isotretinoin and Carcinoma--Squamous-Cell

Solid organ transplant recipients (SOTRs) are at an increased risk of epithelial malignancies, mainly squamous cell carcinoma, and its precursor lesions such as actinic keratoses, warts, and porokeratosis, which may respond to retinoid therapy.. To review the published evidence on the efficacy and safety of topical and systemic retinoids for the treatment and prophylaxis of malignant and premalignant conditions that mostly afflict SOTRs.. Systematic review of the literature to summarize the level of evidence and grade of recommendation for retinoid therapy with emphasis in the SOTR population.. Acitretin has the highest strength of recommendation (Grade A) for prophylaxis of nonmelanoma skin cancer (NMSC) and treatment and prophylaxis of actinic keratoses in SOTR. In nonimmunosuppressed patients, acitretin and isotretinoin have a Grade B recommendation for treatment of recalcitrant warts. Topical retinoids have not shown efficacy in preventing NMSC in immunocompetent patients.. Retinoids constitute a highly efficacious alternative for the management of the most common conditions that affect SOTRs. Acitretin has the most robust evidence for chemoprophylaxis in SOTRs. Knowledge about the specific indications and expected side effects of topical and systemic retinoids may help optimize their therapeutic potential.

Topics: Acitretin; Administration, Cutaneous; Administration, Oral; Carcinoma, Squamous Cell; Dermatologic Agents; Dermatology; Evidence-Based Medicine; Graft Rejection; Humans; Immunosuppressive Agents; Isotretinoin; Keratosis, Actinic; Organ Transplantation; Skin Neoplasms; Transplant Recipients; Treatment Outcome; Warts

Chemoprevention is one of the cancer prevention methods, applied for the oral squamous cell carcinoma and its main precursor lesions--leukoplakia and erythroplakia. Presently, the most extensive clinically studied group used in such cases are retinoids: vitamin A (retinol), 13-cis-retinic acid (isotretinoin), N-(4-hydroxyphenyl)retinamide (fenretinide) and precursor of vitamin A--beta-carotene. However, despite good short-time effectiveness, retinoids do not prevent recurrences of the lesions and insignificantly increase cancer-free survival. Moreover, they are also characterized by relatively high toxicity. Vitamin E, Bowman-Birkprotease inhibitor, Spirulina fusiformis and green tee extracts as well as traditional Chinese herbs known as ZengShengPing were also found as effective agents. Lack of activity was reported for cyclooxygenase inhibitors--ketorolac and celecoxib. More promising data was collected from animal experimental studies with chemically induced oral squamous cell carcinoma. Chemopreventive activity was revealed for various agents including plant-derived compounds like resveratrol, green and black tee polyphenols, as well as protocatechuic, ellagic and caffeic acids.

Topics: Animals; Antineoplastic Agents; beta Carotene; Carcinoma, Squamous Cell; Chemoprevention; Drugs, Chinese Herbal; Fenretinide; Humans; Isotretinoin; Mouth Neoplasms; Neoplasm Recurrence, Local; Phytotherapy; Precancerous Conditions; Vitamin A

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

Three patients developed erosive pustular dermatosis of the scalp (EPDS). Two of them, both males, had previously undergone surgical excision for squamous cell carcinoma and basal cell carcinoma, and a female experienced avulsive trauma of the scalp. The erosive lesions and crusts were located at the site of a skin graft; microbiological cultures were negative for bacterial and fungal growth. Histological examination ruled out pustular bullous disorders. Topical therapy with corticosteroids and antibiotics resulted in clinical remission in only 2 cases. The third case showed a tendency to recur despite numerous therapeutic attempts with oral dapsone and isotretinoin. We conclude that surgical trauma is a possible cause of EPDS. Our patients seem to be the first reported cases of EPDS in skin grafts following plastic surgical procedures.

Topics: Administration, Cutaneous; Administration, Oral; Aged; Anti-Bacterial Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Bacteria; Betamethasone; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Dapsone; Female; Fungi; Gentamicins; Humans; Isotretinoin; Keratolytic Agents; Male; Middle Aged; Recurrence; Remission Induction; Scalp; Scalp Dermatoses; Skin Diseases, Vesiculobullous; Skin Neoplasms; Skin Transplantation

Topics: Aged; Aged, 80 and over; Aminolevulinic Acid; Antineoplastic Agents; Bowen's Disease; Carcinoma; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Evaluation Studies as Topic; Female; Humans; Interferon-alpha; Interferons; Isotretinoin; Keratolytic Agents; Male; Neoplasm Metastasis; Photochemotherapy; Photosensitizing Agents; Retinoids; Skin Neoplasms

Recurrent and metastatic cervical carcinoma has very poor prognosis, mainly because there is no effective systemic therapy which would increase the duration of survival. Biologic agents have recently been found to have activity in cervical carcinoma. The combination of interferon (IFN)-alpha and 13-cis-retinoic acid had additive and synergistic antitumor activity. Both have antiviral, immunoregulatory and antiangiogenic properties, and are known to modulate malignant cell differentiation and proliferation. We report two patients with recurrent squamous cell carcinoma (SCC) of the cervix who had small-volume progressive metastatic disease, and were treated with a combination of IFN-alpha and 13-cis-retinoic acid. The first patient had pelvic lymph node metastases and the other had lung metastases. The previously progressive diseases remained stable for a prolonged period of time, 3 and 4 years, with a good quality of life. These cases suggest the possibility of using IFN-alpha and 13-cis-retinoic acid as a treatment for small-volume residual disease or as postinduction therapy in patients at high risk for disease recurrence.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Female; Humans; Interferon-alpha; Isotretinoin; Pregnancy; Uterine Cervical Neoplasms

We report on a 63-year-old female patient with Muir-Torre syndrome (MTS). In the course of this disease two carcinomas of the colon, a kerato-acanthoma and multiple sebaceous gland tumours, including four sebaceous carcinomas, appeared. This case is thought to be a hereditary form as one of daughters was also found to have a sebaceous epithelioma. MTS is a mostly autosomal-dominant disease with the association of sebaceous gland tumours and internal carcinomas. As the malignant tumours only show slight aggressiveness the prognosis is quite favourable. Oral isotretinoin therapy was successfully used for the inhibition of sebaceous gland proliferation. A narrower definition is presented and an updated survey of the published cases is given. Furthermore, the histopathologic peculiarities of sebaceous gland tumours, especially of sebaceous gland carcinomas, are discussed and compared to sebaceous gland tumours not connected with MTS. A total number of 100 of the 135 published cases of MTS were included and analysed regarding sebaceous gland tumours and other skin tumours. The data on internal carcinomas were taken from the work of Cohen et al. (1991) and 11 current cases were added.

Topics: Adenocarcinoma; Adenoma, Sweat Gland; Adenomatous Polyposis Coli; Administration, Oral; Carcinoma; Carcinoma, Squamous Cell; Chromosome Aberrations; Chromosome Disorders; Diagnosis, Differential; Facial Neoplasms; Female; Genes, Dominant; Humans; Isotretinoin; Keratoacanthoma; Middle Aged; Neoplasm Recurrence, Local; Neoplasms, Multiple Primary; Neoplastic Syndromes, Hereditary; Sebaceous Gland Neoplasms; Sweat Glands; Syndrome

Various combinations of retinoids, metabolic and synthetic derivatives of vitamin A, and interferons (IFNs) have demonstrated synergistic antiproliferative, differentiating, and antiangiogenic activity in some human hematologic and solid-tumor systems. This synergistic antitumor activity may be due to enhanced gene expression. In several cell systems, the actions of IFNs are enhanced by differentiation of cells with retinoic acid (RA). Combined RA-IFN effects have been correlated with the induction of higher levels of IFN-stimulated genes than the levels induced by either agent alone. Natural and synthetic retinoids have been found to augment the antiproliferative activity of IFNs in several squamous cell carcinoma (SCC) and breast tumor cell lines. Results of recent clinical trials indicate substantial activity of 13-cis-RA (13cRA) combined with IFN against advanced SCC of the skin and cervix, and possibly against other solid tumors. Two phase II trials have confirmed activity against locally advanced SCC of the cervix. Successful integration of this regimen with radiotherapy appears to be the most probable means of optimizing clinical outcome. Further studies are needed to determine the mechanistic details of the RA-IFN interaction.

Topics: 2',5'-Oligoadenylate Synthetase; Adult; Aged; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Clinical Trials, Phase II as Topic; Drug Synergism; Enzyme Induction; Female; Humans; Interferon-alpha; Isotretinoin; Mice; Protein Kinases; Skin Neoplasms; Tumor Cells, Cultured; Uterine Cervical Neoplasms

Preclinical data indicate that the combination of retinoids and interferons have synergistic antiproliferative and differentiating effects in some hematologic and solid tumor models. These observations have led to clinical trials in which 13-cis-retinoic acid (13cRA) 1 mg/kg/day was combined with interferon alpha-2a (IFN alpha) 3 or 6 x 10(6) U/day. The first two such trials produced exciting results: 50% response rate in patients with previously untreated stages IB-IVA cervix cancer and 68% in patients with advanced squamous cell skin cancer. These data led to a number of additional trials of the combination, but the high response rates seen in the initial cervix and skin trials have not been duplicated in the other squamous tumors tested (head and neck, lung, pretreated cervix). In addition, trials in two non-squamous histologies were negative (lung and melanoma). However, the regimen was not always studied in an optimal population of previously untreated patients and the negative results in pretreated cervix patients point to the relevance of this consideration. Nevertheless, the observation that the combination of 13cRA and IFN alpha (both of which bind to specific receptors and change gene expression) is able to induce regression in advanced tumors, must be regarded as highly important. Key questions to be addressed include an understanding of the biologic mechanism of specific tumor sensitivity (why some squamous tumors and not others?), and mechanisms of resistance in sensitive tumor types (e.g. cervix). Such data may lead to trials targeted to tumor types with defined biologic features having a high likelihood of clinical benefit. In the meantime, studies integrating this combination with other active treatment modalities such as radiation is warranted in cervix and skin carcinomas.

Topics: Carcinoma, Squamous Cell; Clinical Trials, Phase II as Topic; Combined Modality Therapy; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Male; Neoplasms; Recombinant Proteins; Skin Neoplasms; Uterine Cervical Neoplasms

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

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Ear, External; Fluorouracil; Humans; Isotretinoin; Male; Middle Aged; Skin Neoplasms

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

To determine the utility of isotretinoin oral rinses as a method of chemoprevention for recurrent oral cavity squamous cell carcinoma (SCC), carcinoma in situ, and dysplasia.. Retrospective cohort study.. One hundred forty-three patients were initially enrolled in the study; however, 18 were excluded due to inability to tolerate therapy. The included patients were classified into four groups. Group 1 included patients with multiple early stage oral cavity lesions following initial resection. Group 2 included patients with SCC in situ after excision. Group 3 included patients with multifocal dysplasia following initial CO. Using a Bonferroni correction, the significance threshold was 0.0125. By that cutoff, isotretinoin rinses were found to be associated with lower recurrence in groups 1 and 3 (P = .00014, P = .00002, respectively) but not in groups 2 and 4 (P = .4, P = .3846, respectively).. Oral isotretinoin as chemoprophylaxis for patients treated for oral cavity squamous cell carcinoma, in situ disease, or dysplasia may be beneficial in decreasing recurrence rate.. 4. Laryngoscope, 127:1595-1599, 2017.

Topics: Carcinoma in Situ; Carcinoma, Squamous Cell; Cohort Studies; Combined Modality Therapy; Female; Humans; Isotretinoin; Laser Therapy; Leukoplakia, Oral; Male; Middle Aged; Mouth Neoplasms; Mouthwashes; Neoplasm Recurrence, Local; Neoplasm Staging; Precancerous Conditions; Retrospective Studies; Secondary Prevention

Overexpression of bcl-2 is a mechanism of drug resistance in cervical cancer. Agents that down-regulate bcl-2 may decrease tumor cell threshold and sensitize tumor cells to chemotherapy. The objective of this multi-institutional phase 2 trial was to evaluate the efficacy and toxicity of paclitaxel and bcl-2 modulators (13-cis retinoic acid and interferon alfa-2b) in patients with advanced-stage or recurrent cervical cancer.. Patients had biopsy-proven metastatic, first relapse, or persistent cervical cancer with no prior chemotherapy except for chemosensitizing agents. The treatment consisted of oral 13-cis retinoic acid, 1 mg/kg, and subcutaneous interferon alfa-2b, 6 mU/m, days 1 to 4, and intravenous paclitaxel, 175 mg/m, day 4 until disease progression or adverse events prohibited treatment. The primary endpoint was overall response rate.. Thirty-three patients were enrolled between March 2001 and June 2009. Thirty-one patients were eligible for evaluation of treatment response. Twenty-seven patients (82%) received prior concurrent chemoradiation or radiotherapy alone before study enrollment. The overall response rate was 30% (6 complete responses and 4 partial responses). Furthermore, 7 patients (21%) had stable disease. Grade 3 or 4 adverse events included neutropenia (n =16 [48%]), febrile neutropenia (n = 1 [3%]), and anemia (n = 1 [3%]). There were no treatment-related deaths. The median progression-free survival was 3.4 months (95% confidence interval, 2.0-7.4 months), and overall survival was 11.2 months (95% confidence interval, 7.5-26.2 months). Of 6 patients with complete responses, 5 patients survived more than 2 years.. Combination therapy with paclitaxel, 13-cis retinoic acid, and interferon alfa-2b is feasible and safe in treating patients with advanced and recurrent cervical cancer.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Carcinoma, Squamous Cell; Dermatologic Agents; Female; Follow-Up Studies; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Paclitaxel; Prognosis; Recombinant Proteins; Survival Rate; Uterine Cervical Neoplasms

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

Patients with oral premalignant lesion (OPL) have a high risk of developing oral cancer. Although certain risk factors, such as smoking status and histology, are known, our ability to predict oral cancer risk remains poor. The study objective was to determine the value of gene expression profiling in predicting oral cancer development. Gene expression profile was measured in 86 of 162 OPL patients who were enrolled in a clinical chemoprevention trial that used the incidence of oral cancer development as a prespecified endpoint. The median follow-up time was 6.08 years and 35 of the 86 patients developed oral cancer over the course. Gene expression profiles were associated with oral cancer-free survival and used to develop multivariate predictive models for oral cancer prediction. We developed a 29-transcript predictive model which showed marked improvement in terms of prediction accuracy (with 8% predicting error rate) over the models using previously known clinicopathologic risk factors. On the basis of the gene expression profile data, we also identified 2,182 transcripts significantly associated with oral cancer risk-associated genes (P value < 0.01; univariate Cox proportional hazards model). Functional pathway analysis revealed proteasome machinery, MYC, and ribosomal components as the top gene sets associated with oral cancer risk. In multiple independent data sets, the expression profiles of the genes can differentiate head and neck cancer from normal mucosa. Our results show that gene expression profiles may improve the prediction of oral cancer risk in OPL patients and the significant genes identified may serve as potential targets for oral cancer chemoprevention.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Squamous Cell; Female; Gene Expression Profiling; Humans; Isotretinoin; Male; Middle Aged; Mouth Neoplasms; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Neoplasm; Survival Rate; Teratogens; Treatment Outcome; Young Adult

Using data from a randomized, double blind, study of the efficacy of retinol or isotretinoin vs. placebo on recurrence of nonmelanoma skin cancer in high-risk subjects, a reanalysis of the original intent to treat analysis was performed in a dose-response format. Cox proportional hazards models describe the relationship between dose quartiles of isotretinoin and retinol use and time to first occurrence of squamous cell carcinoma (SCC) or basal cell carcinoma (BCC) in crude and adjusted models. Neither the isotretinoin nor retinol models showed any significance at any quartile for reduction in first BCC or SCC occurrence. Crude and adjusted retinol models show a statistically significant increase in risk of developing an SCC in the first quartile, whereas only the crude model shows a statistically significant increase in risk in the first quartile of the isotretinoin model. For retinol and SCC, hazard ratios (HRs) for the first quartile were as follows: HR = 2.92, 95% confidence interval (CI) = 1.67-5.10 crude; HR = 1.95, 95% CI = 1.00-3.80 adjusted. For isotretinoin and SCC, HRs for the first quartile were as follows: HR = 2.38, 95% CI = 1.35-4.19 crude; HR = 1.69, 95% CI = 0.87-3.31 adjusted. Test for trend was not significant in any of the models. These analyses confirm the results of the original intent to treat analyses and raise an interesting question related to the potential for increased risk for patients in the first quartile of retinol dose.

Topics: Aged; Antineoplastic Agents; Arizona; California; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Isotretinoin; Male; Middle Aged; Neoplasm Recurrence, Local; Patient Dropouts; Proportional Hazards Models; Skin Neoplasms; Vitamin A

The risk of malignant transformation of oral preneoplastic lesion (OPL) is difficult to assess. DeltaNp63 is an early oncoprotein associated with mucosal tumorigenesis. The purpose of this study was to assess DeltaNp63 expression in OPL and its role as a marker of oral cancer risk.. DeltaNp63 expression was determined using immunohistochemistry in 152 OPL patients included in a clinical trial comparing retinyl palmitate alone or plus beta-carotene with low-dose 13-cis-retinoic acid. The associations between DeltaNp63 expression as well as DeltaNp63 expression with other potential risk factors for oral cancer development were analyzed.. DeltaNp63 expression was positive in 41 (27%) patients, clusters of intraepithelial inflammatory cells (EIC) were noted in 37 (26%) patients, and podoplanin (previously reported) was positive in 56 (37%) patients. Significantly more patients whose lesions were DeltaNp63 positive or exhibited EIC developed oral cancers. In the multicovariate analysis including age, treatment, and histologic status as cofactors, positive DeltaNp63 expression was associated with an increased hazard ratio of 3.308 (95% confidence interval, 1.663-6.580; P = 0.0007). Patients whose lesions showed positive DeltaNp63, podoplanin, and EIC had the highest oral cancer risk with a hazard ratio of 4.372 (95% confidence interval, 1.912-9.992; P = 0.0005) and 61% oral cancer development rate at 5 years compared with 15% of other OPL patients (P < 0.0001).. DeltaNp63 overepression in OPL is associated with increased oral cancer risk. Together, DeltaNp63, podoplanin, and EIC may be used as biomarkers to identify OPL patients with substantially high oral cancer risk.

Topics: Antineoplastic Combined Chemotherapy Protocols; beta Carotene; Biomarkers, Tumor; Carcinoma, Squamous Cell; Diterpenes; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Humans; Inflammation; Isotretinoin; Leukoplakia, Oral; Male; Membrane Glycoproteins; Middle Aged; Mouth Neoplasms; Prognosis; Retinyl Esters; Trans-Activators; Transcription Factors; Tumor Suppressor Proteins; Up-Regulation; Vitamin A

To conduct a phase III trial of adjuvant 13-cis-retinoic acid (13cRA) plus interferon alfa (IFN-alpha) for preventing tumor recurrence and second primary tumors (SPTs) of skin squamous cell carcinoma (SCC) among patients with aggressive skin SCC.. Sixty-six patients with aggressive skin SCC were randomly assigned to receive either 6 months of combined 13cRA (1 mg/kg/d orally) and IFN-alpha (3 x 10(6) U subcutaneously three times per week) or no adjuvant therapy (control group) after SCC surgery and/or radiation.. At 21.5 months median follow-up, treatment did not improve the time to tumor recurrence and SPT versus control (hazard ratio [HR], 1.13; 95% CI, 0.53 to 2.41), time to tumor recurrence (HR, 1.08; 95% CI, 0.43 to 2.72), or time to SPT (HR, 0.89; 95% CI, 0.27 to 2.93). Adjuvant 13cRA and IFN-alpha was moderately tolerable; 29% of patients in the treatment arm required dose reductions for grade 3 or 4 toxicities.. Results of this phase III trial do not support 13cRA plus IFN-alpha for adjuvant therapy of aggressive skin SCC. With high rates of tumor recurrence and SPTs, patients with aggressive skin SCC continue to have an unmet medical need, with devastating mortality, morbidity, and financial consequences. Promising agents with preclinical and early clinical results relevant to aggressive skin SCC deserve a high priority for future clinical drug development.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasms, Second Primary; Prognosis; Prospective Studies; Recombinant Proteins; Skin Neoplasms; Survival Rate

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 recessive dystrophic epidermolysis bullosa (RDEB) are at high risk of developing squamous cell carcinoma on or after midadolescence, and most patients die of metastatic squamous cell carcinoma within 5 years of diagnosis of their first squamous cell carcinoma.. We sought to determine whether isotretinoin can be safely administered to patients with RDEB as a possible chemopreventive agent.. A total of 20 patients with RDEB aged 15 years or older were treated daily for 8 months with isotretinoin (with a targeted dosage of 0.5 mg/kg/d).. No unusual adverse reactions were noted in this patient population. Several patients experienced reduced blistering at lower doses and increased mechanical fragility at maintenance dosage.. Isotretinoin, at least up to a dosage of 0.5 mg/kg/d, may be safely used in patients with RDEB. Although increased fragility may occur, patients tolerated this drug well and were receptive to its long-term use for possible chemoprevention of cancer. Whether such an effect will occur is yet to be proven.

Topics: Adolescent; Adult; Aged; Carcinoma, Squamous Cell; Dermatologic Agents; Epidermolysis Bullosa Dystrophica; Female; Humans; Isotretinoin; Male; Middle Aged; Risk Factors; Skin Neoplasms

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

Combined biological therapy with 13-cis-retinoic acid (13-cRA) and interferon alpha-2a (IFN alpha-2a) was reported to be highly effective in squamous cell carcinoma of the cervix and skin. Squamous cell carcinoma of the penis is rare in the United States, accounting for less than 1/2% of all male malignancies. Because of the association of infection with human papillomavirus with both carcinomas of the cervix and penis and their shared squamous cell histology, we carried out a phase II study of 13-cRA and IFN alpha-2a in carcinoma of the penis.. Eighteen ambulatory patients with surgically unresectable, recurrent, and/or metastatic squamous cell carcinoma of the penis were treated with IFN alpha-2a, 3MU/day administered subcutaneously and 13-cRA, 1 mg/kg orally daily for at least eight weeks, unless intolerable toxicity occurred.. One patient was ineligible; one patient withdrew prior to treatment. Among the 16 eligible, treated patients, there was one complete response. Fourteen patients had progressive disease as their only treatment effect. Two patients were unevaluable for tumor response because they had no follow-up tumor measurements. No unexpected treatment-related toxicities were found on study. The only common form of grade 3 toxicity was hypertriglyceridemia found in eight of the 17 patients (47%). No toxicities above grade 3 were observed.. In contrast to its benefit in squamous cell carcinomas of the cervix and skin, the combination of 13-cRA and IFN alpha-2a has low efficacy in advanced carcinoma of the penis.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Disease Progression; Fatigue; Fever; Humans; Hypertriglyceridemia; Interferon alpha-2; Interferon-alpha; Isotretinoin; Life Tables; Male; Middle Aged; Penile Neoplasms; Recombinant Proteins; Survival Analysis; Treatment Failure

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

Dysplastic oral leukoplakia (DOL) has been the index lesion in prevention trials for upper aerodigestive tract squamous cell carcinoma (SCC). Vitamin A derivatives, including 13-cis retinoic acid (13-CRA), have been used to treat DOL and to reduce the risk of subsequent SCC. Results from a trial of 13-CRA in patients with DOL are presented here. Transforming growth factor-alpha (TGF-alpha) and the epidermal growth factor receptor messenger RNA (mRNA) expression were studied to validate their use as surrogate endpoint biomarkers in prevention trials for SCC.. In a prospective, randomized, double-blind trial of 13-CRA in 28 patients with DOL, TGF-alpha and epidermal growth factor receptor mRNA expression were analyzed in sequential biopsy specimens of DOL and of adjacent normal-appearing mucosa, utilizing a quantitative, competitive, reverse transcriptase polymerase chain reaction and were compared using the Wilcoxon signed-rank test for paired comparisons.. In biopsy specimens of DOL, TGF-alpha mRNA expression at baseline, but not baseline expression of epidermal growth factor receptor mRNA, was significantly elevated when compared with its expression in specimens from adjacent normal-appearing mucosa (p = 0.003). In patients randomized to 13-CRA who had > or = 50% clearance of DOL during treatment, significant modulation of TGF-alpha mRNA overexpression was seen after 6 months of treatment (p = 0.016). TGF-alpha mRNA overexpression at baseline predicted a subsequent response to 13-CRA (p 0.066).. The full extent of the association between TGF-alpha overexpression and the development of SCC is unknown. Evidence is presented in this article that TGF-alpha overexpression mediates the relationship between 13-CRA and DOL, but there is no direct evidence that it mediates the relationship between 13-CRA and the prevention of SCC. Determination of the extent to which TGF-alpha overexpression mediates this relationship and complete validation of TGF-alpha's role as a surrogate endpoint biomarker await the results of animal and human trials that utilize reduction in the incidence of SCC as their endpoint.

Topics: Aged; Biomarkers, Tumor; Carcinoma, Squamous Cell; Disease Progression; Double-Blind Method; ErbB Receptors; Female; Gene Expression Regulation, Neoplastic; Humans; Isotretinoin; Leukoplakia, Oral; Male; Mouth Neoplasms; Prospective Studies; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor alpha

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

The purpose of this study was to test interferon alfa (IFNalpha), 13-cis-retinoic acid (13cRA), and cisplatin biochemotherapy in advanced squamous cell carcinoma (SCC) of the skin.. Patients with advanced skin SCC received IFNalpha (5 x 10(6) IU/m(2), subcutaneous injection, three times a week), 13cRA (1 mg/kg, orally, daily), and cisplatin (20 mg/m(2), intravenous injection, weekly) in a phase II trial. The growth inhibition, cell-cycle, and apoptosis activity of these agents was evaluated in two skin SCC cell lines (SRB1-m7 and SRB12-p9).. Thirty-nine patients were enrolled. All were assessable for survival, 35 for response and toxicity (median follow-up was 38 months). The overall and complete response rates were 34% and 17%, respectively, with median durations of 9 and 35.4 months, respectively. The response rate was higher in locally advanced (67%) than metastatic (17%) disease (P =.007). Median survival was 14.6 months. One-, 2-, and 5-year survival rate estimates were 58%, 32%, and 21%, respectively. Toxicity included generally mild to moderate fatigue and mucocutaneous dryness, moderate to severe neutropenia (38%), and neutropenic fever (6%). There were no treatment-related deaths. In vitro growth inhibition and apoptosis effects of cisplatin were differential and inversely associated with those of retinoic acid and especially IFNalpha in two skin SCC lines.. The rising incidence, morbidity, and mortality of advanced skin SCC are a major challenge for clinical oncologists. Combined 13cRA, IFNalpha, and cisplatin was clinically active in extensive locally advanced disease. Each agent had independent, non-cross-resistant biologic effects in vitro, which may account for the combination's clinical activity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Squamous Cell; Cell Cycle; Cisplatin; Fatigue; Female; Fever; Humans; Injections, Intravenous; Injections, Subcutaneous; Interferon-alpha; Isotretinoin; Male; Middle Aged; Neutropenia; Skin Neoplasms; Survival Analysis; Treatment Outcome; Tumor Cells, Cultured

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

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

Interferon in combination with 5-fluorouracil has been shown to be active in squamous cell carcinoma (SCC) and adenocarcinoma (AC) of the esophagus. 13-cis-retinoic acid (CRA) has chemopreventive activity in SCC of the head and neck, and, in combination with interferon, has antitumor activity in SCC of the skin and cervix.. The activity and toxicity of CRA and interferon-alpha-2a (IFN) in patients with advanced esophageal carcinoma was evaluated in a Phase II single institution trial. Patients had unresectable or metastatic AC or SCC of the esophagus. One prior chemotherapy regimen was allowed. IFN was given by daily subcutaneous injection at a dose of 3 million U and CRA was taken orally at a dose of 1 mg/kg/day in 2 divided doses. Treatment was given in cycles of 4 weeks and continued until documented disease progression.. Of the 19 patients entered, 15 were evaluable for response and toxicity. One patient was evaluable for response only and one patient was evaluable for toxicity only. Evaluable patients were predominantly male (15 patients), and had AC (13 patients). All had AJCC Stage IV disease and 12 were pretreated. Patients completed an average of two cycles of therapy (range, one to six cycles) prior to progression of disease. National Cancer Institute Common Toxicity Criteria Grade 3/4 toxicity was notable for nausea (25%) and fatigue (31%). No major objective responses were recorded. Eleven patients with AC and 3 patients with SCC had rapid progression of disease. One patient with AC was found to have a minor response for 22 weeks and 1 patient with AC had stable disease for 45 weeks.. This regimen had no significant activity in patients with advanced AC of the esophagus. Further evaluation of IFN plus CRA, using this dose and schedule, is not recommended. In comparison with prior trials of this therapy, a surprising amount of severe nausea and fatigue was observed in this trial.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Esophageal Neoplasms; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Male; Middle Aged; Recombinant Proteins

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

We have evaluated the tumor tissue pO2 in cervical cancers in patients treated with 13-cis-retinoic acid and interferon-alpha-2a prior to and during radiotherapy.. From June 1995 through April 1997, 22 patients with squamous cell carcinoma FIGO IIB/III of the cervix who were scheduled for definitive radiotherapy with curative intent received additional treatment with 13-cis-retinoic acid (cRA, isotretinoin) plus interferon-alpha-2a (IFN-alpha-2a) as part of a phase-II protocol. cRA/IFN-alpha-2a started 14 days prior to radiotherapy (1 mg per kilogramme body weight cRA orally daily plus 6 x 10(6) IU IFN-alpha-2a subcutaneously daily). After this induction period, standard radiotherapy was administered (external irradiation with 50.4 Gy in 28 fractions of 1.8 Gy plus HDR-brachytherapy). During radiotherapy, cRA/IFN-alpha-2a treatment was continued with 50% of the daily doses. Tumor tissue pO2-measurements were performed prior to and after the cRA/IFN-induction period as well as at 20 Gy and at the end of radiotherapy with an Eppendorf-pO2-histograph.. In 11 out of the 22 patients, pO2-measurements were performed prior to the cRA/IFN-induction therapy. The median pO2 of these untreated tumors was 17.7 +/- 16.3 mm Hg. The relative frequency of hypoxic readings with pO2-values below 5 mm Hg ranged from 0% to 60.6% (mean 24.3 +/- 21.0%). After the 2-week induction period with cRA/IFN, the median pO2 had increased from 17.7 +/- 16.3 mm Hg to 27.6 +/- 19.1 mm Hg (not significant). In all 5 patients with hypoxic tumors prior to cRA/IFN (median pO2 of 10 mm Hg or less), the median pO2 was above 20 mm Hg after the 2-week cRA/IFN-induction. In this subgroup of hypoxic tumors, the median pO2 increased from 6.3 +/- 2.7 mm Hg to 27.0 +/- 5.6 mm Hg (p = 0.004, t-test for paired samples). The frequency of hypoxic readings (pO2-values < 5 mm Hg) decreased from 44.7 +/- 17.1% to 2.0 +/- 2.5% (p = 0.012, t-test for paired samples). There was, however, no obvious volume reduction after 14 weeks of cRA/IFN on clinical examination. A complete clinical remission of the local tumor was observed in 19/22 patients after radiotherapy and additional cRA/IFN-alpha-2a-treatment. In primarily hypoxic tumors (with a median pO2 below 10 mm Hg prior to treatment), 4/5 achieved complete remission.. Pretreatment with cRA/IFN improves oxygenation of primarily hypoxic cervical cancers. The mechanisms of action remain unclear and further investigation of the combination regimen is recommended.

Topics: Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Hypoxia; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Keratolytic Agents; Middle Aged; Oxygen; Radiotherapy Dosage; Recombinant Proteins; Time Factors; Uterine Cervical Neoplasms

From January 1993 through January 1996, 37 patients with unresectable squamous carcinoma of the cervix were entered on study and scheduled to receive oral isotretinoin 1 mg/kg per day with subcutaneous alpha interferon 6,000,000 units/day. A course was defined as 4 continuous weeks of therapy. The mean number of four-course cycles delivered was 1.8. One patient was ineligible because of wrong cell type and two were never treated. Thus, 34 patients were evaluable for toxicity. Eight patients were inevaluable for response. Five did not receive a complete 4-week course and three did not have additional tumor measurements; thus 26 were evaluable for response. Prior radiotherapy had been given to 25 patients and prior chemotherapy to 23 patients. There was no grade 4 neutropenia. The incidence of Gynecologic Oncology Group (GOG) grade 3 granulocytopenia and thrombocytopenia was 8.8% and 5.8%, respectively. Six patients (17.6%) developed grade 3 or worse nausea and vomiting. Four (11.7%) patients developed grade 3 neurologic symptoms. There were no complete responses and one partial response. The overall response rate was 3.8% (95% confidence interval, 0.1-19.6%). In this pretreated population, isotretinoin and alpha interferon in the dose and schedule employed exhibit minimal activity.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Drug Therapy, Combination; Female; Humans; Interferon-alpha; Isotretinoin; Keratolytic Agents; Middle Aged; Neoplasm Recurrence, Local; Uterine Cervical Neoplasms

Preclinical and clinical data support the study of retinoids and interferon-alpha (IFN-alpha) in advanced squamous cell carcinoma of the uterine cervix (SCC). This phase II randomized trial of the Southwest Oncology Group sought to estimate the response rate for IFN-alpha plus either 13-cis-retinoic acid (13cRA) or all-trans-retinoic acid (ATRA) in women with recurrent cervical SCC.. Eligibility for this trial required bidimensionally measurable locally recurrent or metastatic squamous or adenosquamous carcinoma of the uterine cervix; SWOG performance status of

Topics: Adult; Aged; Carcinoma, Squamous Cell; Female; Humans; Interferon-alpha; Isotretinoin; Middle Aged; Neoplasm Recurrence, Local; Tretinoin; Uterine Cervical Neoplasms

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

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Esophageal Neoplasms; Female; 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

The objective of this study was to examine the effect of retinol and isotretinoin on the incidence of nonmelanoma skin cancer in high-risk subjects. A total of 525 participants with a history of at least four basal cell carcinomas (BCCs) and/or cutaneous squamous cell carcinomas (SCCs) were entered into a randomized, double-blind, placebo-controlled trial, performed in free-standing study clinics. Participants were randomly assigned to receive oral retinol (25,000 units), isotretinoin (5-10 mg), or placebo supplementation daily for 3 years. The time to first new occurrence of BCC or cutaneous SCC was used as the outcome measure. During the study period, 319 BCCs and 125 cutaneous SCCs were diagnosed clinically and pathologically. There were no differences between those who received retinol, isotretinoin, or the placebo, with regard to the time to first occurrence or to the total number of tumors noted. No beneficial effects were noted with regard to the prevention of nonmelanoma skin cancer with either retinol or isotretinoin.

Topics: Adult; Aged; Blood Chemical Analysis; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Double-Blind Method; Female; Humans; Isotretinoin; Keratolytic Agents; Liver Function Tests; Male; Middle Aged; Proportional Hazards Models; Skin Neoplasms; Vitamin A

Retinoids are strong inhibitors of epithelial cancer promotion and progression in experimental carcinogenesis. Recently, therapeutic trials of retinoids have demonstrated activities in cervical cancer and precancerous lesion of cervix. Our purpose was to determine whether additional administration of 13-cis-retinoic acid would improve the treatment effect of neoadjuvant chemotherapy in patients with squamous cell carcinoma of the cervix. From January 1994 through January 1995, 40 patients with invasive cervical cancer were enrolled in this prospective study and randomized into the two groups. Group 1 had neoadjuvant chemotherapy alone and group 2 had neoadjuvant chemotherapy plus 13-cis-retinoic acid (RA) at a dosage of 1 mg/kg/day for 1 month. Patients in group 1 and group 2 were similar with respect to age, parity, clinical stage, and histological subtype. Therapeutic responses were compared using Fisher's exact test, Mann-Whitney test, and Wilcoxon signed-rank test. RA increased the complete response rate of neoadjuvant chemotherapy from 0% in group 1 to 5% in group 2. However, a difference of overall clinical response rate between the two groups was not evident. The drug toxicities in group 1 and group 2 included anemia in 30.0% and 23.7%, leukopenia in 6.7% and 15.2%, and hepatotoxicity in 6.7% and 6.8%, respectively. More frequent incidence of mucocutaneous side effects was seen in group 2 than group 1, but these side effects were mild and reversible. The clinical response rate achieved in this trial indicates that the combination of 13-cis-retinoic acid and neoadjuvant chemotherapy, at least when used on the schedule reported herein, is not superior to treatment of neoadjuvant chemotherapy alone for patients with squamous cell carcinoma of the cervix. However, a single patient achieved a complete response on this therapy, and the impact of such a treatment on survival needs to be explored.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Female; Humans; Isotretinoin; Middle Aged; Prospective Studies; Uterine Cervical Neoplasms; Vincristine

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

The aim of this study was to investigate the possible therapeutic effect of 13-cis-retinoic acid plus interferon alpha-2a in patients with inoperable squamous cancer of the esophagus. Patients with advanced, measurable, histologically confirmed squamous carcinoma of the esophagus with an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 who had adequate bone marrow, liver, and renal function were eligible for study. Patients were given cis-retinoic acid 1 mg/kg/day per mouth continuously and interferon alpha-2a 3 Mu/day for 3 days followed by 6 Mu subcutaneously daily thereafter. Seventeen patients were entered on study. Fifteen patients were evaluable for toxicity. The most common toxicities were grade 1 and 2 cheilitis, dry skin and flu-like symptoms which occurred in all patients. Two patients had grade 3 toxicity (1 anorexia and 1 fatigue). No grade 4 toxicity occurred. Fifteen patients were evaluable for response. No objective response was documented. The median survival time was 15 weeks. With no response seen it is unlikely that the combination of treatment as used in this study will be of benefit in patients with advanced squamous cancer of the esophagus.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Esophageal Neoplasms; Female; Humans; Injections, Subcutaneous; Interferon alpha-2; Interferon-alpha; Isotretinoin; Male; Middle Aged; Recombinant Proteins

The combination of 13-cis-retinoic acid (13-cRA) and interferon (IFN)-alpha 2a has been reported to be highly active in previously untreated squamous carcinoma of the cervix. In this phase II study, 13-cRA was given at a dose of 1 mg/kg/day and IFN-alpha 2a was given subcutaneously at a dose of 3 million units/m2/day. Thirteen of 14 patients enrolled in this study are evaluable for response and toxicity. There were no complete or partial responses. Ten patients had progressive disease and the remaining three had stable disease. Principle toxicities were fatigue, nausea, and vomiting. This regimen appears cross-resistant with radiotherapy and/or platinum-based cytotoxic therapy in heavily pretreated patients with squamous carcinoma of the cervix.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Combined Modality Therapy; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Middle Aged; Recombinant Proteins; Uterine Cervical Neoplasms

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Calcitriol; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Female; Humans; Isotretinoin; Male; Middle Aged; Precancerous Conditions; Skin Neoplasms

Recent in vitro and in vivo studies hypothesize a synergistic effect of 13-cis-Retinoic Acid (13cRA) and recombinant alpha-IFN 2a (alpha-IFN) in the treatment of squamous cell carcinoma (SqCC).. 35 patients with SqCC in several sites were treated with 13cRA (0.6-1 mg/kg/day) combined with alpha-IFN (6 x 10(6) I.U./day), continuously for 3 months.. We observed an objective response in 41% of cases (13/32 evaluable patients) with 5 complete and 8 partial responses. Toxicity was mild and always rapidly reversible, with no haematological side effects.. These preliminary data confirm the feasibility and effectiveness of the combination of 13cRA and alpha-IFN in the therapy of SqCC, also in pre-treated patients, with acceptable toxicity and good compliance.

Topics: Adult; Aged; Aged, 80 and over; Anorexia; Carcinoma, Squamous Cell; Combined Modality Therapy; Fatigue; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Male; Middle Aged; Recombinant Proteins; Remission Induction

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: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Middle Aged; Recombinant Proteins; Uterine Cervical Neoplasms

The combination of interferon (IFN)-alpha 2a and 13-cis-retinoic acid (13-cRA) has demonstrated significant antitumor activity in patients with advanced squamous cell cancer of the skin and cervix. We performed a prospective phase II trial of this combination in patients with locally advanced or metastatic squamous cell lung cancer. Twenty-one patients were enrolled on the study. All patients were evaluable for toxicity and 17 were evaluable for response, four with locally advanced and 13 with metastatic disease. One partial response was obtained in a patient with locally advanced disease. Toxicity consisted mainly of constitutional side effects (fatigue, anorexia), which resulted in eight patients coming off-study. The combination of IFN-alpha 2a and 13-cRA is unlikely to exhibit significant clinical activity in patients with metastatic squamous cell lung cancer, but activity in patients with locally advanced disease has not been excluded.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Drug Therapy, Combination; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Lung Neoplasms; Male; Middle Aged; Prospective Studies; Recombinant Proteins

Retinoids (vitamin A derivatives) and interferon-alpha (IFN-alpha) are potent regulators of malignant cell differentiation and proliferation, and both have immunomodulatory and antiangiogenesis activity. A large body of preclinical and clinical data supports the use of combination therapy with 13-cis-retinoic acid (13-cRA) and IFN-alpha in patients with squamous cell carcinoma of the skin. This carcinoma is an extremely common and frequently severely disfiguring cancer, for which about 10% of patients remain uncured following standard local therapy.. Our purpose was to test whether a 20% or greater complete response rate could be achieved using a combination of these two agents in patients with advanced squamous cell carcinoma of the skin in whom local therapy had failed or was unfeasible or who had regional and/or distant metastases.. Thirty-two patients with heavily pretreated, advanced inoperable cutaneous squamous cell carcinoma of the skin were given a combination of oral 13-cRA (1 mg/kg per day) and subcutaneous recombinant human IFN alpha-2a (3 million units per day) for at least 2 months, unless disease progressed earlier, in a phase II trial.. Nineteen (68%) of the 28 assessable patients responded, seven (25%) of whom had complete responses. Response rates were 93% (13 of 14) in patients with advanced local disease (six complete responses), 67% (four of six) in patients with regional disease (no complete responses), and 25% (two of eight) in patients with distant metastases (one complete response). The relationship between decreased response rate and increased extent of disease was highly statistically significant (P less than .005, chi-square test). The median response duration was greater than 5 months. No life-threatening toxic effects occurred in assessable patients treated with this combination, although dose reductions were required in 18 patients. The major limiting side effect in this elderly patient population (median age, 67 years) was cumulative fatigue.. These results indicate that combined systemic therapy with 13-cRA and IFN alpha-2a is highly effective in patients with advanced squamous cell carcinoma of the skin.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Drug Evaluation; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Male; Middle Aged; Recombinant Proteins; Remission Induction; Skin Neoplasms

Chemotherapeutic study of cervical squamous cell carcinoma has shown some positive results. Complete plus partial (overall) response rates of 15%-35% (complete response rate, less than 5%) were achieved with the use of a small number of cytotoxic single agents in patients with advanced disease. In addition, overall response rates of 60%-70% (complete response rates, 10%-20%) were achieved with cisplatin-based, multiagent regimens in patients with primary, locally advanced disease. However, the lack of clear evidence that existing chemotherapy can achieve a survival benefit, coupled with the worldwide annual deaths of hundreds of thousands of women from cervical cancer, indicates the urgent need for effective systemic therapy for this disease.. In view of the preclinical and clinical evidence that supports testing of the novel combination of 13-cis-retinoic acid (13-cRA) plus interferon-alpha (IFN-alpha) in cervical squamous cell carcinoma, we conducted a phase II study of this regimen in locally advanced disease.. Twenty-six patients with untreated, locally advanced squamous cell carcinoma of the cervix were treated daily for at least 2 months with oral 13-cRA (1 mg/kg) and subcutaneous recombinant human IFN alpha-2a (6 million units). In 21 patients (81%), the disease was stage II or higher.. Thirteen patients (50%) experienced major responses (tumor regression greater than or equal to 50%) in association with resolution of symptoms; one achieved complete response, and 12 experienced partial response. Seven with partial response are improving further, four are being maintained in partial response, and one responder has relapsed during therapy. The response rate is 58% (11 of 19) in patients with stage IIB or higher disease and 66% (10 of 15) in patients with bulky disease (at least one dimension greater than or equal to 10 cm). Of the 13 non-responders, nine have stable disease and four have had disease progression during therapy. Toxicity was minimal.. These preliminary results indicate that systemic 13-cRA plus IFN alpha-2a is a highly active, well-tolerated therapy for locally advanced cervical cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Drug Evaluation; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Middle Aged; Recombinant Proteins; Remission Induction; Uterine Cervical Neoplasms

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

To confirm reports that skin cancer can be prevented with retinoids, we conducted a three-year controlled prospective study of oral isotretinoin (also called 13-cis retinoic acid) in five patients with xeroderma pigmentosum who had a history of multiple cutaneous basal-cell or squamous-cell carcinomas. Patients were treated with isotretinoin at a dosage of 2 mg per kilogram of body weight per day for two years and then followed for an additional year, without the drug. Before, during, and after treatment, biopsies of all suspicious lesions were performed, and skin cancers were surgically removed. The patients had a total of 121 tumors (mean, 24; range, 8 to 43) in the two-year interval before treatment. During two years of treatment with isotretinoin, there were 25 tumors (mean, 5; range, 3 to 9), with an average reduction in skin cancers of 63 percent (P = 0.019). After the drug was discontinued, the tumor frequency increased a mean of 8.5-fold (range, 2- to 19-fold) over the frequency during treatment (P = 0.007). Although all patients experienced mucocutaneous toxic effects, and triglyceride, liver-function, or skeletal abnormalities developed in some, high-dose oral isotretinoin was effective in the chemoprophylaxis of skin cancers in patients with xeroderma pigmentosum.

Topics: Administration, Oral; Adolescent; Adult; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Child; Clinical Trials as Topic; Female; Humans; Isotretinoin; Male; Prospective Studies; Skin Neoplasms; Tretinoin; Xeroderma Pigmentosum

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

Epidermodysplasia verruciformis (also known as Lewandowsky-Lutz dysplasia) is an extremely rare autosomal recessive genodermatosis, in which the skin is unusually sensitive to human papilloma viruses (HPV). It is associated with a high risk of developing non-melanocytic skin tumors. Treatment with keratolytic retinoids is currently considered to be the most effective therapy. Retinoids have a broad spectrum of activity and inhibit the growth of squamous cell carcinoma and other malignant tumors. We report the case of an 81-year-old woman who had been receiving prophylactic treatment with oral isotretinoin at a daily dose of 1.0-0.33 mg/kg bodyweight for about 18 years because of her epidermodysplasia verruciformis (HPV types 9 & 57 detected). We observed a reduction of the incidence of squamous cell carcinomas of the skin and presume a causal relationship between the treatment with this retinoid and the reduction of squamous cell carcinomas of the skin in this patient.

Topics: Administration, Oral; Aged, 80 and over; Carcinoma, Squamous Cell; Dermatologic Agents; Epidermodysplasia Verruciformis; Female; Humans; Isotretinoin; Skin Neoplasms

Cutaneous squamous cell carcinoma (CSCC) is one of the most common cancers worldwide, requiring effective therapeutic interventions. Retinoids are important chemopreventive and therapeutic agents for a variety of human cancers including CSCC. In this study we synthesized a novel retinoic derivative N-(4-ethoxycarbonylphenyl) isoretinamide (ECPIRM) and evaluated its biological activities and possible mechanisms in human cutaneous squamous cell lines. ECPIRM had better inhibitory effect on the proliferation of squamous carcinoma cells SCL-1 and colo-16, compared with All-trans retinoic acid and 13-cis retinoic acid. ECPIRM had less toxicity to normal keratinocyte cell line HaCaT. Mechanistically, ECPIRM induced G1 cell cycle arrest in SCL-1 cells, via the downregulation of CDK2, CDK4, cycling D1 and cyclin E expression and upregulation of p21. In addition, these effects were at least partially due to the inhibition of JNK/ ERK-AP-1 signaling pathway by ECPIRM. Importantly, these effects of ECPIRM are independent of the classical retinoid receptor pathway, suggesting that the novel compound will have less side-effects in chemotherapy. These findings demonstrate that ECPIRM is a potential inhibitor of MPAK-AP-1 pathway, and is a potential therapeutic agent against CSCC.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Cycle Checkpoints; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Humans; Isotretinoin; MAP Kinase Signaling System; Phosphorylation; Receptors, Retinoic Acid; Skin Neoplasms; Transcription Factor AP-1

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Anus Neoplasms; Buschke-Lowenstein Tumor; Carcinoma, Squamous Cell; Chemoradiotherapy; Genital Neoplasms, Male; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Male; Perineum; Recombinant Proteins; Remission Induction; Time Factors; Treatment Outcome

Retinoid therapy is used for chemo-prevention in immuno-suppressed patients at high risk of developing skin cancer. The retinoid signalling molecule, tripartite motif protein 16 (TRIM16), is a regulator of keratinocyte differentiation and a tumour suppressor in retinoid-sensitive neuroblastoma. We sought to determine the role of TRIM16 in skin squamous cell carcinoma (SCC) pathogenesis. We have shown that TRIM16 expression was markedly reduced during the histological progression from normal skin to actinic keratosis and SCC. SCC cell lines exhibited lower cytoplasmic and nuclear TRIM16 expression compared with primary human keratinocyte (PHK) cells due to reduced TRIM16 protein stability. Overexpressed TRIM16 translocated to the nucleus, inducing growth arrest and cell differentiation. In SCC cells, TRIM16 bound to and down regulated nuclear E2F1, this is required for cell replication. Retinoid treatment increased nuclear TRIM16 expression in retinoid-sensitive PHK cells, but not in retinoid-resistant SCC cells. Overexpression of TRIM16 reduced SCC cell migration, which required the C-terminal RET finger protein (RFP)-like domain of TRIM16. The mesenchymal intermediate filament protein, vimentin, was directly bound and down-regulated by TRIM16 and was required for TRIM16-reduced cell migration. Taken together, our data suggest that loss of TRIM16 expression plays an important role in the development of cutaneous SCC and is a determinant of retinoid sensitivity.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Dermatologic Agents; DNA-Binding Proteins; Down-Regulation; Humans; Immunohistochemistry; In Vitro Techniques; Isotretinoin; Protein Binding; Skin Neoplasms; Transcription Factors; Tripartite Motif Proteins; Tumor Cells, Cultured; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases; Vimentin

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

Oral squamous cell carcinoma (OSCC) is responsible for about 90% of oral malignancies and its incidence is increasing. Despite various treatment protocols, survival rate of OSCC is low. Chemotherapy that is used for treating this carcinoma in advanced stages is systemic therapy that destroys carcinogenic cells, and controls tumor metastasis. Chemotherapy is very toxic and has limitations, especially for patients in advanced stages. Considering positive effects of retinoid and vitamin D3 derivatives in treating some carcinomas, we decided to evaluate the effect of combination of these drugs on OSCC. In this study the effects of combination of 5-fluorouracil, 13-cis retinoic acid and vitamin D3 on cultured cell of OSCC have been evaluated.. OSCC cells were cultured in culture media and different concentration of 5-fluorouracil, 13-cis retinoic acid and vitamin D3 were added to cultured cell as separately and in combinations. The effect of treatment on cell proliferation and induction of apoptosis were evaluated by MTT and TUNEL assays respectively.. Combination of 5-fluorouracil and 13- cis retinoic acid had the highest inhibitory effect on SCC cell proliferation. Combination of two drugs had more apoptotic effect than each of them separately, and combination of three drugs had more effect than combination of two drugs.. Because combination of drugs had more inhibitory effect on cell proliferation than one of them and combination of three drugs had the most apoptotic effect than one of these drugs separately, these drugs may have synergic effect on OSCC.. Combination of three drugs has more inhibitory effect on cell proliferation and apoptotic effect than one of these drugs.

Topics: Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Cholecalciferol; Drug Combinations; Drug Synergism; Fluorouracil; Humans; In Situ Nick-End Labeling; Isotretinoin; Mouth Neoplasms; Tetrazolium Salts; Thiazoles

We have previously conducted phase II trials with a combination of 13-cis-retinoic acid (13-cRA), interferon-alpha2a (IFN-alpha2a), and alpha-tocopherol (alpha-TF) in patients with advanced oral premalignant lesions and locally advanced head and neck cancer in the adjuvant settings and achieved promising outcomes. The present study was conducted in vitro to elucidate the mechanisms of anti-tumor activity of this 3-drug combination in squamous cell carcinoma of the head and neck (SCCHN).. Five SCCHN cell lines were treated with 13-cRA, IFN-alpha2a, and alpha-TF as single agents or 2- to 3-drug combinations for 72 hours. Inhibition of cell growth and cell cycle progression and induction of apoptosis by the treatments were evaluated.. Our results demonstrated that although each single-agent and 2-drug combination showed a certain level of cell growth inhibition, the 3-drug combination apparently further inhibited cell growth in comparison to any single agents and 2-drug combinations in the 5 SCCHN cell lines. Cell cycle analysis on Tu212 and 886LN cells by flow cytometry exhibited significant accumulation of the cells at S phase in the 3-drug combination. On the other hand, Annexin-V binding assay demonstrated that the 3-drug combination induced more profound apoptosis than any of the single agents or 2-drug combinations. In parallel, proteolytic cleavages of pro-caspase-8, -9, -3 and poly (ADP ribose) polymerase as well as caspase-3 activity induced by the 3-drug treatment were observed.. Our data suggests that 3-drug combination biochemopreventive regimen has cooperative inhibitory effect on the growth of SCCHN cells. Both cell cycle arrest and apoptosis contribute to cell growth inhibition of this 3-drug combination therapy.

Topics: alpha-Tocopherol; Apoptosis; Carcinoma, Squamous Cell; Caspase 3; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Chemoprevention; Drug Therapy, Combination; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Otorhinolaryngologic Neoplasms; Recombinant Proteins

Previous studies showed that many chemotherapeutic agents can induce immuno-suppression at therapeutic drug concentrations whereas low drug doses induce immuno-augmentation.. The effect of low-dose cisplatin, interferon-alpha, and 13-cis retinoic acid on receptors involved in immune-mediated apoptosis (Fas/CD95), cell growth (epidermal growth factor receptor) and lymphocyte adhesion (intercellular adhesion molecule-1) was investigated in two oral cancer cell lines (UT-SCC-20A and UT-SCC-24A). Different methods for cell preparation were studied: mechanical and enzymatic detachment, and culture on chamber slides. Receptor expression was investigated using immunohistochemical staining. The amount of soluble and cell-bound Fas was determined with the ELISA technique, and the functional relevance of Fas expression, apoptosis induction, was analyzed.. Cisplatin enhanced cytoplasm and membrane staining for Fas in both cell lines. After cisplatin treatment, the amount of soluble Fas was increased in UT-SCC-20A cultures, but no effect was observed in the UT-SCC-24A cell line. Apoptosis, measured as enhanced caspase-3 activity, was induced by an agonistic Fas antibody (CH11) after cisplatin treatment in UT-SCC-24A cells.. Low-dose cisplatin treatment enhanced Fas expression in both cell lines and increased susceptibility to apoptosis in one of them.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Adhesion; Cell Line, Tumor; Cell Proliferation; Cisplatin; ErbB Receptors; fas Receptor; Humans; Immunologic Factors; Intercellular Adhesion Molecule-1; Interferon-alpha; Isotretinoin; Mouth Neoplasms

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

The purpose of this study was to determine whether the progression of low-grade squamous intraepithelial lesions of the cervix in women with the human immunodeficiency virus can be predicted reliably by standard cytologic testing.. As part of a previously reported trial, 288 biopsy specimens were collected from 117 women with the human immunodeficiency virus. These specimens underwent central and local interpretation, which were compared and correlated with cytologic results. Ninety-two subjects had matched cytologic/histologic pairs at study termination, which were compared to determine whether cytologic testing was predictive of progression.. Of the central histologic interpretations, 26 of 288 interpretations (9%) differed from local results, 97 of 246 cytologic/histologic pairs (39%) were discordant, and 21 subjects had progression to high-grade squamous intraepithelial lesions by histologic evidence. Cytologic testing showed high-grade squamous intraepithelial lesions in 4 of 21 specimens (sensitivity, 19%). The remaining cytologic specimens were either low-grade squamous intraepithelial lesions or were normal.. This substudy of pathologic results from a randomized clinical trial suggests that, although the risk of progression of low-grade squamous intraepithelial lesions is low, follow-up cytologic testing is unreliable. Colposcopic evaluation with directed biopsies should be continued.

Topics: Antineoplastic Agents; Biopsy; Carcinoma, Squamous Cell; Cervix Uteri; Clinical Trials, Phase III as Topic; Colposcopy; Disease Progression; Female; Follow-Up Studies; HIV Infections; Humans; Isotretinoin; Predictive Value of Tests; Prognosis; Randomized Controlled Trials as Topic; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Vaginal Smears

Topics: Carcinoma, Squamous Cell; Facial Dermatoses; Female; Gels; Humans; Isotretinoin; Lymphatic Metastasis; Middle Aged; Radiotherapy

Small open studies of patients at high risk for squamous cell carcinoma (SCC) of the skin suggest that oral retinoid use reduces the risk of these tumors. Among patients at lower risk, randomized trials of low doses of retinoids did not demonstrate significant chemopreventive effects. Patients with psoriasis treated with oral psoralen-UVA have a high risk of SCC development. Oral retinoids are used to treat psoriasis. We performed a nested cohort study to assess whether oral retinoids reduce skin cancer risk among patients with psoriasis exposed to psoralen-UVA.. From 1985 to 2000, 135 patients (11.3% of surviving patients in our cohort) used retinoids for at least 26 weeks in 1 year or more. For these 135 patients, we compared each person's SCC and basal cell carcinoma incidence during years of substantial oral retinoid use and other years. We used Poisson regression models to adjust for potential confounders.. In a paired analysis, which compared each patient's own tumor experience while using and not using retinoids, retinoid use was associated with a 30% reduction in SCC incidence (196 SCCs/1000 and 302 SCCs/1000 years of use and no use, respectively; P =.002). After adjusting for other factors associated with SCC risk, the incidence of SCC was significantly decreased during years of substantial retinoid use (incidence rate ratio = 0.79; 95% confidence interval = 0.65, 0.95). Oral retinoid use and basal cell carcinoma incidence were not significantly associated.. In patients with psoriasis treated with psoralen-UVA, systemic retinoid use reduced SCC risk but did not significantly alter basal cell carcinoma incidence.

Topics: Adult; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Case-Control Studies; Chemoprevention; Female; Humans; Incidence; Isotretinoin; Male; Middle Aged; Multivariate Analysis; Prospective Studies; Psoriasis; PUVA Therapy; Retinoids

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Clinical Trials, Phase III as Topic; Decision Making; Evidence-Based Medicine; Humans; Interferon-alpha; Isotretinoin; Practice Guidelines as Topic; Research Design; Skin Neoplasms

Retinoids have been shown to inhibit the growth of squamous cell carcinoma and other malignancies. They have also been shown to alter gap junctional intercellular communication (GJIC) and the expression of connexins, the protein subunits of gap junctions. We report in this study that the alteration of GJIC by retinoids may be directly related to inhibitory effects on cell growth.. SCC-13 cells were treated with all-trans retinoic acid (tRA) and 13-cis retinoic acid (cRA) at 10(-7) and 10(-6) M concentrations in culture. No treatment and ethanol vehicle controls were included for each experiment. Serial cell counts of parallel cultures were performed to determine cell growth. The parachute technique was performed in combination with fluorescence activated cell sorting (FACS) analysis to determine GJIC. Northern and Western blot analysis were performed to assess connexin mRNA and protein expression.. The growth rate was inhibited for cells treated with tRA (10(-6) M) (P < 0.05) and cRA (10(-6) M) (P = 0.068) vs. vehicle control. GJIC was significantly inhibited with both tRA (10(-7) and 10(-6) M) (P < 0.001) and cRA (10(-7) and 10(-6) M) (P < 0.001) at 24, 48, and 96 h as determined by FACS analysis. To correlate GJIC with cell growth, we studied the effect of glycyrrhetinic acid, a known inhibitor of GJIC. Glycyrrhetinic acid also significantly inhibited cell growth (P < 0.05) vs. control. Connexin 26 and connexin 43 mRNA and protein expression were not significantly altered after retinoid treatment.. Retinoic acids inhibit both cell growth and GJIC in SCC-13 cells. Retinoids may inhibit cell growth through alteration of GJIC in SCC-13 cells.

Topics: Blotting, Northern; Blotting, Western; Carcinoma, Squamous Cell; Cell Communication; Cell Division; Connexin 26; Connexin 43; Connexins; Flow Cytometry; Gap Junctions; Glycyrrhizic Acid; Isotretinoin; Logistic Models; Retinoids; RNA, Messenger; Skin Neoplasms; Tretinoin; Tumor Cells, Cultured

1alpha,25-Dihydroxyvitamin D(3) [1,25(OH)2D3] inhibits growth of cells derived from a variety of tumors in vitro and in vivo. Proliferation in vitro of human SCC25 cells, derived from a primary squamous cell carcinoma (SCC) of the tongue, was blocked by 1,25(OH)2D3 and its analog EB1089. A similar effect was observed with 13-cis retinoic acid (RA), which has been used in chemoprevention of SCC. We identified amphiregulin, a member of the epidermal growth factor family, as a 1,25(OH)2D3 target gene in SCC25 cells. Induction of amphiregulin mRNA by 1,25(OH)2D3 was rapid and sustained over 48 h, and was unaffected by cycloheximide. 1,25(OH)2D3 also induced amphiregulin mRNA in estrogen receptor-positive and -negative human breast cancer cell lines, but not in LNCaP human prostate cancer cells. RAR- or RXR-specific retinoids did not affect amphiregulin mRNA levels in SCC25 cells; however, 13-cis RA partially blocked the response to 1,25(OH)2D3. Amphiregulin partially inhibited growth of SCC25 cells in culture. Our data show that amphiregulin is a 1,25(OH)2D3 target gene, and suggest that its induction may contribute to the growth inhibitory effects of 1,25(OH)2D3.

Topics: Amphiregulin; Antineoplastic Agents; Breast Neoplasms; Calcitriol; Carcinoma, Squamous Cell; Cell Division; Cholecalciferol; Dose-Response Relationship, Drug; EGF Family of Proteins; Gene Expression Regulation, Neoplastic; Glycoproteins; Growth Substances; Humans; Intercellular Signaling Peptides and Proteins; Isotretinoin; RNA, Messenger; Tumor Cells, Cultured

Retinoids inhibit the proliferation of several types of tumour cells, and are used for patients with several malignant tumours. In this study, we examined the effect of retinoic acids (RAs) on the invasive potentials of the oral squamous cell carcinoma (SCC) cells, BHY and HNt. BHY cells expressed all of retinoid nuclear receptors (RARalpha, beta, gamma, and RXRalpha) and cytoplasmic retinoic acid binding proteins (CRABP1 and CRABP2). HNt cells lacked the expression of RARbeta, but expressed other nuclear receptors and CRABPs. All-trans retinoic acid (ATRA) and 13-cis retinoic acid (13-cisRA) (10(-6)and 10(-7)M) inhibited the growth of the cells, but low-dose ATRA and 13-cisRA (10(-8)M) marginally affected the growth of the cells. Surprisingly, low-dose RAs enhanced the activity of tissue-type plasminogen activator (tPA), and activated pro-matrix metalloproteinases (proMMP2 and proMMP9). Activation of proMMP2 and proMMP9 was inhibited by aprotinin, a serine-proteinase, tPA inhibitor. Furthermore, low-dose RAs enhanced the in vitro invasiveness of BHY cells. These results indicate that low-dose RAs enhances the in vitro invasiveness of oral SCC cells via an activation of proMMP2 and proMMP9 probably mediated by the induction of tPA.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Division; Collagenases; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Precursors; Gelatinases; Humans; Isotretinoin; Matrix Metalloproteinase 9; Matrix Metalloproteinases, Membrane-Associated; Metalloendopeptidases; Mouth Neoplasms; Neoplasm Invasiveness; Receptors, Retinoic Acid; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Tissue Plasminogen Activator; Tretinoin; Tumor Cells, Cultured; Urokinase-Type Plasminogen Activator

Topics: Administration, Topical; Antineoplastic Agents; Carcinoma, Squamous Cell; Humans; Isotretinoin; Organ Transplantation; Skin Neoplasms; Tretinoin

Surrogate endpoint biomarkers (SEBs) are detectable molecular, cellular, and tissue changes that take place during tumorigenesis and can be modulated by a chemoprevention agent.. To identify candidate SEBs for invasive squamous cell carcinoma of the upper aerodigestive tract (SCC), we have studied the expression of transforming growth factor-alpha (TGF-alpha) and epidermal growth factor receptor (EGFr) in sequential biopsy specimens of dysplastic oral leukoplakia and adjacent normal-appearing mucosa. Biopsies were taken from patients before, during, and after treatment with 13-cis retinoic acid, a vitamin A derivative. Immunohistochemistry was performed using the Biogenex Super Sensitive Biotin-Streptavidin horseradish peroxidase detection system.. The pretreatment expression of TGF-alpha and EGFr in dysplastic oral leukoplakia was increased when compared with their expression in adjacent normal-appearing mucosa (p = 0.001 and p = 0.01, respectively). Eleven of 14 patients enrolled in the study (78.6%) completed 3 months of treatment with 13-cis retinoic acid (1. 0 mg/kg/day). TGF-alpha expression in dysplastic oral leukoplakia, but not in adjacent normal-appearing mucosa, decreased during treatment (p < 0.05).. TGF-alpha is a candidate SEB for future SCC chemoprevention trials.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Biopsy; Carcinoma, Squamous Cell; Chemoprevention; ErbB Receptors; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Humans; Immunoenzyme Techniques; Immunohistochemistry; Isotretinoin; Keratolytic Agents; Leukoplakia, Oral; Mouth Mucosa; Pilot Projects; Single-Blind Method; Transforming Growth Factor alpha

We report the case of a 7-year old boy with xeroderma pigmentosum and a large squamous cell carcinoma of the cheek. He received a combination of isotretinoin (1 mg/kg/day) and chemotherapy for a period of 3 months and showed complete remission of the tumor. Treatment modalities of malignancies in xeroderma pigmentosum are reviewed and discussed in relation to the literature. The advantages of our protocol were emphasized because of the rapid improvement in a short time with minimal side effects.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Child; Cisplatin; Fluorouracil; Humans; Isotretinoin; Keratolytic Agents; Male; Skin Neoplasms; Treatment Outcome; Xeroderma Pigmentosum

Retinoids and interferon-alpha (IFN-alpha) have been shown to exert antiproliferative and radiosensitizing effects. The present study was designed to determine differential effects of retinoids in combination with IFN-alpha on radiation toxicity of 5 human squamous cell carcinoma (SCC) cell lines.. Using clonogenic assays, the effects of all-trans (ATRA), 13-cis-retinoic acid (13cRA), and IFN-alpha on radiation toxicity were analyzed. Basal mRNA expression of the cytoplasmic retinoic acid binding protein, CRABP I, was determined in retinoid-sensitive and -insensitive cell lines by reverse transcriptase/polymerase chain reaction (RT-PCR).. Treatment with ATRA, 13cRA, or IFN-alpha resulted in a cell line-specific inhibition of clonogenic survival. A comparison of retinoid-sensitive and insensitive cells revealed that retinoid sensitivity seems to be dependent on the basal expression level of CRABP I. ATRA, 13cRA, and IFN-alpha alone or in combination altered radiation sensitivity by affecting predominantly the alpha-component of the linear-quadratic dose-response curve. Likewise, depending upon the treatment condition the surviving fraction at 2 Gy (SF2) was decreased cell line-specifically. Combined treatment with ATRA or 13cRA and IFN-alpha markedly enhanced radiation cytotoxicity.. These in vitro data indicate that the combined treatment with retinoids, IFN-alpha, and ionizing radiation could be beneficial for patients presenting with SCC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Combined Modality Therapy; Dose Fractionation, Radiation; Dose-Response Relationship, Radiation; Humans; Interferon-alpha; Isotretinoin; Neoplasm Proteins; Radiation Tolerance; Radiation-Sensitizing Agents; Receptors, Retinoic Acid; Tretinoin; Tumor Cells, Cultured

Preclinical and clinical trials demonstrated the antiproliferative and chemopreventive potential of 13-cis retinoic acid in combination with interferon-alpha. The present study was designed to determine the radiosensitizing potential of both drugs after single and combined treatment of human squamous-cell carcinoma cells of the oral cavity in vitro.. The study was performed using the human squamous-cell carcinoma cell line SCC4, which was originally established from a tumor of the oral cavity. Based on clonogenic assays, the inhibition of clonogenic activity and radiosensitizing potential of 13-cis retinoic acid and interferon-alpha after single or combined treatment without and with subsequent irradiation was determined.. 13-cis retinoic acid (10 microM) and interferon-alpha (50 IU/ml) showed significant inhibition of clonogenic activity after single treatment. A combined treatment protocol resulted at least in a highly significant additive inhibition of clonogenicity. Treatment with both drugs (5 microM 13-cis retinoic acid, 25 IU/ml IFN-alpha) prior and post irradiation of the cells resulted in a pronounced enhancement of radiation toxicity resulting in significantly decreased SF2- and alpha-values. Combined treatment with both drugs was significantly more effective than single drug treatment.. The data presented indicate that pre- and post-irradiation treatment with 13-cis retinoic acid and interferon-alpha significantly enhance the radiosensitivity of human squamous-cell carcinoma cells, SCC4, in vitro. Therefore, they support the initiation of clinical trials to test the radio-oncological value of such a treatment regime for squamous-cell carcinomas.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Survival; Chemotherapy, Adjuvant; Combined Modality Therapy; Culture Media; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Drug Combinations; Humans; Interferon-alpha; Isotretinoin; Mouth Neoplasms; Radiation-Sensitizing Agents; Radiotherapy Dosage; Time Factors; Tumor Cells, Cultured; Tumor Stem Cell Assay

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

Patients with xeroderma pigmentosum (XP) frequently develop sunlight-induced skin cancer. Infrequently, internal neoplasms may also occur. A 21-year-old patient with XP, who had many skin cancers, developed a rare internal tumour - a grade II diffuse fibrillary spinal cord astrocytoma - during a break in a therapeutic trial of isotretinoin for skin cancer prevention. Treatment of neoplasms in XP patients presents special difficulties because of their defect in DNA repair.. The study objective was to raise awareness of the cancer surveillance process in XP patients and the concerns involved in choice of therapy.. Since the spinal cord tumour was inoperable, the patient was treated with x-radiation, continued on isotretinoin treatment and was followed closely for tumour response.. Despite sensitivity to sunlight, the patient had a normal acute response to the x-ray treatment without excessive skin reaction. Serial examinations by magnetic resonance imaging (MRI) starting 8 months after x-ray treatment was initiated, showed a marked gadolinium enhancement followed by regression. This clearing was first seen at 2 years after biopsy and persisted to at least 9 years after treatment.. In contrast to the exaggerated sensitivity to UV radiation, XP patients may tolerate therapeutic doses of x-radiation. Isotretinoin treatment may have contributed to the good response of this spinal cord astrocytoma.

Topics: Adult; Astrocytoma; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Humans; Isotretinoin; Keratolytic Agents; Male; Skin Neoplasms; Spinal Cord Neoplasms; Xeroderma Pigmentosum

To evaluate prognostic importance of p53, PCNA and vascularization alteration in patients with locally advanced cervical squamous cell carcinoma (SCC) after combination therapy with 13-cis-retinoic acid (13cRA) and interferon-alpha 2a (IFN-alpha 2a).. 13cRA and IFN-alpha 2a were administered to patients with locally advanced cervical SCC. Formalin fixed, paraffin embedded tissues sections obtained at pre- and post-therapy, respectively, were stained immunohistochemically with anti-p53, anti-PCNA and anti CD31.. p53 alteration was demonstrated in 5/10 patients and 3/10 patients pre- and post-therapy, respectively. There was no correlation between p53 alteration and prognosis. After therapy, two patients with complete response had lower PCNA expression whereas the non-responders demonstrated the opposite result. The vascularization showed a correlation with PCNA and prognosis. In the response group, patients had lower microvessel count while the metastatic group exhibited higher count.. The present study suggests that p53 alteration is neither related to the prognosis of cervical SCC nor is it influenced by the combination therapy while PCNA expression and vascularization might be constitute potential markers for tumorigenesis, prognosis and responsiveness to this novel regimen.

Topics: Adult; Antineoplastic Agents; Carcinoma, Squamous Cell; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Middle Aged; Neovascularization, Pathologic; Prognosis; Proliferating Cell Nuclear Antigen; Recombinant Proteins; Tumor Suppressor Protein p53; Uterine Cervical Neoplasms

Retinoids are a group of vitamin A analogues that have shown promise as chemopreventive and therapeutic agents in many types of malignancy and have been entered in clinical trials with some successful results. To better understand the mechanism that mediates retinoid action and the anti-proliferative effects, we treated 7 human oral squamous-cell carcinoma (SCC) cell lines (FADU, HEp-2, CCL-17, SCC-9, SCC-15, SCC-25 and HN-212) with 10(-6) M of all-trans retinoic acid (ATRA), 9-cis and 13-cis retinoic acid (RA) in continuous for different periods of time. We assessed the extent of growth inhibition, the stability of the anti-proliferative effect and the mRNA expression levels (by RT-PCR) of RA receptors (RARs), retinoid X receptors alpha (RXR alpha) and cytosolic RA-binding proteins (CRBP I and CRABP II) in treated cells compared with controls. The data obtained showed that all 3 RAs were able to inhibit the cellular growth of the tested cell lines, although to a different extent. The cis compounds were able to inhibit the proliferation of all cell lines, whereas ATRA was ineffective in inhibiting the proliferation of the CCL-17 cell line, which was naturally resistant to ATRA concentrations in the range between 10(-5) and 10(-6) M. All inhibitory effects were completely reversible since all cell lines restored their normal growth proliferation within few days after drug removal. RT-PCR analysis of the receptor and cell binding protein status of control and treated cells showed a good correlation between growth inhibition and induction of, or increase in, the expression levels of RAR beta in RA-treated cells. No differences were observed in RAR alpha and RXR alpha mRNA expression levels between control and treated cells. CRBP I, CRABP II and RAR gamma mRNA levels increased in some treated cell lines but not in all.

Topics: Alitretinoin; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Cycle; Cell Division; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Growth Inhibitors; Humans; Isotretinoin; Mouth Neoplasms; Neoplasm Proteins; Polymerase Chain Reaction; Receptors, Retinoic Acid; Retinoid X Receptors; Retinol-Binding Proteins; Retinol-Binding Proteins, Cellular; Transcription Factors; Tretinoin; Tumor Cells, Cultured; Up-Regulation

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

Cyclooxygenase-2 expression is up-regulated in transformed cells and tumors. Because this enzyme catalyzes the synthesis of prostaglandins, strategies aimed at suppressing its expression may prove useful in preventing or treating cancer. We investigated the ability of retinoids to suppress phorbol ester-mediated induction of cyclooxygenase-2 in human oral epithelial cells. Treatment with phorbol myristate acetate (PMA) resulted in approximately a 3-fold increase in the production of prostaglandin E2 (PGE2). Retinoids [all-trans-retinoic acid (RA), 13-cis-RA, and retinyl acetate] markedly suppressed PMA-mediated increases in amounts of cyclooxygenase-2 (Cox-2) and the production of PGE2. Retinoids also suppressed the induction of Cox-2 mRNA by PMA. Nuclear run-offs revealed increased rates of Cox-2 transcription after treatment with PMA; this effect was inhibited by all-trans-RA. Transient transfection experiments showed that PMA caused about a 2-fold increase in Cox-2 promoter activity, an effect that was suppressed by all-trans-RA. Our data indicate that treatment of oral epithelial cells with PMA is associated with enhanced transcription of Cox-2 and increased production of PGE2. These effects of PMA were inhibited by retinoids.

Topics: Anticarcinogenic Agents; Biotransformation; Carcinoma, Squamous Cell; Cyclooxygenase 2; Dinoprostone; Diterpenes; Enzyme Induction; Gene Expression Regulation, Neoplastic; Humans; Isoenzymes; Isotretinoin; Membrane Proteins; Mouth Neoplasms; Neoplasm Proteins; Peroxidases; Prostaglandin-Endoperoxide Synthases; Retinyl Esters; Tetradecanoylphorbol Acetate; Transcription, Genetic; Tretinoin; Tumor Cells, Cultured; Vitamin A

The carotenoids beta-carotene and canthaxanthin and the retinoid 13-cis-retinoic acid (13-RA) have inhibited oral carcinogenesis in the hamster cheek pouch (16 wks, 3 times/wk at 1.4 mg/kg) induced by an 0.5% solution of 7, 12-dimethylbenz[a]anthracene (DMBA). However, 13-RA at a higher dose (> 2.0 mg/kg per treatment) increased squamous cell carcinoma growth (Eur J Cancer Clin Oncol 24, 839-850, 1988). 13-RA, beta-carotene, and canthaxanthin administered to 60 hamsters (16 wks, 3 times/wk, 10 mg/kg) altered neovascularization characterized by immunohistochemistry for transforming growth factor-alpha (TGF-alpha) and factor VIII. 13-RA + DMBA resulted in more smaller-sized tumors, with a reduced volume and tumor burden (tumor controls, 185.9; 13-RA + DMBA, 151.0). The carotenoids reduced the number and the sizes of the carcinomas formed (beta-carotene, 60 tumors, 142.3 x 10(3) mm3; canthaxanthin, 30 tumors, 116.1 x 10(3) mm3). Factor VIII and TGF-alpha were expressed in high intensity at cancer sites of the 13-RA + DMBA and DMBA groups with > 50 and > 10 cells, respectively, per x 400 field. In contrast, beta-carotene- and canthaxanthin + DMBA-treated pouches showed > 20 and 5 cells, respectively, per x 400 field for factor VIII and TGF-alpha. These results suggest that 13-RA treatment may increase vascular growth, but the carotenoids also produced enhanced levels of endothelial cell growth and TGF-alpha compared with the untreated mucosa. The carotenoids may enhance tumor growth under the appropriate carcinogenic environment.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; beta Carotene; Canthaxanthin; Carcinoma, Squamous Cell; Cheek; Cricetinae; Dose-Response Relationship, Drug; Factor VIII; Immunoenzyme Techniques; Isotretinoin; Male; Mesocricetus; Mouth Mucosa; Mouth Neoplasms; Neovascularization, Pathologic; Transforming Growth Factor alpha

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bowen's Disease; Carcinoma, Squamous Cell; Female; Humans; Interferon-alpha; Isotretinoin; Neoplasms, Multiple Primary; Skin Neoplasms

Topics: Anticarcinogenic Agents; Antineoplastic Agents; Blotting, Northern; Blotting, Western; Carcinogens; Carcinoma, Squamous Cell; Cyclooxygenase 2; Dinoprostone; Diterpenes; Gene Expression Regulation, Enzymologic; Humans; Isoenzymes; Isotretinoin; Membrane Proteins; Peroxidases; Phorbol Esters; Prostaglandin-Endoperoxide Synthases; Retinoids; Retinyl Esters; Tretinoin; Tumor Cells, Cultured; Vitamin A

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

Patients with metastasising carcinoma of the uterine cervix or recurrent disease, in whom local treatment as surgery or radiotherapy has failed, are still an unsolved problem. Platinum-based multi-agent chemotherapies achieve overall response rates up to 60%, but side effects are serious and so far no survival benefit has been proven. Recent publications report on a synergistic effect of combination therapy using 13-cis-retinoic acid and interferon alpha-2 a in the treatment of squamous cell carcinoma of the cervix. In a pilot study we include 6 patients with locally recurrent or metastasising squamous cell carcinomas, five of the uterine cervix, one of the vulva. The systemic therapy consisted of-orally administered 13-cis-retinoic acid (80 mg q. d.) and subcutaneously injected interferon alpha-2 a (6 x 10(6) I.E. q. d.). All patients were primarily treated by surgical and/or radiation therapy. In each case chemotherapy had been either already performed or rejected by the patient. Median duration of treatment was 52 days, median survival time 107 days. Out of 6 patients 3 experienced progression of disease uninfluenced by therapy. One patient with multiple subcutaneous lymph node metastases showed mixed response for a short period of 3 weeks before progression and eventual death. One patient had no change or disease for 13 months with subsequent progression and eventual death after 22 months. One patient could not be evaluated for an allergic reaction after only 15 days of treatment. Other side effects were "flu-like symptoms", skin irritations, conjunctivitis sicca and chileitis, all WHO 1-2. Overall toxicity must be rated low compared to standard chemotherapy, but is not negligible. In our study the positive reports in literature concerning the treatment of primary advanced cervical cancer and recurrent advanced carcinoma of the skin could not be reproduced. This might be due to the small number of cases, which is a common problem in immunotherapeutic studies. Moreover, very unfavourable patient selection criteria in our study compared to primarily untreated patients may also have contributed to different response rates. However, in our opinion the tested regimen cannot be considered sufficiently effective in patients suffering from pretreated, recurrent squamous cell carcinoma of the cervix or vulva.

Topics: Administration, Oral; Adult; Aged; Carcinoma, Squamous Cell; Combined Modality Therapy; Female; Humans; Injections, Subcutaneous; Interferon alpha-2; Interferon-alpha; Isotretinoin; Lymphatic Metastasis; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Pilot Projects; Recombinant Proteins; Survival Rate; Uterine Cervical Neoplasms; Vulvar Neoplasms

It is well known that patients with heritable cutaneous diseases may have excess tumors during their lifetime. This relationship has been shown for such diverse conditions as xeroderma pigmentosum, Bloom syndrome, basal cell nevus syndrome, and psoriasis. However, multiple cutaneous tumors have not been previously described in people with lamellar ichthyosis. This article describes the cases of two such patients, possible treatment, and a previously undescribed ichthyosis syndrome.

Topics: Adolescent; Adult; Biopsy; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Etretinate; Humans; Ichthyosis; Isotretinoin; Male; Neoplasms, Second Primary; Scalp; Skin Neoplasms

In contrast to squamous cell carcinoma of the penis, scrotal carcinoma has historically been associated with exposure to environmental or industrial carcinogens and has only rarely been correlated with human papillomavirus. We report on a patient with squamous cell carcinoma of the scrotum in which human papillomavirus type 16 was integrated into the tumor cell genome, suggesting a causal role of human papillomavirus in the development of squamous cell carcinoma of the scrotum. Other unique features of our case include the presence of Darier's disease, an uncommon genodermatosis, and treatment with oral retinoids, which have prophylactic value in the prevention of cutaneous malignancies.

Topics: Amino Acid Sequence; Carcinoma, Squamous Cell; Darier Disease; DNA, Viral; Genital Neoplasms, Male; Humans; Isotretinoin; Male; Middle Aged; Molecular Sequence Data; Papillomaviridae; Papillomavirus Infections; Scrotum; Tumor Virus Infections

The important therapeutic activity of 13-cRA and IFN-alpha-2a in carcinoma of squamous cells, cervical, without previous treatment, is confirmed. An unexpected result was the early toxicity of the biologic agents on the colon mucosa when they are combined with radiotherapy.

Topics: Adult; Aged; Brachytherapy; Carcinoma, Squamous Cell; Cesium Radioisotopes; Cobalt Radioisotopes; Colon; Combined Modality Therapy; Evaluation Studies as Topic; Female; Humans; Interferon alpha-2; Interferon-alpha; Intestinal Mucosa; Isotretinoin; Middle Aged; Radiotherapy; Radiotherapy Dosage; Recombinant Proteins; Uterine Cervical Neoplasms

The ability of the collagenase inhibitor minocycline and of beta-carotene to act as positive modulators of cytotoxic anticancer agents was assessed in vitro and in vivo. Cell-culture studies were conducted using the human SCC-25 squamous carcinoma cell line. Simultaneous exposure of the cells to minocycline and beta-carotene or 13-cis-retinoic acid along with cisplatin (CDDP) resulted in a small decrease in the cytotoxicity of the CDDP. The addition of each of the modulator combinations for 1 h or 24 h to treatment with melphalan (L-PAM) or carmustine (BCNU) resulted in greater-than-additive cytotoxicity with each of four regimens. The modulator combinations of minocycline and beta-carotene applied for 1 h or 24 h and the modulator combination of minocycline and 13-cis-retinoic acid produced greater-than-additive cytotoxicity at 50 microM 4-hydroperoxycyclophosphamide (4-HC), whereas minocycline and 13-cis-retinoic acid applied for 1 h was antagonistic with 4-HC and the other modulator treatments at low concentrations of 4-HC resulted in subadditive cytotoxicity. The effect of treatment with beta-carotene alone and in combination with several different anticancer agents was examined in two murine solid tumors, the FSaII fibrosarcoma and the SCC VII carcinoma. Administration of the modulators alone or in combination did not alter the growth of either tumor. Whereas increases in tumor growth delay occurred with the antitumor alkylating agents and beta-carotene and with minocycline and beta-carotene, a diminution in tumor growth delay was produced by 5-fluorouracil in the presence of these modulators. The modulator combination also resulted in increased tumor growth delay with adriamycin and etoposide. Tumor-cell survival assay showed increased killing of FSaII tumor cells with the modulator combination and melphalan or cyclophosphamide as compared with the drugs alone. These results indicate that further investigation of this modulator strategy is warranted.

Topics: Animals; Antineoplastic Agents; beta Carotene; Carcinoma, Squamous Cell; Carotenoids; Dose-Response Relationship, Drug; Drug Interactions; Fibrosarcoma; Humans; Isotretinoin; Male; Mice; Mice, Inbred C3H; Minocycline; Tumor Cells, Cultured

The effect of 13-cis-retinoic acid (cRA) and all-trans-retinoic acid (tRA) used alone or in combination with interferon alpha-2a (alpha-IFN 2a) was tested on three established human cell lines: KB (epidermoid carcinoma of the oral cavity), SCC-25 (tongue squamous cell carcinoma) and MCF-7 (mammary carcinoma). Both retinoids significantly decreased cell proliferation (growth curves) and colony forming efficiency (CFE) in all cell lines, in a dose-dependent way (at a concentration ranging from 10(-5) to 10(-9) M) and differing from line to line, following the pattern: MCF-7 > SCC-25 > KB. Retinoids at any concentration (already at 10(-7) M) combined with alpha-IFN 2a (ranging from 100 to 500 IU/ml) were more effective in inhibiting cell proliferation than each of the two compounds alone. This was particularly evident with SCC-25 cells. Concerning MCF-7 cells, on the contrary, the effects produced by the association suggested a possible additive more than synergistic amplification of growth inhibition.

Topics: Breast Neoplasms; Carcinoma, Squamous Cell; Cell Division; Drug Screening Assays, Antitumor; Drug Synergism; Humans; Interferon-alpha; Isotretinoin; Mouth Neoplasms; Tretinoin; Tumor Cells, Cultured

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

Retinoic acid has been advocated for use in several premalignant and malignant epithelial lesions of the head and neck, including benign recurrent respiratory papillomatosis, with varying results. We describe a 24-year-old man with extensive tracheoesophageal and bronchoalveolar papillomatosis that degenerated into squamous cell carcinoma. Multiple endoscopic carbon dioxide laser excisions, at one point performed on a weekly basis, as well as a prolonged trial of interferon, failed to control the progression of his disease. Isotretinoin (13-cis-retinoic acid) therapy (1 mg/kg per day) was instituted, with dramatic clinical, radiographic, and functional improvement. The patient experienced no significant toxic effects and required no endoscopic procedures over a 6-month period. We propose that isotretinoin may be an effective adjuvant therapy for aggressive respiratory papillomatosis.

Topics: Administration, Oral; Adult; Carcinoma, Squamous Cell; Humans; Isotretinoin; Male; Neoplasm Recurrence, Local; Neoplasms, Multiple Primary; Papilloma; Radiography; Respiratory Tract Neoplasms

Topics: Aged; Carcinoma, Squamous Cell; Drug Therapy, Combination; Facial Neoplasms; Humans; Interferon-alpha; Isotretinoin; Male; Remission Induction; Skin Neoplasms; Treatment Outcome

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

Xeroderma pigmentosum is a rare recessive disease with sun sensitivity, increased freckling and defective DNA repair. Xeroderma pigmentosum patients have more than a 1000-fold increased risk of developing skin cancer including basal cell carcinoma, squamous cell carcinoma and melanoma. We studied chemoprevention of new skin cancers with oral retinoids in xeroderma pigmentosum patients who had multiple skin cancers. Xeroderma pigmentosum patients were cleared of all pre-existing tumors surgically and then treated with high dose (2 mg/kg/day) oral isotretinoin (13-cis retinoic acid, Accutane) for two years and then for one year off treatment. Patients were examined at regular intervals for new tumor formation and for side effects. Five xeroderma pigmentosum patients had a total of 121 basal or squamous cell carcinomas in 2 years before treatment and only 25 tumors during 2 years of treatment. The tumor frequency increased 8.5-fold after the drug was discontinued (New Engl J Med 318: 1633-1637, 1988). Toxicity (cutaneous, triglyceride, liver-function or skeletal abnormalities) prompted subsequent use of a low dose protocol. Patients were treated initially with 0.5 mg/kg/day oral isotretinoin and the dose was increased sequentially to 1.0 or 1.5 mg/kg/day. We found that toxicity was less with the lower doses. The lowest effective, least toxic dose varied among the xeroderma pigmentosum patients.

Topics: Administration, Oral; Adolescent; Adult; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Child; Female; Humans; Isotretinoin; Male; Middle Aged; Skin Neoplasms; Xeroderma Pigmentosum

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

Topics: Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Combined Modality Therapy; Drug Evaluation; Humans; Interferon-alpha; Isotretinoin; Middle Aged; Skin Neoplasms

Topics: Adult; Aged; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cell Differentiation; Drug Evaluation; Female; Humans; Immunoenzyme Techniques; Isotretinoin; Keratins; Male; Micronucleus Tests; Middle Aged; Mouth Neoplasms; Protein Precursors; Transglutaminases

Controlled localized radiofrequency heating and systemic isotretinoin were used serially as therapy in a hairless dog that developed multiple cutaneous squamous cell carcinomas in chronically sun-damaged skin. During the course of therapy, four superficial tumors regressed completely, both clinically and histologically. Two larger, deeper tumors showed clinical signs of regression but histologic clearing did not occur. Both treatment modalities are known to have antitumor effects independently and may exert their effects in an additive fashion. However, it is also possible that heat-induced injury to tumor cells could lead to retinoid-mediated enhancement of an immunologic response to tumor antigens or some other process that might lead to regression.

Topics: Animals; Carcinoma, Squamous Cell; Combined Modality Therapy; Dog Diseases; Dogs; Hot Temperature; Isotretinoin; Male; Neoplasms, Multiple Primary; Radio Waves; Skin Neoplasms

Murine squamous carcinoma cells (KLN205) grown in a medium supplemented with the retinoid, 13-cis retinoic acid (RA), had dose-dependent, selective increases in the expression of certain lectin receptors, which correlated with a dramatic decrease in the ability to form pulmonary colonies (P = .0003) (Couch MJ, Pauli BU, Weinstein RS, Coon JS: JNCI, 78:971-977, 1987). These findings suggest a possible relationship between the RA-induced glycoconjugate alterations and the decreased experimental metastatic behavior. We further define the mechanism of RA's action. The finding that RA treatment (5 X 10(-6) M, 5 X 10(-7) M) did not perturb the cell cycle of KLN205 cells provides further proof that the decreased metastatic behavior is not attributable to any inhibition in the rate of growth or to alterations in the cell cycle. Furthermore, since stable subpopulations with variable lectin binding could not be detected, the mechanism of RA's action does not appear to be due to selection of variant tumor-cell subpopulations. Finally, in a series of experiments designed to determine the reversibility of the RA treatment, the RA-induced decrease in metastatic behavior reverted back to a more metastatic state in the same time frame (3 days) as the reversion of the RA-induced changes in cell-surface glycoconjugate expression. This reversion provides further evidence for a close relationship between the RA-induced modulation of tumor cell-surface glycoconjugate expression and the decreased metastatic behavior; it suggests that transient, reversible modulation of the tumor cell surface may play a role in determining metastatic behavior.

Topics: Animals; Carcinoma, Squamous Cell; Cell Cycle; Flow Cytometry; Glycoconjugates; Isotretinoin; Lectins; Lung Neoplasms; Male; Mice; Neoplasm Metastasis; Receptors, Mitogen; Tretinoin; Tumor Cells, Cultured

The effect of algae extract on tumor regression was studied. Phycotene (extract of Spirulina and Dunaliella algae) 250 micrograms in 0.1 ml MEM (minimum essential medium) was injected locally into DMBA (7, 12 dimethylbenz(a)anthracene)-induced squamous cell carcinomas of hamster buccal pouch in 20 animals. DMBA-induced carcinomas in 20 hamsters were injected locally with beta carotene 250 micrograms in 0.1 ml MEM; DMBA-induced carcinomas in 20 animals were injected locally with canthaxanthin, 250 micrograms in 0.1 ml MEM, and DMBA-induced carcinomas in 20 animals were injected locally with 13-cis-retinoic acid, 250 micrograms in 0.1 ml MEM. Twenty animals with DMBA-induced carcinomas were sham-injected controls using 0.1 ml MEM. The various agents were injected into the tumor bearing right buccal pouches twice-weekly for four weeks. Total tumor regression was found in 30% of phycotene animals, 20% of beta carotene animals and 15% of canthaxanthin animals after four weeks. Partial tumor regression was found in the remaining 70% of phycotene animals, 80% of beta carotene animals and 85% of canthaxanthin animals. None of the 13-cis-retinoic acid animals had total tumor regression, but 70% showed partial regression. No tumor regression was found in the DMBA control group and the sham-injected group.

Topics: Animals; Canthaxanthin; Carcinoma, Squamous Cell; Carotenoids; Chlorophyta; Cricetinae; Cyanobacteria; Isotretinoin; Male; Mesocricetus; Mouth Mucosa; Mouth Neoplasms; Neoplasms, Multiple Primary; Plant Extracts; Remission Induction; Tretinoin; Vitamin E

To determine the efficacy of oral isotretinoin in refractory advanced squamous cell carcinoma of the skin.. Case series trial.. Tertiary care center at a university hospital.. A consecutive collection of four patients with advanced squamous cell carcinoma of the skin who failed to respond to standard surgical or radiation therapy.. Isotretinoin in gelatin capsules was given at a total daily dose of 1 mg/kg body weight in two divided doses for at least 4 weeks.. Bidimensional tumor measurements at monthly intervals showed striking responses to isotretinoin in all four patients. Response durations ranged from 2 to more than 23 months. The drug produced reversible moderate mucocutaneous side effects and asymptomatic laboratory abnormalities.. Impressive responses to isotretinoin occurred in our four patients and in six of ten other reported patients. Retinoic acid's mechanisms of action in cutaneous squamous cell carcinoma is not precisely known, but may involve the modulation of epidermal growth factor receptors and certain protein kinases. These in-vitro findings and the clinical data suggest that retinoids may be an effective and well-tolerated therapy for refractory advanced squamous cell carcinoma of the skin. The absence of any other effective systemic therapy indicates the need for continuing trials with retinoids in this disease.

Topics: Aged; Carcinoma, Squamous Cell; Combined Modality Therapy; Humans; Isotretinoin; Male; Middle Aged; Neoplasm Recurrence, Local; Skin Neoplasms; Tretinoin

An 83-year-old woman with multiple squamous cell carcinomas and keratoacanthomas of the legs was treated with orally administered isotretinoin (13 cis-retinoic acid). Complete regression of the tumors was noted during the initial six-month treatment period. In the subsequent 36 months, four new cutaneous tumors were excised. There have been no recurrences of lesions that regressed while the patient was receiving retinoid therapy.

Topics: Administration, Oral; Aged; Carcinoma, Squamous Cell; Female; Humans; Isotretinoin; Keratoacanthoma; Leg; Skin Diseases; Skin Neoplasms; Tretinoin

We investigated the effect of the synthetic vitamin A derivative isotretinoin (13-cis-retinoic acid) on advanced cancers in 103 patients and on preneoplastic lesions in five patients. Six of 14 patients with squamous cell epithelial cancers had objective regressions of skin or subcutaneous metastases. Three of five patients with preneoplastic lesions had objective responses. The major dose-limiting toxic effects were reversible dermatitis, emotional lability, and headaches. We conclude that the growth of some squamous cell epithelial malignancies can be inhibited by isotretinoin and suggest that other retinoids should be evaluated as antitumor agents.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Drug Eruptions; Drug Evaluation; Emotions; Headache; Humans; Isotretinoin; Neoplasms; Precancerous Conditions; Tretinoin

In order to determine whether 13-cis-retinoic acid, an analog of vitamin A, has antitumor activity in an oral cancer model system, the following study was undertaken. Fifty-three adult hamsters were divided into four groups. Group 1 was tested with a 0.5 percent solution of 9,10-dimethyl-1,2-benzanthracene (DMBA) in heavy mineral oil, which was painted on the right buccal pouch three times per week for 12 weeks. Group 2 received DMBA plus 13-cis-retinoic acid (RA) incorporated into gelatinized beadlets and mixed with a powdered commercial diet (dosage, 300 mg per kilogram of diet). Group 3 received only RA; Group 4 received a placebo. The animals were killed at 6, 12, and 18 weeks and tissues were studied clinically and histologically in a routine manner. Results show that all groups receiving DMBA developed epidermoid carcinomas. However, there were several other changes. In the RA-treated animals, particularly those treated with DMBA, there was an ingrowth of surface epithelium with development of ductal structures in the buccal pouch. There were changes in surface epithelium, and there were dense aggregates of lymphoid tissue with development of exophytic nodules suggestive of lymphoma. Animals fed RA showed a relative weight loss. The findings suggest that there was a hypervitaminosis A state yielding prominent epithelial metaplastic changes but not affecting the progression or production of carcinoma.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Benz(a)Anthracenes; Carcinoma, Squamous Cell; Cheek; Cricetinae; Female; Isotretinoin; Male; Mesocricetus; Mouth Neoplasms; Neoplasms, Experimental; Tretinoin

Sixty-four male and female Syrian hamsters, 3 months of age and weighing 90 to 120 grams, were divided into four equal experimental groups. In animals of Groups 1 and 2 the right posterior lateral border of the tongue was painted three times weekly with a 0.5 percent solution of DMBA in acetone. Group 2 animals also received 10 mg. of 13-cis-retinoic acid in peanut oil administered orally twice weekly by pipette. Carcinogen and retinoid were administered on alternate days. Group 3 animals received only 13-cis-retinoic acid. Group 4 animals served as untreated controls. Four animals in each group were killed at 12, 14, 16, and 18 weeks. The Group 2 animals, receiving 13-cis-retinoic acid, exhibited a significant delay in the development of lingual tumors, both grossly and microscopically. At 14 weeks carcinomas were found in the DMBA animals, but only dysplasia and areas of carcinoma in situ were found in the DMBA-retinoid animals. After 18 weeks the DMBA animals exhibited large lingual tumors with surfacenecrosis, while the DMBA-retinoid animals presented smaller tumors with less invasion of underlying tissue.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinoma, Papillary; Carcinoma, Squamous Cell; Cricetinae; Female; Isotretinoin; Leukoplakia, Oral; Male; Mesocricetus; Neoplasms, Experimental; Tongue; Tongue Neoplasms; Tretinoin

Sixty-four male and female Syrian hamsters, 3 months of age and weighing 90 to 120 grams, were divided into four equal experimental groups. In animals of Groups 1 and 2 the left buccal pouch was painted three times weekly with a 0.5% solution of DMBA in heavy mineral oil. Group 2 animals also received 10 mg. of 13-cis-retinoic acid in peanut oil administered orally twice a week by pipette. Carcinogen retinoid were administered on alternate days. Group 3 animals served as controls, receiving only 13-cis-retinoic acid. Group 4 animals served as untreated controls. Four animals in each group (two males and two females) were killed at 10, 12, 14, and 16 weeks. The Group 2 animals, which received 13-cis-retinoic acid, exhibited a significant delay in DMBA carcinogenesis of buccal pouch mucosa, as studied both grossly and histologically. Both groups eventually demonstrated well-differentiated epidermoid carcinomas, but the tumors were smaller in the DMBA-retinoid animals.

Topics: Animals; Carcinoma, Papillary; Carcinoma, Squamous Cell; Cheek; Cricetinae; Female; Isotretinoin; Keratosis; Leukoplakia, Oral; Male; Mesocricetus; Mouth Mucosa; Mouth Neoplasms; Neoplasms, Experimental; Tretinoin