MRI evaluation following partial HIFU therapy for localized prostate cancer: A single-center study

25 septembre 2016

Auteurs : L. Hoquetis, B. Malavaud, X. Game, J.B. Beauval, D. Portalez, M. Soulie, P. Rischmann
Référence : Prog Urol, 2016, 9, 26, 517-523




 




Introduction


The goal of focal PCa therapy is the maintenance of patient QoL without compromising life expectancy, by index tumor destruction and preservation of non-malignant prostatic and normal adjacent tissue in order to limit erectile dysfunction and urinary incontinence [1].


European guidelines recommend TRUS biopsies after focal therapy [2] but it is not realized in all studies as revealed in the latest systematic review of focal therapy [3].


While randomized biopsies may miss any tumor resurgence, targeted biopsies have good sensitivity [4, 5, 6].


The primary objective of this study was to evaluate the utility of MRI in cancer control monitoring following hemi-HIFU therapy of localized PCa. Secondary objectives were to study changes in prostate morphology induced by HIFU, and to evaluate the safety and efficacy of hemi-HIFU therapy in localized PCa.


Materials and methods


Population


Patients were treated into the current study from October 2009 to March 2014 in an academic hospital.


They must meet the following inclusion criteria: age<80 years old; unifocal or multifocal localized PCa (clinical stage≤T2N0M0); PSA<15ng/mL; Gleason score≤7 and no grade 4 predominant; no prior local or systemic treatment of prostate cancer; and no contraindications to MRI.


The clinical stage was assigned according to the 2002 TNM staging system, prostate biopsy cores were obtained under transrectal ultrasound guidance, using a 12-core biopsy protocol, and pretreatment PSA was measured before digital rectal examination. Dedicated genitourinary pathologists assessed biopsy grading according to the modified ISUP Gleason score.


Systematic TURP before HIFU was realized except if patient had prostate volume less than 40mL and no LUTS (defined by IPSS<7).


MRI localization and definition of target tumor volume


Data obtained by baseline MRI included prostate volume, lesion characteristics, ESUR score, and detection of incidental lesion.


Unilateral dominant tumor, defined by the index lesion, was measured by length and width, and volume estimated using the ellipsoid formula (L×l2×0.53). Accessories lesions were measured by the same way. The Dickinson 27 Sectors definition was applied to determine spatial characteristics of the lesion [7]. The therapeutic index was defined as the ratio of MRI-measured treated volume to tumor volume (mL). All MRI images were analyzed by a single uroradiologist with expertise in prostate MRI interpretation.


Partial HIFU


We used the definition of Ahmed et al. [1] to characterize partial prostate treatment as treatment of one-half or two-thirds of the gland. Ablatherm (EDAP-TMS, Vaux-en-Velin, France) technique was used. Treatment was realized with total anesthesia, and a security limit defined by 1mm above the prostatic apex.


Peri- and postoperative data were obtained from the surgery report and the hospital discharge.


Post-HIFU evaluation


Patients were evaluated during post-HIFU follow-up with digital rectal examination (DRE) and PSA measurement every 3 months, and control mpMRI at 6 months.


Randomized control biopsies were done except if a target was seen. If so, targeted biopsies were performed.


Biochemical assessment


Serum PSA levels were obtained at baseline, and throughout patient follow-up. The following PSA parameters were evaluated.


Biochemical disease-free survival used the Phoenix definition of biochemical failure [8]. PSA density (PSAd) measured the persistence of untreated prostatic tissue, calculated by the ratio of post-HIFU (±TURP) PSA level to residual tissue volume measured by control MRI.


Morphology assessment


Control MRI was used for assessing changes in prostate morphology following HIFU, and were assessed by pre- and post-HIFU prostate volume; evaluation of capsular retraction or development of peri-prostatic fibrosis; and determination of apex sparing.


The radiologist reviewing all post-treatment MRI images was blinded to the operative report.


Side effects


Erectile function and continency were evaluated every 3 months during follow-up.


Statistical analysis


Conventional descriptive statistics were used to summarize demographic and clinical data. Group comparisons were analyzed using the Pearson Chi2 test, and comparisons of qualitative variables were performed using the Fisher exact test.


The Spearman rank test was used to assess the correlation Statistical analysis was performed using DM 90® software.


Patients' informed consent was not obtained.


Results


Baseline measurements


Clinical characteristics


Twenty-five patients were evaluated in this study. At baseline, patients had a mean age of 66.6±7.2 years old and PSA: 6.1±2.0ng/mL. Tumor characteristics included clinical stage T1c in 68% (n =17) and T2a in 32% (n =8); Gleason score was 6 (3+3) in 76% (n =19) and 7 (3+4) in 24% (n =6). Multifocal tumor was found in 28% of patients.


Patients were followed a median 21.2±16.8 months, and 18 patients met PRIAS criteria for AS [9]. Summaries of the study population clinical characteristics are shown in Table 1 and tumor characteristics in Table 2.


MRI characteristics


Initial diagnostic MRI was performed in all patients. A single target was found in 20 patients, 2 targets were found in 5 patients. The index lesion was detected in one sector in 19 cases, and 2 sectors in 6 cases. The total number of sectors with MRI-visible lesion was 30.


Targeted tumor volume


MRI pre-HIFU tumor volumes ranged from 0.004mL to 0.9mL. Tumor volume<0.5mL was found in 20 patients.


The targeted tumor volume on initial MRI was correlated with tumor aggressiveness, Gleason score (P <0.01).


The relative risk of Gleason score 7 (3+4) tumor with MRI-measured tumor volume>0.5mL was 4.38.


HIFU treatment


Fourteen patients had a half-gland treatment and 11 patients two third of the gland.


Post-HIFU outcomes


Histological results


Control biopsies were performed in all patients at a median time of 7.44±6.6 months. No malignancies were found in treated prostate areas, and contralateral tumor was found in four patients, for a positive contralateral tumor rate at follow-up of 16%. All contralateral tumors were GS 6, showed one positive biopsy core, and a tumor length from 2 to 5mm. Management of contralateral tumors consisted of a second HIFU session (n =2) and AS (n =2). Final PSA levels in these patients ranged from 0.1 to 1.0ng/mL.


Biochemical results


Median values found the initial PSA 6.13±2.5ng/mL, PSA nadir 1.45±1.4ng/mL, and final PSA 1.8±1.9ng/mL.


Mean values found the initial PSA 6.1ng/mL, PSA nadir 1.72ng/mL and final PSA 2.36ng/mL.


Post-treatment PSA evolution decreased until reaching nadir PSA, the mean evolution of PSA corresponded to initial PSA divided by 3.54.


Biochemical failure occurred in three patients by last follow-up. PSA values in these patients were 4.55, 5.35, and 6.5ng/mL; and PSA nadir was 1.5, 3.3, and 4.1ng/mL, respectively. Results from biopsy and MRI imaging following biochemical failure were negative for tumors or lesions in all 3 patients.


At last follow-up, twelve patients had PSA density (PSAd)≥0.1ng/mL2.


PSAd was a significant predictor of contralateral tumor (Fisher's exact test; P =0.042); all four patients with contralateral tumor had PSAd≥0.1ng/mL2.


Control MRI


Control mpMRI images were obtained at a median time of 15.4±17.2 (range: 1.2-48) months following HIFU.


With MRI-targeted biopsy using the Koelis system, an MRI target with ESUR score 10/15 was biopsied and no tumor was found. In another patient, an MRI target with a 5/15 ESUR score was found in a treated area, but the patient had already undergone control randomized biopsies with negative results and no guided biopsy was therefore performed.


Morphologic changes


As measured by initial and control MRI, the median initial and post-HIFU prostate volumes were 45.0mL (20-100) and 25.3mL (5-52), respectively, indicating the post-treatment volume was 56% of the initial volume after TURP and HIFU.


Evaluation for each patient of index and associated tumor localization and estimated volume by initial MRI; percentage of treated gland, and the presence and volume of targets with ≥9 ESUR score by control MRI are shown in Table 3.


Side effects


The most frequent HIFU-related morbidities were mild urinary incontinence persisting less than 6 months (n =2), and erectile dysfunction requiring PDE-5 inhibitor therapy (n =4) (Clavien grade 2). Throughout follow-up, no patient experienced urinary retention, urinary tract infection, serious adverse events, or recto-urethral fistula.


Discussion


Over the past decade, the potential of focal therapy to provide cancer control and limit morbidity has been recognized. The inability to accurately localize and characterize tumors has imposed barriers to clinical use. With availability of multiparametric MRI (mpMRI) methods and direction for its optimal application, focal therapy has recently become a feasible alternative to radical therapy and AS for localized PCa.


Study population


We found pre-HIFU tumor volume significantly correlated with tumor aggressiveness (reflected by Gleason score). Several previous studies have reported a correlation between tumor aggressiveness and volume≥0.5mL. In 131 patients imaged with mpMRI prior to RP, tumor volume>0.5mL was significantly associated with Gleason score≥7 (P =0.0033) [10]. Similarly, Styles et al. [11] and Karademir et al. [12] reported identical correlations in two retrospective RP series with smaller samples (n =38 and n =61, respectively).


Cancer control outcomes


Biochemical


In the present study, the mean PSA nadir of initial PSA divided by 3.54 was in line with post-treatment PSA decreases reported in other recent focal therapy studies. Mean PSA nadir values from two focal cryotherapy studies were initial PSA divided by 2.6 and 2.3, respectively [13, 14]. A focal HIFU therapy trial of 42 patients reported a nadir PSA value of median initial PSA divided by 3.5 [1], while a recently published focal HIFU therapy trial of 56 patients with sole ablation of the index lesion showed median PSA values of 7.4ng/mL at baseline and a 2.4ng/mL nadir [15].


The predictive value of nadir PSA has been demonstrated in radical HIFU therapy studies, with two trials finding PSA nadir significantly predictive of PSA failure on multivariate analysis [16, 17]. Data analysis from a larger radical HIFU study [18] found PSA nadir≤1.0ng/mL a significant predictive factor for freedom from disease progression (P <0.001).


Histological


We found a positive contralateral tumor rate of 16%. Focal PCa therapy is based on the principle of preserving non-cancerous prostatic and surrounding tissue, to maintain their respective functional levels. Radical prostatectomy studies have found multifocal PCa rates of 50-76% [19, 20]. More recently introduced have been the concepts of "index" and "secondary" tumor [21, 22], and differentiating features such as index lesions accounting for 80% of total tumor volume and 90% of extra-prostatic extensions. Secondary tumor presence and volume are believed by some researchers to have negligible impact on biochemical recurrence after RP [23].


MRI outcomes


Consistent with our control biopsy findings, control MRI did not identify tumor recurrence in treated areas, giving control mpMRI a negative predictive value of 100% for detecting residual tumor in treated areas following focal HIFU therapy. Four tumors in untreated areas confirmed by control biopsy were not detected, giving control mpMRI a negative predictive value of 81% for detection of residual tumor in untreated areas. In a study of 15 patients receiving MRI at 1 and 6 months following radical HIFU therapy, MRI tumor visualization was not possible in 4 of 5 patients with biopsy-confirmed recurrence [24]. This study used 1.5T MRI with T2 sequences and DCE. Technological refinements and strong direction for optimal use of mpMRI [7, 25] after this study was published may explain the better results of our study.


The reduction of prostate volume after treatment, which is measured at 56% of pretreatment volume may be mainly distorted by TURP but reflects the objective of providing a hemi treatment.


In our analysis of PSAd kinetics, all 4 patients with contralateral tumor detected by control biopsy showed PSAd≥0.1ng/mL2, and PSAd≥0.1ng/mL2 was significantly predictive of contralateral tumor (P =0.042). PSA density was suggested as a predictor of localized tumor recurrence as early as 1994 [21] and confirmed in 2005 by the ERSPC trial [26], showing that PSAd cut-off≤0.1ng/mL2 predicted organ-confined tumor <0.5mL in 94% of patients (P <0001).


We demonstrated a significant relationship between PSAd≥0.1ng/mL2 and contralateral tumor recurrence despite our small sample size, and encourage others to assess for PSAd increase≥0.1ng/mL2 following focal HIFU therapy. A study of 26 patients who received radical HIFU therapy compared dynamic contrast-enhanced (DCE) MRI with serial PSA for detecting post-HIFU residual disease. Three radiologists interpreted the MRI images. The sensitivity and specificity for MRI was 73-87% and 73-82%, respectively; and for PSA nadir >0.2ng/mL, 73% and 100%, respectively [27].


We found negative MRI at 6-month follow-up confirmatory of cancer control.


Biopsy should be performed of any lesion identified by control MRI, optimally using an MRI-ultrasound fusion device. Patients with apparent absence of lesion on control MRI can be monitored for cancer control by serial PSA levels to avoid systematic biopsies, with biopsy reserved for patients showing PSAd≥0.1ng/mL2. Our results indicate that limiting control biopsy to patients with PSAd≥0.1ng/mL2 would have spared our patients 13 control biopsies and reduced overall biopsies by 44%.


Our results should be interpreted with consideration of several limitations. These include the small sample size, brief follow-up period, retrospective study.


Further studies should be performed in order to confirm our results.


Conclusion


Focal therapy is now an alternative management option for patients with localized PCa. The effect of hemi-HIFU therapy on prostate morphology was characterized using mpMRI, which showed devascularization and atrophy with increasing intensity over time until roughly 6 months post-treatment; and also showed an average 61% decrease in prostate volume after treatment. We found the negative predictive value of mpMRI for tumor recurrence was 100% in treated areas and 84% in untreated areas, and that a post-treatment PSAd value ≥0.1ng/mL2 was a predictor of contralateral tumor (P =0.042).


These results suggest that mpMRI could, in the near future, replace control biopsies for cancer control monitoring after hemi-HIFU therapy. Control biopsy would be indicated if PSAd ≥0.1ng/mL2, or MRI-guided biopsy if a target was identified by control mpMRI. Longer patient follow-up is needed to evaluate the durability results with hemi-HIFU as first-line therapy in patients with low- and intermediate-risk localized PCa.


Disclosure of interest


The authors declare that they have no competing interest.




Table 1 - Clinical characteristics of the population.
  Mean (min-max)  Median±SD 
Age (years)  66.0 (52-80)  66.4±7.3 
PSA (ng/mL)  6.13 (3.1-13)  5.7±2.5 
Prostatic volume (mL)  46 (20-109)  40±22 
PSAd (ng/mL2 0.15 (0.05-0.38)  0.14±0.05 
Length of hospitalization (days)  3.0 (1-5)  3±0.9 
Time for urethral catheter (days)  4.7 (2-10)  3±3.07 
Follow-up (months)  25.1 (6-73)  21.2±16 





Table 2 - Tumor characteristics.
  Population (%) 
TNM    
T1c  17 (68) 
T2a  8 (32) 
Localization (cores)    
Apex 
Middle  14 
Base 
Unifocal tumor  16 (72) 
Multifocal tumor  7 (28) 
Gleason score    
6 (3+3)  19 (76) 
7 (3+4)  6 (24) 
Total tumor length    
<3mm  11 
Between 3mm et 10mm 
>10mm 
NC 





Table 3 - Results of MRI evaluation before and after HIFU.
  Initial MRI 
Control MRI 
  Index target 
Associated target 
Atrophic volume (%)  Therapeutic index  Target 
  Sector  Volume (mL)  Sector  Volume (mL)      Sector  Volume (mL) 
Patient 1  4p  0.172      88.98  181 
Patient 2  10p  0.21  4p  0.119  10.24  25 
Patient 3  10p9p  0.159      26.48  98 
Patient 4  4p  0.153      7.35  26 
Patient 5  4p  0.076  10p  0.033  76.78  513 
Patient 6  4p  0.373      28.54  50 
Patient 7  7p9p  0.901      44.49  20 
Patient 8  10p  0.898      28.84  26 
Patient 9  4p  0.373      44.49  119 
Patient 10  9p10p  0.312  3p  0.339  44.49  50 
Patient 11  9p10p  0.954      69.19  26 
Patient 12  6a  0.386      32.3  33 
Patient 13  7p8p  0.364      44.49  32 
Patient 14  10p  0.795      44.49  21 
Patient 15  7p  0.407      20.18  23 
Patient 16  3a14as  0.127  5p  0.08  75.13  213 
Patient 17  10p  0.305      44.49  52 
Patient 18  3p  0.441      44.49  44 
Patient 19  8p  0.042      34.03  193 
Patient 20  3p  0.019      26.07  273 
Patient 21  10p  0.004      10.24  603 
Patient 22  3a  0.687      88.98  26 
Patient 23  9p  0.153      30.49  110 
Patient 24  2p  0.373      20.18  17 
Patient 25  3p  0.47  12p  0.08  20.93  287  3p4p  2.078 




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