Clinical, radiological and molecular responses to combination chemotherapy with MAPK pathway inhibition in relapsed and refractory Langerhans cell histiocytosis.

Optimal therapeutic approaches for advanced Langerhans cell histiocytosis (LCH) are not known. We assessed the safety and efficacy of combined chemotherapy with MAPK pathway inhibition in 10 patients with refractory systemic disease and/or LCH-associated neurodegeneration. Overall response rate was 9/10 (90%) for the entire cohort: 5/5 (100%) for patients with systemic disease and 6/7 (86%) for patients with central nervous system disease. BRAFV600E+ peripheral blood fraction decreased in 5/6 (83%). Toxicities included fever, skin rash, myalgias, neuropathy, cytopenias and hypocalcaemia. Prospective trials are required to optimize combination strategies, determine potential to achieve cure and compare outcomes to chemotherapy or MAPK inhibitor monotherapy.

Clofarabine monotherapy in aggressive, relapsed and refractory Langerhans cell histiocytosis.

Over 50% of patients with systemic LCH are not cured with front-line therapies, and data to guide salvage options are limited. We describe 58 patients with LCH who were treated with clofarabine. Clofarabine monotherapy was active against LCH in this cohort, including heavily pretreated patients with a systemic objective response rate of 92.6%, higher in children (93.8%) than adults (83.3%). BRAFV600E+ variant allele frequency in peripheral blood is correlated with clinical responses. Prospective multicentre trials are warranted to determine optimal dosing, long-term efficacy, late toxicities, relative cost and patient-reported outcomes of clofarabine compared to alternative LCH salvage therapy strategies.

Treatment pattern and outcomes of leptomeningeal carcinomatosis in India - a retrospective study.

Background: Leptomeningeal carcinomatosis (LMC), the metastatic spread of cancer to the leptomeninges, is a rare complication and has a dismal prognosis. Due to limited data available on LMC from India, we conducted a country-wise audit of LMC across 15 centres in India. Methods: The current study conducted in 2020, was a retrospective, multicentric audit of adult patients (aged ≥18 years) with diagnosis of LMC and who received treatment during 2010-2020. Baseline characteristics, details related to previous treatments, cancer sites, LMC diagnosis, treatment pattern and overall survival (OS) were collected. Descriptive statistics were performed, and Kaplan Meier analysis was performed for the estimation of OS. Findings: Among the patients diagnosed with LMC (n = 84), diagnosis was confirmed in 52 patients (61.9%) and 'probable' in 32 (38.1%) patients. The three most common cause of malignancy were non-small cell lung cancer (NSCLC), breast cancer and gastrointestinal cancer with 45 (53.6%), 22 (26.1%) and 9 (10.7%) patients respectively. Intrathecal therapy was offered in 33 patients (39.3%). The most common intrathecal agent was methotrexate in 23 patients (27.4%). The median OS was 90 days (95% CI 48-128). Among tested variables, intrathecal therapy administration (hazard ratio [HR] = 0.36, 95% CI 0.19-0.68) and primary in lung (HR = 0.43, 95% CI 0.23-0.83) had a favourable impact on OS. Interpretation: Prognosis with leptomeningeal carcinomatosis is poor with a significant burden of morbidity and mortality in India. This data aims to highlight the current outcomes and facilitate further research on LMC. Funding: None.

Real-world analysis of the use of lenvatinib in differentiated thyroid cancers.

Introduction: Lenvatinib is one of the approved treatments for radioiodine-refractory differentiated thyroid cancers. However, there is very limited data from India on real-world efficacy and adverse events of Lenvatinib and hence this analysis was performed. Methods: This was a retrospective analysis in which patients of radioiodine-refractory differentiated thyroid cancer as per the SELECT study criteria, who received lenvatinib, were selected for the study over the last 4 years. The baseline demographic characteristics, adverse events of lenvatinib, the date of progression and the date of overall survival (OS) were extracted from the electronic medical records of Tata Memorial Hospital. SPSS version 20 was used for analysis. Results: The median starting dose of lenvatinib was 20 mg. Fifteen events for progression had occurred and the median progression-free survival (PFS) was 12.2 months [95% CI: 4.4-not available (NA)]. The events for OS analysis were 12. The median OS was 35.3 months (95% CI: 11.4-NA). There was no impact on starting dose on PFS or OS. Conclusion: The real-world data of Lenvatinib suggest a lot of variability in the starting dose. In spite of this variability, the response rates and OS are similar to that noted in pivotal study. This suggests a case for need for more studies evaluating lower doses of Lenvatinib.

Metronomic adjuvant chemotherapy evaluation in locally advanced head and neck cancers post radical chemoradiation - a randomised trial.

Background: Locally advanced head and neck cancers treated with radical chemoradiation have unsatisfactory outcomes. Oral metronomic chemotherapy improves outcomes in comparison to maximum tolerated dose chemotherapy in the palliative setting. Limited evidence suggests that it may do so in an adjuvant setting. Hence this randomized study was conducted. Methods: Patients of head and neck (HN) cancer with primary in oropharynx, larynx or hypopharynx, with PS 0-2 post radical chemoradiation with documented complete response were randomized 1:1 to either observation or oral metronomic adjuvant chemotherapy (MAC) for 18 months. MAC consisted of weekly oral methotrexate (15 mg/m2) and celecoxib (200 mg PO BD). The primary endpoint was OS and the overall sample size was 1038. The study had 3 planned interim analyses for efficacy and futility. Trial registration- Clinical Trials Registry- India (CTRI): CTRI/2016/09/007315 [Registered on: 28/09/2016] Trial Registered Prospectively. Findings: 137 patients were recruited and an interim analysis was done. The 3 year PFS was 68.7% (95% CI 55.1-79.0) versus 60.8% (95% CI 47.9-71.4) in the observation and metronomic arm respectively (P value = 0.230). The hazard ratio was 1.42 (95% CI 0.80-2.51; P value = 0.231). The 3 year OS was 79.4% (95% CI 66.3-87.9) versus 62.4% (95% CI 49.5-72.8) in the observation and metronomic arm respectively (P value = 0.047). The hazard ratio was 1.83 (95% CI 1.0-3.36; P value = 0.051). Interpretation: In this phase 3 randomized study, oral metronomic combinations of weekly methotrexate and daily celecoxib failed to improve the PFS or OS. Hence observation post-complete response post radical chemoradiation remains the standard of care. Funding: ICON funded this study.

Long term outcomes of phase I/II study of palliative triple metronomic chemotherapy in platinum-refractory/early failure oral cancer.

Background: Triple metronomic chemotherapy is one of the options of treatment in platinum-refractory/early failure oral cancer. However, long term outcomes with this regimen are unknown. Methods: Adult patients with platinum-refractory/early-failure oral cancer were enrolled in the study. Patients were administered triple metronomic chemotherapy ie erlotinib 150 mg once daily celecoxib 200 mg twice daily and methotrexate weekly (phase 1 in variable dose 15-6 mg/m2 & 9 mg/m2 in phase 2), all taken orally till progression of disease or development of intolerable adverse events. The primary objective was to estimate the long-term overall survival and factors impacting it. The Kaplan Meier method was used for time-to-event analysis. Cox proportional hazard model was used to identify factors impacting overall survival (OS) and progression-free survival (PFS). The factors included in the model were age, sex, Eastern Cooperative Oncology Group - performance status (ECOG PS), tobacco exposure and a subsite of primary and circulating endothelial cell levels at baseline. A p-value of 0.05 was considered significant. Clinical trials information: CTRI/2016/04/006834. Results: A total of 91 patients were recruited (15 in phase 1 & 76 in phase 2), the median follow-up was 41 months and 84 events of death had occurred. The median OS was 6.7 months (95% CI 5.4-7.4). The 1-year, 2-years and 3-year OS' were 14.1% (95% CI 7.8-22.2), 5.9% (95% CI 2.2-12.2) and 5.9% (95% CI 2.2-12.2) respectively. The only factor favorably impacting OS was the detection of circulating endothelial cells at baseline (HR = 0.46; 95% CI 0.28-0.75, P = 0.0020). The median PFS was 4.3 months (95% CI 4.1-5.1) and the 1-year PFS was 13.0% (95% CI 6.8-21.2). The factors with statistically significant impact on PFS were detection of circulating endothelial cells at baseline (HR = 0.48; 95% CI 0.30-0.78, P = 0.0020) and no tobacco exposure at baseline (HR = 0.51; 95% CI 0.27-0.94, P = 0.030). Interpretation: The long-term outcomes with triple oral metronomic chemotherapy ie erlotinib, methotrexate and celecoxib are unsatisfactory. Detection of circulating endothelial cells at baseline is a biomarker predicting efficacy of this therapy. Funding: The study was funded by an intramural grant from Tata Memorial Center Research Administration Council (TRAC) and Terry Fox foundation.

Retrospective analysis: checkpoint inhibitor accessibility for thoracic and head and neck cancers and factors influencing it in a tertiary centre in India.

Background: Access to cancer care is an issue in low and low middle-income countries. The problem is worse with respect to access to new therapies like checkpoint inhibitors. Hence, we decided to audit our practice in the head and neck and thoracic medical oncology unit from 2015 to 2019 to study the accessibility of checkpoint inhibitors and factors influencing it. Methods: All patients who were registered in the head and neck and thoracic medical oncology unit between 2015 and 2019 were included in the study. Patients who received immunotherapy were identified from the prospective database of immunotherapy maintained by the department. We made a list of patients who were eligible for immunotherapy per year and identified how many of them received recommended immunotherapy. The indication for eligibility of immunotherapy was based on published pivotal data and it was applicable from the date of publication of the study online. Descriptive statistics were performed. For nominal and ordinal variable percentage with 95% confidence intervals (95% CI) was provided. Factors impacting the accessibility of immunotherapy were identified. Findings: A total of 15,674 patients were identified who required immunotherapy; out of them only 444 (2.83%, 95% CI: 2.58-3.1) received it. Among head and neck cancer patients, 4.5% (156 out of 3,435) received immunotherapy versus 2.35% (288 out of 12,239) among thoracic cancer patients (p < 0.001). Among the general category (low socioeconomic), 0.29% (28 out of 9,405 ) versus 6.6% (416 out of 6,269) among the private category (high socioeconomic) received immunotherapy (p < 0.001). While 3.7% (361 out of 9,737) among males versus 1.39% (83 out of 5,937) females received immunotherapy (p < 0.001). There was also a temporal trend seen in the accessibility of immunotherapy (p < 0.001). Conclusion: The accessibility of immunotherapy is below 3% in India. Patients with head and neck cancers, those registered as private category and male patients had higher access to this therapy. There was also a temporal trend observed suggesting increased accessibility over the years.

Audit of screen failure in 15 randomised studies from a low and middle-income country.

Background: Growth and development in patient management occurs via randomised studies. Screen failure is a significant hurdle while conducting randomised studies. There is limited data available from low and middle-income countries about factors resulting in screen failure. Hence, this audit was performed to identify the proportion of patients who screen failed and to elucidate reasons for the same. Methods: This was an audit of 15 randomised studies performed by medical oncology solid tumour unit II of Tata Memorial Centre. The screening logs of these studies were acquired. From the screening logs, data regarding the number of patients who had screen failed & reason for the same were obtained. Descriptive statistics were performed. Results: A total of 7,481 patients were screened for 15 randomised clinical studies. Out of these, 3,666 (49.0%) patients were enrolled into trials and 3,815 (51.0%) screen failed. The most common reason for screen failure was 'not meeting inclusion criteria' (54.9%) followed by declining to take treatment (22.2%). Other factors that affect enrolment were 'not willing to stay in the locality of the trial site' (6.2%), being recruited in other studies (3.7%), poor performance status (PS) (3.4%), non-compliance (2.2%), meeting exclusion criteria (0.9%) and 'other' (6.5%). Conclusion: The commonest causes of screen failure in lower and middle-income countries are non-meeting of inclusion criteria followed by declining to take treatment, not willing to stay in locality of trial site, recruited into other studies, poor PS, non-compliance, meeting exclusion criteria & 'other'. This information would help analysing and hence planning of newer strategies to decrease the rate of screen failure.