Short Androgen Suppression and Radiation Dose Escalation in Prostate Cancer: 12-Year Results of EORTC Trial 22991 in Patients With Localized Intermediate-Risk Disease.

PURPOSE: The European Organisation for Research and Treatment of Cancer (EORTC) trial 22991 (NCT00021450) showed that 6 months of concomitant and adjuvant androgen suppression (AS) improves event- (EFS, Phoenix) and clinical disease-free survival (DFS) of intermediate- and high-risk localized prostatic carcinoma, treated by external-beam radiotherapy (EBRT) at 70-78 Gy. We report the long-term results in intermediate-risk patients treated with 74 or 78 Gy EBRT, as per current guidelines. PATIENT AND METHODS: Of 819 patients randomly assigned between EBRT or EBRT plus AS started on day 1 of EBRT, 481 entered with intermediate risk (International Union Against Cancer TNM 1997 cT1b-c or T2a with prostate-specific antigen (PSA) ≥ 10 ng/mL or Gleason ≤ 7 and PSA ≤ 20 ng/mL, N0M0) and had EBRT planned at 74 (342 patients, 71.1%) or 78 Gy (139 patients, 28.9%). We report the trial primary end point EFS, DFS, distant metastasis-free survival (DMFS), and overall survival (OS) by intention-to-treat stratified by EBRT dose at two-sided α = 5%. RESULTS: At a median follow-up of 12.2 years, 92 of 245 patients and 132 of 236 had EFS events in the EBRT plus AS and EBRT arm, respectively, mostly PSA relapse (48.7%) or death (45.1%). EBRT plus AS improved EFS and DFS (hazard ratio [HR] = 0.53; CI, 0.41 to 0.70; P < .001 and HR = 0.67; CI, 0.49 to 0.90; P = .008). At 10 years, DMFS was 79.3% (CI, 73.4 to 84.0) with EBRT plus AS and 72.7% (CI, 66.2 to 78.2) with EBRT (HR = 0.74; CI, 0.53 to 1.02; P = .065). With 140 deaths (EBRT plus AS: 64; EBRT: 76), 10-year OS was 80.0% (CI, 74.1 to 84.7) with EBRT plus AS and 74.3% (CI, 67.8 to 79.7) with EBRT, but not statistically significantly different (HR = 0.74; CI, 0.53 to 1.04; P = .082). CONCLUSION: Six months of concomitant and adjuvant AS statistically significantly improves EFS and DFS in intermediate-risk prostatic carcinoma, treated by irradiation at 74 or 78 Gy. The effects on OS and DMFS did not reach statistical significance.

Validation of dose distribution computation on sCT images generated from MRI scans by Philips MRCAT.

AIM: To evaluate calculation of treatment plans based on synthetic-CT (sCT) images generated from MRI. BACKGROUND: Because of better soft tissue contrast, MR images are used in addition to CT images for radiotherapy planning. However, registration of CT and MR images or repositioning between scanning sessions introduce systematic errors, hence suggestions for MRI-only therapy. The lack of information on electron density necessary for dose calculation leads to sCT (synthetic CT) generation. This work presents a comparison of dose distribution calculated on standard CT and sCT. MATERIALS AND METHODS: 10 prostate patients were included in this study. CT and MR images were collected for each patient and then water equivalent (WE) and MRCAT images were generated. The radiation plans were optimized on CT and then recalculated on MRCAT and WE data. 2D gamma analysis was also performed. RESULTS: The mean differences in the majority of investigated DVH points were in order of 1% up to 10%, including both MRCAT and WE dose distributions. Mean gamma pass for acceptance criteria 1%/1 mm were greater than 82.5%. Prescribed doses for target volumes and acceptable doses for organs at risk were met in almost all cases. CONCLUSIONS: The dose calculation accuracy on MRCAT was not significantly compromised in the majority of clinical relevant DVH points. The introduction of MRCAT into practise would eliminate systematic errors, increase patients' comfort and reduce treatment expenses. Institutions interested in MRCAT commissioning must, however, consider changes to established workflow.

Comparing morbidity and cancer control after 3D-conformal (70/74 Gy) and intensity modulated radiotherapy (78/82 Gy) for prostate cancer.

PURPOSE: The purpose of this work was to compare toxicity and cancer control between patients with prostate cancer treated using three-dimensional conformal radiotherapy (3D-CRT) and those treated using intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS: A total of 553 patients with prostate cancer were treated with 3D-CRT 70-74 Gy (3D-CRT 70, 3D-CRT 74) or IMRT 78-82 Gy (IMRT 78, IMRT/SIB 82). Late toxicity was scored according to FC-RTOG/LENT criteria. Biochemical failure was defined using the Phoenix and ASTRO definitions. RESULTS: The 5-year risk of grade 2-4 genitourinary toxicity was 26.3 % (3D-CRT 70), 27.2 % (3D-CRT 74), 17.3 % (IMRT 78), and 25.1 % (IMRT/SIB 82) without statistical differences. The 5-year risk of grade 2-4 gastrointestinal toxicity was 19.4 % (3D-CRT 70), 42.1 % (3D-CRT 74), 20.5 % (IMRT 78), and 26.6 % (IMRT/SIB 82). The differences between 3D-CRT 74 and 3D-CRT 70 and between 3D-CRT 74 and IMRT 78 were statistically significant (log rank p = 0.03). The 5-year Phoenix PSA relapse-free survival (PSA-RFS) in low-risk, intermediate-risk, and high-risk patients treated using 3D-CRT were 89.4, 65.5, and 57.8 %, respectively. Patients treated with IMRT achieved the following results: 90.9, 89.4, and 83.9 %. Clinical relapse-free survival (C-RFS) in patients treated using 3D-CRT vs. IMRT for the aforementioned groups were 94.7 vs. 100 %, 86.8 vs. 98.6 %, and 84.4 vs. 94.5 %. Disease-free survival (DFS) for patients treated using 3D-CRT were 83.1, 70.9, and 71.5 %. The IMRT group reached 95.8, 89.1, and 87.6 %. The PSA-RFS for intermediate- and high-risk patients were statistically significant, while C-RFS and DFS were marginally better. CONCLUSION: Dose escalation with IMRT was associated with improved cancer control in intermediate- and high-risk patients in comparison with 3D-CRT, without compromising toxicity.

Utilization of cone beam CT for reconstruction of dose distribution delivered in image-guided radiotherapy of prostate carcinoma - bony landmark setup compared to fiducial markers setup.

The purpose of this study was to compare two different styles of prostate IGRT: bony landmark (BL) setup vs. fiducial markers (FM) setup. Twenty-nine prostate patients were treated with daily BL setup and 30 patients with daily FM setup. Delivered dose distribution was reconstructed on cone-beam CT (CBCT) acquired once a week immediately after the alignment. Target dose coverage was evaluated by the proportion of the CTV encompassed by the 95% isodose. Original plans employed 1 cm safety margin. Alternative plans assuming smaller 7 mm margin between CTV and PTV were evaluated in the same way. Rectal and bladder volumes were compared with initial ones. While the margin reduction in case of BL setup makes the prostate coverage significantly worse (p = 0.0003, McNemar's test), in case of FM setup with the reduced 7 mm margin, the prostate coverage is even better compared to BL setup with 10 mm margin (p = 0.049, Fisher's exact test). Moreover, partial volumes of organs at risk irradiated with a specific dose can be significantly lowered (p < 0.0001, unpaired t-test). Reducing of safety margin is not acceptable in case of BL setup, while the margin can be lowered from 10 mm to 7 mm in case of FM setup.

Psychosocial implications and the duality of life outcomes for patients with prostate carcinoma after bilateral orchiectomy.

OBJECTIVES: The study presented focuses on patients' psychosocial status after a prostate cancer diagnosis that underwent a bilateral orchiectomy. METHODS: We evaluated the psychosocial implications of 89 patients with prostate cancer after performing castration and a bilateral orchiectomy. RESULTS: Patients suffered significantly more from sleep disorders during hospitalisation when compared to their time prior to an orchiectomy (p<0.0005). There were some increases in the severity of sleep disorder after discharge (level of evidence p<0.05). However, no additional medications for sleep disorders were required. Additionally, there was a significant reduction in the abuse of medication (p<0.001). Ten per cent of the patients were in the care of a psychologist or a psychiatrist before their diagnosis, and 21% asked for the help of a psychologist or a psychiatrist after having a bilateral orchiectomy. The occurrence of mood disorders is also very different than the occurrence of sleep disorders. Mood disorders occurred much less often after orchiectomy and discharge (p>0.085) compared with the period before surgery. Forty per cent of the patients had mood disorders before their operation, while only 37% still had these after discharge. There was a significant decrease in abuse of medication for anxiety. Twenty-four per cent of the patients took medication during hospitalisation, and only 10% continued after orchiectomy. CONCLUSIONS: The results of the study show that patients who were notified about their cancer diagnosis, particularly their health status, exhibited moderate stress and psychological impact.

Utilization of cone-beam CT for offline evaluation of target volume coverage during prostate image-guided radiotherapy based on bony anatomy alignment.

AIM: To assess target volume coverage during prostate image-guided radiotherapy based on bony anatomy alignment and to assess possibility of safety margin reduction. BACKGROUND: Implementation of IGRT should influence safety margins. Utilization of cone-beam CT provides current 3D anatomic information directly in irradiation position. Such information enables reconstruction of the actual dose distribution. MATERIALS AND METHODS: Seventeen prostate patients were treated with daily bony anatomy image-guidance. Cone-beam CT (CBCT) scans were acquired once a week immediately after bony anatomy alignment. After the prostate, seminal vesicles, rectum and bladder were contoured, the delivered dose distribution was reconstructed. Target dose coverage was evaluated by the proportion of the CTV encompassed by the 95% isodose. Original plans employed a 1 cm safety margin. Alternative plans assuming a smaller 7 mm margin between CTV and PTV were evaluated in the same way. Rectal and bladder volumes were compared with the initial ones. Rectal and bladder volumes irradiated with doses higher than 75 Gy, 70 Gy, 60 Gy, 50 Gy and 40 Gy were analyzed. RESULTS: In 12% of reconstructed plans the prostate coverage was not sufficient. The prostate underdosage was observed in 5 patients. Coverage of seminal vesicles was not satisfactory in 3% of plans. Most of the target underdosage corresponded to excessive rectal or bladder filling. Evaluation of alternative plans assuming a smaller 7 mm margin revealed 22% and 11% of plans where prostate and seminal vesicles coverage, respectively, was compromised. These were distributed over 8 and 7 patients, respectively. CONCLUSION: Sufficient dose coverage of target volumes was not achieved for all patients. Reducing of safety margin is not acceptable. Initial rectal and bladder volumes cannot be considered representative for subsequent treatment.

Intensity-modulated radiotherapy in the treatment of subhepatic carcinomas.

BACKGROUND/AIMS: The aim of our study was to evaluate preliminary results of intensity modulated radiotherapy (IMRT) in patients with inoperable subhepatic tumors. METHODOLOGY: Thirteen patients with inoperable cholangiocarcinoma or gall bladder carcinoma were treated by biliary drainage and intensity modulated radiotherapy. In patients with tumors limited to the biliary duct only tumor stenosis was irradiated to the dose of 50-60 Gy. In patients with bulky extraductal tumors the dose was 50 Gy/25 fractions to the whole tumor and an integrated boost was used to raise the dose to the malignant stenosis to 60 Gy/25 fractions. RESULTS: Doses to organs at risk (duodenum, small intestine, liver) were in tolerable limits. In four patients transient fever occurred; one patient had duodenal bleeding that resolved after conservative treatment. Recurrent dilatation of the biliary tract was observed in 4 patients and was managed by exchange of the internal biliary drainage. Median survival was 10.4 months, 5 patients survived for more than one year following diagnosis. CONCLUSIONS: IMRT of inoperable extrahepatic biliary tract tumors allows application of high doses of radiation to the tumor with effective sparing of healthy tissues. The control of jaundice is good. In selected cases IMRT may prolong overall survival.

Radical prostatectomy in high-grade prostate cancer, salvage and adjuvant radiotherapy.

INTRODUCTION: Prostate cancer with a Gleason score (GS) of 8-10 is linked to a higher risk of recurrence and progression. The aim of this paper is to evaluate treatment results of our high-risk patient cohort. PATIENTS AND METHODS: The cohort of 42 patients with radical prostatectomy (RP) specimen histology GS 8-10 was assessed. The patients were followed up after RP and radiotherapy (RT) was delivered in case of a biochemical relapse. Adjuvant radiotherapy (aRT) was delivered only in case of a positive surgical margin (PSM). The following parameters were evaluated: biochemical progression-free survival (BPFS), overall survival (OS) and cancer-specific survival (CSS). The second objective was to evaluate adverse effects of RP and RT. RESULTS: The median follow-up time was 88 months (18-168). RP led to BPFS in 16 patients (38%). Five patients with PSM underwent aRT and 20 underwent salvage radiotherapy (sRT). One patient died of myocardial infarction and 1 patient died of metastatic disease. Skeletal metastases were recorded in 2 patients. The BPFS in RP combinations with sRT or aRT was reached in 29 patients (69%). The OS and CSS in our cohort reached 95 and 98%, respectively. CONCLUSION: Management with aRT only in PSM was very effective, according to our retrospective study.

Daily prostate volume and position monitoring using implanted gold markers and on-board imaging during radiotherapy.

PURPOSE: This study aimed to evaluate prostate volume changes and prostate motions during radiotherapy. METHODS: In 2010, twenty-five patients were treated for prostate cancer by external beam radiotherapy with implanted fiducial markers. Coordinates of three gold markers on kilovoltage images were calculated daily. Volume changes in target structure were observed through changes in intermarker distances. Differences in patient position between laser-tattoo alignment and gold marker localization were evaluated. Intrafraction motion was assessed by measuring marker displacement on kilovoltage images acquired before and after fraction delivery. RESULTS: Prostate shrinkage was observed in 60% of patients. The average shrinkage was 7% of the prostate's initial volume. Corrections after laser-tattoo alignment remained mostly below 1 cm. The difference between marker centroid position on the actual images and the planning images was 2 +/- 1 mm on average. The extension of intrafraction movements was 7.6 +/- 0.2 mm on average. CONCLUSIONS: In our retrospective study, the possibility for prostate volume changes during radiotherapy was revealed. Intrafraction movements turned out to be the limiting factor in safety margin reduction.

Dose escalation in prostate radiotherapy up to 82 Gy using simultaneous integrated boost: direct comparison of acute and late toxicity with 3D-CRT 74 Gy and IMRT 78 Gy.

PURPOSE: To compare acute and late toxicity after three-dimensional conformal radiotherapy to the prostate to 74 Gy (3D-CRT) with intensity-modulated radiotherapy to 78 Gy (IMRT 78) and IMRT using simultaneous integrated boost to 82 Gy (IMRT/SIB 82). PATIENTS AND METHODS: 94 patients treated with 3D-CRT to the prostate and base of seminal vesicles to 74 Gy represented the first group. The second group consisted of 138 patients subjected to IMRT covering the prostate and base of seminal vesicles to 78 Gy. The last group was treated with IMRT using SIB. The prescribed doses were 82 Gy and 73.8 Gy in 42 fractions to the prostate and seminal vesicles. Late toxicity was prospectively scored according to the RTOG/FC-LENT scale. RESULTS: Acute gastrointestinal toxicity >or= grade 2 occurred in 35.1% of patients treated with 3D-CRT, in 16% subjected to IMRT 78, and in 7.7% receiving IMRT/SIB 82. Acute genitourinary toxicity >or= grade 2 was observed in 26.6% (3D-CRT), 33% (IMRT 78), and 30.7% (IMRT/SIB 82). At 3 years, the estimated cumulative incidence of grade 3 late gastrointestinal toxicity was 14% for 3D-CRT, 5% for IMRT 78, and 2% for IMRT/SIB 82. The difference became significant (log rank p = 0.02). The estimated cumulative incidence of grade 3 late genitourinary toxicity was 9% (3D-CRT), 7% (IMRT 78), and 6% (IMRT/SIB 82) without statistical differences (log rank p = 0.32) CONCLUSION: SIB enables dose escalation up to 82 Gy with a lower rate of gastrointestinal toxicity grade 3 in comparison with 3D-CRT up to 74 Gy.

The technique of intensity-modulated radiotherapy in the treatment of cholangiocarcinoma.

AIMS AND BACKGROUND: Conventional radiotherapy in inoperable cholangiocarcinoma is limited by radiotolerance of the surrounding tissues. The aim of our dosimetric study was an evaluation of intensity-modulated radiotherapy in the treatment of inoperable bile duct carcinoma. METHODS: Four patients with inoperable cholangiocarcinoma treated by self-expandable stent placed to the biliary tree and radiotherapy were studied. The rotational technique, conformal 3D BOX technique and intensity-modulated radiotherapy plan were compared. Dose volume histograms and the normal tissue complication probability concept were used for comparison. The stent was used for target motion verification. RESULTS: The intensity-modulated radiotherapy plans showed favorable dose distribution in planning target volume and remarkable sparing of organs at risk. CONCLUSIONS: The intensity-modulated radiotherapy technique in bile duct carcinomas deserves further research and clinical evaluation.

IMRT with the use of simultaneous integrated boost in treatment of head and neck cancer: acute toxicity evaluation.

Acute toxicity has been evaluated in head and neck cancer patients treated with intensity-modulated radiotherapy using simultaneous integrated boost (SIB-IMRT). The basis of the treatment protocol is an irradiation in 30 fractions with a total dose: 66 Gy to the region of macroscopic tumor, 60 Gy to the region of high-risk subclinical disease and 54 Gy to the region of low-risk subclinical disease. Between December 2003 and September 2005, 38 patients with carcinoma of different locations in the head and neck region were irradiated. Five patients underwent concurrent chemotherapy (weekly cisplatin). Acute toxicity was evaluated according to Radiation Therapy Oncology Group toxicity scale for skin, mucous membrane, salivary glands, pharynx and esophagus and larynx. All 38 patients completed the therapy without urgency of interruption due to acute toxicity of radiotherapy. No patient experienced grade 4 toxicity. More severe toxicity was observed in patients with concurrent chemotherapy. The results confirm that the irradiation according to our SIB-IMRT protocol is a therapy with acceptable toxicity and there is a space for radiobiological enhancement of this regimen by concurrent chemotherapy, e.g. weekly cisplatin.