Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography Is Associated with Improved Oncological Outcome in Men Treated with Salvage Radiation Therapy for Biochemically Recurrent Prostate Cancer.

BACKGROUND: Radiolabeled prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) has shown superior diagnostic accuracy to conventional imaging for the detection of prostate cancer deposits . Consequently, clinical management changes have been reported in patients with biochemical recurrence (BCR) of disease after robot-assisted radical prostatectomy (RARP). We hypothesized that, due to the exclusion of patients with metastatic disease on PSMA-PET/CT, those who underwent local salvage radiation therapy (SRT) after restaging PSMA-PET/CT for BCR may have better oncological outcomes than patients who underwent "blind" SRT. OBJECTIVE: To compare the oncological outcome of a patient cohort that underwent PSMA-PET imaging prior to SRT with that of a patient cohort that did not have PSMA-PET imaging before SRT. DESIGN, SETTING, AND PARTICIPANTS: We included 610 patients who underwent SRT, of whom 298 underwent PSMA-PET/CT prior to SRT and 312 did not. No additional hormonal therapy was prescribed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: To compare both cohorts, case-control matching was performed, using the prostate-specific antigen (PSA) value at the initiation of SRT, pathological grade group, pathological T stage, surgical margin status, and biochemical persistence after RARP as matching variables. The outcome variable was biochemical progression at 1 yr after SRT, defined as either a rise of PSA ≥0.2 ng/ml above the nadir after SRT or the start of additional treatment. RESULTS AND LIMITATIONS: After case-control matching, 216 patients were matched in both cohorts (108 patients per cohort). In the patient cohort without PSMA-PET/CT prior to SRT, of 108 patients, 23 (21%) had biochemical progression of disease at 1 yr after SRT, compared with nine (8%) who underwent restaging PSMA-PET/CT prior to SRT (p = 0.007). CONCLUSIONS: PSMA-PET/CT is found to be associated with an improved oncological outcome in patients who undergo SRT for BCR after RARP. PATIENT SUMMARY: Performing prostate-specific membrane antigen positron emission tomography/computed tomography imaging in patients with biochemical recurrence of disease after robot-assisted radical prostatectomy, before initiating salvage radiation therapy, resulted in improved short-term oncological outcomes.

Platinum exposure and cause-specific mortality among patients with testicular cancer.

BACKGROUND: Although testicular cancer (TC) treatment has been associated with severe late morbidities, including second malignant neoplasms (SMNs) and ischemic heart disease (IHD), cause-specific excess mortality has been rarely studied among patients treated in the platinum era. METHODS: In a large, multicenter cohort including 6042 patients with TC treated between 1976 and 2006, cause-specific mortality was compared with general population mortality rates. Associations with treatment were assessed with proportional hazards analysis. RESULTS: With a median follow-up of 17.6 years, 800 patients died; 40.3% of these patients died because of TC. The cumulative mortality was 9.6% (95% confidence interval [CI], 8.5%-10.7%) 25 years after TC treatment. In comparison with general population mortality rates, patients with nonseminoma experienced 2.0 to 11.6 times elevated mortality from lung, stomach, pancreatic, rectal, and kidney cancers, soft-tissue sarcomas, and leukemia; 1.9-fold increased mortality (95% CI, 1.3-2.8) from IHD; and 3.9-fold increased mortality (95% CI, 1.5-8.4) from pneumonia. Seminoma patients experienced 2.5 to 4.6 times increased mortality from stomach, pancreatic, bladder cancer and leukemia. Radiotherapy and chemotherapy were associated with 2.1 (95% CI, 1.8-2.5) and 2.5 times higher SMN mortality (95% CI, 2.0-3.1), respectively, in comparison with the general population. In a multivariable analysis, patients treated with platinum-containing chemotherapy had a 2.5-fold increased hazard ratio (HR; 95% CI, 1.8-3.5) for SMN mortality in comparison with patients without platinum-containing chemotherapy. The HR for SMN mortality increased 0.29 (95% CI, 0.19-0.39) per 100 mg/m2 platinum dose administered (Ptrend  < .001). IHD mortality was increased 2.1-fold (95% CI, 1.5-4.2) after platinum-containing chemotherapy in comparison with patients without platinum exposure. CONCLUSIONS: Platinum-containing chemotherapy is associated with a dose-dependent increase in the risk of SMN mortality.

Risk of diabetes after para-aortic radiation for testicular cancer.

BACKGROUND: While the risk of diabetes is increased following radiation exposure to the pancreas among childhood cancer survivors, its association among testicular cancer (TC) survivors has not been investigated. METHODS: Diabetes risk was studied in 2998 1-year TC survivors treated before 50 years of age with orchidectomy with/without radiotherapy between 1976 and 2007. Diabetes incidence was compared with general population rates. Treatment-specific risk of diabetes was assessed using a case-cohort design. RESULTS: With a median follow-up of 13.4 years, 161 TC survivors were diagnosed with diabetes. Diabetes risk was not increased compared to general population rates (standardised incidence ratios (SIR): 0.9; 95% confidence interval (95% CI): 0.7-1.1). Adjusted for age, para-aortic radiotherapy was associated with a 1.66-fold (95% CI: 1.05-2.62) increased diabetes risk compared to no radiotherapy. The excess hazard increased with 0.31 with every 10 Gy increase in the prescribed radiation dose (95% CI: 0.11-0.51, P = 0.003, adjusted for age and BMI); restricted to irradiated patients the excess hazard increased with 0.33 (95% CI: -0.14 to 0.81, P = 0.169) with every 10 Gy increase in radiation dose. CONCLUSION: Compared to surgery only, para-aortic irradiation is associated with increased diabetes risk among TC survivors.

Optimal High-Dose-Rate Brachytherapy Fractionation Scheme After Keloid Excision: A Retrospective Multicenter Comparison of Recurrence Rates and Complications.

PURPOSE: To determine the optimal brachytherapy dose and fractionation scheme for keloid treatment. METHODS AND MATERIALS: Patient cohorts from 3 centers treated with keloid excision followed by 2 × 9 Gy, 3 × 6 Gy, or 2 × 6 Gy high-dose-rate brachytherapy were retrospectively compared regarding recurrence (after at least 12 months' follow-up) and complications (after at least 1 month's follow-up), using logistic regression analyses. RESULTS: A total of 238 keloids were treated. An overall full recurrence rate of 8.3% was found. After correction for confounders (sex, skin color, keloid location, keloid duration) no statistically significant differences in recurrence rates could be discerned between fractionation schemes. There were 12.8% major and 45.6% minor complication rates. Lower radiation dose resulted in significantly fewer complications (odds ratio 0.35, P=.015). CONCLUSIONS: After excision of resistant keloids, high-dose-rate brachytherapy with a biological equivalent dose of approximately 20 Gy is recommended, on the basis of low recurrence and complication rates.

Surgical Excision with Adjuvant Irradiation for Treatment of Keloid Scars: A Systematic Review.

BACKGROUND: Excision followed by adjuvant irradiation is considered safe and most efficacious for treatment of keloid scars. Recently, different authors published successful treatment protocols and recommended the following: (1) the use of high-dose-rate brachytherapy instead of low-dose-rate brachytherapy or external radiation; (2) a short-time interval between operation and irradiation; (3) single fraction instead of multifraction irradiation; and (4) a minimum of 12- to 24-month follow-up post treatment. METHODS: This study evaluates the above recommendations with a systematic review of the English-language literature, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement. Both PubMed and EMBASE were searched. Studies were graded according to the American Society of Plastic Surgeons Rating Levels of Evidence. RESULTS: Thirty-three studies were selected. Six studies were graded as level of evidence type II studies and 27 as type III. High-dose-rate brachytherapy showed lower recurrence rates compared with low-dose-rate brachytherapy and external radiation. A short-time (<7 hours) interval between scar excision and irradiation results in a lower recurrence rate compared with long-time intervals (>24 hours). Single-fraction irradiation showed promising results in terms of recurrence rate and patient convenience. Finally, scar recurrences were seen between 2 and 36 months, with a mean of 15 months. CONCLUSIONS: Based on this systematic review of the literature, the evidence confirms the recommendations stated by authors in the recent years. However, due to the lack of high-quality randomized studies, the quality of this evidence is limited. More randomized studies will generate stronger recommendations.

Phase I Clinical Trial to Determine the Feasibility and Maximum Tolerated Dose of Panitumumab to Standard Gemcitabine-Based Chemoradiation in Locally Advanced Pancreatic Cancer.

PURPOSE: Epidermal growth factor receptor (EGFR) inhibitors may improve both the therapeutic efficacy of radiotherapy and the radiosensitizing activity of gemcitabine. Based on this rationale and the nonoverlapping toxicity profiles of gemcitabine and the monoclonal EGFR antibody panitumumab, we designed a phase I trial to investigate the maximum-tolerated dose (MTD), safety, and activity of panitumumab added to gemcitabine-based chemoradiotherapy (CRT) in patients with locally advanced pancreatic cancer (LAPC). EXPERIMENTAL DESIGN: Patients with LAPC and WHO performance status 0 to 1 were treated with weekly panitumumab at four dose levels (1-2.5 mg/kg), combined with weekly gemcitabine 300 mg/m(2) and radiotherapy (50.4 Gy in 28 fractions) for 6 weeks, followed by gemcitabine 1,000 mg/m(2) weekly for 3 weeks every 4 weeks until disease progression or unacceptable toxicity. Each cohort was monitored during the combination therapy to establish dose limiting toxicity. Tumor evaluation was performed after CRT and during gemcitabine monotherapy. RESULTS: Fourteen patients were enrolled; 14 were evaluable for toxicity and 13 for response. The MTD for panitumumab was 1.5 mg/kg. Three of the 6 patients, treated at MTD, experienced grade 3 adverse events during the combination therapy; neutropenia (n = 2; 33%), fatigue (n = 1; 17%), nausea (n = 1; 17%), and vomiting (n = 1; 17%). Partial response was achieved by 3 patients (23%), 1 in each dose cohort. Median progression free survival of the three cohorts together was 8.9 months. CONCLUSIONS: The addition of panitumumab to gemcitabine-based chemoradiotherapy in LAPC has manageable toxicity and potential clinical efficacy.

High-dose-rate brachytherapy for the treatment of recalcitrant keloids: a unique, effective treatment protocol.

BACKGROUND: Keloids cause aesthetic disfigurement and physical complaints, mainly pain and pruritus. Treatment of these scars is difficult, with high recurrence rates forming the main issue. Surgical excision with adjuvant radiotherapy is considered the most efficacious treatment. At their institution, the authors have been treating keloids with a high-dose-rate brachytherapy procedure for over 10 years, using a protocol with the lowest total radiation dosage known in the literature. METHODS: This prospective study included 43 patients of all Fitzpatrick skin types, with 67 keloids in total. After extralesional excision, a radiation scheme of 2 × 6 Gy was administered in two fractions: the first within 4 hours after surgery and the second within 24 hours. Scars were measured and recurrence was judged. Scar appearance was evaluated using the Patient and Observer Scar Assessment Scale. RESULTS: The recurrence rate was 3.1 percent at a mean follow-up of 33.6 months. A significant average scar surface decrease of 56.7 percent was measured (p = 0.01). Complaints of pain and pruritus decreased by 82.9 and 87.2 percent, respectively. Patients were satisfied with the treatment in 88.6 percent of the cases and with the cosmetic result in 77.1 percent. Pigmentation problems were seen in 21.4 percent of the patients, mostly in Fitzpatrick type V and VI/African American individuals. CONCLUSIONS: The results of this prospective study show a good cosmetic outcome with a low recurrence rate. The unique radiation schedule proves the efficacy and safety of high-dose-rate brachytherapy and suggests the importance of immediate postoperative irradiation. In addition, only one outpatient treatment is required after surgery, enhancing patient convenience. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

The clinical utility of prognostic scoring systems in patients with brain metastases treated with radiosurgery.

PURPOSE: The RTOG recursive partitioning analysis (RPA) classification is the gold standard for assessing the prognosis of patients with brain metastases (BM). Newer prognostic scoring systems for BM patients have been proposed, but their superiority over RPA needs to be established for patients treated with radiosurgery. METHODS: 380 patients with 1-3 BM were treated at the VUmc with radiosurgery (RS) from 2002 to 2011. Using baseline characteristics, patient scores were calculated for RPA, the Rotterdam-system, the score index for radiosurgery (SIR), the basic score for BM (BSBM), the graded prognostic assessment (GPA), the diagnosis-specific GPA, the Rades score, and the Golden grading system (GGS) for comparison with survival time and survival classification (≤3 months or ≥12 months). RESULTS: Median survival after RS was 7.7 months, with 3-month and 1-year overall survival (OS) of 76% and 39%, respectively. Multivariate analysis confirmed the prognostic value of performance status, age, absence of extracranial metastases, primary tumor site, gender, and steroid response for OS. The percentage of patients included within the intermediate prognostic classes ranged from 48% to 77%, and was 64% for the RPA. All scoring systems highly correlated with OS (p<0.001). The specificity for predicting early death ranged from 85% to 98% (RPA 88%), with the unfavorable classes of Rades, GGS, BSBM and SIR performing best. The sensitivity for predicting long-term survival ranged from 10% to 69% (RPA 29%), and was highest for the favorable classes of Rades and GGS. CONCLUSIONS: All prognostic scoring systems correlated very well with OS. All scores shared the limitation of unbalanced proportions of patients within the prognostic classes. As the clinical superiority of more recently developed prognostic scoring systems was only modest in predicting early death and long term survival, the well-known and easy to use RPA system currently remains the standard.

Clinical outcome after repeated radiosurgery for brain arteriovenous malformations.

INTRODUCTION: We assessed the clinical and radiological outcome after repeated radiosurgery for brain arteriovenous malformations (bAVMs) after failure of initial radiosurgery. MATERIALS AND METHODS: Fifteen patients underwent repeated radiosurgery. The mean bAVM volume at first radiosurgery (S1) was 4.6 +/- 4.3 ml and that at second radiosurgery (S2) was 2.1 +/- 2.5 ml. The median marginal dose was 18 Gy at S1, and 21 Gy at S2. Modified Rankin Scale (MRS) score was determined in all patients at last follow-up (FU). RESULTS: Complete obliteration was reached in nine patients (60%). Median time to obliteration was 50 months after S2. An excellent outcome (no new neurologic deficiencies, complete obliteration) was reached in seven patients (47%). Eleven patients (73%) showed a MRS1. Radiation-induced complications occurred in 20%, of which 13% occurred after S2. Radiological complications included cyst formation (n = 1), radiation-related edema (n = 4), and radiation necrosis (n = 1), resulting in an increasing mean MRS of 0.5 at S1, 0.6 at S2, to 0.8 at FU. No (re-)bleedings were encountered during 137-patient years at risk. DISCUSSION: Repeated radiosurgery is a viable option for the treatment of small remnant bAVMs. We report 20% permanent radiation-induced complications. Such complications were mainly seen in relatively large, and therefore difficult to treat, bAVMs.

Stereotactic radiation therapy for large vestibular schwannomas.

BACKGROUND AND PURPOSE: To evaluate the morbidity and tumor-control rate in the treatment of large vestibular schwannomas (VS) after stereotactic radiation therapy in our institution. MATERIAL AND METHODS: Twenty-five consecutive patients (17 men, 8 women) with large VS (diameter 3.0 cm or larger), treated with stereotactic radiotherapy (SRT) or stereotactic radiosurgery (SRS) between 1992 and 2007, were retrospectively studied after a mean follow-up period of three years with respect to tumor-control rate and complications. RESULTS: Actuarial 5-year maintenance of pre-treatment hearing level probability of 30% was achieved. Five of 17 patients suffered permanent new facial nerve dysfunction. The actuarial 5-year facial nerve preservation probability was 80%. Permanent new trigeminal nerve neuropathy occurred in two of 15 patients, resulting in an actuarial 5-year trigeminal nerve preservation probability of 85%. Tumor progression occurred in four of 25 (16%) patients. The overall 5-year tumor control probability was 82%. CONCLUSION: Increased morbidity rates were found in patients with large VS treated with SRT or SRS compared to the published series on regular sized VS and other smaller retrospective studies on large VS.

Volumetric modulated arc radiotherapy for vestibular schwannomas.

PURPOSE: To evaluate volumetric modulated arc radiotherapy (RapidArc [RA]), a novel approach allowing for rapid treatment delivery, for the treatment of vestibular schwannoma (VS). METHODS AND MATERIALS: The RA plans were generated for a small (0.5 cm(3)), intermediate (2.8 cm(3)), and large (14.8 cm(3)) VS. The prescription dose was 12.5 Gy to the encompassing 80% isodose. The RA plans were compared with conventional radiosurgery plans using both a single dynamic conformal arc (1DCA) and five noncoplanar dynamic conformal arcs (5DCA). Conformity indices (CI) and dose-volume histograms of critical organs were compared. The RA plan for the medium-sized VS was measured in a phantom using Gafchromic EBT films and compared with calculated dose distributions. RESULTS: The RA planning was completed within 30 min in all cases, and calculated treatment delivery time (after patient setup) was 5 min vs. 20 min for 5DCA. A superior CI was achieved with RA, with a substantial decrease in low-dose irradiation of the normal brain achieved relative to 5DCA plans. Maximum doses to critical organs were similar for RA and 5DCA but were higher for 1DCA. Film measurements showed the differences between calculated and measured doses to be smaller than 1.5% in the high-dose area and smaller than 3% in the low-dose area. CONCLUSION: The RA plans consistently achieved a higher CI and decrease in areas of low-dose irradiation. This, together with shorter treatment delivery times, has led to RA replacing our conventional five-arc radiosurgery technique for VS.

Linear accelerator-based stereotactic radiosurgery for bilateral vestibular schwannomas in patients with neurofibromatosis type 2.

OBJECTIVE: Patients with neurofibromatosis Type 2 (NF2) patients typically have bilateral vestibular schwannomas (VS) and are at risk for developing bilateral deafness, bilateral trigeminal, and bilateral facial nerve function loss. Previous reports suggested that treatment outcomes in these patients are worse compared with those for patients with sporadic solitary VS. Very few reports, however, have been published on linear accelerator-based radiosurgery (RS) and stereotactic radiation therapy (SRT) in patients with NF2. In particular, in patients with NF2 who already have unilateral hearing loss, avoidance of hearing loss on the opposite side poses a challenge for RS and SRT. We studied our treatment results in patients with NF2 with bilateral VS, treated with linear accelerator-based RS and SRT. METHODS: In 204 patients with VS treated with RS or SRT in Amsterdam starting from 1992, we identified 25 patients with NF2 who had bilateral tumors. Indications for treatment were either tumor progression on sequential magnetic resonance imaging scans and/or progressive hearing loss. Mean tumor diameter was 2.5 cm. Stereotactic irradiation was administered to all patients using five noncoplanar arcs with a single isocenter to a dose of 10 to 12.5 Gy in a single fraction or 20 to 25 Gy in five fractions in 1 week prescribed to the 80% isodose encompassing the tumor. On the untreated side, all patients showed hearing loss and eight (32%) had ipsilateral deafness. Five patients were followed for less than 1 year. Of the remaining 20 patients, five had ipsilateral deafness before treatment. Consequently, 15 patients were at risk for treatment-related hearing loss. They showed a mean pure tone average (PTA) of 51 dB (8-112 dB) before treatment. After treatment all patients were assessed at yearly intervals including magnetic resonance imaging and pure tone audiometry. RESULTS: Median follow-up time was 51 months (12-109 mo). Local tumor control was obtained in all 20 patients, and no treatment-related trigeminal or facial nerve toxicity was observed. Hearing status was assessed yearly after treatment. This assessment revealed that the mean PTA in the 15 hearing patients dropped from 51 to 77 dB (40-120 dB). In six patients (40%) the additional PTA loss ranged from 0 to 15 dB, in another six (40%) it ranged from 15 to 45 dB, and in three of these patients (20%), it was more than 45 dB. No additional hearing loss was observed beyond 36 months after treatment. CONCLUSION: In this largest series in the literature of linear accelerator-based RS and SRT for VS NF2 patients, excellent local control rates were found with minimal facial and trigeminal nerve toxicity. Although more than 40% of the patients retained their hearing level or lost less than 15 dB of PTA on the irradiated side, preservation of hearing remains a major concern.

Stereotactic radiosurgery for brain AVMs: role of interobserver variation in target definition on digital subtraction angiography.

PURPOSE: We evaluated the extent of interobserver variation in contouring arteriovenous malformations (AVMs) on digital subtraction angiography (DSA) with respect to volume, spatial localization, and dosimetry and correlated our findings with the clinical outcome. METHODS AND MATERIALS: Thirty-one patients who had undergone radiosurgery for brain AVMs were studied. Six clinicians independently contoured the nidus on the original DSA. As a measure of variation, the ratio between the volumes of agreement and the corresponding encompassing volumes, as well as the absolute positional shift between the individual target volumes were derived. Using the original treatment plan, the dosimetric coverage of the individually contoured volumes with standard collimators was compared with a similar plan using dynamic conformal arcs. RESULTS: The mean contoured nidus volume was 3.6 +/- 5.6 cm3. The mean agreement ratio was 0.45 +/- 0.18 for all possible pairs of observers. The mean absolute positional shift between individually contoured volumes was 2.8 +/- 2.6 mm. These differences were more marked in previously treated groups and tended to be more pronounced in those with treatment failure. The mean coverage of the individual volumes by the 80% prescription isodose was 88.1% +/- 3.2% using conventional collimators and 78.9% +/- 4.4% using dynamic conformal arcs (p = 0.001). CONCLUSION: Substantial interobserver variations exist when contouring brain AVMs on DSA for the purpose of radiosurgical planning. Such variations may result in underdosage to the AVM and, thereby, contribute to treatment failure. The consequences of contouring variations may increase with the use of more conformal radiosurgical techniques.