Dirk Bottke

Phase III Postoperative Adjuvant Radiotherapy After Radical Prostatectomy Compared With Radical Prostatectomy Alone in pT3 Prostate Cancer With Postoperative Undetectable Prostate-Specific Antigen: ARO 96-02/AUO AP 09/95

PURPOSE Local failure after radical prostatectomy (RP) is common in patients with cancer extending beyond the capsule. Two randomized trials demonstrated an advantage for adjuvant radiotherapy (RT) compared with a wait-and-see policy. We conducted a randomized, controlled clinical trial to compare RP followed by immediate RT with RP alone for patients with pT3 prostate cancer and an undetectable prostate-specific antigen (PSA) level after RP. METHODS After RP, 192 men were randomly assigned to a wait-and-see policy, and 193 men were assigned to immediate postoperative RT. Eligible patients had pT3 pN0 tumors. Patients who did not achieve an undetectable PSA after RP were excluded from treatment according to random assignment (n = 78; 20%). Of the remaining 307 patients, 34 patients on the RT arm did not receive RT and five patients on the wait-and-see arm received RT. Therefore, 114 patients underwent RT and 154 patients were treated with a wait-and-see policy. The primary end point was biochemical progression-free survival. RESULTS Biochemical progression-free survival after 5 years in patients with undetectable PSA after RP was significantly improved in the RT group (72%; 95% CI, 65% to 81%; v 54%, 95% CI, 45% to 63%; hazard ratio = 0.53; 95% CI, 0.37 to 0.79; P = .0015). On univariate analysis, Gleason score more than 6 and less than 7, PSA before RP, tumor stage, and positive surgical margins were predictors of outcome. The rate of grade 3 to 4 late adverse effects was 0.3%. CONCLUSION Adjuvant RT for pT3 prostate cancer with postoperatively undetectable PSA significantly reduces the risk of biochemical progression. Further follow-up is needed to assess the effect on metastases-free and overall survival.

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.

Frequency of asymptomatic choroidal metastasis in patients with disseminated breast cancer: results of a prospective screening programme

AIM To determine the frequency of visually asymptomatic choroidal metastasis in patients with disseminated breast cancer and its dependence on the incidence of metastasis by number and site of other organ metastases. METHODS From January 1995 until April 1997 120 patients irradiated for disseminated breast cancer underwent ophthalmological screening for choroidal metastasis. No patient was symptomatic for ocular disease. 68 out of 120 patients were found to have metastases in one organ and 52 patients had metastases in more than one organ. 80% of the patients had bone metastases, 25% lung metastases, 22% liver metastases, 15% brain metastases, and 22% had metastases in other organs. RESULTS Six patients (5%) were found to have asymptomatic choroidal metastases. Five patients had unilateral and one patient bilateral metastases. 52 patients with more than one involved organ had a significantly higher risk for asymptomatic choroidal metastasis (6/52, 11%) than 68 patients with metastases in only one organ (0/68) (p=0.006). In univariate analysis a significantly higher risk was seen for patients with lung metastases (14% choroidal metastases versus 2% in patients without lung metastases, p=0.03) and for patients with brain metastases (17% choroidal metastases versus 3% in those without brain metastases, p=0.04). CONCLUSION In disseminated breast cancer the incidence of asymptomatic choroidal metastases was 5% and increased to 11% when more than one organ was involved in metastatic spread. Risk factors for choroidal metastases were dissemination of disease in more than one organ and the presence of lung and brain metastases.

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.

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.

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.

Adjuvant radiotherapy after radical prostatectomy: indications, results and side effects.

Background: Within 5 years following radical prostatectomy, between 15 and 60% of patients with pT3 prostate carcinomas show an increasing prostate-specific antigen (PSA) level as a sign of local and/or systemic tumor progression. Apart from a large number of retrospective investigations, available results are present only from three randomized studies which have either been completely published or are only in abstract form. Results: For pT3 prostate carcinomas the data from the three randomized studies agree, showing an around 20% reduced biochemical progression rate after 4–5 years. With these data the results of numerous retrospective studies have been confirmed. The majority of the authors use total doses of 60 Gy with single doses of 2 Gy. From one randomized study an increased local control rate is proposed as the basis for the extended freedom from biochemical progression. The rate of acute and late side effects after three-dimensional radiotherapy with 60 Gy is very small and the rate of severe side effects is below 2%. The data for pT2 prostate carcinomas with positive margins are worse. Here controversy exists, and further investigations are required. In principle, however, adjuvant radiotherapy seems reasonable also for pT2 carcinomas with positive margins (determined by bNED – no biochemical evidence of disease). Conclusions: The effectiveness of adjuvant radiotherapy for patients with pT3 tumors and positive margins with and without detectable PSA levels is discussed. A survival advantage has not been demonstrated to date. For patients with positive margins in organ-limited prostate carcinomas (pT2 R1) randomized studies are recommended. It is unclear whether adjuvant radiotherapy is superior to radiotherapy for PSA levels increasing from the undetectable range after radical prostatectomy. To answer this question randomized studies are needed.

Fractionated Irradiation Can Induce Functionally Relevant Multidrug Resistance Gene and Protein Expression in Human Tumor Cell Lines

Abstract Bottke, D., Koychev, D., Busse, A., Heufelder, K., Wiegel, T., Thiel, E., Hinkelbein, W. and Keilholz, U. Fractionated Irradiation Can Induce Functionally Relevant Multidrug Resistance Gene and Protein Expression in Human Tumor Cell Lines. Radiat. Res. 170, 41–48 (2008). The molecular basis of radiotherapy-related multidrug resistance (MDR) is still unclear. Here we report on a study investigating the effect of fractionated irradiation on expression of the MDR-associated proteins P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and lung resistance-related protein (LRP), the respective mRNAs, and the functional consequences. Cells of six colon and five breast cancer cell lines were irradiated with a total dose of 27 Gy, five fractions of 1.8 Gy per week. The mRNA expression was measured by quantitative RT-PCR, protein levels and drug sensitivity to cisplatin, doxorubicin and bendamustine were assessed by flow cytometry. Breast cancer cell lines showed enhancement of the mRNAs encoding for P-gp, MRP1 and LRP in comparison to nonirradiated cells. No up-regulation of the three mRNA species was observed in the colon cancer cell lines. After irradiation, three breast cancer cell lines showed an up-regulation of LRP, one line an up-regulation of MRP1, and four lines a small up-regulation of P-gp. In the colon cancer cell lines, radiation induced significant enhancement of all three proteins. In comparison to controls, the irradiated cells lines showed a significant resistance to cisplatin, doxorubicin and bendamustine. This study confirms the prior reports of enhancement of P-gp and MRP1 after irradiation, which is accompanied by a multidrug resistance phenomenon, but in addition proposes a novel mechanism in the appearance of MDR after radiation-induced enhancement of LRP.