Is it time to modify the Japanese Uterine Cervical Cancer Guidelines to recommend a higher dose for radio-resistant tumors?

Abstract

Compared with European or the United States’ uterine cervical cancer management guidelines, which aim to deliver >85 Gy EQD₂ (the equivalent effective dose in 2 Gy per fraction) to the high-risk clinical target volume (CTV_HR) D₉₀ (minimal dose of 90% of the CTV_HR) (1–6), the dose goal of the corresponding Japanese guidelines is less than 70 Gy (7). In Japanese guidelines, pelvic irradiation with a central shield (CS) is recommended in the latter part of external beam radiation therapy (EBRT) to prevent the rectum or bladder from high dose exposure, and in the total dose calculation, adding EBRT and brachytherapy, the dose contribution from CS is ignored. However, it was shown that, in reality, the dose contribution from CS to the CTV is not negligible and that 5–10% of the CS dose is actually delivered to the CTV (8,9). Even though the dose contribution from CS is considered, the total dose delivered to the CTV is still much lower than 85 Gy.

The etiology of uterine cervical cancer is human papillomavirus (HPV) infection, and similar to HPV-related oropharyngeal cancer (10) or anal canal cancer (11), it was suggested that there is a group of cervical cancer patients who can be well-controlled by a lower dose (12,13). To support this finding, several favorable oncologic outcomes treated by the Japanese dose schedule were reported from Japanese institutions both in the form of prospective and retrospective studies (14–18). On the other hand, there is a group of patients whose radiosensitivity is poor and who eventually result in residual disease after delivering the recommended dose by Japanese guidelines. In our department, we re-irradiate local residue/recurrent patients with high dose-rate interstitial brachytherapy (HDR-ISBT) after informing patients with severe late radiation-related adverse effects such as bleeding or fistula (19,20). Most of the patients included in these studies were referred from outside of our hospital and previously received the radiation dose recommended by the Japanese guidelines. In addition, currently, a prospective clinical trial about salvage hysterectomy for local residue/recurrent tumors after primary chemoradiotherapy is under planning in the Japan Clinical Oncology Group, which shows that there is an ineligible number of patients who result in locally residual/recurrent disease after primary radiation therapy with the relatively lower Japanese dosage. According to the IntErnational study on MRI-guided BRAchytherapy in CErvical cancer study (EMBRACE-I) (21), if >85 Gy EQD₂ is delivered to the CTV_HR D₉₀, 90% local control can be expected regardless of T-stage or pathology (21). Therefore, if an adequate dose is delivered to CTV, it is generally not necessary to worry about local residue/recurrence. When we look into details of clinical reports from Japanese image-guided adaptive brachytherapy, the upper dose range is over 85 Gy EQD₂, suggesting that even in the Japanese expert institutions, tumor response during radiation therapy is carefully assessed and it is supposed that additional times of brachytherapy were added above the dosage recommended by the Japanese guidelines if tumors responded poorly to EBRT. On the other hand, it is supposed that in patients with local residue/recurrence who were eventually referred to our department for re-irradiation with salvage HDR-ISBT, even if the residual disease had been suspected, when the dose recommended by Japanese guidelines is delivered, no additional measures were performed and resulted in residual disease (19, 20). The advantage of cervical cancer is the ease with which the tumor can be palpated and the response assessed with physical examination. Therefore, careful response assessment by physical examination during radiation therapy is essential in the management of cervical cancer.

Aside from the favorable local control with CTV_HR D₉₀ > 85 Gy EQD₂, a higher frequency of severe late radiation-related adverse effects was reported with high dose (EMBRACE-I) compared with Japanese clinical outcomes (14–18). It is sometimes difficult to deliver high dose while limiting doses of the organs at risk within the recommended dose constraints (6). This is considered to be one of the reasons why Japanese radiation oncologists hesitate to introduce a higher dose goal in the guidelines advocated by the European and the United States’ guidelines. One possible solution to this problem could be the application of the hybrid of intracavitary and interstitial brachytherapy (IC/IS) for large or irregularly shaped tumors (17, 22–24). Another possible solution could be the application of a gel spacer in brachytherapy (25). It was demonstrated that gel spacer can reduce rectal dose (26), rectal bleeding (27), bladder dose (28) and gel spacer can contribute to increasing CTV_HR D₉₀ without compromising rectal or bladder doses (29).

Local residue/recurrence after primary radiation therapy is essentially a difficult-to-treat disease condition, and only systemic chemotherapy is recommended by the management guidelines (7). However, as mentioned before, if an adequate dose is delivered to the tumor, it is highly likely that local control will be obtained. To avoid patients suffering from residual/recurrence disease due to an inadequate dose, the authors think it is high time to revise the description of the Japanese guidelines to recommend to deliver >85 Gy EQD₂ to the CTV_HR D₉₀ at least for patients with poor response, ideally with the aid of IC/IS and a gel spacer to protect surrounding organs at risk.

Acknowledgements

Not applicable.

Funding

None.

Conflict of interest statement

Dr Hiroshi Igaki reports grants and personal fees from HekaBio, grants from CICS, grants from Elekta KK, personal fees from Itochu, personal fees from HIMEDIC, personal fees from VARIAN, personal fees from AstraZeneca, outside the submitted work.

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