction motion. The mean CBCT-based shifts after initial patient positioning using kV x-rays were 2.2 mm in the vertical axis, 1.8 mm in the longitudinal axis, and 1.6 mm in the lateral axis (n = 335). The percentage of shifts greater than 3 mm and 5 mm represented 39% and 17%, respectively, of all fractions delivered. The mean CBCT-based shifts after treatment were 1.6 mm vertically, 1.5 mm longitudinally, and 1.1 mm laterally (n = 343). Twenty-seven percent and 10% of shifts were greater than 3 mm and 5 mm, respectively. Univariate and multivariable analysis demonstrated a significant association between intrafraction motion with weight and pulmonary function. Kilovoltage x-ray matching to bony anatomy is inadequate for accurate positioning when a conventional 3-5 mm margin is employed prior to lung SBRT. Given the treatment techniques used in this study, CBCT image guidance with a 5-mm planning target volume margin is recommended. Further work is required to find determinants of interfraction and intrafraction motion that may help guide the individualized application of planning target volume margins.
    10/2013; 3(4):307-15. DOI:10.1016/j.prro.2012.10.005

Publication Stats

497 Citations
390.74 Total Impact Points

Institutions

  • 2013–2015
    • University of Washington Seattle
      • Department of Radiation Oncology
      Seattle, Washington, United States
    • Montefiore Medical Center
      • Department of Radiology
      New York, New York, United States
    • Seattle Cancer Care Alliance
      Seattle, Washington, United States
  • 2009–2014
    • University of Pennsylvania
      • Department of Radiation Oncology
      Philadelphia, Pennsylvania, United States
  • 2010–2013
    • William Penn University
      Filadelfia, Pennsylvania, United States
  • 2008–2013
    • Hospital of the University of Pennsylvania
      • Department of Radiation Oncology
      Philadelphia, Pennsylvania, United States
  • 2004–2008
    • Memorial Sloan-Kettering Cancer Center
      • Department of Radiation Oncology
      New York City, NY, United States