A phase III, multicenter, randomized controlled trial of preoperative versus postoperative stereotactic radiosurgery for patients with surgically resectable brain metastases.

BACKGROUND: Postoperative stereotactic radiosurgery (SRS) is a standard management option for patients with resected brain metastases. Preoperative SRS may have certain advantages compared to postoperative SRS, including less uncertainty in delineation of the intact tumor compared to the postoperative resection cavity, reduced rate of leptomeningeal dissemination postoperatively, and a lower risk of radiation necrosis. The recently published ASCO-SNO-ASTRO consensus statement provides no recommendation for the preferred sequencing of radiotherapy and surgery for patients receiving both treatments for their brain metastases. METHODS: This multicenter, randomized controlled trial aims to recruit 88 patients with resectable brain metastases over an estimated three-year period. Patients with ten or fewer brain metastases with at least one resectable, fulfilling inclusion criteria will be randomized to postoperative SRS (standard arm) or preoperative SRS (investigational arm) in a 1:1 ratio. Randomization will be stratified by age (< 60 versus ≥60 years), histology (melanoma/renal cell carcinoma/sarcoma versus other), and number of metastases (one versus 2-10). In the standard arm, postoperative SRS will be delivered within 3 weeks of surgery, and all unresected metastases will receive primary SRS. In the investigational arm, enrolled patients will receive SRS of all brain metastases followed by surgery of resectable metastases within one week of SRS. In either arm, single fraction or hypofractionated SRS in three or five fractions is permitted. The primary endpoint is to assess local control at 12 months in both arms. Secondary endpoints include local control at other time points, regional/distant brain recurrence rates, leptomeningeal recurrence rates, overall survival, neurocognitive outcomes, and adverse radiation events including radiation necrosis rates in both arms. DISCUSSION: This trial addresses the unanswered question of the optimal sequencing of surgery and SRS in the management of patients with resectable brain metastases. No randomized data comparing preoperative and postoperative SRS for patients with brain metastases has been published to date. TRIAL REGISTRATION: Clinicaltrials.gov , NCT04474925; registered on July 17, 2020. Protocol version 1.0 (January 31, 2020). SPONSOR: Alberta Health Services, Edmonton, Canada (Samir Patel, MD).

Dosimetric predictors of toxicity in a randomized study of short-course vs conventional radiotherapy for glioblastoma.

PURPOSE: There is no consensus on appropriate organ at risk (OAR) constraints for short-course radiotherapy for patients with glioblastoma. Using dosimetry and prospectively-collected toxicity data from a trial of short-course radiotherapy for glioblastoma, this study aims to empirically examine the OAR constraints, with particular attention to left hippocampus dosimetry and impact on neuro-cognitive decline. METHODS AND MATERIALS: Data was taken from a randomized control trial of 133 adults (age 18-70 years; ECOG performance score 0-2) with newly diagnosed glioblastoma treated with 60 Gy in 30 (conventional arm) versus 20 (short-course arm) fractions of adjuvant chemoradiotherapy (ClinicalTrials.gov Identifier: NCT02206230). The delivered plan's dosimetry to the OARs was correlated to prospective-collected toxicity and Mini-Mental State Examination (MMSE) data. RESULTS: Toxicity events were not significantly increased in the short-course arm versus the conventional arm. Across all OARs, delivered radiation doses within protocol-allowable maximum doses correlated with lack of grade ≥ 2 toxicities in both arms (p < 0.001), while patients with OAR doses at or above protocol limits correlated with increased grade ≥ 2 toxicities across all examined OARs in both arms (p-values 0.063-0.250). Mean left hippocampus dose was significantly associated with post-radiotherapy decline in MMSE scores (p = 0.005), while the right hippocampus mean dose did not reach statistical significance (p = 0.277). Compared to the original clinical plan, RapidPlan left hippocampus sparing model decreased left hippocampus mean dose by 43 % (p < 0.001), without compromising planning target volume coverage. CONCLUSIONS: In this trial, protocol OAR constraints were appropriate for limiting grade ≥ 2 toxicities in conventional and short-course adjuvant chemoradiotherapy for glioblastoma. Higher left hippocampal mean doses were predictive for neuro-cognitive decline post-radiotherapy. Routine contouring and use of dose constraints to limit hippocampal dose is recommended to minimize neuro-cognitive decline in patients with glioblastoma treated with chemoradiotherapy.

Conventional Versus Hypofractionated Radiation for High-Risk Prostate Cancer Patients (CHIRP): 24-Month Patient-Reported Outcomes of the Randomized Phase 2 CHIRP Trial.

PURPOSE: In this study, we report the 24-month patient-reported outcomes of the randomized phase 2 CHIRP trial that compared conventional and hypofractionated radiation therapy (RT) in the treatment of high-risk prostate cancer. METHODS AND MATERIALS: Men with high-risk localized prostate cancer were randomized to either conventional (78 Gy/39 fractions) or hypofractionated RT (68 Gy/25 fractions). All patients received pelvic nodal RT and adjuvant androgen deprivation therapy. Quality of life (QoL) data were collected through the expanded prostate cancer index composite and the short-form 12 (SF-12) health-related QoL questionnaire at baseline and at 3, 6, 12, 18, and 24 months posttreatment. We assessed change from baseline to account for differences in baseline comorbidities. Independent t test was used to identify differences between the 2 groups. RESULTS: Ninety-six participants were included in the QoL analysis, 49 in the hypofractionation arm and 47 in the standard fractionation arm. Urinary and sexual scores were similar between the 2 arms at all time points. Bowel bother scores exhibited a consistent trend favoring the standard arm from 3- to 18-months posttreatment and were statistically significant at 12 months (P = .016). SF-12 physical component scores showed a consistent trend favoring the hypofractionation arm from 6- to 18-months posttreatment and were statistically significant at 18 months (P = .017). At 24 months, there were no significant differences in QoL scores between the 2 groups. CONCLUSIONS: At 24 months post-RT, there were no major differences in patient-reported QoL between standard and hypofractionated RT. Early statistically significant differences in bowel bother and SF-12 physical component scores were no longer present at 24 months.

Early Metabolic Changes in 1H-MRSI Predictive for Survival in Patients With Newly Diagnosed High-grade Glioma.

BACKGROUND: The purpose of this study was to evaluate the association of specific threshold values for changes in metabolic metrics measured from 1H magnetic resonance spectroscopic imaging (MRSI) to survival of patients with high-grade glioma treated with multimodality therapy. PATIENTS AND METHODS: Forty-four patients with newly diagnosed high-grade glioma were prospectively enrolled. Serial MRI and MRSI scans provided measures of tumor choline, creatine, and N-acetylaspartate (NAA). Cox regression analyses adjusted for patient age, KPS, and delivery of concurrent chemotherapy were used to assess the association of changes in metabolic metrics with survival. RESULTS: Median follow-up time for patients at risk was 13.4 years. Overall survival (OS) was longer in patients with ≤20% increase (vs. >20%) in normalized choline (p=0.024) or choline/NAA (p=0.024) from baseline to week 4 of RT. During this period, progression-free survival (PFS) was longer in patients with ≤40% increase (vs. >40%) in normalized choline (p=0.013). Changes in normalized creatine, choline/creatine, and NAA/creatine from baseline to mid-RT were not associated with OS. From baseline to post-RT, changes in metabolic metrics were not associated with OS or PFS. CONCLUSION: Threshold values for serial changes in choline metrics on mid-RT MRSI associated with OS and PFS were identified. Metabolic metrics at post-RT did not predict for these survival endpoints. These findings suggest a potential clinical role for MRSI to provide an early assessment of treatment response and could enable risk-adapted therapy in clinical trial development and clinical practice.

Clinical Outcomes of the CHIRP Trial: A Phase II Prospective Randomized Trial of Conventionally Fractionated Versus Moderately Hypofractionated Prostate and Pelvic Nodal Radiation Therapy in Patients With High-Risk Prostate Cancer.

PURPOSE: Hypofractionated radiation therapy (HFRT) may offer treatment advantages for patients with prostate cancer. However, HFRT may also increase the risk of gastrointestinal (GI) or genitourinary (GU) toxicity compared with conventionally fractionated radiation therapy (CFRT). Several large trials have found that HFRT is well tolerated in mixed risk population studies. Here, we report on a phase II, randomized controlled study conducted to evaluate these endpoints in exclusively high-risk patients with prostate cancer treated with prostate and pelvic nodal radiation. METHODS AND MATERIALS: After giving informed consent, patients with high-risk prostate cancer were randomly assigned to prostate plus pelvic nodal radiation therapy with either HFRT (68 Gy in 25 fractions) or CFRT (78 Gy in 39 fractions) and 18 months of androgen suppression therapy. Toxicity was scored using the Common Terminology Criteria for Adverse Events (version 4.0). Biochemical failure was determined by the Phoenix definition. Patients were analyzed on an intention-to-treat basis. RESULTS: From 2012 to 2018, 111 patients with high-risk prostate cancer were enrolled and 109 patients were treated. The cumulative incidence of grade 2 or higher acute GI toxicity was not significantly different between the arms (HFRT 18.9% vs CFRT 21.8%; P = .812). Similarly, acute GU (HFRT 30.2% vs CFRT 30.9%; P = 1.00), late GI (HFRT 16.0% vs CFRT 10.0%; P = .554), and late GU (HFRT 16.0% vs CFRT 6.0%; P = .200) were not significantly different between the arms. Median follow-up was 38.0 months (4.8-77.8 months). The 3-year biochemical recurrence-free survival was not significantly different between the 2 arms (97.3% for HFRT vs 91.0% for CFRT; P = .606). The 3-year overall survival was 94.8% in the HFRT arm and 100.0% in the CFRT arm (P = .116). CONCLUSIONS: HFRT and CFRT using intensity modulated radiation therapy were both well tolerated for patients with high-risk prostate cancer and resulted in similar 3-year biochemical recurrence-free survival and overall survival.

Informal caregiver quality of life in a palliative oncology population.

PURPOSE: Many patients with advanced cancer receive primary supports from informal caregivers (IC). As patient health deteriorates, IC assume increasing responsibility, often accompanied by distress. We investigated the quality of life (QOL) of IC of patients referred to a palliative radiotherapy (PRT) program. METHODS: IC accompanying patients to a dedicated PRT clinic completed a survey based on the validated Caregiver Quality of Life Index-Cancer (CQOLC). Demographics, burden, and engagement in support services were evaluated. Summary statistics were calculated, and parameters were assessed for association with CQOLC scores by a generalized linear model. RESULTS: Two hundred one surveys were analyzed representing 197 unique patients. The mean age was 68.3 years, with predominantly lung (25.0%) and prostate (19.3%) malignancies. 24.4% had been in hospital/long-term care within the previous 7 days. IC were 60.8% female, and 60.6% were the patient's spouse. 69.5% lived with the patient and 38.3% were additionally employed. IC spent a daily mean of 6.6 h (SD 7) assisting with instrumental (72.5%) and basic (37.5%) activities of daily living. Mean CQOLC score was 82.1/140 (SD 20). 63.8% of IC had previously accessed support service(s), most commonly home care (37.2%) and pharmacy (29.1%). 55.9% indicated interest in services not yet accessed. Multivariate analysis revealed additional employment, cohabitation, poor patient performance status, and interest in accessing more support services significantly correlated with higher IC burden. CONCLUSIONS: Employing the CQOLC to screen IC of patients referred to a PRT program permits early identification of vulnerable IC to facilitate linkage with appropriate supports.

Patient Reported Outcomes in NRG Oncology RTOG 0938, Evaluating Two Ultrahypofractionated Regimens for Prostate Cancer.

PURPOSE: There is considerable interest in very short (ultrahypofractionated) radiation therapy regimens to treat prostate cancer based on potential radiobiological advantages, patient convenience, and resource allocation benefits. Our objective is to demonstrate that detectable changes in health-related quality of life measured by the bowel and urinary domains of the Expanded Prostate Cancer Index Composite (EPIC-50) were not substantially worse than baseline scores. METHODS AND MATERIALS: NRG Oncology's RTOG 0938 is a nonblinded randomized phase 2 study of National Comprehensive Cancer Network low-risk prostate cancer in which each arm is compared with a historical control. Patients were randomized to 5 fractions (7.25 Gy in 2 weeks) or 12 fractions (4.3 Gy in 2.5 weeks). The co-primary endpoints were the proportion of patients with a change in EPIC-50 bowel score at 1 year (baseline to 1 year) >5 points and in EPIC-50 urinary score >2 points tested with a 1-sample binomial test. RESULTS: The study enrolled 127 patients to 5 fractions (121 analyzed) and 128 patients to 12 fractions (125 analyzed). Median follow-up for all patients at the time of analysis was 3.8 years. The 1-year frequency for >5 point change in bowel score were 29.8% (P < .001) and 28.4% (P < .001) for 5 and 12 fractions, respectively. The 1-year frequencies for >2 point change in urinary score were 45.7% (P < .001) and 42.2% (P < .001) for 5 and 12 fractions, respectively. For 5 fractions, 32.9% of patients had a drop in 1-year EPIC-50 sexual score of ≥11 points (P = .34); for 12 fractions, 30.9% of patients had a drop in 1-year EPIC-50 sexual score of ≥ 11 points (P = .20). Disease-free survival at 2 years is 99.2% (95% confidence interval: 97.5-100) in the 5-fraction arm and 97.5% (95% confidence interval: 94.6-100) in the 12-fraction arm. There was no late grade 4 or 5 treatment-related urinary or bowel toxicity. CONCLUSIONS: This study confirms that, based on changes in bowel and urinary domains and toxicity (acute and late), the 5- and 12-fraction regimens are well tolerated. These ultrahypofractionated approaches need to be compared with current standard radiation therapy regimens.

Initial clinical assessment of "center-specific" automated treatment plans for low-dose-rate prostate brachytherapy.

PURPOSE: To report results of an initial pilot study assessing iodine-125 prostate implant treatment plans created automatically by a new seed-placement method. METHODS AND MATERIALS: A novel mixed-integer linear programming method incorporating spatial constraints on seed locations in addition to standard dose-volume constraints was used to place seeds. The approach, described in detail elsewhere, was used to create treatment plans fully automatically on a retrospective basis for 20 patients having a wide range of prostate sizes and shapes. Corresponding manual plans used for patient treatment at a single institution were combined with the automated plans, and all 40 plans were anonymized, randomized, and independently evaluated by five clinicians using a common scoring tool. Numerical and clinical features of the plans were extracted for comparison purposes. RESULTS: A full 51% of the automated plans were deemed clinically acceptable without any modification by the five practitioners collectively versus 90% of the manual plans. Automated plan seed distributions were for the most part not substantially different from those for the manual plans. Two observed shortcomings of the automated plans were seed strands not intersecting the prostate and strands extending into the bladder. Both are amenable to remediation by adjusting existing spatial constraints. CONCLUSIONS: After spatial and dose-volume constraints are set, the mixed-integer linear programming method is capable of creating prostate implant treatment plans fully automatically, with clinical acceptability sufficient to warrant further investigation. These plans, intended to be reviewed and refined as necessary by an expert planner, have the potential to both save planner time and enhance treatment plan consistency.

Unexpected Seed Migration in Prostate Brachytherapy Implants Coincident with Change in Seed Stranding Product.

PURPOSE: This study was undertaken to determine if significant seed migration occurred when our institution changed seed products by comparing patterns of seed migration in implants containing different stranding material. METHODS AND MATERIALS: Day 0 and Day 30 CT scans were registered by the contoured prostate center of mass. An implant reconstruction program identified seeds on CT according to the pre-plan, enabling one-to-one correspondence between Day 0 and Day 30 seeds. Significant seed migration was defined by review of seeds that migrated > 2 cm outside the prostate or appearance in unexpected locations.   Results: Twenty-five (149, 16.8%) new strands displayed movement > 2 cm between Day 0 and Day 30 compared with just 2/118 (1.7%) of the standard strands. Six out of 26 (23%) patients with new strands displayed significant migration compared with 2/13 (14%) of patients with standard strands. In the six patients with new strands and significant migration, a mean of four strands (17%, range: 2-8 per patient) migrated significantly with 65% due to whole strand migration, 25% due to strand breakage, and 10% strand clumping. In the control group, only two strands (2%) migrated significantly, both due to strand breakage. Despite the greater seed movement with the new strands, Day 0 and Day 30 dosimetry was acceptable. CONCLUSION: In this short report, we identified that a change to a new strand type was associated with unexpected significant seed movement compared to our typical strands. Since seed movement can arise from unexpected causes, it is important to maintain quality assurance practices when a change in technique or infrastructure is instituted.

Quantifying 125I placement accuracy in prostate brachytherapy using postimplant transrectal ultrasound images.

PURPOSE: The quality of a prostate brachytherapy implant depends on the accurate placement of sources. This study quantifies the misplacement of 125I sources from the intended location using intraoperative ultrasound images. METHODS AND MATERIALS: 125I sources were manually identified in the postimplant ultrasound images and compared to the preoperative plan. Due to the subjective nature of the identifying sources, only sources identified with high confidence were included in the analysis. Misplacements from the original intended coordinate were measured along the X, Y, and Z axes and were stratified between overall misplacements and regions of the prostate gland. RESULTS: A total of 1619 125I sources using 357 strands were implanted in 15 patients' prostate glands, with 1197 (74%) confidently identified for misplacement analysis. The overall mean displacement was 0.49 cm and in the X, Y, and Z direction was 0.13, 0.15, and 0.38 cm, respectively. Greater source misplacement occurred in the anterior part of the prostate gland than the posterior part of the prostate gland by a factor 1.33 (p < 0.0001). Comparing sources in the lateral vs. medial regions of the prostate, no statistically significant differences on source misplacement were observed. Comparing misplacement in the base vs. midgland vs. apex identified the greatest difference between the base and midgland by a factor of 1.29 (p < 0.0001). CONCLUSIONS: This study has identified significant misplacement of 125I sources from their intended locations with the greatest error misplacement occurring in the Z direction. Source misplacement tends to occur more commonly in the anterior gland and in the base of the prostate.

Late Toxicity and Outcomes in High-risk Prostate Cancer Patients Treated With Hypofractionated IMRT and Long-term Androgen Suppression Treatment.

OBJECTIVE: To assess late toxicity and outcomes in high-risk prostate cancer patients treated with hypofractionated radiation treatment with androgen suppression therapy. METHODS: Sixty high-risk prostate cancer patients were enrolled. IMRT prescription was 68 Gy/25 fractions (2.7 Gy/fraction) to the prostate and proximal seminal vesicles (SV). The pelvic lymph nodes (PLN) and distal SV concurrently received 45 Gy/25 fractions (1.8 Gy/fraction). The patients were treated with helical TomoTherapy-based IMRT and underwent daily megavoltage CT image-guided verification before each treatment. RTOG Toxicity scores were recorded for a 5-year period. RESULTS: Sixty patients completed RT with median follow-up of 63 months (range, 7 to 80 mo).At 5 years follow-up timepoint: Grade (G)2 and G3 late genitourinary toxicity was experienced in 7 (17.0%) and 1 (2.44%), respectively; gastrointestinal G2 as highest toxicity recorded in only 1 (2.44%) patient. There was no G3 gastrointestinal toxicity recorded at this timepoint.With 63-month median follow-up (mean of 65.41±1.72 mo), the 5-year overall survival was 86.67%; 5 years freedom from biochemical failure was 91.67% and freedom from clinical failure was 96.67%. CONCLUSIONS: Dose escalation and hypofractionated radiation treatment with IMRT treating the prostate and proximal SV concurrently with the pelvic lymph nodes and distal SV and long-term androgen suppression therapy is well tolerated with respect to acute and late toxicity with 5-year actuarial overall survival 86.67%, freedom from biochemical failure 91.38%, and freedom from clinical failure 96.67%. Longer follow-up will provide more information on 10-year survival outcomes.

Role of serial multiparametric magnetic resonance imaging in prostate cancer active surveillance.

AIM: To examine whether addition of 3T multiparametric magnetic resonance imaging (mpMRI) to an active surveillance protocol could detect aggressive or progressive prostate cancer. METHODS: Twenty-three patients with low risk disease were enrolled on this active surveillance study, all of which had Gleason score 6 or less disease. All patients had clinical assessments, including digital rectal examination and prostate specific antigen (PSA) testing, every 6 mo with annual 3T mpMRI scans with gadolinium contrast and minimum sextant prostate biopsies. The MRI images were anonymized of patient identifiers and clinical information and each scan underwent radiological review without the other results known. Descriptive statistics for demographics and follow-up as well as the sensitivity and specificity of mpMRI to identify prostate cancer and progressive disease were calculated. RESULTS: During follow-up (median 24.8 mo) 11 of 23 patients with low-risk prostate cancer had disease progression and were taken off study to receive definitive treatment. Disease progression was identified through upstaging of Gleason score on subsequent biopsies for all 11 patients with only 2 patients also having a PSA doubling time of less than 2 years. All 23 patients had biopsy confirmed prostate cancer but only 10 had a positive index of suspicion on mpMRI scans at baseline (43.5% sensitivity). Aggressive disease prediction from baseline mpMRI scans had satisfactory specificity (81.8%) but low sensitivity (58.3%). Twenty-two patients had serial mpMRI scans and evidence of disease progression was seen for 3 patients all of whom had upstaging of Gleason score on biopsy (30% specificity and 100% sensitivity). CONCLUSION: Addition of mpMRI imaging in active surveillance decision making may help in identifying aggressive disease amongst men with indolent prostate cancer earlier than traditional methods.

A Phase I Study of Tomotherapy in Patients With Primary Benign and Low-grade Brain Tumors: Late Toxicity and Quality of Life.

OBJECTIVES: To evaluate longitudinal quality of life and late neurotoxicity (>12 mo) of tomotherapy in patients with primary benign and low-grade brain tumors. METHODS: Between January 2006 and October 2009, 49 patients with brain tumors were treated with tomotherapy at 2 radiotherapy centers in Canada. The median age of the patients was 51.0 years (range, 21 to 74 y); there were 21 men (42.86%) and 28 women (57.14%). All 49 patients had an initial Karnofsky performance score ≥70. One patient (2.04%) received 45 Gy in 25 fractions, 27 patients (55.10%) received 50.4 Gy in 28 fractions, 15 patients (30.6%) received 54 Gy in 30 fractions, and 5 patients (10.2%) received 60 Gy in 30 fractions. A total of 47 patients were analyzed for late toxicity and outcomes. RESULTS: Changes in the Karnofsky Performance Status of the patients did not reach statistical significance (P>0.05). The majority of the quality of life parameters that reached a statistically significant level (P<0.05) of change at 2 years were changes toward improvement (drowsiness, itchy skin, emotional functioning, fatigue, nausea, and appetite). Statistically significant (P<0.05) interval deterioration in physical, role, and social functioning was observed. Actuarial overall survival at 5 years was 91.6%; disease-free survival at 5 years was 86.6%. CONCLUSIONS: IMRT helical tomotherapy is well tolerated, without statistically significant constitutional and late neurotoxicity up to the 2-year mark.

Does location of prostate cancer by sextant biopsies predict for relapse after (125)I seed implant brachytherapy?

PURPOSE: To report on the importance of cancer location from diagnostic prostate biopsies in predicting biochemical relapse for patients treated with (125)I seed implant brachytherapy as monotherapy for favorable risk disease; specifically, to assess the clinical significance of potentially underdosing the base region of the prostate gland. METHODS AND MATERIALS: Of 1145 consecutive patients, 846 had pretreatment biopsies allowing for sextant analysis and consequent evaluation of biochemical failure tendencies. Biochemical failure was defined as a posttreatment rise in the nadir prostate-specific antigen (PSA) by at least 2 ng/mL. Patient and tumor characteristics, dosimetry, the use of hormone therapy, source strength, and postimplant PSA kinetics were analyzed between sextant subgroups. RESULTS: Sixty-two patients (7.3%) with sextant pathology had biochemical failure. There was no significant difference between the failure locations. There were 528 patients (62.4%) with some element of base involvement (BI), and 318 patients (37.6%) with no evidence of BI. Of the 62 patients with biochemical failure, 42 (67.7%) showed BI on biopsy and 20 (32.3%) had no BI. The 10-year relapse-free survival rate is 88.2% (95% confidence interval: 84.3%, 92.2%) and 92.0% (95% confidence interval: 88.4%, 95.8%) for the BI and no BI groups, respectively (p = 0.17). The mean D90 delivered to the base, midgland, and apex was 140.8 (±21.8) Gy, 170.8 (±22.5) Gy, and 177.9 (±29.5) Gy, respectively, for all patients. CONCLUSIONS: There are no significantly worse outcomes for patients treated with an (125)I seed implant for favorable risk prostate cancer with some element of BI, despite lower doses of radiation delivered to the base region.

Carcinoma of unknown primary in the inguinal lymph node region of squamous cell origin: A case series.

PURPOSE: Cancer of unknown primary (CUP) of the inguinal region is a rare clinical entity that accounts for 1%-3 % of all CUPs. Of the inguinal lymph node region CUPs, about 10%-15% are of squamous cell origin. This study presents a case series of CUP of the inguinal region of squamous cell origin treated in our institution and review of the outcome. METHODS AND MATERIALS: We have identified 9 patients treated during the period of 1990-2010. All patients were treated radically with chemoradiation. Regimens used were 5-fluorouracil (5-FU)/cisplatin combination (n = 8) or 5-FU/mitomycin-C (n = 1) regimen. Tumor doses were 5400 cGy (n = 7), 5500 cGy (n = 1), and 5040 cGy (n = 1). RESULTS: The median duration of follow-up was 56 months (range, 10-76 months) for the whole group. There were no deaths or local or distant recurrences reported till the last recorded date of follow-up. CONCLUSIONS: Our retrospective data showed significant long-term disease control for patients with localized inguinal region CUP of squamous cell origin who received concurrent chemoradiation.

Distinguishing prostate-specific antigen bounces from biochemical failure after low-dose-rate prostate brachytherapy.

PURPOSE: The purpose of this study was to characterize benign prostate-specific antigen (PSA) bounces of at least 2.0 ng/mL and biochemical failure as defined by the Phoenix definition after prostate brachytherapy at our institution, and to investigate distinguishing features between three outcome groups: patients experiencing a benign PSA bounce, biochemical failure, or neither. MATERIAL AND METHODS: Five hundred and thirty consecutive men treated with low-dose-rate brachytherapy with follow-up of at least 3 years were divided into outcome groups experiencing bounce, failure, or neither. A benign bounce was defined as a rise of at least 2.0 ng/mL over the pre-rise nadir followed by a decline to 0.5 ng/mL or below, without intervention. Patient and tumor characteristics, treatment variables, and PSA kinetics were analyzed between groups. RESULTS: Thirty-two (6.0%) men experienced benign bounces and 47 (8.9%) men experienced failure. Men experiencing a bounce were younger (p = 0.01), had a higher 6-month PSA level (p = 0.03), and took longer to reach a final nadir (p < 0.01). Compared to the failure group, men with bounce had a lower pre-treatment PSA level (p = 0.01) and experienced a rise of at least 2.0 ng/mL that occurred sooner after the implant (p < 0.01) with a faster PSA doubling time (p = 0.01). Only time to PSA rise independently differentiated between bounce and failure (p < 0.01), with a benign bounce not being seen after 36 months post-treatment. Prostate-specific antigen levels during a bounce reached levels as high as 12.6 ng/mL in this cohort, and in some cases took over 5 years to decline to below 0.5 ng/mL. CONCLUSIONS: Although there is substantial overlap between the features of benign PSA bounces and failure, physicians may find it useful to evaluate the timing, absolute PSA level, initial response to treatment, and rate of rise when contemplating management for a PSA rise after low-dose-rate brachytherapy.

Single-nucleotide polymorphisms studied for associations with urinary toxicity from (125)I prostate brachytherapy implants.

PURPOSE: To identify clinical, dosimetric, and genetic factors that are associated with late urinary toxicity after a (125)I prostate brachytherapy implant. METHODS AND MATERIALS: Genomic DNA from 296 men treated with (125)I prostate brachytherapy monotherapy was extracted from saliva samples for this study. A retrospective database was compiled including clinical, dosimetric, and toxicity data for this cohort of patients. Fourteen candidate single-nucleotide polymorphism (SNPs) from 13 genes (TP53, ERCC2, GSTP1, NOS, TGFß1, MSH6, RAD51, ATM, LIG4, XRCC1, XRCC3, GSTA1, and SOD2) were tested in this cohort for correlations with toxicity. RESULTS: This study identified 217 men with at least 2 years of followup. Of these, 39 patients developed Grade ≥2 late urinary complications with a transurethral resection of prostate, urethral stricture, gross hematuria, or a sustained increase in their International Prostate Symptom Score. The only clinical or dosimetric factor that was associated with late urinary toxicity was age (p = 0.02). None of the 14 SNPs tested in this study were associated with late urinary toxicity in the univariate analysis. CONCLUSIONS: This study identified age as the only variable being associated with late urinary toxicity. However, the small sample size and the candidate gene approach used in this study mean that further investigations are essential. Genome-wide association studies are emerging as the preferred approach for future radiogenomic studies to overcome the limitations from a candidate gene approach.

The biodistribution and pharmacokinetic evaluation of choline-bound gold nanoparticles in a human prostate tumor xenograft model.

PURPOSE: Gold nanoparticles (GNPs) have attracted significant attention in the treatment of cancer due to their potential as novel radiation enhancers, particularly when functionalized with various targeting ligands. The aim of this study was to assess the biodistribution and pharmacokinetic characteristics of a novel choline-bound GNP (choline-GNP) stabilized with polyethelenimine (PEI). METHODS: Choline bound to 27 nm diameter GNPs was characterized using transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR). Toxicity of choline-GNPs was examined on DU-145 prostate cancer cells using an MTT assay. Using balb/c mice bearing flank DU-145 prostate tumors, choline-GNPs bio-distribution was measured using inductively coupled mass spectroscopy (ICP-MS). Blood, heart, lung, liver, spleen, brain, kidney and tumor gold content were examined at multiple time points over a 24-hour period after tail vein injection. RESULTS: An MTT assay using DU-145 prostate cancer cells yielded a 95% cell viability 72 hours after choline-GNP administration. The tumor GNP area under the concentration-time curve during the first 4 hours (AUC0-4) was 2.2 µg/ml h, representing 13% of the circulating blood GNP concentration over the same time period. The maximum intra-tumor GNP concentration observed was 1.4% of the injected dose per gram of tumor tissue (%ID/g) one hour post injection. CONCLUSIONS: GNPs functionalized with choline demonstrates a viable future nanoparticle platform with increased intra-tumor uptake as compared to unconjugated GNPs. Decreased intra-hepatic accumulation appears to be the reason for the improved systemic bioavailability. The next logical translational investigation will incorporate external beam radiation with the observed maximum intra-tumor uptake.

Comparison of low and intermediate source strengths for (125)I prostate brachytherapy implants.

PURPOSE: To compare the implant quality and clinical outcomes for patients treated with low and intermediate strength (125)I seeds in prostate brachytherapy implants. METHODS AND MATERIALS: This retrospective review included 390 consecutive patients treated with prostate brachytherapy from 1999 to 2006. The first 142 patients were implanted with source strengths lower than 0.415U (0.327mCi), with the subsequent 248 patients implanted with source strengths higher than 0.493U (0.388mCi). Clinical, dosimetric, toxicity, and outcome data were compared between these two cohorts of patients. RESULTS: Despite having similar prostate volumes, fewer sources (median, 95 vs. 113; p<0.0001) and fewer needles (median, 23 vs. 29; p<0.0001) were implanted in the intermediate strength cohort. The postimplant dosimetry demonstrated better quality implants in patients treated with intermediate strength sources (median D90, 160.0Gy vs. 139.6Gy; p<0.0001), with greater dose inhomogeneity identified in the intermediate strength cohort of patients. A higher incidence of late rectal toxicity was identified in patients treated with intermediate strength sources despite lower rectal doses in this cohort. The biochemical relapse-free survival, prostate cancer survival, and overall survival were not significantly different between the two cohorts. CONCLUSIONS: The transition from low to intermediate strength sources has led to fewer resources being used and improved postoperative dosimetry. Although there were more rectal complications identified in the intermediate strength cohort of patients in this analysis, there were no other significantly worse clinical or biochemical outcomes for patients implanted with intermediate strength sources.

Regional treatment margins for prostate brachytherapy.

PURPOSE: This study quantified the treatment margin (TM) around the prostate that received 100% of the prescribed dose and analyzed postimplant dosimetry in different regions of the prostate for (125)I seed implants. METHODS AND MATERIALS: An average target volume (ATV) was created from postoperative MRI scan contours drawn independently by five radiation oncologists in 40 patients. The MRI was fused with the postoperative CT for dosimetry purposes. The TM, defined as the radial distance between the ATV and the 100% isodose line, was measured at 16 points at the base, midgland, and apex. The ATV was divided into four quadrants: anterior-superior, posterior-superior, anterior-inferior, and posterior-inferior quadrants. The values of the dose that covers 90% of the ATV (D90) and the percentage of the ATV receiving the prescribed dose (V100) received by the whole prostate and its four quadrants were documented. RESULTS: The range of the mean TM, in millimeter, was -8.88 to 3.68, 1.12 to 10.42, and 6.27 to 18.25 at the base, midgland, and apex, respectively. The mean D90 was 135.8, 162.8, 191.0, and 194.6 Gy for the anterior-superior, posterior-superior, anterior-inferior, and posterior-inferior quadrants, respectively. CONCLUSIONS: Despite having a relatively uniform preoperative planning target volume, this study identified variable TMs postoperatively in different regions of the prostate. In particular, the anterior base is most underdosed, whereas the lateral regions of the midgland and apex have generous TMs. Postimplant dosimetric parameters were lowest in the anterior-inferior quadrant.