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.

Septal venous channel perforation during left bundle branch area pacing: a prospective study.

AIMS: To characterize the diagnosis, frequency, and procedural implications of septal venous channel perforation during left bundle branch area pacing (LBBAP). METHODS AND RESULTS: All consecutive patients undergoing LBBAP over an 8-month period were prospectively studied. During lead placement, obligatory septal contrast injection was performed twice, at initiation (implant entry zone) and at completion (fixation zone). An intuitive fluoroscopic schema using orthogonal views (left anterior oblique/right anterior oblique) and familiar landmarks is described. Using this, we resolved zonal distribution (I-VI) of lead position on the ventricular septum and its angulation (post-fixation angle θ). Subjects with and without septal venous channel perforation were compared. Sixty-one patients {male 57.3%, median age [interquartile range (IQR)] 69.5 [62.5-74.5] years} were enrolled. Septal venous channel perforation was observed in eight (13.1%) patients [male 28.5%, median age (IQR) 64 (50-75) years]. They had higher frequency of (i) right-sided implant (25% vs. 1.9%, P = 0.04), (ii) fixation in zone III at the mid-superior septum (75% vs. 28.3%, P = 0.04), (iii) steeper angle of fixation-median θ (IQR) [19 (10-30)° vs. 5 (4-19)°, P = 0.01], and (iv) longer median penetrated-lead length (IQR) [13 (10-14.8) vs. 10 (8.5-12.5) mm, P = 0.03]. Coronary sinus drainage of contrast was noted in five (62.5%) patients. Abnormal impedance drops during implantation (12.5% vs. 5.7%, P = NS) were not significantly different. CONCLUSION: When evaluated systematically, septal venous channel perforation may be encountered commonly after LBBAP. The fiducial reference framework described using fluoroscopic imaging identified salient associated findings. This may be addressed with lead repositioning to a more inferior location and is not associated with adverse consequence acutely or in early follow-up.

A case of exaggerated exuberance: Iatrogenic atrioventricular block/intra-Hisian Wenckebach during conduction system pacing.

Isolated sinus node dysfunction with its pursuant long-term risk for atrioventricular (AV) conduction disease poses a unique dilemma for proponents of CSP due to paucity of imprimatur guidelines. In such scenarios, the risk and prognosis of iatrogenic AV block is not well elucidated but is a valid concern. We report a case where CSP was complicated by iatrogenic AV block and peculiarly the rare phenomenon of intra-Hisian Wenckebach.

An unusual site of ablation for a ventricular tachycardia.

Scar-related ventricular tachycardia (VT) ablation involves localizing the critical isthmuses by overdrive pacing maneuvers and three-dimensional activation mapping. Implantable prosthetic devices have been known to complicate this by covering sites of potential isthmuses. We herein present a sentinel report of scar-VT ablation with a protected isthmus localized over an endothelialized post-myocardial infarction ventricular septal defect occluder device.

Phase 3 RCT comparing docetaxel-platinum with docetaxel-platinum-5FU as neoadjuvant chemotherapy in borderline resectable oral cancer.

BACKGROUND: Neoadjuvant chemotherapy (NACT) with TPF (docetaxel, cisplatin, and 5FU) is one of the treatment options in very locally advanced oral cancer with a survival advantage over PF (cisplatin and 5FU). TP (docetaxel and cisplatin) has shown promising results with a lower rate of adverse events but has never been compared to TPF. METHODS: In this phase 3 randomized superiority study, adult patients with borderline resectable locally advanced oral cancers were randomized in a 1:1 fashion to either TP or TPF. After the administration of 2 cycles, patients were evaluated in a multidisciplinary clinic and further treatment was planned. The primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS) and adverse events. RESULTS: 495 patients were randomized in this study, 248 patients in TP arm and 247 in TPF arm. The 5-year OS was 18.5% (95% CI 13.8-23.7) and 23.9% (95% CI 18.1-30.1) in TP and TPF arms, respectively (Hazard ratio 0.778; 95% CI 0.637-0.952; P = 0.015). Following NACT, 43.8% were deemed resectable, but 34.5% underwent surgery. The 5-year OS was 50.7% (95% CI 41.5-59.1) and 5% (95%CI 2.9-8.1), respectively, in the surgically resected versus unresected cohort post NACT (P < 0.0001). Grade 3 or above adverse events were seen in 97 (39.1%) and 179 (72.5%) patients in the TP and TPF arms, respectively (P < 0.0001). CONCLUSION: NACT with TPF has a survival benefit over TP in borderline resectable oral cancers, with an increase in toxicity which is manageable. Patients who undergo surgery achieve a relatively good, sustained survival.

Epidemiological Trend of Esophageal Cancer at a Tertiary Cancer Center in Mumbai, India, Over the Past 15 Years.

BACKGROUND: In developed countries, there has been a definite change in the histopathological spectrum of esophageal cancer towards adenocarcinoma. There are limited data from India regarding the histopathological profile of patients with esophageal cancer. MATERIALS AND METHODS: We retrospectively evaluated patients with histologically proven esophageal cancer who were registered at the Tata Memorial Hospital (Mumbai, India) between 2003 and 2018. The primary aim of the study was to analyze the time-trend of the histological pattern of esophageal cancer. Our secondary objectives included evaluating whether there was any correlation between the histology of the esophageal cancer and the age, sex, socioeconomic status (the paying ability of the patient, which was reflected in the treatment category of the patient, i.e., private [full payment], general [subsidized payment], or no charge), comorbidities, and a history of substance abuse. RESULTS: Among 7874 patients with esophageal cancer, 5092 (64.7%) were men, with a male-to-female ratio of 1.8:1. The median age was 57 years (IQR, 50-65). Of the 4912 patients in whom a history of tobacco or alcohol use had been elicited, 1360 (27.7%) had no history of substance abuse. A majority of the tumors (2942, 37.4%) originated in the middle-third of the esophagus. Squamous cell carcinoma was the predominant histological type, noted in 6413 (81.4%) patients and remained the most common histologic type consistently through the study with no evidence of a time-trend in the histological pattern. On the multivariate analysis, female sex and a history of substance abuse were associated with higher odds of squamous cell carcinoma, while the presence of comorbidities and lower esophageal/gastroesophageal junction primaries were associated with higher odds of adenocarcinoma. CONCLUSIONS: There is no evidence of an epidemiological shift in the histopathologic spectrum of esophageal cancer in India over the last two decades. Four out of five Indian patients with esophageal cancer have squamous cell histology, with the commonest site of origin being the middle third. This is important to recognize, given the varying molecular spectrum and efficacy of therapeutic modalities based on histopathology.

Practice Patterns and Survival in Patients with Resected Pancreatic Ductal Adenocarcinomas (PDAC) - Results from the Multicentre Indian Pancreatic & Periampullary Adenocarcinoma Project (MIPPAP) Study.

BACKGROUND: There is limited data from India with regard to presentation, practice patterns and survivals in resected pancreatic ductal adenocarcinomas (PDACs). METHODS: The Multicentre Indian Pancreatic & Periampullary Adenocarcinoma Project (MIPPAP) included data from 8 major academic institutions across India and presents the outcomes in upfront resected PDACs from January 2015 to June 2019. RESULTS: Of 288 patients, R0 resection was achieved in 81% and adjuvant therapy was administered in 75% of patients. With a median follow-up of 42 months (95% CI: 39-45), median DFS for the entire cohort was 39 months (95% CI: 25.4-52.5), and median overall survival (OS) was 45 months (95% CI: 32.3-57.7). A separate analysis was done in which patients were divided into 3 groups: (a) those with stage I and absent PNI (SI&PNI-), (b) those with either stage II/III OR presence of PNI (SII/III/PNI+), and (c) those with stage II/III AND presence of PNI (SII/III&PNI+). The DFS was significantly lesser in patients with SII/III&PNI+ (median 25, 95% CI: 14.1-35.9 months), compared to SII/III/PNI + (median 40, 95% CI: 24-55 months) and SI&PNI- (median, not reached) (p = 0.036)). CONCLUSIONS: The MIPPAP study shows that resectable PDACs in India have survivals at par with previously published data. Adjuvant therapy was administered in 75% patients. Adjuvant radiotherapy does not seem to add to survival after R0 resection.

Caregiver burden in older Indian patients with cancer- Experience from a tertiary care center.

INTRODUCTION: Most of the long-term care for older adults with chronic or debilitating illnesses is provided by unpaid family members or informal caregivers. There is limited information on caregiver burden among caregivers of older patients with cancer in India. Hence, we assessed the prevalence and severity of caregiver burden among caregivers of older Indian patients with cancer. MATERIALS AND METHODS: This was an observational study conducted at the geriatric oncology clinic at Tata Memorial Centre, Mumbai, India. Caregivers of patients aged 60 years and over with a diagnosis of cancer were assessed for caregiver burden using the Zarit Burden Interview. Descriptive statistics were used for demographic and clinical variables. Factors impacting caregiver burden were analyzed using multiple linear regression analysis. RESULTS: Caregiver burden was assessed among 127 caregivers of older Indian patients with cancer. The median patient age was 69 years (range 60-90). Most patients were men (75.6%). There were 33 female caregivers (26%), and 94 male caregivers (74%). The median caregiver burden score was 12 (IQR 6-20). Caregiver burden was "little/none" in 97 (76.4%), "mild-moderate" in 25 (19.7%), "moderate-severe" in four (3.1%) and "severe" in one (0.8%) of the caregivers assessed. On multivariate analysis, factors that significantly impacted caregiver burden scores were the presence of psychological issues in the patient and the caregiver's educational level. DISCUSSION: Caregiver burden was low among caregivers of older Indian patients with cancer seen at a single center. Caregivers of patients with psychological disorders, and those who had less schooling reported higher caregiver burden.

An Audit of Systemic Therapy in Medullary Carcinoma Thyroid.

There is a paucity of evidence of the impact of sorafenib on MCT and it is the preferred therapy used in India. We decided to do an audit of all patients of MCT who were referred to us for systemic therapy. The objective of this exercise was to identify the treatment pattern, outcomes, and adverse events with therapy in MCT. Baseline demographics (age, gender, ECOG PS, comorbidities, habits), tumor details (site of metastasis), previous treatment details, clinical features at metastasis (symptomatic or asymptomatic), the pattern of treatment, adverse events (CTCAE version 4.02), date of progression, date of death and status, and follow-up were extracted from the rare tumor database and electronic medical records. Out of 75 patients referred for therapy for MCT, 47 (62.7%) patients were considered for immediate tyrosine kinase inhibitors as they had symptomatic status and 28 (37.3%) patients were kept on observation due to the asymptomatic nature of the disease. Out of the 28 patients, 15 (53.6%, n = 28) patients were subsequently started on TKI while in 13 (46.4%, n = 28) patients observation was continued. In the overall cohort, the median PFS was 18.9 months (95% CI 11.9-29.9) and OS was 26.6 months (95% CI 14.4-39.0). Among variables tested, only female gender had an impact on PFS (hazard ratio = 0.364 95% CI 0.148-0.895; P = 0.028) and the absence of lung metastasis had a positive impact on OS (hazard ratio = 0.443 95% CI 0.207-0.95; P = 0.037). Most commonly used TKI was sorafenib (n = 61) and sunitinib in 1 patient. The most common adverse events with TKI were palmo-plantar dysesthesia (50, 80.6%) and oral mucositis (25, 40.2%). The strategy of treating symptomatic MCT and observing in asymptomatic MCT is associated with reasonable PFS and OS. Sorafenib is the most commonly used TKI in our setup and provides similar outcomes as globally.

Audit of Demographics, Treatment Patterns and Outcomes of Differentiated Thyroid Cancers Treated with Tyrosine Kinase Inhibitors.

The real-world patterns of TKI use in differentiated thyroid cancer (DTC) are largely governed by the accessibility and financial feasibility of the patient with more sorafenib use compared to lenvatinib. There are limited data available on the toxicity profile, safety and tolerance of sorafenib and lenvatinib in DTC. Hence, we audited our practice on DTC. This is a retrospective single-centre analysis of patients with DTC who were referred to the Department of Medical Oncology for systemic therapy. Baseline demographics (age, sex, ECOG PS, comorbidities, substance use), tumour details (site of metastasis), previous treatment details, clinical features at metastasis (symptoms), the pattern of treatment, adverse events and outcomes including progression and death were extracted. There were 67 patients with DTC referred for systemic therapy; the median age was 56 (33-81) with a male preponderance (55.6%). The most common reason to start TKI therapy was radioactive iodine (RAI) cumulative dose > 600 milliCurie, followed by low iodine uptake in the RAI low-dose scan done at progression. The most common TKI used in the first line was sorafenib in 56 (83.6%) patients followed by lenvatinib in 9 (13.4%) patients. Papillary thyroid carcinoma was the most common histology (51, 76.1%), and the rest were follicular carcinoma (16, 23.9%). With a median follow-up of 36 months, the median PFS was 13.2 months (95% CI 10.4-16.0). The median OS was 18.8 months (95% CI 10.0-27.6). Among variables tested, no factors had a significant impact on the PFS or OS. The most common adverse events were hand-foot syndrome (54, 80.5%), diarrhoea (23, 33.3%) and transaminitis (24, 34.4%). The pattern of care of patients with RAI-refractory DTC is TKI therapy, especially sorafenib and lenvatinib in the real-world settings with comparable efficacy and safety profile compared to international literature.

Outcomes of non-metastatic triple negative breast cancers: Real-world data from a large Indian cohort.

BACKGROUND: Triple negative Breast tumor (TNBC) is an aggressive tumor with sparse data worldwide. METHODS: We analyzed non-metastatic TNBC from 2013 to 2019 for demographics, practice patterns, and survival by the Kaplan Meir method. Prognostic factors for OS and DFS were evaluated using Cox Proportional Hazard model estimator for univariate and multivariable analysis after checking for collinearity among the variables. RESULTS: There were 1297 patients with median age of 38 years; 41 (33.3%) among 123 tested were BRCA-positives. Among these 593 (45.7%) had stage III disease, 1279 (98.6%) were grade III, 165 (13.0%) had peri-nodal extension (PNE), 212 (16.0%) lympho-vascular invasion (LVI), and 21 (1.6%) were metaplastic; 1256 (96.8%) received chemotherapy including 820 (63.2%) neoadjuvant with 306 (40.0%) pCR. Grade ≥3 toxicities occurred in 155 (12.4%) including two deaths and 3 s-primaries. 1234 (95.2%) underwent surgery [722 (55.7%) breast conservations] and 1034 (79.7%) received radiotherapy. At a median follow-up of 54 months, median disease-free (DFS) was 92.2 months and overall survival (OS) was not reached. 5-year estimated DFS and OS was 65.9% and 80.3%. There were 259 (20.0%) failures; predominantly distant (204, 15.7%) - lung (51%), liver (31.8%). In multivariate analysis presence of LVI (HR-2.00, p-0.003), PNE (HR-2.09 p-0.003), older age (HR-1.03, p-0.002) and stage III disease (HR-4.89, p-0.027), were associated with poor OS. CONCLUSION: Relatively large contemporary data of non-metastatic TNBC confirms aggressive biology and predominant advanced stage presentation which adversely affects outcomes. The data strongly indicate the unmet need for early detection to optimize care.