Neutrophil-to-lymphocyte ratio for the prediction of soft tissue sarcomas response to pre-operative radiation therapy.

PURPOSE/OBJECTIVE: This study aims to assess the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in soft tissue sarcomas (STS) treated with pre-operative hypofractionated radiotherapy (HFRT). MATERIALS/METHODS: This retrospective analysis included patients treated with pre-operative HFRT of 30 Gy in 5 fractions between 2016 and 2023. Clinical, demographic, and complete blood count (CBC) data were collected. NLR was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. Only patients with CBCs conducted within 6 months after radiotherapy were included. Cox proportional-hazard regression models were used to assess the impact of NLR and different variables on outcomes. Kaplan Meier were used to illustrate survival curves. A p-value < 0.05 was considered significant, and 95 % confidence intervals (CI) were employed. RESULTS: A total of 40 patients received HFRT and had CBCs within 6 months after radiotherapy. There were 17 (42.5 %) females and 23 (57.5 %) males with a mean age of 66 years. The mean largest tumor size dimension was 7.1 cm, and the mean NLR post-RT was 5.3. The most frequent histological subtypes were myxofibrosarcoma (17.5 %), pleomorphic spindle cell sarcoma (10 %), leiomyosarcoma (7.5 %), and myxoid liposarcoma (5 %). The median follow-up period was 15.4 months. From all patients, 14 patients had disease progression, 12 metastatic disease and 3 died of disease. Multivariable Cox proportional-hazards regression analysis displayed that a higher post-RT NLR was associated with worse disease-free survival (DFS) (HR: 1.303 [1.098-1.548], p = 0.003), and distant metastasis-free survival (DMFS) (HR: 1.38 [1.115-1.710], p = 0.003). Moreover, post-NLR ≥ 4 as a single variable was associated with worse DFS, DMFS, but not worse local recurrence or overall survival. CONCLUSION: This study is the first to evaluate NLR as a prognostic biomarker in STS patients treated with pre-operative radiotherapy. A higher NLR after pre-operative radiotherapy was associated with increased disease progression.

Benefit of Neoadjuvant Cisplatin-based Chemotherapy for Invasive Bladder Cancer Patients Treated with Radiation-based Therapy in a Real-world Setting: An Inverse Probability Treatment Weighted Analysis.

BACKGROUND: Neoadjuvant chemotherapy (NAC) improves survival for patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy. Studies on the potential benefit of NAC before radiation-based therapy (RT) are conflicting. OBJECTIVE: To evaluate the effect of NAC on patients with MIBC treated with curative-intent RT in a real-world setting. DESIGN, SETTING, AND PARTICIPANTS: The study cohort consisted of 785 patients with MIBC (cT2-4aN0-2M0) who underwent RT at academic centers across Canada. Patients were classified into two treatment groups based on the administration of NAC before RT (NAC vs no NAC). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The inverse probability of treatment weighting (IPTW) with absolute standardized differences (ASDs) was used to balance covariates across treatment groups. The impact of NAC on complete response, overall, and cancer-specific survival (CSS) after RT in the weighted cohort was analyzed. RESULTS AND LIMITATIONS: After applying the exclusion criteria, 586 patients were included; 102 (17%) received NAC before RT. Patients in the NAC subgroup were younger (mean age 65 vs 77 yr; ASD 1.20); more likely to have Eastern Cooperative Oncology Group performance status 0-1 (87% vs 78%; ASD 0.28), lymphovascular invasion (32% vs 20%; ASD 0.27), higher cT stage (cT3-4 in 29% vs 20%; ASD 0.21), and higher cN stage (cN1-2 in 32% vs 4%; ASD 0.81); and more commonly treated with concurrent chemotherapy (79% vs 67%; ASD 0.28). After IPTW, NAC versus no NAC cohorts were well balanced (ASD <0.20) for all included covariates. NAC was significantly associated with improved CSS (hazard ratio [HR] 0.28; 95% confidence interval [CI] 0.14-0.56; p < 0.001) and overall survival (HR 0.56; 95% CI 0.38-0.84; p = 0.005). This study was limited by potential occult imbalances across treatment groups. CONCLUSIONS: If tolerated, NAC might be associated with improved survival and should be considered for eligible patients with MIBC planning to undergo bladder preservation with RT. Prospective trials are warranted. PATIENT SUMMARY: In this study, we showed that neoadjuvant chemotherapy might be associated with improved survival in patients with muscle-invasive bladder cancer who elect for curative-intent radiation-based therapy.

Meta-analysis of 5-day preoperative radiotherapy for soft tissue sarcoma (5D-PREORTS).

BACKGROUND AND PURPOSE: Although the role of conventionally fractionated radiotherapy (RT) in combination with surgery in the limb-sparing treatment of soft tissue sarcoma (STS) patients is well established, the effectiveness and safety of 5-day preoperative radiotherapy (RT) remain controversial. We performed a meta-analysis to evaluate the treatment outcomes of 5-day preoperative RT using ≥ 5 Gy per fraction with contemporary radiotherapy techniques. MATERIALS AND METHODS: Medline, Embase, the Cochrane Library, and the proceedings of annual meetings through March 2022 were used to identify eligible studies. Following the PRISMA and MOOSE guidelines, a meta-regression analysis was performed to assess possible correlations between variables and outcomes. A p-value < 0.05 was considered significant. RESULTS: Nine prospective studies with 786 patients (median follow-up 35 months, 20-60 months) treated with preoperative RT delivered a median total of 30 Gy (25-40 Gy) in 5 fractions. The local control (LC), R0 margins, overall survival (OS), and distant relapse (DR) rates were 92.3% (95% CI: 87---97%), 84.5% (95% CI: 78---90%), 78% (95% CI: 70---86%), and 36% (95% CI: 70---86%). The meta-regression analysis identified a significant relationship between biological equivalent dose (BED) and larger tumor size for LC and R0 margins (p < 0.05). The subgroup analysis reveals that patients receiving BED ≥ 90 (equivalent to 30 Gy in 5 fractions) had a higher LC control rate than BED < 90 (p < 0.0001). The complete pathologic response and amputation rates were 19% (95% CI: 13-26%) and 8.3% (95% CI: 0.5-15%). Amputation rates were higher in studies using the lowest and highest doses and were related to salvage surgery after recurrence and complications, respectively. The rate of wound complication and fibrosis grade 2 or worse was 30% (95% CI 23-38%) and 6.4% (95% CI 1.9-11%). CONCLUSION: A 5-day course of preoperative RT results in high LC and favorable R0 margins, with acceptable complication rates in most studies. Better local control and R0 margins were associated with regimens using higher BED, i.e., doses equal to or higher than 30 Gy when using 5 fractions.

Radiotherapy Plus Cisplatin With or Without Lapatinib for Non-Human Papillomavirus Head and Neck Carcinoma: A Phase 2 Randomized Clinical Trial.

Importance: Patients with locally advanced non-human papillomavirus (HPV) head and neck cancer (HNC) carry an unfavorable prognosis. Chemoradiotherapy (CRT) with cisplatin or anti-epidermal growth factor receptor (EGFR) antibody improves overall survival (OS) of patients with stage III to IV HNC, and preclinical data suggest that a small-molecule tyrosine kinase inhibitor dual EGFR and ERBB2 (formerly HER2 or HER2/neu) inhibitor may be more effective than anti-EGFR antibody therapy in HNC. Objective: To examine whether adding lapatinib, a dual EGFR and HER2 inhibitor, to radiation plus cisplatin for frontline therapy of stage III to IV non-HPV HNC improves progression-free survival (PFS). Design, Setting, and Participants: This multicenter, phase 2, double-blind, placebo-controlled randomized clinical trial enrolled 142 patients with stage III to IV carcinoma of the oropharynx (p16 negative), larynx, and hypopharynx with a Zubrod performance status of 0 to 1 who met predefined blood chemistry criteria from October 18, 2012, to April 18, 2017 (median follow-up, 4.1 years). Data analysis was performed from December 1, 2020, to December 4, 2020. Intervention: Patients were randomized (1:1) to 70 Gy (6 weeks) plus 2 cycles of cisplatin (every 3 weeks) plus either 1500 mg per day of lapatinib (CRT plus lapatinib) or placebo (CRT plus placebo). Main Outcomes and Measures: The primary end point was PFS, with 69 events required. Progression-free survival rates between arms for all randomized patients were compared by 1-sided log-rank test. Secondary end points included OS. Results: Of the 142 patients enrolled, 127 (median [IQR] age, 58 [53-63] years; 98 [77.2%] male) were randomized; 63 to CRT plus lapatinib and 64 to CRT plus placebo. Final analysis did not suggest improvement in PFS (hazard ratio, 0.91; 95% CI, 0.56-1.46; P = .34) or OS (hazard ratio, 1.06; 95% CI, 0.61-1.86; P = .58) with the addition of lapatinib. There were no significant differences in grade 3 to 4 acute adverse event rates (83.3% [95% CI, 73.9%-92.8%] with CRT plus lapatinib vs 79.7% [95% CI, 69.4%-89.9%] with CRT plus placebo; P = .64) or late adverse event rates (44.4% [95% CI, 30.2%-57.8%] with CRT plus lapatinib vs 40.8% [95% CI, 27.1%-54.6%] with CRT plus placebo; P = .84). Conclusion and Relevance: In this randomized clinical trial, dual EGFR-ERBB2 inhibition with lapatinib did not appear to enhance the benefit of CRT. Although the results of this trial indicate that accrual to a non-HPV HNC-specific trial is feasible, new strategies must be investigated to improve the outcome for this population with a poor prognosis. Trial Registration: ClinicalTrials.gov Identifier: NCT01711658.

Radiation-based Therapy for Muscle-invasive Bladder Cancer: Contemporary Outcomes Across Tertiary Centers.

BACKGROUND: Radiation therapy (RT) is an alternative to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). OBJECTIVE: To analyze predictors of complete response (CR) and survival after RT for MIBC. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter retrospective study of 864 patients with nonmetastatic MIBC who underwent curative-intent RT from 2002 to 2018. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Regression models were used to explore prognostic factors associated with CR, cancer-specific survival (CSS), and overall survival (OS). RESULTS AND LIMITATIONS: The median patient age was 77 yr and median follow-up was 34 mo. Disease stage was cT2 in 675 patients (78%) and cN0 in 766 (89%). Neoadjuvant chemotherapy (NAC) was given to 147 patients (17%) and concurrent chemotherapy to 542 (63%). A CR was experienced by 592 patients (78%). cT3-4 stage (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.29-0.63; p < 0.001) and hydronephrosis (OR 0.50, 95% CI 034-0.74; p = 0.001) were significantly associated with lower CR. The 5-yr survival rates were 63% for CSS and 49% for OS. Higher cT stage (HR 1.93, 95% CI 1.46-2.56; p < 0.001), carcinoma in situ (HR 2.10, 95% CI 1.25-3.53; p = 0.005), hydronephrosis (HR 2.36, 95% CI 1.79-3.10; p < 0.001), NAC use (HR 0.66, 95% CI 0.46-0.95; p = 0.025), and whole-pelvis RT (HR 0.66, 95% CI 0.51-0.86; p = 0.002) were independently associated with CSS; advanced age (HR 1.03, 95% CI 1.01-1.05; p = 0.001), worse performance status (HR 1.73, 95% CI 1.34-2.22; p < 0.001), hydronephrosis (HR 1.50, 95% CI 1.17-1.91; p = 0.001), NAC use (HR 0.69, 95% CI 0.49-0.97; p = 0.033), whole-pelvis RT (HR 0.64, 95% CI 0.51-0.80; p < 0.001), and being surgically unfit (HR 1.42, 95% CI 1.12-1.80; p = 0.004) were associated with OS. The study is limited by the heterogeneity of different treatment protocols. CONCLUSIONS: RT for MIBC yields a CR in most patients who elect for curative-intent bladder preservation. The benefit of NAC and whole-pelvis RT require prospective trial validation. PATIENT SUMMARY: We investigated outcomes for patients with muscle-invasive bladder cancer treated with curative-intent radiation therapy as an alternative to surgical removal of the bladder. The benefit of chemotherapy before radiotherapy and whole-pelvis radiation (bladder plus the pelvis lymph nodes) needs further study.

Dose-Escalated Radiation Alone or in Combination With Short-Term Total Androgen Suppression for Intermediate-Risk Prostate Cancer: Patient-Reported Outcomes From NRG/Radiation Therapy Oncology Group 0815 Randomized Trial.

PURPOSE: To report patient-reported outcomes (PROs) of a phase III trial evaluating total androgen suppression (TAS) combined with dose-escalated radiation therapy (RT) for patients with intermediate-risk prostate cancer. METHODS: Patients with intermediate-risk prostate cancer were randomly assigned to dose-escalated RT alone (arm 1) or RT plus TAS (arm 2) consisting of luteinizing hormone-releasing hormone agonist/antagonist with oral antiandrogen for 6 months. The primary PRO was the validated Expanded Prostate Cancer Index Composite (EPIC-50). Secondary PROs included Patient-Reported Outcome Measurement Information System (PROMIS)-fatigue and EuroQOL five-dimensions scale questionnaire (EQ-5D). PRO change scores, calculated for each patient as the follow-up score minus baseline score (at the end of RT and at 6, 12, and 60 months), were compared between treatment arms using a two-sample t test. An effect size of 0.50 standard deviation was considered clinically meaningful. RESULTS: For the primary PRO instrument (EPIC), the completion rates were ≥86% through the first year of follow-up and 70%-75% at 5 years. For the EPIC hormonal and sexual domains, there were clinically meaningful (P < .0001) deficits in the RT + TAS arm. However, there were no clinically meaningful differences by 1 year between arms. There were also no clinically meaningful differences at any time points between arms for PROMIS-fatigue, EQ-5D, and EPIC bowel/urinary scores. CONCLUSION: Compared with dose-escalated RT alone, adding TAS demonstrated clinically meaningful declines only in EPIC hormonal and sexual domains. However, even these PRO differences were transient, and there were no clinically meaningful differences between arms by 1 year.

Dose-Escalated Radiotherapy Alone or in Combination With Short-Term Androgen Deprivation for Intermediate-Risk Prostate Cancer: Results of a Phase III Multi-Institutional Trial.

PURPOSE: It remains unknown whether or not short-term androgen deprivation (STAD) improves survival among men with intermediate-risk prostate cancer (IRPC) treated with dose-escalated radiotherapy (RT). METHODS: The NRG Oncology/Radiation Therapy Oncology Group 0815 study randomly assigned 1,492 patients with stage T2b-T2c, Gleason score 7, or prostate-specific antigen (PSA) value >10 and ≤20 ng/mL to dose-escalated RT alone (arm 1) or with STAD (arm 2). STAD was 6 months of luteinizing hormone-releasing hormone agonist/antagonist therapy plus antiandrogen. RT modalities were external-beam RT alone to 79.2 Gy or external beam (45 Gy) with brachytherapy boost. The primary end point was overall survival (OS). Secondary end points included prostate cancer-specific mortality (PCSM), non-PCSM, distant metastases (DMs), PSA failure, and rates of salvage therapy. RESULTS: Median follow-up was 6.3 years. Two hundred nineteen deaths occurred, 119 in arm 1 and 100 in arm 2. Five-year OS estimates were 90% versus 91%, respectively (hazard ratio [HR], 0.85; 95% CI, 0.65 to 1.11]; P = .22). STAD resulted in reduced PSA failure (HR, 0.52; P <.001), DM (HR, 0.25; P <.001), PCSM (HR, 0.10; P = .007), and salvage therapy use (HR, 0.62; P = .025). Other-cause deaths were not significantly different (P = .56). Acute grade ≥3 adverse events (AEs) occurred in 2% of patients in arm 1 and in 12% for arm 2 (P <.001). Cumulative incidence of late grade ≥3 AEs was 14% in arm 1 and 15% in arm 2 (P = .29). CONCLUSION: STAD did not improve OS rates for men with IRPC treated with dose-escalated RT. Improvements in metastases rates, prostate cancer deaths, and PSA failures should be weighed against the risk of adverse events and the impact of STAD on quality of life.

The Rate of Prostatic Involvement in Men Treated With Radical Cystectomy for Muscle Invasive Bladder Cancer.

PURPOSE: Radical cystoprostatectomy (RC) is one standard treatment for muscle-invasive bladder cancer (MIBC) in male patients. Another therapeutic option is trimodal therapy. Including the prostate in the trimodal therapy radiation therapy volume is based on MIBC surgical series showing prostatic stromal (PS) involvement. Our aim was to establish the rate of pathologic PS involvement by preoperative T stage in men treated with RC for MIBC. METHODS AND MATERIALS: We conducted a retrospective review of men with MIBC treated with RC between 2006 and 2019. Electronic medical records were reviewed, and preoperative clinical staging data were collected. χ2 test was done to test for a statistically significant difference in the rate of prostatic involvement between clinical tumor (cT) stages. Preoperatively identified carcinoma in situ, lymph node involvement, tumor location, and urethral involvement were also analyzed to see if they conferred a higher risk of PS involvement. Multivariate analysis using multiple logistic regression was performed. RESULTS: We identified 283 men with bladder cancer treated with RC. Patients with non-MIBC or incomplete medical data were excluded (n = 72). We analyzed 211 patients, and 46 (22%) had pathologic PS involvement. PS involvement by preoperative T stage was cT2 = 18%, cT3 = 23%, and cT4 = 48%. Twenty-nine (12%) patients had clinical lymph node involvement, of whom 19 (76%) had PS involvement. Thirty-four (16%) had urethral involvement, of whom 17 (50%) had PS involvement. Sixteen percent and 17% of percent of clinical T2 and T3 patients had bladder neck/trigone tumors, of whom 57% and 50% had prostatic involvement. Clinical T2 and T3 were not statistically different with regards to PS involvement (P = .385). Preoperative urethral involvement, lymph node involvement, cT4, and bladder neck/trigone location were statistically significant predictors of pathologic PS involvement (all P < .05). On multivariate analysis, only clinical urethral involvement was significant (P < .0001). CONCLUSIONS: The high rate of pathologic PS involvement seen in cT2 patients and the lack of ability of cT stage to predict PS involvement support routinely treating the prostate in trimodal therapy. Patients with preoperatively identified bladder neck/trigone tumors, urethral involvement, positive lymph nodes, or prostatic involvement are a subset at even higher risk of having pathologic PS involvement.

5-year outcomes after stereotactic ablative body radiotherapy for primary renal cell carcinoma: an individual patient data meta-analysis from IROCK (the International Radiosurgery Consortium of the Kidney).

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is a non-invasive treatment option for primary renal cell carcinoma, for which long-term data are awaited. The primary aim of this study was to report on long-term efficacy and safety of SABR for localised renal cell carcinoma. METHODS: This study was an individual patient data meta-analysis, for which patients undergoing SABR for primary renal cell carcinoma across 12 institutions in five countries (Australia, Canada, Germany, Japan, and the USA) were eligible. Eligible patients had at least 2 years of follow-up, were aged 18 years or older, had any performance status, and had no previous local therapy. Patients with metastatic renal cell carcinoma or upper-tract urothelial carcinoma were excluded. SABR was delivered as a single or multiple fractions of greater than 5 Gy. The primary endpoint was investigator-assessed local failure per the Response Evaluation Criteria in Solid Tumours version 1.1, and was evaluated using cumulative incidence functions. FINDINGS: 190 patients received SABR between March 23, 2007, and Sept 20, 2018. Single-fraction SABR was delivered in 81 (43%) patients and multifraction SABR was delivered in 109 (57%) patients. Median follow-up was 5·0 years (IQR 3·4-6·8). 139 (73%) patients were men, and 51 (27%) were women. Median age was 73·6 years (IQR 66·2-82·0). Median tumour diameter was 4·0 cm (IQR 2·8-4·9). 96 (75%) of 128 patients with available operability details were deemed inoperable by the referring urologist. 56 (29%) of 190 patients had a solitary kidney. Median baseline estimated glomerular filtration rate (eGFR) was 60·0 mL/min per 1·73 m2 (IQR 42·0-76·0) and decreased by 14·2 mL/min per 1·73 m2 (IQR 5·4-22·5) by 5 years post-SABR. Seven (4%) patients required dialysis post-SABR. The cumulative incidence of local failure at 5 years was 5·5% (95% CI 2·8-9·5) overall, with single-fraction SABR yielding fewer local failures than multifraction (Gray's p=0·020). There were no grade 3 toxic effects or treatment-related deaths. One (1%) patient developed an acute grade 4 duodenal ulcer and late grade 4 gastritis. INTERPRETATION: SABR is effective and safe in the long term for patients with primary renal cell carcinoma. Single-fraction SABR might yield less local failure than multifraction, but further evidence from randomised trials is needed to elucidate optimal treatment schedules. These mature data lend further support for renal SABR as a treatment option for patients unwilling or unfit to undergo surgery. FUNDING: None.

Biopsychosocial Markers of Body Image Concerns in Patients with Head and Neck Cancer: A Prospective Longitudinal Study.

(1) Background: Patients and survivors of head and neck cancer (HNC) are at a high risk of developing body image concerns. Despite the prevalence of body image concerns in patients with HNC, there is a lack of longitudinal research exploring the wide array of its associated determinants. The current longitudinal study examined the determinants and longitudinal course of body image dissatisfaction in patients with HNC. (2) Methods: Patients participated in Structured Clinical Interviews and self-administered questionnaires at four time-points: (T1) upon cancer diagnosis, (T2) at 3 months post-diagnosis, (T3) at 6 months post-diagnosis, and (T4) at 12 months post-diagnosis. They also underwent a disfigurement rating on an objective scale. (3) Results: Two hundred and twenty-four patients participated in our study. Fourteen percent to twenty-eight percent of patients reported at least moderate body image concerns across time points, with the lowest rates at baseline and the highest at 3 months (T1). It was found that patients more predisposed to developing higher levels of body image concerns presented physical markers (i.e., advanced cancer stage, lower physical functioning, higher disfigurement), psychosocial markers (i.e., higher depression, higher anxiety, and higher levels of coping with denial), and health disparities (i.e., younger age, female sex, French language, and marital status, with divorced and widowers most affected). (4) Conclusions: The findings of this study highlight the multifaceted nature of body image concerns in patients with HNC and its biopsychosocial determinants. Clinicians should pay specific attention to these biopsychosocial markers in their clinics to predict high levels of body image concerns and tailor communication/refer for support accordingly.

Meta-analysis of Elective Pelvic Nodal Irradiation Using Moderate Hypofractionation for High-Risk Prostate Cancer.

PURPOSE: Despite several advances in planning and delivery of radiation therapy (RT) for prostate cancer, the role of elective pelvic nodal irradiation (EPNI) remains controversial for high-risk disease. We performed a meta-analysis to evaluate the outcomes of patients treated with moderate hypofractionated RT (MHF-RT) with EPNI using modern RT techniques. METHODS AND MATERIALS: Eligible studies were identified on MEDLINE, Embase, the Cochrane Library, and proceedings of annual meetings through October 2021. We followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) and MOOSE (Meta-analyses of Observational Studies in Epidemiology) guidelines. A metaregression analysis was performed to assess a possible correlation between selected variables and outcomes. A P value <.05 was considered significant. RESULTS: Eighteen studies with a total of 1745 patients (median follow-up, 61 months) treated with EPNI using MHF-RT were included. The biochemical relapse-free survival at 5, 7, and 10 years was 90% (95% confidence interval [CI], 88%-94%), 83% (95% CI, 78%-91%), and 78% (95% CI, 68%-88%). The 5-year prostate cancer-specific survival, disease-free survival, distant metastases-free survival, and overall survival were 98% (95% CI, 97%-99%), 88.7% (95% CI, 85%-93%), 91.2% (95% CI, 88%-92%), and 93% (95% CI, 90%-96%), respectively. The rates of local, pelvic, and distant recurrence were 0.38% (95% CI, 0%-2%), 0.13% (95% CI, 0%-1.5%), and 7.35% (95% CI, 2%-12%), respectively. The rate of late grade ≥2 gastrointestinal and genitourinary toxic effects were 6.7% (95% CI, 4%-9%) and 11.3% (95% CI, 7.6%-15%), with heterogeneity, but with rare cases of grade 3 to 5 toxic effects. CONCLUSIONS: EPNI with concomitant MHF-RT provides satisfactory biochemical relapse-free survival in long-term follow-up, with low rates of genitourinary and gastrointestinal severe toxic effects and minimal pelvic and local failure.

Trimodal therapy vs. radical cystectomy for muscle-invasive bladder cancer: A Canadian cost-effectiveness analysis.

INTRODUCTION: Trimodal therapy (TMT) is a suitable alternative to neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) for patients with muscle-invasive bladder cancer (MIBC). In this study, we conducted a cost-effectiveness evaluation of RC±NAC vs. TMT for MIBC in the universal and publicly funded Canadian healthcare system. METHODS: We developed a Markov model with Monte-Carlo microsimulations. Rates and probabilities of transitioning within different health states (e.g., cure, locoregional recurrence, distant metastasis, death) were input in the model after a scoped literature review. Two main scenarios were considered: 1) academic center; and 2) populational-level. Results were reported in life-years gained (LYG), quality-adjusted life years (QALY), and incremental cost-effectiveness ratio (ICER). A sensitivity analysis was performed. RESULTS: A total of 20 000 patients were simulated. For the academic center model, TMT was associated with increased effectiveness (both in LYG and QALY) at a higher cost compared to RC±NAC at five and 10 years. This resulted in an ICER of $19 746/QALY per patient undergoing the TMT strategy at 10 years of followup. For the populational-level model, RC±NAC was associated with higher effectiveness at 10 years, with an ICER of $3319/QALY per patient. This study was limited by heterogeneity within the studies used to build the model. CONCLUSIONS: In this study, TMT performed in academic centers was cost-effective compared to RC±NAC, with higher effectiveness at a higher cost. On the other hand, RC±NAC was considered cost-effective compared to TMT at the populational-level. Further studies are needed to confirm these results.

Role of Serum Lymphocyte-derived Biomarkers in Nonmetastatic Muscle-invasive Bladder Cancer Patients Treated with Trimodal Therapy.

BACKGROUND: The role of serum lymphocyte-based biomarkers, such as the neutrophil-to-lymphocyte (NLR), lymphocyte-to-monocyte (LMR), and platelet-to-lymphocyte (PLR) ratios, was previously studied in patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy but remains underexplored in patients treated with trimodal therapy (TMT). OBJECTIVE: To analyze the impact of serum lymphocyte-based biomarkers on main oncological outcomes after TMT for MIBC. DESIGN SETTING AND PARTICIPANTS: A retrospective study, including 176 patients treated with TMT for nonmetastatic MIBC (cT2-4/cN0-2) between 2001 and 2017 at a tertiary academic center, was conducted. INTERVENTION: TMT, consisting of initial maximal transurethral resection of the bladder tumor, followed by radiotherapy with concurrent chemotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinicopathological characteristics, serum laboratory tests, and imaging reports were collected. NLR, LMR, and PLR were calculated before and at the end of TMT. Dynamic patterns of NLR, LMR, and PLR during TMT were studied. Multivariable regression models were performed to estimate the effect of these biomarkers on complete response (CR) to TMT and survival. RESULTS AND LIMITATIONS: The median age was 75 yr (interquartile range 66-82). Staging was cT2 in 156 (89%) and cN0 in 159 (90%) patients. A pretreatment NLR (pre-NLR) of ≥4.0 was independently associated with lower CR rates (odds ratio 0.32; p = 0.013). In addition, a pre-NLR of ≥4.0 was associated with worse cancer-specific survival (hazard ratio [HR] 1.88; p = 0.032) and overall survival (OS; HR 1.61; p = 0.033) together with other factors such as hydronephrosis, Eastern Cooperative Oncology Group performance status, and cT stage 3-4a. When both pre- and post-treatment variables were considered, an increase in NLR beyond 75% during TMT (HR 1.63; p = 0.035) was associated with worse OS. This study was limited by its retrospective design. CONCLUSIONS: A high pre-NLR value was independently associated with lower rates of CR and worse survival in MIBC patients undergoing TMT. Prospective validation is needed to implement NLR into clinical practice. PATIENT SUMMARY: In this study, we reported the oncological outcomes of patients with muscle-invasive bladder cancer treated with trimodal therapy. We found that the neutrophil-to-lymphocyte ratio, a cheap and available blood-derived biomarker, was associated with response to trimodal therapy and survival outcomes.

Stereotactic Ablative Radiation Therapy for the Treatment of Upper Urinary Tract Urothelial Carcinoma.

PURPOSE: Urothelial carcinomas (UCs), also known as transitional cell carcinomas, account for the majority of upper urinary tract tumors. The gold-standard therapy for operable patients with localized disease is radical nephroureterectomy. However, some patients are not surgical candidates. Data on the use of modern radiation therapy for upper urinary tract UC (UTUC) are scarce. The purpose of this study was to assess the safety and efficacy of SABR in UTUC. METHODS AND MATERIALS: This retrospective study included all patients with UTUC treated with SABR at one institution. Charts were reviewed to evaluate renal function and the development of toxicity using Common Terminology Criteria for Adverse Events, version 3.0. Tumor response on follow-up imaging with computed tomography or magnetic resonance imaging scans was assessed using the Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: A total of 16 patients (7 patients with UC at the ureter and 9 at the renal pelvis) were identified as treated with SABR. Of the 9 patients with renal pelvis UC, 4 had a previous history of bladder cancer. At the time of treatment, the median age was 85 years (range, 67-95 years). Most patients received 40 Gy in 8 fractions every second day. The median followup was 21 months (range, 3-110 months). Most patients maintained stable renal function, and only 2 patients developed worsening chronic kidney disease, but none required dialysis. Acutely, 4 patients developed grade 1 diarrhea, and 1 patient had new grade 1 hematuria. No chronic side effects were observed. One patient did not have follow-up imaging and was excluded from the tumor-response analysis. Two patients had a complete response of the treated lesion, 9 had a partial response, 2 had stable disease, and 2 had disease progression within the treatment field. CONCLUSIONS: This small case series suggests that SABR for UTUC is safe and well-tolerated, with good radiographic tumor response to ablative doses of radiation therapy.

Impact of sarcopenia on outcomes of patients treated with trimodal therapy for muscle invasive bladder cancer.

OBJECTIVE: We sought to investigate the incidence of sarcopenia and its impact on main oncological outcomes in patients with muscle invasive bladder cancer (MIBC) treated with trimodal therapy (TMT). PATIENTS AND METHODS: This was a retrospective analysis of 141 MIBC patients treated with TMT in the period 2002 to 2018. Sarcopenia was identified through pretreatment computed tomography scans and defined as a skeletal muscle index of <55 cm2/m2 for men and <39 cm2/m2 for women. Body mass index (BMI)-adjusted definition of sarcopenia was used to evaluate for sarcopenic obesity. Uni- and multivariable analyses were performed to assess the impact of sarcopenia on initial complete response and overall survival (OS) to TMT. RESULTS: Median age at diagnosis was 73 years [range: 65-81] and median follow up was 32 months (Inter Quartile Range: 18-66). Median OS was 67 months (95% CI: 53-83). The incidence of sarcopenia and BMI-adjusted sarcopenia was 56.7% and 40.4%, respectively. On multivariable analysis, Eastern Cooperative Oncology Group performance status (HR = 2.37, 95% CI: 2.1-5.67, P = 0.001) and complete response to treatment (HR = 0.26, 95% CI: 0.14-0.049, P = 0.001] were independently associated with improved OS. Sarcopenia and BMI-adjusted sarcopenia were not independently associated with either complete response to TMT or OS. Similarly, in a subpopulation of 74 patients considered fit for radical cystectomy, we found that neither sarcopenia (P = 0.49) nor BMI-adjusted sarcopenia (P = 0.22) had an impact on OS. CONCLUSION: Sarcopenia and BMI-adjusted sarcopenia are prevalent in patients with MIBC undergoing TMT. TMT is a suitable treatment modality for patients with MIBC irrespective of their sarcopenia status.

Practical considerations for prostate hypofractionation in the developing world.

External beam radiotherapy is an effective curative treatment option for localized prostate cancer, the most common cancer in men worldwide. However, conventionally fractionated courses of curative external beam radiotherapy are usually 8-9 weeks long, resulting in a substantial burden to patients and the health-care system. This problem is exacerbated in low-income and middle-income countries where health-care resources might be scarce and patient funds limited. Trials have shown a clinical equipoise between hypofractionated schedules of radiotherapy and conventionally fractionated treatments, with the advantage of drastically shortening treatment durations with the use of hypofractionation. The hypofractionated schedules are supported by modern consensus guidelines for implementation in clinical practice. Furthermore, several economic evaluations have shown improved cost effectiveness of hypofractionated therapy compared with conventional schedules. However, these techniques demand complex infrastructure and advanced personnel training. Thus, a number of practical considerations must be borne in mind when implementing hypofractionation in low-income and middle-income countries, but the potential gain in the treatment of this patient population is substantial.

Phase 1 Trial of Atezolizumab Plus Trimodal Therapy in Patients With Localized Muscle-Invasive Bladder Cancer.

PURPOSE: Immune checkpoint programmed death-ligand 1 inhibitor therapy has shown response in metastatic muscle invasive bladder cancer (MIBC). We evaluated the safety and tolerability of atezolizumab (anti-programmed death-ligand 1) in combination with trimodal therapy in patients with localized MIBC. METHODS AND MATERIALS: A prospective nonrandomized phase 1 study using a 3 + 3 design was conducted in patients with localized MIBC (T2-T4a N0M0) treated on a bladder preservation program. After transurethral resection of bladder tumor, patients received concurrent radiation therapy at a fixed dose of 50 Gy in 20 fractions, gemcitabine (100 mg/m2, intravenously once weekly for 4 weeks) and atezolizumab (1200 mg intravenously every 3 weeks for 16 cycles). The primary endpoint was safety/toxicity profile. RESULTS: Between May 2018 and March 2019, 8 patients (6 male and 2 female) were enrolled. The first 5 patients received atezolizumab at 1200 mg, 3 of whom developed grade 3 side effects (2 of them dose-limiting toxicity). Atezolizumab dose was reduced to 840 mg for 3 additional patients. The study was terminated due to the presence of 3 grade 3 adverse events (2 of which were dose-limiting toxicity) despite the reduced atezolizumab dose. Gastrointestinal events were the main toxicity. No grade 4 to 5 adverse effects were observed. CONCLUSIONS: Concurrent administration of atezolizumab with concomitant hypofractionated radiation therapy and gemcitabine appears to be associated with unacceptable gastrointestinal toxicity. Although the numbers studied are small, our results suggest considerable caution with its concurrent use with trimodal therapy for MIBC.

NRG Oncology Updated International Consensus Atlas on Pelvic Lymph Node Volumes for Intact and Postoperative Prostate Cancer.

PURPOSE: In 2009, the Radiation Therapy Oncology Group (RTOG) genitourinary members published a consensus atlas for contouring prostate pelvic nodal clinical target volumes (CTVs). Data have emerged further informing nodal recurrence patterns. The objective of this study is to provide an updated prostate pelvic nodal consensus atlas. METHODS AND MATERIALS: A literature review was performed abstracting data on nodal recurrence patterns. Data were presented to a panel of international experts, including radiation oncologists, radiologists, and urologists. After data review, participants contoured nodal CTVs on 3 cases: postoperative, intact node positive, and intact node negative. Radiation oncologist contours were analyzed qualitatively using count maps, which provided a visual assessment of controversial regions, and quantitatively analyzed using Sorensen-Dice similarity coefficients and Hausdorff distances compared with the 2009 RTOG atlas. Diagnostic radiologists generated a reference table outlining considerations for determining clinical node positivity. RESULTS: Eighteen radiation oncologists' contours (54 CTVs) were included. Two urologists' volumes were examined in a separate analysis. The mean CTV for the postoperative case was 302 cm3, intact node positive case was 409 cm3, and intact node negative case was 342 cm3. Compared with the original RTOG consensus, the mean Sorensen-Dice similarity coefficient for the postoperative case was 0.63 (standard deviation [SD] 0.13), the intact node positive case was 0.68 (SD 0.13), and the intact node negative case was 0.66 (SD 0.18). The mean Hausdorff distance (in cm) for the postoperative case was 0.24 (SD 0.13), the intact node positive case was 0.23 (SD 0.09), and intact node negative case was 0.33 (SD 0.24). Four regions of CTV controversy were identified, and consensus for each of these areas was reached. CONCLUSIONS: Discordance with the 2009 RTOG consensus atlas was seen in a group of experienced NRG Oncology and international genitourinary radiation oncologists. To address areas of variability and account for new data, an updated NRG Oncology consensus contour atlas was developed.

Refining assessment of response to radiation-based therapy for muscle-invasive bladder cancer: Is post-treatment tumor bed biopsy always necessary?

INTRODUCTION: Radiation-based therapy (RT) has emerged as a suitable alternative to radical cystectomy (RC) and pelvic lymph node dissection for muscle-invasive bladder cancer (MIBC) patients. Routine biopsy after RT to rule out residual disease remains inconsistent across guidelines. Our objective was to review the significance of a bladder biopsy in terms of assessment of response post-RT and its potential impact on survival. PATIENTS AND METHODS: This was a single-center retrospective study on patients with MIBC (cT2-4aN0-2M0) treated with curative intent RT. A total of 169 patients with primary urothelial carcinoma were analyzed. Patients' demographic, clinical and pathological variables, imaging, cystoscopy, urine cytology, and biopsy reports after RT were collected and compiled. Whenever urine cytology was positive or cystoscopy showed any malignant-appearing lesion, the first assessment post-RT was considered suspicious for residual disease. A descriptive population analysis was reported. Cox regression multivariable analysis was performed to identify independent variables associated with survival outcomes. RESULTS: Median age was 75 years (interquartile range 66-82) and clinical staging was cT2 in 152 (90%) patients. Cytology and cystoscopy were normal in 140 (83%) after RT. Of patients with a control biopsy, residual MIBC was present in 3 (5%) and non-MIBC in another 6 (11%). On the contrary, a for-cause biopsy due to a suspicious assessment post-RT did not yield residual cancer in 45% of patients. Multivariable analysis showed that age (hazard ratio [HR] 1.04, P< 0.001), lymphovascular invasion (HR 1.68, P = 0.03) and a suspicious assessment after RT (HR 3.21; P< 0.001) were significantly associated with worse OS. This study was limited by its retrospective design. CONCLUSIONS: A routine biopsy after RT may be warranted to assess treatment response. This might be particularly important for patients who may benefit from early surgical intervention for residual MIBC. Further prospective studies are needed to confirm our findings.