The prognostic significance of a negative PSMA-PET scan prior to salvage radiotherapy following radical prostatectomy.

AIM The optimal management for early recurrent prostate cancer following radical prostatectomy (RP) in patients with negative prostate-specific membrane antigen positron-emission tomography (PSMA-PET) scan is an ongoing subject of debate. The aim of this study was to evaluate the outcome of salvage radiotherapy (SRT) in patients with biochemical recurrence with negative PSMA PET finding. METHODS This retrospective, multicenter (11 centers, 5 countries) analysis included patients who underwent SRT following biochemical recurrence (BR) of PC after RP without evidence of disease on PSMA-PET staging. Biochemical recurrence-free survival (bRFS), metastatic-free survival (MFS) and overall survival (OS) were assessed using Kaplan-Meier method. Multivariable Cox proportional hazards regression assessed predefined predictors of survival outcomes. RESULTS Three hundred patients were included, 253 (84.3%) received SRT to the prostate bed only, 46 (15.3%) additional elective pelvic nodal irradiation, respectively. Only 41 patients (13.7%) received concomitant androgen deprivation therapy (ADT). Median follow-up after SRT was 33 months (IQR: 20-46 months). Three-year bRFS, MFS, and OS following SRT were 73.9%, 87.8%, and 99.1%, respectively. Three-year bRFS was 77.5% and 48.3% for patients with PSA levels before PSMA-PET ≤ 0.5 ng/ml and > 0.5 ng/ml, respectively. Using univariate analysis, the International Society of Urological Pathology (ISUP) grade > 2 (p = 0.006), metastatic pelvic lymph nodes at surgery (p = 0.032), seminal vesicle involvement (p 0.5 ng/ml (p = 0.004), and lack of concomitant ADT (p = 0.023) were significantly associated with worse bRFS. On multivariate Cox proportional hazards, seminal vesicle infiltration (p = 0.007), ISUP score >2 (p = 0.048), and pre SRT PSA level > 0.5 ng/ml (p = 0.013) remained significantly associated with worse bRFS. CONCLUSION Favorable bRFS after SRT in patients with BR and negative PSMA-PET following RP was achieved. These data support the usage of early SRT for patients with negative PSMA-PET findings

PSMA-PET/CT-guided salvage radiotherapy in recurrent or persistent prostate cancer and PSA < 0.2 ng/ml.

PURPOSE The purpose of this retrospective, multicenter study was to assess efficacy of PSMA-PET/CT-guided salvage radiotherapy (sRT) in patients with recurrent or persistent PSA after primary surgery and PSA levels < 0.2 ng/ml. METHODS The study included patients from a pooled cohort (n = 1223) of 11 centers from 6 countries. Patients with PSA levels > 0.2 ng/ml prior to sRT or without sRT to the prostatic fossa were excluded. The primary study endpoint was biochemical recurrence-free survival (BRFS) and BR was defined as PSA nadir after sRT + 0.2 ng/ml. Cox regression analysis was performed to assess the impact of clinical parameters on BRFS. Recurrence patterns after sRT were analyzed. RESULTS The final cohort consisted of 273 patients; 78/273 (28.6%) and 48/273 (17.6%) patients had local or nodal recurrence on PET/CT. The most frequently applied sRT dose to the prostatic fossa was 66-70 Gy (n = 143/273, 52.4%). SRT to pelvic lymphatics was delivered in 87/273 (31.9%) patients and androgen deprivation therapy was given to 36/273 (13.2%) patients. After a median follow-up time of 31.1 months (IQR: 20-44), 60/273 (22%) patients had biochemical recurrence. The 2- and 3-year BRFS was 90.1% and 79.2%, respectively. The presence of seminal vesicle invasion in surgery (p = 0.019) and local recurrences in PET/CT (p = 0.039) had a significant impact on BR in multivariate analysis. In 16 patients, information on recurrence patterns on PSMA-PET/CT after sRT was available and one had recurrent disease inside the RT field. CONCLUSION This multicenter analysis suggests that implementation of PSMA-PET/CT imaging for sRT guidance might be of benefit for patients with very low PSA levels after surgery due to promising BRFS rates and a low number of relapses within the sRT field

Stereotactic or conformal radiotherapy for adrenal metastases: patient characteristics and outcomes in a multicenter analysis

To report outcome (freedom from local progression: FFLP, overall survival: OS, and toxicity) after stereotactic, palliative, or highly conformal fractionated (&gt; 12) radiotherapy (SBRT, Pall-RT, 3DCRT/IMRT) for adrenal metastases in a retrospective multicenter cohort within the framework of the German Society for Radiation Oncology (DEGRO). Adrenal metastases treated with SBRT (≤ 12 fractions, biologically effective dose, (BED10) ≥ 50 Gy), 3DCRT/IMRT (&gt; 12 fractions, BED10 ≥ 50 Gy) or Pall-RT (BED10 &lt; 50 Gy) were eligible for this analysis. In addition to unadjusted FFLP (Kaplan-Meier/Log-rank), we calculated the competing-risk-adjusted local recurrence rate (CRA-LRR). 326 patients with 366 metastases were included by 21 centers (median follow-up: 11.7 months). Treatment was SBRT, 3DCRT/IMRT, and Pall-RT in 260, 27, and 79 cases, respectively. Most frequent primary tumors were non-small-cell lung cancer (NSCLC; 52.5%), SCLC (16.3%), and melanoma (6.7%). Unadjusted FFLP was higher after SBRT v. Pall-RT (p&nbsp;=&nbsp;0.026) while numerical differences in CRA-LRR between groups did not reach statistical significance (1-year CRA-LRR: 13.8%, 17.4%, and 27.7%). OS was longer after SBRT v. other groups (p &lt; 0.05) and increased in patients with locally-controlled metastases in a landmark analysis (p &lt; 0.0001). Toxicity was mostly mild; notably, 4 cases of adrenal insufficiency occurred, 2 of which were likely caused by immunotherapy or tumor progression. RT for adrenal metastases was associated with a mild toxicity profile in all groups and a favorable 1-year CRA-LRR after SBRT or 3DCRT/IMRT. 1-year FFLP was associated with longer OS. Dose-response analyses for the dataset are underway

Development and Validation of a Multi-institutional Nomogram of Outcomes for PSMA-PET-Based Salvage Radiotherapy for Recurrent Prostate Cancer.

IMPORTANCE Prostate-specific antigen membrane positron-emission tomography (PSMA-PET) is increasingly used to guide salvage radiotherapy (sRT) after radical prostatectomy for patients with recurrent or persistent prostate cancer. OBJECTIVE To develop and validate a nomogram for prediction of freedom from biochemical failure (FFBF) after PSMA-PET-based sRT. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study included 1029 patients with prostate cancer treated between July 1, 2013, and June 30, 2020, at 11 centers from 5 countries. The initial database consisted of 1221 patients. All patients had a PSMA-PET scan prior to sRT. Data were analyzed in November 2022. EXPOSURES Patients with a detectable post-radical prostatectomy prostate-specific antigen (PSA) level treated with sRT to the prostatic fossa with or without additional sRT to pelvic lymphatics or concurrent androgen deprivation therapy (ADT) were eligible. MAIN OUTCOMES AND MEASURES The FFBF rate was estimated, and a predictive nomogram was generated and validated. Biochemical relapse was defined as a PSA nadir of 0.2 ng/mL after sRT. RESULTS In the nomogram creation and validation process, 1029 patients (median age at sRT, 70 years [IQR, 64-74 years]) were included and further divided into a training set (n = 708), internal validation set (n = 271), and external outlier validation set (n = 50). The median follow-up was 32 months (IQR, 21-45 months). Based on the PSMA-PET scan prior to sRT, 437 patients (42.5%) had local recurrences and 313 patients (30.4%) had nodal recurrences. Pelvic lymphatics were electively irradiated for 395 patients (38.4%). All patients received sRT to the prostatic fossa: 103 (10.0%) received a dose of less than 66 Gy, 551 (53.5%) received a dose of 66 to 70 Gy, and 375 (36.5%) received a dose of more than 70 Gy. Androgen deprivation therapy was given to 325 (31.6%) patients. On multivariable Cox proportional hazards regression analysis, pre-sRT PSA level (hazard ratio [HR], 1.80 [95% CI, 1.41-2.31]), International Society of Urological Pathology grade in surgery specimen (grade 5 vs 1+2: HR, 2.39 [95% CI, 1.63-3.50], pT stage (pT3b+pT4 vs pT2: HR, 1.91 [95% CI, 1.39-2.67]), surgical margins (R0 vs R1+R2+Rx: HR, 0.60 [95% CI, 0.48-0.78]), ADT use (HR, 0.49 [95% CI, 0.37-0.65]), sRT dose (>70 vs ≤66 Gy: HR, 0.44 [95% CI, 0.29-0.67]), and nodal recurrence detected on PSMA-PET scans (HR, 1.42 [95% CI, 1.09-1.85]) were associated with FFBF. The mean (SD) nomogram concordance index for FFBF was 0.72 (0.06) for the internal validation cohort and 0.67 (0.11) in the external outlier validation cohort. CONCLUSIONS AND RELEVANCE This cohort study of patients with prostate cancer presents an internally and externally validated nomogram that estimated individual patient outcomes after PSMA-PET-guided sRT

Comorbidity indexing for prediction of the clinical outcome after stereotactic body radiation therapy in non-small cell lung cancer

Abstract Purpose To determine the prognostic impact of comorbidity and age in medically inoperable early-stage non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT) using the age-adjusted Charlson Comorbidity Index (aCCI). Patients and methods Between November 2008 and January 2015, 196 consecutive patients with medically inoperable NSCLC were treated with SBRT at a single institution. The prescribed isocenter dose was either 60.0 Gray (Gy) in six fractions for central lung cancer or 56.25 Gy in three fractions for peripheral lung cancer. Baseline comorbidities were retrospectively retrieved according to available outclinic medical records as well as the hospital information system. The aCCI was scored for each patient and subjected according to outcome and toxicity as well as all of the single items of the aCCI and other clinical parameters using univariate and multivariate analysis. Results Thirty-one point 6 % (62/196) of patients were deceased, of whom 17.3% (34/196) died due to lung cancer and 14.3% (28/196) due to comorbidities. The median overall survival (OS) was 15.0 months (95% CI [11.9–18.1]), whereas the median cancer-specific survival (CSS) was not reached. An aCCI ≥7 compared with an aCCI ≤6 was significantly associated with an increased risk of death (HR 1.79, 95% CI [1.02–2.80], p = 0.04) and cancer-specific death (HR 9.26, 95% CI [4.83–24.39], p < 0.001), respectively. Neither OS nor CCS were significantly associated with age, sex, side (left vs. right), lobe, localization (central vs. peripheral), packyears, TNM, or any item of the aCCI. Considering the 14.3% (28/196) of deceased patients who died due to comorbidities, aCCI ≥9 was significantly associated with non-cancer-related death (HR 3.12, 95% CI [1.22–8.33], p = 0.02). The observed cumulative rate of radiation pneumonitis (RP) ≥2 was 12.7% (25/196). The aCCI had no statistical association with RP. Conclusion Advanced age and numerous comorbidities characterizing this patient population were successfully assessed using the aCCI in terms of survival. Therefore, we recommend that age and comorbidity be indexed using the aCCI as a simple scoring system for all patients treated with SBRT for lung cancer

Temporal and spatial dose distribution of radiation pneumonitis after concurrent radiochemotherapy in stage III non-small cell cancer patients

Abstract Background and purpose Radiation pneumonitis (RP) is the most common subacute side effect after concurrent chemoradiotherapy (CRT) for locally advanced non-small cell lung cancer. Several clinical and dose-volume (DV) parameters are associated with a distinct risk of symptomatic RP. The aim of this study was to assess the spatial dose distribution of the RP volume from first occurence to maximum volume expansion of RP. Material and methods Between 2007 and 2015, 732 patients with lung cancer were treated in an institution. Thirty-three patients met the following inclusion criteria: an RP grade II after CRT and a radiation dose ≥60 Gy and no prior medical history of cardiopulmonary comorbidities. The images of the first chest computed tomography (CT) confirming the diagnosis of RP and the CT images showing the maximum expansion of RP were merged with the treatment plan. The RP volume was delineated within the treatment plan, and a DV analysis was performed to evaluate the lung dose volume areas in which the RP manifested over time and whether dose volume changes within the RP volume occurred. Results A change from clinical diagnosis to maximum expansion of RP was observed as the RP at clinical appearance mainly manifested in the lower dose areas of the lung, whereas the RP volume at maximum expansion manifested in the higher dose areas, resulting in a significant shift of the assessed relative mean dose volume proportions within the RP volume. The mean relative dose volume proportion 0- ≤ 20 Gy decreased from 30.2% (range, 0–100) to 21.9% (range, 0–100; p = 0.04) at the expense of the dose volume > 40 Gy which increased from 39.2% (range, 0–100) to 49.8% (range, 0–100; p = 0.02), whereas the dose relative volume proportion > 20- ≤ 40 Gy showed no relevant change and slightly decreased from 30.6% (range, 0–85.7) to 28.3%, (range, 0–85.7; p = 0.34). Conclusion We observed a considerable increase in the relative dose proportions within the RP volume from diagnosis to maximum volume extent from low dose zones below 20 Gy to zones above 40 Gy. Although the clinical impact on RP remains unknown, a reduction of healthy healthy lung tissue receiving >40 Gy (V40) might be an additional parameter for irradiation planning in lung cancer patients

Frequency and risk factors for arm lymphedema after multimodal breast-conserving treatment of nodal positive breast Cancer – a long-term observation

Abstract Background Arm-lymphedema is a major complication after breast cancer. Recent studies demonstrate the validity of predicting Breast Cancer Related Lymphedema (BCRL) by self-reports. We aimed to investigate the rate of BCRL and its risk factors in the long-term using self-reported symptoms. Methods Data was collected from 385 patients who underwent multimodal therapy for nodal positive breast cancer, including breast conserving surgery, axillary dissection, and local or locoregional radiotherapy. Two validated questionnaires were used for the survey of BCRL (i.e. LBCQ-D and SDBC-D). These were analysed collectively with retrospective data of our medical records. Results 23.5% (n = 43) suffered a permanent BCRL (stage II-III) after a median follow-up time of 10.1 years (4.9–15.9 years); further 11.5% (n = 23) reported at least one episode of reversible BCRL (Stage 0-I) during the follow-up time. 87.1% of the patients with lymphedema developed this condition in the first two years. Adjuvant chemotherapy was a significant risk factor for the appearance of BCRL (p = 0.001; 95%-CI 7.7–10.2). Conclusions Breast cancer survivors face a high risk of BCRL, particularly if axillary dissection was carried out. Almost 90% of BCRL occurred during the first two years after radiotherapy. Self-report of symptoms seems to be a suitable instrument of early detection of BCRL

The Prognostic Value of Liquid Biopsies for Benefit of Salvage Radiotherapy in Relapsed Oligometastatic Prostate Cancer

To assess the prognostic value of &ldquo;liquid biopsies&rdquo; for the benefit of salvage RT in oligometastatic prostate cancer relapse, we enrolled 44 patients in the study between the years 2016 and 2020. All the patients were diagnosed as having an oligometastatic prostate cancer relapse on prostate-specific membrane antigen (PSMA)-targeted PET-CT and underwent irradiation at the Department of Radiotherapy at the Hannover Medical School. Tumor cells and total RNA, enriched from the liquid biopsies of patients, were processed for the subsequent quantification analysis of relative transcript levels in real-time PCR. In total, 54 gene transcripts known or suggested to be associated with prostate cancer or treatment outcome were prioritized for analysis. We found significant correlations between the relative transcript levels of several investigated genes and the Gleason score, PSA (prostate-specific antigen) value, or UICC stage (tumor node metastasis -TNM classification of malignant tumors from Union for International Cancer Control). Furthermore, a significant association of MTCO2, FOXM1, SREBF1, HOXB7, FDXR, and MTRNR transcript profiles was found with a temporary and/or long-term benefit from RT. Further studies on larger patients cohorts are necessary to prove our preliminary findings for establishing liquid biopsy tests as a predictive examination method prior to salvage RT

Efficacy of repeated PSMA PET-directed radiotherapy for oligorecurrent prostate cancer after initial curative therapy

Purpose!#!To assess the outcome of prostate cancer (PCa) patients diagnosed with oligorecurrent disease and treated with a first and a second PSMA (prostate-specific membrane antigen ligand) PET(positron-emission tomography)-directed radiotherapy (RT).!##!Patients and methods!#!Thirty-two patients with oligorecurrent relapse after curative therapy received a first PSMA PET-directed RT of all metastases. After biochemical progression, all patients received a second PSMA PET-directed RT of all metastases. The main outcome parameters were biochemical progression-free survival (bPFS) and androgen deprivation therapy-free survival (ADT-FS). The intervals of BPFS were analyzed separately as follows: the interval from the last day of PSMA PET-directed RT to the first biochemical progression was defined as bPFS_1 and the interval from second PSMA PET-directed RT to further biochemical progression was defined as bPFS_2.!##!Results!#!The median follow-up duration was 39.5 months (18-60). One out of 32 (3.1%) patients died after 47 months of progressive metastatic prostate cancer (mPCa). All patients showed biochemical responses after the first PSMA PET-directed RT and the median prostate-specific antigen (PSA) level before RT was 1.70 ng/mL (0.2-3.8), which decreased significantly to a median PSA nadir level of 0.39 ng/mL (range &amp;lt;0.07-3.8; p = 0.004). The median PSA level at biochemical progression after the first PSMA PET-directed RT was 2.9 ng/mL (range 0.12-12.80; p = 0.24). Furthermore, the PSA level after the second PSMA PET-directed RT at the last follow-up (0.52 ng/mL, range &amp;lt;0.07-154.0) was not significantly different (p = 0.36) from the median PSA level (1.70 ng/mL, range 0.2-3.8) before the first PSMA PET-directed RT. The median bPFS_1 was 16.0 months after the first PSMA PET-directed RT (95% CI 11.9-19.2) and the median bPFS_2 was significantly shorter at 8.0 months (95% CI 6.3-17.7) after the second PSMA PET-directed RT (p = 0.03; 95% CI 1.9-8.3). Multivariate analysis revealed no significant parameter for bPFS_1, whereas extrapelvic disease was the only significant parameter (p = 0.02, OR 2.3; 95% CI 0.81-4.19) in multivariate analysis for bPFS_2. The median ADT-FS was 31.0 months (95% CI 20.1-41.8) and multivariate analysis showed that patients with bone metastases, compared to patients with only lymph node metastases at first PSMA PET-directed RT, had a significantly higher chance (p = 0.007, OR 4.51; 95% CI 1.8-13.47) of needing ADT at the last follow-up visit.!##!Conclusion!#!If patients are followed up closely, including PSMA PET scans, a second PSMA PET-directed RT represents a viable treatment option for well-informed and well-selected patients