Due to the poor prognosis of bulky LACC, studies exploring new treatment strategies are therefore highly important. The present study is the first of its kind focused on the treatment of bulky LACC with H101, a type of oncolytic virus, in combination with CCRT. The results demonstrate that H101 combined with CCRT plays a promising role with a high PFS (65%) and OS (74.3%) rate for a 3-year period.
The length of tumor over 6 cm is a significant predictor of poor prognosis for LACC after CCRT [12]. Endo et al [13]. reported that, in 85 patients with cervical cancer that all received CCRT including intracavitary BT, the 3-year OS rates of cervical cancer ≥ 6 cm after CCRT were 50.5% and 23.1%, without and with enlarged pelvic lymph node, respectively. In another study, the median OS of patients with tumor > 6 cm was 38.3 months [14]. Wang et al [15] reported that the 3-year OS rate of cervical cancer patients with FIGO stage ⅡB and tumor length > 6 cm undergoing CCRT followed by intracavity BT was 42.9%. In the present study, the length of cervical tumor ≥ 6 cm was a key criterion for recruitment, and there were 15 (75%) and 16(80%) patients with pelvic and/or paraaortic lymph node metastasis in H101 group and control group, respectively. For control group, the 3-year PFS(43.8%) and OS(54.5%) rates were consistent with historical data. However, the 3-year PFSlocal and PFSregional rates of H101 group were found to be higher as compared with control group. This may be due to the fact that H101 in combination with CCRT shrank the tumor significantly during EBRT, thus creating a condition for BT to deliver a sufficient dose coverage for the whole tumor volume. Better trends of 3-year PFS and 3-year OS rates in H101 group could be observed in survival curve, however, there was no statistical difference between the two groups. This may be due to the small sample size.
BT plays an indispensable role in the radiotherapy of cervical cancer as it can provide local high-dose radiation, and the dose drops quickly to protect any adjacent organs at risk. Tumor size is the key factor affecting the efficacy of BT, since the coverage of high-dose BT is limited. It is difficult to deliver a sufficient dose to the whole bulky cervical tumor volume with intracavitary BT [16]. Intracavitary/interstitial BT can significantly improve the local control rate for bulky cervical tumor compared with intracavitary BT alone. However, intracavitary/interstitial BT requires more resources and skills to implement, which is unrealistic for massive deployment in developing countries where the incidence of bulky cervical cancer is high. An alternative strategy to improve BT efficacy is to minimize tumor size during EBRT. In the present study, H101 was added to CCRT, and intracavitary BT alone was performed to treat LACC patients. Following EBRT, the median tumor length was reduced from 6.6 cm to 4.1 cm, and the median tumor volume was reduced from 88.35 cm3 to 20.8 cm3 for H101 group, the reduction of which was much more than that of control group. The small tumor after EBRT could be addressed by an adequate dose provided by intracavitary BT.
Oncolytic adenovirus H101 is characterized by the deletion of both E1B-55 kDa and 19 kDa of E3 regions in the human adenovirus type 5 by means of genetic engineering technology. The 55 kDa protein encoded by the E1B region of wild-type adenovirus gene can bind with the p53 protein to inhibit the clearance of adenovirus by p53 gene. The H101 virus cannot encode the E1B-55 kDa protein, thus it does not replicate in p53 normal cells. However, in tumor cells with abnormal p53 protein, H101 can replicate in large numbers because there is no inhibitory effect of p53. Thus, H101 can exert an oncolytic effect on tumor cells through the replicating virus, while it does not affect normal cells. The P53 gene mutation is widely found in many kinds of tumor. For cervical cancer that is associated with high-risk human papillomavirus (HPV) infection, some studies have demonstrated that the major transforming HPV E6 and E7 activities include the targeted degradation of p53 [17, 18]. In this study, the rapid tumor regression may be associated with the p53 gene mutation and could be caused by the oncolytic effect of H101. Whether there is a synergistic effect between H101 and CCRT and the relevant mechanism needs to be further investigated. In addition, there are reasonable arguments that oncolytic adenoviruses may play be important in multi-stage immunotherapy [19, 20], therefore, the outlook of H101 combined with CCRT for tumor immunotherapy is highly promising.
In this study, treatment by intratumoral H101 injection combined with CCRT was well-tolerated. The adverse events were similar to those reported previously for H101 therapy [5, 7]. The main adverse effect after H101 intratumoral injection was fever. Specifically, nineteen patients experienced this symptom and 18 of 19 had grade I to II fever. Three patients reported mild to moderate pain during the injection. Leukopenia, neutropenia, anemia, fatigue, diarrhea and nausea were also observed during treatment. However, these adverse effects were similar to those of CCRT previously reported for cervical cancer [21–24]. Therefore, it was considered more likely that they were due to CCRT rather than intratumoral H101 injection.
This study has several limitations. First, it was conducted in a single center with a small sample size. Second, there was no control group of patients receiving concurrent CCRT without the injection of H101, therefore, the data were compared with retrospective and historical control without H101. Third, molecular analysis was not performed to explore the mechanism of H101 effect on cervical cancer and its relationship with CCRT.