Olanzapine as Antiemetic Prophylaxis in Moderately Emetogenic Chemotherapy: A Phase 3 Randomized Clinical Trial.

Importance: The role of olanzapine has not been adequately evaluated in moderately emetogenic chemotherapy (MEC) regimens with or without neurokinin-1 receptor antagonists. Objective: To evaluate whether addition of olanzapine to an MEC regimen reduces nausea, vomiting, and use of nausea rescue medications among patients with solid malignant tumors. Design, Setting, and Participants: This multicenter, open-label phase 3 randomized clinical trial included patients aged 18 years or older with solid malignant tumors who were receiving oxaliplatin-, carboplatin-, or irinotecan-based chemotherapy. The trial was conducted at 3 institutes in India from March 26, 2019, to August 26, 2023; the final cutoff date for analysis was September 10, 2023. Exposure: Patients were randomized 1:1 to dexamethasone, aprepitant, and palonosetron with olanzapine (experimental group) or without olanzapine (observation group). The experimental group received 10 mg of olanzapine orally once at night on days 1 through 3 of the chemotherapy regimen. Main Outcomes and Measures: The primary end point was complete response (CR), defined as the proportion of patients with no vomiting, no significant nausea (scored as <5 on a visual analog scale of 1 to 100), and no use of rescue medications for nausea. Secondary end points included the proportion of patients experiencing nausea and chemotherapy-induced nausea and vomiting (CINV), receiving rescue medications, and experiencing adverse events. Results: A total of 560 patients (259 [64%] male; median age, 51 years [range, 19-80 years]) were randomized. The analysis included 544 patients with evaluable data (274 assigned to olanzapine and 270 to observation). Baseline characteristics were evenly matched between the 2 groups. The proportion of patients with CR was significantly greater in the group with (248 [91%]) than without (222 [82%]) olanzapine in the overall 120-hour treatment period (P = .005). Likewise, there were significant differences between the olanzapine and observation groups for nausea control (264 [96%] vs 234 [87%]; P < .001) and CINV (262 [96%] vs 245 [91%]; P = .02) during the overall assessment period, and the proportion of patients receiving rescue medications significantly increased in the observation group (30 [11%]) compared with the olanzapine group (11 [4%]) (P = .001). Grade 1 somnolence was reported by 27 patients (10%) following administration of chemotherapy and olanzapine and by no patients in the observation group. Conclusions and Relevance: In this randomized clinical trial, the addition of olanzapine significantly improved CR rates as well as nausea and vomiting prevention rates in chemotherapy-naive patients who were receiving MEC regimens containing oxaliplatin, carboplatin, or irinotecan. These findings suggest that use of olanzapine should be considered as one of the standards of care in these chemotherapy regimens. Trial Registration: Clinical Trials Registry-India (CTRI) Identifier: CTRI/2018/12/016643.

Phase III randomized trial comparing palliative systemic therapy to best supportive care in advanced esophageal/GEJ cancer.

No study has unequivocally proven that chemotherapy prolongs overall survival (OS) in advanced esophageal cancer. We conducted a Phase III randomized study in first-line advanced unresectable/metastatic esophageal/GEJ cancer. Patients aged 18-70 years, with performance status 0-2, were randomized to best supportive care (BSC) alone, or BSC with weekly paclitaxel 80 mg/m2. BSC comprised, as indicated, education, counselling, radiation, stenting, feeding tube placement, nutritional supplementation, medications like analgesics, and referral to a support group and palliative care. The primary endpoint was OS; secondary endpoints included progression free survival (PFS), response, toxicity, and QoL. Between May 2016-December 2020, we recruited 281 patients: 143 to chemotherapy and 138 to BSC. Histopathology was squamous in 269 (95.7%) patients. Median number of paclitaxel doses was 12 (IQR, 7-23). Median OS was 4.2 months (95% CI, 3.42-5.32) in BSC, and 9.2 months (95% CI, 8.02-10.48) in chemotherapy; HR, 0.49 (95% CI, 0.39-0.64); p < .001. As compared to BSC, chemotherapy increased response (2.9% to 39%), median PFS (2.1 to 4.2 months), 1-year OS (11% to 32%), 2-year OS (0 to 9%), median dysphagia-free survival (2.9 to 14.8 months), and global and esophagus-specific QoL, without significantly increasing all-grade or grade ≥3 toxicities. Using ESMO clinical benefit scale and ASCO Value Framework, palliative chemotherapy scored as having "substantial value." Our study provides the first level 1 evidence that chemotherapy prolongs survival in advanced esophageal/GEJ carcinoma. BSC alone is no longer appropriate. Weekly paclitaxel is an attractive option, especially in LMICs with limited access to immunotherapy.

Long term update of a phase 3 randomized study comparing once-a-week versus once-every-3-weeks cisplatin along with radiation in head and neck cancer.

PURPOSE: In the weekly-3-weekly (W3W) study, cisplatin at 100 mg/m2 once-every-3-weeks led to superior locoregional control compared to cisplatin 30 mg/m2 once-a-week in combination with radical radiation for locally advanced head and neck squamous cell carcinoma (LAHNSCC). We report the updated analysis of the study. METHODS: In this phase III open label non-inferiority study conducted between 2013 and 2017, 300 patients with LAHNSCC were randomly assigned to receive cisplatin 100 mg/m2 once-in-3-weeks or cisplatin 30 mg/m2 once-a-week, concurrently with radiation. The primary endpoint was locoregional control (LRC). Secondary outcomes were overall survival (OS), progression free survival (PFS) and late adverse events. RESULTS: The median follow-up was 6.91 years (95% CI, 6.12-7.36). The updated 2-year and 5-year LRC rates for the once-a-week cisplatin arm were 58.75% (95% CI, 51.08- 67.58) and 48.09% (95% CI, 40.26-57.43), while for the once-every-3-weeks cisplatin arm were 73.95% (95% CI, 66.93-81.70) and 56.76% (95% CI, 48.46-66.48), respectively; HR=1.44 (95% CI, 1.03-2.03), P=0.034. The 5-year OS was 43.60% (95% CI, 36.29-52.37) in the once-a-week cisplatin arm, and 50.55% (95% CI, 43.06-59.35) in the once-every-3-weeks cisplatin arm; P = 0.19. There was no difference in any grade or grade ≥ 3 late adverse events between the two arms, except for hearing dysfunction, which was significantly more common in patients who received high-dose cisplatin. CONCLUSIONS: Long term follow-up confirms that cisplatin at 100 mg/m2 administered once-every-3-weeks concurrently with radical radiation for LAHNSCC leads to superior locoregional control as compared to cisplatin 30 mg/m2 once-a-week and should remain one of the standard treatment options.

Docetaxel-oxaliplatin-capecitabine/5-fluorouracil (DOX/F) followed by docetaxel versus oxaliplatin-capecitabine/5-fluorouracil (CAPOX/FOLFOX) in HER2-negative advanced gastric cancers.

BACKGROUND: We evaluated whether the addition of docetaxel (D) to a combination comprising 5-fluorouracil/leucovorin (5-FU/LV) or capecitabine (C) plus oxaliplatin (O) (DOF/DOX) improved overall survival (OS) compared with 6 months of 5-fluorouracil (5-FU) or capecitabine in combination with oxaliplatin (FOLFOX/CAPOX) alone in advanced HER2-negative gastroesophageal junction and gastric adenocarcinomas (G/GEJ). METHODS: This study was an investigator-initiated, open-label, multi-institutional, randomized phase III trial in adult patients with HER2-negative advanced G/GEJs. The primary endpoint of the study was a comparison of median OS by Kaplan-Meier method. Next-generation sequencing was performed on tissue. RESULTS: Of the 324 patients randomly assigned between July 2020 and November 2022, 305 patients were evaluable for analysis (FOLFOX/CAPOX: 156; DOF/DOX: 149). With a median follow-up time of 19.2 months (95% Confidence Interval [CI] = 16.5 months to 21.9 months) for the entire cohort, the median OS was 10.1 months (95% CI = 9.2 to 10.9) for FOLFOX/CAPOX and 8.9 months (95% CI = 7.3 to 10.5) for DOF/DOX, and this difference was not statistically significant (P = .70). An increased proportion of grade 3 or grade 4 neutropenia (21% vs 3%; P < .001) and grade 2/3 neuropathy (17% vs 7%; P = .005) was seen in patients receiving DOF/DOX. Genomic profiling revealed a low incidence of microsatellite instability (1%) and a high incidence of BRCA1 (8.4%) and BRCA2 (7.5%) somatic alterations. CONCLUSION: FOLFOX or CAPOX chemotherapy for 6 months remains one of the standards of care in advanced HER2-negative gastroesophageal junction and gastric adenocarcinomas, with no additional survival benefit seen with the addition of docetaxel. Genomic profiling of patients revealed a higher than previously known incidence of somatic BRCA alterations, which requires further evaluation.CTRI (Clinical Trial Registry of India: CTRI/2020/03/023944).

Pharmacokinetics and clinical outcomes of low-dose nivolumab relative to conventional dose in patients with advanced cancer.

PURPOSE: Nivolumab is approved at various doses, including 3 mg/kg, 240 mg and 480 mg flat doses at various dosing intervals. The concept of low-dose immunotherapy is gaining traction in recent years. However, there is a need to better understand the pharmacokinetics and clinical outcomes at lower doses. METHODS: Patients were either administered 40 mg flat dose or 3 mg/kg Q2W/Q3W, depending on affordability as per prevailing hospital practice. All patients were hospitalized on day 1 and pharmacokinetic samples were collected at 0, 0.5, 1.0, 6.0, 24.0, 72.0 h and day 14 following administration of the first dose of nivolumab. Plasma nivolumab levels were measured by ELISA. Patients were followed up for response and toxicity. RESULTS: Twenty five patients were included in the study. Fourteen received nivolumab at conventional dose (3 mg/kg), while 11 patients received low-dose (40 mg flat). The geometric means of dose normalized Cmax and AUC0-t were comparable between those who received conventional dose and low-dose of nivolumab (0.28 versus 0.23 µg/mL/mg and 0.0014 versus 0.0011 d/mL respectively). Nineteen patients were evaluable for response. ORR among patients who received conventional dose was 5/11 (45.5%) whereas it was 4/9 (44.4%) in the low-dose cohort. All 14 (100%) patients in conventional dosing group and 7/11 patients (63.64%) in low-dose group had treatment emergent adverse events. Grade ≥ 3 toxicities were observed in 4/14 patients in conventional dose group and none in low-dose group. CONCLUSION: Low-dose nivolumab leads to lower exposure in patients as compared with conventional dose, but low-dose was better tolerated, while response rates were comparable to conventional dose.

Reduced frequency dosing of osimertinib in EGFR-mutant non-small cell lung carcinoma: real world data.

Introduction: Osimertinib is more efficacious and as safe as first-generation epidermal growth factor receptor (EGFR)-directed tyrosine kinase inhibitors. However, osimertinib is not affordable for most patients in developing nations. Moreover, the minimum biologically effective dose of osimertinib may be less than the approved dose. Materials and methods: This was a retrospective observational multicentric study aimed to describe the efficacy (objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS)) and toxicity of osimertinib 80 mg orally administered less frequently than daily (ranging from every other day to once-a-week) in patients with EGFR-mutated non-small cell lung cancer. Results: Between January 2021 and August 2023, we enrolled 22 patients. Six received osimertinib 80 mg once-a-week, nine received 80 mg once-in-3-days and seven received 80 mg on alternate days. Responses included 0 complete responses, 7 (31.8%) partial responses, 9 (40.9%) stable disease and 5 (22.7%) progressive disease. ORR was 31.8%, and DCR was 72.7%. Median PFS was 9.2 months (95% confidence interval (CI) 2.9-15.7), and median OS was 17.8 months (95% CI, 3.2-32.6). In patients who received reduced frequency osimertinib in the second line and beyond, the ORR was 29.4%, DCR was 70.5%, median PFS was 5.9 months (95% CI, 1.1-10.6) and median OS was 17.6 months (95% CI, 2.9-32.2). Grade 3 and higher toxicities were noted in 8 (36.3%) patients. Conclusion: Less frequent dosing of osimertinib may be a valid treatment option, especially in the second line and beyond setting in patients who cannot afford full dose daily osimertinib. This may provide an additional treatment option with a similar toxicity profile as that of standard dose osimertinib.

The Impact of Baseline Vitamin D Level in Patients Receiving Gefitinib-Directed Therapy for EGFR-Mutant Non-Small-Cell Lung Cancer.

Background: There is contradicting evidence on vitamin D levels and cancer mortality rates. In this study, we aimed to evaluate the impact of baseline vitamin D level on the outcome in patients with estimated glomerular filtration rate (EGFR)-mutant advanced non-small-cell lung cancer (NSCLC) who received either gefitinib or gefitinib with chemotherapy (pemetrexed and carboplatin) as first-line therapy in a prospective randomized study. Methods: This was a post hoc analysis of a phase III randomized trial comparing gefitinib with gefitinib with carboplatin and pemetrexed in patients with advanced NSCLC with activating EGFR mutations in the first-line setting. As a part of regular practice, baseline vitamin D levels were measured using circulating 25(OH) levels in blood. We included 334 patients who had baseline vitamin D levels in the study and evaluated the effect of the vitamin D level on oncologic outcomes. Results: There were 136 (40.7%) patients with a sufficient (>20 ng/mL) baseline vitamin D level, and 198 (59.3%) patients who were deficient in vitamin D (<20 ng/mL). The median progression-free survival (PFS) in patients with normal vitamin D levels was 17 months, whereas that in patients with deficient vitamin D levels was 15 months, with a hazard ratio of 1.45 (95% confidence interval [CI] = 1.03-2.06). The median overall survival (OS) in patients with normal vitamin D levels was 28.6 months, whereas that in patients with deficient vitamin D levels was 28.5 months, with a hazard ratio of 1.17 (95% CI = 0.81-1.68). On multivariate analysis, only 2 factors impacted the PFS, the baseline vitamin D level, and the treatment regimen; other factors like age, sex, disease stage, and performance status did not. Conclusions: Baseline vitamin D levels have a significant impact on PFS, whereas OS is not affected by the baseline vitamin D levels on patients receiving targeted therapy for EGFR-mutant lung cancer. Trial registration: The trial was prospectively registered with the Clinical Trial Registry of India, registration number CTRI/2016/08/007149. The date of the registration was 5 August 2016.

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.

RET Alterations Differentiate Molecular Profile of Medullary Thyroid Cancer.

PURPOSE: Medullary thyroid cancer (MTC) is a rare cancer originating from parafollicular C cells of the thyroid gland. Therapeutically relevant alterations in MTC are predominantly reported in RET oncogene, and lower-frequency alterations are reported in KRAS and BRAF. Nevertheless, there is an unmet need existing to analyze the MTC in the Indian cohort by using in-depth sequencing techniques that go beyond the identification of known therapeutic biomarkers. MATERIALS AND METHODS: Here, we characterize MTC using integrative whole-exome and whole-transcriptome sequencing of 32 MTC tissue samples. We performed clinically relevant variant analysis, molecular pathway analysis, tumor immune-microenvironment analysis, and structural characterization of RET novel mutation. RESULTS: Mutational landscape analysis shows expected RET mutations in 50% of the cases. Furthermore, we observed mutations in known cancer genes like KRAS, HRAS, SF3B1, and BRAF to be altered only in the RET-negative cohort. Pathway analysis showed differential enrichment of mutations in transcriptional deregulation genes in the RET-negative cohort. Furthermore, we observed novel RET kinase domain mutation Y900S showing affinity to RET inhibitors accessed via molecular docking and molecular dynamics simulation. CONCLUSION: Altogether, this study provides a detailed genomic characterization of patients with MTC of Indian origin, highlighting the possible utility of targeted therapies in this disease.

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.

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 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.

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.

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.

Effective management Alopecia totalis by Ayurveda - A case report.

Alopecia areata (AA) is a T-cell-mediated autoimmune illness characterized by intermittent, non-scarring hair loss, Alopecia totalis(AT) is a type of AA characterized by total hair loss on the face and scalp. Unfortunately, it is projected that 10-15 % of people with AA will advance to total hair loss on the scalp (AT) or hair loss on the scalp and body Alopecia Universalis (AU) only 10 % of patients with AT/AU recover completely. Treatment for severe AA is often unsatisfactory. The most popular AT/AU therapy techniques were topical steroid application and oral steroid administration. We present a case of Alopecia totalis that was treated with cupping therapy and ayurvedic treatments such as Punarnava Mandoor, manjistadi Kashaya, asanadi gana Kashaya, purnachandrodaya rasa, a churna combo, and Malatyadi and Dhurdhurapatradi taila for external application over scalp. The treatment's effectiveness is due to the synergistic action of all the herbs and the immunostimulant activity of cupping.

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.