To compare clinical curative effects and toxicity of recombinant human adenovirus-p53 injection (rAd-p53, Gendicine) combining chemoradiotherapy (CRT)/radiotherapy (RT) with those obtained with CRT/RT alone in nasopharyngeal carcinoma (NPC). We searched all the eligible studies from the Pubmed, Cochran Library, Embase, Web of science, Wanfang database and Chinese National Knowledge Infrastructure (CNKI). A total of twelve studies including 566 participants met the criteria to perform a meta-analysis. The results indicated the complete remission (CR) and overall response (OR) in the combination therapy group were significantly improved compared with the CRT/RT group (CR:RR = 2.03, 95% CI 1.66–2.48, p < 0.00001; OR:RR = 1.23, 95% CI 1.13–1.33, p < 0.00001), and patients who received the combination therapy showed significantly prolonged 1- and 2-year overall survival (OS), 2 year disease-free survival (DFS) rate and 2 year recurrence-free survival (RFS) rate (1 year OS:RR = 1.08, 95% CI 1.00–1.17, p = 0.04; 2 year OS:RR = 1.12, 95% CI 1.00–1.26, p = 0.04; 2 year DFS:RR = 1.41, 95% CI 1.09–1.83, p = 0.008; 2 year RFS:RR = 1.16, 95% CI 1.03–1.31, p = 0.02), but there was no significance in 3 year OS rate and 2 year distant metastases-free survival (DMFS) rate (3 year OS:RR = 1.28, 95% CI 1.00–1.62, p = 0.05; 2 year DMFS:RR = 1.05, 95% CI 0.89–1.24, p = 0.55). Furthermore, CRT/RT combined with rAd-p53 could not aggravate the myelosuppression versus CRT/RT alone (RR = 0.79, 95% CI 0.51–1.23, p = 0.30). The results demonstrated CRT/RT combined with rAd-p53 can result in enhanced survival and better clinical responses of patients with NPC. Therefore, rAd-p53 has great potential as an effective therapy for NPC.
Keywords
Nasopharyngeal carcinomaRecombinant human adenovirus-p53ChemoradiotherapyRadiotherapyMeta-analysis
Background
Nasopharyngeal carcinoma (NPC), arising from the nasopharynx epithelium, is a kind of head and neck cancers (Chua et al. 2015). Worldwide, 86,500 cases were diagnosed with NPC in 2012, and the most of new cases were in China, Southeast Asia and other Asian countries. In recent years, Concurrent chemoradiotherapy (CRT) is being used in the treatment of NPC, gradually becoming the predominant method for the treatment of advanced NPC. However, the 5 year survival rate is only 40–50%.
As we know, the p53 tumor suppressor gene mutations or deletions are associated with malignant transformation and tumor progression (Lo et al. 2004; Golubovskaya et al. 2009; Olivier et al. 2002). The wildtype p53-induced phosphatase 1 (Wip1) protein was increased in advanced NPC, which may involve in the processes of proliferation, apoptosis, migration and invasion (Sun et al. 2015). Recombinant human adenovirus-p53 injection (rAd-p53, Gendicine) has been used for the clinical treatment of NPC. Despite the potential advantages of rAd-p53 for NPC, it is still not clear whether CRT/RT combined with rAd-p53 might be better than CRT/RT alone. Here, we performed a meta-analysis on twelve published clinical randomized controlled trials (RCTs) to derive a more precise evaluation of the effect of rAd-p53 in the treatment NPC.
Methods
Search strategy
A systematic literature search was performed though Pubmed, Cochran Library, Embase, Web of science, Wanfang database, Chinese National Knowledge Infrastructure (CNKI), covering all articles published up to October 2015. The search terms included “Recombinant human adenovirus-p53”, “rAd-p53”, “Gendicine”, “nasopharyngeal carcinoma” and “nasopharyngeal neoplasms”. The language was English or Chinese. When overlapping articles were found, we only included the publications that reported the most extensive information.
Selection criteria
This meta-analysis aimed to evaluate the impact of combination therapy on patient survival, clinical responses and safety. So the selection criteria for this study were as follows: Firstly, trials were eligible for the present meta-analysis if they were randomized controlled trials (RCTs) of patients with NPC. Secondly, the patients in the experimental group received CRT/RT combined with rAd-p53, whereas patients in the control group were treated using CRT/RT alone. Thirdly, the endpoints were patient survival, clinical responses and safety.
Data extraction and quality assessment
The extraction of data was operated independently by two investigators (Cheng Yuan and Zhuo Chen). Disagreements were resolved through discussion with a third investigator (Xin-hua Xu). Then the following relevant information was extracted from the selected studies: the first author’s surname, year of publication, number of patients, tumor stages, CRT/RT regimens and dose of RAd-p53.
The quality was evaluated by the Jadad composite scale (Jadad et al. 1996). This scale included the method of randomization (0–2 points), double blinding (0–2 points), and the description of dropouts (0–1 point).
Curative effect evaluation
Survival outcomes were assessed in terms of the overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS) and distant metastases-free survival (DMFS) to evaluate prognosis, and treatment efficacy was assessed in terms of the overall response (OR) and complete response (CR). Toxicity event was assessed in terms of myelosuppression.
Statistical analysis
Results were reported as pooled as relative risk (RR) and their 95% confidence interval (CI). Firstly, heterogeneity was identified. If the heterogeneity was not significant (p > 0.1, I2 < 50.0%), then the fixed-effect model can be performed, otherwise, the random effects model. Results of this meta-analysis were presented by forest plots, and the p value less than 0.05 was considered significant. Publication bias was evaluated though funnel plots. All analyses were performed by Review Manager (version 5.3, the Cochrane collaboration), using two side p values.
Results
Search results and characteristics of studies
Our search strategy identified 115 potentially relevant studies, and a total of twelve literatures were adopted in the end. The characteristics of the twelve studies (Zhang et al. 2006, 2007, 2011; Pan et al. 2009; Lan et al. 2011, 2012; Qin et al. 2012; Wang et al. 2010, 2012; Li 2012; Si et al. 2009; Chen et al. 2003) were summarized in Table 1. A total of 566 patients were included in the meta-analysis, of whom 298 received CRT/RT combined with rAd-p53 and 268 were treated with CRT/RT alone.
RAd-p53 recombinant human adenovirus-p53 injection; RT radiotherapy; CT chemotherapy
Recent efficacy assessments
Recent efficacy was assessed in terms of CR and OR. Twelve studies compared CR, of which 298 patients were treated with CRT/RT combined with rAd-p53 and 268 patients were treated with CRT/RT alone, and ten trials including 464 patients compared OR. As shown in Figs. 1, 2, the analysis results indicated that the CR and OR in the combination therapy group were significantly improved compared with the CRT/RT group (CR:RR = 2.03, 95% CI 1.66–2.48, p < 0.00001; OR:RR = 1.23, 95% CI 1.13–1.33, p < 0.00001).
Fig. 1
Forest plot for the meta-analysis of complete remission (CR) rate of primary tumor
Fig. 2
Forest plot for the meta-analysis of overall response (OR) rates of primary tumor
Survival outcome
There were four eligible studies that reported the endpoints of 1- and 2-year OS rate. CRT/RT combined with rAd-p53 showed significantly increased 1- and 2-year OS rates compared with the rates observed when CRT/RT alone was used (1-year OS:RR = 1.08, 95% CI 1.00–1.17, p = 0.04, Fig. 3a and 2-year OS:RR = 1.12, 95% CI 1.00–1.26, p = 0.04, Fig. 3b). In addition, two studies compared 3 year OS, and the result of meta-analysis showed there was no significance in the outcome of 3-year OS versus control (RR = 1.28, 95% CI 1.00–1.62, p = 0.05; Fig. 3c).
Fig. 3
Forest plot for the meta-analysis of the 1-, 2- and 3-year overall survival (OS) rate
As shown in Fig. 4, patients who received the combination therapy showed significantly prolonged 2 year DFS rate and 2 year RFS rate compared with patients who received CRT/RT alone, but there was no significance in 2 year DMFS rate (2 year DFS:RR = 1.41, 95% CI 1.09–1.83, p = 0.008, Fig. 4a; 2-year RFS:RR = 1.16, 95% CI 1.03–1.31, p = 0.02, Fig. 4b; 2-year DMFS:RR = 1.05, 95% CI 0.89–1.24, p = 0.55, Fig. 4c).
Fig. 4
Forest plot for the meta-analysis of the 2 year disease-free survival (DFS) rate, recurrence-free survival (RFS) rate and distant metastases-free survival (DMFS) rate
Toxicity
Data available regarding the toxicities were limited. The reporting and occurrence of adverse events was rare. The most common side effect was fever which was reported, but it was not compared between the combination therapy group and CRT/RT group. Only 2 of the 12 trials reported the occurrence of myelosuppression. The result indicated CRT/RT combined with rAd-p53 could not aggravate the myelosuppression compared with CRT/RT alone (RR = 0.79, 95% CI 0.51–1.23, p = 0.30; Fig. 5).
Fig. 5
Forest plot for the meta-analysis of the occurrence of myelosuppression
Heterogeneity and publication bias
There was no evidence of heterogeneity in all the recent efficacy, survival outcomes and toxicity in the Chi square and I-square tests, and a fixed effect model was used. Funnel plot was performed to assess the publication bias in all the included studies for evaluation of the CR. Since no more than 10 studies were included in the OR, survival outcomes and toxicity, funnel plot was not performed. As shown in Fig. 6, the funnel plot did not reveal any evidence of significant asymmetry in CR.
Fig. 6
The funnel plot of publication bias
Discussion
To our knowledge, this is the first meta-analysis to explore the curative efficacy of rAd-p53 in the treatment of NPC. During the past decades, despite progress in technique evolution of RT, the long-term survival rate of NPC did not receive fundamental improvement, so that developing new effective therapeutic modality are urgent need (Mitchell et al. 2010). In 2003, a gene therapy product (non-replicating adenovirus) received approval for the treatment of head and neck cancer, and then a replication-selective adenovirus was used to treat NPC (Hughes et al. 2012). Nevertheless, it is very necessary to have a systematic comparison for the curative effects and toxicity between CRT/RT combined with rAd-p53 and CRT/RT alone.
In our study, our meta-analysis including data from twelve published studies with 566 patients indicated that CR and OR in the combination therapy group were significantly improved compared with the CRT/RT group. Combination therapy showed significantly prolonged 1- and 2-year OS rate, 2 year DFS rate and 2 year RFS rate. While, there was no significance in 3 year OS rate and 2 year DMFS rate. In addition, CRT/RT combined with rAd-p53 could not aggravate the myelosuppression versus CRT/RT alone.
For this reason that adeno-associated virus (AAV) cannot replicate on its own, recombinant adeno-associated viruses (rAAV) garnered much attention in the field of gene therapy to the cancer, which can overcome transduction barriers at the level of receptor binding, subcellular trafficking, and transgene expression (Mitchell et al. 2010; Nicolson and Samulski 2014). The wild-type p53 gene (wt-p53) influences cell survival and the response to radiation-induced DNA damage. The studies (Hirao et al. 2000; Ma et al. 2012) found activated p53 transcription promotes can lead to cell cycle arrest, DNA repair, tumor cell apoptosis, and even killing effect on tumor cells. A previous study (Kandioler et al. 2002) suggested that patients were less sensitive to RT if the function of wt-p53 lost, and RT combined with rAd-p53 may increase the sensitivity in vivo and in vitro studies (Shiomitsu et al. 2008; Gudkov and Komarova 2003; Cuddihy and Bristow 2004). RAd-p53 can carry the recombinant human p53 gene and then introduce the p53 gene into tumor cells to express wt-p53 protein, inhibiting cell division and inducing tumor cell apoptosis (Pan et al. 2009).
However, the limitations of the study cannot be ignored. Firstly, the twelve trials included in the meta-analysis were mainly concentrated in the Chinese population, and this may be related to the high incidence of NPC in China. Secondly, there was limited information regarding some patients, and the total sample sizes were small. Thirdly, literatures were searched by English and Chinese, which may lead to potential publication bias, although publication bias was not significant in the study.
In conclusion, our results demonstrated that CRT/RT combined with rAd-p53 therapy can result in enhanced survival and better clinical responses of patients with NPC. Therefore, rAd-p53 has great potential as an effective therapy for NPC.
Abbreviations
CRT:
chemoradiotherapy
RT:
radiotherapy
rAd-p53:
recombinant human adenovirus-p53
NPC:
nasopharyngeal carcinoma
RR:
relative risk
CI:
confidence interval
CR:
complete remission
OR:
overall response
OS:
overall survival
Wip1:
wildtype p53-induced phosphatase 1
RCT:
randomized controlled trial
DFS:
disease-free survival
RFS:
recurrence-free survival
DMFS:
distant metastases-free survival
Declarations
Authors’ contributions
CY and XHX conceived and designed the study. CY reviewed and edited the manuscript. CY and ZC performed the experiments. All authors read and approved the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Authors’ Affiliations
(1)
The First College of Clinical Medical Science, China Three Gorges University & Yichang Central People’s Hospital
(2)
Department of Oncology, China Three Gorges University & Yichang Central People’s Hospital
References
Chen CB, Pan JJ, Xu LY (2003) Recombinant adenovirus p53 agent injection combined with radiotherapy in treatment of nasopharyngeal carcinoma: a phase II clinical trial. Zhonghua Yi Xue Za Zhi 83:2033–2035PubMedGoogle Scholar
Cuddihy AR, Bristow RG (2004) The p53 protein family and radiation sensitivity: yes or no? Cancer Metastasis Rev 23:237–257View ArticlePubMedGoogle Scholar
Golubovskaya VM, Conway-Dorsey K, Edmiston SN, Tse CK, Lark AA, Livasy CA, Moore D, Millikan RC, Cance WG (2009) FAK overexpression and p53 mutations are highly correlated in human breast cancer. Int J Cancer 125:1735–1738View ArticlePubMedPubMed CentralGoogle Scholar
Gudkov AV, Komarova EA (2003) The role of p53 in determining sensitivity to radiotherapy. Nat Rev Cancer 3:117–129View ArticlePubMedGoogle Scholar
Hirao A, Kong YY, Matsuoka S, Wakeham A, Ruland J, Yoshida H, Liu D, Elledge SJ, Mak TW (2000) DNA damage-induced activation of p53 by the checkpoint kinase Chk2. Science (New York, NY) 287:1824–1827ADSView ArticleGoogle Scholar
Hughes J, Alusi G, Wang Y (2012) Gene therapy and nasopharyngeal carcinoma. Rhinology 50:115–121PubMedGoogle Scholar
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17:1–12View ArticlePubMedGoogle Scholar
Kandioler D, Zwrtek R, Ludwig C, Janschek E, Ploner M, Hofbauer F, Kührer I, Kappel S, Wrba F, Horvath M, Karner J, Renner K, Bergmann M, Karner-Hanusch J, Pötter R, Jakesz R, Teleky B, Herbst F (2002) TP53 genotype but not p53 immunohistochemical result predicts response to preoperative short-term radiotherapy in rectal cancer. Ann Surg 235:493–498View ArticlePubMedPubMed CentralGoogle Scholar
Lan G, Su J, Si Y, He C, Huang B, Zhang Z (2011) Clinical effect of rAd-p53 combined with radiotherapy and chemotherapy on treatment of advanced nasopharyngeal carcinoma. J Pract Med 27:2341–2344Google Scholar
Lan G, Si Y, Qin Y, Deng Z, He C, Huang B (2012) Recombinant adenoviral human p53 gene combined with radio- and chemotherapy in treatment of advanced nasopharyngeal carcinoma: a randomized clinical study. J Clin Oncol 30(15 suppl 1):5558Google Scholar
Li HT (2012) Effect of recombinant human P53 adenovirus injection combined with radiotherapy and chemotherapy in treatment of advanced nasopharyngeal carcinoma. J Med Theor Prac 25:1083–1084Google Scholar
Ma JT, Han CB, Zhao JZ, Jing W, Zhou Y, Huang LT, Zou HW (2012) Synergistic cytotoxic effects of recombinant human adenovirus p53 and radiation at various time points in A549 lung adenocarcinoma cells. Oncol Lett 4:529–533PubMedPubMed CentralGoogle Scholar
Nicolson SC, Samulski RJ (2014) Recombinant adeno-associated virus utilizes host cell nuclear import machinery to enter the nucleus. J Virol 88:4132–4144View ArticlePubMedPubMed CentralGoogle Scholar
Olivier M, Eeles R, Hollstein M, Khan MA, Harris CC, Hainaut P (2002) The IARC TP53 database: new online mutation analysis and recommendations to users. Hum Mutat 19:607–614View ArticlePubMedGoogle Scholar
Pan JJ, Zhang SW, Chen CB, Xiao SW, Sun Y, Liu CQ, Su X, Li DM, Xu G, Xu B, Lu YY (2009) Effect of recombinant adenovirus-p53 combined with radiotherapy on long-term prognosis of advanced nasopharyngeal carcinoma. J Clin Oncol 27:799–804View ArticlePubMedGoogle Scholar
Qin Y, Weng J, Lan G, Wei H, Huang B, Sun J, Si Y (2012) Effect of p53 gene therapy on the local immunity and the efficacy of patients with nasopharyngeal carcinoma. J Chin Otorhinolaryngol Head Neck Surg (China) 26:980–983Google Scholar
Shiomitsu K, Sajo E, Xia X, Hunley DW, Mauldin GE, Li S, Mauldin GN (2008) Radiosensitivity of canine osteosarcoma cells transfected with wild-type p53 in vitro. Vet Comp Oncol 6:193–200View ArticlePubMedGoogle Scholar
Si YF, He CC, Lan GP, Huang B, Zhang Z, Lu JL, Zhou RJ, Jiang H (2009) Recombinant adenovirus p53 agent injection combined with radiotherapy and chemotherapy for intermediate and advanced stage nasopharyngeal carcinoma. Chin J Clin Oncol 36:1031–1039Google Scholar
Sun GG, Zhang J, Ma XB, Wang YD, Cheng YJ, Hu WN (2015) Overexpression of wild-type p53-induced phosphatase 1 confers poor prognosis of patients with nasopharyngeal carcinoma. Pathol Oncol Res 21:283–291View ArticlePubMedGoogle Scholar
Wang JC, Wang F, Kong LL, Wu NM, Zhang KL, Zhang L (2010) Recombinant adenovirus p53 combince with radiotherapy in treat ment of nasopharyngeal carcinoma. Acta Universitatis Medicinalis Anhui 45:235–237Google Scholar
Wang XH, Wang JG, Zhang J, Hu WN, Zhang RJ (2012) Clinical observations of recombinant adenovirus-p53 combined with radiotherapy on nasopharyngeal squamous carcinoma. Mod J Int Tradit Chin West Med 21:924–925, 934Google Scholar
Zhang S, Xiao S, Sun Y, Liu C, Su X, Li D, Xu G, Zhu G, Xu B (2006). Clinical trial of recombinant adenovirus-p53 (Gendicine) combined with radiotherapy in nasopharyngeal carcinoma patients. Mol Therapy 13: 280Google Scholar
Zhang SW, Xiao SW, Sun Y, Liu CQ, Su X, Li DM, Xu G, Xu B (2007) Long-Term outcomes of combination of recombinant adenovirus-p53 (Gendicine) with radiotherapy in nasopharyngeal carcinoma. Hum Gene Ther 18:955–993View ArticleGoogle Scholar
Zhang LZ, Zu MZ, Tang TT, Wang JW, Xin YX, Liu GL, Zheng JZ (2011) A phase II study of recombinant adeno-viral human p53 gene combined with radiotherapy and radio- and chemo-therapy in treatment of patients with advanced nasopharyngeal carcinoma. Hum Gene Ther 22:A125View ArticleGoogle Scholar
