Specialist versus primary care prostate cancer follow-up:A process evaluation of a randomized controlled trial

Background: A randomized controlled trial (RCT) is currently comparing the effectiveness of specialist- versus primary care-based prostate cancer follow-up. This process evaluation assesses the reach and identified constructs for the implementation of primary care-based follow-up. Methods: A mixed-methods approach is used to assess the reach and the implementation through the Consolidated Framework for Implementation Research. We use quantitative data to evaluate the reach of the RCT and qualitative data (interviews) to indicate the perspectives of patients (n = 15), general practitioners (GPs) (n = 10), and specialists (n = 8). Thematic analysis is used to analyze the interview transcripts. Results: In total, we reached 402 (67%) patients from 12 hospitals and randomized them to specialist- (n = 201) or to primary care-based (n = 201) follow-up. From the interviews, we identify several advantages of primary care- versus specialist-based follow-up: it is closer to home, more accessible, and the relationship is more personal. Nevertheless, participants also identified challenges: guidelines should be implemented, communication and collaboration between primary and secondary care should be improved, quality indicators should be collected, and GPs should be compensated. Conclusion: Within an RCT context, 402 (67%) patients and their GPs were willing to receive/provide primary care-based follow-up. If the RCT shows that primary care is equally as effective as specialist-based follow-up, the challenges identified in this study need to be addressed to enable a smooth transition of prostate cancer follow-up to primary care. Netherlands Trial Registry, Trial NL7068 (NTR7266)

Patterns of Recurrence and Survival After Pelvic Treatment for Locally Advanced Penile Cancer

BACKGROUND: Penile cancer (PeCa) is rare, and the survival of patients with advanced disease remains poor. A better understanding of where treatment fails could aid the development of new treatment strategies. OBJECTIVE: To describe the disease course after pelvic lymph node (LN) treatment for PeCa. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively analysed 228 patients who underwent pelvic LN treatment with curative intent from 1969 to 2016. The main treatment modalities were neoadjuvant chemotherapy, chemoradiation, and pelvic LN dissection. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: In the case of multiple recurrence locations, the most distant location was taken and recorded as follows: local (penis), regional (inguinal and pelvic LN), and distant (any other location). A competing risk analysis was used to calculate the time to recurrence per location, and a Kaplan-Meier analysis was used for overall survival (OS). RESULTS AND LIMITATIONS: The median follow-up of the surviving patients was 79 mo. The reason for pelvic treatment was pelvic involvement on imaging (29%), two or more tumour-positive inguinal LNs (61%), or inguinal extranodal extension (52%). More than half of the patients (61%) developed a recurrence. The median recurrence-free survival was 11 mo. The distribution was local in 9%, regional in 27%, and distant in 64% of patients. The infield control rate of nonsystemically treated patients was 61% (113/184). From the start of pelvic treatment, the median OS was 17 mo (95% confidence interval 12–22). After regional or distant recurrence, all but one patient died of PeCa with median OS after a recurrence of 4.4 (regional) and 3.1 (distant) mo. This study is limited by its retrospective nature. CONCLUSIONS: The prognosis of PeCa patients treated on their pelvis who recur despite locoregional treatment is poor. The tendency for systemic spread emphasises the need for more effective systemic treatment strategies. PATIENT SUMMARY: In this report, we looked at the outcomes of penile cancer patients in an expert centre undergoing various treatments on their pelvis. We found that survival is poor after recurrence despite locoregional treatment. Therefore, better systemic treatments are necessary

Biochemical Recurrence Surrogacy for Clinical Outcomes After Radiotherapy for Adenocarcinoma of the Prostate

PURPOSE: The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods. MATERIALS AND METHODS: Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the R2). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed. RESULTS: Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R2 values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively. CONCLUSION: BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.</p

Biochemical Recurrence Surrogacy for Clinical Outcomes After Radiotherapy for Adenocarcinoma of the Prostate

PURPOSE: The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods. MATERIALS AND METHODS: Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the R2). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed. RESULTS: Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R2 values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively. CONCLUSION: BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events

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

Background: The 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/Design: The FLAME-trial (Focal Lesion Ablative Microboost 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.Biological, physical and clinical aspects of cancer treatment with ionising radiatio

Radical radiotherapy for invasive bladder cancer: What dose and fractionation schedule to choose?

PURPOSE: To establish the alpha/beta ratio of bladder cancer from different radiotherapy schedules reported in the literature and provide guidelines for the design of new treatment schemes. METHODS AND MATERIALS: Ten external beam radiotherapy (EBRT) and five brachytherapy schedules were selected. The biologically effective dose (BED) of each schedule was calculated. Logistic modeling was used to describe the relationship between 3-year local control (LC3y) and BED. RESULTS: The estimated alpha/beta ratio was 13 Gy (95% confidence interval [CI], 2.5-69 Gy) for EBRT and 24 Gy (95% CI, 1.3-460 Gy) for EBRT and brachytherapy combined. There is evidence for an overall dose-response relationship. After an increase in total dose of 10 Gy, the odds of LC3y increase by a factor of 1.44 (95% CI, 1.23-1.70) for EBRT and 1.47 (95% CI, 1.25-1.72) for the data sets of EBRT and brachytherapy combined. CONCLUSION: With the clinical data currently available, a reliable estimation of the alpha/beta ratio for bladder cancer is not feasible. It seems reasonable to use a conventional alpha/beta ratio of 10-15 Gy. Dose escalation could significantly increase local control. There is no evidence to support short overall treatment times or large fraction sizes in radiotherapy for bladder cancer

Patient-Reported Outcomes in the Acute Phase of the Randomized Hypofractionated Irradiation for Prostate Cancer (HYPRO) Trial

Purpose: Many patients experience bowel and bladder toxicity during the acute phase of radiation therapy for prostate cancer. Recent literature indicates that hypofractionation (HF) might increase this acute response but little is known on patient-reported outcome during this phase with HF. We evaluated the course of patient-reported acute symptoms during HF versus standard fractionated (SF) radiation therapy within the hypofractionated irradiation for prostate cancer (HYPRO) trial. Methods and Materials: In the HYPRO trial patients were treated with either 64.4 Gy (HF) in 19 fractions (3 times per week) or 78 Gy (SF) in 39 fractions (5 times per week). Normalized total dose for 2 Gy/fractions (NTD2Gy)for acute toxicity (α/β ratio of 10) for HF was 72.1 Gy with a similar dose rate of 10.2 Gy per week. Among the 794 patients who were previously eligible for acute grade ≥2 toxicity assessment, 717 had filled out ≥1 symptom questionnaires. For each maximum symptom, we scored “any complaint” and “moderate-severe complaint.” Differences were tested by χ2 test, and associations with clinical factors were tested using logistic regression. Significance was set at P ≤ .008 to adjust for multiple testing. Results: We observed significantly higher rates of moderate-severe painful defecation (HF 10.8%, SF 5.3%), any mucus discharge (HF 47.1%, SF 37.4%), any rectal blood loss (HF 16.1%, SF 9.3%), increased daily stool frequency ≥4 and ≥6 (HF 34.6%/13.8%, SF 25.6%/7.0%), and any urinary straining (HF 69.9%, SF 58.0%). At 3 months postradiation therapy, rates dropped considerably with similar levels for HF and SF. Hormonal treatment was associated with less acute gastrointestinal symptoms. Conclusion: The increased patient-reported acute rectal symptoms with HF confirmed the previously reported results on acute grade ≥2 rectal toxicity. The increase in bladder symptoms with HF was not identified previously. These observations contradict the NTD2Gy calculations. We observed no patterns of persisting complaints with HF after the acute period; therefore, HF is well tolerated and only associated with a temporary increase of symptoms

Fusion of planning CT and cystoscopy images for bladder tumor delineation: a feasibility study.

Bladder tumor delineation and localization during treatment are challenging problems in radiotherapy for bladder cancer. The purpose of this study is to investigate improvement of tumor delineation by the fusion of cystoscopy images with the planning CT-scan using lipiodol markers injected around the visible tumor during cystoscopy. A registration method was developed for the fusion of cystoscopy images with a planning CT-scan and was tested on a phantom and retrospectively on the imaging data of four bladder cancer patients. For the patients, small deposits of lipiodol were injected at the visible margin of the tumor or previous transurethral resection site during cystoscopy. These deposits were clearly visible on the planning CT-scan and served as markers for both tumor delineation and image guidance of the radiotherapy treatment. Here, the markers were used for the registration of cystoscopy images with the planning CT-scan. The registration procedure works as follows: First, coarse registrations were made to orient the cystoscopy image correctly, using the center of gravity of the markers, the center of the CT bladder, and one of N markers as fiducial points in a point matching procedure. Starting from these N orientations, full registrations are performed taking lens deformation into account. Since a cystoscopy image is 2D, each pixel corresponds to a line-of-sight. The distances between the CT markers and the lines-of-sight of the cystoscopy markers were minimized. The final cost function (the root mean square distance between corresponding CT markers and lines-of-sight) was used to quantify the quality of the registration. The registration with the lowest final cost was considered to represent the correct orientation. The CT-based tumor delineation was finally backprojected onto the cystoscopy image. The fusion of cystoscopy images with a planning CT-scan succeeded for the phantom and three out of four patients. The fiducial registration error (FRE) for the phantom image registration based on five markers was 1.1 mm, while the target registration error was 1.2-1.7 mm. The FREs for the patient images were 0.1-3.6 mm. The registration procedure failed for one patient, since it was not possible to indicate unambiguously the corresponding lipiodol marker locations in the cystoscopy image and the planning CT-scan. The difference between the CT and cystoscopy defined tumor outlines clearly exceeded the registration accuracy. Registration of cystoscopy images and planning CT-scan is feasible and allows for improvement of tumor delineation. However, the lipiodol injection protocol needs to be improved to facilitate identification of markers on both cystoscopy images and planning CT-scan

Hybrid registration of prostate and seminal vesicles for image guided radiation therapy.

Fiducial markers are a good surrogate for the prostate but provide little information on the position and orientation of the seminal vesicles (SVs). Therefore, a more advanced localization method is warranted if the SVs are part of the target volume. The purpose of this study was to develop a hybrid registration technique for the localization of the prostate and SVs. Twenty prostate patients implanted with 2 or 3 elongated fiducial markers had cone beam computed tomography (CBCT) scans acquired at every fraction. The first step of the hybrid registration was to localize the prostate by CBCT-to-planning-CT alignment of the fiducial markers, allowing both translations and rotations. Using this marker registration as a starting point, the SVs were registered based on gray values, allowing only rotations around the lateral axis. We analyzed the differential rotation between the prostate and SVs and compared the required SV margins for 3 correction strategies. The SV registration had a precision of 2.7° (1 standard deviation) and was successful for 96% of the scans. Mean (M), systematic (Σ), and random (σ) differences between the orientation of the prostate and SV were M = -0.4°, Σ = 7.2°, and σ = 6.4°. Daily marker-based corrections required an SV margin of 11.4 mm (translations only) and 11.6 mm (translations + rotations). Rotation corrections of the SVs reduced the required margin to 8.2 mm. We found substantial differences between the orientation of the prostate and SVs. The hybrid registration technique can accurately detect these rotations during treatment. Rotation correction of the SVs allows for margin reduction for the SV