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The role of radiation therapy in stages A2 and B adenocarcinoma of the prostate
0360-3016/H $3.00 + .@I copyright 0 1988 Pergarn0n Press plc
hf. J. Radiafion Oncology Biol P/p.. Vol. 14, pp. 701-709 Printed in the U.S.A. All rights reserved.
??Original Contribution
THE
ROLE
OF RADIATION THERAPY IN STAGES A2 AND ADENOCARCINOMA OF THE PROSTATE
B
GUNAR IS. ZAGARS, M.D.,* ANDREW C. VON ESCHENBACH, M.D.,? DOUGLAS E. JOHNSON, M.D.? AND MARY JANE OSWALD, B.S.* The University of Texas M. D. Anderson Hospital and Tumor Institute, at Houston Between 1965 and11982 definitiveexternalbeamradiationtherapywas given to 114 patientswith clinicallyStaged A2 (32 patients) and B (82 patients) adenocarcinomaof the prostate. These patients were not consideredto be surgical candidatesbecause of age, comorbidityor disease extent, or because they had refused surgery. Total prostatic doses rangedfrom 60 to 70 Gy. For 90 surviving patients, follow-up duration ranged from 32 to 188 months with a median of 5 years. The 5- and lo-year uncorrected survival rates for all patients, which were 89% and 68% respectively, were no different from the survival expectation of age-matched men in the general population. Disease-free survival rates at the same time periods were 89% and 86%. There were no significant differences in disease-free survival between Stage A2 and Stage B. Four patients (3.5%) developed local recurrence. Bone metastases, which occurred in 9 of 11 treatment failures were the predominant cause of failure. An analysis of 11 potential prognostic factors was fruitless. Pelvic node irradiation did not improve the outcome. The incidence of complications was, acceptable. Anorectal problems developed in 20% of patients and urinary manifestations occurred in 20%, and only 2 patients (1.8%) developed serious problems. We concluded that localized external beam high-
energy radiation therapy provides excellent local control for disease limited to the prostate, with survival rates that rival those of radical surgery. Prostatic carcinoma, Stage B, Radiation therapy.
1NTB:ODUCTION
in determining the outcome after XRT; and (e) the definition of optimal XRT dose and fractionation parameters. Moreover, several recent reports in the urologic literature have displayed considerable antipathy toward XRT for early prostate cancer,15P36,38 even to the extent of claiming that radiation therapy is of no therapeutic value in the management of patients with prostatic adenocarcinoma. This retrospective review of 114 patients with Stages A2 and B prostatic adenocarcinoma treated by XRT was done to address the questions raised regarding long-term outcome for this disease and to see whether the antipathy toward XRT is in any way justified.
With few exceptions,4.5.‘2 most authorities recommend some form of radical treatment for prostatic adenocarcinema when disease is clinically confined to the prostate (Stages A2 and B). The traditional and time-honored approach to this stage of disease is radical prostatecHowever, the presumed superiority of tomy. 10~17~‘9~22~30~33
radical surgery has been brought into question over the past lo- 15 years by reports that radiation therapy (XRT) is also highly effective.‘,3*25,39,41*49 This has led to an increasing use of XRT in patients with early prostatic carcinoma. A recent survey by the American College of Surgeons showed that in the 9 13 U.S. institutions reviewed in 1983, XRT was the single most common modality employed for clinical Stage B disease.42 Nevertheless, some important issues remain unsettled, including (a) the radiocurability of early-stage disease; (b) the need for pelvic node irradiation; (c) the long-term local control rate; (d) the significance of various biologic factors, including stage,
METHODS
AND
MATERIALS
Patient characteristics Between January 1965 and December 1982, 114 patients with clinical Stage A2 or B adenocarcinoma of the
* Dept. of Clinical Radiotherapy. t Dept. of Urology. Reprint requests to: G. K;. Zagars, M.D., Department of Clinical Radiotherapy, Division of Radiotherapy, The University of Texas M. D. Anderson Ho:spital and Tumor Institute, at Houston, 1515 Holcombe Blvd., Houston, TX 77030.
This study was supported in part by Grant number CA-06294 awarded by the National Cancer Institute, U.S. Department of Health and Human Services. Accepted for publication 4 November 1987.
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prostate were treated with external beam megavoltage radiation at The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston. Stage A2 was defined as multifocal or diffuse carcinoma not evident by rectal palpation of the prostate,3’ and Stage B was palpable carcinoma without palpatory evidence of extension beyond the gland. Patients in both stages had no clinicalradiographic evidence of lymphatic or hematogenous metastases. During the years encompassed by this review, patients with Stage A2 or B disease were offered radical prostatectomy unless co-morbidity contraindicated surgery or disease was felt to be adjacent to the prostatic capsule, especially at the apex. Thus, the patients in this series are those for whom surgical intervention was considered inappropriate or who refused prostatectomy. Thirty-two patients had Stage A2 and 82 had Stage B disease. Patients with Stage A2 generally had obstructive urinary symptoms, and 30 of these (94%) underwent transurethral resection of the prostate (TURP). One Stage A2 patient was diagnosed after suprapubic enucleation of the prostate and one had a positive “blind” transrectal biopsy. Among the patients with Stage B, the disease was detected on routine physical examination in 28 (34%) and 2 had suprapubic enucleation for obstructive symptoms. Among the Stage B patients, the disease was confined to the right lobe in 34 (42%), to the left lobe in 24 (29%), and involved both lobes in 24 (29%). For the 58 patients with disease in one lobe, we were unable to quantitate disease volume retrospectively into discrete nodules versus involvement of the entire lobe. Each patient’s histopathologic diagnosis was confirmed by the department of pathology at U.T. M. D. Anderson Hospital, and histologic grading according to the M. D. Anderson Hospital system’ was available in 43 cases (38%). Staging evaluation varied according to the availability of modalities during the 18 years encompassed by this review. Serum prostatic acid phosphatase was determined in 108 cases (95%) and was measured using the BesseyLowry method in 16 cases and the Roy method in 92 cases.43 Radionuclide bone scans were performed in 103 cases (90%) and skeletal surveys were done in 33 cases (29%). Excretory urography was done in 70 patients (6 l%), and in recent years the upper urinary tracts were evaluated from the radionuclide bone scan images. Bipedal lymphangiography (LAG) was performed in 78 patients (68%). During the time period of this study, staging pelvic lymphadenectomy was not performed. Treatment methods The policy for patients with Stages A2 and B prostate cancer was to reserve endocrine manipulation for treatment failure, but, 3 patients had undergone orchiectomy and 16 patients had received estrogen for a median time of 3 months before referral to our institution. Estrogen was discontinued in 14 of these 16 patients. Thus, significant early endocrine manipulation occurred in 5 patients (3 orchiectomy, 2 estrogen). Patients who had undergone
April 1988, Volume 14, Number 4
TURP began XRT after a minimum healing time of 6 weeks. One hundred and twelve patients were treated with high-energy (18-25 MV) photon beams, and 2 patients received 360” cobalt rotation. Treatment volume varied according to the policy regarding pelvic node irradiation. Before 1977 no attempt was made to treat pelvic nodes systematically,34 and the vast majority of patients were treated through a four-field arrangement using 10 X 10 cm anterior and posterior portals and 10 X 8 cm lateral portals. The inferior margin of these fields was at or just superior to the lower border of the ischial tuberosities and the posterior border of the lateral fields bisected the rectal lumen. After delivering 50 Gy in 5 weeks at 2 Gy per fraction, a reduced volume usually measuring 8 X 8 cm was given an additional 1O-20 Gy either with anteroposterior opposed fields or with a four-field technique. After 1977 the initial 50-Gy dose was delivered to a slightly larger volume using 13 cm wide and 11 cm high anteroposterior portals and 11 X 8 cm lateral fields. After 1978 fields were further enlarged to 14- 15 cm in width and 12 cm in height to cover the external iliac nodes. The smallvolume coned-down prostatic fields were 8 X 8 cm in 97 cases, 9 X 9 cm in 11 cases, 10 X 8 cm in 2 cases, and 9 X 8 cm in 2 cases. There were no systematic differences in irradiated volumes between Stage A2 and Stage B patients. Treatment techniques varied also over the years, again largely as a matter of policy. From 1965 to 1977, 29 patients were treated with four fields to 50 Gy followed by anteroposterior coned-down fields only, and one field was treated daily. From 1978 on, four fields were used throughout treatment and one field was treated daily in 46 patients, whereas 37 patients had more than one field treated daily. Cobalt rotation, used in only 2 patients, was abandoned in 1967. Radiation doses were delivered at 2 Gy daily specified at the tumor along the central axis of each beam. After 50 Gy in 5 weeks, coned-down volumes were given an additional lo-20 Gy in 5 to 10 fractions. For patients with Stage A2 disease, doses were distributed as follows: 60.00-61.99 Gy for 2 patients; 62.00-63.99 Gy for 4 patients, 64.00-65.99 Gy for 15, 66.00-67.99 Gy for 9, 68.00-69.99 Gy for 1, and 70.00-7 1.00 Gy for 1. For patients with Stage B disease, doses were distributed as follows: (60.00 Gy for 3 patients, 60.00-6 1.99 Gy for 2, 62.00-63.99 Gy for 7, 64.00-65.99 Gy for 24, 66.0067.99 Gy for 28, 68.00-69.99 Gy for 7, and 70.00-7 1.OO Gy for 11. Generally, patients who relapsed received hormonal management. Of the 11 who failed, 5 received oral estrogen, 4 had an orchiectomy and were given estrogen, and 2 had nonendocrine treatment. Follow-up The majority of patients were seen regularly at the U.T. M. D. Anderson Hospital; and the rest were seen by the
Stage B prostatic cancer 0 G. K. ZAGARSet al.
referring urologist, and follow-up data were obtained from these physicians or by correspondence with the patients. Follow-up generally consisted of 3-monthly evaluations for 2 to 3 years, semiannually thereafter up to 5 years, and then yearly. At each follow-up visit the patients underwent a rectal examination, X ray examination of the pelvis and lumbar spine, analysis of prostatic acid phosphatase, and routine blood work. Radionuclide bone scans were done yearly or more often if indicated. Routine prostatic biopsies were not done. The duration of follow-up for all 90 surviving patients ranged from 32 to 188 months with a mean of 5.9 years and a median of 5 .Oyears. For Stage B patients, the followup was longer (32- 188 months, 6.4 years mean, 5.7 years median) than for those with Stage A2 (40-108 months, 4.6 years mean, 4 years median). Data analysis methods
Survival curves were calculated using the actuarial Berkson and Gage method. All times were calculated from .the date XRT began. In this population of elderly men intercurrent disease and prostatic cancer are competing causes of mortality. In our analysis we did not use survival curves corrected for death caused by intercurrent disease because death caused by prostate cancer and death resulting from intercurrent illness when prostate cancer is present cannot always be distinguished with confidence. Instead, a survival curve for a normal population of males of similar age was constructed from U.S. Vital Statistics data.44 Although this “expected survival curve” includes deaths caused by prostate cancer in the general population, a comparison with the observed survival in this series yields an approximate assessment of the excess mortality brought on by this disease. Disease-free survival (DFS) curves were also constructed using the actuarial method. These curves give the probability that a patient has not experienced any disease manifestation on the assumption that he is alive at the time in question. It is possible and, indeed, probable that DFS defined in this way is higher than actual survival when death caused by intercurrent illness is common. DFS differs from the concept “alive and free of disease”, because the latter is the probability of being both alive and never having relapse:d up to the time in question. In analyzing DFS, local control, and complications one patient was excluded. He died within 6 months of XRT completion as a result of intercurrent disease, and he was regarded as inevaluable for disease control and development of complications. Thus, all DFS, local control and complication data are based on 113 patients, whereas survival curves are based on all 114 patients. Local control in a patilent was defined as a persistently normal prostate gland by palpation even in the presence of obstructive symptoms if TURP revealed no cancer. To make allowance for the slow regression rate of the primary lesion after XRT, we adopted the following convention. Patients who achieved complete clinical regression of their
703
primary lesion before developing metastatic disease were scored as being in remission at the time that XRT began. All other patients were scored as having failed treatment because of local recurrence at the beginning of XRT. The actual time course of regression of the primary lesion was analyzed separately. Patients scored as initial remissions who then experienced local recurrence were scored as failing at the time of regrowth. Tests of significance between actuarial curves were done with the log-rank statistic,14 and tests of significance for the differences between proportions were done with the chi-square statistic. RESULTS The survival experience of patients in this series is shown in Figure 1. at 5 years, the actuarial survival for Stage A2 patients was 74%, and for Stage B patients 93%. Too few patients were available to derive 1O-year data for Stage A2, but among Stage B patients the lo-year survival was 70%. The survival experience for patients with Stage B was at least as good as the expected survival of an agematched man in the general population. The survival of Stage A2 patients was statistically significantly inferior to that of Stage B patients (p = 0.02). As the DFS show (Fig. 2) both Stage A2 and Stage B patients had 5-year DFS of about 90%; at 10 years the DFS for Stage B patients was 85%. For patients with both stages combined, survival was 84% and 68% at 5 and 10 years respectively, and DFS was 89% and 86% at the same time periods. The “alive and disease-free” survival was 82% and 64% at 5 and 10 years for all 114 patients; for the Stage B patients it was 85% and 64% at the same time periods. Patterns offailure
Eleven of 113 evaluable patients relapsed (9.7%). Treatment failed for 2 of 32 (6%) Stage A2 patients, and 9 of 8 1 evaluable Stage B2 patients relapsed (11%). Sites of relapse were as follows: metastatic in 6, metastatic and local in 3, metastatic and regional pelvic nodal in 1, and
Expected Survival 65 yr. old white male
20
-
stageA
Stage B
# Pts. at 5 yr. 6 51
10 yr. 12
Fig. 1. Actuarial survival for Stages A2 and Stage B adenocarcinema of the prostate. Vertical bars are 95% confidence intervals.
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local and regional pelvic nodal in 1. Thus, local failure in the prostate occurred in 4 patients (3.5%), metastatic failure in 10 (SW), and regional failure in 2 (2%). Nine of the 10 metastatic recurrences were in bone, and 1 was in the para-aortic and supraclavicular regions. We recognized that the incidence of pelvic and para-aortic nodal failure was almost certainly underestimated. The sites of first recognized relapse were metastatic, 8; local, 2; local and metastatic, 1. Both patients who developed local recurrence as the first site of failure subsequently developed additional sites of recurrence within 9 months of local recurrence. The median survival of the 11 relapsing patients was 45 months from their date of relapse and actuarial survival from first relapse was 39% at 5 years.
April 1988, Volume 14, Number 4
vious endocrine treatment. Notable is the lack of significance of TURP and of bilobar (B2) disease. The influence of pelvic node irradiation was evaluated in terms of the lateral width of the anteroposterior treatment portal. For 55 patients treated with portals I 11 cm in width DFS was 87% and 83% at 5 and 10 years. For 22 patients for whom the portals used were 2 12 cm wide, DFS was 92% at 5 and 8 years respectively (p = 0.81). Thus, we could find no significant correlation between DFS and pelvic node irradiation.
Complications Acute proctitis and cystitis lasting up to 1 month after completion of XRT are common accompaniments of XRT for prostate cancer and were not scored as compliLocal control cations. Sexual potency could not be evaluated in this No patient with Stage A2 developed local recurrence. retrospective study. Delayed complications developed in For Stage B patients, actuarial local control was 97% at 39 of 113 evaluable patients (35%). In 13 patients (12%) 5 years and 88% at 10 years. All 8 1 evaluable Stage B the complications were minor consisting of one or a few patients achieved complete regression of the primary leepisodes of hematuria (3 cases) or of the occasional passage sion in times varying from 2 to 24 months after compleof blood-tinged stools (10 patients). Mild to moderate tion of XRT (mean 6 months, median 5 months). Comcomplications occurred in 26 patients (23%). Two patients plete regression was delayed beyond 12 months in 8 pa( 1.8%) developed severe complications involving the tients. The 4 patients who developed local recurrence did bladder; one of these patients required urine diversion so at times ranging from 22 to 97 months after initial and the other underwent cystectomy. complete regression (median 45 months, mean 52 Anorectal complications consisting of rectal bleeding, months). Biopsy confirmation was obtained in 2 of the pain, tenesmus, mucous discharge, diarrhea, fecal soiling, patients who experienced local recurrence. rectal ulcer or rectal stricture were seen in 23 of 113 evalThe incidence of only 4 local recurrences precluded uable patients (20%) at times ranging from 3 to 38 months meaningful statistical analysis of dose versus control. Two after completion of XRT with an average of 16 months recurrences occurred at the dose range of 64.00 to 67.99 and a median of 13 months. In all cases these manifesGy and two at the 70.00 to 7 1.OOGy range. Tumor factors tations resolved spontaneously or responded satisfactorally potentially adverse to local control also could not be evalto conservative management. No patient required a diuated in the light of only 4 failures. verting colostomy. Urinary complications consisting of frequency, dysuria, Prognosticfactors bladder spasms, hematuria, bladder ulceration, contracted Table 1 contains a summary of the results of a pairwise bladder or urethral stricture occurred in 23 of 113 evalanalysis of 11 potential prognostic factors in Stage B disuable cases (20%) at times ranging from 4 to 57 months ease. None of the analyzed factors was significant for after completion of XRT with an average delay of 22 overall survival. The only factor adverse to DFS was premonths and a median delay of 18 months. In 2 1 patients, the symptoms resolved but one patient required urine diversion and one required cystectomy. The incidence of complications did not differ signifi,: ..“.............“‘..,....,,,,,,,,,,,,,..,..,,,,,....,,.,,,,,,,,,,.,.,,,. [ cantly between Stage A2 (2 1% urinary complications and 2 1% anorectal complications) and Stage B patients (20% urinary complications and 20% anorectal complications). Stage A2 patients, however, had no severe complications. Urinary complications increased as radiation dose increased, the incidence at various doses being: ~62.00 Gy, #P&at 0 of 8; 62.00-65.99 Gy, 6 of 49 (12%); 66.00-67.99 Gy, 5 yr. 10 yr. 10 of 36 (28%); 68.00-7 1.OOGy, 7 of 20 (35%) (p < 0.0 1 20 stage A2 6 for trend). Both serious urinary complications occurred SbgeB 46 10 in patients receiving 70 Gy. In the use of only one field per day, a trend appeared toward increased bladder and anorectal complications, but this was not statistically significant. Field size was not a significant factor in compliFig. 2. Disease-free survival for Stages A2 and B adenocarcinoma of the prostate..Vertical bars are 95% confidence intervals. cations. Of 78 patients treated with anteroposterior fields
j--“-q
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Stage B prostatic cancer 0 G. K. ZAGARSet al.
Table 1. Factors potentially significant for survival and disease-free survival in stage B prostatic carcinoma* Number of patients
Actuarial survival % (disease-free survival) 5-year
p valuet for survival (disease-free survival)
34 48 28 44
94 (93) 94 (86) 93 (84) 93 (89)
0.28 (0.3 1) 0.93 (0.6 1)
61 21
95 (92) 90 (78)
0.15 (0.13)
67 15
92 (93) 100 (72)
0.98 (0.04)
27 35
100 (93) 88 (94)
0.18 (0.82)
LAG performed No LAG
53 29
96 (92) 90 (84)
0.07 (0.54)
Scan negative No bone scan
73 9
93 (91) 100 (78)
0.35 (0.25)
Lobes involved One Both
58 24
93 (90) 96 (86)
0.47 (0.74)
No TURP TURP
52 30
96 (91) 90 (85)
0.64 (0.49)
Grade 1 Grades 2 & 3 Grade 4
14 11 0
100 (92) 80 (36) -
0.14 (0.12)
Early hormones No Yes
77 5
93 (90) 100 (80)
0.64 (0.90)
Factor ~64 years 264 years Incidental nodule Prostatism Diagnosis-XRT 12 months >2 months Prior endocrine No Yes Normal Normal
treatment
PAP <0.37 PAP ~0.37
* Figures in parentheses are disease-free survival rates and their p values. t Log-rank statistic. Abbreviations: PAP, prostatic acid phosphatase, Roy method, normal < 0.8 mu/ml; resection of prostate.
I 11 cm in width, 15 ( 19%) experienced anorectal complications and 20 (26%) developed urinary complications. Of 35 patients whose corresponding field was > 11 cm, 8 (23%) developed anorectal problems and 3 (9%) developed urinary problems. Both patients who developed severe bladder complications were treated with fields c 11 cm in size. The incidence of anorectal complications showed a trend, although not a statistically significant one, to higher frequency as dose increased.
LAG, lymphangiogram;
TURP, transurethral
DISCUSSION The 89% and 68% 5- and IO-year survival rates in this series for all 114 patients with disease limited to the prostate are in accord with results reported in many series employing a variety of treatment modalities. As is summarized in Table 2, reported 5-year survival rates were in the range of 8 1% to 94%, and lo-year survival rates varied from 52% to 68% with no striking differences be-
Table 2. Results in clinical Stage A and B prostatic
adenocarcinoma
Survival % Number of patients 309 159 119 477 153 (N-) 114 S, radical surgery; XRT,
Treatment
5-year
1O-year
Study
s s S XRT S XRT
82 84 85 81 94 89
59 52 53 59 67 68
Boxer et al. 1977” Veenema et al. 19774s Hodges et al. 197928 Bagshaw 1985 3 Middleton et al. 1986 33 Present series (M.D.A.H.)
radiation
therapy;
N-,
negative
nodes by lymphadenectomy.
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April 1988, Volume 14, Number 4
tween surgical and XRT series. Since the survival expectation to 10 years in our series was no different from the expected survival of age-matched men in the general population, it is unlikely that any treatment modality could achieve significantly better survival rates in a similar patient population. A common and valid criticism’9,29,30*36~46 leveled at many XRT series and applicable to ours, is that only 5- or lo-year data are available. This disease may follow a protracted course so that 15 and 20-year data are necessary to draw firm conclusions about the curative potential of any treatment modality. Ultimately, we simply have to wait to achieve the desired follow-up; meanwhile, the data available (Figs. 1 and 2) give us no reason to suppose that relative patient survival will take a significant downward turn beyond 10 years. In our series, because DFS at 10 years (86%) was superior to survival at 10 years (68%), in the long term, intercurrent diseaserelated death poses a more serious hazard than prostate cancer. The 5-, lo-, 15-, and 20-year survival data from the Stanford XRT series3 did not reveal any significant unexpected attrition of patients beyond 10 years. Only one prospective randomized study compared surgical intervention with XRT for patients with Stages A2 and B prostatic carcinoma.38 In that study 106 patients with clinical Stages A2 or B disease and with negativestaging pelvic lymphadenectomy were randomly assigned to either XRT or surgery. Sixteen patients were excluded from analysis and 7 patients were nonrandomly crossed over to the other treatment arm. At 5 years, about 40% of the XRT patients had disease progression, compared with only 12% of the surgical patients (p = 0.037). The conclusion was “that a radical operation is more effective than megavoltage radiation in controlling prostatic adenocarcinoma that is confined to the anatomic limits of the gland. . . .“38 Unfortunately, for unknown reasons, the XRT results in that study were particularly poor. In our series of nonlaparotomy-staged patients, the 5-year DFS was 89% compared with about 60% in the Uro-Oncology Group series. In the Stanford series3 51 laparotomy-negative clinical Stage A2 and B patients had a DFS of about 90% at 5 years.
no demarcation criteria have been universally accepted. In our series no patient had only one or two microscopic foci of disease,3’ and all A2 cases were in the “multifocal or diffuse” category. The 74% 5-year survival for Stage A2 patients was significantly inferior to that of 93% for patients with Stage B. However, the DFS for patients in both stages was identical at 90% indicating that patients with Stage A2 prostate cancer had a significantly higher mortality from intercurrent disease than those with Stage B disease. At up to 5 years from diagnosis, there was no evidence that Stage A2 represents a biologically more aggressive disease than Stage B. The suggestion that Stage A2 carcinoma may be biologically more aggressive than the disease at early B stages is based on a relatively high incidence of involved pelvic nodes,23,24,48on the occurrence of poorly differentiated lesions,‘3V23*24*29,48 and on apparently poor results following surgery24 in patients with Stage A2 disease. Table 3 summarizes some results of surgery and/or endocrine management in Stage A disease. In contrast to the surgical viewpoints on this stage of disease, most XRT series report 5-year survivals and DFS at least as good, if not better, than the results for Stage B (Table 4). The reasons for the better outcome in XRT series of patients with A2 disease are unclear, but this fact argues strongly in favor of irradiation as the optimal modality. Jewett29 also concluded that XRT was better than prostatectomy for A2 disease. Since local control was achieved in all our Stage A2 patients with the doses used, we now recommend the use of 62.00 Gy for that stage.
Stage B The 93% and 70% survival rates at 5 and 10 years respectively and the corresponding 89% and 85% DFS rates found in our series compare well with the results of many other XRT series (Table 5) and with the results of surgical series (Table 6). Although we are mindful of the difficulties inherent in retrospective inter-institutional comparisons, an appraisal of the results summarized in Tables 5 and 6 leaves little doubt of the efficacy of XRT relative to radical surgery in Stage B disease. XRT series cannot yet provide definitive 15-year data, but, as already discussed, there are no compelling reasons to suppose that survival and Stage A2 DFS will take dramatic downward turns in the 1O-to- 15Despite evidence that the distinction between Al and year interval. Moreover, survival for this stage was equal A2 prostatic cancer is prognostically significant,5,‘3~‘6,20*24,29 to the expected survival of age-matched men in the general Table 3. Results of surgery and/or hormonal therapy for Stage A adenocarcinoma
of the prostate
Survival % Number of patients
Treatment
5-year
1O-year
Study
28 100 26 43 46
S S, TURP, H H H S
75 67 48 60 78
60 41 28 34 43
Nichols et al. 1977 35 Heaney et al. 1977 27 White et al. 197748 Byar (VACURG) 1980” Byar (VACURG) 1980”
S, radical surgery; H, endocrine management;
TURP, transurethral
resection of prostate.
StageB prostaticcancer0 G. K. ZAGARS Table 4. Results of radiation therapy in Stage A adenocarcinoma of the prostate Number of patients
S-year survival % (disease-free survival)
13 10 17 25 10 32
88 100 (56) 100 96 (84) 100 (100) 14 (90)
Study Harisiadis et al. 197826 Rangala et af. 198240 Aristizabel et al. 1984’ Rosen et al. 19844’ Perez et al. 198639 Present series (M. D. Anderson Hospital)
population which makes it unlikely that superior survival rates could follow with any other modality. Under these circumstances modality choice should be made on the basis of comparative morbidity. Table 1, in which we summarized prognostic factors for Stage B, showed only that one factor was significantpatients who had undergone endocrine treatment (hormones or orchiectomy) had a significantly poorer DFS than patients without such pretreatment. Since patients with a treatment delay longer than 2 months did no worse than those treated early (Table l), it seems unlikely, though possible, that a delay in XRT accounts for the poorer outcome of hormonally pretreated patients. A more likely explanation is that some of the pretreated patients had more extensive disease, especially extracapsular extension, which mgressed and led to downstaging. In our series, the only patient who had an elevated prostatic acid phosphatase (:>0.8 mu/ml by the Roy method) remains alive and well. We were unable to demonstrate any difference in outcome for patients with unilobar or bilobar disease, in marked contrast to surgical series in which B2 patients fared substantially worse than Bl patients even at 10 years of follow-up.‘oY’9,29*33,46 In our study, as in the XRT patterns of care study,25 TURP was not an adverse factor in Stage B. In view of the small number of pathologically graded cases, we can make no definitive statements about the inlfluence of grade on outcome.
et
707
al.
The occurrence of only 4 local recurrences, 2 at moderate and 2 at high doses precludes any meaningful doseresponse analysis. Since complications increased as dose increased, however, especially above 68 Gy, we have ‘elected to recommend 64 Gy as the optimal dose for Stage B disease. This dose was also found to be optimal in the XRT patterns of care study.25 Regional pelvic nodes Elective irradiation of regional pelvic nodes did not improve DFS or survival. With few exceptions,‘,32*40most XRT series reported that no benefit accrues from elective pelvic nodal XRT,26*34*4’,47*49 and the Stanford trial addressing this question failed to show a statistically significant superiority for nodal XRT regardless of whether nodes were surgically positive or negative.2 Likewise, prevailing surgical opinion holds that pelvic lymphadenectomy is not a therapeutic procedure.7,22*24*29”6*46 Despite this, regional pelvic nodal recurrence is an uncommonly documented event in prostatic carcinoma both in XR~‘,3,26,32,39,40,41,47,49
and
surgicd
se~es.6,10,17,19,22,30,33,35,45
The expected incidence of pelvic nodal disease in a series of mixed Stages A2 and B patients was about 20%25%.7,23,24,36,48,49 The low incidence of manifest nodal failure may be caused partly by difficulties in clinical detection of pelvic nodal masses, but it may also involve undefined host-tumor interactions that prevent the progression of early nodal disease to gross clinically detectable lymphadenopathy. Strong evidence for this phenomenon is provided by the NSABP studies of breast cancer.2’ Complications The incidence of complications in our series was similar to that reported for most XRT series,‘,3,26,39*“c*4’ and a major complication rate of 1.8% compares favorably with the major complications reported for surgical studies.6,‘,‘0,‘9,28,30,35,36,45 Whether “neme_spafing” prosta_ tectomy18 proves to be an adequate cancer operation remains to be seen. We note parenthetically that endocrine manipulation is not without toxicity.1’,‘2 We identified
Table 5. Results of radiation therapy for Stage B adenocarcinoma of the prostate Survival % Number of patients
5-year
21 25 24
Z (59) (61)
101 85 138* 155t 113 82
$; (68) 88 89 (72) 93 (89)
* Selected B 1 patients only. t Iodine- 125 implantation.
1O-year (disease-free survival)
15-year
Study
-
-
-
52 -
74 (60) ’ 70 (85)
Harisiadis et al. 197826 Rangala et al. 198240 Werf-Messing et al. 198447 Aristizabal et al. 1984 ’ Rosen et al. 19844L Bagshaw 1985’ Whitmore et al. 1985 49 Perez et al. 1986 39 Present series (M. D. Anderson Hospital)
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April 1988, Volume 14, Number 4
Table 6. Results of radical surgery in Stage B adenocarcinoma
of the prostate
Survival % Number of patients
S-year
185 (c)
78
1O-year (disease-free survival)
15-year 31 54 (27)
55 (48) -
160 (cB1) 200 (P) 110 (c)
86 (75)
55 72 (57) 62 (58)
195 (c) 320 (P, No) 102 (c, No)
95 (86) 92 (93) 93 (88)
74 (67) 81 (83) -
-
Study
(38)
Belt, Schroeder 1972 6 Culp, Meyer 1973” Boxer et al. 1977 I0 Elder et al. 1982” Jewett 1980 3o Gibbons et al. 1984” Benson et al. 1984’ Middleton et al. 1986 33
c, clinical stage; p, pathologic stage; No, nodes negative at lymphadenectomy.
the use of too high a dose (>68 Gy) and the treatment of only one field per day as adverse factors for complications, and we expect serious afteraffects will diminish even further when these deficiencies are rectified. CONCLUSIONS 1. Radiation therapy is a highly effective modality for early Stage (A2 and B) adenocarcinoma of the prostate, producing local control in the vast majority of patients and yielding long-term survival rates that rival those achieved by radical prostatectomy.
2. Delayed XRT-related complications occur at an acceptably low rate and can be minimized by limiting total doses to approximately 64.00 Gy. 3. Pelvic node irradiation is not indicated for patients with clinical Stage A2 or B disease. 4. The prognosis of Stage A2 or B disease treated with external XRT is overall so good that no adverse prognostic subgroups can be identified. 5. Hematogenous metastasis is the most significant cancer-related threat to these patients and further therapeutic improvements require the development of adequate systemic therapy.
REFERENCES 1. Aristizabal, S.A., Steinbronn, D., Heusinkveld R.S.: External
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3. 4.
5. 6. 7.
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beam radiotherapy in cancer ofthe prostate. The University of Arizona experience. Radiother. Oncol. 1: 309-3 15, 1984. Bagshaw, M.A.: Radiotherapeutic treatment of prostatic carcinoma with pelvic node involvement. Ural. Clin. North Amer. 11: 297-304, 1984. Bagshaw, M.A.: Potential for radiotherapy alone in prostatic cancer. Cancer 55:2079-2085, 1985. Barnes, R., Hadley, H., Axford, P., Kronholm, S.: Conservative treatment of early carcinoma of prostate. Comparison of patients less than seventy with those over seventy years of age. Urology 14: 359-362, 1979. Barnes, R.W., Ninan C.A.: Carcinoma of the prostate: Biopsy and conservative therapy. J. Ural. 108: 897-900, 1972. Belt, E., Schroeder, F.H.: Total perineal prostatectomy for prostate carcinoma. J. Ural. 107: 9 l-96, 1972. Benson, R.C., Tomera, K.M., Zincke, H., Fleming, T.R., Utz, DC.: Bilateral pelvic lymphadenectomy and radical retropubic prostatectomy for adenocarcinoma confined to the prostate. J. Urol. 131: 1103-l 106, 1984. Berkson, J., Gage, R.P.: Calculation of survival rates for cancer. Mayo Clin. Proc. 25: 270-286, 1950. Brawn, P.N., Ayala, A.G., von Eschenbach, A.C., Hussey, D.H., Johnson, D.E.: Histologic grading study of prostate adenocarcinoma: The development of a new system and comparison with other methods-A preliminary study. Cancer 49: 525-532, 1982. Boxer, R.J., Kaufman, J.J., Goodwin, W.E.: Radical prostatectomy for carcinoma of the prostate: 195 1- 1976. A review of 329 patients. J. Urol. 117: 208-213, 1977. Byar, D.P.: VACURG studies of post-prostatectomy sur-
vival. Stand. J. Urol. Nephrol. 55(Suppl.): 113-116, 1980. 12. Byar, D.P., Corle, D.K.: VACURG randomized trial of radical prostatectomy for Stages I and II prostate cancer. Urology 27(Suppl.): 7- 11, 198 1. 13. Cantrell, B.B., DeKlerk, D.P., Eggleston, J.C., Boitnott, J.K., Walsh, P.C.: Pathologic factors that influence prognosis in Stage A prostatic cancer: the influence of extent versus grade. J. Urol. 125: 516-520,
1981.
14. Coldman, A.J., Elwood, J.M.: Examining survival data. CMA J. 121: 1065-1071, 1979. 15. Conant, J.K., Flannery, J.T., Graydon, R.J., Ely, M.G., Berlin, B.B.: Survival with localized carcinoma: Radical prostatectomy vs radiation therapy. Urology 25: 347-349, 1985.
16. Correa, R.J., Anderson, R.G., Gibbons, R.P., Mason, J.T.: Latent carcinoma of the prostate-Why the controversy? J. Ural. 111: 644-646, 1974. 17. Culp, O.S., Meyer, J.J.: Radical prostatectomy in the treatment of prostatic cancer. Cancer 32: 1113-l 118, 1973. 18. Eggleston, J.C., Walsh, P.C.: Radical prostatectomy with preservation of sexual function: Pathological findings in the first 100 cases. J. Ural. 134: 1146-l 148, 1985. 19. Elder, J.S., Jewett, H.J., Walsh, P.C.: Radical perineal prostatectomy for clinical Stage B2 carcinoma of the prostate. J. Urol. 127: 704-706,
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20. Epstein, J.I., Paull, G., Eggleston, J.C., Walsh, PC.: Prognosis of untreated Stage Al prostatic carcinoma: A study of 94 cases with extended followup. J. Urol. 136: 837-839, 1986.
21. Fisher, B., Redmond, C., Fisher, E.R., Batter, M., Wolmark, N., Wickerman, L., Deutsch, M., Montague, E., Margolese,
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R., Foster, R.: Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. N. Engl. J. Med. 312: 674-681,
35.
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22. Gibbons, R.P., Correa, R.J., Brannen, G.E., Mason, J.T.: Total prostatectomy for localized prostatic cancer. J. Ural. 131: 73-76, 1984. 23. Golimbu, M., Morales, P.: Stage A2 prostatic carcinoma. Should staging system .be reclassified? Urology 13: 592-596, 1979. 24. Golimbu, M., Schinella, R., Morales, P., Kurusu, S.: Differences in pathologic characteristics and prognosis of clinical A2 prostatic cancer from Al and B disease. J. Ural. 119: 618-622, 1978. 25. Hanks, G.E.: Optimizing the radiation treatment and outcome of prostate cancer. Znt. J. Radiat. Oncol. Biol. Phys. 11: 1235-1245, 1985. 26. Harisiadis, L., Veenema, R.J., Senyszyn, J.J., Puchner, P.J., Tretter, P., Romas, N..4., Chang, C.H., Lattimer, J.K., Tannenbaum, M.: Carcin,oma of the prostate: treatment with external radiotherapy. Cancer 41: 2131-2142, 1978. 27. Heaney, J.A., Chang, H.C., Daly, J.J., Prout, G.R.: Prognosis of clinically undiagnosed prostatic carcinoma and the influence of endocrine therapy. J. Ural. 118: 283-287, 1977. 28. Hodges, C.V., Pearse, H.D., Stille, L.: Radical prostatectomy for carcinoma: 30-yea:r experience and 15-year survivals. J. Ural. 122: 180-182, 1979. 29. Jewett, H.J.: The present status of radical prostatectomy for Stages A and B prosta.tic cancer. Ural. Clin. North Am. 2: 105-124,
1975.
30. Jewett, H.J.: Radical yperineal prostatectomy for palpable, clinically localized, non-obstructive cancer: Experience at the Johns Hopkins Hospital 1909-1963. J. Ural. 124: 492494, 1980.
31. Johnson, D.E., Bracken, R.B., Wallace, S., Samuels, M.L., Hussey, D.H., Miller, L.S., Ayala, A.G.: Urologic cancer. In Cancer Patient Care at M. D. Anderson Hospital and Tumor Institute, Clark, R.L., Howe, D.C. (Eds.). Chicago, Year Book Medical Publishers. 1976, p. 374. 32. McGowan, D.G.: The value of extended field radiation therapy in carcinoma of the prostate. Znt. J. Radiat. Oncol. Biol. Phys. 7: 1333-1339, 1981. 33. Middleton, R.G., Smith, J.A., Melzer, R.B., Hamilton, P.E.: Patient survival and local recurrence rate following radical prostatectomy for prostatic carcinoma. J. Ural. 136: 422424, 1986. 34. Neglia, W.J., Hussey, D.H., Johnson, D.E.: Megavoltage
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radiation therapy for carcinoma of the prostate. Znt. J. Radiat. Oncol. Biol. Phys. 2: 873-882, 1977. Nichols, R.T., Barry, J.M., Hodges, C.V.: The morbidity of radical prostatectomy for multifocal Stage I prostatic adenocarcinoma. J. Ural. 117: 83-84, 1977. Olsson, CA., Babyan, R., White R.: Surgical management of Stage B or C prostatic carcinoma: radical surgery vs radiotherapy. Urology 25(Suppl.): 30-35, 1985. Paulson, D.F.: Editorial comment. J. Ural. 135: 5 19, 1986. Paulson, D.F., Lin, G.H., Hinshaw, W., Stephanie, S: Radical surgery versus radiotherapy for adenocarcinoma of the prostate. J. Ural. 128: 502-504, 1982. Perez, C.A., Pilepich, M.V., Zivnuska, F.: Tumor control in definite irradiation of localized carcinoma of the prostate. Znt. J. Radiat. Oncol. Biol. Phys. 12: 523-531, 1986. Rangala, N., Cox, J.D., Byhardt, R.W., Wilson, J.F., Greenburg, M., da Conceicas, A.L.: Local control and survival after external irradiation for adenocarcinoma of the prostate. Znt. J. Radiat. Oncol. Biol. Phys. 8: 1909-1914, 1982. Rosen, E.M., Cassady, J.R., Connolly, J., Chaffey, J.T.: Radiotherapy for localized prostatic carcinoma. Znt. J. Radiat. Oncol. Biol. Phys. 10: 2201-2210, 1984. Schmidt, J.D., Mettlin, C.J., Natarajan, N., Pearce, B.B., Beart, R.W., Winchester, D.P., Murphy, G.P.: Trends in patterns of care for prostatic cancer 1974- 1983: Results of surveys by the American College of Surgeons. J. Ural. 136: 416-421,
1986.
43. Sodeman, T.M., Batsakis, G.G.: Acid phosphatase. In Urologic Pathology: The Prostate, Tannenbaum, M. (Ed.). Philadelphia, Lea & Febiger. 1977, pp. 129-139. 44. U.S. Department of Health, Education and Welfare: Vital Statistics of The United States, 1975. Hytattsville, Maryland, Public Health Service National Center For Health Statistics. 45. Veenema, R.J., Gussel, E.O., Lattimer, J.K.: Radical retropubic prostatectomy for cancer: A 20-year experience. J. Ural. 117: 330-331,
1977.
46. Walsh, PC., Jewett, H.J.: Radical surgery for prostatic cancer. Cancer 45: 1906- 19 11, 1980. 47. Werf-Messing van der B.H.P., Menon, R.S., Putten van, W.L.J.: Prostatic cancer treated by external irradiation at the Rotterdam Radiotherapy Institute. Strahlentherapie 160: 293-500,
1984.
48. White, R., Paulson, D.F., Glenn, J.F.: The clinical spectrum of prostate cancer. J. Ural. 117: 323-327, 1977. 49. Whitmore, W.F., Hilaris, B., Batata, M., Sogani, P., Hert, H., Morse, M.: Interstitial radiation: short-term palliation or curative therapy? Urology 25(Suppl.): 24-29, 1985.
hf. J. Radiafion Oncology Biol P/p.. Vol. 14, pp. 701-709 Printed in the U.S.A. All rights reserved.
??Original Contribution
THE
ROLE
OF RADIATION THERAPY IN STAGES A2 AND ADENOCARCINOMA OF THE PROSTATE
B
GUNAR IS. ZAGARS, M.D.,* ANDREW C. VON ESCHENBACH, M.D.,? DOUGLAS E. JOHNSON, M.D.? AND MARY JANE OSWALD, B.S.* The University of Texas M. D. Anderson Hospital and Tumor Institute, at Houston Between 1965 and11982 definitiveexternalbeamradiationtherapywas given to 114 patientswith clinicallyStaged A2 (32 patients) and B (82 patients) adenocarcinomaof the prostate. These patients were not consideredto be surgical candidatesbecause of age, comorbidityor disease extent, or because they had refused surgery. Total prostatic doses rangedfrom 60 to 70 Gy. For 90 surviving patients, follow-up duration ranged from 32 to 188 months with a median of 5 years. The 5- and lo-year uncorrected survival rates for all patients, which were 89% and 68% respectively, were no different from the survival expectation of age-matched men in the general population. Disease-free survival rates at the same time periods were 89% and 86%. There were no significant differences in disease-free survival between Stage A2 and Stage B. Four patients (3.5%) developed local recurrence. Bone metastases, which occurred in 9 of 11 treatment failures were the predominant cause of failure. An analysis of 11 potential prognostic factors was fruitless. Pelvic node irradiation did not improve the outcome. The incidence of complications was, acceptable. Anorectal problems developed in 20% of patients and urinary manifestations occurred in 20%, and only 2 patients (1.8%) developed serious problems. We concluded that localized external beam high-
energy radiation therapy provides excellent local control for disease limited to the prostate, with survival rates that rival those of radical surgery. Prostatic carcinoma, Stage B, Radiation therapy.
1NTB:ODUCTION
in determining the outcome after XRT; and (e) the definition of optimal XRT dose and fractionation parameters. Moreover, several recent reports in the urologic literature have displayed considerable antipathy toward XRT for early prostate cancer,15P36,38 even to the extent of claiming that radiation therapy is of no therapeutic value in the management of patients with prostatic adenocarcinoma. This retrospective review of 114 patients with Stages A2 and B prostatic adenocarcinoma treated by XRT was done to address the questions raised regarding long-term outcome for this disease and to see whether the antipathy toward XRT is in any way justified.
With few exceptions,4.5.‘2 most authorities recommend some form of radical treatment for prostatic adenocarcinema when disease is clinically confined to the prostate (Stages A2 and B). The traditional and time-honored approach to this stage of disease is radical prostatecHowever, the presumed superiority of tomy. 10~17~‘9~22~30~33
radical surgery has been brought into question over the past lo- 15 years by reports that radiation therapy (XRT) is also highly effective.‘,3*25,39,41*49 This has led to an increasing use of XRT in patients with early prostatic carcinoma. A recent survey by the American College of Surgeons showed that in the 9 13 U.S. institutions reviewed in 1983, XRT was the single most common modality employed for clinical Stage B disease.42 Nevertheless, some important issues remain unsettled, including (a) the radiocurability of early-stage disease; (b) the need for pelvic node irradiation; (c) the long-term local control rate; (d) the significance of various biologic factors, including stage,
METHODS
AND
MATERIALS
Patient characteristics Between January 1965 and December 1982, 114 patients with clinical Stage A2 or B adenocarcinoma of the
* Dept. of Clinical Radiotherapy. t Dept. of Urology. Reprint requests to: G. K;. Zagars, M.D., Department of Clinical Radiotherapy, Division of Radiotherapy, The University of Texas M. D. Anderson Ho:spital and Tumor Institute, at Houston, 1515 Holcombe Blvd., Houston, TX 77030.
This study was supported in part by Grant number CA-06294 awarded by the National Cancer Institute, U.S. Department of Health and Human Services. Accepted for publication 4 November 1987.
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I. J. Radiation Oncology 0 Biology 0 Physics
prostate were treated with external beam megavoltage radiation at The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston. Stage A2 was defined as multifocal or diffuse carcinoma not evident by rectal palpation of the prostate,3’ and Stage B was palpable carcinoma without palpatory evidence of extension beyond the gland. Patients in both stages had no clinicalradiographic evidence of lymphatic or hematogenous metastases. During the years encompassed by this review, patients with Stage A2 or B disease were offered radical prostatectomy unless co-morbidity contraindicated surgery or disease was felt to be adjacent to the prostatic capsule, especially at the apex. Thus, the patients in this series are those for whom surgical intervention was considered inappropriate or who refused prostatectomy. Thirty-two patients had Stage A2 and 82 had Stage B disease. Patients with Stage A2 generally had obstructive urinary symptoms, and 30 of these (94%) underwent transurethral resection of the prostate (TURP). One Stage A2 patient was diagnosed after suprapubic enucleation of the prostate and one had a positive “blind” transrectal biopsy. Among the patients with Stage B, the disease was detected on routine physical examination in 28 (34%) and 2 had suprapubic enucleation for obstructive symptoms. Among the Stage B patients, the disease was confined to the right lobe in 34 (42%), to the left lobe in 24 (29%), and involved both lobes in 24 (29%). For the 58 patients with disease in one lobe, we were unable to quantitate disease volume retrospectively into discrete nodules versus involvement of the entire lobe. Each patient’s histopathologic diagnosis was confirmed by the department of pathology at U.T. M. D. Anderson Hospital, and histologic grading according to the M. D. Anderson Hospital system’ was available in 43 cases (38%). Staging evaluation varied according to the availability of modalities during the 18 years encompassed by this review. Serum prostatic acid phosphatase was determined in 108 cases (95%) and was measured using the BesseyLowry method in 16 cases and the Roy method in 92 cases.43 Radionuclide bone scans were performed in 103 cases (90%) and skeletal surveys were done in 33 cases (29%). Excretory urography was done in 70 patients (6 l%), and in recent years the upper urinary tracts were evaluated from the radionuclide bone scan images. Bipedal lymphangiography (LAG) was performed in 78 patients (68%). During the time period of this study, staging pelvic lymphadenectomy was not performed. Treatment methods The policy for patients with Stages A2 and B prostate cancer was to reserve endocrine manipulation for treatment failure, but, 3 patients had undergone orchiectomy and 16 patients had received estrogen for a median time of 3 months before referral to our institution. Estrogen was discontinued in 14 of these 16 patients. Thus, significant early endocrine manipulation occurred in 5 patients (3 orchiectomy, 2 estrogen). Patients who had undergone
April 1988, Volume 14, Number 4
TURP began XRT after a minimum healing time of 6 weeks. One hundred and twelve patients were treated with high-energy (18-25 MV) photon beams, and 2 patients received 360” cobalt rotation. Treatment volume varied according to the policy regarding pelvic node irradiation. Before 1977 no attempt was made to treat pelvic nodes systematically,34 and the vast majority of patients were treated through a four-field arrangement using 10 X 10 cm anterior and posterior portals and 10 X 8 cm lateral portals. The inferior margin of these fields was at or just superior to the lower border of the ischial tuberosities and the posterior border of the lateral fields bisected the rectal lumen. After delivering 50 Gy in 5 weeks at 2 Gy per fraction, a reduced volume usually measuring 8 X 8 cm was given an additional 1O-20 Gy either with anteroposterior opposed fields or with a four-field technique. After 1977 the initial 50-Gy dose was delivered to a slightly larger volume using 13 cm wide and 11 cm high anteroposterior portals and 11 X 8 cm lateral fields. After 1978 fields were further enlarged to 14- 15 cm in width and 12 cm in height to cover the external iliac nodes. The smallvolume coned-down prostatic fields were 8 X 8 cm in 97 cases, 9 X 9 cm in 11 cases, 10 X 8 cm in 2 cases, and 9 X 8 cm in 2 cases. There were no systematic differences in irradiated volumes between Stage A2 and Stage B patients. Treatment techniques varied also over the years, again largely as a matter of policy. From 1965 to 1977, 29 patients were treated with four fields to 50 Gy followed by anteroposterior coned-down fields only, and one field was treated daily. From 1978 on, four fields were used throughout treatment and one field was treated daily in 46 patients, whereas 37 patients had more than one field treated daily. Cobalt rotation, used in only 2 patients, was abandoned in 1967. Radiation doses were delivered at 2 Gy daily specified at the tumor along the central axis of each beam. After 50 Gy in 5 weeks, coned-down volumes were given an additional lo-20 Gy in 5 to 10 fractions. For patients with Stage A2 disease, doses were distributed as follows: 60.00-61.99 Gy for 2 patients; 62.00-63.99 Gy for 4 patients, 64.00-65.99 Gy for 15, 66.00-67.99 Gy for 9, 68.00-69.99 Gy for 1, and 70.00-7 1.00 Gy for 1. For patients with Stage B disease, doses were distributed as follows: (60.00 Gy for 3 patients, 60.00-6 1.99 Gy for 2, 62.00-63.99 Gy for 7, 64.00-65.99 Gy for 24, 66.0067.99 Gy for 28, 68.00-69.99 Gy for 7, and 70.00-7 1.OO Gy for 11. Generally, patients who relapsed received hormonal management. Of the 11 who failed, 5 received oral estrogen, 4 had an orchiectomy and were given estrogen, and 2 had nonendocrine treatment. Follow-up The majority of patients were seen regularly at the U.T. M. D. Anderson Hospital; and the rest were seen by the
Stage B prostatic cancer 0 G. K. ZAGARSet al.
referring urologist, and follow-up data were obtained from these physicians or by correspondence with the patients. Follow-up generally consisted of 3-monthly evaluations for 2 to 3 years, semiannually thereafter up to 5 years, and then yearly. At each follow-up visit the patients underwent a rectal examination, X ray examination of the pelvis and lumbar spine, analysis of prostatic acid phosphatase, and routine blood work. Radionuclide bone scans were done yearly or more often if indicated. Routine prostatic biopsies were not done. The duration of follow-up for all 90 surviving patients ranged from 32 to 188 months with a mean of 5.9 years and a median of 5 .Oyears. For Stage B patients, the followup was longer (32- 188 months, 6.4 years mean, 5.7 years median) than for those with Stage A2 (40-108 months, 4.6 years mean, 4 years median). Data analysis methods
Survival curves were calculated using the actuarial Berkson and Gage method. All times were calculated from .the date XRT began. In this population of elderly men intercurrent disease and prostatic cancer are competing causes of mortality. In our analysis we did not use survival curves corrected for death caused by intercurrent disease because death caused by prostate cancer and death resulting from intercurrent illness when prostate cancer is present cannot always be distinguished with confidence. Instead, a survival curve for a normal population of males of similar age was constructed from U.S. Vital Statistics data.44 Although this “expected survival curve” includes deaths caused by prostate cancer in the general population, a comparison with the observed survival in this series yields an approximate assessment of the excess mortality brought on by this disease. Disease-free survival (DFS) curves were also constructed using the actuarial method. These curves give the probability that a patient has not experienced any disease manifestation on the assumption that he is alive at the time in question. It is possible and, indeed, probable that DFS defined in this way is higher than actual survival when death caused by intercurrent illness is common. DFS differs from the concept “alive and free of disease”, because the latter is the probability of being both alive and never having relapse:d up to the time in question. In analyzing DFS, local control, and complications one patient was excluded. He died within 6 months of XRT completion as a result of intercurrent disease, and he was regarded as inevaluable for disease control and development of complications. Thus, all DFS, local control and complication data are based on 113 patients, whereas survival curves are based on all 114 patients. Local control in a patilent was defined as a persistently normal prostate gland by palpation even in the presence of obstructive symptoms if TURP revealed no cancer. To make allowance for the slow regression rate of the primary lesion after XRT, we adopted the following convention. Patients who achieved complete clinical regression of their
703
primary lesion before developing metastatic disease were scored as being in remission at the time that XRT began. All other patients were scored as having failed treatment because of local recurrence at the beginning of XRT. The actual time course of regression of the primary lesion was analyzed separately. Patients scored as initial remissions who then experienced local recurrence were scored as failing at the time of regrowth. Tests of significance between actuarial curves were done with the log-rank statistic,14 and tests of significance for the differences between proportions were done with the chi-square statistic. RESULTS The survival experience of patients in this series is shown in Figure 1. at 5 years, the actuarial survival for Stage A2 patients was 74%, and for Stage B patients 93%. Too few patients were available to derive 1O-year data for Stage A2, but among Stage B patients the lo-year survival was 70%. The survival experience for patients with Stage B was at least as good as the expected survival of an agematched man in the general population. The survival of Stage A2 patients was statistically significantly inferior to that of Stage B patients (p = 0.02). As the DFS show (Fig. 2) both Stage A2 and Stage B patients had 5-year DFS of about 90%; at 10 years the DFS for Stage B patients was 85%. For patients with both stages combined, survival was 84% and 68% at 5 and 10 years respectively, and DFS was 89% and 86% at the same time periods. The “alive and disease-free” survival was 82% and 64% at 5 and 10 years for all 114 patients; for the Stage B patients it was 85% and 64% at the same time periods. Patterns offailure
Eleven of 113 evaluable patients relapsed (9.7%). Treatment failed for 2 of 32 (6%) Stage A2 patients, and 9 of 8 1 evaluable Stage B2 patients relapsed (11%). Sites of relapse were as follows: metastatic in 6, metastatic and local in 3, metastatic and regional pelvic nodal in 1, and
Expected Survival 65 yr. old white male
20
-
stageA
Stage B
# Pts. at 5 yr. 6 51
10 yr. 12
Fig. 1. Actuarial survival for Stages A2 and Stage B adenocarcinema of the prostate. Vertical bars are 95% confidence intervals.
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I. J. Radiation Oncology 0 Biology 0 Physics
local and regional pelvic nodal in 1. Thus, local failure in the prostate occurred in 4 patients (3.5%), metastatic failure in 10 (SW), and regional failure in 2 (2%). Nine of the 10 metastatic recurrences were in bone, and 1 was in the para-aortic and supraclavicular regions. We recognized that the incidence of pelvic and para-aortic nodal failure was almost certainly underestimated. The sites of first recognized relapse were metastatic, 8; local, 2; local and metastatic, 1. Both patients who developed local recurrence as the first site of failure subsequently developed additional sites of recurrence within 9 months of local recurrence. The median survival of the 11 relapsing patients was 45 months from their date of relapse and actuarial survival from first relapse was 39% at 5 years.
April 1988, Volume 14, Number 4
vious endocrine treatment. Notable is the lack of significance of TURP and of bilobar (B2) disease. The influence of pelvic node irradiation was evaluated in terms of the lateral width of the anteroposterior treatment portal. For 55 patients treated with portals I 11 cm in width DFS was 87% and 83% at 5 and 10 years. For 22 patients for whom the portals used were 2 12 cm wide, DFS was 92% at 5 and 8 years respectively (p = 0.81). Thus, we could find no significant correlation between DFS and pelvic node irradiation.
Complications Acute proctitis and cystitis lasting up to 1 month after completion of XRT are common accompaniments of XRT for prostate cancer and were not scored as compliLocal control cations. Sexual potency could not be evaluated in this No patient with Stage A2 developed local recurrence. retrospective study. Delayed complications developed in For Stage B patients, actuarial local control was 97% at 39 of 113 evaluable patients (35%). In 13 patients (12%) 5 years and 88% at 10 years. All 8 1 evaluable Stage B the complications were minor consisting of one or a few patients achieved complete regression of the primary leepisodes of hematuria (3 cases) or of the occasional passage sion in times varying from 2 to 24 months after compleof blood-tinged stools (10 patients). Mild to moderate tion of XRT (mean 6 months, median 5 months). Comcomplications occurred in 26 patients (23%). Two patients plete regression was delayed beyond 12 months in 8 pa( 1.8%) developed severe complications involving the tients. The 4 patients who developed local recurrence did bladder; one of these patients required urine diversion so at times ranging from 22 to 97 months after initial and the other underwent cystectomy. complete regression (median 45 months, mean 52 Anorectal complications consisting of rectal bleeding, months). Biopsy confirmation was obtained in 2 of the pain, tenesmus, mucous discharge, diarrhea, fecal soiling, patients who experienced local recurrence. rectal ulcer or rectal stricture were seen in 23 of 113 evalThe incidence of only 4 local recurrences precluded uable patients (20%) at times ranging from 3 to 38 months meaningful statistical analysis of dose versus control. Two after completion of XRT with an average of 16 months recurrences occurred at the dose range of 64.00 to 67.99 and a median of 13 months. In all cases these manifesGy and two at the 70.00 to 7 1.OOGy range. Tumor factors tations resolved spontaneously or responded satisfactorally potentially adverse to local control also could not be evalto conservative management. No patient required a diuated in the light of only 4 failures. verting colostomy. Urinary complications consisting of frequency, dysuria, Prognosticfactors bladder spasms, hematuria, bladder ulceration, contracted Table 1 contains a summary of the results of a pairwise bladder or urethral stricture occurred in 23 of 113 evalanalysis of 11 potential prognostic factors in Stage B disuable cases (20%) at times ranging from 4 to 57 months ease. None of the analyzed factors was significant for after completion of XRT with an average delay of 22 overall survival. The only factor adverse to DFS was premonths and a median delay of 18 months. In 2 1 patients, the symptoms resolved but one patient required urine diversion and one required cystectomy. The incidence of complications did not differ signifi,: ..“.............“‘..,....,,,,,,,,,,,,,..,..,,,,,....,,.,,,,,,,,,,.,.,,,. [ cantly between Stage A2 (2 1% urinary complications and 2 1% anorectal complications) and Stage B patients (20% urinary complications and 20% anorectal complications). Stage A2 patients, however, had no severe complications. Urinary complications increased as radiation dose increased, the incidence at various doses being: ~62.00 Gy, #P&at 0 of 8; 62.00-65.99 Gy, 6 of 49 (12%); 66.00-67.99 Gy, 5 yr. 10 yr. 10 of 36 (28%); 68.00-7 1.OOGy, 7 of 20 (35%) (p < 0.0 1 20 stage A2 6 for trend). Both serious urinary complications occurred SbgeB 46 10 in patients receiving 70 Gy. In the use of only one field per day, a trend appeared toward increased bladder and anorectal complications, but this was not statistically significant. Field size was not a significant factor in compliFig. 2. Disease-free survival for Stages A2 and B adenocarcinoma of the prostate..Vertical bars are 95% confidence intervals. cations. Of 78 patients treated with anteroposterior fields
j--“-q
705
Stage B prostatic cancer 0 G. K. ZAGARSet al.
Table 1. Factors potentially significant for survival and disease-free survival in stage B prostatic carcinoma* Number of patients
Actuarial survival % (disease-free survival) 5-year
p valuet for survival (disease-free survival)
34 48 28 44
94 (93) 94 (86) 93 (84) 93 (89)
0.28 (0.3 1) 0.93 (0.6 1)
61 21
95 (92) 90 (78)
0.15 (0.13)
67 15
92 (93) 100 (72)
0.98 (0.04)
27 35
100 (93) 88 (94)
0.18 (0.82)
LAG performed No LAG
53 29
96 (92) 90 (84)
0.07 (0.54)
Scan negative No bone scan
73 9
93 (91) 100 (78)
0.35 (0.25)
Lobes involved One Both
58 24
93 (90) 96 (86)
0.47 (0.74)
No TURP TURP
52 30
96 (91) 90 (85)
0.64 (0.49)
Grade 1 Grades 2 & 3 Grade 4
14 11 0
100 (92) 80 (36) -
0.14 (0.12)
Early hormones No Yes
77 5
93 (90) 100 (80)
0.64 (0.90)
Factor ~64 years 264 years Incidental nodule Prostatism Diagnosis-XRT 12 months >2 months Prior endocrine No Yes Normal Normal
treatment
PAP <0.37 PAP ~0.37
* Figures in parentheses are disease-free survival rates and their p values. t Log-rank statistic. Abbreviations: PAP, prostatic acid phosphatase, Roy method, normal < 0.8 mu/ml; resection of prostate.
I 11 cm in width, 15 ( 19%) experienced anorectal complications and 20 (26%) developed urinary complications. Of 35 patients whose corresponding field was > 11 cm, 8 (23%) developed anorectal problems and 3 (9%) developed urinary problems. Both patients who developed severe bladder complications were treated with fields c 11 cm in size. The incidence of anorectal complications showed a trend, although not a statistically significant one, to higher frequency as dose increased.
LAG, lymphangiogram;
TURP, transurethral
DISCUSSION The 89% and 68% 5- and IO-year survival rates in this series for all 114 patients with disease limited to the prostate are in accord with results reported in many series employing a variety of treatment modalities. As is summarized in Table 2, reported 5-year survival rates were in the range of 8 1% to 94%, and lo-year survival rates varied from 52% to 68% with no striking differences be-
Table 2. Results in clinical Stage A and B prostatic
adenocarcinoma
Survival % Number of patients 309 159 119 477 153 (N-) 114 S, radical surgery; XRT,
Treatment
5-year
1O-year
Study
s s S XRT S XRT
82 84 85 81 94 89
59 52 53 59 67 68
Boxer et al. 1977” Veenema et al. 19774s Hodges et al. 197928 Bagshaw 1985 3 Middleton et al. 1986 33 Present series (M.D.A.H.)
radiation
therapy;
N-,
negative
nodes by lymphadenectomy.
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J. Radiation Oncology 0 Biology0 Physics
April 1988, Volume 14, Number 4
tween surgical and XRT series. Since the survival expectation to 10 years in our series was no different from the expected survival of age-matched men in the general population, it is unlikely that any treatment modality could achieve significantly better survival rates in a similar patient population. A common and valid criticism’9,29,30*36~46 leveled at many XRT series and applicable to ours, is that only 5- or lo-year data are available. This disease may follow a protracted course so that 15 and 20-year data are necessary to draw firm conclusions about the curative potential of any treatment modality. Ultimately, we simply have to wait to achieve the desired follow-up; meanwhile, the data available (Figs. 1 and 2) give us no reason to suppose that relative patient survival will take a significant downward turn beyond 10 years. In our series, because DFS at 10 years (86%) was superior to survival at 10 years (68%), in the long term, intercurrent diseaserelated death poses a more serious hazard than prostate cancer. The 5-, lo-, 15-, and 20-year survival data from the Stanford XRT series3 did not reveal any significant unexpected attrition of patients beyond 10 years. Only one prospective randomized study compared surgical intervention with XRT for patients with Stages A2 and B prostatic carcinoma.38 In that study 106 patients with clinical Stages A2 or B disease and with negativestaging pelvic lymphadenectomy were randomly assigned to either XRT or surgery. Sixteen patients were excluded from analysis and 7 patients were nonrandomly crossed over to the other treatment arm. At 5 years, about 40% of the XRT patients had disease progression, compared with only 12% of the surgical patients (p = 0.037). The conclusion was “that a radical operation is more effective than megavoltage radiation in controlling prostatic adenocarcinoma that is confined to the anatomic limits of the gland. . . .“38 Unfortunately, for unknown reasons, the XRT results in that study were particularly poor. In our series of nonlaparotomy-staged patients, the 5-year DFS was 89% compared with about 60% in the Uro-Oncology Group series. In the Stanford series3 51 laparotomy-negative clinical Stage A2 and B patients had a DFS of about 90% at 5 years.
no demarcation criteria have been universally accepted. In our series no patient had only one or two microscopic foci of disease,3’ and all A2 cases were in the “multifocal or diffuse” category. The 74% 5-year survival for Stage A2 patients was significantly inferior to that of 93% for patients with Stage B. However, the DFS for patients in both stages was identical at 90% indicating that patients with Stage A2 prostate cancer had a significantly higher mortality from intercurrent disease than those with Stage B disease. At up to 5 years from diagnosis, there was no evidence that Stage A2 represents a biologically more aggressive disease than Stage B. The suggestion that Stage A2 carcinoma may be biologically more aggressive than the disease at early B stages is based on a relatively high incidence of involved pelvic nodes,23,24,48on the occurrence of poorly differentiated lesions,‘3V23*24*29,48 and on apparently poor results following surgery24 in patients with Stage A2 disease. Table 3 summarizes some results of surgery and/or endocrine management in Stage A disease. In contrast to the surgical viewpoints on this stage of disease, most XRT series report 5-year survivals and DFS at least as good, if not better, than the results for Stage B (Table 4). The reasons for the better outcome in XRT series of patients with A2 disease are unclear, but this fact argues strongly in favor of irradiation as the optimal modality. Jewett29 also concluded that XRT was better than prostatectomy for A2 disease. Since local control was achieved in all our Stage A2 patients with the doses used, we now recommend the use of 62.00 Gy for that stage.
Stage B The 93% and 70% survival rates at 5 and 10 years respectively and the corresponding 89% and 85% DFS rates found in our series compare well with the results of many other XRT series (Table 5) and with the results of surgical series (Table 6). Although we are mindful of the difficulties inherent in retrospective inter-institutional comparisons, an appraisal of the results summarized in Tables 5 and 6 leaves little doubt of the efficacy of XRT relative to radical surgery in Stage B disease. XRT series cannot yet provide definitive 15-year data, but, as already discussed, there are no compelling reasons to suppose that survival and Stage A2 DFS will take dramatic downward turns in the 1O-to- 15Despite evidence that the distinction between Al and year interval. Moreover, survival for this stage was equal A2 prostatic cancer is prognostically significant,5,‘3~‘6,20*24,29 to the expected survival of age-matched men in the general Table 3. Results of surgery and/or hormonal therapy for Stage A adenocarcinoma
of the prostate
Survival % Number of patients
Treatment
5-year
1O-year
Study
28 100 26 43 46
S S, TURP, H H H S
75 67 48 60 78
60 41 28 34 43
Nichols et al. 1977 35 Heaney et al. 1977 27 White et al. 197748 Byar (VACURG) 1980” Byar (VACURG) 1980”
S, radical surgery; H, endocrine management;
TURP, transurethral
resection of prostate.
StageB prostaticcancer0 G. K. ZAGARS Table 4. Results of radiation therapy in Stage A adenocarcinoma of the prostate Number of patients
S-year survival % (disease-free survival)
13 10 17 25 10 32
88 100 (56) 100 96 (84) 100 (100) 14 (90)
Study Harisiadis et al. 197826 Rangala et af. 198240 Aristizabel et al. 1984’ Rosen et al. 19844’ Perez et al. 198639 Present series (M. D. Anderson Hospital)
population which makes it unlikely that superior survival rates could follow with any other modality. Under these circumstances modality choice should be made on the basis of comparative morbidity. Table 1, in which we summarized prognostic factors for Stage B, showed only that one factor was significantpatients who had undergone endocrine treatment (hormones or orchiectomy) had a significantly poorer DFS than patients without such pretreatment. Since patients with a treatment delay longer than 2 months did no worse than those treated early (Table l), it seems unlikely, though possible, that a delay in XRT accounts for the poorer outcome of hormonally pretreated patients. A more likely explanation is that some of the pretreated patients had more extensive disease, especially extracapsular extension, which mgressed and led to downstaging. In our series, the only patient who had an elevated prostatic acid phosphatase (:>0.8 mu/ml by the Roy method) remains alive and well. We were unable to demonstrate any difference in outcome for patients with unilobar or bilobar disease, in marked contrast to surgical series in which B2 patients fared substantially worse than Bl patients even at 10 years of follow-up.‘oY’9,29*33,46 In our study, as in the XRT patterns of care study,25 TURP was not an adverse factor in Stage B. In view of the small number of pathologically graded cases, we can make no definitive statements about the inlfluence of grade on outcome.
et
707
al.
The occurrence of only 4 local recurrences, 2 at moderate and 2 at high doses precludes any meaningful doseresponse analysis. Since complications increased as dose increased, however, especially above 68 Gy, we have ‘elected to recommend 64 Gy as the optimal dose for Stage B disease. This dose was also found to be optimal in the XRT patterns of care study.25 Regional pelvic nodes Elective irradiation of regional pelvic nodes did not improve DFS or survival. With few exceptions,‘,32*40most XRT series reported that no benefit accrues from elective pelvic nodal XRT,26*34*4’,47*49 and the Stanford trial addressing this question failed to show a statistically significant superiority for nodal XRT regardless of whether nodes were surgically positive or negative.2 Likewise, prevailing surgical opinion holds that pelvic lymphadenectomy is not a therapeutic procedure.7,22*24*29”6*46 Despite this, regional pelvic nodal recurrence is an uncommonly documented event in prostatic carcinoma both in XR~‘,3,26,32,39,40,41,47,49
and
surgicd
se~es.6,10,17,19,22,30,33,35,45
The expected incidence of pelvic nodal disease in a series of mixed Stages A2 and B patients was about 20%25%.7,23,24,36,48,49 The low incidence of manifest nodal failure may be caused partly by difficulties in clinical detection of pelvic nodal masses, but it may also involve undefined host-tumor interactions that prevent the progression of early nodal disease to gross clinically detectable lymphadenopathy. Strong evidence for this phenomenon is provided by the NSABP studies of breast cancer.2’ Complications The incidence of complications in our series was similar to that reported for most XRT series,‘,3,26,39*“c*4’ and a major complication rate of 1.8% compares favorably with the major complications reported for surgical studies.6,‘,‘0,‘9,28,30,35,36,45 Whether “neme_spafing” prosta_ tectomy18 proves to be an adequate cancer operation remains to be seen. We note parenthetically that endocrine manipulation is not without toxicity.1’,‘2 We identified
Table 5. Results of radiation therapy for Stage B adenocarcinoma of the prostate Survival % Number of patients
5-year
21 25 24
Z (59) (61)
101 85 138* 155t 113 82
$; (68) 88 89 (72) 93 (89)
* Selected B 1 patients only. t Iodine- 125 implantation.
1O-year (disease-free survival)
15-year
Study
-
-
-
52 -
74 (60) ’ 70 (85)
Harisiadis et al. 197826 Rangala et al. 198240 Werf-Messing et al. 198447 Aristizabal et al. 1984 ’ Rosen et al. 19844L Bagshaw 1985’ Whitmore et al. 1985 49 Perez et al. 1986 39 Present series (M. D. Anderson Hospital)
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I. J. Radiation Oncology ??Biology ??Physics
April 1988, Volume 14, Number 4
Table 6. Results of radical surgery in Stage B adenocarcinoma
of the prostate
Survival % Number of patients
S-year
185 (c)
78
1O-year (disease-free survival)
15-year 31 54 (27)
55 (48) -
160 (cB1) 200 (P) 110 (c)
86 (75)
55 72 (57) 62 (58)
195 (c) 320 (P, No) 102 (c, No)
95 (86) 92 (93) 93 (88)
74 (67) 81 (83) -
-
Study
(38)
Belt, Schroeder 1972 6 Culp, Meyer 1973” Boxer et al. 1977 I0 Elder et al. 1982” Jewett 1980 3o Gibbons et al. 1984” Benson et al. 1984’ Middleton et al. 1986 33
c, clinical stage; p, pathologic stage; No, nodes negative at lymphadenectomy.
the use of too high a dose (>68 Gy) and the treatment of only one field per day as adverse factors for complications, and we expect serious afteraffects will diminish even further when these deficiencies are rectified. CONCLUSIONS 1. Radiation therapy is a highly effective modality for early Stage (A2 and B) adenocarcinoma of the prostate, producing local control in the vast majority of patients and yielding long-term survival rates that rival those achieved by radical prostatectomy.
2. Delayed XRT-related complications occur at an acceptably low rate and can be minimized by limiting total doses to approximately 64.00 Gy. 3. Pelvic node irradiation is not indicated for patients with clinical Stage A2 or B disease. 4. The prognosis of Stage A2 or B disease treated with external XRT is overall so good that no adverse prognostic subgroups can be identified. 5. Hematogenous metastasis is the most significant cancer-related threat to these patients and further therapeutic improvements require the development of adequate systemic therapy.
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