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© 2003 American Society for Clinical Oncology Prostate Cancer DNA Ploidy and Response to Salvage Hormone Therapy After Radiotherapy With or Without Short-Term Total Androgen Blockade: An Analysis of RTOG 8610From the Department of Radiation Oncology, Fox Chase Cancer Center, and Radiation Therapy Oncology Group, Philadelphia, PA; Department of Pathology, Karmanos CA Institute, and Department of Radiation Oncology, Wayne State University, Detroit, MI; Radiation Therapy Oncology Group, Philadelphia, PA; Department of Pathology, LDS Hospital, Salt Lake City, Utah; Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI; Radiation Oncology Center, Sacramento; and Department of Radiation Oncology, University of California, San Francisco, CA; Division of Radiation Oncology, Johns Hopkins Hospital, Baltimore, MD; and Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA. Address reprint requests to Alan Pollack, MD, PhD, Department of Radiation Oncology, Fox Chase Cancer Center, 7701 Burholme Ave, Philadelphia, PA 19111; email: A_Pollack{at}FCCC.edu.
Purpose: DNA ploidy has consistently been found to be a correlate of prostate cancer patient outcome. However, a minority of studies have used pretreatment diagnostic material and have involved radiotherapy (RT)-treated patients. In this retrospective study, the predictive value of DNA ploidy was evaluated in patients entered into Radiation Therapy Oncology Group protocol 8610. The protocol treatment randomization was RT alone versus RT plus short-course (  4 months) neoadjuvant and concurrent total androgen blockade (RT+TAB). Patients and Methods: The study population consisted of 149 patients, of whom 74 received RT alone and 75 received RT+TAB. DNA content was determined by image analysis of Feulgen stained tissue sections; 94 patients were diploid and 55 patients were nondiploid. Kaplan-Meier univariate survival, the cumulative incidence method, and Cox proportional hazards multivariate analyses were used to evaluate the relationship of DNA ploidy to distant metastasis and overall survival. Results: DNA nondiploidy was not associated with any of the other prognostic factors in univariate analyses. In Kaplan-Meier analyses, 5-year overall survival was 70% for those with diploid tumors and 42% for nondiploid tumors. Cox proportional hazards regression revealed that nondiploidy was independently associated with reduced overall survival. No correlation was observed between DNA ploidy and distant metastasis. The diminished survival in the absence of an increase in distant metastasis was related to a reduction in the effect of salvage androgen ablation; patients treated initially with RT+TAB and who had nondiploid tumors had reduced survival after salvage androgen ablation. Conclusions: Nondiploidy was associated with shorter survival, which seemed to be related to reduced response to salvage hormone therapy for those previously exposed to short-term TAB.
DNA PLOIDY has been investigated as a potential prognostic factor for prostate cancer for many years, and in the vast majority of reports, it has been found to be predictive of patient outcome.1–20 However, most of these studies were done using tissue from prostatectomy specimens. Far fewer have examined DNA ploidy as a pretreatment correlate of patient outcome using diagnostic material. Moreover, there are few reports wherein the predictive value of DNA ploidy was investigated in prostate cancer patients treated with definitive radiotherapy (RT). Conclusions about the association of DNA ploidy with outcome after RT are unclear because the findings have been somewhat divergent.21–26 In this analysis, DNA ploidy was characterized in the diagnostic material from patients participating in Radiation Therapy Oncology Group (RTOG) protocol 8610.27 RTOG protocol 8610 was a phase III randomized clinical trial designed to assess the effect of RT plus short-term neoadjuvant and concurrent total androgen blockade (RT+TAB) as compared with RT alone. The patients enrolled had locally advanced disease; tumors had a palpable surface area of 25 cm2 or greater. In addition, nearly one third of the patients had Gleason score 8 to 10 disease and 8% had documented lymph node involvement.27 The purpose of this analysis was to assess the prognostic significance of DNA ploidy, as determined by image analysis, for prostate cancer patients with high-risk features and to determine whether the addition of androgen ablation to RT affected the prognostic value of these measurements. There were 456 evaluable patients entered into the trial, and of these, 149 (33%) had tissue available for DNA ploidy analysis. These patients are the subjects of this report.
Study Population Characteristics The study population included patients entered into RTOG protocol 8610, entitled "A phase III trial of Zoladex and flutamide used as cytoreductive agents in locally advanced carcinoma of the prostate treated with definitive radiotherapy."27 This phase III randomized clinical trial for locally advanced prostate cancer was closed in 1991 and accrued a total of 471 patients, 456 of whom were evaluable. TAB with flutamide and goserelin acetate (Zoladex) was given for a total of 4 months, starting 2 months before radiotherapy and continuing during RT. Tissue blocks were obtained from 261 (57%) of the 456 evaluable patients. After hematoxylin- and eosin-stained samples were sectioned and reviewed, sufficient tumor for DNA ploidy analysis was present in 149 patient samples. The diagnostic material, which consisted of 113 samples from needle biopsies and 36 samples from transurethral resectates, was requested from participating institutions (> 100), reviewed centrally by the study pathologist (D.J. Grignon) in 98% of cases, and graded according to Gleason.28 A global Gleason score was assigned. The distribution of patients by Gleason score for the study group was 22 in Gleason score 2 to 5, 16 in Gleason score 6, 60 in Gleason score 7, and 50 in Gleason score 8 to 10; one patient case was not graded. The distribution of patients by clinical T category was 38 in T2 and 111 in T3. At the time the trial was initiated, pretreatment prostate-specific antigen (PSA) was not routinely used in the clinic. Pretreatment serum PSA values were available for only 19 (15%) patients of the study cohort and, as a consequence, are not included in the statistical analyses. A prior immunohistochemical analysis of p53 status was done in 129 patients29 who participated in RTOG protocol 8610. In that report, abnormal p53 expression (p53-positive by immunohistochemistry) was found to be significantly correlated with reduced survival. For this reason, p53 status is included in the analysis here. p53 status and DNA ploidy were determined in 113 patients.
DNA Content Measurements by Image Analysis Measurements were obtained at x200 magnification using 560-nm monochromatic light. DNA quantification was performed using the Image Measure software program (Phoenix Technology, Inc, Seattle, WA), with a PCVision Plus digitizing frame-grabber board (Imaging Technology, Inc, Woburn, MA) and a Logitech mouse (Fremont, CA). Both a Pulnix TM-745 camera (Sunnyvale, CA) mounted on an Olympus BH-2 microscope (Lake Success, NY) and a Sony monitor (San Jose, CA) were used to scan the specimens. For each sample, tumor cell and control cell nuclei were taken from the same slide. Each area of interest in the tissue was designated on the slide using a marking pen. For each slide, a black level and incident light level were set for calibration. Each designated area was scanned from left to right covering each field only once. Nuclei were chosen because they appeared not to be overlapped by other nuclei. For each sample, 100 control nuclei (endogenous fibroblasts) and 200 tumor nuclei were measured. The DNA content was plotted as Feulgen-stained DNA versus cell number and displayed in histograms. The DNA content mean, SD, and coefficient of variation (CV) were calculated for the control cells (2C control). The mean was used to calculate the DNA index (DI), which was the ratio of the mean nuclear cell DNA content of tumor population divided by the mean of the 2C control population. Tumor nuclei populations were considered diploid if the main peak DI was 0.80 to 1.20 with less than 35% of other DNA measurements outside of 2C + 2SD (on the basis of the control nuclei population). Populations were considered aneuploid if the main peak DI was less than 0.80 (hypodiploid) or greater than 1.20 (hyperdiploid) and were not considered tetraploid. Tetraploid populations had a DNA index of 1.80 to 2.20. Patients who had multiple peaks were considered aneuploid if more than 35% of the tumor nuclei population formed peaks in the range greater than 2C ± 2SD.
Definition of End Points
Statistical Analysis
The distributions of patient characteristics and treatment assignments were compared by the Pearson Multivariate Cox proportional hazard models were applied to each of the three end points. The initial multivariate analyses were restricted to only patients who had DNA ploidy determination. The analyses determined whether DNA content was of prognostic value after adjusting for treatment assignment and Gleason score as fixed covariates.36 All factors were considered as dichotomous variables and coded as follows: treatment assignment (0 for RT alone v 1 for RT + hormones), grouped Gleason sums (0 for sums 2 to 6 v 1 for sums 7 to 10), p53 (0 for negative v 1 for positive), and DNA content (0 for diploid v 1 for nondiploid). The fitted parameter from the Cox model was used to estimate the relative risk associated with each prognostic variable and the corresponding 95% confidence interval. A ratio of 1 would indicate no difference between the two subgroups. The larger the difference from 1, the greater the difference in the failure rates between the two subgroups. The treatment effect was modeled in such a way that a value less than 1 favored the addition of hormones. DNA ploidy was modeled in a way that a value greater than 1 indicates a greater risk of failure for DNA nondiploidy. All of the statistical comparisons were made with two-tailed tests. Another multivariate analysis adjusted for two additional factors: p53 and missing tumor determinations. Of the 456 evaluable patients, 149 (33%) had ploidy determinations, and 129 (28%) had p53 determinations. In only 113 (25%) patients were both ploidy and p53 determinations available. There are potential problems caused by the missing values. Selection bias may occur, wherein the patients in whom the assays were done do not constitute a random sample from the whole study. Consequently, the study cohort may have a better or worse outcome than the parent cohort. Moreover, when patients with missing values are excluded in the analysis, the number of patients to be analyzed may be relatively small, compromising the statistical power needed to detect clinically meaningful differences. To adjust for the problem of missing values in the second multivariate analysis, two variables instead of one were used to evaluate each marker. For DNA ploidy, patients were divided into three categories: determination not done, diploid, and nondiploid. For p53, patients were divided into three categories: determination not done, negative, and positive. The first variable for DNA ploidy would then be 0 for diploid/not done versus 1 for nondiploid, and the second variable would be 0 for nondiploid/not done versus 1 for diploid. The estimated relative risk of DNA ploidy was figuratively obtained by subtracting out the two variables. The 27 patients without centrally reviewed Gleason scores were excluded, leaving 429 patients for the analysis.
On the basis of DNA content measurement, 94 patients were classified as diploid, nine patients were classified as tetraploid, and 46 patients were classified as aneuploid. Because the number of tetraploid patients was small and not amenable to separate analysis, the nondiploid patients (tetraploid plus aneuploid; n = 55) were pooled, as has been described previously.22 Table 1  shows the distribution of patients by pretreatment characteristics and DNA ploidy. There were no statistically significant differences in the distribution of patients between the diploid and nondiploid groups, although a borderline significant relationship was seen with Gleason score. Of those that were nondiploid, 83% had a Gleason score of 7 to 10, as opposed to 69% for those that were diploid (P = .057). In a prior analysis of this patient cohort,29 abnormal p53 expression was reported to be a significant correlate of decreased overall survival and so is included here. There was no association between the distribution of patients by p53 status and DNA ploidy (correlation coefficient = 0.05).
Five-year Kaplan-Meier estimates of overall survival and any failure rates for all patients with the listed variable are shown in Table 2 . Five-year estimates of distant failure rates derived using the cumulative incidence method are also shown in Table 2. All factors listed in the table, including DNA ploidy, affected overall survival (assigned treatment and p53 status were borderline). Estimated 5-year overall survival was only 42% when nondiploidy was present, versus 70% in diploid patients (Fig 1). Figure 2 shows the breakdown of overall survival rates by protocol treatment assignment and DNA ploidy. Reduced survival rates were observed with nondiploidy in both treatment groups, but the difference between diploid and nondiploid only reached significance for the patients treated with RT+TAB. The patients in RTOG protocol 8610 had advanced disease, and this is reflected in the high failure of any type and low overall survival rates. Although the main end point of the study was overall survival, the other end points shed light into how survival was affected.
Gleason score, assigned treatment on protocol, and p53 status were associated with all of the end points shown in Table 2  . These associations demonstrate a logical relationship between progression, distant metastasis, and overall survival. Such a pattern, however, was not discerned for DNA ploidy in univariate or Cox proportional hazards regression analyses. Survival was worse when DNA nondiploidy was found, whereas any failure and distant metastasis rates were not related to ploidy status.
The initial multivariate analyses were performed using the 149 patients with a DNA ploidy determination. DNA ploidy was associated with overall survival after controlling for assigned treatment and Gleason score (Table 3
DNA ploidy was related to overall survival in multivariate analysis, yet no association with distant metastasis was observed. From these data, it is not intuitive how DNA ploidy affected survival. The lack of a significant correlation between nondiploidy and distant metastasis, although reduced survival was evidenced, led us to examine survival after the institution of salvage hormone therapy. Figure 3 shows that overall survival at 5 years after salvage hormone therapy was significantly lower in the presence of nondiploidy (45% v 23%; P = .018). Because the difference in overall survival could be related to an imbalance of intercurrent deaths, disease-specific survival results were compared. Even though there were fewer patients available for the analysis of disease-specific survival (n = 40), and therefore power was reduced, a borderline significant trend favoring the diploid population was observed (63% v 25% at 3 years; P = .06). The disease-specific survival results mirror those of overall survival.
Figure 4 indicates that the reduced survival of nondiploidy patients after salvage hormone therapy was the result of salvage hormone therapy resistance of these patients when they were assigned randomly to RT+TAB. This apparent resistance might be explained by an unequal distribution of patients with distant metastasis at the time salvage hormone therapy was initiated. Figure 5 shows that the same pattern was observed for RT+TAB-treated patients who did not have evidence of distant metastasis at the start of salvage hormone therapy. Overall survival at 5 years for patients who had distant metastasis at the time of salvage hormone therapy was 15% (n = 14) for patients randomly assigned to RT alone and 11% (n = 10) for those randomly assigned to RT+TAB. Subdivision by DNA ploidy had no effect on these relationships.
Figure 6 is an analysis of time to distant metastasis after salvage hormone therapy for patients who were free of distant metastasis at that time. The results indicate that it is not the absolute rate of distant metastasis that translated into reduced survival, but probably more rapid progression to death once distant metastasis was discernible. Prior treatment with TAB in nondiploid patients may promote resistance to salvage hormone therapy, thereby shortening survival.
Other potential DNA ploidy-associated differences in treatment outcome based on the protocol treatment assignments of RT alone versus RT+TAB are explored in Table 7 . In general, failure rates were more significantly reduced by RT+TAB compared with RT alone for those with diploid tumors than for those with nondiploid tumors. These results combined with the findings that survival after salvage hormone therapy is shortened indicate that short-term adjuvant TAB is not advisable in the presence of nondiploidy. Such subgroup analyses are fraught with potential errors related to the influence of unevenly distributed prognostic factors. Nonetheless, the results support consideration of DNA ploidy analysis in future trials of short-term RT+TAB.
Pretreatment prognostic factors have proven valuable in determining prostate cancer patient treatment strategies, especially in defining patients who should receive androgen ablation in combination with RT. The core factors used in clinical practice are serum PSA, Gleason score, and clinical stage.37 Apart from these, and possibly the proportion of cancer in the biopsy specimens,38 the most widely investigated and promising marker of disease progression and reduced survival is DNA nondiploidy.37 However, DNA ploidy analysis has not established a foothold in clinical practice. One explanation is that the majority of prior studies have not analyzed diagnostic material. For patients managed by RT, only a handful of reports have examined the association of DNA ploidy with outcome.21–26 Although the results have not been entirely consistent, nondiploidy has been related to poor patient outcome in the majority of studies. These reports have involved relatively small numbers of patients, and additional characterizations of DNA ploidy as a prognostic factor are needed. To our knowledge, no reports have described the predictive value of DNA ploidy for patients managed by RT+TAB.
The data presented revealed a number of relationships between DNA ploidy and patient outcome. For the multivariate analyses using the 149 patients with DNA ploidy determinations (Table 3 The prostate cancer patient population studied in RTOG protocol 8610 was clearly locally advanced and not typical of those treated with RT today. Overall, biochemical failure was 78% at 5 years, indicating that the treatments used were inadequate. This biochemical failure rate translated into a 36% distant metastasis rate. The rates of distant metastasis in the presence of diploidy and nondiploidy were 35% and 39%, respectively, which were not different statistically in univariate or multivariate analyses. Because the number of patients exhibiting distant failures was 46 of 94 and 22 of 55 for the diploid and nondiploid cases, respectively, there were sufficient events to measure the effect of DNA ploidy. In multivariate analysis, p53 status and Gleason score were independent correlates of distant metastasis. DNA nondiploidy, in this locally advanced high-risk cohort, was not a predictor of distant metastasis.
DNA nondiploidy has been correlated with reduced prostate cancer patient survival in numerous reports.37 This correlation was also observed in the data presented here, despite the lack of a relationship between nondiploidy and distant metastasis. The results in Fig 3
The data presented, however, are not conclusive for a number of reasons. First, there was no evidence of an increased rate of distant metastasis in those with nondiploidy. The compromised survival rate of nondiploid patients treated with RT+TAB after salvage hormone therapy seemed to be independent of distant metastasis rates (Fig 6 In conclusion, DNA ploidy shows promise in predicting the outcome of prostate cancer patients. Few reports exist on the relationship of DNA ploidy to outcome after RT, although there is ample evidence that nondiploidy is an independent adverse factor that should be considered in treatment planning. Pretreatment diagnostic material provides a reasonable representation of prostate DNA ploidy status,12,45,46 which may be measured on thin sections using image analysis. The image analysis technique for quantifying DNA content used in this report is the preferred method for the analysis of DNA ploidy status in diagnostic needle biopsy specimens because it requires less tissue than flow cytometry and allows for the histologic separation of normal epithelial and stromal cells from diploid tumor cells (a problem that plagues flow cytometric analyses). The data presented show that locally advanced patients with nondiploidy have reduced survival. The most striking association was that RT plus short-term neoadjuvant and concurrent TAB may predispose patients with nondiploidy to reduced survival after salvage hormone therapy. As with all retrospective tumor marker studies, this is a subset analysis, and although we attempted to correct for selection bias, it is possible that the findings are not representative. One should consider, however, that these data are consistent with prior reports that affirm the independent merit of DNA ploidy. DNA ploidy will likely become an important factor for the stratification of patients in future trials.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test with the Yates correction factor. Overall survival and any failure estimates were derived using the Kaplan-Meier method.
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