isotretinoin and Head-and-Neck-Neoplasms

Head and neck squamous cell carcinoma affects >45,000 Americans annually. Patients who are successfully treated for their primary tumor are at high risk of developing a second primary tumor, making effective preventive strategies highly desirable for this disease. Although a landmark study in 1990 suggested some benefit of high-dose retinoids in head and neck cancer prevention, subsequent trials using more tolerable doses have shown limited clinical success. Newer preventive strategies have included bioadjuvant therapy combining retinoids with interferon and alpha-tocopherol, combinations of molecularly targeted agents, and oncolytic viruses. Furthermore, considerable evidence has supported a cancer protective role for several nutrients, including green tea and curcumin analogs. Natural compounds such as these with favorable long-term safety profiles might be particularly suited to the cancer prevention setting, in which patients will usually tolerate only moderate risk and toxicity.

Topics: Adenoviridae; Anticarcinogenic Agents; Carcinoma, Squamous Cell; Cyclooxygenase 2 Inhibitors; Diterpenes; ErbB Receptors; Etretinate; Head and Neck Neoplasms; Humans; Interferon-alpha; Isotretinoin; Neoadjuvant Therapy; Randomized Controlled Trials as Topic; Retinoids; Retinyl Esters; Viral Vaccines; Vitamin A

Topics: Head and Neck Neoplasms; Humans; Isotretinoin; Leukoplakia; Lung Neoplasms; Models, Genetic; Respiratory Mucosa; Retinoids

Topics: Biomarkers, Tumor; Head and Neck Neoplasms; Humans; Isotretinoin; Lung Neoplasms; Mouth Neoplasms; Neoplasms, Second Primary; Retinoids

There is a clear change in the treatment strategies for solid tumours towards the treatment of early rather than advanced disease. Retinoids represent a potentially useful class of drugs in chemoprevention. Preclinical data and clinical experience suggests that different retinoids may have different spectra of antitumour activity and synergistic interactions between retinoids and cytokines have also been reported. 13-cis retinoic acid has shown some promising activity in preventing the onset of second primary tumours in head and neck cancer and fenretinide is being tested in the prevention of second primary breast cancers. An understanding fo the role of the different retinoid receptors could lead to the design of compounds with a better therapeutic index. Despite these early indications that retinoids could be useful in this area, the development of such drugs is far from easy. Appropriate study designs for screening differentiating agents in the clinic, and the relevance of preclinical models of chemoprevention are challenges to be addressed. Unresolved issues include optimal patient selection, long clinical trial times, optimal dose, schedule and treatment duration. The use of biological surrogate markers for longer time-dependent trial endpoints could significantly contribute to more rapid development. Ongoing clinical studies, particularly in tobacco-related diseases, will better define the role of retinoids in this clinical setting. Clinicians should be encouraged to enter patients into large well organized clinical studies.

Topics: Breast Neoplasms; Female; Fenretinide; Head and Neck Neoplasms; Humans; Isotretinoin; Lung Neoplasms; Male; Neoplasms; Retinoids; Risk Factors

Topics: Antioxidants; beta Carotene; Carcinoma, Squamous Cell; Carotenoids; Head and Neck Neoplasms; Humans; Isotretinoin

Several clinical trials have demonstrated the efficacy as chemopreventive agents on upper aerodigestive tract (UADT) cancer of vitamin A or its natural precursor, beta-carotene, or its synthetic analogues, retinoids. Particularly, 13-cis-retinoic acid (cRA) has been shown to reverse oral leukoplakia and to reduce the frequency of second primary tumours in patients treated for head and neck cancer. Since chemopreventive treatments must be of very long-term duration (even years), and because of apparent 'good health' of treated patients, the toxicity of used drugs and the compliance with treatment need to be carefully considered. Current clinical research has evaluated the efficacy of low doses of cRA in larger numbers of patients, and the increased effectiveness of cRA when used in combination with recombinant alpha-interferon 2a (r-alpha-IFN 2a) has also produced high objective response rate in patients affected with squamous cell carcinoma of the head and neck. In vitro and in vivo studies to verify the validity of several biomarkers (in particular micronuclei) as intermediate end-points in chemoprevention studies are continuing, to allow the short-term screening of promising chemopreventive drugs to be used in clinical trials. The published literature on this matter is reviewed, with special attention to retinoid treatment and toxicity/compliance-related problems, and compared with our own experience.

Topics: Carcinoma, Squamous Cell; Clinical Trials as Topic; Drug Screening Assays, Antitumor; Head and Neck Neoplasms; Humans; Isotretinoin; Leukoplakia, Oral; Patient Compliance; Remission Induction

Chemoprevention is a clinical strategy to block or reverse carcinogenesis before the development of invasive cancer. Studies of chemoprevention in the lungs and upper aerodigestive tract have relied on the field carcinogenesis hypothesis, which predicts that diffuse epithelial injury will result from exposure of that epithelium to carcinogens. This hypothesis is supported by the frequent occurrence of multiple primary tumors within the exposed field. In addition, the understanding of carcinogenesis as a multistep process supports the use of interventions in damaged epithelium before the development of clinically invasive cancer. Current efforts are focused on applying to chemoprevention studies the increasing knowledge of the molecular events in carcinogenesis. In our program, clinical trials in lung and head and neck chemoprevention have focused on individuals with evidence of field carcinogenesis, i.e., a history of previous epithelial cancer or the presence of premalignant lesions. These trials include studies to develop clinically applicable intermediate markers of carcinogenesis and large Phase III trials to evaluate the efficacy of the retinoid isotretinoin in preventing second primary tumors following head and neck or lung cancers.

Topics: Anticarcinogenic Agents; Diterpenes; Etretinate; Head and Neck Neoplasms; Humans; Isotretinoin; Leukoplakia; Lung Neoplasms; Mouth Neoplasms; Retinoids; Retinyl Esters; Vitamin A

Topics: Animals; Anticarcinogenic Agents; Etretinate; Head and Neck Neoplasms; Humans; Isotretinoin; Retinoids; Tretinoin

Chemoprevention entails using specific agents to suppress carcinogenesis and thereby prevent the development of primary or second primary cancers. Because the concept of chemoprevention in patients with or at risk of lung cancer is new, ongoing clinical trials are based on data from epidemiologic and preclinical research, as well as on results of chemoprevention studies in head and neck cancer. The latter studies have provided a model for such studies in lung cancer, considering the two diseases have a similar etiology and biology of field carcinogenesis. Beta-carotene, natural vitamin A, and the retinoids may be effective chemopreventive agents. However, chronic administration of such agents may be required to prevent the development of cancer. Results of chemoprevention trials in head and neck cancer have demonstrated effective inhibition of the development of second primary tumors with the synthetic retinoid 13-cis-retinoic acid; investigators are hopeful this will be repeated in patients with lung cancer. Results of ongoing phase III trials and continued advances in the epidemiologic and biologic study of lung carcinogenesis should contribute to future research in this area.

Topics: beta Carotene; Carotenoids; Head and Neck Neoplasms; Humans; Isotretinoin; Leukoplakia, Oral; Lung Neoplasms; Neoplasms, Second Primary; Risk Factors; Vitamin A

Topics: Anticarcinogenic Agents; Antineoplastic Agents; Breast Neoplasms; Drug Design; Female; Gastrin-Releasing Peptide; Growth Substances; Head and Neck Neoplasms; Humans; Isotretinoin; Lung Neoplasms; Male; Neoplasms, Second Primary; Oncogenes; Peptides; Retrospective Studies; Sputum; Tamoxifen; United States

13-Cis retinoic acid (13-CRA) is a synthetic vitamin A derivative. High-dose 13-CRA in patients with squamous cell cancers of the head and neck (SCCHNs) reduces the incidence of second primary tumors (SPTs). The authors report long-term results from a phase 3 randomized trial that compared treatment with low-dose 13-CRA versus placebo for patients who had early stage SCCHN, with a focus on the development of SPTs and overall survival (OS).. In total, 176 patients who received treatment for stage I/II SCCHN were randomized to receive either low-dose 13-CRA (weight-based dose of 7.5 mg or 10 mg) or placebo for 2 years. A competing-risk approach and the log-rank test were used to compare the time to SPT and OS, respectively, between groups.. 13-CRA neither significantly reduced the cumulative incidence of SPT (P = .61) nor improved the time to SPT (hazard ratio [HR] for 13-CRA/placebo; 0.86; P = .61). Despite limited power, there was a trend toward improved OS for the 13-CRA arm (HR, 0.75; P = .14), particularly among patients whose index tumor was surgically excised (N = 26; HR, 0.50; P = .057) and among women (N = 39; HR, 0.44; P = .065) and never/former smokers (N = 129; HR, 0.61; P = .055), with a median follow-up of 16 years. The main 13-CRA related toxicities were dry skin and cheilitis.. Treatment with low-dose 13-CRA for 2 years did not decrease the incidence of SPT; subset analysis indicates a potential survival advantage among patients who are women and never/former smokers. More targeted interventions based on clinical risk factors and molecular characterization of tumors may yield greater success in future prevention trials. Cancer 2017;123:4653-4662. © 2017 American Cancer Society.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Dermatologic Agents; Double-Blind Method; Female; Follow-Up Studies; Head and Neck Neoplasms; Humans; Isotretinoin; Male; Middle Aged; Neoplasm Staging; Neoplasms, Second Primary; Prognosis; United States

Head and neck squamous cell carcinoma (HNSCC) patients are at an increased risk of developing a second primary tumor (SPT) or recurrence following curative treatment. 13-cis-retinoic acid (13-cRA) has been tested in chemoprevention clinical trials, but the results have been inconclusive. We genotyped 9,465 single nucleotide polymorphisms (SNP) in 450 patients from the Retinoid Head and Neck Second Primary Trial. SNPs were analyzed for associations with SPT/recurrence in patients receiving placebo to identify prognosis markers and further analyzed for effects of 13-cRA in patients with these prognostic loci. Thirteen loci identified a majority subgroup of patients at a high risk of SPT/recurrence and in whom 13-cRA was protective. Patients carrying the common genotype of rs3118570 in the retinoid X receptor (RXRA) were at a 3.33-fold increased risk (95% CI, 1.67-6.67) and represented more than 70% of the study population. This locus also identified individuals who received benefit from chemoprevention with a 38% reduced risk (95% CI, 0.43-0.90). Analyses of cumulative effect and potential gene-gene interactions also implicated CDC25C:rs6596428 and JAK2:rs1887427 as 2 other genetic loci with major roles in prognosis and 13-cRA response. Patients with all 3 common genotypes had a 76% reduction in SPT/recurrence (95% CI, 0.093-0.64) following 13-cRA chemoprevention. Carriers of these common genotypes constituted a substantial percentage of the study population, indicating that a pharmacogenetic approach could help select patients for 13-cRA chemoprevention. The lack of any alternatives for reducing risk in these patients highlights the need for future clinical trials to prospectively validate our findings.

Topics: Carcinoma, Squamous Cell; Cohort Studies; DNA, Neoplasm; Female; Genotype; Head and Neck Neoplasms; Humans; Isotretinoin; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasms, Second Primary; Placebos; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Retinoid X Receptor alpha; Risk Factors; Survival Rate; Treatment Outcome

Isotretinoin (13-cis-retinoic acid) is a synthetic vitamin A derivative, or retinoid, widely used in the treatment of cystic acne. Preclinical and clinical studies of high-dose isotretinoin in patients with head and neck squamous cell cancer (HNSCC) have produced encouraging results. We conducted a phase III randomized trial of low-dose isotretinoin versus placebo in early-stage HNSCC patients to assess its effect on second primary tumor incidence and survival.. We randomly assigned 1190 patients who had been treated for stage I or II HNSCC to receive either low-dose isotretinoin (30 mg/day) or placebo for 3 years. The patients were monitored for up to 4 more years. Survival was analyzed by the Kaplan-Meier method, and Cox proportional hazards models were used for multivariable survival analysis. All statistical tests were two-sided.. Isotretinoin did not statistically significantly reduce the rate of second primary tumors (hazard ratio [HR] = 1.06, 95% confidence interval [CI] = 0.83 to 1.35) or increase survival (HR = 1.03, 95% CI = 0.81 to 1.32) compared with placebo in patients with early-stage HNSCC. Current smokers had a higher rate of second primary tumors than that of never (HR = 1.64, 95% CI = 1.08 to 2.50) or former (HR = 1.32, 95% CI = 1.01 to 1.71) smokers. The hazard ratio of death from any cause for current smokers versus never smokers was 2.51 (95% CI = 1.54 to 4.10) and for current smokers versus former smokers was 1.60 (95% CI = 1.23 to 2.07). Major sites of second primary tumors (n = 261) included lung (31%), oral cavity (17%), larynx (8%), and pharynx (5%).. Low-dose isotretinoin was not effective in reducing the rate of second primary tumors or death or smoking-related disease. Smoking statistically significantly increased the rate of second primary tumors and death. Ongoing trials are testing higher doses of isotretinoin as part of combination bioadjuvant therapeutic methods for patients with locally advanced HNSCC.

Topics: Aged; Anticarcinogenic Agents; Antineoplastic Agents; Carcinoma, Squamous Cell; Disease-Free Survival; Drug Administration Schedule; Female; Head and Neck Neoplasms; Humans; Isotretinoin; Male; Multivariate Analysis; Neoplasm Staging; Neoplasms, Second Primary; Odds Ratio; Patient Selection; Proportional Hazards Models; Risk Factors; Smoking; Survival Analysis; Treatment Failure

The objective of this study was to evaluate the effects of polymorphisms in 2 genes in the glutathione S-transferase (GST) family and the mutagen-sensitivity phenotype on the risk of second primary tumors (SPTs) in patients with previously diagnosed early-stage head and neck squamous cell carcinoma. Data were available for 303 patients who were enrolled in a placebo-controlled chemoprevention trial of low-dose 13-cis-retinoic acid to reduce the occurrence of SPTs.. A Cox proportional hazards model and survival tree analysis were used to evaluate the association between specified genetic variations and the development of SPTs. The average number of bleomycin-induced chromatid breaks per cell was used to quantify mutagen sensitivity as an individual patient's degree of sensitivity to genotoxicity.. The GST-M1 null genotype was associated with an increased risk for any SPTs (hazard ratio [HR], 1.99; 95% confidence interval [95% CI], 1.11-3.56) and for tobacco-related SPTs (HR, 2.16; 95% CI, 1.01-4.62) after adjusting for covariates. The GST-T1 null genotype and bleomycin-induced chromatid breaks were not associated with a statistically significant increased risk for SPTs or tobacco-related SPTs after similar adjustment. Simultaneous nonnull status for both GST genotypes was associated with a decreased risk for any SPTs (HR, 0.52; 95% CI, 0.28-0.96) and tobacco-related SPTs (HR, 0.50; 95% CI, 0.22-1.11) compared with null status for GST-M1 accompanied by nonnull status for GST-T1.. An association was observed between the development of SPTs and the GST-M1 null genotype after successful treatment for early-stage head and neck squamous cell carcinoma. The GST-T1 null genotype and bleomycin-induced chromatid breaks were not associated with an increased risk, and no significant interactions were identified.

Topics: Aged; Alcohol Drinking; Bleomycin; Carcinoma, Squamous Cell; Chemoprevention; Chromosome Breakage; Disease-Free Survival; Female; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Genotype; Glutathione Transferase; Head and Neck Neoplasms; Humans; Isotretinoin; Male; Middle Aged; Mutagens; Neoplasms, Second Primary; Odds Ratio; Polymorphism, Genetic; Proportional Hazards Models; Risk Factors; Smoking; Time Factors

To evaluate the long-term effects of the combination of isotretinoin, interferon alfa-2a, and vitamin E in locally advanced squamous cell carcinoma of the head and neck.. Phase 2 prospective study.. Tertiary care academic medical centers.. Forty-five patients entered this study. All patients had stage III or IV squamous cell carcinoma of the head and neck and had been treated with surgical resection, radiation, or both. All patients were then treated with bioadjuvant chemopreventive treatment for 12 months. We previously reported a 24-month median follow-up of this phase 2 trial of the combination of isotretinoin, interferon alfa-2a, and vitamin E as bioadjuvant therapy after definitive local therapy. In that study, all 45 patients completed treatment, but 1 patient was excluded from analysis of recurrence and development of second primary tumors. Main Outcome Measure Longer-term (49.4-month median) follow-up.. Among the 45 patients treated under the protocol, only 7 patients (16%) had died. Nine (20%) of 45 patients experienced progressive disease. Only 1 second primary tumor (acute promyelocytic leukemia) occurred during follow-up, and no aerodigestive second primary tumors occurred among the 45 patients. The 5-year progression-free survival and overall survival percentages were 80% (95% confidence interval, 65.1%-89.1%) and 81.3% (95% confidence interval, 63.7%-90.9%), respectively. These results are significantly better than the historical 5-year overall survival for advanced squamous cell carcinoma of the head and neck (approximately 40%).. The bioadjuvant combination is highly effective in preventing recurrence and second primary tumors, and its role as standard therapy in advanced squamous cell carcinoma of the head and neck is being investigated in a randomized phase 3 study.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Drug Therapy, Combination; Head and Neck Neoplasms; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Neoplasms, Second Primary; Prospective Studies; Recombinant Proteins; Vitamin E

The combination of interferon alfa (IFNalpha) and isotretinoin has shown a direct antiproliferative effect on human melanoma cell lines, but it remained unclear whether this combination is more effective than IFNalpha alone in patients with metastatic melanoma. We evaluated safety and efficacy of IFNalpha and isotretinoin compared with IFNalpha alone as adjuvant treatment in patients with primary malignant melanoma stage IIA and IIB.. In a prospective, randomized, double-blind, placebo-controlled trial, 407 melanoma patients in stage IIA (301 patients) and IIB (106 patients) were randomly assigned to either IFNalpha and isotretinoin (isotretinoin group; 206 patients) or IFNalpha and placebo (placebo group; 201 patients) after excision of the primary tumor. IFNalpha was administered three times a week at a dose of 3 million units subcutaneously for 24 months. Isotretinoin at a dose of 20 mg for patients < or = 73 kg, 30 mg for patients greater than 73 kg, or placebo daily for 24 months.. A scheduled interim analysis revealed no significant differences in survival rates, with the isotretinoin group and the placebo group showing 5-year disease-free survival rates of 55% (95% CI, 46% to 65%) and 67% (95% CI, 59% to 75%), respectively, and overall 5-year survival rates of 76% (95% CI, 67% to 84%) and 81% (95% CI, 74% to 88%), respectively. The trial was stopped for futility.. The addition of isotretinoin to an adjuvant treatment of low-dose IFNalpha in patients with stage IIA and IIB melanoma had no significant effect on disease-free or overall survival and is therefore not recommended.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Disease-Free Survival; Double-Blind Method; Europe; Female; Head and Neck Neoplasms; Humans; Hyperlipidemias; Interferon-alpha; Isotretinoin; Male; Melanoma; Middle Aged; Multivariate Analysis; Neoplasm Staging; Prognosis; Prospective Studies; Quality of Life; Skin Diseases; Treatment Outcome

Patients with squamous cell carcinoma of the head and neck (HNSCC) after being treated radically remain at high risk for both recurrent and second primary tumours. 13-cis retinoic acid (13-cRA) was demonstrated to reverse pre-malignant lesions of the oral cavity and to reduce the incidence of second primary tumours in patients treated radically for HNSCC. Synergism between retinoids and interferon in tumoural cell lines have been demonstrated. Based on these data, the Italian Head and Neck Chemoprevention Study Group started a randomized chemoprevention study in patients radically treated for stage III and IV HNSCC. From February 1992 to January 1996, 267 patients were randomized: 126 were allocated to the control group, 126 were randomized to receive 13-cRA at a dose of 0.5 mg/kg per day per os and 15 patients have been assigned to the group of 13-cRA plus interferon alpha2a (IFN-alpha2a) at a dose of 3,000,000 UI 3 times a week (randomization in this arm interrupted due to administrative financial problems). The mean follow-up was 39 months. The 5-year actuarial survival was 58.9% for patients of the 13-cRA group and 57.2% for those of the control group (P=0.94). Among evaluable patients, disease progression was observed in 45 of 123 patients (36.6%) of the 13-cRA group and in 42 of 124 (33.9%) of the control group. The 5-year actuarial relapse-free survival was 48.9% for the 13-cRA group and 55.6% for the control group (P=0.62). Adverse effects, mostly of grade I were reported in 69.4% of treated patients (haematologic disorders, mucositis, conjunctivitis, cutaneous toxicity, hypertriglyceridemia and hypercholesterolemia). Only 5 patients (4.1%) reported grade III-IV toxicity. Low-dose of 13-cRA given for 1 year is ineffective as chemoprevention in patients with radically treated HNSCC.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Chemoprevention; Combined Modality Therapy; Female; Follow-Up Studies; Head and Neck Neoplasms; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Male; Middle Aged; Neoplasm Staging; Recombinant Proteins; Survival Analysis

This study evaluated the joint effects of tobacco smoking and alcohol consumption on the risk of second primary tumors (SPT) in patients with early-stage head and neck squamous cell carcinoma (HNSCC).. Data are presented for 1181 patients enrolled in a placebo-controlled chemoprevention trial of 13-cis-retinoic acid. Nearly 17% of patients presented with a SPT. The log rank test and Cox proportional hazards model were used to examine risk factors for SPT development.. After adjusting for the time from the index diagnosis to randomization, age at diagnosis, stage, and site of the primary cancer, the factors that emerged as simultaneous predictors of SPT development were continued smoking and alcohol intake after the index diagnosis. Increased SPT risk was associated with older age (RR = 2.1; 95% CI 1.5-2.8); stage II diagnosis (RR = 1.5; 95% CI 1.1-2.1); index diagnosis of pharyngeal cancer (RR = 1.6; 95% CI 1.1-2.5); current smoking at registration (RR = 2.1; 95% CI 1.3-3.6) and continued alcohol consumption post-diagnosis (RR = 1.3; 95% CI 1.0-1.7).. Important associations exist between SPT development and continued smoking and alcohol consumption after treatment for HNSCC.

Topics: Aged; Alcohol Drinking; Carcinoma, Squamous Cell; Disease-Free Survival; Head and Neck Neoplasms; Humans; Isotretinoin; Middle Aged; Neoplasms, Second Primary; Proportional Hazards Models; Prospective Studies; Smoking

This study investigated the toxicity and efficacy of a 13-cis retinoic acid, carboplatin, and paclitaxel (Taxol) regimen in 18 patients with recurrent or metastatic squamous cell carcinomas (12 head and neck, 4 cervix, 1 esophagus, and 1 anus). Three patients were treated at each dose level with fenretamide (Accutane) 1 mg/kg/d orally for 14 days, carboplatin AUC of 5 mg/ml.min intravenously (IV) and paclitaxel at a dose of 135, 155, 175, 195, 205, or 225 mg/m(2) IV on day 8 every 4 weeks for 6 cycles. Fifteen evaluable patients had a total of 72 treatment cycles. There were 21 grade III or IV toxicities distributed among all the dose levels, including neutropenia, anemia, thrombocytopenia, elevated prothrombin time/partial thromboplastin time, elevated alkaline phosphatase, weight loss, alopecia, and three deaths from aspiration pneumonia and septic shock. The maximum tolerated dosage included 205 mg/m(2) paclitaxel. There was one complete response, three partial responses, and 2 stable diseases. The three partial responses were in the four patients with cervical cancer. Responses did not correlate with expression of retinoic acid receptor subtypes. Toxicity profiles and overall response rates were comparable to prior studies with similar chemotherapy regimens alone. The data support further study in a phase II trial.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Squamous Cell; Drug Synergism; Female; Head and Neck Neoplasms; Humans; Isotretinoin; Male; Middle Aged; Paclitaxel; Remission Induction; Uterine Cervical Neoplasms

Retinoids and interferons (IFNs) have single-agent and synergistic combined effects in modulating cell proliferation, differentiation, and apoptosis in vitro and clinical activity in vivo in the head and neck and other sites. Alpha-tocopherol has chemopreventive activity in the head and neck and may decrease 13-cis-retinoic acid (13-cRA) toxicity. We designed the present phase II adjuvant trial to prevent recurrence or second primary tumors (SPTs) using 13-cRA, IFN-alpha, and alpha-tocopherol in locally advanced-stage head and neck cancer.. After definitive local treatment with surgery, radiotherapy, or both, patients with locally advanced SCCHN were treated with 13-cRA (50 mg/m(2)/d, orally, daily), IFN-alpha (3 x 10(6) IU/m(2), subcutaneous injection, three times a week), and alpha-tocopherol (1,200 IU/d, orally, daily) for 12 months, with a dose modification. Screening for recurrence or SPTs was performed every 3 months.. Tumors of 11 (24%) of the 45 treated patients were stage III, and 34 (76%) were stage IV. Thirty-eight (86%) of 44 patients completed the full 12-month treatment (doses modified as needed). Toxicity generally was consistent with previous IFN and 13-cRA reports and included mild to moderate mucocutaneous and flu-like symptoms; occasional significant fatigue (grade 3 in 7% of patients), mild to moderate hypertriglyceridemia in 30% of patients who continued treatment along with antilipid therapy, and mild hematologic side effects. Six patients did not complete the planned treatment because of intolerable toxicity or social problems. At a median 24-months of follow-up, our clinical end point rates were 9% for local/regional recurrence (four patients), 5% for local/regional recurrence and distant metastases (two patients), and 2% for SPT (one patient), which was acute promyelocytic leukemia (ie, not of the upper aerodigestive tract). Median 1- and 2-year rates of overall survival were 98% and 91%, respectively, and of disease-free survival were 91% and 84%, respectively.. The novel biologic agent combination of IFN-alpha, 13-cRA, and alpha-tocopherol was generally well tolerated and promising as adjuvant therapy for locally advanced squamous cell carcinoma of the head and neck. We are currently conducting a phase III randomized study of this combination (v no treatment) to confirm these phase II study results.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Drug Synergism; Female; Head and Neck Neoplasms; Humans; Interferon-alpha; Isotretinoin; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasms, Second Primary; Survival Analysis; Survival Rate; Vitamin E

Second primary tumors (SPTs) develop at an annual rate of 3-7% in patients with head and neck squamous cell cancer (HNSCC). In a previous Phase III study, we observed that high doses of 13-cis-retinoic acid reduced the SPT rate in this disease. In 1991, we launched an intergroup, placebo-controlled, double-blind study to evaluate the efficacy of low-dose 13-cis-retinoic acid in the prevention of SPTs in patients with stage I or II squamous cell carcinoma of the larynx, oral cavity, or pharynx who had been previously successfully treated with surgery, radiotherapy, or both, and whose diagnoses had been established within 36 months of study entry. As of September 16, 1999, the Retinoid Head and Neck Second Primary (HNSP) Trial had completed accrual with 1384 registered patients and 1191 patients randomized and eligible. All of the patients were followed for survival, SPT development, and index cancer recurrence. Smoking status was assessed at study entry and during study. Smoking cessation was confirmed biochemically by measurement of serum cotinine levels. The annual rate of SPT development was analyzed in terms of smoking status and tumor stage. As of May 1, 2000, SPTs have developed in 172 patients. Of these, 121 (70.3%) were tobacco-related SPTs, including 113 in the aerodigestive tract (57 lung SPTs, 50 HNSCC SPTs, and 6 esophageal SPTs) and 8 bladder SPTs. The remaining 51 cases included 23 prostate adenocarcinomas, 8 gastrointestinal malignancies, 6 breast cancers, 3 melanomas, and 11 other cancers. The annual rate of SPT development observed in our study has been 5.1%. SPT development related to smoking status was marginally significant (active versus never, 5.7% versus 3.5%; P = 0.053). Significantly different smoking-related SPT development rates were observed in current, former, and never smokers (annual rate = 4.2%, 3.2%, and 1.9%, respectively, overall P = 0.034; current versus never smokers, P = 0.018). Stage II HNSCC had a higher overall annual rate of SPT development (6.4%) than did stage I disease (4.3%; P = 0.004). When evaluating the development of smoking-related SPTs, stage was also highly significant (4.8% for stage II versus 2.7% for stage I; P = 0.001). Smoking-related SPT incidence was significant for site as well (larynx versus oral cavity, P = 0.015; larynx versus pharynx, P = 0.011). Primary tumors recurred at an annual rate of 2.8% in a total of 97 patients. The rate of recurrence was higher in patients with stage II disease (4.

Topics: Adult; Aged; Chemoprevention; Cotinine; Dermatologic Agents; Double-Blind Method; Female; Head and Neck Neoplasms; Humans; Incidence; Isotretinoin; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasms, Second Primary; Smoking

Ifosfamide (IFO) and cisplatin (CDDP) are active drugs in the treatment of patients with squamous cell carcinoma (SCC) of the head and neck. 13-Cis retinoic acid (RA), along with its antiproliferative and differentiating activity on SCC cell lines, has immunomodulatory and chemopreventive effects. The objective of the current Phase I-II study was to evaluate the combination of CDDP, IFO, and RA in patients with advanced or recurrent SCC of the head and neck.. Patients with measurable recurrent, metastatic, or locally advanced SCC of the head and neck were eligible. Patients received a fixed dose of 20 mg/m(2) CDDP, and IFO was administered with sodium mercaptoethanesolfonate in three-dose increments (1000 mg/m(2), 1200 mg/m(2), and 1500 mg/m(2)) up to dose limiting toxicity. Both drugs were given for 5 consecutive days every 3 weeks. RA (0.5 mg/kg) was given orally for 5 days per week.. Fifty-two patients either with locoregional recurrence or distant metastases (50%) or with locally advanced SCC of the head and neck beyond surgery or radiation therapy (50%) were entered into the trial. Fifteen patients were enrolled in the Phase I study, during which the maximum tolerated dose of IFO was 1500 mg/m(2). In the Phase II study (CDDP 20 mg/m(2) and IFO 1200 mg/m(2)), the response rate was 72% (95% confidence interval, 57-83%). After a median follow-up of 23 months, the median time to disease progression was 10.4 months (range, 2.9-47.2+ months), and the median overall survival was 12.95 months (range, 1.7-47.2+ months). Two patients were converted from a partial response to a complete response with RA. Toxicity was relatively well tolerated and caused no deaths. Grade 3-4 neutropenia was observed in 16 patients, and Grade 2-3 diarrhea toxicity occurred in 9 patients.. The dose and schedule for the combination of CDDP, IFO, and RA that were used in this study are feasible and active in the treatment of patients with SCC of the head and neck, with durable responses and a relatively well tolerated toxicity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Female; Head and Neck Neoplasms; Humans; Ifosfamide; Isotretinoin; Male; Middle Aged; Neoplasm Recurrence, Local; Survival Analysis

Topics: Anticarcinogenic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Transformation, Neoplastic; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Immunohistochemistry; Interferon-alpha; Isotretinoin; Mutation; Precancerous Conditions; Prospective Studies; Treatment Outcome; Tumor Suppressor Protein p53; Vitamin E

Preclinical and clinical data have suggested antitumor efficacy in squamous cell carcinoma (SCC) of interferon (IFN)-alpha and 13-cis-retinoic acid (13-c-RA) as single agent with greater activity in combination. Cisplatin was added to potentiate activity. Twenty-three patients with pretreated advanced or metastatic head and neck squamous cell carcinoma were given a combination of IFN-alpha (6 x 10(6) U/day, 84 days s.c.), 13-c-RA (1 mg/kg/day, 84 days) and cisplatin (40 mg/kg/day, day 1, 28 and 56). Seventeen patients had discontinuation of treatment and three patients received overall treatment without dose reduction. Hematological toxicity was more frequent; only three patients experiencing grade 3 or higher extra-hematological toxicity. Four out of 14 evaluable patients were in response, with one in complete pathological response. Median duration of response was 6 months with a 9 month median survival. Association of IFN-alpha, 13-c-RA and cisplatin induces modest but definite antitumor activity with moderate and manageable toxicity. Further studies of different combination modality therapy with chemotherapy and differentiating agents need to be performed in less pretreated patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Female; Head and Neck Neoplasms; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Male; Middle Aged; Recombinant Proteins; Time Factors; Treatment Outcome

Cis-platinum and 13-cis-retinoic acid have received much attention in the treatment of head and neck squamous cell cancer. Even though they have different mechanisms of action, little information is available on their interaction. This paper reviews experimental evidence for retinoic acid-cis-platinum synergy and presents toxicity data from patients with stage IV head and neck squamous cell cancer participating in a phase I trial combining 13-cis-retinoic acid and cis-platinum.. Patients were given 13-cis-retinoic acid orally daily for 7 days before and daily during high-dose (150 mg/m2 per week for 4 weeks) intraarterial cis-platinum treatment with concurrent radiation. Toxicity was scored with use of the cancer and leukemia group B scale.. In the phase I clinical trial, 15 patients were treated to determine a maximum tolerated dosage for 13-cis-retinoic acid of 20 mg/day. Grade 4 hematologic toxicity was dose limiting in 3 of 8 patients treated with 40 mg/day and in 1 patient treated with 60 mg/day. There were no deaths caused by toxicity; 12 of the 15 patients received all four weekly doses and the remaining 3 received three doses. Of 10 patients with fully evaluable data, all achieved a complete response at the primary site and 9 had a complete response in the neck. One patient had persistent neck disease after chemoradiation, and this tumor was removed with neck dissection.. 13-Cis-retinoic acid and cis-platinum are strongly synergistic against head and neck squamous cell cancer in vitro. Pretreatment with retinoic acid results in stronger synergy than concurrent drug exposure alone. Preliminary clinical experience with combined retinoic acid and cis-platinum in a design that parallels the in vitro study indicates that toxicity is acceptable with 13-cis-retinoic acid dosages of 20 mg/day in a high-dose-intensity intraarterial chemoradiation regimen.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Cohort Studies; Drug Administration Schedule; Drug Synergism; Female; Head and Neck Neoplasms; Humans; Injections, Intra-Arterial; Isotretinoin; Male; Middle Aged; Neoplasm Staging; Radiotherapy, Adjuvant; Remission Induction; Survival Rate; Treatment Outcome

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Female; Head and Neck Neoplasms; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Male; Middle Aged; Recombinant Proteins

This study describes the outcomes of an eight-week placebo run-in period in a head and neck cancer chemoprevention trial. Of 391 former cancer patients who entered the run-in over the first two years of the trial, 91% were randomized. Pill counts showed that adherence rates ranged from 0% to 120% (mean 96%, SD = 15%). The trial did not randomize subjects who were no longer interested in trial participation (n = 20), who did not return within 10 weeks of enrollment date (n = 3), or who did not achieve a drug adherence level of at least 75% (n = 9). Three subjects were not randomized for other reasons. Univariate predictors of run-in outcome (randomized or not randomized) included ethnicity, education level, cancer site, cancer stage, and Karnofsky performance score. Multivariate analyses resulted in a logistic model with Karnofsky performance and education level as significant predictors of randomization. Persons with a Karnofsky score of 100 had 2.3 higher odds of randomization (95% CI = 1.1, 4.9) than persons with compromised Karnofsky scores, and persons with more than a high school education had 2.1 higher odds of randomization (95% CI = 1.0, 4.9) than persons with less education. These results suggest that the use of a run-in period may compromise the external validity of randomized prevention trials. More research is needed to understand further the behavioral factors underlying the observed differences so that prevention researchers can develop effective interventions for facilitating trial participation, especially in under-represented, trial-eligible groups. Investigators should expand the objectives of a run-in period to (1) evaluate why eligible persons refuse trial enrollment or fail to be randomized at the end of the run-in and (2) use the run-in period for a systematic evaluation of levels and costs of intervention strategies designed to promote trial enrollment and adherence.

Topics: Anticarcinogenic Agents; Bias; Carcinoma, Squamous Cell; Dose-Response Relationship, Drug; Follow-Up Studies; Head and Neck Neoplasms; Humans; Isotretinoin; Neoplasms, Second Primary; Patient Dropouts; Treatment Outcome

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Drug Therapy, Combination; Female; Head and Neck Neoplasms; Humans; Interferon-alpha; Isotretinoin; Male; Middle Aged; Treatment Outcome

Sixteen patients with unresectable recurrent head and neck carcinomas were treated with 13-cis-retinoic acid and interferon-alpha. All patients had presented with recurrences after having been treated primarily with surgery and radiotherapy, while two of them had also received induction chemotherapy. The site of relapse was strictly locoregional in all cases (only at the primary site in three cases, at the cervical lymph nodes only in four cases and both at the primary site and the neck in the remaining nine cases. Two patients were female, and 14 male, with an age range of 47-72 years (median 61 years). Interferon-alpha was administered subcutaneously at a dose of 3 x 10(6) IU every second day. The dose of retinoids was 40 mg per os every day. The duration of treatment was two to 14 months (median seven months). There were two cases of partial response (tumour regression > 50 per cent), eight cases of stable disease lasting for three to seven months (median four months) and six cases presented with progressive disease. All patients died after a survival of three to 17 months (median 9.5 months). Toxicity was generally minimal. We believe that the results are not encouraging, but also not disappointing. The fact that toxicity was indeed mild, with not a single case of life-threatening sequellae even after prolonged administration of the two agents, allows us to conclude that an increase of the dose of IFN-alpha might be more beneficial. Selection of patients with more 'favourable' recurrences will give a better chance to the treatment combination to prove its real efficacy. Larger numbers of patients have to be treated and evaluated before definite conclusions can be reached.

Topics: Aged; Carcinoma, Squamous Cell; Combined Modality Therapy; Drug Administration Schedule; Female; Head and Neck Neoplasms; Humans; Immunotherapy; Interferon-alpha; Isotretinoin; Male; Middle Aged; Neoplasm Recurrence, Local; Survival Rate

Topics: Head and Neck Neoplasms; Humans; Isotretinoin; Neoplasms, Second Primary

Chemoprevention is a clinical strategy to block or reverse carcinogenesis before the development of invasive cancer. Studies of chemoprevention in the lungs and upper aerodigestive tract have relied on the field carcinogenesis hypothesis, which predicts that diffuse epithelial injury will result from exposure of that epithelium to carcinogens. This hypothesis is supported by the frequent occurrence of multiple primary tumors within the exposed field. In addition, the understanding of carcinogenesis as a multistep process supports the use of interventions in damaged epithelium before the development of clinically invasive cancer. Current efforts are focused on applying to chemoprevention studies the increasing knowledge of the molecular events in carcinogenesis. In our program, clinical trials in lung and head and neck chemoprevention have focused on individuals with evidence of field carcinogenesis, i.e., a history of previous epithelial cancer or the presence of premalignant lesions. These trials include studies to develop clinically applicable intermediate markers of carcinogenesis and large Phase III trials to evaluate the efficacy of the retinoid isotretinoin in preventing second primary tumors following head and neck or lung cancers.

Topics: Anticarcinogenic Agents; Diterpenes; Etretinate; Head and Neck Neoplasms; Humans; Isotretinoin; Leukoplakia; Lung Neoplasms; Mouth Neoplasms; Retinoids; Retinyl Esters; Vitamin A

Topics: Carcinoma, Squamous Cell; Digestive System Neoplasms; Double-Blind Method; Follow-Up Studies; Head and Neck Neoplasms; Humans; Isotretinoin; Neoplasms, Second Primary; Respiratory Tract Neoplasms; Survival Analysis

13-cis-retinoic acid (isotretinoin) and interferon-alpha have limited activity as single agents in advanced cancer. Preclinical data indicate that these agents have different mechanisms of action and, in combination have greater activity (that is, the ability to modulate growth and differentiation) in a number of malignant cell types than either agent alone. In clinical trials, the new biological regimen of 13-cis-retinoic acid and interferon-alpha was shown to have major activity in advanced squamous cell carcinoma of the skin and cervix. We conducted a phase II trial of this regimen in recurrent squamous cell carcinoma of the head and neck. Of the 21 evaluable patients, none had a complete response, and only one had a partial response (5%). Two patients had minor responses, four had stable disease, and 14 experienced disease progression. Five patients developed grade 3 toxic effects, including skin toxicity, fatigue, headache, and anorexia/weight loss. The median survival duration was 25.5 weeks (range, 4-95). The combination of 13-cis-retinoic acid and interferon-alpha at this dose and schedule is ineffective for the treatment of recurrent squamous cell carcinoma of the head and neck.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Female; Head and Neck Neoplasms; Humans; Interferon-alpha; Isotretinoin; Male; Middle Aged; Neoplasm Recurrence, Local

High-dose isotretinoin therapy has been determined to be an effective treatment for leukoplakia. However, a high rate of relapses and toxic reactions led us to conduct a trial of a much lower dose of isotretinoin in the hope of maintaining a response and limiting toxicity.. In the first phase of the study, 70 patients with leukoplakia underwent induction therapy with a high dose of isotretinoin (1.5 mg per kilogram of body weight per day) for three months; in the second phase, patients with responses or stable lesions were randomly assigned to maintenance therapy with either beta carotene (30 mg per day) or a low dose of isotretinoin (0.5 mg per kilogram per day) for nine months.. In the first phase, the rate of response to high-dose induction therapy in the 66 patients who could be evaluated was 55 percent (36 patients). The lesions of seven patients progressed, and therefore they did not participate in the second phase of the trial. Of the 59 patients included in the second phase, 33 were assigned to beta carotene therapy and 26 to low-dose isotretinoin therapy; these two groups did not differ significantly in prognostic factors. Of the 53 patients who could be evaluated, 22 in the low-dose isotretinoin group and 13 in the beta carotene group responded to maintenance therapy or continued to have stable lesions (92 percent vs. 45 percent, P < 0.001). In situ carcinoma developed in one patient in each group, and invasive squamous-cell carcinoma in five patients in the beta carotene group. Toxicity was generally mild, though greater in the group given low-dose isotretinoin therapy.. When preceded by high-dose induction therapy, low-dose isotretinoin therapy was significantly more active against leukoplakia than beta carotene and was easily tolerated.

Topics: Adult; Aged; Aged, 80 and over; beta Carotene; Carcinoma, Squamous Cell; Carotenoids; Female; Head and Neck Neoplasms; Humans; Immunologic Factors; Isotretinoin; Leukoplakia, Oral; Male; Middle Aged; Mouth Neoplasms; Remission Induction

Topics: Acetylcysteine; Animals; Antineoplastic Agents; Diet; Digestive System Neoplasms; Diterpenes; Head and Neck Neoplasms; Humans; Isotretinoin; Lung Neoplasms; Neoplasms, Second Primary; Retinyl Esters; Smoking Prevention; Vitamin A

Chemoprevention involves efforts to block or reverse carcinogenesis before the development of invasive cancer. Natural agents, such as retinol and beta carotene, as well as synthetic retinoids have been studied as potential chemopreventive agents. In the head and neck, chemoprevention studies have included efforts both to reverse premalignant lesions such as oral leukoplakia and to prevent the development of second primary tumors. In one recent trial, high-dose 13-cis-retinoic acid treatment resulted in a dramatic reduction in the incidence of second primary tumors. However, significant toxicities were associated with the high dosage. This trial, as well as previous studies of oral leukoplakia, have led to the development of a chemoprevention trial using a low dose of 13-cis-retinoic acid to prevent second primary tumors following head and neck cancer. The rationale and design of this study are discussed in detail.

Topics: Head and Neck Neoplasms; Humans; Isotretinoin; Leukoplakia, Oral; Neoplasms, Second Primary

Topics: Anticarcinogenic Agents; Antineoplastic Agents; Breast Neoplasms; Drug Design; Female; Gastrin-Releasing Peptide; Growth Substances; Head and Neck Neoplasms; Humans; Isotretinoin; Lung Neoplasms; Male; Neoplasms, Second Primary; Oncogenes; Peptides; Retrospective Studies; Sputum; Tamoxifen; United States

Patients with head-and-neck cancers who are free of disease after local therapy remain at high risk for both recurrent and second primary tumors. Retinoids have proved efficacious in the treatment of premalignant oral lesions and are promising agents for the prevention of epithelial carcinogenesis.. We prospectively studied 103 patients who were disease-free after primary treatment for squamous-cell cancers of the larynx, pharynx, or oral cavity. After completion of surgery or radiotherapy (or both), these patients were randomly assigned to receive either isotretinoin (13-cis-retinoic acid) (50 to 100 mg per square meter of body-surface area per day) or placebo, to be taken daily for 12 months.. There were no significant differences between the two groups in the number of local, regional, or distant recurrences of the primary cancers. However, the isotretinoin group had significantly fewer second primary tumors. After a median follow-up of 32 months, only 2 patients (4 percent) in the isotretinoin group had second primary tumors, as compared with 12 (24 percent) in the placebo group (P = 0.005). Multiple second primary tumors occurred in four patients, all of whom were in the placebo group. Of the 14 second cancers, 13 (93 percent) occurred in the head and neck, esophagus, or lung.. Daily treatment with high doses of isotretinoin is effective in preventing second primary tumors in patients who have been treated for squamous-cell carcinoma of the head and neck, although it does not prevent recurrences of the original tumor.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Combined Modality Therapy; Female; Head and Neck Neoplasms; Humans; Isotretinoin; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasms, Multiple Primary; Patient Compliance; Prospective Studies; Randomized Controlled Trials as Topic; Smoking

Retinoids, the analogs of vitamin A, are active in vitro and in vivo against squamous cell carcinoma in animals and against certain epithelial precancers and cancers in humans. These data led us to design a prospective, multi-institutional, randomized phase II trial of isotretinoin in advanced head and neck squamous cell carcinoma. We randomly assigned 40 patients to receive isotretinoin or methotrexate, the best-studied and most active single agent for this disease. Overall, the study patients had extremely poor prognoses, i.e., low performance statuses and recurring disease after surgery and/or irradiation. Three objective responses (16%), including one complete response, occurred in the 19 evaluable isotretinoin-treated patients. Only one minor response (5%) occurred in the methotrexate-treated group. Toxicity occurred with both drugs, but was manageable and never life threatening in the retinoid group. These results and the established activity of retinoids in oral leukoplakia (a precursor of head and neck cancer) indicate the need for further study of this class of drugs in head and neck cancer.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Drug Evaluation; Female; Head and Neck Neoplasms; Humans; Isotretinoin; Male; Methotrexate; Middle Aged; Random Allocation; Tretinoin

Ten cats with a total of 15 cancerous or precancerous lesions were examined for clinical response to and histopathologic changes after treatment with 13-cis-retinoic acid. Before treatment was started, the lesions were graded according to clinical severity and biopsied for histopathologic examination. Serum samples were prepared for determining vitamin A concentrations. For comparison, serum vitamin A concentrations in 10 clinically healthy cats were determined. 13-cis-Retinoic acid (approx 3.0 mg/kg) was given to affected cats once a day for an average of 68 days. At the completion of the therapeutic trial, additional biopsy tissues were obtained for histopathologic examination, and serum was assayed for 13-cis-retinoic acid. Of the 15 lesions examined, only 1 showed partial clinical and microscopic improvement during the therapy period. The mean serum vitamin A concentration of the affected cats was not statistically different from that of the 10 healthy cats. The results of this trial indicated that 13-cis-retinoic acid used at this dosage, daily frequency, and duration did not have therapeutic efficacy for squamous cell carcinomas or preneoplastic lesions in the cat and that the mean serum vitamin A concentration did not differ between the affected cats and clinically healthy cats.

Topics: Animals; Carcinoma, Squamous Cell; Cat Diseases; Cats; Clinical Trials as Topic; Head and Neck Neoplasms; Isotretinoin; Precancerous Conditions; Tretinoin; Vitamin A

The development of second primary tumors (SPT) or recurrence alters prognosis for curatively treated head and neck squamous cell carcinoma (HNSCC) patients. The 13-cis-Retinoic acid (13-cRA) has been tested as a chemoprevention agent in clinical trials with mixed results. Therefore, we investigated whether genetic variants in the PI3K/PTEN/AKT/mTOR pathway could serve as biomarkers to identify which patients are at high risk of an SPT/recurrence, while also predicting response to 13-cRA chemoprevention.. A total of 137 pathway single-nucleotide polymorphisms were genotyped in 440 patients from the Retinoid Head and Neck Second Primary Trial and assessed for SPT/recurrence risk and response to 13-cRA. Risk models were created based on epidemiology, clinical, and genetic data.. Twenty-two genetic loci were associated with increased SPT/recurrence risk, with six also being associated with a significant benefit following chemoprevention. Combined analysis of these high-risk/high-benefit loci identified a significant (P = 1.54 × 10(-4)) dose-response relationship for SPT/recurrence risk, with patients carrying four to five high-risk genotypes having a 3.76-fold [95% Confidence Interval (CI), 1.87-7.57] increase in risk in the placebo group (n = 215). Patients carrying four to five high-risk loci showed the most benefit from 13-cRA chemoprevention, with a 73% reduction in SPT/recurrence (95% CI, 0.13-0.58) compared with those with the same number of high-risk genotypes who were randomized to receive placebo. Incorporation of these loci into a risk model significantly improved the discriminatory ability over models with epidemiology, clinical, and previously identified genetic variables.. These results show that loci within this important pathway could identify individuals with a high-risk/high-benefit profile and are a step toward personalized chemoprevention for HNSCC patients.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Disease-Free Survival; Head and Neck Neoplasms; Humans; Insulin Receptor Substrate Proteins; Isotretinoin; Neoplasm Recurrence, Local; Neoplasms, Second Primary; Phosphatidylinositol 3-Kinases; Polymorphism, Single Nucleotide; Protein Serine-Threonine Kinases; PTEN Phosphohydrolase; Randomized Controlled Trials as Topic; Ribosomal Protein S6 Kinases, 90-kDa; Risk Factors; ROC Curve; Signal Transduction; Treatment Outcome; Tumor Suppressor Proteins

The study reported by Lee and colleagues in this issue of the journal (beginning on page 185) incorporated global genetic variation within a new assessment of the outcome of a previously reported phase-III trial of low-dose 13-cis-retinoic acid (13-cRA) for preventing second primary tumors (SPT) or the recurrence of head-and-neck cancer. This analysis identified genotypes of common single-nucleotide polymorphisms (SNP) and cumulative effect and potential gene-gene interactions that were highly associated with increased placebo-arm risk (prognostic) and/or with reduced treatment-arm risk and longer event-free survival (predictive). For example, the wild-type rs3118570 SNP of the retinoid X receptor alpha gene (carried by 71% of the 13-cRA trial population) marked a 3.33-fold increased SPT/recurrence risk in the placebo arm and a 38% reduced risk in the treatment arm. Adding two other informative genotypes strengthened the treatment-arm risk reduction to 76%, although the genotype trio reflected only 13% of the trial population. This report extends the concept of personalized therapy to cancer prevention.

Topics: Head and Neck Neoplasms; Humans; Isotretinoin; Neoplasm Recurrence, Local; Neoplasms, Second Primary; Polymorphism, Single Nucleotide; Precision Medicine; Retinoid X Receptor alpha; Survival Rate; Treatment Outcome

Topics: Anticarcinogenic Agents; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Squamous Cell; Clinical Trials, Phase III as Topic; Head and Neck Neoplasms; Humans; Isotretinoin; Neoplasms, Second Primary; Randomized Controlled Trials as Topic; Receptors, Retinoic Acid; Retinoid X Receptors; Signal Transduction; Treatment Failure

Early-stage head and neck cancer patients are at high risks for tumor recurrence and secondary primary tumor (SPT) development. We hypothesized that latent genetic instability and proliferation potential may be associated with elevated risks of SPT and recurrence.. We conducted a nested case-control study within a randomized, placebo-controlled chemoprevention trial in patients with early-stage head and neck cancer. We compared prediagnostic bleomycin-induced chromatid breaks in peripheral blood lymphocyte cultures (as an indicator of latent genetic instability) between 298 cases (patients with SPT/recurrence) and 693 controls (patients without SPT/recurrence). We also determined the joint effects of latent genetic instability and elevated proliferation potential [indicated by serum insulin-like growth factor (IGF) level] in modulating the risk of SPT and recurrence.. In the Cox proportional hazards model, patients with higher mutagen sensitivity (using a cutoff of > or =0.50 breaks per cell) exhibited a significantly increased risk of developing SPT/recurrence [hazard ratio, 1.38; 95% confidence interval (95% CI), 1.02-1.86]. Cases also exhibited significantly higher levels of IGF-I and IGF-binding protein-3 than controls (P = 0.022 and 0.042, respectively). Moreover, there were joint effects between mutagen sensitivity and IGFs in modulating SPT/recurrence risk. Using patients with low IGF-I level and low mutagen sensitivity profile as the reference group, the odds ratios of developing SPT/recurrence for patients with high IGF-I level alone, high mutagen sensitivity alone, and both high IGF-I level and high mutagen sensitivity were 2.85 (95% CI, 0.92-8.82), 3.92 (95% CI, 1.28-11.97), and 6.16 (95% CI, 2.03-18.71), respectively. A similar joint effect was observed for mutagen sensitivity and IGF-binding protein-3 level.. This is the largest prospective study to evaluate mutagen sensitivity as a prognosis marker in head and neck cancer because mutagen sensitivity data were derived from baseline samples drawn before the development of SPT or tumor recurrence. The results also show for the first time that latent genetic instability and elevated proliferation potential jointly elevate the risk of second tumors in early-stage head and neck cancers.

Topics: Bleomycin; Case-Control Studies; Chromatids; Female; Follow-Up Studies; Head and Neck Neoplasms; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Isotretinoin; Lymphocytes; Male; Middle Aged; Mutagens; Neoplasm Staging; Placebos; Predictive Value of Tests; Prognosis; Prospective Studies; Risk Factors; Sensitivity and Specificity; Structure-Activity Relationship; Treatment Outcome

Topics: Antineoplastic Agents; Chemotherapy, Adjuvant; Head and Neck Neoplasms; Humans; Interferon-alpha; Isotretinoin; Melanoma; Neoplasm Staging; Risk Factors; Treatment Outcome

Three nasopharyngeal carcinoma (NPC) cell lines (CNE-1, CNE-2 and NPC/HK-1), two squamous cell carcinoma (SCC) cell lines (T2/CUHK and PWH-S1) and six head and neck cancer specimens (NPC [n = 4], SCC tongue [n = 1] and a thyroid cancer [n = 1]) were incubated with interferon (IFN)-alpha (5 x 10(4) iu/mL) and/or 13-cis retinoic acid (13RA; 10(-5) mol/L) for two days at 37 degrees C. In vitro chemosensitivity was measured using MTT assay. Mild growth inhibition of the five cell lines by IFN-alpha ranged from 7.1% to 51.8% (mean: 18.5%), whereas with 13RA it was zero to 19.7% (mean: 7%). Greater inhibition (14.8-51.0%, mean: 31.8%) was achieved when the two drugs were used in combination. Growth inhibition of the six surgical specimens ranged from 6.9% to 21% (mean: 13.6%) with IFN-alpha; zero to 10.3% (mean: 6.0%) with 13RA; and 6.6-26.5% (mean: 17.7%) when the two agents were combined. Four of the 11 samples showed synergistic antitumour effect when IFN-alpha and 13RA were combined, and six showed subadditive effect. The results show that IFN-alpha and 13RA have a mild in vitro antitumour effect on head and neck cancer cells, and the drug synergistic effect demonstrated in this study suggests that the two agents should be used in combination in clinical application.

Topics: Antineoplastic Agents; Cell Division; Drug Synergism; Head and Neck Neoplasms; Humans; Interferon Type I; Isotretinoin; Recombinant Proteins; Tumor Cells, Cultured

Topics: Aged; Antimetabolites, Antineoplastic; Bleomycin; Carcinoma, Squamous Cell; Clinical Trials, Phase III as Topic; Female; Head and Neck Neoplasms; Humans; Isotretinoin; Male; Middle Aged; Multicenter Studies as Topic; Mutagens; Proportional Hazards Models; Randomized Controlled Trials as Topic; Risk Factors; Teratogens; Treatment Failure

The goal of chemoprevention is to reduce the risk of cancer development by reversing or blocking the tumorigenic process through the use of pharmacologic or natural agents. To determine the potential role of genetic alterations in assessing cancer risk and in evaluating the efficacy of chemopreventive agents, we studied 22 patients with advanced premalignant lesions of the head and neck who were part of a prospective cancer prevention trial that is investigating a regimen of 13-cis-retinoic acid, interferon alfa, and alpha-tocopherol administered for 12 months or until disease progression.. We used polymerase chain reaction analysis of microsatellite DNA sequences in cells from precancerous lesions to determine the frequencies of genetic alterations--namely, loss of heterozygosity (LOH) and microsatellite instability--at chromosomal loci that are commonly deleted in head and neck cancer.. Prior to treatment, 17 (81%) of 21, eight (44%) of 18, and eight (42%) of 19 patients who were informative (i.e., heterozygous) at chromosomes 9p21, 3p14, and 17p13, respectively, exhibited LOH in at least one of their lesion biopsy specimens. Among nine patients who exhibited LOH at chromosome 9p21 in pretreatment biopsy specimens and who had completed at least 5 months of therapy, the genetic loss persisted in eight--including three of the four patients who exhibited complete histologic responses (i.e., no evidence of dysplasia in their biopsy specimens).. Our data suggest that clinical and histologic assessments of the response to chemopreventive agents may be insufficient to determine their efficacy and that critical genetic alterations could be used as independent biomarkers to augment the ability to evaluate the efficacy of such agents.

Topics: Antineoplastic Agents; Chromosomes, Human, Pair 9; DNA, Neoplasm; Female; Genotype; Head and Neck Neoplasms; Humans; Interferon-alpha; Isotretinoin; Loss of Heterozygosity; Male; Microsatellite Repeats; Phenotype; Polymerase Chain Reaction; Precancerous Conditions; Prospective Studies; Vitamin E

Topics: Anticarcinogenic Agents; beta Carotene; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Follow-Up Studies; Head and Neck Neoplasms; Humans; Isotretinoin; Mouth Neoplasms; Time Factors; Treatment Outcome

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

Topics: Carcinoma, Squamous Cell; Female; Head and Neck Neoplasms; Humans; Interferon-alpha; Isotretinoin; Male; Uterine Cervical Neoplasms

The treatment of locally advanced squamous cell carcinomas of the head and neck presents a challenge for oncologists. Radiation therapy alone fails to control many of these tumors. Chemotherapy added to radiation therapy has not clearly demonstrated an improvement in survival in the majority of trials reported to date. In this study, we have evaluated whether IFN-alpha-2a and/or 13-cis-retinoic acid (RA) enhance radiation cytotoxicity in a head and neck squamous cell carcinoma cell line (FaDu). Using a clonogenic cell survival assay, IFN-alpha-2a (1000 units/ml) or RA (1 microM) alone did not significantly enhance radiation cytotoxicity. The combination of the two agents, however, significantly increased the cytotoxicity of radiation against FaDu cells. The calculated survival fraction at 2 Gy was decreased from 0.649 with radiation alone to 0.477 when combined with the other two agents (P = 0.016), and the MID was decreased from 3.318 to 2.499 Gy (P = 0.028). A Phase I clinical trial to combine IFN-alpha-2a and/or RA in patients with unresectable head and neck cancer has been initiated.

Topics: Carcinoma, Squamous Cell; Cell Division; Head and Neck Neoplasms; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Radiation-Sensitizing Agents; Recombinant Proteins; Tumor Cells, Cultured; Tumor Stem Cell Assay

The serum concentrations of all-trans (atRA) and 13-cis (13cRA) retinoic acid were determined by high performance liquid chromatography in 27 patients with squamous cell carcinoma of the head and neck and in 80 healthy controls. This investigation seemed relevant as ethanol is an aetiological factor in these cancers and has been suggested to interfere with the synthesis of atRA. Neither the serum concentration of atRA nor that of 13cRA differed between patients and controls. The serum atRA concentration did not differ between fasting and non-fasting patients, but the serum 13cRA concentration was significantly higher in non-fasting than in fasting patients, probably due to the dietary retinoid content.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Case-Control Studies; Chromatography, High Pressure Liquid; Fasting; Female; Head and Neck Neoplasms; Humans; Isotretinoin; Male; Middle Aged; Tretinoin

Clinical Trials Referral Resource is designed to serve as a ready reference for oncologists to help identify clinical trials that might be suitable for their patients. We hope it also will enhance accrual to clinical trials by informing practicing oncologists of ongoing protocols. Currently in the United States less than 10% of eligible adult patients are entered on clinical trials. The result is a delay in answering important therapeutic and scientific questions and disseminating therapeutic advances to the general oncology community. It should be emphasized that including a specific trial does not imply that it is more important than another trial. Among the criteria for selection are that the trial is addressing an important question and is not expected to close in the immediate future (less than 1 year), and that initial staging or laboratory tests required for patient eligibility are widely practiced and available. Information on other protocols can be accessed via Physician's Data Query (PDQ). We emphasize that this is an attempt to encourage referral of patients to these trials. We are specifically not soliciting additional members for the cooperative groups, nor are we suggesting how practicing oncologists should be treating patients not in a study. This month's installment of Clinical Trials Referral Resource is devoted to cancer chemoprevention trials. For patient entry information contact the person listed in each individual trial.

Topics: Adult; Aspirin; Colorectal Neoplasms; Double-Blind Method; Head and Neck Neoplasms; Humans; Isotretinoin; Lung Neoplasms; Neoplasms; Neoplasms, Second Primary

Topics: Carcinoma, Squamous Cell; Combined Modality Therapy; Female; Head and Neck Neoplasms; Humans; Interferon-alpha; Isotretinoin; Male; Neoplasms; Papillomaviridae; Papillomavirus Infections; Skin Neoplasms; Tumor Virus Infections; Uterine Cervical Neoplasms

Topics: beta Carotene; Carcinoma, Squamous Cell; Carotenoids; Cell Transformation, Neoplastic; Head and Neck Neoplasms; Humans; Immunologic Factors; Isotretinoin; Leukoplakia, Oral; Mouth Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Congresses as Topic; Female; Head and Neck Neoplasms; Humans; Insurance, Pharmaceutical Services; Interferon-alpha; Isotretinoin; Medical Oncology; Melanoma; Ovarian Neoplasms; Societies, Medical; United States

Topics: Carcinoma, Squamous Cell; Head and Neck Neoplasms; Humans; Isotretinoin

A pharmacokinetic study of 13-cis-retinoic acid was performed in nine patients following administration of a single oral dose of 80 mg. An average lag time of 1.2 hours was observed, followed by fast absorption, with a mean half-life of 0.5 hour. Peak plasmatic concentration of 733 ng/ml occurred at 2.3 hours. The disposition profile showed a rapid distribution half-life of 1.3 hours and a terminal elimination half-life of 24.7 hours. No 13-cis-retinoic acid was detected unchanged in urine. An important interpatient variability was noted.

Topics: Administration, Oral; Chromatography, High Pressure Liquid; Drug Evaluation; Half-Life; Head and Neck Neoplasms; Humans; Isotretinoin; Kinetics; Male; Tretinoin