Total wash elimination for solid phase peptide synthesis.

We present a process for solid phase peptide synthesis (SPPS) that completely eliminates all solvent intensive washing steps during each amino acid addition cycle. A key breakthrough is the removal of a volatile Fmoc deprotection base through bulk evaporation at elevated temperature while preventing condensation on the vessel surfaces with a directed headspace gas flushing. This process was demonstrated at both research and production scales without any impact on product quality and when applied to a variety of challenging sequences (up to 89 amino acids in length). The overall result is an extremely fast, high purity, scalable process with a massive waste reduction (up to 95%) while only requiring 10-15% of the standard amount of base used. This transformation of SPPS represents a step-change in peptide manufacturing process efficiency, and should encourage expanded access to peptide-based therapeutics.

Outcomes of 3D MRI based HDR brachytherapy with hybrid multichannel vaginal cylinder applicator and freehand needles for treatment of vaginal disease.

Freehand needles can be used with multichannel vaginal cylinders (MCVC) to cover vaginal cancer >7 mm thick or with supra-vaginal extension. We report our institutional outcomes using this novel hybrid technique. Patients with vaginal malignancies treated with HDR BT using MCVC plus freehand needles from 2014-2021 at our institution were identified. Clinical characteristics, details of brachytherapy, initial response, and overall local control (LC) outcomes were recorded. LC was analyzed via Kaplan-Meier method. 34 patients were identified with median follow-up 1.9 years. 19 patients had primary endometrial cancer with vaginal recurrence/disease, and remaining had primary vaginal cancer or other primaries. 7 patients had recurrence after previous RT course. 25 patients received EBRT with median dose 45 Gy in 25 fractions, and rest received BT alone. Median HR-CTV D90 for patients treated with EBRT plus BT was 77.4 Gy. 30 patients had complete local response to BT on initial examination and/or follow-up imaging. 1 and 2-year LC rates in patients without prior RT treated with EBRT + BT were 94.1% and 94.1%, respectively. 1 and 2-year LC rates for those without prior RT were 88.1% and 76.4%, respectively. 1 and 2-year LC rates for those with prior RT were 68.6% and 34.3%, respectively. 1 patient had vaginal laceration requiring surgical repair, and 1 patient developed small bowel obstruction 1 month after BT, with no additional acute grade 3+ toxicities identified. Our approach with MCVC plus freehand needles with MRI-based planning was feasible and safe, with excellent initial local response and low rate of serious toxicities.

Intraprostatic calcification and biochemical recurrence in men treated with cesium-131 prostate brachytherapy.

PURPOSE: Baseline intraprostatic calcification (IC) has been shown to be associated with a higher rate of biochemical recurrence (BCR) in men treated with iodine-125 prostate brachytherapy (PB). We evaluated this association in a cohort of men treated with cesium-131 PB. METHODS AND MATERIALS: We retrospectively reviewed the charts of all low- and intermediate-risk prostate cancer patients treated with cesium-131 PB +/- external beam radiotherapy (EBRT) at our institution from 2/2011 to 7/2018. Patients with < 24 months of follow up or those who received androgen deprivation therapy were excluded. Baseline IC status (defined as one or more ICs ≥ 5 mm) was determined on post-PB CT scans. Cox analysis was used to assess predictors of BCR and Kaplan-Meier survival curves were calculated. RESULTS: Two hundred and sixteen low- and intermediate-risk prostate cancer patients treated with cesium-131 PB +/- EBRT were included. Median follow up was 56.9 months (range 24.1-111.4). Overall, 76 (35.2%) patients had baseline IC and 140 (64.8%) did not. Baseline disease characteristics did not differ significantly between groups. On univariate Cox analysis, only risk group (p = 0.047) and initial PSA (p = 0.016) were significant predictors of BCR, whereas baseline IC was not (p = 0.11). The 5-year BCR-free survival in patients with versus without baseline IC was 97.7% versus 93.8% (p = 0.405), respectively. CONCLUSIONS: In a cohort of low- and intermediate-risk prostate cancer patients treated with cesium-131 PB, the rate of BCR in men with baseline IC was low and baseline IC was not associated with a higher risk of BCR.

Acute patient-reported bowel quality of life and rectal bleeding with the combination of prostate external beam radiation, low-dose-rate brachytherapy boost, and SpaceOAR.

PURPOSE: This study evaluates acute patient-reported bowel quality of life (QOL) and rectal bleeding in prostate cancer patients treated with combination external beam radiation (EBRT), low-dose-rate brachytherapy (LDR-BT), and SpaceOAR. MATERIALS AND METHODS: A retrospective review of prostate cancer patients treated with EBRT (45 Gy), cesium-131 LDR-BT (85 Gy), and SpaceOAR was conducted. Patient-reported acute (≤3 months after LDR-BT) bowel QOL and rectal bleeding was analyzed from Expanded Prostate Cancer Index Composite (EPIC) questionnaires. Five-point changes in mean bowel QOL scores were considered clinically significant. Clinically significant rectal bleeding was bleeding occurring more than "rarely" ("about half the time," "usually," or "always"), and clinically significant bleeding bother was considering bleeding a "small, moderate, or big problem." Outcomes were analyzed using descriptive statistics and paired t-tests. RESULTS: 69 patients were identified. Bowel summary, function, and bother scores clinically and significantly decreased 2 weeks after LDR-BT (79.9 ± 15.6, 80.5 ± 15.4, and 79.4 ± 18.1, respectively) compared with pre-EBRT scores (92.3 ± 9.1, 93.3 ± 9.0, and 92.6 ± 11.9, respectively) and pre-LDR-BT scores (91.1 ± 11.0, 91.6 ± 9.8, and 90.6 ± 13.3, respectively), but returned to clinical and statistical baseline pre-EBRT values at 3 months (88.7 ± 12.4, 88.8 ± 11.1, and 88.7 ± 14.5, respectively). The 3-month cumulative incidence of clinically significant rectal bleeding and bleeding bother was 4.35% and 2.90%, respectively. CONCLUSIONS: With combination EBRT, LDR-BT, and SpaceOAR, bowel QOL returned to the baseline 3 months after LDR-BT. Clinically significant rectal bleeding was <5%. Further followup will confirm if low acute rectal toxicity translates to reduced late toxicity.

Cesium-131 prostate brachytherapy: A single institutional long-term experience.

AIMS: To report on the PSA outcomes in men undergoing prostate seed implant (PSI) with Cesium-131 at a single institution. MATERIALS AND METHODS: All patients who underwent prostate brachytherapy with Cesium-131 (131Cs) at our institution and had the potential for at least 24 months of follow up were included in this study. Results are reported for the by NCCN risk group (low, low/high-intermediate, and high), as well as by treatment received (monotherapy, combination external beam radiation + PSI, or trimodal therapy with androgen deprivation). The Phoenix definition (absolute nadir plus 2 ng/mL) was used to define biochemical freedom from disease (BFD). RESULTS: Eight hundred and six men have undergone prostate brachytherapy with Cesium-131 at our institution, and 669 men were included in analysis. Median follow up was 60.0 months (range: 0-144 months). According to NCCN risk categories, 29.9% were low-, 55.6% intermediate-, and 14.5% high-risk. Using the Phoenix criteria, 5/10-year BFD was 97.1/95.3% for patients in the low-risk category, 94.0/90.1% for patients in the intermediate-risk category, and 86.2/56.6% for patients in the high-risk category. PSA ≤0.2 ng/dL at 4 years was predictive of 10 year biochemical control: 96.3% vs 70.4%, p < 0.001. CONCLUSIONS: The present study demonstrates that prostate brachytherapy with 131Cs achieves excellent long-term biochemical control.

Assessment of deep inspiration breath hold technique setup reproducibility using mega voltage imaging for left breast cancer radiation therapy-integrated network study.

We evaluated daily setup reproducibility of deep inspiration breath hold (DIBH) using mega voltage (MV) imaging for left breast cancer radiation therapy. Analysis of 109 left breast cancer patients across UPMC Hillman Cancer Center network treated using DIBH technique with daily MV imaging was done. Patient characteristics, MV imaging procedure used and inter-fraction directional shifts were collected. For the statistical analyses, we separated all patients into 2 groups in each of the following 3 categories; (1) obese (BMI ≥ 30) vs nonobese, (2) mastectomy vs lumpectomy, (3) internal mammary node (IMN) treatment vs no IMN treatment. The group mean inter-fraction directional shifts were as following: (1) 0.7 mm (superior), 0.8 mm (inferior); (2) 0.65 mm (left), 0.64 mm (right); (3) 0.89 mm (anterior), 0.83 mm (posterior). Also, any directional shift ≥ 2 mm, ≥ 3 mm, ≥ 4 mm, ≥ 5 mm, ≥ 10 mm was found to be 52.9%, 37.6%, 30.9%, 21.9%, 3.7% of total fractions, respectively. In the stratified analysis, obese patients had larger directional shifts (p < 0.05) and highly associated with number of fractions for ≥ 5 mm in any directional shift compared to nonobese patients (29% vs 17%; p = 0.04). DIBH setup for left breast cancer treatment at our large cancer center network was reproducible with any mean directional shifts less than 1.0 mm using MV imaging. Daily imaging would be more beneficial for obese patients compared to nonobese patients.

Early clinical experience with varian halcyon V2 linear accelerator: Dual-isocenter IMRT planning and delivery with portal dosimetry for gynecological cancer treatments.

PURPOSE: Varian Halcyon linear accelerator version 2 (The Halcyon 2.0) was recently released with new upgraded features. The aim of this study was to report our clinical experience with Halcyon 2.0 for a dual-isocenter intensity-modulated radiation therapy (IMRT) planning and delivery for gynecological cancer patients and examine the feasibility of in vivo portal dosimetry. METHODS: Twelve gynecological cancer patients were treated with extended-field IMRT technique using two isocenters on Halcyon 2.0 to treat pelvis and pelvic/or para-aortic nodes region. The prescription dose was 45 Gy in 25 fractions (fxs) with simultaneous integrated boost (SIB) dose of 55 or 57.5 Gy in 25 fxs to involved nodes. All treatment plans, pretreatment patient-specific QA and treatment delivery records including daily in vivo portal dosimetry were retrospectively reviewed. For in vivo daily portal dosimetry analysis, each fraction was compared to the reference baseline (1st fraction) using gamma analysis criteria of 4 %/4 mm with 90% of total pixels in the portal image planar dose. RESULTS: All 12 extended-field IMRT plans met the planning criteria and delivered as planned (a total of 300 fractions). Conformity Index (CI) for the primary target was achieved with the range of 0.99-1.14. For organs at risks, most were well within the dose volume criteria. Treatment delivery time was from 5.0 to 6.5 min. Interfractional in vivo dose variation exceeded gamma analysis threshold for 8 fractions out of total 300 (2.7%). These eight fractions were found to have a relatively large difference in small bowel filling and SSD change at the isocenter compared to the baseline. CONCLUSION: Halcyon 2.0 is effective to create complex extended-field IMRT plans using two isocenters with efficient delivery. Also Halcyon in vivo dosimetry is feasible for daily treatment monitoring for organ motion, internal or external anatomy, and body weight which could further lead to adaptive radiation therapy.

Image-based multichannel vaginal cylinder brachytherapy for the definitive treatment of gynecologic malignancies in the vagina.

PURPOSE: Brachytherapy is integral to vaginal cancer treatment and is typically delivered using an intracavitary single-channel vaginal cylinder (SCVC) or an interstitial brachytherapy (ISBT) applicator. Multi-channel vaginal cylinder (MCVC) applicators allow for improved organ-at-risk (OAR) sparing compared to SCVC while maintaining target coverage. We present clinical outcomes of patients treated with image-based high dose-rate (HDR) brachytherapy using a MCVC. METHODS AND MATERIALS: Sixty patients with vaginal cancer (27% primary vaginal and 73% recurrence from other primaries) were treated with combination external beam radiotherapy (EBRT) and image-based HDR brachytherapy utilizing a MCVC if residual disease thickness was 7 mm or less after EBRT. All pts received 3D image-based BT to a total equivalent dose of 70-80 Gy. RESULTS: The median high-risk clinical target volume was 24.4 cm3 (interquartile range [IQR], 14.1), with a median dose to 90% of 77.2 Gy (IQR, 2.8). After a median follow-up of 45 months (range, 11-78), the 4-year local-regional control, distant control, DFS, and OS rates were 92.6%, 76.1%, 64.0%, and 67.2%, respectively. The 4-year LRC rates were similar between the primary vaginal (92%) and recurrent (93%) groups (p = 0.290). Pts with lymph node positive disease had a lower rate of distant control at 4 years (22.7% vs. 89.0%, p < 0.001). There were no Grade 3 or higher acute complications. The 4-year rate of late Grade 3 or higher toxicity was 2.7%. CONCLUSIONS: Clinical outcomes of pts with primary and recurrent vaginal cancer treated definitively in a systematic manner with combination EBRT with image-guided HDR BT utilizing a MCVC applicator demonstrate high rates of local control and low rates of severe morbidity. The MCVC technique allows interstitial implantation to be avoided in select pts with ≤7 mm residual disease thickness following EBRT while maintaining excellent clinical outcomes with extended 4-year follow-up in this rare malignancy.

Workflow and efficiency in MRI-based high-dose-rate brachytherapy for cervical cancer in a high-volume brachytherapy center.

PURPOSE: We report the clinical workflow and time required for MRI-based image-guided brachytherapy (MR-IGBT) of cervical cancer patients in a high-volume brachytherapy center with 10 years of experiences to provide a practical guideline for implementing MR-IGBT into clinical use. METHODS AND MATERIALS: We recorded the time and workflow of each procedure step within the 40 consecutive ring and tandem applicator fractions of MR-IGBT by our multidisciplinary team. We divided the entire procedure into four sections based on where the procedure was performed: (1) applicator insertion under sedation, (2) MR imaging, (3) planning, and (4) treatment delivery. In addition, we compared the current procedure time to the initial procedure time when first implementing MR-IGBT in 2007-2008 via a retrospective review. RESULTS: Mean total procedure time was 149.3 min (SD 17.9, ranges 112-178). The multidisciplinary team included an anesthesia team, radiologist, radiation oncologist, nurses, radiation therapists, MRI technicians, dosimetrists, and physicists. The mean procedure time and ranges for each section (min) were as follows: (1) 56.2 (28.0-103.0), (2) 31.0 (19.0-70.0), (3) 44.3 (21.0-104.0), and (4) 17.8 (9.0-34.0). Under current setting, the combined mean procedure time for MR imaging and planning was 63.2 min. In comparison, the same procedure took 137.7 min in 2007-2008 period, which was significantly longer than the current workflow (p < 0.001). CONCLUSIONS: A skilled and dedicated multidisciplinary team is required for an efficient clinical workflow and delivery of MR-IGBT. Over the years, we have improved efficiency with clinical experience and continuous efforts in staff education.

Use of Functional Magnetic Resonance Imaging in Cervical Cancer Patients With Incomplete Response on Positron Emission Tomography/Computed Tomography After Image-Based High-Dose-Rate Brachytherapy.

PURPOSE: To investigate the correlation between positron emission tomography/computed tomography (PET/CT) response and outcome in the era of magnetic resonance imaging (MRI)-based planning and to assess whether the addition of diffusion-weighted MRI (DW-MRI) could more accurately classify treatment response and prognosis. METHODS AND MATERIALS: A retrospective chart review identified 244 consecutive patients with International Federation of Gynecology and Obstetrics stage IB1-IVA cervical cancer treated with concurrent chemoradiation, including high-dose-rate image-based brachytherapy, between 2007 and 2016. Image-based brachytherapy was delivered with 5 intracavitary/interstitial fractions, each 5 to 6 Gy per fraction. RESULTS: An complete response on posttreatment PET/CT (PET-CR) was discovered in 50 of 244 patients (20%) at a median interval of 3.3 months (range, 2.1-7.7 months) after treatment. After a median follow-up of 27 months, 2-year overall survival was 83% in all patients. Metabolic response significantly impacted 2-year overall survival (94% complete response on posttreatment PET/ CT vs 62.4% PET-IR, P < .001). Of those with a PET-IR, 16 of 50 patients (32%) suffered a local recurrence. A total of 27 of 50 patients with a PET-IR underwent DW-MRI; 11 of 27 posttreatment DW-MRI scans (40%) were interpreted as positive by central review (median apparent diffusion coefficient of 0.973 × 10-3 mm2/s). Of the DW-MRI-positive patients, 9 of 11 (81.8%) suffered a histologically confirmed local recurrence, and 2 of 11 patients are without evidence of disease. Additionally, 16 of 27 DW-MRI studies were interpreted as negative, and 2 of 16 (12.5%) of these patients suffered a local recurrence. Diffusion-weighted MRI findings significantly impacted 2-year overall survival (83% negative DW-MRI vs 36% positive DW-MRI, P = .049). CONCLUSION: Incomplete PET/CT response was documented in 20% of patients after image-based brachytherapy for locally advanced cervical cancer. Integration of DW-MRI helped accurately identify patients at risk for persistent disease and worse long-term outcome. The value of DW-MRI requires further validation in a large prospective dataset as this modality may allow earlier evaluation and salvage treatment in those with PET-IR.

Crystal structure of di-µ-chlorido-bis-[di-chlorido-bis-(methanol-κO)iridium(III)] dihydrate: a surprisingly simple chlorido-iridium(III) dinuclear complex with methanol ligands.

The reaction between IrCl3·xH2O in methanol led to the formation of small amounts of the title compound, [Ir2Cl6(CH3OH)4]·2H2O, which consists of two IrCl4O2 octa-hedra sharing an edge via chloride bridges. The mol-ecule lies across an inversion center. Each octa-hedron can be envisioned as being comprised of four chloride ligands in the equatorial plane with methanol ligands in the axial positions. A lattice water mol-ecule is strongly hydrogen-bonded to the coordinating methanol ligands and weak inter-actions with coordinating chloride ligands lead to the formation of a three-dimensional network. This is a surprising structure given that, while many reactions of iridium chloride hydrate are carried out in alcoholic solvents, especially methanol and ethanol, this is the first structure of a chloridoiridium compound with only methanol ligands.

MRI-guided high-dose-rate intracavitary brachytherapy for treatment of cervical cancer: the University of Pittsburgh experience.

PURPOSE: Image-based brachytherapy is increasingly used for gynecologic malignancies. We report early outcomes of magnetic resonance imaging (MRI)-guided brachytherapy. METHODS AND MATERIALS: Consecutive patient cases with FIGO stage IB1 to IVA cervical cancer treated at a single institution were retrospectively reviewed. All patients received concurrent cisplatin with external beam radiation therapy along with interdigitated high-dose-rate intracavitary brachytherapy. Computed tomography or MRI was completed after each application, the latter acquired for at least 1 fraction. High-risk clinical target volume (HRCTV) and organs at risk were identified by Groupe Européen de Curiethérapie and European SocieTy for Radiotherapy and Oncology guidelines. Doses were converted to equivalent 2-Gy doses (EQD2) with planned HRCTV doses of 75 to 85 Gy. RESULTS: From 2007 to 2013, 128 patients, median 52 years of age, were treated. Predominant characteristics included stage IIB disease (58.6%) with a median tumor size of 5 cm, squamous histology (82.8%), and no radiographic nodal involvement (53.1%). Most patients (67.2%) received intensity modulated radiation therapy (IMRT) at a median dose of 45 Gy, followed by a median brachytherapy dose of 27.5 Gy (range, 25-30 Gy) in 5 fractions. At a median follow up of 24.4 months (range, 2.1-77.2 months), estimated 2-year local control, disease-free survival, and cancer-specific survival rates were 91.6%, 81.8%, and 87.6%, respectively. Predictors of local failure included adenocarcinoma histology (P<.01) and clinical response at 3 months (P<.01). Among the adenocarcinoma subset, receiving HRCTV D90 EQD2 ≥84 Gy was associated with improved local control (2-year local control rate 100% vs 54.5%, P=.03). Grade 3 or greater gastrointestinal or genitourinary late toxicity occurred at a 2-year actuarial rate of 0.9%. CONCLUSIONS: This study constitutes one of the largest reported series of MRI-guided brachytherapy in North America, demonstrating excellent local control with acceptable morbidity. Dose escalation may be warranted when feasible for adenocarcinomas to offset the risk of local failure.

Image-based multichannel vaginal cylinder brachytherapy for vaginal cancer.

PURPOSE: To investigate the clinical feasibility and treatment outcomes of image-based high-dose-rate (HDR) brachytherapy using an intracavitary multichannel vaginal cylinder for the definitive treatment of vaginal cancers. METHODS AND MATERIALS: A total of 41 patients with vaginal cancer (24% primary vaginal and 76% recurrence from other gynecologic primaries) treated with definitive radiotherapy ± chemotherapy including image-based HDR brachytherapy with a multichannel vaginal cylinder were included in the study. Image-based brachytherapy was completed using either CT- (41%) or MR-based planning (59%) with each fraction. The high-risk clinical target volume was defined based on the pre- and postexternal beam radiotherapy gross tumor volume. Doses were converted to equivalent dose of 2Gy per fraction. Endpoints examined were dose-volume parameters and early clinical outcomes. RESULTS: The median high-risk clinical target volume was 24.2 cc (interquartile range [IQR], 12.6), with a median dose to 90% (D90) of 77.1 Gy (IQR, 3.4). The median dose to 2 cc (D(2 cc)) for the bladder, rectum, and sigmoid were 59.4 Gy (IQR, 5.6), 58.2 Gy (IQR, 4.1), and 52.3 Gy (IQR, 5.5), respectively. After a median followup of 16 months (range, 3-35), complete clinical response was documented in 98% of the patients. The 2-year local, regional, and distant control; and disease-free and overall survival were 93%, 100%, 81%, 78%, and 88%, respectively. The 2-year actuarial rate of late Grade 3 or higher toxicity was 4% overall with 0%, 0%, 0%, and 4% for vaginal, bladder, urethral, and gastrointestinal, respectively. CONCLUSIONS: Image-based HDR brachytherapy using an intracavitary multichannel cylinder seems feasible in definitive vaginal cancer treatment. The described clinical implementation shows promising early clinical outcomes with high rates of local control and little toxicity, which should be validated with extended followup.

Definitive salvage for vaginal recurrence of endometrial cancer: the impact of modern intensity-modulated-radiotherapy with image-based HDR brachytherapy and the interplay of the PORTEC 1 risk stratification.

PURPOSE: Data for salvage radiotherapy for recurrent endometrial cancer are limited especially in the era of modern radiotherapy including IMRT and 3-dimensional image-based HDR brachytherapy. Theoretically, modern radiotherapy reduces the dose to critical organs-at-risk and maximizes dose to the target volume, possibly decreasing morbidity and increasing tumor control. MATERIALS AND METHODS: Forty-one patients completing definitive salvage radiotherapy for vaginal recurrence of endometrial cancer from June 2004 to December 2013 were retrospectively reviewed. HDR Brachytherapy was completed using image-based planning with contouring/optimization with each fraction to a median dose of 23.75 Gy in 5 fractions. HDR brachytherapy was preceded by external beam radiotherapy predominately using an IMRT technique (90%) to a median dose of 45 Gy in 25 fractions. Toxicity was reported according to CTCAEv4. RESULTS: At a median follow-up of 18 months (range: 3-78), the clinical complete response rate was 95%. The 3-year local control, distant control, recurrence free survival, and overall survival were 95%, 61%, 68%, and 67%. Significant predictors of both distant failure and overall survival were primary prognostic factors of depth of myometrial invasion, FIGO stage, and FIGO grade. There was no grade 3+ acute toxicity; the 3-year rate of grade 3+ late toxicity was 8%. CONCLUSIONS: Salvage IMRT plus 3-dimensional image-based HDR brachytherapy shows excellent tumor control and minimal morbidity for vaginal recurrence of endometrial cancer. Anticipated salvage rates must be taken in the context of primary risk factors including depth of myometrial invasion, FIGO stage, and FIGO grade.

Neoadjuvant radiotherapy with or without chemotherapy followed by extrafascial hysterectomy for locally advanced endometrial cancer clinically extending to the cervix or parametria.

PURPOSE: For locally-advanced uterine cancer clinically extending to the cervix, two treatment paradigms exist: surgical staging radical hysterectomy with tailored adjuvant therapy or neoadjuvant therapy followed by a less extensive simple hysterectomy. Currently, insufficient data exists to guide consensus guidelines and practical application of preoperative radiotherapy. MATERIALS AND METHODS: Retrospective IRB approved cohort study from 1999 to 2014 of 36 endometrial cancer patients with clinical involvement of cervix±parametria treated with neoadjuvant external beam radiotherapy (45-50.4Gy in 25-28 fractions) and image-based HDR brachytherapy (5-5.5Gy times 3-4 fractions)±chemotherapy followed by extrafascial hysterectomy performed at a median of 6weeks after radiotherapy. RESULTS: All patients had clinical cervical extension, 50% also had parametria extension, and 31% had nodal involvement. At the time of surgery 91% had no clinical cervical involvement, 58% had no pathologic cervical involvement, and all had margin negative resection. The pathologic complete response rate was 24%. Median follow-up from the time of surgery was 20months (range: 0-153). The 3-year local control, regional control, distant control, disease free survival and overall survival rates were 96%, 89%, 84%, 73%, and 100%. The 3-year rate of grade 3 complications was 11%, with no grade 4+ toxicity. CONCLUSIONS: Neoadjuvant radiation therapy±chemotherapy followed by extrafascial hysterectomy appears to be a viable option for patients with endometrial cancer clinically extending to the cervix and parametria. The HDR brachytherapy schema of 5-5.5Gy times 3-4 fractions, for a cumulative EQD2 of 60-70Gy, is well tolerated with high rates of clinical and pathological response.

Urethral dosimetry and toxicity with high-dose-rate interstitial brachytherapy for vaginal cancer.

PURPOSE: The tolerance and complication rates of the urethra are unknown for the interstitial high-dose-rate brachytherapy (HDR-BT) for vaginal cancer. METHODS AND MATERIALS: Patients with vaginal cancer near/involving the urethra who were treated with HDR-BT between 2008 and 2011 were included. Patients received mean external beam dose of 48.0Gy followed by mean HDR-BT dose of 4.5Gy/fraction for five fractions. With CT-based planning, the urethra was contoured from the bladder neck to the meatus. Doses were converted to the biologically equivalent dose in 2Gy/fraction (EQD2). RESULTS: A total of 16 patients were included, and the EQD2D90 was 74.9Gy. The urethral volume was 1.31cm(3), and the EQD2 to 0.1 and 1cm(3) were 76.2 and 48.9Gy, respectively. Two of the 6 patients with urethral involvement developed urethral necrosis. The D90 for these 2 patients was 76.8Gy, and the urethral doses to 0.1 and 1cm(3) were 95.1 and 45.8, respectively. Those who developed severe urethral toxicity had a trend to urethral EQD2 (95.1Gy vs. 73.4Gy, p=0.1) and significantly higher dose per fraction of HDR-BT to 0.1cm(3) of the urethra (5.7Gy vs. 3.7Gy, p=0.02) when compared with those who did not develop severe urethral toxicity. CONCLUSIONS: This study is among the first to assess urethral dosimetry for patients treated with HDR-BT for vaginal cancer. Patients who received five fractions of higher than 5Gy/fraction to 0.1cm(3) of urethra (estimated EQD2 of 85Gy) are at increased risk of severe urethral toxicity.

Is there an advantage to delivering breast boost in the lateral decubitus position?

BACKGROUND: The purpose of this study was to compare the change in depth of target volume and dosimetric parameters between the supine and lateral decubitus positions for breast boost treatment with electron beam therapy. METHODS: We analyzed 45 patients who were treated, between 2009-2010, with whole breast radiation (WBRT) followed by a tumor bed boost in the lateral decubitius position. Tumor bed volume, distance from skin to the maximal depth of the tumor bed, D90 (dose covering 90% of the tumor bed volume), maximal dose, electron energy and doses to heart and lungs were compared. Additional variables of body mass index (BMI) and tumor bed location were also analyzed to see if there was a benefit limited to any subgroup. RESULTS: Median BMI for the 45 patients treated was 30.6 (20.6-42.4). When comparing the supine scan to the lateral decubitus scan, there was no significant difference in the tumor bed volume (p = 0.116). There was a significant difference between depth to the tumor bed in the supine scan and lateral decubitus scan (p < 0.001). The mean maximum doses and D90 between the two scans were 110.7 (100.0-133.0)% vs 106.1 (95.1-116.9)% (p < 0.05) and 93.9 (81.3-01.0-101.0)% vs. 98.2 (89.1-108.0)% (p = 0.004) respectively. There was no difference in dose delivered to the lungs or heart between the two scans (p = 0.848 and p = 0.992 respectively). On subset analysis, there was a difference in depth to tumor that was seen across all BMI classes, including normal (p ≤ 0.001, overweight (p ≤ 0.001) and obese (p ≤ 0.001). The majority of patients had a tumor in the upper outer quadrant (77.8%) and on subset analysis, there was a significant difference in tumor bed volume (p < 0.01), depth to tumor (p < 0.01), tumor bed coverage [D90] (p < 0.05), maximum dose (p < 0.05) and energy (p < 0.001) for this location. CONCLUSIONS: Delivering a tumor bed boost in the lateral decubitus position reduces the distance to the tumor bed allowing for a lower energy treatment to be used to treat breast cancer. It improves coverage and decreases maximal dose to the target volume, all of which would help reduce skin morbidities and should be considered for patients with upper outer quadrant disease, irrespective of BMI status.

High-dose-rate interstitial computed tomography-based brachytherapy for the treatment of cervical cancer: early results.

PURPOSE: There is limited published data on high-dose-rate interstitial brachytherapy (HDRBT) for cervical cancer resulting in no consensus on a fractionation schedule. This study reports our experience of CT-based HDRBT for treating locally advanced cervical cancer. METHODS AND MATERIALS: Forty-seven patients diagnosed with Stage IIB-IVA cervical cancer not suitable for intracavitary brachytherapy were treated with HDRBT from March 2005 to November 2010. All patients received external beam radiation therapy with a median dose of 45Gy and all had one interstitial implantation followed by 3.75-5Gy×5 fractions in a twice daily (BID) schedule. Total doses for clinical target volume and organs at risk, including rectum, bladder, and sigmoid, were summated and normalized to a biologically equivalent dose of 2Gy per fraction. At 3 months posttherapy, early response was assessed with clinical examination and positron emission tomography (PET/CT) imaging. RESULTS: Median clinical target volume D(90) (dose delivered to 90% of the clinical target volume) was 76.3 (59.0-86.9) Gy and the 2cc dose to the bladder, rectum, and sigmoid colon organs were 70.2 (55.9-77.7), 65.8 (54.9-80.6), and 56.5 (45.0-71.2) Gy, respectively. Posttreatment, 12 patients had evidence of persistent disease on PET/CT. Eleven of the 35 patients who had complete response developed recurrences. Two patients developed late Radiation Therapy Oncology Group ≥3 rectal toxicities. Two-year actuarial local control, disease-free survival, overall survival, and Grade ≥3 toxicities were 61%, 43%, 59%, and 10%, respectively. CONCLUSION: Our approach of a single implantation procedure followed by five fractions of HDRBT was well tolerated with early results demonstrating a moderate response and local control rate with acceptable toxicities.

Is there any advantage to three-dimensional planning for vaginal cuff brachytherapy?

PURPOSE: To evaluate whether the three-dimensional (3D) CT-based high-dose rate planning for vaginal cuff brachytherapy offers any advantage over the 2D orthogonal film-based library plans for adjuvant treatment of endometrial cancers. METHODS AND MATERIALS: Eighty-four consecutive postoperative patients with endometrial cancers treated with vaginal brachytherapy as an adjuvant treatment were analyzed. Patients had CT imaging-based plans. Clinical target volume (CTV) was defined by expanding the upper 2.5cm of the cylinder by 5mm in all directions and editing to exclude any bladder and rectum. The dose prescribed was 7Gy with three fractions at 5mm depth with a goal of D(90) ≥100% for CTV. All dosimetric parameters were compared with library-based plans. RESULTS: Both the 2D- and 3D-based plans allowed sufficient dosage to the CTV (D(90) for CTV ≥95%). The doses of 0.1, 1, and 2cc to rectum and bladder were significantly higher for 2D-based plans (p≤0.001 in each parameter). D(2 cc) with 2D plan for rectum and bladder was >100% (range: 103-116%) in 7 (8%) and 6 (7%) patients, respectively. In contrast, no patients had D(2 cc) >100% with 3D planning for both organs. CONCLUSION: Three-dimensional CT-based planning for high-dose rate vaginal cuff brachytherapy helps to decrease dose to critical organs without compromising coverage of CTV by customizing the dosimetry according to individual patient anatomy.

Radiation dose delivered to the proximal penis as a predictor of the risk of erectile dysfunction after three-dimensional conformal radiotherapy for localized prostate cancer.

PURPOSE/OBJECTIVE: In this study, we evaluated in a serial manner whether radiation dose to the bulb of the penis is predictive of erectile dysfunction, ejaculatory difficulty (EJ), and overall satisfaction with sex life (quality of life) by using serial validated self-administered questionnaires. METHODS AND MATERIALS: Twenty-nine potent men with AJCC Stage II prostate cancer treated with three-dimensional conformal radiation therapy alone to a median dose 72.0 Gy (range: 66.6-79.2 Gy) were evaluated by determining the doses received by the penile bulb. The penile bulb was delineated volumetrically, and the dose-volume histogram was obtained on each patient. RESULTS: The median follow-up time was 35 months (range, 16-43 months). We found that for D(30), D(45), D(60), and D(75) (doses to a percent volume of PB: 30%, 45%, 60%, and 75%), higher than the corresponding median dose (defined as high-dose group) correlated with an increased risk of impotence (erectile dysfunction firmness score = 0) (odds ratio [OR] = 7.5, p = 0.02; OR = 7.5, p = 0.02; OR = 8.6, p = 0.008; and OR = 6.9, p = 0.015, respectively). Similarly, for EJD D(30), D(45), D(60), and D(75), doses higher than the corresponding median ones correlated with worsening ejaculatory function score (EJ = 0 or 1) (OR = 8, p = 0.013; OR = 8, p = 0.013; OR = 9.2, p = 0.015; and OR = 8, p = 0.026, respectively). For quality of life, low (< or =median dose) dose groups of patients improve over time, whereas high-dose groups of patients worsen. CONCLUSIONS: This study supports the existence of a penile bulb dose-volume relationship underlying the development of radiation-induced erectile dysfunction. Our data may guide the use of inverse treatment planning to maximize the probability of maintaining sexual potency after radiation therapy.