Adenocarcinoma of the prostate treated with external-beam radiation therapy: 5-year minimum follow-up

Radiotherapy and Oncology, 18 (1990) 235-246 Elsevier

235

RADION 00707

Adenocarcinoma of the prostate treated with external-beam radiation therapy: 5-year minimum follow-up R. J. A m d u r * , J. T. Parsons, L. T. Fitzgerald and R. R. Million Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, Florida, U.S.A. (Received 25 July 1989, revision received 21 November 1989, accepted 18 January 1990)

Key words." Prostatic neoplasms; Radiation therapy

Summary This is a retrospective analysis of 225 patients with localized adenocarcinoma of the prostate who were treated with continuous-course external-beam radiation therapy at the University of Florida between October 1964 and August 1982. All patients were treated 5 or more years prior to the date of analysis, and 30 % were eligible for 10-year follow-up. Hormonal treatment was used only in the management of recurrent disease. Ten-year results by stage were as follows: local control - A, 96 % ; B 1, 92 % ; B2, 51% ; C1, 57~/o ; C2, 76%. Relapse-free survival - A, 96% ; B1, 58% ; B2, 38% ; C1, 43% ; C2, 61%. Absolute survival - A, 69%; B1, 29%; B2, 47%; C1, 35%; C2, 50~o. Freedom from distant metastasis - A, 100%; B1, 55% ; B2, 71% ; C1, 65%; C2, 77%. Tumor grade was an important prognostic variable in most of the subgroups analyzed. The 5-year rate of distant metastasis was significantly greater in patients with stage C disease when the biopsy was made by transurethral resection of the prostate (TURP) rather than by needle biopsy. In stage B patients, the biopsy method was not prognostically important. For the 48 patients who developed recurrent tumor in the prostate gland, with or without concurrent metastasis, the 5-year absolute survival rate calculated from the date of recurrence was 26 ~o, compared with 10 % for the 34 patients who developed distant metastasis alone. Severe complications developed in 5 out of 225 patients (2 %) and included three severe rectal injuries, one bladder neck contracture, and one femoral head necrosis. Moderate complications developed in 48 out of 225 patients (21%), with rectosigrnoiditis (8 %) and hematuria (5 %) being the most common problems. For both moderate and severe complications, there was a clear trend toward an increasing complication rate with increasing dose. The method of diagnosis appeared to be a factor in the development of urinary incontinence following irradiation: needle biopsy, o/lo6 (0 %); TURP, 3/112(3 ~o); subtotal prostatectomy, 1/7 (needle biopsy versus TURP or prostatectomy, p = 0.076). The frequency of peripheral edema following irradiation was influenced by a

Address for correspondence: Dr. Robert J. Amdur, Department of Radiation Oncology, Box J-385, J. Hitlis Miller Health Center, Gainesville FL 32610-0385, U.S.A. * Acknowledgement of support: Dr. Amdur is an American Cancer Society Clinical Oncology Fellow. 0167-8140/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)

236 history of surgical disruption of the pelvic lymphatics: staging lymphadenectomy, 2/16 (13 ~), versus no lymphadenectomy, 0/209 (p = 0.005). A comparison with other series is presented.

Introduction

It is well documented that a significant percentage of recurrences following potentially curative therapy for localized prostate cancer will not present until 5 or more years following treatment [8,26]. In spite of this, there is a limited number of published series with long-term follow-up on a significant number of patients [ 1,8,10,26-28]. Because of this, a retrospective analysis was performed at the University of Florida of patients with localized adenocarcinoma of the prostate who were treated with radical external-beam irradiation at least 5 years prior to the date of analysis and who did not receive concomitant hormone therapy.

Materials and methods

This is a retrospective analysis of 225 patients who were treated by external-beam irradiation alone with curative intent in the Department of Radiation Oncology at the University of Florida between October 1964 and September 1982 (date of analysis, September 1987). Patients who did not meet all of the following criteria were excluded from the analysis. (1) Histologic proof of invasive adenocarcinoma of the prostate. (2) No evidence of regional or distant metastasis based on some combination of the following staging studies: physical examination, 225 patients (100~o); chest roentgenogram, 225 patients (100%); serum acid phosphatase, 212 patients (94~o); bone scan, 210 patients (93~o); intravenous pyelogram, 214patients (95~o); bipedal lymphangiogram, 20 patients (9%); computerized axial tomography of the pelvis, 11 patients (5%); staging lymphadenectomy, 16 patients (7 ~o). As the pelvic lymphatics were not routinely evaluated, only six patients were excluded from

analysis solely because of metastasis to the pelvic lymph nodes. At the time of last follow-up, two of these patients were alive without disease, one was alive with local and distant disease present, and three had died of distant metastasis without local recurrence. (3) Initial treatment consisting of only externalbeam radiation therapy. Patients who were referred for irradiation following radical prostatectomy or who underwent any type of elective hormonal manipulation before, during, or after irradiation, other than for the treatment of recurrent disease, were excluded from the analysis. Ten patients were excluded from the analysis because a portion of their radiation therapy was given with interstitial seed implants. (4) Planned continuous-course irradiation. Twentyfive patients who received planned split-course irradiation were excluded from analysis. However, patients in whom continuous-course irradiation was planned but who had unplanned treatment interruptions (e.g. acute side-effects, intercurrent problems) were included. Follow-up was calculated from the first day of irradiation. Every patient in this study was treated at least 5 years prior to the date of analysis, and 68 (30 ~ ) were eligible for 10-year follow-up. The mean age at the time of treatment was 66 years (range, 45 to 81 years). Two hundred and four patients (91 ~o) were white, 20 (9~o) were black, and one was oriental. Sixty-eight patients (30 ~o) were referred from affiliated Veterans Administration hospitals. The diagnosis of cancer was made by transurethral resection of the prostate (TURP) in 114 patients (51 ~o), transperineal or transrectal needle biopsy in 104 patients (46~o), and subtotal prostatectomy in seven patients (3 ~o). Histologic slides from all patients were reviewed at either Shands Teaching Hospital or affiliated Veterans Administration hospitals. The

237 original pathology report was used to grade the tumor as well, moderately, or poorly differentiated. Based on digital examination, patients were grouped according to the following staging system: stage A, occult tumor (A 1, well differentiated and ~<3 T U R P chips containing tumor; A2, moderately or poorly differentiated or > 3 chips containing tumor); stage B, palpable tumor confined to the prostate gland (B 1, less than one lobe; B2, at least one entire lobe); stage C, palpable tumor extending beyond the prostatic capsule (C 1, involvement of the seminal vesicle or lateral sulcus; C2, extension to the pelvic sidewall, bladder, or rectum). The distribution of patients by stage and tumor grade is shown in Table I. Although treatment was individualized, the majority of patients with stage A or B 1 disease received 6500 c G y in 7-7.5 weeks, while stage B2-C patients usually received 6500-7000 cGy in 7-8.5 weeks. All patients were treated once a day, 5 days a week. In 214 patients ( 9 5 ~ ) , the true pelvis was initially treated to 4500-5000 cGy in 5-5.5 weeks (178-180 c G y per treatment) using a four-field box technique (Fig. 1). In the majority of patients, a compression cone was used on the anterior and posterior fields in an effort to decrease patient thickness and to move bowel out of

TABLE I Distribution by stage and grade (225 patients). Stage Grade a

A1 A2

Total

Well Moderately Poorly

Not specified

3 17

1 -

-

3

3

B1

9

15

3

1

B2 C1 C2

16 32 6

33 33 13

8 16 7

2 3 1

4 23 28 59 84 27

a Degree of histologic differentiation.

the field. When using the box technique, the tumor dose was specified at the intersection of the central axes of the four fields. In the 214 patients initially treated with the four-field box technique, 210 (93 ~ ) had two fields treated per day and four ( 2 ~ ) had only one field treated per day. Following pelvic irradiation, the dose to the prostate gland and adjacent tissues was usually boosted through 8 x 8 cm fields to the final tumor dose using bilateral 120 ° arcs (182 patients), a four field box technique (28 patients), or opposed

f

Fig. 1. Fields used for the initial dose of 4500 cGy in 5 weeks to 5000 cGy in 5.5 weeks for patients treated with the four-field box technique. (A) Anterior and posterior fields (usual dimensions, 11-12 cm by 12-14 cm). A 2 cm-wide block is used to decrease the dose to a portion of the rectosigrnoid colon (slanted lines). (B)Right and left lateral fields (usual dimensions, 11-12 cm by 8-9 cm).

238 anterior and posterior fields (four patients). The central axis of the reduced field was located at the midpoint of the prostate gland. When using rotational therapy, the tumor dose was specified at the isocenter. Eleven patients with stage A disease were treated with bilateral 120 ° arc fields covering only the prostate gland and adjacent tissues. Thirty-five patients ( 1 6 ~ ) received the final 200-500 cGy in 1-3 fractions through a direct perineal field. In 196 patients (87 ~o), a 2 cm-wide lead block (i.e. "sigmoid block") was placed approximately 2 cm into the superior portion of the anterior and posterior pelvic fields to decrease the dose to the sigmoid colon (Fig. 1A). In 197 patients (88~), 6°Co (80 cm SSD) was used for the entire treatment; in 23patients (10~), 6°Co was used for the whole-pelvis portion of the treatment and 17 MV photons for the reduced, bilateral 120 ° arc fields. The remaining five patients (2 ~ ) received their entire treatment with 17 MV photons. Because prostate cancer is a disease of older men, intercurrent disease and cancer are competing causes of death. Furthermore, the indolent nature and responsiveness of prostate cancer to hormonal treatment are such that a significant number of patients live for years following the development of recurrent disease. For these reasons, the effect of therapy on survival was analyzed with both an absolute and a relapse-free calculation. For the calculation of absolute survival, patients were scored as dead regardless of the cause of death or were scored as alive regardless of the status of their cancer at the time of last follow-up. For relapse-free survival calculations, patients were scored as dead at the time of detection of recurrent cancer. Patients who remained continuously free of recurrent disease were counted as alive (i.e. censored) at the date of death or last follow-up. The presence or absence of recurrent disease in the prostate gland was usually determined by digital examination. Progressive enlargement or induration as judged by experienced examiners was the criterion for the diagnosis of recurrence. Histologic documentation of local control or

recurrence was not a criterion for inclusion in this study. In the calculation of local control, a patient was scored as controlled only if the prostate gland had been continuously free of recurrent tumor throughout the follow-up period. If the patient was placed on hormonal therapy for distant metastases and had no evidence of local recurrence then or later, the patient was scored as controlled and censored from the local control analysis on the date hormonal therapy began. However, if local recurrence developed at any time in the course of the disease, the patient was scored as recurrent, regardless of the history of hormonal manipulation. Patients who died with no evidence of local recurrence were censored from the analysis at the date of death. All patients were included in the local control analysis. The efficacy of therapy was also analyzed in terms of the probability of remaining free from distant metastasis. Patients whose initial site of failure was in the pelvic lymph nodes (one patient) or who developed tumor recurrence in the prostate gland (48 patients) were excluded from this analysis in an effort to distinguish systemic relapse due to dissemination of locally recurrent disease from systemic relapse due to subclinical metastases present at the time of initial treatment. Therefore, the number of patients eligible for the freedom from distant metastasis analysis in each stage category was as follows: A 1, 4; A2, 22; B 1, 26; B2, 40; C1, 62; C2, 22. For actuarial calculations, the Cutler-Ederer modification of the Berkson-Gage method was used [5]. Times were calculated from the first day of radiation therapy. The curves were compared using the Gehan test [7]. Proportions were compared using a binomial test [4] or Fisher's exact test [ 19]. All 225 patients were included in the analysis of acute side effects and treatment-related complications. Acute side effects refer to problems causing minimal discomfort and resolving spontaneously within 3 months. Mild complications were those that resulted in minor discomfort for more than 3 months but resolved with minimal medical intervention. As mild complications often

239 were not documented, they are not presented in this study. Moderate or severe complications were classified according to the following criteria:

Moderate: Requiring a minor surgical procedure

Severe:

(e.g. urethral dilatation) or significant medical management and/or producing minor disability. Resulting in a major surgical procedure (e.g. colostomy) or causing significant disability.

The 10-year rates of local control for A and B 1 disease were in excess of 90~o. Only 2 of 27 patients with stage A disease developed any kind of recurrence. Despite their high rate of local control, a significant percentage of patients with stage B1 disease developed distant metastasis between 5 and 10 years. The local control rate for stage B2 fell from 7 4 ~ at 5 years to 51~o by 10 years. Approximately two thirds of stage C lesions remained locally controlled at 10 years.

Effect of histologic grade Results

Analysis of local control survival andfreedom from distant metastasis The 5- and 10-year local control, relapse-free survival, absolute survival, and freedom from distant metastasis results are listed in Table II. To facilitate comparisons with other series in the literature, the major stage categories were subdivided several different ways.

In order to obtain adequate patient numbers for the analysis of the effect of histologic grade on prognosis, patients with stage B 1 and B2 disease were grouped together (stage B), as were patients with stage C1 and C2 disease (stage C). Patients with stage A disease were excluded from the analysis because after stratification by histologic grade, there were too few patients in each subgroup. The 5-year rates of local control, relapse-free survival, and absolute survival according to tumor grade are given in Table III;

TABLE II Results a according to stage (225 patients). Stage

A1 A2 A (total) B1 B2 B (total) A + B C1 C2 C (total)

No. of patients b

4 23 27 28 59 87 114 84 27 111

Local control (%)

RFS (%)

5 yr

10 yr

5 yr

I00 95 96 100 74 82 85 80 81 80

100 95 96 92 51 62 69 57 76 63

100 95 96 90 65 72 78 60 66 61

Absolute survival (%)

FDM (%)

10 yr

5 yr

10 yr

5 yr

10 yr

100 95 96 58 38 44 54 43 61 48

75 74 74 69 66 67 69 71 78 73

75 68 69 29 47 41 46 35 50 38

100 100 100 90 83 85 90 70 77 72

100 100 100 55 71 66 75 65 77 69

a Cutler-Ederer version of the Berkson-Gage method [5]. b Number of patients for local control, relapse-free survival, and absolute survival analyses. See text for number of patients at risk for distant metastases. Abbreviations: RFS = relapse-free survival; F D M = freedom from distant metastasis in patients whose disease remained locally controlled.

240 T A B L E III Effect o f histologic grade: 5-year results. No. o f p a t i e n t s

Local control ( ~o )

Relapse-free survival ( ~ )

Absolute survival (~o)

25 48 11

85 a 85 59 a

85 b 73 44 b

75 ~ 70 27 ~

38 46 23

90 a 75 69 d

87 ~ 51 40 ~

81 f 67 64 r

Stage B Well Moderate Poor

Stage C Well Moderate Poor

ap = 0.005; ep < 0.001; fp = 0.020.

Significance levels [5]: ap = 0.201; bp = 0.047; Cp = 0.015;

all three endpoints were affected by histologic grade.

Effect of TURP on prognosis The rates of local control, re!apse-free survival, and freedom from distant metastasis were compared for patients who underwent T U R P for

diagnosis versus those who had a transperineal or transrectal needle biopsy (Table IV). Results for patients with stage A disease are not shown because all but one patient had T U R P for diagnosis. Only 5-year results are reported, because the numbers of patients within the subgroups were too small to allow confidence in the 10-year figures. The seven patients whose

T A B L E IV T h e effect o f T U R P o n prognosis. Stage

Method of diagnosis (No. o f p a t i e n t s ) a

Local control at 5 yrs ( % )

RFS at 5 yrs (~o)

FDM at 5 yrs (~o)

B1

TURP Needle TURP Needle TURP Needle TURP Needle TURP Needle TURP Needle

100 100 76 72 82 81 75 b 85 b 77 b 83 b 75 f 84 f

88 b 92 b 67 64 71 b 74 b 46 c 72 c 56 b 71 b 48 ~ 72 c

86 b 91 b 81 b 88 b 82 b 89 b 58 d 79 ° 68 e 82 e 61 ¢ 80 c

B2 B1 + B2 C1 C2 C1 + C2

(10) (18) (26) (31) (36) (49) (39) (45) (12) (14) (51) (59)

a N u m b e r o f p a t i e n t s for local control a n d R F S . See text for n u m b e r o f patients at risk for d i s t a n t m e t a s t a s i s . bp > 0.1; Cp = 0.005; ap = 0.083; ep = 0.070; fp = 0.04. Abbreviations: R F S = relapse-free survival; F D M = f r e e d o m from d i s t a n t m e t a s t a s i s .

241 diagnosis was made by subtotal prostatectomy were excluded from this analysis. After stratification by stage, the distribution of patients by tumor grade did not differ significantly for the T U R P and needle biopsy groups. For patients with stage C1 and C2 disease, the 5-year freedom from distant metastasis rates were 15-20 percentage points higher for patients whose diagnosis was made by needle biopsy (p = 0.08 and 0.07, respectively).

Recurrence: timing, patterns, survival The cumulative time to detection of any recurrence (local, regional, or distant) for the 83 patients who developed some type of treatment failure is shown in Fig. 2. At 2 years, only 30 of 83 recurrences (36~o) had been detected, compared with 61 (73~o) at 5years and 80 (96~o) at 10 years. The latest recurrence to date (local and distant simultaneously) occurred 12.5 years after irradiation. For 'the 48 patients who developed recurrent tumor in the prostate gland (with or without distant metastasis) 10 (21 ~o) of 48 recurrences had been detected by 2 years, 31 (65 %o) by 5 years, and 46 (96~o) by 10 years. The time to local recurrence paralleled the time to any recurrence. For the 34 patients who developed distant metastases but remained continuously free of recurrence in the prostate gland throughout the follow-up period, the metastasis had been de-

tected in 20 (59~o) by 2 years, in 29 (85~o) by 5 years, and in 33 (97~o) by 10 years. One additional patient developed a pelvic lymph node recurrence a year after treatment. Overall, 83 of 225 patients (37~o) developed recurrent tumor during the follow-up period. The initial sites of failure were prostate gland alone, 36 (43 ~o); prostate gland and synchronous distant metastasis, 12 (14~o); distant metastasis alone, 34 (41~o); and pelvic node alone, 1 (1 ~o). Local recurrences were confirmed by biopsy in 31 of 48 patients (65~o). No patients developed a local recurrence after distant metastasis, possibly because of the routine use of hormonal therapy at the time metastases were detected. Hormonal therapy was given at the time of relapse in 33 of 48 patients (69~o) who developed a local recurrence and in 27 of 34 patients (79~o) who developed distant metastasis alone. No patients who developed local recurrence underwent salvage prostatectomy or reirradiation. The absolute survival rates following local recurrence or distant metastasis are presented in Fig. 3.

Acute side-effects Acute side-effects of therapy, usually diarrhea or dysuria, occurred in 150 of 225 patients (67~o)

100© -~80

%

0 F R E C U R R E N C E S

100

~

~

LR * / - DM (n-48)

[ --)<- DM Alone (n-34)

__-~

80

% RvV 60 40 u

S

I

. . . . .

60

A L 20

40

26%(.=) %

20 0 0 0

1

2

3

4

5

6

7

8

TIME(Years)

i 9

i 10

i 11

i 12

13

Fig. 2. Cumulative time to local, regional, and/or distant recurrence (83 patients).

~

10% (n-e)

L

I

1

2

I

I

a

3

4

5

TIME(Years)

Fig. 3. Absolute survival following recurrence (Cutler-Ederer modification of the Berkson-Gage method) [5]. By the G e h a n method [7],p = 0.096. LR = local recurrence; D M = distant metastases.

242 TABLE V Complications (225 patients).

Rectosigrnoiditis Fecal incontinence Partial small bowel obstruction Urinary incontinence Urethral stricture Bladder neck contracture Hematuria Peripheral edema Femoral head necrosis Hematospermia Total complications Total patients with complicationse a b c d e

Moderate

Severe

Total

(%)

(%)

(%)

19 (8) a 5 (2)

Ib

20 (9)

2o

7 (3)

1

-

1

4 (2) 6 (3) 6 (3)

•-

11 (5)

-

2 (1) m

1.

1

1

-

1

4 (2)

-

6 (3)

1'd

55 48 (21)

7 (3) ll

(5)

2 (1)

5 5 (2)

60 53 (24)

See text for definition. Required abdominoperineal resection. Refused colostomy. Required permanent suprapubic catheter. Seven patients had two moderate complications each.

and resolved spontaneously within 3 months of completion of therapy.

Complications Moderate complications developed in 48 patients (21~), and severe complications in five (2~o) (Table V). Rectal injury requiring colostomy occurred in one patient ( < 1 ~ ) . Two additional patients ( < 1 ~o) developed persistent fecal incontinence but refused colostomy. The frequency of radiation-induced erectile dysfunction could not be determined because specific information was often not available both before and after therapy. The effect of tumor dose on the frequency of all moderate and severe complications is shown in Table VI. For both moderate and severe complications, there was a trend toward an increasing complication rate with increasing dose. Doses of 6500 and 7000 cGy were important dividing lines, above and below which the frequency of complications differed significantly, as follows: for moderate complications, ~<6500 cGy (13/90 versus > 6 5 0 0 cGy (35/134), p = 0 . 0 2 5 ; ~ 7 0 0 0 cGy

(36/187) vers~s ">7000 cGy (12/38), p ().070; for moderate plus severe complications, ~<6500 cGy (14/90 versus > 6 5 0 0 c G y (39/134), p = 0 . 0 1 3 ; ~<7000cGy (4o/187) versus > 7 0 0 0 c G y (13/38), p = 0.068. For severe complications alone, there was a trend toward increasing frequency of complications with increasing dose, but the difference =

TABLE VI Dose-effect analysis for complications (225 patients). Dose (cGy)

<6000 6000-6500 6501-7000 >7000 Total

No. of patients

Moderate

Severe

(%)

(%)

2 89 96 38

1 12 (13) 23 (24) 12 (32)

0 1 (1) 3 (3) 1 (3)

225

48 (21)

5 (2)

Note: Patients with multiple complications were scored

according to the most severe complication. See text for definition of degrees of complication and comparisons of significance.

243

was not statistically significant: ~<6500 cGy, 1/91 (1 ~o), versus >6500 cGy, 4/134 (3~/o) (p = 0.327). The effect of tumor dose on the frequency of moderate and severe rectosigmoiditis was analyzed separately. To eliminate the potential effect of different treatment techniques, analysis was limited to 182 patients treated by a four-field box technique for the initial 4500-5000 cGy (with two fields treated per day) followed by bilateral 120 ° arc fields covering only the prostate and periprostatic tissues. The frequency of rectosigmoiditis according to tumor dose was as follows: 6000-6500 cGy, 4/72 ( 6 ~ ) ; 6501-7000 cGy, 9/73 (12~o); >7000 cGy, 6/37 (16~o). The only case of severe rectosigrnoiditis occurred following 7450 cGy tumor dose in 43 treatments over 62 days with 6°Co. This patient required both colostomy and abdominoperineal resection. The frequency of rectosigmoiditis above and below 6500 and 7000 cGy was as follows: ~<6500 cGy (4/72) versus > 6 5 0 0 c G y (15/11o), p = 0.067; ~<7000cGy (13/145) versus > 7 0 0 0 c G y (6/37), p = 0.161. Use of the sigmoid block decreased the frequency of rectosigmoiditis; this will be the subject of a separate analysis. The frequency of moderate and severe urethral stricture and/or bladder neck contracture appeared to correlate with multiple T U R P procedures prior to irradiation [0-1 TURPs, 10/206 (5~o) versus 3/19 (16~o) following i>2 T U R P procedures; p = 0.085 ]. There was no significant difference in the frequency of strictures or contractures in patients who had undergone one T U R P versus those who had never had a TURP. None of the seven patients who had a history of subtotal prostatectomy developed a urethral stricture or bladder neck contracture following irradiation. The frequency of moderate urinary incontinence was analyzed according to the method of diagnosis: needle biopsy, °/lO6 (0 ~o); TURP, 3/112 (3 ~o); subtotal prostatectomy, 1/7 (14 ~o) [needle biopsy versus TURP, p = 0.134; needle biopsy versus T U R P or subtotal prostatectomy (4/119), p = 0.076]. The frequency of genital or pedal edema was

influenced by a history of surgical disruption of the pelvic lymphatics. Two of 16 patients (13 ~o) who underwent preirradiation staging pelvic lymphadenectomy developed moderate edema versus °/209 patients who did not have pelvic lymphadenectomy (p = 0.005).

Discussion

Analysis of local control, survival and freedom from distant metastasis The 10-year results for four series are listed in Table VII. The outcome of patients with stage A disease treated at the University of Florida is similar to that from other institutions. Five-year results in patients with stage A2 disease at the M.D. Anderson Hospital were as follows: local control, 100~; relapse-free survival, 92~o; and absolute survival, 74~o [27]. The local control results for patients with stage B disease treated at the University of Florida are not as good as those reported from other institutions. In our series, the factors of overall treatment time and dose appear to be important determinants of local control. This is the subject of a separate analysis. Based on analysis of these and other data, our time-dose schedules for patients with prostate cancer have been modified to treat patients at 1000 cGy per week to a smaller volume than prescribed in the present study. Our control and survival data for patients with stage C disease are similar to those reported in other major series.

The effect of histologic grade In this series, the degree of tumor differentiation was a prognostically important variable for all three endpoints: local control, relapse-free survival, and absolute survival (Table III). Similar results have been reported by many other institutions [2,9,13,14,22].

244 T A B L E VII Literature review: 10-year actuarial results. No. o f patients

Local control

RFS a

Survival

(%)

(%)

(%)

60 34 41 27

97 96

77 40 96

61 60 45 69

312 100 458 82 185 87

71 88 62

40 40 85 60 44

46 50 58 70 58 41

296 63 385 551 328 111

65 81 63

38 30 46 36 48

38 30 36 47 38 38

Stage A P a t t e r n s o f care [10] S y r a c u s e [25] M a l l i n c k r o d t [23] University of Florida

Stage B P a t t e r n s o f care [10] S y r a c u s e [25] S t a n f o r d b [1] M D A H [24] M a l l i n c k r o d t [23] University of Florida

Stage C P a t t e r n s o f care [10] S y r a c u s e [25] S t a n f o r d [1] M D A H [25] M a l l i n c k r o d t [23] University of Florida a R F S = relapse-free survival. b I n c l u d e d stages A a n d B.

Effect of TURP on prognosis The influence of the method of diagnosis (TURP versus needle biopsy) on patient outcome is controversial [ 11,12,15,17,18]. Our data lend support to series that claim that diagnosis by T U R P reduces the likelihood of long-term relapse-free survival (Table IV). In the 84 stage C patients whose disease remained continuously locally controlled, the 5-year rate of freedom from metastasis was as follows: TURP, 6 0 ~ , versus needle biopsy, 80~/o (p = 0.052). The method of diagnosis was not prognostically important in patients with stage B disease, regardless of local tumor status.

Recurrence Our data confirm the concept of prostate cancer as a relatively indolent neoplasm that often recurs

many years after therapy. In our series, greater than one third of all local recurrences were detected after 5 years. Similar findings have been reported in patients treated with surgery alone. At the Mason Clinic, the average interval to local or distant recurrence was 6 years (range 1 to 15 years) in patients with clinical stage B disease treated with radical prostatectomy [8]. In many reported series, the minimum period of follow-up (e.g. 1 year) [6] or median follow-up (e.g. < 4 years) [21] is short or not clearly stated [20]. Because of possible late recurrences, these series tend to overestimate the efficacy of treatment. Following local and/or distant recurrence, the prognosis for long-term survival is poor, with a median survival of 2.2 years and a 5-year survival of 18~o (Fig. 3). These results are similar to those reported by Bagshaw [ 1].

245

Complications T h e severe c o m p l i c a t i o n rate o f 2~o in this series is similar to t h a t r e p o r t e d by other institutions [ 10,16,24]. I n addition to this series, the positive relationship b e t w e e n t u m o r d o s e a n d treatmentrelated c o m p l i c a t i o n s has been d e m o n s t r a t e d b y the P a t t e r n s o f C a r e S t u d y [16] a n d the M . D . A n d e r s o n H o s p i t a l [27,28], but w a s n o t c o n firmed by the R T O G study 77-06 [24]. T h e University o f F l o r i d a d a t a suggest t h a t the f r e q u e n c y o f urethral a n d b l a d d e r n e c k complic a t i o n s (stricture, i n c o n t i n e n c e ) is i n c r e a s e d b y prior T U R P . This is n o t surprising, in view o f the recent article by B r u s k e w i t z a n d c o - w o r k e r s [3], in w h i c h the incidences o f urethral stricture a n d b l a d d e r n e c k c o n t r a c t u r e in 69 patients undergoing T U R P for benign disease (no radiation t h e r a p y ) were 4 a n d 9~o, respectively.

Acknowledgement T h e a u t h o r s t h a n k the R a d i a t i o n O n c o l o g y r e s e a r c h staff for their help in p r e p a r i n g this manuscript.

References 1 Bagshaw, M.A. Potential for radiotherapy alone in prostatic cancer. Cancer 55: 2079-2085, 1985. 2 Barzell, W., Bean, M. A., Hilaris, B. S. and Whitmore, W.F. Prostatic adenocarcinoma: relationship of grade and local extent to the pattern of metastases. J. Urol. 118: 278-282. 1977. 3 Bruskewitz, R.C., Larsen, E.H., Madsen, P.O. and Dorflinger, T. 3-year follow-up of urinary symptoms after transurethral resection of the prostate. J. Urol. 136: 613-615, 1986. 4 Colton, T. In: Statistics in Medicine, Little Brown & Co., Boston, pp. 163-167, 1974. 5 Cutler, S. J. and Ederer, F. Maximum utilization of the life-table method in analyzing survival. J. Chronic Dis. 8: 699-712, 1958. 6 Forman, J. D., Zinreich, E., Lee, D. J., Wharam, M. D., Baumgardner, R.A. and Order, S.E. Improving the therapeutic ratio of external beam irradiation for carcinoma of the prostate. Int. J. Radiat. Oncol. Biol. Phys. 11: 2073-2080, 1985.

7 Gehan, E.A. A generalized Wilcoxon test for comparing arbitrarily singly-censored samples. Biometrika 52: 203-223, 1965. 8 Gibbons, R.P., Correa, R.J., Jr., Brannen, G.E. and Mason, J.T. Total prostateetomy for localized prostatic cancer. J. Urol. 131: 73-76, 1984. 9 Gleason, D. F. Histologic grading and clinical staging of prostatic cancer. In: Urologic Pathology: The Prostate, M. Tannenbaum. pp. 171-197. Editor: Lea & Febiger, Philadelphia, 1977. 10 Hanks, G. E., Diamond, J. J., Krall, J. M., Martz, K. L. and Kramer, S. A ten-year follow-up of 682 patients treated for prostate cancer with radiation therapy in the United States. Int. J. Radiat. Oncol. Biol. Phys. 13: 499-505, 1987. 11 Hanks, G. E., Leibel, S. and Kramer, S. The dissemination of cancer by transurethral resection of locally advanced prostate cancer. J. Urol. 129: 309-311, 1983. 12 Hanks, G. E., Pilepich, M. V., Krall, J. M., Sause, W. T., Johnson, R. J., Russ, H. H., Perez, C. A., Zinninger, M. and Martz, K. L. The adverse effect of TURP as method of diagnosis in 494 patients with stage C prostate cancer treated within RTOG protocol 75-06 (Abstr. 30). Int. J. Radiat. Oncol. Biol. Phys. 12 (Suppl. 1): 106, 1986. 13 Hussey, D.H. Carcinoma of the prostate. In: Textbook of Radiotherapy. G.H. Fletcher, pp. 894-914. Editor: Lea & Febiger, Philadelphia, 1983. 14 Kramer, S. A., Spahr, J., Brendler, C. B., Glenn, J. F. and Paulson, D.F. Experience with Gleason's histopathologie grading in prostatic cancer. J. Urol. 124: 223-225, 1980. 15 Kuban, D.A., El-Mahdi, A.M. and Schellhammer, P.F. The effect of TURP on prognosis in prostatic carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 13: 1653-1659, 1987. 16 Leibel, S. A., Hanks, G. E. and Kramer, S. Patterns of Care outcome studies: results of the national practice in adenocarcinoma of the prostate. Int. J. Radiat. Oncol. Biol. Phys. 10: 401-409, 1984. 17 McGowan, D.G. The adverse influence of prior transurethral resection on prognosis in carcinoma of prostate treated by radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 6: 1121-1126, 1980. 18 McGowan, D.G. The effect of transurethral resection on prognosis in carcinoma of the prostate: Real or imaginary? Int. J. Radiat. Oncol. Biol. Phys. 15: 1057-1064, 1988. 19 Mendenhall, W., Ott, L. and Larson, R.F. In: Statistics: A Tool for the Social Sciences, pp. 333-336. Duxbury Press, North Scituate, MA, 1974. 20 Paulson, D. F., Lin, G. H., Hinshaw, W. and Stephani, S. The Uro-Oncology Research Group. Radical surgery versus radiotherapy for adenocareinoma of the prostate. J. Urol. 128: 502-504, 1982. 21 Paulson, D. F., Hodge, G. B., Jr. and Hinshaw, W. The

246 Uro-Oncology Research Group. Radiation therapy versus delayed androgen deprivation for stage C carcinoma of the prostate. J. Urol. 131: 901-902, 1984. 22 Perez, C.A. Carcinoma ofthe prostate, avexingbiological and clinical enigma. Int. J. Radiat. Oncol. Biol. Phys. 9: 1427-1438, 1983. 23 Perez, C. A., Garcia, D., Simpson, J. R., Zivnuska, F. and Lockett,M. A. Factors influencingoutcome of definitive radiotherapy for localized carcinoma of the prostate. Radiother. Oncol. 16: 1-21, 1989. 24 Pilepich, M.V., Asbell, S.O., Krall, J.M., Baerwald, W.H., Sause, W.T., Rubin, P., Emami, B.N. and Pidcock, G.M. Correlation ofradiotherapeutic parameters and treatment related morbidity - analysis of RTOG study 77-06. Int. J. Radiat. Oncol. Biol. Phys. 13: 1007-1012, 1987.

25 Sagerman, R. H., Chun, H. C., King, G. A., Chung, C. T. and Dalai, P.S. External beam radiotherapy for carcinoma of the prostate. Cancer 63: 2468-2474, 1989. 26 Walsh, P. C. and Jewett, H.J. Radical surgery of prostatic cancer. Cancer 45: 1906-1911, 1980. 27 Zagars, G. K., von Esehenbach, A. C., Johnson, D.E. and Oswald, M.J. The role of radiation therapy in stages A2 and B adenocarcinoma of the prostate. Int. J. Radiat. Oncol. Biol. Phys. 14: 701-709, 1988. 28 Zagars, G. K., von Esehenbach, A. C., Johnson, D.E. and Oswald, M.J. Stage C adenocarcinoma of the prostate. An analysis of 551 patients treated with externalbeam irradiation. Cancer 60: 1489-1499, 1987.