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Navneet Singh



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    MA 03 - Chemotherapy (ID 651)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      MA 03.02 - Timing of B12/Folate Supplementation in NSCLC Patients on Pemetrexed Based Chemotherapy: Final Results of the PEMVITASTART Randomized Trial (ID 7957)

      11:00 - 12:30  |  Presenting Author(s): Navneet Singh

      • Abstract
      • Presentation
      • Slides

      Background:
      Vitamin B12 and folic acid supplementation(B12-FAS) reduces the incidence and severity of hematological toxicity[HTox] in pemetrexed-based chemotherapy. It is recommended to initiate B12-FAS 5-7 days before the first cycle. Observational and prospective single-arm studies have not shown any increase in HTox when pemetrexed was started earlier than the recommended duration of B12-FAS.

      Method:
      An open-label, randomized trial (PEMVITASTART; NCT02679443) was conducted to evaluate differences in HTox between patients initiated on pemetrexed-platinum chemotherapy following 5-7 days of B12-FAS (Delayed Arm; DA) versus those receiving B12-FAS simultaneously(≤24 hours) with chemotherapy initiation (Immediate Arm; IA). Eligible patients had locally advanced/metastatic non-squamous NSCLC AND ECOG PS=0-2. Block randomization was 1:1 into DA and IA. All enrolled patients received 3-weekly pemetrexed-platinum doublet [500mg/m[2] AND cisplatin(65mg/m[2]) OR carboplatin(AUC 5.0mg/mL/min) each on D1] for maximum of six cycles. Supplementation was 1000µgm FA PO daily and 3-weekly 1000µgm i/m vitamin B12. Primary outcome was any grade HTox while secondary outcomes were grade 3/4 HTox, relative dose intensity(RDI) delivered, inter-cycle delays(ICDs), supportive therapies usage (ESA/G-CSF/PRBC transfusions) and changes in serum levels of B12/FA/homocysteine.

      Result:
      Of 161 patients recruited (81 IA, 80 DA), 150 patients (77 IA, 73 DA) received ≥1 cycle and were included in modified ITT analysis. Baseline parameters were matched except for gender (IA=10.4%, DA=23.3%, p=0.03) and baseline thrombocytopenia (IA=7.8%, DA=0%, p=0.03). Baseline anemia(Hb<12gm/dL) was present in 34.7% (IA=32.5%, DA=37.0%; p=0.56). Incidence of any grade anemia, leukopenia, neutropenia and thrombocytopenia was 87.0% vs. 87.7%(p=0.90), 37.7% vs. 28.8%(p=0.25), 20.8% vs. 15.1%(p=0.36) and 31.2% vs. 16.4%(p=0.04) in IA and DA respectively. Grade 3/4 anemia was 18.2% vs. 12.3%(p=0.32) in IA and DA respectively while other cytopenias were similar (<5% in each arm). Supportive therapies usage in IA vs. DA were 22.1% vs. 12.3% for PRBC transfusions (p=0.12), 3.9% vs. 6.8% for G-CSF (p=0.49) and 10.4% vs. 1.4% for ESAs (p=0.03). ICDs occurred in 14.3% of IA vs. 8.2% in DA (p=0.24). RDI delivered (median 93.5% for pemetrexed and 91.0% for platinum) was similar in both arms. Following continued B12-FAS, after C3(compared to baseline), serum homocysteine was lower (median 10.0µmol/L vs. 17.6µmol/L;p<0.001) while FA (median 17.9ng/ml vs. 5.7ng/ml;p<0.001) and B12 levels (mean 1926.3pg/ml vs. 880.2pg/ml;p<0.001) were higher. In DA, serum FA and B12 on Day1 of C1(following 5-7days of B12-FAS) were significantly higher than baseline but homocysteine levels were similar.

      Conclusion:
      Simultaneous B12-FAS initiation with pemetrexed-based chemotherapy is feasible with acceptable HTox profile. Serum homocysteine levels are unaffected by 5-7 days of B12-FAS.

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    P1.03 - Chemotherapy/Targeted Therapy (ID 689)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 1
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      P1.03-018 - Effectiveness of Supportive Care Drugs in Lung Cancer Patients Undergoing 1st Line Chemotherapy in a Resource Limited Setting (ID 7895)

      09:30 - 16:00  |  Author(s): Navneet Singh

      • Abstract
      • Slides

      Background:
      Lung cancer(LC) chemotherapy is associated with several adverse effects(AEs). Data regarding supportive care medications(SCMs) offered to prevent/treat chemotherapy-related AEs in resource-limited settings and compliance to these therapies is lacking. A prospective observational study was therefore carried out in an attempt to ascertain effectiveness of SCMs in real life setting.

      Method:
      Consecutive patients with newly-diagnosed LC initiated on first-line chemotherapy at a tertiary referral centre in North India (from July 2014-September 2015) were enrolled. Details of chemotherapy-related AEs including incidence, timing of onset, duration and grades were recorded. Compliance with use of mandatory SCMs prescribed after each chemotherapy cycle was assessed by a structured questionnaire. Patients were also instructed to maintain a symptom diary to record various symptoms, frequency of use of need-based SCMs, visits to local health-care providers and hospitalization(if any) during the inter-cycle period.

      Result:
      Of 112 patients enrolled, majority were males(83.9%,n=94), current/ex-smokers(82.1%,n=92), had advanced stage [IIIB=33.9%(n=38), IV=46.4%(n=52)] and of non-small-cell type (NSCLC; 72.3%,n=81). A total of 602 chemotherapy cycles were administered with AEs being reported in 580 cycles(96.3%). Diarrhea was the commonest AE(180 cycles,29.9%) developing after a mean (SD) duration of 3.6(2.5) days and lasting for 4(3.3) days. Vomiting(138 cycles,22.9%) beginning after a mean (SD) of 3.5(2.7) days, lasting for 3.8(3.1) days; and constipation(121 cycles,20.1% mean[SD] onset after 2.9[1.7]days, lasting for mean[SD] of 6.5[6 .1]) were the other common AEs. Grade3/4 AEs occurred in 6.7%(39/580) cycles. Compliance to dexamethasone and proton-pump inhibitors prescribed as part of mandatory SCMs was 98.2% and 98.3% respectively. Need based SCMs were required in 479 of the 580 cycles(82.6%) reporting AEs. Need-based SCMs were effective in relieving most symptoms (100% episodes of pain, cough and epigastric pain). Local physician consultation was sought in 18.1% and 15.8% episodes of vomiting and pain respectively. Proportion of patients with grade 3/4 AEs and requiring hospitalization was highest for mucositis(16.1% grade 3/4 and 9.7% hospitalized); followed by vomiting(10.1% grade3/4 and 8.7% hospitalized) and diarrhea(10.6% grade 3/4 and6.7% hospitalized). Hiccups, despite occurring in only 5 chemotherapy cycles(0.9%) did not improve with need based SCMs in 40%. Anemia was observed in 441(73.3% prevalence) chemotherapy cycles and was treated with blood transfusions, erythropoiesis-stimulating agents and intravenous iron supplementation in 47(10.7%), 30(6.8%) and four(0.9%) cycles respectively.

      Conclusion:
      This study highlights a high prevalence of AEs during LC chemotherapy. However, majority of episodes were grade 1-2 and were controlled with need-based SCMs, without requiring hospitalization or local physician consultation.

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    P2.03 - Chemotherapy/Targeted Therapy (ID 704)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 1
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      P2.03-053 - A Five-Year Audit of EGFR and ALK Testing at a Tertiary Care Centre in North India: More Sensitive Methods Do Make a Difference! (ID 10427)

      09:30 - 16:00  |  Author(s): Navneet Singh

      • Abstract

      Background:
      Detection of targetable driver mutations in NSCLC may depend on the method employed. We carried out an audit to determine whether the EGFR mutation (EGFR-M) and ALK rearrangement (ALK-R) detection rate is dependent upon on the testing method used. We also sought to assess if EGFR-M and ALK-R was associated with baseline demographic characteristics.

      Method:
      Retrospective analysis of NSCLC patients who underwent testing for EGFR-M and ALK-R from January 2012 till May 2017. Methods used for EGFR-M were Real time ARMS PCR and gene sequencing while Break Apart FISH and D5F3 immunohistochemistry(IHC) were used for ALK-R testing.

      Result:
      Of the 599 patients tested for EGFR-M, 541 (90.3%) had interpretable results with an overall prevalence of 21.4%(n=116). Real time ARMS-PCR and gene sequencing yielded 95.9% and 81.9% interpretable results respectively. ALK-R testing was done in 462 patients of whom 431 (93.3%) had interpretable results, of which 8.6%(n=37) were positive. D5F3 IHC and Break Apart FISH yielded 94.7% and 82% interpretable results respectively. Mean age was 59.2 and 54.0 years respectively for EGFR-M and ALK-R patients with 54.3% and 45.1% being females. Mutations in exon 19 were the most common (n=81, 69.8%) followed by exon 21 L858R (n=30, 25.9%). 87/116 (75%) and 19/37 (51.4%) of EGFR-M and ALK-R patients received EGFR-TKIs and crizotinib respectively. Table shows differences in prevalence of EGFR-M and ALK-R prevalence in relation to gender, smoking status, histology and testing method used.

      Table 1 Smoking, gender and histologic profile of the patients tested for EGFR mutations and ALK rearrangements
      EGFR-M positive (n=116) ALK-R positive (=37)
      Overall 21.4% 8.6%
      Adenocarcinoma only 23.8% 9.5%
      Females vs. males 37.1% vs. 14.3% 12.5% vs. 6.8%
      Non-smokers vs. smokers 34.6% vs. 11.9% 11.6% vs. 6.5%
      Female non smokers 39.9% 12.4%
      Male non-smokers 26.1% 10.5%
      Male smokers 11.1% 6.3%
      Females with adenocarcinoma 40.7% 13.3%
      Method used for testing 23.1% Real time ARMS PCR vs. 17.8% gene sequencing 9.0% D5F3 IHC vs. 4.9% Break Apart FISH


      Conclusion:
      Real time ARMS-PCR and D5F3 IHC are more sensitive methods for detecting EGFR-M and ALK-R respectively. Prevalence of a targetable driver in North Indian NSCLC patients ranges from 52.3% amongst female non-smokers to 17.4% of male smokers which are very encouraging results from both the patients and the treating oncologists perspectives. Higher percentage of EGFR-M patients receive targeted therapy as compared to ALK-R.

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    P2.06 - Epidemiology/Primary Prevention/Tobacco Control and Cessation (ID 707)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Epidemiology/Primary Prevention/Tobacco Control and Cessation
    • Presentations: 1
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      P2.06-004 - Role of Polymorphic Variants of BER and DSBR Pathway Genes in Modulating Lung Cancer Susceptibility and Prognosis of North Indian Population (ID 8873)

      09:30 - 16:00  |  Author(s): Navneet Singh

      • Abstract
      • Slides

      Background:
      DNA repair system uphold individuals’ genomic content from consistence impertinence implicated by continuous exposure to DNA damaging agents present in tobacco smoke, ionizing radiations,air pollution etc. BER (Base excision repair) and DSBR (Double strand break repair) are the two important pathways in this respect. However, polymorphic DNA repair genes might modulate the repair capacity and ultimately the survival.

      Method:
      Genotyping for the SNPs for genes OGG1, MUTYH, XRCC1, XRCC3, XRCC4, XRCC6, XRCC7.was done. Statistical analysis was done using MEDCALC. Logistic regression was used to evaluate the odds ratio. We even did use data mining tools MDR (Multi-dimensionality Reduction) and CART (Classification and regression tree analysis) to analyze the high interacting groups posing high risk. Survival analysis was done using Kaplan meier, and Cox regression analysis.

      Result:
      Statistical analysis revealed some interesting facts in relation to susceptibility. It was revealed that OGG1 Ser[326]Cys possessed a potent risk (OR=2.4, p= 0.0003) towards lung cancer whereas mutant genotype (GG) was protective towards lung cancer (OR=0.4, p=0.0185). Further analysis revealed XRCC1 Gln[632]Gln (OR=2.67, p=<0.001) depicted an overall high risk towards lung cancer. Histological analysis suggested mutant genotype in case of XRCC1 Pro[206]Pro implied a protective effect for SCLC subtype (OR=0.29, p=0.0017) on the contrary XRCC1 Gln[632]Gln showed a high risk in SQCC diseased group (OR=4.16, p=<0.0001). A high risk was observed on combining XRCC1 Gln[632]Gln with XRCC1 Pro[206]Pro (OR=5.6, p<0.0004) and Arg[194]Trp (OR=2.10, p=0.03). MDR analysis showed three factor model including XRCC1 206, 632, 280 was the best model (CVC=10, prediction error=0.34). Further Classification and Regression tree (CART) analysis revealed terminal node 1 carrying mutant of XRCC1 632 and wild type of XRCC1 280 represented the highest risk group. Further, survival analysis revealed a minor involvement of XRCC1 SNPs in survival. It was observed mutant genotype for XRCC1 Arg[399]Gln showed an insignificant better survival (MST=9.6). XRCC1 Gln[632]Gln showed a high hazards rate for SCLC subtype (H.R=0.26, p=0.05). An interesting finding of the study was related to chemotherapy regimen where Cisplatin/Carboplatin+ Docetaxel was observed to increase survival for XRCC1 399 mutant genotype (AA) (H.R=0.26, p=0.05). Cisplatin/Carboplatin+ Irinotecan increased survival in both heterozygotes (GA) and combined variants (GA+AA) (HR=0.22, p=0.014; H.R=0.23, p=0.012).

      Conclusion:
      To conclude the polymorphic DNA repair genes affect the susceptibility in lung cancer patients of North Indian population. However, the prognosis is not much altered. The analysis of individualized chemotherapy would help us to develop prognostic biomarkers for individualized therapy.

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    YI 01 - Young Investigator and First Time Attendee Session (ID 588)

    • Event: WCLC 2017
    • Type: Young Investigator
    • Track: Education/Publication/Career Development
    • Presentations: 1
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      YI 01.02 - Planning an Academic Career in Lung Cancer (ID 7846)

      08:00 - 11:30  |  Presenting Author(s): Navneet Singh

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Decision making in life is not always easy. This is applicable not just for patient care but also for matters related to our own-self and is particularly true in the context of career options in medicine. Over the past few decades, the level of expertise provided by health-care providers has enhanced considerably from having comprehensive ‘all-in-one’ doctors to specialists to super-specialists and currently focused super-specialists. This has been associated with the practice of medicine having changed from ‘evidence-based-medicine’ to ‘personalized medicine’ and currently of ‘precision medicine’ and ‘tailor-made’ therapies. This has largely been based on an increase in the quantity and quality of research being conducted worldwide. A majority of this research occurs in academic medical centers/university hospitals wherein faculty/attending consultants are not just involved in patient care but have to devote a substantial percentage of their time in planning and conducting research as well as teaching undergraduate/postgraduate residents and fellows. So the natural questions that crop up for someone in training are: 1) ‘How do I decide whether I am inclined to be working in an academic institute?’ [Will I be able to ‘gel-in’ or be a complete misfit?] ‘2) What is the time-point during my training/post-training period when I need to take the decision of pursuing an academic career?’ 3) ‘What are the essential and desirable qualities/traits that are conducive to working in an academic set-up?’ There are no straightforward answers to any of these. However, generally during the final year of fellowship, most individuals are able to decide whether they would like to continue working in an academic centre or not. This is often possible with guidance from course faculty. The chief-guide under whom the individual has been pursuing research (thesis/dissertation) may be able to identify if the latter has an ‘academic bent of mind’ and provide mentorship and help the transition from ‘fellow’ (in-training) to full-time faculty [‘attending’ consultant]. It is important for anyone intending to pursue an academic career to realize that conducting and participating in research is an integral part as opposed to working in non-academic centers where patient care is the primary focus. Inclination towards research may sometimes manifest as being able to identify ‘grey’ areas in practice of medicine (clinical situations for which there are no clear-cut answers). The best researchers are and often have been those who are able to identify these areas of uncertainty related to diagnosis and treatment of a particular condition or disease and carry out research directed to answer the queries that they had in their minds when picking up these uncertainties. Keeping abreast of the latest developments in one's focus area (by regularly accessing and reading the latest publications in peer reviewed journals) as well as publishing one's own experience/research in such journals is thus part and parcel of one's job profile while working in an academic center. For lung cancer – a disease that carries the highest cancer-related mortality amongst both gender combined and the commonest cancer in males, there have been very encouraging developments in the last couple of decades and especially the last five years. We now have five pillars for treatment – targeted therapy and more lately immunotherapy coming in as very useful additions to traditional modalities (surgery, chemotherapy and radiotherapy). And these are truly exciting times for carrying out research in lung cancer in several ways: 1) Number of investigational molecules (targeted therapy and immunotherapy) being developed/tested in preclinical/clinical trials is increasing at an unparalleled rate 2) Conventional pathway followed for testing [preclinical, phase-1, phase-2, phase-3 clinical trials] is being modified to reduce time to clinical approval for successful drugs by having combined phase 1/2 or phase 2/3 trials. 3) Intense efforts are being made to expand indications for already approved/available drugs e.g. assessing utility of targeted agents in early stage/resectable NSCLC and of combination regimens (EGFR-TKIs/ALK inhibitors+ chemotherapy, PD-1/PD-L1 immune check-point inhibitors+ chemotherapy). Several unaddressed issues exist in lung cancer currently which require concerted efforts and inputs from researchers worldwide including: 1) Improving the screening algorithm for early detection such that false positive results and need for/number of invasive procedures required is reduced. Development of blood, sputum or exhaled-breath based screening tests could find greater acceptability and applicability worldwide. 2) Improving the genomic understanding of SCLC – a histological subtype without significant advances in the past leading treatment to be essentially with two modalities (chemotherapy and radiation). Identifying ‘targetable’ molecular aberrations can revolutionize management of this aggressive histological type while ongoing efforts to establish the role of immune check-point inhibitors continue. 3) Detection of EGFR sensitizing mutations and acquired T790M resistance-conferring mutation (for initiating 1[st]/2[nd] generation EGFR-TKIs and osimertinib respectively) in circulating tumor DNA (ctDNA; sometimes called circulating free tumor DNA - cfDNA) is already applicable in clinical practice and potentially can be used for monitoring treatment responses also. Next-generation-sequencing(NGS) platforms appear promising in detecting both somatic point-mutations and rearrangements/fusions with minimal tissue and/or ctDNA. Development and validation of methods for non-invasive biological monitoring of responses to chemotherapy, radiation, immunotherapy and non-EGFR targeted therapies in the complete spectrum of histological types (SCLC, squamous and non-squamous NSCLC) and disease stage distribution (neoadjuvant treatment preceding surgery, post surgery – adjuvant setting, locally advanced NSCLC following induction concurrent chemo-radiation and metastatic setting) will make it more convenient for patients and treating oncologists alike. The advantages of working in an academic setup in lung cancer are apparent both for the clinician and his/her colleagues in other clinical departments/basic sciences. Current research and clinical practice requires collaboration of different disciplines [pulmonology, diagnostic and interventional radiology (including nuclear imaging), pathology (histopathology, cytopathology, molecular pathology), thoracic surgery/surgical oncology, radiation oncology and medical oncology]. Based upon the academic institute’s geographical location, the number/work profile of departments that exist for a given discipline may vary considerably. These variations notwithstanding, the bottom-line is that reaching out to and working together with colleagues from other departments and disciplines [multidisciplinary team approach] is mandatory for attempting conduct of high-quality research and delivery of high-quality patient care in thoracic oncology. This potential advantage and benefit also comes with several challenges. One is required to carefully balance and utilize working hours for patient care, research and training while attempting to do the best in all three fields. This invariably, if not mandatorily, leads to spill-over of work into ‘off-work’ hours and impinges on ‘family-hours’ or ‘personal-time.’ The support of one's spouse, parents and children in such settings cannot be undermined or understated. One needs to keep a balance between ‘All-work-and-no-play makes Jack a frustrated man’ versus ‘Jack-of-all-trades and master-of-none’. Neither is desirable and the ultimate aim is to have a satisfying career in thoracic oncology while working in an academic setting wherein one is able to: 1) provide patients (often under-privileged and belonging to poor socio-economic strata) the best diagnostic and treatment facilities (despite presence of resource constraints) – Patient Care 2) be involved in clinically relevant basic and translational research that has the potential to improve patient care in one’s own geographical location – Research 3) share one’s experience with residents/fellows and colleagues within the institute and outside – Medical Education Navneet Singh MD DM Email: [The author is a thoracic medical oncologist-cum-pulmonologist currently working as an Associate Professor of Pulmonary Medicine at the Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. He is a member of IASLC’s Staging & Prognostic Factors Committee; Publications Committee and is IASLC’s Regent for the Indian Subcontinent. Additionally, he is Chair-Elect of the American Society of Clinical Oncology’s (ASCO) International Development and Education Award (IDEA) Working Group and a member of its Multidisciplinary Cancer Management Course Working Group and Thoracic Cancer Guideline Advisory Group. His detailed profile is accessible at http://www.linkedin.com/in/navneet-singh-160012.]

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