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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 1  |  Page : 406-410

Feasibility of brachytherapy as monotherapy for high-volume, low-risk prostate cancer


1 Department of Radiation Oncology, Johns Hopkins Hospital, Baltimore, MD, USA
2 Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, USA
3 Department of Urology, Saint Anne's Hospital, Fall River, MA, USA
4 Department of Radiation Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA

Date of Web Publication13-Apr-2016

Correspondence Address:
Mark D Hurwitz
Bodine Center, Suite G-301, 111 South 11th Street, Philadelphia, PA 19107
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.180083

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 > Abstract 

Background: We sought to determine whether patients with high-volume, low-risk prostate cancer are suitable candidates for ultrasound-guided brachytherapy, monotherapy alone, without supplemental external beam radiation. Materials and Methods: The study cohort comprised 200 consecutive patients who received ultrasound.guided monotherapy from November 02, 1998 to March 26, 2010. Real.time intraoperative treatment planning was performed for all patients. 145. Gy with I125 was prescribed to the prostate with no margin. The primary endpoint was time to prostate-specific antigen. (PSA) failure using the phoenix definition. Cox multivariable regression analysis was used to determine the factors significantly associated with time to PSA failure. Results: Median follow-up was 59 months (range 1.2–146.8 months). The median PSA was 5.0 ng/ml. For the overall cohort, both 5- and 8-year PSA failure-free survival was 92.3% (95% confidence interval [95% CI]: 86.5–95.7%). Low-risk patients per the NCCN criteria had 5- and 8-year PSA failure-free survival of 93.6%. On cox multivariable analysis, only baseline PSA (adjusted hazard ratio: 1.29 [95% CI: 1.02–1.65], P = 0.036) was associated with outcome. Among patients with <33% cores positive, 33–<50% cores positive, and ≥50% cores positive, the 5-year PSA failure-free survival was 92.3% (95% CI: 85.1–96.1%), 91.0% (95% CI: 68.5–97.6%), and 93.3% (95% CI: 61.2–99.0%), respectively. Conclusions: Our analysis indicates that patients with a high number of cores positive for cancer can be adequately treated with modern brachytherapy as monotherapy and be spared the additional morbidity and cost of supplemental external beam radiation or androgen deprivation therapy.

Keywords: Brachytherapy, percent positive cores, prognostic factors, prostate, prostate-specific antigen


How to cite this article:
Parekh A, Nguyen PL, West LJ, Duarte C, Graham PL, Larock DR, Yeung V, Hurwitz MD. Feasibility of brachytherapy as monotherapy for high-volume, low-risk prostate cancer. J Can Res Ther 2016;12:406-10

How to cite this URL:
Parekh A, Nguyen PL, West LJ, Duarte C, Graham PL, Larock DR, Yeung V, Hurwitz MD. Feasibility of brachytherapy as monotherapy for high-volume, low-risk prostate cancer. J Can Res Ther [serial online] 2016 [cited 2019 Nov 23];12:406-10. Available from: http://www.cancerjournal.net/text.asp?2016/12/1/406/180083




 > Introduction Top


Current guidelines state that men with low-risk prostate cancer based on having clinical T1c or T2a, Gleason ≤6, and prostate-specific antigen (PSA) <10 diseases are suitable candidates for brachytherapy monotherapy.[1],[2] However, based on prior data that men with a high number of cores positive for cancer, face a greater risk of adverse prostate cancer outcomes, many practitioners are reluctant to offer brachytherapy monotherapy for patients with ≥50% cores.[3],[4] We sought to determine whether modern brachytherapy monotherapy, as delivered in a community setting, could be a feasible treatment option for men with low-risk but high-volume prostate cancer.


 > Materials and Methods Top


Ethics

The study was approved by our Institutional Review Board.

Patient selection

The study cohort consisted of 200 consecutive patients who were treated with ultrasound-guided transperineal permanent prostate brachytherapy monotherapy from November 02, 1998 to March 26, 2010. All implants were performed by a radiation oncologist and urologist. Real-time intraoperative treatment planning was performed for all patients. Biplanar ultrasound and fluoroscopic guidance were used to assist with needle placement. 145 Gy with I 125 was prescribed to the prostate with no margin, thus restricting the planning target volume to the clinical target volume.

Endpoints and statistical analysis

The primary endpoint of our study was time to PSA failure. Biochemical failure was defined using the phoenix definition (i.e., nadir + 2 or initiation of salvage androgen deprivation therapy [ADT]).

Univariable and multivariable cox regression was used to determine factors that are associated with PSA failure. Continuous variables in the analysis included time to failure and baseline PSA. Categorical variables included Gleason score, and whether percent positive cores were <33%, 33–<50%, or ≥50%.

For the multivariable analysis, we were not able to include T-category because there were no events among the patients with T2a disease. Adjusted hazard ratios and 95% confidence intervals (95% CIs) were reported for the covariates, and P < 0.05 was used as a cut-off to indicate significance. For the purpose of illustration, Kaplan–Meier analysis was used to estimate the PSA failure-free survival, stratified by variables of interest.

Intercooled Stata 8.0, StataCorp, College Station, TX, the USA, for Windows was used to perform all statistical analyses.


 > Results Top


Patient baseline characteristics

Median follow-up was 59 months (range 1.2–146.8 months). The median PSA was 5.0 ng/ml. The cohort included 3% of patients who were Gleason <6, 90% Gleason 6, and 7% Gleason 3 + 4 = 7. There were 163 and 37 patients classified as T1c and T2a, respectively [Table 1]. One hundred eighty-one patients (90.5%) and 19 patients (9.5%) of patients were classified as low- and intermediate-risk respectively, per NCCN guidelines.
Table 1: Baseline patient characteristics

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Prostate-specific antigen failure-free survival

For the overall cohort, 5-year PSA failure-free survival was 92.3% (95% CI: 86.5–95.7%), and 8-year was 92.3% (95% CI: 86.5–95.7%). Two additional failures were noted with longer-term follow-up beyond 8 years however most failures occurred within 5 years. One patient who was scored as a treatment failure per the phoenix definition had a peak PSA level of 2.7 ng/ml, with subsequent decline in PSA which stabilized under 1 ng/ml, with 2 years of additional follow-up.

Factors associated with outcome

On univariable analysis, only baseline PSA was significantly associated with outcome (hazard ratio 1.29 [95% CI: 1.02–1.65], P = 0.031). Patients with a PSA ≤10 had a 5- and 8-year PSA failure-free survival rate of 93.6% (95% CI: 87.9–96.6%), as compared to 55.5% (95% CI: 73.4–87.6%) at 5- and 8-year for those with a PSA <10 at baseline [Figure 1]. Those with low-risk prostate cancer had 5- and 8-year PSA failure-free survival rates of 93.6% (95% CI: 87.6–96.8%), whereas those with intermediate-risk disease, had PSA failure-free survival rates of 80.8% (95% CI: 50.5–93.5%).
Figure 1: Failure-free survival and prostate-specific antigen

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Of note, percent of cores positive was not significantly associated with outcome. Specifically, among patients with <33% cores positive (n = 159), 33–<50% cores positive (n = 26), and ≥0% cores positive (n = 15), the 5-year PSA failure-free survival was 92.3% (95% CI: 85.1–96.1%), 91.0% (95% CI: 68.5–97.6%), and 93.3% (95% CI: 61.2–99.0%), respectively as illustrated in [Figure 2].
Figure 2: Failure-free survival and percent positive cores

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On Cox multivariable analysis, only baseline PSA was significantly associated with failure rates [Table 2]. The percentage of positive cores and Gleason score were not associated with failure rate. In addition, patients with 33–<50% cores and ≥50% cores positive did not have significantly higher failure rates compared to those with <33% positive biopsies (hazard ratio for 33–<50% cores vs. <33% = 1.02 [95% CI: 0.22–473], P = 0.97; hazard ratio for ≥50% vs. <33% = 0.868 [95% CI: 0.10–6.89], P = 0.109).
Table 2: Cox regression analysis

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 > Discussion Top


In this analysis, we assessed results of brachytherapy monotherapy in a community setting to determine whether percent of positive cores should be used as selection criteria for men considering monotherapy. We found that in this cohort of men with mainly low- and favorable-intermediate-risk disease receiving modern brachytherapy, only baseline PSA was associated with outcome, and percentage of cores positive for cancer was not a significant adverse prognostic factor. Specifically, the 5-year PSA failure-free survival for men with <33% cores positive, 33–<50% cores positive, and ≥50% cores positive was 92.3%, 91.0%, and 93.3%, respectively. Our data suggest that for men with low or favorable intermediate-risk prostate cancer, modern brachytherapy monotherapy provides an effective treatment regardless of the percentage of cores positive for tumor.

Currently, both the NCCN guidelines and the American Brachytherapy Society guidelines state that brachytherapy monotherapy is appropriate for all men with low-risk prostate cancer (i.e., cT1c or T2a, PSA <10, and Gleason 6), but in practice, it is common for practitioners to add additional therapy for men with a high percentage of cores positive (e.g., <50%) out of concern that this portends high-volume disease that may not be curable with brachytherapy alone.[1],[2] An additional concern is that due to dose heterogeneity in the prostate, “cold spots” due to suboptimal brachytherapy seed placement may increase the risk of local recurrence in men with extensive disease within the prostate. A physician survey conducted by Frank et al. on patterns of care with respect to brachytherapy found that expert genitourinary radiation oncologists were hesitant to use brachytherapy alone with high-volume disease.[4] For example, the survey found that up to 90% of physicians would add external beam radiation therapy (EBRT) to brachytherapy implants in patients with 50% biopsy cores positive and either Gleason 7 (3 + 4) or serum PSA between 10 and 20 ng/ml.[4]

The weight that practitioners place on percent positive cores as a prognostic factor is illustrated in a current clinical trial RTOG 0924, which assesses the role of ADT and pelvic radiation for unfavorable intermediate-risk or high-risk patients. In addition, to the risk of lymph node involvement and other intermediate or high-risk factors, patients with Gleason score 6+ >50% biopsies are eligible. Our results suggest that patients with Gleason 6 and <50% positive cores may not require such extensive treatment and could do well with high-quality brachytherapy implants to the prostate alone, thereby avoiding the additional morbidity of ADT and supplemental external beam radiation as well as significantly lowering the cost of therapy.[5],[6],[7],[8],[9] This finding is plausible for a number of reasons. First, patients with low-grade prostate cancer rarely develop metastases; therefore, Gleason 6 tumors with a high number of cores positive likely represent high-volume localized disease.[10] With modern attention to treatment planning and postoperative dosimetry, brachytherapy can provide excellent coverage to the entire prostate, often with ≥150% of the dose going to areas of known tumor in the peripheral zone, which may be more than adequate to eliminate high-volume localized disease. In addition, Davis et al. have shown that men with low-risk prostate cancer typically have at most 3 mm of extracapsular extension at prostatectomy, and brachytherapy can often deliver tumoricidal doses to about 5 mm beyond the capsule.[11]

The presence of controversy regarding the predictive value of percent positive cores; however, must be acknowledged. Many studies have investigated the use of percent positive cores in predicting PSA failure-free survival in EBRT [12],[13],[14],[15],[16] and brachytherapy [17],[18],[19] with some studies demonstrating prognostic significance while others do not.

Similar to our findings, in a study done by Merrick et al. there was no clinical significance found to percent positive cores with regards to 5-year biochemical free survival. No significant difference was found in failure rate between those with <34%, 34–50%, or <50% positive cores, and they concluded that this was a result of dose escalation achieved with seed implants not easily achieved with other radiation modalities.[20] Merrick et al. also found in a randomized controlled trial of 20 versus 44 Gy supplemental EBRT for intermediate to high-risk disease following brachytherapy that overall survival was equivalent.[21] This suggests that high-quality brachytherapy makes supplemental EBRT less important, even for unfavorable risk disease.

On the other hand, Guzzo et al. for example, retrospectively evaluated patients who received brachytherapy for factors that predicted biochemical failure, including prebrachytherapy PSA, percent positive prostate needle biopsies, and biopsy Gleason score.[22] They found a significant association between biochemical failure and percent positive biopsies above the median, 27%. Of note, dichotomization using the Guzzo cutoff of 27% positive biopsies was neither significant in our cohort nor dichotomization using our median percent positive biopsies of 16.7%. Additional studies will be needed to help resolve this controversy.

The lack of consensus regarding the predictive value of percent positive cores is similar to the diversity of practice seen with perineural invasion (PNI). Although the association between PNI and biochemical failure after EBRT has been demonstrated in some studies, the prognostic role of PNI in the context of brachytherapy is less clear.[23],[24],[25] Piña et al. reported excellent biochemical control in men treated with I 125 interstitial implants, with a 5-year actuarial rate of 92.9%, and the authors suggest that a biopsy positive for PNI should not preclude the possibility of brachytherapy for treatment, again potentially reflecting the ability of brachytherapy monotherapy to deliver very high tumorical doses to within the prostate and a few millimeters beyond it.[23] On the other hand, Ding et al. demonstrated a 6 times increase in biochemical failure in PNI positive patients treated with permanent seed prostate brachytherapy, suggesting a benefit of EBRT in these patients.[24],[25] This controversy remains to be delineated in larger studies.

There are some points however that deserve consideration in our study. Our findings are based on a patient population in which few had high-volume disease. Out of our cohort of 200 patients, only 20% of the patients had 33% or more of their cores positive, which somewhat limits the ability to detect a difference due to the percent of cores positive. Furthermore, the median follow-up was 59 months, and it is possible that greater differences in outcome may emerge over time although most failures occurred within 5 years. A study that includes a larger percentage of patients with high-volume and low-risk disease as well as longer follow-up will add value to the current literature and help elucidate the prognostic value of percent positive cores on biopsy even further.


 > Conclusions Top


In summary, our study suggests that with a high-quality implant and escalated-dose achievable with brachytherapy, there was no association between percent positive cores on biopsy and biochemical failure. Thus, it demonstrates that contrary to conventional practice by many physicians, patients with high-volume disease may be successfully implanted with brachytherapy alone.[4] If these results are validated in larger series, men with high-volume, low-risk disease can be treated with brachytherapy monotherapy and can avoid the morbidity and cost of supplemental therapies that may not be needed. In addition, it is important to consider the emerging data that continues to support the use of high-dose rate (HDR) monotherapy, with the theoretical advantage of more consistent implant quality and lower acute and late toxicity.[26] However, longer follow-up is needed to fully define the role of HDR monotherapy.[27]

Financial support and sponsorship

Nil

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Mohler J, Bahnson RR, Boston B, Busby JE, D'Amico A, Eastham JA, et al. NCCN clinical practice guidelines in oncology: Prostate cancer. J Natl Compr Canc Netw 2010;8:162-200.  Back to cited text no. 1
    
2.
Nag S, Beyer D, Friedland J, Grimm P, Nath R. American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 1999;44:789-99.  Back to cited text no. 2
    
3.
D'Amico AV, Whittington R, Malkowicz SB, Schultz D, Fondurulia J, Chen MH, et al. Clinical utility of the percentage of positive prostate biopsies in defining biochemical outcome after radical prostatectomy for patients with clinically localized prostate cancer. J Clin Oncol 2000;18:1164-72.  Back to cited text no. 3
    
4.
Frank SJ, Grimm PD, Sylvester JE, Merrick GS, Davis BJ, Zietman A, et al. Interstitial implant alone or in combination with external beam radiation therapy for intermediate-risk prostate cancer: A survey of practice patterns in the United States. Brachytherapy 2007;6:2-8.  Back to cited text no. 4
    
5.
Saylor PJ, Smith MR. Adverse effects of androgen deprivation therapy: Defining the problem and promoting health among men with prostate cancer. J Natl Compr Canc Netw 2010;8:211-23.  Back to cited text no. 5
    
6.
Albert M, Tempany CM, Schultz D, Chen MH, Cormack RA, Kumar S, et al. Late genitourinary and gastrointestinal toxicity after magnetic resonance image-guided prostate brachytherapy with or without neoadjuvant external beam radiation therapy. Cancer 2003;98:949-54.  Back to cited text no. 6
    
7.
Stone NN, Stone MM, Rosenstein BS, Unger P, Stock RG. Influence of pretreatment and treatment factors on intermediate to long-term outcome after prostate brachytherapy. J Urol 2011;185:495-500.  Back to cited text no. 7
    
8.
Hurwitz MD, Halabi S, Archer L, McGinnis LS, Kuettel MR, DiBiase SJ, et al. Combination external beam radiation and brachytherapy boost with androgen deprivation for treatment of intermediate-risk prostate cancer: Long-term results of CALGB 99809. Cancer 2011;117:5579-88.  Back to cited text no. 8
    
9.
Lawton CA, Yan Y, Lee WR, Gillin M, Firat S, Baikadi M, et al. Long-term results of an RTOG Phase II trial (00-19) of external-beam radiation therapy combined with permanent source brachytherapy for intermediate-risk clinically localized adenocarcinoma of the prostate. Int J Radiat Oncol Biol Phys 2012;82:e795-801.  Back to cited text no. 9
    
10.
Albertsen PC, Hanley JA, Fine J. 20-year outcomes following conservative management of clinically localized prostate cancer. JAMA 2005;293:2095-101.  Back to cited text no. 10
    
11.
Davis BJ, Pisansky TM, Wilson TM, Rothenberg HJ, Pacelli A, Hillman DW, et al. The radial distance of extraprostatic extension of prostate carcinoma: Implications for prostate brachytherapy. Cancer 1999;85:2630-7.  Back to cited text no. 11
    
12.
D'Amico AV, Schultz D, Silver B, Henry L, Hurwitz M, Kaplan I, et al. The clinical utility of the percent of positive prostate biopsies in predicting biochemical outcome following external-beam radiation therapy for patients with clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 2001;49:679-84.  Back to cited text no. 12
    
13.
Spalding AC, Daignault S, Sandler HM, Shah RB, Pan CC, Ray ME. Percent positive biopsy cores as a prognostic factor for prostate cancer treated with external beam radiation. Urology 2007;69:936-40.  Back to cited text no. 13
    
14.
Wong WW, Schild SE, Vora SA, Halyard MY. Association of percent positive prostate biopsies and perineural invasion with biochemical outcome after external beam radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 2004;60:24-9.  Back to cited text no. 14
    
15.
Huang J, Vicini FA, Williams SG, Ye H, McGrath S, Ghilezan M, et al. Percentage of positive biopsy cores: A better risk stratification model for prostate cancer? Int J Radiat Oncol Biol Phys 2012;83:1141-8.  Back to cited text no. 15
    
16.
Qian Y, Feng FY, Halverson S, Blas K, Sandler HM, Hamstra DA. The percent of positive biopsy cores improves prediction of prostate cancer-specific death in patients treated with dose-escalated radiotherapy. Int J Radiat Oncol Biol Phys 2011;81:e135-42.  Back to cited text no. 16
    
17.
Kestin LL, Goldstein NS, Vicini FA, Martinez AA. Percentage of positive biopsy cores as predictor of clinical outcome in prostate cancer treated with radiotherapy. J Urol 2002;168:1994-9.  Back to cited text no. 17
    
18.
Pe ML, Trabulsi EJ, Kedika R, Pequignot E, Dicker AP, Gomella LG, et al. Effect of percentage of positive prostate biopsy cores on biochemical outcome in low-risk PCa treated with brachytherapy or 3D-CRT. Urology 2009;73:1328-34.  Back to cited text no. 18
    
19.
Rossi PJ, Clark PE, Papagikos MA, McCullough DL, Lee WR. Percentage of positive biopsies associated with freedom from biochemical recurrence after low-dose-rate prostate brachytherapy alone for clinically localized prostate cancer. Urology 2006;67:349-53.  Back to cited text no. 19
    
20.
Merrick GS, Butler WM, Galbreath RW, Lief JH, Adamovich E. Relationship between percent positive biopsies and biochemical outcome after permanent interstitial brachytherapy for clinically organ-confined carcinoma of the prostate gland. Int J Radiat Oncol Biol Phys 2002;52:664-73.  Back to cited text no. 20
    
21.
Wallner K, Merrick G, True L, Sherertz T, Sutlief S, Cavanagh W, et al. 20 Gy versus 44 Gy supplemental beam radiation with Pd-103 prostate brachytherapy: Preliminary biochemical outcomes from a prospective randomized multi-center trial. Radiother Oncol 2005;75:307-10.  Back to cited text no. 21
    
22.
Guzzo TJ, Levin BM, Lee R, Guo M, Chen Z, Whittington R, et al. Relationship of biochemical outcome to percentage of positive biopsies in men with clinically localized prostate cancer treated with permanent interstitial brachytherapy. Urology 2008;71:723-7.  Back to cited text no. 22
    
23.
Piña AG, Crook JM, Kwan P, Borg J, Ma C. The impact of perineural invasion on biochemical outcome after permanent prostate iodine-125 brachytherapy. Brachytherapy 2010;9:213-8.  Back to cited text no. 23
    
24.
Beard C, Schultz D, Loffredo M, Cote K, Renshaw AA, Hurwitz MD, et al. Perineural invasion associated with increased cancer-specific mortality after external beam radiation therapy for men with low- and intermediate-risk prostate cancer. Int J Radiat Oncol Biol Phys 2006;66:403-7.  Back to cited text no. 24
    
25.
Ding W, Lee J, Chamberlain D, Cunningham J, Yang L, Tay J. Twelve-month prostate-specific antigen values and perineural invasion as strong independent prognostic variables of long-term biochemical outcome after prostate seed brachytherapy. Int J Radiat Oncol Biol Phys 2012;84:962-7.  Back to cited text no. 25
    
26.
Morton GC, Hoskin PJ. Brachytherapy: Current status and future strategies – Can high dose rate replace low dose rate and external beam radiotherapy? Clin Oncol (R Coll Radiol) 2013;25:474-82.  Back to cited text no. 26
    
27.
Zaorsky NG, Doyle LA, Hurwitz MD, Dicker AP, Den RB. Do theoretical potential and advanced technology justify the use of high-dose rate brachytherapy as monotherapy for prostate cancer? Expert Rev Anticancer Ther 2014;14:39-50.  Back to cited text no. 27
    


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