Arun Chandrasekharan

Once-a-Week Versus Once-Every-3-Weeks Cisplatin Chemoradiation for Locally Advanced Head and Neck Cancer: A Phase III Randomized Noninferiority Trial

Purpose Chemoradiation with cisplatin 100 mg/m2 given once every 3 weeks is the standard of care in locally advanced head and neck squamous cell cancer (LAHNSCC). Increasingly, low-dose once-a-week cisplatin is substituted because of perceived lower toxicity and convenience. However, there is no level 1 evidence of comparable efficacy to cisplatin once every 3 weeks. Patients and Methods In this phase III randomized trial, we assessed the noninferiority of cisplatin 30 mg/m2 given once a week compared with cisplatin 100 mg/m2 given once every 3 weeks, both administered concurrently with curative intent radiotherapy in patients with LAHNSCC. The primary end point was locoregional control (LRC); secondary end points included toxicity, compliance, response, progression-free survival, and overall survival. Results Between 2013 and 2017, we randomly assigned 300 patients, 150 to each arm. Two hundred seventy-nine patients (93%) received chemoradiotherapy in the adjuvant setting. At a median follow-up of 22 months, the estimated cumulative 2-year LRC rate was 58.5% in the once-a-week arm and 73.1% in the once-every-3-weeks arm, leading to an absolute difference of 14.6% (95% CI, 5.7% to 23.5%); P = .014; hazard ratio (HR), 1.76 (95% CI, 1.11 to 2.79). Acute toxicities of grade 3 or higher occurred in 71.6% of patients in the once-a-week arm and in 84.6% of patients in the once-every-3-weeks arm ( P = .006). Estimated median progression-free survival in the once-a-week arm was 17.7 months (95% CI, 0.42 to 35.05 months) and in the once-every-3-weeks arm, 28.6 months (95% CI, 15.90 to 41.30 months); HR, 1.24 (95% CI, 0.89 to 1.73); P = .21. Estimated median overall survival in the once-a-week arm was 39.5 months and was not reached in the once-every-3-weeks arm (HR, 1.14 [95% CI, 0.79 to 1.65]; P = .48). Conclusion Once-every-3-weeks cisplatin at 100 mg/m2 resulted in superior LRC, albeit with more toxicity, than did once-a-week cisplatin at 30 mg/m2, and should remain the preferred chemoradiotherapy regimen for LAHNSCC in the adjuvant setting.

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.

Weekly paclitaxel as metronomic palliative chemotherapy in small cell lung cancer

Background: Topotecan is the standard second line agent used in relapsed small cell lung cancer (SCLC). However, the erratic availability and the cost of the drug has been a prohibitive factor for its use in second-line setting in India. Paclitaxel has shown antitumor activity in heavily pretreated patients with SCLC. Hence, this audit was performed to study the efficacy of weekly paclitaxel as a form of metronomic therapy in the second-line setting in SCLC. Materials and Methods: Fifty-seven patients of relapsed SCLC who presented to the thoracic medical oncology unit of Tata Memorial Centre, Mumbai between January 2011 and December 2015 were selected for this analysis. Weekly paclitaxel at a dose of 80 mg/m 2 was administered until progression or development of intolerable side effects or patient refusal. Data regarding baseline demographics, previous treatment history, response rate, progression-free survival, overall survival (OS), and toxicity to weekly paclitaxel was extracted from a prospectively maintained database in the thoracic medical oncology unit and was analyzed using SPSS version 16 (IBM, New York, USA). Kaplan-Meier survival analysis was performed. Results: Median age of the cohort was 58 years (40-77 years). Etoposide with carboplatin was the regimen used in 40 patients (70.2%) whereas the remaining 17 patients received etoposide with cisplatin (29.8%). Eastern Cooperative Oncology Group performance status at relapse was 1 in 3 (5.3%), 2 in 49 (86.0%), and 3 in 5 (8.7%) patients. The response rate and clinical benefit rate were 9.1% (5 patients) and 52.7% (29 patients), respectively. Grade 3-4 toxicities were seen in 10.5% (6 patients). The median PFS was 145 days (95% confidence interval [CI]: 116.6-173.5 days) whereas the median OS was 168 days (95% CI: 112.5-223.5 days). Conclusion: Weekly paclitaxel as a second line agent in relapsed small cell cancer of the lung is a feasible and well-tolerated agent.

Comparison of paclitaxel-cetuximab chemotherapy versus metronomic chemotherapy consisting of methotrexate and celecoxib as palliative chemotherapy in head and neck cancers

BACKGROUND The present match pair analysis was planned to compare the efficacy of cetuximab-paclitaxel-based chemotherapy versus metronomic therapy. MATERIALS AND METHODS Sixty patients with metastatic/recurrent head and neck squamous cell cancer treated with weekly paclitaxel (80 mg/m2) and cetuximab were matched with sixty patients treated with oral metronomic chemotherapy consisting of methotrexate and celecoxib. The progression-free survival (PFS) and overall survival (OS) between the cohorts were compared using log-rank test. Cox proportional regression model was used to identify independent factors affecting PFS and OS. RESULTS The median OS was 191 days (95% confidence interval [CI]: 122.2-259.8 days) in metronomic cohort and 256 days (95% CI 177.0-334.9 days) in cetuximab cohort (hazard ratio: 0.58, 95% CI: 0.35-0.95, P = 0.031). On Cox proportional hazard model, Eastern Cooperative Oncology Group Performance Status (0-1 vs. 2) and therapy (cetuximab versus metronomic) had a statistically significant impact on OS. CONCLUSION Cetuximab-based chemotherapy leads to a significant improvement in OS in the match pair analysis in comparison to metronomic chemotherapy.

Metronomic palliative chemotherapy in maxillary sinus tumor

Background: Metronomic chemotherapy consisting of methotrexate and celecoxib recently has shown promising results in multiple studies in head and neck cancers. However, these studies have not included patients with maxillary sinus primaries. Hence, the role of palliative metronomic chemotherapy in patients with maxillary sinus carcinoma that is not amenable to radical therapy is unknown. Methods: This was a retrospective analysis of carcinoma maxillary sinus patients who received palliative metronomic chemotherapy between August 2011 and August 2014. The demographic details, symptomatology, previous treatment details, indication for palliative chemotherapy, response to therapy, and overall survival (OS) details were extracted. SPSS version 16 was used for analysis. Descriptive statistics have been performed. Survival analysis was done by Kaplan-Meier method. Results: Five patients had received metronomic chemotherapy. The median age was 60 years (range 37-64 years). The proportion of patients surviving at 6 months, 12 months, and 18 months were 40%, 40%, and 20%, respectively. The estimated median OS was 126 days (95% confidence interval 0-299.9 days). The estimated median survival in patients with an event-free period after the last therapy of <6 months was 45 days, whereas it was 409 days in patients with an event-free period postlast therapy above 6 months (P = 0.063). Conclusion: Metronomic chemotherapy in carcinoma maxillary sinus holds promise. It has activity similar to that seen in head and neck cancers and needs to be evaluated further in a larger cohort of patients.

Efficacy and safety of sorafenib in advanced renal cell cancer and validation of Heng criteria

INTRODUCTION Sorafenib is an established upfront treatment option for metastatic RCC (mRCC). There is no published literature regarding its performance in Indian Patients. We present an analysis of Sorafenib use in our institute and attempt to validate the Heng criteria as a prognostic score in these patients. MATERIALS AND METHODS Patients who received Sorafenib as first line treatment for advanced RCC from June 2012 to December 2015 were prognosticated by Heng criteria and retrospectively analysed for baseline demographics, toxicity, response and outcomes. RESULTS 82 patients (65 males, 17 females) with a median age of 57 years were included for final analysis. Median ECOG PS was 1, 95.2 % of the patients had Stage IV disease and clear cell was the predominant histology (79.4%). 23.2%, 42.7% and 34.1% of patients were classified as low, intermediate and high risk by Hengs criteria, respectively. Dose reduction was required in 24.4% of patients, while 14.6% required permanent cessation of Sorafenib due to intolerable or recurrent side effects. Common adverse events included HFS (68.2%), mucositis (35.3%), fatigue (35.3%), rash (32.9%) and hypertension (25.6%). Response rate observed was 18.2%, while clinical benefit rate was 57.2% in the 57 patients where response was evaluable. Median progression free survival was 7.75 months (5.45-10.05) and median overall survival (OS) was 12.18 months (9.61 - 14.76). Median OS was 19.6, 16.1 and 10.3 months respectively for low, intermediate and high risk patients by Heng criteria and the criteria was statistically discriminatory for the 3 groups for OS (p=0.045, chi-square test). CONCLUSION Sorafenib is a viable upfront treatment option for metastatic RCC in Indian patients with acceptable PFS, although a high incidence of HFS, mucositis and rash is observed. The Heng score has discriminatory value in mRCC with Sorafenib and can be considered for routine use in the clinic.

Long-term survival outcomes of technically unresectable carcinoma maxilla postinduction chemotherapy

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Quality of life and quality-adjusted time without toxicity in palliatively treated head-and-neck cancer patients

Background: Quality-adjusted time without toxicity (Q-TWiST) and quality of life (QOL) are indicators of benefit provided by different chemotherapy regimens. Methods: This was a prospective study, in which adult head-and-neck (H and N) cancer patients, treated with metronomic chemotherapy were enrolled. The Functional Assessment of Cancer Therapy-General H and N (FACT-G and H and N) version 4 pro formas were self-administered before the start of chemotherapy and then at 2, 4, and 6 months. FACT QOL and Q-TWiST analysis were then performed. Results: There was an improvement in the social well-being (P = 0.370), emotional well-being (P = 0.000), functional well-being (P = 0.000), H and N cancer subscale (P = 0.001), FACT H and N trial outcome index (P = 0.000), FACT G-total score (P = 0.000), and FACT H and N total score (P = 0.000) with palliative chemotherapy. The QTWiST value for a utility score of 0.25 for toxicity and relapse state was 145.93 days. Conclusion: Metronomic chemotherapy is associated with improvement in QOL and has a low duration of time spent in toxicity state.

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.

Outcomes in Treatment-Naïve Patients With Metastatic Extremity Osteosarcoma Treated With OGS-12, a Novel Non–High-Dose Methotrexate–Based, Dose-Dense Combination Chemotherapy, in a Tertiary Care Cancer Center

Purpose Metastatic osteosarcoma is largely treated with high-dose methotrexate (HDMTX)–based therapy, especially in the pediatric population. This mandates complex pharmacokinetic monitoring in a costly inpatient setting to mitigate unpredictable serious toxicities. Hence, a non-HDMTX–based regimen is worth exploring, especially in India and low- and middle-income countries. Materials and Methods All consecutive treatment-naïve patients with metastatic osteosarcoma were prospectively treated on the novel OGS-12 protocol consisting of sequential doublets of doxorubicin, cisplatin, and ifosfamide. Four cycles were administered as neoadjuvant therapy followed by planned curative intent surgery and metastasectomy when feasible, followed by four cycles of adjuvant chemotherapy. Baseline characteristics, histologic response, event-free survival (EFS), overall survival (OS), and toxicity data were prospectively collected. Results Three hundred seventeen patients were enrolled onto the OGS-12 protocol from 2011 to 2014, of whom 80 (25%) had metastatic disease; median age was 17 years. The majority of patients were nutritionally challenged with high-risk features. At presentation, 83% of patients (66 patients) had lung metastases. After neoadjuvant chemotherapy, 57% of patients were histologically good responders. Four-year EFS and OS rates were 24% and 27%, respectively, in the intent-to-treat population and 27% and 29%, respectively, in the per-protocol analysis. Significant grade 3 or 4 toxicities were febrile neutropenia (51%), thrombocytopenia (36%), and anemia (54%). Histologic response was an independent predictor for EFS and OS in patients who underwent surgery. Surgical intervention was found to be significant for survival in univariable analysis. Conclusion The novel, low-cost, non-HDMTX–based, dose-dense OGS-12 regimen has shown comparable outcomes to international standards in metastatic osteosarcomas and is worthy of wider clinical application. An aggressive multimodality approach may result in long-term survival in a select group of patients and, hence, is worth considering.