Phase I trial of carboplatin/paclitaxel/bortezomib and concurrent radiotherapy followed by surgical resection in Stage III non-small cell lung cancer.

INTRODUCTION: Despite advances in Stage III NSCLC, the mortality from the disease remains >70%. Disease recurrence can occur both locally and systemically. Trimodality therapy may improve outcome by maximizing local control. The purpose of this study was to perform a phase I trial of bortezomib (PS-341, Velcade) in addition to chemotherapy with carboplatin AUC=2 and paclitaxel 50mg/m(2) and concurrent radiotherapy (61 Gy) as induction treatment in a trimodality approach. METHODS: Patients with pathologically documented Stage III a (N2) or selected IIIb (N3) disease were eligible. Bortezomib was administered on days 1, 4, 15, 18 during the 6-week induction chemoradiotherapy. Cohorts of three patients were entered and observed for toxicity during chemoradiotherapy and for 2 weeks afterwards. Surgical resection was attempted in the patients who had mediastinal sterilization. All patients were to receive consolidation chemotherapy with carboplatin AUC=6 and paclitaxel 200mg/m(2). RESULTS: Twelve patients in three cohorts were enrolled. The addition of bortezomib was well tolerated, with no unexpected toxicities during the induction phase. However, there were three postoperative deaths (two pneumonitis and one from failure of the bronchopulmonary flap). The trial was halted as a consequence of these toxicities. CONCLUSIONS: While this approach was well tolerated in terms of acute toxicity, the apparently delayed toxicity was severe and unpredictable. It does not appear that bortezomib can be safely administered as part of preoperative chemoradiotherapy for lung cancer. However, there was a high incidence of complete pathologic response and cautious exploration of this agent in the non-operative setting is appropriate.

Eicosanoid modulation in advanced lung cancer: cyclooxygenase-2 expression is a positive predictive factor for celecoxib + chemotherapy--Cancer and Leukemia Group B Trial 30203.

PURPOSE: Increased expression of eicosanoids in cancer has been associated with adverse prognosis. We performed a randomized phase II trial to test the hypothesis that inhibitors of two eicosanoid pathways (cyclooxygenase-2 [COX-2], celecoxib and 5-lipoxygenase [5-LOX], zileuton) added to chemotherapy would improve outcome in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with advanced NSCLC, a performance status of 0 to 2, and no prior therapy were eligible. All patients received carboplatin area under the curve (AUC) 5.5 mg/mL x min day 1 + gemcitabine (1,000 mg/m(2)) days 1 and 8. Patients were randomly assigned to: (a) zileuton 600 mg PO qid, (b) celecoxib 400 mg PO bid, or (c) celecoxib and zileuton at the same doses. Immunohistochemical staining for COX-2 and 5-LOX was performed without knowledge of outcomes. RESULTS: One hundred forty patients were entered and 134 were eligible and treated. There was no survival difference between the arms. COX-2 expression was a negative prognostic marker for overall survival (OS; hazard ratio [HR] = 2.51, P = .019 for index >or= 4; HR = 4.16, P = .005 for index = 9) for patients not receiving celecoxib. Patients with increased COX-2 expression (index >or= 4), receiving celecoxib had better survival than did COX-2-expressing patients not receiving drug (HR = .342, P = .005 for OS; HR = .294, P = .002 for failure-free survival). Multivariate analysis confirmed the interaction of COX-2 and celecoxib on survival. 5-LOX expression was neither prognostic nor predictive. CONCLUSION: This study failed to demonstrate the value of dual eicosanoid inhibition or benefit from either agent alone in addition to chemotherapy. However, a prospectively defined subset analysis suggests an advantage for celecoxib and chemotherapy for patients with moderate to high COX-2 expression.

Phase II trial of gemcitabine/carboplatin followed by paclitaxel in patients with performance status=2,3 or other significant co-morbidity (HIV infection or s/p organ transplantation) in advanced non-small cell lung cancer.

INTRODUCTION: The role of chemotherapy in patients with advanced non-small cell lung cancer and poor performance status or who have HIV disease or organ transplantation is unclear. While survival appears to be enhanced, serious toxicity may occur. We evaluated the efficacy of sequential, dose attenuated carboplatin/gemcitabine followed by paclitaxel in patients with PS=2,3, HIV infection or after solid organ transplantation. PATIENTS AND METHODS: Chemotherapy naive patients with PS 2,3 or who were HIV positive or post solid organ transplantation were eligible. Treatment consisted of gemcitabine: 1000 mg/m(2) d 1,8 carboplatin: AUC=5 d 1 q 21d x 2 followed by paclitaxel 80 mg/m(2) q wk x 6 followed by a 2 week break and then repeated until progression. RESULTS: 47 patients were entered. Stage IIIb/IV: 8/39, PS 2/3=26/19, HIV infection=2, solid organ transplantation=2. 12 (25%) had brain metastases. Thirty-nine patients completed two cycles of carboplatin/gemcitabine and 29 pts received at least one cycle of paclitaxel. Overall response rate was 19% (95% CI 1.2-31.7%). Median event free, overall and 1-year survivals were 3.3 months, 5.8 months and 8.4%. Toxicity was moderate with 19% experiencing grade 4 neutropenia (11% with febrile neutropenia). CONCLUSIONS: Sequential carboplatin/gemcitabine to paclitaxel is well tolerated and active in this population. The survival seen is comparable to that of other regimens utilized in PS=2 patients with superior tolerability however, the prognosis for these patients is very poor even with treatment. This is the first trial to prospectively evaluate chemotherapy for patients with HIV disease or organ transplantation and NSCLC.

Phase II trial of the novel retinoid, bexarotene, and gemcitabine plus carboplatin in advanced non-small-cell lung cancer.

PURPOSE: Platinum-based chemotherapy is the standard treatment for advanced non-small-cell lung cancer (NSCLC). Unfortunately, a plateau in efficacy with currently available agents has been reached. Previous studies of the retinoid, bexarotene, a retinoid X receptor-specific ligand, have indicated that it may improve outcome in advanced NSCLC. PATIENTS AND METHODS: Patients with previously untreated stage IIIB or stage IV disease, a performance status of 0 to 2, and adequate organ status were entered. Treatment consisted of up to six cycles of carboplatin (area under the curve = 5.0 on day 1) and gemcitabine (1,000 mg/m2 on days 1 and 8) administered every 21 days. Bexarotene 400 mg/m2 orally was to be administered continuously beginning on day 1 and until progression of disease. All patients received atorvastatin 10 mg orally beginning before bexarotene. The objective was to demonstrate a 1-year survival rate of more than 50%. RESULTS: Forty-eight patients were entered; all were assessable for survival, and 47 were assessable for toxicity and response. The therapeutic regimen was well tolerated except for hypertriglyceridemia. The median time to progression was 6.7 months, and overall median survival was 12.7 months. There was a 25% response rate and a 1-year survival rate of 53%. These results were compared with the outcome of 33 patients treated at our institution with two-drug, platinum-based chemotherapy on controlled trials with similar entry criteria in the previous 5 years. CONCLUSION: Bexarotene can be safely added to platinum-based chemotherapy provided that there is aggressive prophylaxis of hypertriglyceridemia. The median time to progression and overall survival are promising and warrant further evaluation of bexarotene in advanced NSCLC.

Management of common symptoms of advanced lung cancer.

Disease-directed treatment of lung cancer reduces the morbidity and extends life for patients. However, as providers we must recognize that treating the symptoms of the disease may be as important as the treatment of the disease itself. This is particularly true in advanced disease and after disease-directed therapies have been exhausted. Aggressive assessment of symptoms and use of palliative therapies can significantly reduce the symptomatology of advanced lung cancer. Though the impact of these symptoms (ie, pain, dyspnea, and cachexia) are well known, they tend to be under-treated. In addition, simple maneuvers such as opiate rotation for pain relief are underutilized. The diagnosis of lung cancer and its associated symptoms may result in severe psychosocial stress for the patient and further exacerbate the symptoms in a vicious cycle. Understanding of coping strategies may aid the medical provider in assisting the patient during his or her illness.

Sexual relationships, condom use, and concerns about pregnancy, HIV/AIDS, and other sexually transmitted diseases.

As we move further into the 21st century, there are increasing numbers of teenagers and young adults infected with sexually transmitted diseases and acquired immunodeficiency syndrome. Aside from sexual abstinence, condom use is the best way to protect oneself from sexually transmitted diseases, including human immunodeficiency virus/acquired immunodeficiency syndrome. Participants in this study were predominantly female, predominantly Caucasian psychology students who experienced sexual intercourse with an opposite sex partner in the past year. Slightly fewer than half of these participants reported condom use at their last episode of vaginal intercourse and type of partner did not affect their condom use, nor did concern about human immunodeficiency virus/acquired immunodeficiency syndrome and sexually transmitted diseases. Findings such as these challenge advanced practice nurses to generate innovative strategies to promote condom use in all types of relationships. We propose that teaching about the link between cervical cancer and lack of condom use could be one of these new strategies.