High-dose-rate brachytherapy and hypofractionated external beam radiotherapy combined with long-term hormonal therapy for high-risk and very high-risk prostate cancer: outcomes after 5-year follow-up

The purpose of this study was to report the outcomes of high-dose-rate (HDR) brachytherapy and hypofractionated external beam radiotherapy (EBRT) combined with long-term androgen deprivation therapy (ADT) for National Comprehensive Cancer Network (NCCN) criteria-defined high-risk (HR) and very high-risk (VHR) prostate cancer. Data from 178 HR (n = 96, 54%) and VHR (n = 82, 46%) prostate cancer patients who underwent 192Ir-HDR brachytherapy and hypofractionated EBRT with long-term ADT between 2003 and 2008 were retrospectively analyzed. The mean dose to 90% of the planning target volume was 6.3 Gy/fraction of HDR brachytherapy. After five fractions of HDR treatment, EBRT with 10 fractions of 3 Gy was administered. All patients initially underwent ≥6 months of neoadjuvant ADT, and adjuvant ADT was continued for 36 months after EBRT. The median follow-up was 61 months (range, 25–94 months) from the start of radiotherapy. The 5-year biochemical non-evidence of disease, freedom from clinical failure and overall survival rates were 90.6% (HR, 97.8%; VHR, 81.9%), 95.2% (HR, 97.7%; VHR, 92.1%), and 96.9% (HR, 100%; VHR, 93.3%), respectively. The highest Radiation Therapy Oncology Group-defined late genitourinary toxicities were Grade 2 in 7.3% of patients and Grade 3 in 9.6%. The highest late gastrointestinal toxicities were Grade 2 in 2.8% of patients and Grade 3 in 0%. Although the 5-year outcome of this tri-modality approach seems favorable, further follow-up is necessary to validate clinical and survival advantages of this intensive approach compared with the standard EBRT approach.


INTRODUCTION
In the field of radiation oncology, the current strategy for treating high-risk prostate cancer is to combine external beam radiation therapy (EBRT) with long-term androgen deprivation therapy (ADT). Randomized trials have shown not only an improved biochemical control rate, but also an improved overall survival rate (OS) with this combination compared with radiation alone [1,2] or hormonal therapy alone [3].
Among modern radiotherapeutic techniques, brachytherapy is expected to provide an effective approach for delivering radiation doses more safely and precisely compared with 3D conformal radiotherapy or intensity-modulated radiotherapy [4]. In addition, hypofractionated radiotherapy may prove advantageous for treating prostate cancer when compared with other types of cancer, because of the low α:β ratio [5]. We have been treating prostate cancer patients with HDR brachytherapy combined with hypofractionated EBRT using a fractional dose of 3 Gy administered five times per week [6].
The purpose of this study was to report the long-term outcomes of HDR brachytherapy combined with hypofractionated EBRT with long-term ADT for localized prostate cancer.

Patients
The institutional review board approved this retrospective study. A total of 200 consecutive patients with National Comprehensive Cancer Network (NCCN) criteria-defined high-risk (HR) and very high-risk (VHR) prostate cancer were treated using HDR brachytherapy between December 2003 and January 2008. Clinical Stage T3a, a Gleason score of 8-10, and a prostate-specific antigen (PSA) level >20 ng/ ml were defined as HR factors. Clinical stage T3b-T4 was defined as the VHR factor. Patients with a single HR factor were classified as HR, and patients with at least the single VHR factor or two HR factors were classified as VHR. Pretreatment evaluation included clinical history, physical examination, blood laboratory findings, pelvic computed tomography (CT), and a bone scan. Magnetic resonance imaging (MRI) was recommended on request. No lymph node dissection was performed. Patients with positive lymph nodes or distant metastasis were excluded. International Prostate Symptom Score (IPSS), previous transurethral resection, and prostate volume were not considered in the selection criteria.
Of the 200 patients, 6 failed to complete the scheduled protocol, and another 16 were lost to follow-up. Analyses were thus performed for 178 of the 200 patients. Characteristics of these 178 patients are shown in Table 1.

Radiotherapy and hormonal therapy
All patients initially underwent ≥6 months (mean, 14 months; median, 12 months; range, 7-74 months) of neoadjuvant ADT, and adjuvant ADT was continued for 36 months after completion of radiotherapy. Neoadjuvant ADT comprised combined androgen blockade with monthly gonadotropin-releasing hormone agonist (GnRHa) injections and 125 mg of flutamide twice daily. Adjuvant ADT consisted of monthly injections of GnRHa. Briefly, patients in the operating room were placed in a lithotomy position under epidural anesthesia. Treatment was initiated using placement of a closed transperineal hollow needle under transrectal ultrasound guidance. Multiple 20-to 25-cm-long, closedend, 15-G plastic hollow needles were inserted transperineally using a Syed-Neblett plastic template (Alpha-Omega Services, Bellflower, CA). Routinely, 18 needles were implanted. Twelve needles were inserted in the peripheral portion and six needles were inserted in the central portion of the prostate. Flexible cystoscopy was conducted to check that the urethra had not been penetrated by the implanted tubes. The needle tips were left within the urinary bladder, 1.5 cm above the sonographically or cystoscopically defined base of the prostate. Metallic marker seeds were placed transperineally into the base and apex.
After all of these procedures had been completed, the patient underwent CT to obtain scans at 5-mm intervals for CT-based planning. Contours of the planning target volume (PTV), urethra and rectum were outlined according to transverse CT images. The PTV was defined as the prostate gland with or without proximal seminal vesicles, with an additional 3-to 5-mm margin all around. Reference points for the urethra were set on the center of the urethral catheter, and Values are number or median (range) PSA, prostate specific antigen; LNI, lymph-node involvement ADT; androgen deprivation therapy those for the rectal wall were set 5 mm behind the edge of the anterior rectal wall on transverse CT images with 10-mm intervals. Reference points for the PTV were automatically distributed on the surface of the PTV. Dose limitation was set as 10 Gy/fraction for urethral reference points and 4 Gy/ fraction for rectal reference points, and we attempted to prescribe 7.5 Gy/fraction to reference points of the PTV (unless the dose limitation was violated) using inverse planning and geometric optimization. Because of urethral and rectal dose limitations, covering the periphery of the PTV with the prescribed dose was difficult in some patients. The mean dose to 90% of the PTV (D90), the prostate volume receiving at least 6 Gy (V6), and the prostate volume receiving at least 9 Gy (V9) were 6.3 ± 0.6 Gy, 91 ± 5%, and 53 ± 9% per fraction, respectively. Five fractions of HDR treatment were administered. After CT-based planning using a Nucletron planning system (Veenendaal, the Netherlands), the first treatment session of HDR brachytherapy was conducted using the Nucletron microSelectron HDR 192 Ir remote afterloading system. Dwell positions were activated at 5-mm intervals along each catheter. The deepest dwell position could be set at 6.5 mm from the catheter tip if needed. Catheter positions were checked by fluoroscopy before every treatment session and corrected if interfraction needle movements >5 mm were noted. The first treatment session was conducted on the day of implantation, with the subsequent four treatment sessions administered twice daily with an interval of at least 6 h between fractions. Treatment duration was thus 3 days. At 6 days after completion of HDR brachytherapy, patients received EBRT using a dynamic-arc conformal technique, administered with high-energy photons comprising 10-MV X-rays to a total dose of 30 Gy. Total dose was administered in five weekly fraction doses of 3 Gy. The radiation field was limited to the prostate gland with or without proximal seminal vesicles with a 7-mm leaf margin using multileaf collimators.

Follow-up
Duration of follow-up was calculated from the start of HDR brachytherapy. Toxicities were evaluated using the Radiation Therapy Oncology Group scale [7] at every visit, and all patients were followed up at 3-month intervals during the first year and at 3-to 6-month intervals thereafter. Acute toxicity was defined as toxicity occurring ≤3 months after implantation and late toxicity as that occurring after >3 months. Median follow-up for all patients was 61 months (range, 25-94 months). Biochemical failure was defined according to the Phoenix definition [8]. Biochemical non-evidence of disease rate (bNED) was calculated for all living patients and reflected biochemical failures. Freedom from clinical failure rate (FFcF) was calculated for all living patients and reflected all clinical events (local, regional or distant failure) and salvage ADT. OS reflected all deaths, cancer-related or otherwise.

Efficacy
The with lung metastasis, 1 patient with distant lymph-node metastasis, 1 patient with regional lymph-node metastasis, 1 patient with positive biopsy, and 1 patient who underwent salvage ADT. Five patients died during follow-up including 1 patient who died of interstitial pneumonitis, 1 patient who died of bladder cancer, 2 patients who died of prostate cancer, and 1 patient who died due to an accident.
toxicities. The highest RTOG-defined late GU toxicities were Grade 2 in 13 patients (7.3%) and Grade 3 in 17 patients (9.6%). Most Grade 3 GU toxicities were urinary retention or urethral stricture, which were managed successfully by temporary catheterization or internal urethrotomy. The highest late GI toxicities were Grade 2 in 5 patients (2.8%). No patients showed Grade 3 toxicities. No patients experienced acute Grade 4 or 5 toxicity. Actuarial rates of late GU toxicity are shown in Fig. 2. Table 2 shows the results of uni-and multivariate analyses for factors predicting bNED and FFcF. On univariate analysis, clinical T stage, Gleason score and NCCN risk-group were detected as predictive factors for bNED. Clinical T stage, NCCN risk-group and prostate volume were significant predictors for FFcF. On multivariate analysis, however, no risk factor reached the level of statistical significance.

DISCUSSION
With more than 5 years of follow-up, HDR and hypofractionated EBRT combined with long-term ADT produced encouraging results. Even with VHR patients, a 5-year bNED of 81.9% could be achieved with this combination.
On the other hand, Japanese-specific high-sensitivity to hormonal therapy may have some impacts on our outcomes [26]. Table 4 shows selected Japanese series of high-risk prostate cancer patients treated with conventional EBRT and     [27][28][29][30][31]. These favorable outcomes seem to be equal to our HDR approach. From the data of the 5-year follow up, it seems that our tri-modality therapy did not show any advantages over conventional EBRT with hormonal therapy. Regarding late toxicities, 9.6% of our patients suffered from Grade 3 urethral toxicities after treatment. Meanwhile, the incidence of Grade 3 toxicity after EBRT was very rare [28]. HDR brachytherapy is associated with relatively severe GU toxicities, such as urethral stricture [11,23,24,32]. Although the severity of GU toxicities in our study population was relatively high, all cases were manageable by medical or surgical intervention. Compared with patients (n = 298) treated before June 2008 when more strict urethral dose limitation was applied, the patients treated after that month (n = 279) show a significantly lower rate of Grade 3 late GU toxicity (11% vs 1%), although follow-up duration for the latter group was immature (54 months vs 30 months). Detailed data about updated DVH analysis is planned for publication in another study.
Although the data for ADT toxicities were not available in our study, ADT may lead to numerous toxicities, such as osteoporosis, obesity, sarcopenia, lipid alterations, insulin resistance, and increased risk for diabetes and cardiovascular morbidity [33]. These potential side-effects may reduce quality of life and overall survival. Combining ADT with EBRT is warranted because it will improve overall survival in high-risk patients [1]. However, there has been no randomized trial of the combination of ADT and HDR brachytherapy. Further trial is needed for exploring whether ADT really improves overall survival when it is combined with HDR brachytherapy.
Without whole pelvic irradiation, only 1 patient in our study population showed regional lymph node recurrence. The probability of lymph node involvement based on the Roach equation [34] was >30% for half of our patients. It is generally considered that whole pelvic irradiation may have potential benefit for these HR patients [35]. In our population, however, potential lymph-node metastasis was controlled by ADT alone, without irradiation. Unknown mechanisms and/or tumor-specific immune responses such as cytotoxic T lymphocyte (CTL) activity might be evoked through our protocol, although this remains to be established [36,37].
Several limitations must be considered when interpreting the results of this study. First, our protocol did not apply a uniform duration of neoadjuvant ADT. Many of our patients had been on waiting lists for >6 months because of our limited capacity; they were treated with ADT while on the waiting list, and half of our patients received neoadjuvant ADT for ≥12 months. Second, the lack of testosterone data may confound the interpretation of the bNED results. After long-term ADT, delays in PSA recovery may lead to delays in biochemical failure. Third, our median follow-up of 61 months may have been insufficient, considering the provision of long-term

CONCLUSION
Although the 5-year outcome of this tri-modality approach seems favorable, further follow-up is necessary to validate clinical and survival advantages of this intensive approach compared with the standard EBRT approach.

FUNDING
This work was supported by JSPS KAKENHI Grant Number 24791334.