Biologically Effective Dose and Rectal Bleeding in Definitive Proton Therapy for Prostate Cancer

Purpose and Objectives With increasing use of hypofractionation and extreme hypofractionation for prostate cancer, rectal dose-volume histogram (DVH) parameters that apply across dose fractionations may be helpful for treatment planning in clinical practice. We present an exploratory analysis of biologically effective rectal dose (BED) and equivalent rectal dose in 2 Gy fractions (EQD2) for rectal bleeding in patients treated with proton therapy across dose fractionations. Materials and Methods From 2016 to 2018, 243 patients with prostate cancer were treated with definitive proton therapy. Rectal DVH parameters were obtained from treatment plans, and rectal bleeding events were recorded. The BED and EQD2 transformations were applied to each rectal DVH parameter. Univariate analysis using logistic regression was used to determine DVH parameters that were significant predictors of grade ≥ 2 rectal bleeding. Youden index was used to determine optimum cutoffs for clinically meaningful DVH constraints. Stepwise model-selection criteria were then applied to fit a “best” multivariate logistic model for predicting Common Terminology Criteria for Adverse Events grade ≥ 2 rectal bleeding. Results Conventional fractionation, hypofractionation, and extreme hypofractionation were prescribed to 117 (48%), 84 (34%), and 42 (17.3%) patients, respectively. With a median follow-up of 20 (2.5-40) months, 10 (4.1%) patients experienced rectal bleeding. On univariate analysis, multiple rectal DVH parameters were significantly associated with rectal bleeding across BED, EQD2, and nominal doses. The BED volume receiving 55 Gy > 13.91% was found to be statistically and clinically significant. The BED volume receiving 55 Gy remained statistically significant for an association with rectal bleeding in the multivariate model (odds ratio, 9.81; 95% confidence interval, 2.4-40.5; P = .002). Conclusion In patients undergoing definitive proton therapy for prostate cancer, dose to the rectum and volume of the rectum receiving the dose were significantly associated with rectal bleeding across conventional fractionation, hypofractionation, and extreme hypofractionation when using BED and EQD2 transformations.

Rectal dose-sparing effect with bioabsorbable spacer placement in carbon ion radiotherapy for sacral chordoma: dosimetric comparison of a simulation study

It is difficult to treat patients with an inoperable sarcoma adjacent to the gastrointestinal (GI) tract using carbon ion radiotherapy (C-ion RT), owing to the possible development of serious GI toxicities. In such cases, spacer placement may be useful in physically separating the tumor and the GI tract. We aimed to evaluate the usefulness of spacer placement by conducting a simulation study of dosimetric comparison in a patient with sacral chordoma adjacent to the rectum treated with C-ion RT. The sacral chordoma was located in the third to fourth sacral spinal segments, in extensive contact with and compressing the rectum. Conventional C-ion RT was not indicated because the rectal dose would exceed the tolerance dose. Because we chose spacer placement surgery to physically separate the tumor and the rectum before C-ion RT, bioabsorbable spacer sheets were inserted by open surgery. After spacer placement, 67.2 Gy [relative biological effectiveness (RBE)] of C-ion RT was administered. The thickness of the spacer was stable at 13–14 mm during C-ion RT. Comparing the dose–volume histogram (DVH) parameters, Dmax for the rectum was reduced from 67 Gy (RBE) in the no spacer plan (simulation plan) to 45 Gy (RBE) in the spacer placement plan (actual plan) when a prescribed dose was administered to the tumor. Spacer placement was advantageous for irradiating the tumor and the rectum, demonstrated using the DVH parameter analysis.

Analysis of rectal dose during prostate stereotactic body radiotherapy in MR-guided radiotherapy.

242 Background: The Unity MR-Linac combines a 7-MV Linac with 1.5T magnetic resonance (MR) imaging capability and it enables adaptive radiotherapy, whereby the target and organs at risk are recontoured and a plan is optimised daily. During treatment a session MR image is taken first, on which the target and organs-at-risk are contoured, and a plan created. A verification image is taken prior to dose delivery to identify intra-fractional changes. If present, the daily treatment plan is shifted to reflect the anatomy. A post-treatment image is acquired at the end of treatment. This study evaluates the dosimetric changes to the rectum caused by intra-fractional changes during treatment delivery for prostate stereotactic body radiotherapy (SBRT) calculated on the verification and post-treatment images. Methods: The first five patients treated on the MR-Linac with 5-fraction SBRT to the prostate are included in this study. For each patient, the rectum was contoured on the verification and post-treatment MR images for each of the five fractions. The dose delivered to the rectum with the original treatment plan was then calculated on each image and the V36Gy rectal dose constraint was noted. Results: Out of the 25 fractions, a post treatment image was not performed in one fraction; 24 fractions were therefore analysed in total. The rectal V36Gy dose constraint exceeded the mandatory target of 2cc on 50% of the verification images and 46% of the post-treatment images. In 6 fractions the rectal V36Gy was greater than 2cc on both the verification and post-treatment images suggesting this rectal constraint was exceeded throughout treatment. In 17% of patients, the volume of rectum receiving 36Gy increased at each timepoint an image was taken during the treatment workflow. Conclusions: The rectal V36Gy dose constraint is susceptible to minor changes in rectal filling, which may often lead to higher than the accepted dose constraint. Thus, a single planning CT scan is unlikely to be representative of dose delivered. Adaptive radiotherapy can reduce this uncertainty somewhat, but intra-fraction dose re-optimisation would be required to ensure the rectal V36Gy remains acceptable at all times.

Pharmacokinetic study of rectal artesunate in children with severe malaria in Africa

When severe malaria is suspected in children, WHO recommends pre-treatment with a single rectal dose of artesunate before referral to an appropriate facility. This was an individually randomized, open-label, 2-arm, cross-over clinical trial in 83 Congolese children with severe falciparum malaria, to characterize the pharmacokinetics of rectal artesunate. At admission, children received a single dose of rectal artesunate (10 mg/kg) followed 12 hours later by intravenous artesunate (2.4 mg/kg) or the reverse order. All children also received standard doses of intravenous quinine. Artesunate and dihydroartemisinin were measured at eleven fixed intervals, following 0- and 12-hour drug administrations. Clinical, laboratory and parasitological parameters were measured. After rectal artesunate, artesunate and dihydroartemisinin showed large inter-individual variability (peak concentrations of dihydroartemisinin ranged from 5.63 to 8,090 nM). The majority of patients however, reached previously suggested in vivo IC50 (98.7%) and IC90 (92.5%) values of combined concentrations of artesunate and dihydroartemisinin between 15 to 30 minutes after drug administration. The median (IQR) time above IC50 and IC90 was 5.68 hours (2.90-6.08) and 2.74 hours (1.52-3.75), respectively. The absolute rectal bioavailability (IQR) was 25.6% (11.7-54.5) for artesunate and 19.8% (10.3-35.3) for dihydroartemisinin. The initial 12-hour parasite reduction ratio was comparable between rectal and intravenous artesunate: median (IQR) 84.3% (50.0-95.4) vs. 69.2% (45.7-93.6), respectively (p=0.49). Despite large inter-individual variability, rectal artesunate can initiate and sustain rapid parasiticidal activity in most children with severe falciparum malaria, while they are transferred to a facility where parenteral artesunate is available. (www.clinicalTrials.gov : NCT02492178)

Rectal Dose Is the Other Dosimetric Factor in Addition to Small Bowel for Prediction of Acute Diarrhea during Postoperative Whole-Pelvic Intensity-Modulated Radiotherapy in Gynecologic Patients

We studied the association of rectal dose with acute diarrhea in patients with gynecologic malignancies undergoing whole-pelvic (WP) intensity-modulated radiotherapy (IMRT). From June 2006 to April 2019, 108 patients with previous hysterectomy who underwent WP IMRT were enrolled in this cohort study. WP irradiation of 39.6–45 Gy/22–25 fractions was initially delivered to the patients. Common Terminology Criteria for Adverse Events (CTCAE) version 3 was used to evaluate acute diarrhea during radiotherapy. Small bowel volume at different levels of isodose curves (Vn%) and mean rectal dose (MRD) were measured for statistical analysis. The multivariate analysis showed that the MRD ≥ 32.75 Gy (p = 0.005) and small bowel volume of 100% prescribed (V100%) ≥ 60 mL (p = 0.008) were independent factors of Grade 2 or higher diarrhea. The cumulative incidence of Grade 2 or higher diarrhea at 39.6 Gy were 70.5%, 42.2%, and 15.0% (p < 0.001) in patients with both high (V100% ≥ 60 mL and MRD ≥ 32.75 Gy), either high, and both low volume-dose factors, respectively. Strict constraints for the rectum/small bowel or image-guided radiotherapy to reduce these doses are suggested.

Preliminary analysis of prostate positional displacement using hydrogel spacer during the course of proton therapy for prostate cancer

In recent years, a novel technique has been employed to maintain a distance between the prostate and the rectum by transperineally injecting a hydrogel spacer (HS). However, the effect of HS on the prostate positional displacement is poorly understood, despite its stability with HS in place. In this study, we investigated the effect of HS insertion on the interfraction prostate motion during the course of proton therapy (PT) for Japanese prostate cancer patients. The study population consisted of 22 cases of intermediate-risk prostate cancer with 11 cases with HS insertion and 11 cases without HS insertion. The irradiation position and preparation were similar for both groups. To test for reproducibility, regular confirmation computed tomography (RCCT) was done four times during the treatment period, and five times overall [including treatment planning CT (TPCT)] in each patient. Considering the prostate position of the TPCT as the reference, the change in the center of gravity of the prostate relative to the bony anatomy in the RCCTs of each patient was determined in the left–right (LR), superior–inferior (SI) and anterior–posterior (AP) directions. As a result, no significant difference was observed across the groups in the LR and SI directions. Conversely, a significant difference was observed in the AP direction (P &lt; 0.05). The proportion of the 3D vector length ≤5 mm was 95% in the inserted group, but 55% in the non-inserted group. Therefore, HS is not only effective in reducing rectal dose, but may also contribute to the positional reproducibility of the prostate.