Publications by authors named "Ritsuko Komaki"

413 Publications

Short Communication: Interim toxicity analysis for patients with limited stage small cell lung cancer (LSCLC) treated on CALGB 30610 (Alliance) / RTOG 0538.

Lung Cancer 2021 06 18;156:68-71. Epub 2021 Apr 18.

University of Chicago Comprehensive Cancer Center, Chicago, IL, United States.

Introduction: The CALGB 30610/RTOG 0538 randomized trial was designed to test whether high-dose thoracic radiotherapy (TRT) would improve survival compared with 45 Gy twice-daily (BID) TRT in limited stage small cell lung cancer (LSCLC). Two piloted experimental TRT regimens were of interest to study, 70 Gy daily (QD) and 61.2 Gy concomitant boost (CB). Driven by concerns about adequate patient accrual, a study design was employed that eliminated one experimental TRT arm based on early interim toxicity and tolerability, with the study then continuing as a traditional 2-arm phase III study.

Methods: Patients with LSCLC were assigned to receive four cycles of cisplatin and etoposide chemotherapy with one of 3 TRT regimens starting with either the first or second cycle of chemotherapy. The interim endpoint was the cumulative highest toxicity calculated from a scoring system based on treatment-related grade 3 and higher toxicity and the ability to complete therapy in the experimental arms.

Results: The final interim analysis was performed after 70 patients accrued to each experimental cohort, and a difference in treatment related toxicity scoring was not found (p = 0.739). Severe esophageal toxicity was comparable in both cohorts. Pulmonary toxicity was low overall, though 4 patients (5.7 %) on the 61.2 Gy arm developed grade 4 dyspnea, which was not observed in the 70 Gy arm. A protocol mandated decision was made to discontinue the 61.2 Gy arm following review of toxicity with the Data and Safety Monitoring Board.

Conclusion: A randomized trial design using a planned early interim toxicity analysis to discriminate between experimental treatment arms is feasible in a phase III setting. Refinement of the design could increase the likelihood of detecting clinically meaningful differences in toxicity in future studies.
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http://dx.doi.org/10.1016/j.lungcan.2021.04.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418826PMC
June 2021

Cancer associated macrophage-like cells and prognosis of esophageal cancer after chemoradiation therapy.

J Transl Med 2020 11 4;18(1):413. Epub 2020 Nov 4.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.

Background: Cancer Associated Macrophage-Like cells (CAMLs) are polynucleated circulating stromal cells found in the bloodstream of numerous solid-tumor malignancies. Variations within CAML size have been associated with poorer progression free survival (PFS) and overall survival (OS) in a variety of cancers; however, no study has evaluated their clinical significance in esophageal cancer (EC).

Methods: To examine this significance, we ran a 2 year prospective pilot study consisting of newly diagnosed stage I-III EC patients (n = 32) receiving chemoradiotherapy (CRT). CAML sizes were sequentially monitored prior to CRT (BL), ~ 2 weeks into treatment (T1), and at the first available sample after the completion of CRT (T2).

Results: We found CAMLs in 88% (n = 28/32) of all patient samples throughout the trial, with a sensitivity of 76% (n = 22/29) in pre-treatment screening samples. Improved 2 year PFS and OS was found in patients with CAMLs < 50 μm by the completion of CRT over patients with CAMLs ≥ 50 μm; PFS (HR = 12.0, 95% CI = 2.7-54.1, p = 0.004) and OS (HR = 9.0, 95%CI = 1.9-43.5, p = 0.019).

Conclusions: Tracking CAML sizes throughout CRT as a minimally invasive biomarker may serve as a prognostic tool in mapping EC progression, and further studies are warranted to determine if presence of these cells prior to treatment suggest diagnostic value for at-risk populations.
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http://dx.doi.org/10.1186/s12967-020-02563-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640696PMC
November 2020

Postoperative Radiotherapy for Locally Advanced NSCLC: Implications for Shifting to Conformal, High-Risk Fields.

Clin Lung Cancer 2021 05 28;22(3):225-233.e7. Epub 2020 Jun 28.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

Background: To examine the effect of radiotherapy field size on survival outcomes and patterns of recurrence in patients treated with postoperative radiotherapy (PORT) for non-small-cell lung cancer (NSCLC).

Methods: We retrospectively reviewed the records of 216 patients with T1-4 N1-2 NSCLC following surgery and PORT using whole mediastinum (WM) or high-risk (HR) nodal fields from 1998 to 2015. Survival rates were calculated using the Kaplan-Meier method. Univariate and multivariable analyses were conducted using Cox proportional hazards modeling for outcomes and logistic regression analysis for treatment toxicities.

Results: Median follow-up was 28 months (interquartile range [IQR] 13-75 months) and 38 months (IQR 19-73 months) for WM (n = 131) and HR (n = 84) groups, respectively. Overall survival (OS) was not significantly different between groups (median OS: HR 49 vs. WM 32 months; P = .08). There was no difference in progression-free survival (PFS), freedom from locoregional recurrence (LRR), or freedom from distant metastasis (P > .2 for all). Field size was not associated with OS, PFS, or LRR (P > .40 for all). LRR rates were 20% for HR and 26% for WM groups (P = .30). There was no significant difference in patterns of initial site of LRR between groups (P > .1). WM fields (OR 3.73, P = .001) and concurrent chemotherapy (odds ratio 3.62, P = .001) were associated with grade ≥2 toxicity.

Conclusions: Locoregional control and survival rates were similar between PORT groups; an improved toxicity profile was observed in the HR group. Results from an ongoing prospective randomized clinical trial will provide further insight into the consequences of HR PORT fields.
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http://dx.doi.org/10.1016/j.cllc.2020.06.018DOI Listing
May 2021

Rates of Overall Survival and Intracranial Control in the Magnetic Resonance Imaging Era for Patients With Limited-Stage Small Cell Lung Cancer With and Without Prophylactic Cranial Irradiation.

JAMA Netw Open 2020 04 1;3(4):e201929. Epub 2020 Apr 1.

Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston.

Importance: Historical data suggest that there is an overall survival benefit associated with prophylactic cranial irradiation (PCI) in patients with small cell lung cancer (SCLC). However, as the fidelity of magnetic resonance imaging (MRI) of the brain continues to improve, this idea is now being questioned, with recent research showing no survival benefit associated with PCI in extensive-stage SCLC; however, the role for PCI is not clear in patients with limited-stage SCLC (LS-SCLC).

Objective: To report the overall survival and rates of intracranial control for patients with LS-SCLC, all staged with MRI, who either did or did not undergo PCI.

Design, Setting, And Participants: This cohort study included 297 patients with LS-SCLC at a large US academic cancer center. Patients were treated with thoracic radiation; 205 also underwent PCI and 92 did not. All patients underwent at least baseline MRI, with restaging brain MRI and/or computed tomography; they did not have disease progression after thoracic radiation treatment. A propensity score-matching analysis was undertaken in an attempt to adjust for potential bias. Of the 297 patients who met the inclusion criteria, the propensity score was calculated for 295 patients, using patient, tumor, and treatment characteristics. Data were analyzed in October 2019.

Intervention: Prophylactic cranial irradiation in patients with LS-SCLC.

Main Outcomes And Measures: The rate of overall survival and intracranial control.

Results: Of the 297 patients, 162 (54.5%) were men. The median age was 62.2 years (range, 27.0-85.0 years) for patients who underwent PCI and 68.6 years (range, 40.0-86.0 years) for those who did not undergo PCI. The 3-year cumulative incidence rate of brain metastases was higher in the no-PCI group vs the PCI group, when counting death as a competing risk, but the difference was not statistically significant (20.40% [95% CI, 12.45%-29.67%] vs 11.20% [95% CI, 5.40%-19.20%]; P = .10). The use of PCI was not associated with a difference in overall survival between the patient groups (hazard ratio, 0.844; 95% CI, 0.604-1.180; P = .32).

Conclusions And Relevance: These findings suggest that patients with LS-SCLC staged with MRI who undergo PCI after thoracic radiation treatment were not associated with a decreased risk of developing new brain metastases compared with patients who do not undergo PCI. The use of PCI was not associated with an overall survival benefit for such patients.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.1929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113726PMC
April 2020

Randomized Phase IIB Trial of Proton Beam Therapy Versus Intensity-Modulated Radiation Therapy for Locally Advanced Esophageal Cancer.

J Clin Oncol 2020 05 11;38(14):1569-1579. Epub 2020 Mar 11.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: Whether dosimetric advantages of proton beam therapy (PBT) translate to improved clinical outcomes compared with intensity-modulated radiation therapy (IMRT) remains unclear. This randomized trial compared total toxicity burden (TTB) and progression-free survival (PFS) between these modalities for esophageal cancer.

Methods: This phase IIB trial randomly assigned patients to PBT or IMRT (50.4 Gy), stratified for histology, resectability, induction chemotherapy, and stage. The prespecified coprimary end points were TTB and PFS. TTB, a composite score of 11 distinct adverse events (AEs), including common toxicities as well as postoperative complications (POCs) in operated patients, quantified the extent of AE severity experienced over the duration of 1 year following treatment. The trial was conducted using Bayesian group sequential design with three planned interim analyses at 33%, 50%, and 67% of expected accrual (adjusted for follow-up).

Results: This trial (commenced April 2012) was approved for closure and analysis upon activation of NRG-GI006 in March 2019, which occurred immediately prior to the planned 67% interim analysis. Altogether, 145 patients were randomly assigned (72 IMRT, 73 PBT), and 107 patients (61 IMRT, 46 PBT) were evaluable. Median follow-up was 44.1 months. Fifty-one patients (30 IMRT, 21 PBT) underwent esophagectomy; 80% of PBT was passive scattering. The posterior mean TTB was 2.3 times higher for IMRT (39.9; 95% highest posterior density interval, 26.2-54.9) than PBT (17.4; 10.5-25.0). The mean POC score was 7.6 times higher for IMRT (19.1; 7.3-32.3) versus PBT (2.5; 0.3-5.2). The posterior probability that mean TTB was lower for PBT compared with IMRT was 0.9989, which exceeded the trial's stopping boundary of 0.9942 at the 67% interim analysis. The 3-year PFS rate (50.8% 51.2%) and 3-year overall survival rates (44.5% 44.5%) were similar.

Conclusion: For locally advanced esophageal cancer, PBT reduced the risk and severity of AEs compared with IMRT while maintaining similar PFS.
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http://dx.doi.org/10.1200/JCO.19.02503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213588PMC
May 2020

Metabolic Responses to Metformin in Inoperable Early-stage Non-Small Cell Lung Cancer Treated With Stereotactic Radiotherapy: Results of a Randomized Phase II Clinical Trial.

Am J Clin Oncol 2020 04;43(4):231-235

Department of Radiation Oncology, Division of Radiation Oncology.

Background: Metformin reduces glucose uptake in physiologic tissues and has been shown to affect non-small cell lung cancer (NSCLC) metabolism. We hypothesized that positron emission tomography (PET) scans could detect the impact of metformin on glucose uptake in NSCLC and we sought to test this hypothesis in a prospective clinical trial.

Materials And Methods: A single-blinded phase II clinical trial was performed with subjects randomized 6:1 to 3 to 4 weeks of metformin versus placebo for inoperable early-stage NSCLC. PET scans were performed at baseline, mid-treatment (after 2 wk study medication), and 6 months postradiation. The primary endpoint of the trial was tumor metabolic response to metformin by PERCIST before definitive radiation. Stereotactic body radiotherapy to 50 Gy in 4 fractions was used for peripheral tumors and 70 Gy in 10 fractions for central tumors.

Results: There were 14 subjects randomized to the metformin and 1 to placebo. Histologies were 60% adenocarcinoma, 33.3% squamous cell carcinoma, and 6.7% poorly differentiated carcinoma. At mid-treatment PET scan, 57% of subjects randomized to metformin met PERCIST criteria for metabolic response, of which 75% had progressive metabolic disease and 25% had partial metabolic response, whereas the placebo subject had stable metabolic disease. At 6 months, the metformin arm had 69% complete metabolic response, 23% partial metabolic response and 1 progressive metabolic disease, and the subject treated with placebo had a complete metabolic response. There were no CTCAE grade ≥3 toxicities.

Conclusions: Despite low accrual, majority of subjects treated with metformin had metabolic responses by PERCIST criteria on PET imaging. Contrary to the effect of metformin on most physiologic tissues, most tumors had increased metabolic activity in response to metformin.
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http://dx.doi.org/10.1097/COC.0000000000000632DOI Listing
April 2020

Long-Term Results of NRG Oncology RTOG 0617: Standard- Versus High-Dose Chemoradiotherapy With or Without Cetuximab for Unresectable Stage III Non-Small-Cell Lung Cancer.

J Clin Oncol 2020 03 16;38(7):706-714. Epub 2019 Dec 16.

The University of Texas Southwestern Medical Center, Dallas, TX.

Purpose: RTOG 0617 compared standard-dose (SD; 60 Gy) versus high-dose (HD; 74 Gy) radiation with concurrent chemotherapy and determined the efficacy of cetuximab for stage III non-small-cell lung cancer (NSCLC).

Methods: The study used a 2 × 2 factorial design with radiation dose as 1 factor and cetuximab as the other, with a primary end point of overall survival (OS).

Results: Median follow-up was 5.1 years. There were 3 grade 5 adverse events (AEs) in the SD arm and 9 in the HD arm. Treatment-related grade ≥3 dysphagia and esophagitis occurred in 3.2% and 5.0% of patients in the SD arm 12.1% and 17.4% in the HD arm, respectively ( = .0005 and < .0001). There was no difference in pulmonary toxicity, with grade ≥3 AEs in 20.6% and 19.3%. Median OS was 28.7 20.3 months ( = .0072) in the SD and HD arms, respectively, 5-year OS and progression-free survival (PFS) rates were 32.1% and 23% and 18.3% and 13% ( = .055), respectively. Factors associated with improved OS on multivariable analysis were standard radiation dose, tumor location, institution accrual volume, esophagitis/dysphagia, planning target volume and heart V5. The use of cetuximab conferred no survival benefit at the expense of increased toxicity. The prior signal of benefit in patients with higher H scores was no longer apparent. The progression rate within 1 month of treatment completion in the SD arm was 4.6%. For comparison purposes, the resultant 2-year OS and PFS rates allowing for that dropout rate were 59.6% and 30.7%, respectively, in the SD arms.

Conclusion: A 60-Gy radiation dose with concurrent chemotherapy should remain the standard of care, with the OS rate being among the highest reported in the literature for stage III NSCLC. Cetuximab had no effect on OS. The 2-year OS rates in the control arm are similar to the PACIFIC trial.
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http://dx.doi.org/10.1200/JCO.19.01162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048161PMC
March 2020

Phase II Trial of Ipilimumab with Stereotactic Radiation Therapy for Metastatic Disease: Outcomes, Toxicities, and Low-Dose Radiation-Related Abscopal Responses.

Cancer Immunol Res 2019 12 28;7(12):1903-1909. Epub 2019 Oct 28.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Ipilimumab is effective for patients with melanoma, but not for those with less immunogenic tumors. We report a phase II trial of ipilimumab with concurrent or sequential stereotactic ablative radiotherapy to metastatic lesions in the liver or lung (NCT02239900). Ipilimumab (every 3 weeks for 4 doses) was given with radiotherapy begun during the first dose (concurrent) or 1 week after the second dose (sequential) and delivered as 50 Gy in 4 fractions or 60 Gy in 10 fractions to metastatic liver or lung lesions. In total, 106 patients received ≥1 cycle of ipilimumab with radiation. Median follow-up was 10.5 months. Median progression-free survival time was 2.9 months (95% confidence interval, 2.45-3.40), and median overall survival time was not reached. Rates of clinical benefit of nonirradiated tumor volume were 26% overall, 28% for sequential versus 20% for concurrent therapy ( = 0.250), and 31% for lung versus 14% for liver metastases ( = 0.061). The sequential lung group had the highest rate of clinical benefit at 42%. There were no differences in treatment-related adverse events between groups. Exploratory analysis of nontargeted lesions revealed that lesions receiving low-dose radiation were more likely to respond than those that received no radiation (31% vs. 5%, = 0.0091). This phase II trial of ipilimumab with stereotactic radiotherapy describes satisfactory outcomes and low toxicities, lending support to further investigation of combined-modality therapy for metastatic cancers.
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891218PMC
December 2019

Single-Fraction Stereotactic vs Conventional Multifraction Radiotherapy for Pain Relief in Patients With Predominantly Nonspine Bone Metastases: A Randomized Phase 2 Trial.

JAMA Oncol 2019 Jun;5(6):872-878

Department of Orthopedic Oncology, The University of Texas MD Anderson Cancer Center, Houston.

Importance: Consensus is lacking as to the optimal radiotherapy dose and fractionation schedule for treating bone metastases.

Objective: To assess the relative efficacy of high-dose, single-fraction stereotactic body radiotherapy (SBRT) vs standard multifraction radiotherapy (MFRT) for alleviation of pain in patients with mostly nonspine bone metastases.

Design, Setting, And Participants: This prospective, randomized, single-institution phase 2 noninferiority trial conducted at a tertiary cancer care center enrolled 160 patients with radiologically confirmed painful bone metastases from September 19, 2014, through June 19, 2018. Patients were randomly assigned in a 1:1 ratio to receive either single-fraction SBRT (12 Gy for ≥4-cm lesions or 16 Gy for <4-cm lesions) or MFRT to 30 Gy in 10 fractions.

Main Outcomes And Measures: The primary end point was pain response, defined by international consensus criteria as a combination of pain score and analgesic use (daily morphine-equivalent dose). Pain failure (ie, lack of response) was defined as worsening pain score (≥2 points on a 0-to-10 scale), an increase in morphine-equivalent opioid dose of 50% or more, reirradiation, or pathologic fracture. We hypothesized that SBRT was noninferior to MFRT.

Results: In this phase 2 noninferiority trial of 96 men and 64 women (mean [SD] age, 62.4 [10.4] years), 81 patients received SBRT and 79 received MFRT. Among evaluable patients who received treatment per protocol, the single-fraction group had more pain responders than the MFRT group (complete response + partial response) at 2 weeks (34 of 55 [62%] vs 19 of 52 [36%]) (P = .01), 3 months (31 of 43 [72%] vs 17 of 35 [49%]) (P = .03), and 9 months (17 of 22 [77%] vs 12 of 26 [46%]) (P = .03). No differences were found in treatment-related toxic effects or quality-of-life scores after SBRT vs MFRT; local control rates at 1 and 2 years were higher in patients receiving single-fraction SBRT.

Conclusions And Relevance: Delivering high-dose, single-fraction SBRT seems to be an effective treatment option for patients with painful bone metastases. Among evaluable patients, SBRT had higher rates of pain response (complete response + partial response) than did MFRT and thus should be considered for patients expected to have relatively long survival.

Trial Registration: ClinicalTrials.gov identifier: NCT02163226.
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http://dx.doi.org/10.1001/jamaoncol.2019.0192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487911PMC
June 2019

James Daniel Cox, MD, FASTRO, FACR.

Int J Radiat Oncol Biol Phys 2019 03;103(4):784-785

The University of Texas MD Anderson Cancer Center, Houston, Texas.

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http://dx.doi.org/10.1016/j.ijrobp.2018.09.025DOI Listing
March 2019

Prognostic Significance of Total Lymphocyte Count, Neutrophil-to-lymphocyte Ratio, and Platelet-to-lymphocyte Ratio in Limited-stage Small-cell Lung Cancer.

Clin Lung Cancer 2019 03 29;20(2):117-123. Epub 2018 Nov 29.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

Background: We sought reliable markers of survival and disease control among patients treated for limited-stage small-cell lung cancer (LS-SCLC).

Patients And Methods: Subjects were 122 patients given (chemo)radiotherapy for LS-SCLC at MD Anderson in 2002 through 2015. Pretreatment total lymphocyte count (TLC), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were analyzed for associations with overall (OS) and progression-free survival. Optimal cutoff values were identified with receiver operating characteristic curves and survival probabilities with the Kaplan-Meier method.

Results: Pretreatment TLC was 1.86 × 10/μL (±0.88); NLR, 3.44 (±3.69); and PLR, 170.53 (±101.56); corresponding cutoffs were 1.9, 2.9, and 140.1. Higher TLC was associated with superior median and 2-year OS (17.4 vs. 15.7 months and 33% vs. 29%; P = .029), and higher NLR and PLR with worse median and 2-year OS (NLR: 14.9 vs. 17.8 months, 29% vs. 31%; P = .026; PLR: 14.8 vs. 18.9 months, 24% vs. 37%; P = .009). Multivariate Cox regression adjusted for age, disease stage, number of chemotherapy cycles, and use of prophylactic cranial irradiation confirmed the links between high TLC and superior OS (hazard ratio [HR] 0.55; 95% confidence interval [CI], 0.32-0.94; P = .028) and between high NLR and PLR and inferior OS (NLR: HR, 1.86; 95% CI, 1.15-3.01; P = .011; PLR: HR, 1.72; 95% CI, 1.06-2.82; P = .030).

Conclusions: Baseline lymphopenia was an indicator of poor prognosis in patients with LS-SCLC.
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http://dx.doi.org/10.1016/j.cllc.2018.11.013DOI Listing
March 2019

Outcomes of re-irradiation for brain recurrence after prophylactic or therapeutic whole-brain irradiation for small cell lung Cancer: a retrospective analysis.

Radiat Oncol 2018 Dec 29;13(1):258. Epub 2018 Dec 29.

Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030-4009, USA.

Background: Small cell lung cancer (SCLC) can recur in the brain after whole-brain irradiation (WBI). We documented outcomes after treatment of such recurrences and sought predictors of local control and overall survival (OS).

Materials And Methods: Eighty-five patients with SCLC and brain recurrence after prophylactic or therapeutic WBI in 1998-2015 were identified and data were extracted from the medical records. Survival was estimated with the Kaplan-Meier method, and univariate and multivariate Cox proportional hazards modeling was used to identify factors associated with OS or further brain progression.

Results: Brain recurrence was treated by stereotactic radiosurgery (SRS) in 33 patients (39%), repeat WBI in 14 (16%), chemotherapy-only in 16 (19%), and observation in 22 (26%). Median OS time after brain recurrence (OSrec) was 4.3 months for all patients; 6-month OSrec rates were 58% after SRS, 21% after repeat WBI, 50% after chemotherapy-only, and 5% after observation (P < 0.001). Inferior OSrec was associated with poor performance status (ECOG score ≥ 3) and uncontrolled extracranial disease. Superior OSrec was associated with receipt of ≥4 chemotherapy cycles before brain recurrence and receipt of chemotherapy, SRS, or repeat WBI afterward. Receipt of chemotherapy after brain recurrence correlated with brain progression.

Conclusions: Some patients with brain recurrence after WBI for SCLC can survive for extended periods with appropriate intervention, especially those with adequate performance status or controlled extracranial disease.
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http://dx.doi.org/10.1186/s13014-018-1205-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310962PMC
December 2018

An Economic Analysis of Radiation Therapy Oncology Group 94-10: Cost-Efficacy of Concurrent vs. Sequential Chemoradiotherapy.

J Radiat Oncol 2018 Jun 10;7(2):195-201. Epub 2018 Mar 10.

Wiship Cancer Institute, Emory University, Atlanta GA.

Background: Cost can be a major issue in therapeutic decision-making, and in particular for patients with locally advanced non-small cell lung cancer (LA-NSCLC).

Methods: The specific aim of this analysis was to evaluate the costs and outcomes of patients treated on Radiation Therapy Oncology Group (RTOG) 94-10, Medicare Part A and Part B costs from all for patients treated from 1991 to 1996 on RTOG 94-10, a phase III trial showing a survival benefit for concurrent chemoradiation (STD RT) over sequential (RT day 50) chemoradiation in LA-NSCLC with intermediate outcome for concurrent twice daily radiation and chemotherapy (HFX RT). 26-month expected costs for each arm of the trial in 1996 dollars were determined, with Kaplan Meier sampling average estimates of survival probabilities for each month and mean monthly costs. The analysis was performed from a payer's perspective. Incremental cost-effectiveness ratios were calculated comparing RT on day 50 and HFX RT to the STD RT.

Results: Of the 610 patients entered, Medicare cost data and clinical outcomes were available for 92 patients. In this subset, compared to STD RT, RT on day 50 proved less costly but resulted in reduced survival at 1 year. In addition, HFX RT cost slightly more than STD RT but was less effective in this cohort of patients.

Conclusions: In patients with Medicare insurance and with significant toxicity burden, RT on day 50 is the least expensive but also least effective treatment in this subset of patients treated on RTOG 94-10.
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http://dx.doi.org/10.1007/s13566-018-0346-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294122PMC
June 2018

Long-term Follow-up on NRG Oncology RTOG 0915 (NCCTG N0927): A Randomized Phase 2 Study Comparing 2 Stereotactic Body Radiation Therapy Schedules for Medically Inoperable Patients With Stage I Peripheral Non-Small Cell Lung Cancer.

Int J Radiat Oncol Biol Phys 2019 04 1;103(5):1077-1084. Epub 2018 Dec 1.

Washington University, St. Louis, Missouri.

Purpose: To present long-term results of RTOG 0915/NCCTG N0927, a randomized lung stereotactic body radiation therapy trial of 34 Gy in 1 fraction versus 48 Gy in 4 fractions.

Methods And Materials: This was a phase 2 multicenter study of patients with medically inoperable non-small cell lung cancer with biopsy-proven peripheral T1 or T2 N0M0 tumors, with 1-year toxicity rates as the primary endpoint and selected failure and survival outcomes as secondary endpoints. The study opened in September 2009 and closed in March 2011. Final data were analyzed through May 17, 2018.

Results: Eighty-four of 94 patients accrued were eligible for analysis: 39 in arm 1 and 45 in arm 2. Median follow-up time was 4.0 years for all patients and 6.0 years for those alive at analysis. Rates of grade 3 and higher toxicity were 2.6% in arm 1 and 11.1% in arm 2. Median survival times (in years) for 34 Gy and 48 Gy were 4.1 versus 4.6, respectively. Five-year outcomes (95% confidence interval) for 34 Gy and 48 Gy were a primary tumor failure rate of 10.6% (3.3%-23.1%) versus 6.8% (1.7%-16.9%); overall survival of 29.6% (16.2%-44.4%) versus 41.1% (26.6%-55.1%); and progression-free survival of 19.1% (8.5%-33.0%) versus 33.3% (20.2%-47.0%). Distant failure as the sole failure or a component of first failure occurred in 6 patients (37.5%) in the 34 Gy arm and in 7 (41.2%) in the 48 Gy arm.

Conclusions: No excess in late-appearing toxicity was seen in either arm. Primary tumor control rates at 5 years were similar by arm. A median survival time of 4 years for each arm suggests similar efficacy, pending any larger studies appropriately powered to detect survival differences.
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http://dx.doi.org/10.1016/j.ijrobp.2018.11.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454873PMC
April 2019

A pooled analysis of individual patient data from National Clinical Trials Network clinical trials of concurrent chemoradiotherapy for limited-stage small cell lung cancer in elderly patients versus younger patients.

Cancer 2019 02 21;125(3):382-390. Epub 2018 Oct 21.

Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina.

Background: Platinum and etoposide with thoracic radiation followed by prophylactic cranial irradiation constitute the standard treatment for limited-stage small cell lung cancer (LS-SCLC). Many patients with LS-SCLC are elderly with comorbidities.

Methods: Individual patient data were collected from 11 phase 2 or 3 trials for LS-SCLC conducted by the National Clinical Trials Network and activated from 1990 to 2010. The primary endpoint was overall survival (OS); the secondary endpoints were progression-free survival (PFS), the rate of severe adverse events, and off-treatment reasons. The outcomes were compared for patients 70 years old or older (elderly patients) and patients younger than 70 years (younger patients).

Results: Individual patient data from 1049 younger patients (81%) and 254 elderly patients (19%) were analyzed. In the multivariate model, elderly patients, in comparison with younger patients, had worse OS (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.18-1.63; median OS for elderly patients, 17.8 months; OS for younger patients, 23.5 months) and worse PFS (HR, 1.19; 95% CI, 1.03-1.39; median PFS for elderly patients, 10.6 months; median PFS for younger patients, 12.3 months). Elderly patients, in comparison with younger patients, experienced more grade 5 adverse events (8% vs 3%; P < .01) and more grade 3 or higher dyspnea (11% vs 7%; P = .03) but less grade 3 or higher esophagitis/dysphagia (14% vs 19%; P = .04) and less grade 3 or higher vomiting (11% vs 17%; P = .01). Elderly patients completed treatment less often, discontinued treatment because of adverse events and patient refusal more frequently, and died during treatment more frequently.

Conclusions: Elderly patients with LS-SCLC have worse PFS and OS and more difficulty in tolerating therapy. Future trials should incorporate assessments of elderly patients, novel monitoring of adverse events, and more tolerable radiation and systemic therapies.
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http://dx.doi.org/10.1002/cncr.31813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340765PMC
February 2019

Twice-daily Thoracic Radiotherapy for Limited-stage Small-cell Lung Cancer Does Not Increase the Incidence of Acute Severe Esophagitis.

Clin Lung Cancer 2018 11 22;19(6):e885-e891. Epub 2018 Aug 22.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

Purpose: Acute esophagitis is common after thoracic radiation therapy (TRT) given with chemotherapy for limited-stage small-cell lung cancer (LS SCLC). Although twice-daily TRT to 45 Gy in 30 fractions is considered standard, some clinicians are reluctant to use this schedule because of its perceived impracticality and risk of severe esophagitis. We reviewed a single-institution experience with severe (grade ≥ 3) esophagitis after TRT with chemotherapy for LS SCLC.

Patients And Methods: A total of 504 patients were identified as having received TRT (≥45 Gy) with platinum-containing chemotherapy for LS SCLC at MD Anderson Cancer Center in 1987 through 2012. Patients with complete or good partial response were offered prophylactic cranial irradiation. Esophagitis was scored retrospectively with the Common Terminology Criteria for Adverse Events, V3.0. Clinical variables were analyzed for possible association with acute grade ≥ 3 esophagitis.

Results: At a median follow-up time of 23.9 months (range, 1.2-240.8 months), 103 (20%) patients had experienced grade ≥ 3 esophagitis. In univariate analysis, TRT dose ≥ 60 Gy was the only factor associated with severe esophagitis (odds ratio [OR], 1.84; 95% confidence interval [CI], 1.02-3.30; P = .043); use of twice-daily TRT was not (OR, 0.96; 95% CI, 0.61-1.52; P = .867). The significance of TRT to ≥ 60 Gy was maintained in multivariate Cox regression analysis adjusted for tumor size (OR, 1.91; 95% CI, 1.05-3.46; P = .034).

Conclusions: TRT to ≥ 60 Gy predicted acute severe esophagitis, but twice-daily fractionation did not. Standard-dose 45-Gy twice-daily TRT should not be avoided for fear of severe esophagitis.
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http://dx.doi.org/10.1016/j.cllc.2018.08.012DOI Listing
November 2018

Anticancer therapy and lung injury: molecular mechanisms.

Expert Rev Anticancer Ther 2018 10 23;18(10):1041-1057. Epub 2018 Jul 23.

a Department of Radiation Oncology , Baylor College of Medicine , Houston , Texas , USA.

Introduction: Chemotherapy and radiation therapy are two mainstream strategies applied in the treatment of cancer that is not operable. Patients with hematological or solid tumor malignancies substantially benefit from chemotherapeutic drugs and/or ionizing radiation delivered to the site of malignancy. However, considerable adverse effects, including lung inflammation and fibrosis, are associated with the use of these treatment modalities. Areas covered: As we move toward the era of precision health, we are compelled to understand the molecular basis of chemoradiation-induced pathological lung remodeling and to develop effective treatment strategies that mitigate the development of chronic lung disease (i.e. fibrosis) in cancer patients. The review discusses chemotherapeutic agents that are reported to induce or associate with acute and/or chronic lung injury. Expert commentary: There is a need to molecularly understand how chemotherapeutic drugs induce or associate with respiratory toxicities and whether such characteristics are inherently related to their antitumor effect or are collateral. Once such mechanisms have been identified and/or fully characterized, they may be able to guide disease-management decisions including effective intervention strategies for the adverse effects. In the meantime, radiation oncologists should be judicious on the dose of radiation delivered to the lungs, the volume of lung irradiated, and concurrent use of chemotherapeutic drugs.
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http://dx.doi.org/10.1080/14737140.2018.1500180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290681PMC
October 2018

Clinical and Dosimetric Factors Predicting Grade ≥2 Radiation Pneumonitis After Postoperative Radiotherapy for Patients With Non-Small Cell Lung Carcinoma.

Int J Radiat Oncol Biol Phys 2018 07 12;101(4):919-926. Epub 2018 Apr 12.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Purpose: To identify clinical and dosimetric factors that would predict grade ≥2 radiation pneumonitis (RP) for patients undergoing postoperative radiation therapy (PORT) for non-small cell lung cancer (NSCLC); and to use the factors identified to generate a predictive model to quantify risk of RP in such patients.

Methods And Materials: We retrospectively reviewed radiation therapy, radiographic, and clinical data from 199 patients who had received PORT, with or without chemotherapy, for NSCLC. Potential associations between dosimetric and clinical factors and RP were evaluated in univariate and multivariate Cox regression hazard models and competing risk analysis. Kaplan-Meier analysis was used to estimate overall survival and the cumulative incidence of RP, and receiver operating characteristic curve analysis to identify cutpoints for variables found to influence RP risk. The endpoint was grade ≥2 RP (symptomatic, requiring steroids or limiting instrumental activities of daily living).

Results: Thirty-seven patients (19%) developed grade ≥2 RP. Patient-related factors, type of surgery or chemotherapy, and radiation therapy-related factors were not associated with grade ≥2 RP; only lung V10 > 30% and lung V20 > 20% predicted grade ≥2 RP. Risk groupings were as follows: high risk, V10 > 30% and V20 > 20% (24 of 72 patients, 33%); intermediate risk, V10 > 30% and V20 ≤ 20% or V10 ≤ 30% and V20 > 20% (6 of 26 patients, 23%); and low risk, V10 ≤ 30% and V20 ≤ 20% (6 of 101 patients, 6%) (P < .0001). In a subgroup analysis of patients who had had lobectomy, corresponding incidences of RP were as follows: high risk, 20 of 59 (34%); intermediate risk, 5 of 22 (23%); and low risk, 6 of 70 (9%) (P = .001).

Conclusions: The lung dose-volume variables V10 and V20 predicted risk of grade ≥2 RP among patients who underwent PORT for NSCLC.
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http://dx.doi.org/10.1016/j.ijrobp.2018.04.012DOI Listing
July 2018

Hematologic variables associated with brain failure in patients with small-cell lung cancer.

Radiother Oncol 2018 09 12;128(3):505-512. Epub 2018 Jun 12.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. Electronic address:

Background And Purpose: We sought factors associated with the development of brain metastases after treatment of small cell lung cancer (SCLC) in patients without brain involvement at diagnosis.

Methods: We analyzed 293 patients with SCLC without brain metastases who received chemotherapy, thoracic radiation therapy (TRT), or both in 2001-2015. Pretreatment hematologic markers (platelet count, neutrophil count, lymphocyte count, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and lactate dehydrogenase) and other clinical characteristics were evaluated for correlation with brain metastases-free survival (BMFS). Cutoffs were established with receiver operating characteristics curves. Factors significant in univariate analysis were used to build a multivariate Cox model for BMFS.

Results: Median follow-up time was 14.3 months. Brain metastases developed in 115 patients (39%)-32% of those with low pretreatment platelet counts (PPC) (≤270 × 10/L) and 46% of those with high PPC (>270 × 10/L). Median BMFS time for all patients was 27.9 months. Two-year BMFS rates were worse for patients with high PPC (14.6% vs. 22.1% low, P = 0.009). High PPC was independently associated with inferior BMFS (P = 0.038), as were receipt of TRT <45 Gy and no prophylactic cranial irradiation (both P < 0.001).

Conclusions: High PPC was associated with increased rates of brain metastasis in patients with SCLC with no evidence of brain disease at diagnosis.
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http://dx.doi.org/10.1016/j.radonc.2018.05.026DOI Listing
September 2018

Is prophylactic cranial irradiation indicated for patients with extensive-stage small cell lung cancer with a complete response to first-line treatment?

Radiother Oncol 2018 06 7;127(3):339-343. Epub 2018 May 7.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. Electronic address:

Prophylactic cranial irradiation (PCI) has been considered standard of care for patients with limited-stage small-cell lung cancer who achieve complete response to definitive treatment after a meta-analysis revealed its favorable effects on survival. In a European trial, PCI was also shown to confer a survival advantage for patients with extensive-stage (ES) SCLC who experienced any positive response after initial chemotherapy, leading to PCI also being considered a standard treatment for these patients as well. However, a recent Japanese trial investigating PCI for patients with ES-SCLC was stopped early when an interim analysis failed to confirm a survival benefit. This finding has motivated the thoracic oncology community to rethink the role of PCI in ES-SCLC.
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http://dx.doi.org/10.1016/j.radonc.2018.03.034DOI Listing
June 2018

Nomograms incorporating genetic variants in BMP/Smad4/Hamp pathway to predict disease outcomes after definitive radiotherapy for non-small cell lung cancer.

Cancer Med 2018 06 9;7(6):2247-2255. Epub 2018 May 9.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, 77030.

Hepcidin is crucial in regulating iron metabolism, and increased serum levels were strongly linked with poor outcomes in various malignancies. Thus, we investigated if genetic variants in the BMP/Smad4/Hamp hepcidin-regulating pathway were associated with outcomes in patients receiving definitive radiotherapy for NSCLC. Subjects were 664 NSCLC patients who received ≥60 Gy radiotherapy for NSCLC retrospectively identified from a single-institution database. Potentially, functional and tagging single nucleotide polymorphisms (SNPs) of BMP2 (rs170986, rs1979855, rs1980499, rs235768, and rs3178250), BMP4 (rs17563, rs4898820, and rs762642), Smad4 (rs12456284), and Hamp (rs1882694, rs10402233, rs10421768, and rs12971321) were genotyped by TaqMan real-time polymerase chain reaction. Cox proportional hazard's analyses were used to assess potential influences of SNPs on overall survival (OS), local-regional progression-free survival (LRPFS), progression-free survival (PFS), and distant metastasis-free survival (DMFS). Nomogram of each endpoint model was developed using R project. The median patient age was 66 years. Most (488 [73.2%]) had stage III NSCLC. Age, disease stage, receipt of concurrent chemotherapy, and gross tumor volume were independent factors of OS. Hamp rs1882694 AC/CC genotypes were associated with poor OS, LRPFS, PFS, and DMFS in multivariate analyses. Besides, BMP2 rs1979855, rs3178250, and rs1980499 associated with PFS; Hamp rs10402233 and BMP2 rs1979855 associated with LRPFS; BMP2 rs3178250 associated with DMFS after adjustment for clinical factors. After adding SNPs to each model, all the likelihood ratios were increased; the nomograms were improved significantly to predict LRPFS (P < 0.001) and PFS (P < 0.001), and marginally to predict OS (P = 0.056) and DM (P = 0.057). Our nomograms incorporating significant SNPs in the BMP/Smad4/Hamp hepcidin-regulating pathway could improve the prediction of outcomes in patients given definitive radiotherapy for NSCLC. Intensified follow-ups would be recommended for patients with unfavorable outcomes identified in nomograms. Due to the rapid developments of targeted therapies and immunotherapies for NSCLC, it is necessary to further validate our findings in patients receiving such treatments.
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http://dx.doi.org/10.1002/cam4.1349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010922PMC
June 2018

Actionable Locoregional Relapses after Therapy of Localized Esophageal Cancer: Insights from a Large Cohort.

Oncology 2018 27;94(6):345-353. Epub 2018 Apr 27.

Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.

Objective: The goal of surveillance after therapy of localized esophageal cancer (LEC) is to identify actionable relapses amenable to salvage; however, the current surveillance algorithms are not optimized. We report on a large cohort of LEC patients with actionable locoregional relapses (LRRs).

Methods: Between 2000 and 2013, 127 (denominator = 752) patients with actionable LRR were identified. Histologic/cytologic confirmation was the gold standard. All surveillance tools (imaging, endoscopy, fine needle aspiration) were assessed.

Results: Most patients were men (89%), had adenocarcinoma (79%), and had no new symptoms (72%) when diagnosed with LRR. In trimodality patients, endoscopic confirmation of positron emission tomography-computed tomography-suspected LRR occurred in only 44%, and 56% required additional tools (e.g., fine needle aspiration). Alternatively, in bimodality patients, endoscopy confirmed LRRs in 81%. Trimodality patients had a higher risk of subsequent LRR/distant metastases after the first LRR than the bimodality patients (p = 0.03). In all patients, 78% of the subsequent relapses were distant. For patients who were salvaged, survival was significantly prolonged (50.6 vs. 25.1 months, p < 0.01).

Conclusions: Patients live longer after successful salvage of the LRR than if salvage is not possible. After LRR, patients have a high risk of subsequent distant metastasis and whether the second relapse is local or distant, survival is uniformly poor.
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http://dx.doi.org/10.1159/000486720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067648PMC
June 2018

Phase 2 Study of Stereotactic Body Radiation Therapy and Stereotactic Body Proton Therapy for High-Risk, Medically Inoperable, Early-Stage Non-Small Cell Lung Cancer.

Int J Radiat Oncol Biol Phys 2018 07 2;101(3):558-563. Epub 2018 Mar 2.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Purpose: To report the feasibility of conducting a randomized study to compare the toxicity and efficacy of stereotactic body radiation therapy (SBRT) versus stereotactic body proton therapy (SBPT) for high-risk, medically inoperable, early-stage non-small cell lung cancer (NSCLC).

Patients And Methods: Patients with medically inoperable NSCLC with high-risk features (centrally located or <5 cm T3 tumor or isolated lung parenchymal recurrences) were randomly assigned to SBRT or SBPT. Radiation dose was 50 Gy(relative biological effectiveness [RBE]) in 4 12.5-Gy(RBE) fractions prescribed to the planning target volume. Stereotactic body radiation therapy was given using 3-dimensional conformal radiation therapy or intensity modulated radiation therapy, and SBPT was given using passive scattering. Consistency in patient setup was ensured with on-board cone beam computed tomography for the SBRT group and with orthogonal X rays for the SBPT group.

Results: The study closed early owing to poor accrual, largely because of insurance coverage and lack of volumetric imaging in the SBPT group. Ultimately, 21 patients were enrolled, and 19 patients who received 50 Gy in 4 fractions were included for analysis (9 SBRT, 10 SBPT). At a median follow-up time of 32 months, median overall survival time was 28 months in the SBRT group and not reached in the SBPT group. Three-year overall survival was 27.8% and 90%, 3-year local control was 87.5% (8 of 9) and 90.0% (9 of 10), and 3-year regional control was 47.6% (5 of 9) and 90% (9 of 10) in the SBRT and SBPT groups, respectively. One patient in the SBPT group developed grade 3 skin fibrosis. No patients experienced grade 4/5 toxicity.

Conclusion: Poor accrual, due to lack of volumetric imaging and insurance coverage for proton therapy, led to early closure of the trial and precluded accurate assessment of efficacy and toxicity. Comparable maturity of 2 radiation therapy modalities, particularly on-board imaging, and better insurance coverage for SBPT should be considered for future studies.
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http://dx.doi.org/10.1016/j.ijrobp.2018.02.022DOI Listing
July 2018

Association of lung fluorodeoxyglucose uptake with radiation pneumonitis after concurrent chemoradiation for non-small cell lung cancer.

Clin Transl Radiat Oncol 2017 Jun 11;4:1-7. Epub 2017 May 11.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Increased uptake of fluorodeoxyglucose (FDG) by lung tissue could reflect inflammatory changes related to radiation pneumonitis (RP). In this secondary analysis of a clinical trial, we examined potential associations between posttreatment lung FDG uptake and RP severity in patients with non-small cell lung cancer (NSCLC) for up to 12 months after concurrent chemoradiation (CRT).

Methods: Subjects were 152 patients with NSCLC who had received concurrent CRT as part of the prospective trial NCT00915005. The following lung FDG variables were evaluated after CRT: maximum, mean, and peak standardized uptake values (SUVmax, SUVmean, SUVpeak) and global lung glycolysis (GLG; lung SUVmean × lung volume). RP severity was scored with the Common Terminology Criteria for Adverse Events v3.0.

Results: Significant associations were noted between PET findings and RP severity at 1-6 months (all  < 0.05), but not at 7-12 months after therapy (all  > 0.05). Lung FDG uptake at 1-3 months after treatment predicted later development of grade ≥2 RP (all  < 0.05), with cutoff values as follows: 4.54 for SUVmax, 3.69 for SUVpeak, 0.78 for SUVmean, and 2295 for GLG.

Conclusions: Lung FDG uptake correlated significantly with RP severity during the first 6 months after CRT. The cutoff values seem clinically meaningful for identifying patients at risk of developing RP after such therapy.
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http://dx.doi.org/10.1016/j.ctro.2017.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833918PMC
June 2017

Patient-reported lung symptoms as an early signal of impending radiation pneumonitis in patients with non-small cell lung cancer treated with chemoradiation: an observational study.

Qual Life Res 2018 06 16;27(6):1563-1570. Epub 2018 Mar 16.

Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Purpose: Clinician ratings of concurrent chemoradiation (CRT)-induced radiation pneumonitis (RP) in patients with non-small cell lung cancer (NSCLC) are based on both imaging and patient-reported lung symptoms. We compared the value of patient-reported outcomes versus normal-lung uptake of F-fluoro-2-deoxyglucose in positron emission computed tomography (FDG PET/CT) during the last week of treatment, for indicating the development of grade ≥ 2 RP within 4 months of CRT completion.

Methods: 132 patients with NSCLC-reported RP-related symptoms (coughing, shortness of breath) repeatedly using the validated MD Anderson Symptom Inventory lung cancer module. Of these patients, 68 had FDG PET/CT scans that were analyzed for normal-lung mean standardized FDG uptake values (SUV) before, during, and up to 4 months after CRT. Clinicians rated RP using CTCAE version 3. Logistic regression models examined potential predictors for developing CTCAE RP ≥ 2.

Results: For the entire sample, patient-rated RP-related symptoms during the last week of CRT correlated with clinically meaningful CTCAE RP ≥ 2 post-CRT (OR 2.74, 95% CI 1.25-5.99, P = 0.012), controlled for sex, age, mean lung radiation dose, comorbidity, and baseline symptoms. Moderate/severe patient-rated RP-related symptom score (≥ 4 on a 0-10 scale, P = 0.001) and normal-lung FDG uptake (SUV > 0.78, P = 0.002) in last week of CRT were equally strong predictors of post-CRT CTCAE RP ≥ 2 (C-index = 0.78, 0.77).

Conclusions: During the last week of CRT, routine assessment of moderate-to-severe RP-related symptoms provides a simple way to identify patients with NSCLC who may be at risk for developing significant post-CRT RP, especially when PET/CT images of normal-lung FDG uptake are not available.
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http://dx.doi.org/10.1007/s11136-018-1834-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953814PMC
June 2018

My Path from Hiroshima to Houston.

Authors:
Ritsuko Komaki

Pract Radiat Oncol 2019 01 14;9(1):1-2. Epub 2017 Oct 14.

Radiation Oncology, Gloria Lupton Tennison Distinguished Endowed Professorship in Lung Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

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http://dx.doi.org/10.1016/j.prro.2017.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899690PMC
January 2019

Potentially Functional Variants of ATG16L2 Predict Radiation Pneumonitis and Outcomes in Patients with Non-Small Cell Lung Cancer after Definitive Radiotherapy.

J Thorac Oncol 2018 05 15;13(5):660-675. Epub 2018 Feb 15.

Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina; Department of Population Health Sciences, Duke University School of Medicine, Durham, North Carolina. Electronic address:

Introduction: Autophagy not only plays an important role in the progression of cancer but is also involved in tissue inflammatory response. However, few published studies have investigated associations between functional genetic variants of autophagy-related genes and radiation pneumonitis (RP) as well as clinical outcomes in patients with NSCLC after definitive radiotherapy.

Methods: We genotyped nine potentially functional single-nucleotide polymorphisms (SNPs) in four autophagy-related genes (autophagy related 2B gene [ATG2B], autophagy related 10 gene [ATG10], autophagy related 12 gene [ATG12], and autophagy related 16 like 2 gene [ATG16L2]) in 393 North American patients with NSCLC treated by definitive radiotherapy and assessed their associations with RP, local recurrence-free survival (LRFS), progression-free survival (PFS), and overall survival (OS) in multivariable Cox proportional hazard regression analyses.

Results: We found that patients with the ATG16L2 rs10898880 CC variant genotype had a better LRFS, PFS, and OS (adjusted hazard ratio = 0.59, 0.64, and 0.64; 95% confidence interval: 0.45-0.79, 0.48-0.84, and 0.48-0.86; p = 0.0004, 0.002, and 0.003, respectively), but a greater risk for development of severe RP (adjusted hazard ratio = 1.80, 95% confidence interval: 1.04-3.12, p = 0.037) than did patients with AA/AC genotypes. Further functional analyses suggested that the ATG16L2 rs10898880 C variant allele modulated expression of the ATG16L2 gene.

Conclusion: This is the first report that one potentially functional SNP rs10898880 in ATG16L2 may be a predictor of RP, LRFS, PFS, and OS in patients with NSCLC after definitive radiotherapy. Additional larger, prospective studies are needed to confirm these findings.
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http://dx.doi.org/10.1016/j.jtho.2018.01.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124306PMC
May 2018

Prognostic significance of pretreatment total lymphocyte count and neutrophil-to-lymphocyte ratio in extensive-stage small-cell lung cancer.

Radiother Oncol 2018 Mar 2;126(3):499-505. Epub 2018 Feb 2.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. Electronic address:

Background: We evaluated pretreatment total lymphocyte count (TLC, marker of immunosuppression), neutrophil-to-lymphocyte ratio (NLR, marker of inflammation), and overall survival (OS) in patients with extensive-stage small-cell lung cancer (ES-SCLC).

Methods: Pretreatment blood characteristics, age, sex, performance status, race, stage (M1a vs. M1b), number and location of metastases, weight loss, smoking status, chemotherapy cycles (<4 vs. ≥4), thoracic radiotherapy dose (<45 vs. ≥45 Gy), and receipt of prophylactic cranial irradiation (PCI) were evaluated in 252 patients with ES-SCLC treated in 1998-2015. Factors significant in univariate analysis were selected as covariates for a multivariate Cox model.

Results: Pretreatment TLC was below normal (<1.0 × 10/µL) in 58 patients (23%). Median OS time was 11.0 months and was worse for those with TLC ≤ 1.5 × 10/µL (9.8 vs. 12.0 months) and pretreatment NLR > 4.0 (9.4 vs. 13.9 months). Multivariate analysis identified low TLC (hazard ratio [HR] 0.734, 95% confidence interval [CI] 0.565-0.955, P = 0.021) and high NLR (HR 1.521, 95% CI 1.172-1.976, P = 0.002) as predicting inferior survival. Age (>63 y), sex (male), performance status (≥2), chemotherapy cycles (<4), radiation dose (<45 Gy), and no PCI also predicted worse OS (P < 0.05).

Conclusions: Pretreatment TLC and NLR may be useful for stratifying patients with ES-SCLC for treatment approaches.
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http://dx.doi.org/10.1016/j.radonc.2017.12.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856620PMC
March 2018

Barriers to Combined-Modality Therapy for Limited-Stage Small Cell Lung Cancer.

JAMA Oncol 2018 08 9;4(8):e174504. Epub 2018 Aug 9.

Division of Radiation of Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston.

Importance: Combined-modality therapy with chemotherapy and radiation therapy plays a crucial role in the upfront treatment of patients with limited-stage small cell lung cancer (SCLC), but there may be barriers to utilization in the United States.

Objective: To estimate utilization rates and factors associated with chemotherapy and radiation therapy delivery for limited-stage SCLC using the National Cancer Database.

Design, Setting, And Participants: Analysis of initial management of all limited-stage SCLC cases from 2004 through 2013 in the National Cancer Database.

Main Outcomes And Measures: Utilization rates of chemotherapy and radiation therapy at time of initial treatment. Multivariable analysis identified independent clinical and socioeconomic factors associated with utilization and overall survival.

Results: A total of 70 247 cases met inclusion criteria (55.3% female; median age, 68 y [range, 19-90 y]). Initial treatment was 55.5% chemotherapy and radiation therapy, 20.5% chemotherapy alone, 3.5% radiation therapy alone, and 20.0% neither (0.5% not reported). Median survival was 18.2 (95% CI, 17.9-18.4), 10.5 (95% CI, 10.3-10.7), 8.3 (95% CI, 7.7-8.8), and 3.7 (95% CI, 3.5-3.8) months, respectively. Being uninsured was associated with a lower likelihood of both chemotherapy (odds ratio [OR], 0.65; 95% CI, 0.56-0.75; P < .001) and radiation therapy (OR, 0.75; 95% CI, 0.67-0.85; P < .001) administration on multivariable analysis. Medicare/Medicaid insurance had no impact on chemotherapy use, whereas Medicaid (OR, 0.79; 95% CI, 0.72-0.87; P < .001) and Medicare (OR, 0.86; 95% CI, 0.82-0.91; P < .001) were independently associated with a lower likelihood of radiation therapy delivery. Lack of health insurance (HR, 1.19; 95% CI, 1.13-1.26; P < .001), Medicaid (HR, 1.27; 95% CI, 1.21-1.32; P < .001), and Medicare (HR, 1.12; 95% CI, 1.09-1.15; P < .001) coverage were independently associated with shorter survival on adjusted analysis, while chemotherapy (HR, 0.55; 95% CI, 0.54-0.57; P < .001) and radiation therapy (HR, 0.62; 95% CI, 0.60-0.63; P < .001) were associated with a survival benefit.

Conclusions And Relevance: Substantial proportions of patients documented in a major US cancer registry did not receive radiation therapy or chemotherapy as part of initial treatment for limited-stage SCLC, which, in turn, was associated with poor survival. Lack of radiation therapy delivery was uniquely associated with government insurance coverage, suggesting a need for targeted access improvement in this population. Additional work will be necessary to conclusively define exact population patterns, specific treatment deficiencies, and causative factors leading to heterogeneous care delivery.
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http://dx.doi.org/10.1001/jamaoncol.2017.4504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885163PMC
August 2018

Bayesian Adaptive Randomization Trial of Passive Scattering Proton Therapy and Intensity-Modulated Photon Radiotherapy for Locally Advanced Non-Small-Cell Lung Cancer.

J Clin Oncol 2018 06 2;36(18):1813-1822. Epub 2018 Jan 2.

Zhongxing Liao, J. Jack Lee, Ritsuko Komaki, Daniel R. Gomez, Michael S. O'Reilly, Frank V. Fossella, George R. Blumenschein Jr, John V. Heymach, Ara A. Vaporciyan, Stephen G. Swisher, Pamela K. Allen, Stephen M. Hahn, James D. Cox, Charles S. Lu, and Radhe Mohan, The University of Texas MD Anderson Cancer Center, Houston, TX; and Noah Chan Choi and Thomas F. DeLaney, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

Purpose This randomized trial compared outcomes of passive scattering proton therapy (PSPT) versus intensity-modulated (photon) radiotherapy (IMRT), both with concurrent chemotherapy, for inoperable non-small-cell lung cancer (NSCLC). We hypothesized that PSPT exposes less lung tissue to radiation than IMRT and thereby reduces toxicity without compromising tumor control. The primary end points were grade ≥ 3 radiation pneumonitis (RP) and local failure (LF). Patients and Methods Eligible patients had stage IIB to IIIB NSCLC (or stage IV NSCLC with a single brain metastasis or recurrent lung or mediastinal disease after surgery) who were candidates for concurrent chemoradiation therapy. Pairs of treatment plans for IMRT and PSPT were created for each patient. Patients were eligible for random assignment only if both plans satisfied the same prespecified dose-volume constraints for at-risk organs at the same tumor dose. Results Compared with IMRT (n = 92), PSPT (n = 57) exposed less lung tissue to doses of 5 to 10 Gy(RBE), which is the absorbed Gy dose multiplied by the relative biologic effectiveness (RBE) factor for protons; exposed more lung tissue to ≥ 20 Gy(RBE), but exposed less heart tissue at all dose levels between 5 and 80 Gy(RBE). The grade ≥ 3 RP rate for all patients was 8.1% (IMRT, 6.5%; PSPT, 10.5%); corresponding LF rates were 10.7% (all), 10.9% (IMRT), and 10.5% (PSPT). The posterior probability of IMRT being better than PSPT was 0.54. Exploratory analysis showed that the RP and LF rates at 12 months for patients enrolled before versus after the trial midpoint were 21.1% (before) versus 18.2% (after) for the IMRT group (P = .047) and 31.0% (before) versus 13.1% (after) for the PSPT group (P = .027). Conclusion PSPT did not improve dose-volume indices for lung but did for heart. No benefit was noted in RP or LF after PSPT. Improvements in both end points were observed over the course of the trial.
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http://dx.doi.org/10.1200/JCO.2017.74.0720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008104PMC
June 2018
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