Search

BACKGROUND Prior literature has suggested synergy between immune checkpoint therapy (ICT) and radiotherapy (RT) for the treatment of brain metastases (BrM), but to the authors' knowledge the optimal timing of therapy to maximize this synergy is unclear. METHODS A total of 199 patients with melanoma and non-small cell lung cancer with BrM received ICT and RT between 2007 and 2016 at the study institution. To reduce selection biases, individual metastases were included only if they were treated with RT within 90 days of ICT. Concurrent treatment was defined as RT delivered on the same day as or in between doses of an ICT course; all other treatment was considered to be nonconcurrent. Multivariable Cox proportional hazards models were used to assess time to response and local disease recurrence on a per-metastasis basis, using a sandwich estimator to account for intrapatient correlation. RESULTS The final cohort included 110 patients with 340 BrM, with 102 BrM treated concurrently and 238 BrM treated nonconcurrently. Response rates were higher with the use of concurrent treatment (70% vs 47%; P

OBJECTIVEConcurrent use of anti-PD-1 therapies with stereotactic radiosurgery (SRS) have been shown to be beneficial for survival and local lesional control in melanoma patients with brain metastases. It is not known, however, if immunotherapy (IT) confers the same outcome advantage in lung cancer patients with brain metastases treated with SRS.METHODSThe authors retrospectively reviewed 85 non–small cell lung cancer (NSCLC) patients with brain metastases who were treated with SRS between January 2006 and December 2016. Thirty-nine PD-L1 antibody–positive patients received anti-PD-1 therapy with SRS (IT group) and 46 patients received chemotherapy (CT) with SRS (CT group). Results were obtained using chi-square, Kaplan-Meier, and Mann-Whitney U tests and Cox regression analyses.RESULTSMedian survival following first radiosurgical treatment in the whole study group was 11.6 months (95% CI 8–15.5 months). Median survival times in the IT group and CT group were 10 months (95% CI 8.3–13.2 months) and 11.6 months (95% CI 7.7–15.6 months), respectively (p = 0.23). A Karnofsky Performance Status (KPS) score < 80 (p = 0.001) and lung-specific molecular marker Graded Prognostic Assessment (lungmol GPA) score < 1.5 (p = 0.02) were found to be predictive of worse survival.Maximal percent lesional shrinkage and time to maximal shrinkage were not significantly different between the CT and IT groups. Of the lesions for which a complete response occurred, 94.8% had pre-SRS volumes < 500 mm3. The amount of lesion shrinkage and time to maximal shrinkage were not different between the IT and CT groups for lesions with volumes < 500 mm3. However, in lesions with volume > 500 mm3, 90% of lesions shrank after radiosurgery in the IT group compared with 47.8% in the CT group (p = 0.001). Median times to initial response and times to maximal shrinkage were faster in the IT group than in the CT group: initial response 49 days (95% CI 33.7–64.3 days) versus 84 days (95% CI 28.1–140 days), p = 0.001; maximal response 105 days (95% CI 59–150 days) versus 182 days (95% CI 119.6–244 days), p = 0.12.CONCLUSIONSUnlike patients with melanoma, patients with NSCLC with brain metastases undergoing SRS showed no significant benefit—either in terms of survival or total amount of lesional response—when anti-PD-1 therapies were used. However, in lesions with volume > 500 mm3, combining SRS with IT may result in a faster and better volumetric response which may be particularly beneficial in lesions causing mass effect or located in neurologically critical locations.

Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment over the past decade. However, although the immune landscape suggests a strong rationale for the use of these agents in patients with head and neck squamous cell carcinoma, the available clinical evidence indicates that most patients currently do not respond to ICI monotherapy. Radiotherapy is a primary treatment modality for many patients with locally advanced head and neck cancer. While ionizing radiation traditionally has been thought to act in a purely cytotoxic fashion, a growing body of preclinical studies have demonstrated additional profound immunomodulatory effects. Consequently, there has been a surge of interest in the potential synergy between radiotherapy and immunotherapy, both the potential for radiotherapy to augment the systemic anti-tumor immune response and the potential for immunotherapy to improve in-field tumor response to radiation. In this review, we summarize the current preclinical and clinical evidence for radioimmunotherapy, with a particular focus on studies directly relevant to head and neck squamous cell carcinoma, as well as existing challenges and future directions for this emerging field.

Vaginal dilators (VD) are recommended following vaginal or pelvic radiotherapy for patients with endometrial carcinoma (EC) to prevent vaginal stenosis (VS). The time course of VS is not fully understood and the optimal duration of VD use is unknown. We reviewed 243 stage IA–II EC patients who received adjuvant brachytherapy (BT) at an academic tertiary referral center. Patients were instructed to use their VD three times per week for at least 1-year duration. The primary outcome was development of grade ≥ 1 VS using CTCAEv4 criteria during the follow-up period. The log-rank test and multivariable Cox proportional hazards modeling were used to evaluate the effect of VD use (noncompliance vs. standard compliance [up to 1 year] vs. extended compliance [over 1 year]) on VS. The median follow-up was 15.2 months over the 5-year study period. At 15 months, the incidence of VS was 38.8% for noncompliant patients, 33.5% for those with standard compliance, and 21.4% for those with extended compliance (median time to grade ≥ 1 VS was 17.5 months, 26.7 months, and not yet reached for these groups, respectively). On multivariable Cox regression analysis, extended compliance remained a significant predictor of reduced VS risk when compared to both noncompliance (HR 0.38, 95% CI 0.18–0.80, p = 0.012) and standard compliance (HR 0.43, 95% CI 0.20–0.89, p = 0.023). The risk of VS persists beyond 1 year after BT. Extended VD compliance beyond 1 year may mitigate this risk.

PURPOSE/OBJECTIVE(S) Automated target segmentation for non-small cell lung cancer (NSCLC) patients has the potential to support radiation treatment planning. Artificial intelligence (AI) has demonstrated great promise in medical image segmentation tasks. However, most studies have been confined to in silico validation in small internal cohorts, lacking data on real-world clinical utility. In this study, we developed primary tumor and involved lymph node segmentation algorithms in computed tomography (CT) images. Validation is performed in multiple large multi-institutional cohorts to assess model generalizability. MATERIALS/METHODS Simulation CTs and ground truth annotations were collected from multiple public and private sources (total n = 2584). We employed the following benchmarks: Inter-observer (6 radiation oncologists, n = 20, median volumetric dice 0.83, 95% CI 0.82-0.84) and intra-observer (1 radiation oncologist, 3 reads, n = 21, median volumetric dice 0.88, 95% CI 0.84-0.9). We developed two segmentation algorithms: seed-point assisted and fully automated. Model training data (n = 787) comprised NSCLC-Radiomics (stages I-IIIB, n = 422) and LungRT-1 (stages IA-IV, n = 365). Validation was first performed in an internal dataset annotated by a single thoracic radiation oncologist (LungRT-1, n = 136). Additional validation included: (1) an internal dataset annotated by other radiation oncologists, including generalists, in our center (LungRT-2, n = 1075), (2) an external clinical trial dataset from 185 different institutions (RTOG-0617, n = 403), and (3) a dataset of early-stage surgical patients annotated for diagnostic purposes by radiologists (NSCLC-Radiogenomics, n = 142). Volumetric dice, using expert manual segmentations as ground truth, was used as an evaluation metric. RESULTS The model performance is comparable to the benchmarks when validated on internal data, with degrading performance in cohorts annotated by other radiation oncologists. CONCLUSION The results highlight the importance of assessing segmentation style among annotators and understanding model generalizability in external cohorts, all while cautioning against degrading performance in increasingly external data. Differences between radiologists and radiation oncologists performing the same segmentation task underscore the importance of clinical context in AI model deployment. Further validation includes studying the dosimetric impact of AI-generated segmentations, and conducting human subject experiments to assess AI output acceptance and time savings.

PURPOSE/OBJECTIVE(S) Radiation (RT)-associated lymphopenia may adversely affect treatment outcomes, particularly in the era of immunotherapy. We sought to determine dosimetric factors (DF) correlated with lymphopenia following palliative RT in a cohort of patients with advanced cancer treated with anti-PD-1 immune checkpoint inhibitors (ICIs). MATERIALS/METHODS We included patients with metastatic lung cancer, melanoma, or renal cell carcinoma who were treated with either pembrolizumab or nivolumab and received palliative RT to an extracranial site. Baseline and nadir absolute lymphocyte count (ALC) within 6 weeks of RT were recorded. Heart, lungs, liver, kidneys, spleen, bone, and large blood vessels (LBV) were contoured for each RT course, and various DF were extracted from the corresponding dose-volume histograms (DVHs). To model RT dose to circulating lymphocytes, we also input these DVHs into a whole-body blood flow model that simulates the spatiotemporal distribution of blood particles in organs based on blood volumes and flow rates from ICRP-89. Associations between DF with ALC nadir and ALC change were assessed with Spearman correlation coefficients. DF with the strongest correlations were dichotomized at the median and evaluated for association with grade 3+ lymphopenia (ALC < 500cells/mL) post-RT by univariable logistic regression. RESULTS We analyzed 55 patients who underwent 80 total courses of palliative RT; most (94%) were treated with 3D conformal RT. Doses to whole body, bone, and LBV were negatively correlated with ALC nadir, with the strongest correlations seen at V15 (rs = -0.38, -0.43, and -0.36, P = 0.0004, 0.0001, and 0.001, respectively). Doses to other organs were not significantly correlated with ALC nadir. The modeled dose to circulating lymphocytes was also negatively correlated with ALC nadir and ALC change (for D2%, rs = -0.31 and -0.38, P = 0.005 and 0.0007, respectively). Associations between these DF and grade 3+ lymphopenia are shown in the Table. CONCLUSION RT dose to whole body, bone, and large blood vessels were correlated with lymphopenia in patients treated with palliative RT and anti-PD-1 ICIs. The modeled dose to circulating lymphocytes in our dynamic model correlated with lymphopenia as well, validating our model and enabling future investigation into dose rate and fractionation effects. These dose parameters may help guide RT planning to minimize lymphopenia risk, though additional studies are required to elicit the relative importance of each factor.

Background Numerous studies suggest that radiation can boost antitumor immune response by stimulating release of tumor-specific antigens. However, the optimal timing between radiotherapy and immune checkpoint blockade to achieve potentially synergistic benefits is unclear. Material and methods Multi-institutional retrospective analysis was conducted of ninety-nine metastatic melanoma patients from 2007 to 2014 treated with ipilimumab who later received stereotactic radiosurgery (SRS) for new brain metastases that developed after starting immunotherapy. All patients had complete blood count acquired before SRS. Primary outcomes were intracranial disease control and overall survival (OS). Results The median follow-up time was 15.5 months. In the MD Anderson cohort, patients who received SRS after 5.5 months (n = 20) of their last dose of ipilimumab had significantly worse intracranial control than patients who received SRS within 5.5 months (n = 51) (median 3.63 vs. 8.09 months; hazard ratio [HR] 2.07, 95% confidence interval [CI] 1.03–4.16, p = 0.041). OS was not different between the two arms. The improvement in intracranial control was confirmed in an independent validation cohort of 28 patients treated at Yale-New Haven Hospital. Circulating absolute lymphocyte count before SRS predicted for treatment response as those with baseline counts >1000/µL had reduced risk of intracranial recurrence compared with those with ≤1000/µL (HR 0.46, 95% CI 0.0.23–0.94, p = 0.03). Conclusions In this multi-institutional study, patients who received SRS for new brain metastases within 5.5 months after ipilimumab therapy had better intracranial disease control than those who received SRS later. Moreover, higher circulating lymphocyte count was associated with improved intracranial disease control.

Purpose An increasing number of clinical trials are studying immunotherapy for the treatment of brain metastases. The role of local therapy in this setting has not been well described. Methods and Materials Twenty-three melanoma patients with brain metastases were treated with pembrolizumab in a prospective phase 2 trial, NCT02085070, and included in this secondary analysis. Patients had at least 1 untreated or progressive brain metastasis, 5 to 20 mm in size, without any associated neurologic symptoms. Local therapy (stereotactic radiosurgery, surgery, or laser interstitial thermal therapy) was used to treat concerning lesions immediately before trial enrollment and was also allowed on trial in patients whose brain metastases were progressing, but who were otherwise deriving benefit. Results In total, 13 out of 23 patients (57%) received local therapy immediately before or during the trial—4 patients received local therapy before the trial owing to lesion size or location in sensitive areas; 6 during the trial because of tumor growth, hemorrhage, or radiation necrosis/cystic changes; and 3 both before and during the trial. Of the 10 patients who did not receive local therapy immediately before or during the trial, 8 patients (35%) did not later receive local therapy owing to rapid disease progression, and only 2 patients (9%) lived for 2 years without requiring any local therapy. Conclusions Local therapy continues to play an important role in the management of melanoma patients with brain metastases being treated with immunotherapy. These patients should be closely monitored via serial brain imaging, with a multidisciplinary team involved in clinical decision making to ensure each patient's neurologic safety.

BACKGROUND Growing evidence suggests that immunotherapy and radiation therapy can be synergistic in the treatment of cancer. This study was performed to determine the effect of the relative timing and type of immune checkpoint therapy on the response of melanoma brain metastases (BrMets) to treatment with stereotactic radiosurgery (SRS). METHODS Seventy-five melanoma patients with 566 BrMets were treated with both SRS and immune checkpoint therapy between 2007 and 2015 at a single institution. Immunotherapy and radiosurgery treatment of any single lesion were considered concurrent if SRS was administered within 4 weeks of immunotherapy. The impact of the timing and type of immunotherapy on the lesional response was determined with the Wilcoxon rank-sum test, which was used to compare the median percent lesion volume change 1.5, 3, and 6 months after SRS treatment, with significance determined by P = .0167 according to the Bonferroni correction for multiple comparisons. RESULTS Concurrent use of immunotherapy and SRS resulted in a significantly greater median percent reduction in the lesion volume at 1.5 (−63.1% vs −43.2%, P

BACKGROUND: The BRAF mutation has been identified as a potent target for the treatment of metastatic melanoma and BRAF inhibitors (BRAFi) have demonstrated promising results against melanoma brain metastases (BM). OBJECTIVE: To further investigate the effectiveness of this combined treatment regimen. METHODS: In this multicenter retrospective cohort study, 198 patients with known BRAF mutation status and treated with stereotactic radiosurgery (SRS) between 2011 and 2015 were identified. Kaplan–Meier methodology and multivariate regression analysis was then used to compare survival based on each parameter. RESULTS: The median survival after the diagnosis of BM in patients with BRAF mutation who received BRAFi was increased compared to survival in patients with wild-type BRAF (BRAF wt). In multivariate analysis, the BRAF mutation was an independent, positive prognostic factor with a hazard ratio of 0.59. BRAF mutated Patients who received BRAFi following SRS had improved survival compared to patients who received it before (P

Brain metastases are common in non-small cell lung cancer (NSCLC) and traditionally have been treated with whole brain radiation therapy, surgery, or stereotactic radiosurgery, with a limited role for systemic therapy. However, the development of highly active small molecule tyrosine kinase inhibitors for patients with NSCLC characterized by key driver mutations has generated interest in the use of systemic therapy as an alternative to potentially morbid local therapy for brain metastases. We present the case of a 59 year old Caucasian female with anaplastic lymphoma kinase (ALK) rearranged NSCLC who developed a large symptomatic brain metastasis not initially amenable to stereotactic radiosurgery (SRS) while receiving the ALK inhibitor crizotinib. The lesion regressed quickly after initiation of ceritinib, a next generation ALK inhibitor with known activity against crizotinib refractory ALK rearranged NSCLC, thereby allowing SRS as an alternative to standard craniotomy and consolidative whole brain radiation therapy.

Objective To examine the outcomes (tolerability, toxicity, and recurrence) of vaginal brachytherapy (VBT) among endometrial cancer (EC) patients treated with small cylinder size. Methods Patients with EC who received adjuvant VBT between September 2011 and December 2015 were reviewed. Patients were fitted with the largest vaginal cylinder they could comfortably accommodate, from 2.0–3.0 cm diameter. Small cylinders were defined as size 2.3 cm or less. Patient, tumor, or treatment characteristics were correlated with need for small cylinders. Treatment tolerability, measures of gastrointestinal (GI), genitourinary (GU), and vaginal toxicity, and rates of recurrence were analyzed. Results Three hundred four patients were included. Small cylinders were used in 51 patients (17%). Normal body mass index (BMI; p

The response assessment in neuro-oncology (RANO) working group recently proposed standardized response criteria for brain metastases (RANO-BM). We sought to compare RANO-BM to other criteria in an ongoing brain metastasis trial. The first 36 patients enrolled on NCT02085070, an ongoing trial of pembrolizumab for patients with untreated brain metastases, were included in this analysis. As RANO-BM had not been proposed when the protocol was written, response on trial was assessed using an institutional modification of RECIST 1.1 (mRECIST), wherein minimum target brain lesion size was 5 mm in longest diameter and up to five target brain lesions were followed. We here additionally assessed response using standard RECIST 1.1, RANO high-grade glioma (RANO-HGG), and RANO-BM. Comparison between the four criteria sets using cases eligible across the board revealed excellent concordance (kappa statistic > 0.8), with only one discordant case. However, compared to RECIST 1.1 or RANO-BM, using a 5 mm threshold for target brain lesions in mRECIST allowed enrollment of 13 additional patients, five of whom had durable responses. Compared to RANO-HGG, 19 additional patients were enrolled using mRECIST, eight of whom had durable responses. Consequently, this resulted in response rates ranging from 12% with RANO-HGG to 28% with mRECIST. This study supports using a 5 mm threshold for target brain lesions when using high resolution MRI with ≤2 mm slices to facilitate accrual to similar clinical trials and provide earlier access to novel therapies for brain metastasis patients. Concordance among the four criteria studied was otherwise very high.

Radiotherapy and DNA-damaging chemotherapy are frequently utilized in the treatment of solid tumors. Innate or acquired resistance to these therapies remains a major clinical challenge in oncology. The development of small molecules that sensitize cancers to established therapies represents an attractive approach to extending survival and quality of life in patients. Here, we demonstrate that YU238259, a member of a novel class of DNA double-strand break repair inhibitors, exhibits potent synthetic lethality in the setting of DNA damage response and DNA repair defects. YU238259 specifically inhibits homology-dependent DNA repair, but not non-homologous end-joining, in cell-based GFP reporter assays. Treatment with YU238259 is not only synergistic with ionizing radiation, etoposide, and PARP inhibition, but this synergism is heightened by BRCA2 deficiency. Further, growth of BRCA2-deficient human tumor xenografts in nude mice is significantly delayed by YU238259 treatment even in the absence of concomitant DNA-damaging therapy. The cytotoxicity of these small molecules in repair-deficient cells results from an accumulation of unresolved DNA double-strand breaks. These findings suggest that YU238259 or related small molecules may have clinical benefit to patients with advanced BRCA2-negative tumors, either as a monotherapy or as an adjuvant to radiotherapy and certain chemotherapies. Implications: We have identified a novel series of compounds that demonstrate synthetic lethality in DNA repair–deficient cell and animal models and have strong potential for clinical translation. Mol Cancer Res; 13(10); 1389–97. ©2015 AACR . This article is featured in Highlights of This Issue, [p. 1359][1] [1]: /lookup/volpage/13/1359?iss=10