Shrividya Iyer

Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer

BACKGROUND In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown. METHODS We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen. Patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. RESULTS The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval [CI], 0.37 to 0.64; P<0.001). The response rates were 65% (95% CI, 58 to 72) with crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy. CONCLUSIONS Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement. (Funded by Pfizer; ClinicalTrials.gov number, NCT00932893.).

First-line crizotinib versus chemotherapy in ALK-positive lung cancer.

BACKGROUND The efficacy of the ALK inhibitor crizotinib as compared with standard chemotherapy as first-line treatment for advanced ALK-positive non-small-cell lung cancer (NSCLC) is unknown. METHODS We conducted an open-label, phase 3 trial comparing crizotinib with chemotherapy in 343 patients with advanced ALK-positive nonsquamous NSCLC who had received no previous systemic treatment for advanced disease. Patients were randomly assigned to receive oral crizotinib at a dose of 250 mg twice daily or to receive intravenous chemotherapy (pemetrexed, 500 mg per square meter of body-surface area, plus either cisplatin, 75 mg per square meter, or carboplatin, target area under the curve of 5 to 6 mg per milliliter per minute) every 3 weeks for up to six cycles. Crossover to crizotinib treatment after disease progression was permitted for patients receiving chemotherapy. The primary end point was progression-free survival as assessed by independent radiologic review. RESULTS Progression-free survival was significantly longer with crizotinib than with chemotherapy (median, 10.9 months vs. 7.0 months; hazard ratio for progression or death with crizotinib, 0.45; 95% confidence interval [CI], 0.35 to 0.60; P<0.001). Objective response rates were 74% and 45%, respectively (P<0.001). Median overall survival was not reached in either group (hazard ratio for death with crizotinib, 0.82; 95% CI, 0.54 to 1.26; P=0.36); the probability of 1-year survival was 84% with crizotinib and 79% with chemotherapy. The most common adverse events with crizotinib were vision disorders, diarrhea, nausea, and edema, and the most common events with chemotherapy were nausea, fatigue, vomiting, and decreased appetite. As compared with chemotherapy, crizotinib was associated with greater reduction in lung cancer symptoms and greater improvement in quality of life. CONCLUSIONS Crizotinib was superior to standard first-line pemetrexed-plus-platinum chemotherapy in patients with previously untreated advanced ALK-positive NSCLC. (Funded by Pfizer; PROFILE 1014 ClinicalTrials.gov number, NCT01154140.).

Subcutaneous Methylnaltrexone for Treatment of Opioid-Induced Constipation in Patients With Chronic, Nonmalignant Pain: A Randomized Controlled Study

UNLABELLED Methylnaltrexone is effective for opioid-induced constipation (OIC) in advanced illness patients. This 4-week, double-blind, randomized, placebo-controlled study investigated the effect of subcutaneous methylnaltrexone on OIC in patients receiving opioids for chronic, nonmalignant pain. Patients (N = 460) received subcutaneous methylnaltrexone 12 mg once daily (QD) or every other day (alternating with placebo) compared with placebo. Assessments included bowel movement count, time of bowel movement, straining, sense of complete evacuation, Bristol Stool Form Scales, and quality of life. Within 4 hours of first dose, 34.2% of patients in both methylnaltrexone groups had rescue-free bowel movements (RFBMs) versus 9.9% on placebo (P < .001). The estimated number needed to treat was about 4. On average, 28.9% of methylnaltrexone QD and 30.2% of methylnaltrexone alternate-day dosing resulted in RFBMs within 4 hours versus 9.4% QD and 9.3% alternate-day placebo injections (both P < .001). Both methylnaltrexone groups had significantly shorter time to first RFBM (P < .001) and greater increase in number of weekly RFBMs (P < .05) versus placebo. Adverse events included abdominal pain, diarrhea, nausea, and hyperhidrosis. Bristol Stool Form Scale scores (P = .002) and sensation of complete evacuation (P < .04) were significantly superior with methylnaltrexone QD; both methylnaltrexone groups reported no or mild straining during RFBMs in the first 2 weeks (P < .02). At 4 weeks, a significantly greater improvement in patient-reported, constipation-specific quality of life was seen in the alternate-day dosing (P < .05) and QD (P < .001) groups. PERSPECTIVE We present data demonstrating that subcutaneous methylnaltrexone 12 mg given once daily (QD) or every other day provides significant relief of OIC and was generally well tolerated in patients with chronic, nonmalignant pain. These results expand on prior effectiveness observed for the treatment of OIC in advanced illness patients to a broader population.

Symptom burden and quality of life in advanced non-small cell lung cancer patients in France and Germany

BACKGROUND To assess patient reported symptom burden and impact on disease specific health related quality of life (HRQOL) in advanced non-small cell lung cancer (NSCLC) patients. METHODS Patients with advanced (stage IIIB/IV) NSCLC in France (n = 613) and Germany (n = 600) were recruited into a multicenter, patient record-based cross-sectional study. Patient reported symptoms using the Lung Cancer Symptom Scale, which assesses fatigue, loss of appetite, shortness of breath, cough, pain and blood in sputum on a 0-100 visual analog scale. Disease specific and generic HRQOL were assessed using the Functional Assessment of Cancer Therapy-Lung (FACT-L) and the EuroQol five-dimensional questionnaire (EQ-5D) respectively. A multivariate regression analysis was performed with total FACT-L score as the dependent variable and symptom scores as predictors. Age, gender, stage and performance status were used as control variables. RESULTS Majority of the patients were male (67%), Caucasian (93%) with an average age of 63 years. Fatigue, loss of appetite, shortness of breath, cough and pain were reported by ≥ 90% of patients. The mean health utility index score was found to be 0.58 and the mean general health status score was 58.0. Fatigue (β = -0.122; p < 0.001), loss of appetite (β = -0.170; p < 0.001), pain (β = -0.145; p < 0.001), shortness of breath (β = -0.118; p < 0.001) were found to be significant predictors of lung cancer specific quality of life as measured by the FACT-L total score. CONCLUSION Fatigue, loss of appetite, shortness of breath and pain have a significant negative impact on patient reported disease specific HRQOL in advanced NSCLC patients.

Impact of Constipation on Opioid Use Patterns, Health Care Resource Utilization, and Costs in Cancer Patients on Opioid Therapy

Patterns of opioid use, resource utilization, and costs in cancer patients with and without constipation were compared using retrospective insurance claims data. Inclusion criteria were ≥30 days of opioid use and continuous plan coverage for ≥6 months before and ≥12 months following first opioid claim (index date). Constipation was defined as ≥1 ICD-9-CM diagnosis codes in the range of 564.0x during the 12 months postindex date. Of the 8836 opioid initiators with cancer initially considered, approximately 9.3% (n = 821) had a diagnosis of constipation during follow-up. Opioid use patterns were compared between patients with constipation and matched controls. Two-part semilogarithmic regression models assessed the impact of constipation on resource utilization and associated costs. Compared with controls without constipation, patients with constipation had higher rates of concurrent use of ≥2 opioids (P < .0001), opioid discontinuation (P = .0002), opioid switching (P < .0001), nausea with vomiting (P < .0001), and respiratory depression (P = .0003). Compared with controls, more patients with constipation received inpatient (P < .0001), hospice (P = .0086), home health (P < .0001), laboratory (P = .0015), other outpatient (P < .0001), emergency (P < .0001), office visit (P < .0001), and nursing home care (P = .0266). Compared with controls, patients with constipation had substantially higher total costs (P < .0001). This study suggests that in opioid-treated cancer patients, constipation significantly impacts opioid-use patterns, resource utilization, and costs. Alleviation of constipation may optimize opioid therapy and reduce costs.

Quality of Life With Palbociclib Plus Fulvestrant in Previously Treated Hormone Receptor–Positive, HER2-Negative Metastatic Breast Cancer: Patient-Reported Outcomes From the PALOMA-3 Trial

In treating HR+, HER2− metastatic breast cancer, novel agents that enhance endocrine therapy activity but do not worsen quality of life (QoL) are clinically desired. Patient-reported outcomes data from the PALOMA-3 study suggest palbociclib plus fulvestrant allow patients to maintain good QoL in the endocrine resistance setting while experiencing a substantially delayed disease progression.

Effect of subcutaneous methylnaltrexone on patient-reported constipation symptoms.

BACKGROUND Methylnaltrexone, a selective peripheral acting mu-opioid receptor antagonist, alleviates the constipating effects of opioids without affecting centrally mediated analgesia. OBJECTIVES To assess the effect of subcutaneous (SC) methylnaltrexone injection on patient-reported constipation symptoms and pain scores. METHODS A total of 469 subjects on opioids for chronic non-malignant pain with opioid-induced constipation were randomized to methylnaltrexone SC with once daily (QD) or every other day (QOD) dosing or placebo for 4 weeks. Constipation symptoms and pain were assessed using the patient assessment of constipation-symptoms (PAC-SYM) questionnaire and a 11-point scale, respectively, at baseline, Day 14 and Day 28. Change from baseline in PAC-SYM and pain scores were compared between methylnaltrexone and placebo arms at Day 28 using analysis of covariance, with treatment group as factor and baseline score as covariate. RESULTS A majority of patients were women (60%), average age was 49 years old, and back pain (60%) was the primary pain condition. At Day 28, the methylnaltrexone SC QD group showed a significant improvement over placebo for rectal symptoms (-0.56 vs. -0.30; P < 0.05), stool symptoms (-0.76 vs. -0.43; P < 0.001) and global scores (-0.62 vs. -0.37; P < 0.001). Improvement in stool symptoms (-0.69 vs.-0.43; P < 0.05) and the global scores (-0.52 vs. -0.37; P < 0.05) were significantly greater than placebo in the methylnaltrexone QOD group. Differences in change from baseline in abdominal symptoms and pain scores between the methylnaltrexone SC QD or QOD dosing arms and placebo were not significant. CONCLUSION The results of our study indicate significant improvement in constipation symptoms with methylnaltrexone QD or QOD dosing compared to placebo without a significant effect on pain scores.

Incidence-based cost-of-illness model for metastatic breast cancer in the United States.

OBJECTIVES This study aims to estimate the annual U.S. societal costs associated with treatment of metastatic breast cancer (MBC) patients using an incidence-based cost-of-illness (COI) framework. METHODS An incidence-based COI model was constructed in which MBC patients were simulated from diagnosis through active treatment, palliative care, and death over 5 years. Key model parameters included: annual incidence of breast cancer in the metastatic stage, utilization of cancer therapies and other medical care resources, treatment-related adverse events, unit costs, work days missed by patient and caregiver, and wage rates. Overall survival was based on SEER data and costs were assigned to living patients monthly, according to their disease management phase. The outcomes measures were total discounted societal costs, cost/year, and cost/patient-year. RESULTS The annual incidence of MBC in the United States in 2007 was estimated to be 49,674 patients (de novo and progressed from earlier stages). The total discounted cost to society attributable to MBC was

Effect of pioglitazone on metabolic syndrome risk factors: results of double-blind, multicenter, randomized clinical trials.

12.2 billion for the incident cohort, or

Patient-Reported Outcomes and Quality of Life in PROFILE 1007: A Randomized Trial of Crizotinib Compared with Chemotherapy in Previously Treated Patients with ALK-Positive Advanced Non–Small-Cell Lung Cancer

98,571 per patient-year. The 5-year direct medical cost of this incident cohort was