isotretinoin and Carcinoma--Non-Small-Cell-Lung

Treatment of lung cancer remains frustrating. Most patients with lung cancer are not candidates for curative therapy, and new therapies have not made a substantial impact on survival. Consequently, some clinical investigators have focused their efforts on developing prevention strategies. Chemoprevention, the administration of agents to block or reverse carcinogenesis, is being investigated in ongoing trials. Studies of chemoprevention in lung cancer have included trials to reverse premalignant lesions such as sputum atypia or squamous metaplasia of the bronchial epithelium. Clinical trials of lung cancer prevention have often studied groups of participants with tobacco or asbestos exposure. Other clinical trials are being conducted among patients who have been treated for an early-stage lung cancer. As the result of diffuse epithelial injury, these patients are at very high risk for developing second primary tumors, predominantly in the lungs and upper aerodigestive tract. It is our hope that these studies may establish a new strategy for preventing lung cancer.

Topics: Anticarcinogenic Agents; beta Carotene; Carcinoma, Non-Small-Cell Lung; Carotenoids; Clinical Trials as Topic; Humans; Isotretinoin; Lung Neoplasms; Neoplasms, Second Primary; Precancerous Conditions; Randomized Controlled Trials as Topic

Consideration of a range of clinical and basic studies conducted at the National Cancer Institute which explore the nature of the tumor biology of lung identify the limitations of using chemotherapy for the treatment of advanced lung cancer. No single mechanistic explanation for lung cancer's chemoresistance is apparent, although considerable information about the biology of lung cancer and some of its clinical consequences have been elucidated. In contrast to previous works from our group, this presentation will focus principally on studies of the nature of drug resistance with non-small cell cancer. An alternative combined modality strategy for lung cancer control is to focus on epithelial progression of lung cancer using local modalities while it is still confined to the bronchial epithelium. Particular high risk populations may be appropriate to determine if local tools such as photodynamic laser therapy can be effective in this application. To deal with the underlying biochemical perturbations resulting from critical exposure of the bronchial epithelium to carcinogens, rational biochemical intervention with 13 cis retinoic acid are being evaluated in several clinical trials. An evolution towards more effective lung cancer control may involve the combined modalities of laser ablation of accessible dysplastic epithelium and chronic administration of intervention agents, such as retinoids, to neutralize cancer promotion dynamics in the more remote areas of the lung epithelium.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Chemotherapy, Adjuvant; Cisplatin; Clinical Trials, Phase II as Topic; Combined Modality Therapy; Drug Resistance; Etoposide; Humans; Isotretinoin; Lung Neoplasms; Neoplasms, Second Primary; Neoplastic Stem Cells; Oncogenes; Phenotype; Tumor Cells, Cultured

In 2001, we reported that mortality may have been higher with isotretinoin (30 mg/d for 3 years) than with placebo in the subgroup of current smokers among the 1,166 patients with definitively resected early-stage non-small cell lung cancer who participated in the randomized, controlled Lung Intergroup Trial. We report the overall and cause (cancer, cardiovascular disease, or other)-specific mortality associated with long-term isotretinoin after an extended median follow-up of 6.2 years that included the capture of cause-of-death data from 428 deceased patients. Overall mortality was 36.7% in each of the two trial arms, about two thirds related to cancer and one third to other or unknown causes. Overall and cancer deaths increased in current smokers in the isotretinoin arm during the treatment and the extended follow-up period. No mortality end point increased among never smokers and former smokers taking isotretinoin, and cancer deaths decreased marginally in this combined subgroup. Isotretinoin also increased deaths from cardiovascular disease in current smokers. The present analysis supports the safety of protracted isotretinoin use in the combined group of never smokers and former smokers, which has important public health implications, for example, for treating acne in young people. The increased mortality in current smokers in this study is further evidence of the multifaceted danger of active smoking. The overall indications of this study have public health implications for treating acne in young people and other uses of retinoids in smokers.

Topics: Acne Vulgaris; Aged; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cardiovascular Diseases; Cause of Death; Cocarcinogenesis; Combined Modality Therapy; Disease-Free Survival; Female; Follow-Up Studies; Humans; Infections; Isotretinoin; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Neoplasms; Pneumonectomy; Proportional Hazards Models; Smoking

The incidence of second primary lung cancers (SPLC) after resection of nonsmall cell lung cancer (NSCLC) is estimated to be 1% to 4% per patient year. The overall effect of SPLC on survival after resection of stage I NSCLC is unknown. Here we report the incidence, management, and outcome of SPLC in a large prospective cohort of patients who underwent careful follow-up.. National Cancer Institute Intergroup Trial NCI #I91-0001 examined the effectiveness of isotretinoin A for chemoprevention of second primary tumors, the primary endpoint in that trial. Prospective data from patients randomly assigned to the placebo arm were analyzed.. Five hundred sixty-nine patients underwent complete resection of pathologic stage I NSCLC. The median follow-up was 5.9 years. Second primary tumors developed in 88 (15%) patients. Of these, 49 (56%) were SPLC (incidence = 1.99/100 patient-years), with a median interval from initial surgery of 4.2 years. Second primary lung cancer never developed in patients who had never smoked (n = 44, p = 0.046; never versus ever smokers). Current smokers had a higher incidence of SPLC than former smokers (hazard ratio = 1.91, p = 0.03). Age, sex, stage, histology, tumor location and initial surgery had no effect on SPLC development. Despite semiannual follow-up with chest radiographs, 12 (24%) patients had metastatic disease at the time of diagnosis of SPLC. Surgical resection was performed in 31 (63%) SPLC patients. Median survival was 4.1 years in those who underwent surgery and 1.4 years in those who did not (p = 0.003). Overall SPLC-related mortality in the original cohort was 3.7%.. Patients who undergo surgery for SPLC can achieve prolonged survival. Despite close follow-up however many patients with SPLC present with advanced disease. That indicates a need for continued lifelong postoperative surveillance.

Topics: Carcinoma, Non-Small-Cell Lung; Female; Humans; Isotretinoin; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Neoplasms, Second Primary; Prospective Studies

Promising data have suggested that retinoid chemoprevention may help to control second primary tumors (SPTs), recurrence, and mortality of stage I non-small-cell lung cancer (NSCLC) patients.. We carried out a National Cancer Institute (NCI) Intergroup phase III trial (NCI #I91-0001) with 1166 patients with pathologic stage I NSCLC (6 weeks to 3 years from definitive resection and no prior radiotherapy or chemotherapy). Patients were randomly assigned to receive a placebo or the retinoid isotretinoin (30 mg/day) for 3 years in a double-blind fashion. Patients were stratified at randomization by tumor stage, histology, and smoking status. The primary endpoint (time to SPT) and the secondary endpoints (times to recurrence and death) were analyzed by log-rank test and the Cox proportional hazards model. All statistical tests were two-sided.. After a median follow-up of 3.5 years, there were no statistically significant differences between the placebo and isotretinoin arms with respect to the time to SPTs, recurrences, or mortality. The unadjusted hazard ratio (HR) of isotretinoin versus placebo was 1.08 (95% confidence interval [CI] = 0.78 to 1.49) for SPTs, 0.99 (95% CI = 0.76 to 1.29) for recurrence, and 1.07 (95% CI = 0.84 to 1.35) for mortality. Multivariate analyses showed that the rate of SPTs was not affected by any stratification factor. Rate of recurrence was affected by tumor stage (HR for T(2) versus T(1) = 1.77 [95% CI = 1.35 to 2.31]) and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking status = 3.11 [95% CI = 1.00 to 9.71]). Mortality was affected by tumor stage (HR for T(2) versus T(1) = 1.39 [95% CI = 1.10 to 1.77]), histology (HR for squamous versus nonsquamous = 1.31 [95% CI = 1.03 to 1.68]), and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking = 4.39 [95% CI = 1.11 to 17.29]). Mucocutaneous toxicity (P<.001) and noncompliance (40% versus 25% at 3 years) were higher in the isotretinoin arm than in the placebo arm.. Isotretinoin treatment did not improve the overall rates of SPTs, recurrences, or mortality in stage I NSCLC. Secondary multivariate and subset analyses suggested that isotretinoin was harmful in current smokers and beneficial in never smokers.

Topics: Adult; Aged; Aged, 80 and over; Anticarcinogenic Agents; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Female; Humans; Isotretinoin; Lung Neoplasms; Male; Middle Aged; Multivariate Analysis; Neoplasm Staging; Neoplasms, Second Primary; Placebos; Smoking

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Female; Humans; Interferon-alpha; Isotretinoin; Lung Neoplasms; Male; Middle Aged; Treatment Outcome

Erlotinib is useful in advanced non-small cell lung cancer although compliance and efficacy are diminished by skin rash in a high proportion of patients, often necessitating dose reduction or drug withdrawal. No effective treatment for the rash is available.. We carried out a preliminary investigation on isotretinoin and clindamycin. Among 56 advanced lung cancer patients treated with erlotinib, 31 (53%) developed rash. Seven (35%) of the 20 G2/G3 cases agreed to treatment with clindamycin (450 mg/d, days 1-10; 300 mg/d, days 11-20) plus isotretinoin (20 mg/d, days 11-20) after being informed of the experimental nature of the combination.. In 6 of 7 (86%) patients, the rash resolved (G1/G0) without dose reduction; in the other patient (G3), the erlotinib dose also had to be reduced. Median time to resolution was 14 days (range 7-20 days). No rash-treatment adverse events occurred during 20 days of administration.. Isotretinoin plus clindamycin promises to be the first effective treatment for erlotinib rash and is being tested further.

Topics: Anti-Bacterial Agents; Carcinoma, Non-Small-Cell Lung; Clindamycin; Dermatologic Agents; ErbB Receptors; Erlotinib Hydrochloride; Exanthema; Humans; Isotretinoin; Lung Neoplasms; Protein Kinase Inhibitors; Quinazolines; Survival Rate; Treatment Outcome

The growth inhibitory effects of four retinoic acid (RA) derivatives, 9-cis RA, 13-cis RA, N-(4-hydroxyphenyl) retinamide (4-HPR), and all-trans retinoic acid (ATRA) were compared. In addition, the effects of various combinations of these four agents were examined on non-small cell lung carcinoma (NSCLC) cell-lines, and on the expressions of retinoic acid receptors (RARs) and retinoid X receptors (RXRs) on these cells. At the clinically achievable concentration of 1 microM, only 4-HPR inhibited the growths of H1299 and H460 cells-lines. However, retinoic acid receptor beta(RAR beta) expression was up-regulated on H460 and H1299 cells treated with 1 microM of ATRA, 13-cis RA, or 9-cis RA. All NSCLC cell lines showed growth inhibition when exposed sequentially to 1 microM ATRA and 0.1 microM 4-HPR. In particular, sequential treatment with 1 microM ATRA or 13-cis RA and 4-HPR markedly inhibited H1703 cell growth; these cells exhibited no basal RAR beta expression and were refractory to 4-HPR. However, in NSCLC cell lines that expressed RAR beta, the expressional levels of RAR beta were up-regulated by ATRA alone and by sequential treatment with ATRA and 4-HPR. 4-HPR was found to be the most active of the four agents in terms of NSCLC growth-inhibition. Moreover, sequential treatments with ATRA or 13-cis RA followed by 4-HPR were found to have synergistic growth-inhibitory effects and to regulate RAR expression.

Topics: Alitretinoin; Base Sequence; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; DNA Primers; Drug Therapy, Combination; Fenretinide; Gene Expression; Humans; Isotretinoin; Lung Neoplasms; Receptors, Retinoic Acid; Retinoid X Receptors; Tretinoin

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Combined Modality Therapy; Feasibility Studies; Female; Head and Neck Neoplasms; Humans; Interferon-alpha; Isotretinoin; Lung Neoplasms; Male; Middle Aged; Prospective Studies; Uterine Cervical Neoplasms

We assessed the antiproliferative effect of human recombinant interferon -alpha (IFN-alpha) or -beta in combination with 5-fluorouracil (5-FU), cisplatin, or cis- or trans-retinoic acid on two human nonsmall cell lung carcinoma cell lines (SK-LU-1 and SK-MES-1) and on one human small cell lung carcinoma cell line (NCI-H69). Results were obtained by direct cell count and/or by the clonigenic assay. The three cell lines differed in their sensitivities to the antiproliferative effects of the different agents. However, both NSCLC cell lines were more responsive to IFN-beta than to IFN-alpha. The SK-MES cell line was more resistant to both IFNs than the SK-LU-1. The NCI-H69 cells were resistant to all the drugs tested, except trans-retinoic acid. The dose and time of exposure were found to be important factors in the case of IFNs and cytotoxic agents, with lower surviving fractions obtained with the higher doses and longer exposures. This finding, however, did not hold true for the retinoic acids, which showed no antiproliferative effect. Within the sensitivity of our system, we did not identify any synergistic interaction in any of the cell lines with IFN-alpha or IFN-beta and 5-FU or cisplatin. A slight synergistic interaction was observed with IFN and cis- or trans-retinoic acid in the SK-LU-1 cell line which was not thought to be clinically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cell Division; Cisplatin; Drug Synergism; Fluorouracil; Humans; Interferon Type I; Interferon-beta; Isotretinoin; Lung Neoplasms; Recombinant Proteins; Tretinoin; Tumor Cells, Cultured

Topics: Adult; Aged; Carcinoma, Non-Small-Cell Lung; Diagnosis-Related Groups; Drug Evaluation; Female; Humans; Isotretinoin; Lung Neoplasms; Male; Middle Aged; Tretinoin