Arvind Sahu

Crizotinib: A comprehensive review

Anaplastic lymphoma kinase (ALK) gene rearrangements are present in a small subset of non-small-cell lung cancers. ALK-positivity confers sensitivity to small-molecule ALK kinase inhibitors, such as crizotinib. The integration of crizotinib into standard treatment practice in NSCLC will rest on the widespread implementation of an effective screening system for newly diagnosed patients with NSCLC which is flexible enough to incorporate new targets as treatments are developed for them. Phase I and II studies of crizotinib in ALK-positive lung cancer have demonstrated significant activity and impressive clinical benefit, which led to its early approval by USFDA in 2011. Although crizotinib induces remissions and extends the lives of patients, there have been reports of emerging resistance to Crizotinib therapy. In this review, we discuss the history, mechanism of action, uses, adverse effects, dose modifications and future challenges and opportunities for patients with ALK-positive lung cancers.

Clinical Outcome in Definitive Concurrent Chemoradiation With Weekly Paclitaxel and Carboplatin for Locally Advanced Esophageal and Junctional Cancer.

There are little data on the efficacy and safety of taxane/platinum with definitive radiotherapy (RT) for esophageal/GEJ cancer. This article is a retrospective analysis of patients who received weekly paclitaxel 50 mg/m(2) and carboplatin AUC 2 with radical definitive RT for locally advanced esophageal/GEJ cancer. Between February 2011 and July 2014, 179 patients were included. The median age was 54 years. Ninety-two percent of patients had squamous histology. Mean RT dose was 58.7 Gy in 32 fractions over 53 days, with mean of six chemotherapy cycles. Fifty-six percent of patients developed ≥grade 3 acute toxicities, commonly febrile neutropenia (12%) and infection (11%); ≥grade 3 laboratory abnormalities included hyponatremia (38%), leukopenia (49%), neutropenia (27%), and anemia (16%). Twelve percent of patients developed ≥grade 3 chronic toxicity. Fatal toxicities included six during CRT, eight within 30 days of completing CRT, and three chronic. Radiologic response was 49% (CR 5.6%, PR 43%). Follow-up endoscopy showed remission in 53% and residual disease in 14%. At a median follow-up of 28 months, median PFS was 11 months (95% CI: 8-13.9), median OS was 19 months (95% CI: 15.4-22.6), and estimated 1-year, 2-year, and 3-year survivals were 70%, 47%, and 39%, respectively. Weekly paclitaxel-carboplatin concurrently with definitive RT is efficacious with manageable toxicity. [The trial was registered with the Clinical Trials Registry-India (CTRI), registration number: CTRI/2014/07/004776.].

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.

Dihydro pyrimidine dehydrogenase deficiency in patients treated with capecitabine based regimens: a tertiary care centre experience

BACKGROUND Dihydropyrimidine dehydrogenase (DPD) enzyme is the rate limiting step in the metabolism of capecitabine, and its deficiency leads to severe toxicities and rarely, death. METHODS A total of 506 patients were treated in the GI Medical Oncology unit of our institution with capecitabine containing regimens with a dose range of 1,250 to 2,000 mg/m(2)/day during the period from June 2013 to June 2015. Patients with grade (Gr) 3/4 toxicities requiring in-patient care (life threatening complications) were planned for DPD activity testing by peripheral blood PCR sequencing. RESULTS Thirty-one patients developed Gr 3/4 toxicities during cycle 1 of capecitabine. This included mucositis in 24 (77%), diarrhea in 29 (94%), hand-foot syndrome (HFS) in 13 (42%) and myelosuppression in 5 (16%) patients. Twenty-two (81.4%) were found to be DPD deficient with 6 patients negative for DPD mutation. Three patients did not undergo the DPD analysis as advised. More than one mutation was seen in 11 patients. The relative frequencies of the mutations were IVS14+1G→A in 39%, with 13% having homozygosity, 85 T→C in 36%, 1627 A→G in 32%, 496 A→G in 18% and 2194 G→A in 18%, respectively. After dose reduction in cycle 2 in 17 patients of the DPD mutation positive cohort, statistically significant reduction in the toxicities was seen. CONCLUSIONS Dose reduction in DPD deficient patients, reduces risk of life threatening complications significantly but not completely. Upfront screening for DPD deficiency in Indian patients should be evaluated further in view of potentially high homozygous DPD mutation prevalence.

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.

Adherence to and Implementation of ASCO Antiemetic Guidelines in Routine Practice in a Tertiary Cancer Center in India

BACKGROUND Nonadherence of antiemetic prescriptions to evidence-based antiemetic guidelines is associated with an increased proportion of chemotherapy-induced nausea and vomiting. The current project was carried out to improve the quality of antiemetic prescriptions at our institute. METHODS We initially performed a retrospective analysis of 1,211 consecutive antiemetic prescription records of adult patients with solid tumors who received outpatient chemotherapy regimens. The antiemetic prescription records were classified as either ASCO-guideline adherent or nonadherent, and the impact on emesis was studied. These data were used to educate clinicians regarding the importance of adherence to guidelines. We then revised our antiemetic prescription policies and made their use mandatory. In addition, a double-check system was introduced to ensure implementation. A reaudit was performed to study the impact of these interventions. RESULTS ASCO-guideline-adherent prescriptions in the initial part of our study were associated with a lower rate of vomiting (6.6% v 21.9%; P < .001), emergency visits (2.6% v 5.8%; P = .006), and hospitalization for emesis (0.9% v 4.9%; P < .001). The proportion of prescriptions classified as ASCO-guideline adherent in the initial audit and the reaudit were 63.6% and 98.5%, respectively ( P < .001). The proportion of patients for whom antiemetic prescriptions were overused was significantly lower on the reaudit (41.3% v 68.3% before the interventions; P = .001). CONCLUSION Mandatory, semirigid corrective steps as carried out in this audit led to an improvement in antiemetic-guideline adherence rate.

Neoadjuvant imatinib: longer the better, need to modify risk stratification for adjuvant imatinib

BACKGROUND Multimodality treatment of gastrointestinal stromal tumor (GIST) with surgery and adjuvant imatinib mesylate (IM), along with an emerging role for neoadjuvant IM prior to evaluation for resectability has resulted in high survival rates. METHODS We conducted a retrospective analysis of prospectively collected data of patients who underwent surgery for GIST, prior to or followed by IM therapy. A total of 112 patients underwent surgery between January 2009 and March 2015 at our centre. This included 27 patients with upfront resectable disease, 76 patients with locally advanced GIST who received neoadjuvant IM followed by surgery and 9 patients with metastatic disease who had excellent response to IM and were taken for surgery. RESULTS The primary tumor in the non metastatic patients was in the stomach (53%), duodenum (16%), rectum (12%), jejunum (11%), ileum (7%), and others (2%). Median duration of neoadjuvant IM was 5 months with 4 patients showing disease progression during neoadjuvant IM. Ninety-three percent of all patients had R0 resections, while 7% had R+ resections. The estimated 3- and 5-year DFS in non-metastatic patients was 86.1% and 67% respectively with a 3- and 5-year median OS of 95.4% and 91.7% respectively. Five-year PFS and OS for the metastatic patients was 88.8% and 100% respectively. Lack of adjuvant IM was the only factor related to inferior PFS and OS. CONCLUSIONS Longer duration of neoadjuvant IM should be considered in locally advanced GIST prior to surgery and resection may be considered in responding metastatic 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.

Clinical practice and outcomes in advanced gastrointestinal stromal tumor: Experience from an Indian tertiary care center

Background: Management of advanced Gastrointestinal stromal tumors (GIST) has been revolutionized with the use of Imatinib guided by mutation analysis. Data from India remains scarce. Materials and Methods: Patients with metastatic GIST who were treated at Department of Gastro-intestinal & Hepaticopancreaticobiliary Oncology Unit at Tata Memorial Hospital, Mumbai between December, 2004 and December 2015 were included in the analysis. Clinical and radiological data was retrieved from stored medical records and charts. Results: A total of 83 patients with metastatic GIST were available for analysis. Median age was 54 years with a 3:1 male predominance. Stomach was the most common site of primary with liver being the most common site of metastasis. c-Kit mutation analysis results were available for 44 patients with exon 11 mutant being the most common mutation. With a median follow up of 33 months, the 10 years estimated progression free and overall survival (OS) was 18% and 51% respectively. Overall response rate to first line imatinib was 37.6% and estimated 3 years OS to first line therapy was significantly better for Exon 11 mutated patients (p=0.016). 34 patients received second line therapy in the form of either sunitinib, pazopanib or increased dose imatinib with a clinical benefit rate of 73.5%. C-Kit mutated patients had a better median OS compared to non mutated patients. Conclusions: GIST diagnosed and treated in the Indian subcontinent appears to show improved outcomes. The importance of c-Kit mutation analysis in determining the prognosis and outcomes of patients with advanced GIST is emphasized.

Metastatic anorectal melanomas – An exploratory retrospective analysis on the benefits of systemic therapy versus best supportive care in a resource-limited setting from India

Aim: Data regarding the optimal management of metastatic anorectal melanoma (mARM) is scarce. The primary aim was to evaluate the potential benefits of systemic therapy in mARM. Materials and Methods: This is a retrospective analysis of all mARM who presented between July 2013 and June 2015 at the Department of GI Medical Oncology, Tata Memorial Hospital. Results: Of a total of 37 patients, twelve patients were planned for best supportive care (BSC) only while the remaining 25 patients received systemic therapy. The median overall survival (OS) for the whole cohort was 27 weeks. The OS was significantly better in patients who received first-line therapy as compared to those who were offered BSC (median OS: 14 vs. 33 weeks; P = 0.04). Patients with PS of 1 did significantly better than PS of 2 more (OS 70 vs. 17 weeks; P = 0.015). Conclusion: mARM should be offered chemotherapy, especially in good performance patients. Paclitaxel/Platinum or Capecitabine/Temozolomide regimens can be considered as the preferred regime in the resource-limited setting where immunotherapy may not be a feasible option.