Amit Janu

The Importance of Brain Metastasis in EGFR Mutation Positive NSCLC Patients

Introduction. Brain metastasis is a poor prognostic marker in lung cancer. However it is not known whether amongst patients with EGFR mutation those with brain metastases have a worse outcome. Methods. We compared the survival outcomes between EGFR mutation positive patients with and without brain metastases. In this retrospective analysis of prospective database of all metastatic lung cancer patients at our centre between July 2009 and December 2012, patients were treated with either combination chemotherapy or oral TKI. All patients with brain metastases received whole brain radiation. Kaplan Meier method was used for survival analysis and compared using log rank test. Results. 101 patients with EGFR mutated, metastatic lung cancer were studied. Fourteen had brain metastases and 87 did not. The common EGFR mutations were exon 19 deletion (61.3%) and exon 21 L858R mutation (28.7%). Overall response was 64% in extracranial metastasis group as compared to 50% in brain metastasis group. There was a significant worsening of median OS in the patients with brain metastases (11.6 months) compared with only extracranial metastases (18.7 months), P = 0.029. Conclusion. Amongst patients with EGFR mutant NSCLC, the presence of brain metastases leads to a worse outcome as compared to patients with extracranial metastases alone.

EGFR mutation in squamous cell carcinoma of the lung: does it carry the same connotation as in adenocarcinomas?

Background EGFR tyrosine kinase inhibitors (TKIs) have greatly improved the outcomes of EGFR mutation-positive adenocarcinomas of the lung. In contrast, the significance of EGFR mutation in metastatic squamous cell carcinoma (SCC) of the lung has been debated. Methods All patients with metastatic SCC who underwent EGFR mutation testing at our center from 2010 to 2015 were included for analysis. EGFR kinase domain mutations were tested using Taqman-based real-time polymerase chain reaction (PCR). Response assessment was done using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. Kaplan–Meier method was used for calculating progression-free survival (PFS) and overall survival (OS). Results EGFR mutation was detected in 29 out of 639 patients with SCC. Furthermore, 19 out of the 29 patients received TKIs at some point during their treatment. TKI therapy led to a partial response in 5 out of 19 patients and stable disease in 4 out of 19 patients. The median PFS of patients treated with TKIs was 5.0 months. The median OS of the whole EGFR-positive SCC cohort was 6.6 months. On univariate analysis, patients having received TKI therapy was the only factor associated with a significantly better OS of 13.48 months versus 2.58 months (P=0.000). On multivariate analysis, patients receiving TKI therapy, Eastern Cooperative Oncology Group–Performance Scale (ECOG-PS) score <2, EGFR exon 19 mutation and nonsmoking status were associated with significantly better OS. Conclusion EGFR mutation in SCC of the lung predicts a better outcome if the patient is given TKI, but it may be inferior to the outcomes seen in EGFR-positive adenocarcinomas treated with TKI.

ALK Positive Lung Cancer: Clinical Profile, Practice and Outcomes in a Developing Country

Objectives To evaluate the performance and treatment profile of advanced EML4—ALK positive Non-small cell lung cancer (NSCLC) patients in a developing country with potentially restricted access to Crizotinib. Materials and Methods A retrospective analysis of advanced ALK positive NSCLC patients who were treated from June 2012 to September 2015 was conducted. The primary goal was to evaluate outcomes of advanced ALK positive NSCLC in our practice and examine the logistic constraints in procuring Crizotinib. Results 94 patients were available for analysis. 21 (22.3%) patients were started on Crizotinib upfront, 60 (63.8%) on chemotherapy, 10 (10.6%) on Tyrosine kinase inhibitors (in view of poor PS) and 3 (3.2%) patients were offered best supportive care. Reasons for not starting Crizotinib upfront included symptomatic patients needing early initiation of therapy (23.3%), ALK not tested upfront (23.3%) and financial constraints (21.9%). 69 patients (73.4%) received Crizotinib at some stage during treatment. Dose interruptions (> 1 week) with Crizotinib were seen in 20 patients (29%), with drug toxicity being the commonest reason (85%). Median Progression free survival (PFS) on first line therapy for the entire cohort was 10 months, with a significant difference between patients receiving Crizotinib and those who did not ever receive Crizotinib (10 months vs. 2 months, p = 0.028). Median Overall Survival (OS) was not reached for the entire cohort, with 1 year survival being 81.2%. Patients with an ECOG Performance Status (PS) of >2 had a significantly reduced PFS compared to patients with PS < = 2 (1.5 months vs. 11 months, p< 0.001). 47 patients with financial constraints (68.1%) received Crizotinib completely free via various extramural support schemes. Conclusion A majority of our ALK positive NSCLC patients were exposed to Crizotinib through the help of various support mechanisms and these patients had similar outcomes to that reported from previously published literature.

Phase III study of gefitinib or pemetrexed with carboplatin in EGFR-mutated advanced lung adenocarcinoma

Objective Oral tyrosine kinase inhibitor has been shown to prolong progression-free survival (PFS) in epidermal growthfactor receptor (EGFR) mutation positive adenocarcinoma; however, the comparator arm has not included the current standard adenocarcinoma regimen (pemetrexed carboplatin induction followed by maintenance pemetrexed) and patients from Indian subcontinent. Hence, this study was carried out in Indian patients to compare gefitinib with the above-mentioned chemotherapy regimen. Methods This was an open-labelled, randomised, parallel group study comparing gefitinib (250 mg orally daily) with pemetrexed (500 mg/m2) and carboplatin (area under the curve 5) doublet intravenous induction chemotherapy regimen followed by maintenance pemetrexed (500 mg/m2) in patients with EGFR-activating mutation-positive stage IIIB or stage IV adenocarcinoma lung in the first-line setting. The primary endpoint for the study was PFS. 260 patients were required to demonstrate a 50% improvement in PFS of gefitinib over chemotherapy, with 80% power and 5% type 1 error. With an expected 5% dropout rate, the sample size was 290 patients. Results The median PFS in gefitinib arm was 8.4 months (95% CI 6.3 to 10.5 months) compared with 5.6 months (95% CI 4.2 to 7.0 months) in pemetrexed–carboplatin arm (HR: 95% CI 0.513 to 0.851; p −0.001). The impact of gefitinib on PFS was seen across all subgroups.There was no statistically significant difference in overall survival between the two arms. Haematologicalgrade3–4toxicities likeanaemia,neutropaenia and thrombocytopaenia were common in the pemetrexed–carboplatin arm while grade3–4 acneiform rash and diarrhoeawere common in the gefitinib arm. Conclusion The study confirms the superiority of gefitinib in prolonging PFS against the most active chemotherapy regimen of pemetrexed–carboplatin followed by maintenance pemetrexed in EGFR-mutated lung adenocarcinoma. The median PFS in Indian patients in gefitinib arm is similar to that reported in east Asians and Caucasians.

Maintenance pemetrexed in nonsmall cell lung carcinoma: Outcome analysis from a tertiary care center

Background: Maintenance pemetrexed is a standard treatment option for selected non squamous nonsmall cell lung carcinoma patients having a response to platin based doublet. We conducted a clinical audit of such selected patients and report the outcome among the Indian population. Aim: To evaluate the outcomes with maintenance pemetrexed in the patients with locally advanced and metastatic adenocarcinoma lung. Objectives: To calculate the progression free survival (PFS), overall survival (OS), and factors affecting the outcome. Materials and Methods: Data of patients with locally advanced and metastatic adenocarcinoma lung were retrieved from prospectively maintained lung cancer database registered between June 2011 and March 2014. The patients who achieved partial response (n = 87) or stable disease (n = 101) after 6 cycles of pemetrexed platin based doublet and received the maintenance pemetrexed were selected for final analysis (n = 188). Kaplan-Meir survival analysis was used for PFS and OS. Log rank test was used to evaluate the factors affecting the outcome. Results: Median follow-up is 14 months. The median number of maintenance pemetrexed cycles received is 6 (1-38). Common reason for the discontinuation are disease progression (n = 127), renal toxicity (n = 4), and social/financial (n = 7). Median PFS and OS are 8 months and 20 months, respectively. The patients with baseline pleural effusion had better PFS (9 months vs. 7 months, P = 0.02) and OS (26 months vs. 18 months, P = 0.05). The patients receiving more than 6 cycles of maintenance had improved PFS (12 vs. 7 months, P = 0.002) and OS (26 vs. 16 months, P = 0.05). Conclusion: Maintenance pemetrexed is feasible and well tolerated by the majority of Indian patients who achieved the response after platin based doublet. The patients with baseline pleural effusion benefit more with maintenance pemetrexed.

Nomograms based on preoperative multiparametric magnetic resonance imaging for prediction of molecular subgrouping in medulloblastoma: results from a radiogenomics study of 111 patients

Background Novel biological insights have led to consensus classification of medulloblastoma into 4 distinct molecular subgroups-wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4. We aimed to predict molecular subgrouping in medulloblastoma based on preoperative multiparametric magnetic resonance imaging (MRI) characteristics. Methods A set of 19 MRI features were evaluated in 111 patients with histologic diagnosis of medulloblastoma for prediction of molecular subgrouping. MRI characteristics were correlated with molecular subgroups derived from tissue samples in 111 patients (WNT = 17, SHH = 44, Group 3 = 27, and Group 4 = 23). Multinomial logistic regression of imaging parameters was performed on a training cohort (TC) of 76 patients, representing two-thirds of randomly selected patients from each of 4 molecular subgroups, to generate binary nomograms. Validation of these nomograms was performed on the remaining 35 patients as the validation cohort (VC). Results Medulloblastoma subgroups could be accurately predicted by preoperative MRI features in 74% of cases. Predictive accuracy was excellent for SHH (95%), acceptably high for Group 4 (78%), modest for Group 3 (56%) and worst for WNT (41%) subgroup medulloblastoma. SHH-specific nomogram was associated with excellent correlation between TC and VC, with area under the curve (AUC) of 0.939 and 0.991, respectively. AUC for Group 4 was acceptable at 0.851 and 0.788 in TC and VC, respectively; however, these values were consistently suboptimal in WNT and Group 3 medulloblastoma. Conclusion The predictive accuracy of MRI-based nomograms was excellent for SHH and encouraging for Group 4 medulloblastoma. Further work is needed for Group 3 and WNT-pathway medulloblastoma.

Efficacy of gefitinib in epidermal growth factor receptor-activating mutation-positive nonsmall cell lung cancer: Does exon 19 deletion differ from exon 21 mutation?

Background: This study was designed to evaluate the differential effect of epidermal growth factor receptor (EGFR) mutation status (exon 19 vs. 21) on progression-free survival (PFS) and overall survival (OS) in treatment-naïve advanced EGFR mutation-positive nonsmall cell lung cancer (NSCLC) treated with gefitinib as first-line agent. Methods: This was a post hoc analysis of EGFR-mutated (exon 19 and 21) advanced-stage (Stage IIIB or IV), chemotherapy-naive NSCLC patients treated with gefitinib as first line in a phase 3 randomized study. Patients were treated with gefitinib 250 mg daily. Patients underwent axial imaging for response assessment on D42, D84, D126, and subsequently every 2 months till progression. Responding or stable patients were treated until progression or unacceptable toxicity. SPSS was used for statistical analysis. Kaplan–Meier method was used for survival estimation and log-rank test for comparison. Cox proportion hazard model was used for multivariate analysis. Results: One hundred and forty-one patients were eligible for analysis, of which 78 were males and 63 were females. A total of 127 patients (90.1%) were ECOG 0–1 while 14 patients (9.1%) were ECOG >1. Exon 21 mutation was present in 65 patients (46.1%) and exon 19 mutation in 76 patients (53.9%). One hundred and thirty-three of 141 patients were evaluable for response. Response rate of patients having exon 19 mutation was 72.9% (51 patients, n = 70) while it was 55.6% in patients having exon 21 mutation (35 patients, n = 63) (P = 0.046). Median PFS in exon 19-mutated patients was 9.3 months (95% confidence interval [CI] 6.832–11.768) compared to 7.8 months (95% CI 5.543–10.0) (P = 0.699) in exon 21-mutated patients. The median OS in exon 19-mutated patients was 19.8 months (95% CI 16.8–22.7), and it was 16.5 months (95% CI 10.9–22.1) in exon 21-mutated patients (P = 0.215). Conclusion: There were no differential outcomes in the Indian patients of advanced-stage NSCLC with exon 19 and 21 EGFR mutations treated with gefitinib.

Quality of life analysis of Pemetrexed versus Erlotinib maintenance in EGFR mutation negative advanced non small cell lung cancer.

9024Background: Both Pemetrexed and Erlotinib have shown survival benefit when used as maintenance therapy in advanced non small cell lung cancer (NSCLC) after platinum doublet chemotherapy. Hence ...

Outcomes with palliative weekly paclitaxel in advanced, recurrent, and metastatic esophageal cancer - Real world experience

Background: In advanced esophageal cancer, combination chemotherapy regimens provide effective palliation but result in substantial toxicity. Aim: The aim of the study was to evaluate outcomes of recurrent and metastatic esophageal carcinoma treated with weekly paclitaxel. Objectives: The objective of the study was to determine the clinical and laboratory factors predicting response and affecting overall survival (OS) in patients receiving palliative chemotherapy for advanced esophageal/gastroesophageal cancer. Materials and Methods: Retrospective analysis of patients with advanced esophageal cancer, not amenable to definitive intent therapy that was treated with intravenous weekly paclitaxel was done. Progression-free survival (PFS) and OS were calculated with Kaplan–Meir analysis while factors affecting outcome were subjected to log rank test and multivariate analysis. Results: Between September 2010 and October 2014, 350 patients were included in analysis. Median follow-up is 8 months. Median age was 55 years, with a male:female ratio of 2.4:1. Nearly 34.5% were mid esophageal and 51% were lower third and gastroesophageal junction tumors. Almost 58% of the tumors had squamous histology. Performance status was >2 in 25.4%. Almost 62% patients had received prior therapy. Median number of cycles of weekly paclitaxel delivered was 12 with median duration of 3 months. Nearly 51% of patients had improvement in dysphagia, with time to symptom improvement of 20 days. In 31% patients, feeding nasogastric tube could be removed. Overall response rate was 32% (complete remission, 2.5% + partial remission, 29.5%). Median PFS was 4.0 months (95% confidence interval [CI]: 3.6–4.3 months) and median OS was 10 months (95% CI: 8.5–11.4 months). Performance status and pretreatment albumin significantly affected OS. Conclusion: Metronomic weekly paclitaxel chemotherapy provides good palliative benefit in advanced unresectable/metastatic esophageal cancer with minimal toxicity. Eastern Cooperative Oncology Group Performance Status (PS 0 and 1) and baseline serum albumin level >3.7 g/dl significantly improved survival.

ROS1 rearranged nonsmall cell lung cancer and crizotinib: An Indian experience

ROS1 rearrangement acts as a driver mutation in 1-2% of NSCLC. Crizotinib is approved in this situation both in treatment naïve and pre-treated patients. Here we report our experience with crizotinib in patients with advanced NSCLC harbouring ROS1 rearrangement. Eleven patients were included in our study. More than half of our patients had associated comorbidities and one fourth of them had a compromised performance status. Out of 11 patients, 5 of them were exposed to crizotinib .The response rates among crizotinib treated patients was 80%. With a median follow up of 9 months, median PFS and OS were 5.4 months and 8.5 months respectively for the entire population. Analyzing the outcomes separately , median PFS and OS was not reached for those who received crizotinib compared to median PFS of 2.5 months and median OS of 4.2 months in those who were not exposed to crizotinib. The difference was statistically significant. Estimated 1 year OS was 80% for those who received crizotinib compared to 18% for who did not receive crizotinib. In conclusion, crizotinib is effective with acceptable side effect profile in patients with ROS1 rearranged NSCLC in our population.