Five-Fraction High-Conformal Ultrahypofractionated Radiotherapy for Primary Tumors in Metastatic Breast Cancer.

PURPOSE: To report on the local control and toxicity of 5-fraction, high-conformal ultrafractionated radiation therapy (RT) for primary tumors in patients with metastatic breast cancer (MBC) who did not undergo planned surgical intervention. METHODS: We retrospectively reviewed 27 patients with MBC who underwent 5-fraction high-dose ultrafractionated intensity-modulated RT for their primary tumors between 2017 and 2022 at our institution. A median dose of 66.8 Gy (range, 51.8-83.6 Gy) was prescribed to the gross tumor, calculated in 2-Gy equivalents using an α/ß ratio of 3.5, along with a simultaneous integrated boost of 81.5%. The primary endpoint of this study was local control. RESULTS: The median tumor size and volume were 5.1 cm and 112.4 cm3, respectively. Treatment was generally well tolerated, with only 15% of the patients experiencing mild acute skin toxicity, which resolved spontaneously. The best infield response rate was 82%, with the objective response observed at a median time of 10.8 months post-RT (range, 1.4-29.2), until local progression or the last follow-up. At a median follow-up of 18.3 months, the 2-year local control rate was 77%. A higher number of prior lines of systemic therapy was significantly associated with poorer 2-year local control (one-two lines, 94% vs three or more lines, 34%; p = 0.004). Post-RT, 67% of the patients transitioned to the next line of systemic therapy, and the median duration of maintaining the same systemic therapy post-RT was 16.3 months (range, 1.9-40.3). CONCLUSION: In our small dataset, 5-fraction, high-conformal ultrahypofractionated breast RT offered promising 2-year local control with minimal toxicity. Further studies are warranted to investigate the optimal dose and role in this setting.

Single vs. multiple fraction non-inferiority trial of stereotactic ablative radiotherapy for the comprehensive treatment of oligo-metastases/progression: SIMPLIFY-SABR-COMET.

BACKGROUND: Radiotherapy delivery regimens can vary between a single fraction (SF) and multiple fractions (MF) given daily for up to several weeks depending on the location of the cancer or metastases. With limited evidence comparing fractionation regimens for oligometastases, there is support to explore toxicity levels to nearby organs at risk as a primary outcome while using SF and MF stereotactic ablative radiotherapy (SABR) as well as explore differences in patient-reported quality of life and experience. METHODS: This study will randomize 598 patients in a 1:1 ratio between the standard arm (MF SABR) and the experimental arm (SF SABR). This trial is designed as two randomized controlled trials within one patient population for resource efficiency. The primary objective of the first randomization is to determine if SF SABR is non-inferior to MF SABR, with respect to healthcare provider (HCP)-reported grade 3-5 adverse events (AEs) that are related to SABR. Primary endpoint is toxicity while secondary endpoints include lesional control rate (LCR), and progression-free survival (PFS). The second randomization (BC Cancer sites only) will allocate participants to either complete quality of life (QoL) questionnaires only; or QoL questionnaires and a symptom-specific survey with symptom-guided HCP intervention. The primary objective of the second randomization is to determine if radiation-related symptom questionnaire-guided HCP intervention results in improved reported QoL as measured by the EuroQoL-5-dimensions-5levels (EQ-5D-5L) instrument. The primary endpoint is patient-reported QoL and secondary endpoints include: persistence/resolution of symptom reporting, QoL, intervention cost effectiveness, resource utilization, and overall survival. DISCUSSION: This study will compare SF and MF SABR in the treatment of oligometastases and oligoprogression to determine if there is non-inferior toxicity for SF SABR in selected participants with 1-5 oligometastatic lesions. This study will also compare patient-reported QoL between participants who receive radiation-related symptom-guided HCP intervention and those who complete questionnaires alone. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT05784428. Date of Registration: 23 March 2023.

Upfront Versus Delayed Systemic Therapy in Patients With Oligometastatic Cancer Treated With SABR in the Phase 2 SABR-5 Trial.

PURPOSE: The optimal sequencing of local and systemic therapy for oligometastatic cancer has not been established. This study retrospectively compared progression-free survival (PFS), overall survival (OS), and SABR-related toxicity between upfront versus delay of systemic treatment until progression in patients in the SABR-5 trial. METHODS AND MATERIALS: The single-arm phase 2 SABR-5 trial accrued patients with up to 5 oligometastases across SABR-5 between November 2016 and July 2020. Patients received SABR to all lesions. Two cohorts were retrospectively identified: those receiving upfront systemic treatment along with SABR and those for whom systemic treatment was delayed until disease progression. Patients treated for oligoprogression were excluded. Propensity score analysis with overlap weighting balanced baseline characteristics of cohorts. Bootstrap sampling and Cox regression models estimated the association of delayed systemic treatment with PFS, OS, and grade ≥2 toxicity. RESULTS: A total of 319 patients with oligometastases underwent treatment on SABR-5, including 121 (38%) and 198 (62%) who received upfront and delayed systemic treatment, respectively. In the weighted sample, prostate cancer was the most common primary tumor histology (48%) followed by colorectal (18%), breast (13%), and lung (4%). Most patients (93%) were treated for 1 to 2 metastases. The median follow-up time was 34 months (IQR, 24-45). Delayed systemic treatment was associated with shorter PFS (hazard ratio [HR], 1.56; 95% CI, 1.15-2.13; P = .005) but similar OS (HR, 0.90; 95% CI, 0.51-1.59; P = .65) compared with upfront systemic treatment. Risk of grade 2 or higher SABR-related toxicity was reduced with delayed systemic treatment (odds ratio, 0.35; 95% CI, 0.15-0.70; P < .001). CONCLUSIONS: Delayed systemic treatment is associated with shorter PFS without reduction in OS and with reduced SABR-related toxicity and may be a favorable option for select patients seeking to avoid initial systemic treatment. Efforts should continue to accrue patients to histology-specific trials examining a delayed systemic treatment approach.

Should organs at risk (OARs) be prioritized over target volume coverage in stereotactic ablative radiotherapy (SABR) for oligometastases? a secondary analysis of the population-based phase II SABR-5 trial.

BACKGROUND AND PURPOSE: Stereotactic ablative radiotherapy (SABR) for oligometastases may improve survival, however concerns about safety remain. To mitigate risk of toxicity, target coverage was sacrificed to prioritize organs-at-risk (OARs) during SABR planning in the population-based SABR-5 trial. This study evaluated the effect of this practice on dosimetry, local recurrence (LR), and progression-free survival (PFS). METHODS: This single-arm phase II trial included patients with up to 5 oligometastases between November 2016 and July 2020. Theprotocol-specified planning objective was to cover 95 % of the planning target volume (PTV) with 100 % of the prescribed dose, however PTV coverage was reduced as needed to meet OAR constraints. This trade-off was measured using the coverage compromise index (CCI), computed as minimum dose received by the hottest 99 % of the PTV (D99) divided by the prescription dose. Under-coverage was defined as CCI < 0.90. The potential association between CCI and outcomes was evaluated. RESULTS: 549 lesions from 381 patients were assessed. Mean CCI was 0.88 (95 % confidence interval [CI], 0.86-0.89), and 196 (36 %) lesions were under-covered. The highest mean CCI (0.95; 95 %CI, 0.93-0.97) was in non-spine bone lesions (n = 116), while the lowest mean CCI (0.71; 95 % CI, 0.69-0.73) was in spine lesions (n = 104). On multivariable analysis, under-coverage did not predict for worse LR (HR 0.48, p = 0.37) or PFS (HR 1.24, p = 0.38). Largest lesion diameter, colorectal and 'other' (non-prostate, breast, or lung) primary predicted for worse LR. Largest lesion diameter, synchronous tumor treatment, short disease free interval, state of oligoprogression, initiation or change in systemic treatment, and a high PTV Dmax were significantly associated with PFS. CONCLUSION: PTV under-coverage was not associated with worse LR or PFS in this large, population-based phase II trial. Combined with low toxicity rates, this study supports the practice of prioritizing OAR constraints during oligometastatic SABR planning.

Effectiveness of radiotherapy for local control in T3N0 rectal cancer managed with total mesorectal excision: a meta-analysis.

INTRODUCTION: The total mesorectal excision (TME) significantly improved rectal cancer outcomes. Radiotherapy's benefit in T3N0 rectal cancer patients managed with TME has not been clearly demonstrated. A systematic review and meta-analysis were undertaken to determine whether radiotherapy altered the risk of locoregional recurrence (LR) in T3N0 rectal cancer patients managed with a TME. MATERIALS AND METHODS: Studies indexed on PubMed or Embase were systematically searched from inception to October 18, 2020. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were observed for the literature search, study screening, and data extraction; the Newcastle Ottawa Scale evaluated bias; Grades of Recommendation, Assessment, Development, and Evaluation Working Group system evaluated certainty; and all were performed independently by at least two investigators. Studies that reported LR data specific to T3N0 rectal cancer patients managed with TME, treated with and without radiotherapy, were included. Data was pooled using a random-effects model. Meta-analyses of the relative risk of local recurrence were conducted. RESULTS: Five retrospective cohort studies involving 932 unique patients reported LR outcomes; no prospective studies met eligibility criteria. Median follow-up ranged from 38.4-78 months. Adjuvant radiotherapy was provided in 3 studies. Chemotherapy was delivered and reported in 4 studies, providing both concurrent and adjuvant chemotherapy. A non-significant LR reduction with radiotherapy alongside TME was estimated, mean relative risk (RR) 0.63 (95% Confidence Interval 0.31-1.29; I2 = 41.8%). CONCLUSIONS: A non-significant LR benefit with radiotherapy's addition was estimated. Meta-analysis of exclusively retrospective cohort studies was concerning for biased results. Adequately powered randomized trials are warranted.

Treatment With Stereotactic Ablative Radiotherapy for Up to 5 Oligometastases in Patients With Cancer: Primary Toxic Effect Results of the Nonrandomized Phase 2 SABR-5 Clinical Trial.

Importance: After the publication of the landmark SABR-COMET trial, concerns arose regarding high-grade toxic effects of treatment with stereotactic ablative body radiotherapy (SABR) for oligometastases. Objective: To document toxic effects of treatment with SABR in a large cohort from a population-based, provincial cancer program. Design, Setting, and Participants: From November 2016 to July 2020, 381 patients across all 6 cancer centers in British Columbia were treated in this single-arm, phase 2 trial of treatment with SABR for patients with oligometastatic or oligoprogressive disease. During this period, patients were only eligible to receive treatment with SABR in these settings in trials within British Columbia; therefore, this analysis is population based, with resultant minimal selection bias compared with previously published SABR series. Interventions: Stereotactic ablative body radiotherapy to up to 5 metastases. Main Outcomes and Measures: Rate of grade 2, 3, 4, and 5 toxic effects associated with SABR. Findings: Among 381 participants (122 women [32%]), the mean (SD; range) age was 68 (11.1; 30-97) years, and the median (range) follow-up was 25 (1-54) months. The most common histological findings were prostate cancer (123 [32%]), colorectal cancer (63 [17%]), breast cancer (42 [11%]), and lung cancer (33 [9%]). The number of SABR-treated sites were 1 (263 [69%]), 2 (82 [22%]), and 3 or more (36 [10%]). The most common sites of SABR were lung (188 [34%]), nonspine bone (136 [25%]), spine (85 [16%]), lymph nodes (78 [14%]), liver (29 [5%]), and adrenal (15 [3%]). Rates of grade 2, 3, 4, and 5 toxic effects associated with SABR (based on the highest-grade toxic effect per patient) were 14.2%; (95% CI, 10.7%-17.7%), 4.2% (95% CI, 2.2%-6.2%), 0%, and 0.3% (95% CI, 0%-0.8%), respectively. The cumulative incidence of grade 2 or higher toxic effects associated with SABR at year 2 by Kaplan-Meier analysis was 8%, and for grade 3 or higher, 4%. Conclusions and Relevance: This single-arm, phase 2 clinical trial found that the incidence of grade 3 or higher SABR toxic effects in this population-based study was less than 5%. Furthermore, the rates of grade 2 or higher toxic effects (18.6%) were lower than previously published for SABR-COMET (29%). These results suggest that SABR treatment for oligometastases has acceptable rates of toxic effects and potentially support further enrollment in randomized phase 3 clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02933242.

Predictors of Early Polymetastatic Relapse After SABR for up to 5 Oligometastases: A Secondary Analysis of the Phase II SABR-5 Trial.

PURPOSE: A subset of patients with oligometastatic cancer experience early widespread cancer dissemination and do not benefit from metastasis-directed therapy such as SABR. This study aimed to identify factors associated with early polymetastatic relapse (PMR). METHODS AND MATERIALS: The SABR-5 trial was a single arm phase 2 study conducted at all 6 regional cancer centers across British Columbia (BC), Canada. SABR for oligometastases was only offered on trial. Patients with up to 5 oligometastatic lesions (total, progressing, or induced) received SABR to all lesions. Patients were 18 years of age or older, Eastern Cooperative Oncology Group 0 to 2 and life expectancy ≥6 months. This secondary analysis evaluated factors associated with early PMR, defined as disease recurrence within 6 months of SABR, which is not amenable to further local treatment. Univariable and multivariable analyses were performed using binary logistic regression. The Kaplan-Meier method and log-rank tests assessed PMR-free survival and differences between risk groups, respectively. RESULTS: Between November 2016 and July 2020, 381 patients underwent treatment on SABR-5. A total of 16% of patients experienced PMR. Worse performance status (Eastern Cooperative Oncology Group 1-2 vs 0; hazard ratio [HR] = 2.01, P = .018), nonprostate/breast histology (HR = 3.64, P <.001), and oligoprogression (HR = 3.84, P <.001) were independent predictors for early PMR. Risk groups were identified with median PMR-free survival ranging from 5 months to not yet reached at the time of analysis. Rates of 3-year overall survival were 0%, 53% (95% confidence interval [CI], 48-58), 77% (95% CI, 73-81), and 93% (95% CI, 90-96) in groups 1 to 4, respectively (P <.001). CONCLUSIONS: Four distinct risk groups for early PMR are identified, which differ significantly in PMR-free survival and overall survival. The group with all 3 risk factors had a median PMR-free survival of 5 months and may not benefit from local ablative therapy alone. This model should be externally validated with data from other prospective trials.

Dosimetric Modeling of Lymphopenia in Patients With Metastatic Cancer Receiving Palliative Radiation and PD-1 Immune Checkpoint Inhibitors.

PURPOSE: Radiation therapy (RT)-associated lymphopenia may adversely affect treatment outcomes, particularly in the era of immunotherapy. We sought to determine dosimetric factors correlated with lymphopenia after palliative RT in a cohort of patients with advanced cancer treated with anti-PD-1 immune checkpoint inhibitors. METHODS AND MATERIALS: 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 counts (ALCs) within 6 weeks of RT were recorded. Dosimetric factors were extracted from the corresponding dose-volume histograms and also used to model the dose to circulating lymphocytes via a whole-body blood flow model that simulates the spatiotemporal distribution of blood particles in major organs during RT. RESULTS: We analyzed 55 patients who underwent 80 total courses of palliative RT; most (94%) were treated with 3-dimensional conformal RT. Doses to the whole body, bone, and large blood vessels (LBVs) were negatively correlated with the ALC nadir, with the strongest correlations seen at V15 (rs, -0.38, -0.43, and -0.37, and P = .0004, .0001, and .0008, respectively). Doses to other organs were not significantly correlated with the ALC nadir. The modeled dose to circulating lymphocytes was also negatively correlated with the ALC nadir and percent ALC change (for D2%, rs, -0.31 and -0.44, and P = .005 and .0001, respectively). Grade ≥3 lymphopenia was associated with LBV V15 (odds ratio [OR], 1.16; 95% CI, 1.07-1.26; P < .001), bone V15 (OR, 1.04; 95% CI, 1.01-1.08; P = .03), body V15 (OR, 1.003; 95% CI, 1.001-1.006; P = .008), and modeled lymphocyte dose (OR, 1.45; 95% CI, 1.16-1.82; P < .001). CONCLUSIONS: The RT dose to the whole body, bone, and LBVs and the modeled dose to circulating lymphocytes were correlated with lymphopenia in patients treated with palliative RT and anti-PD-1 immune checkpoint inhibitors. These findings may inform future radiation planning in this setting.

"Living Well with Chronic Pain": Integrative Pain Management via Shared Medical Appointments.

OBJECTIVE: To evaluate the effectiveness of a multidisciplinary, nonpharmacological, integrative approach that uses shared medical appointments to improve health-related quality of life and reduce opioid medication use in patients with chronic pain. DESIGN: This is a retrospective, pre-post review of "Living Well with Chronic Pain" shared medical appointments (August 2016 through May 2018). SETTING: The appointments included eight 3-hour-long visits held once per week at an outpatient wellness facility. SUBJECTS: Patients with chronic, non-cancer-related pain. METHODS: Patients received evaluation and evidence-based therapies from a team of integrative and lifestyle medicine professionals, as well as education about nonpharmacological therapeutic approaches, the etiology of pain, and the relationship of pain to lifestyle factors. Experiential elements focused on the relaxation techniques of meditation, yoga, breathing, and hypnotherapy, while patients also received acupuncture, acupressure, massage, cognitive behavioral therapy, and chiropractic education. Patients self-reported data via the Patient-Reported Outcomes Measurement Information System (PROMIS-57) standardized questionnaire. Use of opioid medications was evaluated in morphine milligram equivalents. RESULTS: A total of 178 participants completed the PROMIS-57 questionnaire at the first and the last visits. Statistically significant improvements in all domains (Physical Functioning, Anxiety, Depression, Fatigue, Social Roles, Pain Interference, and Sleep Disturbance) were observed (P < 0.001) between the pre-intervention (visit 1) and post-intervention (visit 8) scores. Average opioid use decreased nonsignificantly over the 8-week intervention, but the lower rate of opioid use was not sustained at 6 and 12 months' follow-up. CONCLUSIONS: Patients suffering from chronic pain who participated in a multidisciplinary, nonpharmacological treatment approach delivered via shared medical appointments experienced reduced pain and improved measures of physical, mental, and social health without increased use of opioid pain medications.

A Randomized Phase 2 Study of Pembrolizumab With or Without Radiation in Patients With Recurrent or Metastatic Adenoid Cystic Carcinoma.

PURPOSE: We evaluated the safety and efficacy of pembrolizumab (pembro) ± radiation therapy (RT) in a phase 2 study among patients with progressive, metastatic adenoid cystic carcinoma (ACC). METHODS AND MATERIALS: Eligible patients had metastatic ACC with progression within the last year and ≥1 measurable lesion. Patients were randomized to pembro alone or with RT to 30 Gy in 5 fractions (pembroRT). The primary endpoint was objective response rate outside the RT field. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and local RT responses. RESULTS: We randomized 20 patients (10 per arm) from 2017 to 2018. We did not observe objective response outside of the radiation treatment field; stable disease (SD) was the best response in 12 (60%) patients and was not different per arm (7 pembro, 5 pembroRT, P = .65). A tumor growth rate decrease (TGR) of >25% was noted among 7 of 12 patients and >75% in 4 patients. There were local responses in the irradiated field among all evaluable pembroRT patients. Median PFS and OS were 4.5/not reached for pembroRT and 6.6 / 27.2 months for pembro patients. One patient developed grade 3 liver enzyme elevation after 27 cycles of therapy. Correlative analyses confirm low levels of programmed death-ligand 1 expression (PD-L1), and CD8 infiltrating T-cells. We identified associations between local response and both MYB/NFIB translocation and PD-L1 expression and between changes in systemic immune populations and RT. CONCLUSIONS: Pembrolizumab and pembroRT were well tolerated. We observed no objective responses, but 60% of patients with PD before the study achieved SD, the majority with decreased TGR and half (n = 10) with clinical benefit (SD >6 months). We observed favorable local responses within the RT field. Additional strategies are needed to further delay progression and effect response.

PACIFIC: shifting tides in the treatment of locally advanced non-small cell lung cancer.

The treatment paradigm of stage III, unresectable non-small cell lung cancer (NSCLC) has had few advancement since concurrent chemoradiotherapy was established as standard of care treatment. Despite modifications to radiotherapy, chemotherapy and surgical approaches, loco-regional and distant relapse remain high, which unfortunately has translated to poor survival outcomes. The PACIFIC study introduced immunotherapy to the domain of stage III NSCLC and has emerged as the fourth pillar in cancer treatment for these patients. The positive results of the study have excited both the radiation and medical oncology communities, demonstrating improvements in overall and progression-free survival (PFS). In this review, we discuss the details and impacts of the PACIFIC study, as well as the future implications for the treatment of stage III NSCLC.

Palliative Radiation Therapy for Vertebral Metastases and Metastatic Cord Compression in Patients Treated With Anti-PD-1 Therapy.

Background: There is increasing use of immune checkpoint blockade (ICB) across multiple cancer types, including in patients at risk for vertebral metastases and cord compression. These patients are often treated with palliative radiotherapy (PRT); however, data evaluating the combination of PRT and ICB in patients with vertebral metastases is limited. Furthermore, patients with cord compression are generally excluded from prospective clinical trials. Therefore, we retrospectively evaluated outcomes following PRT and PD-1 inhibition in patients with vertebral metastases. Methods: We performed a retrospective chart review of 37 consecutive patients (total 57 lesions) treated with radiation for vertebral metastases who also received PD-1 inhibition. Patient, treatment and outcomes data were abstracted from the medical records. Results: Histologies included non-small cell lung cancer (n = 21), renal cell carcinoma (n = 9) and melanoma (n = 7). Out of 57 lesions,18 involved >1 segments of the vertebral column. There were isolated lesions in thoracic (16), lumbar (9), cervical (6), and sacral (8) vertebrae. Presenting symptoms included pain (19), numbness (10), and weakness (3). Eleven patients were asymptomatic. Radiologic cord compression was present in 12, epidural extension in 28 and compression fracture in 14. Eleven patients underwent surgical decompression prior to the onset of RT. Median radiation dose was 24 Gy (range 8-30 Gy). Stereotactic radiation was delivered in 4 patients; 33 patients received conformal RT. 21 patients received PD-1 inhibition after RT, 9 before RT and 7 with RT. Seven patients received concurrent CTLA-4 inhibitors with anti-PD-1 therapy. Treatment was in general well-tolerated. Toxicities included fatigue (6), transient pain flare (1), nausea/vomiting (1) and G1 skin changes (1). All patients reported some degree of pain relief. Numbness/weakness was improved in 6 of 13 patients with baseline symptoms (46%) and this was more likely in patients that received vertebral radiation after starting PD-1 inhibitors (71 vs. 17%, p = 0.04). Most patients (22 of 33 evaluable patients, 67%) had stability of irradiated lesions on subsequent follow up imaging performed at median of 30 days from RT, whereas 3 had a complete local response and 4 had a partial local response. Conclusions: We demonstrate that PRT administered to vertebral metastases was well-tolerated and effective in patients treated with PD-1 inhibitors. There was an encouraging rate of pain reduction and neurological improvement.

Stereotactic body radiotherapy for centrally located stage I non-small cell lung cancer.

Stereotactic body radiotherapy (SBRT) has become the standard of care for the treatment of early stage non-small cell lung cancer in high risk or medically inoperable patients. It is very well tolerated when given to peripherally located tumors and is associated with high rates of local control. Centrally located tumors represent a bigger challenge as they are closer to a number of critical structures, namely the major bronchi, esophagus, large vessels and brachial plexus, that can be damaged by the high ablative doses of SBRT needed for optimal tumor control. Thus, the fractionation schedule for centrally located tumors needs to balance the need for tumor control while minimizing the risk of significant radiotherapy toxicity. In this article, we review the current evidence, summarize the prospective and retrospective studies of SBRT for centrally located tumors, and highlight several practical considerations.

Radiation dose mapping and anastomotic complications after trimodality therapy for esophageal cancers.

BACKGROUND AND PURPOSE: There is conflicting evidence with respect to the correlation between neoadjuvant chemoradiation and anastomotic complications following trimodality therapy in patients with esophageal cancer. We aimed to analyze the relationship between their dosimetry and any resulting anastomotic complications. MATERIALS AND METHODS: The medical records of 51 consecutive patients who underwent trimodality therapy between 2007 and 2014 were retrospectively reviewed. We analyzed the differences in the mean dose received by regions of the esophagus relative to the landmark of the azygous vein and the stomach to correlate the development of an anastomotic complication using nonparametric rank-sum tests. RESULTS: Anastomotic leakage and stricture rates were 12% and 22%, respectively. Patients with anastomotic complications received a statistically significant higher mean dose to the esophagus at the level of the azygous vein (0.0 cm) and lower (up to -2.7 cm) (28.4-42.2 Gy vs. 10.3-27.6 Gy, p < 0.04). There were no differences noted in mean gastric doses. Median follow up time was 30.9 months. Median overall survival and disease free survival of our patient cohort was 34.4 months and 22.5 months, respectively. The development of an anastomotic complication did not affect survival outcomes. CONCLUSION: Patients who experienced anastomotic complication after trimodality therapy for esophageal cancer were more likely to have received a higher mean esophageal dose around the proximity of the azygous vein, where intrathoracic anastomoses most commonly occur. Communication between surgical and radiation oncologists regarding the anastomotic location may be an important consideration in planning for trimodality therapy in reducing potential anastomotic complications.

Radiotherapy for HCC: Ready for prime time?

Stereotactic body radiation therapy (SBRT) has an evolving role in the management of hepatocellular carcinoma (HCC), largely due to recent advances in imaging technology. Often utilized in situations where other locoregional therapies are not feasible, SBRT has been demonstrated to be an effective treatment that confers high rates of durable local control. However, there is limited evidence to firmly establish its place in the treatment paradigm for HCC. In this article, we review the current evidence and highlight specific considerations in the multiple settings where SBRT may be used, including for primary HCC treatment and bridging/downstaging, as well as exploring the potential for SBRT in the treatment of extrahepatic oligo-metastatic HCC.

The Impact of Radiation Therapy on Lymphocyte Count and Survival in Metastatic Cancer Patients Receiving PD-1 Immune Checkpoint Inhibitors.

PURPOSE: Therapeutic radiation has conflicting immune effects: radiation therapy (RT)-induced immunogenic cell death can contribute to immune response, but lymphocytes are also sensitive to RT. It is unknown whether palliative RT leads to lymphopenia in patients treated with immune checkpoint inhibitors (ICIs) and whether this affects outcomes. As such, we sought to assess the impact of palliative RT on circulating lymphocyte count and neutrophil-to-lymphocyte ratio in patients being treated with PD-1-directed ICI and associations with survival. METHODS AND MATERIALS: We identified patients from 5 radiation oncology centers, treated with palliative RT and either pembrolizumab or nivolumab with non-small cell lung cancer, metastatic melanoma, and renal cell carcinoma. Patients who received intervening cytotoxic chemotherapy were excluded. We recorded absolute lymphocyte count (ALC) and neutrophil-to-lymphocyte ratio before and after palliative RT and at the start of ICI. Survival was analyzed using the Kaplan-Meier method and Cox proportional hazard models. RESULTS: One hundred ten patients received 225 courses of palliative RT. Median change in ALC after RT was -161 cells/mL. Decreases in ALC were greater with RT to the spine, lung/mediastinum, and chest wall compared with the brain, extremity, or abdomen/pelvis (P = .002) and after courses >5 fractions (P = .003). Extracranial and >5-fraction RT was associated with increased odds of severe lymphopenia (ALC <500) at the end of RT (odds ratio [OR], 3.7; P = .001; and OR, 3.9; P = .001, respectively). Patients who developed RT-induced severe lymphopenia were more likely to have severe lymphopenia when ICI was initiated (OR, 6.4; P = .0001), particularly when RT was administered in the previous 3 months (OR, 189; P < .0001). Severe lymphopenia at onset of ICI therapy was associated with increased mortality on multivariable analysis (hazard ratio, 2.1; P = .03). CONCLUSIONS: Extracranial or prolonged courses of RT increase the risk of severe lymphopenia, which is associated with poorer survival in patients treated with ICI.

Immunotherapy and radiotherapy for metastatic cancers.

Immune checkpoint inhibitors have emerged as a breakthrough therapy in the treatment in various metastatic cancers. In parallel, the role of radiotherapy in metastatic cancers has been expanding to include stereotactic ablative radiotherapy for oligometastases, in addition to the more conventional palliation of symptoms. Thus, many patients are appropriate candidates for both radiation and immunotherapy-highlighting the need for data to guide this treatment combination in patients with metastatic disease. Here, we review the literature to address questions regarding the safety of combined treatment (focusing on radionecrosis and pneumonitis), and the impact of dose, timing and site of radiotherapy. Finally, we highlight ongoing work investigating the potential local and systemic benefit to combining these therapies.

Prophylactic Cranial Irradiation in Extensive Stage Small Cell Lung Cancer: Outcomes at a Comprehensive Cancer Centre.

PURPOSE: The role of prophylactic cranial irradiation (PCI) remains controversial in extensive stage small cell lung cancer (ES-SCLC) with the publication of 2 randomized control trials demonstrating differing outcomes in overall survival. The aim of this study is to determine the impact of PCI on survival and the development of brain metastasis while addressing the disparate use of postchemotherapy brain imaging in the aforementioned trials. METHODS AND MATERIALS: The medical records of 397 consecutive patients with ES-SCLC between Jan. 1, 2005 and Dec. 31, 2011 were retrospectively reviewed. In those eligible patients (n = 155) without baseline brain metastases and who had at least a partial response to chemotherapy, overall survival and time to brain metastasis were estimated using the Kaplan-Meier method comparing patients receiving PCI or not, using both univariate and multivariate analyses. Patients were stratified by their receipt of initial postchemotherapy brain imaging. Follow-up did not include serial brain imaging, which was performed when clinically indicated. Differences between the groups with covariates were analyzed using χ2 statistics and Student's t-tests. RESULTS: By multivariate analysis, statistically significant predictors of overall survival were the presence of extrathoracic metastases, performance status and use of PCI. There was a statistically significant difference in overall survival (HR 0.55; 95% CI: 0.39-0.77; P = .0005) and time to brain metastasis (HR 0.40; 95% CI: 0.23-0.66; P = .0004) with the use of PCI. Median survival for the PCI and non-PCI groups was 13.5 and 8.5 months respectively. A survival difference with PCI was observed in both patients that received postchemotherapy brain imaging (HR 0.55; 95% CI: 0.35-0.88; P = .012) and those who did not (HR 0.48; 95% CI: 0.29-0.77; P = .0025). CONCLUSIONS: PCI in the setting of at least a partial response to chemotherapy was found to have a survival benefit and prolongation of the time to development of brain metastases, when factoring in the use of initial postchemotherapy but not routine surveillance brain imaging.