Purpose: To disclose effectiveness of substitution of conformal radiotherapy (CRT) with intensity-modulated radiotherapy (IMRT) in combined with 125I permanent seed brachytherapy(BT) in reducing a rectal dose-volume parameter recently proven to be correlated with late rectal bleeding after the combined radiotherapy.

Materials/Methods: A CT image set obtained a month after BT was used for CRT and tentative IMRT planning as well as dosimetry of BT (post plan). Physical dose of each DICOM-RT was converted to biologically effective dose under α/β of 3(Gy3 ) for three dimensional summation of rectal volume exposed to 150 Gy3 (rV150 (3)). Alteration of the value along BT, BT combined with CRT (BT+CRT), and BT combined with IMRT (BT+IMRT) was traced individually, and the mean value were statistically compared between the modalities.

Results: The elevation rate of rV150 (3) from BT to BT+CRT is proportional to their rV150 (3) of BT. All rV150 (3) was decreased from BT+CRT to BT+IMRT except 3 cases with smaller rV150 (3) at BT+CRT. The mean rV150 (3) values of BT, BT+CRT, and BT+IMRT were 0.06 ± 0.09 cc, 1.41 ± 0.88, and 1.18 ± 0.75 cc, respectively, showing significant differences between all values.

Conclusions: The substitution of CRT with IMRT in conjunction with seed implant brachytherapy reduces the rectal dose predisposing bleeding. Avoiding rectal exposure to high doses during BT is important even in BT+IMRT.

Nakamura R, Kikuchi K, Yamaguchi S, Kakuhara H, Sugawara J, et al. (2017) Intensity-Modulated vs. Conformal Radiotherapy after Prostate Seed Implant Brachytherapy Regarding Summed Rectal Dose. J Radiol Radiat Ther 5(1): 1066.

•    Prostate cancer
•    Brachytherapy
•    Rectal bleeding
•    Dose-volume histogram

IMRT: Intensity-Modulated Radiotherapy; CRT: Conformal Radiotherapy; BT: Brachytherapy; OPC: Organ-confined Prostate Cancer; EBRT: External Beam Radiotherapy; DVH: Dose-volume Histogram; DICOM-RT: Digital Imaging and Communication in Medicine in Radiotherapy; RTP: Radiotherapy Treatment Planning; CTV: Clinical Target Volume; PTV: Planning Target Volume; BED: Biologically Effective Dose

A combination of seed implant brachytherapy (BT) and external beam radiotherapy (EBRT) has become a standard option for intermediate- or high-risk organ-confined prostate cancer (OCP) [1,2] with favorable outcomes in biochemical control rates [3,4]. However, the combined radiotherapy has been associated with an increased probability of rectal morbidities compared to either modality alone [5,6]. To avoid toxicity, threedimensional conformal radiotherapy (CRT) has been replaced by intensity-modulated radiotherapy (IMRT) as the EBRT portion of the combined radiotherapy. However, the substitution showed relatively limited effects in the reduction of rectal bleeding rate: from 15% to 9% [7] or 11% to 7% [8]. Rectal dose-volume histogram (DVH) indices in treatment planning system (TPS) have been correlated with the frequency of rectal bleeding. They are rectal volumes exposed to doses from 50 to 77 Gy in EBRT for OCP [9-11], or to the prescription dose (rV100) calculated using computed tomography (CT) images obtained 1 month after seed implant (post plan) in BT [12,13]. In the combined radiotherapy, a rectal dose delivered by BT is superimposed to a summed dose during subsequent EBRT, which has been shown to substantially determine the probability of rectal bleeding. We preliminarily examined the efficacy of substituting CRT with IMRT in decreasing the rectal dose presumed to be predisposing bleeding.

DICOM-RT sets

Between June 2006 and April 2011, 64 OCP patients underwent BT and CRT under a protocol approved by the institutional review board of Iwate Medical University Hospital. A CT image set obtained a month after BT was used for CRT planning as well as dosimetry of BT (post plan). The top 20 pairs of BT post plan and CRT plan were selected based on large rV100 values following BT treatment.

BT

125I free seeds (0.28–0.335 mCi; Source Tec 1251 NIST99; Bard, NJ) were implanted by using a Mick applicator system (Mick Radio nuclear Instruments, New York, USA). Real-time interactive seed insertion was optimized using BT-TPS (Variseed version 7.2; Varian Medical Systems, Palo Alto, CA) to consider dose constraints of pD90 (the dose covering 90% of the prostate volume)>110 Gy, pV100 (% prostate volume exposed to 110 Gy)>95%, pV150 (% prostate volume exposed to 165 Gy)<60%, and rV100 (rectal volume exposed to 110 Gy)<1.0 cc.

BT post plan

CT (Aquillion; Toshiba, Tokyo, Japan) images with a 3-mm pitch of the pelvis, with the patient in the supine position, were acquired 30 days after BT, and were imported into the BT-TPS. In addition to the prostate, the rectum was contoured as a solid structure defined by the outer wall on all slices that showed seeds, without attempting to differentiate the inner wall or the contents. All doses were defined using the TG43 formalism from a 1-mm grid size at each seed location, determined by the seed finder module.

CRT

The CT data were also imported into another TPS (Eclipse version 8.0; Varian Medical Systems, CA) for subsequent CRT planning. The clinical target volume (CTV) included the prostate and proximal half or whole of the seminal vesicle. The planning target volume (PTV) was defined by adding a 2-cm margin to the volume surrounding the CTV, except on the rectal side where only 1 cm was added. Irradiation with 10 MV-photons was delivered from a linear accelerator (Clinac 2100C; Varian Medical Systems, CA) by using a conformal 4-field technique at a dose of 2 Gy per fraction, with 5 fractions per week; the total dose was 40 Gy. The dose delivered to the prostate and rectum was calculated with a 5-mm grid size. The rectum was contoured in the slices including the PTV.

Tentative IMRT

Using the same CT image set a tentative IMRT plan by 7 coplanar beams was devised with the dose covering 95% of the target volume set at 40 Gy. The CTV for the IMRT plan was the same as that for the CRT plan, and included a 5-mm CTV-PTV margin in all directions. The normalization was performed by application of typical dose constraints used for definitive IMRT of 78 Gy/39 fractions

Summation of BT and EBRT doses

The physical doses in the DICOM-RT of BT-post plan, CRT, and tentative IMRT were converted to BED using a previously published equation [14,15], with an α/β ratio of 3 (Gy3 ). The modified DICOM-RT doses were added to the CRT-TPS, and summation using the ‘sumplan’ module created actual (BT followed by CRT: BT+CRT) and tentative (BT followed by IMRT: BT+IMRT) rectal DVHs.

Study Design

The rectal volume exposed to 150 Gy3 (rV150(3)) in the combined radiotherapy is presumed to be the predictive variable [16]. Statistical differences in mean rV150 (3) for BT, BT+CRT, and BT+IMRT were compared by using paired t-tests. Statistical analysis was performed using SPSS version 11.01j (SPSS Japan, Tokyo, Japan). Differences were significant if p-values were less than 0.05.

During BT, an average of 49.6 (range (R), 33–74) seeds was inserted per prostate, which had a mean volume of 23.7 (R, 13.8– 39.5) cc. The BT post plan revealed average pD90, pV100, pV150, and rV100 values of 122 (R, 88–150) Gy, 93.5 (R, 83.2–99.4%), 63.3 (R, 30.9–85.8%), and 0.40 (R, 0–2.48) cc, respectively. CRT was administered an average of 33.7 (R, 22–76) days after BT. Tentative IMRT planning satisfied entire of dose constraints, with the total dose presumed to be 40 Gy instead of 78 Gy.

The mean rV150(3) of BT, BT+CRT, and BT+IMRT was 0.06 ± 0.09, 1.41 ± 0.88, and 1.18 ± 0.75 cc, respectively. A significant difference was found between BT and BT+CRT (p<0.001) and between BT+CRT and BT+IMRT (p < 0.001). rV150 (3) of BT unanimously increased at BT+CRT, and then decreased at BT+IMRT except in 3 cases that showed a further increase in rV150 (3) at BT+IMRT (Figure 1).

The elevation rate of rV150 (3) from BT to BT+CRT in each case is proportional to their rV150 (3) of BT as shown in Figure 1. The largerrV150 (3) is surrounded by a broader rectal wall exposed to a sub toxic dose during BT that should be easily recruited into rV150 (3) by CRT. This also means that rV150 (3) of BT is located in the rectal anterior wall, which is unexceptionally irradiated during CRT. Although substitution of CRT with IMRT substantially reduces rV150 (3), it is not enough to lessen the number of patients receiving rectal doses beyond the safe range. In order to reduce rV150 (3) in combined radiotherapy, it is essential to maintain rV150 (3) as small as possible in BT.

IMRT optimizes the prostate dose within the fixed rectal dose constraints in its monotherapy. Meanwhile, situations in the combined radiotherapy are different. When rV150 (3) of BT is large, the posterior edge of the prostate should be already covered by a sufficient dose, requiring less additional doses. The reverse may also apply, with a small rV150 (3) requiring more additional doses. Under these conditions, it is misleading to set fixed dose constraints for supplemental IMRT. Hence, we must establish a method to individually determine the dose constraints in IMRT according to the inconsistent prostate and rectal doses delivered by BT in each case.

Some limitations should be acknowledged in this study. There was a notable difference in PTV margins between CRT and IMRT treatment plans, reflected actual transition in EBRT systems within our hospital. The CRT for OPC has been performed with a generous margin in previous studies [17-18] and during this study, whereas IMRT margins are much smaller, owing to the image-guided radiotherapy system [19]. The smaller PTV margin of IMRT compared to CRT should partially account for the decrease in rectal exposure by the substitution [20]. The α/β ratio used for BED calculation in this study is another premise that should be referred because it is computed from clinical data based on changes in total is effective target dose after changes in prescribed dose per fraction disregarding differences among patients in the volumes of normal tissue irradiated [21].

The substitution of CRT with IMRT in conjunction with seed implant brachytherapy reduces the mean rectal dose predisposing bleeding. Avoiding rectal exposure to high doses during BT is important even in BT+IMRT.

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