Phase III Study Comparing Cisplatin Plus Gemcitabine With Cisplatin Plus Pemetrexed in Chemotherapy-Naive Patients With Advanced-Stage Non-Small-Cell Lung Cancer.

PURPOSE: Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non-small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting. PATIENTS AND METHODS: This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m2 on day 1 and gemcitabine 1,250 mg/m2 on days 1 and 8 (n = 863) or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 (n = 862) every 3 weeks for up to six cycles. RESULTS: Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P ≤ .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common. CONCLUSION: In advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.

Distinct patterns of occurrence, common associations, and survival of patients with second primary maligancies: A 5-year single institute experience with review of literature.

BACKGROUND: Multiple primary malignancy (MPM) is defined as occurrence of two or more synchronous or metachronous primary malignancies. With the rise in cancer burden and meticulous screening of index primary malignancy (IPM) during treatment, increased incidence of second primary malignancy (SPM) is expected. This study was undertaken with an attempt to analyze the incidence, commonest associations, management strategies, and clinical outcomes of MPM. MATERIALS AND METHODS: This is an observational retrospective study carried out in a single institute with patients registered between 1st January 2015 and 31st August 2019. The International Association of Cancer Registries and International Agency for Research on Cancer (IACR/IARC) definition was used for identification of IPM and SPM. Synchronous SPM was defined as malignancy occurring within 6 months from the diagnosis of IPM. RESULTS: Out of 16,461 registered patients during the study interval, 44 (0.26%) cases were found to have MPM. A total of 31 (70.5%) cases were women and 13 (29.5%) cases were men. Median age at presentation of IPM was 48 years and of SPM was 56 years, with median duration between two primaries being 38 months. Seven patients (15.9%) had synchronous malignancies. Gynecological tumors were the most common site of IPM presentation (n = 14, 31.8%) followed by breast (n = 09, 20.5%) and head and neck tumors (n = 07, 15.9%), respectively. The most common SPM was gynecological tumors (n = 12, 27.3%) followed by gastrointestinal malignancies (n = 10, 23.3%). Curative treatment was offered to 88% of patients with IPM and 70% patients with SPM. At a median follow-up of 365 days, 21 (47.72%) patients were disease free, six (13.6%) died of disease and nine (20.5%) were lost to follow-up. CONCLUSION: The study emphasizes the importance of detecting SPM as a result of improved diagnostic and screening procedures. Clinicians should be aware of it and offer multidisciplinary management.

Organising Home-based Palliative Care Services: A Quality Improvement project at the Homi Bhabha Cancer Hospital and Research Centre, Vishakhapatnam.

OBJECTIVES: The key component of a comprehensive palliative care (PC) unit is provision of a regular and sustainable home-based PC (HBPC) service. This quality improvement project aimed to plan, organise and sustain a regular HBPC service in a government cancer centre in Southeast India. The aim was to regularise and increase the number of home care visits among the patients identified for HBPC services through sustainable interventions. MATERIALS AND METHODS: The A3 methodology with its team-based, structured problem-solving approach was the tool used. The situational process map at baseline was followed up with a sequential cause and effect analysis and team discussions to create sustainable and reliable interventions. These included creating the electronic data system for data collection in PC, allocation of resources and implementation of systems to coordinate HBPC services. The roles and ownership to maintain improvement were established by designation and this requirement has been included in the job description to ensure reliability and sustainability. RESULTS: The regularisation of home care services with a consistent increase in the number of home visits from 2/week to over 6/week helped achieve the Specific, Measurable, Achievable, Relevant and Time bound goal. Better documentation, coordination and accountability were also positive outcomes. Working with different departments and teams along the project helped build trust and understanding along with a sound base for collaborative research. CONCLUSION: The A3 way of problem solving through dialogue and consensus helped to organise HBPC services and this methodology can be extended to other areas in future.

Influence of Caspase-9 polymorphisms on the development of Chronic Myeloid Leukemia- A case-control study.

INTRODUCTION: Chronic Myeloid Leukemia (CML) is a myeloproliferative disorder, characterized by the overproduction of myeloid cells in all stages of maturation. It is usually defined by three sequential stages (Chronic, Accelerated and Blast-crisis) where the transition from chronic to accelerated to blast phases is presumed to occur due to secondary genetic changes, viz. accumulation of mutations, activation of downstream pathways and failure of apoptosis. Caspase 9 is the initiator caspase involved in mitochondrial-mediated apoptotic pathway. Polymorphisms in the promoter (-1263 A>G, -712C>T, -293 del) and coding (Ex5 +32G>A) regions of CASP9 gene are found to influence the expression levels by either impairing the activation or loss of expression of CASP9 or insufficient formation of apoptosome. METHODS: The present case-control study was carried out on 999 individuals, comprised of 485CML cases reported at Nizams Institute of Medical Sciences (NIMS), Hyderabad and 514 age and gender-matched healthy individuals from local population. DNA was isolated by non-enzymatic/salting-out method and was genotyped using RFLP technique. RESULTS: It was observed that the presence of G allele of CASP9 -1263A>G polymorphism enhanced the risk for CML while CASP9 -712C>T and CASP9 -293del SNPs conferred protection against development of CML. Haplotype analysis of promoter and exonic polymorphisms had revealed increased risk associated with two haplotypes G_C_del (+)_G (OR-1.61, 95% CI-0.97-2.65, p-0.06#) and G_C_del (-)_G (OR-2.09, 95% CI-0.94-4.66, p-0.07#) suggesting the role of G allele of CASP9 -1263A>G in conferring risk independent of other SNPs. Pairwise LD analysis performed for all the four SNPs revealed the presence of LD among the SNPs. CONCLUSION: The results of the present study therefore concludes the role of CASP9 -1263A>G polymorphism in increasing the risk for the development and progression while CASP9 -712C>T and CASP9 -293del SNPs conferred protection and CASP9 Ex5 +32G>A was involved in conferring resistance which could be in combination with other SNPs or factors affecting them.

Targeted Therapy for Medullary Thyroid Cancer: A Review.

Medullary thyroid cancers (MTCs) constitute between 2 and 5% of all thyroid cancers. The 10-year overall survival (OS) rate of patients with localized disease is around 95% while that of patients with regional stage disease is about 75%. Only 20% of patients with distant metastases at diagnosis survive 10 years which is significantly lower than for differentiated thyroid cancers. Cases with regional metastases at presentation have high recurrence rates. Adjuvant external radiation confers local control but not improved OS. The management of residual, recurrent, or metastatic disease till a few years ago was re-surgery with local measures such as radiation. Chemotherapy was used with marginal benefit. The development of targeted therapy has brought in a major advantage in management of such patients. Two drugs-vandetanib and cabozantinib-have been approved for use in progressive or metastatic MTC. In addition, several drugs acting on other steps of the molecular pathway are being investigated with promising results. Targeted radionuclide therapy also provides an effective treatment option with good quality of life. This review covers the rationale of targeted therapy for MTC, present treatment options, drugs and methods under investigation, as well as an outline of the adverse effects and their management.

Lifelong vegetarianism and breast cancer risk: a large multicentre case control study in India.

BACKGROUND: The lower incidence of breast cancer in Asian populations where the intake of animal products is lower than that of Western populations has led some to suggest that a vegetarian diet might reduce breast cancer risk. METHODS: Between 2011 and 2014 we conducted a multicentre hospital based case-control study in eight cancer centres in India. Eligible cases were women aged 30-70 years, with newly diagnosed invasive breast cancer (ICD10 C50). Controls were frequency matched to the cases by age and region of residence and chosen from the accompanying attendants of the patients with cancer or those patients in the general hospital without cancer. Information about dietary, lifestyle, reproductive and socio-demographic factors were collected using an interviewer administered structured questionnaire. Multivariate logistic regression models were used to estimate the odds ratio (OR) and 95% confidence intervals for the risk of breast cancer in relation to lifelong vegetarianism, adjusting for known risk factors for the disease. RESULTS: The study included 2101 cases and 2255 controls. The mean age at recruitment was similar in cases (49.7 years (SE 9.7)) and controls (49.8 years (SE 9.1)). About a quarter of the population were lifelong vegetarians and the rates varied significantly by region. On multivariate analysis, with adjustment for known risk factors for the disease, the risk of breast cancer was not decreased in lifelong vegetarians (OR 1.09 (95% CI 0.93-1.29)). CONCLUSIONS: Lifelong exposure to a vegetarian diet appears to have little, if any effect on the risk of breast cancer.

Isolated humeral recurrence in endometrial carcinoma.

Isolated skeletal metastasis in endometrial carcinoma at recurrence is very rare. We report a 52-year-old woman diagnosed to have FIGO Stage 1b, Grade 1 endometrioid adenocarcinoma, presenting with isolated distal humerus metastasis, 2 years after surgery and adjuvant radiotherapy for primary disease. Imaging, bone scintigraphy, and cytology confirmed the diagnosis of poorly differentiated metastatic adenocarcinoma. She was treated with local radiotherapy followed by six cycles of paclitaxel and carboplatin chemotherapy along with zoledronic acid, monthly. She is symptom-free after the treatment and at a first follow-up visit after 3 months.

Paclitaxel injection concentrate for nanodispersion versus nab-paclitaxel in women with metastatic breast cancer: a multicenter, randomized, comparative phase II/III study.

Paclitaxel is widely used in the treatment of patients with metastatic breast cancer (MBC). Formulations of paclitaxel contain surfactants and solvents or albumin derived from human blood. The use of co-solvents such as polyoxyethylated castor oil is thought to contribute to toxicity profile and hypersensitivity reactions as well as leaching of plasticizers from polyvinyl chloride bags and infusion sets. Currently, nab-paclitaxel, an albumin-bound paclitaxel in nanometer range continues to be the preferred taxane formulation used in clinic. This study (CTRI/2010/091/001116) investigated the efficacy and tolerability of a polyoxyethylated castor oil- and albumin-free formulation of paclitaxel [paclitaxel injection concentrate for nanodispersion (PICN)] compared with nab-paclitaxel in women with refractory MBC. The current study was a multicenter, open-label, parallel-group, randomized, comparative phase II/III trial evaluating the efficacy and safety of PICN (260 mg/m(2) [n = 64] and 295 mg/m(2) [n = 58] every 3 weeks) compared with nab-paclitaxel (260 mg/m(2) every 3 weeks [n = 58]) in women 18 and 70 years old with confirmed MBC. Overall response rate (ORR) was assessed with imaging every 2 cycles. An independent analysis of radiologic data was performed for evaluable patients. Progression-free survival (PFS) was a secondary efficacy measure. Independent radiologist-assessed ORRs in the evaluable population of women aged ≥70 years were 35, 49, and 43 % in the PICN 260 mg/m(2), PICN 295 mg/m(2), and nab-paclitaxel 260 mg/m(2) arms, respectively. Median PFS in the evaluable population was 23, 35, and 34 weeks in the PICN 260 mg/m(2), PICN 295 mg/m(2), and nab-paclitaxel 260 mg/m(2) arms, respectively. Adverse events occurred in similar proportions of patients across treatment arms. Hypersensitivity reactions were not frequently observed with the clinical use of PICN across the treatment cohorts. In women with metastatic breast cancer, PICN at 260 and 295 mg/m(2) every 3 weeks was effective and well tolerated and showed similar tolerability compared with nab-paclitaxel 260 mg/m(2) every 3 weeks. Statistically, significant differences were not observed in the PICN and nab-paclitaxel treatment arms for radiologist-assessed ORR or median PFS. The novel paclitaxel formulation, PICN, offers apart from efficacy, potential safety advantage of decreased use of corticosteroid pretreatment and the absence of the risk of transmission of blood product-borne disease.

Significance of ATM Gene Polymorphisms in Chronic Myeloid Leukemia - a Case Control Study from India.

BACKGROUND: Development of chronic myeloid leukemia (CML) involves formation of double strand breaks (DSBs) which are initially sensed by the ataxia telangiectasia mutated (ATM) signal kinase to induce a DNA damage response (DDR). Mutations or single nucleotide polymorphisms in ATM gene are known to influence the signaling capacity resulting in susceptibility to certain genetic diseases such as cancers. MATERIALS AND METHODS: In the present study, we have analyzed -5144A>T (rs228589) and C4138T (rs3092856) polymorphisms of theATM gene through polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) in 925 subjects (476 CML cases and 449 controls). RESULTS: The A allele of -5144A>T polymorphism and T allele of C4138T polymorphism which were known to be influencing ATM signaling capacity are significantly associated with enhanced risk for CML independently and also in combination (evident from the haplotype and diplotype analyses). Significant elevation in the frequencies of both the risk alleles among high risk groups under European Treatment and Outcome Study (EUTOS) score suggests the possible role of these polymorphisms in predicting the prognosis of CML patients. CONCLUSIONS: This study provides the first evidence of association of functional ATM gene polymorphisms with the increased risk of CML development as well as progression.

Artificial neural network-based exploration of gene-nutrient interactions in folate and xenobiotic metabolic pathways that modulate susceptibility to breast cancer.

In the current study, an artificial neural network (ANN)-based breast cancer prediction model was developed from the data of folate and xenobiotic pathway genetic polymorphisms along with the nutritional and demographic variables to investigate how micronutrients modulate susceptibility to breast cancer. The developed ANN model explained 94.2% variability in breast cancer prediction. Fixed effect models of folate (400 µg/day) and B12 (6 µg/day) showed 33.3% and 11.3% risk reduction, respectively. Multifactor dimensionality reduction analysis showed the following interactions in responders to folate: RFC1 G80A × MTHFR C677T (primary), COMT H108L × CYP1A1 m2 (secondary), MTR A2756G (tertiary). The interactions among responders to B12 were RFC1G80A × cSHMT C1420T and CYP1A1 m2 × CYP1A1 m4. ANN simulations revealed that increased folate might restore ER and PR expression and reduce the promoter CpG island methylation of extra cellular superoxide dismutase and BRCA1. Dietary intake of folate appears to confer protection against breast cancer through its modulating effects on ER and PR expression and methylation of EC-SOD and BRCA1.

Prevalence and outcome of epidermal growth factor receptor mutations in non-squamous non-small cell lung cancer patients.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutation analysis has become an important part of the initial workup of non-squamous non-small cell lung cancer (NS-NSCLC) patients as it is now recognized both as a prognostic and predictive marker to therapy with EGFR tyrosine kinase inhibitors (TKI). AIM: In this retrospective study conducted at a University hospital, we evaluated the prevalence of EGFR mutations in patients with NS-NSCLC, clinico-pathological correlation and outcome to treatment with EGFR TKIs. MATERIALS AND METHODS: Case records of 147 patients of NS-NSCLC in whom EGFR mutation status was tested were screened. EGFR mutation analysis was done using DNA sequencing by real time polymerase chain reaction method from tissue and cell blocks prepared from core biopsy, fine needle aspiration cytology and pleural fluid specimens. RESULTS: EGFR mutations were seen in 30.6% of the 111 evaluable specimens, with a significantly higher rate in females (44% vs 19.6% P = 0.0072) as compared to men and non-smokers (41% vs 12% P = 0.0013) as against smokers. Most common mutations were observed in exons 19 (71%) and 21 (25%). The estimated median progression free survival for patients with and without mutations when treated with upfront TKIs was 12 months and 3 months respectively and the estimated median overall survival for patients with and without mutations was 20 and 9 months respectively. CONCLUSION: This study from India, further establishes the importance of upfront EGFR mutation testing in all NS-NSCLC patients, not only to prognosticate, but also to identify that subset of patients who could benefit from EGFR TKI therapy, early in the course of their disease.

Correlation of C/EBPα expression with response and resistance to imatinib in chronic myeloid leukaemia.

OBJECTIVE: Altered differentiation is a common feature of haematopoietic malignancies with poor prognosis. CAAT/enhancer binding protein alpha (C/EBPα) is a key transcription factor that regulates myeloid differentiation. This study is aimed to know the prognostic value of CAAT/enhancer binding protein alpha expression and correlate its expression with response to imatinib therapy. METHODS: We quantified the expression of C/EBPα gene in 126 chronic myeloid leukaemia samples (82 from newly diagnosed and 44 from imatinib-resistant patients) and 20 control samples. C/EBPα mRNA level was measured by real-time quantitative polymerase chain reaction using the ΔΔCT method. RESULTS: C/EBPα expression level was significantly lower in the imatinib-resistant group than in the pretreatment and control group (P = 0.0398). Low CAAT/enhancer binding protein alpha levels in the imatinib-resistant group were significantly associated with advanced phase (P = 0.04), with more peripheral blasts (P = 0.0001), high BCR-ABL levels (P = 0.018) and T315I and P-loop mutations (P = 0.0002). In the pretreatment group, low expression showed association with high EUTOS risk score (P = 0.03) and possible partial cytogenetic response (P = 0.010). CONCLUSIONS: Our results suggest that low expression of CAAT/enhancer binding protein alpha might have a role in the response to imatinib and progression of disease in patients with chronic myeloid leukaemia.

Role of the MDM2 promoter polymorphism (-309T>G) in acute myeloid leukemia development.

BACKGROUND: The human homologue of the mouse double minute 2 (MDM2) gene is a negative regulator of Tp53. MDM2-309T>G a functional promoter polymorphism was found to be associated with overexpression thereby attenuation of Tp53 stress response and increased cancer susceptibility. We have planned to evaluate the possible role of MDM2-309T>G polymorphism with risk and response to chemotherapy in AML. MATERIALS AND METHODS: A total of 223 de novo AML cases and 304 age and sex matched healthy controls were genotyped for the MDM2-309T>G polymorphism through the tetra-primer amplification refractory mutation system (ARMS)-PCR method. In order to assess the functional relationship of -309T>G SNP with MDM2 expression level, we quantified MDM2 mRNA in 30 primary AML blood samples through quantitative RT-PCR. Both the (-309T>G) genotypes and the MDM2 expression were correlated with disease free survival (DFS) rates among patients who have achieved complete remission (CR) after first induction chemotherapy. RESULTS: MDM2-309T>G polymorphism was significantly associated with AML development (p<0.0001). The presence of either GG genotype or G allele at MDM2-309 confered 1.79 (95% CI: 1.12-2.86; p<0.001) and 1.46 fold (95%CI: 1.14-1.86; p=0.003) increased AML risk. Survival analysis revealed that CR+ve cases with GG genotype had significantly increased DFS rates (16months, p=0.05) compared to CR+ve TT (11 months) and TG (9 months) genotype groups. Further, MDM2 expression was also found to be significantly elevated in GG genotype patients (p=0.0039) and among CR+ve cases (p=0.0036). CONCLUSIONS: The MDM2-309T>G polymorphism might be involved in AML development and also serve as a good prognostic indicator.

Final analysis of the efficacy and safety of omacetaxine mepesuccinate in patients with chronic- or accelerated-phase chronic myeloid leukemia: Results with 24 months of follow-up.

BACKGROUND: Omacetaxine, a protein synthesis inhibitor, is indicated in the United States for the treatment of patients with chronic-phase (CP) or accelerated-phase (AP) chronic myeloid leukemia (CML) with resistance and/or intolerance to 2 or more tyrosine kinase inhibitors. METHODS: The final analysis, with 24 months of follow-up, included additional efficacy and safety analyses to assess the benefit of long-term omacetaxine administration (1.25 mg/m(2) twice daily for 14 days every 28 days followed by 7 days every 28 days) in CP-CML and AP-CML patients receiving >3 cycles. RESULTS: Eighteen percent of CP-CML patients achieved a major cytogenetic response (MCyR) with a median duration of 12.5 months (95% confidence interval [CI], 3.5 months to not reached [NR]); responses were maintained for ≥12 months in 3 of 14 responders, and the median overall survival (OS) was 40.3 months (95% CI, 23.8 months to NR). Among patients with AP-CML, 14% achieved or maintained a major hematologic response for a median of 4.7 months (95% CI, 3.6 months to NR); MCyR was not achieved, and the median OS was 14.3 months (95% CI, 6.7-18.7 months). In patients with CP-CML and patients with AP-CML who received >3 cycles of treatment (n = 50 and n = 14, respectively), the median OS was 49.3 months (95% CI, 23.8 months to NR) and 24.6 months (95% CI, 12-37.2 months), respectively. Grade 3 or higher hematologic toxicities were the major side effects (79% and 73% for CP-CML and AP-CML, respectively), with discontinuation due to toxicity in 10% of CP patients and in 5% of AP patients. CONCLUSIONS: These results suggest that the long-term administration of omacetaxine is feasible with dose adjustments to manage toxicities and that omacetaxine provides a durable benefit for some patients.