The FORECAST study — Focal recurrent assessment and salvage treatment for radiorecurrent prostate cancer

doi:10.1016/j.cct.2015.07.004

Contemporary Clinical Trials

Volume 44, September 2015, Pages 175-186

https://doi.org/10.1016/j.cct.2015.07.004 Get rights and content

Abstract

Background

One-third of men may experience biochemical failure by 8 years following radical radiotherapy for localised prostate cancer. Over 90% of men are started on androgen deprivation therapy (ADT) which is non-curative and confers systemic side-effects. Focal salvage therapy (FST) limits collateral tissue damage and may improve therapeutic ratios. In order to deliver FST, distant disease must be ruled-out and intra-prostatic disease must be accurately detected, localised and characterised.

Aim

FORECAST – Focal Recurrent Assessment and Salvage Treatment – is a study designed to evaluate a novel imaging-based diagnostic and therapeutic complex intervention pathway for men who fail radiotherapy.

Methods

Men with biochemical failure following radical prostate radiotherapy, prior to salvage therapy will be recruited. They will undergo whole-body multi-parametric MRI (WB-MRI), choline PET/CT, bone-scan and pelvic-mpMRI and then MRI transperineal-targeted biopsies (MRI-TB) and Transperineal Template Prostate Mapping Biopsy (TPM). Those suitable for FST will undergo either high intensity focused ultrasound (HIFU) or cryotherapy.

Results

Primary outcome measures: a) the accuracy of WB-MRI to detect distant metastatic disease; b) accuracy of prostate mpMRI in local detection of radiorecurrent prostate cancer; c) detection accuracy of MRI-TB; and d) rate of urinary incontinence following FST.

Conclusion

Focal salvage therapy may confer lower rates of morbidity whilst retaining disease control. In order to deliver FST, intra- and extra-prostatic disease must be detected early and localised accurately. Novel diagnostic techniques including WB-MRI and MRI-TB may improve the detection of distant and local disease whilst reducing healthcare burdens compared with current imaging and biopsy strategies.

Section snippets

Background

Radiotherapy is effective in treating early localised prostate cancer. However, up to one-third of men may experience biochemical failure by 8 years [1], [2]. It is estimated that about half of those who eventually have radiorecurrent disease have metastases (either overt on imaging or micro-metastases). The median time from biochemical failure to development of distant metastases is approximately 3 years [3]. Therefore, a significant proportion have localised recurrence alone with a potential

Primary objectives

1.
To evaluate the accuracy of whole-body MRI to detect and rule-out regional lymph node and distant metastatic prostate cancer in men with biochemical recurrence following radiotherapy.
2.
To evaluate the accuracy of multi-parametric MRI targeted prostate biopsies in identifying areas of radiorecurrent prostate cancer compared to transperineal template prostate mapping biopsies.
3.
Presence of urinary incontinence (any pad usage plus any leakage of urine) as determined by the UCLA-EPIC urinary continence

Study protocol

FORECAST is a prospective, multi-centre, diagnostic and therapeutic, investigator-led study. It is a prospective cohort validating study conforming to level I evidence for diagnostic test evaluation and conforming to IDEAL guidelines stage 2b evaluation study for assessment of focal salvage therapy. [60] Monitoring of subject safety and study compliance is being managed by Data Monitoring and Trial Steering Committees, comprising an impartial (medically qualified) chairperson, the co-chief

Summary of protocol

FORECAST is one of the first prospective diagnostic and treatment trials that could change the current management pathway for men with radiorecurrent prostate cancer. The fact that men are recruited from initial point of potential relapse from radiotherapy, are accurately staged using imaging and transperineal mapping biopsy, are treated with salvage therapy and then followed up for one year, makes the study unique compared to other studies that simply focus on one aspect of the management

Conclusions

A third of men fail radiotherapy for localised prostate cancer. A significant proportion of these men are eligible for salvage treatment. However a number of these men are not promptly and accurately re-staged or provided with salvage treatment. FORECAST is one of the first prospective diagnostic and treatment trials that could change the current management pathway for men with radiorecurrent prostate cancer.

Acknowledgements

This study is funded by Pelican Cancer Foundation, (award no 158315) National Institute of Health and Research, (1r01ca135089) Prostate Cancer UK (award no. 162268) and Medical Research Council (award no. 160502).

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Cited by (23)

The Role of Multiparametric MRI and MRI–targeted Biopsy in the Diagnosis of Radiorecurrent Prostate Cancer: An Analysis from the FORECAST Trial
2024, European Urology
The role of multiparametric magnetic resonance imaging (MRI) for detecting recurrent prostate cancer after radiotherapy is unclear.
To evaluate MRI and MRI-targeted biopsies for detecting intraprostatic cancer recurrence and planning for salvage focal ablation.
FOcal RECurrent Assessment and Salvage Treatment (FORECAST; NCT01883128) was a prospective cohort diagnostic study that recruited 181 patients with suspected radiorecurrence at six UK centres (2014 to 2018); 144 were included here.
All patients underwent MRI with 5 mm transperineal template mapping biopsies; 84 had additional MRI-targeted biopsies. MRI scans with Likert scores of 3 to 5 were deemed suspicious.
First, the diagnostic accuracy of MRI was calculated. Second, the pathological characteristics of MRI-detected and MRI-undetected tumours were compared using the Wilcoxon rank sum test and chi-square test for trend. Third, four biopsy strategies involving an MRI-targeted biopsy alone and with systematic biopsies of one to two other quadrants were studied. Fisher’s exact test was used to compare MRI-targeted biopsy alone with the best other strategy for the number of patients with missed cancer and the number of patients with cancer harbouring additional tumours in unsampled quadrants. Analyses focused primarily on detecting cancer of any grade or length. Last, eligibility for focal therapy was evaluated for men with localised (≤T3bN0M0) radiorecurrent disease.
Of 144 patients, 111 (77%) had cancer detected on biopsy. MRI sensitivity and specificity at the patient level were 0.95 (95% confidence interval [CI] 0.92 to 0.99) and 0.21 (95% CI 0.07 to 0.35), respectively. At the prostate quadrant level, 258/576 (45%) quadrants had cancer detected on biopsy. Sensitivity and specificity were 0.66 (95% CI 0.59 to 0.73) and 0.54 (95% CI 0.46 to 0.62), respectively. At the quadrant level, compared with MRI-undetected tumours, MRI-detected tumours had longer maximum cancer core length (median difference 3 mm [7 vs 4 mm]; 95% CI 1 to 4 mm, p < 0.001) and a higher grade group (p = 0.002). Of the 84 men who also underwent an MRI-targeted biopsy, 73 (87%) had recurrent cancer diagnosed. Performing an MRI-targeted biopsy alone missed cancer in 5/73 patients (7%; 95% CI 3 to 15%); with additional systematic sampling of the other ipsilateral and contralateral posterior quadrants (strategy 4), 2/73 patients (3%; 95% CI 0 to 10%) would have had cancer missed (difference 4%; 95% CI –3 to 11%, p = 0.4). If an MRI-targeted biopsy alone was performed, 43/73 (59%; 95% CI 47 to 69%) patients with cancer would have harboured undetected additional tumours in unsampled quadrants. This reduced but only to 7/73 patients (10%; 95% CI 4 to 19%) with strategy 4 (difference 49%; 95% CI 36 to 62%, p < 0.0001). Of 73 patients, 43 (59%; 95% CI 47 to 69%) had localised radiorecurrent cancer suitable for a form of focal ablation.
For patients with recurrent prostate cancer after radiotherapy, MRI and MRI-targeted biopsy, with or without perilesional sampling, will diagnose cancer in the majority where present. MRI-undetected cancers, defined as Likert scores of 1 to 2, were found to be smaller and of lower grade. However, if salvage focal ablation is planned, an MRI-targeted biopsy alone is insufficient for prostate mapping; approximately three of five patients with recurrent cancer found on an MRI-targeted biopsy alone harboured further tumours in unsampled quadrants. Systematic sampling of the whole gland should be considered in addition to an MRI-targeted biopsy to capture both MRI-detected and MRI-undetected disease.
After radiotherapy, magnetic resonance imaging (MRI) is accurate for detecting recurrent prostate cancer, with missed cancer being smaller and of lower grade. Targeting a biopsy to suspicious areas on MRI results in a diagnosis of cancer in most patients. However, for every five men who have recurrent cancer, this targeted approach would miss cancers elsewhere in the prostate in three of these men. If further focal treatment of the prostate is planned, random biopsies covering the whole prostate in addition to targeted biopsies should be considered so that tumours are not missed.
Magnetic Resonance Imaging and Targeted Biopsies Compared to Transperineal Mapping Biopsies Before Focal Ablation in Localised and Metastatic Recurrent Prostate Cancer After Radiotherapy
2022, European Urology
Citation Excerpt :
Second, FORECAST evaluated functional and oncological outcomes after focal ablation in eligible and consenting patients with localised cancer alone and those with intraprostatic recurrence of cancer in the presence of metastases (Strengthening the Reporting of Observational Studies in Epidemiology [STROBE] checklist in the Supplementary material). Full details are available in the previously published full protocol [9] and the Supplementary material. All patients with biochemical failure detected as a rising PSA level after prior external beam radiotherapy (EBRT) or interstitial low-dose-rate or high-dose-rate brachytherapy with or without neoadjuvant/adjuvant ADT were eligible.
Recurrent prostate cancer after radiotherapy occurs in one in five patients. The efficacy of prostate magnetic resonance imaging (MRI) in recurrent cancer has not been established. Furthermore, high-quality data on new minimally invasive salvage focal ablative treatments are needed.
To evaluate the role of prostate MRI in detection of prostate cancer recurring after radiotherapy and the role of salvage focal ablation in treating recurrent disease.
The FORECAST trial was both a paired-cohort diagnostic study evaluating prostate multiparametric MRI (mpMRI) and MRI-targeted biopsies in the detection of recurrent cancer and a cohort study evaluating focal ablation at six UK centres. A total of 181 patients were recruited, with 155 included in the MRI analysis and 93 in the focal ablation analysis.
Patients underwent choline positron emission tomography/computed tomography and a bone scan, followed by prostate mpMRI and MRI-targeted and transperineal template-mapping (TTPM) biopsies. MRI was reported blind to other tests. Those eligible underwent subsequent focal ablation. An amendment in December 2014 permitted focal ablation in patients with metastases.
Primary outcomes were the sensitivity of MRI and MRI-targeted biopsies for cancer detection, and urinary incontinence after focal ablation. A key secondary outcome was progression-free survival (PFS).
Staging whole-body imaging revealed localised cancer in 128 patients (71%), with involvement of pelvic nodes only in 13 (7%) and metastases in 38 (21%). The sensitivity of MRI-targeted biopsy was 92% (95% confidence interval [CI] 83–97%). The specificity and positive and negative predictive values were 75% (95% CI 45–92%), 94% (95% CI 86–98%), and 65% (95% CI 38–86%), respectively. Four cancer (6%) were missed by TTPM biopsy and six (8%) were missed by MRI-targeted biopsy. The overall MRI sensitivity for detection of any cancer was 94% (95% CI 88–98%). The specificity and positive and negative predictive values were 18% (95% CI 7–35%), 80% (95% CI 73–87%), and 46% (95% CI 19–75%), respectively. Among 93 patients undergoing focal ablation, urinary incontinence occurred in 15 (16%) and five (5%) had a grade ≥3 adverse event, with no rectal injuries. Median follow-up was 27 mo (interquartile range 18–36); overall PFS was 66% (interquartile range 54–75%) at 24 mo.
Patients should undergo prostate MRI with both systematic and targeted biopsies to optimise cancer detection. Focal ablation for areas of intraprostatic recurrence preserves continence in the majority, with good early cancer control.
We investigated the role of magnetic resonance imaging (MRI) scans of the prostate and MRI-targeted biopsies in outcomes after cancer-targeted high-intensity ultrasound or cryotherapy in patients with recurrent cancer after radiotherapy. Our findings show that these patients should undergo prostate MRI with both systematic and targeted biopsies and then ablative treatment focused on areas of recurrent cancer to preserve their quality of life.
This trial is registered at ClinicalTrials.gov as NCT01883128.
Long-Term Prostate Specific Antigen Stability and Predictive Factors of Failure after Permanent Seed Prostate Brachytherapy
2018, Journal of Urology
Citation Excerpt :
In current practice biopsies are not usually considered before PSA reaches at least 2 ng/ml and, thus, biopsy was not considered in patients with slowly rising PSA who had not reached nadir + 2. In the future advanced imaging using multiparametric magnetic resonance imaging or positron emission tomography-computerized tomography may be useful to detect the disease site at PSA less than 2 ng/ml.28–30 Finally, we could not arrive at 1 simple predictive equation for clinical use.
Defining biochemical failure as nadir + 2 may overestimate cure after radiotherapy. We assessed long-term prostate specific antigen stability after low dose rate prostate brachytherapy and predictors of biochemical failure when prostate specific antigen was slowly rising below the nadir + 2 ng/ml threshold.
A total of 2,339 patients with low or intermediate risk prostate cancer received ¹²⁵iodine brachytherapy from 1998 to 2010 with a minimum 3-year followup. In addition, 49.7% of the patients received 6 months of androgen deprivation. Clinical, dosimetric and prostate specific antigen data were retrieved from a prospective database. Biochemical results were classified as stable or rising prostate specific antigen (0.2 ng/ml or greater and increased 0.1 ng/ml or greater during the preceding 2 years), or biochemical failure (defined as nadir + 2). Multivariate analysis was done to identify predictors of failure used to create logistic regression models.
At a median followup of 89 months (range 37 to 199) prostate specific antigen was stable (nadir 0.03 ng/ml and at 60 months 0.04 ng/ml) in 2,004 patients (86%) and rising (nadir 0.16 ng/ml and at 60 months 0.29 ng/ml) in 145 (6%) while biochemical failure (nadir 0.51 ng/ml, p <0.001) was noted in 190 (8%). When there was no prior androgen deprivation therapy, the prostate specific antigen nadir and prostate specific antigen at 60 months were the strongest predictors of failure (OR 20.6 and 18.3, respectively, each p <0.0001). The logistic regression model had 85% sensitivity and 98% specificity, and predicted failure in 8 of 82 men (9.8%). A second model was created for the group with androgen deprivation therapy and rising prostate specific antigen using the predictive factors prostate specific antigen at 60 months (OR 53.9, p <0.0001) and T stage (OR 0.25, p = 0.0008). This model predicted biochemical failure in 30 of 56 men (54%) with 85% sensitivity and 93% specificity. The 2 predictive models yield an anticipated 90% cure rate in the entire cohort.
Brachytherapy is highly curative with stable prostate specific antigen at a surgical ablation level in 86% of patients. Rising prostate specific antigen is rare at a 6% incidence and often innocuous.
Development and internal validation of prediction models for biochemical failure and composite failure after focal salvage high intensity focused ultrasound for local radiorecurrent prostate cancer: Presentation of risk scores for individual patient prognoses
2018, Urologic Oncology: Seminars and Original Investigations
Citation Excerpt :
First and foremost, external validation of this model is necessary. The plan for this to occur will be once an on-going prospective multicentre trial has completed and matured [29]. Furthermore, the model is most likely only applicable in patients undergoing similar staging procedures, as MRI is necessary to obtain 3/5 parameters contained within the model.
Patient selection for focal salvage remains difficult. Therefore, we developed and internally validated prediction models for biochemical failure (BF) and a composite endpoint (CE) following focal salvage high intensity focused ultrasound (HIFU) for radiorecurrent prostate cancer.
A prospective HIFU registry identified 150 cases (November 2006–August 2015). Recurrence was assessed with multiparametric magnetic resonance imaging (MRI) combined with template prostate mapping biopsies, targeted biopsies, or systematic transrectal ultrasound-guided biopsies. Metastatic disease was ruled out with a positron emission tomography-computed tomography and a bone scan. Focal salvage HIFU consisted of quadrant-ablation, hemi-ablation, or index-lesion ablation. Cox-regression was used for BF (Phoenix-definition) and CE (BF/MRI+/biopsies+/local or systemic treatment/metastases+/prostate cancer specific mortality+). Internal validation was performed using bootstrap resampling (500 datasets) after which C-statistic and hazard ratios were adjusted. Models were calibrated and risk scores created.
Median follow-up was 35 months (interquartile range: 22–52). Median biochemical disease-free survival (DFS) was 33 months (95% CI: 23–45). Median CE-free survival was 24 months (95% CI: 21–35). After multivariable analysis, DFS interval after primary radiotherapy, presalvage prostate-specific antigen (PSA), PSA-doubling time, prostatic volume, and T-stage (both MRI based) predicted BF. For the CE, PSA-doubling time was not predictive but additionally, primary Gleason score was. The adjusted C-statistics were 0.68 and 0.64 for BF and CE, respectively. Calibration was accurate until 48 months. The risk scores showed 3 groups, with biochemical DFS of 60%, 35%, and 7% and CE-free survival of 40%, 24%, and 0% at 4 years.
Our model, once externally validated, could allow for better selection of patients for focal salvage HIFU.
Focal Ablation of Early-Stage Prostate Cancer: Candidate Selection, Treatment Guidance, and Assessment of Outcome
2017, Urologic Clinics of North America
Citation Excerpt :
There is a growing body of evidence, however, that treatment of the primary disease even in the presence of metastases may improve survival and focal ablation itself may also promote an antitumor immune response.31–34 Such a strategy is under investigation.35 A majority of evidence for the 7 modalities of focal therapy consists of early-phase studies up to stage 2b7 and more recently an RCT.8
Options for Salvage of Radiation Failures for Prostate Cancer
2017, Seminars in Radiation Oncology
Citation Excerpt :
The sensitivity for detecting bone lesions was higher with the WB-MRI (98% vs 86%, P < 0.04), but was similar in detecting enlarged lymph nodes. The use of WB-MRI is currently undergoing furthermore evaluation in clinical trials such as the FORECAST study (NCT01883128).27 Perhaps the most promising imaging tool for evaluation of biochemical recurrence (BCR) after definitive treatment is functional imaging using a small molecule ligand of prostate membrane-specific antigen (PSMA).
Biochemical failure after primary external beam radiotherapy for prostate cancer is common, and a significant proportion of these failures are due to local residual or recurrent disease. Early or delayed palliation using androgen deprivation therapy is the most common approach. Although a conservative approach is appropriate for many individuals, selected patients would benefit from retreatment with curative intent. We review the pertinent literature on salvage of locally recurrent prostate cancer after primary radiotherapy, including the modalities of surgery, cryotherapy, high-intensity focused ultrasound, or reirradiation with brachytherapy or stereotactic body radiotherapy. We discuss patient selection, outcomes, and toxicities. Patients with local recurrence and sufficient life expectancy, in the absence of metastatic disease, could be considered for local salvage. Although highly dependent on patient selection, the efficacy of the various salvage options seems comparable, with biochemical-recurrence-free survivals ranging approximately 50% at 5 years. The toxicity profiles differ, but all salvage treatments are more toxic than primary treatment. Management of isolated local failure after radiotherapy remains challenging. However, with the recent progress in salvage techniques, and more sensitive functional imaging for tumor localization and staging, salvage treatments are likely to play an increasingly important role.

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