Outcome and predictive factors for patients with Gleason score 7 prostate carcinoma treated with three-dimensional conformal external beam radiation therapy
2000; Wiley; Volume: 89; Issue: 12 Linguagem: Inglês
10.1002/1097-0142(20001215)89
ISSN1097-0142
AutoresPenny R. Anderson, Alexandra L. Hanlon, Eric M. Horwitz, Wayne H. Pinover, Gerald E. Hanks,
Tópico(s)Lymphoma Diagnosis and Treatment
ResumoCancerVolume 89, Issue 12 p. 2565-2569 Original ArticleOpen Access Outcome and predictive factors for patients with Gleason score 7 prostate carcinoma treated with three-dimensional conformal external beam radiation therapy Penny R. Anderson M.D., Corresponding Author Penny R. Anderson M.D. P_Anderson@fccc.edu Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PennsylvaniaDepartment of Radiation Oncology, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111;===Search for more papers by this authorAlexandra L. Hanlon Ph.D., Alexandra L. Hanlon Ph.D. Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PennsylvaniaSearch for more papers by this authorEric Horwitz M.D., Eric Horwitz M.D. Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PennsylvaniaSearch for more papers by this authorWayne Pinover D.O., Wayne Pinover D.O. Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PennsylvaniaSearch for more papers by this authorGerald E. Hanks M.D., Gerald E. Hanks M.D. Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PennsylvaniaSearch for more papers by this author Penny R. Anderson M.D., Corresponding Author Penny R. Anderson M.D. P_Anderson@fccc.edu Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PennsylvaniaDepartment of Radiation Oncology, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111;===Search for more papers by this authorAlexandra L. Hanlon Ph.D., Alexandra L. Hanlon Ph.D. Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PennsylvaniaSearch for more papers by this authorEric Horwitz M.D., Eric Horwitz M.D. Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PennsylvaniaSearch for more papers by this authorWayne Pinover D.O., Wayne Pinover D.O. Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PennsylvaniaSearch for more papers by this authorGerald E. Hanks M.D., Gerald E. Hanks M.D. Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PennsylvaniaSearch for more papers by this author First published: 20 December 2000 https://doi.org/10.1002/1097-0142(20001215)89:12 3.0.CO;2-ICitations: 16AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract BACKGROUND The purpose of this study was to determine the biochemical outcome and factors predictive of outcome in prostate carcinoma patients with Gleason score 7 tumors who were treated with three-dimensional conformal radiation therapy (3DCRT). METHODS Between August 1990 and October 1997, 163 T1–T3NXM0 prostate carcinoma patients with Gleason score 7 were treated with definitive 3DCRT alone. The median follow-up, International Commission on Radiological Units dose, and pretreatment prostate specific antigen (PSA) for the entire group were 50 months, 76 grays (Gy), and 11.4 ng/mL, respectively. Independent predictors based on multivariate results were used to stratify the patients into prognostic groups for which biochemical no evidence of disease (bNED) control was reported. Biochemical NED failure was defined according to the American Society for Therapeutic Radiology and Oncology Consensus Panel definition. RESULTS The 5-year bNED control for all patients was 66%. Stratified by pretreatment PSA, 5-year bNED control rates were 83%, 65%, and 21% for 0–9.9 ng/mL, 10–19.9 ng/mL, and ≥20 ng/mL, respectively. Dose to the central axis was found to be a significant treatment factor, with patients receiving ≥76 Gy experiencing 76% 5-year bNED control versus 54% when treated with <76 Gy to isocenter. Pretreatment PSA, dose, and palpation stage were significant independent predictors for bNED control upon multivariate analysis. Patients with a PSA 10 ng/mL or received radiation therapy doses of <76 Gy. CONCLUSIONS Patients with Gleason score 7 adenocarcinoma who had a pretreatment PSA <10 ng/mL and received doses of ≥76 Gy had excellent 5-year bNED control, emphasizing the importance of higher central axis doses in treating Gleason 7 tumors. Patients with intermediate PSA (10–19.9 ng/mL) also required doses ≥76 Gy. Pretreatment PSA ≥20 ng/mL portends a very poor bNED outcome for Gleason 7 patients treated with radiation therapy alone, and thus efforts should be directed toward multimodal or long term hormonal treatment strategies. Cancer 2000;89:2565–9. © 2000 American Cancer Society. There have been few studies analyzing the outcome of patients with prostate carcinoma treated with definitive radiation therapy based on Gleason score.1, 2 Several surgical series have reported a correlation between higher Gleason score and adverse pathologic findings and clinical outcomes.3, 4 Our institution previously has reported a radiation therapy series demonstrating that a Gleason score of 7 predicted worse biochemical no evidence of disease (bNED) outcome compared with a Gleason score of 2–4 and 5–6 for patients with prostate carcinoma treated with definitive radiation therapy.5 However, to the best of our knowledge, there has been no radiation series to date that has specifically and solely analyzed outcome of patients with prostate carcinoma with Gleason score 7 (Medline literature search from 1980 to 2000). The objective of this analysis was to determine the biochemical outcome and factors predictive of outcome for patients with prostate carcinoma with Gleason score 7 tumors who were treated with three-dimensional conformal radiation therapy (3DCRT). MATERIALS AND METHODS Between August 1990 and October 1997, 163 men with clinically localized or locally advanced prostate carcinoma (T1–T3NXM0) with Gleason score 7 (Fox Chase pathology review) were treated with definitive 3DCRT at the Fox Chase Cancer Center. The median follow-up for the entire group was 50 months (range, 10–106 months). The median International Commission on Radiological Units (ICRU) dose was 76 grays (Gy; range, 68–84 Gy). The median pretreatment prostate specific antigen (PSA) was 11.4 ng/mL (range, 0.7–132 ng/mL). See Table 1 for the complete distribution of the patient population by pretreatment characteristics. All patients were treated with our 3DCRT technique, which has been described previously.6 After informed consent was obtained, every patient was treated in a customized immobilization cast, utilizing a four-field technique. Macroscopic tumor volume, clinical target volume (CTV), and planning target volume (PTV) were defined according to ICRU 50. Patients with an estimated risk of lymph node involvement ≥15% received elective pelvic lymph node irradiation.7 Elective pelvic fields were treated with 46–50 Gy in 1.8–2.0-Gy fractions 5 days a week to the center of the volume. This was followed by sequential cone down boost fields utilizing 2.0-Gy fractions per day to the prostate and seminal vesicles and then prostate or to the prostate alone to deliver the total center of prostate dose (median, 76 Gy; range, 68–84 Gy). For patients with an estimated lymph node involvement of <15%, the prostate gland only with or without the seminal vesicles were treated. A margin of 1 cm around the CTV was used for the PTV. Doses were expressed near the center of the target, as recommended by the ICRU 50. Table 1. Patient Characteristics Characteristic Patient no. (n = 163) Pretreatment PSA (ng/mL) 0–9.9 82 10–19.9 47 ≥ 20 34 Palpation stage T1/T2a 113 T2b/T3 50 Perineural invasion Absent 139 Present 24 Central axis dose (Gy) < 76 76 ≥ 76 87 PSA: prostate specific antigen; Gy: gray. Predictors of bNED control were evaluated univariately using Kaplan–Meier methodology8 and the log rank test9 and multivariately using Cox proportional hazards modeling.10 Covariates considered were pretreatment PSA, palpation classification, presence of perineural invasion, and central axis dose. Independent predictors based on multivariate results then were used to stratify the patients into prognostic groups for which bNED control was reported. Also, the patient subgroup of Gleason 3 + 4 tumors was compared with the Gleason 4 + 3 group to determine differences in bNED outcome by using Kaplan–Meier methodology and the log rank test. Biochemical NED failure was defined according to the American Society for Therapeutic Radiology and Oncology Consensus Panel definition.11 RESULTS The overall bNED control for the entire patient population was 66%. Univariate and multivariate results of pretreatment and treatment factors for bNED control (for patients treated with radiation therapy alone) are shown in Table 2. Univariately, pretreatment PSA, dose, and palpation stage were found to be predictive for bNED control. Five-year bNED control rates according to pretreatment PSA were 83% for 0–9.9 ng/mL, 65% for 10–19.9 ng/mL, and 21% for ≥20 ng/mL (P < 0.0001; Fig. 1). Dose to the central axis also was found to be a significant treatment factor upon univariate analysis, with patients receiving ≥76 Gy experiencing 76% 5-year bNED control versus 54% when treated with <76 Gy to isocenter (P = 0.0019; Fig. 2). There was a difference in bNED rates between early localized disease (T1/T2a) versus advanced tumor classification (T2b/T3) of 73% versus 50%, respectively (P = 0.0008). The presence of perineural invasion was not significant in this analysis. Pretreatment PSA, palpation classification, perineural invasion, central axis dose, and Gleason 3 + 4 versus 4 + 3 were entered into a Cox multivariate regression analysis to evaluate the relative effect of these variables on bNED control. After adjustment for the covariates, pretreatment PSA (P = 0.0001), dose (P = 0.0003), and stage (P = 0.035) were the only significant independent predictors for bNED control upon multivariate analysis. Table 2. Results of Univariate and Multivariate Analyses for bNED Control Prognostic factor Groupings Univariate 5-yr (%) UVA P value MVA P value Pretx PSAaa Continuous measures on MVA. 0–9.9 vs. 10–19.9 vs. ≥ 20 83 vs. 65 vs. 21 0.0001 0.0001 Palpation stage T1/T2a vs. T2b/T3 73 vs. 50 0.0008 0.0353 Perineural invasion Absent vs. present 67 vs. 66 0.3225 NS Doseaa Continuous measures on MVA. < 76 vs. ≥ 76 Gy 54 vs. 76 0.0019 0.0003 Gleason score 3 + 4 vs. 4 + 3 74 vs. 65 0.2630 NS bNED: biochemical no evidence of disease; UVA: univariate analysis; MVA: multivariate analysis; PSA: prostate specific antigen; NS: not significant; Gy: gray. a Continuous measures on MVA. Figure 1Open in figure viewerPowerPoint Comparison of bNED control rates for patients with pretreatment PSA 0–9.9 ng/mL versus 10–19.9 ng/mL versus 20+ ng/mL. bNED: biochemical no evidence of disease; 3DCRT: three-dimensional conformal radiation therapy; PSA: prostate specific antigen. Figure 2Open in figure viewerPowerPoint Comparison of bNED control rates for patients receiving <76 versus 76+ Gy. bNED: biochemical no evidence of disease; 3DCRT: three-dimensional conformal radiation therapy; Gy: grays. Based on the two most significant independent predictors of pretreatment PSA and central axis dose derived from the multivariate analysis, patients were stratified into prognostic groups and bNED control was reported (Table 3). It is evident that patients with Gleason score 7 adenocarcinoma who had a pretreatment PSA <10 ng/mL and who received doses of ≥76 Gy (thus considered our most favorable group) had excellent bNED control of 100% at 5 years compared with 70% in those patients receiving 10 ng/mL or dose <76 Gy) had bNED control of 50% compared with the 100% bNED for the favorable group (P < 0.0001; Fig. 3). This clearly emphasizes the importance of higher central axis doses in treating Gleason score 7 tumors. Patients with intermediate PSA (10–19.9 ng/mL) also experienced improved bNED control with doses ≥76 Gy compared with <76 Gy (83% vs. 42%; P = 0.01). Pretreatment PSA ≥20 ng/mL portends a very poor bNED outcome for Gleason 7 patients treated with definitive radiation therapy alone, regardless of dose (21% for <76 Gy vs. 20% for ≥76 Gy; P = 0.15). Table 3. Outcome Based on Pretreatment PSA and Dose PSA Dose (Gy) No. of patients 5-yr bNED (%) P value < 10 < 76 45 70 < 10 ≥ 76 37 100 0.002 10–19.9 < 76 18 42 10–19.9 ≥ 76 29 83 0.01 ≥ 20 < 76 13 21 ≥ 20 ≥ 76 21 20 0.15 PSA: prostate specific antigen; Gy: gray; bNED: biochemical no evidence of disease. Figure 3Open in figure viewerPowerPoint Comparison of bNED control rates between the unfavorable patient group (PSA >10 ng/mL or dose 76 Gy) versus the favorable patient group (PSA 76 Gy). bNED: biochemical no evidence of disease; 3DCRT: three-dimensional conformal radiation therapy; PSA: prostate specific antigen; Gy: grays. Comparison of bNED control between patients with Gleason 3 + 4 tumors versus Gleason 4 + 3 tumors demonstrated a worse outcome for the Gleason 4 + 3 subgroup, but this was not a statistically significant difference (74% vs. 65%; P = 0.26; Fig. 4), most likely because of the low numbers of patients (63 and 37 patients, respectively). Data regarding the exact histologic pattern (i.e., 3 + 4 vs. 4 + 3) were available only for 100 of the 163 patients with Gleason 7 tumors, thus explaining the denominator in Figure 4. Figure 4Open in figure viewerPowerPoint Comparison of bNED control rates between patients with Gleason 3 + 4 tumors versus Gleason 4 + 3 tumors. bNED: biochemical no evidence of disease; 3DCRT: three-dimensional conformal radiation therapy. DISCUSSION It has been well established that the histologic pattern of prostate carcinoma strongly correlates with malignant potential and clinical outcome.12 Patients with a Gleason score of 7, utilizing the Gleason system, represent an intermediate prognosis group. There have been several surgical series that have analyzed the outcome of patients with prostate carcinoma based on Gleason score. Kupelian et al.3 reported on 337 patients with clinical classification T1–T2 prostate carcinoma treated with radical prostatectomy alone. Surgical Gleason score, margin status, and capsular penetration all were found to be independent predictors of progression after radical prostatectomy. Oefelein et al.4 reported on the efficacy of radical prostatectomy for men with clinically localized, poorly differentiated (Gleason score ≥7) prostate carcinoma. Fifty-two patients had a Gleason score of 7. The authors demonstrated a 5-year likelihood of having an undetectable PSA of 50% for those patients with a Gleason score of 7 (biochemical failure was defined as an increase in the serum PSA level >0.4 ng/mL on 2 separate occasions). Gleason score also was found to be the most powerful predictor of disease progression and survival after radical prostatectomy. More recently, Epstein et al.13 reported on disease progression after radical prostatectomy in a subset of patients with Gleason score 7 tumors. The authors studied 488 men whose radical prostatectomy specimen revealed Gleason score 7 tumor without involvement of seminal vesicles or lymph nodes. Surgical margin status was the strongest predictor of disease progression. Moreover, patients with organ-confined disease and negative surgical margins of resection had a 64% progression free probability (with a mean follow-up of 4.15 years). The patients, however, were not stratified by pretreatment PSA. Several radiation series have evaluated the prognostic importance of Gleason grade in patients with prostate carcinoma treated with definitive radiation therapy. Zagars et al.2 grouped 648 T1–T4NXM0 prostate carcinoma patients according to Gleason Grades 2–3, 4–6, 7, and 8–10. The authors demonstrated that Gleason 7 was correlated with increasing local recurrence, distant failure, and worse survival. However, patients were not stratified by pretreatment PSA, and bNED control was not evaluated. Our institution previously has demonstrated that a Gleason score of 7 predicts worse bNED outcome compared with Gleason score of 2–4 and 5–6 for patients with prostate carcinoma treated with definitive radiation therapy.5 It was concluded that Gleason score 7 tumors represent a different biologic potential, presumably due to the presence of Gleason Grade 4 and therefore should not be grouped with Gleason 5–6 tumors. Stamey et al.14 reported a retrospective analysis of a cohort of 379 men with prostate carcinoma who were treated only by radical prostatectomy. The authors utilized a Stanford modified Gleason scale to estimate the proportion of each cancer that was poorly differentiated in each of the radical prostatectomy specimens. Briefly, they combined Gleason Grades 1, 2, and 3 into a single well differentiated category. The percentage of each cancer occupied by Gleason Grades 4 and 5 (labeled % Gleason Grade 4/5) was estimated for each radical prostatectomy specimen. The main outcome measure was biochemical progression of prostate carcinoma as defined by a serum PSA level of 0.07 ng/mL and rising. With a median follow-up of 5.73 years, the authors demonstrated that %Gleason Grade 4/5 was a highly significant independent predictor of biochemical failure, with only a 5.6% failure rate in men with no evidence of Gleason Grade 4/5 carcinoma compared with a failure rate ultimately approaching 87% for those men with evidence of Gleason Grade 4/5 carcinoma. These data suggest that patients with tumors with Gleason Grade 4 (i.e., tumors that are Gleason score 7) do worse compared with those who lack Gleason Grade 4. Our current report showed a difference in bNED outcome between Gleason 4 + 3 tumors compared with Gleason 3 + 4 tumors ( 64% vs. 72%), which was not statistically significant, but this may be due to low patient numbers within the 2 subgroups. Our current study demonstrates that patients with Gleason score 7 adenocarcinoma who had a pretreatment PSA <10 ng/mL who were treated with ≥76 Gy had excellent bNED control of 100% at 5 years compared with 70% in those patients receiving <76 Gy. In addition, patients with an intermediate pretreatment PSA of 10–19.9 ng/mL who received ≥76 Gy also enjoyed an improved bNED outcome of 83%, compared with 42% for those patients who received <76 Gy. These current data strongly support treating patients with low to intermediate PSA levels and the adverse feature of Gleason score 7 with higher central axis doses to achieve long term biochemical control. Patients with Gleason 7 tumors, however, who had pretreatment PSA levels ≥20 ng/mL experienced very poor bNED outcome when treated with radiation therapy alone, regardless of dose, and thus efforts should be directed toward multimodal or long term hormonal treatment strategies. CONCLUSIONS This study represents the first radiation therapy series to report solely on outcome of patients with prostate carcinoma with Gleason 7 tumors. Patients with Gleason score 7 adenocarcinoma who had a pretreatment PSA <10 ng/mL and received doses of ≥76 Gy had excellent bNED control at 5 years compared with patients receiving <76 Gy (100% vs. 70%), emphasizing the importance of higher central axis doses in treating Gleason 7 tumors. Patients with intermediate PSA (10–19.9 ng/mL) also enjoyed improved bNED control with doses ≥76 Gy compared with <76 Gy (83% vs. 42%). Pretreatment PSA ≥20 ng/mL portends a very poor bNED outcome for Gleason 7 patients treated with radiation therapy alone, regardless of dose, and thus efforts should be directed toward multimodal or long term hormonal treatment strategies. REFERENCES 1 Bagshaw MA, Cox RS, Ramback JE. Radiation therapy for localized prostate cancer: justification of long-term follow-up. Urol Clin N Am 1990; 17: 787– 802. CASPubMedWeb of Science®Google Scholar 2 Zagars GK, Ayala AG, von Eschenbach AC, Pollack A. The prognostic importance of Gleason grade in prostatic adenocarcinoma: a long-term follow-up study of 648 patients treated with radiation therapy. Int J Radiat Oncol Biol Phys 1995; 31: 237– 45. CrossrefCASPubMedWeb of Science®Google Scholar 3 Kupelian P, Katcher J, Levin H, Zippe C, Klein E. Correlation of clinical and pathologic factors with rising prostate-specific antigen profiles after radical prostatectomy alone for clinically localized prostate cancer. Urology 1996; 48: 249– 60. CrossrefCASPubMedWeb of Science®Google Scholar 4 Oefelein MG, Grayhack JT, McVary KT. Survival after radical retropubic prostatectomy of men with clinically localized high grade carcinoma of the prostate. Cancer 1995; 76: 2535– 42. Wiley Online LibraryPubMedWeb of Science®Google Scholar 5 Green GA, Hanlon AL, Al-Saleem T, Hanks GE. A Gleason score of 7 predicts a worst outcome for prostate carcinoma patients treated with radiotherapy. Cancer 1998; 83: 971– 6. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 6 Hanks GE, Schultheiss TE, Hunt M. Clinical experience with 3D radiotherapy treating prostate cancer. Proceedings of International Symposium of 3DRT of Prostate Cancer, St. Louis, MO; April 1993. Google Scholar 7 Partin AW, Kattan MW, Subong EN, Walsh PC, Wojno KJ, Oesterling JE, et al. Combination of prostate-specific antigen, clinical classification, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA 1997; 277: 1445– 51. CrossrefCASPubMedWeb of Science®Google Scholar 8 Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 447– 57. PubMedGoogle Scholar 9 Mantel N. Estimation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966; 50: 163– 70. CASPubMedGoogle Scholar 10 Cox DR. Regression methods and life tables [with discussion]. J R Stat Soc 1972; 34: 187– 220. Wiley Online LibraryGoogle Scholar 11 American Society for Therapeutic Radiology and Oncology Consensus Panel. Consensus statement: guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys 1997; 37: 1035– 41. PubMedWeb of Science®Google Scholar 12 Gleason DF. Classification of prostatic carcinomas. Cancer Chemother Rep 1966; 50: 125– 8. CASPubMedGoogle Scholar 13 Epstein JI, Pound CR, Partin AW, Walsh PC. Disease progression following radical prostatectomy in men with Gleason score 7 tumor. J Urol 1998; 160: 97– 101. CrossrefCASPubMedWeb of Science®Google Scholar 14 Stamey TA, McNeal JE, Yemoto CM, Sigal BM, Johnstone IM. Biological determinants of cancer progression in men with prostate cancer. JAMA 1999; 281: 1395– 1400. CrossrefCASPubMedWeb of Science®Google Scholar Citing Literature Volume89, Issue1215 December 2000Pages 2565-2569 FiguresReferencesRelatedInformation
Referência(s)