ELSEVIER

Int. J. Radiation Oncology Biol. Phys., Vol. 39. No. 5, pp. 101 I-1018, 1997 Copyright 0 1997 Elsevier Science Inc.

Printed in the USA. All rights reserved 0360-3016/97 $17.00 + .oO

PI1 SO360-3016(97)00508-7

l Clinical Investigation

EXTERNAL BEAM RADIOTHERAPY DOSE RESPONSE OF PROSTATE CANCER

ALAN POLLACK, M.D., PH.D. AND GUNAR K. ZAGARS, M.D.

Department of Radiation Oncology, The University of Texas, M. D. Anderson Cancer Center, Houston, TX

Purpose: To determine the external beam radiotherapy dose response of palpable Stage Tl-T4, mostly Nx, patients with adenocarcinoma of the prostate. Methods and Materials: There were 938 men consecutively treated between 1987 and 1995 who had pretreatment prostate specific antigen (PSA) levels. Posttreatment failure was defined as disease recurrence and/or two elevations in PSA on consecutive follow-up visits. The radiotherapy technique consisted of a four-field box with a small four-field reduction after 46 Gy in 844 patients (total dose of 60-70 Gy) or with a six-field conformal boost after 46 Gy in 94 patients (total dose of 74-78 Gy). Neoadjuvant or adjuvant androgen ablation was not used in any patient. Median follow-up was 40 months. Results: The mean and median radiotherapy doses for the entire group were 67.8 + 13.3 Gy (kSEM) and 66 Gy. The mean radiotherapy dose was higher in those who had Stage T3/T4 disease, Gleason scores of 8-10, or pretreatment PSAs of >4 nglml. In general, patients with more aggressive pretreatment prognostic features were treated to higher doses; yet, those that relapsed or had a rising PSA were treated to significantly lower doses. Actuarial analyses were facilitated by dividing patients into three dose groups: 567, >67-77, and >77 Gy. The actuarial freedom from failure rates at 3 years were 61, 74, and 96% for the low, intermediate, and high dose groups. Stratification of the patients by pretreatment PSA revealed that dose was a significant correlate of freedom from relapse or a rising PSA for those with PSAs >4-10, >lO-20, and >20 @ml. The only patients in which an improvement in outcome was not related to higher doses were those with a pretreatment PSA 54 @ml. Dose was significantly associated with freedom from failure for Stage TUT2 and Stage T3/T4 patients, as well as for those stratified by Gleason score. Multivariate analysis using Cox proportional hazards models showed that dose was an independent and highly significant predictor of relapse or a rising PSA. Conclusion: This retrospective review strongly indicates that radiotherapy dose to the prostate is critical to the cure of prostate cancer, even for favorable patients with pretreatment PSAs of >4-10 @ml, Stages Tl/T2, or Gleason scores of 2-6. Final conknation awaits the results of our randomized trial. 0 1997 Elsevier Science Inc.

Radiotherapy, Dose, Prostate-specific antigen.

INTRODUCTION

While dose response for the treatment of prostate cancer with external beam radiotherapy is presupposed, relatively few series have provided documentation. Probably most widely quoted are the Patterns of Care data (3, 5) and the cohort treated at Washington University in St. Louis (7, 8). More recently Hanks et al. (2, 4) have described the dose response of patients treated in the PSA era with conformal radiotherapy. They found that the benefit of increasing the dose to the prostate was restricted to patients with pretreat- ment PSAs > 10 rig/ml. Until recently (4), these conclusions had not been confirmed in multivariate analysis.

We describe here a large cohort of patients (n = 938) treated relatively uniformly in the PSA era from 1987- 1995. The uniqueness of this patient population is that no patient received androgen ablation, no patient received whole pelvis treatment, all were treated with the same

four-field arrangement to 46 Gy, and when conformal ra- diotherapy was used it was limited to the boost that was begun after 46 Gy. Thus, dose escalation was performed in a stepwise fashion over the years from 60 to 78 Gy using uniform fields, with the exception of the conformal boost in those treated to above 70 Gy. The data show that not only do patients with high-risk prognostic features have im- proved freedom from failure rates when treated to higher doses, but also those with pretreatment PSAs of >4-10 rig/ml, Gleason scores of 2-6, or Stage Tl/T2 disease exhibit the same dose response.

METHODS AND MATERIALS

Patient characteristics There were 938 consecutive men with adenocarcinoma of

the prostate that were treated at M. D. Anderson Cancer

Reprint requests to: Alan Pollack, M.D., Ph.D., Department of CA 06294 and CA 16672 awarded by the National Cancer Insti- Radiation Oncology (Box 97), M. D. Anderson Cancer Center, tute, U.S. Department of Health and Human Services, and an 15 15 Holcombe Boulevard, Houston, TX 77030. American Cancer Society Career Development Award (A.P.). Acknowledgements-This study was supported in part by Grants Accepted for publication 3 July 1997.

1011

1012 I. J. Radiation Oncology l Biology l Physics Volume 39, Number 5, 1997

300 264

k 122 = 100 is 62 z 50 4 '2 n

0’ ‘;1 ’ !‘I ‘,I ’ ! ’ 1,’ 1 I ‘-’ ,,

I I 60 65 70 75 80

Total isocenter dose (Gy)

Fig. 1. Distribution of patients by isocenter dose given. The num- ber of patients at each dose level is shown over each histogram bar.

Center between 1987 and 1995, and had pretreatment PSA values available. None of the patients were treated with neoadjuvant or adjuvant androgen ablation, or had evidence of clinical or radiographic lymph nodal or hematogenous metastases.

The patient cohort has been described in detail previously (17). In brief, the mean and median patient ages were 68 and 69 years, respectively, with a range of 47-84 years. Median follow-up from the completion of radiotherapy for those that were living was 40 months (range 6-l 11 months). The breakdown by palpable T-stage is 3% in TlA, 8% in TlB, 20% in TIC, 14% in T2A, 18% in T2B, 6% in T2C, 9% in T3A, < 1% in T3B, 21% in T3C, and < 1% in T4B. Gleason scoring was not assigned in 12 cases; the distribution was 1% Gleason 2,5% Gleason 3, 15% Gleason 4, 18% Gleason 5, 24% Gleason 6, 24% Gleason 7, 10% Gleason 8, 3% Gleason 9, and < 1% Gleason 10. Transurethral resection of the prostate (TURP) was performed in 159 patients prior to radiotherapy and of these 27 had Stage T3/T4. Staging pelvic lymphadenectomy was performed and was negative (Stage NO) in 97 patients.

The mean and median pretreatment PSA values were 12.6 and 9.0 r&ml respectively, with a range of 0.3-150 q/ml. The Hybritech assay (lower limit 0.3 rig/ml) was used until 1993, at which time the TOSOH assay (lower limit 0.1 rig/ml) was used (9). The mean and median pretreatment serum prostatic acid phosphatase (PAP) levels by the enzy- matic assay (12) were 0.4 and 0.3 mu/ml. PAP levels were available in 880 patients (94%).

The radiotherapy treatment involved a standard four-field box for all patients for the first 46 Gy. In all cases, 18 MV photons were used, the fraction size was 2 Gy, and elective lymph node irradiation was not performed. As previously outlined (10, 17), the typical field size was 11 X 11 cm anteroposteriorly and 11 X 9 cm laterally. In the lateral fields, small blocks were routinely placed over the anterior- superior aspect of the bladder and in some the rectal block was shaped to split the rectum, although in most the colli-

mator border was used. The AP:PA fields were not blocked. In 843 patients the reduction after 46 Gy was delivered using the same four-field arrangement, typically 9 X 9 cm anteroposteriorly and laterally. The original blocks were left in place for the reduction. For the other 95 patients a six-field conformal boost was employed as detailed previ- ously (10). The total doses in the conformal boost group ranged between 74-78 Gy. Informed consent was obtained for the 82 patients treated to 78 Gy, as they participated in a randomized trial comparing 70 Gy conventional to 78 Gy conformal radiotherapy (10). As described previously (lo), the conformal prostate boost involved three-dimensional treatment planning using 0.5 cm spaced CT-scan images with margins of 1.25-1.5 cm anteriorly and inferiorly, and 0.75 posteriorly and superiorly from the target volume (prostate plus seminal vesicles) to the blocked edge. The dose was specified to the isocenter in all cases.

The primary endpoint used herein was disease relapse or a rising PSA profile. The rising PSA profile was defined as two or more increasing values on consecutive follow-up examinations. Follow-up was typically at 3-month intervals for the first 2 years and every 6 months thereafter. There were a total of 6,241 PSA values for the 938 patients, an average of 6.7 per patient.

The Berkson-Gage and Kaplan-Meier methods were used to calculate the actuarial curves and statistically significance differences were determined using the log rank test (6). Cox proportional hazards analysis (1) was used to determine the independence of one covariate from another in predicting actuarial freedom from relapse or a rising PSA (freedom from failure).

RESULTS

Figure 1 displays the distribution of patients by the radi- ation dose at isocenter. The major dose levels used were 64 Gy (n = 202), 66 Gy (n = 264), 68 Gy (n = 122), 70 Gy (n = 221), and 78 Gy (n = 82). These different dose levels reflect changes in treatment policy, with the dose gradually increased over the study period. For example, in the late 1980s those with favorable, intermediate, and poor prog- nostic features received 60-62, 64-66, and 66-68 Gy, respectively. From 1990-1992 only two patients received 562 Gy. From 1993-1995 only three patients received ~68 Gy. Table 1 summarizes this trend wherein the mean dose was 64 Gy in 1987-1989, compared to 72 Gy in 1994-

Table 1. Radiotherapy dose by year of treatment

Dose (Gy)

Year n Mean t SE* Median Ranee

1987-1989 163 64.3 + 13.5 64 60-68 1990-1991 269 65.1 k 7.5 66 60-68

1992-1993 291 69.0 k 20.0 68 60-78

1994-1995 215 72.1 + 25.2 70 66-78

* p < 0.0001, Kendall-Spearman Correlation. SE = standard error.

Dose response of prostate cancer l A. POLLACK AND G. K. ZACARS 1013

Table 2. Relationship of mean radiotherapy dose to various prognostic factors and the incidence of treatment failures

Factors n Mean 2 SE Median Range

Palpable stage TllT2 643 67.4 5 16.3 66 60-78 T3lT4 295 68.7 L 22.4* 68 60-78

Gleason score 2-6 580 67.0 +- 16.0 66 60-78 7 224 68.7 + 26.7 68 60-78 8-10 122 69.8 t 39.8+ 70 64-78

Pretreatment PSA 54 167 66.0 k 27.3 64 60-78 NV10 363 68.4 + 22.1 68 60-78 >lo-20 259 68.4 2 26.0 68 60-78 >20 149 67.1 ? 28.4* 66 60-78

Pretreatment PAP so.4 680 67.6 -c 15.4 66 60-78 >0.4-0.8 189 68.1 5 31.9 66 60-78 >0.8 11 68.0 2 97.2 68 64-76

TURP in T3/T4 No 268 68.8 !I 24.1 68 60-78 Yes 27 67.6 ? 50.1 66 6678

Failure No 665 68.5 ? 17.0 68 60-78 Yes 273 66.2 -c 15.7* 66 6c-78

*p < 0.05 Mann-Whitney; ‘p < 0.05 Kendall-Spearman Correlation. PSA = prostate-specific antigen; PAP = prostatic acid phosphatase; TURP = transurethral resection of the prostate; Failure = relapse

or a rising PSA; SE = standard error.

1995. Conformal boost radiotherapy was begun in the 1992-1993 time period as described earlier (10). The shift in treatment policy to use higher doses is most evident between 1990-1991 and 1992-1993, when the mean dose went from 65 Gy to 69 Gy.

The general treatment policy, particularly in the late 1980s and early 1990s was to treat Stage T3/T4 disease to a slightly higher dose than Stage TUT2 disease. Table 2 shows that the mean differences by stage, while slight, were statistically significant. Mean differences in dose were also statistically significant when stratified by Gleason score and pretreatment PSA. In general, those with worse prognostic features received slightly higher doses. Despite this trend, patients who remained free of failure received significantly higher mean doses than those who failed. These data sug-

p < 0.0001

0.6

0.0 * I I I I I 60 65 70 75 80

Total isocenter dose (Gy)

Fig. 2. Logistic regression curve for isocenter dose by fraction failing (relapse or a rising PSA). The solid circles represent the results for pooled data between the dose levels of 562, >62-65, >65-67, >67-69, >69-71, >71-77, and >77 Gy.

gest that dose is an important determinant of treatment success.

Logistic regression analysis of failure by radiotherapy dose is displayed in Fig. 2. The relationship between failure and dose was highly significant; the greater the dose, the lower the risk of relapse or a rising PSA. Such calculations are based on nonactuarial data and are subject to inaccura- cies due to differences in follow-up for patients treated to different doses. Differences in follow-up clearly exist in the data set described. Dividing the patients into three dose

Table 3. Correlation of grouped dose to other potential prognostic factors

Percent (n)

Factor 567 Gy >67-77 Gy >77 Gy P*

Palpable stage Tl/T2 T3fT4

Gleason score 2-6 7 8-10

Pretreatment PSA 54 >4-10 > lo-20 >20

Pretreatment PAP so.4 >0.4-0.8 >0.8

TURP in T3/T4 No Yes

71 (354) 29 (146)

74 (365) 18 (87) 8 (9)

23 (115) 32 (162) 25 (124) 20 (99)

78 (379) 21 (101)

1 (5)

90 (131) 10 (15)

66 (235) 66 (54) 34 (121) 34 (28) 0.28

50 (177) 46 (38) 32 (114) 28 (23) 18 (62) 26 (21) <O.OOOl

13 (45) 9 (7) 45 (161) 49 (40) 30 (106) 35 (29) 12 (44 7 (6) <0.0001

78 (248) 70 (53) 20 (65) 30 (23) 2 (6) 0 (0) 0.22

91 (110) 96 (27) 9 (11) 4 (1) 0.53

* Chi-square. PSA = prostate-specific antigen; PAP = prostatic acid phos-

phatase; TURP = transurethral resection of the prostate.

1014 I. J. Radiation Oncology 0 Biology l Physics Volume 39, Number 5, 1997

1.0

-. - -

=0.007 'EI 0.6 + 8 c=67Gy

(I: -B- >67-77Gy n -.- '77Gy Overall p < 0.0001 0

0.4 .I f E R 0.2 MONTH: 0 14 48

DOSE<67: 500 320 146

4 DOSE%7-77: 356 142 6 DOSE>77 82 25 -

o.o).,.,.,.,.,.,.,.,.,.,.,.,

0 5 10 15 20 25 30 35 40 45 50 55 60 Months after radiotherapy

Fig. 3. Actuarial dose response for all patients divided into the dose levels of 167, >67-77, and >77 Gy. The table insert shows the number of patients at risk before treatment start and at 24 and 48 months after the completion of treatment. The overall p-value and thep-values for the pairwise comparisons of 567, vs. >67-77 Gy and >67-77 vs. >77 Gy are shown.

Pretreatment PSA <=4

o 5 IO 15 20 25 30 35 40 45 50 55 60 ccc 0

%

Pretreatment PSA >lO - 20

0.6

0.6

MONTH: 0 2 48 0.2 DOSE<67: 124 78 27

DOSE>67-77: 106 44 4 DOSW77: 29 10 -

o.o,.,.,.,.,.,. I. I, I* II I * I.1 0 5 10 15 20 25 30 35 40 45 50 55 60

groups revealed that follow-up was significantly different. For those treated to 567 Gy the mean and median follow-up was 60 and 59 months (range 7-111 months), >67-77 Gy the mean and median follow-up was 27 months (range 6-77 months), and >77 Gy the mean and median follow-up was 20 and 19 months (range 6-37). These dose categories, therefore, are representative of the gradual dose escalation that took place over the study period.

Table 3 illustrates the distribution of patients by prognos- tic factors using these dose groupings. In the late 1980s and early 1990s the general policy was to treat more advanced patients with higher doses and such a pattern is evident. The most pronounced differences were between those that re- ceived 567 Gy vs. >67-77 Gy. The ~67 Gy dose group had a greater proportion of Stage Tl/T2, Gleason 2-6, and pretreatment PSA 14 rig/ml patients. The >77 Gy had fewer patients with pretreatment PSA >20 rig/ml and PAP >0.8, reflecting a change in policy to treat such patients with androgen ablation plus radiotherapy. Actuarial analy- ses were then undertaken to account for the differences in follow-up, with multivariate Cox proportional hazards anal-

Pretreatment PSA >4 - 10

0.6

0.6

. p = 0.001 0.4-

MONTH: 0 24 &3 0.2- DOSE<67: 162 111 46

DOSE>67-77: 161 58 1 DOSE>77: 40 10 -

0.0 .,I,.,. g .,I,. 4. I- I * I - I, I 0 5 10 15 20 26 30 35 40 45 50 55 60

Pretreatment PSA >20

U.d MONTH: 0 2 48 DOSE<67: 99 29 6 DOSE>61-77: 44 13 -

,.,I \\ DOSE>77: 6 2 -

O.O!.,.,.,.,.,.,.,.,.,.,.,‘, 0 5 10 15 20 25 30 35 40 45 50 55 60

Months after radiotherapy

Fig. 4. Actuarial dose response of patients grouped by pretreatment PSA. The table inserts shows the number of patients at risk before treatment start and at 24 and 48 months after the completion of treatment. The overall p-values are shown.

Dose response of prostate cancer l A. POLLACK AND G. K. ZAGARS 1015

yses to account for the unequal distribution of prognostic factors.

Figure 3 shows that dose was significantly related to actuarial freedom from failure. Other factors that have been found to significantly correlate with freedom from failure include pretreatment PSA, stage, and Gleason score (17). The effect of dose on freedom from failure when grouped by the other significant prognostic factors was examined.

The division of patients by pretreatment PSA revealed that dose significantly affected outcome in all patients ex- cept those with pretreatment PSAs 54 rig/ml (Fig. 4). Likewise, dose was significantly associated with freedom from failure across the categories of Gleason score (Fig. 5) and stage (Fig. 6) tested. Because there were much fewer patients and follow-up was shorter in the >77 Gy group, the overall statistical differences seen in Figs. 4, 5 and 6 were more a consequence of the pairwise differences between the 567 and <67-77 Gy groups.

The independence of dose as a predictor of freedom from failure was confirmed in Cox proportional hazards analyses. Table 4 shows that dose was only second to pretreatment PSA in importance. The fact that these findings were not dependent on whether dose was included as a categorical or continuous variable indicates that the groupings that were used were representative of the overall pattern.

DISCUSSION

The dose response of prostate cancer to external beam radiotherapy has been described in a relatively small num- ber of series, considering the vast literature on treatment outcome. One contributing factor may be that single insti- tutions usually have treatment policies that restrict doses to a limited range. Large numbers of patients are required to make such determinations since an increase in dose of 8 -10 Gy is unlikely to cause a dramatic enhancement in disease end points, i.e., local control, particularly for those with Tl-T2 disease. In pre-PSA era reports of dose response, retrospective reviews of two patient groups came to similar conclusions and have been widely quoted.

Perez et al. (7, 8) provided evidence, albiet weak, that a dose response between 60-70 Gy existed. The initial report from St. Louis (8) revolved around 139 Stage C patients, which necessitated that subgroups consist of small numbers; for example, there were only 13 patients receiving less than 60 Gy. An update of these data were included in a summary of their experience treating pros- tate cancer with external beam radiotherapy and was therefore limited (7). They described a borderline dose response for Stage C patients (p = 0.07) and found no relationship between dose and pelvic control for Stage B patients (p = 0.24). Of note, there were only 13 patients in the low-dose group with Stage B disease; the lack of statistical difference might have been related to small patients numbers since a promising difference of about 15% (31-16% approximately) in pelvic relapse between the low-dose and high-dose groups was seen.

Hanks et al. (3) described the dose response of a larger

Gleason 2-6

- - -.- ‘77 GY p = 0.0001 0.4-

MONTH: 0 24 48

0.2- DOSE<67: 365 250 126

DOSE>67-77: 177 85 4

DOSE>77: 38 10 -

O.O~.,.,.,.,.,~,~,~,.,~,‘,~l 0 5 10 15 20 25 30 35 40 45 50 55 60

Gleason 7

g 1.0

2 0.8 E ccc 0 0.6

o 5 IO 15 20 25 30 35 40 45 50 55 60

Gleason 8-10

0 5 10 15 20 25 30 35 40 45 50 55 60

Months after radiotherapy Fig. 5. Actuarial dose response of patients grouped by biopsy Gleason score. The table inserts show the number of patients at risk before treatment start and at 24 and 48 months after the completion of treatment. The overall p-values are shown.

patient cohort using the Patterns of Care database. A sig- nificant relationship between dose and local control was observed. A breakdown of the patients by stage revealed

l = 0.8- 84

%

ii 0.8- z

ctl

g 0.4-

-,

I. J. Radiation Oncology l Biology l Physics

Stage TUT2

>67-77Gy >77Gy p = 0.0001

MONTH: 0 24 48 DOSEz67: 354 243 109 DOSE>67-77: 235 90 - DOSE>77: 54 16 -

h o.oh 0 5 10 15 20 25 30 35 40 45 50 55 60

Volume 39, Number 5, 1997

Stage T3/T4

0.8

0.6

MONTH: 0.2 DOSEs67:

DOSE>67-77: DOSE>77:

146 77 37 121 52 6 28 9 -

o.o:.,.,.,.,. ,.,.,* ,.I. ,. ,‘I 0 5 10 15 20 25 30 35 40 45 50 55 60

Months after radiotherapy Fig. 6. Actuarial dose response of patients grouped by palpable stage. The table inserts shows the number of patients at risk before treatment start and at 24 and 48 months after the completion of treatment.

that only T3 patients experienced a clinically relevant ben- efit from the use of higher doses. Local control for Stage T2 patients was high and minimally different for those that received 55-~65 Gy (=83%, n = 34) vs. 65>70 Gy

(=88%, iz = 91). A somewhat convincing case was made for a dose response in Stage T3 patients, yet, based on local control the benefit of higher doses for Stage T2 patients remained to be established. Similar conclusions were reached in another report (5), pooling the data from three patterns of care surveys (n = 1516).

There is a randomized prospective trial using a conformal proton boost to achieve prostate doses of 75.6 Gy (cobalt Gray equivalent) in one arm, compared to 67.2 Gy in the other arm using photons throughout (13). Although the results were reported in 1995, this is a pre-PSA study that was begun in 1982. The trial was designed for Stage T3/T4 patients. Comparing clinical end points such as local control and survival did not reveal any differences between the treatment arms when the entire group was compared. Sub- group analysis disclosed that for patients with higher Glea-

Table 4. Independent correlates of relapse or a rising PSA in Cox proportional hazards analyses

Variable Chi-square df p

Grouped analysis Pretreatment PSA Categorical 116 3 <0.0001 Isocenter dose Categorical 44 2 <0.0001 Gleason score Categorical 26 2 <0.0001 Palpable stage Categorical 24 1 <0.0001

Ungrouped analysis Pretreatment PSA Continuous 59 I ~0.0001 Isocenter dose Continuous 39 1 <0.0001 Gleason score Categorical 25 2 <o.ooo 1 Stage Categorical 44 1 <0.0001

df = degrees of freedom; PSA = prostate-specific antigen.

son scores outcome was improved in the high dose arm. Because the patients enrolled were clinically very advanced and pretreatment PSA would likely have been high if it were available, it is probable that most would receive combined modality therapy today. As a consequence, the results may not be applicable to patients treated in the PSA era.

The application of PSA to assess patient outcome using the rising PSA profile and as a pretreatment prognostic factor (14) has established that clinical local control as an end point is wholly inadequate as a determinant of treatment efficacy. Our data have demonstrated that a rising posttreat- ment PSA signifies local disease persistence in the vast majority, and that for this reason a high pretreatment PSA signifies radioresistance (15, 16). In examining dose-re- sponse relationships today, the rising PSA profile must be included in the determination of treatment outcome, patients must be stratified by known prognostic factors including pretreatment PSA, and, in the absence of a randomized trial, multivariate analysis must be performed to account for any unequal distribution of prognostic factors. Another key de- terminant to detecting a dose response is that follow-up must be sufficient, and this is notably critical for low-risk patients.

With the recognition of increased failure rates based on PSA and the advent of conformal radiotherapy, single in- stitutions now have treated patients with prostate cancer to a wider range of doses. A recent report by Hanks et al. (2)

involving 375 patients treated at Fox Chase Cancer Center was the first in the PSA era to examine dose response. Despite a median follow-up of only 21 months, a dose response for patients with pretreatment PSAs >lO rig/ml was documented. Most comparisons were made using ac- tuarial 24 months freedom from biochemical failure rates, which in our opinion is too short to evaluate favorable patients with pretreatment PSAs <lO rig/ml. Although the same conclusions were reached in a recent update of their

conformal dose escalation study (4) involving 233 patients followed for a minimum of 3 years, more patients or a broader dose range may be needed to delineate the smaller differences in biochemical failure in more favorable patients with pretreatment PSAs <lo rig/ml. Indeed our data (Fig. 4) and those of Roach et al. (11) show that dose was a significant correlate of outcome for patients with pretreat- ment PSAs in the 4-10 rig/ml range.

In a preliminary report of 524 evaluable patients, the Memorial group also described a dose response for patients treated in the PSA era (18). Dose escalation was accom- plished in a nonrandomized fashion using conformal photon radiotherapy. The primary endpoint was PSA nadir levels of 51 rig/ml at 2-3 years postradiotherapy. They found that dose (c75.6 vs. 275.6 Gy) was the strongest independent correlate of realizing this PSA nadir level. Pretreatment PSA and Stage were also significant in multivariate analy- sis, while Gleason score was not.

The series and analyses reported here are unique to others that have examined the dose response of prostate cancer in several respects. This is the largest (n = 938) PSA era single-institution series, has the longest median follow-up (40 months), is comprised of patients with pretreatment and frequent posttreatment PSA assessment, and consists of patients treated consecutively to a broad range of doses using limited fields-not whole pelvis. Uniformity of the field arrangements was even extended to those that received doses above 70 Gy because the conformal portion of the treatment was restricted to the boost and the initial 46 Gy was delivered with a standard four-field box arrangement. Whereas such uniformity in treatment is unprecedented, there was an unequal distri-

Dose response of prostate cancer l A. POLLACK AND G. K. ZAGARS 1017

bution of prognostic factors in the dose groups tested. In general, this was the consequence of a policy to take the prostate to higher doses when adverse prognostic features were present. Other possibly confounding conditions, such as the treatment of many high-risk patients with androgen ablation plus radiation that would exclude them from the analyses presented, could have contributed to the results observed. This ostensibly obvious flaw in retrospective comparisons necessitates multivariate anal- yses to correct for such imbalances. Our results clearly demonstrate that dose is a strong independent predictor of relapse or a rising PSA (Table 4). Counter to the conclu- sions of Hanks et al. (2, 4), in our series patients with favorable prognostic features such as pretreatment PSA between 4-10 (Fig. 41, Gleason score 56 (Fig. 5) or Stage Tl-T2 (Fig. 6) benefited significantly from the administration of higher doses. No dose-response rela- tionship was seen for patients with PSAs 54 nglml; however, it is conceivable that with longer follow-up and larger patient numbers a difference would be manifested.

Considering the pitfalls of retrospective analyses, and that the only randomized trial was initiated in the pre-PSA era and was essentially negative (13), another randomized trial is warranted. At present, we have enrolled over 250 patients in such a study, with the objective of 300 patients. As described previously (IO), the randomization is between 70 Gy using four-field conventional radiotherapy vs. 78 Gy using four-field conventional treatment to 46 Gy, followed

by six-field conformal treatment. To date, side effects for the two treatment groups have been identical, and no patient has had a severe complication requiring surgical interven- tion. We anticipate completion in l-2 years.

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cancer and radiation therapy-The message conveyed by se- rum prostate-specific antigen. Int. J. Radiat. Oncol. Biol. Phys. 33:23-25; 1995.

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