Moderate risk-adapted dose escalation with three-dimensional conformal radiotherapy of localized prostate cancer from 70 to 74 Gy. First report on 5-year morbidity and biochemical control from a prospective Austrian-German multicenter phase II trial.

PURPOSE: Evaluation of late side effects and biochemical control (bNED) 5 years after three-dimensional radiotherapy with moderate, risk-adapted dose escalation. PATIENTS AND METHODS: From 03/1999 to 07/2002, 486 patients have been registered in the prospective Austrian-German multicenter phase II trial (AUGE). 399 (82%) localized prostate cancer patients (T1-3 Nx/N0 M0) were evaluated. The low- and intermediate-risk groups were treated with 70 Gy, the high-risk group with 74 Gy, respectively. Additional hormonal therapy (HT) was recommended for intermediate- and high-risk group patients. Late toxicity (EORTC/RTOG) and bNED (ASTRO and Phoenix) were prospectively assessed. RESULTS: Median follow-up was 65 months. Distribution concerning risk groups (low-, intermediate-, high-risk group) showed 29%, 50% and 21% of patients, respectively. HT was given in 87% of patients. The 5-year actuarial rates of late side effects grade > or = 2 for 70 Gy/74 Gy were 28%/30% (gastrointestinal; p = 0.73) and 19%/34% (urogenital; p = 0,06). The 5-year actuarial bNED rate stratified by risk groups (low-, intermediate-, high-risk group) was 74%, 66% and 50% (ASTRO), and 81%, 80% and 60% (Phoenix), respectively. Within multivariate analysis T-stage and initial prostate specific antigen were significant factors influencing bNED (ASTRO) whereas Gleason Score and duration of HT were not. CONCLUSION: Dose escalation within standard three-dimensional conformal radiotherapy (3D-CRT) up to a level of 74 Gy did not result in significantly increased gastrointestinal side effects, whereas urogenital side effects showed an increase close to significance. However, the total number of patients with severe toxicity was low. To achieve high tumor control rates with acceptable treatment-related morbidity, local doses of at least 74 Gy should be considered, in particular for intermediate- or high-risk patients applying 3D-CRT.

Proctitis after external-beam radiotherapy for prostate cancer classified by Vienna Rectoscopy Score and correlated with EORTC/RTOG score for late rectal toxicity: results of a prospective multicenter study of 166 patients.

PURPOSE: To evaluate the Vienna Rectoscopy Score (VRS) as a feasible and effective tool for detecting and classifying pathologic changes in the rectal mucosa after radiotherapy (RT) for prostate cancer, and, also, to correlate its findings with the European Organization for Research and Treatment of Cancer (EORTC)/Radiation Therapy Oncology Group (RTOG) score for late rectal toxicity. METHODS AND MATERIALS: A total of 486 patients with localized prostate cancer underwent external-beam RT up to 70 or 74 Gy within an Austrian-German prospective multicenter trial. In 166 patients, voluntary rectal sigmoidoscopy was performed before and at 12 and/or 24 months after RT. Pathologic findings such as telangiectasia, congested mucosa, and ulcers were graded (Grades 0-3) and summarized according to the VRS. Late rectal side effects (EORTC/RTOG) were documented and correlated with the corresponding VRS. RESULTS: Before RT, 99% had a VRS score of 0. The median follow-up was 40 months. Overall, a late rectal side effects grade or score 1-3 was detected in 43% by EORTC/RTOG compared with 68% by VRS (p < 0.05). Grades 0, 1, 2, and 3 late rectal side effects were found using EORTC/RTOG in 57%, 11%, 28%, and 3%, respectively; the corresponding percentages were 32%, 22%, 32%, and 14% for a VRS of 0, 1, 2, and 3, respectively. A significant coherence between the VRS and EORTC/RTOG was found (p < 0.01). CONCLUSIONS: The VRS is a feasible and effective tool for describing and classifying pathologic findings in the rectal mucosa after RT within a multicenter trial. The VRS and EORTC/RTOG showed a high coherence. However the VRS was significantly more sensitive.

3-D Conformal radiotherapy of localized prostate cancer within an Austrian-German multicenter trial: a prospective study of patients' acceptance of the rectal balloon during treatment.

PURPOSE: Patients with localized prostate cancer are treated with 3D radiotherapy using a rectal balloon catheter for internal immobilization of the prostate, thereby reducing the radiation dose to the dorsal rectal wall. The purpose of the study was to investigate clinical feasibility and the influence of acute rectal side effects and pre-existing hemorrhoids on patients' acceptance of the rectal balloon catheter. METHODS AND MATERIALS: 442 patients who underwent primary radiation therapy for localized prostate cancer were included in this prospective Austrian-German multicenter trial. The total radiation dose was either 70 Gy or 74 Gy. Acute rectal side effects were documented using the EORTC/RTOG grading score (European Organisation for Research and Treatment of Cancer/Radiation Therapy 225 Oncology Group) at weeks 2, 4 and 7 of radiation treatment. Within the same time intervals patients were interviewed about their tolerance of the rectal balloon catheter, evaluating five categories of acceptance (1 = no major complaints, 2 = pain at/during application, 3 = signs of blood at the balloon catheter after application but without any pain, 4 = signs of blood at the balloon catheter after application and pain, 5 = balloon application had to be stopped). Voluntary rectoscopy prior to radiotherapy was performed in 310 patients. RESULTS: 429/442 patients (97 %) were treated with the balloon catheter. No major complaints were reported in 79 % of the patients and no acute rectal side effects were seen in 52 % of the patients. Grade 1 side effects were seen in 31 % patients, Grade 2 in 17 % and Grade 3 in 0.5 %. Balloon use had to be stopped in only 4 % of the patients. There was significant correlation between balloon discomfort and rectal side effects (p < 0.01). The presence of hemorrhoids in 36 % patients prior to irradiation had no influence on balloon tolerance. CONCLUSIONS: The rectal balloon can be used in 3D radiotherapy of localized prostate cancer with a high degree of acceptance by the patients. Use of the balloon is safe within daily clinical treatment. Patients reporting acute rectal side effects experienced significantly more balloon discomfort, but the presence of hemorrhoids was not found to influence acceptance of the balloon.

[Evaluation of flat-rate payment in radiation oncology. German experience with disease-related groups for inpatient funding in radiation oncology]. / Evaluation von Fallpauschalen in der Radioonkologie: Abbildungsqualität radioonkologischer stationärer Therapien und Anpassung der G-DRG-Systeme 2003-2006.

PURPOSE: In Germany a new casemix-related reimbursement system with "diagnosis related groups" (DRGs) for inpatient treatment was started in 2003. The first German system G-DRG 1.0 was developed on the basis of the Australian AR-DRG version 4.1. German inpatient treatment in radiation oncology was not specifically represented in this system due to the very different health care systems. As the DRG system was planned as a pricing system with severe effects on the funding of radiation oncology departments, an adjustment was urgently needed. For the modification, national data about pattern of care and economic relevance were needed. METHODS: For 3,689 cases treated in radiation oncology departments from eleven hospitals data were collected prospectively concerning diagnosis, length of stay, procedures and high-cost drugs and treatments. The DRGs were analyzed for homogeneity in length of stay and costs. Readmission frequency and interval were analyzed and the relevance of existing reimbursement regulations for this situation was evaluated. RESULTS: It could be shown, that radiation therapy implicated additional expenses for oncologic inpatients. These additional costs were not represented in the G-DRG 1.0 reimbursement system. Chemotherapy was an additional cause for economically inhomogeneous oncologic DRGs. The complex sequence of cases for the same patient could be shown, and that the rules for reimbursement of readmissions have to take these sequential treatments into account. Based on these data, modifications of the reimbursement system were suggested. In the following G-DRG version for the year 2004, 21 DRGs were designed for patients receiving radiation therapy. The regulations concerning the readmission of oncologic patients were modified. The correlation between the number of radiation therapy fractions and the total expense was acknowledged in the following year (G-DRG system 2005) and resulted in 35 DRGs. The version for 2006 showed the solidity of these solutions with almost unchanged definitions of these DRGs. CONCLUSION: This evaluation revealed the deficits in the G-DRG system 1.0 (and the AR-DRG system 4.1) related to the inpatient treatment in radiation oncology departments. Modifications could be proposed for following years. In 2004-2006, the regulatory boards adopted several implications of these data for the improvement of the German casemix-based hospital-financing system.

3-D conformal radiotherapy of localized prostate cancer: a subgroup analysis of rectoscopic findings prior to radiotherapy and acute/late rectal side effects.

BACKGROUND AND PURPOSE: To identify endoscopic pathological findings prior to radiotherapy and a possible correlation with acute or chronic rectal side effects after three-dimensional conformal radiotherapy (3D-CRT) for prostate cancer. PATIENTS AND METHODS: Between 03/99 and 07/02, a total of 298 patients, who consented in a voluntary rectoscopy prior to radiotherapy were included into the analysis. Patients were treated with a total dose of either 70 or 74 Gy. Pathological rectoscopic findings like hemorrhoids, polyps or diverticula were documented. Acute and late rectal side effects were scored using the EORTC/RTOG score. RESULTS: The most frequent pathological endosopic findings were hemorrhoids (35%), polyps (24%) and diverticula (13%). Rectal toxicity was mostly low to moderate. Grade 0/1 cumulative acute and late rectal side effects were 82 and 84%, grade 2 were 18 and 17%, respectively. We could not identify any correlation between preexisting pathological findings and rectal side effects by statistical analysis. CONCLUSIONS: There is no evidence that prostate cancer patients presenting with endoscopic verified pathological findings in the rectal mucosa at diagnosis are at an increased risk to develop rectal side effects when treated with 3D-CRT of the prostatic region.

Intensity modulated radiotherapy for high risk prostate cancer based on sentinel node SPECT imaging for target volume definition.

BACKGROUND: The RTOG 94-13 trial has provided evidence that patients with high risk prostate cancer benefit from an additional radiotherapy to the pelvic nodes combined with concomitant hormonal ablation. Since lymphatic drainage of the prostate is highly variable, the optimal target volume definition for the pelvic lymph nodes is problematic. To overcome this limitation, we tested the feasibility of an intensity modulated radiation therapy (IMRT) protocol, taking under consideration the individual pelvic sentinel node drainage pattern by SPECT functional imaging. METHODS: Patients with high risk prostate cancer were included. Sentinel nodes (SN) were localised 1.5-3 hours after injection of 250 MBq 99mTc-Nanocoll using a double-headed gamma camera with an integrated X-Ray device. All sentinel node localisations were included into the pelvic clinical target volume (CTV). Dose prescriptions were 50.4 Gy (5 x 1.8 Gy / week) to the pelvis and 70.0 Gy (5 x 2.0 Gy / week) to the prostate including the base of seminal vesicles or whole seminal vesicles. Patients were treated with IMRT. Furthermore a theoretical comparison between IMRT and a three-dimensional conformal technique was performed. RESULTS: Since 08/2003 6 patients were treated with this protocol. All patients had detectable sentinel lymph nodes (total 29). 4 of 6 patients showed sentinel node localisations (total 10), that would not have been treated adequately with CT-based planning ('geographical miss') only. The most common localisation for a probable geographical miss was the perirectal area. The comparison between dose-volume-histograms of IMRT- and conventional CT-planning demonstrated clear superiority of IMRT when all sentinel lymph nodes were included. IMRT allowed a significantly better sparing of normal tissue and reduced volumes of small bowel, large bowel and rectum irradiated with critical doses. No gastrointestinal or genitourinary acute toxicity Grade 3 or 4 (RTOG) occurred. CONCLUSION: IMRT based on sentinel lymph node identification is feasible and reduces the probability of a geographical miss. Furthermore, IMRT allows a pronounced sparing of normal tissue irradiation. Thus, the chosen approach will help to increase the curative potential of radiotherapy in high risk prostate cancer patients.

Hyperfractionated accelerated radiotherapy alone and with concomitant chemotherapy to the head and neck: treated within and outside of randomized clinical trials.

PURPOSE: A German multicenter randomized trial (ARO 95-6) compared hyperfractionated accelerated radiotherapy (RT) alone (to a total radiation dose of 77.6 Gy) with hyperfractionated accelerated radiochemotherapy (to 70.6 Gy) using concurrent mitomycin C and 5-fluorouracil. We analyzed the baseline patient characteristics and the influence of physician selection bias on treatment outcome for patients who were and were not enrolled in the randomized Phase III trial, with the therapies administered according to the trial protocols. METHODS AND MATERIALS: Between February 1996 and May 2000 at Tübingen University, 42 on-study patients and 41 off-study patients with Stage III-IV nonmetastatic squamous cell carcinoma of the head and neck were treated. The median follow-up for patients at risk (living at last evaluation) was 44 months, with a minimal follow-up of 2 years. RESULTS: The 4-year rate of overall survival, disease-specific survival, and locoregional tumor control was 25%, 40%, and 54%, respectively, for all 83 patients. Among patients enrolled in the study, the 4-year rate of overall survival for those receiving accelerated hyperfractionated radiochemotherapy was 33%, and that for patients receiving accelerated hyperfractionated RT alone was 18% (p = 0.25); among off-study patients, the comparable rates were 48% and 0% (p = 0.004). The 4-year rate of disease-specific survival among on-study patients receiving radiochemotherapy and RT alone was 41% and 36%, respectively (p = 0.5); among off-study patients the respective rates were 58% and 0% (p = 0.2). The rate of 4-year locoregional tumor control associated with radiochemotherapy and RT, respectively, was 51% and 54% among on-study patients and 72% and 23% among off-study patients (p = 0.08). CONCLUSION: Patients with advanced head-and-neck cancer who were entered into the randomized trial did not have statistically significantly different survival than patients treated according to the same protocol but outside the trial. Also, outside the trial, the physicians' selection bias in determining which patient received which treatment showed a much greater benefit from combined modality treatment than that found in the randomized trial.

Postmastectomy electron-beam-rotation irradiation in locally advanced breast cancer prognostic factors of locoregional tumor control.

BACKGROUND: Different radiotherapy techniques are used for postmastectomy irradiation. We review the results with the electron-beam-rotation technique in advanced breast cancer patients. Main endpoint was local tumor control. PATIENTS AND METHODS: From 1990 to 1998 119 patients with adverse pathology features (pT3 17% of patients, pT4 42%, multicentricity 36%, pN >/= 3 positive nodes and/or pN1biii 81%, close margins 30%) underwent electron-beam-rotation irradiation of the chest wall with daily fractions of 2.0-2.5 Gy per day to 50 Gy total dose after modified radical mastectomy and axillary lymph node dissection. A local boost of 10 Gy and/or irradiation of locoregional lymph nodes were applied depending on the completeness of resection and lymph node involvement. RESULTS: After a median follow-up of 73 months for patients at risk the 5-year local tumor control, local tumor control first event, disease-free, and overall survival were 82%, 92%, 57%, and 63% (Kaplen Meier analysis), respectively. Significant predictors of poor local tumor control were maximal tumor diameter >/= 5 cm (p = 0.01), "close margins" or residual tumor (p < 0.01), four or more involved axillary lymph nodes (p = 0.02), two or more involved lymph node levels (p = 0.04), negative estrogen receptor status (p = 0.03), and high-grade histopathology (GIIb-III, p < 0.01). The subgroup analysis showed a high local failure rate of 37% for high-grade (GIIb-III) and estrogen receptor negative tumors, whereas no local recurrence was found in low-grade (GI-Iia) and receptor positive tumors (p = 0.01). The multivariate analysis revealed maximal tumor diameter >/= 5 cm, four or more involved axillary lymph nodes and high-grade histopathology (GIIb-III) as independent predictors of poor local tumor control. CONCLUSION: In high-risk breast cancer patients postmastectomy irradiation with the electron-beam-rotation technique is an effective therapy, resulting in a 5-year local failure rate of 8%. Intensified local therapy needs further investigation in subgroups of patients with additional risk factors.

Selective lymph node dissection following hyperfractionated accelerated radio-(chemo-)therapy for advanced head and neck cancer.

BACKGROUND: 2-year results of a German multicenter randomized trial showed that accelerated chemoradiation with MMC/5-FU to 70.6 Gy is more effective than accelerated radiation to 77.6 Gy alone at equivalent levels of acute and late radiation morbidity. Frequency, histopathology and impact on local tumor control of selective lymph node dissection were analyzed. PATIENTS AND METHODS: Between February 1996 and October 2000 at Tübingen University 42 randomized patients plus 45 non-randomized patients with stage III/IV MO head and neck cancer were treated according to this protocol. After completion of hyperfractionated accelerated (chemo-)radiation a selective lymph node dissection was performed, if the primary tumor was in complete remission and clinical plus computed tomography proved residual lymph node disease. 17 of 38 patients with residual node metastasis underwent uni- or bilateral selective node dissection, the remaining patients had residual primary tumors, clinical deterioration or refused neck dissection. RESULTS: After a median follow-up of 26 months, the Kaplan-Meier analysis showed a 2-year overall survival of 49%, disease-specific survival of 64% and loco-regional tumor control of 60%, respectively. 3-year loco-regional tumor control in randomized patients was 52% compared to 58% in non-randomized patients (log rank p = 0.23). 2-year loco-regional tumor control in stage cT4cN0 was 76% compared to 57% in cT2-4 cN1-3 tumors. Subgroup analysis of patients with involved nodes revealed a 2-year loco-regional tumor control of 74% after complete remission of primary tumor and neck disease, 53% after complete remission of primary tumor and partial remission of neck disease. In patients with selective lymph node dissection loco-regional tumor control was 62%. Histopathological examination showed viable tumor in eight of 17 patients. CONCLUSIONS: Selective lymph node dissection of residual neck masses after completion of hyperfractionated accelerated radio-(chemo-)therapy is likely to contribute to loco-regional tumor control in advanced head and neck cancer.