Partial tumor irradiation plus pembrolizumab in treating large advanced solid tumor metastases.

BACKGROUNDWe previously demonstrated the safety of stereotactic body radiotherapy followed by pembrolizumab (SBRT+P) in patients with advanced solid tumors. This phase I clinical trial was expanded to study the safety of partial tumor irradiation (partial-Rx). We assessed irradiated local failure (LF) and clinical outcomes with correlations to biomarkers including CD8+ T cell radiomics score (RS) and circulating cytokines.METHODSPatients received SBRT to 2-4 metastases and pembrolizumab for up to 7 days after SBRT. Tumors measuring up to 65 cc received the full radiation dose (complete-Rx), whereas tumors measuring more than 65 cc received partial-Rx. Landmark analysis was used to assess the relationship between tumor response and overall survival (OS). Multivariable analysis was performed for RS and circulating cytokines.RESULTSIn the combined (expansion plus original) cohort, 97 patients (219 metastases) were analyzed and received SBRT+P. Forty-six (47%) patients received at least 1 partial-Rx treatment. There were 7 (7.2%)dose-limiting toxicities (DLTs). 1-year LF was 7.6% overall, and 13.3% and 5.4% for partial-Rx and complete-Rx tumors, respectively (HR 2.32, 95% CI 0.90-5.97, P = 0.08). The overall, unirradiated, and irradiated objective response rates were 22%, 12%, and 34%, respectively. Irradiated tumor response to SBRT+P was associated with prolonged OS; 1-year OS was 71% (responders), 42% (mixed-responders), and 0% (nonresponders) (P < 0.01). High-RS was significantly associated with improved LF, progression-free survival (PFS), and OS. Elevated circulating IL-8 was independently associated with inferior PFS and OS.CONCLUSIONSBRT+P is safe in patients with large, advanced solid tumors. Additional studies are warranted to assess noninferiority of complete versus partial irradiation of tumors in the setting of immunotherapy.TRIAL REGISTRATIONClinicaltrials.gov NCT02608385FUNDINGMerck Investigator Studies Program; Hillman Fellows for Innovative Cancer Research Program; NIH grants UM1CA186690-06, P50CA254865-01A1, P30CA047904-32, and R01DE031729-01A1.

A prospective clinical and transcriptomic feasibility study of oral-only hormonal therapy with radiation for unfavorable prostate cancer in men 70 years of age and older or with comorbidity.

BACKGROUND: Androgen deprivation therapy (ADT) improves outcomes in unfavorable-risk prostate cancer (PCa) treated with radiation therapy (RT). It was hypothesized that replacing luteinizing hormone-releasing hormone (LHRH) agonists with a 5-α-reductase inhibitor (5-ARI) would improve hormonal health-related quality of life (HRQOL) without differentially suppressing androgen-responsive (AR) gene expression. METHODS: Patients with localized unfavorable-risk PCa, aged ≥70 years or Charlson Comorbidity Index score ≥2 were treated with oral ADT (oADT), consisting of 4 months of bicalutamide, a 5-ARI, and RT at 78 Gy. The primary end point was Expanded Prostate Cancer Index Composite HRQOL at 6 months ≤30%, and improvement compared with a synchronous standard of care (SOC) cohort receiving 4 months of bicalutamide and long-term LHRH agonist with RT. RNA sequencing was performed from matched pre-/post-ADT prostate tumor biopsies in a subset of men. Differential gene and pathway expressional changes were examined using gene set enrichment. RESULTS: Between 2011 and 2018, 40 and 30 men were enrolled in the oADT and SOC cohorts, respectively. Median follow-up was 40 months. Those with ≤30% decline in hormonal HRQOL at 6 months was 97% (oADT) and 93% (SOC). The average 6-month hormonal decline was 1% (oADT) versus 12% (SOC; P = .04). The 4-year freedom from biochemical failure was 88% (oADT) versus 81% (SOC; P = .48). RNA sequencing (n = 9) showed similar numbers of downregulated and upregulated genes between the treatment groups (fold-change = 2; false-discovery rate-adjusted P ≤ .05). Both treatments comparably decreased the expression of 20 genes in canonical androgen receptor signaling. CONCLUSIONS: For men with PCa undergoing RT, oral versus standard ADT may improve 6-month QOL and appears to have a similar impact on androgen-responsive gene expression.

Adjuvant treatment for high-risk salivary gland malignancies and prognostic stratification based on a 20-year single institution experience.

BACKGROUND AND AIM: Retrospective analysis of the utility of adjuvant radiation (RT) or chemoradiation (CRT) and identify prognostic features for patients with high-risk head and neck salivary gland cancers. METHODS: From 1/1997 to 12/2017, 108 patients underwent surgery, and RT (n = 50) or CRT (n = 58) for positive lymph node(s), extracapsular extension, perineural invasion, lymphovascular space invasion, positive/close margin, and/or grade 3 disease. Outcomes were estimated with the Kaplan-Meier method. Significant predictors identified through regression analyses were incorporated into multivariable regression (MVA). Toxicities were compared using chi-square. RESULTS: The median follow-up was 52 months (range: 3-226). The number of risk factors (RFs) between RT and CRT groups were: 0 to 1 (44% vs 7%), 2 to 3 (48% vs 41%), or 4 to 6 (8% vs 52%), respectively (P < .01). On MVA, stage 3 or 4 disease predicted worse outcomes including overall survival (HR 4.55, P = .01). Increasing number of RFs predicted worse disease-free survival, distant metastasis-free survival, and overall survival (2-3 RFs: HR 3.38, P = .03; 4-6 RFs: HR 5.78, P < .01), but not locoregional control (P = .54). So, adjuvant CRT may have provided comparable locoregional control for patients with more adverse features, but the CRT did not translate into improved distant control. There was no difference in acute or late grade 3+ toxicities, or parenteral nutrition (P = .98, P = .85, and P = .83), respectively. CONCLUSIONS: Adjuvant CRT provides adequate locoregional control in patients with more adverse RFs. The absolute number of RFs serves prognostic significance and should be considered in future prospective trials.

Improved Survival Associated with Local Tumor Response Following Multisite Radiotherapy and Pembrolizumab: Secondary Analysis of a Phase I Trial.

PURPOSE: Multisite stereotactic body radiotherapy followed by pembrolizumab (SBRT+P) has demonstrated safety in advanced solid tumors (ASTs). However, no studies have examined the relationships between irradiated tumor response, SBRT-induced tumor gene expression, and overall survival (OS). PATIENTS AND METHODS: Patients with AST received SBRT (30-50 Gy in 3-5 fractions) to two to four metastases followed by pembrolizumab (200 mg i.v. every 3 weeks). SBRT was prescribed to a maximum tumor volume of 65 mL. Small metastases received the complete prescribed coverage (complete-Rx), while larger metastases received partial coverage (partial-Rx). Treated metastasis control (TMC) was defined as a lack of progression for an irradiated metastasis. Landmark analysis was used to assess the relationship between TMC and OS. Thirty-five biopsies were obtained from 24 patients: 19 pre-SBRT and 16 post-SBRT (11 matched) prior to pembrolizumab and were analyzed via RNA microarray. RESULTS: Sixty-eight patients (139 metastases) were enrolled with a median follow-up of 10.4 months. One-year TMC was 89.5% with no difference between complete-Rx or partial-Rx. On multivariable analysis, TMC was independently associated with a reduced risk for death (HR, 0.36; 95% confidence interval, 0.17-0.75; P = 0.006). SBRT increased expression of innate and adaptive immune genes and concomitantly decreased expression of cell cycle and DNA repair genes in the irradiated tumors. Elevated post-SBRT expression of DNASE1 correlated with increased expression of cytolytic T-cell genes and irradiated tumor response. CONCLUSIONS: In the context of SBRT+P, TMC independently correlates with OS. SBRT impacts intratumoral immune gene expression associated with TMC. Randomized trials are needed to validate these findings.

Proceedings of the ASTRO-RSNA Oligometastatic Disease Research Workshop.

PURPOSE: On June 13 to 14, 2019, the American Society for Radiation Oncology and the Radiological Society of North America convened a workshop on the treatment of oligometastatic disease in Washington, DC. The workshop was initiated for several reasons. First, oligometastatic disease is of increasing academic and community interest and has been identified by the American Society for Radiation Oncology membership as a top research priority. Second, emerging imaging and diagnostic technologies are more readily defining and detecting oligometastatic disease, making contemporary discussion of oligometastatic disease especially relevant. Third, radiosurgery and radiation in general are theorized to be ideal noninvasive therapy for the treatment of oligometastatic disease. Finally, innovations in targeted therapy and immune therapy have the potential to reverse widely disseminating disease into an oligometastatic state. METHODS AND MATERIALS: The workshop was organized into 2 keynote addresses, 6 scientific sessions, and 3 group discussions during an end-of-workshop breakout session. New scientific work was presented in the form of 4 oral presentations and a poster session. Workshop participants were charged with attempting to answer 3 critical questions: (1) Can we refine the clinical and biological definitions of oligometastatic disease; (2) how can we better treat oligometastatic disease; and (3) what clinical trials are needed? RESULTS: Here, we present the proceedings of the workshop. CONCLUSIONS: The clinical implications of improved treatment of oligometastatic disease are enormous and immediate. Radiation oncology and diagnostic radiology should rightly be at the forefront of the characterization and treatment of oligometastatic disease. Focused effort is required so that we can translate current efforts of large numbers of studies with few patients to larger studies of larger impact.

The clinical utility of imaging methods used to measure hypoxia in cervical cancer.

While it is well-established that hypoxia is a major factor that affects clinical outcomes in cervical cancer, widespread usage of clinically available methods to detect and evaluate hypoxia during the course of treatment have not been established. This review compares these methods, summarizes their strengths and weaknesses, and assesses the pathways for their useful employment to alter clinical practice. We conducted a search on PubMed for literature pertaining to imaging hypoxic cervical cancer, and implemented keywords related to oxygen measurement tools to improve the relevance of the search results.Oxygenation level-dependent applications of MRI have demonstrated hypoxia-induced radioresistance, and changes in cervix tumor oxygenation from hyperoxic therapy.The hypoxic areas within tumors can be indirectly identified in dynamic contrast-enhanced images, where they generally display low signal enhancement, and diffusion-weighted images, which demonstrates areas of restricted diffusion (which correlates with hypoxia). Positron emmision tomography, used independently and with other imaging modalities, has demonstrated utility in imaging hypoxia through tracers specific for low oxygen levels, like Cu-ATSM tracers and nitroimidazoles. Detecting hypoxia in the tumors of patients diagnosed with cervical cancer via medical imaging and non-imaging tools like electron paramagnetic resonance oximetry can be utilized clinically, such as for guiding radiation and post-treatment surveillance, for a more personalized approach to treatment. The merits of these methods warrant further investigation via comparative effectiveness research and large clinical trials into their clinical applications.

The Evolution (and Future) of Stereotactic Body Radiotherapy in the Treatment of Oligometastatic Disease.

This review outlines the history of the oligometastatic state from its first proposal to the current formulation. The article discusses the accumulating evidence for the biology of oligometastases, including clinical parameters, such as number and rate of progression, as well as ongoing molecular profiling efforts. The authors then discuss the current state of prospective clinical trials. They review the early site-specific as well as subsite agnostic studies using stereotactic body radiation therapy. Moreover, the article makes the case for why phase II trials should not be practice changing, and highlights the pivotal importance of accruing to phase III clinical trials.

Predictors of Lymph Node Involvement by Soft Tissue Sarcoma of the Trunk and Extremity: An Analysis of the National Cancer Database.

Background and Objectives Lymph node metastases (LNM) in soft tissue sarcoma (STS) of the trunk and extremity are rare but are associated with worse survival. Established risk factors for LNM in this group are based on small institutional retrospective reviews. This study identifies the risk factors associated with LNM in otherwise non-metastatic trunk/extremity STS patients using the National Cancer Database (NCDB) and sought out to delineate a high-risk group that may be considered for pathologic nodal evaluation. Methods The files of 10,731 patients with STS of the trunk/extremity without distant metastasis from 2004 - 2015 were evaluated. Exclusion criteria included neoadjuvant therapy and a lack of pathologic nodal evaluation. Univariate and multivariable logistic regression models were performed to evaluate variables associated with LNM. Results Of the total of 10,731 patients, 223 (2.1%) had LNM. On multivariable analysis, LNM was associated with Grade 3 tumors (odds ratio (OR) 15.6, 95% confidence interval (CI) 6.36 - 38.04, p < 0.001) and clear cell/angiosarcoma/rhabdomyosarcoma/epithelioid (CARE) histology (OR 4.72, 95% CI 3.35 - 6.66, p < 0.001), lymphovascular invasion (LVI) (OR 5.86, 95% CI 3.33 - 10.31, p < 0.001, and bone invasion (BI) (OR 2.73, 95% CI 1.32 - 5.61, p = 0.006). Patients with Grade 3 CARE tumors (n = 402) had an 11.9% risk of LNM vs. 1.7% of adults without all these characteristics (p < 0.001). Patients with Grade 3 CARE tumors and either LVI or BI (n = 36) had a 33.3% risk of LNM. Conclusions High-grade and CARE histology are associated with LNM in STS. Adult patients with both features have an overall 11.9% risk of LNM and may be considered for pathologic LN assessment, particularly with the presence of LVI or BI.

Radiation-Induced Sarcoma After Heterotopic Ossification Prophylaxis: A Case Report.

CASE: Heterotopic ossification (HO) is a pathological formation of bone in nonosseous tissue and is a common complication of orthopaedic procedures. Radiotherapy is often used to prevent HO despite the small risk of secondary malignancy. Here, we report a case of a patient who developed a periprosthetic, radiation-induced sarcoma after delivery of a single fraction of 7 Gy for HO prophylaxis. This sarcoma was found to lie entirely within the treatment field and occurred within 5 years of radiation. CONCLUSION: Appropriate counseling regarding radiation-induced sarcoma formation should be provided to patients considering radiotherapy for this HO prophylaxis.

The Yin and Yang of Cytoreductive SBRT in Oligometastases and Beyond.

Background: Oligometastatic disease has emerged as a possibly distinct metastatic phenotype in numerous cancer histologies. With the advancement in treatment modalities including stereotactic body radiation therapy (SBRT), certain patients may derive benefits from local ablative therapy. SBRT alone has already shown to have potential benefits in certain oligometastatic disease types. However, more understanding of the immunologic modulation and microenvironment is needed to guide which patients may benefit from SBRT alone or with combination therapy, if at all. Purpose: The purpose of this review is to offer an update on the emerging data testing SBRT combined with immunotherapy, review the pro-inflammatory and immunosuppressive effects of the tumor microenvironment, discuss novel molecular targets used to augment the immune response, and review potential methods used to decrease toxicity in order to improve the therapeutic ratio.

Clinical and Dosimetric Implications of Intrafractional Cylinder Movement During Vaginal Cuff Brachytherapy.

Introduction To quantify the dosimetric and clinical effects of intrafractional cylinder movement in patients receiving high-dose-rate vaginal cuff brachytherapy (VBT) without a formal immobilization device and the implication of motion on institutional clinical outcomes. Methods From 2013-2018, 119 patients were treated with VBT with no formal immobilization device at a single institution. As a quality assessment study, pre-and post-cylinder brachytherapy kilovoltage (kV) images were acquired for 37 fractions in nine consecutive patients who underwent VBT and clinical care representative of institutional practice standards. The D90 and D90 EqD2 were calculated according to each patient's average intrafractional movement throughout the treatment course. The D2cc for organs-at-risk (OARs) were also re-evaluated following the simulated movements. The survival outcomes and toxicity were recorded from the 119 patients. Toxicity was graded as per Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Results The measured mean ± standard deviation movement was 5.0 mm ± 3.5, with 62% moving caudad. The D90 from each patient's maximum and average movements were lower than the pre-planned doses: 71%, and 89%, respectively. The doses to the OARs were lower than the pre-planned doses. After a median follow-up of 20 months, there were three local recurrences with a median time of 14.5 months (range: 10-31). There were two acute grade 3+ toxicities and one late grade 3+ toxicity. There was a moderate correlation (r = 0.40) between body mass index (BMI) and intrafraction movement with caudad being more common in smaller BMIs (p = 0.0216). Conclusions Intrafractional vaginal cylinder movement without a table fixation device is about 5.0 mm, with the majority of movements moving caudad. While institutional outcomes suggest that local control may not be compromised, consideration of more formal immobilization devices is warranted, especially for those patients with lower BMIs.

Institutional experience using interstitial brachytherapy for the treatment of primary and recurrent pelvic malignancies.

PURPOSE: The study assessed the outcomes of patients at a single institution with locally advanced primary and recurrent pelvic malignancies treated with interstitial high-dose-rate (HDR) or low-dose-rate (LDR) brachytherapy (BT), using a modified Syed-Neblett template. MATERIAL AND METHODS: Between 1996 and 2010, 60 patients with primary or recurrent pelvic malignancies were treated with interstitial BT. Thirty three patients had primary malignancies with 6.1% being stage I, 33.3% stage II, 45.5% stage III, and 15.2% stage IV; the remaining 27 patients were recurrent malignancies. Fifty four patients received external beam radiotherapy (EBRT) as part of their treatment course. The median EBRT, BT, and EBRT + BT doses were 45 Gy, 20 Gy, and 65 Gy, respectively. Thirty eight patients received concurrent chemotherapy with EBRT. Complete response (CR) was defined by absence of clinical and radiographic disease on first follow-up. Toxicity was graded as per Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: The median follow-up was 37 months (4-234 months) and initial CR was achieved in 91%. For primary cancers at diagnosis, 5-year local control (LC), 5-year progression-free survival (PFS), 5-year overall survival (OS) were 65%, 64%, and 42% respectively. For recurrent cancers at diagnosis, 5-year LC, 5-year PFS, and 5-year OS were 80%, 51%, and 37%, respectively. There was a significant difference in both OS and PFS among different tumor sites (p < 0.05), with vaginal cancers having the best 5-year OS (55%) and PFS (84%). There was a total of 1 acute toxicity ≥ grade 3, 6 late grade 3 toxicities, and late grade 4 toxicity. CONCLUSIONS: Our series suggests that interstitial BT using a modified Syed-Neblett template is a safe and effective treatment for primary or recurrent pelvic malignancies. This technique allowed effective LC and 97% of patients had preservation of both bladder and rectal function.