Local Salvage Therapy Research Articles

Efficacy and Toxicity Following Salvage High-Dose-Rate Brachytherapy for Locally Recurrent Prostate Cancer after Radiotherapy: A Single Center Retrospective Analysis

According to the NCCN guidelines, Salvage Brachytherapy is a treatment option for pathologically confirmed local recurrence after EBRT or brachytherapy. We retrospectively evaluated the feasibility and the toxicity of high dose rate (HDR) brachytherapy at our institution. Between November 2013 and February 2018, 30 consecutive patients with biopsy proven intraprostatic recurrence of cancer after definitive radiation therapy underwent a salvage re-irradiation using HDR brachytherapy. Treatment regimen was 24 Gy delivered to the whole gland in 2 implants of 12 Gy performed 2-4 weeks apart. All patients had had no severe side effect of the previous radiotherapy course and underwent a rectoscopy to ascertain the absence of radiation proctitis prior to salvage procedure. Biochemical control was assessed according to the Phoenix definition. Secondary outcomes included survival and toxicities. Median age at the salvage brachytherapy was 68.5 years (range 61.3-83.2). The median interval between salvage HDR brachytherapy and the first radiotherapy course was 9.1 years (range 0.8-22.4). The median PSA at salvage brachytherapy was 4.9 ng/mL (range 1.3-40) and 6 pts (20%) were castration-resistant. After a median follow-up of 1.7 years, a total of 19 pts (63%) presented a biochemical relapse with a median time of 1.3 years (range 0.2 – 3.9) and 16 a clinical relapse (4 local only, 2 local and regional, 5 regional and metastatic and 5 metastatic only). Local relapses occurred after a median time of 2.7 y (range 0.9-4.7). Overall toxicity profile was good, with no severe grade 3 or higher acute or late gastrointestinal or genitourinary toxicity recorded. Salvage HDR brachytherapy for locally recurrent prostate cancer after radiotherapy is feasible and associated with an acceptable toxicity profile. The high rate of clinical relapse warrants further investigation to define the subgroup of patients who will benefit from salvage local therapy.

Patterns of Prostate Cancer Recurrence after Brachytherapy Imaged with PSMA-Targeting 18F-Dcfpyl PET/CT

Brachytherapy is a highly effective treatment in localized prostate cancer. A previous study from our institution indicated a low rate of local failure after prostate brachytherapy (Lo, IJROBP 2015). However the study was limited by the absence of post-implant prostate biopsy and by utilization of conventional imaging to document local, regional and distant recurrence. In this study, we evaluate patterns of recurrence after brachytherapy utilizing positron emission tomography (PET) tracers that target the prostate specific membrane antigen (PSMA). The study included patients enrolled in our ongoing institutional prospective trial, "PSMA PET/CT for Assessment of Recurrent Prostate Cancer” (NCT02899312). Patients with recurrent prostate cancer were eligible if they were candidates for salvage local therapy and there was no recurrent disease visualized on conventional cross-sectional imaging and bone scans. Biochemical and PSMA PET/CT recurrence were defined according to PHOENIX (Roach, IJROBP 2006) and PROMISE (Eiber, JNM 2018) criteria respectively. Between July 20, 1998 and August, 2018, 6380 patients have been treated with brachytherapy at our institution. Between March 2017 and August 2018, 208 patients were enrolled in the PSMA PET/CT trial, open for 13 months during this time. During the same time period, 1349 brachytherapy patients had follow up PSA recorded and 81 experienced biochemical recurrence. In these patients with biochemical recurrence, median follow-up was approximately 7 years and median time to biochemical recurrence was 50 months. 35 out of 208 study patients were identified as receiving brachytherapy as part of initial curative treatment. In these brachytherapy patients, 68.6% had local recurrence in the prostate, 37.1% had seminal vesicle involvement, 34.3% had nodal recurrence and 28.6% had distant metastases. The basal segments of prostate were involved in 80.0% of local recurrences, which was significantly different than involvement of the mid (31.4%) and apical (11.4%) segments; p < 0.001. Contrary to previous evidence, our study showed that local failure is a common pattern of recurrence in patients who experience biochemical relapse after prostate brachytherapy. Further study is underway to correlate implant dosimetry with the location of intra-prostatic recurrence.

Stereotactic Body Versus Hypofractionated Radiation Therapy for Local Control of Prostate Cancer Bone Metastases

To compare the rate of radiographic in field failure (IFF) for prostate cancer bone metastases treated with single fraction stereotactic body radiation therapy (SBRT) and hypofractionated radiation therapy (HRT), and secondarily describe the rate of subsequent distant failure (DF). An institutional, retrospective review was conducted of all patients with prostate cancer receiving RT to bone metastases between January 2013 and May 2017. Patients were excluded if less than 6 months of clinical and imaging follow-up was available. IFF was defined as any increase in the size and/or radiotracer avidity of the treated lesion, subsequent use of a secondary local salvage therapy to the treated site, or the appearance of a new lesion within the initial 50% isodose line. DF, defined as new metastatic disease following RT, was a secondary outcome. The cumulative incidence of IFF and DF was determined using the Fine-Gray method with death as a competing risk. Hazard ratios (HR) for single variable associations with outcomes were calculated using the Cox model and a P value of 0.05 was set to determine significance. A total of 201 patients with 249 metastases (191 SBRT, 58 HRT) with a median follow-up of 2.2 (IQR 1.2-3.0) years were analyzed. Patients treated with SBRT more frequently had 1-3 metastases compared to those receiving HRT (85% vs 40%, P<0.0001). The presence of castrate resistant disease was not significantly different between the SBRT and HRT groups (41% vs 35%, P=0.39). The SBRT prescription dose ranged from 16 to 24 Gy in a single fraction, with most receiving 18 (46%) or 20 (47%) Gy. HRT was mainly 8 Gy in 1 fraction (57%) or 20 Gy in 5 fractions (41%). Imaging follow-up was primarily with 11C-choline PET/CT (79%), technetium 99m-MDP bone scan (10%), or CT scan (5%). The one and three-year IFF rates were 34% (95% CI 20-46) and 53% (34-67) for lesions treated with HRT compared to 5% (1.4-7.5) and 13% (7-19) in those treated with SBRT. On single variable regression, the HR for IFF with HRT compared to SBRT was 6.8 (3.7-12.5; P <.0001). No other variables assessed, including Gleason score, castrate resistant disease status, or anatomical location of metastasis were associated with an increased risk of IFF (P >0.05). There was no difference in DF for patients treated with HRT compared with SBRT [3-year cumulative incidence estimate 94% (77-98) vs. 82% (75-88); HR 1.33 (0.97-1.81), P=0.08]. Single fraction SBRT at doses ≥ 16 Gy is an effective means of local therapy and significantly improves radiographic IFF compared to HRT in prostate cancer patients with bone metastases. In this large cohort of patients, local control using SBRT was 95% and 87% at one and three years respectively. The subsequent risk of DF was high. Thus, optimizing patient selection and multidisciplinary management of local and systemic therapies remains essential.

Clinical outcomes following biochemical recurrence among patients with Gleason score 9-10 prostate adenocarcinoma.

102 Background: Patients with Gleason score (GS) 9-10 prostate cancer (PCa) have a high risk of early biochemical recurrence (BCR). Salvage therapy options differ depending on the upfront management strategy. Patients who received upfront surgery (RP) may be curable with salvage external beam radiation therapy (EBRT). However those who underwent EBRT or EBRT with a brachytherapy boost (EBRT+BT) are less likely to receive local salvage therapy and are commonly treated with androgen deprivation therapy (ADT). In this study, we examine the risk of distant metastases (DM) and prostate-cancer specific mortality (PCSM) among patients with GS 9-10 PCa who had BCR following RP, EBRT, or EBRT+BT. Methods: 712 patients with GS 9-10 PCa treated between 2000-2013 at 12 institutions who had BCR were included (346 RP, 282 EBRT, 84 EBRT+BT). Time to DM and PCSM were compared between groups using Cox proportional hazards models with propensity score adjustment. Propensity scores were calculated using age, T-stage, PSA, and GS. Results: In patients who had a BCR, incidence rates of DM and PCSM after RP were 40% and 28%. Rates after EBRT were 60% and 46% and after EBRT+BT were 49% and 31%. Median times to DM and PCSM were 3.5 and 4.9 years after RP, 3.7 and 5.1 years after EBRT, and 3.3 and 6.8 years after EBRT+BT. The rates of local salvage RT and systemic salvage therapy among RP patients were 38% and 59%, respectively. Local and systemic salvage rates were 5% and 31% for EBRT patients and 5% and 28% for EBRT+BT patients. EBRT patients had a shorter time interval to DM compared with RP (HR 1.4, p = .02) and EBRT+BT (HR 1.9, p &lt; .01). EBRT patients also had a shorter time interval to PCSM compared with RP (HR 1.5, p = .02). Conclusions: Among patients with GS 9-10 PCa who experience BCR after definitive management, those treated with EBRT have a shorter time interval to DM and PCSM compared with RP and EBRT+BT. While this analysis is confounded by the differential thresholds for diagnosing a BCR after different modalities, it does suggest that outcomes following BCR after EBRT+BT and RP are similar. It also suggests that extreme dose escalation delays the onset of DM and PCSM even after BCR, when compared with conventionally-dosed EBRT alone.

Salvage robot-assisted radical prostatectomy (sRARP) for radiation resistant prostate cancer in a group of initially high risk patients

Introduction: Salvage robot-assisted radical prostatectomy (sRARP) is seen as an attractive option for salvage treatment of radiation therapy -recurrent prostate cancer (PC), thanks in part to the good visualisation that is possible using this modality. However, the results of fewer than 200 salvage sRARPs have been published in the literature. We report the outcomes in a cohort of initially high risk patients of robot-assisted radical prostatectomy as salvage local therapy for radiation-resistant PC in a Scandinavian healthcare setting.&#x0D; Materials and methods: A retrospective review of the charts of all patients who underwent sRARP for biochemical failure (BCF) after primary radiation treatment for localised PC at a single institution was performed.&#x0D; Results: Twenty-two patients, median age 67 years (range 57 to 72), had sRARP performed between June 2008 to July 2013. A median follow-up of 26 months (range 2 to 63) was observed. Perioperative complications occurred in 4 patients (18%), with one patient sustaining a rectal injury. Histo-pathological diagnosis was pT2 in three, pT3a in five, pT3b in twelve and pTx in one patient. Ten patients (45%) had a positive surgical margin (PSM). At follow-up, 54 % of patients were free of biochemical progression and 41% were continent.&#x0D; Conclusions: We showed that salvage RARP is technically feasible in a cohourt of patients with predominantly high risk disease. This study adds to the limited data already in the literature, demonstrating the high frequency of locally advanced (pT3b) PC, a patient group that is usually not included in salvage treatments, as e.g. high frequency ultrasound or salvage brachytherapy. Further, given that the historical barriers to salvage RP with higher rates of rectal injury and poor urinary control no longer seem to be applicable in the modern era, we think that more patients should be considered candidates for this potentially curative salvage treatment of radiation-resistant PC. However, long-term follow-up is needed to confirm if the additional burden on these patients confers to oncological control following the procedure.

Salvage radical prostatectomy after distance radiation therapy: a systematic review of modern approaches

Radical external radiation therapy (RERT) is the standard for the treatment of prostate cancer patients (PCa). Despite this, the incidence of intraprostatic recurrence after primary RERT is still significant, there is still no consensus on the best treatment for these patients after ineffective RERT. For such patients, local salvage therapy may be indicated, namely, radical prostatectomy, cryotherapy, or brachytherapy.The objective: analysis of possible criteria for careful selection of relevant patients, assessment of cancer outcomes and complications of each method.Patients and methods. A review of the literature was carried out to identify studies on local salvage therapy in patients who had an ineffectiveness of primary RERT in localized PCa.Results. Most studies suggest that local salvage therapy after RERT can provide long-term local control in correctly selected patients, although there is toxicity of treatment.Conclusion. The results of the study suggest that for localized prostate cancer after external radiation radiotherapy, the choice of the local treatment model should be applied on the basis of an individual approach to each patient. Further research is continuing that it provides the best oncological and comorbid results, in particular by improving the selection criteria and the integral determination of biochemical disorders for all salvage methods.

Stereotactic Ablative Body Radiotherapy for the Treatment of Spinal Oligometastases

AimsTo report multicentre outcomes of patients with spinal oligometastases treated with stereotactic ablative body radiotherapy (SABR). The primary objective was to estimate the widespread failure-free survival (WFFS) at 2 years – defined as freedom from metastases not amenable to local salvage therapy and death. Materials and methodsPatients with one to three metastases treated with spinal SABR between January 2010 and July 2014 at four academic institutions were included in this retrospective review. The median dose/fractionation was 24 Gy (range 16–52.5 Gy) in two fractions (range one to three) and the median biologically effective dose (α/β=10) was 52.5 Gy (range 40–144.4 Gy). The WFFS, overall survival, freedom from local progression and toxicity rates were described using Kaplan–Meier statistics. ResultsIn total, 60 patients with 72 spinal metastases were analysed. The median follow-up was 21 months. Patients had a median age of 66 years, Eastern Cooperative Oncology Group performance 0–1 in 97% and metachronous oligometastases in 85%. The 1 and 2 year WFFS rates were 67% (95% confidence interval 55–80) and 59% (95% confidence interval 47–75), respectively. The 1 and 2 year overall survival rates were 90% (95% confidence interval 83–98) and 76% (95% confidence interval 64–91), respectively. The 1 and 2 year freedom from local progression were 92% (95% confidence interval 85–99) and 86% (95% confidence interval 75–99), respectively. There were four cases (6.7%) of vertebral compression fracture and no cases of radiation myelopathy. ConclusionDespite the use of relatively low biological doses respecting spinal cord constraints, SABR results in excellent 2 year local control rates with low morbidity. Through careful selection of patients with oligometastases, most patients are alive and free from widespread metastases at 2 years. This cohort warrants further investigation in clinical trials of SABR.

18F-Choline Positron Emission Tomography/Computed Tomography and Multiparametric Magnetic Resonance Imaging for the Detection of Early Local Recurrence of Prostate Cancer Initially Treated by Radiation Therapy: Comparison With Systematic 3-Dimensional Transperineal Mapping Biopsy

To compare the diagnostic performance of 18F-fluorocholine positron emission tomography/computed tomography (FCH-PET/CT), multiparametric prostate magnetic resonance imaging (mpMRI), and a combination of both techniques for the detection of local recurrence of prostate cancer initially treated by radiation therapy. This was a retrospective, single-institution study of 32 patients with suspected prostate cancer recurrence who underwent both FCH-PET/CT and 3T mpMRI within 3months of one another for the detection of recurrence. All included patients had to be cleared for metastatic recurrence. The reference procedure was systematic 3-dimensional (3D)-transperineal prostate biopsy for the final assessment of local recurrence. Both imaging modalities were analyzed by 2 experienced readers blinded to clinical data. The analysis was made per-patient and per-segment using a 4-segment model. The median prostate-specific antigen value at the time of imaging was 2.92ng/mL. The mean prostate-specific antigen doubling time was 14months. Of the 32 patients, 31 had a positive 3D-transperineal mapping biopsy for a local relapse. On a patient-based analysis, the detection rate was 71% (22 of 31) for mpMRI and 74% (23 of 31) for FCH-PET/CT. On a segment-based analysis, the sensitivity and specificity were, respectively, 32% and 87% for mpMRI, 34% and 87% for FCH-PET/CT, and 43% and 83% for the combined analysis of both techniques. Accuracy was 64%, 65%, and 66%, respectively. The interobserver agreement was κ=0.92 for FCH-PET/CT and κ=0.74 for mpMRI. Both mpMRI and FCH-PET/CT show limited sensitivity but good specificity for the detection of local cancer recurrence after radiation therapy, when compared with 3D-transperineal mapping biopsy. Prostate biopsy still seems to be mandatory to diagnose local relapse and select patients who could benefit from local salvage therapy.

Abstract B003: A randomized controlled phase II clinical trial on mRNA electroporated autologous dendritic cells for stage III/IV melanoma patients who are disease-free following the local treatment of macrometastases

Abstract Autologous monocyte-derived synthetic mRNA electroporated dendritic cells (TriMixDC-MEL) are immunogenic and can induce anti-tumor activity in pretreated advanced melanoma patients when administered by the intradermal (id) and intravenous (iv) route. We investigated the safety and activity of TriMixDC-MEL in stage III/IV melanoma patients who are disease free following the local treatment of macrometastases. We performed a randomized, controlled, non-comparative phase II clinical trial where TriMixDC-MEL was administered iv (20.106 DCs) and id (4.106 DCs) at 2 separate sites of the body every 2 weeks for a total of 4 administrations and a fifth administration after 16 weeks in patients randomized to the treatment arm. Patients on the control arm did not receive treatment but were allowed to “cross-over” and be treated with TriMixDC-MEL at the time of non-salvageable recurrence. Tumor evaluations on both arms were performed by total-body 18-FDG-PET/CT every 12 weeks. The primary endpoint was the percentage of patients who were alive and free from melanoma macrometastases at 1 year following randomization. Patients were allowed to undergo local salvage treatments for loco-regional melanoma recurrences during the study (week 0-52). If local salvage treatment during the study resulted in a disease-free status that was confirmed at any of the planned assessment, but not earlier than 16 weeks after the salvage treatment, these patients were considered not to have reached the primary endpoint of the study. Between November 2012 and November 2014, 41 eligible patients were randomized between the TriMixDC-MEL treatment arm (n = 21) and control-arm (n = 20). Baseline characteristics (22M/19F; median age 57.5y (range 24-81); AJCC stage III/IV-M1a/-M1b/-M1c: 33/1/6/1 patients, ulcerated primary melanoma: 12 patients) were well balanced between both groups. After a median follow-up of 28 months (range 15 to 40 months) 21 patients experienced a non-salvageable melanoma recurrence (7 on the DC- and 14 on the control-arm). The rate of patients who were disease-free at 1 year (evaluable population = 41 patients) was higher in the TriMixDC-MEL treated group (68% [95%CI 46-86] vs. 35% [14-55]). The time-to-non-salvageable melanoma recurrence was significantly lower in the TriMixDC-MEL treated group (log-rank p = .021). Seven patients in the TriMixDC-MEL group and 3 patients in the control arm were offered local salvage therapy at first recurrence (surgery: 9 patients; RT: 1pt). TriMixDC-MEL was well tolerated (there were no grade ≥3 AE related to TriMixDC-MEL). AE were limited to: local skin injection reactions (grade 1-2; 17/21 patients), flu-like symptoms (grade 1-2; 4/21 patients), and post-infusion chills (grade 1-2; 4 [19%] patients). The results of this non-comparative randomized controlled phase II clinical trial of TriMixDC-MEL id/iv versus observation support the further evaluation of TriMixDC-MEL as a well-tolerated adjuvant therapy for melanoma patients following the resection of macrometastases. Citation Format: Bart Neyns, Yanina Jansen, Jurgen Corthals, Sofie Wilgenhof, Max Schreuer, Carlo Heirman, Kris Thielemans. A randomized controlled phase II clinical trial on mRNA electroporated autologous dendritic cells for stage III/IV melanoma patients who are disease-free following the local treatment of macrometastases [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B003.

Medium-term Outcomes after Whole-gland High-intensity Focused Ultrasound for the Treatment of Nonmetastatic Prostate Cancer from a Multicentre Registry Cohort

BackgroundHigh-intensity focused ultrasound (HIFU) is a minimally-invasive treatment for nonmetastatic prostate cancer. ObjectiveTo report medium-term outcomes in men receiving primary whole-gland HIFU from a national multi-centre registry cohort. Design, setting, and participantsFive-hundred and sixty-nine patients at eight hospitals were entered into an academic registry. InterventionWhole-gland HIFU (Sonablate 500) for primary nonmetastatic prostate cancer. Redo-HIFU was permitted as part of the intervention. Outcome measurements and statistical analysisOur primary failure-free survival outcome incorporated no transition to any of the following: (1) local salvage therapy (surgery or radiotherapy), (2) systemic therapy, (3) metastases, or (4) prostate cancer-specific mortality. Secondary outcomes included adverse events and genitourinary function. Results and limitationsMean age was 65 yr (47–87 yr). Median prostate-specific antigen was 7.0 ng/ml (interquartile range 4.4–10.2). National Comprehensive Cancer Network low-, intermediate-, and high-risk disease was 161 (28%), 321 (56%), and 81 (14%), respectively. One hundred and sixty three of 569 (29%) required a total of 185 redo-HIFU procedures. Median follow-up was 46 (interquartile range 23–61) mo. Failure-free survival at 5 yr after first HIFU was 70% (95% confidence interval [CI]: 64–74). This was 87% (95% CI: 78–93), 63% (95% CI: 56–70), and 58% (95% CI: 32–77) for National Comprehensive Cancer Network low-, intermediate-, and high-risk groups, respectively. Fifty eight of 754 (7.7%) had one urinary tract infection, 22/574 (2.9%) a recurrent urinary tract infection, 22/754 (3%) epididymo-orchitis, 227/754 (30%) endoscopic interventions, 1/754 (0.13%) recto-urethral fistula, and 1/754 (0.13%) osteitis pubis. Of 206 known to be pad-free pre-HIFU, 183/206 (88%) remained pad free, and of 236 with good baseline erectile function, 91/236 (39%) maintained good function. The main limitation is lack of long-term data. ConclusionsWhole-gland HIFU is a repeatable day-case treatment that confers low rates of urinary incontinence. Disease control at a median of just under 5 yr of follow-up demonstrates its potential as a treatment for nonmetastatic prostate cancer. Endoscopic interventions and erectile dysfunction rates are similar to other whole-gland treatments. Patient summaryIn this report we looked at the 5-yr outcomes following whole-gland high-intensity focused ultrasound treatment for prostate cancer and found that cancer control was acceptable with a low risk of urine leakage. However, risk of erectile dysfunction and further operations was similar to other whole-gland treatments like surgery and radiotherapy.

Clinical impact of 11C-Choline PET/CT in selection and outcome of salvage cryoablation in patients with recurrent prostate cancer after radiotherapy.

276 Background: Salvage cryoablation is an effective but toxic treatment for local recurrent prostate cancer after primary radiotherapy. To assess the location of recurrent prostate cancer, an 11C-choline PET/CT can be used. We studied the clinical impact of 11C-choline PET/CT on the choice for and the results of salvage cryoablation. Methods: A total of 141 patients with a biochemical recurrence (BCR according to ASTRO-Phoenix criteria) after radiotherapy, and thus candidates for salvage cryoablation, were included. Patients were re-staged with an 11C-choline PET/CT, complementary prostate biopsies, when indicated a pelvic lymph node dissection and/or additional imaging. Change in choice of therapy was defined as major (no salvage cryoablation because of metastases or lack of local recurrence on PET/CT), minor (local salvage treatment was performed, but different technique of after additional diagnostics) or none (salvage cryoablation was performed). The impact of selection of patients for cryoablation with PET/CT on outcome was measured by time from cryoablation to BCR (according to Astro-Phoenix), first distant metastasis and start of hormonal therapy. Results: In 71 of 141 patients (51%) a change in therapy was implemented because of the result of 11C-choline PET/CT. A major impact was observed in 48 (34%) patients. In 83 patients, a salvage cryoablation was performed (59%). 18% of this group showed no PSA response. Of the remaining patients with PSA response, 37% developed a BCR after mean 25.7 months. 47% of patients are still in remission after a mean follow-up of 43 months. In 16 of 83 patients (19%) metastases were proven after mean 55.4 months (SD 26.3). 15 patients started with hormonal therapy, mean 29.5 months (SD 20.1) after cryoablation. Conclusions: 11C-choline PET/CT showed a significant impact on selection for salvage cryoablation. The choice for local salvage therapy was abandoned in 34% of patients. Of the men who underwent a salvage cryoablation, 47% stayed free of biochemical recurrence during mean 43 months follow-up.

Local salvage therapy for late (≥2 years) metastatic and local relapse of renal cell cancer is a potentially curative treatment irrespective of the site of recurrence

ObjectiveThe primary treatment approach to locoregional renal cell carcinoma (RCC) is surgical resection. Most relapses occur within the first 2 years but some patients experience late recurrences. Surgical resection of oligometastatic disease may be considered a curative option for relapsed RCC. However, limited data are available of long-term follow-up of late relapse regarding treatment choice. Patients and methodsWe identified 104 patients with RCC from our database, who relapsed after≥2 years from resection of their primary tumor. Median age at primary diagnosis was 61 years and sex distribution was F:M = 40:64. Histology was clear cell, n = 103 and papillary, n = 1. Sites of relapse were local, n = 14 (13.4%); lung only, n = 25 (24.0%); or extrapulmonary, n = 65 (62.5%). Treatment at first relapse was local therapy (LT) in n = 60 (57.7%) patients, of these, n = 55 patients had surgery done and n = 5 patients had underwent radiotherapy. Systemic therapy was used in n = 9 (8.7%) patients. Overall, 35 patients received best supportive care (33.7%). ResultsWe found a median overall survival (OS) of 49.8 months (95% CI: 29.3–70.2) and a progression-free survival (PFS) of 21.6 months (95% CI: 12.6–30.5) for all patients. Patients receiving LT had a median OS of 99.9 months (95% CI: 77.2–122.6) and a PFS of 31.1 months (95% CI: 21.5–40.7). Patients treated with systemic therapy, in turn, had an OS of 21.1 months (95% CI: 8.4–33.8) and a PFS of 4 months (95% CI: 1.0–6.2). Patients who received best supportive care had an OS of 10 months (95% CI: 1.3–18.7). This difference was highly significant (log rank for PFS: P<0.001; log rank for OS: P<0.003). Subgroup analysis of the LT group showed a superior outcome for local relapses (OS: not reached, PFS: 61.4mo [95% CI: 28.5–9.2]) compared to visceral relapses (OS: 35.5mo [95% CI: 17.9–53.1], PFS: 21.1mo [95% CI: 19.2–22.9]). ConclusionLocal salvage therapy should be considered the first therapeutic option in late relapse of RCC irrespective of the site of relapse.

Brachytherapy: state‐of‐the‐art radiotherapy in prostate cancer

Brachytherapy: state‐of‐the‐art radiotherapy in prostate cancer

Does focal high-intensity focused ultrasound have a role in treating localized prostate cancer in the elderly?

133 Background: There is an increase in the ageing population leading a significant proportion of men diagnosed with prostate cancer being over 75 years of age. Misconceptions regarding treating the elderly are still rife. The body of evidence that has recently emerged shows that this cohort of patients should be offered the same curative therapies as their counterparts. This study looks at the feasibility of focal HIFU in treating localised prostate cancer in those aged over 75 years of age. Methods: Our independent academic HIFU registry incorporates a total of 60 patients who were diagnosed with low, intermediate and high risk localized adenocarcinoma of the prostate, stage T2a-T3aN0M0 and treated with focal HIFU using Sonablate500, between 2004 and 2014. We divided the patient cohort into those that were treated within the remit of a trial protocol, and those that were not. Results: As biochemical failure is difficult to define, we looked at the medium-term transition rates to redo HIFU, local salvage and systemic therapy. 12% required re-treatment with HIFU. 8% transitioned into local salvage or systemic therapy of which 1 patient had radiotherapy and 4 were subsequently treated with androgen deprivation therapy). The table below outlines the complication rates associated with focal HIFU. Conclusions: Focal HIFU has been shown to be both feasible and effective in the elderly population. It is a safe modality of treatment to use in this patient cohort with a low complication profile. Long-term studies are however necessary. [Table: see text]

Controlled release dexamethasone implants in the round window niche for salvage treatment of idiopathic sudden sensorineural hearing loss.

To evaluate the feasibility and hearing outcome of a biocompatible degradable dexamethasone releasing implant for continuous drug delivery to the round window membrane in patients with idiopathic sudden sensorineural hearing loss (ISSHL) and insufficient recovery after systemic high dose glucocorticoid therapy. Five patients with profound or moderate-to-severe hearing loss after systemic high-dose prednisolone for ISSHL received local salvage therapy with a controlled release dexamethasone implant in the middle ear. Pieces of a sterile rod shaped poly(D,L-lactide-co-glycolide) PLGA polymer matrix containing a total of 0.7 mg dexamethasone, which is approved for intravitreal use were implanted into the round window niche. Intraoperative handling and feasibility and hearing recovery as measured by change in pure tone threshold, final word recognition score, and categories of improvement were evaluated. The implants were surgically placed without major difficulties. The mean hearing threshold significantly improved at follow up by 31 ± 31 dB HL (from 94 ± 27 to 63 ± 36 dB HL; p < 0.05). Two of five patients recovered completely. One patient showed partial hearing recovery with serviceable hearing. Although no drugs are currently approved for local therapy of inner ear disorders, there is increasing evidence that intratympanic glucocorticoids are effective as salvage therapy in ISSHL. The present study has shown encouraging results with a biodegradable polymer delivery system, demonstrating the translation of preclinical studies with controlled drug delivery into clinical practice.

PSMA, EpCAM, VEGF and GRPR as imaging targets in locally recurrent prostate cancer after radiotherapy.

In this retrospective pilot study, the expression of the prostate-specific membrane antigen (PSMA), the epithelial cell adhesion molecule (EpCAM), the vascular endothelial growth factor (VEGF) and the gastrin-releasing peptide receptor (GRPR) in locally recurrent prostate cancer after brachytherapy or external beam radiotherapy (EBRT) was investigated, and their adequacy for targeted imaging was analyzed. Prostate cancer specimens were collected of 17 patients who underwent salvage prostatectomy because of locally recurrent prostate cancer after brachytherapy or EBRT. Immunohistochemistry was performed. A pathologist scored the immunoreactivity in prostate cancer and stroma. Staining for PSMA was seen in 100% (17/17), EpCAM in 82.3% (14/17), VEGF in 82.3% (14/17) and GRPR in 100% (17/17) of prostate cancer specimens. Staining for PSMA, EpCAM and VEGF was seen in 0% (0/17) and for GRPR in 100% (17/17) of the specimens’ stromal compartments. In 11.8% (2/17) of cases, the GRPR staining intensity of prostate cancer was higher than stroma, while in 88.2% (15/17), the staining was equal. Based on the absence of stromal staining, PSMA, EpCAM and VEGF show high tumor distinctiveness. Therefore, PSMA, EpCAM and VEGF can be used as targets for the bioimaging of recurrent prostate cancer after EBRT to exclude metastatic disease and/or to plan local salvage therapy.

Underutilization of local salvage therapy after radiation therapy for prostate cancer

ObjectiveTo evaluate the rates at which patients are offered and receive local salvage therapy (LST) after failure of primary radiotherapy for localized prostate cancer, as it is the only potentially curative treatment for localized recurrence but appears to be underutilized when compared with androgen-deprivation therapy (ADT) or observation. Materials and methodsPatients with localized prostate cancer who received primary radiotherapy with curative intent between 1999 and 2000 were identified in the British Columbia Tumour Registry. Exclusion criteria included patient age >72 years, prostate-specific antigen>40ng/ml, and clinical stage T4 at diagnosis. Data on clinicopathologic features, primary therapy, prostate-specific antigen kinetics, and salvage therapy were collected retrospectively. Radiation failure was defined as biochemical recurrence according to the Phoenix criteria or by initiation of salvage therapy. ResultsOf 1,782 patients treated in the study period, 1,067 met inclusion criteria. Of these, 257 failed radiation therapy. Radiation therapy failure was managed with observation (>12mo) in 126 patients and ADT in 119. Of the observed patients, 66 subsequently received ADT. Five patients (1.8%) received LST (3 radical prostatectomy and 2 brachytherapy). ConclusionsOnly 2% of patients relapsing after radiation therapy for localized prostate cancer received LST. Although the benefits of LST are unproven, these findings reveal a possible underutilization of LST and indicate a need for enhanced collaboration between specialties to optimize care of this challenging cohort.

Pelvic exenteration in patients with nonmetastatic, locally advanced castration-resistant prostate cancer.

168 Background: A subset of patients who present with localized prostate cancer (PCa) do not develop metastatic disease and recur locally after definitive primary therapy, local salvage therapy, hormones, and systemic intervention. We report our experience in patients with non-metastatic, locally advanced castration resistant prostate cancer (CRPC) treated with radical cystectomy or pelvic exenteration (RC/PEx). Methods: Institutional review board (IRB) approved retrospective review of all patients undergoing RC/PEx for non-metastatic, locally recurrent CRPC after definitive and salvage therapies. Patients were excluded if RC/PEx was for complications of definitive therapy alone. Results: Of 31 patients who had RC/PEx for PCa, 20 met inclusion criteria. Initial therapy was RP (4), XRT (6), brachytherapy (4), brachy/XRT (3), ADT/chemo (2), and ADT alone (1). Five patients had salvage XRT. All received ADT at relapse and 11 had chemotherapy prior to RC/PEx. RC/PEx was performed a median of 8.16 years (0.7 to 24.5) after PCa diagnosis. Patients had pT2b (1), pT3 (5), and pT4 (14) disease at surgery. Lymph nodes were clinically negative in all patients but pathologically positive in six, negative in nine, and not resected in five. Concurrent resections included rectum (12), pelvic wall (6), pubis (1), and iliac vein (1). Eighty five percent of patients had symptoms attributable to locally progressive PCa at RC/PEx including pain, genitourinary or gastrointestinal obstruction and bleeding. All symptomatic patients had relief of disease-related symptoms until recurrence. After a median follow-up of 3.12 years (0.7 to 13.4), nine patients are alive (four have no evidence of disease, five alive with disease), nine dead of disease, and two dead of other causes. Median time to death after RC/PEx was 2.8 years (0.8 to 5.9). For 14 patients who relapsed, metastases developed a median of 398 days (110 to 1,679) after RC/PEx. Ten patients received chemotherapy and 16 had androgen-deprivation therapy after surgery for local recurrence or distant metastases. Median time to chemotherapy after RC/PEx was 346 days (96 to 1,709). Conclusions: For patients with non-metastatic, locally advanced CRPC, RC/PEx to resect symptomatic disease is feasible and appears clinically beneficial. In addition to local control, it may confer significant disease free intervals and relief of symptoms. Even after relapse, performance status was sufficient to undergo systemic therapy.

Salvage low-dose-rate (125)I partial prostate brachytherapy after dose-escalated external beam radiotherapy.

PurposeTo report outcomes on 5 patients treated with salvage partial low-dose-rate (LDR) 125-iodine (125I) permanent prostate seed brachytherapy (BT) for biopsy-proven locally persistent prostate cancer, following failure of dose-escalated external beam radiotherapy (EBRT).Material and methodsA retrospective review of the Fox Chase Cancer Center prostate cancer database identified five patients treated with salvage partial LDR 125I seed implant for locally persistent disease following dose-escalated EBRT to 76-84 Gy in 2 Gy per fraction equivalent. All patients had post-EBRT biopsies confirming unilateral locally persistent prostate cancer. Pre-treatment, EBRT and BT details, as well as post-treatment characteristics were documented and assessed.ResultsThe median follow-up post-implant was 41 months. All five patients exhibited low acute genitourinary and gastrointestinal toxicities. Increased erectile dysfunction was noted in three patients. There were no biochemical failures following salvage LDR 125I seed BT to date, with a median post-salvage PSA of 0.4 ng/mL.ConclusionsIn carefully selected patients with local persistence of disease, partial LDR 125I permanent prostate seed implant appears to be a feasible option for salvage local therapy with an acceptable toxicity profile. Further study is needed to determine long-term results of this approach.

Patterns of response and progression in patients with BRAF‐mutant melanoma metastatic to the brain who were treated with dabrafenib

BACKGROUNDDabrafenib has activity in patients with brain metastases, but little is known of the relative efficacy of treatment within and outside the brain. This study sought to examine the intracranial (IC) and extracranial (EC) patterns of response and progression in patients with active melanoma brain metastases treated with dabrafenib.METHODSClinicopathologic parameters were collected on patients with active brain metastases enrolled in the phase 1 and 2 studies of dabrafenib at a single institution. RECIST (Response Evaluation Criteria In Solid Tumors) response and progression‐free survival (PFS) were prospectively assessed by disease site (IC versus EC). Treatments received after disease progression were also assessed.RESULTSA total of 23 patients were studied. Response rates were similar in IC (78%) and EC (90%) sites (P = .416). IC and EC response was concordant in 71% of patients. Median site‐specific PFS was identical in both IC and EC sites (23.6 weeks, P = .465), and exceeded whole‐body PFS determined by RECIST (16.3 weeks). Of 20 patients with progressive disease (PD), 6 had IC PD only, 6 had EC PD only, and 8 had PD in both sites. In those with isolated intracranial PD, 5 of 6 underwent local therapy to the brain and continued on dabrafenib longer than 30 days.CONCLUSIONSIC and EC melanoma metastases respond similarly to dabrafenib. There is no dominant site or pattern of disease progression in patients with brain metastases treated with dabrafenib. Salvage local therapy is possible in most patients after IC disease progression, with ongoing dabrafenib treatment possible in a subset of patients. Cancer 2014;120:530–536. © 2013 American Cancer Society.