Cancer Trials Ecosystem in India-Ready for Prime Time?

Executing global clinical trials for cancer is a long, expensive, and complex undertaking. While selecting countries global studies, sponsors must consider several aspects including patient pool, quality of trained investigators, competing trials, availability of infrastructure, and financial investment versus returns. With a large, often treatment-naïve, and diverse patient pool, relatively low cost, good quality health care facilities in urban areas, and a robust and well-trained workforce, India offers several advantages for conducting oncology clinical trials. However, there remains challenges, including a shifting regulatory environment in recent decades. With the implementation of the New Drugs and Clinical Trial Rules in 2019, India's regulatory atmosphere seems to have stabilized. In this article, we present a review of the evolving clinical trial landscape in India, highlight the current regulatory scenario, and discuss the advantages and challenges of selecting India as a potential location for conducting global oncology clinical trials.

N0 neck trial: Does intensification of follow-up (Ultrasound + Physical Examination) influence outcomes in early-stage oral cancer?

AIM OF THE STUDY: We previously reported a survival benefit of elective neck dissection (END) over therapeutic neck dissection (TND) in patients with clinically node-negative early-stage oral cancer. We now report the results of the second question in the same study addressing the impact of adding neck ultrasound to physical examination during follow-up on outcomes. METHODS: Patients with lateralized T1/T2 oral squamous cell carcinoma (SCC) were randomized to END or TND and to follow-up with physical-examination plus neck ultrasound (PE+US) versus physical-examination (PE). The primary endpoint was overall survival (OS). RESULTS: Between January 2004 and June 2014, 596 patients were enrolled. This is an intention to treat analysis of 592 analysable patients, of whom 295 were allocated to PE+US and 297 to PE with a median follow-up of 77.47 months (interquartile range (IQR) 54.51-126.48). There was no significant difference (unadjusted hazard ratio [HR], 0.92, 95% CI, 0.71-1.20, p = 0.54) in 5-year OS between PE+US (70.8%, 95% CI, 65.51-76.09) and PE (67.3%, 95% CI, 61.81-72.79). Among 131 patients with neck node relapse as the first event, the median time to relapse detection was 4.85 (IQR 2.33-9.60) and 7.62 (IQR 3.22-9.86) months in PE+US and PE arms, respectively. The N stage in the PE+US arm was N1 33.8%, N2a 7.4%, N2b/c 44.1% and N3 14.7% while in PE was N1 28.6%, N2a 9.5%, N2b/c 39.7%, N3 20.6% and unknown 1.6%. CONCLUSION: Adding neck ultrasound to physical examination during follow-up detects nodal relapses earlier but does not improve overall survival.

Drug-Resistant Epithelial Ovarian Cancer: Current and Future Perspectives.

Epithelial ovarian cancer (EOC) is a complex disease with diverse histological subtypes, which, based on the aggressiveness and course of disease progression, have recently been broadly grouped into type I (low-grade serous, endometrioid, clear cell, and mucinous) and type II (high-grade serous, high-grade endometrioid, and undifferentiated carcinomas) categories. Despite substantial differences in pathogenesis, genetics, prognosis, and treatment response, clinical diagnosis and management of EOC remain similar across the subtypes. Debulking surgery combined with platinum-taxol-based chemotherapy serves as the initial treatment for High Grade Serous Ovarian Carcinoma (HGSOC), the most prevalent one, and for other subtypes, but most patients exhibit intrinsic or acquired resistance and recur in short duration. Targeted therapies, such as anti-angiogenics (e.g., bevacizumab) and PARP inhibitors (for BRCA-mutated cancers), offer some success, but therapy resistance, through various mechanisms, poses a significant challenge. This comprehensive chapter delves into emerging strategies to address these challenges, highlighting factors like aberrant miRNAs, metabolism, apoptosis evasion, cancer stem cells, and autophagy, which play pivotal roles in mediating resistance and disease relapse in EOC. Beyond standard treatments, the focus of this study extends to alternate targeted agents, including immunotherapies like checkpoint inhibitors, CAR T cells, and vaccines, as well as inhibitors targeting key oncogenic pathways in EOC. Additionally, this chapter covers disease classification, diagnosis, resistance pathways, standard treatments, and clinical data on various emerging approaches, and advocates for a nuanced and personalized approach tailored to individual subtypes and resistance mechanisms, aiming to enhance therapeutic outcomes across the spectrum of EOC subtypes.

Evaluation of Metronomic Therapy as a Low-Cost, Sustainable, Standard-of-Care Option in Desmoid Fibromatosis: Real-World Data From a Tertiary Care Center in India.

PURPOSE: Desmoid fibromatosis (DF) is a locally aggressive tumor with low mortality but significant morbidity. There is a lack of standard of care, and existing therapies are associated with significant barriers including access, cost, and toxicities. This study aimed to explore the efficacy and safety of the metronomic therapy (MT) in DF in a large, homogenous cohort from India. PATIENTS AND METHODS: This study involved histologically confirmed DF cases treated with MT comprising vinblastine (6 mg) and methotrexate (15 mg) both once a week, and tamoxifen (40 mg/m2) in two divided doses once daily between 2002 and 2018. RESULTS: There were 315 patients with a median age of 27 years; the commonest site was extremity (142 of 315; 45.0%). There were 159 (50.1%) male patients. Of the 123 (39.0%) prior treated patients, 119 had surgery. Of 315 patients, 263 (83.5%) received treatment at our institute (MT-151, 77-local treatment, 9-tyrosine kinase inhibitor, and 26 were observed). Among the MT cohort (n = 163, 61.2%), at a median follow-up of 36 (0.5-186) months, the 3-year progression-free and overall survival were 81.1% (95% CI, 74.3 to 88.4) and 99.2% (95% CI, 97.6 to 100), respectively. There were 35% partial responses. Ninety-two patients (56.4%) completed 1-year therapy, which was an independent prognosticator (P < .0001; hazard ratio, 0.177 [95% CI, 0.083 to 0.377]). MT was well tolerated. Predominant grade ≥3 toxicities were febrile neutropenia, 12 (7.4%) without any chemotoxicity-related death. The annual cost of MT was $130 US dollars. CONCLUSION: The novel, low-cost MT qualifies as one of the effective, less toxic, sustainable, standard-of-care options for the treatment of DF with global reach and merits wide recognition.

Out-of-pocket payment and financial risk protection for breast cancer treatment: a prospective study from India.

Background: Available data on cost of cancer treatment, out-of-pocket payment and reimbursement are limited in India. We estimated the treatment costs, out-of-pocket payment, and reimbursement in a cohort of breast cancer patients who sought treatment at a publicly funded tertiary cancer care hospital in India. Methods: A prospective longitudinal study was conducted from June 2019 to March 2022 at Tata Memorial Centre (TMC), Mumbai. Data on expenditure during each visit of treatment was collected by a team of trained medical social workers. The primary outcome variables were total cost (TC) of treatment, out-of-pocket payment (OOP), and reimbursement. TC included cost incurred by breast cancer patients during treatment at TMC. OOP was defined as the total cost incurred at TMC less of reimbursement. Reimbursement was any form of financial assistance (cashless or repayment), including social health insurance, private health insurance, employee health schemes, and assistance from charitable trusts, received by the patients for breast cancer treatment. Findings: Of the 500 patients included in the study, 45 discontinued treatment (due to financial or other reasons) and 26 died during treatment. The mean TC of breast cancer treatment was ₹258,095/US$3531 (95% CI: 238,225, 277,934). Direct medical cost (MC) accounted for 56.3% of the TC. Systemic therapy costs (₹50,869/US$696) were higher than radiotherapy (₹33,483/US$458) and surgery costs (₹25,075/US$343). About 74.4% patients availed some form of financial assistance at TMC; 8% patients received full reimbursement. The mean OOP for breast cancer treatment was ₹186,461/US$2551 (95% CI: 167,666, 205,257), accounting for 72.2% of the TC. Social health insurance (SHI) had a reasonable coverage (33.1%), followed by charitable trusts (29.6%), employee health insurance (5.1%), private health insurance (4.4%) and 25.6% had no reimbursement. But SHI covered only 40.1% of the TC of treatment compared to private health insurance that covered as much as 57.1% of it. Both TC and OOP were higher for patients who were younger, belonged to rural areas, had a comorbidity, were diagnosed at an advanced stage, and were from outside Maharashtra. Interpretation: In India, the cost and OOP for breast cancer treatment are high and reimbursement for the treatment flows from multiple sources. Though many of the patients receive some form of reimbursement, it is insufficient to prevent high OOP. Hence both wider insurance coverage as well as higher cap of the insurance packages in the health insurance schemes is suggested. Allowing for the automatic inclusion of cancer treatment in SHI can mitigate the financial burden of cancer patients in India. Funding: This work was funded by an extramural grant from the Women's Cancer Initiative and the Nag Foundation and an intramural grant from the International Institute of Population Sciences, Mumbai.

Clinical outcomes of adaptive intracavitary and interstitial brachytherapy technique in locally advanced cervical cancer: A real-world data.

PURPOSE: To evaluate clinical outcomes of CT-based adaptive intracavitary and interstitial brachytherapy (IC followed by IC-ISBT) in locally advanced cervical cancer (LACC) in resource-constrained settings. METHODS AND MATERIALS: LACC patients treated with adaptive brachytherapy techniques were analyzed to evaluate treatment characteristics and clinical outcomes. The Kaplan-Meier method was used for survival analysis, and the log-rank test for univariate analysis. RESULTS: Out of 141 eligible patients with LACC, 87 (61.7%) patients received external beam radiotherapy (EBRT) in referral hospitals, while 54 (38.3%) were treated at our center. We divided our cohort into two groups: poor EBRT responder group (n = 70 [49.6%]) where IC-ISBT was adapted to achieve optimum tumor doses and OAR optimization group 71 (50.4%) where IC-ISBT was performed to reduce OAR doses. Median HRCTV-D90 dose was 88 Gy (range 70-109 Gy) with median HRCTV volume 33cc (range 15-96). Median D2cc doses to OARs were 90 Gy (range 70-107), 71 Gy (range 55-105) and 70 Gy (range 47-90) to bladder, rectum and sigmoid, respectively. At median follow-up of 32 months, 3-year local control (LC), locoregional control (LRC), disease-free survival (DFS) and overall survival (OS) were 83%, 75%, 64% and 72%, respectively. Subgroup analysis revealed significantly better outcomes for OAR optimization compared to poor EBRT responders, with 3-year LC (95% vs. 70.1%, p < 0.001), LRC (87.3% vs. 62.7%, p < 0.001), DFS (79.2% vs. 49.4%, p < 0.001), and OS (86.2% vs. 57.4%, p < 0.001) CONCLUSION: In resource-constrained settings, implementation of Adaptive IC-ISBT is a viable alternative for optimizing OAR doses in LACC. However proactive approach employing IC-ISBT for tumor dose-escalation from first fraction of BT is warranted for improving LC in poor EBRT responders.

RECIST 1.1 versus clinico-radiological response assessment for locally advanced cervical cancer: implications on interpreting survival outcomes of future trials.

OBJECTIVE: To investigate differences in standard clinico-radiological evaluation versus Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 for reporting survival outcomes in patients with locally advanced cervical cancer treated with chemoradiation and brachytherapy. METHODS: Between November 2017 and March 2020, patients recruited in cervical cancer trials were identified. MRI at diagnosis and at least one follow-up imaging was mandatory. Disease-free survival and progression-free survival were determined using standard evaluation (clinical examination and symptom-directed imaging) and RECIST 1.1. Agreement between criteria was estimated using κ value. Sensitivity analysis was done to test the sensitivity, specificity, and accuracy of RECIST 1.1 in detecting response to treatment. RESULTS: Sixty-nine eligible patients had at least one target lesion. Thirty-three patients (47.8%) had pathological lymph nodes. Of these 33 patients, RECIST 1.1 classified only 18% (6/33) as 'target nodal lesions' and the remaining nodes as 'non-target'. There were 6 (8.7%) and 8 (11.6%) patients with disease events using RECIST 1.1 and standard evaluation, respectively. The disease-free survival at 12, 18, and 24 months using RECIST 1.1 was 94.2%, 91.2%, 91.2%, and with standard evaluation was 94.2%, 89.7%, and 88.2%, respectively (p=0.58). Whereas, progression-free survival at 12, 18, and 24 months using RECIST 1.1 and standard evaluation were same (94.2%, 91.2%, and 91.2%, respectively). The κ value was 0.84, showing strong agreement in assessing disease-free survival, although an absolute difference of 3% between endpoint assessment methodologies. RECIST 1.1 had a sensitivity of 75% (95% CI 34.91% to 96.81%), specificity of 100% (95% CI 94.13% to 100%), and accuracy of 97.1% (95% CI 89.92% to 99.65%). CONCLUSIONS: The study showed 1.5% and 3% difference in disease-free survival at 18 and 24 months and no difference in progression-free survival between RECIST 1.1 and standard evaluation in a patient cohort with low event rate.

An Open-Label, Single-Arm, Multicenter, Observational Study Evaluating the Safety and Effectiveness of Akynzeo® in the Management of Chemotherapy-Induced Nausea and Vomiting in India.

Background Chemotherapy-induced nausea and vomiting is a common and unpleasant treatment-related side effect reported by cancer patients receiving chemotherapy. Akynzeo® or NEPA (NEtupitant + PAlonosetron) is the first fixed combination of netupitant and palonosetron that targets both critical pathways involved in emesis while providing a convenient, single oral dose therapy. The current study aimed to assess the effectiveness and safety of NEPA in a real-world setting in India. Methodology This was an open-label, multicenter, prospective, single-arm study conducted at six different locations across India. The study included patients of either gender, aged ≥18 years, naive to chemotherapy, scheduled to receive highly or moderately emetogenic chemotherapy (HEC/MEC), and scheduled to receive oral NEPA, as determined by the investigator. Results A total of 360 people were screened and enrolled in the study. HEC was prescribed to 289 (81.64%) patients, while MEC was prescribed to 65 (18.36%) patients. Complete response was achieved in 94.92% of patients during the acute phase, 95.20% during the delayed phase, and 93.22% during the overall phase. During the overall phase, 92.73% and 95.38% of patients on the HEC and MEC regimens, respectively, achieved complete response. Adverse events were reported in 3.88% of patients. Conclusions Oral NEPA was found to be effective in the Indian real-world setting, eliciting a >90% complete response with HEC and MEC regimens across the acute, delayed, and overall phases.

A prospective health economic evaluation to determine the productivity loss due to premature mortality from oral cancer in India.

INTRODUCTION: India contributes two-thirds of the global mortality due to oral cancer and has a younger population at risk. The societal costs of this premature mortality are barely discussed. METHODS: Using the human capital approach, we aimed to estimate the productivity lost due to premature mortality, valued using individual socioeconomic data, related to oral cancer in India. A bottom-up approach was used to prospectively collect data of 100 consecutive patients with oral cancer treated between 2019 and 2020, with a follow-up of 36 months. RESULTS: The disease-specific survival for early and advanced stage was 85% and 70%, with a median age of 47 years. With 671 years lost prematurely, the loss of productivity was $41 900/early and $96 044/advanced stage. Based on population level rates, the total cost of premature mortality was $5.6 billion, representing 0.18% of GDP. CONCLUSION: India needs to implement tailored strategies to reduce the economic burden from premature mortality.

Cost-Effectiveness of Novel Agent Regimens for Transplant-Eligible Newly Diagnosed Multiple Myeloma Patients in India.

BACKGROUND: Survival outcomes for multiple myeloma have improved dramatically since the introduction of novel therapeutic agents. While these drugs are highly effective in improving survival outcomes and quality of life in patients with multiple myeloma, they come at a significant cost. We assessed the cost-effectiveness of bortezomib-based triplet or quadruplet drug regimens in isolation and followed by autologous hematopoietic stem cell transplantation (AHSCT) for the treatment of newly diagnosed multiple myeloma (NDMM) in the Indian context. METHODS: A Markov model was developed to assess the health and economic outcomes of novel drug regimens with and without AHSCT for the treatment of NDMM in India. We estimated the lifetime quality-adjusted life-years (QALYs) and costs in each scenario. The incremental cost-effectiveness ratios (ICERs) were computed and compared against the current willingness-to-pay threshold of a one-time per capita gross domestic product of ₹146,890 (US$1,927.70) for India. Parameter uncertainty was assessed through Monte Carlo probabilistic sensitivity analysis. RESULTS: Among seven treatment sequences, the VCd (bortezomib, cyclophosphamide, dexamethasone) alone arm has the lowest cost and health benefits as compared to four treatment sequences, namely VTd (bortezomib, thalidomide, dexamethasone) alone, VRd (bortezomib, lenalidomide, dexamethasone) alone, VRd plus AHSCT and DVRd (Daratumumab, bortezomib, lenalidomide, dexamethasone) plus AHSCT. It was found that VTd plus AHSCT and VCd plus AHSCT arms were extendedly dominated (ED) by combination of two alternative treatments. Among the five non-dominated strategies, VRd has a lowest incremental cost of ₹ 2,20,093 (US$2,888) per QALY gained compared to VTd alone followed by VRd plus AHSCT [₹3,14,530 (US$4,128) per QALY gained] in comparison to VRd alone. None of the novel treatment sequences were found to be cost-effective at the current WTP threshold of ₹1,46,890 (US$1,927.7). CONCLUSION: At the current WTP threshold of one-time per capita GDP (₹ 146,890) of India, VRd alone and VRd plus AHSCT has 38.1% and 6.9% probability to be cost-effective, respectively. Reduction in current reimbursement rates of novel drugs, namely VRd, lenalidomide, and pomalidomide plus dexamethasone under national insurance program and societal cost of transplant by 50%, would make VRd plus AHSCT and VTd plus AHSCT cost-effective at an incremental cost of ₹40,671 (US$34) and ₹97,639 (US$1,281) per QALY gained, respectively.

Longitudinal Costs of Image-Guided Intensity-Modulated Radiation Therapy Versus Three-Dimensional Conformal Radiation: Lessons From Phase III PARCER Trial for Shaping Resource-Stratified Guidelines in Low- and Middle-Income Countries.

PURPOSE: The PARCER trial provided level I evidence for image-guided intensity-modulated radiation therapy (IG-IMRT) in patients with cervical cancer. Further information regarding long-term financial impact is imperative for adoption into the National Cancer Grid of India cervical cancer resource-stratified guidelines. METHODS: Patient data from the PARCER trial were analyzed to evaluate the cost implications of transitioning to IG-IMRT. Lacking differences in outcomes between the three-dimensional conformal radiation (3D-CRT) and IG-IMRT, differences in treatment costs, adverse event incidence, and toxicity management costs were examined. The overall financial impact was estimated by adding the treatment costs, toxicity management, and wage loss. This was extrapolated nationally to determine if a transition to IG-IMRT would be feasible for the Indian health care system. RESULTS: Of the 300 patients in the PARCER trial, 93 faced grades ≥2 adverse events (3D-CRT = 59, IG-IMRT = 34). Patients in the 3D-CRT and IG-IMRT arms spent an average of 2.39 years and 1.96 years in toxicity, respectively. The average toxicity management and the yearly financial impact per patient were, respectively, 1.50 and 1.44 times higher for 3D-CRT patients compared with IG-IMRT patients. Extrapolation to the national level showed that treatment with 3D-CRT led to a 2.88 times higher cost ratio when compared with treatment with IG-IMRT. CONCLUSION: Although the initial costs of IG-IMRT are high, on the basis of longitudinal data, it is financially inefficient to treat with 3D-CRT. Resource-stratified guidelines should include longitudinal health intervention costs rather than solely initial costs for policy decisions to implement advanced radiation technology.

Tata Memorial Centre Evidence Based Management of Breast cancer.

ABSTRACT: The incidence of breast cancer is increasing rapidly in urban India due to the changing lifestyle and exposure to risk factors. Diagnosis at an advanced stage and in younger women are the most concerning issues of breast cancer in India. Lack of awareness and social taboos related to cancer diagnosis make women feel hesitant to seek timely medical advice. As almost half of women develop breast cancer at an age younger than 50 years, breast cancer diagnosis poses a huge financial burden on the household and impacts the entire family. Moreover, inaccessibility, unaffordability, and high out-of-pocket expenditure make this situation grimmer. Women find it difficult to get quality cancer care closer to their homes and end up traveling long distances for seeking treatment. Significant differences in the cancer epidemiology compared to the west make the adoption of western breast cancer management guidelines challenging for Indian women. In this article, we intend to provide a comprehensive review of the management of breast cancer from diagnosis to treatment for both early and advanced stages from the perspective of low-middle-income countries. Starting with a brief introduction to epidemiology and guidelines for diagnostic modalities (imaging and pathology), treatment has been discussed for early breast cancer (EBC), locally advanced, and MBC. In-depth information on loco-regional and systemic therapy has been provided focusing on standard treatment protocols as well as scenarios where treatment can be de-escalated or escalated.

Health-related quality of life and its determinants among cancer patients: evidence from 12,148 patients of Indian database.

BACKGROUND: Cancer survivors experience a decrement in health-related quality of life (HRQoL) resulting from the disease as well as adverse effects of therapy. We evaluated the HRQoL of cancer patients, stratified by primary cancer site, stage, treatment response and associated adverse events, along with its determinants. METHODS: Data were collected from 12,148 patients, sampled from seven purposively chosen leading cancer hospitals in India, to elicit HRQoL using the EuroQol questionnaire comprising of 5-dimensions and 5-levels (EQ-5D-5L). Multiple linear regression was used to determine the association between HRQoL and various socio-demographic as well as clinical characteristics. RESULTS: Majority outpatients (78.4%) and inpatients (81.2%) had solid cancers. The disease was found to be more prevalent among outpatients (37.5%) and inpatients (40.5%) aged 45-60 years and females (49.3-58.3%). Most patients were found to be in stage III (40-40.6%) or stage IV (29.4-37.3%) at the time of recruitment. The mean EQ-5D-5 L utility score was significantly higher among outpatients [0.630 (95% CI: 0.623, 0.637)] as compared to inpatients [0.553 (95% CI: 0.539, 0.567)]. The HRQoL decreased with advancing cancer stage among both inpatients and outpatients, respectively [stage IV: (0.516 & 0.557); stage III (0.609 & 0.689); stage II (0.677 & 0.713); stage I (0.638 & 0.748), p value < 0.001]. The outpatients on hormone therapy (B = 0.076) showed significantly better HRQoL in comparison to patients on chemotherapy. However, palliative care (B=-0.137) and surgery (B=-0.110) were found to be associated with significantly with poorer HRQoL paralleled to chemotherapy. The utility scores among outpatients ranged from 0.305 (bone cancer) to 0.782 (Leukemia). Among hospitalized cases, the utility score was lowest for multiple myeloma (0.255) and highest for testicular cancer (0.771). CONCLUSION: Older age, lower educational status, chemotherapy, palliative care and surgery, advanced cancer stage and progressive disease were associated with poor HRQoL. Our study findings will be useful in optimising patient care, formulating individualized treatment plan, improving compliance and follow-up.

Indian Society of Critical Care Medicine and Indian Association of Palliative Care Expert Consensus and Position Statements for End-of-life and Palliative Care in the Intensive Care Unit.

End-of-life care (EOLC) exemplifies the joint mission of intensive and palliative care (PC) in their human-centeredness. The explosion of technological advances in medicine must be balanced with the culture of holistic care. Inevitably, it brings together the science and the art of medicine in their full expression. High-quality EOLC in the ICU is grounded in evidence, ethical principles, and professionalism within the framework of the Law. Expert professional statements over the last two decades in India were developed while the law was evolving. Recent landmark Supreme Court judgments have necessitated a review of the clinical pathway for EOLC outlined in the previous statements. Much empirical and interventional evidence has accumulated since the position statement in 2014. This iteration of the joint Indian Society of Critical Care Medicine-Indian Association of Palliative Care (ISCCM-IAPC) Position Statement for EOLC combines contemporary evidence, ethics, and law for decision support by the bedside in Indian ICUs. How to cite this article: Mani RK, Bhatnagar S, Butola S, Gursahani R, Mehta D, Simha S, et al. Indian Society of Critical Care Medicine and Indian Association of Palliative Care Expert Consensus and Position Statements for End-of-life and Palliative Care in the Intensive Care Unit. Indian J Crit Care Med 2024;28(3):200-250.

Surgical Tumor Resection Deregulates Hallmarks of Cancer in Resected Tissue and the Surrounding Microenvironment.

Surgery exposes tumor tissue to severe hypoxia and mechanical stress leading to rapid gene expression changes in the tumor and its microenvironment, which remain poorly characterized. We biopsied tumor and adjacent normal tissues from patients with breast (n = 81) and head/neck squamous cancers (HNSC; n = 10) at the beginning (A), during (B), and end of surgery (C). Tumor/normal RNA from 46/81 patients with breast cancer was subjected to mRNA-Seq using Illumina short-read technology, and from nine patients with HNSC to whole-transcriptome microarray with Illumina BeadArray. Pathways and genes involved in 7 of 10 known cancer hallmarks, namely, tumor-promoting inflammation (TNF-A, NFK-B, IL18 pathways), activation of invasion and migration (various extracellular matrix-related pathways, cell migration), sustained proliferative signaling (K-Ras Signaling), evasion of growth suppressors (P53 signaling, regulation of cell death), deregulating cellular energetics (response to lipid, secreted factors, and adipogenesis), inducing angiogenesis (hypoxia signaling, myogenesis), and avoiding immune destruction (CTLA4 and PDL1) were significantly deregulated during surgical resection (time points A vs. B vs. C). These findings were validated using NanoString assays in independent pre/intra/post-operative breast cancer samples from 48 patients. In a comparison of gene expression data from biopsy (analogous to time point A) with surgical resection samples (analogous to time point C) from The Cancer Genome Atlas study, the top deregulated genes were the same as identified in our analysis, in five of the seven studied cancer types. This study suggests that surgical extirpation deregulates the hallmarks of cancer in primary tumors and adjacent normal tissue across different cancers. IMPLICATIONS: Surgery deregulates hallmarks of cancer in human tissue.

Natural History of Germline BRCA1 Mutated and BRCA Wild-type Triple-negative Breast Cancer.

We report a deep next-generation sequencing analysis of 13 sequentially obtained tumor samples, eight sequentially obtained circulating tumor DNA (ctDNA) samples and three germline DNA samples over the life history of 3 patients with triple-negative breast cancer (TNBC), 2 of whom had germline pathogenic BRCA1 mutation, to unravel tumor evolution. Tumor tissue from all timepoints and germline DNA was subjected to whole-exome sequencing (WES), custom amplicon deep sequencing (30,000X) of a WES-derived somatic mutation panel, and SNP arrays for copy-number variation (CNV), while whole transcriptome sequencing (RNA-seq) was performed only on somatic tumor.There was enrichment of homologous recombination deficiency signature in all tumors and widespread CNV, which remained largely stable over time. Somatic tumor mutation numbers varied between patients and within each patient (range: 70-216, one outlier). There was minimal mutational overlap between patients with TP53 being the sole commonly mutated gene, but there was substantial overlap in sequential samples in each patient. Each patient's tumor contained a founding ("stem") clone at diagnosis, which persisted over time, from which all other clones ("subclone") were derived ("branching evolution"), which contained mutations in well-characterized cancer-related genes like PDGFRB, ARID2, TP53 (Patient_02), TP53, BRAF, BRIP1, CSF3R (Patient_04), and TP53, APC, EZH2 (Patient_07). Including stem and subclones, tumors from all patients were polyclonal at diagnosis and during disease progression. ctDNA recapitulated most tissue-derived stem clonal and subclonal mutations while detecting some additional subclonal mutations. RNA-seq revealed a stable basal-like pattern, with most highly expressed variants belonging to stem clone. SIGNIFICANCE: In germline BRCA1 mutated and BRCA wild-type patients, TNBC shows a branching evolutionary pattern of mutations with a single founding clone, are polyclonal throughout their disease course, and have widespread copy-number aberrations. This evolutionary pattern may be associated with treatment resistance or sensitivity and could be therapeutically exploited.

Clinical Internal Dosimetry and Biodistribution of 177 Lu-DOTA-Trastuzumab in HER2-Positive Metastatic and Locally Advanced Breast Carcinoma.

OBJECTIVE: The aim of this study was to assess the biodistribution and dosimetry of 177 Lu-DOTA-trastuzumab in patients with HER2-positive breast carcinoma using whole-body (WB) planar imaging at multiple time points. PATIENTS AND METHODS: This study was a prospective evaluation of HER2-positive metastatic/locally advanced breast carcinoma patients who underwent gamma camera imaging for dosimetry and biodistribution studies by using 177 Lu-DOTA-trastuzumab. The standard diagnostic dosimetry protocol was followed, which included cold trastuzumab injection followed by in-house produced 177 Lu-DOTA-trastuzumab. Serial WB planar images (anterior and posterior) were obtained on gamma camera after the infusion of 177 Lu-DOTA-trastuzumab at multiple time points. Whole-body and organ regions of interest were drawn, and the numbers of disintegrations were obtained. The mean absorbed doses for the liver, spleen, kidneys, heart, red marrow, and tumor were obtained from OLINDA EXM v2.1.1 and ORIGIN software. RESULTS: The study included a cohort of 21 female breast carcinoma patients. Tracer activity ( 177 Lu-DOTA-trastuzumab) was noted in the physiological organs such as the liver, spleen, kidneys, heart, as well as in the tumors. On visual analysis of 177 Lu-DOTA-trastuzumab biodistribution, the liver activity showed gradual clearance over time, and although spleen was comparatively faintly visualized than liver and similarly, kidneys were faintly visualized suggestive of the alternate route of tracer excretion. The maximum number of patients (n = 12) showed 2 components of clearance, namely, fast and slow. The average effective half-life of all the patients (including single and 2 components of clearance) was 106.25 ± 22.14 hours (84.11-128.39 hours). The mean absorbed dose for the liver, spleen, kidneys, heart, whole body, and red marrow was 1.0702 ± 0.731, 1.4114 ± 0.462, 1.4232 ± 0.364, 1.4719 ± 0.602, 0.2412 ± 0.0295, and 0.1485 ± 0.0213 mGy/MBq, respectively, by OLINDA EXM and 0.5741 ± 0.333, 0.8096 ± 0.224, 0.7943 ± 0.235, 1.8971 ± 0.713, and 0.09619 ± 0.0144 for liver, spleen, kidneys, heart and whole body respectively by ORIGIN. The absorbed radiation dose for tumor was 1.94E+2 by OLINDA EXM software and 1.78E+2 by ORIGIN software. In this study, during and after infusion of 177 Lu-DOTA-trastuzumab, no major adverse effects were noted in any patient except 1 patient who had grade 1 nausea and managed conservatively by antiemetic drug. CONCLUSIONS: The results of our study demonstrated expected and favorable biodistribution and dosimetry with 177 Lu-DOTA-trastuzumab in HER2-positive breast carcinoma patients. We noticed the mean absorbed dose to the normal organs within the limits of maximum tolerable dose, and also tumor dose was higher than the normal liver dose. Therefore, we conclude that 177 Lu-DOTA-trastuzumab radioimmunotherapy is feasible and a safe treatment option for treating HER2-positive breast carcinoma patients.

Oncofertility and Pregnancy in Adolescent and Young Adult Cancers: Physicians' Knowledge and Preferences in India.

PURPOSE: The treatment outcomes of adolescent and young adult (AYA) cancers have improved with advanced oncology care. Hence, fertility preservation (FP) and post-therapy pregnancies (PTPs) become vital issues. MATERIALS AND METHODS: An online survey link with 17 questions regarding oncofertility and PTPs was circulated among oncologists to assess the knowledge, understand the oncofertility care patterns, and seek suggestions to improve oncofertility services. RESULTS: The median age of 179 respondents, predominantly medical oncologists (68.7%), was 37 years (IQR, 10; range, 29-74), working in academic centers (39%) having a median experience of 4 years (IQR, 4; range, 1-42); 23 (12.8%) had dedicated AYA cancer units. Although a quarter (19%-24%) of respondents discussed fertility issues in >90% of AYA patients with cancer, only a tenth (8%-11%) refer >90% for FP, with significantly higher (P < .05) discussions and referrals in males and by more experienced oncologists (P < .05). Forty-six (25.6%) were not well versed with international guidelines for FP. Most (122, 68.1%) oncologists knew about the referral path for semen cryopreservation; however, only 46% were knowledgeable about additional complex procedures. One hundred and ten (61.5%) oncologists never or rarely altered the systemic treatment for FP. Prominent barriers to FP were ignorance, lack of collaboration, and fear of delaying cancer treatment. Lead thrust areas identified to improve FP practices are education, and enhanced and affordable access to FP facilities. Seventy-four (41.3%) respondents knew about international guidelines for PTPs; however, only half (20%) of them often monitored fertility outcomes in survivors. Oncologists have conflicting opinions and uncertainties regarding pregnancy safety, assisted reproductive techniques, breastfeeding, and pregnancy outcomes among survivors. CONCLUSION: Oncologists are uncertain about the guidelines, FP practices, referral pathways, and PTPs. Multipronged approaches to improve awareness and provision for affordable oncofertility facilities are needed to enhance AYA cancer outcomes in India, which will be applicable to other low- and middle-income countries too.

Low-dose versus standard-dose olanzapine with triple antiemetic therapy for prevention of highly emetogenic chemotherapy-induced nausea and vomiting in patients with solid tumours: a single-centre, open-label, non-inferiority, randomised, controlled, phase 3 trial.

BACKGROUND: Olanzapine is an effective antiemetic agent but it results in substantial daytime somnolence when administered at the standard dose. Our aim was to compare the efficacy of low-dose versus standard-dose olanzapine after highly emetogenic chemotherapy in patients with solid tumours. METHODS: This was a single-centre, open-label, non-inferiority, randomised, controlled, phase 3 trial done in a tertiary care referral centre in India (Tata Memorial Centre, Homi Bhabha National Institute, Mumbai). Patients aged 13-75 years with an Eastern Cooperative Oncology Group performance status of 0-2, who were receiving doxorubicin-cyclophosphamide or high-dose cisplatin for a solid tumour were eligible. Patients were randomly assigned (1:1), with block randomisation (block sizes of 2 or 4) and stratified by sex, age (≥55 or <55 years), and chemotherapy regimen, to receive low-dose (2·5 mg) oral olanzapine or standard-dose (10·0 mg) oral olanzapine daily for 4 days, in combination with a triple antiemetic regimen. Study staff were masked to treatment allocation but patients were aware of their group assignment. The primary endpoint was complete control, defined as no emetic episodes, no rescue medications, and no or mild nausea in the overall phase (0-120 hours), assessed in the modified intention-to-treat (mITT) population (ie, all eligible patients who received protocol-specified treatment, excluding those who had eligibility violations and who withdrew consent after randomisation). Daytime somnolence was the safety endpoint of interest. Non-inferiority was shown if the upper limit of the one-sided 95% CI for the difference in the complete control proportions between the treatment groups excluded the non-inferiority margin of 10%. This study is registered with the Clinical Trial Registry India, CTRI/2021/01/030233, is closed to accrual, and this is the final data analysis. RESULTS: Between Feb 9, 2021, and May 30, 2023, 356 patients were pre-screened for eligibility, of whom 275 patients were enrolled and randomly assigned (134 to the 2·5 mg olanzapine group and 141 to the 10·0 mg olanzapine group). 267 patients (132 in the 2·5 mg group and 135 in the 10·0 mg group) were included in the mITT population, of whom 252 (94%) were female, 15 (6%) were male, and 242 (91%) had breast cancer. 59 (45%) of 132 patients in the 2·5 mg olanzapine group had complete control in the overall phase versus 59 (44%) of 135 in the 10·0 mg olanzapine group (difference -1·0% [one-sided 95% CI -100·0 to 9·0]; p=0·87). In the overall phase, there were significantly fewer patients in the 2·5 mg olanzapine group than in the 10·0 mg olanzapine group with daytime somnolence of any grade (86 [65%] of 132 vs 121 [90%] of 135; p<0·0001) and of severe grade on day 1 (six]5%] vs 54 [40%]; p<0·0001). INTERPRETATION: Our findings suggest that olanzapine 2·5 mg is non-inferior to 10·0 mg in antiemetic efficacy and results in reduced occurrence of daytime somnolence among patients receiving highly emetic chemotherapy and should be considered as a new standard of care. FUNDING: Progressive Ladies Welfare Association.