Dosimetric and radiobiological analyses of a de-escalation strategy for elective nodal regions in human papillomavirus-associated oropharyngeal cancer.

Introduction: In this simulation study, we examined the effects of a de-escalation strategy with a reduced dose to subclinical nodal regions in patients with human papillomavirus (HPV)-associated oropharyngeal carcinoma (OPC). Methods: We created two patterns of intensity-modulated radiotherapy for 16 patients with HPV-associated OPC. In the standard and de-escalation plans, the initial field including elective nodal regions received 46 and 30 Gy, followed by 20 and 36 Gy to the cutdown field, respectively. Comparison metrics were set for each organ at risk (OAR). We compared these metric values and the probability of adverse effects based on the normal tissue complication probability (NTCP) model between the two plans. Results: Both plans generally met the dose constraints for the targets and all OAR. Among the comparison metrics, the mean doses to the brain, pharyngeal constrictor muscle, thyroid, and skin and the dose to a 1 % volume of the skin were higher in the standard plan than in the de-escalation plan (P = 0.031, 0.007, < 0.001, < 0.001, and 0.006, respectively). NTCP analyses revealed that the probability of adverse effects in the ipsilateral parotid gland and thyroid was higher in the standard plan than in the de-escalation plan (standard vs. de-escalation plans: ipsilateral parotid gland, 6.4 % vs. 5.0 %, P = 0.016; thyroid, 3.3 % vs. 0.5 %, P < 0.001). Conclusions: A de-escalation strategy with elective nodal regions is a promising treatment to prevent a decline in the quality of life in patients with HPV-associated OPC, particularly xerostomia, dysphagia, and hypothyroidism.

Insights into the catalytic mechanism of Grimontia hollisae collagenase through structural and mutational analyses.

Grimontia hollisae collagenase (Ghcol) exhibits high collagen-degrading activity. To explore its catalytic mechanism, its substrate (Gly-Pro-Hyp-Gly-Pro-Hyp, GPOGPO)-complexed crystal structure was determined at 2.0 Å resolution. A water molecule was observed near the active-site zinc ion. Since this water was not observed in the product (GPO)-complexed Ghcol, it was hypothesized that the GPOGPO-complexed Ghcol structure reflects a Michaelis complex, providing a structural basis for understanding the catalytic mechanism. Analyses of the active-site geometry and site-directed mutagenesis of the active-site tyrosine residues revealed that Glu493 and Tyr564 were essential for catalysis, suggesting that Glu493 functions as an acid and base catalyst while Tyr564 stabilizes the tetrahedral complex in the transition state. These results shed light on the catalytic mechanism of bacterial collagenase.

Vaginal Fistulas of the Bladder and Small Bowel After Two-Dimensional Intracavitary Brachytherapy in a Patient With Cervical Cancer.

Image-guided brachytherapy (IGBT) is commonly used for patients with cervical cancer, but two-dimensional intracavitary brachytherapy (2D-ICBT) is also still utilized for certain patients. We report a patient with cervical cancer who developed vaginal fistulas of the bladder and small bowel after chemoradiotherapy with 2D-ICBT. A 61-year-old woman with stage IIB cervical cancer underwent a combination of external beam radiotherapy (EBRT) at a dose of 50.4 Gy in 28 fractions and 2D-ICBT at a dose of 22 Gy in four fractions. As packs were well inserted around the uterus in all fractions of 2D-ICBT, the doses to the surrounding organs at risk (OAR) could be likely to be kept at low levels. She developed a huge fistula between the vagina and bladder approximately 2.5 years after radiotherapy (RT). She also developed a fistula between the vagina and small bowel approximately seven years after RT and underwent bypass from the small bowel to the transverse colon. The OAR were delineated using computed tomography for EBRT planning, and the cumulative dose of 2D-ICBT plus EBRT was evaluated as the source of toxicity. The cumulative dose converted to the equivalent dose in 2-Gy fractions (EQD2) was calculated using the linear-quadratic model with α/ß = 3 for the OAR. The cumulative EQD2 values of the minimum dose to the most irradiated 2 cc (D2cc) of the bladder and small bowel were 90.2 Gy and 79.5 Gy, respectively. These values exceeded the upper limits of the dosimetric criteria of the OAR, suggesting an association with both vaginal fistulas. As the adoption of IGBT is too slow in some countries, it is noteworthy that a reduced bladder volume may result in a significant increase in the dose to the small bowel and bladder in 2D-ICBT.

Relationship between radiation doses to heart substructures and radiation pneumonitis in patients with thymic epithelial tumors.

Radiation doses to the heart are potentially high in patients undergoing radiotherapy for thymoma or thymic carcinoma because of their origin site and propensity for pericardial invasion. We investigated potential relationships between radiation pneumonitis (RP) and the dosimetric parameters of lung and heart substructures in patients with thymic epithelial tumors. This retrospective study included 70 consecutive patients who received definitive or postoperative radiotherapy at a median dose of 58.3 Gy. Heart substructures were delineated according to a published atlas. The primary end point of ≥ grade 2 RP was observed in 13 patients (19%) despite a low lung dose; median lung V20 (i.e. percentage of the volume receiving at least 20 Gy) was only 16.6%. In a univariate analysis, four lung parameters, heart V35, three pulmonary artery (PA) parameters, two left ventricle parameters, and left atrium V35 were associated with the development of RP. In a multivariate analysis, only PA V35 remained significant (hazard ratio 1.04; 95% CI 1.01-1.07, p = 0.007). PA V35 of the RP versus non-RP groups were 84.2% versus 60.0% (p = 0.003). The moderate dose sparing of PA could be a candidate as a planning constraint for reducing the risk of RP in thoracic radiotherapy.

Impact of advanced radiotherapy techniques and dose intensification on toxicity of salvage radiotherapy after radical prostatectomy.

The safety and efficacy of dose-escalated radiotherapy with intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT) remain unclear in salvage radiotherapy (SRT) after radical prostatectomy. We examined the impact of these advanced radiotherapy techniques and dose intensification on the toxicity of SRT. This multi-institutional retrospective study included 421 patients who underwent SRT at the median dose of 66 Gy in 2-Gy fractions. IMRT and IGRT were used for 225 (53%) and 321 (76%) patients, respectively. At the median follow-up of 50 months, the cumulative incidence of late grade 2 or higher gastrointestinal (GI) and genitourinary (GU) toxicities was 4.8% and 24%, respectively. Multivariate analysis revealed that the non-use of either IMRT or IGRT, or both (hazard ratio [HR] 3.1, 95% confidence interval [CI] 1.8-5.4, p < 0.001) and use of whole-pelvic radiotherapy (HR 7.6, CI 1.0-56, p = 0.048) were associated with late GI toxicity, whereas a higher dose ≥68 Gy was the only factor associated with GU toxicities (HR 3.1, CI 1.3-7.4, p = 0.012). This study suggested that the incidence of GI toxicities can be reduced by IMRT and IGRT in SRT, whereas dose intensification may increase GU toxicity even with these advanced techniques.

Geometric discrepancy of image-guided radiation therapy in patients with prostate cancer without implanted fiducial markers using a commercial pseudo-CT generation method.

MR-only simulations provide pseudo-CT images which are segmented into 5 kinds of tissues from DIXON-based images. However, it is difficult to register pseudo-CT images to cone-beam CT (CBCT) images collected for image-guided radiation therapy (IGRT), because of the lack of contrasts among tissues. We validated gaps of IGRT between pseudo-CT or planning CT and CBCT for patients without implanted markers. We also propose calcification-assisted registration for MR-only simulation. We conducted retrospective analyses to verify the registration accuracy in 15 patients who underwent volumetric modulated arc therapy (VMAT) for prostate cancer. They underwent planning CT and pseudo-CT. Pseudo-CT images after deformable image registration (DIR) to planning CT images were rendered automatic pelvic bone matching to CBCT images. Patient positions on the pseudo-CT images after DIR were shifted on the basis of tissues around the prostate. We compared registration gaps between the images of planning CT and pseudo-CT with DIR, assuming that the tissue-based matching between the planning CT and CBCT was the gold standard. To the pseudo-CT images with DIR, calcifications detected on planning CT were added. We validated IGRT accuracy for a calcification-assisted registration. The absolute registration errors of the pseudo-CT, in comparison with the planning CT, were 0.34 ± 0.50 (lateral), 1.3 ± 1.3 (longitudinal), and 1.1 ± 1.0 mm (vertical). The absolute registration errors of the pseudo-CT with calcification contouring, in comparison with the planning CT, were 0.41 ± 1.0 (lateral), 0.87 ± 0.92 (longitudinal), and 0.74 ± 0.64 mm (vertical). Reduced absolute registration errors were observed in the proposed approach in the longitudinal (P < 0.01) and vertical (P < 0.01) dimensions when using calcification-assisted registration. The tissue-based registration using the MR-only simulation was not sufficient for use in patients with prostate cancer without implanted markers. The calcification-assisted registration might help to improve IGRT accuracy using MRI alone.