Publications by authors named "Umesh Mahantshetty"

170 Publications

Low-Dose-Rate versus High-Dose-Rate intracavitary brachytherapy in cervical cancer - Final Results of a Phase III randomized trial.

Brachytherapy 2021 Sep 28. Epub 2021 Sep 28.

HCG-ICH Khubchandani Cancer Center, Mumbai, India.

Purpose: Intracavitary brachytherapy using High-Dose-Rate (HDR) and Low-dose-rate (LDR) in cervical cancer has been utilized. We report the long-term final results of a large randomized trial in terms of toxicities and efficacy.

Methods And Materials: Between 1996 to 2005, 816 patients were randomized to LDR (n = 441 patients) or HDR brachytherapy (n = 369 patients) stratified by FIGO Stage grouping. Patients with Stage I-II received external irradiation of 40 Gy in 20 fractions (with midline block (MLB)) followed by either 2 LDR Intracavitary applications of 30 Gy to point A (2-3 weeks apart) or 5 HDR Intracavitary applications of 7 Gy to point A once weekly. Patients with Stage III received 50 Gy in 25 fractions (with MLB after 40 Gy) followed by either one application of LDR 30 Gy to point A or three applications of HDR 7 Gy to point A once weekly.

Results: With a median follow-up was 64 months (interquartile range [IQR]: 21 - 111), moderate to severe rectal and bladder complications were higher in LDR arm as compared to HDR arm (9.7% vs. 3.6%; p = 0.02) and (10.5% vs. 5.5%; p = 0.06) for Stage I-II. No difference in rectal or bladder complications for Stage III patients. Disease free and overall survivals were similar in both the arms for all stages.

Conclusions: HDR intracavitary brachytherapy with 7 Gy per fraction weekly is superior to LDR in terms of late rectal and bladder complications. Local control rates and survivals are similar irrespective of stages.
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http://dx.doi.org/10.1016/j.brachy.2021.08.012DOI Listing
September 2021

Late Toxicity After Adjuvant Conventional Radiation Versus Image-Guided Intensity-Modulated Radiotherapy for Cervical Cancer (PARCER): A Randomized Controlled Trial.

J Clin Oncol 2021 Sep 10:JCO2002530. Epub 2021 Sep 10.

Department of Radiation Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Parel, Mumbai, Maharashtra, India.

Purpose: Postoperative Adjuvant Radiation in Cervical Cancer (PARCER), a phase III randomized trial, compared late toxicity after image-guided intensity-modulated radiotherapy (IG-IMRT) with three-dimensional conformal radiation therapy (3D-CRT) in women with cervical cancer undergoing postoperative radiation.

Methods: Patients were randomly assigned to receive either IG-IMRT or 3D-CRT after stratification for the type of hysterectomy and use of concurrent chemotherapy. The primary end point was 3-year grade ≥ 2 late GI toxicity assessed using Common Toxicity Criteria for Adverse Events v 3.0 and estimated using time-to-event, intention-to-treat analysis, with a study level type I error of 0.05 and a nominal α of .047 after accounting for one interim analysis. Secondary end points included acute toxicity, health-related quality of life, and pelvic relapse-free, disease-free, and overall survival.

Results: Between 2011 and 2019, 300 patients were randomly assigned (IG-IMRT 151 and 3D-CRT 149). At a median follow-up of 46 (interquartile range 20-72) months, the 3-year cumulative incidence of grade ≥ 2 late GI toxicity in the IG-IMRT and 3D-CRT arms were 21.1% versus 42.4% (hazard ratio [HR] 0.46; 95% CI, 0.29 to 0.73; < .001). The cumulative incidence of grade ≥ 2 any late toxicity was 28.1% versus 48.9% (HR 0.50; 95% CI, 0.33 to 0.76; < .001), respectively. Patients reported reduced diarrhea ( = .04), improved appetite ( = .008), and lesser bowel symptoms ( = .002) with IG-IMRT. However, no difference was observed in the time by treatment interaction. The 3-year pelvic relapse-free survival and disease-free survival in the IG-IMRT versus the 3D-CRT arm were 81.8% versus 84% (HR 1.17; 95% CI, 0.68 to 1.99; = .55) and 76.9% versus 81.2% (HR 1.03; 95% CI, 0.62 to 1.71; = .89), respectively.

Conclusion: IG-IMRT results in reduced toxicity with no difference in disease outcomes.
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http://dx.doi.org/10.1200/JCO.20.02530DOI Listing
September 2021

Risk factors for nodal failure after radiochemotherapy and image guided brachytherapy in locally advanced cervical cancer: An EMBRACE analysis.

Radiother Oncol 2021 Sep 2;163:150-158. Epub 2021 Sep 2.

University Medical Center Utrecht, Department of Radiation Oncology, Utrecht, The Netherlands.

Objective: To assess risk factors for nodal failure (NF) after definitive (chemo)radiotherapy and image-guided brachytherapy for locally advanced cervical cancer (LACC) for patients treated in the EMBRACE I study.

Materials And Methods: Data for pelvic NF and para-aortic (PAO) NF (NF) were analysed. After multiple imputation, univariable and multivariable Cox-regression was performed for clinical and treatment-related variables. For patients with affected pelvic nodes but no PAO nodes at diagnosis, additional analyses were performed for two subgroups: 1. 'small pelvis' nodes in internal and external iliac, obturator, parametrial, presacral and/or common iliac (CI) region and 2. any CI nodes (subgroup of 1).

Results: 1338 patients with 152 NF and 104 NF events were analysed with a median follow-up of 34.2 months (IQR 16.4-52.7). For the entire group, larger tumour width, nodal risk groups (in particular any CI nodes without PAO nodes), local failure, and lower Hb-nadir increased the risk of NF. Elective PAO-irradiation was independently associated with a decreased risk of NF (HR 0.53, 95%-CI 0.28-1.00, p = 0.05). For subgroup 1, having 'any CI nodes without PAO nodes' and local failure significantly increased NF risk. Additionally, elective PAO-irradiation was associated with less risk of NF (HR 0.38, 95%-CI 0.17-0.86, p = 0.02). For subgroup 2 only local failure was associated with higher risk of NF.

Conclusion: In this patient cohort, nodal disease and tumour width at diagnosis, as well as local failure, are risk factors for NF after definitive treatment. Having either 'any PAO nodes' (with or without pelvic nodes) or 'any CI nodes' (without PAO nodes) are stronger risk factors than involvement of nodes in the small pelvis alone. Elective PAO-irradiation was associated with significantly less NF, particularly in patients with nodal disease in the 'small pelvis' and/or CI region at time of diagnosis.
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http://dx.doi.org/10.1016/j.radonc.2021.08.020DOI Listing
September 2021

Impact of Vaginal Symptoms and Hormonal Replacement Therapy on Sexual Outcomes After Definitive Chemoradiotherapy in Patients With Locally Advanced Cervical Cancer: Results from the EMBRACE-I Study.

Int J Radiat Oncol Biol Phys 2021 Sep 1. Epub 2021 Sep 1.

Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands; Department of Radiotherapy, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands.

Purpose: To evaluate patient-reported sexual outcomes after chemoradiation therapy and image-guided adaptive brachytherapy for locally advanced cervical cancer in the observational, prospective, multicenter EMBRACE-I study.

Methods And Materials: Sexual outcomes were assessed prospectively with the European Organization for Research and Treatment of Cancer Qualify of Life Questionnaire (EORTC-QLQ-CX24) at baseline and follow-up. Crude incidence and prevalence rates of sexual activity, vaginal functioning problems (dryness, shortening, tightening, pain during intercourse), and sexual enjoyment were evaluated. Associations between pain during intercourse and vaginal functioning problems or sexual enjoyment were calculated, pooling observations over all follow-ups (Spearman correlation coefficient). In patients who were frequently sexually active (≥50% of follow-ups), the effects of regular hormonal replacement therapy (HRT) on vaginal functioning problems were evaluated (Pearson χ).

Results: The analysis involved 1045 patients with a median follow-up of 50 months. Sexual activity was reported by 22% of patients at baseline and by 40% to 47% of patients during follow-up (prevalence rates). Vaginal functioning problems in follow-up were dryness (18%-21%), shortening (15%-22%), tightening (16%-22%), pain during intercourse (9%-21%), and compromised enjoyment (37%-47%). Pain during intercourse was significantly associated with vaginal tightening (r = 0.544), shortening (r = 0.532), and dryness (r = 0.408) and negatively correlated with sexual enjoyment (r = -0.407). Regular HRT was associated with significantly less vaginal dryness (P = .015), shortening (P = .024), pain during intercourse (P = .003), and borderline higher sexual enjoyment (P = .062).

Conclusions: Vaginal functioning problems are associated with pain and compromised sexual enjoyment. Further effort is required for the primary prevention of vaginal morbidity with dose optimization and adaptation. Secondary prevention strategies, including HRT for vaginal and sexual health after radiation therapy in locally advanced cervical cancer, should be considered and sexual rehabilitation programs should be developed further.
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http://dx.doi.org/10.1016/j.ijrobp.2021.08.036DOI Listing
September 2021

Positron Emission Tomography-Guided Bone Marrow-Sparing Radiation Therapy for Locoregionally Advanced Cervix Cancer: Final Results From the INTERTECC Phase II/III Trial.

Int J Radiat Oncol Biol Phys 2021 Aug 20. Epub 2021 Aug 20.

Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California; La Jolla Center for Precision Radiation Medicine, La Jolla, California. Electronic address:

Purpose: To test effects of positron emission tomography (PET)-based bone marrow-sparing (BMS) image-guided intensity modulated radiation therapy (IG-IMRT) on efficacy and toxicity for patients with locoregionally advanced cervical cancer.

Methods And Materials: In an international phase II/III trial, patients with stage IB-IVA cervical carcinoma were treated with either PET-based BMS-IG-IMRT (PET-BMS-IMRT group) or standard image-guided IMRT (IMRT group), with concurrent cisplatin (40 mg/m weekly), followed by brachytherapy. The phase II component nonrandomly assigned patients to PET-BMS-IMRT or standard IMRT. The phase III trial randomized patients to PET-BMS-IMRT versus IMRT, with a primary endpoint of progression-free survival (PFS) but was closed early for futility. Phase III patients were analyzed separately and in combination with phase II patients, comparing acute hematologic toxicity, cisplatin delivery, PFS, overall survival (OS), and patterns of failure. In a post-hoc exploratory analysis, we investigated the association between pretreatment absolute lymphocyte count (ALC) and OS.

Results: In total, 101 patients were enrolled on the phase II/III trial, including 29 enrolled in phase III (PET-BMS-IMRT group: 16; IMRT group: 13) before early closure. Median follow-up was 33 months for phase III patients and 39 months for all patients. PFS and OS at 5 years for all patients were 73.6% (95% confidence interval [CI], 64.9%-84.3%) and 84% (95% CI, 76%-92.9%]), respectively. There were no differences in number of cisplatin cycles, OS, PFS, or patterns of failure between groups for the combined cohort. The incidence of acute grade ≥ 3 neutropenia was significantly lower in the PET-BMS-IMRT group compared with IMRT for randomized patients (19% vs 54%, χP = .048) and in the combined cohort (13% vs 35%, χP = .01). Patients with pretreatment ALC ≤ 1.5 k/µL had nonsignificantly worse OS on multivariable analysis (HR 2.85; 95% CI, 0.94-8.62; adjusted P = .216), compared with patients with ALC > 1.5 k/µL. There was no difference in posttreatment ALC by treatment group.

Conclusions: PET-BMS-IMRT significantly reduced acute grade ≥3 neutropenia, but not treatment-related lymphopenia, compared with standard IMRT. We found no evidence that PET-BMS-IMRT affected chemotherapy delivery or long-term outcomes, and weak evidence of an association between pretreatment ALC and OS.
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http://dx.doi.org/10.1016/j.ijrobp.2021.08.019DOI Listing
August 2021

Development and clinical validation of Knowledge-based planning for Volumetric Modulated Arc Therapy of cervical cancer including pelvic and para aortic fields.

Phys Imaging Radiat Oncol 2021 Apr 26;18:61-67. Epub 2021 May 26.

Homi Bhabha National Institute, Mumbai, India.

Background And Purpose: Knowledge-based planning (KBP) is based on a model to estimate dose-volume histograms, configured using a library of historical treatment plans to efficiently create high quality plans. The aim was to report configuration and validation of KBP for Volumetric Modulated Arc Therapy of cervical cancer.

Materials And Methods: A KBP model was configured from the institutional database (n = 125), including lymph node positive (n = 60) and negative (n = 65) patients. KBP Predicted plans were compared with Clinical Plans (CP) and Re-plans (Predicted plan as a base-plan) to validate the model. Model quality was quantified using coefficient of determination R2, mean square error (MSE), standard two-tailed paired t-test and Wilcoxon signed rank test.

Results: Estimation capability of the model was good for the bowel bag (MSE = 0.001, R2 = 0.84), modest for the bladder (MSE = 0.008) and poor for the rectum (MSE = 0.02 R2 = 0.78). KBP resulted in comparable target coverage, superior organ sparing as compared to CP. Re-plans outperformed CP for the bladder, V30 (66 ± 11% vs 74 ± 11%, p < .001), V40 (48 ± 14% vs 52 ± 14%, p < .001), however sparing was modest for the bowel bag V30 (413 ± 191cm vs 445 ± 208cm, p = .037) V40 (199 ± 105cm vs 218 ± 127cm, p = .031). All plans were comparable for rectum, while KBP resulted in significant sparing for spinal cord, kidneys and femoral heads.

Conclusion: KBP yielded comparable and for some organs superior performance compared to CP resulting in conformal and homogeneous target coverage. Improved organ sparing was observed when individual patient geometry was considered.
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http://dx.doi.org/10.1016/j.phro.2021.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254199PMC
April 2021

Single Application Multifractionated Image Guided Adaptive High-Dose-Rate Brachytherapy for Cervical Cancer: Dosimetric and Clinical Outcomes.

Int J Radiat Oncol Biol Phys 2021 Nov 17;111(3):826-834. Epub 2021 Jun 17.

Department of Medical Oncology, Tata Memorial Hospital, HBNI, Mumbai, India.

Purpose: A prospective phase 2 study was conducted to evaluate the feasibility and safety of single-application multifractionated (SA-MF), high-dose-rate (HDR), image guided adaptive brachytherapy (IGABT) for cervical cancer.

Methods And Materials: Patients (N = 41) with International Federation of Gynaecology and Obstetrics 2009 stage IIB-IVA disease recruited between 2017 and 2019 underwent SA-MF. After completion of external beam radiation therapy of 50 Gy in 25 fractions, patients received magnetic resonance IGABT. The IGABT protocol consisted of a single brachytherapy (BT) application and treatment with 3 fractions of HDR (9 Gy on day 1; 2 fractions of 7 Gy with a minimum 6-hour gap on day 2) after achieving planning aims of the high-risk clinical target volume (HRCTV) receiving >84 Gy EQD2 and 2 cm of the bladder and rectum/sigmoid receiving ≤85 Gy and <71 Gy, respectively. Interfraction variation was addressed by performing computed tomography planning and coregistration using a mutual information-based coordinate system on day 2 before the second fraction. Organ at risk contouring was done on computed tomography, and doses were re-evaluated and reoptimized if required.

Results: Thirty-eight patients were treated as per the protocol. All patients underwent Intracavitary + Interstitial BT with needles (median, 4; range, 3-11). The mean ± standard deviation HRCTV volume was 41 ± 21 cm and HRCTV D90 dose was 87.2 ± 3.6Gy. The 0.1 cm and 2 cm to bladder, rectum, and sigmoid were -103.2 ± 10.6 Gy and -84.6 ± 6.8 Gy, 82.2 ± 9.5 Gy and -68.3 ± 5.7 Gy, and 83.5 ± 9.8 Gy and -69.5 ± 5.9 Gy, respectively. Six patients required reoptimization before the second fraction to meet planning aims. Mean overall treatment time was 47 ± 6 days. With a median follow up of 22 months (range, 2-37), 2-year local control and disease-free and overall survival were 90.1%, 85%, and 94.5%, respectively. So far 1 patient with grade II and 2 patients with grade III rectal toxicities have been reported.

Conclusion: Magnetic resonance IGABT with SA-MF BT was feasible in 95% of patients. The dosimetric parameters and clinical results achieved so far look promising.
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http://dx.doi.org/10.1016/j.ijrobp.2021.06.014DOI Listing
November 2021

Cervical Cancer Treatment in HIV-Positive Patients: A Survey of Treatment Practices in India.

JCO Glob Oncol 2021 06;7:843-848

Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Purpose: Chemoradiation remains a challenge in women living with HIV (WLWH) and cervical cancer primarily because of concerns regarding immune status. With limited literature available to help guide the management of these patients, clinical practices among oncologists are variable across India. Hence, we conducted a survey among radiation oncologists in India to assess the patterns of current practices of treating cervical cancer with chemoradiation in WLWH.

Materials And Methods: A questionnaire consisting of 12 questions related to the treatment of cervical cancer in WLWH was distributed to radiation oncologists at two national conferences in India.

Results: The questionnaire was distributed to 105 radiation oncologists, and 90 (85.7%) responses were received. 95.5% of respondents reported that patients with advanced cervical cancer constituted the majority of their practice. Chemoradiation was reported as the most common modality of planned treatment. Ninety-four percentage of respondents reported that they referred patients to an antiretroviral therapy clinic before starting definitive treatment. The majority of respondents (68%) do not plan for concurrent chemotherapy if CD4 counts were < 200 cells/mm. As many as 50% of respondents reported that they would only start antiretroviral therapy when CD4 counts drop. Poor social support (37.6%), concurrent infections during treatment (28.2%), acute toxicities (21.2%), and poor nutrition (13%) were cited as the most common reasons for treatment interruption in cervical cancer patients with HIV.

Conclusion: This survey highlights the prevalent inconsistencies in treatment protocols employed by radiation oncologists in India for the management of locally advanced cervical cancer in WLWH. It also reflects the need for social and nutritional support to help improve compliance and thereby improve outcomes in these patients.
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http://dx.doi.org/10.1200/GO.21.00081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457850PMC
June 2021

Quality of life in long term survivors of cervical cancer: A cross sectional study.

Indian J Cancer 2021 Apr-Jun;58(2):171-178

Department of Gynecological Oncology, Tata Memorial Centre, Homi Bhabha National University, Mumbai, Maharashtra, India.

Background: Quality of life (QOL) is an important parameter to evaluate and modify in patients treated for cervical cancer as long-term survival is excellent in early-stage and reasonably good in locally advanced stage compared to other solid cancers. The aim of the study was the cross sectional evaluation of the quality of life in survivors completing at least 3 years of follow-up after curative therapy for cervical cancer at a tertiary cancer institute.

Methods: All patients, following primary curative treatment with no evidence of recurrence and completing at least 3 years follow-up, were assessed for QOL using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-30 and its cervical cancer module (Cx24). Patients were subdivided based on the modality of treatment. Analysis was done using Kruskal-Wallis and Mann-Whitney U test.

Results: One hundred seven patients were analyzed out of the 113 patients initially included. Treated patients showed good global QOL (mean value: 84.07) and functional scores (covering all domains). In the cervical cancer module, sexual activity, sexual enjoyment, and sexual function were low in the majority of the respondents. Chronic lymphedema, symptom experience, and sexual worry were significant across all the treatment arms.

Conclusion: Cervical cancer survivors have an overall good QOL. However, certain concerns related to the sexual quality of life, symptom experience, and chronic lymphedema need to be addressed appropriately.
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http://dx.doi.org/10.4103/ijc.IJC_712_18DOI Listing
June 2021

Impact of COVID-19 on cancer care in India: a cohort study.

Lancet Oncol 2021 07 27;22(7):970-976. Epub 2021 May 27.

Bhagwan Mahaveer Cancer Hospital and Research Centre, Jaipur, India.

Background: The COVID-19 pandemic has disrupted health-care systems, leading to concerns about its subsequent impact on non-COVID disease conditions. The diagnosis and management of cancer is time sensitive and is likely to be substantially affected by these disruptions. We aimed to assess the impact of the COVID-19 pandemic on cancer care in India.

Methods: We did an ambidirectional cohort study at 41 cancer centres across India that were members of the National Cancer Grid of India to compare provision of oncology services between March 1 and May 31, 2020, with the same time period in 2019. We collected data on new patient registrations, number of patients visiting outpatient clinics, hospital admissions, day care admissions for chemotherapy, minor and major surgeries, patients accessing radiotherapy, diagnostic tests done (pathology reports, CT scans, MRI scans), and palliative care referrals. We also obtained estimates from participating centres on cancer screening, research, and educational activities (teaching of postgraduate students and trainees). We calculated proportional reductions in the provision of oncology services in 2020, compared with 2019.

Findings: Between March 1 and May 31, 2020, the number of new patients registered decreased from 112 270 to 51 760 (54% reduction), patients who had follow-up visits decreased from 634 745 to 340 984 (46% reduction), hospital admissions decreased from 88 801 to 56 885 (36% reduction), outpatient chemotherapy decreased from 173634 to 109 107 (37% reduction), the number of major surgeries decreased from 17 120 to 8677 (49% reduction), minor surgeries from 18 004 to 8630 (52% reduction), patients accessing radiotherapy from 51 142 to 39 365 (23% reduction), pathological diagnostic tests from 398 373 to 246 616 (38% reduction), number of radiological diagnostic tests from 93 449 to 53 560 (43% reduction), and palliative care referrals from 19 474 to 13 890 (29% reduction). These reductions were even more marked between April and May, 2020. Cancer screening was stopped completely or was functioning at less than 25% of usual capacity at more than 70% of centres during these months. Reductions in the provision of oncology services were higher for centres in tier 1 cities (larger cities) than tier 2 and 3 cities (smaller cities).

Interpretation: The COVID-19 pandemic has had considerable impact on the delivery of oncology services in India. The long-term impact of cessation of cancer screening and delayed hospital visits on cancer stage migration and outcomes are likely to be substantial.

Funding: None.

Translation: For the Hindi translation of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S1470-2045(21)00240-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159191PMC
July 2021

IBS-GEC ESTRO-ABS recommendations for CT based contouring in image guided adaptive brachytherapy for cervical cancer.

Radiother Oncol 2021 07 18;160:273-284. Epub 2021 May 18.

Division of Radiation Oncology, Department of Radiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

MR Imaging is regarded asthe gold standardfor Image Gudied Adaptive Brachytherapy (IGABT) for cervical cancer. However, its wide applicability is limited by its availability, logistics and financial implications. Use of alternative imaging like CTand Ultrasound (US) for IGABT has been attempted. In order to arrive at a systematic, uniform and international approach for CT based definition and contouring of target structures, GEC ESTRO, IBS and ABS agreed to jointly develop such recommendations based on the concepts and terms as published in the ICRU Report 89. The minimum requirements are clinical examination & documentation, CT or MR imaging at diagnosis and at a minimum, CT imaging with the applicator in place. The recommendations are based on (i) assessment of the GTV at diagnosis and at brachytherapy, (ii) categorizing the response to external radiation into different clinical remission patterns, (iii) defining various clinico-radiological environments and (iv) definition & delineation of a target on CT imaging at the time of brachytherapy with the applicator in situ. CT based target contouring recommendations based on 4 remission categories within 8 defined environments, aim at improving the contouring accuracy for IGABT using CT, US and MRI as available. For each clinico-radiological environment, there is an attempt to minimize the specific uncertainties in order to arrive at the best possible contouring accuracy. Evaluating feasibility & reproducibility, to achieve a benchmark towards a gold standard MR IGABT and further clinical research including outcomes with CT Based IGABT will become the next steps.
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http://dx.doi.org/10.1016/j.radonc.2021.05.010DOI Listing
July 2021

Nomogram Predicting Overall Survival in Patients With Locally Advanced Cervical Cancer Treated With Radiochemotherapy Including Image-Guided Brachytherapy: A Retro-EMBRACE Study.

Int J Radiat Oncol Biol Phys 2021 09 29;111(1):168-177. Epub 2021 Apr 29.

Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.

Purpose: To present a nomogram for prediction of overall survival (OS) in patients with locally advanced cervical cancer (LACC) undergoing definitive radiochemotherapy including image-guided adaptive brachytherapy (IGABT).

Methods And Materials: Seven hundred twenty patients with LACC treated with radiochemotherapy including IGABT in 12 institutions (median follow-up 56 months) were analyzed; 248 deaths occurred. Thirteen candidate predictors for OS were a priori chosen on the basis of the literature and expert knowledge. Missing data (7.2%) were imputed using multiple imputation and predictive mean matching. Univariate analysis with a multivariable Cox regression model for OS stratified by center was performed. Stepwise selection of predictive factors with the Akaike Information Criterion was used to obtain a predictive model and construct a nomogram for OS predictions 60 months from diagnosis; this was internally validated by concordance probability as a measure of discrimination and a calibration plot.

Results: Thirteen potential predictive factors were evaluated; 10 factors reached statistical significance in univariate analysis (age, Hemoglobin, FIGO Stage, tumor width, corpus involvement, lymph node involvement, concurrent chemotherapy, dose to 90% of the high-risk clinical target volume volume of CTV at the first brachytherapy [CTVVolumeBT], overall treatment time [OTT]). Four factors were confirmed significant within the multivariable Cox regression model (FIGO Stage, lymph node involvement, concurrent chemotherapy, CTVVolumeBT). The predictive model and corresponding nomogram were based on 7 Akaike Information Criterion-selected factors (age, corpus involvement, FIGO Stage, lymph node involvement, concurrent chemotherapy, CTVVolumeBT, OTT) and showed promising calibration and discrimination (cross-validated concordance probability c = 0.73).

Conclusions: This is the first nomogram to predict OS in patients with LACC treated with IGABT. In addition to previously reported factors (age, FIGO stage, corpus involvement, chemotherapy delivery, OTT, lymph node involvement), status of primary tumor at the time of brachytherapy seems to be an essential outcome predictor. These results can facilitate individualized tailoring of treatment and patient counseling during the treatment.
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http://dx.doi.org/10.1016/j.ijrobp.2021.04.022DOI Listing
September 2021

Multinational Study to Assess Stress Levels Among the Health Care Workers of Radiation Oncology Community at the Outset of the COVID-19 Pandemic.

JCO Glob Oncol 2021 04;7:464-473

Department of Radiation Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India.

Purpose: To evaluate stress levels among the health care workers (HCWs) of the radiation oncology community in Asian countries.

Methods: HCWs of the radiation oncology departments from 29 tertiary cancer care centers of Bangladesh, India, Indonesia and Nepal were studied from May 2020 to July 2020. A total of 758 eligible HCWs were identified. The 7-Item Generalized Anxiety Disorder, 9-Item Patient Health Questionnaire, and 22-Item Impact of Events Scale-Revised were used for assessing anxiety, depression, and post-traumatic stress disorder. Univariate and multivariate analysis was done to identify the causative factors affecting mental health.

Results: A total of 758 participants from 794 HCWs were analyzed. The median age was 31 years (IQR, 27-28). The incidence of moderate to severe levels of anxiety, depression, and stress was 34.8%, 31.2%, and 18.2%, respectively. Severe personal concerns were noticed by 60.9% of the staff. On multivariate analysis, the presence of commonly reported symptoms of COVID-19 during the previous 2 weeks, contact history (harzard ratio [HR], 2.04; CI, 1.15 to 3.63), and compliance with precautionary measures (HR, 1.69; CI, 1.19 to 2.45) for COVID-19 significantly predicted for increasing anxiety (HR, 2.67; CI, 1.93 to 3.70), depression (HR, 3.38; CI 2.36 to 4.84), and stress (HR, 2.89; CI, 1.88 to 4.43) ( < .001). A significant regional variation was also noticed for anxiety, stress, and personal concerns.

Conclusion: This survey conducted during the COVID-19 pandemic revealed that a significant proportion of HCWs in the radiation oncology community experiences moderate to severe levels of anxiety, depression, and stress. This trend is alarming and it is important to identify and intervene at the right time to improve the mental health of HCWs to avoid any long-term impacts.
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http://dx.doi.org/10.1200/GO.20.00647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081510PMC
April 2021

MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study.

Lancet Oncol 2021 04;22(4):538-547

Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.

Background: The concept of the use of MRI for image-guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer was introduced 20 years ago. Here, we report on EMBRACE-I, which aimed to evaluate local tumour control and morbidity after chemoradiotherapy and MRI-based IGABT.

Methods: EMBRACE-I was a prospective, observational, multicentre cohort study. Data from patients from 24 centres in Europe, Asia, and North America were prospectively collected. The inclusion criteria were patients older than 18 years, with biopsy-proven squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix, The International Federation of Gynecology and Obstetrics (FIGO) stage IB-IVA disease or FIGO stage IVB disease restricted to paraaortic lymph metastasis below the L1-L2 interspace, suitable for curative treatment. Treatment consisted of chemoradiotherapy (weekly intravenous cisplatin 40 mg/m, 5-6 cycles, 1 day per cycle, plus 45-50 Gy external-beam radiotherapy delivered in 1·8-2 Gy fractions) followed by MRI-based IGABT. The MRI-based IGABT target volume definition and dose reporting was according to Groupe Européen de Curiethérapie European Society for Radiation Oncology recommendations. IGABT dose prescription was open according to institutional practice. Local control and late morbidity were selected as primary endpoints in all patients available for analysis. The study was registered with ClinicalTrials.gov, NCT00920920.

Findings: Patient accrual began on July 30, 2008, and closed on Dec 29, 2015. A total of 1416 patients were registered in the database. After exclusion for not meeting patient selection criteria before treatment, being registered but not entered in the database, meeting the exclusion criteria, and being falsely excluded, data from 1341 patients were available for analysis of disease and data from 1251 patients were available for assessment of morbidity outcome. MRI-based IGABT including dose optimisation was done in 1317 (98·2%) of 1341 patients. Median high-risk clinical target volume was 28 cm (IQR 20-40) and median minimal dose to 90% of the clinical target volume (D) was 90 Gy (IQR 85-94) equi-effective dose in 2 Gy per fraction. At a median follow-up of 51 months (IQR 20-64), actuarial overall 5-year local control was 92% (95% CI 90-93). Actuarial cumulative 5-year incidence of grade 3-5 morbidity was 6·8% (95% CI 5·4-8·6) for genitourinary events, 8·5% (6·9-10·6) for gastrointestinal events, 5·7% (4·3-7·6) for vaginal events, and 3·2% (2·2-4·5) for fistulae.

Interpretation: Chemoradiotherapy and MRI-based IGABT result in effective and stable long-term local control across all stages of locally advanced cervical cancer, with a limited severe morbidity per organ. These results represent a positive breakthrough in the treatment of locally advanced cervical cancer, which might be used as a benchmark for clinical practice and all future studies.

Funding: Medical University of Vienna, Aarhus University Hospital, Elekta AB, and Varian Medical Systems.
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http://dx.doi.org/10.1016/S1470-2045(20)30753-1DOI Listing
April 2021

Reporting of dose-volume specifications for "Martinez Universal Perineal Interstitial Template-based interstitial high-dose-rate brachytherapy for gynecological cancers" according to International Commission on Radiation Units and Measurements 58 with early clinical outcomes.

Brachytherapy 2021 May-Jun;20(3):550-556. Epub 2021 Feb 27.

Department of Radiation Oncology, Homi Bhabha Cancer Hospital and Research Centre, Visakhapatnam, India.

Purpose: The study is an audit of reporting dose and volume specifications as per the ICRU 58 for MUPIT-based interstitial brachytherapy in gynecological cancers. Correlation between total reference air kerma (TRAK) and isodose surface was also evaluated to understand the intensity of treatment in interstitial brachytherapy.

Methods And Materials: Forty-two patients underwent HDR MUPIT-based interstitial brachytherapy 20 Gy in five fractions after EBRT during 2017-2019. Treated volume, high and low-dose regions, mean central dose, Dose Homogeneity Index (DHI), organ at risk doses, and TRAK values were computed.

Results: High-dose regions V150 mean was 12.4 cc and V200 was 4.58 cc; and low-dose region was 75.92 cc. The mean treated volume was 59.8 cc. The mean central dose was 3.7 Gy. DHI was 79%. The mean D2cm bladder and rectum were 2.9 Gy and 2.8 Gy. The mean TRAK was 0.16 cGy per fraction per hour at 1 m. TRAK values showed significant correlation with various isodose volumes (TRAK and V100: r = 0.943 p < 0.0005; and TRAK and V50: r = 0.953; p < 0.0005). A positive correlation was observed between TRAK and the number of needles (r = 0.746; p < 0.0005). At a median followup of 16 months, 4 of 42 patients (9.5%) had local recurrences.

Conclusions: Our study shows compliance with ICRU 58 recommendations along with certain deviations. Local recurrence rate is acceptable. TRAK shows correlation with surface isodose in MUPIT-based brachytherapy and should to be evaluated in future studies.
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http://dx.doi.org/10.1016/j.brachy.2021.01.004DOI Listing
October 2021

Risk factors and dose-effects for bladder fistula, bleeding and cystitis after radiotherapy with imaged-guided adaptive brachytherapy for cervical cancer: An EMBRACE analysis.

Radiother Oncol 2021 05 3;158:312-320. Epub 2021 Feb 3.

Department of Oncology, Aarhus University Hospital, Denmark.

Purpose: To identify patient- and treatment-related risk factors for fistula, bleeding, cystitis, pain and difficulty in voiding in locally advanced cervical cancer patients treated with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT).

Material And Methods: Morbidity within the EMBRACE-I study was prospectively reported for physician-assessed (CTCAE) fistula, bleeding and cystitis and patient-reported (EORTC) pain and difficulty in voiding. Analysis of risk factors was performed in patients without bladder infiltration. Risk factors were tested with Cox regression for grade (G) ≥ 3 cystitis, for G ≥ 2 fistula, bleeding and cystitis, and for EORTC "very much" and "quite a bit" or worse.

Results: Of 1416 patients enrolled, 1153 and 884 patients without bladder infiltration were evaluable for the analysis of CTCAE and EORTC items, respectively. Median follow-up was 48[3-120] months. Crude incidence rates for G ≥ 2 fistula, bleeding and cystitis were 0.7%, 2.7% and 8.8%, respectively, and 16% and 14% for "quite a bit" or worse pain and difficulty in voiding, respectively. Baseline urinary morbidity and overweight/obesity were significant risk factors for most endpoints. Bladder D correlated with G ≥ 2 fistula, bleeding and cystitis, while ICRU bladder point dose correlated with EORTC pain "quite a bit" or worse. An increase from 75 Gy to 80 Gy in bladder D resulted in an increase from 8% to 13% for 4-year actuarial estimate of G ≥ 2 cystitis.

Conclusion: Clinical and treatment-related risk factors for bladder fistula, bleeding and cystitis were identified within a prospective and multi-institutional setting. A dose-effect was established with bladder D, reinforcing the importance of continued optimization during individualized IGABT planning.
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http://dx.doi.org/10.1016/j.radonc.2021.01.019DOI Listing
May 2021

Prostate-Only Versus Whole-Pelvic Radiation Therapy in High-Risk and Very High-Risk Prostate Cancer (POP-RT): Outcomes From Phase III Randomized Controlled Trial.

J Clin Oncol 2021 04 26;39(11):1234-1242. Epub 2021 Jan 26.

Department of Radiation Oncology, Tata Memorial Hospital and Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Homi Bhabha National Institute (HBNI), Mumbai, India.

Purpose: We report the clinical outcomes of a randomized trial comparing prophylactic whole-pelvic nodal radiotherapy to prostate-only radiotherapy (PORT) in high-risk prostate cancer.

Methods: This phase III, single center, randomized controlled trial enrolled eligible patients undergoing radical radiotherapy for node-negative prostate adenocarcinoma, with estimated nodal risk ≥ 20%. Randomization was 1:1 to PORT (68 Gy/25# to prostate) or whole-pelvic radiotherapy (WPRT, 68 Gy/25# to prostate, 50 Gy/25# to pelvic nodes, including common iliac) using computerized stratified block randomization, stratified by Gleason score, type of androgen deprivation, prostate-specific antigen at diagnosis, and prior transurethral resection of the prostate. All patients received image-guided, intensity-modulated radiotherapy and minimum 2 years of androgen deprivation therapy. The primary end point was 5-year biochemical failure-free survival (BFFS), and secondary end points were disease-free survival (DFS) and overall survival (OS).

Results: From November 2011 to August 2017, a total of 224 patients were randomly assigned (PORT = 114, WPRT = 110). At a median follow-up of 68 months, 36 biochemical failures (PORT = 25, WPRT = 7) and 24 deaths (PORT = 13, WPRT = 11) were recorded. Five-year BFFS was 95.0% (95% CI, 88.4 to 97.9) with WPRT versus 81.2% (95% CI, 71.6 to 87.8) with PORT, with an unadjusted hazard ratio (HR) of 0.23 (95% CI, 0.10 to 0.52; < .0001). WPRT also showed higher 5-year DFS (89.5% 77.2%; HR, 0.40; 95% CI, 0.22 to 0.73; = .002), but 5-year OS did not appear to differ (92.5% 90.8%; HR, 0.92; 95% CI, 0.41 to 2.05; = .83). Distant metastasis-free survival was also higher with WPRT (95.9% 89.2%; HR, 0.35; 95% CI, 0.15 to 0.82; = .01). Benefit in BFFS and DFS was maintained across prognostic subgroups.

Conclusion: Prophylactic pelvic irradiation for high-risk, locally advanced prostate cancer improved BFFS and DFS as compared with PORT, but OS did not appear to differ.
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http://dx.doi.org/10.1200/JCO.20.03282DOI Listing
April 2021

Complications of intracavitary brachytherapy for gynecologic cancers and their management: A comprehensive review.

Brachytherapy 2021 Sep-Oct;20(5):984-994. Epub 2021 Jan 19.

Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA.

Intracavitary gynecologic brachytherapy in the form of tandem-based brachytherapy and vaginal cylinder-based brachytherapy represents a fundamental component of the treatment of women with cervical or uterine cancer due to the ability to deliver a therapeutic dose of radiation with sharp dose falloff. This results in highly effective treatment in terms of oncologic outcomes with an overall favorable toxicity profile. Still, complications and side effects of brachytherapy do exist. While advances in brachytherapy techniques have led to a significant decrease in the rates of toxicity, a thorough understanding of the potential complications is crucial to ensuring optimal outcomes for women with gynecologic cancer undergoing brachytherapy. Use of equivalent dose at 2 Gy per fraction (EQD2) models has allowed incorporation of external beam radiotherapy dose to the brachytherapy dose leading to development of consolidated dose constraints for organs-at-risk in the modern era. This manuscript offers a comprehensive review of potential complications associated with intracavitary brachytherapy for gynecologic cancer including predictive factors, mitigation tactics, and management strategies.
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http://dx.doi.org/10.1016/j.brachy.2020.11.011DOI Listing
January 2021

Results of image guided brachytherapy for stage IB cervical cancer in the RetroEMBRACE study.

Radiother Oncol 2021 04 19;157:24-31. Epub 2021 Jan 19.

Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna, Austria.

Objective: Multiple treatment options are used in early local-stage cervical cancer, including combinations of surgery with neoadjuvant/adjuvant radiotherapy and chemotherapy. Our aim was to determine the outcome for definitive chemoradiation with image guided brachytherapy (IGBT).

Methods: FIGO staging system was used in our study. We included 123 patients with stage IB cervical cancer, treated at 12 centers with external beam radiotherapy (EBRT) ± Chemotherapy and IGBT. Three- and 5-year actuarial local control (LC), pelvic control (PC), overall survival (OS), cancer-specific survival (CSS) and late morbidity (CTCAE v 3.0) were computed.

Results: Median age was 48 (23-82) years. FIGO stage distribution was: IB1 68% and IB2 32%; 41% of the entire cohort had nodal metastases and 73% squamous-cell carcinoma. MRI-based tumor size was >40 mm in 63%. Median EBRT dose was 45 (40-50) Gy; 84% received chemotherapy. At IGBT, mean CTV-HR D90 was 93 ± 17 Gy (EQD2). D2cc for bladder was 76 ± 14 Gy, rectum 66 ± 11 Gy, sigmoid 66 ± 10 Gy, bowel 67 ± 7 Gy (EQD2). At 43-months median follow-up, 9% of patients had systemic, 6% paraaortic, 3% pelvic-nodal and 2% local failure. Five-year LC was 98%, PC 96%, CSS 90%, OS 83%. Intestinal G3--4 morbidity was 8%, urinary 7% and vaginal 0%.

Conclusions: Chemoradiation with IGBT for FIGO stage IB cervical cancer leads to excellent loco-regional control with limited morbidity. In IB node-negative disease, it can be regarded equivalent to surgery in terms of oncologic outcome. In tumors with unfavorable pre-treatment characteristics, chemoradiation is the first choice to avoid combining surgery with adjuvant therapy.
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http://dx.doi.org/10.1016/j.radonc.2021.01.005DOI Listing
April 2021

Ten years and counting: Survival in stage IV metastatic squamous cell carcinoma of anal canal following radical treatment.

J Cancer Res Ther 2020 Dec;16(Supplement):S227-S229

Department Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India.

A 60-year-old male ptient presented with a 2-month history of altered bowel habits and occasional bleeding per rectum. On evaluation, he was diagnosed with squamous cell carcinoma of the anal canal (SCCAC) with an isolated hepatic lesion in segment II estimated as 4.3 cm × 3.5 cm on ultrasound. Subsequent needle biopsy confirmed metastatic squamous cell carcinoma deposits. The final diagnosis was SCCAC, cT4N1M1 (Stage IV). The patient was offered radical intent treatment. As per institutional protocol, the patient received two cycles of induction cisplatin + 5fluorouracil (FU) followed by chemo-radiation. 5FU and mitomycin C was given concurrently with irradiation. The primary and metastatic sites were irradiated using 6 MV photons on helical tomotherapy using conventional fractionation. Fluorodeoxyglucose positron emission tomograph-computed tomography performed 4 months after treatment completion showed a complete metabolic and morphological response. As of the date of writing, the patient is alive and disease free, 10 years after treatment with no long term sequelae.
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http://dx.doi.org/10.4103/jcrt.JCRT_118_18DOI Listing
December 2020

Brachytherapy in head and neck malignancies: Indian Brachytherapy Society (IBS) recommendations and guidelines.

J Contemp Brachytherapy 2020 Oct 30;12(5):501-511. Epub 2020 Oct 30.

Department of Oncoanesthesia, Jupiter Lifelines Hospital, Thane, India.

Purpose: Brachytherapy (BT) forms major treatment modality in squamous cell carcinoma of head and neck cancers (HNC). However, there is a dearth of literature and guidelines for the use in various indications. High-dose-rate brachytherapy (HDR-BT) in Indian scenario is an important treatment modality, and the recommendations in this guidelines aim to provide the necessary recommendations for the use of HDR-BT for uniform application across the country in patients with HNC.

Material And Methods: A panel consisting of members of the Indian Brachytherapy Society (IBS), based on their clinical experience was invited. The process involved defining important steps, precautions, target volumes and indications, thorough literature review, and discussion with fellow members. The guidelines were established and formulated the recommendations for HDR-BT based on available evidences and individual experience for sites, relevant to Indian settings.

Results: The IBS recommends the use of HDR brachytherapy as a part of treatment of head and neck tumors. The scope of these guidelines and recommendations included practical suggestions, ensuring efficient use of brachytherapy treatment as radical with external beam radiotherapy (EBRT) boost, palliative and adjuvant as definitive, or re-radiation as salvage for HNC in India. The IBS has made specific site-wise recommendations for previously untreated and recurrent HNC patients on their selection criteria, implant techniques, target volume definition, and HDR treatment parameters, such as time, dose rate, total dose, and fractionation schedules. Limited experience exists with HDR-BT in patients with head and neck cancers in India and across the globe.

Conclusions: IBS provided a consensus statement and guidelines for the head and neck brachytherapy and believed that these recommendations will overcome the fear of practicing radiation oncologists. This should generate interest amongst students and will help radiation oncologists all across the country to use the art of brachytherapy carefully in HNC patients, with better curative and salvage options.
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http://dx.doi.org/10.5114/jcb.2020.100385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701929PMC
October 2020

Outcomes of locally advanced cervical cancer presenting with obstructive uropathy: An institutional audit.

Indian J Cancer 2020 Oct-Dec;57(4):416-422

Department of Radiation Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India.

Background: There is paucity of outcome data of patients with cervical cancer presenting with malignant obstructive uropathy. The present retrospective study describes outcomes of patients with cervical cancer who presented with obstructive uropathy at the time of diagnosis and underwent urinary diversion with percutaneous nephrostomy (PCN) before/during treatment.

Methods: Patients who underwent PCN from January 2010 to June 2015 were included. Intent of treatment (radical or palliative) was decided within multidisciplinary team depending on disease stage, Karnofsky performance status (KPS), and degree of renal derangement. Treatment and outcome details were retrieved from electronic records. Time to normalization of creatinine, feasibility of delivering planned treatment, and overall survival (OS) were determined. Impact of various prognostic factors on outcomes was determined using univariate or multivariate analysis.

Results: After PCN and double-J stenting, 50% were eligible for (chemo) radiation. All radically treated patients (26/52) received brachytherapy. The median EQD2 to point A was 78 Gy (72-84 Gy). The median OS was 10 (0.5-60) months. Patients who completed chemoradiation had median OS of 31 months. Those receiving radical radiation and palliative radiation had median OS of 11 and 6 months, respectively. On univariate analysis, smaller tumor size (p = 0.03), high KPS (P = 0.04), and radical intent of treatment (P = 0.05) predicted for OS.

Conclusion: Patients presenting with obstructive uropathy have median OS less than a year despite urinary diversion. Select cohort with good performance status, small tumor size, and serum creatinine of ≤3 mg/dL may be selected for diversion procedures and potential radical treatment.
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http://dx.doi.org/10.4103/ijc.IJC_704_18DOI Listing
June 2021

Dose-Volume Effects and Risk Factors for Late Diarrhea in Cervix Cancer Patients After Radiochemotherapy With Image Guided Adaptive Brachytherapy in the EMBRACE I Study.

Int J Radiat Oncol Biol Phys 2021 03 14;109(3):688-700. Epub 2020 Oct 14.

Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.

Purpose: To evaluate patient- and treatment-related risk factors associated with incidence and persistence of late diarrhea after radiochemotherapy and image guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer.

Materials And Methods: Of 1416 patients from the EMBRACE I study, 1199 were prospectively evaluated using physician-reported (Common Terminology Criteria for Adverse Events version 3 [CTCAEv3]) assessment for diarrhea; median follow-up 48 months. Patient-reported outcome (EORTC) was available in 900 patients. Incidence of CTCAE G≥2, G≥3, and EORTC "very much" diarrhea was analyzed with Cox proportional hazards regression. Binary logistic regression was used for analysis of persistent G≥1 and EORTC "quite a bit" - "very much" (≥"quite a bit") diarrhea, defined if present in at least half of all follow-ups.

Results: Crude incidences of G≥2 and G≥3 diarrhea were 8.3% and 1.5%, respectively, and 8% of patients reported "very much" diarrhea. Persistent G≥1 and ≥"quite a bit" diarrhea was present in 16% and 7%, respectively. Patient-related risk factors were baseline diarrhea, smoking, and diabetes with hazard ratios of 1.4 to 7.3. Treatment-related risk factors included prescribed dose, V43 Gy, V57 Gy (lymph node boost), and para-aortic irradiation for external beam radiation therapy (EBRT). G≥2 diarrhea at 3 years increased from 9.5% to 19.9% with prescribed dose 45 Gy versus 50 Gy, 8.7% to 14.0% with V43 Gy <2500 cm versus >3000 cm and 9.4% to 19.0% with V57 Gy <165 cm versus ≥165 cm. Brachytherapy-related bowel and rectum D were also associated with diarrhea.

Conclusion: Dose and volume effects have been established for late diarrhea after radiochemotherapy and IGABT in both CTCAE and EORTC reporting. The risk of diarrhea was lower with a pelvic EBRT prescription of 45 Gy, and higher with larger lymph node boosts volumes (ie, ≥165 cm). The importance of EBRT volumes as determinants of late toxicity underline the need for continuous quality assurance of target contouring, dose planning, and conformity. The findings of brachytherapy dosimetric factors related to the intestines may become more important with highly conformal EBRT.
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http://dx.doi.org/10.1016/j.ijrobp.2020.10.006DOI Listing
March 2021

Importance of the ICRU bladder point dose on incidence and persistence of urinary frequency and incontinence in locally advanced cervical cancer: An EMBRACE analysis.

Radiother Oncol 2021 05 14;158:300-308. Epub 2020 Oct 14.

Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.

Purpose: To identify patient- and treatment-related risk factors and dose-effects for urinary frequency and incontinence in locally advanced cervical cancer (LACC) treated with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT).

Material And Methods: Physician-assessed (CTCAE) and patient-reported (EORTC) frequency and incontinence recorded in the EMBRACE-I study were analysed. Risk factors analysis was performed in patients without bladder infiltration and with baseline morbidity available. Cox regression was used for CTCAE grade (G) ≥ 3 and G ≥ 2 and for EORTC "very much" and "quite a bit" or worse. Logistic regression was used for late persistent morbidity defined when CTCAE G ≥ 1 or EORTC ≥ "quite a bit" were scored in at least half of follow-ups.

Results: Longitudinal data on 1153 and 884 patients were available for CTCAE and EORTC analysis, respectively. Median follow-up was 48[3-120] months. Crude incidence rates of G≥2 were 13% and 11% for frequency and incontinence, respectively. Baseline morbidity and overweight-obesity were risk factors for both symptoms. Elderly patients were at higher risk for incontinence. Patients receiving conformal-radiotherapy were at higher risk for frequency. ICRU bladder point (ICRU-BP) dose was a stronger predictor for incontinence than bladder D. The 5-year actuarial estimate of G ≥ 2 incontinence increased from 11% to 20% with ICRU-BP doses > 75 Gy compared to ≤ 65 Gy. Frequency showed weaker associations with dose.

Conclusion: ICRU-BP dose, in addition to clinical parameters, is a risk factor for urinary incontinence and shows a dose-effect after radio(chemo)therapy and IGABT. ICRU-BP dose should be monitored during treatment planning alongside volumetric parameters. Frequency seems associated with larger irradiated volumes.
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http://dx.doi.org/10.1016/j.radonc.2020.10.003DOI Listing
May 2021

Brachytherapy in India: Learning from the past and looking into the future.

Brachytherapy 2020 Nov - Dec;19(6):861-873. Epub 2020 Sep 15.

Department of Radiation Oncology, Apollo Cancer Institute, Hyderabad, India.

India has a longstanding tradition in the practice of brachytherapy and has actively contributed to the scientific literature by conducting prospective studies, clinical audits, developing innovative techniques, and performing randomized studies. Indian investigators have also contributed to international collaborative research, education, training programs along with guideline development for brachytherapy in cervix and head and neck cancers. The present article summarizes the key contributions to scientific literature, current infrastructure, skill set for brachytherapy, existing challenges, and strategy to further strengthen brachytherapy practice in the next decade.
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http://dx.doi.org/10.1016/j.brachy.2020.08.019DOI Listing
June 2021

Persistence of Late Substantial Patient-Reported Symptoms (LAPERS) After Radiochemotherapy Including Image Guided Adaptive Brachytherapy for Locally Advanced Cervical Cancer: A Report From the EMBRACE Study.

Int J Radiat Oncol Biol Phys 2021 01 25;109(1):161-173. Epub 2020 Aug 25.

Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna/General Hospital of Vienna, Vienna, Austria.

Purpose: This report describes the persistence of late substantial treatment-related patient-reported symptoms (LAPERS) in the multi-institutional EMBRACE study on magnetic resonance image guided adaptive brachytherapy in locally advanced cervical cancer (LACC).

Methods And Materials: Patient-reported symptoms (European Organization for Research and Treatment of Cancer [EORTC]-C30/CX24) and physician-assessed morbidity (Common Terminology Criteria for Adverse Events [CTCAE], version 3.0) were assessed at baseline and regular timepoints during follow-up. Patients with sufficient EORTC follow-up (baseline and ≥3 late follow-up visits) were analyzed. LAPERS events were defined as the presence of substantial EORTC symptoms (quite a bit/very much) for at least half of the assessments (persistence) and progression beyond baseline condition (treatment-related). For each EORTC symptom, the ratio between LAPERS rates and crude incidence rates of substantial symptoms was calculated to represent the proportion of symptomatic patients with persisting symptoms. For 9 symptoms with a corresponding EORTC/CTCAE assessment, the overlap of LAPERS and severe morbidity events (grades 3-5) was evaluated.

Results: Of 1047 patients with EORTC available, 741 had sufficient follow-up for the LAPERS analyses. The median follow-up was 59 months (interquartile range, 42-70 months). Across all symptoms, the proportion of patients with LAPERS events (LAPERS rates) was in median 4.6% (range, 0.0% vaginal bleeding to 20.4% tiredness). Urinary frequency, neuropathy, fatigue, insomnia, and menopausal symptoms revealed LAPERS rates of >10%. Vomiting, blood in stool, urinary pain/burning, and abnormal vaginal bleeding displayed LAPERS rates of <1%. A median of 19% of symptomatic patients (interquartile range, 8.0%-28.5%) showed persistent long-term symptoms (LAPERS events). In symptoms with a corresponding EORTC/CTCAE assessment, 12% of LAPERS events were accompanied by a severe CTCAE event.

Conclusions: Within this large cohort of survivors of LACC, a subgroup of patients with persistent symptoms (LAPERS events) was identified. For symptoms with a corresponding EORTC/CTCAE assessment, the vast majority of LAPERS events occurred in patients without corresponding severe physician-assessed morbidity. These findings emphasize the importance of distinguishing between transient and persisting symptoms in the aftercare of LACC survivors.
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http://dx.doi.org/10.1016/j.ijrobp.2020.08.044DOI Listing
January 2021

Evaluation of outcomes in patients of cervical Cancer with lower one third vaginal involvement: A single institutional experience.

Gynecol Oncol 2020 11 20;159(2):359-364. Epub 2020 Aug 20.

Department of Radiation Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI) Mumbai, India; Director, Homi Bhabha Cancer Hospital and Research Centre, Visakhapatnam, India. Electronic address:

Objective(s): The objective of this study was to evaluate the clinical outcomes and prognostic factors affecting survival of cervical cancer patients presenting with lower third vaginal involvement.

Materials/methods: The patients with histologically proven invasive cervical cancer with clinical FIGO-2009 stage IIIA and IIIB with lower one-third vaginal involvement, treated with radio (chemo) therapy between 2010 and 2016 at our institution were retrospectively analyzed.

Results: There were 118 cervical cancer patients with lower third vaginal involvement with median age of 56.5 years (Range: 33-77 years). Forty-five patients were of FIGO stage IIIA, 73 patients staged as stage IIIB at diagnosis with predominant squamous histology. At a median follow up of 30 months, 12 patients (10.1%) developed local vaginal recurrences and 4 patients (3.3%) had developed loco regional recurrences, 27 patients (23%) developed distant and 2 patients developed loco-regional and distant relapses. The 3- year DFS and OS rates were 61.5% and 69.8% respectively. The 3-year DFS and OS of patients with IIIA was significantly better than IIIB patients (71% vs 56%, p: 0.02 and 76% vs 66%, p: 0.01 respectively) on univariate analysis. Concurrent chemotherapy and absence of persistent disease emerged as independent predictors of survival on multi-variate analysis.

Conclusion: The outcome of patients with FIGO IIIA is better than IIIB with lower vaginal involvement. Elderly patients, patients not receiving concomitant chemotherapy and presence of residual disease at BT are associated with poorer outcomes.
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http://dx.doi.org/10.1016/j.ygyno.2020.08.011DOI Listing
November 2020

Meeting the Global Need for Radiation Therapy in Cervical Cancer-An Overview.

Semin Radiat Oncol 2020 Oct;30(4):348-354

Department of Radiation Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India; Homi Bhabha Cancer Hospital and Research Centre, Visakhapatnam, India. Electronic address:

Cervical cancer is the fourth most frequently diagnosed cancer and the fourth leading cause of cancer death in women. The discrepancy in cervical cancer incidence and mortality between developed and developing nations has become increasingly apparent with 84% of the incidence and 88% of the mortality of cervical cancer occurring in low income countries. Access to comprehensive cancer care is a challenge and in particular the radiotherapy facilities. The radiotherapy infrastructure requirement is grossly inadequate with only 30% of the needs available and is even worst in LIC's with only 3% facilities. Additionally, lack of brachytherapy facilities and expertise in LIC's and LMIC's compounds the issue further. Even with continued HPV vaccination programs, there will still be a substantial burden of cervical cancer patients for treatment. Introspection and review in international and national policies, augmentation of (i) infrastructure - affordable & sustainable, (ii) manpower and rigorous training in accessible regions would be vital. International and National collaborative efforts among global organizations and societies, periodic peer reviews, resource stratified treatment guidelines and research, and health education would contribute further to women health. The amalgamation of palliative and hospice care services and radiotherapy facilities seamlessly would be a major step for comprehensive management of cervical cancer patients.
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http://dx.doi.org/10.1016/j.semradonc.2020.05.004DOI Listing
October 2020

Evidence-Based Dose Planning Aims and Dose Prescription in Image-Guided Brachytherapy Combined With Radiochemotherapy in Locally Advanced Cervical Cancer.

Semin Radiat Oncol 2020 10;30(4):311-327

Medical University/General Hospital of Vienna, Department of Radiation Oncology-Comprehensive Cancer Center, Vienna, Austria.

The last 2 decades have witnessed the development and broad adoption of image-guided adaptive brachytherapy (IGABT) combined with radiochemotherapy in patients with locally advanced cervical cancer. A variety of brachytherapy techniques and dose/fractionation schedules have been applied, and until recently, there was no strong evidence available for preferring one approach to another. However, large volumes of data have now provided high level clinical evidence for dose-effect relations for both disease and morbidity endpoints. It is therefore now possible to apply evidence based dose planning aims and dose prescription protocols in IGABT for locally advanced cervical cancer. This review gives an overview of targets/organs-at-risk and disease/morbidity endpoints which are relevant in the context of treatment planning and dose prescription in IGABT. The dosimetric and clinical evidence is summarized to support the implementation of dose prescription protocols which include hard and soft constraints for targets and organs at risk.
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http://dx.doi.org/10.1016/j.semradonc.2020.05.008DOI Listing
October 2020
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