Cervical carcinoma in late stages were believed the radio-resistant due to the tumor hypoxia, which resulted from the associated anemia. Therefore, to achieve good outcome, high dose of radiotherapy is necessary. The external irradiation followed by brachytherapy irradiation, intracavitary or interstitial implantation, has been the standard irradiation technique. Typically, patients were irradiated with external beam radiotherapy of 45 to 50 Gy, and followed by intracavitary brachytherapy with 3 to 5 fractions of 5 to 7 Gy per fraction (BED10 of 72.6Gy- 119.5 Gy). However, intracavitary brachytherapy might not deliver a sufficient dose to extensive and bulky tumors in stage III or IVA disease [13–14]. In that case, interstitial brachytherapy could be used [15–16]. However, it was invasive and had limited indications. In an effort to exclude brachytherapy, the dosimetric comparison studies had been done between external irradiation plus brachytherapy and external irradiation alone with stereotactic radiotherapy or IMRT [17–18]. However, the high dose to central tumors by brachytherapy could not be reproduced by stereotactic radiotherapy or IMRT. Moreover, a retrospective analysis showed that curative external irradiation and brachytherapy achieved a higher 5-year cancer specific survival than external irradiation alone in cervical carcinoma, which implied the important role of brachytherapy . However, intracavitary or interstitial implantation brachytherapy brought patients inconvenience, or procedures was invasive. Therefore, most advanced irradiation techniques were tried to deliver intensive doses in a hope to skip the brachytherapy.
Although our analysis was a retrospective study, we had some basic considerations to implement PCRT for cervical SCC. Our intention was to exclude brachytherapy from the combination of external beam and brachytherapy, and meanwhile to keep a similar outcome as that in the external and brachytherapy. From dosimetric comparative study of cervical carcinoma, intensity-modulated proton radiotherapy (IMPT) had a significant reduction for the mean dose of small bowel and functional bone marrow than photon techniques such as IMRT, helical tomotherapy and RapidArc [5–6]. Furthermore, mean dose to the bladder and rectum was decreased by 7-9 Gy with IMPT in patents with pelvic radiation . Volume of pelvic bone marrow receiving 10 Gy-20 Gy or 40Gy was associated with hematologic toxicity [20–24]. Thus, protons offered the best sparing of small bowel, rectum and pelvic bone marrow, and could contribute to a significant reduction of acute and late gastrointestinal and hematologic toxicity in cervical carcinoma radiotherapy, especially when combined with concurrent chemotherapy. However, on the other hand, cervical carcinoma often contained a large percentage of radio-resistant hypoxic cells due to the associated anemia. The proton, as low LET beam, would probably not be effective enough to sterilize hypoxic cells. Carbon ion beam is a high LET beam and possesses both physical and biological advantages. From experimental and clinical studies, it had shown strong capabilities to inactivate malignancies with RBE of 2 to 3. Moreover, it could overcome tumor hypoxia with decreased OER of around 2. Actually, CIRT had been used to treat cervical carcinomas and yielded good outcome for locally advanced bulky cervical SCC . Therefore, we irradiated the cervical tumor and pelvic nodes by proton of 46Gy (RBE), and followed by CIRT boost doses to cervical gross tumor and the metastatic nodes.
From 16 consecutively treated patients in our center by PCRT with 76 Gy (RBE) -85.6 Gy (RBE) (BED10 of 93.9Gy-112.2Gy), LC and OS rates at 1-year, 2-year and 3-year were 86.7%, 86.7% and 78.0%; 100%, 100% and 77.9% respectively. This result was as good as that reported by modern external irradiation and brachytherapy (Table 6) [3–4, 25–30]. Also it was comparable to NIRS reports [29, 30]. All acute toxicity in our patients were Grade 1-2, and no severe late toxicity occurred during the follow-up period. Compared with that in external beam radiotherapy plus brachytherapy, or CIRT, the toxicity of PCRT seemed to be less [3, 25–28, 30–31].
As proton and CIRT are new radiation techniques for cervical carcinomas, some technical problems we have to deal with, including uterine motion , and position variations of bladder and rectum . The above problems would result in dose delivery uncertainty. We applied some measurements to decrease the gas in intestine and colon, to keep the same bladder urine volume and rectum empty. Recently we took CT by in-room CT just before the dose delivery and confirmed the effectiveness of those measurements on keeping anatomy position consistent.
Concurrent platinum-based chemotherapy is a part of the current standard treatment for patients with FIGO stage IB2-IVA. NIRS carried out a dose-escalation study on locally advanced cervical SCC by CIRT alone in 2014, and showed 2-year OS and LC were 64% and 68.2%, respectively . In 2019, NIRS did another phase 1/2 study on CIRT, but with concurrent chemotherapy, and the 2-year OS and LC were 82% and 67%, respectively . The 2-year OS was improved from 64–82% in concurrent chemo-radiation study, which demonstrated again the importance of concurrent chemotherapy in CIRT as the same as in photon irradiation. However, concurrent chemotherapy did not improve the outcome in our study probably due to the small example size.
Univariate analysis in our study showed that only stage and tumor size were related to OS as that reported in literature . If we could make the disease down staged before irradiation, it would be of help. Induction chemotherapy might be a strategy to reduce tumor burden in locally advanced cervical carcinomas. A British phase II trail included 46 patients with FIGO stage Ib2-IVa cervical carcinoma showed a good response rate to induction chemotherapy before CCRT, and the 5-year OS was 67% , which was better than the outcome after CCRT alone . An international randomized multicenter phase III trial, INTERLACE (NCT01566240) is going on to compare the induction chemotherapy followed by CCRT and CCRT alone. In our center, we are planning to initiate a prospective clinical trial of induction chemotherapy, and concurrent chemotherapy and PCRT for locally advanced cervical carcinomas to further confirm PCRT feasibility and its efficacy.