Precision Endpoints for Contemporary Precision Oncology Trials.

SUMMARY: Traditional endpoints such as progression-free survival and overall survival do not fully capture the pharmacologic and pharmacodynamic effects of a therapeutic intervention. Incorporating mechanism-driven biomarkers and validated surrogate proximal endpoints can provide orthogonal readouts of anti-tumor activity and delineate the relative contribution of treatment components on an individual level, highlighting the limitation of solely relying on aggregated readouts from clinical trials to facilitate go/no-go decisions for precision therapies.

Proton therapy in Asia Pacific: current resources, international disparities and steps forward.

The burden of cancer in Asia Pacific, a region home to over four billion people, is growing. Because of sheer demographics alone, the Asia Pacific region arguably has the highest number of patients who can benefit from protons over conventional x-rays. However, only 39 out of 113 proton facilities globally are in Asia Pacific, and 11 of them are in low- and middle-income countries where 95% of the regional population reside. We draw attention to present resource distribution of proton therapy in Asia Pacific, highlight disparities in access, and suggest steps forward.

Discordance in Recommendation Between Next-Generation Sequencing Test Reports and Molecular Tumor Boards in India.

PURPOSE: Accurate understanding of the genomic and transcriptomic data provided by next-generation sequencing (NGS) is essential for the effective utilization of precision oncology. Molecular tumor boards (MTBs) aim to translate the complex data in NGS reports into effective clinical interventions. Often, MTB treatment recommendations differ from those in the NGS reports. In this study, we analyze the discordance between these recommendations and the rationales behind the discordances, in a non-high-income setting, with international input to evaluate the necessity of MTB in clinical practice. METHODS: We collated data from MTB that were virtually hosted in Chennai, India. We included patients with malignancies who had NGS reports on solid tissue or liquid biopsies, and excluded those with incomplete data. MTB forms and NGS reports of each clinical case were analyzed and evaluated for recommendation concordance. Concordance was defined as an agreement between the first recommendation in the MTB forms and the therapeutic recommendations suggested in the NGS report. Discordance was the absence of the said agreement. The rationales for discordance were identified and documented. RESULTS: Seventy MTB reports were analyzed with 49 cases meeting the inclusion criteria. The recommendation discordance was 49% (24 of 49). Discordant recommendations were mainly due to low level of evidence for the drug (75% of cases). CONCLUSION: The discordance between MTB and NGS vendor recommendations highlights the clinical utility of MTB. The educational experiences provided by this initiative are an example of how virtual academic collaborations can enhance patient care and provider education across geographic borders.

A Practice Pilot Survey on the Current Use of Corticosteroid Therapy in Brain Tumor Patients.

Background: This pilot survey aims to provide an insight into the variations of corticosteroid prescription among health care professionals across the Indian subcontinent and serve as a prerequisite for the future development of corticosteroid therapy guidelines in brain tumor patients. Materials and Methods: Participants of this anonymized online questionnaire-based survey included health care professionals involved in treating brain tumor patients. Unique links were electronically mailed to health care professionals from a database populated from professional associations. Descriptive statistical analysis, Chi-square test, and/or exact test were used for data analysis. Results: Seventy-three percent of the respondents were radiation oncologists followed by neurosurgeons (23%), medical oncologists (2%), and other specialties (2%). Raised intracranial pressure (90%) was the commonest indication for prescribing corticosteroids. Fifty percent of neurosurgeons preferred corticosteroids to be given routinely for all patients undergoing surgery for brain tumors while 64% of the radiation oncologists would prescribe based on imaging findings and/or on appearance of neurologic symptoms. Most of the respondents (90%) used a flat dosage pattern for determining the starting dose of corticosteroids. Emerging data about the long-term use of corticosteroids having a negative impact on the survival of brain tumor patients were not known by 52% of the respondents. The majority of the practitioners (94%) agreed regarding the formulation of evidence-based guidelines for prescribing corticosteroids in brain tumor patients. Conclusion: In view of the wide variations of corticosteroid therapy practices among health care professionals across various parts of the world, our pilot survey provides significant information which can act as a suitable benchmark to form uniform practice guidelines.

Comparison of Estimated Late Toxicities between IMPT and IMRT Based on Multivariable NTCP Models for High-Risk Prostate Cancers Treated with Pelvic Nodal Radiation.

Purpose: To compare the late gastrointestinal (GI) and genitourinary toxicities (GU) estimated using multivariable normal tissue complication probability (NTCP) models, between pencil-beam scanning proton beam therapy (PBT) and helical tomotherapy (HT) in patients of high-risk prostate cancers requiring pelvic nodal irradiation (PNI) using moderately hypofractionated regimen. Materials and Methods: Twelve consecutive patients treated with PBT at our center were replanned with HT using the same planning goals. Six late GI and GU toxicity domains (stool frequency, rectal bleeding, fecal incontinence, dysuria, urinary incontinence, and hematuria) were estimated based on the published multivariable NTCP models. The ΔNTCP (difference in absolute NTCP between HT and PBT plans) for each of the toxicity domains was calculated. A one-sample Kolmogorov-Smirnov test was used to analyze distribution of data, and either a paired t test or a Wilcoxon matched-pair signed rank test was used to test statistical significance. Results: Proton beam therapy and HT plans achieved adequate target coverage. Proton beam therapy plans led to significantly better sparing of bladder, rectum, and bowel bag especially in the intermediate range of 15 to 40 Gy, whereas doses to penile bulb and femoral heads were higher with PBT plans. The average ΔNTCP for grade (G)2 rectal bleeding, fecal incontinence, stool frequency, dysuria, urinary incontinence, and G1 hematuria was 12.17%, 1.67%, 2%, 5.83%, 2.42%, and 3.91%, respectively, favoring PBT plans. The average cumulative ΔNTCP for GI and GU toxicities (ΣΔNTCP) was 16.58% and 11.41%, respectively, favoring PBT. Using a model-based selection threshold of any G2 ΔNTCP >10%, 67% (8 patients) would be eligible for PBT. Conclusion: Proton beam therapy plans led to superior sparing of organs at risk compared with HT, which translated to lower NTCP for late moderate GI and GU toxicities in patients of prostate cancer treated with PNI. For two-thirds of our patients, the difference in estimated absolute NTCP values between PBT and HT crossed the accepted threshold for minimal clinically important difference.

Proton therapy for skull-base adenoid cystic carcinomas: A case series and review of literature.

Purpose: An indolent nature, with a high risk of local recurrence along with the potential for distant metastases, makes the relatively rare adenoid cystic carcinomas (ACCs) of the head-and-neck region, a unique entity. In the base of skull (BOS) region, these cancers require radiation doses as high as 70-72 GyE in proximity to critical structures. Proton therapy (PT) confers physical and radiobiological advantages and local control at 2-5 years exceeding 80% in most series, compared with below 60% with photon-based techniques. We report a case series of ACCs of the BOS, treated with image-guided, intensity-modulated PT (IMPT). Materials and Methods: During 2019-2020, we treated six patients with skull-base ACC IMPT with on-board, cross-sectional image guidance. Dosimetric data, toxicity, and early outcomes were studied, and a comparative review of literature was done. Results: Three patients underwent PT/proton-photon treatment for residual/inoperable lesions and three patients underwent reirradiation for recurrent lesions. The prescription was 70 GyE in 31-35 fractions, and 95% of the clinical target volume (CTV) received 98% of the prescribed dose in five of the six patients. Grade 3 mucositis and skin reactions were noted in two patients and one patient, respectively. Five of the six patients were controlled locally at a median follow-up of 15 months. Conclusion: The radiobiological and physical characteristics of PT help to deliver high doses with excellent CTV coverage in skull-base ACCs, adjacent to critical neurological structures.

Drug Development in Low- and Middle-Income Countries: Opportunity or Exploitation?

Low- and middle-income countries (LMICs) represent a diverse group of regions with varied cancer presentation. Drug development and accessibility across these regions have primarily been dependent on the trials initiated and conducted across high-income countries. Representation of LMIC regions in these trials in terms of study population has been minimal, leading to inequitable distribution of optimal and affordable cancer care. In spite of many challenges, LMICs have now increasingly been able to contribute to anticancer drug development. The opportunities present in LMICs must be explored and used in conjunction with due collaborative efforts from high-income countries, health care planners, and regulatory agencies. Global drug development trials should not only factor in suitable representation of LMICs but also design studies with pragmatic objectives and endpoints so that the trial results lead to equitable and affordable cancer care. Strengthening collaboration between cancer researchers from LMICs and high-income countries and empowering the local investigator with adequate resources will help remove current disparities.

Encouraging early outcomes with image guided pencil beam proton therapy for cranio-spinal irradiation: first report from India.

BACKGROUND: To report our experience with image guided pencil beam proton beam therapy (PBT) for craniospinal irradiation (CSI). MATERIALS AND METHODS: Between January 2019 and December 2021, we carried out a detailed audit of the first forty patients treated with PBT. We had recorded acute toxicities, reporting early outcomes and discuss limitations of current contouring guidelines during CSI PBT planning. RESULTS: Median age of the patient cohort was 8 years, and histologies include 20 medulloblastoma, 7 recurrent ependymoma, 3 pineoblastoma, 3 were germ cell tumors and remaining 7 constituted other diagnoses. Forty percent patients received concurrent chemotherapy. Median CSI dose was 23.4 Gy (Gray; range 21.6-35 Gy). Thirty-five patients (87.5%) completed their CSI without interruption, 5 required hospital admission. No patient had grade 2/ > weight loss during the treatment. Forty-five percent (18) developed grade 1 haematological toxicities and 20% (8) developed grade 2 or 3 toxicities; none had grade 4 toxicities. At median follow up of 12 months, 90% patients are alive of whom 88.9% are having local control. Special consideration with modification in standard contouring used at our institute helped in limiting acute toxicities in paediatric CSI patients. CONCLUSION: Our preliminary experience with modern contemporary PBT using pencil beam technology and daily image guidance in a range of tumours suitable for CSI is encouraging. Patients tolerated the treatment well with acceptable acute toxicity and expected short-term survival outcome. In paediatric CSI patients, modification in standard contouring guidelines required to achieve better results with PBT.

Upfront Therapy of Aggressive/High-Risk Low-Grade Glioma: Single-Institution Outcome Analysis of Temozolomide-Based Radio-Chemotherapy and Adjuvant Chemotherapy.

OBJECTIVE: To report clinical outcomes of temozolomide (TMZ)-based radio-chemotherapy and adjuvant chemotherapy in patients with aggressive/high-risk low-grade glioma (LGG). METHODS: Medical records of patients defined as aggressive/high-risk LGG based on clinicoradiologic and/or histomorphologic features treated between 2009 and 2016 in an academic neuro-oncology unit with upfront postoperative radiotherapy at time of initial diagnosis with concurrent and adjuvant TMZ were reviewed, retrospectively. RESULTS: In total, 64 patients with median age of 38 years at initial diagnosis were included. Histomorphologically, patients were classified into oligodendroglioma, mixed oligoastrocytoma, and astrocytoma. Molecular markers such as isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion were used to classify 37 of 64 (58%) patients into molecularly defined entities comprising oligodendroglioma (IDH-mutant with 1p/19q codeletion), IDH-mutant astrocytoma (immunohistochemistry or gene sequencing), and IDH-wild-type astrocytoma (gene sequencing). All 64 patients completed planned conventionally fractionated focal conformal radiotherapy (median dose 55.8 Gy) with concurrent TMZ. Fifty-nine patients received further adjuvant TMZ for a median of 12 cycles. Adjuvant TMZ was stopped prematurely in 6 (9%) patients due to toxicity or early disease progression. At a median follow-up of 56.7 months, 5-year Kaplan-Meier estimates of progression-free survival and overall survival for the study cohort were 74.6% and 84.3%, respectively. Five-year overall survival was 87.5%, 90.4%, and 71.9% for oligodendroglioma, mixed oligoastrocytoma, and astrocytoma, respectively (P = 0.42) Similar estimates for molecularly defined oligodendroglioma, IDH-mutant astrocytoma, and IDH-wild-type astrocytoma were 85.8%, 90%, and 66.7%, respectively (P = 0.87). CONCLUSIONS: Upfront TMZ-based concurrent radio-chemotherapy and adjuvant TMZ chemotherapy provides acceptable survival outcomes in aggressive/high-risk LGG with modest toxicity.

Adapting Management of Sarcomas in COVID-19: An Evidence-Based Review.

With the novel coronavirus disease (COVID-19) being declared a global pandemic by the World Health Organization, the Indian healthcare sector is at the forefront to deliver optimal care. Patients with cancer especially are at serious risk for increased chances of morbidity and mortality due to their immunocompromised state. Currently there is a paucity of definitive guidelines for the management of sarcomas during the pandemic in a resource-constrained and diverse population setting like India. Health care professionals from various specialties involved in the management of sarcomas have collaborated to discuss various aspects of evidence-based sarcoma management during the COVID-19 pandemic. This article provides structured recommendations for HCP to adapt to the situation, optimize treatment protocols with judicious use of all resources while providing evidence-based treatment for sarcoma patients.

Preliminary Experience of Treating Children and Young Adults With Image-Guided Proton Beam Therapy in India.

PURPOSE: Proton beam therapy (PBT) has been a preferred modality in pediatric malignancies requiring radiotherapy. We report our preliminary experience of treating consecutive patients younger than 25 years with image-guided pencil beam scanning PBT from the first and only center on the Indian subcontinent. METHODS: Patients were selected for PBT on the basis of a multidisciplinary tumor board decision. Patient demographic data, as well as tumor and treatment-related characteristics of the cohort, were captured. Patient and treatment-related factors and their association with acute toxicities were analyzed using univariable and multivariable analyses. RESULTS: Forty-seven patients (27 with CNS and 20 with non-CNS tumors) with a median age of 9 years (range, 2-25 years) were evaluated. Most common diagnoses were ependymoma, rhabdomyosarcoma, and glioma. Seventy-seven percent of patients traveled more than 500 km, and 70% of them lived in metropolitan cities. Forty-nine percent of patients had recurrent disease at presentation, and 15% had received a previous course of radiation. The median dose delivered was 54.8 cobalt gray equivalents (range, 40.0-70.4 cobalt gray equivalents) to a median clinical target volume of 175 mL (range, 18.7-3,083.0 mL), with 34% of patients requiring concurrent chemotherapy (CCT). Acute grade 2 and grade 3 dermatitis, mucositis, and hematologic toxicity was noted in 45% and 2%, 34% and 0%, and 38% and 30% of patients, respectively. Grade 2 fatigue was noted in 26% of patients. On multivariable analysis, for CNS tumors, both CCT and craniospinal irradiation were independently associated with ≥ 2 grade hematologic toxicity, whereas among non-CNS tumors, a clinical target volume > 150 mL was associated with ≥ 2 grade fatigue, head and neck irradiation was associated with ≥ 2 grade mucositis, and CCT was associated with grade ≥ 2 hematologic toxicity. CONCLUSION: This study demonstrates safe implementation of a PBT program for children and young adults on the Indian subcontinent. Image-guided pencil beam scanning PBT in judiciously selected patients is feasible and can be delivered with acceptable acute toxicities.

Total marrow and lymphoid irradiation with helical tomotherapy: a practical implementation report.

PURPOSE: To standardize the technique; evaluate resources requirements and analyze our early experience of total marrow and lymphoid irradiation (TMLI) as part of the conditioning regimen before allogenic bone marrow transplantation using helical tomotherapy. MATERIALS AND METHODS: Computed tomography (CT) scanning and treatment were performed in head first supine (HFS) and feet first supine (FFS) orientations with an overlap at mid-thigh. Patients along with the immobilization device were manually rotated by 180° to change the orientation after the delivery of HFS plan. The dose at the junction was contributed by a complementary dose gradient from each of the plans. Plan was to deliver 95% of 12 Gy to 98% of clinical target volume with dose heterogeneity <10% and pre-specified organs-at-risk dose constraints. Megavoltage-CT was used for position verification before each fraction. Patient specific quality assurance and in vivo film dosimetry to verify junction dose were performed in all patients. RESULTS: Treatment was delivered in two daily fractions of 2 Gy each for 3 days with at least 8-hour gap between each fraction. The target coverage goals were met in all the patients. The average person-hours per patient were 16.5, 21.5, and 25.75 for radiation oncologist, radiation therapist, and medical physicist, respectively. Average in-room time per patient was 9.25 hours with an average beam-on time of 3.32 hours for all the 6 fractions. CONCLUSION: This report comprehensively describes technique and resource requirements for TMLI and would serve as a practical guide for departments keen to start this service. Despite being time and labor intensive, it can be implemented safely and robustly.

PITChing (professional organisations, innovative trial designs and collaborative approach) for evidence generation for proton therapy.

Developments in the field of proton beam therapy (PBT) have recently crossed the tipping point wherein the modality is now more versatile than ever before, with possibilities and likely indications expanding rapidly.However the pace of evidence generation lags behind the developments in the field.Generating quality evidence has its own set of challenges owing to complexities of conducting randomized controlled trials, which are the hallmark of level 1 evidence generation.Here we discuss various challenges to clinical evidence generation in PBT and have suggested certain solutions including collaborative approaches and alternative study designs to mitigate these challenges.

Translation and validation of European Organization for Research and Treatment for Cancer quality of life questionnaire-OV-28 module into Indian languages (Hindi and Marathi) to study quality of life of ovarian cancer patients from a tertiary care cancer center.

AIM: The aim is to translate and validate the European Organization for Research and Treatment for Cancer (EORTC) ovarian cancer (OC) module (OV-28) into Hindi and Marathi to use for patients and scientific community. METHODS AND RESULTS: The EORTC OV-28 was translated into Hindi and Marathi languages using prescribed guidelines by the EORTC. The process included forward translation by four translators (2 each for Hindi and Marathi). The questionnaires obtained were then given to independent backward-translators who then translated them back into English. These 2 questionnaires were then compared with the original EORTC questionnaire and the second intermediate questionnaires were formed. The second intermediate questionnaire was subsequently administered in twenty patients (10 each for Hindi and Marathi) diagnosed with OC who had never seen the questionnaire before, for pilot testing. Each of these ten patients after filling up the questionnaire themselves was then interviewed for any difficulty encountered during the filling up of the questionnaires. These were in the form of specific modules including difficulty in answering, confusion while answering, and difficulty to understand, whether the questions were upsetting and if patients would have asked the question in any different way. The suggestions were incorporated into the second intermediate questionnaires to form the final Hindi and Marathi ON-28 questionnaires. These questionnaires were then sent to the EORTC for the final approval to be used in clinical studies. CONCLUSION: We have successfully translated EORTC OV-28 module into Hindi and Marathi languages, and EORTC approved them to be used in clinical practice and studies for OC patients.

Aggressive Surgery in Palliative Setting of Lung Cancer: Is it Helpful?

With increase in survival and progression-free survival in the advanced metastatic cancers, the expectation of quality of life (QOL) has increased dramatically. Palliative care plays a vital role in the management of these advanced cancer patients. At present scenario, palliative care in advanced cancer has seen a completely different approach. Aggressive surgical procedures have been performed to improve the QOL in the advanced cancer patients. We report a case of advanced lung cancer with pathological femur fracture, treated with extensive total femur replacement surgery to provide better QOL.