Acra Oncologica Vol. 30 No. 2 1991

FROM THE DIVISION OF UROLOGY, DEPARTMENT OF SURGERY, DUKE UNIVERSITY MEDICAL CENTER, DURHAM, NORTH CAROLINA, USA.

RADICAL SURGERY VERSUS RADIATION THERAPY IN EARLY

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PROSTATIC CARCINOMA C. N. ROBERTSON and D. F. PAULSON

Abstract

Randomized trial data

risk and, upon identification of such anatomic distribution of disease, to compare the relative impact of surgery or radiation in the management of that malignancy ( I , 2). In this study, 509 men with newly diagnosed, biopsy-proven prostatic adenocarcinoma were assigned a preliminary clinical stage based on rectal examination, colorimetric serum acid phosphatase level, a plain chest x-ray and a bone survey. Staging studies, designed to evaluate the anatomic extent of disease were sequenced to progress from those studies that demonstrated the most wide-spread evidence of disease to those which gradually focussed on the prostate. All men who presented with an elevated acid phosphatase were believed to have systemic disease and were excluded from the randomization schema. All men who demonstrated no evidence of osteoblastic disease on skeletal films were subjected to a technetium-99 bone scan. Approximately 25% of all patients with no bone metastases identified on routine skeletal x-rays had bone disease on the basis of radionuclide bone scanning. The frequency of bone disease increased as the volume of local disease increased (Fig. 1). Following the exclusion of disease in the axial and appendicular skeleton, next assessed were the nodes of the prostatic lymphatics. The margins of the node dissection were limited to the triangle bordered by the external iliac vasculature, the pelvic floor, and the hypogastric vasculature; all node-bearing tissue in this area was removed, including the node-bearing tissue surrounding the obturator nerve and vessels (Fig. 2). As anticipated, the incidence

In the mid 1970s, a multi-institutional cooperative group involving 13 major medical centers and their associated Veterans Administration Hospitals set out to determine the accuracy of then current staging studies to assess the anatomic distribution of disease in any single patient at

Presented at the Conference on Early prostatic Cancer. The WHO Collaborating Centre for Urological Tumours, Karolinska Hospital, Stockholm, March 21-23, 1990. Accepted for publication 29 November 1990.

Patients with organ-confined prostatic cancer, as determined by digital examination, bone scans and serum acid phosphatase determination, were randomized to radical prostatectomy or external-beam radiation therapy. With respect to first evidence of treatment failure, there was a significant difference in favor of the patients who had surgical treatment. In the patients given radiotherapy there was no essential difference in time to failure as compared with comparable patients in two recent observationonly trials on record. Key words: Prostatic cancer, surgical therapy, radiation therapy.

Despite the current enthusiasm for the use of radical prostatectomy to control apparent organ-confined prostatic malignancy, there remains considerable controversy over the relative importance of surgery or radiation therapy. This controversy occurs as there is a variable biologic course and it is difficult to predict outcome in a specific patient. For this reason, single institutional trials which are non-randomized have the potential of being biased due to the selection of either high-biologic risk or low-biologic risk patients in the population under study. Randomized trials have been established to avoid this difficulty. In the discussion which follows, we will examine the only randomized trial designed to evaluate the relative impact of radical surgery versus radiation therapy for patients with apparent organ-confined disease.

239

240

C. N. ROBERTSON AND D. F. PAULSON

Table

INCIDENCE OF PQStTlVE BONE SCAN AND NEGATIVE BONE SURVfl

Node biopsy

0 Negotive gone Surrey

W

Positive Bone Scon Gleason sum

Positive

Negative

Oh

YO

Group n

2-5 6 7 8 9-10

13.9 32.4 49.9 75.0 100.0

86.1 67.6 50.1 25.0 0

36 34 21 12 I

33.0

66.1

12

No diagnosis

p 6 0.0005

Reliminory Clinical Sloge

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Fig. 1. Patients with bone disease detected by radionuclide scanning who were considered disease-free by skeletal survey.

Ob

Fig. 2. Shaded area indicates area of limited pelvic lymph node dissection for staging of prostate carcinoma.

of node-positive disease was found to increase as the volume of local disease increased (Fig. 3). In an attempt to determine whether the histopathologic characteristics of the tumor tissue biopsied (to establish the diagnosis of cancer) could be used to predict the presence or absence of nodal extension, the investigators

UNegoiive Pelvic Nodes tzzz) Positive Pelvic Nodes

100

%

50

I-A

I-B

II III E - A IS!-6 Preliminary Clinicol Stage

IE-C

Fig. 3. Incidence of pelvic node extension as a function of preliminary clinical stage in patients with no bone disease as determined by radionuclide bone scan.

analyzed the incidence of positive nodes as a function of the Gleason sum. This analysis demonstrated that both high- and low-grade disease (determined by the Gleason sum) functioned as relatively accurate predictors of nodepositive disease, equivalent to that of the imaging modalities. Eighty-six percent of the patients with a Gleason sum less than 5 had node-negative disease, whereas 100% of those with a Gleason sum of 9 or 10 had node-positive disease (Table). With some minor variations, this general trend has been substantiated by other investigators. Patients whose disease was confined to the prostate as determined by digital examination, and who had no evidence of bone- or node-positive disease were assumed to have organ-confined disease and were randomized to radical prostatectomy or external-beam radiation therapy in balanced groups of 4 by institution (3). Patients were followed at two-month intervals for the first year and at three-month intervals thereafter. Serum biochemical profiles with acid phosphatase determinations, Karnofsky performance ratings, and a physical examination were obtained at each follow-up; chest x-rays and radionuclide bone scans were obtained as six-month intervals. The impact of treatment was determined with firstevidence-of-treatment-failure as the endpoint. Investigators chose use of first-evidence-of-recurrent disease rather than survival to avoid confounding the impact of the first therapy by the subsequent application of a second therapy that could alter the survival experience. Survival data was not accrued as funding was withdrawn by the National Cancer Institute, and patient follow-up and data analysis could not be completed as originally projected. Furthermore, lack of funding precluded analysis of morbidity data and follow-up of accrued morbidity data. Treatment failure was identified by acid phosphatase elevation on two consecutive follow-ups or by the appearance of bone or parenchymal disease with or without concomitant acid phosphatase elevation. A new appearance of increased radionuclide uptake was identified as the presence of bone metastases. The appearance of such metastases was either progressive on subsequent scans or was accompanied by elevation of serum acid phosphatase levels. Identification of cancer in the prostate on follow-up biopsy after

24 1

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SURGERY VERSUS RADIATION THERAPY IN PROSTATE CANCER

radiation therapy did not signify treatment failure in assessment of relative treatment efficacy. Curves representing non-parametric estimates of time-to-first-evidence of treatment failure were generated according to the KaplanMeier method (4). Treatment efficacy in pairs of subgroups was assessed for differences by the Cox-Mantel text ( 5). Fifty-six patients received external-beam radiation therapy, and 41 underwent radical prostatectomy. An analysis of the time-to-failure curves of the 2 treatment groups indicated that radical surgery possessed a distinct advantage (p = 0.037) over radiation therapy in controlling disease (Fig. 4). This study was criticized; detractors argued that patients with more aggressive disease had been assigned to radiation therapy and the length of follow-up was too short. All patients were examined prerandomization by both radiotherapist and surgeon and both had to agree that the disease was clinical stage T1 or T2. The average Gleason grade in the radiation therapy arm was 5.1, with an average Gleason sum of 5.5 in the radical surgery arm. If the Gleason sum functions as an indicator of biologic aggressiveness, the two groups seem equivalent, although those undergoing surgery had a slightly higher Gleason sum than those receiving radiation treatment. It may be of value to compare these results to a population of observed-only patients. Two such studies have been published. George (6) examined the clinical course of 120 patients with apparent localized disease only for 7 years. Objective evidence of bone disease appeared in 13 ( 1 1YO) of the 120 patients with the mean time to scan conversion being 35.8 months (Fig. 5). Two additional patients most probably had bone metastases but the scans were felt to be equivocal at the time of evaluation. Twenty-three patients of these 120 were treated with androgen deprivation because of concern over local tumor growth. The inclusion of these 23 patients among those being observed for failure could bias the outcome as other studies have demonstrated that androgen deprivation will delay the appearance of bone extension. One can argue that these 23 patients

Obiscliue

80 N.13

% Without Metastases

Possible

60

N.15

4 200 1

0

12

36 48 Months

24

84

should be excluded from the study, reducing the observed population to 97 and increasing the percentage of patients with progression to 19%. A second study by Johansson et al. (7) examined the clinical course of 223 patients with clinically localized disease. Seventy-two of these patients had focal occult disease, 34 had diffuse occult disease, 13 had TI nodules and 104 had T2 nodules. It should also be noted that of the 223 patients, 148 were grade I , 67 grade 2, and 9 grade 3. Nonetheless, despite the fact that the population base was biased by patients with low-volume and low-grade disease, when these patients were evaluated for progression as defined by tumor growth through the prostatic capsule and/or a rising serum level of acid phosphatase, clinical deterioration, signs of distant metastases, and/or skeletal pain, only 72% of the patients were progression-free 5 years after diagnosis. This number of 72% is considerably less than the 88% progression-free survival seen in the population of patients who received radical prostatectomy in the randomized study and only 5 percentage points higher than those who received radiation treatment in this same study. When reviewed by grade (Fig. 6), it is seen that tumor grade was the dominant predictor of progression. The progression rates in these two observation-only

* .-

. -.

-.

.-. - . - . -.

--__

'.

80%

Progression survival

free

60%

0

-

72

Fig. 5. Time to development of bone metastases in localized untreated prostatic cancer (h = 120). (Reprinted with permission from: George, et al: Lancet March 5, 1988.)

,

Fig. 4. Time to treatment failure for patients randomized to radiation therapy or radical surgery whose disease is confined to the prostate. Radiation therapy ( n = 56) 0 0 - 0; radical surgery ( n = 4 1 ) O - - O - - O ; p=O.O37.

60

I

. .

--- - _ _--, . . . . .

2

4

6

8

10

Years after diagnosis

Fig. 6. Cumulative proportion of patients without local or systemic progression of disease by tumor grade. (Reprinted with permission from: Johansson, et al: Lancet April 15, 1989.)

242

C. N. ROBERTSON AND D. F. PAULSON

trials parallelled more closely the outcome observed after irradiation for cure than the outcome observed after surgery for cure. The suggestion that irradiation has little impact on prostatic malignancy is even further strengthened when one notes that among T3NOMO patients randomized to either external beam irradiation or observation, there is no difference in time to failure (Fig. 3). This suggests that the purported impact of radiation therapy may be nothing more than an observation of the natural history of the disease. In conclusion, radical surgery appears superior to either irradiation or observation in producing disease control among patients with Tl-T2NOMO disease.

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Corresponding author: Dr. Cary N. Robertson, Division of Urology, Duke University Medical Center, P.O. Box 3707, Durham, NC 27710, USA.

REFERENCES 1. Paulson DF, Uro-Oncology Research Group The impact of current staging procedures in assessing disease extent of prostatic adenocarcinoma. J Urol 1979; 121: 300-5. 2. Paulson DF, Uro-Oncology Research Group Predictors of lymphatic spread in prostatic adenocarcinoma. J Urol 1980; 123: 697-9. 3. Paulson DF, Lin GH, Hinshaw W, et a1 Radical surgery vs. radiotherapy for stage A2 and stage B (Tl-2MONO) adenocarcinoma of the prostate. J Urol 1982; 128: 502-4. 4. Kaplan EL, Meier P Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457-81. 5. Cox DR Regression models and life tables. JR Stat SOC1972; 3 4 187-220. 6. George NJR Natural history of localized prostatic cancer managed by conservative therapy alone. Lancet 1988; 1: 494-7. 7. Johansson JE, Adami 10, Anderson SO, et a1 Natural history of localised prostatic cancer. Lancet 1989; 1: 799-803.

Radical surgery versus radiation therapy in early prostatic carcinoma.

Patients with organ-confined prostatic cancer, as determined by digital examination, bone scans and serum acid phosphatase determination, were randomi...
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