Ten-year follow-up of outcomes, patterns of care, and psychosocial burden in adolescent and young adult (AYA) patients with bone sarcomas from a large cohort in a low-income and middle-income country (LMIC).

BACKGROUND: The care of adolescents and young adults (AYAs) with bone sarcomas involves unique challenges. The objectives of this study were to identify challenges and evaluate long-term outcomes of these patients from India who received treatment with novel protocols. METHODS: This prospective cohort study included AYA patients (aged 15-39 years) with osteosarcoma and Ewing sarcoma (ES), who were treated uniformly at the authors' institute using unique protocols (OGS-12 and EFT-2001) from 2011 to 2021 and from 2013 to 2018, respectively. RESULTS: The cohorts included 688 of 748 (91.9%) treatment-naive AYA patients with osteosarcoma and 126 of 142 (88.7%) treatment-naive AYA patients with ES. Among 481 of 561 patients (85.7%) who had nonmetastatic osteosarcoma treated according to protocol, at a median follow-up of 59.7 months, the 5-year event-free survival (5-EFS) rate was 58.6% (95% confidence interval, 54.1%-63.5%) and for 142 patients (20.6%) who had metastatic osteosarcoma, the 5-EFS rate was 18.7%. The 5-EFS rate was 66.4% and 21.9% for 104 patients (73%) with nonmetastatic ES and 38 patients (27%) with metastatic ES, respectively. Treatment-naive patients had better outcomes, similar to compliance in the form of protocol completion (hazard ratio, 1.93 [p = .0043] and 2.66 [p < .0001], respectively. Only 230 of 377 (61.0%) male patients and 10 of 134 (7.4%) female patients reached out to fertility specialists. In addition, 17 of 161 (10.6%) eligible male survivors and 14 of 61 (22.9%) eligible female survivors got married posttreatment. Furthermore, 14 of 17 (82.4%) males and 14 of 14 (100%) females conceived. Among 311 patients who were working or attending school during diagnosis, greater than 90% had interruptions. CONCLUSIONS: Homogenous treatment with the OGS-12 and EFT-2001 protocols resulted in internationally comparable long-term outcomes in the cohorts with nonmetastatic and metastatic AYA bone sarcomas. Treatment compliance, timely referral to sarcoma reference centers (avoiding prior inadvertent treatment), and streamlining fertility-preservation practices constitute unmet needs that demand prioritization.

Quality and Safety With Technological Advancements in Radiotherapy: An Overview and Journey Narrative From a Low- and Middle-Income Country Institution.

PURPOSE: To present an overview of quality and safety in radiotherapy from the context of low- and middle-income countries on the basis of a recently conducted annual meeting of our institution and our experience of implementing an error management system at our center. METHODS: The minutes of recently concluded annual Evidence-Based Medicine (EBM-2021) meeting on the basis of technology in radiation oncology were reviewed. The session on quality and safety, which had international experts as speakers, was reviewed. Along with this, we reviewed the literature for preventive and reactive measures proposed to manage errors including error reporting and learning systems (ILSs). Concise summary for the same was prepared for this article. RESULTS: We also reviewed the journey of development of our institutional ILS and present here a summary of achievements, challenges, and future vision. CONCLUSION: Preventive and reactive measures must be followed to achieve high-quality and safe radiotherapy. Despite resource constraints, a successful ILS program can be developed in a low- and middle-income country center by first understanding the patterns of error and developing one that suits the working ecosystem.

Radiation Therapy Dose Escalation in Unresectable Ewing Sarcoma: Final Results of a Phase 3 Randomized Controlled Trial.

PURPOSE: Our aim was to assess the effect of radiation therapy (RT) dose escalation on outcomes in surgically unresectable Ewing sarcoma (ES)/primitive neuroectodermal tumor (PNET). METHODS AND MATERIALS: Patients with nonmetastatic unresectable ES/PNET (excluding intracranial/chest wall) receiving vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide chemotherapy, planned for definitive RT, were accrued in this single-institution, open-label, phase 3 randomized controlled trial. Randomization was between standard dose RT (SDRT; 55.8 Gy/31 fractions/5 days a week) versus escalated dose RT (EDRT; 70.2 Gy/39 fractions/5 days a week) with a primary objective of improving local control (LC) by 17% (65%-82%). Secondary outcomes included disease-free survival (DFS), overall survival (OS), and functional outcomes by Musculoskeletal Tumor Society score. RESULTS: Between April 2005 and December 2015, 95 patients (SDRT 47 and EDRT 48) with a median age of 17 years (interquartile range, 13-23 years) were accrued. The majority of patients were male (59%). Pelvis was the most common site of primary disease (n = 60; 63%). The median largest tumor dimension (9.7 cm) and the median maximum standardized uptake value (8.2) on pretreatment fluorodeoxyglucose positron emission tomography-computed tomography were similar. At a median follow-up of 67 months, the 5-year LC, DFS, and OS for the entire cohort was 62.4%, 41.3%, and 51.9%, respectively. The 5-year LC was significantly better in EDRT compared with SDRT (76.4% vs 49.4%; P = .02). The differences in DFS and OS at 5 years (for EDRT vs SDRT) did not achieve statistical significance (DFS 46.7% vs 31.8%; P = .22 and OS 58.8% vs 45.4%; P = .08). There was a higher incidence of Radiation Therapy Oncology Group grade >2 skin toxic effects (acute) in the EDRT arm (10.4% vs 2.1%; P = .08) with excellent functional outcomes (median Musculoskeletal Tumor Society score = 29) in both arms. CONCLUSIONS: EDRT results in improved LC with good functional outcomes without a significant increase in toxic effects. Radiation dose escalation should be considered for surgically unresectable nonmetastatic ES/PNET.

Optimizing Postoperative Adjuvant Therapy in Elderly Patients with Newly Diagnosed Glioblastoma: Single-Institution Audit of Clinical Outcomes from a Tertiary-Care Comprehensive Cancer Center in India.

BACKGROUND: There is lack of consensus regarding optimal adjuvant therapy in elderly glioblastoma (GBM). We have been treating elderly (≥60 years) GBM patients with normofractionated or hypofractionated radiotherapy (RT) plus temozolomide (TMZ) based on Karnofsky performance status (KPS). Herein we report clinical outcomes in this cohort treated at our institute using this approach. METHODS: Medical records of elderly GBM patients (≥60 years) treated between 2013 and 2017 with either normofractionated RT (59.4-60 Gy/30-33 fractions/6-6.5 weeks) or hypofractionated RT (35 Gy/10 fractions/2 weeks) plus TMZ were reviewed retrospectively. Outcomes of interest included progression-free survival (PFS), overall survival (OS), and ≥grade 3 myelotoxicity. Time-to-event outcomes were analyzed with Kaplan-Meier methods, compared using log-rank test, and reported as point estimates with 95% confidence interval (CI). RESULTS: The normofractionated cohort (n = 126) was characterized by a higher proportion of patients younger than age 65 years, KPS ≥70, methylated O6-methylguanine DNA methyltransferase (MGMT), and receiving adjuvant TMZ including extended adjuvant TMZ (>6 cycles) compared with the hypofractionated cohort (n = 20), confirming selection bias. At a median follow-up of 13 months, 1-year Kaplan-Meier estimates of PFS and OS were 43% (95% CI: 36%-52%) and 56% (95% CI: 48%-64%), yielding median PFS and OS of 11.0 months and 13.1 months, respectively. Higher KPS, methylated MGMT, normofractionated RT, and extended adjuvant TMZ emerged as favorable prognostic factors. TMZ was well tolerated with a low risk of ≥grade 3 myelotoxicity. CONCLUSIONS: Our single-institution clinical audit confirms poor survival in elderly GBM with suboptimal performance status but demonstrates acceptably fair outcomes in patients with preserved KPS comparable with the nonelderly cohort.

Outcomes of osteosarcoma, chondrosarcoma and chordoma treated with image guided-intensity modulated radiation therapy.

BACKGROUND & PURPOSE: To evaluate the efficacy and toxicity of dose-escalated image guided-intensity modulated radiation therapy (IG-IMRT) in osteosarcoma (OGS), chondrosarcoma (CS) and chordoma (CH) of head and neck (H&N) and pelvis. METHODS AND MATERIALS: In this prospective non-randomized study, 65 patients of H&N or pelvic OGS (24), CS (7) and CH (34) mandating definitive or post-operative radiotherapy from May 2013 to December 2018 were included. Radiotherapy doses in definitive setting were 72.0 Gy for CH and 70.2 Gy for OGS and CS; while in post-operative setting it was 66.6 Gy and 64.8 Gy respectively (at 1.8 Gy per fraction). RESULTS: Planned doses of radiotherapy could be completed in 61 (93.8%) patients; with grade III or higher acute and late toxicities of 3% and 0% respectively. With a median follow-up of 52 (range 6-92) months, the five-year actuarial local control (LC) rates were 66% in OGS, 38.1% in CS and 75.9% in CH; while cause-specific survival (CSS) rates were 54.7%, 64.3% and 92.2% respectively. There was no statistically significant difference in outcomes for patients receiving definitive and post-operative radiotherapy. Locally controlled disease at first follow-up after radiotherapy was associated with improved CSS and OS in CS (p = 0.014) and CH (p < 0.001). Radiotherapy resulted in significant and sustained improvement in Musculoskeletal tumour society (MSTS) score and reduction in pain score. Salvage re-irradiation was feasible in local progression after radiotherapy, with good outcomes and tolerability. CONCLUSION: Dose-escalated IG-IMRT results in good LC & functional improvement with minimal toxicity in OGS, CS and CH.

Diagnostic Performance of Pretreatment 18F-Fluorodeoxyglucose Positron Emission Tomography With or Without Computed Tomography in Patients With Primary Central Nervous System Lymphoma: Updated Systematic Review and Diagnostic Test Accuracy Meta-analyses.

This review aimed to assess diagnostic performance of 18F-flouro-deoxy-glucose positron emission tomography (FDG-PET) with or without computed tomography (CT) scan in primary central nervous system lymphoma (PCNSL). Eligible studies reporting diagnostic accuracy of pretreatment FDG-PET(CT) scan in immunocompetent adults with PCNSL were identified through systematic literature search. Data on diagnostic performance from individual studies was summarized in a 2 × 2 table classifying patients as true positives, true negatives, false positives, and false negatives using histopathologic diagnosis as reference standard. Random-effects model was used to calculate weighted-mean pooled sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic odds ratio with 95% confidence intervals (95% CI). Twenty-nine primary studies involving 967 patients were included. Weighted-mean pooled sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic odds ratio was 87% (95% CI, 83%-90%), 85% (95% CI, 81%-88%), 84% (95% CI, 81%-88%), 87% (95% CI, 84%-90%), and 29.78 (95% CI, 18.34-48.35), respectively, demonstrating acceptably high diagnostic accuracy of pretreatment FDG-PET(CT) scan in immunocompetent patients with PCNSL.

Clinical approach to re-irradiation for recurrent diffuse intrinsic pontine glioma.

BACKGROUND: We present our institutional approach for re-irradiation in diffuse intrinsic pontine glioma and their outcomes. METHODS: Consecutive patients of recurrent diffuse intrinsic pontine glioma treated with re-irradiation (January 2015-September 2019) were reviewed retrospectively to describe the clinical-response-based approach followed for the dose and volume decision. Outcomes were defined with clinical and steroid response criteria and survival endpoints included progression-free survival and overall survival as cumulative(c) overall survival and re-irradiation overall survival (re-irradiation starting to death). The Kaplan-Meier method and log-rank test were used for survival analysis. RESULTS: Twenty-patient cohort with a median (m) age of 7.5 years, m-progression-free survival of 8.4 months and m-Lansky performance score of 50 received re-irradiation of which 17 (85%) were called clinical responders. The median re-irradiation-overall survival with 39.6-41.4, 43.2 and 45 Gy were 5.8, 7 and 5.3 months, respectively. One-month post-re-irradiation steroid independent status was a significant predictor of better survival outcomes (overall survival, P≤0.004). No ≥ grade 3 toxicities were noticed. Two patients succumbed to intra-tumoral hemorrhage. CONCLUSIONS: Higher doses of re-irradiation based on a clinical-response-based approach show improvement in survival and steroid dependence rates with acceptable toxicity. Steroid independent status at 1-month post-re-irradiation predicts better outcomes. Prospective studies may validate this with quality of life data.

Locoregional recurrence after cystectomy in muscle invasive bladder cancer: Implications for adjuvant radiotherapy.

PURPOSE: We report the patterns of locoregional recurrence (LRR) in muscle invasive bladder cancer (MIBC), and propose a risk stratification to predict LRR for optimizing the indication for adjuvant radiotherapy. MATERIALS AND METHODS: The study included patients of urothelial MIBC who underwent radical cystectomy with standard perioperative chemotherapy between 2013 and 2019. Recurrences were classified into local and/or cystectomy bed, regional, systemic, or mixed. For risk stratification modelling, T stage (T2, T3, T4), N stage (N0, N1/2, N3) and lymphovascular invasion (LVI positive or negative) were given differential weightage for each patient. The cohort was divided into low risk (LR), intermediate risk (IR) and high risk (HR) groups based on the cumulative score. RESULTS: Of the 317 patients screened, 188 were eligible for the study. Seventy patients (37.2%) received neoadjuvant chemotherapy (NACT) while 128 patients (68.1%) had T3/4 disease and 66 patients (35.1%) had N+ disease. Of the 55 patients (29%) who had a recurrence, 31 (16%) patients had a component of LRR (4% cystectomy bed, 11.5% regional 0.5% locoregional). The median time to LRR was 8.2 (IQR 3.3-18.8) months. The LR, IR and HR groups for LRR based on T, N and LVI had a cumulative incidence of 7.1%, 21.6%, and 35% LRR, respectively. The HR group was defined as T3, N3, LVI positive; T4 N1/2, LVI positive; and T4, N3, any LVI. The odds ratio for LRR was 3.37 (95% CI 1.16-9.73, P = 0.02) and 5.27 (95% CI 1.87-14.84, P = 0.002) for IR and HR respectively, with LR as reference. CONCLUSION: LRR is a significant problem post radical cystectomy with a cumulative incidence of 35% in the HR group. The proposed risk stratification model in our study can guide in tailoring adjuvant radiotherapy in MIBC.

Pilot testing and vernacular translation of a questionnaire for assessment of satisfaction in patients on radiotherapy in India.

BACKGROUND: Patient satisfaction has emerged as a yardstick to measure success of healthcare ecosystems. OUTPATSAT-35RT is a questionnaire to assess patient satisfaction on outpatient radiotherapy (RT). However, it is yet to be translated and/or validated in any of the common Indian languages. METHODS: English version of OUTPATSAT-35RT was pilot tested in 20 patients with working knowledge of English undergoing fractionated radiotherapy. Subsequently, the questionnaire was translated into two Indian vernacular languages (Hindi and Marathi) using standardized methodology. The process included forward translation into vernacular language by two professional translators independently, generating an intermediate version of the questionnaire. The intermediate questionnaire was then back-translated into English by another duo of professional translators and compared with the English version of the original OUTPATSAT-35RT questionnaire for final reconciliation. This was subsequently administered to 20 patients each (fluent in respective vernacular language) for pilot testing. All 60 patients (20 per language) underwent semi-structured interviews for reporting any difficulty encountered during filling and suggesting any corrections/modifications to the questionnaire. RESULTS: The pilot testing of the English version of OUTPATSAT-35RT in 20 Indian patients did not reveal any difficulty or suggest corrections/modifications, leading to its successful translation into Hindi and Marathi languages. Pilot testing of the translated questionnaires in 20 patients each (fluent in the respective vernacular language) did not find any major difficulty. No corrections/modifications were suggested by the respondents resulting in adoption of the reconciled vernacular questionnaires as final Hindi and Marathi versions of OUTPATSAT-35RT questionnaire. CONCLUSION: The English version of OUTPATSAT-35RT has been successfully translated into Hindi and Marathi languages using standardized methodology. Its psychometric properties are being tested for validation in a larger Indian cohort.

Diagnostic Yield of Extensive Systemic Staging Including Whole-body 18F-fluoro-deoxy-glucose Positron Emission Tomography With or Without Computed Tomography in Patients With Primary Central Nervous System Lymphoma: Systematic Review and Meta-analysis.

The extent of staging required to evaluate for systemic involvement in patients with primary central nervous system lymphoma (PCNSL) remains controversial. Eligible studies reporting on diagnostic yield of extensive systemic staging, including pre-treatment whole-body 18F-fluoro-deoxy-glocose positron emission tomography with or without computed tomography, in immuno-competent adults with PCNSL were identified through systematic literature search. Diagnostic yield was defined as the proportion of patients with abnormal test results outside the neuraxis that led to detection of concordant systemic high-grade lymphoma on an individual patient basis (true positives). Data were pooled using random-effects model to produce summary estimates with 95% confidence intervals (CIs). Weighted-mean pooled analysis involving 1099 patients from 14 primary studies provided an overall diagnostic yield of 6% (95% CI, 4%-8%) for extensive systemic staging in PCNSL with implications for diagnosis, prognosis, and therapy. Summary estimates of false positivity were just marginally lower at 5% (95% CI, 3%-8%) for such systemic staging.