Local Salvage Therapy Research Articles

Prostate-specific Membrane Antigen Positron Emission Tomography Before Reaching the Phoenix Criteria for Biochemical Recurrence of Prostate Cancer After Radiotherapy: Earlier Detection of Recurrences

Background and objectiveBiochemical recurrence (BCR) of prostate cancer (PCa) after curative radiotherapy (RT) is defined according to the Phoenix criteria, which is a prostate-specific antigen (PSA) rise of ≥2.0 ng/ml above the PSA nadir. Prostate-specific membrane antigen (PSMA)-based positron emission tomography/computed tomography (PET/CT) can identify PCa recurrences at very low PSA values. Our aim was to investigate the detection rate and extent of PCa recurrences using PSMA PET/CT after curative RT among patients with a PSA rise of ≥2.0 ng/ml above the nadir (Phoenix positive, Ph+) and patients not reaching this threshold (Phoenix negative, Ph−) and to compare therapeutic management and clinical outcomes in terms of time to androgen deprivation therapy (ADT) and castration-resistance PCa (CRPC), as well as overall survival. MethodsWe conducted a retrospective analysis of the Prostate Cancer Network Amsterdam (2015–2023) cohort of 568 patients who received curative-intent RT for PCa. Data on PSMA PET/CT outcomes, therapeutic management, and clinical follow-up were collected, including (re)initiation of ADT, progression to CRPC, and survival. Results were compared between groups using logistic regression and survival analyses. Key findings and limitationsThe study cohort comprised 222 patients (39.1%) classified as Ph− and 346 (60.9%) classified as Ph+. PSMA-avid lesions were detected in 170 Ph− patients (76.6%) and 322 (93.1%) Ph+ patients. In these groups, 75.9% of Ph− patients and 45.0% of Ph+ patients were eligible for local salvage therapy (odds ratio [OR 3.84]; p < 0.001). Distant metastases were less frequent in the Ph− group (n = 37, 21.8%) than in the Ph+ group (n = 157, 48.8%; OR 0.29; p < 0.001). Survival analyses revealed longer times to ADT (re)initiation and progression to CRPC, as well as lower overall mortality, in the Ph− group (log-rank p < 0.001). The retrospective study design is the main limitation. Conclusions and clinical implicationsFor patients with PCa recurrence, PSMA PET/CT can detect this recurrence in the majority of cases not meeting the Phoenix criteria for BCR. Early imaging detects recurrences at a less advanced disease stage, allowing potential salvage treatments. In addition, early PSMA PET/CT is associated with longer times to ADT (re)initiation and progression to CRPC, as well as longer overall survival. These positive clinical implications warrant confirmation of our results in prospective studies to reduce potential leadtime bias. Patient summaryWe investigated early use of a special type of scan called PSMA PET (prostate-specific membrane antigen positron emission tomography) in patients with suspicion of recurrence of their prostate cancer after radiotherapy. Early scans can detect recurrence before the cancer progresses to a more advanced stage.

Systematic review and recommendations for re-irradiation for intraprostatic radiorecurrent prostate cancer after definitive radiation therapy.

Intraprostatic recurrence (IRR) of prostate cancer after radiation therapy is increasingly identified. Our objective was to review the literature to determine the optimal workup for identifying IRR, the management options, and practical considerations for the delivery of re-irradiation as salvage local therapy. We performed a systematic review of available publications and ongoing studies on the topics of IRR, with a focus on salvage re-irradiation. Work up of biochemically recurrent prostate cancer includes PSMA PET/CT and multiparametric MRI, followed by biopsy to confirm IRR. Management options include continued surveillance, palliative hormonal therapy, and salvage local therapy. Salvage local therapy can be delivered using re-irradiation with low dose rate brachytherapy, high dose rate (HDR) brachytherapy, and stereotactic body radiotherapy (SBRT), as well as non-radiation modalities, such as cryotherapy, high-intensity focused ultrasound, irreversible electroporation and radical prostatectomy. Data demonstrate that HDR brachytherapy and SBRT have similar efficacy compared to the other salvage local therapy modalities, while having more favorable side effect profiles. Recommendations for radiation therapy planning and delivery using HDR and SBRT based on the available literature are discussed. Salvage re-irradiation is safe and effective and should be considered in patients with IRR.

Local salvage therapies in patients with radio-recurrent prostate cancer following external beam radiotherapy: a systematic review and meta-analysis.

To date, radio-recurrent prostate cancer (PCa) ranks as the fourth most common urological malignancy when considering the number of men with localized PCa who undergo radiation treatment and subsequently experience a biochemical recurrence. This systematic review aimed to summarize available evidence about the outcomes of local salvage strategies in patients with local PCa recurrence following primary external-beam radiation therapy (EBRT). We conducted a comprehensive bibliographic search on MEDLINE, Scopus, and Web of Science Core Collection databases in October 2023 to identify studies published in the last 20 years evaluating outcomes of local salvage procedures in patients with locally radio-recurrent PCa following EBRT. The meta-analysis was performed using ProMeta 3 software when two or more studies reported the same outcome. The effect size (ES) was estimated using rates reported with its 95% confidence interval (CI). Overall, 28 studies (6 prospective and 22 retrospective) including 1544 patients were included in the review. Two-year recurrence-free survival (RFS) was 84.0% (95% CI: 67.0-93.0%), 69.0% (95% CI: 42.0-87.0%), 58.0% (95% CI: 43.0-71.0%), and 45% (95% CI: 38.0-52.0%), for patients undergoing brachytherapy (BT), EBRT, Cryotherapy and High-Intensity Focused Ultrasound (HIFU), respectively. After salvage prostatectomy, RFS ranged from 75% to 78.5% at a median follow-up ranging from 18 to 35 months. Estimates for severe gastrointestinal toxicity were 2%, 3%, 3%, 4%, and 11% following cryotherapy, BT, HIFU, EBRT, and salvage radical prostatectomy, respectively. In patients who underwent EBRT as primary treatment, prostate salvage re-irradiation through BT or EBRT represents the modality providing the best balance between efficacy and safety. Unfortunately, due to the low level of evidence, strong recommendations regarding the choice of any of these techniques cannot be made.

Nonsurgical salvage options for locally recurrent prostate cancer after primary definitive radiotherapy: a systematic review and meta-analysis.

To conduct a meta-analysis to provide the latest evidence of nonsurgical local salvage options in the first-line radiotherapy (RT) failure setting for localized prostate cancer patients. Recurrence of localized prostate cancer after primary RT remains a clinical challenge. There is no consensus on optimal nonsurgical local salvage therapies, which mainly consist of cryotherapy (CRYO), high-intensity focused ultrasound (HIFU), high/low-dose-rate brachytherapy (HDR/LDR), and stereotactic body radiotherapy (SBRT). Our study was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The authors systematically searched PubMed, Web of Science, Cochrane Library, and ClinicalTrials.gov up to September 2023 to identify potentially relevant studies. The risk of bias was assessed using the European Association of Urology (EAU) items. Biochemical recurrence-free survival (bRFS) and genitourinary/gastrointestinal toxicities were the outcomes of interest. Pooled rates with 95% CIs were evaluated. A total of 99 studies comprising 8440 patients were included. The pooled rate of 1-year biochemical control (BC) was highest for LDR (0.88, 95% CI: 0.72-0.95) and lowest for SBRT (0.68, 95% CI: 0.49-0.83). The pooled rate of 5-year BC was highest for CRYO (0.52, 95% CI: 0.33-0.69) and lowest for HDR (0.23, 95% CI: 0.08-0.51). HIFU presented the worst outcome of grade ≥3 genitourinary toxicities (GU3), with a rate of 0.22 (95% CI: 0.12-0.3). Conversely, CRYO (0.09, 95% CI: 0.04-0.14), HDR (0.05, 95% CI: 0.02-0.07), LDR (0.10, 95% CI: 0.06-0.14), and SBRT (0.06, 95% CI: 0.03-0.09) presented low rates of GU3. All subgroups induced a quite low incidence of grade ≥3 gastrointestinal toxicities (GI3). Nonsurgical salvage therapies are promising modalities for prostate cancer in the local radiorecurrence setting. Based on the preliminary evidence from this study, CRYO and SBRT might present a relatively steady efficacy of BC with acceptable treatment-related toxicities.

Evaluation of Recurrent Disease after Radiation Therapy for Patients Considering Local Salvage Therapy: Past vs. Contemporary Management.

Recurrent prostate cancer after primary treatment with radiation therapy is a common problem. Patients with localized recurrence may benefit from salvage therapy, but careful patient selection is crucial because not all patients will benefit from local salvage therapy, and salvage therapy has increased morbidity compared to primary treatments for prostate cancer. This review aims to provide an overview of the evaluation of patients with recurrent disease after radiation therapy and how it is continuing to evolve with increasing data on outcomes, as well as improving technologies and techniques. Our enhanced understanding of treatment outcomes and risk stratification has influenced the identification of patients who may benefit from local salvage treatment. Advances in imaging and biopsy techniques have enhanced the accuracy of locating the recurrence, which affects treatment decisions. Additionally, the growing interest in image-targeted ablative therapies that have less morbidity and complications than whole-gland therapies for suitable patients influences the evaluation process for those considering focal salvage therapy. Although significant changes have been made in the diagnostic evaluation of patients with recurrent disease after radiation therapy, it remains unclear whether these changes will ultimately improve patient outcomes.

The Importance of Multi-Parametric MRI, PET/CT, and Biopsy for Identifying and Delineating the Extent of Locally Radiorecurrent Prostate Cancer: A Multi-institutional Analysis of the F-SHARP Clinical Trial.

Up to 50% of clinical recurrences after curative-intent radiation are intraprostatic local radiorecurrences (LRR), with improved detection through the recent incorporation of multi-parametric MRI and PET/CT in workup. Salvage local therapy (SLT) is increasingly being offered, particularly focal SLT to try to reduce toxicity due to prior radiation. Limited data exist on the incremental value of each imaging modality and biopsy in defining LRR. The objective of this study is to compare the findings of MRI, PET/CT and biopsy in patients with LRR prostate cancer, and the impact each modality has on identifying recurrence and defining the extent of prostate involvement. This is a secondary analysis of 58 patients enrolled on the ongoing F-SHARP phase I/II clinical trial of salvage HDR brachytherapy from 3 institutions who underwent PSMA or fluciclovine PET/CT, MRI, and biopsy prior to enrollment. Recurrent tumor was delineated on each imaging modality and by inclusion of involved regions on biopsy. Descriptive statistics were used to compare the imaging-defined tumor with biopsy findings to assess the congruence between the imaging modalities and generate the percentage of patients with disease involvement on biopsy outside of the image-defined targets. Initial therapy was conventional/moderately hypofractionated photons in 35 patients, LDR in 13, proton therapy in 7, SBRT in 2, and neutrons in 1. Recurrence Gleason grade groups included 1 (n = 3), 2 (17), 3 (12), 4 (8), 5 (9), and uninterpretable (9). MRI/TRUS sextant + fusion biopsy was performed in 40 patients, TRUS saturation biopsy in 4, and TRUS systematic biopsy in 14. The median number of cores involved and obtained were 6 and 14. The median number of discrete lesions on biopsy in different quadrants of the prostate was 3 (1-6). The median number of discrete lesions seen on MRI was 1 (0-4). MRI did not identity a discrete lesion in 4 patients. The sensitivity of MRI for detection of the LRR was 92.8%. The false negative rate for not detecting the focus of LRR on MRI was 7.2%. 68.4% of patients had biopsy-proven cancer outside of the MRI-defined target. Fluciclovine PET/CT was used in 45 patients, and 13 had PSMA PET/CT. The median number of lesions on PET/CT was 1 (0-2). PET/CT did not identify a discrete lesion in 8 patients. The pooled sensitivity of PET/CT in detecting the focus of LRR was 86.2% (Fluciclovine: 82.2%, PSMA: 100%). PET/CT false negative rate of PET/CT for not detecting the focus of LRR was 13.8% (Fluciclovine: 17.8%, PSMA 0%). 72.41% of patients had biopsy-proven cancer outside of the PET/CT-defined target (Fluciclovine: 77.8%, PSMA: 53.8%). Although mpMRI and PET/CT are valuable tools for identifying LRR and delineating the extent of prostate/SV involvement, a thorough biopsy is mandatory if pursuing focal SLT. Such treatment should optimally be performed on a clinical trial with robust integration of all imaging and histopathologic data.

Biochemical recurrence in patients with prostate cancer after primary definitive therapy: treatment based on risk stratification.

Nearly one-third of patients with prostate cancer (PCa) experience biochemical recurrence (BCR) after primary definitive treatment. BCR increases the risk of distant metastasis and mortality in patients with prognostically unfavorable features. These patients are best managed with a tailored treatment strategy incorporating risk stratification using clinicopathological factors, next-generation imaging, and genomic testing. This narrative review examines the utility of risk stratification for the management of patients with BCR in the context of clinical trial data, referencing the latest recommendations by European and US medical societies. PubMed was searched for relevant studies published through May 21 2023 on treatment of patients with BCR after radical prostatectomy (RP) or external beam radiotherapy (EBRT). European and US guidelines support the risk-stratified management of BCR. Post-RP, salvage EBRT (with or without androgen deprivation therapy [ADT]) is an accepted treatment option for patients with BCR. Post-EBRT, local salvage therapies (RP, cryotherapy, high-intensity focused ultrasound, stereotactic body radiotherapy, and low-dose-rate and high-dose-rate brachytherapy) have demonstrated comparable relapse-free survival rates but differing adverse event profiles, short and long term. Local salvage therapies should be used for local-only relapses while ADT should be considered for regional or distant relapses. In practice, patients often receive ADT, with varying guidance for intermittent ADT vs. continuous ADT, due to consideration of quality-of-life effects. Despite a lack of consensus for BCR treatment among guideline associations and medical societies, risk stratification of patients is essential for personalized treatment approaches, as it allows for an informed selection of therapeutic strategies and estimation of adverse events. In lower-risk disease, observation is recommended while in higher-risk disease, after failed repeat local therapy, ADT and/or clinical trial enrollment may be appropriate. Results from ongoing clinical studies of patients with BCR should provide consensus for management.

The Role of Salvage Radical Prostatectomy in Patients with Radiation-Resistant Prostate Cancer.

There are multiple treatment strategies for patients with localized prostate adenocarcinoma. In intermediate- and high-risk patients, external beam radiation therapy demonstrates effective long-term cancer control rates comparable to radical prostatectomy. In patients who opt for initial radiotherapy but have a local recurrence of their cancer, there is no unanimity on the optimal salvage approach. The lack of randomized trials comparing surgery to other local salvage therapy or observation makes it difficult to ascertain the ideal management. A narrative review of existing prospective and retrospective data related to salvage radical prostatectomy after radiation therapy was undertaken. Based on retrospective and prospective data, post-radiation salvage radical prostatectomy confers oncologic benefits, with overall survival ranging from 84 to 95% at 5 years and from 52 to 77% at 10 years. Functional morbidity after salvage prostatectomy remains high, with rates of post-surgical incontinence and erectile dysfunction ranging from 21 to 93% and 28 to 100%, respectively. Factors associated with poor outcomes after post-radiation salvage prostatectomy include preoperative PSA, the Gleason score, post-prostatectomy staging, and nodal involvement. Salvage radical prostatectomy represents an effective treatment option for patients with biochemical recurrence after radiotherapy, although careful patient selection is important to optimize oncologic and functional outcomes.

Favorable prognosis of breast cancer brain metastases patients with limited intracranial and extracranial metastatic lesions

BackgroundBreast cancer brain metastases (BCBM) are highly heterogenous with widely differing survival. The prognosis of the oligometastatic breast cancer (BC) patients with brain metastases (BM) has not been well studied. We aimed to investigate the prognosis of BCBM patients with limited intracranial and extracranial metastatic lesions.MethodsFour hundred and forty-five BCBM patients treated between 1st January 2008 and 31st December 2018 at our institute were included. Clinical characteristics and treatment information were obtained from patient’s medical records. The updated breast Graded Prognostic Assessment (Breast GPA) was calculated.ResultsThe median OS after diagnosis of BM were 15.9 months. Median OS for patients with GPA 0–1.0, 1.5–2, 2.5–3 and 3.5–4 were 6.9, 14.2, 21.8, 42.6 months respectively. The total number of intracranial and extracranial metastatic lesions, in addition to the Breast GPA, salvage local therapy and systemic therapy (anti-HER2 therapy, chemotherapy and endocrine therapy) were demonstrated to be associated with prognosis. One hundred and thirteen patients (25.4%) had 1–5 total metastatic lesions at BM diagnosis. Patients with 1–5 total metastatic lesions had a significantly longer median OS of 24.3 months compared to those with greater than 5 total metastatic lesions with a median OS of 12.2 months (P < 0.001; multivariate HR 0.55, 95% CI, 0.43–0.72). Among the patients with 1–5 metastatic lesions, median OS for GPA 0–1.0 was 9.8 months, compared to 22.8, 28.8 and 71.0 for GPA 1.5–2.0, 2.5–3.0 and 3.5–4.0 respectively, which is much longer than the corresponding patients with greater than 5 total metastatic lesions, with medium OS of 6.8, 11.6, 18.6 and 42.6 months respectively for GPA 0–1.0, 1.5–2.0, 2.5–3.0 and 3.5–4.0.ConclusionsThe patients with 1–5 total metastatic lesions demonstrated better OS. The prognostic value of the Breast GPA and the survival benefit of salvage local therapy and continuation of systemic therapy after BM were confirmed.

Potential efficacy of local therapy for progressive lesions after nivolumab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.

In recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN), local therapy (LT) such as surgery or radiotherapy can be treatment options for improved survival or quality of life. To date, however, few reports have addressed the efficacy of LT for sites of disease progression after immune checkpoint inhibitors, including other cancers. We conducted a retrospective analysis of patients with R/M SCCHN originating from the oral cavity, oropharynx, hypopharynx, and larynx and treated with nivolumab. We extracted patients undergoing salvage LT or palliative radiotherapy (RT) to the selected progressive lesion at any time after initiation of nivolumab. Twenty-four patients received LT. Salvage LT was performed in 9 (37.5%) patients, including surgery and definitive RT in 5 and 4 patients, respectively. Palliative RT was performed in 15 (62.5%) patients. LT was provided in 10 (41.7%) patients for oligoprogressive disease. Twelve (50.0%) patients received subsequent systemic therapy immediately after LT. Classification based on patient treatment divided the population into four subgroups with different prognoses (salvage LT followed by subsequent systemic therapy [n = 3], salvage LT alone [n = 6], palliative RT followed by subsequent systemic therapy [n = 9], and palliative RT alone [n = 6]). Median OS in this order was 24.5, 9.0, 7.3, and 2.4months (p = 0.001). All patients in the salvage LT followed by subsequent systemic therapy group continued nivolumab. In R/M SCCHN patients who have received nivolumab, salvage LT for the selected progressive lesion with continuation of nivolumab potentially provides an excellent survival prognosis.

Local treatment Associated With Prognosis among Men With Metastatic Prostate Cancer: A SEER-Based Study.

In order to identify the impact of local treatment on overall survival (OS) and cancer-specific survival(CSS) in men with mPCa. Men with mPCa undergoing local treatment by radical prostatectomy (RP), radiotherapy (RT) including beam radiation and brachytherapy or no local treatment identified from Surveillance, Epidemiology, and End Results (SEER) database (2010-2015). To evaluate local therapy impact on OS and CSS in relation to baseline characteristics, univariate and multivariable Cox regression analysis was used to predict the prognostic value of local therapy in OS and CSS. A total of 902 (25.8%) patients received local treatment and 2598 (74.2%) patients did not receive local treatment in this study. The Kaplan-Meier curves showed that there was significant difference in OS between patients underwent local treatment and patients without local treatment (P=.013) but not in CSS (P=.068). While multivariate Cox regression analysis showed that local treatment may not significantly improve OS(P=.724). In subgroup analysis, Among patients with prostate-specific antigent (PSA)<10ng/ml, local treatment could significantly improve OS and CSS (all P < .05). Multivariate Cox regression analysis showed that local treatment could be used as an independent prognostic factor to improve OS in mPCa patients with PSA<10ng/ml (P=.031). Another multivariate Cox regression analysis demonstrated that patients with mPCa undergoing RP had better OS and CSS (all P < .05). Our results showed that local salvage therapy did not seem to be an independent prognostic factor in all mPCa patients, but we found that local therapy can show a better prognosis in patients with lower PSA levels. Compared with RT, patients who had experienced RP may have better prognosis. We still need prospective research to further study the application value of local treatment in mPCa patients.

Locoregional Recurrence of Esophageal Cancer Treated with Curative Intent Local Salvage Therapy: A Single Center Experience.

Locoregional recurrence of esophageal carcinoma after neoadjuvant therapy and en bloc esophagectomy, although uncommon, is challenging to manage. Currently, there are no standard treatment approaches prompting many health care providers to adopt a palliative approach. We describe our experience and outcomes of treating this specific group of patients with a focus on salvage curative intent local therapy. All patients undergoing en bloc esophagectomy following neoadjuvant therapy between 2007 and 2017 at the McGill University Health Centre, a tertiary referral center for esophageal cancer, were identified. Patient follow-up included a structured surveillance protocol with serial endoscopic and cross-sectional imaging studies. Local recurrence was defined as histologically confirmed recurrences at the anastomosis. Regional recurrence was defined as radiological evidence of celiac, mediastinal, or para-esophageal/conduit lymphadenopathy. Demographic, pathologic, therapeutic variables were extracted as well as disease free and overall survival. Of 755 patients identified, locoregional recurrences occurred in 27 patients (3.6%) of whom 18 were included in the analysis. The median disease-free survival post index operation was 15months (IQR 10-23). The sites of recurrence were local (6/18, 33.3%); regional (8/18, 44.4%); and locoregional (4, 22.2%). Chemoradiation was the most common modality used to treat recurrence (10/18, 55.6%) whilst 4 (22.2%) underwent surgery. Following treatment for locoregional recurrence, 1-year overall survival was 61.1% and at 5years was 22.2%. Consolidative salvage local therapy for locoregional recurrence after en bloc esophagectomy is feasible and can entail prolonged survival in a subset of patients.

Oncological and Functional Outcomes for Men Undergoing Salvage Whole-gland Cryoablation for Radiation-resistant Prostate Cancer

BackgroundThere is no consensus on the optimal approach for salvage local therapy in radiation-resistant/recurrent prostate cancer (RRPC). ObjectiveTo investigate oncological and functional outcomes for men treated with salvage whole-gland cryoablation (SWGC) of the prostate for RRPC. Design, setting, and participantsWe retrospectively reviewed our prospectively collected cryosurgery database between January 2002 and September 2019 for men who were treated with SWGC of the prostate at a tertiary referral center. InterventionSWGC of the prostate. Outcome measurements and statistical analysisThe primary outcome was biochemical recurrence–free survival (BRFS) according to the Phoenix criterion. Secondary outcomes included metastasis-free survival, cancer-specific survival, and adverse events. Results and limitationsA total of 110 men with biopsy-proven RRPC were included in the study. Median follow-up for patients without biochemical recurrence (BCR) after SWGC was 71 mo (interquartile range [IQR] 42.3–116). BRFS was 81% at 2 yr and 71% at 5 yr. A higher prostate-specific antigen (PSA) nadir after SWGC was associated with worse BRFS. The median International Index of Erectile Function-5 score was 5 (IQR 1–15.5) before SWGC and 1 (IQR 1–4) after SWGC. Stress urinary incontinence, strictly defined as the use of any pads after treatment, was 5% at 3 mo and 9% at 12 mo. Clavien-Dindo grade ≥3 adverse events occurred in three patients (2.7%). ConclusionsIn patients with localized RPPC, SWGC achieved excellent oncological outcomes with a low rate of urinary incontinence, and represents an alternative to salvage radical prostatectomy. Patients with fewer positive cores and lower PSA tended to have better oncological outcomes following SWGC. Patient summaryFor men with prostate cancer that persists after radiotherapy, a freezing treatment applied to the whole prostate gland can achieve excellent cancer control. Patients who did not have elevated prostate-specific antigen (PSA) at 6 years after this treatment appeared to be cured.

Randomized, double-blinded phase II study of ketoconazole (keto), hydrocortisone (HC), and anti-PSMA antibody J591 labeled with 177Lu or 111In in patients (pts) with high-risk non-metastatic (met) castration-resistant prostate cancer (M0 CRPC).

LBA21 Background: Up to 1/3 of pts develop biochemical relapse following primary therapy. Many are not cured with salvage local therapy, likely because of undetectable distant disease. PSMA is expressed on most PC and can be targeted by radiolabeled J591. 177Lu is a predominantly β-emitting radionuclide and also has γ emission which allows imaging. 111In is predominantly a γ emitter, also with some auger emission for therapy. Hormonal therapy is effective and may increase PSMA expression and radiosensitize. In this DOD-funded study initiated in the pre-PSMA PET and AR signaling inhibitor era, we hypothesized that 177Lu prolongs 18-month (mo) met-free survival (MFS) more than 111In in pts with high risk, M0 CRPC when targeting PSMA via J591 in combo with keto and HC. Methods: Pts with high-risk M0 CRPC defined by PSA DT &lt; 8 mo and/or absolute PSA &gt; 20 ng/mL and serum testosterone &lt; 50 ng/mL with no evidence of metastatic disease on CT/MRI and bone scan were eligible. Treatment included a minimum 4 week lead-in with keto 400 mg TID and HC 20 mg AM, 10 mg PM (both of which could be continued until unacceptable toxicity or development of mets) and a single infusion of J591 with 2:1 randomization to 177Lu (70 mCi/m2) or 111In (5 mCi) in double-blinded fashion. The final version of the protocol was designed to randomize 55 pts for 80% power to detect a difference in 18-mo MFS with one-sided alpha of 10%. Secondary endpoints include median MFS, PSA response, overall survival, and toxicity. Results: 55 pts with median age 68 (range 52 - 88), 75% prostatectomy, 23% primary radiation, 2% primary ADT; 19% local salvage therapy. Median PSA doubling time 3 mo (range 0.87 – 7.85), median baseline PSA 8.0 (range 1-78). In intent to treat analysis (5 without imaging and 4 lost to follow up by 18 mo), 50% developed mets by 18 mo with 177Lu vs 76% with 111In (p=0.066). Median MFS was 23.8 mo vs 20.8 mo, and biochemical PFS was 18.67 vs 8.87 mo, favoring 177Lu in analyses censoring start of new treatment. Confirmed &gt;50% PSA decline occurred in 82% with 177Lu and 71% with 111In. Grade &gt;3 heme AEs were more common with 177Lu vs 111In, including neutropenia (57% vs 11%, with 1 febrile neutropenia) and thrombocytopenia (77% vs 11%, with 25% vs 6% platelet transfusions), whereas Gr &gt;3 non-heme AEs were less common with 177Lu vs 111In, including abdominal pain (0 vs 11%), ALT increase (3.3% vs 22%), and diarrhea (0 vs 22%). Conclusions: Anti-PSMA mAb J591 with keto/HC when radiolabeled with 177Lu leads to improved 18-month met-free survival vs 111In. Most pts had significant PSA decline with either version of radiolabeled J591 with keto/HC. Hematologic toxicity is more common with 177Lu. This supports the development of anti-PSMA radioimmunotherapy for low volume advanced PC, though the optimal radionuclide and targeting agent is unknown. Clinical trial information: NCT00859781 .

Management of patients with brain metastases from NSCLC without a genetic driver alteration: upfront radiotherapy or immunotherapy?

Lung cancer is the second most common cancer and the most common cause of cancer-related death in the United States. Brain metastases (BM) are detected in 21% of patients with lung cancer at the time of diagnosis and are the sole metastatic site in 35% of patients with stage IV disease. The best upfront therapy for non-small-cell lung cancer depends on both tumor programmed death 1 ligand-1 (PD-L1) expression and the presence or absence of a targetable genetic alteration in genes such as epidermal growth factor receptor and anaplastic lymphoma kinase. In the absence of a targetable genetic alteration, options include chemotherapy, immune checkpoint inhibitors (ICIs), and ICI combined with chemotherapy. Upfront local therapy followed by systemic therapy is the current standard of care for the management of BM, and may include whole brain radiotherapy, stereotactic radiosurgery (SRS), or craniotomy for surgical resection followed by consolidative SRS. This paradigm is effective in achieving local control, but it remains unclear if this approach is necessary for every patient. Prospective and retrospective data suggest that ICIs with or without chemotherapy can have activity against BM; however, appropriately selecting patients who are able to safely forgo local therapy and start an ICI-based treatment remains a challenge. To be considered for upfront ICI-based therapy, a patient should be free of neurologic symptoms, lesions should be small and not located in a critical region of the central nervous system, if corticosteroids are indicated the requirement should be low (prednisone 10 mg/d or less), and PD-L1 expression should be high. The decision to proceed with upfront ICI without local therapy to BM should be made in a multidisciplinary fashion and patients should undergo frequent surveillance imaging so that salvage local therapy can be administered when necessary. Prospective clinical trials are needed to validate this approach before it can be widely adopted.

Importance of magnetic resonance imaging and prostate-specific membrane antigen PET-CT in patients treated with salvage radical prostatectomy for radiorecurrent prostate cancer.

Accurate staging and identification of optimal candidates for local salvage therapy, such as salvage radical prostatectomy (SRP), is necessary to ensure optimal care in patients with radiorecurrent prostate cancer (PCa). We aimed to analyze performance of magnetic resonance imaging (MRI) and prostate-specific membrane antigen (PSMA)-positron emission tomography (PET)/computed tomography (CT) for predicting pathologic nonorgan confined disease (pT3) and lymph node involvement (pN+) in patients treated with SRP for radiorecurrent PCa. We retrospectively reviewed the institutional database to identify patients who underwent MRI or 68 Ga-PSMA-PET/CT before SRP for radiorecurrent PCa. The diagnostic estimates of MRI and PSMA-PET/CT for pT3 and pN+, were calculated. We identified 113 patients with radiorecurrent PCa who underwent preoperative MRI followed by SRP; 53 had preoperative 68 Ga-PSMA-PET/CT. For the detection of pT3 disease, the overall accuracy of MRI was 70% (95% confidence interval [CI] 61-78), sensitivity 40% (95%CI 26-55) and specificity 94% (95%CI 85-98); PSMA-PET/CT had slightly higher accuracy of 77% (95%CI 64-88), and higher sensitivity of 90% (95%CI 68-99), but lower specificity of 70% (95%CI 51-84). For pN+ disease, MRI had poor sensitivity of 14% (95%CI 3-36), specificity of 50 (95% CI 39-61) and total accuracy of 43% (95%CI 34-53); PSMA-PET/CT had an accuracy of 85% (95%CI 72-93), sensitivity of 27% (95%CI 6-61), and specificity of 100% (95%CI 92-100). In patients with radiorecurrent PCa, both, MRI, and 68 Ga-PSMA PET/CT are valuable tools for the pre-SRP staging and should be integrated into the standard workup. For lymph node metastases, 68 Ga-PSMA PET/CT is a strong rule-in test with nearly perfect specificity; in contrast MRI had a low accuracy for lymph node metastases.

Pattern of failure and clinical value of local therapy for oligo-recurrence in locally advanced non-small cell lung cancer after definitive chemoradiation: Impact of driver mutation status.

Considerable differences of treatment response and pattern of failure may exist between definitive chemoradiation (CRT) treated locally advanced non-small cell lung cancer (LA-NSCLC) patients. The clinical value of additional tyrosine kinase inhibitors (TKIs) before disease recurrence and salvage local therapy after initial recurrent disease remain controversial. Consecutive LA-NSCLC patients receiving definitive CRT and having definite results about driver mutations (EGFR, ALK and ROS1) were retrospectively reviewed. Initial recurrent disease was classified as in-field recurrence, out-of-field recurrence and distant metastasis. Recurrent disease occurred only in the brain or limited to ≤3 extra-cranial organs and ≤5 extra-cranial lesions, was defined as oligo-recurrence. Progression free survival and overall survival (OS) were calculated from diagnosis to disease progression or death, and to death, respectively. OS2 was measured from initial disease recurrence to death among patients who had recurrent disease. Of the 153 enrolled patients, 39 had driver mutations and 13 received additional TKI therapy besides definitive CRT. Patients harboring driver mutations but without additional TKI therapy had a similar PFS and significantly longer OS (p=0.032) than those without driver mutations. Additional TKI therapy prolonged PFS (p=0.021) but not OS among patients with driver mutations. No significant difference of pattern of failure was observed between patient subgroups stratified by the status of driver mutations and the usage of additional TKI therapy. Furthermore, 57 of the 95 patients with initial recurrent disease developed oligo-recurrence and salvage local therapy significantly improved OS2 (p=0.01) among patients with oligo-recurrence disease. LA-NSCLC patients receiving definitive CRT generally had similar PFS and pattern of treatment failure, regardless of driver mutation status. Additional TKI therapy besides definitive CRT could prolong PFS but not OS. The majority of recurrent disease after definitive CRT belongs to oligo-recurrence and salvage local therapy may provide survival benefit.

Performance of Multiparametric MRI and PET Imaging in Identifying and Localizing Locally Radiorecurrent Prostate Cancer in a Phase I/II Trial of Focal Salvage HDR

<h3>Purpose/Objective(s)</h3> Salvage local therapy (SLT) with brachytherapy or SBRT for local radiorecurrence (LRR) of prostate cancer after prior radiotherapy (RT) is increasingly being used due to growing data demonstrating the safety and efficacy of SLT, as well as the availability of advanced imaging to identify LRR, such as multiparametric MRI (mpMRI) and molecular PET imaging (18F-fluciclovine or 18F-DCFPyL PSMA). Further, advanced imaging has led to investigation into focal SLT to improve the therapeutic ratio of reirradiation. Yet, data are limited on the ability of mpMRI and PET to detect LRR and how well they localize the area(s) of recurrence in the prostate to guide focal SLT. Our objective was to determine the ability of mpMRI and PET imaging to detect the presence and full extent of the areas of involvement in men with LRR. <h3>Materials/Methods</h3> We conducted a cohort study of men with LRR of prostate cancer enrolled in the FSHARP phase I/II trial of salvage focal HDR brachytherapy at our institution. Workup included PET/CT, mpMRI of the prostate, and a biopsy documenting the LRR prior to enrollment. Descriptive statistics were used to compare mpMRI and PET detection and localization with biopsy findings to determine the sensitivity/false negative rate (FNR) of each imaging modality, and the frequency with which biopsy reveals disease that would have been missed if the imaging abnormality alone was used to define the focal salvage HDR target. <h3>Results</h3> A total of 40 men were included in this analysis. Median age was 70.5 yrs (Range: 58-83). Median time from initial RT was 9.5 yrs (2-28). Initial NCCN risk groups were as follow: 13 had low risk, 21 had intermediate risk and 2 had high risk. 26 were treated with conventionally fractionated photon RT, 7 with LDR brachytherapy, 4 with protons, 2 with SBRT and 1 with neutron therapy. Regarding recurrence biopsy, 24 men had MRI/TRUS fusion biopsy and 16 had TRUS biopsy alone. A median of 14 cores were obtained and a median of 6 cores were positive. Gleason grade grouping (GG) was as follows: 1 had GG 1, 11 had GG 2, 12 had GG 3, 6 had GG 4, and 4 had GG 5. The median number of MRI target lesions was 1 (0-4), and the median number of lesions on PET was 1 (0-2). 38 men had fluciclovine and 2 had PSMA PET. The table depicts the sensitivity and FNR of each imaging modality, and frequency of pathologically identified disease outside of the imaging target. <h3>Conclusion</h3> Our study emphasizes that though mpMRI and PET are valuable tools for restaging and target volume delineation in LRR of prostate cancer, there are limitations to their use. These imaging modalities cannot be relied upon alone if pursuing focal salvage due to a high FNR, and because the full extent of disease is rarely identified, leading to the risk of marginal misses.

A Pilot Study of Salvage HDR Brachytherapy in Recurrent Prostate Cancer: 5 Year Toxicity and Outcomes

<h3>Purpose/Objective(s)</h3> Until recently, Androgen Deprivation Therapy (ADT) was the main treatment option for recurrent prostate cancer after primary radiation treatment. However, ADT is not curative and is associated with several side effects. Local ablative therapy can be curative and reduce long-term side effects associated with ADT. We designed a single institution prospective pilot study to evaluate the toxicities and outcomes of HDR brachytherapy as a salvage local therapy. <h3>Materials/Methods</h3> Sixty (60) patients with a biopsy-proven local relapse after a previous treatment with radiation were included in this study. A negative bone scan and CT scan of the abdomen and pelvis at the time of relapse was mandatory. Primary objective was to assess both early and late genitourinary (GU) and gastrointestinal (GI) toxicities. Biochemical disease-free survival (bDFS) was also assessed as a secondary objective. Toxicities were reported using CTCAE v5 scale and the IPSS. Short-course ADT could be used if deemed clinically indicated by the physician. HDR brachytherapy regimen was 32Gy delivered in 4 fractions to the whole prostate and, for the last 10 patients recruited, 27Gy in 2 fractions administered focally, due to concerns with toxicities. CT-based treatment planning using an inverse planning algorithm (IPSA) was performed for patients with whole prostate treatment (n = 50). Real-time ultrasound-based treatment planning was used for patients undergoing focal salvage radiation (n = 10). <h3>Results</h3> Median follow-up was 58.4 months (0.8-106.8 months). GI toxicities were acceptable with 3.6% and 14.5% of patients experiencing early and late grade 2 toxicities. No G3 GI toxicities were reported. Early G2 GU toxicities were overestimated at 100% (all patients used an alpha-blocker in the postoperative setting) and one patient had G3 early toxicity. Late GU toxicities were significant, with 14.5% of patients experiencing late G3 toxicity (10.0% at the last follow-up). Of interest, the use of ADT before HDR brachytherapy (n = 17) was associated with lower GU toxicities (no G3) although the association was not statistically significant (Chi-Square p-value 0.201). Good biochemical control was achieved with a bDFS of 73.9% at 48 months. <h3>Conclusion</h3> Salvage HDR brachytherapy after primary radiation to the prostate offers good biochemical control but at the cost of significant G3 GU morbidities. Patients can benefit from local therapy after primary radiation but whole-gland radiation should be used with caution because of concern with toxicities. Focal therapy to partial gland might be a good alternative to achieve local control and avoid severe toxicities.

Patterns of Failure by Driver Mutation Status for Patients with Locally Advanced Non-Small Cell Lung Cancer Treated with Chemoradiation and Consolidative Durvalumab

<h3>Purpose/Objective(s)</h3> The standard of care for patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC) is concurrent chemoradiation (CRT) followed by consolidative durvalumab. Increasingly, mutational profiling has been used to guide treatment decisions. In this study, we investigated whether driver mutation status influences the patterns of failure and rates of oligometastatic disease. <h3>Materials/Methods</h3> Using a single institution database, we identified patients who were treated with CRT followed by consolidative durvalumab for LA-NSCLC from June 2017 to May 2020 and divided them by whether they had driver mutations as defined by EGFR exon 19 deletion, EGFR exon 20 insertion, HER2 exon 20 insertion, EGFR exon 21 mutation (L858R), ALK-EML4 fusion, MET exon 14 skipping, NTRK2 fusion, or KRAS mutation. There mutations were all targetable with the exception that only KRAS G12C is a targetable KRAS mutation. We then identified patients who had disease progression and recorded their patterns of failure (distant vs locoregional) and oligometastatic status (3 or fewer sites). These rates were compared by driver mutation status using Chi-squared tests. Comparisons of time to second progression (PFS2) by oligometastatic and driver mutation status were made using Kaplan-Meier analyses. <h3>Results</h3> The 63 patients in our cohort (of which 36 had driver mutations) had a median follow up of 21.5 months, age of 64.8 yrs, and ECOG of 1 at completion of CRT. 52% were female, 86% had a history of smoking, and 87% were white. 65% had adenocarcinoma. All were treated with concurrent CRT with radiation doses ranging from 60Gy to 77Gy. All received at least one dose of consolidative durvalumab prior to disease progression. A similar proportion of first progressions were distant failures in patients with driver mutations and those without (64% vs. 59%, p=0.71). They also had similar rates of oligometastatic disease (28% vs 48%, p=0.09). Patients with oligometastatic disease did not have improved PFS2 (5.9 months vs 5.9 months, p=0.76) compared to those with polymetastatic disease. However, oligometastatic patients with targetable driver mutations who received salvage local therapy (surgery and/or radiation) without tyrosine kinase inhibitors (TKIs) had dramatically worse PFS2 (4.1 months vs 21.4 months, p=0.01) compared to all patients with driver mutations. Conversely, the use of local therapy without systemic therapy did not lead to worse PFS2 in oligometastatic patients without targetable driver mutations (3.5 months vs 4.5 months, p=0.46). <h3>Conclusion</h3> We show similar patterns of failure and rates of oligoprogression for unresectable LA-NSCLC patients treated with concurrent CRT and consolidative durvalumab regardless of driver mutation status. Initial oligometastatic disease did not decrease the likelihood of subsequent progression. Oligometastatic patients with targetable driver mutations should not receive salvage local therapy alone without initiation of TKIs.