Alessandra Siegmann

Adjuvant Radiotherapy Versus Wait-and-See After Radical Prostatectomy: 10-year Follow-up of the ARO 96–02/AUO AP 09/95 Trial

BACKGROUND Local failure after radical prostatectomy (RP) is common in patients with cancer extending beyond the capsule. Three prospectively randomized trials demonstrated an advantage for adjuvant radiotherapy (ART) compared with a wait-and-see (WS) policy. OBJECTIVE To determine the efficiency of ART after a 10-yr follow-up in the ARO 96-02 study. DESIGN, SETTING, AND PARTICIPANTS After RP, 388 patients with pT3 pN0 prostate cancer (PCa) were randomized to WS or three-dimensional conformal ART with 60 Gy. The present analysis focuses on intent-to-treat patients who achieved an undetectable prostate-specific antigen after RP (ITT2 population)--that is, 159 WS plus 148 ART men. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary end point of the study was progression-free survival (PFS) (events: biochemical recurrence, clinical recurrence, or death). Outcomes were compared by log-rank test. Cox regression analysis served to identify variables influencing the course of disease. RESULTS AND LIMITATIONS The median follow-up was 111 mo for ART and 113 mo for WS. At 10 yr, PFS was 56% for ART and 35% for WS (p<0.0001). In pT3b and R1 patients, the rates for WS even dropped to 28% and 27%, respectively. Of all 307 ITT2 patients, 15 died from PCa, and 28 died for other or unknown reasons. Neither metastasis-free survival nor overall survival was significantly improved by ART. However, the study was underpowered for these end points. The worst late sequelae in the ART cohort were one grade 3 and three grade 2 cases of bladder toxicity and two grade 2 cases of rectum toxicity. No grade 4 events occurred. CONCLUSIONS Compared with WS, ART reduced the risk of (biochemical) progression with a hazard ratio of 0.51 in pT3 PCa. With only one grade 3 case of late toxicity, ART was safe. PATIENT SUMMARY Precautionary radiotherapy counteracts relapse after surgery for prostate cancer with specific risk factors.

Salvage radiotherapy after prostatectomy - what is the best time to treat?

PURPOSE Salvage radiotherapy (SRT) is applied routinely in patients with biochemical relapse after radical prostatectomy (RP). However, only ∼30% of these patients achieve a durable response after 10 years. As a standard, 66 Gy are given, ideally with a PSA below 0.5 ng/ml. We tried to determine more precisely the optimal PSA for starting SRT. MATERIAL AND METHODS In 301 prostate cancer patients without hormonal treatment, we analysed the impact on the biochemical response (bNED) to SRT of two pre-SRT PSA levels, namely below or above the median of 0.28 ng/ml. RESULTS The median follow-up time for the entire group was 30 months. In 151 patients, SRT commenced at a PSA ≤ 0.28 ng/ml, in 150 at > 0.28 ng/ml. Eighty-two patients (27%) developed biochemical progression during follow up. The calculated two-year bNED was 74% for the entire group, 78% versus 61% for a PSA ≤ or > 0.28 ng/ml, respectively. In multivariate analysis, pT(3b), resection status, pre-SRT PSA dichotomized at median, PSA post-SRT undetectable, and PSA doubling time were statistically significant independent predictors of progression after SRT. CONCLUSIONS Our findings suggest that a PSA of ≤ 0.28 ng/ml improves bNED compared with a PSA before SRT of > 0.28 ng/ml.

Phase 3 Study of Adjuvant Radiotherapy Versus Wait and See in pT3 Prostate Cancer: Impact of Pathology Review on Analysis

BACKGROUND In a randomised trial, radical prostatectomy (RP) followed by adjuvant radiotherapy (aRT) was compared with RP alone in patients with pT3 pN0 prostate cancer with or without positive margin at local pathology (German Cancer Society trial numbers ARO 96-02/AUO AP 09/95). OBJECTIVE A pathology review was performed on 85% of RP specimens of patients to investigate the influence of pathology review on the analysis. DESIGN, SETTING, AND PARTICIPANTS Patients post-RP (n=385) were randomised before achieving an undetectable prostate-specific antigen (PSA) level to either wait and see (n=192) or 60Gy aRT (n=193). Of 307 patients with undetectable PSA after RP, 262 had pathology review. These results were included prospectively into the analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Agreement between local and review pathology was measured by the total percentage of agreement and by simple kappa statistics. The prognostic reliability for the different parameters was analysed by Cox regression model. Event-free rates were determined by Kaplan-Meier analysis with a median follow-up of 40 mo for the wait-and-see arm and 38.5 mo for the aRT arm. RESULTS AND LIMITATIONS There was fair concordance between pathology review and local pathologists for seminal vesicle invasion (pT3c: 91%; κ=0.76), surgical margin status (84%; κ=0.65), and for extraprostatic extension (pT3a/b: 75%; κ=0.74). Agreement was much less for Gleason score (47%; κ=0.42), whereby the review pathology resulted in a shift to Gleason score 7. In contrast to the analysis of progression-free survival with local pathology, the multivariate analysis including review pathology revealed PSMs and Gleason score >6 as significant prognostic factors. CONCLUSIONS Phase 3 studies of postoperative treatment of prostate cancer should be accomplished in the future with a pathology review. In daily practice, a second opinion by a pathologist experienced in urogenital pathology would be desirable, in particular, for high-risk patients after RP.

Dose Escalation for Patients with Decreasing PSA during Radiotherapy for Elevated PSA after Radical Prostatectomy Improves Biochemical Progression-Free Survival

AbstractPurpose:The optimal dose for salvage radiotherapy (SRT) after radical prostatectomy (RP) is still not defined. It should be at least 66 Gy. In the present study, the suitability of PSA regression as a selection criterion for an SRT dose escalation to 70.2 Gy was examined.Patients and Methods:Between 1997 and 2007, 301 prostate cancer patients received SRT after RP at the Charité – University Medicine Berlin, Campus Benjamin Franklin. None of the patients had antihormone therapy prior to SRT. A total of 234 patients received 66.6 Gy. From 2002 on, 67 patients with a PSA decrease during SRT were irradiated with 70.2 Gy. The influence of this selection and dose escalation on freedom from biochemical progression (bNED) was analyzed.Results:The median follow-up of the whole group was 30 months, the median pre-SRT PSA was 0.28 ng/ml. Of the patients, 27% (82/301) developed biochemical progression, 31% from the 66.6 Gy cohort (73/292) and 13% from the 70.2 Gy cohort (9/67) (p = 0.01). The calculated 2-years bNED was 74% for the whole group, 88% vs. 71% after 70.2 Gy and 66.6 Gy, respectively (p = 0.01). In a multivariate analysis, the total dose (p = 0.017), the re-achievement of an undetectable PSA after SRT (p = 0.005), and the infiltration of the seminal vesicles (p = 0.049) were independent parameters of bNED.Conclusion:Our analysis suggests that patient selection during SRT for a dose escalation to 70.2 Gy can improve the freedom from biochemical progression in patients with SRT after RP.ZusammenfassungZiel:Die optimale Dosis der Salvage-Strahlentherapie (SRT) nach radikaler Prostatektomie (RP) ist derzeit nicht definiert. Sie sollte mindestens 66 Gy betragen. In der vorliegenden Arbeit wird die Bedeutung des PSA-Abfalls unter laufender SRT als Selektionskriterium für eine Dosiserhöhung auf 70,2 Gy untersucht.Patienten und Methode:Zwischen 1997 und 2007 wurden 301 Patienten mit Prostatakarzinom nach radikaler Prostatektomie an der Charité Universitätsmedizin, Campus Benjamin Franklin, Berlin, einer SRT unterzogen. Kein Patient hatte eine antihormo-nelle Therapie vor der SRT. 234 Patienten erhielten eine SRT-Dosis von 66,6 Gy. Seit 2002 wurden 67 Patienten mit einem PSA-Abfall unter SRT mit einer erhöhten Gesamtdosis von 70,2 Gy bestrahlt. Der Einfluss dieser Selektion mit der erhöhten Gesamtdosis auf die biochemische Progressionsfreiheit (bNED) nach SRT wird analysiert.Ergebnisse:Die mediane Nachbeobachtungszeit für die Gesamtgruppe war 30 Monate, der mediane Prä-SRT-PSA war 0,28 ng/ml. 27% (82/301) der Patienten entwickelten eine biochemische Progression, 31% in der Behandlungsgruppe mit 66,6 Gy (73/292) und 13% in der Gruppe mit 70,2 Gy (9/67), (p = 0,01). Die berechnete bNED nach 2 Jahren war 74% für die Gesamtgruppe und 88% vs. 71% bei 70,2 Gy bzw. 66.6 Gy (p = 0,01). In der multivariaten Analyse zeigten sich die Gesamtdosis (p = 0,017) das Wiedererreichen des PSA-Null-Bereichs nach SRT (p = 0,005) und die Samenblaseninfiltration (p = 0,049) als unabhängige Einflussfaktoren auf die bNED.Schlussfolgerung:Unsere Untersuchungen weisen darauf hin, dass eine Patientenselektion unter SRT in Verbindung mit einer Dosiseskalation auf 70,2 Gy die biochemische Progressionsfreiheit von Patienten mit SRT nach RP verbessern kann.

Pelvic sidewall involvement in recurrent rectal cancer

Background and aimsThe lateral pelvic sidewall is an area not routinely dissected during standard operative procedures in surgery for rectal cancer in Western countries. This study analyzed data to evaluate the pattern of recurrence in rectal cancer with special emphasis on lateral tumor extension in a recently treated patient population.Patients and methodsIn a multicenter retrospective study 123 patients were evaluated by our own CT-based three-dimensional datafile system and an extensive questionnaire. Patients had histological confirmation, clear bone destruction, a positive PET scan, and at least three minor criteria: progressive soft tissue mass, invasion of adjacent organs on follow-up CT or MRI, rising tumor markers, and typical appearance in cross-sectional imaging. Clinical or serological signs of inflammation were exclusion criteria. Initially 54% of the evaluated patients were N0, and the others were distributed evenly between N1 and N2; initial T stage was T1 in 2%, T2 in 24%, T3 in 60%, and T4 in 13%.ResultsRecurrent tumors were situated mainly in the posterior part of the bony pelvis. The pelvic side wall was a rare site of recurrence and involved in fewer than 5%. When abdominoperineal resection was compared to low anterior resection as primary operation, there was a significant difference in extension of recurrent tumors in the inferior parts of the pelvis; no significant differences were found in superior or lateral parts of the pelvis.ConclusionBecause most tumor recurrences arise in the central pelvis, extending surgery to include dissecting the iliac vessels would probably offer only a moderate benefit, which must be balanced against potential side effects.

Recurrent Rectal Cancer within the Pelvis

Background and Purpose:Recommendations for radiation ports in adjuvant radiation therapy for rectal cancer are mainly based on analysis of recurrence patterns. To evaluate whether changes in surgical technique have influenced this pattern of recurrence, a multicenter retrospective analysis was carried out on a patient population treated recently.Patients and Methods:123 patients were evaluated with the help of a CT-based self-developed 3-D data file system and an extensive questionnaire. Major inclusion criteria (one sufficient) for eligibility were: histological confirmation, clear bone destruction, and a positive PET scan, or at least three minor criteria: progressive soft tissue mass, invasion of adjacent organs on follow-up CT or MRI, rising tumor markers, and typical appearance in cross-sectional imaging. Clinical or serologic signs of inflammation were exclusion criteria.Results:Initially, 54% of the evaluated patients were N0; in the remainder, N1 and N2 were distributed evenly. Initial T-category was T1 in 2%, T2 in 24%, T3 in 60%, and T4 in 13%, the male-to-female ratio was 2 : 1. Recurrent tumors were mainly situated in the posterior part of the bony pelvis as displayed in the figures. When abdominoperineal resection was compared to low anterior resection as primary operation, there was a significant difference in extension of recurrent tumors in the inferior parts of the pelvis (p < 0.025 in all statistical tests applied), whereas no significant difference was found in the superior parts of the pelvis.Conclusion:Based on these results, a modest field size reduction in adjuvant radiotherapy for rectal cancer seems feasible, offering the perspective of a reduction in acute and late side effects.Hintergrund und Ziel:Die Empfehlungen zur Wahl der Strahlenfelder bei der adjuvanten Therapie des Rektumkarzinoms basieren hauptsächlich auf Auswertungen der Rezidivverteilungsmuster. Um zu untersuchen, ob aktuelle operative Techniken Einfluss auf dieses Rezidivmuster haben, wurde eine retrospektive Multicenteranalyse an einem aktuell behandelten Krankengut unternommen.Patienten und Methodik:123 Patienten wurden anhand einer CT-basierten selbst entwickelten 3-D-Datenbank und eines umfangreichen Fragebogens ausgewertet. Die Diagnose wurde als gesichert angesehen, wenn ein Major-Kriterium (histologische Sicherung, eindeutige Osteodestruktion oder ein positiver PET-Scan) oder mindestens drei Minor-Kriterien (progredienter Weichteiltumor in Verlaufs-CTs oder MRTs, Anstieg der Tumormarker, Invasion bzw. Infiltration in Nachbarorgane und typisches Aussehen in der Schnittbilddiagnostik) vorlagen. Patienten mit klinischen oder serologischen Entzündungszeichen wurden ausgeschlossen.Ergebnisse:Initial fand sich bei 54% der ausgewerteten Patienten eine N0-Situation; bei den restlichen Patienten waren N1 and N2 gleich häufig. Initiale T-Kategorie war T1 in 2%, T2 in 24%, T3 in 60% und T4 in 13%; die Geschlechtsverteilung (männlich zu weiblich) betrug 2 : 1. Die Rezidivtumoren waren überwiegend in der posterioren Beckenhälfte gelegen, wie in den Abbildungen dargestellt. Beim Vergleich von abdominoperinealer Amputation mit tiefer anteriorer Resektion zeigte sich ein signifikanter Unterschied in der Tumorausdehnung der Rezidive nur in den kaudalen Beckenanteilen (p < 0,025 in allen angewendeten statistischen Tests).Schlussfolgerung:Auf der Basis der Ergebnisse kann bei der adjuvanten Radiotherapie eine moderate Verringerung der Feldgrößen empfohlen werden, die wahrscheinlich eine Reduktion der Rate an akuten und späten Nebenwirkungen ermöglichen wird.

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

Abstract 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.

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.