Prabhat Singh Malik

Metronomics as maintenance treatment in oncology: time for chemo-switch.

The “cell kill” paradigm associated with maximum-tolerated dose (MTD) chemotherapy has shown remarkable success in many hematological malignancies, but unfortunately has failed to demonstrate sustained responses in majority of common advanced solid tumors. This failure can be attributable to heterogeneity of cancer cells within the tumor in terms of the rate of cell proliferation, genetic makeup, and micro-environmental selection giving rise to development of treatment resistance. In this context, Gatenby’s hypothesis of controlling tumor growth rather than eradicating it and treating it like a chronic disease may be more meaningful (1). The use of metronomic regimens alone or in combination with other new targeted therapies after MTD chemotherapy as maintenance treatment for longer period may pave the way for long-term cost-effective treatment.

Clinico-pathological profile of lung cancer at AIIMS: a changing paradigm in India.

BACKGROUND Lung cancer is one of the commonest and most lethal cancers throughout the world. The epidemiological and pathological profile varies among different ethnicities and geographical regions. At present adenocarcinoma is the commonest histological subtype of non-small cell lung cancer (NSCLC) in most of the Western and Asian countries. However, in India squamous cell carcinoma has been reported as the commonest histological type in most of the series. The aim of the study was to analyze the current clinico-pathological profile and survival of lung cancer at our centre. MATERIALS AND METHODS We analyzed 434 pathologically confirmed lung cancer cases registered at our centre over a period of three years. They were evaluated for their clinical and pathological profiles, treatment received and outcome. The available histology slides were reviewed by an independent reviewer. RESULTS Median age was 55 years with a male:female ratio of 4.6:1. Some 68% of patients were smokers. There were 85.3% NSCLC and 14.7% SCLC cases. Among NSCLCs, adenocarcinoma was the commonest histological subtype after the pathology review. Among NSCLC, 56.8% cases were of stage IV while among SCLC 71.8% cases had extensive stage disease. Some 29% of patients could not receive any anticancer treatment. The median overall and progression free survivals of the patients who received treatment were 12.8 and 7.8 months for NSCLC and 9.1 and 6.8 months for SCLC. CONCLUSIONS This analysis suggests that adenocarcinoma may now be the commonest histological subtype also in India, provided a careful pathological review is done. Most of the patients present at advanced stage and outcome remains poor.

Comparison of BEAM vs. LEAM regimen in autologous transplant for lymphoma at AIIMS

BEAM (BCNU, etoposide, cytarabine, melphalan) is the most widely used high dose chemotherapy regimen for autologous transplant in lymphoid malignancies. We report our early experience with an alternative regimen LEAM where BCNU was replaced with the oral analogue CCNU (lomustine) to tide over the non-availability of BCNU. Fifty one patients of relapsed or refractory lymphoma who received BEAM (n= 34) and LEAM (n= 17) from September 2001 to February 2012 were analyzed. From October 2009 onwards LEAM was used as the conditioning regimen instead of conventional BEAM. Patients in the LEAM group had more chemorefractory disease (35% vs 9%, p = 0.045) and high risk comorbidity score (24% vs 0%, p = 0.019). Grade 3 and 4 oral mucositis (67.6% vs. 64.7%, p = 0.834) and diarrhea (47% vs. 41.1%, p = 0.691) were similar. No difference was noted between the two groups in terms of engraftment, documented infections, antibiotic use, cumulative toxicity risk, length of hospital stay and 100 day transplant related mortality. The estimated 2 year overall survival (61.7% vs. 62.7%, p = 0.928) and event free survival (44.6% vs. 41.1%, p = 0.510) of the regimens BEAM and LEAM respectively were comparable. Thus LEAM appeared equivalent to BEAM in terms of toxicity and efficacy and can be used as an alternative to BEAM.

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Advanced Non-Small Cell Lung Cancer.

The advent of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has led to a paradigm shift in the management of advanced adenocarcinoma of the lung. The key to success of these therapies lies in the precise identification of their molecular targets, i.e. sensitizing EGFR mutations. The variations in the prevalence of these mutations among different ethnicities necessitate regional studies for a better understanding of the molecular epidemiology of the disease and clinical decision-making. This is even more relevant for countries like India where genetic heterogeneity is a rule. Here, we make an attempt to review the epidemiology of EGFR mutations in India versus other Asian countries and the West. We also review the clinical experience with EGFR TKIs and suggest the way forward in a resource-limited setting.

Evaluation of epidermal growth factor receptor mutations based on mutation specific immunohistochemistry in non-small cell lung cancer: A preliminary study

Background & objectives: Studies have shown that immunohistochemical (IHC) staining using epidermal growth factor receptor (EGFR) mutation specific antibodies, is an easy and cost-effective, screening method compared with molecular techniques. The purpose of present study was to assess the percentage positivity of IHC using EGFR mutation specific antibodies in lung biopsy samples from patients with primary lung adenocarcinoma (ADC). Methods: Two hundred and six biopsies of primary lung ADC were subjected to EGFR mutation specific antibodies against del E746-A750 and L858R. Detection of EGFR mutation done by high resolution melting analysis (HRM) was used as gold standard. A concordance was established between molecular and IHC results. Frequency of IHC positivity was assessed. Results: Of the 206 patients, 129 were male and 77 were female patients, with a mean age of 54.1 yr. Fifty five (26.6%) patients (36 men; 19 women) showed positivity for IHC of del E746-A750 (33) and L858R (22). HRM results were available in 14 patients which showed EGFR mutations in correspondence with del E746-750 or L858R in 64.2 per cent cases. Positive cases on HRM were further confirmed by DNA sequencing and fragment analysis. Three patients showed exon20 variation. Two cases were negative for mutation. The genotype of del E746-750 mutation was more common than L858R. A concordance was established between molecular mutation and IHC in 85.7 per cent cases. Interpretation & conclusions: In this preliminary study from India mutation specific IHC was used for assessment of mutation status of EGFR. Although the number tested was small, a good concordance was observed between molecular EGFR mutation and IHC expression. IHC methodology is a potentially useful tool to guide clinicians for personalized treatment in lung ADC, especially where facilities for molecular analysis are not readily available and for use in small biopsies where material is scant for molecular tests.

Underutilization of Curative Treatment among Patients with Non Small Cell Lung Cancer: Experience from a Tertiary Care Centre in India

BACKGROUND Lung cancer is one of the commonest and most lethal cancers throughout the world. The majority of the patients present at advance stage and are not suitable for curative intent treatment. Even among patients with localized disease, there has been underutilization of curative treatment modalities. The aim of this study was to analyze the radical treatment utilization rates in patients with non small cell lung cancer (NSCLC) treated at our centre. MATERIALS AND METHODS We analyzed case records of 104 patients with a pathologically confirmed diagnosis of NSCLC having stage 1-3B disease who were treated at our centre over last 3 years, to assess the utilization of curative treatment modalities i.e. surgery or radical radiotherapy. RESULTS The median age of this cohort was 58 years. Out of 104 patients only 33 (31.7%) received curative intent treatment, 14 undergoing curative resection and 19 receiving radical doses of radiotherapy. The baseline characteristics of both the groups (with or without radical treatment) were not different. Major factors associated with underutilization with curative treatment were progressive disease or loss of follow up after chemotherapy and inappropriate use of TKI and/ or palliative radiotherapy in patients with stage 1-3B disease. Patients who did not receive radical treatment had inferior PFS and OS than those who received radical treatment. CONCLUSIONS In our practice we observed gross underutilization of curative intent treatment modalities in patients with NSCLCs which is associated with inferior survival.

Clinicopathologic correlation of programmed death ligand-1 expression in non-small cell lung carcinomas: A report from India

INTRODUCTION Increased expression of Programmed death ligand-1 (PD-L1) on cancer cells and immune cells predict response to PD-1/PDL1 inhibitors. Data regarding frequency and pattern of PD-L1 expression in NSCLC from India is not available. OBJECTIVES To analyse PD-L1 expression on tumour cells (TC) and immune cells (IC) and to correlate PD-L1 expression with baseline clinico-pathological characteristics, oncogenic drivers and outcome data. MATERIALS AND METHODS PD-L1 expression on tumour cells and immune cells was analysed. RESULTS Eighty-nine cases of resected NSCLC were included. Squamous cell carcinoma was more common than adenocarcinoma. IC were present in almost all cases. Immunopositivity for PD-L1 in TC and IC was 27% and 18% respectively. PD-L1 immunopositivity in TC or IC did not correlate with age, sex, stage or mutation status however sarcomatoid carcinoma and solid predominant adenocarcinomas showed higher positivity rates. PD-L1 immunopositivity in ICs was found to correlate with better disease free survival. CONCLUSION PD-L1 immunopositivity was seen in a quarter of NSCLC patients in India. PDL1 positivity on immune cells may be associated with better prognosis in resected NSCLC. However the prognostic value of PD-L1 and clinical response to check point inhibitors in Indian population need to be validated in larger studies.

Study of clinicopathological features, hormone immunoexpression, and loss of ATRX and DAXX expression in pancreatic neuroendocrine tumors

ABSTRACT Objectives: Neuroendocrine tumors of the pancreas (PanNETs) are rare neoplasms, and not much is known about their pathogenesis. We aimed to evaluate ATRX/DAXX immunoexpression in PanNETs a cohort of well-characterized PanNETs. Methods: PanNETs diagnosed over a 10-year period were retrieved and clinicopathogical features reviewed. Immuohistochemistry for pancreatic hormones, and for ATRX and DAXX was performed. Results: Sixty-eight PanNETs were included (30 males and 38 females) with median age of 39 years. Histologically, there were 37 Grade 1 (54.4%), 27 Grade 2 (39.7%), and 4 Grade 3 (5.9%) cases. On immunostaining for hormones, insulin expression was most frequent (22 cases; 38.6%), followed by gastrin (7 cases; 12.3%); 25 cases (43.9%) were negative for all hormones. Loss of ATRX/DAXX immunoexpression was noted in 18 cases (39.1%), and was significantly more frequent in tumors larger than 5 cm. Lymphovascular invasion, infiltrative borders, and infiltration of adjacent organs were also more frequent in tumors with loss of ATRX/DAXX immunoreactivity. A little over half the tumors with ATRX/DAXX loss showed negative immunostaining for all hormones (55.6%). Conclusion: Loss of ATRX/DAXX expression is frequent in PanNETs, indicating a role in their pathogenesis. As ATRX/DAXX loss is more frequent in larger tumors, and in those with lymphovascular invasion, adjacent organ infiltration and infiltrative borders, this suggests that loss of ATRX/DAXX expression is a late event in pathogenesis and is associated with an aggressive phenotype. Immunohistochemical detection of ATRX/DAXX loss is a simple method for ATRX/DAXX evaluation and can easily be incorporated into routine pathological evaluation of PanNETs.

Chemotherapy and targeted therapy in the management of cervical cancer

Management of cervical cancer has undergone refinement in the past two decades; concurrent chemo-radiation (CCRT) (with cisplatin alone or in combination) is currently the standard treatment approach for patients with locally advanced disease (FIGO stage IIB-IVA). About 30%-40% of such patients fail to achieve complete response; alternative approaches are needed to improve outcome for them. Treatment with bevacizumab (an inhibitor of vascular endothelial growth factor) along with chemotherapy is associated with improved survival in patients with recurrent or metastatic cervical cancer. Weekly paclitaxel and carboplatin for 4-6 weeks as dose dense chemotherapy prior to CCRT is currently under study in a phase III, multicentric trial. Role of adjuvant chemotherapy after CCRT in patients with positive lymph nodes, larger tumor volume and those with stage III-IVA disease needs further exploration. Novel agents targeting molecular pathways are currently being studied. Recent development of immune check point inhibitors is exciting, results of ongoing studies are awaited with interest.

Use of Exfoliative Specimens and Fine-Needle Aspiration Smears for Mutation Testing in Lung Adenocarcinoma

Objective: Cytology specimens are considered to be a promising alternative for detecting driver mutations in lung cancer patients. We aimed to explore the suitability and utility of various cytology samples of non-small-cell lung cancer (NSCLC) patients for mutation testing. In addition to mutation detection, the importance of preanalytic factors was discussed. Design: A total of 116 cytology samples including 32 controls comprising pleural effusions, bronchial washings, and direct fine-needle aspiration (FNA) smears were included in the study for the detection of EGFR, KRAS, and Her-2/neu gene mutations. Tumor content was checked by microscopic evaluation. Tumor enrichment was done by scraping direct smears. DNA yield was assessed before selecting the method of mutation detection. Sanger sequencing and real-time PCR-based methods were used. Results: Overall, 20.23% EGFR mutations and 2.74% KRAS mutations were observed in this study. Nondriver genetic polymorphisms were observed in EGFR exon 20 in 37% cases. The coexistence of the EGFR mutation and EGFR polymorphism was seen in 7 cases. DNA yield was better in pleural effusions and bronchial washings. Real-time PCR was used in specimens of low DNA yield. Conclusions: Cytology samples are useful in ascertaining molecular diagnostic information for treatment purposes if they are optimized judiciously in their preanalytic phase.