Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma.

The combination of temsirolimus (TEM), an MTOR inhibitor, and hydroxychloroquine (HCQ), an autophagy inhibitor, augments cell death in preclinical models. This phase 1 dose-escalation study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with TEM in cancer patients. In the dose escalation portion, 27 patients with advanced solid malignancies were enrolled, followed by a cohort expansion at the top dose level in 12 patients with metastatic melanoma. The combination of HCQ and TEM was well tolerated, and grade 3 or 4 toxicity was limited to anorexia (7%), fatigue (7%), and nausea (7%). An MTD was not reached for HCQ, and the recommended phase II dose was HCQ 600 mg twice daily in combination with TEM 25 mg weekly. Other common grade 1 or 2 toxicities included fatigue, anorexia, nausea, stomatitis, rash, and weight loss. No responses were observed; however, 14/21 (67%) patients in the dose escalation and 14/19 (74%) patients with melanoma achieved stable disease. The median progression-free survival in 13 melanoma patients treated with HCQ 1200mg/d in combination with TEM was 3.5 mo. Novel 18-fluorodeoxyglucose positron emission tomography (FDG-PET) measurements predicted clinical outcome and provided further evidence that the addition of HCQ to TEM produced metabolic stress on tumors in patients that experienced clinical benefit. Pharmacodynamic evidence of autophagy inhibition was evident in serial PBMC and tumor biopsies only in patients treated with 1200 mg daily HCQ. This study indicates that TEM and HCQ is safe and tolerable, modulates autophagy in patients, and has significant antitumor activity. Further studies combining MTOR and autophagy inhibitors in cancer patients are warranted.

Spontaneous smoking cessation before lung cancer diagnosis.

INTRODUCTION: We have observed that many patients with lung cancer stop smoking before diagnosis, usually before clinical symptoms, and often without difficulty. This led us to speculate that spontaneous smoking cessation may be a presenting symptom of lung cancer. METHODS: Patients from the Philadelphia Veterans Affairs Medical Center with lung cancer and for comparison, prostate cancer and myocardial infarction underwent a structured interview about their smoking habits preceding diagnosis. Severity of nicotine addiction was graded using the Fagerström Test for Nicotine Dependence. Among former smokers, dates of cessation, onset of symptoms, and diagnosis were recorded. Difficulty quitting was rated on a scale of 0 to 10. Distributions of intervals from cessation to diagnosis were compared between groups. RESULTS: All 115 patients with lung cancer had been smokers. Fifty-five (48%) quit before diagnosis, and only six of these (11%) were symptomatic at quitting. Patients with lung cancer who quit were as dependent on nicotine, when smoking the most, as those who continued to smoke, unlike the other groups. Despite this, 31% quit with no difficulty. The median interval from cessation to diagnosis was 2.7 years for lung cancer, 24.3 years for prostate cancer, and 10.0 years for patients with myocardial infarction. CONCLUSIONS: These results challenge the notion that patients with lung cancer usually quit smoking because of disease symptoms. The hypothesis that spontaneous smoking cessation may be a presenting symptom of lung cancer warrants further investigation.

Phase I study of Paclitaxel given by seven-week continuous infusion concurrent with radiation therapy for locally advanced non-small cell lung cancer.

BACKGROUND: Paclitaxel is active in non-small-cell lung cancer (NSCLC) and is a radiosensitizer with a dose-response relationship that depends more on duration of exposure than peak concentration. A continuous infusion prolongs exposure and may maximize the drug-radiation interaction. The goal of this National Cancer Institute-sponsored phase I study was to determine the feasibility and toxicity of a continuous infusion paclitaxel (24 hours/day, 7 days/week, 7 weeks total) concurrent with standard radiation therapy (RT) for locally advanced NSCLC. METHODS: Eligible patients had locally advanced (T4, N1-3, M0 or Tany, N2-3, M0) NSCLC, performance status less than or equal to 2, and adequate hematological, hepatic, renal, and pulmonary function. RT was given to a total dose of 64.8 Gy at 1.8 Gy/day. Paclitaxel was delivered by infusion beginning 48 hours before and then continuously throughout the 7 weeks of RT. The paclitaxel concentration was escalated in sequential dose cohorts ranging from 0.5 to 17 mg/m/d, and each contained at least three patients in a standard phase I design. RESULTS: Twenty-nine patients were enrolled. Significant grade 3+ toxicity was observed in one patient, who experienced grade 3 pneumonitis at the 6.5-mg/m/day dose level. This cohort was expanded, but none of four additional patients experienced significant toxicity. Three patients completed the 15-mg/m/day dose level without serious or dose-limiting toxicity. The two patients entered at the 17-mg/m/day dose level had grade 4 neutropenia requiring a delay in therapy of more than 1 week. The median survival of all patients was 12 months; however, 4 of 27 patients (15%) survived longer than 60 months (mean 63.4 months). CONCLUSION: The maximally tolerated and recommended phase II paclitaxel dose delivered by protracted continuous infusion is 15 mg/m/day when combined with thoracic RT. This schedule allows for the delivery of more total paclitaxel than other published regimens and may have less esophagitis than weekly paclitaxel regimens. This regimen has the potential to achieve a radiosensitizing serum concentration of paclitaxel continuously for 7 weeks without exceeding levels associated with neutropenia or neurotoxicity. There were four long-term survivors in this phase I study. These data suggest that continuous paclitaxel infusion with concurrent RT is safe and should be of interest to explore in combination with other cytotoxic or targeted therapies.

A population-based study of lung carcinoma in Pennsylvania: comparison of Veterans Administration and civilian populations.

BACKGROUND: Lung carcinoma remains the major cause of cancer death in North America and is even more common among military veterans. The objective of this study was to determine whether there were differences in the characteristics and survival of Pennsylvania patients with lung carcinoma in the Veterans Administration (VA) hospital system compared with patients in the rest of the state. METHODS: The Pennsylvania Cancer Registry was used to identify all patients who were diagnosed with lung carcinoma in the State of Pennsylvania from 1995 to 1999. Patients who were treated within the Veterans Administration Health Care Network were identified by hospital code. Survival from the date of diagnosis of lung carcinoma was determined by using the Pennsylvania state mortality files from 1995 to 2001. RESULTS: From 1995 to 1999, 48,994 patients were newly diagnosed with lung carcinoma in Pennsylvania (41.2% women), including 856 patients in the VA system (6 women). The current analysis was restricted to male patients (n = 28,798 men). There was no major difference in age of VA patients compared with non-VA patients, and the proportions of patients who had localized or regional stage disease were similar (49% of VA patients vs. 48% of non-VA patients). The proportion of black patients was much higher in the VA population (23%) compared with the non-VA population (9%). The median survival was 6.3 months for VA patients compared with 7.9 months for patients in the rest of the state, and the 5-year overall survival rate was 12% for VA patients compared with 15% for patients in the rest of the state. When survival was analyzed according to race, there was a significant difference in the age-adjusted survival of white patients in the VA system compared with patients in the rest of the state (P = 0.0007), but no significant difference was observed among black patients (P = 0.92). CONCLUSIONS: The overall survival of VA patients with lung carcinoma in Pennsylvania was inferior to that of patients in the remainder of the state and this was due primarily to differences in survival among the white patients. Further investigation will be necessary to determine whether this disparity was caused by differences in socioeconomic status or comorbidities or whether there are systematic differences in the diagnosis, staging, or treatment of lung carcinoma between VA patients and civilian patients.

A phase I, dose escalation trial of ZD0473, a novel platinum analogue, in combination with gemcitabine.

PURPOSE: To develop a combination regimen for clinical testing, we performed a dose escalation study of ZD0473 in combination with gemcitabine. ZD0473 is a novel platinum analogue with an aliphatic cyclic carrier ligand. In vitro and in vivo studies suggest that it possesses a different spectrum of antitumor activity from cisplatin and carboplatin. In single-agent studies of ZD0473, myelosuppression was the predominant toxicity and responses wer observed. METHODS: In this combination phase I trial, 36 patients with advanced cancer were accrued to four dose levels, with doses of ZD0473 and gemcitabine ranging from 60 to 120 mg/m2 and 600 to 750 mg/m2, respectively ZD0473 was administered on day 1 and gemcitabine was given on days 1 and 8 of a 21-day cycle. RESULTS: Hematologic toxicity was dose-limiting. Grade 3 and 4 thrombocytopenia and neutropenia occurred during 60% and 41% of all cycles. Nonhematologic toxicities were mild and reversible. Two partial responses and 19 patients with stable disease were observed. CONCLUSIONS: The recommended phase II doses are 90 mg/m2 of ZD0473 and 750 mg/m2 of gemcitabine for lightly pretreated patients and 600 mg/m2 for heavily pretreated patients. The combination of ZD0473 and gemcitabine is associated with dose-dependent thrombocytopenia and neutropenia as well as having promising clinical activity.

Two commonly used neoadjuvant chemoradiotherapy regimens for locally advanced stage III non-small cell lung carcinoma: long-term results and associations with pathologic response.

BACKGROUND: We performed this study to determine the outcomes (pathologic response, survival, local-regional control, and toxicity) in patients treated with neoadjuvant chemoradiotherapy and planned operation for stage IIIA non-small cell lung carcinoma. METHODS: Patients treated from 1993 to 2000 with neoadjuvant chemoradiotherapy and a predetermined plan for subsequent surgical resection for stage III non-small cell lung carcinoma were analyzed. All patients underwent pretreatment evaluation at the university's Multidisciplinary Lung Cancer Center. Most patients (87%) had complete mediastinoscopy staging, and all were believed to be poor candidates for up-front operation because of bulky extent of disease. The radiotherapy program used conventional, 2-dimensionally planned treatment to 45 to 54 Gy in 1.8- to 2-Gy fraction size. Concurrent chemotherapy consisted of etoposide/cisplatin or carboplatin/paclitaxel. Study end points included resectability, pathologic response, local-regional control, survival, and toxicity. An exploratory comparison between pathologic response and long-term survival was performed. An exploratory comparison between older chemotherapy (etoposide/cisplatin) and third-generation chemotherapy (carboplatin/paclitaxel) was also performed. RESULTS: Of 53 patients, 45 (85%) were deemed surgical candidates after induction therapy. Twenty-two (42% of the initial cohort) patients had a major pathologic response to stage 0, I, or II disease. The 5-year actuarial survival was 31%. Major pathologic response was associated with improved survival (48% vs 24%; P =.027). The overall rate of early death potentially related to therapy in this series was 9%; this mostly occurred in patients who underwent right pneumonectomy. There was no difference in efficacy or mortality between etoposide/cisplatin and radiotherapy versus carboplatin/paclitaxel and radiotherapy, although the latter regimen was associated with less grade 3 or higher acute toxicity necessitating interruption or hospitalization during neoadjuvant treatment (P =.02). In-field local control was achieved in 83% of all patients (90% of the patients who underwent resection). Brain metastases as the first site of treatment failure occurred in 23% of all patients. CONCLUSIONS: Neoadjuvant concurrent chemoradiation delivers high resectability, major pathologic response rate, and excellent local-regional control, with encouraging long-term survival considering the patient population studied. Major pathologic response correlates with long-term survival. Neoadjuvant carboplatin/paclitaxel and radiotherapy is an appropriate framework on which to add new therapies.

Dose escalation study of tezacitabine in combination with cisplatin in patients with advanced cancer.

BACKGROUND: The authors performed a dose escalation study of cisplatin and the novel deoxycytidine analog, tezacitabine, to determine the maximum tolerated dose of the combination. METHODS: Twenty-three patients with advanced cancer and good performance status were accrued to 3 dose levels of tezacitabine (150-270 mg/m(2)) and cisplatin (50 mg/m(2)). Using a 28-day treatment cycle, both drugs were administered on Days 1 and 15. RESULTS: Hematologic toxicity was the most frequently observed side effect and was dose limiting. Grade 3 or 4 neutropenia and thrombocytopenia complicated 75% and 31% of all cycles, respectively. Nonhematologic toxicities were mild. Among 18 evaluable patients, 2 with upper gastrointestinal tract tumors achieved partial responses and 4 had stable disease. CONCLUSIONS: Based on dose-limiting neutropenia and thrombocytopenia at the highest dose level, the recommended Phase II doses are 200 mg/m(2) of tezacitabine and 50 mg/m(2) of cisplatin.

Clinical and molecular features of small cell lung cancer.

Small cell lung cancer is a common malignancy found in smokers. It has a poor long-term prognosis despite initial sensitivity to chemotherapy and radiation. The clinical features of small cell lung cancer are unique among lung cancers and other neuroendocrine tumors. In order to better understand the pathogenesis of small cell lung cancer, there has been a great effort to identify the genetic alterations involved in the development and progression of the disease, and to translate these to novel molecular strategies for treatment.