A nested case-control study on radiation dose-response for cardiac events in breast cancer patients in Germany.

BACKGROUND: Previous studies with the majority of breast cancer (BC) patients treated up to 2000 provided evidence that radiation dose to the heart from radiotherapy (RT) was linearly associated with increasing risk for long-term cardiac disease. RT techniques changed substantially over time. This study aimed to investigate the dose-dependent cardiac risk in German BC patients treated with more contemporary RT. METHODS: In a cohort of 11,982 BC patients diagnosed in 1998-2008, we identified 494 women treated with 3D-conformal RT who subsequently developed a cardiac event. Within a nested case-control approach, these cases were matched to 988 controls. Controls were patients without a cardiac event after RT until the index date of the corresponding case. Separate multivariable conditional logistic regression models were used to assess the association of radiation to the complete heart and to the left anterior heart wall (LAHW) with cardiac events. RESULTS: Mean dose to the heart for cases with left-sided BC was 4.27 Gy and 1.64 Gy for cases with right-sided BC. For controls, corresponding values were 4.31 Gy and 1.66 Gy, respectively. The odds ratio (OR) per 1 Gy increase in dose to the complete heart was 0.99 (95% confidence interval (CI): 0.94-1.05, P = .72). The OR per 1 Gy increase in LAHW dose was 1.00 (95% CI: 0.98-1.01, P = .68). CONCLUSIONS: Contrary to previous studies, our study provided no evidence that radiation dose to the heart from 3D-conformal RT for BC patients treated between 1998 and 2008 was associated with risk of cardiac events.

Cardiac late effects after modern 3D-conformal radiotherapy in breast cancer patients: a retrospective cohort study in Germany (ESCaRa).

PURPOSE: Radiotherapy (RT) was identified as a risk factor for long-term cardiac effects in breast cancer patients treated until the 1990s. However, modern techniques reduce radiation exposure of the heart, but some exposure remains unavoidable. In a retrospective cohort study, we investigated cardiac mortality and morbidity of breast cancer survivors treated with recent RT in Germany. METHODS: A total of 11,982 breast cancer patients treated between 1998 and 2008 were included. A mortality follow-up was conducted until 06/2018. In order to assess cardiac morbidity occurring after breast cancer treatment, a questionnaire was sent out in 2014 and 2019. The effect of breast cancer laterality on cardiac mortality and morbidity was investigated as a proxy for radiation exposure. We used Cox Proportional Hazards regression analysis, taking potential confounders into account. RESULTS: After a median follow-up time of 11.1 years, there was no significant association of tumor laterality with cardiac mortality in irradiated patients (hazard ratio (HR) for left-sided versus right-sided tumor 1.09; 95% confidence interval (CI) 0.85-1.41). Furthermore, tumor laterality was not identified as a significant risk factor for cardiac morbidity (HR = 1.05; 95%CI 0.88-1.25). CONCLUSIONS: Even though RT for left-sided breast cancer on average incurs higher radiation dose to the heart than RT for right-sided tumors, we found no evidence that laterality is a strong risk factor for cardiac disease after contemporary RT. However, larger sample sizes, longer follow-up, detailed information on individual risk factors and heart dose are needed to assess clinically manifest late effects of current cancer therapy.

Heart atlas for retrospective cardiac dosimetry: a multi-institutional study on interobserver contouring variations and their dosimetric impact.

PURPOSE: Cardiac effects after breast cancer radiation therapy potentially affect more patients as survival improves. The heart's heterogeneous radiation exposure and composition of functional structures call for establishing individual relationships between structure dose and specific late effects. However, valid dosimetry requires reliable contouring which is challenging for small volumes based on older, lower-quality computed tomography imaging. We developed a heart atlas for robust heart contouring in retrospective epidemiologic studies. METHODS AND MATERIALS: The atlas defined the complete heart and geometric surrogate volumes for six cardiac structures: aortic valve, pulmonary valve, all deeper structures combined, myocardium, left anterior myocardium, and right anterior myocardium. We collected treatment planning records from 16 patients from 4 hospitals including dose calculations for 3D conformal tangential field radiation therapy for left-sided breast cancer. Six observers each contoured all patients. We assessed spatial contouring agreement and corresponding dosimetric variability. RESULTS: Contouring agreement for the complete heart was high with a mean Jaccard similarity coefficient (JSC) of 89%, a volume coefficient of variation (CV) of 5.2%, and a mean dose CV of 4.2%. The left (right) anterior myocardium had acceptable agreement with 63% (58%) JSC, 9.8% (11.5%) volume CV, and 11.9% (8.0%) mean dose CV. Dosimetric agreement for the deep structures and aortic valve was good despite higher spatial variation. Low spatial agreement for the pulmonary valve translated to poor dosimetric agreement. CONCLUSIONS: For the purpose of retrospective dosimetry based on older imaging, geometric surrogate volumes for cardiac organs at risk can yield better contouring agreement than anatomical definitions, but retain limitations for small structures like the pulmonary valve.

Changes of Radiation Treatment Concept Based on 68Ga-PSMA-11-PET/CT in Early PSA-Recurrences After Radical Prostatectomy.

BACKGROUND AND PURPOSE: Salvage radiotherapy (SRT) is the main potentially curative treatment option for prostate cancer patients with post-prostatectomy PSA progression. Improved diagnostics by positron emission tomography/computed tomography (PET/CT) can lead to adjustments in treatment procedures (e.g. target volume of radiotherapy, androgen deprivation therapy). We analyzed the impact of 68Ga-PSMA-11-PET/CT on the target volume in early biochemical recurrence (PSA up to 0.5 ng/ml). PATIENTS AND METHODS: We retrospectively analyzed 76 patients with biochemical recurrence after radical prostatectomy in whom SRT was planned after 68Ga-PSMA-11-PET/CT. All patients had a PSA ≤0.5 ng/ml. An experienced radiation oncologist determined the radiotherapy concept, first with consideration of the PET/CT, second hypothetically based on the clinical and pathological features excluding PET/CT results. RESULTS: Without considering the PET/CT, all 76 patients would have been assigned to RT, 60 (79%) to the bed of the prostate and seminal vesicles alone, and 16 (21%) also to the pelvic lymph nodes because of histopathologic risk factors. Uptake indicative for tumor recurrence in 68Ga-PSMA-11-PET/CT was found in 54% of the patients. The median pre-PET/CT PSA level was 0.245 ng/ml (range 0.07-0.5 ng/ml). The results of the PET/CT led to a change in the radiotherapeutic target volume in 21 patients (28%). There were major changes in the target volume including the additional irradiation of lymph nodes or the additional or exclusive irradiation of bone metastases in 13 patients (17%). Minor changes including the additional irradiation of original seminal vesicle (base) position resulted in eight patients (11%). CONCLUSION: Using 68Ga-PSMA-11-PET/CT for radiation planning, a change in the treatment concept was indicated in 28% of patients. With PET/CT, the actual extent of the tumor can be precisely determined even with PSA values of ≤0.5 ng/ml. Thus, the treatment concept can be improved and individualized. This may have a positive impact on progression free survival. Our results warrant further prospective studies.

Defining the Most Informative Intermediate Clinical Endpoints for Patients Treated with Salvage Radiotherapy for Prostate-specific Antigen Rise After Radical Prostatectomy.

Intermediate clinical endpoints (ICEs) might aid in trial design and potentially expedite study results. However, little is known about the most informative ICE for patients receiving salvage radiation therapy (sRT) after radical prostatectomy. To investigate the most informative ICE for patients receiving sRT, we used a multi-institutional database encompassing patients treated at eight tertiary centers. Overall, 1301 men with node-negative disease who had not received any form of androgen deprivation therapy were identified. Associations of biochemical (BCR) and clinical recurrence (CR) within 1, 3, 5, and 7yr after surgery with the risk of overall mortality were evaluated using multivariable Cox regression analyses fitted at the landmark points of 1, 3, 5, and 7yr after sRT. The discriminative ability of each model for predicting overall survival (OS) was assessed using Harrell's c index. Median follow-up for survivors was 5.6yr (interquartile range 2.0-8.8). On multivariable analysis, progression to CR within 3yr from sRT (hazard ratio 4.19, 95% confidence interval 1.44-11.2; p= 0.008) was the most informative ICE for predicting OS (c index 0.78) compared to CR within 1, 5, and 7yr (c index 0.72, 0.75, and 0.71). In conclusion, progression to CR within 3yr after sRT, irrespective of the time of surgery, was the most informative ICE for prediction of OS. Our study is hypothesis-generating. If these results are confirmed in future prospective studies and surrogacy is met, this information could be applied for study design and could potentially expedite earlier release of results from ongoing randomized controlled trials. PATIENT SUMMARY: Clinical recurrence of prostate cancer within 3yr after salvage radiation therapy, irrespective of the time of radical prostatectomy, represents the most informative intermediate clinical endpoint for the prediction of overall survival. This information could be applied in the design of future studies and could potentially expedite earlier release of results from ongoing randomized controlled trials.

Lead-time bias does not falsify the efficacy of early salvage radiotherapy for recurrent prostate cancer.

BACKGROUND: In prostate cancer (PCa) recurring after radical prostatectomy (RP), salvage radiotherapy (SRT) is recommended to be given at PSA <0.5 ng/ml. It has been speculated, that the advantage from early SRT is mainly caused by lead-time bias: Calculating from time of SRT, earlier treatment would per-se result in longer time to event/censoring compared with later treatment, but not extend the interval from RP to post-SRT failure. METHODS: In 603 consecutive PCa patients receiving SRT between 1997 and 2017, we compared outcomes, calculating from time of irradiation vs. time of surgery. RESULTS: In multivariable analysis, tumor stage pT3-4, pathological Gleason score GS ≤6 vs. GS 7 vs. GS ≥8, post-RP PSA persistence (nadir ≥0.1 ng/ml), and the pre-SRT PSA (continuous or with cutoff 0.4 ng/ml) were significant risk-factors for biochemical progression (BCR) and progression-free survival (PFS) post-SRT and post-RP. A pre-SRT PSA <0.4 ng/ml was a significant discriminator for Kaplan-Meier rates of BCR and PFS. The Cox model for overall survival (OS) included age at RP (continuous), pT2 vs. pT3-4, and pre-SRT PSA (continuous) as significant predictors. However, no significant cutoff for the pre-SRT PSA could be identified to differentiate Kaplan-Meier estimates of OS, possibly because there were too few events, as 88% of the patients were still alive at last follow-up. CONCLUSIONS: The pre-SRT PSA has a significant impact on BCR, PFS and potentially on OS, calculating either from RP or from SRT to event/censoring, respectively. This contradicts the hypothesis of lead-time bias falsifying the advantage from early SRT.

Results of a randomized trial of treatment modalities in patients with low or early-intermediate risk prostate cancer (PREFERE trial).

PURPOSE: The optimal treatment for patients with low to early-intermediate risk prostate cancer (PCa) remains to be defined. The randomized PREFERE trial (DRKS00004405) aimed to assess noninferiority of active surveillance (AS), external-beam radiotherapy (EBRT), or brachytherapy by permanent seed implantation (PSI) vs. radical prostatectomy (RP) for these patients. METHODS: PREFERE was planned to enroll 7600 patients. The primary endpoint was disease specific survival. Patients with PCa stage ≤ cT2a, cN0/X, M0, PSA ≤ 10 ng/ml and Gleason-Score ≤ 3 + 4 at reference pathology were eligible. Patients were allowed to exclude one or two of the four modalities, which yielded eleven combinations for randomization. Sixty-nine German study centers were engaged in PREFERE. RESULTS: Of 2251 patients prescreened between 2012 and 2016, 459 agreed to participate in PREFERE. Due to this poor accrual, the trial was stopped. In 345 patients reference pathology confirmed inclusion criteria. Sixty-nine men were assigned to RP, 53 to EBRT, 93 to PSI, and 130 to AS. Forty patients changed treatment shortly after randomization, 21 to AS. Forty-eight AS patients with follow-up received radical treatment. Median follow-up was 19 months. Five patients died, none due to PCa; 8 had biochemical progression after radical therapy. Treatment-related acute grade 3 toxicity was reported in 3 RP patients and 2 PSI patients. CONCLUSIONS: In this prematurely closed trial, we observed an unexpected high rate of termination of AS and an increased toxicity related to PSI. Patients hesitated to be randomized in a multi-arm trial. The optimal treatment of low and early-intermediate risk PCa remains unclear.

Interobserver variability, detection rate, and lesion patterns of 68Ga-PSMA-11-PET/CT in early-stage biochemical recurrence of prostate cancer after radical prostatectomy.

PURPOSE: 68Ga-PSMA-11-PET/CT is increasingly used in early-stage biochemical recurrence of prostate cancer to detect potential lesions for an individualized radiotherapy concept. However, subtle findings especially concerning small local recurrences can still be challenging to interpret and are prone to variability between different readers. Thus, we analyzed interobserver variability, detection rate, and lesion patterns systematically in a homogeneous patient population with low-level biochemical recurrence. METHODS: We analyzed 68Ga-PSMA-11-PET/CTs in 116 patients with status post-prostatectomy and PSA levels up to 0.6 ng/ml. None of them received ADT or radiotherapy beforehand. Images were interpreted and blinded by two nuclear medicine physicians (R1 and R2). Findings were rated using a 5-point scale concerning local recurrence, lymph nodes, bone lesions, and other findings (1: definitely benign, 2: probably benign, 3: equivocal, 4: probably malignant, 5: definitely malignant). In findings with substantial discrepancies of 2 or more categories and/or potentially leading to differences in further patient management, a consensus reading was done with a third reader (R3). Interobserver agreement was measured by Cohens Kappa analysis after sub-categorizing our classification system to benign (1 + 2), equivocal (3), and malignant (4 + 5). Time course of PSA levels after salvage treatment of patients rated as positive (4 + 5) was analyzed. RESULTS: The overall detection rate (categories 4 and 5) was 50% (R1/R2, 49%/51%) and in the PSA subgroups 0-0.2 ng/ml, 0.21-0.3 ng/ml, and 0.31-0.6 ng/ml 24%/27%, 57%/57%, and 65%/68%, respectively. Local recurrence was the most common lesion manifestation followed by lymphatic and bone metastases. The overall agreement in the Cohens Kappa analysis was 0.74 between R1 and R2. For local, lymphatic, and bone sites, the agreement was 0.76, 0.73, and 0.58, respectively. PSA levels of PSMA PET/CT-positive patients after salvage treatment decreased in 75% (27/36) and increased in 25% (9/36). A decrease of PSA, although more frequent in patients with imaging suggesting only local tumor recurrence (86%, 18/21), was also observed in 67% (10/15) of patients with findings of metastatic disease. CONCLUSIONS: In a highly homogeneous group of prostate cancer patients with early-stage biochemical recurrence after radical prostatectomy, we could show that 68Ga-PSMA-11-PET/CT has a good detection rate of 50% which is in accordance with literature, with clinically relevant findings even in patients with PSA < 0.21 ng/ml. The interobserver variability is low, particularly concerning assessment of local recurrences and lymph nodes. Therefore, PSMA-PET/CT is a robust diagnostic modality in this patient group for therapy planning.

The impact of prostate-specific antigen persistence after radical prostatectomy on the efficacy of salvage radiotherapy in patients with primary N0 prostate cancer.

OBJECTIVE: To test whether salvage radiotherapy (SRT) in patients with lymph node negative (N0) prostate cancer is equally effective with persistent prostate-specific antigen (PSA) and PSA rising from the undetectable range (<0.1 ng/mL) after radical prostatectomy (RP). PATIENTS AND METHODS: We assessed post-SRT PSA progression-free survival (PFS) in 555 patients with prostate cancer. The entire cohort was compared with a risk-adjusted subgroup of 112 patient pairs with matching pre-RP PSA level (±10 ng/mL), Gleason score (≤6 vs 7 vs ≥8), and pre-SRT PSA level (±0.5 ng/mL). RESULTS: The median follow-up was 6.1 years. After RP, PSA was undetectable in 422 and persistent in 133 patients. PSA persistence and a pre-SRT PSA level of ≥0.5 ng/mL reduced Kaplan-Meier rates of PFS significantly. In multivariate analysis of the entire cohort and after risk adjustment, the pre-SRT PSA level but not post-RP PSA persistence was a significant parameter. In the matched cohort's subgroup with early SRT at a PSA level of <0.5 ng/mL, a trend towards a worse outcome with post-RP PSA persistence was observed. Delayed SRT with a PSA level ≥0.5 ng/mL led to a PFS of <30%, irrespective of the post-RP PSA level. CONCLUSION: In patients with N0 prostate cancer with post-RP PSA persistence, early SRT at a PSA level <0.5 ng/mL seems to be less effective than in recurrent patients with post-RP undetectable PSA. They might benefit from intensified therapy, but larger case numbers are required to substantiate this conclusion. In patients with a PSA level ≥0.5 ng/mL and higher-risk features associated with post-RP PSA persistence, SRT alone is unlikely to provide long-term freedom from further progression.

Assessing the Role and Optimal Duration of Hormonal Treatment in Association with Salvage Radiation Therapy After Radical Prostatectomy: Results from a Multi-Institutional Study.

BACKGROUND: The optimal duration of hormonal therapy (HT) when associated with postprostatectomy radiation therapy (RT) remains controversial. OBJECTIVE: To test the impact of HT duration among patients treated with postprostatectomy RT, stratified by clinical and pathologic characteristics. DESIGN, SETTING, AND PARTICIPANTS: The study included 1264 patients who received salvage RT (SRT) to the prostatic and seminal vesicle bed at eight referral centers after radical prostatectomy (RP). Patients received SRT for either rising prostate-specific antigen (PSA) or PSA persistence after RP, defined as PSA ≥0.1ng/ml at 1mo after surgery. Administration of concomitant HT was at the discretion of the treating physician. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcome of interest was clinical recurrence (CR) after SRT, as identified by imaging. Multivariable Cox regression analysis was used to test the association between CR and HT duration. We applied an interaction test between HT duration and baseline risk factors to assess the hypothesis that CR-free survival differed by HT duration according to patient profile. Three risk factors were prespecified for evaluation: pT stage ≥pT3b, pathologic Gleason ≥8, and PSA level at SRT >0.5 ng/ml. The relationship between HT duration and CR-free survival rate at 8yr was graphically explored according to the number of risk factors (0 vs 1 vs ≥2). RESULTS AND LIMITATIONS: Overall, 1125 men (89%) received SRT for rising PSA and 139 (11%) were treated for PSA persistence. Concomitant HT was administered to 363 patients (29%), with a median HT duration of 9mo. At median follow-up of 93mo after surgery, 182 patients developed CR. The 8-yr CR-free survival was 92%. On multivariable analysis, HT duration was inversely associated with the risk of CR (hazard ratio 0.95; p=0.022). A total of 531 (42%) patients had none of the prespecified risk factors, while 507 (40%) had one and 226 (18%) had two or more risk factors. The association between HT duration and CR was significantly different by risk factors (0 vs 1, p=0.001; 0 vs ≥2, p<0.0001). We observed a significant effect of HT duration for patients with two or more risk factors, for whom HT administration was beneficial when given for up to 36mo. This effect was attenuated among patients with one risk factor, with concomitant HT slightly beneficial when administered for a shorter time (<12mo). Conversely, for patients with no risk factors, the risk of CR remained low and constant regardless of HT duration. CONCLUSIONS: The oncologic benefit of HT duration among men receiving SRT for increasing PSA after RP depends on their clinical and pathologic characteristics. Our data suggested a significant effect of long-term HT for patients with two or more adverse features. Conversely, short-term HT was sufficient for patients with a single risk factor, whereas patients without any risk factors did not show a significant benefit from concomitant HT. PATIENT SUMMARY: We tested the impact of hormonal therapy (HT) duration during radiation therapy after radical prostatectomy. We identified three risk factors and observed a different impact of HT duration by clinical and pathologic characteristics. Patients with more adverse features benefit from long-term concomitant HT. On the contrary, for patients with a single risk factor, short-term HT may be reasonable. Patients without any risk factors did not show a significant benefit from concomitant HT.

Effect of early salvage radiotherapy at PSA < 0.5 ng/ml and impact of post-SRT PSA nadir in post-prostatectomy recurrent prostate cancer.

BACKGROUND: For patients with recurrent prostate cancer after radical prostatectomy (RP), salvage radiotherapy (SRT) offers a second chance of cure. European guidelines (EAU) recommend SRT at a PSA < 0.5 ng/ml. We analyze the efficacy of SRT given according to this recommendation and investigate the predictive power of the post-SRT PSA nadir. METHODS: Between 1998 and 2013, 301 patients of two university hospitals received SRT at a PSA < 0.5 ng/ml (median 0.192 ng/ml, IQR 0.110-0.300). Patients, who previously received androgen deprivation therapy, were excluded. All patients had 3D-conformal RT or intensity-modulated radiotherapy (IMRT, n = 59) (median 66.6 Gy). The median follow-up was 5.9 years. Progression and overall survival were the endpoints. RESULTS: After SRT, 252 patients re-achieved an undetectable PSA. In univariate analysis, pre-RP PSA ≥ 10 ng/ml, pT3-4, Gleason score (GS) 7-10 or 8-10, negative surgical margins, post-RP PSA ≥ 0.1 ng/ml, pre-SRT PSA ≥ 0.2 ng/ml and post-SRT PSA nadir ≥ 0.1 ng/ml correlated unfavorably with post-SRT progression. In a multivariable Cox model, pT3-4, GS 7-10, negative margins and a pre-SRT PSA ≥ 0.2 ng/ml were significant risk factors. If the post-SRT PSA was added to the analysis, it dominated the outcome (HR = 9.00). Of the patients with a pre-SRT PSA < 0.2 ng/ml, only 9% failed re-achieving an undetectable PSA. Overall survival in these patients was 98% after 5.9 years compared to 91% in patients with higher pre-SRT PSA (Logrank p = 0.004). CONCLUSIONS: SRT at a PSA < 0.2 ng/ml correlates significantly with achieving a post-SRT undetectable PSA (<0.1 ng/ml) and subsequently with improved freedom from progression. Given these overall favorable outcomes, whether additional androgen deprivation therapy is required for these men requires further study.

More Extensive Lymph Node Dissection at Radical Prostatectomy is Associated with Improved Outcomes with Salvage Radiotherapy for Rising Prostate-specific Antigen After Surgery: A Long-term, Multi-institutional Analysis.

Up to 50% of patients recur after salvage radiation therapy (sRT) for prostate-specific antigen (PSA) rise following radical prostatectomy (RP). Notably, the importance of lymph node dissection (LND) at the time of RP with regard to recurrence risk following sRT has not been previously determined. Therefore, we evaluated the association between nodal yield at RP and recurrence after sRT. We performed a multi-institutional review of men with a rising PSA after RP treated with sRT. Clinicopathologic variables were abstracted, and the associations between lymph node yield and biochemical (BCR) as well as clinical recurrence (CR) after sRT were assessed using multivariable Cox proportional hazards regression models. In total, 728 patients were identified; of these, 221 and 116 were diagnosed with BCR and CR, respectively, during a median follow-up of 8.4 (interquartile range: 4.2-11.2) yr. On multivariable analysis, the risk of BCR after sRT was inversely associated with the number of nodes resected at RP (hazards ratio [HR]: 0.98; 95% confidence interval [CI]: 0.96-0.99; p=0.049). Increased extent of dissection was also independently associated with a decreased risk of CR after sRT (HR: 0.97; 95%CI: 0.94-0.99; p=0.042). These data support the importance of an extensive LND at surgery and may be used in prognosis assessment when sRT is being considered. PATIENT SUMMARY: We found that patients who had increased number of lymph nodes resected at surgery had improved outcomes after the receipt of salvage radiation therapy. These findings support the use of the extended lymph node dissection at initial surgery and should serve to improve counseling among patients who require salvage radiation therapy.

Prostate-specific antigen after salvage radiotherapy for postprostatectomy biochemical recurrence predicts long-term outcome including overall survival.

BACKGROUND: For patients with recurrent prostate cancer after radical prostatectomy (RP), salvage radiotherapy (SRT) is a second chance of cure. However, depending on risk factors, 40-70% of the patients experience further progression. With a focus on the pre- and post-SRT serum level of the prostate-specific antigen (PSA), we assessed the determinants of the long-term outcome after SRT. PATIENT AND METHODS: Between 1997 and 2011, 464 patients received 3D-conformal SRT with median 66.6 Gy. The median PSA level before SRT was 0.31 ng/ml. In our retrospective analysis, post-SRT progression was defined as either a rising PSA >0.2 ng/ml above the nadir, or the application of anti-androgens or clinical recurrence. A PSA <0.1 ng/ml was termed undetectable. We analyzed the data with the Kaplan-Meier method (Logrank test) and multivariable Cox regression. RESULTS: The median follow-up was 5.9 years. Overall, 178 patients had recurrence, 13 developed distant metastases and 30 died. Univariate, a pre-RP PSA <10 ng/ml, pathological stage pT <3, Gleason score <8, positive surgical margins, a pre-SRT PSA <0.2 ng/ml and a post-SRT PSA nadir <0.1 ng/ml correlated with fewer and later second recurrences. In a multivariable Cox model, pT, Gleason score, margin status and pre-SRT PSA were significant covariates of progression. If the post-SRT PSA response was included in the regression analysis, then a nadir ≥0.1 ng/ml was the strongest risk factor. Initiating SRT at a PSA <0.2 ng/ml correlated with a post-SRT PSA <0.1 ng/ml. Men who achieved an undetectable post-SRT PSA nadir also had lower rates of metastases and a better overall survival. However, there were too few events for Cox regression analysis of these two endpoints. CONCLUSIONS: Early SRT at a PSA <0.2 ng/ml correlates with re-achieving an undetectable PSA, which predicts improved freedom from progression and metastases and better overall survival.

Defining biochemical recurrence after radical prostatectomy and timing of early salvage radiotherapy : Informing the debate.

BACKGROUND: The optimal prostate-specific antigen (PSA) level after radical prostatectomy (RP) for defining biochemical recurrence and initiating salvage radiation therapy (SRT) is still debatable. Whereas adjuvant or extremely early SRT irrespective of PSA progression might be overtreatment for some patients, SRT at PSA >0.2 ng/ml might be undertreatment for others. The current study addresses the optimal timing of radiation therapy after RP. PATIENTS AND METHODS: Cohort 1 comprised 293 men with PSA 0.1-0.19 ng/ml after RP. Cohort 2 comprised 198 men with SRT. PSA progression and metastases were assessed in cohort 1. In cohort 2, we compared freedom from progression according to pre-SRT PSA (0.03-0.19 vs. 0.2-0.499 ng/ml). Multivariable Cox regression analyses predicted progression after SRT. RESULTS: In cohort 1, 281 (95.9%) men had further PSA progression ≥0.2 ng/ml and 27 (9.2%) men developed metastases within a median follow-up of 74.3 months. In cohort 2, we recorded improved freedom from progression according to lower pre-SRT PSA (0.03-0.19 vs. 0.2-0.499 ng/ml: 69 vs. 53%; log-rank p = 0.051). Patients with higher pre-SRT PSA ≥0.2 ng/ml were at a higher risk of progression after SRT (hazard ratio: 1.8; p < 0.05). CONCLUSION: The vast majority of patients with PSA ≥0.1 ng/ml after RP will progress to PSA ≥0.2 ng/ml. Additionally, early administration of SRT at post-RP PSA level <0.2 ng/ml might improve freedom from progression. Consequently, we suggest a PSA threshold of 0.1 ng/ml to define biochemical recurrence after RP.

Self-reported long-term cardiac morbidity in breast cancer patients: a retrospective cohort study in Germany (PASSOS Heart Study).

PURPOSE: Improved survival after locoregional breast cancer has increased the concern about late adverse effects after therapy. In particular, radiotherapy was identified as a risk factor for major cardiac events in women treated until the 1990s. While modern radiotherapy with computerized planning based on 3D-imaging can help spare organs at risk, heart exposure may remain substantial. In a retrospective cohort study of women treated for locoregional breast cancer, we investigated whether current radiotherapy is associated with an elevated long-term cardiac morbidity risk. METHODS: The study included 11,982 women diagnosed with breast cancer in Germany in 1998-2008. After an individual mortality follow-up, 9338 questionnaires on cardiac events before or after therapy and on associated risk factors were sent out in 2014. Based on 4434 questionnaires from women with radiotherapy, we used Cox regression to analyze the association between self-reported cardiac morbidity and breast cancer laterality as a surrogate measure of radiation exposure. RESULTS: After a median follow-up of 8.3 years, there was no significant association of tumor laterality with cardiac morbidity in irradiated patients (458 events, hazard ratio for left-sided vs. right-sided tumors 1.07, 95% CI 0.89-1.29). Significant risk factors for any cardiac event included age at diagnosis, chemotherapy, hypertension, hypercholesteremia, and chronic kidney disease. CONCLUSIONS: For contemporary radiotherapy, we found no evidence for a significantly elevated cardiac morbidity risk in left-sided versus right-sided breast cancer. Possible reasons for failing to confirm earlier reports on increased risk include shorter follow-up, application of newer radiotherapy techniques, and improved health monitoring.

Predicting Heart Dose in Breast Cancer Patients Who Received 3D Conformal Radiation Therapy.

Cardiac late effects are a major health concern for long-term survivors after radiotherapy for breast cancer. Large cohort studies to better understand the exact dose-response relationship require individual estimates of radiation dose to the heart. To predict individual cardiac dose from information that is typically available for all members of a retrospective epidemiological cohort study, 774 female breast cancer patients treated with megavoltage tangential field radiotherapy in 1998-2008 were examined. All dose distributions were calculated using Eclipse with the anisotropic analytical algorithm (AAA) for photon fields and the electron Monte Carlo algorithm for electron boost fields. Based on individual dose volume histograms, the authors calculated absorbed dose in the complete heart as well as in six functional substructures. Statistical models were developed to predict absorbed dose using only covariate information from patients' clinical records on tumor location, patient anatomy and radiotherapy prescription. The out-of-sample prediction error for mean heart dose was 54% (coefficient of variation). The prediction error in functional substructures ranged from 49-68% for mean dose and from 52-86% for extreme dose. The authors conclude that based on a patient sample with exact heart dosimetry, it is possible to use clinical information alone to predict absorbed heart dose in the remaining cohort with a quantified error suitable for dose-response analyses of cardiac late effects.

3D conformal radiotherapy is not associated with the long-term cardiac mortality in breast cancer patients: a retrospective cohort study in Germany (PASSOS-Heart Study).

PURPOSE: In breast cancer patients treated in the 1970s and 1980s, radiation therapy (RT) for left-sided tumors has been associated with an elevated risk of cardiac mortality. In recent years, improved RT techniques have reduced radiation exposure of the heart and major coronary vessels, but some exposure remains unavoidable. In a retrospective cohort study, we investigated the long-term cardiac mortality risk of breast cancer survivors treated with modern RT in Germany. METHODS: A total of 11,982 women were included who were treated for breast cancer between 1998 and 2008. A systematic mortality follow-up was conducted until December 2012. The effect of breast cancer laterality on cardiac mortality and on overall mortality was investigated as a surrogate measure of exposure. Using Cox regression, we analyzed survival time as the primary outcome measure, taking potential confounding factors into account. RESULTS: We found no evidence for an effect of tumor laterality on mortality in irradiated patients (N = 9058). For cardiac mortality, the hazard ratio was 0.94 (95% CI 0.64-1.38) for left-sided versus right-sided tumors. For all causes of death, the hazard ratio was 0.95 (95% CI 0.85-1.05). A diagnosis of cardiac illness prior to breast cancer treatment increased both cardiac mortality risk and overall mortality risk. CONCLUSIONS: Contemporary RT seems not to be associated with an increased risk of cardiac mortality or overall mortality for left-sided breast cancer relative to right-sided RT. However, an extended follow-up period and exact dosimetry might be necessary to confirm this observation.

Long-term Impact of Adjuvant Versus Early Salvage Radiation Therapy in pT3N0 Prostate Cancer Patients Treated with Radical Prostatectomy: Results from a Multi-institutional Series.

BACKGROUND: Three prospective randomised trials reported discordant findings regarding the impact of adjuvant radiation therapy (aRT) versus observation for metastasis-free survival (MFS) and overall survival (OS) among patients with pT3N0 prostate cancer treated with radical prostatectomy (RP). None of these trials systematically included patients who underwent early salvage radiation therapy (esRT). OBJECTIVE: To test the hypothesis that aRT was associated with better cancer control and survival compared with observation followed by esRT. DESIGN, SETTING, AND PARTICIPANTS: Using a multi-institutional cohort from seven tertiary referral centres, we retrospectively identified 510 pT3pN0 patients with undetectable prostate-specific antigen (PSA) after RP between 1996 and 2009. Patients were stratified into two groups: aRT (group 1) versus observation followed by esRT in case of PSA relapse (group 2). Specifically, esRT was administered at a PSA level ≤0.5ng/ml. INTERVENTION: We compared aRT versus observation followed by esRT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The evaluated outcomes were MFS and OS. Multivariable Cox regression analyses tested the association between groups (aRT vs observation followed by esRT) and oncologic outcomes. Covariates consisted of pathologic stage (pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), surgical margin status (negative vs positive), and year of surgery. An interaction with groups and baseline patient risk was tested for the hypothesis that the impact of aRT versus observation followed by esRT was different by pathologic characteristics. The nonparametric curve fitting method was used to explore graphically the relationship between MFS and OS at 8 yr and baseline patient risk (derived from the multivariable analysis). RESULTS AND LIMITATIONS: Overall, 243 patients (48%) underwent aRT, and 267 (52%) underwent initial observation. Within the latter group, 141 patients experienced PSA relapse and received esRT. Median follow-up after RP was 94 mo (interquartile range [IQR]: 53-126) and 92 mo (IQR: 70-136), respectively (p=0.2). MFS (92% vs 91%; p=0.9) and OS (89% vs 92%; p=0.9) at 8 yr after surgery were not significantly different between the two groups. These results were confirmed in multivariable analysis, in which observation followed by esRT was not associated with a significantly higher risk of distant metastasis (hazard ratio [HR]: 1.35; p=0.4) and overall mortality (HR: 1.39; p=0.4) compared with aRT. Using the nonparametric curve fitting method, a comparable proportion of MFS and OS at 8 yr among groups was observed regardless of pathologic cancer features (p=0.9 and p=0.7, respectively). Limitations consisted of the retrospective nature of the study and the relatively small size of the patient population. CONCLUSIONS: At long-term follow-up, no significant differences between aRT and esRT were observed for MFS and OS. Our study, although based on retrospective data, suggests that esRT does not compromise cancer control and potentially reduces overtreatment associated with aRT. PATIENT SUMMARY: At long-term follow-up, no significant differences in terms of distant metastasis and mortality were observed between immediate postoperative adjuvant radiation therapy (aRT) and initial observation followed by early salvage radiation therapy (esRT) in case of prostate-specific antigen relapse. Our study suggests that esRT does not compromise cancer control and potentially reduces overtreatment associated with aRT.