Selective intra-arterial infusion of rAd-p53 with chemotherapy for advanced oral cancer: a randomized clinical trial

BMC Medicine

Bo Han³  Yuan-Ding Huang¹  Chen-Yuan Liang¹  Ning Gao¹  Zhuang Zhang¹  Li-Juan Wang²  Long-Jiang Li³  Yi Li³ 

[1] State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China;West China Health Hospital, Sichuan University, Chengdu, PR China;Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China

关键词: p53;    Intra-arterial infusion;    Chemotherapy;    Gene therapy;    Oral carcinoma;   

Others  :  855040
DOI  :  10.1186/1741-7015-12-16

 received in 2013-06-13, accepted in 2014-01-08,  发布年份 2014

【 摘 要 】

Background

In this study, a combination of recombinant adenoviral p53 (rAd-p53) gene therapy and intra-arterial delivery of chemotherapeutic agents for treatment of oral squamous cell carcinoma was evaluated.

Methods

In total, 99 patients with stage III or IV oral carcinoma who had refused or were ineligible for surgery were enrolled in a randomized, placebo-controlled, double-blind, phase III clinical trial. They were randomly assigned to group I (n = 35; intra-arterial infusion of rAd-p53 plus chemotherapy), group II (n = 33; intra-arterial infusion of rAd-p53 plus placebo chemotherapy), or group III (n = 31; intra-arterial infusion of placebo rAd-p53 plus chemotherapy).

Results

The median length of follow-up was 36 months (range, 3 to 86 months). During follow-up, 16 patients in group I, 20 in group II, and 22 in group III died. Group I (48.5%) had a higher complete response rate than groups II (16.7%) and III (17.2%) (P = 0.006). The rate of non-responders in group I was significantly lower than that in groups II and III (P < 0.020). A log-rank test for survival rate indicated that group I had a significantly higher survival rate than group III (P = 0.019). The survival rate of patients with stage III but not stage IV oral cancer was significantly higher in group I than in group III (P = 0.015, P = 0.200, respectively). The survival rate of patients with stage IV did not differ significantly among the three groups. Or the 99 patients, 63 patients experienced adverse events of either transient flu-like symptoms or bone marrow suppression, while 13 patients had both these conditions together. No replication-deficient virus was detected in patient serum, urine, or sputum. rAd-p53 treatment increased Bax expression in the primary tumor of 80% of patients, as shown by immunohistochemical staining.

Conclusions

Intra-arterial infusion of combined rAd-p53 and chemotherapy significantly increased the survival rate of patients with stage III but not stage IV oral cancer, compared with intra-arterial chemotherapy. Intra-arterial infusion of combined rAd-p53 and chemotherapy may represent a promising alternative treatment for oral squamous cell carcinoma.

Trial registration

ChiCTR-TRC-09000392 (Date of registration: 2009-05-18).

【 授权许可】

   
2014 Li et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Bagnardi V, Blangiardo M, La Vecchia C, Corrao G: Alcohol consumption and the risk of cancer: a meta-analysis. Alcohol Res Health 2001, 25:263-270.
• [2]Lewin F, Norell SE, Johansson H, Gustavsson P, Wennerberg J, Biorklund A, Rutqvist LE: Smoking tobacco, oral snuff, and alcohol in the etiology of squamous cell carcinoma of the head and neck: a population-based case-referent study in Sweden. Cancer 1998, 82:1367-1375.
• [3]Fakhry C, Gillison ML: Clinical implications of human papillomavirus in head and neck cancers. J Clin Oncol 2006, 24:2606-2611.
• [4]National Comprehensive Cancer Network (NCCN), Clinical Practice Guidelines in Oncology: Head and Neck Cancers. Head and Neck Cancers. V.1; 2010. [In Book Clinical Practice Guidelines in Oncology] Available from http://www.nccn.org webcite. Accessed April 20, 2010
• [5]Brown AE, Langdon JD: Management of oral cancer. Ann R Coll Surg Engl 1995, 77:404-408.
• [6]Hyde NC, Prvulovich E, Newman L, Waddington WA, Visvikis D, Ell P: A new approach to pre-treatment assessment of the N0 neck in oral squamous cell carcinoma: the role of sentinel node biopsy and positron emission tomography. Oral Oncol 2003, 39:350-360.
• [7]Forastiere A, Koch W, Trotti A, Sidransky D: Head and neck cancer. N Engl J Med 2001, 345:1890-1900.
• [8]Lippman SM, Hong WK: Second malignant tumors in head and neck squamous cell carcinoma: the overshadowing threat for patients with early-stage disease. Int J Radiat Oncol Biol Phys 1989, 17:691-694.
• [9]Edelman J, Nemunaitis J: Adenoviral p53 gene therapy in squamous cell cancer of the head and neck region. Curr Opin Mol Ther 2003, 5:611-617.
• [10]Clayman GL, El-Naggar AK, Lippman SM, Henderson YC, Frederick M, Merritt JA, Zumstein LA, Timmons TM, Liu TJ, Ginsberg L, Roth JA, Hong WK, Bruso P, Goepfert H: Adenovirus-mediated p53 gene transfer in patients with advanced recurrent head and neck squamous cell carcinoma. J Clin Oncol 1998, 16:2221-2232.
• [11]Clayman GL, Frank DK, Bruso PA, Goepfert H: Adenovirus-mediated wild-type p53 gene transfer as a surgical adjuvant in advanced head and neck cancers. Clin cancer Res 1999, 5:1715-1722.
• [12]Nemunaitis J, Clayman G, Agarwala SS, Hrushesky W, Wells JR, Moore C, Hamm J, Yoo G, Baselga J, Murphy BA, Menander KA, Licato LL, Chada S, Gibbons RD, Olivier M, Hainaut P, Roth JA, Sobol RE, Goodwin WJ: Biomarkers predict p53 gene therapy efficacy in recurrent squamous cell carcinoma of the head and neck. Clin Cancer Res 2009, 15:7719-7725.
• [13]Ries JC, Schreiner D, Steininger H, Girod SC: p53 mutation and detection of p53 protein expression in oral leukoplakia and oral squamous cell carcinoma. Anticancer Res 1998, 18:2031-2036.
• [14]Sakai E, Tsuchida N: Most human squamous cell carcinomas in the oral cavity contain mutated p53 tumor-suppressor genes. Oncogene 1992, 7:927-933.
• [15]Li Y, Li LJ, Zhang ST, Wang LJ, Zhang Z, Gao N, Zhang YY, Chen QM: In vitro and clinical studies of gene therapy with recombinant human adenovirus-p53 injection for oral leukoplakia. Clin Cancer Res 2009, 15:6724-6731.
• [16]Johnstone RW, Ruefli AA, Lowe SW: Apoptosis: a link between cancer genetics and chemotherapy. Cell 2002, 108:153-164.
• [17]Liloglou T, Scholes AG, Spandidos DA, Vaughan ED, Jones AS, Field JK: p53 mutations in squamous cell carcinoma of the head and neck predominate in a subgroup of former and present smokers with a low frequency of genetic instability. Cancer Res 1997, 57:4070-4074.
• [18]Gao WM, Mady HH, Yu GY, Siegfried JM, Luketich JD, Melhem MF, Keohavong P: Comparison of p53 mutations between adenocarcinoma and squamous cell carcinoma of the lung: unique spectra involving G to A transitions and G to T transversions in both histologic types. Lung Cancer 2003, 40:141-150.
• [19]Tetu B, Brisson J, Plante V, Bernard P: p53 and c-erbB-2 as markers of resistance to adjuvant chemotherapy in breast cancer. Modern Pathol 1998, 11:823-830.
• [20]Brand K, Klocke R, Possling A, Paul D, Strauss M: Induction of apoptosis and G2/M arrest by infection with replication-deficient adenovirus at high multiplicity of infection. Gene Ther 1999, 6:1054-1063.
• [21]Spitz FR, Nguyen D, Skibber JM, Meyn RE, Cristiano RJ, Roth JA: Adenoviral-mediated wild-type p53 gene expression sensitizes colorectal cancer cells to ionizing radiation. Clin Cancer Res 1996, 2:1665-1671.
• [22]Swisher SG, Roth JA, Nemunaitis J, Lawrence DD, Kemp BL, Carrasco CH, Connors DG, El-Naggar AK, Fossella F, Glisson BS, et al.: Adenovirus-mediated p53 gene transfer in advanced non-small-cell lung cancer. J Natl Cancer Inst 1999, 91:763-771.
• [23]Parker LP, Wolf JK, Price JE: Adenoviral-mediated gene therapy with Ad5CMVp53 and Ad5CMVp21 in combination with standard therapies in human breast cancer cell lines. Ann Clin Lab Sci 2000, 30:395-405.
• [24]Modesitt SC, Ramirez P, Zu Z, Bodurka-Bevers D, Gershenson D, Wolf JK: In vitro and in vivo adenovirus-mediated p53 and p16 tumor suppressor therapy in ovarian cancer. Clin Cancer Res 2001, 7:1765-1772.
• [25]Lang FF, Bruner JM, Fuller GN, Aldape K, Prados MD, Chang S, Berger MS, McDermott MW, Kunwar SM, Junck LR, et al.: Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma: biological and clinical results. J Clin Oncol 2003, 21:2508-2518.
• [26]Schuler M, Herrmann R, De Greve JL, Stewart AK, Gatzemeier U, Stewart DJ, Laufman L, Gralla R, Kuball J, Buhl R, et al.: Adenovirus-mediated wild-type p53 gene transfer in patients receiving chemotherapy for advanced non-small-cell lung cancer: results of a multicenter phase II study. J Clin Oncol 2001, 19:1750-1758.
• [27]Buller RE, Runnebaum IB, Karlan BY, Horowitz JA, Shahin M, Buekers T, Petrauskas S, Kreienberg R, Slamon D, Pegram M: A phase I/II trial of rAd/p53 (Sch 58500) gene replacement in recurrent ovarian cancer. Cancer Gene Ther 2002, 9:553-566.
• [28]Moon C, Oh Y, Roth JA: Current status of gene therapy for lung cancer and head and neck cancer. Clin Cancer Res 2003, 9:5055-5067.
• [29]Weill D, Mack M, Roth J, Swisher S, Proksch S, Merritt J, Nemunaitis J: Adenoviral-mediated p53 gene transfer to non-small cell lung cancer through endobronchial injection. Chest 2000, 118:966-970.
• [30]Pagliaro LC, Keyhani A, Williams D, Woods D, Liu B, Perrotte P, Slaton JW, Merritt JA, Grossman HB, Dinney CP: Repeated intravesical instillations of an adenoviral vector in patients with locally advanced bladder cancer: a phase I study of p53 gene therapy. J Clin Oncol 2003, 21:2247-2253.
• [31]Han DM, Huang ZG, Zhang W, Yu ZK, Wang Q, Ni X, Chen XH, Pan JH, Wang H: Effectiveness of recombinant adenovirus p53 injection on laryngeal cancer: phase I clinical trial and follow up. Zhonghua Yi Xue Za Zhi 2003, 83:2029-2032.
• [32]Chen CB, Pan JJ, Xu LY: Recombinant adenovirus p53 agent injection combined with radiotherapy in treatment of nasopharyngeal carcinoma: a phase II clinical trial. Zhonghua Yi Xue Za Zhi 2003, 83:2033-2035.
• [33]Zhang SW, Xiao SW, Liu CQ, Sun Y, Su X, Li DM, Xu G, Cai Y, Zhu GY, Xu B, Lu YY: Treatment of head and neck squamous cell carcinoma by recombinant adenovirus-p53 combined with radiotherapy: a phase II clinical trial of 42 cases. Zhonghua Yi Xue Za Zhi 2003, 83:2023-2028.
• [34]Pan JJ, Zhang SW, Chen CB, Xiao SW, Sun Y, Liu CQ, Su X, Li DM, Xu G, Xu B, Lu YY: Effect of recombinant adenovirus-p53 combined with radiotherapy on long-term prognosis of advanced nasopharyngeal carcinoma. J Clin Oncol 2009, 27:799-804.
• [35]Alemany R: Cancer selective adenoviruses. Mol Aspects Med 2007, 28:42-58.
• [36]Reid T, Warren R, Kirn D: Intravascular adenoviral agents in cancer patients: lessons from clinical trials. Cancer Gene Ther 2002, 9:979-986.
• [37]Robbins KT, Homma A: Intra-arterial chemotherapy for head and neck cancer: experiences from three continents. Surg Oncol Clin N Am 2008, 17:919-933. xi
• [38]Fuwa N, Kodaira T, Furutani K, Tachibana H, Nakamura T: A new method of selective intra-arterial infusion therapy via the superficial temporal artery for head and neck cancer. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008, 105:783-789.
• [39]Wu CF, Huang CJ, Chang KP, Chen CM: Continuous intra-arterial infusion chemotherapy as a palliative treatment for oral squamous cell carcinoma in octogenarian or older patients. Oral Oncol 2010, 46:559-563.
• [40]Fuwa N, Kodaira T, Furutani K, Tachibana H, Nakamura T, Nakahara R, Tomoda T, Inokuchi H, Daimon T: Intra-arterial chemoradiotherapy for locally advanced oral cavity cancer: analysis of therapeutic results in 134 cases. Br J Cancer 2008, 98:1039-1045.
• [41]Kovacs AF: Intra-arterial induction high-dose chemotherapy with cisplatin for oral and oropharyngeal cancer: long-term results. Br J Cancer 2004, 90:1323-1328.
• [42]Peng Z: Current status of gendicine in China: recombinant human Ad-p53 agent for treatment of cancers. Hum Gene Ther 2005, 16:1016-1027.
• [43]Zhang SW, Xiao SW, Liu CQ, Sun Y, Su X, Li DM, Xu G, Zhu GY, Xu B: Recombinant adenovirus-p53 gene therapy combined with radiotherapy for head and neck squamous-cell carcinoma. Zhonghua Zhong Liu Za Zhi 2005, 27:426-428.
• [44]Peng Z: Points to Consider for Human Gene Therapy and Product Quality Control State Food and Drug Administration of China. http://www.biopharminternational.com/biopharm/article/articleDetail.jsp?id=95486 webcite
• [45]Gurnani M, Lipari P, Dell J, Shi B, Nielsen LL: Adenovirus-mediated p53 gene therapy has greater efficacy when combined with chemotherapy against human head and neck, ovarian, prostate, and breast cancer. Cancer Chemother Pharmacol 1999, 44:143-151.
• [46]Ohba S, Yokoyama J, Fujimaki M, Ito S, Kojima M, Shimoji K, Ikeda K: Significant improvement in superselective intra-arterial chemotherapy for oral cancer by using indocyanine green fluorescence. Oral Oncol 2012, 48:1101-1105.
• [47]Weinrib L, Li JH, Donovan J, Huang D, Liu FF: Cisplatin chemotherapy plus adenoviral p53 gene therapy in EBV-positive and -negative nasopharyngeal carcinoma. Cancer Gene Ther 2001, 8:352-360.
• [48]Zhang S, Li Y, Li L, Zhang Y, Gao N, Zhang Z, Zhao H: Phase I study of repeated intraepithelial delivery of adenoviral p53 in patients with dysplastic oral leukoplakia. J Oral Maxillofac Surg 2009, 67:1074-1082.