isotretinoin and Laryngeal-Neoplasms

The purpose of this study was to evaluate adjuvant drug therapies combined with standard laser excision in the treatment of recurrent respiratory papillomatosis. Previous studies have presented conflicting data on the efficacy of various treatments, including interferon and isotretinoin. A retrospective study of 34 patients with moderate to severe papillomatosis who underwent both laser surgery and adjuvant therapy was therefore performed. All patients were treated with interferon. Five interferon failures received isotretinoin, and three with recalcitrant disease received methotrexate. Interferon produced a complete response in 16 patients and partial response in 12 patients. Juvenile-onset disease had a slightly higher response to interferon than adult-onset disease. isotretinoin produced no response in all five patients. Methotrexate demonstrated a marked improvement in both severity of disease and treatment interval in all three patients. Serious side effects were limited to one interferon patient with febrile seizures, which resolved with discontinuation of therapy. We conclude that adjuvant therapy including interferon and methotrexate is clearly of benefit in the treatment of patients with respiratory papillomatosis. A detailed approach to surgery combined with an interferon dosing regimen is presented. Further study of methotrexate appears warranted.

Topics: Adolescent; Adult; Age of Onset; Aged; Chemotherapy, Adjuvant; Child; Child, Preschool; Drug Administration Schedule; Female; Humans; Interferons; Isotretinoin; Laryngeal Neoplasms; Laser Therapy; Male; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Papilloma; Remission Induction; Retrospective Studies; Tracheal Neoplasms

In a previous trial, we found that combined 13-cis-retinoic acid, IFN-alpha, and alpha-tocopherol more effectively reversed advanced premalignant lesions of the larynx than of the oral cavity and that cyclin D1 (CD1) G/A870 single nucleotide polymorphism correlated with cancer risk. We conducted the present trial primarily to confirm the clinical activity of the combination in advanced laryngeal premalignancy and to confirm and extend our findings on CD1, both genotype and protein expression, in association with cancer risk in this setting. Twenty-seven moderate-to-severe laryngeal dysplasia patients underwent induction with combined 13-cis-retinoic acid daily, alpha-IFN twice weekly, and alpha-tocopherol daily for 1 year; 14 nonprogressing patients then were randomized to maintenance fenretinide or placebo for 2 years. During induction, two patients had pathologic complete responses, six had partial responses (30% overall response rate), and five developed laryngeal cancer. There were no significant differences between maintenance fenretinide and placebo in response or cancer rates. Ten patients developed cancer overall. Twenty-four patients were evaluated for the CD1 G/A870 genotype, and 23 for pretreatment and posttreatment CD1 protein expression. Consistent with our earlier report, shorter cancer-free survival was associated with the CD1 AA/AG genotype (P = 0.05). Extending our earlier work, high CD1 expression was associated with worse cancer-free survival overall (P = 0.04) and within each CD1 genotype group. These findings support CD1 genotype and protein expression as important risk markers for laryngeal cancer and suggest future trials targeting upstream regulators of CD1 transcription.

Topics: alpha-Tocopherol; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cyclin D1; Female; Fenretinide; Gene Expression; Genotype; Humans; Immunohistochemistry; Interferon-alpha; Isotretinoin; Laryngeal Diseases; Laryngeal Neoplasms; Male; Polymorphism, Single Nucleotide; Precancerous Conditions

Altered cyclin D1 expression in advanced preinvasive lesions of the upper aerodigestive tract (UADT) is associated with an increased risk of developing cancer and histologic progression during and after combination biochemopreventive therapy (13-cis-retinoic acid, alpha-interferon, and alpha-tocopherol). Both alleles of the adenine (A)/guanine (G) cyclin D1 polymorphism located at nucleotide 870 encode two alternatively spliced transcripts, but the A allele preferentially encodes a protein with an extended half-life. We investigated whether the cyclin D1 genotype at nucleotide 870 was associated with baseline levels of cyclin D1 protein, post-treatment modulation of cyclin D1 protein levels, histologic response to treatment, and the outcome for subjects with preinvasive UADT lesions after biochemopreventive therapy.. UADT tissue biopsy samples were obtained before and 6 and 12 months after biochemopreventive treatment from 31 individuals with advanced preinvasive UADT lesions. Tissues were examined for cyclin D1 genotype (by DNA single-strand conformation polymorphism analysis), for cyclin D1 protein expression (by immunohistochemistry), and for cyclin D1 gene copy number (by fluorescence in situ hybridization). Associations of cyclin D1 genotype with histologic response to therapy and time to progression to a higher degree of dysplasia or invasive cancer were investigated. All statistical tests were two-sided.. The A allele was associated with increased baseline cyclin D1 expression in the parabasal epithelial layer (16 of 18 AA/AG subjects versus four of nine GG subjects; P =.02), decreased histologic response to biochemopreventive treatment (six of 21 AA/AG subjects versus four of 10 GG subjects; P =.70), decreased favorable modulation of cyclin D1 expression by the treatment (seven of 18 AA/AG subjects versus eight of nine GG subjects; P =.02), and shorter progression-free survival (P =.05).. The cyclin D1 A allele was associated with a diminished modulation of normal physiologic and treatment-induced decreased expression of cyclin D1, a decreased likelihood of response to biochemopreventive intervention, and an increased rate of progression to cancer development, findings that require validation in a larger cohort.

Topics: alpha-Tocopherol; Antineoplastic Combined Chemotherapy Protocols; Cyclin D1; Disease Progression; Gene Expression Regulation, Neoplastic; Genotype; Humans; Immunohistochemistry; Immunologic Factors; In Situ Hybridization, Fluorescence; Interferon-alpha; Isotretinoin; Laryngeal Neoplasms; Mouth Neoplasms; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Prospective Studies; Treatment Outcome

To evaluate the efficacy and secondarily the toxic effects of biochemopreventive therapy (high-dose isotretinoin [13-cis-retinoic acid], alpha-tocopherol, and interferon alfa) in the reversal of advanced premalignant lesions of the upper aerodigestive tract and to correlate the therapeutic events with modulation of biomarkers.. Prospective, nonrandomized chemoprevention trial.. Tertiary cancer care referral center and ambulatory care.. Thirty-six patients with advanced premalignant lesions of the upper aerodigestive tract, without cancer during the 2 years before the intervention, with evaluable lesions, and without retinoid therapy for 3 months before the trial.. Administration of oral isotretinoin (100 mg/m2 per day), oral alpha-tocopherol (1200 IU/d), and subcutaneous interferon alfa (3 megaunits per square meter twice weekly) for 12 months, with serial biopsies and clinical examination at 0, 6, 12, and 18 months from study start.. Clinical and histologic responses to the intervention.. Of the 36 patients, evaluation was possible in 30 for response at 6 months and in 21 at 12 months. At 6 months, there were 10 pathologic complete responses and 7 partial responses; at 12 months, 7 complete and 3 partial responses. A striking difference in response was observed in favor of laryngeal lesions (9/19 [47%] complete response rate at 6 months and 7/14 [50%] at 12 months vs 1/11 [9%] and 0/7 [0%], respectively, for oral lesions). Toxic effects were acceptable and did not exceed grade 3.. Biochemoprevention is a promising biologic approach for laryngeal dysplasia and needs to be investigated further.

Topics: Adult; Aged; Antineoplastic Agents; Chemoprevention; Female; Humans; Interferon-alpha; Isotretinoin; Laryngeal Neoplasms; Male; Middle Aged; Mouth Neoplasms; Precancerous Conditions; Prospective Studies; Treatment Outcome; Vitamin E

Laryngeal papillomatosis often involves a relentless growth of papillomas on the vocal cords, requiring repeated excisions to maintain an adequate airway. Because of its antiproliferative effects on epithelial tissues, 13-cis-retinoic acid (0.5-2.0 mg/kd/day p.o.) was used in five patients whose disease was poorly controlled by laser beam surgery. Control of disease for 24+, 5+, and 12 months has been achieved in three of the patients, with two complete and one partial responses. Side effects of treatment were mild and rapidly reversible, following a 25-50% reduction in drug dose.

Topics: Adult; Aged; Antineoplastic Agents; Child; Child, Preschool; Combined Modality Therapy; Drug Evaluation; Female; Humans; Isotretinoin; Laryngeal Neoplasms; Laser Therapy; Male; Middle Aged; Papilloma; Tretinoin