Optimum Radiotherapy Schedule for Uterine Cervical Cancer based-on the Detailed Information of Dose Fractionation and Radiotherapy Technique

Cho, Jae Ho; Kim, Hyun Chang; Suh, Chang Ok; Lee, Chang Geol; Keum, Ki Chang; Cho, Nam Hoon; Lee, Ik Jae; Shim, Su Jung; Suh, Yang Kwon; Seong, Jinsil; Kim, Gwi Eon

Abstract

BACKGROUND: The best dose-fractionation regimen of the definitive radiotherapy for cervix cancer remains to be clearly determined. It seems to be partially attributed to the complexity of the affecting factors and the lack of detailed information on external and intra-cavitary fractionation. To find optimal practice guidelines, our experiences of the combination of external beam radiotherapy (EBRT) and high-dose-rate intracavitary brachytherapy (HDR-ICBT) were reviewed with detailed information of the various treatment parameters obtained from a large cohort of women treated homogeneously at a single institute.
MATERIALS AND METHODS
The subjects were 743 cervical cancer patients (Stage IB 198, IIA 77, IIB 364, IIIA 7, IIIB 89 and IVA 8) treated by radiotherapy alone, between 1990 and 1996. A total external beam radiotherapy (EBRT) dose of 23.4~59.4 Gy (Median 45.0) was delivered to the whole pelvis. High-dose-rate intracavitary brachytherapy (HDR-ICBT) was also performed using various fractionation schemes. A Midline block (MLB) was initiated after the delivery of 14.4~43.2 Gy (Median 36.0) of EBRT in 495 patients, while in the other 248 patients EBRT could not be used due to slow tumor regression or the huge initial bulk of tumor. The point A, actual bladder & rectal doses were individually assessed in all patients. The biologically effective dose (BED) to the tumor (alpha/beta=10) and late-responding tissues (alpha/beta=3) for both EBRT and HDR-ICBT were calculated. The total BED values to point A, the actual bladder and rectal reference points were the summation of the EBRT and HDR-ICBT. In addition to all the details on dose-fractionation, the other factors (i.e. the overall treatment time, physicians preference) that can affect the schedule of the definitive radiotherapy were also thoroughly analyzed. The association between MD-BED Gy3 and the risk of complication was assessed using serial multiple logistic regression models. The associations between R-BED Gy3 and rectal complications and between V-BED Gy3 and bladder complications were assessed using multiple logistic regression models after adjustment for age, stage, tumor size and treatment duration. Serial Coxs proportional hazard regression models were used to estimate the relative risks of recurrence due to MD-BED Gy10, and the treatment duration.
RESULTS
The overall complication rate for RTOG Grades 1~4 toxicities was 33.1%. The 5-year actuarial pelvic control rate for all 743 patients was 83%. The midline cumulative BED dose, which is the sum of external midline BED and HDR-ICBT point A BED, ranged from 62.0 to 121.9 Gy10 (median 93.0) for tumors and from 93.6 to 187.3 Gy3 (median 137.6) for late responding tissues. The median cumulative values of actual rectal (R-BED Gy3) and bladder point BED (V-BED Gy3) were 118.7 Gy3 (range 48.8~265.2) and 126.1 Gy3 (range: 54.9~267.5), respectively. MD-BED Gy3 showed a good correlation with rectal (p=0.003), but not with bladder complications (p=0.095). R-BED Gy3 had a very strong association (p=<0.0001), and was more predictive of rectal complications than A-BED Gy3. B-BED Gy3 also showed significance in the prediction of bladder complications in a trend test (p=0.0298). No statistically significant dose-response relationship for pelvic control was observed. The Sandwich and Continuous techniques, which differ according to when the ICR was inserted during the EBRT and due to the physicians preference, showed no differences in the local control and complication rates; there were also no differences in the 3 vs. 5 Gy fraction size of HDR-ICBT.
CONCLUSION
The main reasons optimal dose-fractionation guidelines are not easily established is due to the absence of a dose-response relationship for tumor control as a result of the high-dose gradient of HDR-ICBT, individual differences in tumor responses to radiation therapy and the complexity of affecting factors. Therefore, in our opinion, there is a necessity for individualized tailored therapy, along with general guidelines, in the definitive radiation treatment for cervix cancer. This study also demonstrated the strong predictive value of actual rectal and bladder reference dosing therefore, vaginal gauze packing might be very important. To maintain the BED dose to less than the threshold resulting in complication, early midline shielding, the HDR-ICBT total dose and fractional dose reduction should be considered.