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.

Can 18F FDG PET/CT metabolic parameters be used to noninvasively differentiate between different histopathological subtypes and Fuhrman grades of renal cell cancer?

AIM: To evaluate relationship between metabolic PET metabolic parameters and size of the primary tumor, various histopathological subtypes of renal cell carcinoma (RCC) and Fuhrman grade of the tumors. MATERIAL AND METHODS: Retrospective analysis of 93 biopsy-proven RCC patients who underwent pretreatment flourine 18 flourodeoxyglucose PET/computed tomography (18F FDG PET/CT) was performed. Quantitative PET parameters, size of the primary tumor, histopathological subtypes and Fuhrman grades of the tumor were extracted. We tried to assess if there was any significant difference in the metabolic patterns of various histopathological subtypes of RCCs, Fuhrman grade of the tumors and size of the primary tumor. RESULTS: A significant correlation was noted between the size of primary tumor and maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) (P < 0.01, P < 0.001 and P < 0.001, respectively). SUVmax values correlated significantly with the histopathological subtype (P < 0.001). Further sub-analyses was also done by segregating the patients into Low grade (Fuhrman grade 1 and 2) vs. High grade (Fuhrman grade 3 and 4). SUVmax, MTV and TLG were significantly different between high grade vs. low grade tumors. ROC analysis yielded cut off values for SUVmax, MTV and TLG to differentiate between high grade from low grade tumors. CONCLUSION: FDG PET/CT with the use of metabolic PET parameters can differentiate between different histopathological subtypes of RCC. Incorporation of metabolic parameters into clinical practice can potentially noninvasively identify patients with low-grade vs. high-grade RCC.

Gefitinib vs Gefitinib Plus Pemetrexed and Carboplatin Chemotherapy in EGFR-Variant Lung Cancer-Long-Term Results of a Randomized Clinical Trial.

This randomized clinical trial examines whether adding chemotherapy with pemetrexed and carboplatin to gefitinib improves survival among patients with epidermal growth factor receptor (EGFR)­variant non­small cell lung cancer.

SALTT study: A retrospective analysis of 111 SAlivary gland tumors of Lung and Tracheobronchial Tree.

INTRODUCTION: Primary pulmonary salivary gland-type tumours (PPSGT) are rare lung neoplasms arising from submucosal seromucinous glands in the central airway. METHODS AND RESULTS: We retrospectively analysed the clinicopathological features of 111 PPSGTs diagnosed at our institute between 2003 and 2021. The mean age at diagnosis was 43.8 years(range 6-78 years) and a male-to-female ratio of 2:1. On imaging, 92 % of cases had centrally located tumours and 37.3 % were early stage. The histopathological types included 70 cases (63 %) of mucoepidermoid carcinoma (MEC), 31 cases (27.7 %) of adenoid cystic carcinoma (ADCC), two cases of myoepithelial carcinoma, one case each of acinic cell carcinoma (ACC), clear cell carcinoma (CCC), epithelial myoepithelial carcinoma (EMC) and 5 others [including adenocarcinoma of minor salivary gland origin(n = 3), carcinoma with sebaceous differentiation(n = 1) and poorly differentiated carcinoma of salivary gland type(n = 1)]. The size of the tumours found in the resection specimens ranged from 1 cm to 13 cm, with an average size of 4.9 cm. High-risk attributes such as lymphovascular invasion (LVI), perineural invasion (PNI), pleural involvement, positive resection margins, and nodal metastasis were identified in 15.3 %, 15.3 %, 13.6 %,15.2 % and 6.7 % of cases, respectively. These attributes were found to be more frequent in ADCC than in MEC. Surgery was the main treatment modality [68/84 (80 %) cases]. ADCC cases had more recurrence and distant metastasis than MEC cases. The 3- year overall-survival (OS) and recurrence-free survival(RFS) were better in patients with age lesser than 60 years(p-value <0.0001), low pT stage (p-value 0.00038) and lower grade of MEC(p-value-0.0067). CONCLUSION: It is crucial to have an acquaintance with the morphologic spectrum and immunophenotypic characteristics of PPSGT to recognize them in this unusual location. In tandem, it is crucial to differentiate them from conventional primary non-small cell lung carcinoma, as the management protocols and prognostic implications differ significantly.

Clinical characteristics, outcomes and prognostic factors in KRAS mutant lung cancers: experience from a tertiary care cancer center in India.

Objectives: Kirsten rat sarcoma viral oncogene homologue (KRAS) mutations in lung cancers, long considered untargetable, have had a recent rise in interest due to promising data of agents targeting KRAS p.G12C. As Indian data are scarce, we sought to identify baseline clinical characteristics, prognostic factors and outcomes of lung cancer patients with KRAS mutations at our hospital. Methods: Patients with KRAS mutant lung cancers treated at our institute from 2016 to 2022 were analysed. Results: 133 patients with KRAS mutant lung cancers were identified. Median age was 57 (interquartile range 28-78) years, and 58 (43.6%) were smokers. 17 (12.7%) had brain metastases. The commonest variant was p.G12C, seen in 53 (39.8%) patients. Six (4.5%) had programmed death ligand 1 (PDL-1) expression >50% by Ventana SP263 PDL-1 assay, and 13 (9.7%) had epidermal growth factor mutation. Of 92 patients with available treatment details, the majority received intravenous chemotherapy, nine (9.8%) received tyrosine kinase inhibitors and four (4.4%) received immunotherapy (pembrolizumab). Median progression-free survival (PFS) with first-line therapy was 6 (95% confidence interval (CI) 2.8-9.2) months and median overall survival (OS) was 12 (CI 9.2-14.8) months. The incidence of brain metastases was higher in patients with G12C mutations (p = 0.025). Brain metastases (HR: 3.57, p < 0.001), Eastern Cooperative Oncology Group performance status (PS) ≥ 2 (HR: 2.13, p = 0.002) and G12C mutation (HR: 1.84, p = 0.011) were associated with inferior PFS, while brain metastases (HR: 4.6, p < 0.001), PS ≥ 2 (HR: 2.33, p = 0.001) and G12C mutation (HR: 1.93, p = 0.01) were associated with inferior OS. Conclusion: This is the largest dataset of KRAS mutant lung cancers from India. Brain metastases were higher in patients with G12C mutations and associated with poorer PFS and OS. G12C mutation and PS ≥ 2 were also associated with inferior PFS and OS. Experience with targeted therapy for KRAS mutations remains an area of future exploration due to the unavailability of these agents in India.

Clinical Profile and Outcomes of Carcinoma Penis Patients Receiving Systemic Therapy at an Indian tertiary care Center: A Retrospective Observational Study.

BACKGROUND: Penile cancer is a rare malignancy with scant data on the impact of systemic therapy on outcomes. METHODS: Retrospective observational study of patients with a histological diagnosis of carcinoma penis treated with systemic therapy at the Tata Memorial Centre (Mumbai, India) between August 2010 and February 2018. Primary objective was overall survival (OS); secondary objectives included assessment of clinical characteristics, treatment approaches, and toxicity profiles. RESULTS: We included 91 patients with penile carcinoma who received systemic therapy at our center. Intent of therapy was curative in 71 patients (78%), and palliative in 20 (22%). Median age was 57 years (interquartile range [IQR], 50-65.5) for curatively treated patients and 58.5 years (IQR, 44-65.2) for those with advanced disease. Common presenting symptoms were lumps (70%), and pain (57%). Neoadjuvant chemotherapy (NACT) with paclitaxel + platinum was administered to 19 patients (20.9%), of which 7 (37%) attained complete or partial response. Six patients (31.5%) underwent R0 surgery post-NACT. All 71 patients underwent primary surgery; 47 (66.2%) undergoing partial penectomy. Of the 20 patients treated with palliative first-line chemotherapy, 4(20%) attained a partial response. Median OS of patients treated in curative and palliative settings was 33.8 months (95% CI, 17.2-not recorded) and 11.4 months (95% CI, 9.53-23.3), respectively. CONCLUSIONS: Patients with penile cancer treated with systemic therapy have poor outcomes. Little over a third of the patients respond to neoadjuvant chemotherapy and those with advanced disease have poor survival despite systemic therapy, emphasizing the need for early detection and optimum management of primary and nodal disease.

Clinical outcomes of ROS1-positive non-small cell lung cancer with limited access to ROS1-tyrosine kinase inhibitors (TKIs): experience from an Indian tertiary referral centre.

Introduction: ROS1 as a driver mutation is observed in approximately 1%-2% of all non-small cell lung cancer (NSCLC). Given its rarity, we share our experience regarding ROS1-positive NSCLC including the access to ROS1 tyrosine kinase inhibitors (TKIs) in a low-middle income country like India. Methods: It is a retrospective analysis of ROS1-positive NSCLC patients registered between January 2015 to December 2021 for demographics, treatment patterns and outcomes i.e., overall survival (OS) and progression free survival (PFS). Results: Baseline characteristics were available for 70 patients of 78 patients positive for ROS1 by fluorescent in situ hybridisation. Median age at presentation was 52 years, 39 (55.7%) were males, most (51, 72.86%) were non-smokers and ten patients (14.3%) had poor Eastern Cooperative Oncology Group (ECOG) performance status (PS) i.e., PS >2 at presentation. A total of 67 patients receiving cancer directed therapy were analysed for survival. The first line (1L) therapies included - ROS1 TKIs in 38, chemotherapy in 20, epidermal growth factor receptor TKI in eight and chemotherapy-bevacizumab in one only. ROS1 TKI was provided to 20 patients as part of an assistance programme. The median OS for patients who received ROS1 TKI was not attained (95% CI 37.85-NA), while it was 8.11 (95% CI 6.31-NA) months for those who did not (HR-0.1673). The median PFS for the 1L ROS1 TKI compared to the no-TKI group was 27.07 (95% CI 24.28-NA) months versus 5.78 (95% CI 3.42-12) months (HR: 0.2047). Poor ECOG PS at presentation was the only independent prognosticator for survival. Conclusion: Using ROS1 TKI improves clinical outcomes in all-comers though statistically not significant. To further improve outcomes, future trials should pay special attention to patients with poor PS and find a way to increase the current limited access to TKI.

Deep-Learning-Based Predictive Imaging Biomarker Model for EGFR Mutation Status in Non-Small Cell Lung Cancer from CT Imaging.

PURPOSE: The authors aimed to develop and validate deep-learning-based radiogenomic (DLR) models and radiomic signatures to predict the EGFR mutation in patients with NSCLC, and to assess the semantic and clinical features that can contribute to detecting EGFR mutations. METHODS: Using 990 patients from two NSCLC trials, we employed an end-to-end pipeline analyzing CT images without precise segmentation. Two 3D convolutional neural networks segmented lung masses and nodules. RESULTS: The combined radiomics and DLR model achieved an AUC of 0.88 ± 0.03 in predicting EGFR mutation status, outperforming individual models. Semantic features further improved the model's accuracy, with an AUC of 0.88 ± 0.05. CT semantic features that were found to be significantly associated with EGFR mutations were pure solid tumours with no associated ground glass component (p < 0.03), the absence of peripheral emphysema (p < 0.03), the presence of pleural retraction (p = 0.004), the presence of fissure attachment (p = 0.001), the presence of metastatic nodules in both the tumour-containing lobe (p = 0.001) and the non-tumour-containing lobe (p = 0.001), the presence of ipsilateral pleural effusion (p = 0.04), and average enhancement of the tumour mass above 54 HU (p < 0.001). CONCLUSIONS: This AI-based radiomics and DLR model demonstrated high accuracy in predicting EGFR mutation, serving as a non-invasive and user-friendly imaging biomarker for EGFR mutation status prediction.

Assessing frailty in older Indian patients before cancer treatment: Comparative analysis of three scales and their implications for overall survival.

INTRODUCTION: Frailty, characterized by ageing-related vulnerability, influences outcomes in older adults. Our study aimed to investigate the relationship between frailty and clinical outcomes in older Indian patients with cancer. MATERIALS AND METHODS: Our observational single-centre study, conducted at Tata Memorial Hospital from February 2020 to July 2022, enrolled participants aged 60 years and above with cancer. Frailty was assessed using the Clinical Frailty Scale (CFS), G8, and Vulnerable Elders Survey (VES)-13. The primary objective was to explore the correlation between baseline frailty and overall survival. Statistical analyses include Kaplan-Meier, Cox proportional hazards, and Harrell's C test. RESULTS: A total of 1,177 patients (median age 68, 76.9% male) were evaluated in the geriatric oncology clinic. Common malignancies included lung (40.0%), gastrointestinal (35.8%), urological (11.9%), and head and neck (9.0%), with 56.5% having metastatic disease. Using CFS, G8, and VES-13 scales, 28.5%, 86.4%, and 38.0% were identified as frail, respectively. Median follow-up was 11.6 months, with 43.3% deaths. Patients fit on CFS (CFS 1-2) had a median survival of 28.02 months, pre-frail (CFS 3-4) 13.24 months, and frail (CFS ≥5) 7.79 months (p < 0.001). Abnormal G8 (≤14) and VES-13 (≥3) were associated with significantly lower median survival (p < 0.001). Multivariate analysis confirmed CFS's predictive power for mortality (p < 0.001), with hazard ratios [HRs] for pre-frail at 1.61(95% confidence interval [CI] 1.25 to 2.06) and frail at 2.31 (95%CI 1.74 to 3.05). G8 ≤ 14 had HR 2.00 (95%CI 1.42 to 2.83), and abnormal VES-13 had HR 1.36 (95%CI 1.11-1.67). In the likelihood ratio test, CFS significantly improved the model fit (p < 0.001). Harrell's C index for survival prediction was 0.62 for CFS, 0.54 for G8, and 0.58 for VES-13. DISCUSSION: In conclusion, our study highlights varying frailty prevalence and prognostic implications in older Indian patients with cancer, emphasizing the need for personalized care in oncology for this aging population. We would recommend using CFS as a tool to screen for frailty for older Indian patients with cancer.

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.

Performance of potentially inappropriate medications assessment tools in older Indian patients with cancer.

BACKGROUND: Polypharmacy and potentially inappropriate medication (PIM) use are common problems in older adults. Safe prescription practices are a necessity. The tools employed for the identification of PIM sometimes do not concur with each other. METHODS: A retrospective analysis of patients ≥60 years who visited the Geriatric Oncology Clinic of the Tata Memorial Hospital, Mumbai, India from 2018 to 2021 was performed. Beer's-2015, STOPP/START criteria v2, PRISCUS-2010, Fit fOR The Aged (FORTA)-2018, and the EU(7)-PIM list-2015 were the tools used to assess PIM. Every patient was assigned a standardized PIM value (SPV) for each scale, which represented the ratio of the number of PIMs identified by a given scale to the total number of medications taken. The median SPV of all five tools was considered the reference standard for each patient. Bland-Altman plots were utilized to determine agreement between each scale and the reference. Association between baseline variables and PIM use was determined using multiple logistic regression analysis. RESULTS: Of the 467 patients included in this analysis, there were 372 (79.66%) males and 95 (20.34%) females with an average age of 70 ± 5.91 years. The EU(7)-PIM list was found to have the highest level of agreement given by a bias estimate of 0.010, the lowest compared to any other scale. The 95% CI of the bias was in the narrow range of -0.001 to 0.022, demonstrating the precision of the estimate. In comparison, the bias (95%) CI of Beer's criteria, STOPP/START criteria, PRISCUS list, and FORTA list were -0.039 (-0.053 to -0.025), 0.076 (0.060 to 0.092), 0.035 (0.021 to 0.049), and -0.148 (-0.165 to -0.130), respectively. Patients on polypharmacy had significantly higher PIM use compared to those without (OR = 1.47 (1.33-1.63), p = <0.001). CONCLUSIONS: The EU(7)-PIM list was found to have the least bias and hence can be considered the most reliable among all other tools studied.

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.

A Comparative Study Evaluating the Quality of Life and Survival Outcomes in Patients Receiving Chemotherapy Versus Oral Tyrosine Kinase Inhibitor in the Third Line and Beyond Setting for Advanced NSCLC.

Introduction: The outcomes in advanced NSCLC have improved owing to the availability of more effective systemic and improved supportive care. This has increased the number of patients who seek treatment in the third line and beyond setting. We conducted this study to compare the quality of life (QoL), toxicity, and outcomes in patients receiving chemotherapy and EGFR tyrosine kinase inhibitors (TKIs) in this setting. Methods: In this phase 3, randomized, open-label study, patients with stage III or IV NSCLC with disease progression on at least two prior lines of chemotherapy, with a life expectancy of at least 3 months, without prior EGFR TKI exposure, and stable brain metastases (if any) were included. Patients were randomized to receive chemotherapy (gemcitabine or docetaxel or paclitaxel or vinorelbine) or an EGFR TKI (erlotinib or gefitinib). The primary end point was the change in QoL at 8 to 10 weeks; the secondary outcomes were safety and overall survival (OS). Patients underwent clinical evaluation at every visit, and toxicity was assessed as per Common Terminology Criteria for Adverse Events version 4.03. A radiological tumor response assessment was done every 8 to 12 weeks from the start of therapy. The QoL was assessed using the EORTC QLQ C30 and LC13 questionnaires. The change in QoL scores was calculated as the difference between scores at baseline and scores at 8 to 10 weeks (Δ) for each QoL domain. The Mann-Whitney U test was used to compare the mean difference (Δ) for each domain. OS and progression-free survival (PFS) were determined using the Kaplan-Meier method and Cox proportional regression analysis. Results: A total of 246 patients were enrolled in the study, with 123 in each arm. There was a male predominance with 69.1% male patients in the chemotherapy arm and 70.7% in the EGFR TKI arm. The median age of patients in the chemotherapy arm was 54 years and 55 years in the chemotherapy and EGFR TKI arms, respectively. There was no significant difference in the change in QoL at baseline and the second visit (Δ) in both arms in all domains of EORTC QLQ C30 except cognitive function (p = 0.0045) and LC13 except alopecia (0.01249). The mean Δ Global Health Status was -28 in the chemotherapy arm and -26.8 in the EGFR TKI arm; this was not statistically significant (p = 0.973). The median follow-up was 88.1 months (95% confidence interval [CI]: 39.04-137.15). On the intention-to-treat analysis, the median PFS was 3.13 months (95% CI: 2.15-4.11) in the chemotherapy arm and 2.26 months (95% CI: 2.1-2.43) in the EGFR TKI arm, with hazard ratio at 1.074 (95% CI: 0.83-1.38) (p = 0.58). There were 120 deaths in each arm. The median OS was 7.63 months (95% CI: 5.96-9.30) in the chemotherapy arm and 7.5 months in the EGFR TKI arm (95% CI: 5.85-9.14); hazard ratio at 1.033 (95% CI: 0.80-1.33) (p = 0.805). The toxicity profile was similar in both arms except for a significantly higher incidence of fatigue (p = 0.043), peripheral neuropathy (0.000), alopecia, hypokalemia (0.037), and pedal edema (0.007) in the chemotherapy arm and dry skin (p = 0.000) and skin rash (p = 0.019) in the EGFR TKI arm. Conclusions: There was no significant difference in most QoL scales (except cognitive function and alopecia), OS, and PFS of patients with advanced NSCLC receiving an EGFR TKI as compared with chemotherapy TKI in the third-line setting. The toxicity profile is consistent with the known toxicities of the agents.

Long-term outcomes of neo-adjuvant chemotherapy on borderline resectable oral cavity cancers: Real-world data of 3266 patients and implications for clinical practice.

BACKGROUND: Neo-adjuvant chemotherapy (NACT) followed by response assessment is the standard treatment algorithm for locally advanced oral cavity squamous cell carcinomas (OCSCC) in the Indian subcontinent. The 3-drug NACT regimen (Docetaxel-Cisplatin-5-FU) has shown improvement in overall survival over 2-drug regimen (Docetaxel-Cisplatin) in a phase-3 randomised study. We have analysed the 10-year outcomes with this treatment algorithm. METHODS: This was an institutional review board approved retrospective analysis of a prospectively collected dataset of borderline resectable OCSCC patients who underwent NACT. Patients who became resectable after NACT underwent surgery followed by appropriate adjuvant therapy. Patients who were unresectable received definitive chemoradiation (CTRT), palliative chemotherapy, radiotherapy or best supportive care based on general condition. RESULTS: A total of 3266 patients were included. The most common subsite was buccal mucosa and the most frequent indication was peri-tumoral edema upto zygoma. More than 2-drugs NACT was offered to 32.9% patients. Overall, 32.5% patients had a response to NACT. A total of 1358 patients were offered curative treatment, of which 929 (32%) underwent surgery and the rest underwent definitive chemo-radiation (14.8%). Patients who received more than 2-drugs NACT versus those who received 2-drugs had a 10-years OS of 21% vs 5.1% (p < 0.001). Patients who underwent surgery versus those who did not had a 10-year OS of 21.8% vs 4.1% (p < 0.001). Patients who achieved pCR had a 5-year OS of 45.3% vs 13.3% for those who did not (p < 0.001). CONCLUSION: NACT leads to long term survival benefit in patients of borderline resectable oral cavity cancer.

Whole exome sequencing uncovers HRAS mutations as potential mediators of resistance to metronomic chemotherapy.

OBJECTIVES: The aim of this pilot study is to identify the genetic factors that contribute to the response of metronomic chemotherapy in head and neck squamous cell carcinoma (HNSCC) patients using whole-exome sequencing (WES). This study would facilitate the identification of predictive biomarkers, which would enable personalized treatment strategies and improve treatment outcomes for patients with HNSCC. MATERIALS AND METHODS: We have selected patients with recurrent head and neck cancer who underwent metronomic chemotherapy. Sequential tumor biopsies were collected from the patients at different stages of treatment to capture the genomic alterations and tumor evolution during metronomic chemotherapy and sequenced using WES. RESULTS: We identified several known HNSCC hallmark genes reported in COSMIC, including KMT2B, NOTCH1, FAT1, TP53, HRAS, CASP8, and CDKN2A. Copy number alteration analysis revealed amplifications and deletions in several oncogenic and tumor suppressor genes. COSMIC Mutational Signature 15 associated with defective DNA mismatch repair was enriched in 73% of HNSCC samples. Further, the comparison of genomic alterations between responders and non-responders identified HRAS gene uniquely mutated in non-responders that could potentially contribute to resistance against metronomic chemotherapy. DISCUSSION: Our findings corroborate the molecular heterogeneity of recurrent HNSCC tumors and establish an association between HRAS mutations and resistance to metronomic chemotherapy, suggesting HRAS as a potential therapeutic target. Combining HRAS inhibitors with metronomic regimens could improve treatment sensitivity in HRAS-mutated HNSCC patients. Further studies are needed to fully elucidate the genomic mechanisms underlying the response to metronomic chemotherapy.

Role of imaging in the management of thyroglossal duct cyst carcinomas (TGC-TIRADS): a single centre retrospective study over 16 years.

Introduction: Thyroglossal duct cyst (TGDC) is the most frequently encountered developmental anomaly in thyroid genesis with a reported incidence of 7% in the adult population. The cyst is known to develop anywhere along the pathway of thyroid descent but is more frequently seen in the infrahyoid neck in the midline. The incidence of malignancy in a TGDC is approximately 1%; a majority of these are papillary carcinomas. This study was conducted at a single tertiary care centre which spanned over a decade which adds practice changing evidence-based knowledge to existing literature on this rare entity. A comprehensive study which conclusively establishes the imaging features predictive of malignancy in TGDC carcinomas (TGDCa), the protocol for optimal management, clinical outcome and long-term survival of these patients is not available. Although TGDC carcinoma is thought to have an excellent prognosis, there is not enough data available on the long-term survival of these patients. The aim of this study was to identify whether neck ultrasound (US) can serve as an accurate imaging tool for the preoperative diagnosis of TGDC carcinomas. Methods: We accessed the electronic medical records of 86 patients with TGDC between January 2005 to December 2021. Of these, 22 patients were detected with TGDC papillary carcinoma on histopathologic examination. Relevant imaging, treatment and follow up information for all cases of TGDC carcinoma were retrospectively reviewed. We compared US characteristics predictive of malignancy across outcomes groups; malignant vs benign using the Chi-square test. Based on the results, a TGC-TIRADS classification was proposed with calculation of the percentage likelihood of malignancy for each category. Results: Compared to benign TGDCs, malignant TGDCs were more likely to present with following US characteristics: irregular or lobulated margins (90.40 vs. 38.10%), solid-cystic composition (61.90 vs. 17.07%), internal vascularity (47.62 vs. 4.88 %), internal calcification (76.19 vs. 7.32 %) (each p value < 0.005). Calcifications and internal vascularity were the most specific while irregular/lobulated margins were the most sensitive feature for malignancy. AUC under the ROC curve was 0.88. Allpatients were operated and were disease free at the end of 5 years or till the recent follow up. Discussion: US is the imaging modality of choice for pre-operative diagnosis of TGDC carcinoma. Thepre-operative diagnosis and risk stratification of thyroglossal lesions will be aided by the application of the proposed TGC-TIRADS classification, for which the percentage likelihood of malignancy correlated well with the results in our study. Sistrunk procedure is adequate for isolated TGDC carcinoma; suspicious neck nodes on imaging also necessitates selective nodal dissection. Papillary carcinomas have an excellent prognosis with low incidence of disease recurrence.

Understanding the Impact of Population and Cancer Type on Tumor Mutation Burden Scores: A Comprehensive Whole-Exome Study in Cancer Patients From India.

PURPOSE: The purpose of this study was to understand the impact of population diversity and geographic variation on tumor mutation burden (TMB) scores across cancers and its implication on stratification of patients for immune checkpoint inhibitor (ICI) therapy. MATERIALS AND METHODS: This retrospective study used whole-exome sequencing (WES) to profile 1,233 Indian patients with cancer across 30 different cancer types and to estimate their TMB scores. A WES-based pipeline was adopted, along with an indigenously developed strategy for arriving at true somatic mutations. A robust unsupervised machine learning approach was used to understand the distribution of TMB scores across different populations and within the population. RESULTS: The results of the study showed a biphasic distribution of TMB scores in most cancers, with different threshold scores across cancer types. Patients with cancer in India had higher TMB scores compared with the Caucasian patients. We also observed that the TMB score value at 90th percentile (predicting high efficacy to ICI) was high in four different cancer types (sarcoma, ovary, head and neck, and breast) in the Indian cohort as compared with The Cancer Genome Atlas or public cohort. However, in lung and colorectal cancers, the TMB score distribution was similar between the two population cohorts. CONCLUSION: The findings of this study indicate that it is crucial to benchmark both cancer-specific and population-specific TMB distributions to establish a TMB threshold for each cancer in various populations. Additional prospective studies on much larger population across different cancers are warranted to validate this observation to become the standard of care.

Repurposing pantoprazole in combination with systemic therapy in advanced head and neck squamous cell carcinoma: a phase I/II randomized study.

Pantoprazole decreases the acidity of the tumor microenvironment by inhibiting proton pumps on the cancer cell. This possibly leads to increased sensitivity to cytotoxic therapy. We conducted a phase I/II randomized controlled trial in adult patients with head and neck squamous cell carcinoma (HNSCC) planned for first-line palliative chemotherapy. Patients were randomized to chemotherapy + / - intravenous (IV) pantoprazole. The primary endpoint in phase I was to determine the maximum safe dose of intravenous pantoprazole, whereas it was progression-free survival (PFS) in phase II. The dose of IV pantoprazole established in phase I was 240 mg. Between Nov'18 and Oct'20, we recruited 120 patients in phase II, 59 on pantoprazole and 61 on the standard arm. Median age was 51 years (IQR 43-60), 80% were men. Systemic therapy was IV cisplatin in 22% and oral-metronomic-chemotherapy (OMC) in 78%. Addition of pantoprazole did not prolong PFS, which was 2.2 months (95% CI 2.07-3.19) in the pantoprazole arm and 2.5 months (95% CI 2.04-3.81, HR, 1.14; 95% CI 0.78-1.66; P = 0.48) in the standard arm. Response rates were similar; pantoprazole arm 8.5%, standard arm 6.6%; P = 0.175. Overall survival was also similar; 5.6 months (95% CI 4.47-8.51) in the pantoprazole arm and 5.4 months (95% CI 3.48-8.54, HR 1.06; 95% CI 0.72-1.57; P = 0.75) in the standard arm. Grade ≥ 3 toxicities were similar. Thus, pantoprazole 240 mg IV added to systemic therapy does not improve outcomes in patients with advanced HNSCC.