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.

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.

European association of urology risk stratification predicts outcome in patients receiving PSMA-PET-planned salvage radiotherapy for biochemical recurrence following radical prostatectomy.

PURPOSE: The European Association of Urology (EAU) proposed a risk stratification (high vs. low risk) for patients with biochemical recurrence (BR) following radical prostatectomy (RP). Here we investigated whether this stratification accurately predicts outcome, particularly in patients staged with PSMA-PET. METHODS: For this study, we used a retrospective database including 1222 PSMA-PET-staged prostate cancer patients who were treated with salvage radiotherapy (SRT) for BR, at 11 centers in 5 countries. Patients with lymph node metastases (pN1 or cN1) or unclear EAU risk group were excluded. The remaining cohort comprised 526 patients, including 132 low-risk and 394 high-risk patients. RESULTS: The median follow-up time after SRT was 31.0 months. The 3-year biochemical progression-free survival (BPFS) was 85.7 % in EAU low-risk versus 69.4 % in high-risk patients (p = 0.002). The 3-year metastasis-free survival (MFS) was 94.4 % in low-risk versus 87.6 % in high-risk patients (p = 0.005). The 3-year overall survival (OS) was 99.0 % in low-risk versus 99.6 % in high-risk patients (p = 0.925). In multivariate analysis, EAU risk group remained a statistically significant predictor of BPFS (p = 0.003, HR 2.022, 95 % CI 1.262-3.239) and MFS (p = 0.013, HR 2.986, 95 % CI 1.262-7.058). CONCLUSION: Our data support the EAU risk group definition. EAU risk grouping for BCR reliably predicted outcome in patients staged lymph node-negative after RP and with PSMA-PET before SRT. To our knowledge, this is the first study validating the EAU risk grouping in patients treated with PSMA-PET-planned SRT.

Salvage radiotherapy is effective in patients with PSMA-PET-negative biochemical recurrence- results of a retrospective study.

BACKGROUND/PURPOSE: The present study aimed to assess whether SRT to the prostatic fossa should be initiated in a timely manner after detecting biochemical recurrence (BR) in patients with prostate cancer, when no correlate was identified with prostate-specific membrane antigen positron emission tomography (PSMA-PET). MATERIALS AND METHODS: This retrospective, multicenter analysis included 1222 patients referred for PSMA-PET after a radical prostatectomy due to BR. Exclusion criteria were: pathological lymph node metastases, prostate-specific antigen (PSA) persistence, distant or lymph node metastases, nodal irradiation, and androgen deprivation therapy (ADT). This led to a cohort of 341 patients. Biochemical progression-free survival (BPFS) was the primary study endpoint. RESULTS: The median follow-up was 28.0 months. The 3-year BPFS was 71.6% in PET-negative cases and 80.8% in locally PET-positive cases. This difference was significant in univariate (p = 0.019), but not multivariate analyses (p = 0.366, HR: 1.46, 95%CI: 0.64-3.32). The 3-year BPFS in PET-negative cases was significantly influenced by age (p = 0.005), initial pT3/4 (p < 0.001), pathology scores (ISUP) ≥ 3 (p = 0.026), and doses to fossa > 70 Gy (p = 0.027) in univariate analyses. In multivariate analyses, only age (HR: 1.096, 95%CI: 1.023-1.175, p = 0.009) and PSA-doubling time (HR: 0.339, 95%CI: 0.139-0.826, p = 0.017) remained significant. CONCLUSION: To our best knowledge, this study provided the largest SRT analysis in patients without ADT that were lymph node-negative on PSMA-PET. A multivariate analysis showed no significant difference in BPFS between locally PET-positive and PET-negative cases. These results supported the current EAU recommendation to initiate SRT in a timely manner after detecting BR in PET negative patients.

Impact of Dose Escalation on the Efficacy of Salvage Radiotherapy for Recurrent Prostate Cancer-A Risk-Adjusted, Matched-Pair Analysis.

Previous randomized trials have not provided conclusive evidence about dose escalations and associated toxicities for salvage radiotherapy (SRT) in prostate cancer. Here, we retrospectively analyzed whether dose escalations influenced progression-free survival in 554 patients that received salvage radiotherapy for relapses or persistently elevated prostate cancer antigen (PSA) after a radical prostatectomy. Patients received SRT between 1997 and 2017 at two University Hospitals in Germany. We compared patient groups that received radiation doses <7000 cGy (n = 225) or ≥7000 cGy (n = 329) to analyze the influence of radiation dose on progression-free survival. In a second matched-pair analysis of 216 pairs, we evaluated prognostic factors (pT2 vs. pT3−4, Gleason score [GS] ≤ 7 vs. GS ≥ 8, R0 vs. R1, and pre-SRT PSA <0.5 vs. ≥0.5 ng/mL). After a median follow-up of 6.8 (4.2−9.2) years, we found that escalated doses significantly improved progression-free survival (p = 0.0042). A multivariate analysis indicated that an escalated dose, lower tumor stages (pT2 vs. pT3/4), and lower GSs (≤7 vs. 8−10) were associated with improved progression-free survival. There was no significant effect on overall survival. Our data suggested that escalating the radiation dose to ≥7000 cGy for SRT after a prostatectomy significantly improved progression-free survival. Longer follow-ups are needed for a comprehensive recommendation.

Salvage Radiotherapy versus Observation for Biochemical Recurrence following Radical Prostatectomy for Prostate Cancer: A Matched Pair Analysis.

BACKGROUND: Salvage radiotherapy (SRT) improves oncologic outcomes in prostate cancer (PCa) patients who develop biochemical recurrence (BCR) after radical prostatectomy (RP). However, evidence on hard clinical endpoints is scarce. We compare long-term oncologic outcomes of SRT versus no radiotherapy (noRT) in patients with BCR after RP. PATIENTS AND METHODS: Within a multi-institutional database, we identified patients with BCR after RP between 1989 and 2016 for PCa. Patients with lymph node invasion, with adjuvant radiotherapy, or with additional androgen deprivation therapy at BCR were excluded. In all patients with SRT, SRT was delivered to the prostatic bed only. Propensity score matching (PSM) was performed to account for differences in pathologic tumor characteristics. Kaplan-Meier analyses and Cox regression models tested the effect of SRT versus no RT on metastasis-free (MFS) and overall survival (OS). RESULTS: Of 1832 patients with BCR, 32.9% (n = 603) received SRT without ADT. The median follow-up was 95.9 months. Median total SRT dose was 70.2 Gy. After 1:1 PSM, at 15 years after RP, MFS and OS rates were 84.3 versus 76.9% (p < 0.001) and 85.3 versus 74.4% (p = 0.04) for SRT and noRT, respectively. In multivariable Cox regression models, SRT was an independent predictor for metastasis (HR: 0.37, p < 0.001) and OS (HR: 0.64, p = 0.03). CONCLUSION: This is the first matched-pair analysis investigating the impact of SRT versus observation only in post-RP recurrent PCa. After compensating for established risk factors, SRT was associated with better long-term MFS and OS. These results on clinical endpoints underline the curative potential of SRT.

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.

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.

A Multi-Institutional Analysis of Prostate Cancer Patients With or Without 68Ga-PSMA PET/CT Prior to Salvage Radiotherapy of the Prostatic Fossa.

INTRODUCTION: 68Ga-PSMA PET/CT is associated with unprecedented sensitivity for localization of biochemically recurrent prostate cancer at low PSA levels prior to radiotherapy. Aim of the present analysis is to examine whether patients undergoing postoperative, salvage radiotherapy (sRT) of the prostatic fossa with no known nodal or distant metastases on conventional imaging (CT and/or MRI) and on positron emission tomography/computed tomography (68Ga-PSMA PET/CT) will have an improved biochemical recurrence-free survival (BRFS) compared to patients with no known nodal or distant metastases on conventional imaging only. MATERIAL AND METHODS: This retrospective analysis is based on 459 patients (95 with and 364 without 68Ga-PSMA PET/CT). BRFS (PSA < post-sRT Nadir + 0.2 ng/ml) was the primary study endpoint. This was first analysed by Kaplan-Meier and uni- and multivariate Cox regression analysis for the entire cohort and then again after matched-pair analysis using tumor stage, Gleason score, PSA at time of sRT and radiation dose as matching parameters. RESULTS: Median follow-up was 77.5 months for patients without and 33 months for patients with 68Ga-PSMA PET/CT. For the entire cohort, tumor stage (pT2 vs. pT3-4; p= <0.001), Gleason score (GS ≤ 7 vs. GS8-10; p=0.003), pre-sRT PSA (<0.5 vs. ≥0.5ng/ml; p<0.001) and sRT dose (<70 vs. ≥70Gy; p<0.001) were the only factors significantly associated with improved BRFS. This was not seen for the use of 68Ga-PSMA PET/CT prior to sRT (p=0.789). Matched-pair analysis consisted of 95 pairs of PCa patients with or without PET/CT and no significant difference in BRFS based on the use of PET/CT was evident (p=0.884). CONCLUSION: This analysis did not show an improvement in BRFS using 68Ga-PSMA PET/CT prior to sRT neither for the entire cohort nor after matched-pair analysis after excluding patients with PET-positive lymph node or distant metastases a priori. As no improved BRFS resulted with implementation of 68Ga-PSMA PET in sRT planning, sRT should not be deferred until the best "diagnostic window" for 68Ga-PSMA PET/CT.

Longitudinal analysis of quality of life in patients receiving conformal radiation therapy for prostate cancer.

PURPOSE: To prospectively assess quality of life (QoL) in patients receiving conformal radiation therapy (CRT) for prostate cancer. PATIENTS AND METHODS: 78 men with definitive CRT for prostate cancer were entered into the study. Patients were assessed before CRT, at 40 and 60 Gy, and 2, 12 and 24 months after the end of treatment. QoL was assessed using the EORTC Quality of Life Questionnaire C30 and the prostate module PR25. Changes in mean QoL scores with time of >or= 10 points were considered clinically relevant. RESULTS: Global QoL did not change statistically significant during CRT and was slightly above baseline levels during follow-up. CRT had a statistically significant negative short-term impact on role functioning, fatigue, and PR25 urinary symptoms. The scores recovered within 2 months to 1 year after CRT. Emotional functioning and social functioning scores slightly increased during and after CRT. Role functioning decreased by > 10 points at 60 Gy and urinary symptoms decreased by > 10 points at 40 and 60 Gy. All other differences were < 10 points. A high number of concomitant diseases and having no children were negative pretreatment predictors for long-term global QoL. CONCLUSION: Definitive CRT for prostate cancer does not compromise global QoL during therapy and up to 2 years after treatment. It has a limited negative effect on role functioning, urinary symptoms and, to a lesser extent, on fatigue with restitution within 2 months to 1 year after treatment.

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.

Disease presentation and treatment outcome in very young patients with brain metastases from lung cancer.

BACKGROUND: While elderly patients with brain metastases from lung cancer appear to have an unfavorable prognosis, little information is available on disease presentation and treatment outcome in very young patients. PATIENTS AND METHODS: Retrospective evaluation of radiation therapy in this particular subpopulation. The database with 149 lung cancer patients contained 9 patients aged <40 years. The majority received whole-brain radiation therapy with 30 Gy in 10 fractions plus steroids, with or without other local or systemic measures according to the institutional policy. RESULTS: Five patients had small-cell histology. Median Karnofsky performance score was 70. In 6 cases, brain metastases were present already at first diagnosis. Eight patients had multiple lesions. Of 8 patients with complete follow-up, only 1 died from spread to the central nervous system (CNS), all others from extracranial disease. Maximum survival was 26 months (median 7 months). CONCLUSION: Very young patients with brain metastases did not achieve a better outcome than intermediate age groups. Radiation therapy was able to provide durable CNS control in nearly all patients, while systemic failures remained the leading cause of death. Prospective studies on treatment intensification and quality of life in these patients appear warranted.

Is whole-brain radiotherapy effective and safe in elderly patients with brain metastases?

OBJECTIVE: The outcome of whole-brain radiotherapy in elderly patients with brain metastases is not well documented. As the number of such patients is expected to increase, we evaluated our results. METHODS: Seventeen patients aged 75-82 years were identified for this retrospective analysis. The majority received 30 Gy in 10 fractions plus steroids (without other local or systemic measures). The median Karnofsky performance score (KPS) was 70. RESULTS: Symptomatic improvement was observed in 53%. Median survival of the responding patients was 4.5 months. However, median survival of the non-responding patients was 1.4 months only. All patients that survived for more than 4 months had a KPS > or =70 and metachronous brain metastases. None of the patients with KPS <70 survived for more than 2.2 months. None of the patients developed severe acute toxicity. One patient developed severe late neurotoxicity. CONCLUSIONS: Most elderly patients with brain metastases have an unfavourable prognosis. However, as in other populations, assessment of KPS and few other factors might guide the choice of treatment. Radiation therapy might lead to symptomatic responses in approximately half of the patients, but long-term survivors appear at risk of neurotoxicity. As promising results were published from a retrospective radiosurgery series, prospective trials appear warranted.

Late rectal symptoms and quality of life after conformal radiation therapy for prostate cancer.

BACKGROUND AND PURPOSE: This study was carried out in order to analyze the prevalence of late rectal and anal symptoms after conformal radiation therapy for prostate cancer and to assess their association with quality of life. PATIENTS AND METHODS: Two-hundred and forty nine patients were interviewed at 24-111 months after definitive conformal radiation therapy of localized prostate cancer with a median dose of 70 Gy. Rectal symptoms and fecal incontinence were evaluated with standardized questionnaires. Quality of life was assessed with the EORTC Quality of Life Questionnaire-C30 and the prostate cancer module PR25. RESULTS: Rectal symptoms were mostly intermittent. Daily symptoms occurred in < or =5% of the patients. Incontinence was mostly mild with only 3% of the patients reporting daily incontinence episodes. Quality of life was comparable to that of the male German general population except that cognitive functioning and diarrhea were worse in the study population and pain was worse in the reference population. Global quality of life was associated with fecal incontinence, fecal urge, tenesmus, therapy for rectal symptoms and hormonal therapy for biochemical/clinical recurrence. CONCLUSIONS: Rectal symptoms and fecal incontinence after conformal radiation therapy for prostate cancer are mostly intermittent. Fecal incontinence, fecal urge and tenesmus are associated with lower global quality of life levels.

The PSA-response to salvage radiotherapy after radical prostatectomy correlates with freedom from progression and overall survival.

BACKGROUND AND PURPOSE: In a retrospective analysis, we examined factors influencing the outcome of prostate cancer (PCa) patients receiving salvage radiotherapy (SRT) for PSA recurrence after radical prostatectomy (RP). MATERIAL AND METHODS: 306 patients received 3D-conformal SRT at a median pre-SRT PSA of 0.298 ng/ml. Post-SRT progression was defined as PSA ⩾0.2 ng/ml above nadir and rising further, or hormone treatment, or clinical recurrence. Data were analyzed with the Kaplan-Meier method and multivariable Cox regression. RESULTS: Application of SRT at a PSA <0.2 ng/ml correlated significantly with achieving a post-SRT PSA nadir <0.1 ng/ml and with improved freedom from progression (median follow-up 7.2 years). The post-SRT nadir <0.1 ng/ml correlated significantly with less recurrences and with better overall survival. In multivariable Cox analysis restricted to pre-SRT parameters, a pre-SRT PSA ⩾0.2 ng/ml had the strongest impact (hazard ratio 2.4) on progression. If the post-SRT PSA nadir was included in the model, then failing the nadir was the most important risk factor (hazard ratio 8.1). CONCLUSIONS: Early SRT at a PSA <0.2 ng/ml is a favorable treatment option for post-RP biochemical recurrence. It correlated with a post-SRT PSA-nadir <0.1 ng/ml which was associated with improved freedom from progression and overall survival.

Time-course of radiation-induced chromosomal aberrations in tumor patients after radiotherapy.

PURPOSE: Radiation-induced chromosome aberrations are routinely used in biologic dosimetry to monitor radiation exposure. Translocations are considered stable aberrations with time after exposure. This study was performed to determine the temporal persistence of radiation-induced translocations during a 36-month period in therapeutically irradiated testicular seminoma patients who underwent partial body exposure (>10% of bone marrow). METHODS AND MATERIALS: Chromosome analyses were carried out in peripheral lymphocytes of 11 patients with testicular seminoma (n = 9), germinoma (n = 1), or follicular non-Hodgkin's lymphoma (n = 1). All patients received radiotherapy with photons from a linear accelerator; in 1 case, additional electron beams were used. Doses ranged from 26 Gy (seminoma) to 45 Gy (non-Hodgkin's lymphoma). None of the patients received chemotherapy. From each patient, blood samples were taken during the 36 months after irradiation at defined points. Chromosomal aberrations were scored after fluorescence in situ hybridization painting of chromosomes 1, 4, and 12 in combination with a pancentromeric probe. RESULTS: For 9 patients (7 with testicular seminoma, 1 with germinoma, and 1 with non-Hodgkin's lymphoma), a significant temporal decline of translocations, with a mean decline rate of 4.4% +/- 0.4% monthly, could be detected. Two testicular seminoma patients showed no temporal decline of aberration frequencies. CONCLUSION: Most partial body irradiated patients (9 of 11) showed a significant temporal decline of translocation frequencies during a 36-month period. Thus, reciprocal translocations after partial body irradiation cannot be regarded as stable over time. The temporal decline of aberration frequencies has to be taken into account for retrospective dose estimations.

Reirradiation of recurrent high-grade gliomas using amino acid PET (SPECT)/CT/MRI image fusion to determine gross tumor volume for stereotactic fractionated radiotherapy.

PURPOSE: To develop a valid treatment strategy for recurrent high-grade gliomas using stereotactic hypofractionated reirradiation based on biologic imaging and temozolomide. PATIENTS AND METHODS: The trial included a total of 44 patients with recurrent high-grade gliomas (1 patient with anaplastic oligodendroglioma, 8 with anaplastic astrocytoma, 33 with glioblastoma multiforme, and 2 with gliosarcoma) after previous surgery and postoperative conventional radiotherapy +/- chemotherapy. For fractionated stereotactic radiotherapy (SFRT) treatment planning, the gross tumor volume was defined by (11)C-methionine positron emission tomography (MET-PET) or (123)I-alpha-methyl-tyrosine (IMT) single-photon computed emission tomography (SPECT)/computed tomography (CT)/magnetic resonance imaging (MRI) fusion in 82% of the patients and by CT/T1+gadolinium-MRI image fusion in 18% of the patients. Six fractions of 5 Gy were administered in 6 days. In 29 of 44 patients (66%), chemotherapy with temozolomide (200 mg/m(2) body surface/day) was given in one to two cycles before and four to five cycles after SFRT. The patients were evaluated in follow-up by clinical investigators and MRI or CT every 3 months after SFRT until death. In cases suspicious for radiation necrosis, a MET-PET or IMT-SPECT investigation was performed. RESULTS: The median survival time in the whole group was 8 months. Treatment planning based on PET(SPECT)/CT/MRI imaging was associated with improved survival in comparison to treatment planning using CT/MRI alone: median survival time 9 months vs. 5 months (p = 0.03, log-rank). Median survival time were 11 months for patients who received SFRT based on biologic imaging plus temozolomide and significantly lower, 6 months for patients treated with SFRT without biologic imaging, without temozolomide or without both (p = 0.008, log rank). The most important prognostic factor in univariate analysis was a long interval between initial diagnosis and recurrence (p = 0.0002, log-rank). In the multivariate model, time interval to retreatment (p = 0.006) and temozolomide (p = 0.04) remained statistically significant. No acute neurologic toxicity Grade 3 or higher and no Grade 4 hematologic toxicity was observed. CONCLUSION: This is the first study of biologic imaging optimized SFRT plus temozolomide in recurrent high-grade gliomas. It demonstrates the feasibility and safety of this approach. The most striking result of the trial is the statistically significant longer survival time in the univariate analysis for patients reirradiated using MET-PET or IMT-SPECT/CT/MRI image fusion in the treatment planning, in comparison to patients treated based on MRI/CT alone. Multivariate analysis confirmed a significant survival benefit from multimodal treatment (i.e., addition of temozolomide), despite the limited number of patients. Whether treatment planning with SPECT/PET independently influences survival has to be studied in a larger series of patients.

3D conformal radiation therapy for prostate cancer in elderly patients.

BACKGROUND AND PURPOSE: The aim of this study was to evaluate if conformal radiation therapy for localized prostate cancer with doses of 70 Gy is well tolerated in patients aged 75 years or older, and if the side effects and the biochemical recurrence free (bNED) survival are comparable to younger patients. PATIENTS AND METHODS: Eighty patients>or=75 years received definitive conformal radiotherapy for prostate cancer. Acute and late side effects as well as bNED survival (ASTRO criteria) were compared to 221 patients younger than 75 years who were treated during the same period of time. RESULTS: Median dose to the prostate was 70 Gy in both groups. There were no significant differences in acute or late side effects between age groups. The frequency of grade III late symptoms was low and ranged between 0 and 4% for the evaluated symptoms irrespective of age group. Older patients had a better bNED survival than younger patients (bNED survival at 4 years: 76 vs. 61%, P=0.042). CONCLUSIONS: High-dose conformal radiation therapy for prostate cancer is well tolerated in patients aged 75 years or older. In terms of bNED survival radiation treatment is at least as effective as it is for younger patients.

Prostate-specific antigen persistence after radical prostatectomy as a predictive factor of clinical relapse-free survival and overall survival: 10-year data of the ARO 96-02 trial.

OBJECTIVE: The ARO 96-02 trial primarily compared wait-and-see (WS, arm A) with adjuvant radiation therapy (ART, arm B) in prostate cancer patients who achieved an undetectable prostate-specific antigen (PSA) after radical prostatectomy (RP). Here, we report the outcome with up to 12 years of follow-up of patients who retained a post-RP detectable PSA and received salvage radiation therapy (SRT, arm C). METHODS AND MATERIALS: For the study, 388 patients with pT3-4pN0 prostate cancer with positive or negative surgical margins were recruited. After RP, 307 men achieved an undetectable PSA (arms A + B). In 78 patients the PSA remained above thresholds (median 0.6, range 0.05-5.6 ng/mL). Of the latter, 74 consented to receive 66 Gy to the prostate bed, and SRT was applied at a median of 86 days after RP. Clinical relapse-free survival, metastasis-free survival, and overall survival were determined by the Kaplan-Meier method. RESULTS: Patients with persisting PSA after RP had higher preoperative PSA values, higher tumor stages, higher Gleason scores, and more positive surgical margins than did patients in arms A + B. For the 74 patients, the 10-year clinical relapse-free survival rate was 63%. Forty-three men had hormone therapy; 12 experienced distant metastases; 23 patients died. Compared with men who did achieve an undetectable PSA, the arm-C patients fared significantly worse, with a 10-year metastasis-free survival of 67% versus 83% and overall survival of 68% versus 84%, respectively. In Cox regression analysis, Gleason score ≥8 (hazard ratio [HR] 2.8), pT ≥ 3c (HR 2.4), and extraprostatic extension ≥2 mm (HR 3.6) were unfavorable risk factors of progression. CONCLUSIONS: A persisting PSA after prostatectomy seems to be an important prognosticator of clinical progression for pT3 tumors. It correlates with a higher rate of distant metastases and with worse overall survival. A larger prospective study is required to determine which patient subgroups will benefit most from which treatment option.

Validation of a method for automatic image fusion (BrainLAB System) of CT data and 11C-methionine-PET data for stereotactic radiotherapy using a LINAC: first clinical experience.

PURPOSE: (a) To implement a fully automatic method to integrate (11)C-methionine positron emission tomography (MET-PET) data into stereotactic radiation treatment planning using the commercially available BrainLAB System, by means of CT/MET-PET image fusion. (b) To validate the fully automatic CT/MET-PET image fusion technique with respect to accuracy and robustness. (c) To give a short glance at the clinical consequences for patients with brain tumors. METHODS AND MATERIALS: In 12 patients with brain tumors (9 meningeomas, 3 gliomas), CT, MRI, and MET-PET were performed for stereotactic fractionated radiation treatment planning. The CT and MET-PET investigations were performed using a relocatable mask for head fixation. Fifteen external reference markers (5 on each lateral and 5 on the frontal localizer plate) that could be identified in CT and MET-PET were applied on the stereotactic localizer frame; the marker positions were exactly defined for both investigations. The MRI/CT fusion was done completely automatically. The CT/MET-PET fusion was performed using two different methods: The gold standard was the CT/PET fusion based on the reference markers, and the test method was the automatic, intensity-based CT/PET fusion, independent of the external markers. The markers visible on CT and transmission PET were matched using a point-to-line matching algorithm. To quantify the amount of misregistration, the two fusion methods were compared by calculating the mean value of deviation between corresponding points inside a cubic volume of interest of > or =512 cm(3) defined within the cranial cavity. The gross tumor volume (CT/MRI) outlined on CT and T1-MRI with contrast medium was compared with the gross tumor volume (PET) defined in the reoriented MET-PET data sets. The clinical impact of MET-PET in tumor volume definition for stereotactic radiotherapy will be discussed. RESULTS: The fully automatic integration of MET-PET into stereotactic radiation treatment planning was successfully realized in all patients investigated. Mean deviation of the intensity-based automatic CT/PET fusion compared with the external marker-based gold standard was 2.4 mm; the standard deviation was 0.5. The algorithm's robustness was evaluated, and the discrepancy of fusion results due to different initial image alignments was determined to be below 1 mm inside the test volume of interest. In patients with meningiomas and gliomas, MET-PET was shown to deliver additional information concerning tumor extension. CONCLUSION: The precision of the automatic CT/PET image fusion was high. A mean deviation of 2.4 mm is acceptable, considering that it is approximately equal to the pixel size of the PET data sets. MET-PET improves target volume definition for stereotactic fractionated radiotherapy of meningiomas and gliomas.