Detlef Bartkowiak

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.

Comparative analysis of apoptosis in HL60 detected by annexin‐V and fluorescein‐diacetate

BACKGROUND Our aim was to compare and evaluate apoptosis formation as detected by propidium-iodide (PI)/annexin-V or PI/fluorescein-diacetate (FDA) as dose-response parameters in a human promyelocytic leukemia cell line, HL60. METHODS In exponentially growing HL60 cells, apoptosis was induced by ionizing radiation, hyperthermia, topotecan, and cytosine beta-D-arabinofuranoside. At 4 consecutive days following induction, apoptosis was detected by double-labelling, either with PI/annexin-V or PI/FDA. Forward and side scatter, red (PI), and green (FDA or annexin-V) fluorescence were measured by flow cytometry. RESULTS While light scatter discriminated between morphologically damaged and undamaged cells, fluorescence differentiated vital, apoptotic, and dead cells. Equal proportions of these three subpopulations were detected by both staining techniques. Occasionally, early and mature apoptoses were identified as distinct clusters. During the 4-day observation period, no pronounced maxima of the apoptotic fractions were obtained with either treatment modality. The gradual increases usually showed a delay of 1-2 days. CONCLUSIONS FDA and annexin-V are equally suitable for detecting apoptosis. Separation improves with time after induction, indicating that, with respect to test specificity, mature apoptoses are superior to early stages. However, the sensitivity towards low rates of apoptosis after weak induction appears limited with both staining procedures.

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.

Second cancer after radiotherapy, 1981-2007.

BACKGROUND AND PURPOSE Today, there is growing concern about radiotherapy induced secondary malignancies. We analysed the incidence and dose dependence of second cancer. MATERIAL AND METHODS The study includes 12,000 one-year survivors of radiotherapy, treated between 1981 and 2007. For risk estimates a public databank on cancer in Germany served as reference. Contralateral second breast cancer, second oesophageal and colorectal cancer were analysed with retrospective dosimetry. GI-tract data were used for risk modelling. RESULTS The incidence rate of second cancers (493 cases) was ~1% per year. Contralateral breast cancer was the most frequent entity (relative risk RR=2.8). The scatter-dose gradient (2-3 Gy) across the contralateral breast did not cause a detectable risk gradient. There was an increased risk for second head and neck cancer (RR=5.1) and for male oesophageal cancer (RR=5.8). For both entities, dose response modelling with case-control data predicted maximum curves with peak induction at 1-5 Gy and positive excess absolute risk values at high doses. CONCLUSIONS A survey of second cancer after radiotherapy requires follow-up over decades. Preliminary dose response modelling albeit with low case numbers suggests an increased risk from multiportal techniques. To improve risk assessment, prospective out-of-field dosimetry and long-term multicentre data collection are recommended.

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.

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.

Second Malignancies in High‑Dose Areas of Previous Tumor Radiotherapy

Purpose:To characterize second tumors that developed in or near the high-dose areas of a previous radiotherapy, regarding their frequency, entities, latency, and dose dependence.Patients and Methods:9,995/15,449 tumor patients of the Radiation Oncology Department in Ulm, Germany, treated between 1981 and 2003, survived at least 1 year after radiotherapy. By long-term follow-up and review of treatment documentation, 100 of them were identified who developed an independent second cancer in or near the irradiated first tumor site.Results:Major primary malignancies were breast cancer (27%), lymphoma (24%), and pelvic gynecologic tumors (17%). Main second tumors were carcinomas of the upper (18%) and lower (12%) gastrointestinal tract, head and neck tumors (10%), lymphoma (10%), breast cancer (9%), sarcoma (9%), and lung cancer (8%). Overall median second tumor latency was 7.4 years (1–42 years). For colorectal cancer it was 3.5 and for leukemia 4.3 years, but for sarcoma 11.7 and for breast cancer 17.1 years. The relatively frequent second tumors of the upper gastrointestinal tract were associated with median radiation doses of 24 Gy. By contrast, second colorectal cancer and sarcoma developed after median doses of 50 Gy.Conclusion:The 5- and 15-year probability to develop a histopathologically independent second tumor in or near the irradiated first tumor site, i.e., after intermediate or high radiation doses, was 0.5% and 2.2%, respectively. To identify potentially radiogenic second malignancies, a follow-up far beyond 5 years is mandatory. The incidence and potential dose-response relationship intermediate will be analyzed by a case-case and a case-control study of the Ulm data.ZusammenfassungZiel:Zweitmalignome, die sich im oder nahe am Hochdosisbehandlungsvolumen einer vorangegangenen Strahlentherapie entwickelten, sollten hinsichtlich ihrer Häufigkeit, Entitäten, Latenz und Dosiskorrelation charakterisiert werden.Patienten und Methodik:9 995/15 449 Patienten, die zwischen 1981 und 2003 in der Klinik für Strahlentherapie der Universität Ulm behandelt wurden, überlebten mindestens 1 Jahr. Unter diesen Patienten wurden durch Langzeit-Follow-up und Überprüfung der Behandlungsdokumentation 100 Fälle identifiziert, bei denen sich im oder nahe am Ersttumor-Bestrahlungsvolumen ein unabhängiger Zweittumor entwickelte.Ergebnisse:Die dominanten Erstmalignome waren Mammakarzinome (27%), Lymphome (24%) und gynäkologische Beckentumoren (17%). Häufiger beobachtete Zweittumoren waren Karzinome des oberen (18%) und unteren (12%) Verdauungstrakts, des Kopf-Hals-Bereichs (10%), Lymphome (10%), Mammakarzinome (9%), Sarkome (9%) und Lungentumoren (8%). Die Latenz der Zweittumoren lag insgesamt bei median 7,4 Jahren (1–42 Jahre), für kolorektale Karzinome bei 3,5 und für Leukämien bei 4,3 Jahren, für Sarkome dagegen bei 11,7 und für Mammakarzinome bei 17,1 Jahren. Die relativ häufigen Zweittumoren des oberen Verdauungstrakts entstanden in Arealen, die bei der Ersttherapie median 24 Gy erhielten, kolorektale Karzinom und Sarkome dagegen entwickelten sich nach Mediandosen von 50 Gy.Schlussfolgerung:Die 5- bzw. 15-Jahres-Wahrscheinlichkeit, ein Zweitmalignom im oder nahe am ursprünglichen Behandlungsvolumen, also nach mittleren bis hohen Strahlendosen, zu entwickeln, lag bei 0,5% bzw. 2,2%. Um potentiell radiogene Zweittumoren zu erkennen, sind Nachbeobachtungszeiten von weit über 5 Jahren erforderlich. Inzidenzen und mögliche Dosis-Wirkungs-Beziehungen sollen im Rahmen von Fall-Fall- und Fall-Kontroll-Studien an den Ulmer Daten untersucht werden.

Dose escalation for patients with decreasing PSA during radiotherapy for elevated PSA after radical prostatectomy improves biochemical progression-free survival: results of a retrospective study.

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.

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.

Cell cycle and growth response of CHO cells to X-irradiation: threshold-free repair at low doses.

PURPOSE To test the hypothesis of a threshold for induced repair of DNA damage (IR) and, secondarily, of hyperradiosensitivity (HRS) to low-dose X-irradiation. METHODS AND MATERIALS Exponentially growing Chinese hamster ovary cells (CHO) were X-irradiated with doses from 0.2 to 8 Gy. Survival data were established by conventional colony-forming assay and flow-cytometric population counting. The early cell cycle response to radiation was studied based on DNA-profiles and bromodeoxyuridine pulse-labeling experiments. RESULTS Colony-forming data were consistent with HRS. However, these data were of low statistic significance. Population counting provided highly reproducible survival curves that were in perfect accord with the linear-quadratic (LQ) model. The dominant cell cycle reaction was a dose-dependent delay of G2 M and late S-phase. CONCLUSION There was no evidence for a threshold of IR and for low-dose HRS in X-irradiated CHO cells. It is suggested that DNA damage repair activity is constitutively expressed during S-phase and is additionally induced in a dose-dependent and threshold-free manner in late S-phase and G2. The resulting survival is precisely described by the LQ model.