Kumar Prabhash

Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial.

BACKGROUND Ramucirumab is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. We aimed to assess efficacy and safety of treatment with docetaxel plus ramucirumab or placebo as second-line treatment for patients with stage IV non-small-cell-lung cancer (NSCLC) after platinum-based therapy. METHODS In this multicentre, double-blind, randomised phase 3 trial (REVEL), we enrolled patients with squamous or non-squamous NSCLC who had progressed during or after a first-line platinum-based chemotherapy regimen. Patients were randomly allocated (1:1) with a centralised, interactive voice-response system (stratified by sex, region, performance status, and previous maintenance therapy [yes vs no]) to receive docetaxel 75 mg/m(2) and either ramucirumab (10 mg/kg) or placebo on day 1 of a 21 day cycle until disease progression, unacceptable toxicity, withdrawal, or death. The primary endpoint was overall survival in all patients allocated to treatment. We assessed adverse events according to treatment received. This study is registered with ClinicalTrials.gov, number NCT01168973. FINDINGS Between Dec 3, 2010, and Jan 24, 2013, we screened 1825 patients, of whom 1253 patients were randomly allocated to treatment. Median overall survival was 10·5 months (IQR 5·1-21·2) for 628 patients allocated ramucirumab plus docetaxel and 9·1 months (4·2-18·0) for 625 patients who received placebo plus docetaxel (hazard ratio 0·86, 95% CI 0·75-0·98; p=0·023). Median progression-free survival was 4·5 months (IQR 2·3-8·3) for the ramucirumab group compared with 3·0 months (1·4-6·9) for the control group (0·76, 0·68-0·86; p<0·0001). We noted treatment-emergent adverse events in 613 (98%) of 627 patients in the ramucirumab safety population and 594 (95%) of 618 patients in the control safety population. The most common grade 3 or worse adverse events were neutropenia (306 patients [49%] in the ramucirumab group vs 246 [40%] in the control group), febrile neutropenia (100 [16%] vs 62 [10%]), fatigue (88 [14%] vs 65 [10%]), leucopenia (86 [14%] vs 77 [12%]), and hypertension (35 [6%] vs 13 [2%]). The numbers of deaths from adverse events (31 [5%] vs 35 [6%]) and grade 3 or worse pulmonary haemorrhage (eight [1%] vs eight [1%]) did not differ between groups. Toxicities were manageable with appropriate dose reductions and supportive care. INTERPRETATION Ramucirumab plus docetaxel improves survival as second-line treatment of patients with stage IV NSCLC. FUNDING Eli Lilly.

Three-dimensional conformal radiotherapy (3D-CRT) versus intensity modulated radiation therapy (IMRT) in squamous cell carcinoma of the head and neck: A randomized controlled trial

PURPOSE To compare three-dimensional conformal radiotherapy (3D-CRT) with intensity modulated radiation therapy (IMRT) in curative-intent irradiation of head-neck squamous cell carcinoma (HNSCC). METHODS Previously untreated patients with biopsy-proven squamous carcinoma of oropharynx, larynx, or hypopharynx (T1-3, N0-2b) were randomly assigned using computer-generated permuted-block design to either 3D-CRT or IMRT, with incidence of physician-rated Radiation Therapy Oncology Group (RTOG) grade 2 or worse acute salivary gland toxicity as primary end-point. RESULTS Between 2005 and 2008, 60 patients randomly allocated to either 3D-CRT (n=28 patients) or IMRT (n=32) were included and analyzed on an intention-to-treat basis. The proportion [95% confidence intervals (CI)] of patients with RTOG grade 2 or worse acute salivary gland toxicity was significantly lesser in the IMRT arm [19 of 32 patients (59%, 95%CI: 42-75%)] as compared to 3D-CRT [25 of 28 patients (89%, 95%CI: 72-97%; p=0.009)]. Late xerostomia and subcutaneous fibrosis were also significantly lesser with IMRT. There was significant recovery of salivary function over time in patients treated with IMRT (p-value for trend=0.0036). At 3-years, there were no significant differences in loco-regional control or survival between the two arms. CONCLUSION IMRT significantly reduces the incidence and severity of xerostomia compared to 3D-CRT in curative-intent irradiation of HNSCC.

Overall Survival Improvement in Patients with Lung Cancer and Bone Metastases Treated with Denosumab Versus Zoledronic Acid: Subgroup Analysis from a Randomized Phase 3 Study

Introduction: Denosumab, a fully human anti-RANKL monoclonal antibody, reduces the incidence of skeletal-related events in patients with bone metastases from solid tumors. We present survival data for the subset of patients with lung cancer, participating in the phase 3 trial of denosumab versus zoledronic acid (ZA) in the treatment of bone metastases from solid tumors (except breast or prostate) or multiple myeloma. Methods: Patients were randomized 1:1 to receive monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg. An exploratory analysis, using Kaplan–Meier estimates and proportional hazards models, was performed for overall survival among patients with non–small-cell lung cancer (NSCLC) and SCLC. Results: Denosumab was associated with improved median overall survival versus ZA in 811 patients with any lung cancer (8.9 versus 7.7 months; hazard ratio [HR] 0.80) and in 702 patients with NSCLC (9.5 versus 8.0 months; HR 0.78) (p = 0.01, each comparison). Further analysis of NSCLC by histological type showed a median survival of 8.6 months for denosumab versus 6.4 months for ZA in patients with squamous cell carcinoma (HR 0.68; p = 0.035). Incidence of overall adverse events was balanced between treatment groups; serious adverse events occurred in 66.0% of denosumab-treated patients and 72.9% of ZA-treated patients. Cumulative incidence of osteonecrosis of the jaw was similar between groups (0.7% denosumab versus 0.8% ZA). Hypocalcemia rates were 8.6% with denosumab and 3.8% with ZA. Conclusion: In this exploratory analysis, denosumab was associated with improved overall survival compared with ZA, in patients with metastatic lung cancer.

Espindolol for the treatment and prevention of cachexia in patients with stage III/IV non-small cell lung cancer or colorectal cancer: a randomized, double-blind, placebo-controlled, international multicentre phase II study (the ACT-ONE trial).

Cancer cachexia is a major cause of morbidity and mortality with no widely approved treatment.

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.

Frequency of EGFR Mutations in 907 Lung Adenocarcioma Patients of Indian Ethnicity

Background During the past decade, the incidence of EGFR mutation has been shown to vary across different ethnicities. It occurs at the rate of 10–15% in North Americans and Europeans, 19% in African-Americans, 20–30% in various East Asian series including Chinese, Koreans, and Japanese. Frequency of EGFR mutations in India however remains sparsely explored. Methodology/Principal Findings We report 23% incidence of Epidermal growth factor receptor (EGFR) mutations in 907 Non small cell lung cancer (NSCLC) patients of Indian ethnicity, in contrast to 10–15% known in Caucasians and 27–62% among East Asians. In this study, EGFR mutations were found to be more common in never-smokers 29.4% as compared to smokers 15.3%. Consistent with other populations, mutation rates among adenocarcinoma-males were predominantly lower than females with 32% incidence. However unlike Caucasians, EGFR mutation rate among adenocarcinoma-never-smoker females were comparable to males suggesting lack of gender bias among never smokers likely to benefit from EGFR targeted therapy. Conclusions/Significance This study has an overall implication for establishing relevance for routine EGFR mutation diagnostics for NSCLC patients in clinics and emphasizes effectiveness for adoption of EGFR inhibitors as the first line treatment among Indian population. The intermediate frequency of EGFR mutation among Indian population compared to Caucasians and East Asians is reminiscent of an ancestral admixture of genetic influence from Middle Easterners, Central Asians, and Europeans on modern- Indian population that may confer differential susceptibility to somatic mutations in EGFR.

Epidemiology of lung cancer in India: Focus on the differences between non-smokers and smokers: A single-centre experience

CONTEXT Lung cancer has varied epidemiology depending on the geographic region. Globally, there have been important changes in incidence trends amongst men and women, histology, and incidence in non-smokers. Indian epidemiological data on lung cancer is scarce. AIMS We set out to study the epidemiological patterns and clinical profile of lung cancer in India. MATERIALS AND METHODS We interviewed patients discussed in the thoracic oncology multidisciplinary meetings between 2008 and 2009. Demographic data, smoking history, place of residence, histology, stage at presentation, and treatment details were collected. Data was entered and analyzed in SPSS. RESULTS There were 489 patients, with a median age of 56 years, of which 255 (52%) were non-smokers and 234 (48%) were smokers. One hundred and thirty-three patients had consumed smokeless tobacco. The male-to-female ratio was 3.5:1. Sixty-nine patients (14.1%) were incorrectly diagnosed and treated with anti-tuberculosis treatment, which delayed the diagnosis of lung cancer by four months. Eight percent of patients had small-cell carcinoma; of the 92% patients with non-small-cell carcinoma (NSCLC), the most common histology was adenocarcinoma (43.8%), followed by squamous cell (26.2%), large cell (2.1%) and other (8.3%). Eighteen percent of patients were diagnosed by cytology, therefore were diagnosed as NSCLC, without further histologic subtyping. Most patients (43%) were in Stage III at presentation. Lung followed by bone were the common sites of metastases. The majority of the patients (49%) received palliative chemotherapy. Among definitive therapy, concurrent chemo-radiation (13%) was offered more frequently than surgery (6%). CONCLUSION Considerably higher numbers of Indian patients with lung cancer are non-smokers, compared to the West. The global trend of rise in adenocarcinoma is paralleled in India. Non-tobacco-related risk factors need further investigation.

Final Efficacy and Safety Results of Pemetrexed Continuation Maintenance Therapy in the Elderly from the PARAMOUNT Phase III Study

Introduction: The PARAMOUNT Phase III trial showed that maintenance pemetrexed after pemetrexed plus cisplatin induction was well tolerated and effective for patients with advanced nonsquamous non–small-cell lung cancer. Approximately 17% of patients receiving maintenance therapy in this study were 70 years of age or older. Here we report efficacy and safety results from the PARAMOUNT study for elderly (≥70 years) and non-elderly (<70 years) patients. Methods: Final efficacy and safety data from the PARAMOUNT study were analyzed post hoc using subgroup analyses for elderly and non-elderly patients. Results: The median age was 73 years in the elderly subgroup (n = 92) and 60 years in the non-elderly subgroup (n = 447). Subgroups had similar baseline characteristics, except for a higher percentage of males and patients with a performance status of one in the elderly subgroup. For elderly patients, the median PFS was 6.4 months for pemetrexed and 3.0 months for placebo; the median OS was 13.7 months for pemetrexed and 12.1 months for placebo. For non-elderly patients, the median PFS was 4.0 months for pemetrexed and 2.8 months for placebo; the median OS was 13.9 months for pemetrexed and 10.8 months for placebo. Elderly patients experienced similar levels of low-grade toxicities, but had a higher percentage of grade 3/4 anemia and neutropenia than non-elderly patients, although importantly, this did not translate into increased febrile neutropenia. Conclusions: Continuation maintenance pemetrexed had comparable survival and toxicity profiles in the elderly and non-elderly subgroups. However, grade 3/4 anemia and neutropenia were numerically higher for elderly patients.

A prospective randomized phase II study comparing metronomic chemotherapy with chemotherapy (single agent cisplatin), in patients with metastatic, relapsed or inoperable squamous cell carcinoma of head and neck.

BACKGROUND Cetuximab based treatment is the recommended chemotherapy for head and neck squamous cell cancers in the palliative setting. However, due to financial constraints, intravenous (IV) chemotherapy without cetuximab is commonly used in lesser developed countries. We believe that oral metronomic chemotherapy may be safer and more effective in this setting. METHODS We conducted an open label, superiority, parallel design, randomized phase II trial comparing oral MCT [daily celecoxib (200mg twice daily) and weekly methotrexate (15mg/m(2))] to intravenous single agent cisplatin (IP) (75mg/m(2)) given 3 weekly. Eligible patients had head and neck cancers requiring palliative chemotherapy with ECOG PS 0-2 and adequate organ functions who could not afford cetuximab. The primary end point was progression-free survival. RESULTS 110 Patients were recruited between July 2011 to May 2013, 57 randomized to the MCT arm and 53 to the IP arm. Patients in the MCT arm had significantly longer PFS (median 101 days, 95% CI: 58.2-143.7 days) compared to the IP arm (median 66 days, 95% CI; 55.8-76.1 days) (p=0.014). The overall survival (OS) was also increased significantly in the MCT arm (median 249 days, 95% CI: 222.5-275.5 days) compared to the IP arm (median 152 days, 95% CI: 104.2-199.8 days) (p=0.02). There were fewer grade 3/4 adverse effects with MCT, which was not significant. (18.9% vs. 31.4%, P=0.14). CONCLUSION Oral metronomic chemotherapy has significantly better PFS and OS than single agent platinum in the palliative setting.

Blood stream infections in cancer patients: A single center experience of isolates and sensitivity pattern

BACKGROUND Up to 10% of patients who develop a nosocomial blood stream infection (BSI) in the hospital have an underlying malignancy. The treatment of infections in patients with malignancy often relies on the use of established guidelines along with the consideration of the local microbiology and antibiotic sensitivity patterns of possible etiologic agents. AIMS This study attempts to identify the likely etiologic agents and the antibiotic sensitivity profile of BSIs in cancer patients. SETTINGS AND DESIGN This was a retrospective study. METHODS AND MATERIAL The study was conducted at a tertiary care center for cancer patients, in which samples representing blood stream infections sent from the Medical Oncology services of the hospital during the year of 2007 were analysed. The microbiological profile and antibiotic sensitivity pattern of these isolates was studied. RESULTS There were 484 isolates that represented BSIs. The most common bacterial isolates from patients with cancer were Pseudomonas spp. (30.37%), Staphylococcus aureus (12.6%) and Acinetobacter spp. (11.57%). Meropenem was the most effective antibiotic with 71.2% sensitivity to the bacterial isolates it was tested against. Oxacillin resistance was seen in 18% of S. aureus isolates. CONCLUSION Gram-negative bacteria were more common as etiologic agents of BSIs in cancer patients. The poor activity of the primary empirical agents for infections in cancer namely ceftazidime and piperacillin-tazobactam is alarming.Strict regulation of vancomycin use should be considered in areas where there is a low prevalence of methicillin-resistant S. aureus (MRSA).