Narek Shaverdian

Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial

BACKGROUND Preclinical studies have found radiotherapy enhances antitumour immune responses. We aimed to assess disease control and pulmonary toxicity in patients who previously received radiotherapy for non-small-cell lung cancer (NSCLC) before receiving pembrolizumab. METHODS We assessed patients with advanced NSCLC treated on the phase 1 KEYNOTE-001 trial at a single institution (University of California, Los Angeles, CA, USA). Patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 1 or less, had adequate organ function, and no history of pneumonitis. Patients received pembrolizumab at a dose of either 2 mg/kg of bodyweight or 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks, until disease progression, unacceptable toxicity, or other protocol-defined reasons for discontinuation. Disease response and pulmonary toxicity were prospectively assessed by Immune-related Response Criteria and Common Terminology Criteria for Adverse Events version 4.0. The primary objective of the KEYNOTE-001 trial was to assess the safety, side-effect profile, and antitumour activity of pembrolizumab. For our secondary analysis, patients were divided into subgroups to compare patients who previously received radiotherapy with patients who had not. Our primary objective was to determine whether previous radiotherapy affected progression-free survival, overall survival, and pulmonary toxicity in the intention-to-treat population. The KEYNOTE-001 trial was registered with ClinicalTrials.gov, number NCT01295827. FINDINGS Between May 22, 2012, and July 11, 2014, 98 patients were enrolled and received their first cycle of pembrolizumab. One patient was lost to follow-up. 42 (43%) of 97 patients had previously received any radiotherapy for the treatment of NSCLC before the first cycle of pembrolizumab. 38 (39%) of 97 patients received extracranial radiotherapy and 24 (25%) of 97 patients received thoracic radiotherapy. Median follow-up for surviving patients was 32·5 months (IQR 29·8-34·1). Progression-free survival with pembrolizumab was significantly longer in patients who previously received any radiotherapy than in patients without previous radiotherapy (hazard ratio [HR] 0·56 [95% CI 0·34-0·91], p=0·019; median progression-free survival 4·4 months [95% CI 2·1-8·6] vs 2·1 months [1·6-2·3]) and for patients who previously received extracranial radiotherapy compared with those without previous extracranial radiotherapy (HR 0·50 [0·30-0·84], p=0·0084; median progression-free survival 6·3 months [95% CI 2·1-10·4] vs 2·0 months [1·8-2·1]). Overall survival with pembrolizumab was significantly longer in patients who previously received any radiotherapy than in patients without previous radiotherapy (HR 0·58 [95% CI 0·36-0·94], p=0·026; median overall survival 10·7 months [95% CI 6·5-18·9] vs 5·3 months [2·7-7·7]) and for patients who previously received extracranial radiotherapy compared with those without previous extracranial radiotherapy (0·59 [95% CI 0·36-0·96], p=0·034; median overall survival 11·6 months [95% CI 6·5-20·5] vs 5·3 months [3·0-8·5]). 15 (63%) of 24 patients who had previously received thoracic radiotherapy had any recorded pulmonary toxicity versus 29 (40%) of 73 patients with no previous thoracic radiotherapy. Three (13%) patients with previous thoracic radiotherapy had treatment-related pulmonary toxicity compared with one (1%) of those without; frequency of grade 3 or worse treatment-related pulmonary toxicities was similar (one patient in each group). INTERPRETATION Our data suggest that previous treatment with radiotherapy in patients with advanced NSCLC results in longer progression-free survival and overall survival with pembrolizumab treatment than that seen in patients who did not have previous radiotherapy, with an acceptable safety profile. Further clinical trials investigating this combination are needed to determine the optimal treatment strategy for patients with advanced NSCLC. FUNDING US National Institutes of Health.

68Ga-PSMA-11 PET/CT Mapping of Prostate Cancer Biochemical Recurrence After Radical Prostatectomy in 270 Patients with a PSA Level of Less Than 1.0 ng/mL: Impact on Salvage Radiotherapy Planning

Target volume delineations for prostate cancer (PCa) salvage radiotherapy (SRT) after radical prostatectomy are usually drawn in the absence of visibly recurrent disease. 68Ga-labeled prostate-specific membrane antigen (PSMA-11) PET/CT detects recurrent PCa with sensitivity superior to standard-of-care imaging at serum prostate-specific antigen (PSA) values low enough to affect target volume delineations for routine SRT. Our objective was to map the recurrence pattern of PCa early biochemical recurrence (BCR) after radical prostatectomy with 68Ga-PSMA-11 PET/CT in patients with serum PSA levels of less than 1 ng/mL, determine how often consensus clinical target volumes (CTVs) based on the Radiation Therapy Oncology Group (RTOG) guidelines cover 68Ga-PSMA-11 PET/CT-defined disease, and assess the potential impact of 68Ga-PSMA-11 PET/CT on SRT. Methods: This was a post hoc analysis of an intention-to-treat population of 270 patients who underwent 68Ga-PSMA-11 PET/CT at 4 institutions for BCR after prostatectomy without prior radiotherapy at a PSA level of less than 1 ng/mL. RTOG consensus CTVs that included both the prostate bed and the pelvic lymph nodes were contoured on the CT dataset of the PET/CT image by a radiation oncologist masked to the PET component. 68Ga-PSMA-11 PET/CT images were analyzed by a nuclear medicine physician. 68Ga-PSMA-11–positive lesions not covered by planning volumes based on the consensus CTVs were considered to have a potential major impact on treatment planning. Results: The median PSA level at the time of 68Ga-PSMA-11 PET/CT was 0.48 ng/mL (range, 0.03–1 ng/mL). One hundred thirty-two of 270 patients (49%) had a positive 68Ga-PSMA-11 PET/CT result. Fifty-two of 270 (19%) had at least one PSMA-11–positive lesion not covered by the consensus CTVs. Thirty-three of 270 (12%) had extrapelvic PSMA-11–positive lesions, and 19 of 270 (7%) had PSMA-11–positive lesions within the pelvis but not covered by the consensus CTVs. The 2 most common 68Ga-PSMA-11–positive lesion locations outside the consensus CTVs were bone (23/52, 44%) and perirectal lymph nodes (16/52, 31%). Conclusion: Post hoc analysis of 68Ga-PSMA-11 PET/CT implied a major impact on SRT planning in 52 of 270 patients (19%) with PCa early BCR (PSA < 1.0 ng/mL). This finding justifies a randomized imaging trial of SRT with or without 68Ga-PSMA-11 PET/CT investigating its potential benefit on clinical outcome.

Treatment trends for patients with brain metastases: Does practice reflect the data?

Published guidelines regarding the optimal treatment strategies for brain metastases focus on patients with ≤3 lesions. As delivery techniques for stereotactic radiosurgery (SRS) improve, radiation oncologists are increasingly using it for patients with >3 metastases. In the current study, the authors sought to characterize practice patterns among practitioners to identify areas of controversy.

The patient's perspective on stereotactic body radiation therapy (SBRT) vs. surgery for treatment of early stage non-small cell lung cancer (NSCLC).

OBJECTIVES We investigated the patients perspective on SBRT for treatment of stage I NSCLC and compared the patients perspective of SBRT to that of surgery. MATERIALS AND METHODS IRB approval was obtained to contact patients who had received SBRT for stage I NSCLCs. Patients were asked questions inquiring into their knowledge of SBRT and how their SBRT experience compared to their original expectations. Patients who had undergone prior surgery for a previously diagnosed stage I NSCLC were asked questions comparing their experience between SBRT and surgery. Frequencies of these reported measures were calculated and analysis was done using Fishers exact test. RESULTS 102 patients were contacted with 91 (89%) participating. Among all patients, prior to their radiation oncology consultation, 56% had no knowledge of SBRT and 58% believed SBRT to be as effective as resection. After consultation, 98.9% did not believe they were getting an inferior treatment with SBRT. 92.3% of patients reported less side effects, 59.3% reported SBRT to be more convenient and 87.9% reported SBRT to be less anxiety provoking than compared to their original expectations. Among patients with prior lung surgery (N=39), compared to surgery, 100% reported an easier recovery, less treatment related anxiety and less caregiver strain with SBRT. Overall, 79.5% were more satisfied with SBRT than surgery and 89.7% would have rather had SBRT than surgery as it was performed for their prior NSCLC. CONCLUSION Actual experiences with SBRT are overwhelmingly superior compared to patient expectations. Patients with prior lung surgery reported significantly more satisfaction with SBRT.

Potential impact of 68Ga-PSMA-11 PET/CT on prostate cancer definitive radiation therapy planning

Standard-of-care imaging for initial staging of prostate cancer (PCa) underestimates disease burden. Prostate-specific membrane antigen (PSMA) PET/CT detects PCa metastasis with superior accuracy, having a potential impact on the planning of definitive radiation therapy (RT) for nonmetastatic PCa. Our objectives were to determine how often definitive RT planning based on standard target volumes covers 68Ga-PSMA-11 PET/CT–defined disease and to assess the potential impact of 68Ga-PSMA-11 PET/CT on definitive RT planning. Methods: This was a post hoc analysis of an intention-to-treat population of 73 patients with localized PCa without prior local therapy who underwent 68Ga-PSMA PET/CT for initial staging as part of an investigational new drug trial. Eleven of the 73 were intermediate-risk (15%), 33 were high-risk (45%), 22 were very-high-risk (30%), and 7 were N1 (9.5%). Clinical target volumes (CTVs), which included the prostate, seminal vesicles, and (in accord with the Radiation Therapy Oncology Group consensus guidelines) pelvic lymph nodes (LNs), were contoured on the CT portion of the PET/CT images by a radiation oncologist masked to the PET findings. 68Ga-PSMA-11 PET/CT images were analyzed by a nuclear medicine physician. 68Ga-PSMA-11–positive lesions not covered by planning volumes based on the CTVs were considered to have a major potential impact on treatment planning. Results: All patients had one or more 68Ga-PSMA-11–positive primary prostate lesions. Twenty-five (34%) and 7 (9.5%) of the 73 patients had 68Ga-PSMA-11–positive pelvic LN and distant metastases, respectively. The sites of LN metastases in decreasing order of frequency were external iliac (20.5%), common iliac (13.5%), internal iliac (12.5%) obturator (12.5%), perirectal (4%), abdominal (4%), upper diaphragm (4%), and presacral (1.5%). The median size of the LN lesions was 6 mm (range, 4–24 mm). RT planning based on the CTVs covered 69 (94.5%) of the 73 primary lesions and 20 (80%) of the 25 pelvic LN lesions, on a per-patient analysis. Conclusion: 68Ga-PSMA-11 PET/CT had a major impact on intended definitive RT planning for PCa in 12 (16.5%) of the 73 patients whose RT fields covered the prostate, seminal vesicles, and pelvic LNs and in 25 (37%) of the 66 patients whose RT fields covered the prostate and seminal vesicles but not the pelvic LNs.

Gaps in Radiation Therapy Awareness: Results From an Educational Multi-institutional Survey of US Internal Medicine Residents

PURPOSE Internists and primary care providers play a growing role in cancer care. We therefore evaluated the awareness of radiation therapy in general and specifically the clinical utility of stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC) among current US internal medicine residents. METHODS AND MATERIALS A web-based institutional review board-approved multi-institutional survey was distributed to US internal medicine residency programs. The survey evaluated trainee demographic characteristics, baseline radiation oncology awareness, knowledge of the role of SBRT for early-stage NSCLC, and whether the survey successfully improved awareness. RESULTS Thirty US internal medicine programs participated, with an overall participant response rate of 46% (1177 of 2551). Of the trainees, 93% (n=1076) reported no radiation oncology education in their residency, 39% (n=452) reported confidence in knowing when to consult radiation oncology in an oncologic emergency, and 26% (n=293) reported confidence in knowing when to consult radiation oncology in the setting of a newly diagnosed cancer. Of the participants, 76% (n=850) correctly identified that surgical resection is the standard treatment in operable early-stage NSCLC, but only 50% (n=559) of participants would recommend SBRT to a medically inoperable patient, followed by 31% of participants (n=347) who were unsure of the most appropriate treatment, and 10% (n=117) who recommended waiting to offer palliative therapy. Ninety percent of participants (n=1029) agreed that they would benefit from further training on when to consult radiation oncology. Overall, 96% (n=1072) indicated that the survey increased their knowledge and awareness of the role of SBRT. CONCLUSIONS The majority of participating trainees received no education in radiation oncology in their residency, reported a lack of confidence regarding when to consult radiation oncology, and overwhelmingly agreed that they would benefit from further training. These findings should serve as a call to increase the educational collaboration between internal medicine and radiation oncology departments to ensure optimal cancer care.

Location Matters: Stage I Non–Small-cell Carcinomas of the Lower Lobes Treated With Stereotactic Body Radiation Therapy Are Associated With Poor Outcomes

Introduction The lung is a heterogeneous organ with relative overperfusion of the lung bases. We determined whether a lower lobe primary tumor location was associated with poor outcomes in the setting of stage I non–small‐cell lung cancer (NSCLC) treated with stereotactic body radiation therapy (SBRT). Patients and Methods The data from consecutive patients with stage I NSCLC treated from 2009 to 2014 with curative intent SBRT were analyzed. Primary tumors in the right and left lower lobes were compared against the tumors in all other locations to determine whether a lower lobe location was associated with worse local, regional, and distant control and worse relapse‐free and overall survival. The survival rates were estimated using Kaplan‐Meier analysis, and multivariate analysis was completed using the Cox proportional hazards model, adjusting for age, stage, performance status, and radiation dose. Results A total of 122 patients with early‐stage NSCLC who underwent SBRT were evaluated at a median follow‐up period of 28.6 months. On multivariate analysis, lower lobe tumors were associated with poor relapse‐free survival (hazard ratio [HR], 2.78; 95% confidence interval [CI], 1.21‐7.76; P = .04) and poor overall survival (HR, 2.33; 95% CI, 1.09‐5.64; P = .04). The 3‐year relapse‐free survival for patients with a lower lobe primary was 75% compared with 89% for patients with a non–lower lobe primary (P = .04). Additionally, the 3‐year overall survival rate for patients with a lower lobe primary was 63% versus 82% in patients with a non–lower lobe primary (P = .01). Conclusion Lower lobe stage I NSCLC tumors treated with SBRT are associated with poor relapse‐free and overall survival. Micro‐Abstract Identifying the risk factors for disease progression and death after stereotactic body radiation therapy (SBRT) for stage I non–small‐cell lung cancer (NSCLC) is essential. We evaluated the relationship between tumor location and outcomes in > 100 patients with stage I NSCLC who underwent SBRT and found that patients with lower lobe primary NSCLC had significantly worse relapse‐free and overall survival.

Feasibility evaluation of diffusion-weighted imaging using an integrated MRI-radiotherapy system for response assessment to neoadjuvant therapy in rectal cancer

OBJECTIVE To evaluate the feasibility of on-board diffusion-weighted imaging (DWI) with an integrated low-field MRI radiotherapy system to assess responses to neoadjuvant chemoradiation (NAC) in rectal cancer. METHODS A spin echo-based planar imaging diffusion sequence on a 0.35-T MRI radiotherapy system was acquired over the course of NAC. The apparent diffusion coefficients (ADCs) from the tumour regions of interest (ROIs) were calculated. A functional diffusion map (fDM) was created showing a pixelwise ADC analysis of the ROI over the course of treatment. Surgical pathology was correlated with ADC data. RESULTS Consecutive patients treated on a 0.35-T MRI radiotherapy system were evaluated. Patient A had the worst pathological response to NAC with a tumour regression score of 1 and was the only patient with a negative slope in the change of ADC values over the entire course of NAC, and during both the first and second half of NAC. The fDM from the first half of NAC for Patient A showed discrete dark areas in the tumour ROI, reflecting subregions with decreasing ADC values during NAC. Patient C had the most favourable pathological response to NAC with a Grade 3 response and was the only patient who had an increase in the slope in the change of ADC values from the first to the second half of NAC. CONCLUSION DWI using a low-field MRI radiotherapy system for evaluating the responses to NAC is feasible. Advances in knowledge: ADC values obtained using a 0.35-T MRI radiotherapy system over the course of NAC for rectal cancer correlate with pathological responses.

The significance of PTV dose coverage on cancer control outcomes in early stage non-small cell lung cancer patients treated with highly ablative stereotactic body radiation therapy

OBJECTIVE We evaluated whether patients with early-stage non-small-cell lung cancers (NSCLCs) treated with stereotactic body radiation therapy (SBRT) without full prescription dose coverage of the planning target volume (PTV) had inferior outcomes. METHODS The SBRT regimen was 54 Gy in three fractions. Dosimetric constraints were as per the Radiation Therapy Oncology Group 0236 guidelines. All patients underwent four-dimensional CT (4D-CT) simulation. The internal target volume (ITV) was defined using 4D-CT, and the PTV was defined as a 6-mm longitudinal and a 3-mm axial expansion from the ITV. If normal tissue constraints were beyond tolerance, ITV-based dosing was employed where priority was made for full ITV coverage at the expense of PTV coverage. Patients with and without full PTV dose coverage were compared, and control rates were estimated using Kaplan-Meier analysis. RESULTS 120 NSCLC cases were evaluated with 81% having adequate PTV dose coverage. ITV and PTV were significantly larger in the cohort with inadequate PTV dose coverage (p = 0.0085 and p = 0.0038, respectively), and the mean ITV and PTV doses were higher in patients with adequate PTV dose coverage (p = 0.002 and p < 0.0001, respectively). The 3-year local control rate was 100% for both cohorts. There was no difference in 3-year regional control (p = 0.36), disease-specific survival (p = 0.79) or overall survival (p = 0.73). CONCLUSION When delivering a highly ablative SBRT regimen for early-stage NSCLC, full-dose coverage of the ITV is sufficient for local control. ADVANCES IN KNOWLEDGE Our data are among the first to evaluate the utility of PTV margins in a highly ablative SBRT regimen and suggest that when dosing constraints cannot be met, full tumouricidal dose coverage of the ITV is sufficient for local control.

Treatment-Related Adverse Events Predict Improved Clinical Outcome in NSCLC Patients on KEYNOTE-001 at a Single Center

A retrospective analysis of non–small cell lung carcinoma patients treated with pembrolizumab found that treatment-related adverse events predicted improved clinical outcome. This observation could identify the patients most likely to benefit from anti–PD-1 therapy. We retrospectively analyzed non–small cell lung cancer (NSCLC) patients from a single center treated with pembrolizumab on the KEYNOTE-001 trial and evaluated the association between treatment-related adverse events (trAEs) and clinical outcomes. Investigators reported AEs on trial and graded them according to Common Terminology Criteria for Adverse Events v4.0, labeling them as unlikely, possibly, or probably treatment-related. AEs labeled as possibly/probably related were considered trAEs for this analysis. The relationship between the incidence of a trAE and clinical outcomes was evaluated. Ninety-seven NSCLC patients treated on KEYNOTE-001 at the University of California, Los Angeles were evaluated. Ten percent (85/826) of AEs were trAEs, occurring in 40% (39/97) of patients. The most frequent trAEs were rash (21% patients), fatigue (6% patients), and hypothyroidism (6% patients). The 39 patients that experienced a trAE had increased objective response rate (ORR, 38.5%), progression-free survival (PFS: median, 248 days), and overall survival (OS: median, 493 days), compared with the 58 patients that did not (ORR: 8.9%, PFS: median 60 days, OS: median 144.5 days). The observed association between trAEs and improved clinical outcome persisted when using Cox proportional hazards regression models to assess the confounding effect of covariates and mitigate guarantee-time bias. The association also remained when data were substratified by grade, degree of association, and treatment-related select AE designation. This single-center analysis revealed that trAEs predicted for improved clinical outcome with pembrolizumab, and when controlling for guarantee-time bias and plausible confounders, this association remained. This observed relationship adds to our understanding of anti–PD-1 therapy and could aid clinicians in identifying patients most likely to benefit from therapy. Cancer Immunol Res; 6(3); 288–94. ©2018 AACR.