Although cervical cancer incidence continues to decline, effective tumor control remains a challenge for patients with locally advanced disease, especially for different tumor histologies, such as adenocarcinoma. Our previous study had already confirmed that the combination of Cf-252 neutron ICBT and EBRT was more effective than conventional ICBT radiation for management of both SCC and AC. However, advanced-stage AC cervical cancers are so in frequent that it is difficult to conduct a randomized, controlled trial to compare γ-emitting isotopes with neutron-emitting Cf-252 ICBT[14, 15]. Thus, in the current study, we assessed the outcomes of combined EBRT and Cf-252 neutron vs. Ir-192 gamma ICBT in patients with AC using a matched-pair study design. We observed a possible trend in 5-year regional local control rate in favor of NICBT over PICBT, though the difference was not significant, perhaps due to the relatively small sample examined in this study. Although a large sample of AC patients would be difficult to assemble, due to the relative rarity of AC histology clinically, a larger sample size might yield a significant difference for this comparison. Compared with the NICBT group, the PICBT group had more distant metastasis; correspondingly, the PICBT group had a significantly shorter mean survival time than the NICBT group. The 5-year OS rate and 5-year DFS rate were also significantly shorter in the NICBT group than in the PICBT group.
Unlike conventional photon rays, Cf-252 neutrons employed in NICBT provide high linear energy transfer radiation that damages tumor cell genomic DNA regardless of cell cycle phase, causing a high rate of DNA double-strand breaks[17, 18]. Thus, AC cells that were resistant to conventional γ-ray PICBT were probably sensitive to Cf-252 NICBT. Furthermore, NICBT has radiobiological characteristics, such as higher relative biological effectiveness and lower oxygen enhancement than photon radiotherapy [19].
Cf-252 NICBT has been reported previously to be more effective than conventional radiation ICBT in controlling advanced or bulky cervical cancer (hypoxic IIIb) [16, 20]. These prior studies focused on therapies other than neutron intracavitary brachytherapy in patients with SCC histology, leaving the NICBT for AC uncertain. In this study, although we did not obtain a significant group effect in the analysis of our cancer control data, our survival data analysis nevertheless did yield significant outcomes in favor of NICBT over PICBT in patients with AC. Thus, the current data support the use of Cf-252 neutron ICBT combined with external beam radiotherapy for patients with cervical AC.
Some studies reported that the combination of EBRT and ICBT with concurrent chemotherapy is more effective than the same treatment without chemotherapy for controlling cervical cancer [21, 22]. However, the isotopes most commonly used for ICBT of cervical cancer all have a low linear energy transfer, and the major histology type evaluated thus far has been SCC[23, 24]. As discussed above, because AC is more difficult to control than SCC, treatment for AC should be more aggressive. The data from our former study suggested that concurrent platinum-based chemotherapy provided an efficacy similar to that of pelvic EBRT combined with Cf-252 neutron ICBT for the treatment of locally advanced cervical cancer. Although it did not improve the local tumor control rate, OS, or DFS, relative to treatment without concurrent platinum-based chemotherapy, it did increase the incidence of serious LAC significantly. In the current study, it is noteworthy that patients in the NICBT group achieved better survival outcomes than the PICBT group despite the fact that they were not given concurrent and/or sequential chemotherapy for stage IIB adenocarcinoma of the uterine cervix.
Furthermore, the acute treatment toxicity was mild in both groups of patients, and all patients completed the RT schedule with only grade 1–2 gastrointestinal toxicity. Late complications after RT included only radiation-induced proctitis and cystitis. The total dose of ICBT at point A received by NICBT group patients was higher than that received by the PICBT group, which likely explains why the late radiation proctitis rate was slightly, albeit not significantly, higher in the NICBT group than in the PICBT group. Nevertheless, the late complications experienced were considered acceptable in both groups.
This study has some limitations. For example, it was a retrospective investigation, and the number of patients is quite small, which can lead to bias. Nonetheless, we observed a better outcome for patients treated with NICBT.