diagnosed by transrectal needle biopsy who completed 3DCRT alone be- Center, Philadelphia, Pennsylvania.

Transcription

1 75 Evidence of Increased Failure in the Treatment of Prostate Carcinoma Patients Who Have Perineural Invasion Treated with Three-Dimensional Conformal Radiation Therapy Steven R. Bonin, M.D. 1 BACKGROUND. The detection of perineural invasion () in the diagnostic Alexandra L. Hanlon, M.S. 1 transrectal biopsy of the prostate is associated with a 93% frequency of extracapsu- W. Robert Lee, M.D. 1 lar disease extension in patients treated by prostatectomy for adenocarcinoma Benjamin Movsas, M.D. 1 of the prostate. Extracapsular extension is associated with an inferior outcome T. I. Al-Saleem, M.D. 2 compared with that of patients who have organ-confined disease. This study exam- Gerald E. Hanks, M.D. 1 ined the association of and treatment failure in a consecutive series of patients treated with three-dimensional conformal radiation therapy (3DCRT) alone. 1 Department of Radiation Oncology, Fox Chase METHODS. The authors report actuarial biochemical no evidence of disease (bned) Cancer Center, Philadelphia, Pennsylvania. survival rates for 484 consecutive patients with clinically localized prostate carcinoma 2 Department of Pathology, Fox Chase Cancer diagnosed by transrectal needle biopsy who completed 3DCRT alone be- Center, Philadelphia, Pennsylvania. tween May 1989 and December The median follow-up time was 28 months (range, 2 75 months), and the median dose to the center of the prostate was 7368 centigray (cgy) (range, cgy). Patients were subdivided into 2 groups according to pretreatment prostate specific antigen (PSA) levels (õ20 ng/ml vs. Supported in part by National Cancer Institute contract #CA ng/ml). Pathology records were reviewed for the presence or absence of. bned failure was defined as a PSA level 1.5 ng/ml and rising on 2 consecutive occasions. bned survival rates were calculated using Kaplan-Meier methodology and comparisons of survival curves were accomplished using the log rank test. RESULTS. The 3-year bned survival for all 484 patients was 77%. The presence of predicted decreased bned survival in all patients. This detrimental effect, however, was confined to patients with pretreatment PSA values õ 20 ng/ml. The bned survival rates for patients with pretreatment PSA õ 20 ng/ml demonstrated a highly significant decrease if was present versus when it was absent (65% vs. 88% at 3 years, 39% vs. 65% at 5 years; P Å for overall curve comparison). For patients with pretreatment PSA õ 20 ng/ml, multivariate analysis of prognostic variables demonstrated a significant association between bned survival and (P Å 0.002), palpation stage (P Å 0.02), and pretreatment PSA (P Å 0.006). Gleason score, age, and dose were not independent predictors of bned survival in this group of patients. CONCLUSIONS. To the authors knowledge, this is the first report demonstrating that detected on diagnostic transrectal biopsy is a significant predictor of decreased bned survival in patients treated with radiotherapy. The subgroup of patients affected are those with pretreatment PSA õ 20 ng/ml. This result suggests that such patients may benefit from more aggressive treatment, particularly the use of larger planning Address for reprints: Steven R. Bonin, M.D., target volumes or adjuvant therapies. Cancer 1997; 79: Department of Radiation Oncology, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, 1997 American Cancer Society. PA Received June 3, 1996; revision received September 5, 1996; accepted September 16, KEYWORDS: prostate carcinoma, perineural invasion, radiation therapy, extracapsular extension, prostate specific antigen American Cancer Society

2 76 CANCER January 1, 1997 / Volume 79 / Number 1 I n an effort to offer the appropriate treatment options histologically proven lymph node positive were ex- to patients with prostate carcinoma, clinicians contin- cluded. The diagnosis of prostate carcinoma was made ually attempt to identify those pretreatment factors that by transrectal needle biopsy. Outside pathology slides are predictive of outcome. Examples of factors most were reviewed at Fox Chase Cancer Center and a Gleacommonly associated with inferior outcome in patients son score was assigned to the tumor. Clinical staging treated with definitive radiotherapy include high pre- workup before treatment included a directed history treatment prostate specific antigen (PSA), rapid PSA and physical examination with digital rectal examinadoubling time, high Gleason score, and advanced clinical tion (DRE), bone scan, PSA determination (Hybritech T stage. 1 7 Patients at high risk of treatment failure as method; Hybritech, San Diego, CA) (normal range, 0 determined by these factors are commonly offered more 4 ng/ml), magnetic resonance imaging of the prostate aggressive treatment such as adjuvant total androgen with an endorectal or quadrature type surface coil, deprivation, elective pelvic lymph node irradiation, or and ultrasound of the prostate when performed as part high dose radiotherapy. 2,8 10 of the biopsy procedure. Partin et al. have correlated factors such as pre- The median age of the patients at the time of diagtreatment PSA level, clinical stage, and Gleason score nosis was 70 years (range, years). The pretreatwith extracapsular disease, seminal vesicle involve- ment PSA, Gleason score, AJCC stage, and incidence ment, and lymph node metastasis. 11 This information of for all patients is shown in Table 1. There was no provides a useful bridge to the radiation oncologist consistent pattern in which the presence or absence of between pretreatment factors to which he or she is on prostate biopsy was reported by pathologists privy (PSA, clinical stage, and Gleason score) and the from Fox Chase or referring institutions during the concrete pathologic observations that correlate with time of this study. Although the pathology report these pretreatment characteristics (extracapsular exstated the number of biopsies performed and reviewed tension, seminal vesicle invasion, lymph node metasin most cases, there were many cases in which this tasis, and large tumor bulk). information was not stated. The proportion of biopsies Recent reports have suggested that the presence from any one patient demonstrating was not rouof perineural invasion () is an adverse prognostic tinely commented on. Therefore, was recorded as indicator. Bastacky et al. from Johns Hopkins reviewed present if noted by either the referring or Fox Chase the preoperative needle biopsies of 302 men with adepathologist. nocarcinoma of the prostate who underwent prosta- Three-hundred and eighty-seven patients had tectomy. 12 They noted a strong correlation between pretreatment PSA levels õ 20 ng/ml (median, 8.6 ng/ and capsular penetration in the prostatectomy ml), whereas 97 had pretreatment PSA levels 20 ng/ specimen. Subsequent reports by Epstein et al., also ml (median, 35.6 ng/ml). The relatively small numfrom Johns Hopkins, demonstrated an increased risk of disease progression after prostatectomy in patients bers of patients with pretreatment PSA 20 ng/ml with capsular penetration if the final Gleason score who were treated with radiotherapy alone reflects the was between 5 and 7 (88.2% of their cases). 13 On the authors policy of treating this group of patients with basis of these data from a single institution (Johns combined hormonal management and radiotherapy. Hopkins), one can reasonably conclude that obtablished poor prognosis of patients with pretreatment This cutoff point was selected because of the well esserved on needle biopsy is associated with increased failure in a substantial proportion of patients treated PSA ú 20 ng/ml. 1,2,7,8,14 by prostatectomy. The current study concentrates on 484 consecutive patients treated with three-dimensional confor- Radiation Therapy Techniques mal radiation therapy (3DCRT) alone. The prognostic All 484 patients in this study were treated with 3DCRT, value of demonstrated is assessed and compared which has been described previously. 15 Patients with with established prognostic indicators. a risk of pelvic lymph node metastases 15% were initially treated to a pelvic field to a dose of 46 Gray MATERIALS AND METHODS (Gy) in 1.9-Gy daily fractions. This was followed by Between May 1989 and December 1994, 484 men with sequential boosts at 2.1 Gy per day to the prostate and American Joint Committee on Cancer (AJCC) clinically seminal vesicles and prostate or prostate alone to yield staged T1 3 NX M0 adenocarcinoma of the prostate a final center of prostate dose of 6316 to 8074 centi- were treated with definitive 3DCRT. Patients who refrom grays. Risk of lymph node involvement was calculated ceived any irradiation adjuvant to surgery, any hormonal the pathologic review of the large prostatectomy management, T4 patients, and patients with series published by Partin et al. 11

3 Increased Failure Perineural Invasion/Bonin et al. 77 TABLE 1 Patient Characteristics All patients PSA õ 20 ng/ml PSA 20 ng/ml (n Å 484) (n Å 387) (n Å 97) Gleason score Palpation stage T1/T2AB T2C/T Age (yrs) Mean Median Range õ Dose (Gy) Mean Median Range õ No Yes Follow-up (mos) Mean Median Range Pretreatment PSA (ng/ml) Mean Median Range PSA: prostate specific antigen; Gy: Gray; : perineural invasion. Follow-Up of the most recent follow-up visit. Estimates of rates Patients were initially seen at 3 months and then at for bned survival were calculated using the Kaplan 6-month intervals. Follow-up evaluation included DRE Meier product-limit method. 16 Univariate comparisons and serum PSA level determination. Bone scans and of the time-to-outcome curves were made using other studies were obtained only if the patient had the log rank test for AJCC palpation stage (T1/T2AB clinical evidence of local recurrence, symptoms of metastases, vs. T2C/T3), Gleason score (2 to 6 vs. 7 to 10), Pretreat- or two serial increasing PSA values. A patient ment PSA level (0 9.9 ng/ml vs ng/ml vs. was considered free of disease if there was no clinical, 20 ng/ml), center of prostate dose (õ74 Gy vs. 74 imaging, or biochemical (PSA) evidence of prostate Gy), (present vs. absent or not reported), and age cancer (bned). Biochemical failure was defined as a (õ70 years vs. 70 years). 17 Univariate analysis were PSA level ú 1.5 ng/ml and increasing on 2 consecutive performed on all patients, patients with PSA levels õ measurements after completion of radiotherapy. 20 ng/ml, and patients with PSA levels 20 ng/ml. The median follow-up times for patients with PSA Multivariate analyses were conducted using the Cox levels õ 20 ng/ml and 20 ng/ml were 26 and 38 proportional hazards model to examine the effect of months, respectively. The median follow-up time for clinical and treatment variables on bned survival. 18 all patients was 28 months, with a range of 2 to 75 Specifically, AJCC palpation stage (T1/T2AB vs. T2C/ months. T3), Gleason score (2 to 6 vs. 7 to 10), center of prostate dose (on a continuum), age (on a continuum), and Statistical Analysis (present vs. absent or not reported) were the factors bned survival time was calculated from the start of considered as predictor variables. Also included was 3DCRT to the occurrence of the event or to the date pretreatment PSA, grouped for all patients (0 9.9 ng/

4 78 CANCER January 1, 1997 / Volume 79 / Number 1 TABLE 2 bned Survival at 3 Years 3-year bned survival P value All patients No 79% Yes 62% 0.01 PSA õ 20 ng/ml No 88% Yes 65% PSA 20 ng/ml No 48% Yes 52% a b bned: biochemical no evidence of disease; : perineural invasion; PSA: prostate specific antigen. a Only 10 patients in perineural invasion group for prostate specific antigen 20 ng/ml. b Too few patients to make comparisons. FIGURE 1. Biochemical no evidence of disease survival for patients with pretreatment prostate specific antigen values õ 20 ng/ml based on perineural invasion status of prostate biopsy. bned: no biochemical evidence of disease; PSA: prostate specific antigen; : perineural invasion. ml vs ng/ml vs. 20 ng/ml), and on a continuum for the subsets based on pretreatment PSA. A univariate and multivariate analyses demonstrate imfull model was fit for all patients, but because of the proved bned survival rates for patients with low Gleadisproportionate number of events and number of coson score, lower AJCC palpation stage, lower pretreatvariates in the PSA subgroups, a stepwise modeling ment PSA, central prostate dose 74 Gy, and absence procedure was used to derive a reduced model that of. For patients with pretreatment PSA values õ 20 adequately fit the data. Covariates were entered into ng/ml, univariate analyses showed that low Gleason the stepwise model using the maximum partial-likeliscore, lower AJCC palpation staging, lower pretreathood ratio test. ment PSA, and absence of were associated with improved bned survival. Multivariate analysis demonstrated RESULTS a significant association between bned sur- Thirty-nine of 484 patients (8%) had noted by the vival and AJCC palpation stage, pretreatment PSA, and pathologist on their diagnostic prostatic biopsy. Table. Gleason score, central prostate dose, and age 1 lists the Gleason score, palpation T stage, age, and were not prognostic factors in this group of patients. center of prostate dose according to pretreatment PSA For those patients with pretreatment PSA values level. The group with PSA levels õ 20 ng/ml contained 20 ng/ml, univariate analysis showed an association more patients with a lower Gleason score and more between bned survival and Gleason score, AJCC pal- T1/T2AB patients. pation stage, and central prostate dose. Multivariate Table 2 lists the actuarial bned survival for all analysis demonstrated improved bned survival only patients and for the subgroups with PSA õ or 20 ng/ in patients with lower AJCC palpation stage and central ml based on. At 36 months, the pooled data show prostate dose 74 Gy. Thus, is associated bned survival rates of 62% and 79% for patients with with shortened bned survival in patients whose pretreatment and without, respectively. These differences are PSA is õ20 ng/ml. statistically significant (P Å 0.01 for overall curve comparison). For the group with PSA õ 20 ng/ml, the DISCUSSION corresponding bned rates were 65% and 88%, respectively, Previously published reports have cataloged those predifferences and the curves showed statistically significant treatment factors predictive of outcome or associated (P Å ) (Fig. 1). The bned survival with finding poor pathologic features after either ra- for patients with a pretreatment PSA 20 ng/ml were diotherapy or surgery. Such factors include Gleason not different, with values of 52% if was noted and score, stage, pretreatment PSA,, PSA doubling 48% when it was not present. time, androgen deprivation, conformal versus standard Table 3 lists the results of univariate and multivariate radiotherapy, capsular penetration, positive mar- analysis for the subgroups studied. For all patients, gins, seminal vesicle involvement, and lymph node

5 Increased Failure Perineural Invasion/Bonin et al. 79 TABLE 3 Univariate and Multivariate Analyses for bned Survival Univariate Multivariate All PSA õ 20 PSA 20 All PSA õ 20 PSA 20 Factor patients ng/ml ng/ml patients ng/ml a ng/ml a Gleason score NS NS Palpation stage Pretreatment PSA N/A õ NS Dose NS 0.03 Age NS NS b NS bned: biochemical no evidence of disease; PSA: prostate specific antigen; N/A: not available; NS: not significant; : perineural invasion. a Stepwise multivariate analysis. b Too few patients to make comparisons. metastases. 1 12,13 15,18 24 To date, the single pretreat- treated by prostatectomy, reported that pretreatment ment factor most strongly associated with bned survival PSA, Gleason score, and percent carcinoma in the di- has been the pretreatment PSA level. 1 4,6 8,11,14 agnostic biopsy correlated with capsular perforation The authors have recently reported that pretreatment and seminal vesicle invasion at prostatectomy. 19 PSA, palpation stage, Gleason score, center of prostate was not predictive in the final model from their series. dose, and pretreatment PSA doubling times all have 19 They reported rates of and extracapsular prognostic significance in patients treated with spread of 37% and 33%, respectively. In contrast, The 3DCRT. 1 3,5,8 This study now shows that, with a median Hopkins group reported rates of and extracapsular follow-up of 28 months, is a strong multivariate spread of 20% and 58%, respectively, in a group of predictor of bned survival in patients with a pretreatment similarly staged patients. 12 PSA level õ 20 ng/ml. The authors suspect, and Thus, the significance of in the biopsy of pa- the data from Partin et al. support, that essentially all tients treated with prostatectomy varies between sur- patients with pretreatment PSA values 20 ng/ml gical series and is probably related to the differences in have disease outside the capsule. 11 pathologic definitions of both and extracapsular Bastacky et al. from Johns Hopkins performed a spread of disease. 24 The current series has a rate of retrospective review comparing pretreatment factors of 8% despite the fact that it was considered to with pathologic data after prostatectomy in 302 pa- be present if either the referring pathologist or the tients with clinical Stage B prostatic adenocarcinoma. Fox Chase pathologist reported it, suggesting that only 12 on prostatic biopsy, noted in 20% of pa- cases of obvious were reported. The strength of tients, preceeded the pathologic observation of capsular as a prognostic factor is further suggested by the penetration after prostatectomy 93% of the time. 12 fact that the authors were able to show its detrimental An explanation for the close association between effect on bned survival despite the probable inclusion and capsular penetration has been provided in a of a proportion of positive patients in the negative pathologic review of 176 radical prostatectomy specimens group. Clearly, as the prognostic importance of this by Villers et al. 25 In 95% of the specimens, the finding is brought to light, efforts should be made to finding of capsular penetration was associated with standardize the manner in which it is sought and re-, either alone or in association with direct tumor ported by pathologists. It is now the policy of the Department extension. The authors concluded that extracapsular of Pathology at Fox Chase to comment speextension. spread of prostate carcinoma is almost entirely depen- cifically on the presence or absence of whenever a dent on egress along perineural spaces. A retrospective diagnosis of prostate carcinoma is made or confirmed. analysis of 721 men with clinically localized prostate Treatments previously shown to be of benefit in carcinoma treated by prostatectomy at Johns Hopkins prostate carcinoma patients with a poor prognosis illustrated that the pathologic factors most closely re- may be considered in the management of patients lated to disease progression were Gleason score, capsular with even if their pretreatment PSA is õ20 ng/ml. penetration, and margin status. 13 Bostwick et al. These include adjuvant androgen deprivation, pelvic from the Mayo Clinic, in a review of 314 patients lymph node irradiation, and dose escalation. 9,10,26 Al-

6 80 CANCER January 1, 1997 / Volume 79 / Number 1 though the mechanism by which confers an inferadiation prostatic carcinoma: a randomized comparative trial of the therapy oncology group. Urology 1995;45: rior prognosis in patients treated with radiotherapy 10. Pilepich MV, Caplan R, Byhardt RW, Lawton CA, Gallagher appears to be related to extraprostatic extension, fur- MJ, Mesic JB, et al. Phase III trial of androgen suppression ther study should facilitate specifically directed inter- using goserelin in unfavorable prognosis carcinoma of the ventions. 23,25 prostate treated with definitive radiotherapy (Report of RTOG Protocol 85-31) [Abstract 631]. Proc Am Soc Clin Oncol 1995;14:236. CONCLUSION 11. Partin AW, Yoo J, Carter HB, Pearson JD, Chan DW, Epstein To the authors knowledge, this is the first report of JI, et al. The use of prostate specific antigen, clinical stage the adverse prognostic significance of on prostatic and Gleason score to predict pathologic stage in men with biopsy in patients treated with definitive radiotherapy clinically localized prostate cancer. J Urol 1993;150: for prostate carcinoma. This inferior outcome was only 12. Bastacky SI, Walsh PC, Epstein JI. Relationship between perineural tumor invasion on needle biopsy and radical associated with a pretreatment PSA õ 20 ng/ml, sugprostatectomy capsular penetration in clinical Stage B adegesting that the poor prognosis associated with a high nocarcinoma of the prostate. Am J Surg Pathol 1993;17:336 PSA overrides any additional information that 41. may yield. The pathologic explanation for the detri- 13. Epstein JI, Partin AW, Sauvageot J, Walsh PC. Prediction mental effect of on bned survival is the propen- of progression following radical prostatectomy. 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