James R. Rigas

Preoperative chemotherapy for stage IIIa (N2) lung cancer: The Sloan-Kettering experience with 136 patients

From 1984 to 1991, 136 patients with histologically confirmed non-small cell lung cancer and stage IIIa (N2) disease received two to three cycles of MVP (mitomycin + vindesine or vinblastine + high-dose cisplatin) chemotherapy. All patients had clinical N2 disease, defined as bulky mediastinal lymph node metastases or multiple levels of lymph node involvement in the ipsilateral mediastinum or subcarinal space on chest roentgenograms, computed tomographic scans, or mediastinoscopy. The overall major response rate to chemotherapy was 77% (105/136). Thirteen patients had a complete response and 92 patients had a partial but major response (> 50%). The overall complete resection rate was 65% (89/136) with a complete resection rate of 78% (82/105) in patients with a major response to chemotherapy. There was no histologic evidence of tumor in the resected specimens of 19 patients. The overall survival was 28% at 3 years and 17% at 5 years (median, 19 months). For patients who had complete resection, the median survival was 27 months and the 3-year and 5-year survivals were 41% and 26%, respectively. There were seven treatment-related deaths, five of which were postoperative deaths. To date, 33 patients, all of whom had complete resection, have had no recurrence after treatment. These results demonstrate that (1) preoperative chemotherapy with MVP produces high response rates in stage IIIa (N2) disease, (2) high complete resection rates occur after response to chemotherapy, and (3) survival is longest in patients who have a complete resection after major response to chemotherapy.

Prognostic and Predictive Importance of p53 and RAS for Adjuvant Chemotherapy in Non–Small-Cell Lung Cancer

PURPOSE p53 and RAS are multifunctional proteins that are critical to cell cycle regulation, apoptosis, cell survival, gene transcription, response to stress, and DNA repair. We have evaluated the prognostic and predictive value of p53 gene/protein aberrations using tumor samples from JBR.10, a North American phase III intergroup trial that randomly assigned 482 patients with completely resected stage IB and II non-small-cell lung cancer (NSCLC) to receive four cycles of adjuvant cisplatin plus vinorelbine or observation alone. METHODS p53 protein expression was evaluated by immunohistochemistry. Mutations in exons 5 to 9 of the p53 gene were determined by denaturing high-performance liquid chromatography and confirmed by sequencing. RAS mutations were identified by allelic specific oligonucleotide hybridization. RESULTS Of 253 patients, 132 (52%) were positive for p53 protein overexpression. Untreated p53-positive patients had significantly shorter overall survival than did patients with p53-negative tumors (hazard ratio [HR] = 1.89; 95% CI, 1.07 to 3.34; P = .03). However, these p53-positive patients also had a significantly greater survival benefit from adjuvant chemotherapy (HR = 0.54; P = .02) compared with patients with p53-negative tumors (HR = 1.40; P = .26; interaction P = .02). Mutations of p53 and RAS genes were found in 124 (31%) of 397 and 117 (26%) of 450 patients, respectively. Mutations in these genes were neither prognostic for survival nor predictive of a differential benefit from adjuvant chemotherapy. CONCLUSION p53 protein overexpression is a significant prognostic marker of shortened survival, and also a significant predictive marker for a differentially greater benefit from adjuvant chemotherapy in completely resected NSCLC patients.

Secondary prevention of venous thromboembolic events in patients with active cancer: enoxaparin alone versus initial enoxaparin followed by warfarin for a 180-day period.

This study evaluated enoxaparin alone versus initial enoxaparin followed by warfarin in secondary prevention of venous thromboembolic events in adults with active malignancy. Cancer patients (n = 122) with acute symptomatic venous thromboembolic events were randomly allocated to receive subcutaneous enoxaparin 1.0 mg/kg every 12 hours for 5 days, followed by 1.0 mg/kg daily (group 1a) or 1.5 mg/kg daily (group 1b) for 175 days, or subcutaneous enoxaparin 1.0 mg/kg every 12 hours for at least 5 days and until a stable international normalized ratio of 2 to 3 was achieved on oral warfarin begun on day 2 and continued to day 180 (group 2). There were no significant differences in major and minor bleeding rates between treatment groups. No bleeding events were intracranial or fatal. Enoxaparin treatment was feasible, generally well tolerated, and effective for a 180-day period in the secondary prevention of venous thromboembolic events in patients with active malignancy.

Phase II trial of docetaxel in patients with stage III and IV non-small-cell lung cancer.

PURPOSE This phase II study was conducted to evaluate the efficacy and toxicity of docetaxel in the treatment of patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Docetaxel was administered to 29 patients with unresectable stage III and IV NSCLC at a dose of 100 mg/m2 intravenously (IV) over 1 hour every 21 days. No premedication was given to the first 16 patients. Premedication with diphenhydramine was instituted for the remainder. No patient had previously received chemotherapy. Seven patients had undergone prior radiation therapy. RESULTS All patients were assessable for response and toxicity. Eleven of 29 patients (38%) had a major objective response (95% confidence interval, 21% to 58%). The median duration of response was 5.3 months. Febrile neutropenia occurred in 41% of patients and in 11% of 134 courses of docetaxel. Nonhematologic toxicities included infusion-related hypersensitivity reactions, fluid retention, rash, alopecia, and sensory neuropathy. Premedication with diphenhydramine did not decrease the incidence of infusion-related hypersensitivity reactions. CONCLUSION At this dose and schedule, docetaxel demonstrates significant antitumor activity in patients with advanced NSCLC. Further investigations of this agent in NSCLC are indicated.

Phase II trial of a 75-mg/m2 dose of docetaxel with prednisone premedication for patients with advanced non-small cell lung cancer

Background. A prior Phase II study of a 100‐mg/m2 dose of docetaxel conducted at the Memorial Sloan‐Kettering Cancer Center (New York, NY) demonstrated a 38% response rate with grade 3 or 4 neutropenia in 76% of the patients and a grade 2 or greater rash or infusion‐related reaction in 41% and 34% of the patients, respectively. The current Phase II study sought to determine the activity of a 75‐mg/m2 dose of docetaxel to establish whether this lower dose, combined with prednisone, ameliorates toxicity.

Multi-Institutional Phase I/II Trial of Oral Bexarotene in Combination With Cisplatin and Vinorelbine in Previously Untreated Patients With Advanced Non–Small-Cell Lung Cancer

PURPOSE Bexarotene (Targretin; Ligand Pharmaceuticals, Inc, San Diego, CA) is a retinoid-X-receptor (RXR)-selective retinoid with preclinical antitumor activity in squamous cell cancers. In this phase I/II trial, we combined bexarotene with cisplatin and vinorelbine in the treatment of patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Forty-three patients who had stage IIIB NSCLC with pleural effusion or stage IV NSCLC and had received no prior therapy received bexarotene in combination with cisplatin (100 mg/m2) and vinorelbine (alternating doses of 30 mg/m2 and 15 mg/m2). In the phase I portion, the daily dose of bexarotene was escalated in cohorts of three patients from 150 mg/m2 to 600 mg/m2, beginning 1 week before the start of the cisplatin-vinorelbine regimen. Once the maximum-tolerated dose (MTD) of bexarotene was determined, the study entered the phase II portion. Response rate was the primary end point; median survival time and 1-year survival rate were secondary end points. RESULTS In the phase I portion, the daily MTD of bexarotene was determined to be 400 mg/m2. Eight of 43 patients exhibited major responses. Seven (25%) of the 28 patients in the phase II portion responded to treatment. The median survival time in the phase II portion was 14 months; nine (32%) of the 28 patients were still alive at a minimum follow-up of 2 years. One-year and projected 3-year survival rates were 61% and 30%, respectively. The most common grade 3 and 4 adverse events were hyperlipemia, leukopenia, nausea, vomiting, pneumonia, dyspnea, anemia, and asthenia. Grade 3 and 4 laboratory abnormalities with incidences greater than 5% were decreased hemoglobin levels and WBC, absolute neutrophil, and absolute lymphocyte counts and increased prothrombin time and creatinine and amylase levels. Of the two cases of pancreatitis, one required hospitalization and both were associated with increased triglyceride levels. There was one death secondary to renal insufficiency unrelated to bexarotene treatment. CONCLUSION In patients with advanced NSCLC, bexarotene with cisplatin and vinorelbine yielded acceptable phase II response rates (25%) and was associated with better-than-expected survival (14-month median survival time; 61% 1-year, 32% 2-year, and 30% projected 3-year survival rates). The regimen should be studied in larger clinical trials.

A humanized anti-IL-6 antibody (ALD518) in non-small cell lung cancer

Introduction: Inflammatory pathways may be an important contributor to morbidity and mortality associated with lung cancer. The oncogene-associated inflammatory microenvironment leads to production of inflammatory cytokines such as IL-6. IL-6 is associated with poor prognosis and correlates with debilitating lung-cancer-related symptoms such as fatigue, thromboembolism, cachexia and anemia. IL-6 has been implicated in resistance of lung cancer to EGF inhibitors. A mAb therapy targeting IL-6 may be an effective treatment for the inflammatory microenvironment in lung cancer. Areas covered: An understanding of the inflammatory pathways involved in lung cancer, including the central role of IL-6, and how inflammation affects the course and treatment of lung cancer. The mAb ALD518, which targets IL-6, and its investigational development and use in advanced NSCLC. Preclinical and Phase I and II studies of ALD518 with a focus on NSCLC. How ALD518 could be used in NSCLC in the future. Expert opinion: IL-6-mediated inflammation may contribute to NSCLC-related morbidity and mortality. In preclinical and Phase I and II trials ALD518 targeting IL-6 appears well tolerated and ameliorates NSCLC-related anemia and cachexia. Other clinical outcomes need further study, and may include effects on overall survival, hypercoagulability associated with lung cancer and decreased resistance to EGF-pathway inhibitors.

Dyspnea, anxiety, body consciousness, and quality of life in patients with lung cancer

Dyspnea is a common symptom of lung cancer that can impact patient physical, social, and psychological well-being. Study goals were to evaluate quality of life (QOL) and dyspnea in patients with lung cancer and the relationships between QOL, dyspnea, trait anxiety, and body consciousness. Sociodemographic and cancer-related variables (stage, cell type, performance status) were evaluated. One hundred twenty outpatients with stage I-IV lung cancer participated in the study. Patients completed 5 questionnaires assessing QOL, dyspnea, trait anxiety, body consciousness, and pain. Eighty-seven percent of study participants experienced dyspnea. Patients with high dyspnea scores had lower QOL (P = 0.04). Dyspnea was worse in men than in women (P = 0.02), and there was a trend towards older patients reporting more severe dyspnea than younger patients (P = 0.06). There was no difference in dyspnea based on cancer stage, cell type, or performance status. Pain and anxiety scores were higher in patients with high dyspnea (P = 0.02, P = 0.03). Dyspnea was more severe in patients taking opioid analgesics when compared to non-opioids or no pain medications (P = 0.03). No significant association was found between dyspnea, anxiety, and private body consciousness.

A prospective randomised trial of adjuvant vinorelbine (VIN) and cisplatin (CIS) in completely resected stage 1B and II non small cell lung cancer (NSCLC) Intergroup JBR.10

7018 Background: In meta-analyses platinum based adjuvant chemotherapy using 2nd generation regimens increased cure rate by 5% in completely resected NSCLC. JBR.10 was undertaken to determine whether the 3rd generation regimen VIN/CIS prolonged survival in this clinical setting. METHODS Patients with completely resected stage 1 (T2N0) or stage 2 (excluding T3N0) NSCLC were stratified by nodal status (N0 vs. N1) and ras mutation status (present vs. absent vs. unknown) and randomised to receive 4 cycles of VIN (25mg/m2 weekly x 16 weeks) plus CIS (50mg/m2 days 1 and 8 q 4 weeks x 4) or follow up alone; VIN dose was reduced from 30mg/m2 shortly after the study started due to unacceptable toxicity. The endpoints of the study were survival (OS), recurrence-free survival (RFS), quality of life (QOL) and toxicity. RESULTS 482 patients were randomized between 1994 and 2001. PATIENTS age 61 years, 65% male, 51% PS 1, 53% N1, 24% ras mutation present. 45% of patients had T2N0, 40% T2N1 and 15% T1N1. 53% had adenocarcinoma. Grade 4 neutropenia, was common with febrile neutropenia in 7%, predominantly in patients receiving VIN 30mg/m2. The commonest non-hematologic toxicities for VIN/CIS patients were fatigue (77%), nausea (76%), anorexia (53%), vomiting (46%), sensory neuropathy (45%) and constipation (44%). Two patients died of drug-related toxicity [1 febrile neutropenia, 1 pulmonary fibrosis]. The most common cause of death was NSCLC (including 1 patient with 2nd primary NSCLC), while 3 patients died from toxicity related to later anti-cancer therapy, 9 patients died of other primary malignancies, and 21 from other causes. Overall survival was significantly prolonged for VIN/CIS patients (94 months vs. 73 months; HR 0.69, p=0.011), as was RFS (not reached vs. 46.7 months; HR 0.6, p 0.0003). 5-year survival for VIN/CIS patients was 69% compared to 54% for patients followed expectantly. 38 patients developed 2nd malignancies. CONCLUSIONS This is the first randomized clinical trial demonstrating that a 3rd generation platinum-based doublet prolongs OS and RFS after surgery in early stage NSCLC. [Table: see text].

Epidermal growth factor receptor tyrosine kinase inhibition represses cyclin D1 in aerodigestive tract cancers

Purpose: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are active in cancer therapy. Mechanisms engaged during these clinical responses need to be determined. We reported previously that epidermal growth factor stimulation markedly increased cyclin D1 protein expression in human bronchial epithelial (HBE) cells, and this was opposed by chemoprevention with all-trans-retinoic acid. The current study sought to determine whether the EGFR TKI erlotinib repressed cyclin D1 protein expression in immortalized HBE cells, lung cancer cell lines, and clinical aerodigestive tract cancers. Experimental Design: The BEAS-2B immortalized HBE cell line was exposed to varying concentrations of erlotinib, and effects on proliferation, cell cycle distribution, G1 cyclin expression, and cyclin D1 reporter activity were measured. Non–small-cell lung cancer cell lines were also evaluated for changes in proliferation and cyclin protein expression after erlotinib treatments. A proof of principle clinical trial was conducted. During this study, patients underwent a 9-day course of erlotinib treatment. Pretreatment and posttreatment tumor biopsies were obtained, and changes in candidate biomarkers were determined by immunostaining. Plasma pharmacokinetics and tumor tissue erlotinib concentrations were measured. Results: Erlotinib, at clinically achievable dosages, repressed BEAS-2B cell growth, triggered G1 arrest, and preferentially reduced cyclin D1 protein expression and transcriptional activation. Erlotinib also preferentially repressed proliferation and cyclin D1 protein expression in responsive, but not resistant, non–small-cell lung cancer cell lines. This occurred in the presence of wild-type EGFR sequence at exons 18, 19, and 21. Five patients were enrolled onto an erlotinib proof of principle clinical trial, and four cases were evaluable. Pharmacokinetic studies established therapeutic erlotinib plasma levels in all patients, but tissue levels exceeding 2 μmol/L were detected in only two cases. Notably, these cases had pathological evidence of response (necrosis) in posttreatment biopsies as compared with pretreatment biopsies. In these cases, marked repression of cyclin D1 and the proliferation marker Ki-67 was detected by immunohistochemical assays. Cases without pathological response to erlotinib did not exhibit changes in cyclin D1 or Ki-67 immunohistochemical expression and had much lower erlotinib tissue levels than did responding cases. Conclusions: Taken together, these in vitro and in vivo findings provide direct evidence for repression of cyclin D1 protein as a surrogate marker of response in aerodigestive tract cancers to erlotinib treatment. These findings also provide a rationale for combining an EGFR TKI with an agent that would cooperatively repress cyclin D1 expression in clinical trials for aerodigestive tract cancer therapy or chemoprevention.