Assessing the effect of metastasis-directed therapy in oligometastatic disease using the restricted mean survival time.

BACKGROUND: Metastasis-directed therapy (MDT) with stereotactic body radiotherapy (SBRT) is emerging as an effective therapeutic option for oligometastatic disease (OMD). However, a lack of phase III data, consensus guidelines, and toxicity concerns limit its widespread use. Randomized controlled trials (RCTs) routinely report hazard ratios (HRs) and medians that lack clear clinical and robust interpretation. Restricted-mean survival time (RMST) is the duration of time a patient is expected to survive over the follow-up period, providing a robust and interpretable alternative. We analyzed the efficacy of SBRT using RMST. METHODS: All registered RCTs of ablative radiotherapy in OMD in ClinicalTrials.gov through 2022 were identified. Data were reconstructed from Kaplan-Meier curves, and the HRs and RMST differences were estimated for surrogate endpoints (SEs) and overall survival (OS). RESULTS: Six studies comprising 426 patients met the inclusion criteria. The RMST differences for SEs ranged from 4.6 months in a study by Iyengar et al. to 11.1 months in SABR-COMET. The RMST differences for OS in SABR-COMET, Gomez et al., and SINDAS studies were 12.6, 15 and 7.9 months, respectively. CONCLUSION: RMST demonstrates the efficacy of local treatment in OMD. Representing the expected survival time, this method effectively communicates outcomes to patients and clinicians.

SABR-Dual: a phase II/III trial of two-fraction versus five-fraction stereotactic radiotherapy for localized low- and favorable intermediate-risk prostate cancer.

BACKGROUND: Dose-escalated radiotherapy is known to improve progression free survival in patients with localized prostate cancer, and recent advances have led to the standardization of ultrahypofractionated stereotactic ablative radiotherapy (SABR) delivered in just 5-fractions. Based on the known effectiveness of the accepted though invasive 2-fraction treatment method of high-dose-rate brachytherapy and given the ubiquity of prostate cancer, a further reduction in the number of treatments of external-beam SABR is possible. This study aims to evaluate the safety, efficacy, and non-inferiority of generalizable 2-fraction SABR compared to the current 5-fraction regimen. METHODS: 502 patients will be enrolled on this phase II/III randomized control trial. Eligible patients will have previously untreated low- or favorable intermediate-risk adenocarcinoma of the prostate. Patients will be randomized between standard SABR of 40 Gy in 5 fractions given every-other-day and 27 Gy in 2 fractions at least two days apart but completing within seven days. MRI-based planning, radiopaque hydrogel spacer insertion, and fiducial marker placement are required, and SABR will be delivered on either a standard CT-guided linear accelerator or MR-LINAC. The primary endpoint will be freedom from disease progression, with additional secondary clinical, toxicity, and quality of life endpoints. DISCUSSION: This study will be the largest prospective randomized trial, adequately powered to demonstrate non-inferiority, comparing 2-fraction SABR to standard 5-fraction SABR for localized prostate cancer. As the protocol does not obligate use of an MRI-LINAC or other adaptive technologies, results will be broadly generalizable to the wider community. TRIAL REGISTRATION: This trial is registered on Clinicaltrials.gov: ClinicalTrials.gov Identifier: NCT06027892.

Effect of Radiological Tumor Thickness on Prognosis of Early Glottic-Squamous Cell Carcinoma Treated With Radiation.

OBJECTIVES: Tumor depth of invasion is a known prognostic factor in several head and neck cancers, but data on early laryngeal squamous cell carcinoma (SCC) are sparse. In this study, we aim to determine whether radiological tumor thickness serves as a prognostic factor in early SCC of the glottis treated with radiation. METHODS: One hundred thirty-two adult patients (age >18 years) underwent pretreatment computed tomography (CT) and were treated with radiation for pathologically proven early stage (T1 or T2) glottic SCC. Thirty-eight were excluded because the tumor could not be correctly identified on the CT scan, and an additional three patients because of insufficient data. RESULTS: The final cohort consisted of 91 patients, 84 (90.3%) men and 7 (9.7%) women aged 39.86-86.53 (mean 65.55 ± 12.76) years. Mean tumor thickness was 0.59 ± 0.19 cm in patients with T1 tumors and 0.79 ± 0.21 cm in patients with T2 tumors. The optimal cutoff value for 5-year disease-free survival (DFS), using the Youden index (sensitivity: 81.2%, specificity 65.3%), was 0.7 cm. A significant advantage in 5-year overall survival (OAS) and 5-year DFS for tumor thickness of <0.7 cm (P = 0.01 and P < 0.01, respectively) was found, these findings were consistent also when each stage was examined separately (T1 vs T2). CONCLUSION: Radiological tumor thickness appears to significantly predict OAS and DFS in early glottic SCC patients. IMPLICATION FOR PRACTICE: Tumor thickness may be considered as an auxiliary aid in deciding follow-up time and frequency, proper treatment, and determining prognosis.

40 Gray in 5 Fractions for Salvage Reirradiation of Spine Lesions Previously Treated With Stereotactic Body Radiotherapy.

BACKGROUND AND PURPOSE: A retrospective single-center analysis of the safety and efficacy of reirradiation to 40 Gy in 5 fractions (reSBRT) in patients previously treated with stereotactic body radiotherapy to the spine was performed. METHODS: We identified 102 consecutive patients treated with reSBRT for 105 lesions between 3/2013 and 8/2021. Sixty-three patients (61.8%) were treated to the same vertebral level, and 39 (38.2%) to overlapping immediately adjacent levels. Local control was defined as the absence of progression within the treated target volume. The probability of local progression was estimated using a cumulative incidence curve. Death without local progression was considered a competing risk. RESULTS: Most patients had extensive metastatic disease (54.9%) and were treated to the thoracic spine (53.8%). The most common regimen in the first course of stereotactic body radiotherapy was 27 Gy in 3 fractions, and the median time to reSBRT was 16.4 months. At the time of simulation, 44% of lesions had advanced epidural disease. Accordingly, 80% had myelogram simulations. Both the vertebral body and posterior elements were treated in 86% of lesions. At a median follow-up time of 13.2 months, local failure occurred in 10 lesions (9.5%). The 6- and 12-month cumulative incidences of local failure were 4.8% and 6%, respectively. Seven patients developed radiation-related neuropathy, and 1 patient developed myelopathy. The vertebral compression fracture rate was 16.7%. CONCLUSION: In patients with extensive disease involvement, reSBRT of spine metastases with 40 Gy in 5 fractions seems to be safe and effective. Prospective trials are needed to determine the optimal dose and fractionation in this clinical scenario.

Outcome of radiotherapy for the treatment of laryngeal squamous cell carcinoma in the very elderly population.

BACKGROUND: Treatment selection for squamous cell carcinoma patients aged over 84 years is controversial. This retrospective chart review examined and compared characteristics of laryngeal squamous cell carcinoma in very elderly (over 84 years) and younger patients (approximately 65 years). The secondary objective was to further evaluate the outcome of radiotherapy as a treatment modality in this patient population. METHODS: Of all 23 very elderly patients with laryngeal squamous cell carcinoma treated with radiotherapy, with or without surgery, in the Davidoff Cancer Center, from 1992 to 2012, 19 had sufficient data for analysis, and comprised the study group. RESULTS: Median age at diagnosis was 86 years. Disease stage at diagnosis was I, II, III and IVA in 53 per cent, 21 per cent, 21 per cent and 5 per cent, respectively. Median radiotherapy dose was 60 Gy given in 25 fractions. Three patients had recurrence. No patient discontinued treatment because of toxicity. Median overall survival was 3.6 years (range, 0-10 years). CONCLUSION: Very elderly laryngeal squamous cell carcinoma patients may derive a similar survival advantage as younger counterparts. Modern radiotherapy is effective and safe for treating laryngeal squamous cell carcinoma in this study population. Further, large-scale studies are needed.

Long-term Outcomes from a Phase 1 Dose Escalation Study Using Stereotactic Body Radiotherapy for Patients with Low- or Intermediate-risk Prostate Cancer.

BACKGROUND: Ultrahypofractionated stereotactic body radiation therapy (SBRT) has become a standard treatment intervention for localized prostate cancer. OBJECTIVE: To report final long-term tumor control outcomes and late gastrointestinal (GI) and genitourinary (GU) toxicities from a single-center phase 1 dose escalation study using SBRT for patients with low- or intermediate-risk prostate cancer. DESIGN, SETTING AND PARTICIPANTS: Between 2009 and 2012, 136 patients were enrolled and treated. The initial dose level was 32.5 Gy in five fractions. Doses were then sequentially escalated to 35 Gy, 37.5 Gy, and 40 Gy in five fractions delivered every other day. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was late treatment-related toxicity. Secondary endpoints included prostate-specific antigen (PSA) failure. RESULTS AND LIMITATIONS: The median follow-up was 10.5 yr for the 32.5-Gy group, 9.9 yr for the 35-Gy group, 8.2 yr for the 37.5-Gy group, and 7.3 yr for the 40-Gy group. The 8-yr cumulative incidence of PSA failure was 26% for 32.5 Gy, 15% for 35 Gy, 3.4% for 37.5 Gy, and 6.6% for 40 Gy. Higher radiation dose (37.5-40 Gy) and favorable intermediate risk (vs unfavorable intermediate risk) were associated with better PSA recurrence rates (p = 0.011 and 0.002, respectively). The 8-yr actuarial probability rates for survival free from late grade ≥2 toxicity were 94% for GI toxicity and 86% for GU toxicity. No grade 4 events were recorded. Higher dose levels were not associated with higher rates of late grade ≥2 GI (p = 0.2) or GU (p > 0.9) toxicity. CONCLUSIONS: SBRT doses ranging from 32.5 to 40 Gy were associated with low incidence of moderate or severe toxicities. Higher doses resulted in superior disease control outcomes 8 yr after treatment. PATIENT SUMMARY: We investigated the association between the radiotherapy dose used and the rate of control of prostate cancer. We found that higher doses resulted in more favorable outcomes without excess toxicity. This trial is registered on ClinicalTrials.gov as NCT00911118.

Same-day versus delayed simulation imaging after placement of a perirectal hydrogel spacer for prostate radiotherapy.

Introduction: Placement of a perirectal hydrogel spacer has been demonstrated to reduce the risk of rectal toxicity from prostate radiation. Practices vary regarding the timing of CT simulation after hydrogel placement, and the ideal schedule remains unknown. Methods: Thirty patients with localized prostate adenocarcinoma underwent transrectal ultrasound-guided placement of an iodinated SpaceOAR™ hydrogel prior to radiotherapy. Per evolving practice, 15 completed same-day simulation and 15 returned for simulation 1-2 weeks later. Hydrogel volume, perirectal distance, air-void volume, and rectal dosimetry per NRG GU005 were compared between CT simulation, 1st fraction Cone-Beam-CT (CBCT), and final CBCT. Results: CT simulation occurred 8.8 ± 2.4 days after placement in the delayed group, with no significant difference in the interval between simulation and 1st fraction between groups (p = 0.165). Greater observed de-creases in hydrogel volume (0.57 cc vs. 0.04 cc, p = 0.0002), and perirectal distance at both mid-gland (1.32 mm vs. 0.17 mm) and tallest point (2.40 mm vs. 0.04 mm) were seen on 1st-fraction CBCT in the same-day group (p = 0.0039; p = 0.0002). Per dosimetry recalculated on 1st fraction CBCT, five (D3 cc and D50%) versus one (D50%) rectal dose parameters were exceeded in the same-day and delayed groups, respectively, and 10 versus one parameters had a relative increase of ≥ 20%. Conclusion: Due to the evolving anatomic changes in the days following hydrogel placement, same-day simulation scanning may introduce unintended variability in rectal dosimetry at the time of prostate radiotherapy.

The effect of gastric fundus radiation dose on postoperative anastomotic leakage in esophageal cancer.

Introduction: Standard-of-care treatment for locally advanced esophageal carcinoma (LAEC) includes neoadjuvant chemoradiotherapy followed by esophagectomy. A potentially catastrophic surgical complication is the development of a postoperative anastomotic leak. To date, the association with radiation dose exposure had been inconclusive. We examined the correlation between radiation exposure to the gastric fundus and risk of postoperative leakage using contemporary radiation doses and fractionation. Methods: A total of 69 consecutive patients with LAEC who underwent neoadjuvant chemoradiotherapy followed by esophagectomy in our tertiary center were prospectively followed (median, 27 months). Neoadjuvant regimen included 50.4 Gy in 28 fractions with 5-fluorouracil and cisplatin and 41.4 Gy in 23 fractions with carboplatin and paclitaxel. The gastric fundus was contoured and dosimetric and radiation technique parameters were retrospectively evaluated. Results: Of the total number of patients, 71% and 29% had esophageal and gastroesophageal junction (GEJ) tumors, respectively. Fourteen patients (20.3%) experienced anastomotic leaks within a median of 2 days postoperatively, 78.6% of whom had lower third esophagus or GEJ primaries. Mean and minimum fundus dose did not significantly differ between those with and those without leakage (p = 0.42, p = 0.51). Mean fundus V25, V30, and V35 doses were numerically but not statistically higher in those with anastomotic leak (p = 0.58, p = 0.39, and p = 0.30, respectively). No correlation with incidence of leakage was seen between 3D and IMRT treatment modalities. Conclusions: In our comparatively large prospectively collected series of patients treated for LAEC, radiation dose to the gastric fundus during neoadjuvant combination therapy prior to surgery did not correlate with the risk of postoperative anastomotic leak.

First-line programmed death-1 inhibitor treatment for locoregionally advanced or metastatic cutaneous squamous cell carcinoma - A real-world experience from Israel.

Objective: Cutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer worldwide. It is usually treated surgically, with very high cure rates. However, in 3%-7% of cases, cSCC metastasizes to lymph nodes or distant organs. Many of the affected patients are elderly with comorbidities who are not candidates for standard-of-care curative-intent treatment with surgery and/or radio-/chemotherapy. Immune checkpoint inhibitors, which target programmed cell death protein 1 (PD-1) pathways, have recently emerged as a potent therapeutic option. The present report presents the Israeli experience with PD-1 inhibitors for the treatment of loco-regionally advanced or metastatic cSCC in a diverse and elderly population, with or without the addition of radiotherapy. Material and methods: The databases of two university medical centers were retrospectively searched for patients with cSCC treated with the PD-1 inhibitors cemiplimab or pembrolizumab between January 2019 and May 2022. Data on baseline, disease-related, treatment-related, and outcome parameters were collected and analyzed. Results: The cohort included 102 patients of a median age 78.5 years. Evaluable response data were available for 93. The overall response rate was 80.6%: complete response in 42 patients (45.2%) and partial response in 33 (35.5%). Stable disease was recorded in 7 (7.5%) and progressive disease in 11 (11.8%). Median progression-free survival was 29.5 months. Radiotherapy was administered to the target lesion during PD-1 treatment in 22.5% of patients. mPFS was not significantly different in patients who treated with RT than patients how did not (NR vs 18.4 months, HR=0.93, 95%CI: 0.39 - 2.17, p<0.859). Any-grade toxicity was recorded in 57 patients (55%), including grade _3 in 25, of whom 5 (5% of cohort) died. Compared to toxicity-free patients, patients with drug toxicity had better progression-free survival (18.4 months vs not reached, HR=0.33, 95% CI: 0.13-0.82, p=0.012) and higher overall response rate (87% vs 71.8%, p=0.06). Conclusion: This retrospective real-world study showed that PD-1 inhibitors were effective in the treatment of locally advanced or metastatic cSCC and appeared to be amenable for use in elderly or fragile patients with comorbidities. However, the high toxicity warrants consideration against other modalities. Induction or consolidation radiotherapy may improve the results. These findings need to be corroborated in a prospective trial.

Local Failure after Prostate SBRT Predominantly Occurs in the PI-RADS 4 or 5 Dominant Intraprostatic Lesion.

BACKGROUND: A positive post-treatment prostate biopsy following definitive radiotherapy carries significant prognostic implications. OBJECTIVE: To determine whether local recurrences after prostate stereotactic body radiation therapy (SBRT) are associated with the presence of and occur more commonly within the region of a PI-RADS 4 or 5 dominant intra-prostatic lesion (DIL) identified on pre-treatment multi-parametric magnetic resonance imaging (MRI). DESIGN, SETTING, AND PARTICIPANTS: 247 patients with localized prostate cancer treated with SBRT at our institution from 2009-2018 underwent post-treatment biopsies (median time to biopsy: 2.2 years) to evaluate local control. INTERVENTIONS: Prostate SBRT (median 40 Gy in 5 fractions). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: MRIs were read by a single diagnostic radiologist blinded to other patient characteristics and treatment outcomes. The DIL presence, size, location, and extent were then analyzed to determine associations with the post-treatment biopsy outcomes. RESULTS AND LIMITATIONS: Among patients who underwent post-treatment biopsies, 39/247 (15.8%) were positive for Gleason-gradable prostate adenocarcinoma, of which 35/39 (90%) had a DIL initially present and 29/39 (74.4%) had a positive biopsy within the DIL. Factors independently associated with post-treatment biopsy outcomes included the presence of a DIL (OR 6.95; p = 0.001), radiographic T3 disease (OR 5.23, p < 0.001), SBRT dose ≥40 Gy (OR 0.26, p = 0.003), and use of androgen deprivation therapy (ADT; OR 0.28, p = 0.027). Among patients with a DIL (N = 149), the only factors associated with post-treatment biopsy outcomes included ≥50% percent cores positive (OR 2.4, p = 0.037), radiographic T3 disease (OR 4.04, p = 0.001), SBRT dose ≥40 Gy (OR 0.22, p < 0.001), and use of ADT (OR 0.21, p = 0.014). CONCLUSIONS: Our results suggest that men with PI-RADS 4 or 5 DILs have a higher risk of local recurrence after prostate SBRT and that most recurrences are located within the DIL. PATIENT SUMMARY: We found the presence of a dominant tumor on pre-treatment MRI was strongly associated with residual cancer within the prostate after SBRT and that most recurrences were within the dominant tumor.

Health Disparities in Prostate Cancer and Approaches to Advance Equitable Care.

The American Cancer Society estimates approximately 268,490 new cases of prostate cancer and approximately 34,500 deaths caused by prostate cancer in the United States for 2022. Globally, a total of 1,414,259 new cases of prostate cancer and 375,304 related deaths were reported in 2020. Well-documented health disparities and inequities exist along the continuum of care for prostate cancer management-from screening to diagnostic and staging work-up, surveillance, and treatment-ultimately impacting clinical outcomes. This session-based article discusses innovative patient-centered approaches to advance equitable prostate cancer care. It begins with a review of domestic health disparities in diagnostic imaging and radiotherapy for prostate cancer, and it summarizes barriers and solutions to achieving health equity, such as equity metrics and practice quality improvement projects. Next, a global perspective is provided that describes approaches to address financial and geographic barriers to prostate cancer care, including specific examples of strategies that emphasize the use of the cheapest method of care delivery while maintaining outcomes for drug delivery and radiotherapy.

The Cost of Enfortumab Vedotin Wastage Due to Vial Size-A Real-World Analysis.

Enfortumab Vedotin (EV) is FDA-approved for advanced urothelial cancer in patients previously treated with platinum-based chemotherapy and a checkpoint inhibitor. We conducted a real-world study to determine the extent of EV wastage in a single institution and assessed the financial impact of EV wastage annually in the United States. Systematic examination of the usage and wastage of all standard-of-care EV treatments administered to urothelial cancer patients at Memorial Sloan Kettering Cancer Center (MSKCC) between 1 January 2020 and 31 December 2020 was performed. Drug wastage was calculated by subtracting the actual administered dose from the total dose in an optimal set of vials. We built a pharmacoeconomic model to assess the financial impact of EV wastage annually in the US using the January 2021 Average Sales Prices from the Centers for Medicare and Medicaid Services. Sixty-four patients were treated with standard-of-care EV, with a median of 11 doses per patient (range 1-28). Wastage occurred in 46% of administered doses (367/793), with a mean waste per dose of 2.9% (0-18%). The average drug wastage cost per patient was $3127 ($252/dose). The annual cost of EV wastage in the US is estimated to be $15 million based on wastage data from a single center in the US. In summary, EV wastage due to available vial sizes was 2.9%, which falls under acceptable thresholds. While the percentage of EV wastage is relatively low, waste-minimizing practices may reduce the financial toxicity for the individual patient and for society.

Early outcomes of high-dose-rate brachytherapy combined with ultra-hypofractionated radiation in higher-risk prostate cancer.

PURPOSE: This study evaluated outcomes associated with a high-dose-rate (HDR) brachytherapy boost combined with stereotactic body radiation therapy (SBRT) for patients with higher-risk localized prostate cancer. MATERIALS AND METHODS: We identified 101 patients with National Comprehensive Cancer Network high-risk, unfavorable intermediate-risk, or favorable intermediate-risk with probable extra-prostatic extension treated with HDR brachytherapy (15 Gy x 1 fraction) followed by SBRT (5 Gy x 5 daily fractions to the prostate and/or seminal vesicles and/or pelvic lymph nodes). Androgen deprivation therapy was used in 55.4% of all patients (90% of high-risk, 33% of intermediate-risk). Toxicities according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0 and International Prostate Symptom Scores were prospectively documented at each followup visit. Biochemical relapse was defined as PSA nadir +2ng/mL. RESULTS: The median follow-up time after SBRT was 24.1 months. No grade ≥3 toxicities were observed. The incidence of acute and late grade 2 gastrointestinal toxicities was both 0.99%. Acute and late grade 2 genitourinary (GU) toxicities were observed in 5.9% and 9.9%, respectively. Median time to a grade 2 GU toxicity was 6 months with a 14% 2-year actuarial rate of grade 2 GU toxicity. Median International Prostate Symptom Scores at 24 months was not significantly different than baseline (6 vs. 5; p = 0.24). Inclusion of pelvic lymph nodes and absence of a rectal spacer were significantly associated with more frequent grade ≥1 GU toxicity, but not grade ≥2 GU or gastrointestinal toxicity. The 2-year biochemical relapse free survival was 97%. CONCLUSIONS: HDR brachytherapy combined with SBRT was associated with a favorable early toxicity profile and encouraging cancer control outcomes.

The Impact of Exogenous Estrogen Exposure on the Characteristics and Outcome of Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Early-Stage Breast Cancer.

INTRODUCTION: The impact of exogenous estrogen exposure on breast cancer characteristics and outcomes is not well described. We aimed to investigate the effect of prior treatment with oral contraceptives (OCT), hormone replacement therapy (HRT), and fertility treatments on early-stage, estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. METHODS: This is a single-center retrospective cohort study comprising all women with ER-positive, HER2-negative, early breast cancer whose tumors were sent to Oncotype DX analysis between 2005 and 2012. Data on prior exposures to OCT, HRT, and fertility treatments were collected. The impact of these exposures on prespecified histopathological features was assessed including tumor size, nodal status, intensity of the hormonal receptors, grade, Oncotype recurrence score, Ki67, and lymphovascular and perineural invasion. The impact of these exposures on disease-free survival (DFS) and overall survival (OS) was also evaluated. RESULTS: A total of 620 women were included, of which 19% had prior exposure to OCT, 30% to HRT, and 11% to fertility treatments. OCT use was associated with smaller (≤1 cm) tumors (p = 0.023) and were less likely to have grade 3 disease (p = 0.049). No other associations were found between exogenous estrogen exposure and tumor characteristics. Median follow-up was 10.4 years. Ten-year DFS was 85.7%, and it was not influenced by exogenous exposure. Ten-year OS was 90.2%, and OCT was associated with improved OS in univariate analysis (HR = 0.31, 95% CI: 0.11-0.85), but this difference did not remain significant in multivariate analysis (p = 0.275). CONCLUSION: The impact of exogenous estrogen exposure on ER-positive, HER2-negative early breast cancer characteristics is limited. In the long term, none of the evaluated exposures had negative effect on DFS and OS.

Prognostic impact of HER2-low expression in hormone receptor positive early breast cancer.

BACKGROUND: Recent data suggest that human epidermal growth factor receptor 2 (HER2)-low breast cancer may represent a distinct entity. We aimed to compare disease characteristics and outcomes between HER2-low and HER2-0 in estrogen receptor (ER) positive, early-stage breast cancer. METHODS: A single center retrospective study comprising all women with ER positive, HER2 negative early breast cancer, for whom an Oncotype DX test was performed between 2005 and 2012. Women were grouped to HER2-low (immunohistochemistry +1 or +2 and in situ hybridization not amplified) or HER2-0. Clinico-pathological features and Oncotype recurrence score (RS) were collected. Data on overall-survival (OS), disease-free survival (DFS) and distant disease-free survival (DDFS) were evaluated according to HER2 expression status. RESULTS: 608 women were included, of which 304 women had HER2-0 and 304 had HER2-low disease. Lobular subtype was significantly more common in HER-0 compared to HER2-low disease (17% vs. 8%, p = 0.005). The prevalence of other clinic-pathological characteristics and long-term prognosis were comparable between both groups. For women with high genomic risk (RS > 25), HER2-low expression was associated with significantly favorable OS (HR = 0.31, 95% CI 0.11-0.78, p = 0.01), DFS (HR = 0.40, 95% CI 0.20-0.82, p = 0.01) and DDFS (HR = 0.26, 95% CI 0.11-0.63, P = 0.002) compared to women with HER2-0. For women with low genomic risk (RS ≤ 25), long-term prognosis was unrelated to HER2 expression. CONCLUSION: The prognostic impact of HER2-low expression in early-stage luminal disease varies across the genomic risk, with significant favorable outcomes of HER2-low expression compared to HER2-0 in women with high genomic risk.

Use of Continuous Positive Airway Pressure (CPAP) to Limit Diaphragm Motion-A Novel Approach for Definitive Radiation Therapy for Inoperable Pleural Mesothelioma: A Pilot Study.

Malignant pleural mesothelioma (MPM) is a deadly disease and radiotherapy (RT) plays an important role in its management. Recent developments in technique have made it is possible to deliver RT to MPM in the intact lung. However, it is imperative to reduce normal lung doses. We present a pilot study examining the use of CPAP and VMAT radiotherapy to reduce toxicity when treating MPM, involving three consecutive patients with MPM, not amenable to surgery, who were treated according to Helsinki committee approval. Patients were simulated using four-dimentional CT simulation with the assistance of CPAP lung inflation, then were treated using both IMRT and VMAT techniques. Radiation lung dose was optimized based on accepted lung dose constraints. Patients were followed for toxicity as well as local control and survival. Results: Three patients were treated with CPAP-based IMRT treatment. These patients tolerated the treatment and DVH constraints were able to be met. The comparison plans among the four VMAT arcs and the IMRT static field treatment were able to accomplish the treatment planning objectives without significant advantages with either technique. The treatment combined with CPAP reduced the normal lung dose in MPM patients with intact lungs. This technique is worthy of further investigation.

Next-generation sequencing in thyroid cancers: do targetable alterations lead to a therapeutic advantage?: A multicenter experience.

ABSTRACT: Radioiodine-refractory thyroid cancers (IRTCs) are uncommon and have a poor prognosis. Treatment options for radioiodine-refractory and anaplastic tumors (ATCs) are limited. Although the genomic landscape of thyroid cancer has been studied, there is little evidence on whether next-generation sequencing (NGS) findings translate to tumor control.We analyzed all patients with IRTC and ATC who underwent commercially available NGS in 3 cancer centers.Twenty-two patients were identified, 16 patients with IRTCs and 6 patients with ATCs. Eighteen (82%) had targetable findings in NGS, nine patients were treated accordingly. Median progression-free survival for targeted treatment was 50 months [95% confidence interval (CI95%) 9.8-66.6] and2 months (CI95% 0.2-16.5) for IRTC and ATC, respectively. Of 4 patients who achieved durable responses of 7 to 50 months, 2 are ongoing. The estimated median OS of IRTC receiving targeted treatment was not reached (CI95% 89.7-111.4 months) and was 77.8 months (CI95% 52.5-114.6) for patients treated conventionally (P = .3).NGS may detect clinically significant genetic alterations and benefit patients with advanced thyroid cancers.

Locoregional therapy in de novo metastatic breast cancer: Systemic review and meta-analysis.

BACKGROUND: Locoregional therapy (LRT) in de novo metastatic disease is controversial with inconsistent results from randomized control trials (RCTs). METHODS: RCTs comparing LRT and systemic therapy to standard therapy alone in de novo metastatic breast cancer were identified. Hazard ratios (HRs) and their associated 95% confidence intervals (CIs) were computed and pooled in a meta-analysis using generic inverse variance. Overall survival (OS) and time to locoregional progression data were extracted for the intention to treat (ITT) population. Data on OS for pre-specified subgroups defined by tumor subtype and by site of metastases were also extracted. RESULTS: Analyses included 4 trials comprising 970 patients. LRT included standard surgery to the primary breast tumor in all studies, and adjuvant radiation per standard of care was required in 3 studies. Compared to standard treatment, LRT was not associated with improved OS in the ITT population (HR 0.97, 95% CI 0.72-1.29, p = 0.81). However, LRT was associated with improved time to locoregional progression (HR 0.36, 95% CI 0.14-0.95, p = 0.04). LRT was not associated with improved OS in any tumor subtypes, including hormone receptor positive (HR 0.96, 95% CI 0.65-1.43), triple negative (HR 1.4, 95% CI 0.50-3.91) and human epidermal growth factor receptor 2 positive disease (HR 0.93, 95% CI 0.68-1.28). Additionally, LRT did not improve OS in bone only disease (HR 0.97, 95% CI 0.58-1.62) and in visceral disease (HR = 1.02, 95% CI 0.77-1.35). Our critical appraisal has identified some methodological problems in the design and conduct of the studies included that could affect the meta-analysis result. CONCLUSIONS: LRT in de novo metastatic breast cancer is not associated with improved OS. Results are consistent among different breast cancer subgroups. However, this conclusion should be interpreted with caution in view of the limitations identified in meta-analysis.

Bevacizumab for stereotactic radiosurgery-induced radiation necrosis in patients with non-small cell lung cancer treated with immune check-point inhibitors.

BACKGROUND: Bevacizumab was shown to be effective in the treatment of brain radiation necrosis (RN) attributed to the use of stereotactic radiosurgery (SRS). Data on its efficacy and safety in non-small cell lung cancer (NSCLC) patients treated with immune check-point inhibitors (ICI) is lacking. METHODS: A multi-center retrospective analysis of all consecutive patients with NSCLC treated with ICI, who received bevacizumab for post-SRS RN between April 2017 and June 2020. Improvement in RN-associated symptoms, RN radiological improvement, and decrease in corticosteroid dose following bevacizumab initiation were assessed. RESULTS: Thirteen patients were identified. The median time from diagnosis of RN to initiation of bevacizumab was 3 months (range 1.1-7.8 months), and the median number of bevacizumab cycles before assessment was 2 (range, 1-5). Patients continued ICI during treatment with bevacizumab. Improvement in RN-associated symptoms was observed in 11 patients (85%). In ten patients (77%) the daily dose of dexamethasone was decreased. Radiological improvement of RN occurred in all 11 cases available for radiological assessment (100%). Treatment was withheld in two patients for grade 3-4 toxicity. At a median follow up of 11.9 months (range 2.0-35.4 months), one patient experienced a recurrent episode of RN; the estimated median survival since RN diagnosis was 21.9 months (95% CI 3.8-40.2 months). CONCLUSION: Treatment with bevacizumab appears to be safe and effective for the treatment of SRS-induced RN in patients with NSCLC treated with ICI. This is the first series to report on the use of bevacizumab in this clinical scenario.

BAP1-Altered Malignant Pleural Mesothelioma: Outcomes With Chemotherapy, Immune Check-Point Inhibitors and Poly(ADP-Ribose) Polymerase Inhibitors.

OBJECTIVES: Little is known regarding the outcomes of systemic treatments in BAP1-altered malignant pleural mesothelioma (MPM). MATERIALS AND METHODS: Forty five patients with MPM [group A: eight MPM patients with BAP1 inactivating mutation/copy number loss (FoundationOne® CDx/TEMPUSxT), selected from the electronic databases of four Israeli cancer centers (ICC); group B: 37 consecutive (years 2016-2018) MPM patients selected from the electronic databases of two ICC-of those six patients without a BAP1 alteration (group B1) and 31 patients not tested for BAP1 (group B2)] were analyzed for ORR, PFS (mRECIST), and OS with 1st-line platinum/pemetrexed+/-antiangiogenic drug (CT, n-28), immune check-point inhibitors (ICPi, n-16) and poly (ADP-ribose) polymerase inhibitors (PARPi, n-4). OS since diagnosis (OSDx) was assessed. RESULTS: There were no differences in ORR or mPFS with CT between the groups: ORR-50% vs. 47% vs. 50% vs. 47% (p>0.9), mPFS-9.1mo (95% CI, 1.2-16.1) vs. 9.2mo (95% CI, 2.9-13.3) vs. 7.2mo (95% CI, 2.3-NR) vs. 10.9mo (95% CI, 2.9-20.3) (p>0.8) in groups A, B, B1, and B2, respectively. There were no differences in ORR or mPFS with ICPi between the groups: ORR-0% vs. 27% vs. 33% vs. 25% (p>0.2), mPFS-2.5mo (95% CI, 1.4-3.7) vs. 3.0mo (95% CI, 1.3-10.5) vs. 2.0mo (95% CI, 1.9-NR) vs. 4.5mo (95% CI, 0.3-10.5) (p>0.3) in groups A, B, B1, and B2, respectively. In group A, no responses were seen with PARPi; mPFS with PARPi was 1.8mo (95% CI, 1.8-NR). OSDx was 98.3mo (95% CI, 9.7-98.3) vs. 19.4mo (95% CI, 9.7-47.3) vs. 18.8mo (95% CI, 8.5-NR) vs. 19.5mo (95% CI, 8.3-82.2) in groups A, B, B1, and B2, respectively (p>0.3). CONCLUSIONS: BAP1-altered MPM, as compared to non-selected MPM, is characterized by similar efficacy of CT and ICPi. Numerically longer OS in BAP1-altered MPM may reflect favorable tumor biology. No responses were observed with PARPi.