Patrapim Sunpaweravong

Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma

BACKGROUND Previous, uncontrolled studies have suggested that first-line treatment with gefitinib would be efficacious in selected patients with non-small-cell lung cancer. METHODS In this phase 3, open-label study, we randomly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival. RESULTS The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with carboplatin-paclitaxel. The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority, as compared with carboplatin-paclitaxel, with respect to progression-free survival in the intention-to-treat population (hazard ratio for progression or death, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene (EGFR) mutation, progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin-paclitaxel (hazard ratio for progression or death, 0.48; 95% CI, 0.36 to 0.64; P<0.001), whereas in the subgroup of 176 patients who were negative for the mutation, progression-free survival was significantly longer among those who received carboplatin-paclitaxel (hazard ratio for progression or death with gefitinib, 2.85; 95% CI, 2.05 to 3.98; P<0.001). The most common adverse events were rash or acne (in 66.2% of patients) and diarrhea (46.6%) in the gefitinib group and neurotoxic effects (69.9%), neutropenia (67.1%), and alopecia (58.4%) in the carboplatin-paclitaxel group. CONCLUSIONS Gefitinib is superior to carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib. (ClinicalTrials.gov number, NCT00322452.)

Biomarker Analyses and Final Overall Survival Results From a Phase III, Randomized, Open-Label, First-Line Study of Gefitinib Versus Carboplatin/Paclitaxel in Clinically Selected Patients With Advanced Non–Small-Cell Lung Cancer in Asia (IPASS)

PURPOSE The results of the Iressa Pan-Asia Study (IPASS), which compared gefitinib and carboplatin/paclitaxel in previously untreated never-smokers and light ex-smokers with advanced pulmonary adenocarcinoma were published previously. This report presents overall survival (OS) and efficacy according to epidermal growth factor receptor (EGFR) biomarker status. PATIENTS AND METHODS In all, 1,217 patients were randomly assigned. Biomarkers analyzed were EGFR mutation (amplification mutation refractory system; 437 patients evaluable), EGFR gene copy number (fluorescent in situ hybridization; 406 patients evaluable), and EGFR protein expression (immunohistochemistry; 365 patients evaluable). OS analysis was performed at 78% maturity. A Cox proportional hazards model was used to assess biomarker status by randomly assigned treatment interactions for progression-free survival (PFS) and OS. RESULTS OS (954 deaths) was similar for gefitinib and carboplatin/paclitaxel with no significant difference between treatments overall (hazard ratio [HR], 0.90; 95% CI, 0.79 to 1.02; P = .109) or in EGFR mutation-positive (HR, 1.00; 95% CI, 0.76 to 1.33; P = .990) or EGFR mutation-negative (HR, 1.18; 95% CI, 0.86 to 1.63; P = .309; treatment by EGFR mutation interaction P = .480) subgroups. A high proportion (64.3%) of EGFR mutation-positive patients randomly assigned to carboplatin/paclitaxel received subsequent EGFR tyrosine kinase inhibitors. PFS was significantly longer with gefitinib for patients whose tumors had both high EGFR gene copy number and EGFR mutation (HR, 0.48; 95% CI, 0.34 to 0.67) but significantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation (HR, 3.85; 95% CI, 2.09 to 7.09). CONCLUSION EGFR mutations are the strongest predictive biomarker for PFS and tumor response to first-line gefitinib versus carboplatin/paclitaxel. The predictive value of EGFR gene copy number was driven by coexisting EGFR mutation (post hoc analysis). Treatment-related differences observed for PFS in the EGFR mutation-positive subgroup were not apparent for OS. OS results were likely confounded by the high proportion of patients crossing over to the alternative treatment.

Phase III Trial of Vandetanib Compared With Erlotinib in Patients With Previously Treated Advanced Non–Small-Cell Lung Cancer

PURPOSE Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling. This phase III study assessed the efficacy of vandetanib versus erlotinib in unselected patients with advanced non-small-cell lung cancer (NSCLC) after treatment failure with one to two prior cytotoxic chemotherapy regimens. PATIENTS AND METHODS One thousand two hundred forty patients were randomly assigned to receive vandetanib 300 mg/d (n = 623) or erlotinib 150 mg/d (n = 617). The primary objective was to show superiority in progression-free survival (PFS) for vandetanib versus erlotinib. If the difference did not reach statistical significance for superiority, a noninferiority analysis was conducted. RESULTS There was no significant improvement in PFS for patients treated with vandetanib versus erlotinib (hazard ratio [HR], 0.98; 95.22% CI, 0.87 to 1.10; P = .721); median PFS was 2.6 months for vandetanib and 2.0 months for erlotinib. There was also no significant difference for the secondary end points of overall survival (HR, 1.01; P = .830), objective response rate (both 12%), and time to deterioration of symptoms for pain (HR, 0.92; P = .289), dyspnea (HR, 1.07; P = .407), and cough (HR, 0.94; P = .455). Both agents showed equivalent PFS and overall survival in a preplanned noninferiority analysis. Adverse events (AEs; any grade) more frequent with vandetanib than erlotinib included diarrhea (50% v 38%, respectively) and hypertension (16% v 2%, respectively); rash was more frequent with erlotinib than vandetanib (38% v 28%, respectively). The overall incidence of grade ≥ 3 AEs was also higher with vandetanib than erlotinib (50% v 40%, respectively). CONCLUSION In patients with previously treated advanced NSCLC, vandetanib showed antitumor activity but did not demonstrate an efficacy advantage compared with erlotinib. There was a higher incidence of some AEs with vandetanib.

Randomized study of antiinflammatory and immune-modulatory effects of enteral immunonutrition during concurrent chemoradiotherapy for esophageal cancer.

Concurrent chemoradiotherapy (CCRT) induces toxicities from inflammation and immunological suppression. Omega-3 fatty acids, glutamine, and arginine are therapeutic factors that can attenuate such inflammation and promote cellular immunity. The question is whether immunonutrition (IN) during CCRT reduces inflammation and improves the immune function in patients with esophageal squamous cell carcinoma (ESCC). Seventy-one locally advanced ESCC patients being treated with CCRT (5-FU and cisplatin) were randomized into 2 groups. The IN group received a combination of omega-3 fatty acids, glutamine, and arginine, whereas the control group received standard formula. The levels of C-reactive protein (CRP), tumor necrosis factor (TNF), interferon-gamma (IFN), interleukin (IL-6, IL-10), CD3, CD4, CD8, white blood cells, neutrophils, and total lymphocytes were measured before and during treatment. The levels of CRP (P = 0.001) and TNF (P = 0.014) increased more during treatment in the control group than the treatment group, whereas IFN, IL-6, and IL-10 were similar but not significantly. CD3, CD4, CD8, white blood cells, neutrophils, and total lymphocytes decreased more in the control group than in the treatment group, but not significantly. Enteral IN during CCRT reduced the increase of inflammatory cytokine levels.

Concurrent chemoradiotherapy with carboplatin followed by carboplatin and 5-fluorouracil in locally advanced nasopharyngeal carcinoma.

BackgroundThis study aimed to evaluate acute major toxicities, the response rate, 3-year overall survival and progression-free survival rate of locally advanced nasopharyngeal carcinoma patients on concurrent carboplatin chemoradiotherapy followed by carboplatin and 5-fluorouracil.MethodsA prospective study of fifty patients diagnosed with locally advanced nasopharyngeal carcinoma received conventional radiation therapy with a total dose of 6600-7000 cGy in 6-7 weeks and concurrent chemotherapy of three cycles of carboplatin during radiotherapy, followed by adjuvant chemotherapy using carboplatin plus 5-fluorouracil for two cycles.ResultsWeight loss and mucositis were the two most common acute major grades 3-4 toxicities (42%). Myelosuppression occurred subsequently, including leukopenia (30%), neutropenia (20%), anemia (12%), and thrombocytopenia (6%). Only 8% of patients developed grades 3-4 nausea and vomiting. No patients had renal and electrolyte abnormalities. Regarding the response evaluation, 100% of patients achieved an objective response rate of the primary tumor (92% complete response, and 8% partial response). Similarly, all patients also achieved an objective response rate of the neck node (64% complete response and 36% partial response). The 3-year overall survival rate and progression-free survival rate were 89.7% and 72.7%, respectively.ConclusionsConcurrent chemoradiotherapy with carboplatin followed by carboplatin and 5- fluorouracil could be considered as an alternative regimen for locally advanced nasopharyngeal carcinoma patients pertaining to a good overall response rate, 3-year overall survival and progression-free survival rate with good tolerability.

Recent Developments in Critical Genes in the Molecular Biology of Breast Cancer

The biology of breast cancer is complex, and the increasing knowledge of its molecular biology is having a great impact on the clinical management of this serious condition. This review looks at new findings on the role of various critical genes, including BRCA1, BRCA2, HER2 and p53, in the development of breast cancer and their clinical implications.

Efficacy according to blind independent central review: Post-hoc analyses from the phase III, randomized, multicenter, IPASS study of first-line gefitinib versus carboplatin/paclitaxel in Asian patients with EGFR mutation-positive advanced NSCLC

OBJECTIVE The Phase III, randomized, open-label IPASS study (NCT00322452) of first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) gefitinib versus carboplatin/paclitaxel for Asian patients with advanced non-small-cell lung cancer (NSCLC) showed that investigator-assessed progression-free survival (PFS) and objective response rate (ORR) were significantly prolonged in patients with EGFR mutation-positive NSCLC who received gefitinib versus patients with EGFR mutation-negative NSCLC. We report post-hoc analyses of IPASS data by blind independent central review (BICR), performed at the request of the US FDA, in a subset of patients with EGFR mutation-positive NSCLC. PATIENTS AND METHODS Eligible patients (aged ≥18 years; histologically/cytologically confirmed Stage IIB/IV adenocarcinoma NSCLC; non- or former light-smokers; treatment-naïve) were randomly assigned 1:1 to gefitinib (250mg/day) or carboplatin (dose calculated to produce an area under the curve of 5 or 6 mg/mL/minute)/paclitaxel (200mg/m2). Primary endpoint: PFS. BICR analyses included PFS, ORR, and duration of response (DoR). RESULTS Scans from 186 IPASS patients (gefitinib n=88, carboplatin/paclitaxel n=98) with EGFR mutation-positive NSCLC were available for BICR. Consistent with investigator-assessed results, in patients with EGFR mutation-positive NSCLC: PFS (hazard ratio 0.54; 95% confidence interval [CI] 0.38, 0.79; p=0.0012) and ORR (odds ratio 3.00; 95% CI 1.63, 5.54; p=0.0004) were significantly longer with gefitinib versus carboplatin/paclitaxel. The median DoR by BICR was 9.6 months with gefitinib and 5.5 months with carboplatin/paclitaxel. CONCLUSION BICR analysis of IPASS data support the original, investigator-assessed results. EGFR mutation-positive status remains a significant predictor of response to first-line TKI therapy.

Phase 2 Study of Erlotinib in Combination With Linsitinib (OSI-906) or Placebo in Chemotherapy-Naive Patients With Non–Small-Cell Lung Cancer and Activating Epidermal Growth Factor Receptor Mutations

Introduction: First‐line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment of advanced non–small‐cell lung cancer with EGFR‐activating mutations improves outcomes compared with chemotherapy, but resistance develops in most patients. Compensatory signaling through type 1 insulin‐like growth factor 1 receptor (IGF‐1R) may contribute to resistance; dual blockade of IGF‐1R and EGFR may improve outcomes. Patients and Methods: We performed a randomized, double‐blind, placebo‐controlled phase II study of linsitinib, a dual IGF‐1R and insulin receptor tyrosine kinase inhibitor, plus erlotinib versus placebo plus erlotinib in chemotherapy‐naive patients with EGFR‐mutation positive, advanced non–small‐cell lung cancer. Patients received linsitinib 150 mg twice daily or placebo plus erlotinib 150 mg once daily on continuous 21‐day cycles. The primary end point was progression‐free survival. Results: After randomization of 88 patients (44 each arm), the trial was unblinded early owing to inferiority in the linsitinib arm. The median progression‐free survival for the linsitinib versus the placebo group was 8.4 months versus 12.4 months (hazard ratio, 1.37; P = .29). Overall response rate (47.7% vs. 75.0%; P = .02) and disease control rate (77.3% vs. 95.5%; P = .03) were also inferior. Whereas most adverse events were ≤ grade 2, linsitinib plus erlotinib was associated with increased adverse events that led to decreased erlotinib exposure (median days, 228 vs. 305). No drug‐drug interaction was suggested by pharmacokinetic and pharmacodynamic results. Conclusion: Adding linsitinib to erlotinib resulted in inferior outcomes compared with erlotinib alone. Further understanding of the signaling pathways and a biomarker that can predict efficacy is needed prior to further clinical development of IGF‐1R inhibitors in lung cancer. Micro‐Abstract: This was a phase II study of linsitinib plus erlotinib versus placebo plus erlotinib in chemotherapy‐naive patients with epidermal growth factor receptor‐mutation positive, advanced, non–small‐cell lung cancer. Linsitinib plus erlotinib resulted in inferior outcomes compared with erlotinib alone. Linsitinib combination was associated with increased adverse events that led to decreased erlotinib exposure. Results highlight the complexity of targeting insulin‐like growth factor‐1 receptor signaling.

Common Presentation in an Uncommon Disease: Case Report of a Patient With Primary Diffuse Leptomeningeal Melanocytosis

Case Report A 17-year-old male was referred to our hospital with a 6-month history of uncontrolled generalized tonic clonic seizures. He denied fever, headache, or other constitutional symptoms. After the postictal stage, consciousness was fully regained without residual focal neurological deficit. He was compliant with his antiepileptic drugs (AEDs), including topiramate 50 mg/day and sodium valproate 1,000 mg/day. His medical history was otherwise unremarkable. Physical examination was completely normal. Specifically, he had no fever, lymphadenopathy, concerning skin lesions, or neurologic findings. Magnetic resonance imaging (MRI) of the brain demonstrated diffuse leptomeningeal enhancement without intracranial abnormality (Figs 1A and 1B). Lumbar puncture (LP) was performed, and revealed increased opening pressure at 30 cm H2O. Cerebrospinal fluid (CSF) analysis revealed a minimally increased WBC count (6 cells: 100% mononuclear cells), high protein (143.3 mg/100 mL), and normal CSF/blood glucose ratio (56 mg/100 mL/94 mg/100 mL). Further CSF analysis including gram stain, acid fast bacilli, modified acid fast bacilli, india ink, and CSF cultures did not support an infectious etiology. Subsequently, the patient underwent craniotomy and meningeal biopsy. Intraoperatively, dark pigmentation of the subarachnoid space was detected (Fig 2). Histopathologic and immunohistochemical examinations confirmed the presence of a primary diffuse leptomeningeal melanocytosis. The tumor was composed of an abundance of uniform polygonal cells containing extensive melanin pigment within the arachnoid space but without brain invasion. The tumor cells had nonprominent nucleolus with no atypia. (Fig 3). These cells displayed diffuse and strong staining for the melanocytic marker human melanoma black-45 (HMB-45) (Fig 4). On the basis of a benign histology and diffuse leptomeningeal involvement, there was no definitive treatment available to him. He was treated symptomatically with AEDs adjustment by the neurologist. At the time of this report, 2 years from initial presentation, the patient remains symptomatically well with good seizures control.

Clinical Characteristics and Treatment Outcomes of Patients with Primary Mediastinal Germ Cell Tumors: 10-Years' Experience at a Single Institution with a Bleomycin-Containing Regimen.

Background: Cisplatin-based chemotherapy followed by surgical resection of the residual tumor remains the standard of care for patients with mediastinal germ cell tumors (MGCTs). To prevent pulmonary complications, a non-bleomycin-containing regimen is generally preferred. This study aims to review the clinical characteristics and outcomes of these patients. Methods: A retrospective chart review was undertaken in patients treated for MGCTs between 2003 and 2013. Results: A total of 40 patients were enrolled; 7 patients were diagnosed with seminoma, while 33 patients had non-seminoma. 92% of patients received chemotherapy as a first treatment modality: 87% bleomycin, etoposide and cisplatin; 13% etoposide and cisplatin, with an objective response rate of 61.3%. Among these, 44% achieved a complete serological response. 17 patients underwent surgical resection of the residual tumor. No patient suffered from pulmonary complications after surgery. The 5-year overall survival (OS) was 71.4 and 27.3% in seminoma and non-seminoma patients, respectively (p = 0.051). For those who received chemotherapy followed by surgical resection with no viable tumor or only mature teratoma detected, the 5-year OS was 72.7% compared with 20.7% in patients not treated with surgery (p = 0.02). Conclusion: Our study confirmed the importance of a multimodality approach with primary chemotherapy followed by surgical resection of the residual tumor. A bleomycin-containing regimen can be safely used in this setting.