The role of the maximum involvement of biopsy core in predicting outcome for patients treated with dose-escalated radiation therapy for prostate cancer
- Jure Murgic†1,
- Matthew H Stenmark†1,
- Schuyler Halverson1,
- Kevin Blas1,
- Felix Y Feng1, 2 and
- Daniel A Hamstra1, 3Email author
© Murgic et al.; licensee BioMed Central Ltd. 2012
Received: 17 March 2012
Accepted: 18 May 2012
Published: 1 August 2012
To evaluate the influence of the maximum involvement of biopsy core (MIBC) on outcome for prostate cancer patients treated with dose-escalated external beam radiotherapy (EBRT).
Methods and materials
The outcomes of 590 men with localized prostate cancer treated with EBRT (≥75 Gy) at a single institution were retrospectively analyzed. The influence of MIBC on freedom from biochemical failure (FFBF), freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival (OS) was compared to other surrogates for biopsy tumor volume, including the percentage of positive biopsy cores (PPC) and the total percentage of cancer volume (PCV).
MIBC correlated with PSA, T-stage, Gleason score, NCCN risk group, PPC, PCV, and treatment related factors. On univariate analysis, MIBC was prognostic for all endpoints except OS; with greatest impact in those with Gleason scores of 8–10. However, on multivariate analysis, MIBC was only prognostic for FFBF (hazard ratio [HR] 1.9, p = 0.008), but not for FFM (p = 0.19), CSS (p = 0.16), and OS (p = 0.99).
In patients undergoing dose-escalated EBRT, MIBC had the greatest influence in those with Gleason scores of 8–10 but provided no additional prognostic data as compared to PPC and PCV, which remain the preferable prognostic variables in this patient population.
KeywordsProstate cancer Biopsy prognostic factors Maximum involvement Tumor in Core Radiotherapy
Pretreatment prognostic indices predictive of outcome in patients with clinically localized prostate cancer typically rely on risk-factors including: prostate-specific antigen (PSA), clinical T-stage, and biopsy Gleason score (GS) [1, 2]. More recent models have evaluated the prognostic utility of incorporating biopsy tumor volume. Surrogates for cancer volume have included the percentage of positive cores (PPC) at the time of prostate biopsy [3, 6] and the total percentage of cancer volume (PCV) in all of the biopsy cores [7, 8]. In a recent analysis we demonstrated that in a cohort of patients treated with dose-escalated EBRT, PCV was superior to PPC as a prognostic variable for prediction of clinical outcomes. In addition, PCV was found to add prognostic significance for all end-points, including overall survival (OS) . However, calculating PCV is time consuming; furthermore, it is possible that a moderate volume of cancer involved in a large number of cores is less important than a dominant lesion involving a large volume of cancer in one or more cores. The maximum involvement of a single biopsy core has previously been demonstrated to correlate with worse pathologic features and higher biochemical failure following radical prostatectomy; however, it has not previously been assessed in patients treated with EBRT. Therefore, this study aimed to assess the prognostic significance of the maximum involvement of biopsy core by cancer (MIBC) as compared to both PPC and PCV in a cohort of patients treated with dose-escalated EBRT for prostate cancer.
Patients and methods
From 1998 to 2008, 718 men with clinically localized prostate adenocarcinoma were consecutively treated at the University of Michigan with definitive external beam radiotherapy to a minimum dose of 75 Gy with or without neo-adjuvant and/or adjuvant androgen deprivation therapy (ADT). Prior to treatment, patients were risk stratified into low-, intermediate-, and high-risk groups based on standard NCCN criteria. Staging evaluation was performed per standard clinical practice. Symptomatic patients and/or those with NCCN-defined high-risk features were routinely staged with pelvic CT and bone-scan. Patients with evidence of metastatic disease were excluded from the analysis.
All prostate core biopsies were reviewed by dedicated uropathologists at the University of Michigan who reported Gleason score, number of positive cores, and percent cancer involvement for each core. The maximum involvement of biopsy core (MIBC) was defined as the highest percentage of cancer present in one or more individual biopsy cores from all sampled cores. Percentage of positive cores (PPC) and the percentage cancer volume (PCV) were both calculated as previously described [6, 8].
All patients underwent CT-based treatment planning and were treated with 3D-conformal RT (3D-CRT) or intensity modulated RT (IMRT). The median prescribed dose was 78 Gy (inter-quartile range [IQR] 76–78) using daily fractions of 1.8 to 2.0 Gy. Treatments were planned to ensure 95% coverage of the planning target volume (PTV) by the prescription isodose level. Clinical target volumes (CTV) were typically based upon the NCCN risk-stratification criteria such that low-risk patients were treated to the prostate only, intermediate-risk patients to the prostate and seminal vesicles, and high-risk patients to the pelvic lymph nodes to 45 Gy followed by a boost to the prostate and seminal vesicles. The frequency and duration of ADT were as follows: low-risk (11%, median 4.1 months), intermediate-risk (27%, median 6.6 months), and high-risk (90%, median 23.0 months).
Patients were routinely followed at 3–6 month intervals for the first 5 years and every 6 to 12 months thereafter. Freedom from biochemical failure (FFBF) was defined based upon the ASTRO Phoenix definition (20). Freedom from metastasis (FFM) was defined as the absence of any clinical, radiographic, or pathologic evidence of metastatic disease. Cause specific survival (CSS) was defined as death attributed to prostate cancer or death in any patient with either castrate-resistant prostate cancer or evidence of metastatic disease prior to death. OS was defined as death due to any cause.
One-way analysis of variance (ANOVA) was used for the comparison between MIBC groups and continuous variables while the chi-square (CS) test was used for analysis between MIBC groups and categorical variables. Univariate survival analyses were conducted using the log-rank test and Kaplan-Meier method. Multivariate analyses were conducted using Cox proportional hazards models. Receiver operator characteristic (ROC) curves were used to evaluate the relative predictive capacity of MIBC compared to other cancer volume metrics (PPC, PCV), used as continuous variables and correlated with clinical end-points at 7 years. The cut-point that best discriminated patient outcome based on different metrics was computed using the maximum likelihood ratio. All statistical analysis was performed using MedCalc (v22.214.171.124, MedCalc Software, Mariakerke, Belgium) using 2-sided tests with a p-value <0.05 considered significant.
Data on MIBC, PPC, and PCV was available for 590 of 718 (82%) men with a median age of 69 years (IQR: 63–74) and a median follow-up of 57 months (IQR: 34–81). The median number of biopsy cores sampled was 8 (IQR: 6–12, range: 4–86) with a median PPC of 33.3% (IQR: 17-60%; range: 3.7-100%), a median PCV of 10% (IQR: 2.5-25%; range: 0.14-95%), and a median MIBC of 30.0% (IQR: 10-70%, range 1-100%).
Clinical and treatment characteristics for maximum involvement of biopsy core (MIBC) stratified by quartile
MIBC by quartile
Age (y), median (IQR)
PSA (ng/mL), median (IQR)
Percent cores positive
Percent cancer volume
NCCN risk group
RT dose (Gy), median (IQR)
ADT duration, median (IQR)
Association between MIBC and clinical outcome
Univariate Analysis of Clinical Outcome As A Function of MIBC By Quartile
p-value Quartiles 1-3
To identify the optimal cut-point for MIBC stratification, ROC curves were generated for each endpoint using MIBC as a continuous variable. At 7-years, MIBC was predictive for FFBF (area under the curve [AUC]: 0.67, 95% CI: 0.60-0.74, p < 0.0001), FFM (AUC: 0.67, 95% CI: 0.58-0.75, p = 0.004), and CSS (AUC: 0.79, 95% CI: 0.69-0.87, p = 0.0002), but not OS (AUC: 0.60, 95% CI: 0.51-0.69, p = 0.075). A number of different cut-points could be utilized for further analysis and indeed given close association between increasing risk-features and increasing MIBC if MIBC was addressed in 10% increments any cut-point >10% was associated with BF while any cut-point >40% was associated with metastasis and death from prostate cancer. From these analyses MIBC had the strongest prognostic association with death from prostate cancer (AUC 0.79) and a cut-point of 60% was selected for further evaluation as this value was most closely associated with CSS, (negative predictive value [NPV] 97% and positive predictive value of 30.5%) while still maintaining modest prognostic significance for FFBF (NPV 64%) and FFM (NPV 87%).
Multivariate analysis for all clinical outcomes stratified for NCCN risk group and the best-identified cut-point for MIBC (60%)
HR (95% CI)
HR (95% CI)
HR (95% CI)
HR (95% CI)
NCCN risk group
Univariate and Multivariate Models For Freedom From Biochemical Failure
Multivariate Model # 1 Maximum Core Only
Multivariate Model #2 MIBC + Percent Positive Cores
Multivariate Model #3 MIBC + Percent Cancer Volume
Hazard Ratio (95% CI)
Hazard Ratio (95%CI)
Hazard Ratio (95%CI)
Hazard Ratio (95%CI)
Cancer Volume Metrics
Maximum Biopsy Core
Percent Positive Cores
Percent Cancer Volume
Finally, we evaluated the hypothesis that MIBC would have greater prognostic significance in patients with a low total volume of cancer where the impact of a single high volume core might be more noticeable. Within this data set, we previously identified an optimal cut-point of 22.5% for total biopsy cancer volume (PCV <22.5% n = 393]; PCV ≥22.5% n = 144]), which on multivariate analysis predicted worse outcome for all clinical endpoints, including CSS (HR 3.9, p = 0.01) . Of the 144 patients with a large total cancer volume, MIBC (stratified by 60%) was not prognostic for any end-point (p > 0.3 for all). However, in the 393 patients with a smaller total volume of cancer, 67 patients (17%) had maximum core involvement of ≥60% with a trend toward worse FFBF (HR: 1.7 [95%CI: 0.8-3.9], p = 0.09) and FFM (HR: 2.2 [95%CI:0.7-6.7], p = 0.07) but no impact upon CSS or OS (p > 0.5 for each).
One limitation to predicting outcome in men undergoing radiotherapy for prostate cancer is the poor ability to define the volume of cancer present at the time of diagnosis. Both PPC and PCV have previously been evaluated as prognostic tools for patients treated with radiation therapy [3–8]. In contrast, data on the prognostic impact of MIBC in prostate cancer are scarce; to our knowledge this is the first analysis on the utility of MIBC in patients treated with EBRT.
In one previous report MIBC was identified as an independent determinant of histological disease progression in a cohort of patients with low-risk prostate cancer undergoing active surveillance . Moreover, in a comprehensive analysis done by Brimo et al., the authors tested the prognostic value of seven different morphometric measurements of tumor extent from prostate needle core biopsy tissue, including MIBC, in a group of patients treated with radical prostatectomy. On univariate analysis the time to PSA recurrence was marginally associated with greatest percentage of cancer (p = 0.06) which was defined in a similar manner to how we defined MIBC .
In the present study, MIBC was closely correlated with other clinical risk-features as well as PCV (r = 0.77) and less so with PPC (r = 0.52). Given the close association with clinical risk-features, it is not surprising that on univariate analysis MIBC was associated with clinical outcome for all end-points except OS. However, on multivariate analysis either after controlling for NCCN risk-group or for other clinical and treatment-related features, MIBC only added prognostic value for FFBF, but not for any of the other clinically relevant end-points. Despite limited prognostic significance over all patients; when MIBC was assessed independently in patients with Gleason scores of 8–10 it did correlate significantly with greater BF, metastasis, and death from prostate cancer with borderline association with OS while in those with Gleason scores of 2–7 it only appeared to influence BF.
Conversely, within the same dataset, PCV predicted a worse outcome for all end-points on multivariate analysis, including FFBF (HR 1.9, p = .003), FFM (HR 1.7, p = .09), CSS (HR 3.9, p = .01), and OS (HR 1.8, p = .02) even after accounting for PPC. Thus, at present, PPC and PCV should remain the standard metrics for estimating prostate cancer volume, given the additional prognostic data they provide as compared to MIBC for patients undergoing definitive EBRT. Interestingly, as previously observed when any of the measures of cancer volume (MIBC, PPC, or PCV) were included in multivariate models clinical T-stage was no longer prognostic which is suggestive that these measures of cancer volume are likely more clinically relevant than T-stage assessed by digital rectal exam.[8, 11] The strengths of study include the large patient number, restriction to patients undergoing dose-escalated EBRT, and analysis of clinically relevant endpoints, including FFM, CSS, and OS. Limitations arise from the study are significant given that it represents retrospective analysis from a single institutions without central pathologic review or validation of these findings. In addition, the correlation between MIBC and both the use of pelvic RT and ADT certainly cloud the ability to independently evaluate the impact of each of these factors while the follow-up of only 5 years limits conclusions about more long-term end-points such as metastasis and CSS.
Although a simple and an easily obtained measure of prostate cancer volume, MIBC provided no additional prognostic data compared to PPC and PCV, and indeed was less relevant then either of these other metrics. Therefore, both PPC and PCV are preferable end-points to be used as prognostic tools. However, if future analyses of MIBC are undertaken we would suggest a focus upon patients with the highest Gleason scores where MIBC had the greatest suggestion of possible value.
Maximum involvement of biopsy core
percentage of positive biopsy cores
total percentage of cancer volume
external beam radiation therapy
freedom from biochemical failure
freedom from metastasis
prostate specific antigen
national comprehensive cancer network
androgen deprivation therapy
three-dimensional conformal radiation therapy
intensity modulated radiation therapy
one-way analysis of variance
receiver operator characteristic
area under the curve.
- D'Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick GA, Tomaszewski JE, Renshaw AA, Kaplan I, Beard CJ, et al.: Biochemical Outcome After Radical Prostatectomy, External Beam Radiation Therapy, or Interstitial Radiation Therapy for Clinically Localized Prostate Cancer. JAMA 1998,280(11):969-974. 10.1001/jama.280.11.969View ArticlePubMedGoogle Scholar
- Bahnson RR, Hanks GE, Huben RP, Kantoff P, Kozlowski JM, Kuettel M, Lange PH, Logothetis C, Pow-Sang JM, Roach M, et al.: NCCN Practice Guidelines for Prostate Cancer. Oncology (Williston Park, NY) 2000,14(11):111-119.Google Scholar
- D'Amico AV, Schultz D, Silver B, Henry L, Hurwitz M, Kaplan I, Beard CJ, Renshaw AA: 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(3):679-684. 10.1016/S0360-3016(00)01423-1View ArticlePubMedGoogle Scholar
- 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(1):24-29. 10.1016/j.ijrobp.2004.02.031View ArticlePubMedGoogle Scholar
- 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(5):936-940. 10.1016/j.urology.2007.01.066View ArticlePubMedGoogle Scholar
- 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(3):e135-142. 10.1016/j.ijrobp.2011.01.007View ArticlePubMedGoogle Scholar
- Buyyounouski MK, Hanlon AL, Horwitz EM, Pollack A: Interval to biochemical failure highly prognostic for distant metastasis and prostate cancer-specific mortality after radiotherapy. Int J Radiat Oncol Biol Phys 2008,70(1):59-66. 10.1016/j.ijrobp.2007.05.047View ArticlePubMedGoogle Scholar
- Vance SM, Stenmark MH, Blas K, Halverson S: Hamstra DA. Feng FY: Percentage of Cancer Volume in Biopsy Cores is Prognostic for Prostate Cancer Death and Overall Survival in Patients Treated with Dose-Escalated External Beam Radiotherapy. Int J Radiat Oncol Biol Phys; 2011.Google Scholar
- Venkitaraman R, Norman A, Woode-Amissah R, Fisher C, Dearnaley D, Horwich A, Huddart R, Khoo V, Thompson A, Parker C: Predictors of histological disease progression in untreated, localized prostate cancer. J Urol 2007,178(3 Pt 1):833-837.View ArticlePubMedGoogle Scholar
- Brimo F, Vollmer RT, Corcos J, Kotar K, Begin LR, Humphrey PA, Bismar TA: Prognostic value of various morphometric measurements of tumour extent in prostate needle core tissue. Histopathology 2008,53(2):177-183. 10.1111/j.1365-2559.2008.03087.xView ArticlePubMedGoogle Scholar
- Huang J, Vicini FA, Williams SG, Ye H, McGrath S, Ghilezan M, Krauss D, Martinez AA, Kestin LL: Percentage of Positive Biopsy Cores. Int J Radiat Oncol Biol Phys: A Better Risk Stratification Model for Prostate Cancer?; 2011.Google Scholar
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