Single-fraction radiation retreatment for bone metastases: role of a rapid access clinic.

OBJECTIVES: This study investigates retreatment rates in single-fraction radiation therapy (SFRT) for painful bone metastasis in patients with limited life expectancy. We compared retreatment-free survival (RFS) in patients from a rapid access bone metastases clinic (RABC) and non-RABC patients, identifying factors associated with retreatment. METHODS: In this observational study, we analysed RABC patients who received SFRT between April 2018 and November 2019, using non-RABC SFRT patients as a comparison group. Patients with prior or perioperative radiation therapy (RT) were excluded. The primary endpoint was same-site and any-site retreatment with RT or surgery. Patient characteristics were compared using χ2 and Student's t-tests, with RFS estimates based on a multistate model considering death as a competing risk using Aalen-Johansen estimates. RESULTS: We identified 151 patients (79 RABC, 72 non-RABC) with 225 treatments (102 RABC, 123 non-RABC) meeting eligibility criteria. Of the 22 (10.8%) same-site retreatments, 5 (22.7%) received surgery, 14 (63.6%) received RT and 3 (13.6%) received both RT and surgery. We found no significant differences in any-site RFS (p=0.97) or same-site RFS (p=0.11). CONCLUSIONS: RFS is high and similar comparable in the RABC and non-RABC cohorts. Retreatment rates are low, even in patients with low Eastern Cooperative Oncology Group scores.

Escalated-dose radiotherapy for unresected locally advanced pancreatic cancer: Patterns of care and survival in the United States.

INTRODUCTION: With locally advanced pancreatic cancer (LAPC), uncontrolled local tumor growth frequently leads to mortality. Advancements in radiotherapy (RT) techniques have enabled conformal delivery of escalated-dose RT (EDR), which may have potential local control and overall survival (OS) benefits based on retrospective and early prospective studies. With evidence for EDR emerging, we characterized the adoption of EDR across the United States and its associated outcomes. METHODS: We searched the National Cancer Database for nonsurgically managed LAPC patients diagnosed between 2004 and 2019. Pancreas-directed RT with biologically effective doses (BED10) ≥39 and ≤70 Gy was labeled conventional-dose RT (CDR), and BED10 >70 and ≤132 Gy was labeled EDR. We identified associations of EDR and OS using logistic and Cox regressions, respectively. RESULTS: Among the definitive therapy subset (n = 54,115) of the entire study cohort (n = 91,493), the most common treatments were chemotherapy alone (69%), chemotherapy and radiation (29%), and RT alone (2%). For the radiation therapy subset (n = 16,978), use of pancreas-directed RT remained between 13% and 17% over the study period (ptrend > 0.999). Using multivariable logistic regression, treatment at an academic/research facility (adjusted odds ratio [aOR] 1.46, p < 0.001) and treatment between 2016 and 2019 (aOR 2.54, p < 0.001) were associated with greater receipt of EDR, whereas use of chemotherapy (aOR 0.60, p < 0.001) was associated with less receipt. Median OS estimates for EDR and CDR were 14.5 months and 13.0 months (p < 0.0001), respectively. For radiation therapy subset patients with available survival data (n = 13,579), multivariable Cox regression correlated EDR (adjusted hazard ratio 0.85, 95% confidence interval 0.80-0.91; p < 0.001) with longer OS versus CDR. DISCUSSION AND CONCLUSIONS: Utilization of EDR has increased since 2016, but overall utilization of RT for LAPC has remained at less than one in five patients for almost two decades. These real-world results additionally provide an estimate of effect size of EDR for future prospective trials.

Phase I trial of single-photon emission computed tomography-guided liver-directed radiotherapy for patients with low functional liver volume.

BACKGROUND: Traditional constraints specify that 700 cc of liver should be spared a hepatotoxic dose when delivering liver-directed radiotherapy to reduce the risk of inducing liver failure. We investigated the role of single-photon emission computed tomography (SPECT) to identify and preferentially avoid functional liver during liver-directed radiation treatment planning in patients with preserved liver function but limited functional liver volume after receiving prior hepatotoxic chemotherapy or surgical resection. METHODS: This phase I trial with a 3 + 3 design evaluated the safety of liver-directed radiotherapy using escalating functional liver radiation dose constraints in patients with liver metastases. Dose-limiting toxicities were assessed 6-8 weeks and 6 months after completing radiotherapy. RESULTS: All 12 patients had colorectal liver metastases and received prior hepatotoxic chemotherapy; 8 patients underwent prior liver resection. Median computed tomography anatomical nontumor liver volume was 1584 cc (range = 764-2699 cc). Median SPECT functional liver volume was 1117 cc (range = 570-1928 cc). Median nontarget computed tomography and SPECT liver volumes below the volumetric dose constraint were 997 cc (range = 544-1576 cc) and 684 cc (range = 429-1244 cc), respectively. The prescription dose was 67.5-75 Gy in 15 fractions or 75-100 Gy in 25 fractions. No dose-limiting toxicities were observed during follow-up. One-year in-field control was 57%. One-year overall survival was 73%. CONCLUSION: Liver-directed radiotherapy can be safely delivered to high doses when incorporating functional SPECT into the radiation treatment planning process, which may enable sparing of lower volumes of liver than traditionally accepted in patients with preserved liver function. TRIAL REGISTRATION: NCT02626312.

Safety and Tolerability of Online Adaptive High-Field Magnetic Resonance-Guided Radiotherapy.

Importance: In 2018, the first online adaptive magnetic resonance (MR)-guided radiotherapy (MRgRT) system using a 1.5-T MR-equipped linear accelerator (1.5-T MR-Linac) was clinically introduced. This system enables online adaptive radiotherapy, in which the radiation plan is adapted to size and shape changes of targets at each treatment session based on daily MR-visualized anatomy. Objective: To evaluate safety, tolerability, and technical feasibility of treatment with a 1.5-T MR-Linac, specifically focusing on the subset of patients treated with an online adaptive strategy (ie, the adapt-to-shape [ATS] approach). Design, Setting, and Participants: This cohort study included adults with solid tumors treated with a 1.5-T MR-Linac enrolled in Multi Outcome Evaluation for Radiation Therapy Using the MR-Linac (MOMENTUM), a large prospective international study of MRgRT between February 2019 and October 2021. Included were adults with solid tumors treated with a 1.5-T MR-Linac. Data were collected in Canada, Denmark, The Netherlands, United Kingdom, and the US. Data were analyzed in August 2023. Exposure: All patients underwent MRgRT using a 1.5-T MR-Linac. Radiation prescriptions were consistent with institutional standards of care. Main Outcomes and Measures: Patterns of care, tolerability, and technical feasibility (ie, treatment completed as planned). Acute high-grade radiotherapy-related toxic effects (ie, grade 3 or higher toxic effects according to Common Terminology Criteria for Adverse Events version 5.0) occurring within the first 3 months after treatment delivery. Results: In total, 1793 treatment courses (1772 patients) were included (median patient age, 69 years [range, 22-91 years]; 1384 male [77.2%]). Among 41 different treatment sites, common sites were prostate (745 [41.6%]), metastatic lymph nodes (233 [13.0%]), and brain (189 [10.5%]). ATS was used in 1050 courses (58.6%). MRgRT was completed as planned in 1720 treatment courses (95.9%). Patient withdrawal caused 5 patients (0.3%) to discontinue treatment. The incidence of radiotherapy-related grade 3 toxic effects was 1.4% (95% CI, 0.9%-2.0%) in the entire cohort and 0.4% (95% CI, 0.1%-1.0%) in the subset of patients treated with ATS. There were no radiotherapy-related grade 4 or 5 toxic effects. Conclusions and Relevance: In this cohort study of patients treated on a 1.5-T MR-Linac, radiotherapy was safe and well tolerated. Online adaptation of the radiation plan at each treatment session to account for anatomic variations was associated with a low risk of acute grade 3 toxic effects.

Long-Term Patient-Reported Dyspareunia After Definitive Chemoradiation for Anal Cancer: Using the Anterior Vaginal Wall as an Organ-at-Risk to Define an Actionable Dosimetric Goal.

Purpose: Chemoradiation therapy (CRT) is the standard treatment for squamous cell carcinoma of the anus (SCCA). This study aimed to investigate the relationship between vaginal dosimetry and long-term patient-reported dyspareunia after treatment. We further aimed to use the anterior vaginal wall (AVW) as an organ at risk to define an actionable dosimetric clinical goal to decrease the risk of patient-reported dyspareunia. Methods and Materials: Women with SCCA treated with intensity modulated radiation therapy-based CRT were surveyed at least 2 years after successfully completing therapy. A Female Sexual Function Index (FSFI) pain subscore ≤4 was used to define dyspareunia. Dosimetric parameters were calculated for both the full vaginal canal and AVW. Multivariable linear regression models were created to identify predictors of FSFI pain subscore using backward selection to identify final variables include in the models. An actionable dosimetric predictor for dyspareunia was established using the Youden index method for cutoff optimization. Results: Of 184 women who were contacted, 90 (49%) returned completed surveys. Of those who completed surveys, 51 (56.7%) reported being sexually active, and 47 had dosimetric data available for review. Of sexually active respondents, 32 (68%) had an FSFI pain subscore ≤4. Multiple regression models were generated using the full vaginal canal and AVW as organs at risk, and both models showed similar predictive relationships with volumetric dose parameters emerging as the best dosimetric predictors for dysparenuia. Age over 65 years was also associated with higher FSFI pain subscores (eg, less pain with intercourse) in both models. AVW V35 Gy < 60% was identified as the optimal cutoff to reduce the risk of patient-reported dyspareunia. Conclusions: Increased dose to the vaginal canal is significantly associated with worse patient-reported dyspareunia following CRT for SCCA. Minimizing dose to the AVW to V35 Gy < 60% may reduce the risk of this quality of life-limiting toxicity. Further prospective evaluation is needed to validate these findings.

Implementation and Efficacy of a Large-Scale Radiation Oncology Case-Based Peer-Review Quality Program across a Multinational Cancer Network.

PURPOSE: With expansion of academic cancer center networks across geographically-dispersed sites, ensuring high-quality delivery of care across all network affiliates is essential. We report on the characteristics and efficacy of a radiation oncology peer-review quality assurance (QA) system implemented across a large-scale multinational cancer network. METHODS AND MATERIALS: Since 2014, weekly case-based peer-review QA meetings have been standard for network radiation oncologists with radiation oncology faculty at a major academic center. This radiotherapy (RT) QA program involves pre-treatment peer-review of cases by disease site, with disease-site subspecialized main campus faculty members. This virtual QA platform involves direct review of the proposed RT plan as well as supporting data, including relevant pathology and imaging studies for each patient. Network RT plans were scored as being concordant or nonconcordant based on national guidelines, institutional recommendations, and/or expert judgment when considering individual patient-specific factors for a given case. Data from January 1, 2014, through December 31, 2019, were aggregated for analysis. RESULTS: Between 2014 and 2019, across 8 network centers, a total of 16,601 RT plans underwent peer-review. The network-based peer-review case volume increased over the study period, from 958 cases in 2014 to 4,487 in 2019. A combined global nonconcordance rate of 4.5% was noted, with the highest nonconcordance rates among head-and-neck cases (11.0%). For centers that joined the network during the study period, we observed a significant decrease in the nonconcordance rate over time (3.1% average annual decrease in nonconcordance, P = 0.01); among centers that joined the network prior to the study period, nonconcordance rates remained stable over time. CONCLUSIONS: Through a standardized QA platform, network-based multinational peer-review of RT plans can be achieved. Improved concordance rates among newly added network affiliates over time are noted, suggesting a positive impact of network membership on the quality of delivered cancer care.

Salvage Treatment of Recurrent or Persistent Anal Squamous Cell Carcinoma: The Role of Multi-modality Therapy.

BACKGROUND: The standard treatment for recurrent or persistent anal squamous cell carcinoma is surgical salvage, but disease control and survival are suboptimal. PATIENTS/METHODS: Patients treated for recurrent or persistent anal squamous cell carcinoma at our institution from 2002 to 2022 were included. Patients were classified by type of salvage treatment received: surgery alone vs. reirradiation followed by surgery and by whether they received intraoperative radiation at the time of surgery. Clinical and pathologic variables were collected and assessed for association with risk of second local recurrence and death from any cause. RESULTS: Sixty four patients were included; 55(85.9%) were treated with surgery alone and 9 (14.1%) were treated with reirradiation followed by surgery. Median (IQR) follow up from the time of salvage treatment was 40.0 (20.3-68.0) months. The 3-year cumulative incidence of second local recurrence (95% CI) after salvage surgery was 36% (24%-48%); 39% (26%-52%) for patients treated with surgery alone and 15% (0.46%-51%) for patients treated with reirradiation followed by surgery. Factors associated with increased second local recurrence after salvage surgery included a locoregional recurrence, lymphovascular space invasion and positive surgical margins. The 3-year overall survival (95% CI) after salvage surgery was 70% (59%-83%); 68% (7%-56%) after surgery alone and 89% (10.5%-70.6%) after reirradiation followed by surgery. Factors associated with worse overall survival included male sex, a larger recurrent tumor and positive surgical margins. CONCLUSIONS: Approximately 60% of patients achieved pelvic control after salvage therapy for recurrent or persistent anal squamous cell carcinoma. Although receipt of reirradiation and intraoperative radiation were not associated with improved second local recurrence or overall survival in our cohort, patients with positive surgical margins and lymphovascular space invasion on surgical pathology had higher rates of pelvic recurrence after salvage surgery and may benefit from escalated salvage therapy.

Daily Vaginal Dilator Use During Radiation for Women With Squamous Cell Carcinoma of the Anus: Vaginal Wall Dosimetry and Patient-Reported Sexual Function.

PURPOSE: At our institution, we treat patients with a daily vaginal dilator (VD) during chemoradiation (CRT) for squamous cell carcinoma of the anus (SCCA). We evaluated compliance with daily VD use, radiation dose to the vaginal wall (VW), and anterior vaginal wall (AVW), and patient-reported long-term sexual function. METHODS AND MATERIALS: We included women with SCCA who received definitive, intensity-modulated radiation therapy-based CRT. Women who were alive without evidence of disease received a patient-reported outcome survey, which included the Female Sexual Function Index (FSFI). We identified factors associated with FSFI, such as radiation dose to the VW and AVW using linear regression models and used Youden index analysis to estimate a dose cutoff to predict sexual dysfunction. RESULTS: Three hundred thirty-nine consecutively treated women were included in the analysis; 285 (84.1%) were treated with a daily VD. Of 184 women alive without disease, 90 patients (49%) completed the FSFI, and 51 (56.7%) were sexually active with valid FSFI scores. All received therapy with a daily VD. Forty-one women (80%) had sexual dysfunction. Univariate analysis showed higher dose to 50% (D50%) of the AVW correlated with worse FSFI (ß -.262; P = .043), worse desire FSFI subscore (ß -.056; P = .003), and worse pain FSFI subscore (ß -.084; P = .009). Younger age correlated with worse pain FSFI subscale (ß .067; P = .026). Age (ß .070; P = .013) and AVW D50% (ß -.087; P = .009) were significant on multivariable analysis. AVW D50% >48 Gy predicted increased risk of sexual dysfunction. CONCLUSIONS: Daily VD use is safe and well tolerated during CRT for SCCA. Using a VD during treatment to displace the AVW may reduce the risk for sexual dysfunction. Limiting the AVW D50% <48 Gy may further reduce the risk but additional data are needed to validate this constraint.

Independent Stage Classification for Gastroesophageal Junction Adenocarcinoma.

In gastroesophageal junction (GEJ) adenocarcinoma cases, a prognosis based on ypTNM staging could be affected by preoperative therapy. Patients with esophageal adenocarcinoma and gastric adenocarcinoma who underwent preoperative therapy followed by surgical resection from 2006 through 2017 were identified in the National Cancer Database. To enable stage-by-stage OS comparisons, tumors were classified into four gross ypTNM groups: ypT1/2, N-negative; ypT1/2, N-positive; ypT3/4, N-negative; and ypT3/4, N-positive. Prognostic factors were examined, and an OS prediction nomogram was developed for patients with abdominal/lower esophageal and gastric cardia adenocarcinoma, representing GEJ cancers. We examined 25,463 patient records. When compared by gross ypTNM group, the abdominal/lower esophageal and gastric cardia adenocarcinoma groups had similar OS rates, differing from those of other esophageal or gastric cancers. Cox regression analysis of patients with GEJ cancers showed that preoperative chemoradiotherapy was associated with shorter OS than preoperative chemotherapy after adjustment for the ypTNM group (hazard ratio 1.31, 95% CI 1.24-1.39, p < 0.001), likely owing to downstaging effects. The nomogram had a concordance index of 0.833 and a time-dependent area under the curve of 0.669. OS prediction in GEJ adenocarcinoma cases should include preoperative therapy regimens. Our OS prediction nomogram provided reasonable OS prediction for patients with GEJ adenocarcinoma, and future validation is needed.

Definitive Liver Radiotherapy for Intrahepatic Cholangiocarcinoma with Extrahepatic Metastases.

Introduction: Tumor-related liver failure (TRLF) is the most common cause of death in patients with intrahepatic cholangiocarcinoma (ICC). Though we previously showed that liver radiotherapy (L-RT) for locally advanced ICC is associated with less frequent TRLF and longer overall survival (OS), the role of L-RT for patients with extrahepatic metastatic disease (M1) remains undefined. We sought to compare outcomes for M1 ICC patients treated with and without L-RT. Methods: We reviewed ICC patients that found to have M1 disease at initial diagnosis at a single institution between 2010 and 2021 who received L-RT, matching them with an institutional cohort by propensity score and a National Cancer Database (NCDB) cohort by frequency technique. The median biologically effective dose was 97.5 Gy (interquartile range 80.5-97.9 Gy) for L-RT. Patients treated with other local therapies or supportive care alone were excluded. We analyzed survival with Cox proportional hazard modeling. Results: We identified 61 patients who received L-RT and 220 who received chemotherapy alone. At median follow-up of 11 months after diagnosis, median OS was 9 months (95% confidence interval [CI] 8-11) and 21 months (CI: 17-26) for patients receiving chemotherapy alone and L-RT, respectively. TRLF was the cause of death more often in the patients who received chemotherapy alone compared to those who received L-RT (82% vs. 47%; p = 0.001). On multivariable propensity score-matched analysis, associations with lower risk of death included duration of upfront chemotherapy (hazard ratio [HR] 0.82; p = 0.005) and receipt of L-RT (HR: 0.40; p = 0.002). The median OS from diagnosis for NCDB chemotherapy alone cohort was shorter than that of the institutional L-RT cohort (9 vs. 22 months; p < 0.001). Conclusion: For M1 ICC, L-RT associated with a lower rate of death due to TRLF and longer OS versus those treated with chemotherapy alone. Prospective studies of L-RT in this setting are warranted.

Incidence of Primary End Point Changes Among Active Cancer Phase 3 Randomized Clinical Trials.

Importance: Primary end point (PEP) changes to an active clinical trial raise questions regarding trial quality and the risk of outcome reporting bias. It is unknown how the frequency and transparency of the reported changes depend on reporting method and whether the PEP changes are associated with trial positivity (ie, the trial met the prespecified statistical threshold for PEP positivity). Objectives: To assess the frequency of reported PEP changes in oncology randomized clinical trials (RCTs) and whether these changes are associated with trial positivity. Design, Setting, and Participants: This cross-sectional study used publicly available data for complete oncology phase 3 RCTs registered in ClinicalTrials.gov from inception through February 2020. Main Outcomes and Measures: The main outcome was change between the initial PEP and the final reported PEP, assessed using 3 methods: (1) history of tracked changes on ClinicalTrials.gov, (2) self-reported changes noted in the article, and (3) changes reported within the protocol, including all available protocol documents. Logistic regression analyses were performed to evaluate whether PEP changes were associated with US Food and Drug Administration approval or trial positivity. Results: Of 755 included trials, 145 (19.2%) had PEP changes found by at least 1 of the 3 detection methods. Of the 145 trials with PEP changes, 102 (70.3%) did not have PEP changes disclosed within the manuscript. There was significant variability in rates of PEP detection by each method (χ2 = 72.1; P < .001). Across all methods, PEP changes were detected at higher rates when multiple versions of the protocol (47 of 148 [31.8%]) were available compared with 1 version (22 of 134 [16.4%]) or no protocol (76 of 473 [16.1%]) (χ2 = 18.7; P < .001). Multivariable analysis demonstrated that PEP changes were associated with trial positivity (odds ratio, 1.86; 95% CI, 1.25-2.82; P = .003). Conclusions and Relevance: This cross-sectional study revealed substantial rates of PEP changes among active RCTs; PEP changes were markedly underreported in published articles and mostly occurred after reported study completion dates. Significant discrepancies in the rate of detected PEP changes call into question the role of increased protocol transparency and completeness in identifying key changes occurring in active trials.

HPV-related anal cancer is associated with changes in the anorectal microbiome during cancer development.

Background: Squamous cell carcinoma of the anus (SCCA) is a rare gastrointestinal cancer. Factors associated with progression of HPV infection to anal dysplasia and cancer are unclear and screening guidelines and approaches for anal dysplasia are less clear than for cervical dysplasia. One potential contributing factor is the anorectal microbiome. In this study, we aimed to identify differences in anal microbiome composition in the settings of HPV infection, anal dysplasia, and anal cancer in this rare disease. Methods: Patients were enrolled in two prospective studies. Patients with anal dysplasia were part of a cross-sectional cohort that enrolled women with high-grade lower genital tract dysplasia. Anorectal tumor swabs were prospectively collected from patients with biopsy-confirmed locally advanced SCCA prior to receiving standard-of-care chemoradiotherapy (CRT). Patients with high-grade lower genital tract dysplasia without anal dysplasia were considered high-risk (HR Normal). 16S V4 rRNA Microbiome sequencing was performed for anal swabs. Alpha and Beta Diversity and composition were compared for HR Normal, anal dysplasia, and anal cancer. Results: 60 patients with high-grade lower genital tract dysplasia were initially enrolled. Seven patients had concurrent anal dysplasia and 44 patients were considered HR Normal. Anorectal swabs from 21 patients with localized SCCA were included, sequenced, and analyzed in the study. Analysis of weighted and unweighted UniFrac distances demonstrated significant differences in microbial community composition between anal cancer and HR normal (p=0.018). LEfSe identified that all three groups exhibited differential enrichment of specific taxa. Peptoniphilus (p=0.028), Fusobacteria (p=0.0295), Porphyromonas (p=0.034), and Prevotella (p=0.029) were enriched in anal cancer specimens when compared to HR normal. Conclusion: Although alpha diversity was similar between HR Normal, dysplasia and cancer patients, composition differed significantly between the three groups. Increased anorectal Peptoniphilus, Fusobacteria, Porphyromonas, and Prevotella abundance were associated with anal cancer. These organisms have been reported in various gastrointestinal cancers with roles in facilitating the proinflammatory microenvironment and neoplasia progression. Future work should investigate a potential role of microbiome analysis in screening for anal dysplasia and investigation into potential mechanisms of how these microbial imbalances influence the immune system and anal carcinogenesis.

Clinical Impact of Positive Surgical Margins in Gastric Adenocarcinoma in the Era of Preoperative Therapy.

BACKGROUND: Microscopically positive (R1) surgical margins after gastrectomy increase gastric cancer recurrence risk, but optimal management after R1 gastrectomy is controversial. We sought to identify the impact of R1 margins on recurrence patterns and survival in the era of preoperative therapy for gastric cancer. METHODS: Patients who underwent gastrectomy for adenocarcinoma during 1998-2017 at a major cancer center were enrolled. Clinicopathologic factors associated with positive margins were examined, and incidence, sites, and timing of recurrence and survival outcomes were compared between patients with positive and negative margins. RESULTS: Of 688 patients, 432 (63%) received preoperative therapy. Thirty-four patients (5%) had R1 margins. Compared with patients with negative margins, patients with R1 margins more frequently had aggressive clinicopathologic features, such as linitis plastica (odds ratio [OR] 7.79, p < 0.001) and failure to achieve cT downstaging with preoperative treatment (OR 5.20, p = 0.005). The 5 year overall survival (OS) rate was lower in patients with R1 margins (6% vs 60%; p < 0.001), and R1 margins independently predicted worse OS (hazard ratio 2.37, 95% CI 1.51-3.75, p < 0.001). Most patients with R1 margins (58%) experienced peritoneal recurrence, and locoregional recurrence was relatively rare in this group (14%). Median time to recurrence was 8.5 months for peritoneal dissemination and 15.7 months for locoregional recurrence. CONCLUSION: R1 margins after gastrectomy were associated with aggressive tumor biology, high incidence of peritoneal recurrence after a short interval, and poor OS. In patients with R1 margins, re-resection to achieve microscopically negative margins has to be considered with caution.

Association of Radiotherapy Duration With Clinical Outcomes in Patients With Esophageal Cancer Treated in NRG Oncology Trials: A Secondary Analysis of NRG Oncology Randomized Clinical Trials.

Importance: For many types of epithelial malignant neoplasms that are treated with definitive radiotherapy (RT), treatment prolongation and interruptions have an adverse effect on outcomes. Objective: To analyze the association between RT duration and outcomes in patients with esophageal cancer who were treated with definitive chemoradiotherapy (CRT). Design, Setting, and Participants: This study was an unplanned, post hoc secondary analysis of 3 prospective, multi-institutional phase 3 randomized clinical trials (Radiation Therapy Oncology Group [RTOG] 8501, RTOG 9405, and RTOG 0436) of the National Cancer Institute-sponsored NRG Oncology (formerly the National Surgical Adjuvant Breast and Bowel Project, RTOG, and Gynecologic Oncology Group). Enrolled patients with nonmetastatic esophageal cancer underwent definitive CRT in the trials between 1986 and 2013, with follow-up occurring through 2014. Data analyses were conducted between March 2022 to February 2023. Exposures: Treatment groups in the trials used standard-dose RT (50 Gy) and concurrent chemotherapy. Main Outcomes and Measures: The outcomes were local-regional failure (LRF), distant failure, disease-free survival (DFS), and overall survival (OS). Multivariable models were used to examine the associations between these outcomes and both RT duration and interruptions. Radiotherapy duration was analyzed as a dichotomized variable using an X-Tile software to choose a cut point and its median value as a cut point, as well as a continuous variable. Results: The analysis included 509 patients (median [IQR] age, 64 [57-70] years; 418 males [82%]; and 376 White individuals [74%]). The median (IQR) follow-up was 4.01 (2.93-4.92) years for surviving patients. The median cut point of RT duration was 39 days or less in 271 patients (53%) vs more than 39 days in 238 patients (47%), and the X-Tile software cut point was 45 days or less in 446 patients (88%) vs more than 45 days in 63 patients (12%). Radiotherapy interruptions occurred in 207 patients (41%). Female (vs male) sex and other (vs White) race and ethnicity were associated with longer RT duration and RT interruptions. In the multivariable models, RT duration longer than 45 days was associated with inferior DFS (hazard ratio [HR], 1.34; 95% CI, 1.01-1.77; P = .04). The HR for OS was 1.33, but the results were not statistically significant (95% CI, 0.99-1.77; P = .05). Radiotherapy duration longer than 39 days (vs ≤39 days) was associated with a higher risk of LRF (HR, 1.32; 95% CI, 1.06-1.65; P = .01). As a continuous variable, RT duration (per 1 week increase) was associated with DFS failure (HR, 1.14; 95% CI, 1.01-1.28; P = .03). The HR for LRF 1.13, but the result was not statistically significant (95% CI, 0.99-1.28; P = .07). Conclusions and Relevance: Results of this study indicated that in patients with esophageal cancer receiving definitive CRT, prolonged RT duration was associated with inferior outcomes; female patients and those with other (vs White) race and ethnicity were more likely to have longer RT duration and experience RT interruptions. Radiotherapy interruptions should be minimized to optimize outcomes.

Patient-reported Bowel Function and Bowel-related Quality of Life After Pelvic Radiation for Rectal Adenocarcinoma: The Impact of Radiation Fractionation and Surgical Resection.

INTRODUCTION: Multimodality treatment for locally advanced rectal cancer (LARC) can include long-course radiotherapy (LCRT) or short course radiotherapy (SCRT). Nonoperative management is increasingly pursued for those achieving a complete clinical response. Data regarding long-term function and quality-of-life (QOL) are limited. METHODS: Patients with LARC treated with radiotherapy from 2016 to 2020 completed the Functional Assessment of Cancer Therapy- General (FACT-G7), the Low Anterior Resection Syndrome Score (LARS) and the Fecal Incontinence QOL Scale (FIQOL). Univariate and multivariable linear regression analyses identified associations between clinical variables including radiation fractionation and the use of surgery versus non-operative management. RESULTS: Of 204 patients surveyed, 124 (60.8%) responded. Median (interquartile range) time from radiation to survey completion was 30.1 (18.3-43) months. Seventy-nine (63.7%) respondents received LCRT, and 45 (36.3%) received SCRT; 101 (81.5%) respondents underwent surgery, and 23 (18.5%) pursued nonoperative management. There were no differences in LARS, FIQoL or FACT-G7 between patients receiving LCRT versus SCRT. On multivariable analysis, only nonoperative management was associated with lower LARS score signifying less bowel dysfunction. Nonoperative management and female sex were associated with a higher FIQoL score signifying less disruption and distress from fecal incontinence issues. Finally, lower BMI at the time of radiation, female sex, and higher FIQoL score were associated with higher FACT-G7 scores signifying better overall QOL. CONCLUSIONS: These results suggest long-term patient-reported bowel function and QOL may be similar for individuals receiving SCRT and LCRT for the treatment of LARC, but nonoperative management may lead to improved bowel function and QOL.

Differential Spatial Gene and Protein Expression Associated with Recurrence Following Chemoradiation for Localized Anal Squamous Cell Cancer.

The identification of transcriptomic and protein biomarkers prognosticating recurrence risk after chemoradiation of localized squamous cell carcinoma of the anus (SCCA) has been limited by a lack of available fresh tissue at initial presentation. We analyzed archival FFPE SCCA specimens from pretreatment biopsies prior to chemoradiation for protein and RNA biomarkers from patients with localized SCCA who recurred (N = 23) and who did not recur (N = 25). Tumor cells and the tumor microenvironment (TME) were analyzed separately to identify biomarkers with significantly different expression between the recurrent and non-recurrent groups. Recurrent patients had higher mean protein expression of FoxP3, MAPK-activation markers (BRAF, p38-MAPK) and PI3K/Akt activation (phospho-Akt) within the tumor regions. The TME was characterized by the higher protein expression of immune checkpoint biomarkers such as PD-1, OX40L and LAG3. For patients with recurrent SCCA, the higher mean protein expression of fibronectin was observed in the tumor and TME compartments. No significant differences in RNA expression were observed. The higher baseline expression of immune checkpoint biomarkers, together with markers of MAPK and PI3K/Akt signaling, are associated with recurrence following chemoradiation for patients with localized SCCA. These data provide a rationale towards the application of immune-based therapeutic strategies to improve curative-intent outcomes beyond conventional therapies for patients with SCCA.

Brain Metastases from Biliary Tract Cancer: Case Series and Clinicogenomic Analysis.

BACKGROUND: Limited data from small series have suggested that brain metastases from biliary tract cancers (BrM-BTC) affect ≤2% of patients with BTC. We sought to review our experience with patients with BrM-BTC and to identify associations of tumor-related molecular alterations with outcomes. MATERIALS AND METHODS: A retrospective review of patients with BTC seen at a tertiary referral center from 2005 to 2021 was performed; patients with BrM-BTC were identified, and clinical and molecular data were collected. RESULTS: Twenty-one of 823 patients with BTC (2.6%) developed BrM. For patients with BrM-BTC, median follow-up time was 27.9 months after primary BTC diagnosis and 3.1 months after BrM diagnosis. Median time from primary diagnosis to diagnosis of BrM was 14.4 [range, 1.1-66.0] months. Median overall survival (OS) from primary diagnosis was 31.5 [2.9-99.8] months and median OS from BrM diagnosis was 4.2 [0.2-33.8] months. Patients who underwent BrM-directed therapy trended toward longer OS following BrM diagnosis than patients receiving supportive care only (median 6.5 vs 0.8 months, P = .060). The BrM-BTC cohort was enriched for BRAF (30%), PIK3CA (25%), and GNAS (20%) mutations. patients with BrM-BTC with BRAF mutations trended toward longer OS following BrM diagnosis (median 13.1 vs 4.2 months, P = .131). CONCLUSION: This is the largest series of patients with BrM-BTC to date and provides molecular characterization of this rare subgroup of patients with BTC. Patients with BrM-BTC may be more likely to have BRAF mutations. With advances in targeted therapy for patients with BTC with actionable mutations, continued examination of shifting patterns of failure, with emphasis on BrM, is warranted.

Patient-Reported Sexual Function, Bladder Function and Quality of Life for Patients with Low Rectal Cancers with or without a Permanent Ostomy.

BACKGROUND: Despite the increasing utilization of sphincter and/or organ-preservation treatment strategies, many patients with low-lying rectal cancers require abdominoperineal resection (APR), leading to permanent ostomy. Here, we aimed to characterize overall, sexual-, and bladder-related patient-reported quality of life (QOL) for individuals with low rectal cancers. We additionally aimed to explore potential differences in patient-reported outcomes between patients with and without a permanent ostomy. METHODS: We distributed a comprehensive survey consisting of various patient-reported outcome measures, including the FACT-G7 survey, ICIQ MLUTS/FLUTS, IIEF-5/FSFI, and a specific questionnaire for ostomy patients. Descriptive statistics and univariate comparisons were used to compared demographics, treatments, and QOL scores between patients with and without a permanent ostomy. RESULTS: Of the 204 patients contacted, 124 (60.8%) returned completed surveys; 22 (18%) of these had a permanent ostomy at the time of survey completion. There were 25 patients with low rectal tumors (≤5 cm from the anal verge) who did not have an ostomy at the time of survey completion, of whom 13 (52%) were managed with a non-operative approach. FACTG7 scores were numerically lower (median 20.5 vs. 22, p = 0.12) for individuals with an ostomy. Sexual function measures IIEF and FSFI were also lower (worse) for individuals with ostomies, but the results were not significantly different. MLUTS and FLUTS scores were both higher in individuals with ostomies (median 11 vs. 5, p = 0.06 and median 17 vs. 5.5, p = 0.01, respectively), suggesting worse urinary function. Patient-reported ostomy-specific challenges included gastrointestinal concerns (e.g., gas, odor, diarrhea) that may affect social activities and personal relationships. CONCLUSIONS: Despite a limited sample size, this study provides patient-centered, patient-derived data regarding long-term QOL in validated measures following treatment of low rectal cancers. Ostomies may have multidimensional negative impacts on QOL, and these findings warrant continued investigation in a prospective setting. These results may be used to inform shared decision making for individuals with low rectal cancers in both the settings of organ preservation and permanent ostomy.

Development and Validation of a Predictive Model for Toxicity of Neoadjuvant Chemoradiotherapy in Rectal Cancer in the CAO/ARO/AIO-04 Phase III Trial.

Background: There is a lack of predictive models to identify patients at risk of high neoadjuvant chemoradiotherapy (CRT)-related acute toxicity in rectal cancer. Patient and Methods: The CAO/ARO/AIO-04 trial was divided into a development (n = 831) and a validation (n = 405) cohort. Using a best subset selection approach, predictive models for grade 3−4 acute toxicity were calculated including clinicopathologic characteristics, pretreatment blood parameters, and baseline results of quality-of-life questionnaires and evaluated using the area under the ROC curve. The final model was internally and externally validated. Results: In the development cohort, 155 patients developed grade 3−4 toxicities due to CRT. In the final evaluation, 15 parameters were included in the logistic regression models using best-subset selection. BMI, gender, and emotional functioning remained significant for predicting toxicity, with a discrimination ability adjusted for overfitting of AUC 0.687. The odds of experiencing high-grade toxicity were 3.8 times higher in the intermediate and 6.4 times higher in the high-risk group (p < 0.001). Rates of toxicity (p = 0.001) and low treatment adherence (p = 0.007) remained significantly different in the validation cohort, whereas discrimination ability was not significantly worse (DeLong test 0.09). Conclusion: We developed and validated a predictive model for toxicity using gender, BMI, and emotional functioning. Such a model could help identify patients at risk for treatment-related high-grade toxicity to assist in treatment guidance and patient participation in shared decision making.