Cervical cancer is the fourth most common malignancy in women worldwide and represents a major global health challenge. The Global Cancer Observatory reported approximately 570,000 cases of cervical cancer and 311,000 deaths from the disease in 2018, with approximately 290,000 (51%) of new cases worldwide occurring in women living in low- and middle-income countries (500,000 [88%], including upper-middle-income countries) (1–3).

Radical hysterectomy with pelvic lymphadenectomy remains the standard recommendation for patients with early-stage cervical cancer. The standard treatment for locally advanced cervical cancer is definitive chemoradiotherapy with pelvic radiotherapy (RT) and concurrent cisplatin-based chemotherapy (CT) (4, 5). However, many patients present at an advanced stage owing to the low cervical cancer screening rate (6). While concurrent chemoradiotherapy (CRT) is the standard treatment mode recommended by the National Comprehensive Cancer Network (NCCN) guidelines, 29%–38% of the failure modes are uncontrolled or recurrent disease, with a 5-year survival rate of relapsed patients of only 3.8%–13% (7). Chemotherapy and RT resistance are the major causes of cervical cancer recurrence and mortality (8, 9). Therefore, improving the sensitivity of RT and chemotherapy before treatment is particularly important to guide follow-up treatment (10).

The tumor suppressor gene p53 is widely regarded as the gene guardian of cells and plays a key role in cell cycle control, apoptosis, and the inhibition of tumor cell proliferation. The p53 gene is one of the most frequently mutated genes in human cancers, with over 50% of all cancers harboring p53 mutations (11). Inactivation of p53 function often correlates with increased malignancy, poor patient survival, and resistance to chemotherapy or RT (12–14). Accumulating evidence has demonstrated that the restoration of p53 activity can induce cell cycle arrest and apoptosis, eliminate RT and chemotherapy resistance, and inhibit tumor growth in cervical cancer cells (15). As such, the reactivation of the p53 protein has become an attractive approach for the effective treatment of cervical cancer (16). Recombinant human adenovirus p53 (rAd-p53) can transfer the p53 gene into tumor cells through recombinant human adenovirus-p53, rebuild p53 gene function in tumor cells, and cause tumor cells to undergo programmed death or develop a severe hibernation state, thereby increasing the sensitivity of tumor cells to RT and chemotherapy (17).

This meta-analysis aimed to systematically evaluate the efficacy and safety of rAd-p53 combined with CT/RT/CRT in the treatment of cervical cancer and to provide evidence-based medical data for the treatment of cervical cancer.

This systematic review and meta-analysis was based on a pre-planned protocol constructed according to the standard Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and was prospectively registered on inplasy.com (INPLASY protocol 202150058. doi: 10.37766/inplasy2021.5.0058).

RAd-p53 was approved by the State Food and Drug Administration (SFDA) of China in 2004 as a gene therapy medicinal product for tumors. RAd−p53 is a replication-defective living adenovirus carrying the p53 gene. An advantage of the adenovirus delivery system is that it does not result in the integration of the vector DNA into the host cells (32). Once cells have been infected, virus particles cannot replicate but can import the p53 gene, which exerts biological functions. This method has the advantages of high infection efficiency, no genetic toxicity to the human body, and safe clinical application. The basic mechanisms of rhAd−p53 reagents are as follows: (i) the inhibition of tumor growth by cell cycle arrest and induced programmed cell death; (ii) enhancement of chemotherapy−induced cell cycle arrest and apoptosis; (iii) stimulation of the body to produce an anti−tumor immune such that a large number of immune cells gather at the local injection site of tumors; (iv) inhibition of tumor vascular endothelial growth factor (VEGF) to suppress angiogenesis and tumor growth through the “bystander effect”; thus, the injection site of the local tumor tissue will block blood supply and induce tumor necrosis (33).

RAd-p53 is currently used as a treatment for various cancers and has shown remarkable clinical efficacy in head and neck (34), lung (35), liver (36), colorectal (37), and ovarian (38) cancers. Meta-analysis studies have evaluated the safety and efficacy of rAd-p53 for the treatment of nasopharyngeal cancer (39) and malignant pleural effusion (40). To our knowledge, this is the first meta-analysis to systematically assess the effects and safety of rAd-p53 in the treatment of cervical cancer.

This systematic review included 14 studies involving 737 patients. The results of the meta-analysis showed that CR, PR, and ORR in the rAd-p53 combined therapy group were significantly improved compared with the CT/RT/CRT alone group. Similar results were observed in the subgroup analysis. Two of our included 14 studies investigated the long-term survival of rAd-p53 treating cervical cancer. Zhang Dan et al. used the Kaplan–Meier method to estimate the progression‐free survival (PFS) of patients administered rAd-p53 combined with chemotherapy. They reported that the PFS of the experimental group (6.38 ± 0.14) was higher than that of the control group (4.48 ± 0.14). Su et al. showed that the 5-year overall survival rate (OS) for rAd-p53 combined with radiotherapy was 17.5% higher than that for RT alone (hazard ratio [HR] = 0.551, 95% CI: 0.278–1.095, p = 0.084); the 5-year PFS for rAd-p53 combined with radiotherapy was 17.1% higher than that for RT alone (HR = 0.485,95% CI: 0.234–1.006, p = 0.0470). DNA aneuploidy is thought to reflect the biological behavior of malignancy, in which the higher the DNA aneuploidy of tumor tissue, the higher the degree of malignancy and the worse the prognosis (41). Two of the 14 included articles reported differences in DNA ploidy index before and after rAd-p53 combined with RT for cervical cancer. The results showed no significant difference in DNA aneuploidy between the two groups before treatment. After treatment, the positivity rate of DNA aneuploidy in the rAd-p53 combined group was lower than that in the RT group. The intratumoral injection of rhAd-p53 inhibited VEGF expression and angiogenesis and promoted tumor necrosis and shrinkage in advanced cancer (42). One of the included 14 studies was a related experiment. Xiao et al. determined the expression levels of vascular endothelial VEGF in three sets of cervical cancer specimens (blank control; CT alone; and rAd-p53+CT) before and after treatment by immunohistochemistry. The results showed significantly decreased VEGF expression in the CT alone and rAd-p53+CT groups compared to that in the control. In addition, the rhAd-p53 + CT group showed a more significant decrease in VEGF levels than that in the CT group. Based on the results of the above analyses, rad-p53 may be beneficial in patients with cervical cancer in terms of both short- and long-term effects.

Regarding the incidence of adverse reactions, only the occurrence rate of fever in the rAd-p53 combination group was higher than that in the control group. No significant differences were observed between the groups in myelosuppression, gastrointestinal reaction, radio rectitis, radio cystitis, and liver damage rate. All fevers were transient and self-limited and appeared within 24 h after injection. The grade II fevers resolved spontaneously, while the grade III fevers returned to normal levels after the administration of antipyretics. It is well known that adenovirus vectors can induce a strong immune response in patients, which manifests as a self-limiting fever. Although fever is considered a side effect in clinical use, it also reflects the effectiveness and benefits of Adp53 in mobilizing the immune system. Thus, rAd-p53 was a safe and biologically active treatment for improving the curative effect in patients with cervical cancer.

In conclusion, our results demonstrated that rAd-p53 combined with CT/RT/CRT was more effective and safer for the treatment of cervical cancer. Therefore, rAd-p53 showed great potential as an effective therapy for cervical cancer.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

YG and JC proposed the study concept and design. YG and XZ collected the literature. YG, MF, MX, and YX analyzed the data. All authors contributed to the article and approved the final manuscript.

This work was supported by the National Natural Science Foundation of China (grant no. 81972845), the Research Foundation of Xuzhou Medical University (grant no. D2019033), the Social Development Projects of Xuzhou (KC19144), the Jiangsu Distinguished Professorship Program, the Jiangsu Distinguished Medical Experts program, and the Xuzhou Jinlonghu Distinguished Talents Program.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.