Floris J. Pos

Single blind randomized Phase III trial to investigate the benefit of a focal lesion ablative microboost in prostate cancer (FLAME-trial): study protocol for a randomized controlled trial

BackgroundThe treatment results of external beam radiotherapy for intermediate and high risk prostate cancer patients are insufficient with five-year biochemical relapse rates of approximately 35%. Several randomized trials have shown that dose escalation to the entire prostate improves biochemical disease free survival. However, further dose escalation to the whole gland is limited due to an unacceptable high risk of acute and late toxicity. Moreover, local recurrences often originate at the location of the macroscopic tumor, so boosting the radiation dose at the macroscopic tumor within the prostate might increase local control. A reduction of distant metastases and improved survival can be expected by reducing local failure. The aim of this study is to investigate the benefit of an ablative microboost to the macroscopic tumor within the prostate in patients treated with external beam radiotherapy for prostate cancer.Methods/DesignThe FLAME-trial (F ocal L esion A blative M icroboost in prostatE cancer) is a single blind randomized controlled phase III trial. We aim to include 566 patients (283 per treatment arm) with intermediate or high risk adenocarcinoma of the prostate who are scheduled for external beam radiotherapy using fiducial markers for position verification. With this number of patients, the expected increase in five-year freedom from biochemical failure rate of 10% can be detected with a power of 80%. Patients allocated to the standard arm receive a dose of 77 Gy in 35 fractions to the entire prostate and patients in the experimental arm receive 77 Gy to the entire prostate and an additional integrated microboost to the macroscopic tumor of 95 Gy in 35 fractions. The secondary outcome measures include treatment-related toxicity, quality of life and disease-specific survival. Furthermore, by localizing the recurrent tumors within the prostate during follow-up and correlating this with the delivered dose, we can obtain accurate dose-effect information for both the macroscopic tumor and subclinical disease in prostate cancer. The rationale, study design and the first 50 patients included are described.Trial registrationThis study is registered at ClinicalTrials.gov: NCT01168479

Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial

BACKGROUND Studies have reported a low α/β ratio for prostate cancer, suggesting that hypofractionation could enhance the biological tumour dose without increasing genitourinary and gastrointestinal toxicity. In the multicentre phase 3, HYpofractionated irradiation for PROstate cancer (HYPRO) trial, hypofractionated radiotherapy was compared with conventionally fractionated radiotherapy for treatment of prostate cancer. We have previously reported acute and late incidence of genitourinary and gastrointestinal toxicity; here we report protocol-defined 5-year relapse-free survival outcomes. METHODS We did an open-label, randomised, phase 3 trial at seven Dutch radiotherapy centres. We enrolled patients with intermediate-risk to high-risk T1b-T4NX-N0MX-M0 localised prostate cancer, a prostate-specific antigen concentration of 60 μg/L or less, and a WHO performance status of 0-2. We used a web-based application to randomly assign (1:1) patients to either hypofractionated radiotherapy of 64·6 Gy (19 fractions of 3·4 Gy, three fractions per week) or conventionally fractionated radiotherapy of 78·0 Gy (39 fractions of 2·0 Gy, five fractions per week). Based on an estimated α/β ratio for prostate cancer of 1·5 Gy, the equivalent total dose in fractions of 2·0 Gy was 90·4 Gy for hypofractionation compared with 78·0 Gy for conventional fractionation. The primary endpoint was relapse-free survival. All analyses were done on an intention-to-treat basis in all eligible patients. The HYPRO trial completed recruitment in 2010 and follow-up is ongoing. This trial is registered with ISRCTN, number ISRCTN85138529. FINDINGS Between March 19, 2007, and Dec 3, 2010, 820 patients were enrolled, of whom 804 were eligible and assessable for intention-to-treat analyses. Of these, 407 were assigned hypofractionated radiotherapy and 397 were allocated conventionally fractionated radiotherapy. 537 (67%) of 804 patients received concomitant androgen deprivation therapy for a median duration of 32 months (IQR 10-44). Median follow-up was 60 months (IQR 51-69). Treatment failure was reported in 169 (21%) of 804 patients, 80 (20%) in the hypofractionation group and 89 (22%) in the conventional fractionation group. 5-year relapse-free survival was 80·5% (95% CI 75·7-84·4) for patients assigned hypofractionation and 77·1% (71·9-81·5) for those allocated conventional fractionation (adjusted hazard radio 0·86, 95% CI 0·63-1·16; log-rank p=0·36). There were no treatment-related deaths. INTERPRETATION Hypofractionated radiotherapy was not superior to conventional radiotherapy with respect to 5-year relapse-free survival. Our hypofractionated radiotherapy regimen cannot be regarded as the new standard of care for patients with intermediate-risk or high-risk prostate cancer. FUNDING Dutch Cancer Society.

INFLUENCE OF BLADDER AND RECTAL VOLUME ON SPATIAL VARIABILITY OF A BLADDER TUMOR DURING RADICAL RADIOTHERAPY

PURPOSE To assess the spatial variability of a bladder tumor relative to the planning target volume boundaries during radical radiotherapy, and furthermore to develop strategies to reduce spatial variability. METHODS AND MATERIALS Seventeen patients with solitary T2-T4N0M0 bladder cancer were treated with a technique delivering 40 Gy/2 Gy in 20 fractions to the whole bladder with a concomitant boost to the bladder tumor of 20 Gy in 1 Gy fractions in an overall time of 4 weeks. CT scans were made weekly, immediately after treatment, and matched with the planning CT scan. Spatial variability of the tumor, as well as bladder volume and rectal diameter, were scored for each patient each week. RESULTS In 65% of patients, a part of the tumor appeared outside the planning target volume boundaries at least one time during the course of radiotherapy. No consistent relation of this variability with time was found. Bladder volumes and rectal diameters showed marked variability during the course of treatment. A large initial bladder volume and rectal diameter predicted a large volume variation and a large tumor spatial variability. CONCLUSION In this study, a margin of 1.5 to 2 cm seemed to be inadequate in 65% of the patients with respect to spatial variability. Bladder volume and rectal diameter were found to be predictive for spatial variability of a bladder tumor during concomitant boost radiotherapy.

The influence of a dietary protocol on cone beam CT-guided radiotherapy for prostate cancer patients.

PURPOSE To evaluate the influence of a dietary protocol on cone beam computed tomography (CBCT) image quality, which is an indirect indicator for short-term (intrafraction) prostate motion, and on interfraction motion. Image quality is affected by motion (e.g., moving gas) during imaging and influences the performance of automatic prostate localization on CBCT scans. METHODS AND MATERIALS Twenty-six patients (336 CBCT scans) followed the dietary protocol and 23 patients (240 CBCT scans) did not. Prostates were automatically localized by using three dimensional (3D) gray-value registration (GR). Feces and (moving) gas occurrence in the CBCT scans, the success rate of 3D-GR, and the statistics of prostate motion data were assessed. RESULTS Feces, gas, and moving gas significantly decreased from 55%, 61%, and 43% of scans in the nondiet group to 31%, 47%, and 28% in the diet group (all p < 0.001). Since there is a known relation between gas and short-term prostate motion, intrafraction prostate motion probably also decreased. The success rate of 3D-GR improved from 83% to 94% (p < 0.001). A decrease in random interfraction prostate motion also was found, which was not significant after Bonferronis correction. Significant deviations from planning CT position for rotations around the left-right axis were found in both groups. CONCLUSIONS The dietary protocol significantly decreased the incidence of feces and (moving) gas. As a result, CBCT image quality and the success rate of 3D-GR significantly increased. A trend exists that random interfraction prostate motion decreases. Using a dietary protocol therefore is advisable, also without CBCT-based image guidance.

Urinary Obstruction in Prostate Cancer Patients From the Dutch Trial (68 Gy vs. 78 Gy): Relationships With Local Dose, Acute Effects, and Baseline Characteristics

PURPOSE To investigate the relationship between late urinary obstruction and the details of the dose distribution of irradiated prostate cancer patients, taking into account their baseline symptoms and acute complaints. PATIENTS AND METHODS We selected patients from the Dutch multicenter trial randomized between 68 Gy and 78 Gy, for whom toxicity data and dose data were available (n = 557). The absolute dose surface parameters of the delineated bladder were calculated. Next, we constructed three-dimensional dose maps of the area around the prostate, providing an approximate identification of the corresponding anatomic locations. The dose difference maps were constructed by subtracting the mean dose maps of the patients with and without late urinary obstruction. Selected local dose points were analyzed using Cox regression analysis. RESULTS Urinary obstruction was scored for 40 patients, including 19 of 296 patients who received 68-72 Gy and 21 of 261 patients who received 76-78 Gy. A total of 19 events occurred within 2 years after irradiation and 21 events after 2 years. The bladder surface receiving >or=80 Gy predicted (p <.01) the occurrence of obstruction within 2 years. The dose difference map indicated highly significant differences in the bladder neck situated in the trigonal region (p < .001) that were especially predictive of obstruction after 2 years and of the diagnosis of bladder neck obstruction. Baseline complaints and transurethral resection of the prostate and acute complaints were mainly predictive for obstruction within 2 years. CONCLUSION Relatively early events of urinary obstruction were associated with urinary problems existing before RT, acute toxicity, previous transurethral resection of the prostate, and hotspots in the bladder. Events after 2 years were associated with the local dose in the trigonal area.

Concomitant boost radiotherapy for muscle invasive bladder cancer

PURPOSE To evaluate the feasibility and efficacy of a concomitant partial bladder boost schedule in radiotherapy for invasive bladder cancer, coupling a limited boost volume with shortening of the overall treatment time. METHODS AND MATERIALS Between 1994 and 1999, 50 patients with a T2-T4 N0M0 transitional cell carcinoma of the bladder received radiotherapy delivered in a short overall treatment time with a concomitant boost technique. With this technique a dose of 40 Gy in 2-Gy fractions was administered to the small pelvis with a concomitant boost limited to the bladder tumor area plus margin of 15 Gy in fractions of 0.75 Gy. The total tumor dose was 55 Gy in 20 fractions in 4 weeks. Toxicity was scored according to EORTC/RTOG toxicity criteria. RESULTS The feasibility of the treatment was good. Severe acute toxicity >/=G3 was observed in seven patients (14%). Severe late toxicity >/=G3 was observed in six patients (13%). Thirty-seven patients (74%) showed a complete and five (10 %) a partial remission after treatment. The actuarial 3-year freedom of local progression was 55%. CONCLUSION In external radiotherapy for muscle invasive bladder cancer a concomitant boost technique coupling a partial bladder boost with shortening of the overall treatment time provides a high probability of local control with acceptable toxicity.

Reproducibility of the bladder shape and bladder shape changes during filling

The feasibility of high precision radiotherapy to the bladder region is limited by bladder motion and volume changes. In the near future, we plan to begin treatment delivery of bladder cancer patients with the acquisition of a cone beam CT image on which the complete bladder will be semi-automatically localized. Subsequently, a bladder shape model that was developed in a previous study will be used for bladder localization and for the prediction of shape changes in the time interval between acquisition and beam delivery. For such predictions, knowledge about urinary inflow rate is required. Therefore, a series of MR images was acquired over 1 h with time intervals of 10 min for 18 healthy volunteers. To gain insight in the reproducibility of the bladder shape over longer periods of time, two additional MRI series were recorded for 10 of the volunteers. To a good approximation, the bladder volume increased linearly in time for all individuals. Despite receiving drinking instructions, we found a large variation in the inflow rate between individuals, ranging from 2.1 to 15 cc/min (mean value: 9 +/- 3 cc/min). In contrast, the intravolunteer variation was much smaller, with a mean standard deviation (SD) of 0.4 cc/min. The inflow rate was linearly correlated with age (negative slope). To study the reproducibility of the bladder shape, we compared bladder shapes of equal volume. For all individuals, the caudal part of the bladder was the most reproducible (variations<0.3 cm in all cases). The cranial and posterior parts of the bladder was much less reproducible, with local SD values up to approximately 1.2 cm for bladders with a volume of 200 cc. These large long-term variations were primarily caused by changes in position and filling of the small bowel and rectum. However, for short time intervals, the rectal filling was (nearly) constant. Therefore, the reproducibility of urinary inflow, combined with the previously developed shape model gives us an excellent tool to predict short-term shape changes. We intend to use this tool for further improvement of image-guided radiotherapy for bladder cancer patients.

Acute Toxicity After Image-Guided Intensity Modulated Radiation Therapy Compared to 3D Conformal Radiation Therapy in Prostate Cancer Patients

PURPOSE Image-guided intensity modulated radiation therapy (IG-IMRT) allows significant dose reductions to organs at risk in prostate cancer patients. However, clinical data identifying the benefits of IG-IMRT in daily practice are scarce. The purpose of this study was to compare dose distributions to organs at risk and acute gastrointestinal (GI) and genitourinary (GU) toxicity levels of patients treated to 78 Gy with either IG-IMRT or 3D-CRT. METHODS AND MATERIALS Patients treated with 3D-CRT (n=215) and IG-IMRT (n=260) receiving 78 Gy in 39 fractions within 2 randomized trials were selected. Dose surface histograms of anorectum, anal canal, and bladder were calculated. Identical toxicity questionnaires were distributed at baseline, prior to fraction 20 and 30 and at 90 days after treatment. Radiation Therapy Oncology Group (RTOG) grade ≥1, ≥2, and ≥3 endpoints were derived directly from questionnaires. Univariate and multivariate binary logistic regression analyses were applied. RESULTS The median volumes receiving 5 to 75 Gy were significantly lower (all P<.001) with IG-IMRT for anorectum, anal canal, and bladder. The mean dose to the anorectum was 34.4 Gy versus 47.3 Gy (P<.001), 23.6 Gy versus 44.6 Gy for the anal canal (P<.001), and 33.1 Gy versus 43.2 Gy for the bladder (P<.001). Significantly lower grade ≥2 toxicity was observed for proctitis, stool frequency ≥6/day, and urinary frequency ≥12/day. IG-IMRT resulted in significantly lower overall RTOG grade ≥2 GI toxicity (29% vs 49%, respectively, P=.002) and overall GU grade ≥2 toxicity (38% vs 48%, respectively, P=.009). CONCLUSIONS A clinically meaningful reduction in dose to organs at risk and acute toxicity levels was observed in IG-IMRT patients, as a result of improved technique and tighter margins. Therefore reduced late toxicity levels can be expected as well; additional research is needed to quantify such reductions.

Long-term survival after sequential chemoradiation for limited disease small cell carcinoma of the bladder

ObjectivesTo evaluate response, time to progression and survival of patients with limited disease (LD) small cell carcinoma of the bladder (SCCB) treated with sequential chemoradiation in analogy to LD small cell lung cancer (SCLC).MethodsOf 42 patients with SCCB treated at our institution between 1993 and 2007, 17 with LD SCCB treated with chemoradiation were identified and retrospectively analysed. LD was defined as any pT, cN0-1, cM0. SCCB was defined according to WHO criteria. All patients had platinum-based chemotherapy after transurethral resection (TUR) prior to local radiotherapy with 56–70 Gy.ResultsSixteen patients were male, 1 female. Median age was 62 years. Median overall survival is 32.5 months. All had a clinical local response (15 CR, 2 PR). Systemic progression occurred in 8 (47%) with a median time to progression of 6 months (range 1–16 months), 8 died with a median survival of 17.5 months. Currently, 7 are free of disease (FOD) including 2 at 80 and 87 months. Four (23.5%) had a local recurrence as late as 43 and 50 months; 3 required a salvage cystectomy.ConclusionsClinical results of sequential chemoradiation for LD SCCB are comparable to contemporary series of LD SCCB treated with cystectomy and upfront or adjuvant chemotherapy. Long-term survival of more than 5 years after chemoradiation can be achieved. The risk of local recurrence is lower than reported, but late recurrences occur. These data suggest that bladder sparing with systemic chemotherapy and local control by radiotherapy should be further investigated in this aggressive disease.

Lipiodol injection for target volume delineation and image guidance during radiotherapy for bladder cancer

A technique was developed for bladder tumour demarcation with lipiodol injection through a flexible cystoscope. The technique proved to be simple and useful for image-guided radiotherapy in bladder cancer as well as a helpful aid in the tumour delineation process.