Hans T. Chung

Does Image-Guided Radiotherapy Improve Toxicity Profile in Whole Pelvic-Treated High-Risk Prostate Cancer? Comparison Between IG-IMRT and IMRT

PURPOSE To evaluate the impact of adding image-guided (IG) technique to intensity-modulated radiotherapy (IMRT) on dosimetric avoidance of organs at risk (OAR) and acute toxicities. METHODS AND MATERIALS A total of 25 consecutively treated patients (10 from National University Hospital and 15 from University of California San Francisco) with high-risk prostate cancer formed the study cohort. All received definitive IMRT with prophylactic nodal RT. Similar IMRT contouring and planning techniques were used at both centers. At the University of California, San Francisco, intraprostatic fiducial markers were used for daily pretreatment on-line corrections (IG-IMRT). In contrast, at the National University Hospital, no fiducial markers were used (IMRT). At the University of California, San Francisco, the planning target volume margins to the prostate were 2-3 mm. At the National University Hospital, they were 1 cm circumferentially, except for 0.5 cm posteriorly. The acute rectal and bladder toxicities and dosimetric endpoints to the planning target volume and organs at risk were compared. RESULTS The planning target volume dose coverage was not significantly different between IMRT and IG-IMRT for the prostate, seminal vesicles, and lymph nodes. The volume of rectum and bladder receiving >/=40, >/=60, and >/=70 Gy were all significantly less using IG-IMRT (p <0.001). IG-IMRT yielded lower acute Radiation Therapy Oncology Group Grade 2 rectal (80% vs. 13%, p = 0.004) and bladder (60% vs. 13%, p = 0.014) toxicities. CONCLUSIONS IG-IMRT, using daily target localization with fiducial markers, permits the use of smaller margins and correspondingly lower doses to the organs at risk, such as the rectum and bladder. These tangible gains appear to translate into lower clinically significant toxicities.

Is single fraction 15 Gy the preferred high dose-rate brachytherapy boost dose for prostate cancer?

BACKGROUND AND PURPOSE High dose-rate (HDR) brachytherapy is most commonly administered as a boost in two or more fractions combined with external beam radiotherapy (EBRT). Our purpose is to compare outcomes with a single fraction HDR boost to that with a standard fractionated boost in intermediate risk prostate cancer. MATERIALS AND METHODS Results of two sequential phase II clinical trials are compared. The Single Fraction protocol consists of 15 Gy HDR in one fraction followed by 37.5 Gy EBRT in 15 fractions over 3 weeks; the Standard Fractionation protocol consisted of two HDR fractions each of 10 Gy, 1 week apart, followed by 45 Gy EBRT in 25 fractions. Patients had intermediate risk disease, and were well balanced for prognostic factors. Patients were followed prospectively for efficacy, toxicity and health-related quality of life (Expanded Prostate Index Composite). Efficacy was assessed biochemically using the Phoenix definition, and by biopsy at 2 years. RESULTS The Single Fraction protocol accrued 123 patients and the Standard Fractionation protocol, 60. With a median follow-up of 45 and 72 months, respectively, the biochemical disease-free survival was 95.1% and 97.9% in the Single and Standard Fractionation trials (p=0.3528). Two-year prostate biopsy was positive in only 4% and 8%, respectively. There was no difference in late urinary or rectal toxicity rates, or in health-related quality of life between the two protocols. CONCLUSIONS The Single Fraction HDR protocol results in high disease control rate and low toxicity similar to our previous protocol using two HDR insertions, with significant savings in resources. While mature results with longer follow-up are awaited, a single 15 Gy may be considered as a standard fractionation regimen in combination with EBRT for men with intermediate risk disease.

A prospective comparison of MRI‐US fused targeted biopsy versus systematic ultrasound‐guided biopsy for detecting clinically significant prostate cancer in patients on active surveillance

In active surveillance (AS) patients: (i) To compare the ability of a multiparametric MRI (mpMRI)‐ultrasound biopsy system to detect clinically significant (CS) prostate cancer with systematic 12‐core biopsy (R‐TRUSBx), and (ii) To assess the predictive value of mpMRI with biopsy as the reference standard.

Can All Centers Plan Intensity-Modulated Radiotherapy (IMRT) Effectively? An External Audit of Dosimetric Comparisons Between Three-Dimensional Conformal Radiotherapy and IMRT for Adjuvant Chemoradiation for Gastric Cancer

PURPOSE To compare dosimetric endpoints between three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) at our center with limited IMRT experience, and to perform an external audit of the IMRT plans. METHODS AND MATERIALS Ten patients, who received adjuvant chemoradiation for gastric cancer, formed the study cohort. For standardization, the planning target volume (PTV) and organs at risk were recontoured with the assistance of a study protocol radiologic atlas. The cohort was replanned with CMS Xio to generate coplanar 3D-CRT and IMRT plans. All 10 datasets, including volumes but without the plans (i.e., blinded), were transmitted to an experienced center where IMRT plans were designed using Nomos Corvus (IMRT-C) and ADAC Pinnacle (IMRT-P). All IMRT plans were normalized to D95% receiving 45 Gy. RESULTS Intensity-modulated radiotherapy yielded higher PTV V45 (volume that receives > or = 45 Gy) (p < 0.001) than 3D-CRT. No difference in V20 was seen in the right (p = 0.9) and left (p = 0.3) kidneys, but the liver mean dose (p < 0.001) was superior with IMRT. For the external audit, IMRT-C (p = 0.002) and IMRT-P (p < 0.001) achieved significantly lower left kidney V20 than IMRT, and IMRT-P (p < 0.001) achieved lower right kidney V20 than IMRT. The IMRT-C (p = 0.003) but not IMRT-P (p = 0.6) had lower liver mean doses than IMRT. CONCLUSIONS At our institution with early IMRT experience, IMRT improved PTV dose coverage and liver doses but not kidney doses. An external audit of IMRT plans showed that an experienced center can yield superior IMRT plans.

LONG-TERM RESULTS OF FRONTALIS SUSPENSION USING IRRADIATED, BANKED FASCIA LATA

Summary: This study was undertaken to study the long-term rate of recurrence of ptosis and other postoperative complications after frontalis suspension using banked irradiated fascia lata. One hundred thirty-two lids of 72 patients underwent frontalis suspension between 1980 and 1989. The pre-operative diagnoses included severe congenital ptosis (83%), blepharophi-mosis (10%), third nerve palsy (4%), and chronic progressive external ophthalmoplegia (3%). The age at the time of surgery ranged from 5 months to 19 years, with an average of 3 years and 5 months. In 46 patients (64%), surgery was done before age 3 years. The follow-up time ranged from 6 to 15 years, with a mean and median of 10 years. Good to excellent lid height was achieved immediately after surgery in all but three patients. Recurrence of ptosis occurred in 20 cases (28%), and 28 lids (21%). The time to reoperation ranged from 1 to 7 years, with an average of 3 years. Sixteen patients (80%) with recurrence were younger than 3 years of age. Reaction to donor fascia lata occurred in only two patients (3%). Only one patient suffered from excessive exposure keratopathy and required revision of the sling. Banked fascia lata is easy to use and should be considered as an alternative suspensory material in children younger than 3 years of age with congenital ptosis. The long-term reoperation rate in this cohort of patients was higher than the 5% rate reported for autogenous fascia, but lower than that previously reported for banked fascia lata (50% at 8 years).

Health-Related Quality of Life After Single-Fraction High-Dose-Rate Brachytherapy and Hypofractionated External Beam Radiotherapy for Prostate Cancer

PURPOSE To investigate the change in health-related quality of life for men after high-dose-rate brachytherapy and external beam radiotherapy for prostate cancer and the factors associated with this change. METHODS AND MATERIALS Eligible patients had clinically localized intermediate-risk prostate cancer. The patients received high-dose-rate brachytherapy as a single 15-Gy implant, followed by external beam radiotherapy to 37.5 Gy in 15 fractions. The patients were monitored prospectively for toxicity (Common Terminology Criteria for Adverse Events, version 3.0) and health-related quality of life (Expanded Prostate Cancer Index Composite [EPIC]). The proportion of patients developing a clinically significant difference in the EPIC domain score (minimally important difference of >0.5 standard deviation) was determined and correlated with the baseline clinical and dosimetric factors. The study accrued 125 patients, with a median follow-up of 24 months. RESULTS By 24 months, 23% had Grade 2 urinary toxicity and only 5% had Grade 2 bowel toxicity, with no Grade 3 toxicity. The proportion of patients reporting a significant decrease in EPIC urinary, bowel, sexual, and hormonal domain scores was 53%, 51%, 45%, and 40% at 12 months and 57%, 65%, 51%, and 30% at 24 months, respectively. The proportion with a >1 standard deviation decrease in the EPIC urinary, bowel, sexual, and hormonal domain scores was 38%, 36%, 24%, and 20% at 12 months and 46%, 48%, 19%, and 8% at 24 months, respectively. On multivariate analysis, the dose to 10% of the urethra was associated with a decreasing EPIC urinary domain score (p = .0089) and, less strongly (p = .0312) with a decreasing hormonal domain score. No association was found between the prostate volume, bladder dose, or high-dose volume and urinary health-related quality of life. A high baseline International Index of Erectile Function score was associated (p = .0019) with a decreasing sexual domain score. The optimal maximal dose to 10% of the urethra cutpoint for urinary health-related quality of life was 120% of the prescription dose. CONCLUSION EPIC was a more sensitive tool for detecting the effects on function and bother than were the generic toxicity scales. The urethral dose had the strongest association with a deteriorating urinary quality of life.

Use of cone-beam imaging to correct for catheter displacement in high dose-rate prostate brachytherapy

PURPOSE To determine the magnitude of catheter displacement between time of planning and time of treatment delivery for patients undergoing high dose-rate (HDR) brachytherapy, the dosimetric impact of catheter displacement, and the ability to improve dosimetry by catheter readjustment. METHODS AND MATERIALS Twenty consecutive patients receiving single fraction HDR brachytherapy underwent kilovoltage cone-beam CT in the treatment room before treatment. If catheter displacement was apparent, catheters were adjusted and imaging repeated. Both sets of kilovoltage cone-beam CT image sets were coregistered off-line with the CT data set used for planning with rigid fusion of anatomy based on implanted fiducials. Catheter displacement was measured on both sets of images and dosimetry calculated. RESULTS Mean internal displacement of catheters was 11mm. This would have resulted in a decrease in mean volume receiving 100% of prescription dose (V(100)) from the planned 97.6% to 77.3% (p<0.001), a decrease of the mean dose to 90% of the prostate (D(90)) from 110.5% to 72.9% (p<0.001), and increase in dose to 10% of urethra (urethra D(10)) from 118% to 125% (p=0.0094). Each 1cm of catheter displacement resulted in a 20% decrease in V(100) and 36% decrease in D(90). Catheter readjustment resulted in a final treated mean V(100) of 90.2% and D(90) of 97.4%, both less than planned. Mean urethra D(10) remained higher at126% (p=0.0324). CONCLUSIONS Significantly, internal displacement of HDR catheters commonly occurs between time of CT planning and treatment delivery, even when only a single fraction is used. The adverse effects on dosimetry can be partly corrected by readjustment of catheter position.

Prostate high dose-rate brachytherapy as monotherapy for low and intermediate risk prostate cancer: Early toxicity and quality-of life results from a randomized phase II clinical trial of one fraction of 19 Gy or two fractions of 13.5 Gy

BACKGROUND AND PURPOSE Multi-fraction high dose-rate (HDR) brachytherapy as monotherapy is safe and effective for low and intermediate risk prostate cancer. Two or single fraction regimens have some radiobiological rationale. The purpose is to determine toxicity and effect on health related quality of life (HRQOL) of single fraction 19Gy or 13.5Gy×2. MATERIALS AND METHODS Eligible patients had low or intermediate risk prostate cancer, prostate volume <60cc, and no androgen deprivation use. 170 patients were randomized to receive either a single 19Gy or two fractions of 13.5Gy 1week apart. HRQOL was measured using the Expanded Prostate Index Composite (EPIC), toxicity with Common Terminology for Adverse Events (CTCAE) v4.0 and urinary symptoms with the International Prostate Symptom Score (IPSS). RESULTS Median follow-up is 20months. Grade 2 urinary toxicity occurred in 51% within the first 3months and in 31% thereafter with no significant difference between treatment arms. Ten patients (6%) developed urinary retention in the acute phase, although only 4 (2.4%) required a catheter for more than 48h. One Grade 3 acute (⩽3months) and late (>3months) urinary toxicity occurred. No more than 1% had any Grade 2 GI toxicity. The 2-fraction arm had a higher occurrence of grade 2 erectile dysfunction (29% vs. 11.5%, p=0.0249) and higher IPSS scores for the first year. Mean EPIC urinary scores at 12months decreased by 4.0 and 4.6, and sexual scores decreased by 8 and 15.9 (p=0.035) in the single and 2-fraction arms, respectively. No change occurred in the bowel or hormonal domains. CONCLUSIONS Single 19Gy and 13.5Gy×2 are both well tolerated. During the first 12months, urinary symptoms and erectile dysfunction are more common in the 2-fraction arm.

Outcomes of Adjuvant Chemoradiotherapy After a Radical Gastrectomy and a D2 Node Dissection for Gastric Adenocarcinoma

Purpose:Intergroup 0116 (INT-0116) established adjuvant chemoradiation as the standard of care for resected high-risk adenocarcinoma of the stomach in the United States. However, adjuvant chemoradiation remains controversial in many parts of Asia and Europe, where patients tend to undergo a more thorough D2 dissection. In INT-0116, 90% of patients had a limited or inadequate node dissection (D0 or D1). Also, 17% of patients in the chemoradiation arm had to discontinue treatment because of toxicities. The objectives of this retrospective study are to report the clinical outcomes of a cohort of patients who were mostly treated with a D2 node dissection and received adjuvant chemoradiation as per INT-0116, and the toxicities of chemoradiation in the context of more aggressive surgery. Methods:After the results of INT-0116 became apparent, we adopted an institutional policy whereby patients who would otherwise fit the inclusion criteria of INT-0116 received adjuvant chemoradiation. Between March 1999 and November 2004, 70 consecutive patients with pathologic stage T3, T4, or node-positive disease were treated according to the chemoradiation arm of INT-0116. Patients received intravenous 5-fluorouracil 425 mg/m2 and leucovorin 20 mg/m2 in cycles 1, 3, and 4. Concurrent chemoradiation was given in cycle 2 and consisted of bolus 5-fluorouracil and leucovorin and radiotherapy (45 Gy over 25 fractions in 5 weeks). All patients were operated on by dedicated Japan-trained Surgical Oncologists. Results:Sixty-seven patients (96%) had a D2 nodal dissection. Sixty-five patients (93%) had negative pathologic margins (R0 resection) and 5 (7%) had microscopically involved margins (R1 resection). The median follow-up was 27 months (range, 10.1–60.3). The 3-year overall survival, disease-free survival, and local control were 60.6%, 54.1%, and 84.3%, respectively. Of the 30 patients who relapsed, 5 (17%) had isolated locoregional recurrences only. The National Cancer Institute – Common Terminology Criteria version 3.0 acute grade 3 or 4 gastrointestinal and hematological toxicity rates were 15.7% and 4.3%, respectively. Toxicities led to chemotherapy dose-reductions in 18 patients and dose-delay in 19 patients. Including chemotherapy dose-reductions and delays, 66 patients (94%) completed the entire chemoradiation regimen. There were no toxicity-related deaths. Conclusion:In our cohort of 70 patients who had a more thorough D2 node dissection, adjuvant chemoradiation was well tolerated with acceptable toxicities and reasonable tumor control.

High dose-rate brachytherapy boost for intermediate risk prostate cancer: Long-term outcomes of two different treatment schedules and early biochemical predictors of success

BACKGROUND AND PURPOSE To report long-term cancer control rates following high dose-rate (HDR) brachytherapy boost for intermediate risk prostate cancer and explore early biochemical predictors of success. MATERIAL AND METHODS Results of two sequential phase II trials are updated and compared: (1) Single 15 Gy HDR-boost followed by external beam radiotherapy (EBRT) 37.5 Gy/15fractions, (2) Two HDR fractions of 10 Gy followed by EBRT 45 Gy/25fractions. Patients were followed prospectively for clinical and biochemical outcomes. Nadir PSA (nPSA) and PSA at 3-years were analyzed as continuous variables, and ROC analysis was used to identify the optimal cutoff values. Kaplan-Meier bDFS curves were generated and the log-rank test used to compare different groups RESULTS 183 patients were accrued; 123 to the single fraction trial and 60 to the standard fractionation trial, with a median follow-up of 74 months and 99 months, respectively. The 5-year biochemical relapse-free survival was 97.4% and 92.7%, respectively (p=0.995). Median nPSA was 0.08 ng/ml. Failure to achieve a nPSA <0.4 ng/ml was associated with a significantly higher rate of biochemical relapse (5-year bDFS: 100% vs. 72%; p<0.0001). CONCLUSION HDR boost with single fraction 15 Gy provides durable long-term biochemical disease-free survival. PSA nadir <0.4 ng/ml is associated with very low risk of biochemical failure.