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Phase Ib Study of Chemoprevention with Green Tea Polyphenon E and Erlotinib in Patients with Advanced Premalignant Lesions (APL) of the Head and Neck.
Shin, DM, Nannapaneni, S, Patel, MR, Shi, Q, Liu, Y, Chen, Z, Chen, AY, El-Deiry, MW, Beitler, JJ, Steuer, CE, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2020;(22):5860-5868
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Abstract
PURPOSE On the basis of synergistic effects between green tea polyphenon E (PPE) and EGFR-tyrosine kinase inhibitor in preclinical studies, we conducted a phase Ib study of the PPE and erlotinib combination in patients with advanced premalignant lesions (APL) of the oral cavity and larynx. PATIENTS AND METHODS Patients were treated with a fixed dose of PPE (200 mg three times a day) and dose escalation of erlotinib (50, 75, 100 mg daily) for 6 months with tissue biopsy at baseline and 6 months. Primary endpoints were safety and toxicity; secondary endpoints were evaluation of pathologic response, cancer-free survival (CFS), overall survival (OS), and biomarker modulation. RESULTS Among 21 enrolled patients, 19 began treatment and 17 completed 6 months of treatment with PPE and erlotinib. Main characteristics of treated patients: 15 severe dysplasia or carcinoma in situ and 17 oral cavity. Only skin rash was associated with dose-limiting toxicity and MTD. Recommended doses for phase II studies are PPE 600 mg daily plus erlotinib 100 mg daily for 6 months. Pathologic responses in 17 evaluable patients: pathologic complete response (47%) and pathologic partial response (18%). The 5-year CFS and OS were 66.3% and 93%, respectively. Among tested biomarkers, only phosphorylated ERK was correlated with response to treatment. CONCLUSIONS Treatment with PPE and erlotinib combination was well tolerated in patients with APLs of the head and neck, and showed a high rate of pathologic response with excellent CFS. This combination deserves further investigation for the chemoprevention and/or prevention of second primary tumors in early-stage head and neck cancer.
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Soy Isoflavone Supplementation Increases Long Interspersed Nucleotide Element-1 (LINE-1) Methylation in Head and Neck Squamous Cell Carcinoma.
Rozek, LS, Virani, S, Bellile, EL, Taylor, JMG, Sartor, MA, Zarins, KR, Virani, A, Cote, C, Worden, FP, Mark, MEP, et al
Nutrition and cancer. 2019;(5):772-780
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AIM: Soy isoflavones have been suggested as epigenetic modulating agents with effects that could be important in carcinogenesis. Hypomethylation of LINE-1 has been associated with head and neck squamous cell carcinoma (HNSCC) development from oral premalignant lesions and with poor prognosis. To determine if neoadjuvant soy isoflavone supplementation could modulate LINE-1 methylation in HNSCC, we undertook a clinical trial. METHODS Thirty-nine patients received 2-3 weeks of soy isoflavone supplements (300 mg/day) orally prior to surgery. Methylation of LINE-1, and 6 other genes was measured by pyrosequencing in biopsy, resection, and whole blood (WB) specimens. Changes in methylation were tested using paired t tests and ANOVA. Median follow up was 45 months. RESULTS LINE-1 methylation increased significantly after soy isoflavone (P < 0.005). Amount of change correlated positively with days of isoflavone taken (P = 0.04). Similar changes were not seen in corresponding WB samples. No significant changes in tumor or blood methylation levels were seen in the other candidate genes. CONCLUSION This is the first demonstration of in vivo increases in tissue-specific global methylation associated with soy isoflavone intake in patients with HNSCC. Prior associations of LINE-1 hypomethylation with genetic instability, carcinogenesis, and prognosis suggest that soy isoflavones maybe potential chemopreventive agents in HNSCC.
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Clinical efficacy of targeted biologic agents as second-line therapy of advanced thyroid cancer.
Owonikoko, TK, Chowdry, RP, Chen, Z, Kim, S, Saba, NF, Shin, DM, Khuri, FR
The oncologist. 2013;(12):1262-9
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UNLABELLED Targeted biologic agents showed clinically meaningful efficacy as front-line therapy for advanced radioiodine-refractory and medullary thyroid cancer. The clinical benefit of these agents beyond the front line has yet to be established. METHODS We assessed the clinical benefit of targeted agents in patients with advanced differentiated and medullary thyroid cancer treated at a single academic cancer center. We determined efficacy and compared front-line and second-line benefit using biochemical and anatomic response, time to treatment failure, and progression-free survival (PFS). Statistical differences were assessed by t test and chi-square test. Survival curves were generated by the Kaplan-Meier method. Differences in survival were assessed using the log-rank test, and a p value <.05 was considered significant. RESULTS We identified 39 patients with advanced differentiated and medullary thyroid cancer treated with targeted biologic agents. Median age was 56.3 years. Overall, 25 men and 14 women participated. Histology showed 23% medullary and 77% differentiated cancer. Nineteen patients progressed on front-line therapy and subsequently received second-line therapy. Targeted agents conferred clinically meaningful benefit in the second-line setting in terms of biochemical response (13.3%), clinical benefit (83.3%), median time to treatment failure (4.0 months; 95% confidence interval: 2.6-8.2), and median PFS (4.6 months; 95% confidence interval: 3.2-8.2). Second-line benefit (median PFS) was more modest in comparison to the front-line setting in both genders (women: 3 months vs. 12.2 months; men: 6 months vs. 19.7 months), in differentiated cancers (4.1 months vs. 15.7 months), and with vascular targeting agents (4.4 months vs. 20.1 months). CONCLUSION Patients with advanced thyroid cancer derived meaningful clinical benefit from additional therapy with a biologic agent following disease progression on front-line targeted therapy.
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Randomized phase III trial of low-dose isotretinoin for prevention of second primary tumors in stage I and II head and neck cancer patients.
Khuri, FR, Lee, JJ, Lippman, SM, Kim, ES, Cooper, JS, Benner, SE, Winn, R, Pajak, TF, Williams, B, Shenouda, G, et al
Journal of the National Cancer Institute. 2006;(7):441-50
Abstract
BACKGROUND 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. METHODS 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. RESULTS 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%). CONCLUSIONS 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.
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Phase 2 bioadjuvant study of interferon alfa-2a, isotretinoin, and vitamin E in locally advanced squamous cell carcinoma of the head and neck: long-term follow-up.
Seixas-Silva, JA, Richards, T, Khuri, FR, Wieand, HS, Kim, E, Murphy, B, Francisco, M, Hong, WK, Shin, DM
Archives of otolaryngology--head & neck surgery. 2005;(4):304-7
Abstract
OBJECTIVE 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. DESIGN Phase 2 prospective study. SETTING Tertiary care academic medical centers. PATIENTS 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. RESULTS 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%). CONCLUSION 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.
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Cyclin D1 genotype, response to biochemoprevention, and progression rate to upper aerodigestive tract cancer.
Izzo, JG, Papadimitrakopoulou, VA, Liu, DD, den Hollander, PL, Babenko, IM, Keck, J, El-Naggar, AK, Shin, DM, Lee, JJ, Hong, WK, et al
Journal of the National Cancer Institute. 2003;(3):198-205
Abstract
BACKGROUND Altered cyclin D1 expression in advanced preinvasive lesions of the upper aerodigestive tract (UADT) is associated with an increased risk of developing cancer and histologic progression during and after combination biochemopreventive therapy (13-cis-retinoic acid, alpha-interferon, and alpha-tocopherol). Both alleles of the adenine (A)/guanine (G) cyclin D1 polymorphism located at nucleotide 870 encode two alternatively spliced transcripts, but the A allele preferentially encodes a protein with an extended half-life. We investigated whether the cyclin D1 genotype at nucleotide 870 was associated with baseline levels of cyclin D1 protein, post-treatment modulation of cyclin D1 protein levels, histologic response to treatment, and the outcome for subjects with preinvasive UADT lesions after biochemopreventive therapy. METHODS UADT tissue biopsy samples were obtained before and 6 and 12 months after biochemopreventive treatment from 31 individuals with advanced preinvasive UADT lesions. Tissues were examined for cyclin D1 genotype (by DNA single-strand conformation polymorphism analysis), for cyclin D1 protein expression (by immunohistochemistry), and for cyclin D1 gene copy number (by fluorescence in situ hybridization). Associations of cyclin D1 genotype with histologic response to therapy and time to progression to a higher degree of dysplasia or invasive cancer were investigated. All statistical tests were two-sided. RESULTS The A allele was associated with increased baseline cyclin D1 expression in the parabasal epithelial layer (16 of 18 AA/AG subjects versus four of nine GG subjects; P =.02), decreased histologic response to biochemopreventive treatment (six of 21 AA/AG subjects versus four of 10 GG subjects; P =.70), decreased favorable modulation of cyclin D1 expression by the treatment (seven of 18 AA/AG subjects versus eight of nine GG subjects; P =.02), and shorter progression-free survival (P =.05). CONCLUSIONS The cyclin D1 A allele was associated with a diminished modulation of normal physiologic and treatment-induced decreased expression of cyclin D1, a decreased likelihood of response to biochemopreventive intervention, and an increased rate of progression to cancer development, findings that require validation in a larger cohort.
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Phase II study of pemetrexed with and without folic acid and vitamin B12 as front-line therapy in malignant pleural mesothelioma.
Scagliotti, GV, Shin, DM, Kindler, HL, Vasconcelles, MJ, Keppler, U, Manegold, C, Burris, H, Gatzemeier, U, Blatter, J, Symanowski, JT, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2003;(8):1556-61
Abstract
PURPOSE This phase II clinical study evaluated the efficacy of pemetrexed for the treatment of malignant pleural mesothelioma (MPM). PATIENTS AND METHODS Patients with a histologically proven diagnosis of MPM, chemotherapy-naive measurable lesions, and adequate organ function received pemetrexed (500 mg/m2) intravenously over 10 minutes every 3 weeks. After a protocol change, most patients also received folic acid and vitamin B12 supplementation to improve safety. RESULTS A total of 64 patients were enrolled. Nine (14.1%) of the 64 patients had a partial response. The Kaplan-Meier estimate for median overall survival was 10.7 months. Forty-three patients received vitamin supplementation for all courses of therapy, and 21 patients did not. Seven of the nine responders were vitamin supplemented. The median overall survival was 13.0 months for supplemented patients and 8.0 months for nonsupplemented patients. Vitamin-supplemented patients completed more cycles of therapy than nonsupplemented patients (median, six v two cycles, respectively). Grade 3/4 neutropenia (23.4%) and grade 3/4 leukopenia (18.8%) were the most common laboratory toxicities. Fatigue and febrile neutropenia were the most commonly reported nonlaboratory events (grade 3, 6.3%; grade 4, 0.0% each). The incidence of these toxicities was generally lower in the supplemented patients. CONCLUSION Single-agent pemetrexed for MPM resulted in a moderate response rate (14.1%) and median overall survival of 10.7 months. Patients supplemented with folic acid and vitamin B12 tolerated treatment better (less toxicity and more cycles of treatment) and had a 5-month greater median overall survival than nonsupplemented patients. These results indicate that patients with MPM could benefit from single-agent pemetrexed treatment combined with vitamin supplementation.
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Biologic correlates of a biochemoprevention trial in advanced upper aerodigestive tract premalignant lesions.
Papadimitrakopoulou, VA, Liu, DD, Mao, L, Shin, DM, El-Naggar, A, Ibarguen, H, Lee, JJ, Hong, WK, Hittelman, WN
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2002;(12):1605-10
Abstract
OBJECTIVE To identify tissue biomarkers that might be used to assess an individual's cancer risk and response to chemoprevention, we studied in dysplastic lesions of the larynx and the p.o. cavity, a series of biomarkers extensively used in previous chemoprevention trials, including chromosome polysomy (CP), proliferative status, p53 expression and gene mutations, and loss of heterozygosity at 9p, 3p, and 17p. METHOD Biopsies from 32 participants in a prospective chemoprevention trial using 13-cis-retinoic acid, IFN-alpha, and alpha-tocopherol for 12 months (20 with vocal cord and 12 with p.o. cavity lesions) were analyzed for p53 and Ki-67 expression by immunohistochemistry, loss of heterozygosity by PCR amplification, p53 mutations by PCR-based direct sequencing, and CP by in situ hybridization. RESULTS High CP (> or =4% cells with more than three chromosome copies per nucleus) was more common in p.o. (8 of 10) than laryngeal lesions (4 of 16; P = 0.01), and so was a combination of CP > or = 4% and parabasal layer p53 labeling index > or = 0.2 (P = 0.02). Low CP was a significant predictor of complete histological response (8 of 14 cases with low versus 1 of 12 cases with high CP; P = 0.01). A trend for histological progression or cancer development was observed in cases with high CP and parabasal layer p53 labeling index. CONCLUSION Low CP, more frequently observed in laryngeal lesions, appears to be a predictor of response to chemoprevention and could be used as a screening tool to identify suitable candidates for such approaches. Further investigation of biological parameters of response and cancer risk is warranted.
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Phase II and biologic study of interferon alfa, retinoic acid, and cisplatin in advanced squamous skin cancer.
Shin, DM, Glisson, BS, Khuri, FR, Clifford, JL, Clayman, G, Benner, SE, Forastiere, AA, Ginsberg, L, Liu, D, Lee, JJ, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2002;(2):364-70
Abstract
PURPOSE 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 AND METHODS 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). RESULTS 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. CONCLUSION 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.
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The novel and effective nonplatinum, nontaxane combination of gemcitabine and vinorelbine in advanced nonsmall cell lung carcinoma: potential for decreased toxicity and combination with biological therapy.
Herbst, RS, Khuri, FR, Lu, C, Liu, DD, Fossella, FV, Glisson, BS, Pisters, KM, Shin, DM, Papadimitrakopoulou, VA, Kurie, JM, et al
Cancer. 2002;(2):340-53
Abstract
BACKGROUND Gemcitabine and vinorelbine are two of the most active third-generation agents for the treatment of advanced nonsmall cell lung carcinoma (NSCLC). The authors conducted a formal Phase II trial to evaluate the efficacy of this combination in both untreated and previously treated patients with Stage IIIB (with pleural effusion) or Stage IV NSCLC. METHODS A total of 78 patients were treated on the current Phase II trial of front-line or second/third-line therapy with gemcitabine and vinorelbine in NSCLC. Eligible patients manifested either untreated disease (n = 42) or had received at least one but not more than two prior chemotherapy regimens (n = 36). The median age was 57.5 years (range, 33-79) with 57 men (73%) and 21 women (27%). The median performance status was one (range, one to two). The initial eight patients (four untreated and four previously treated) were treated at a previously established maximum tolerated dose of vinorelbine (30 mg/m(2)) and gemcitabine (1000 mg/m(2)) on Days 1, 8, and 15, with significant myelosuppression seen in five out of eight patients requiring dose omission in the first cycle. The next 70 patients received a reduced dose of vinorelbine (25 mg/m(2)) followed by gemcitabine (900 mg/m(2)) on Days 1, 8, and 15. RESULTS Seventy eight patients were treated. Fifteen (36%) of the 42 evaluable patients who received front-line therapy had objective responses and 14 (33%) had stable disease. In the patients with prior treatment, 6 (17%) of 36 patients had partial response and 18 patients (50%) had stable disease. Median survival time for the previously untreated patient group was 10.1 months, with a one year survival of 43% and a two year survival rate of 32%. For the previously treated patients, the median survival time was 8.5 months, with a one year survival rate of 30%. Toxic effects were notable for significant myelosuppression, with > or =Grade 3 granulocytopenia seen in 55% of the patients on the untreated arm and 67% of the patients on the previously treated arm. Additionally, 9.5% and 13.9% (untreated and previously treated), respectively, of these patients experienced Grades 3 and 4 thrombocytopenia at some point in their treatment. A full dose delivery analysis showed that this myelosuppression resulted in Course 1, Day 15 skipped doses (even at the reduced dose level) in 42% of previously untreated patients and 47% of pretreated patients. Other side effects seen at Grades 3 and 4 in previously untreated and treated patients included anemia (9.5% and 2.8%), asthenia (4.8% and 5.5%), infection (14.3% and 5.6%), pain (9.5% and 19.4%), and pulmonary complications (4.8% and 13.8%). CONCLUSIONS Gemcitabine/vinorelbine is an active, well-tolerated combination in both front-line and second/third-line therapy for Stage IIIB/IV NSCLC. The response rate, median survival rate, and one year survival rate compare favorably with platinum-based regimens. The toxicity profile of the gemcitabine/vinorelbine combination was quite favorable, with minimal Grade 3 and 4 toxic effects aside from granulocytopenia, which resulted in numerous Day 15 skipped doses but no significant febrile neutropenia or infection. The combination of gemcitabine and vinorelbine could be a useful regimen in standard clinical practice and has the potential for efficient combination with biologic/targeted therapy. Multiple randomized trials of this combination versus platinum combinations are now ongoing [corrected].