Radiotherapy following radical prostatectomy in patients with adenocarcinoma of the prostate

hr. J. Radiation Oncology Biol. Phys. Vol. 21, pp. 949-954 Pnnted in the U.S.A. All rights reserved.

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036O-3016/91 $3.00 + .@I 8 1991 Pergamon Press plc

??Original Contribution

RADIOTHERAPY FOLLOWING RADICAL PROSTATECTOMY IN PATIENTS WITH ADENOCARCINOMA OF THE PROSTATE ZBIGNIEW PJZTROVICH, M.D.,* GARY LIESKOVSKY,M.D.,?_ BRYAN LANGHOLZ,PH.D.,$ GARY LUXTON, PH.D.,* GABOR JOZSEF, PH.D.* AND DONALD G. SKINNER, M.D.7 University of Southern California School of Medicine, Los Angeles, California From 1973 to 1986, 160 patients with adenocarcinoma localized to the prostate were treated with radical prostatectomy and pelvic lymphadenectomy. In 78 (49%) patients more advanced stage of disease was found at surgery and they received local pelvic irradiation (RT). This consisted of 45 Gy for microscopic and 55 Gy for macroscopic residual disease. RT was given at 1.8 Gy a day, using the four-field “box” technique with the 23 MV X ray beam. Pelvic lymph node metastases were found in 28 (36%) patients who, in addition to RT, received systemic therapy: 20 with cyclophosphamide alone, 4 combined with 5-Fluorouracil, and 4 patients received DES. The 5- and lo-year overall actuarial survival was 95 and 77%, respectively, and the 5- and loyear disease-free survival was 58 and 43%, respectively. Recurrent tumor was found in 34 (44%) patients. Of these 34 patients, 32 (94%) had distant metastatic tumor and 2 (6%) had local recurrence in the pelvis. The presence of metastatic disease in pelvic lymph nodes had clinical significance since it influenced disease-free survival and the incidence of tumor recurrence. The lo-year disease-free survival for the 50 patients with no lymph node metastases was 51%, as compared to 28% for the 28 patients with such metastases, p = 0.001. Similarly, recurrent tumor was found in 28% of the former and 68% of the latter patients, p = 0.002. Other important parameters predicting recurrence were: clinical stage, p = 0.018, histological grade, p = 0.013, and Gleason’s grade, p= 0.002. This treatment program was very well tolerated and of low toxicity. There was no surgical mortality. Surgical complications were seen in 10 (13%) patients including: minor in 5 and major in 5. At 1 year, 77% of the patients remained continent, while 10% had mild stress incontinence. Of the remaining 13% only 3 (4%) patients had severe incontinence (> 5 pads dally). RT toxicity was mild with 38% experiencing diarrhea. Severe toxicity was seen in 2 (3%) patients who, early in the study, developed scrotal and lower extremity edema. Severe chemotherapy complications were seen in 1 (4%) patient who had severe neutropenic sepsis. Postoperative radiotherapy is a well tolerated, safe and effective treatment in patients who have microscopic or macroscopic residual tumor following radical prostatectomy. Prostate cancer, Postoperative radiotherapy.

INTRODUCTION

In view of the above problems, pathological stage frequently does not agree with the preoperatively established clinical stage. A poor correlation between clinical and pathological stage has been reported in 40 to 80% of radical prostatectomy patients (4, 5, 13, 16). The incidence of clinical understaging sharply rises with the increase in the stage of disease (13). As a result of this frequent understaging, more than one-third of radical prostatectomy patients are expected to have pelvic tumor recurrence (10, 20). The purpose of this report is to present our clinical experience with the use of pelvic irradiation in patients who were found to have extracapsular tumor extension following prostatectomy .

Surgery (S) and Radiotherapy (RT) are curative treatment modalities in patients with adenocarcinoma of the prostate confined to the gland (1, 2, 8, 17, 18, 21). Selection of patients for radical prostatectomy, however, presents a significant problem. In spite of major advances in imaging modalities and progress in the accuracy of clinical staging, it is still difficult to identify patients with intracapsular disease reliably. One particular problem is identifying patients with early extracapsular tumor extension and early invasion of regional lymph nodes. These tumor manifestations sharply reduce the number of patients who can be expected to have prolonged tumor-free survival following radical prostatectomy (17).

* Dept. of Radiation Oncology. t Dept. of Urology. $ Dept. of Preventive Medicine. Reprint requests to: Zbigniew Petrovich, M.D., Departmentof

RadiationOncology, Kenneth Norris Jr. Cancer Hospital and Research Institute, 1441 Eastlake Ave., Los Angeles, CA 90033. Accepted for publication 29 March 1991. 949

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Table 1. Clinical stage

Table 2. Pathological stage

Stage

N

%

A2 Bl l32 C Dl Total

6 24 33 14 1 78

8 31 42 18 1 100

Stage

N

%

A2

1 1 1 18 20 37 78

1.3 1.3 1.3 23.1 25.6 47.4 100

B1 B, Cl* C*? C,$ Total

*Limited extension through the capsule. j+Largertumors with wide extension in the pelvis. *Seminal vesicle involvement.

METHODS AND MATERIALS From 1973 to 1986, 160 patients with localized (A2 and B) adenocarcinoma of the prostate (CaP) were treated with radical prostatectomy and pelvic lymphadenectomy by the same surgeons (DGS and GL). Patients selected for this radical surgery were expected to have at least a lo-year survival. Details on the surgical techniques used in this study have been presented elsewhere (14, 15). Of the 160 patients who underwent prostatectomy, 78 (49%) were found at surgery to have a more advanced stage of disease and received postoperative RT. The mean age of the patients was 63 years (range 47 to 76 years) and most (83%) patients were Caucasians. Preoperative evaluation included: detailed general and urological history and physical examination, nuclear bone scan, radiographs of the chest, complete blood count, urinalysis, serum acid and alkaline phosphatase, prostatic acid phosphatase and, since it became available, prostatic specific antigen. All patients had a histological diagnosis of adenocarcinoma. Well differentiated tumors were found in 19 (24%/o), moderately well in 26 (33%), poorly differentiated in 6 (8%), and in 27 (35%) patients no tumor grade was available. Gleason’s grade was: 1 in 3 (4%), 2 in 14 (18%), 3 in 17 (22%), 4 in 3 (4%), 5 in 1 (1%) and in 40 (51%) patients it was not available. Clinical stage included 81% patients with stage A, and B, and 18% with Stage C disease (Table 1) (14, 15). All patients underwent modified Campbell’s prostatectomy and limited lymph node dissection (14, 15). This included 7 (9%) patients who had bilateral and 4 (5%) who had unilateral nerve sparing procedures. As expected, pathological stage showed more advanced disease in most patients while only 3 (4%) had Stage A, or B disease. This compared to 8 1% stage A, or B seen preoperatively (Tables 1 and 2). Additionally, 28 (36%) patients were found to have metastatic tumor in pelvic lymph nodes (Table 3). Of the 28 patients with lymph node invasion, 14 (50%) had 1 to 2 positive lymph nodes, 7 (25%) had 3 to 5, and 7 (25%) patients had 6 or more positive lymph nodes. A detailed histological examination revealed 29 (37%) patients with lymphatic invasion, 5 (6%) with vascular invasion, and 6 (8%) with atypical hyperplasia.

Postoperative treatment consisted of RT in all patients. Additionally, the 28 patients with lymph node metastases received systemic treatment. Prior to the opening of the USC Kenneth Norris Jr. Cancer Hospital and Research Institute (KNCH) in 1983, 7 (9%) patients received RT at UCLA Medical Center and 6 (8%) were treated at The Good Samaritan Hospital in Los Angeles. The remaining 65 (83%) patients were treated at KNCH. RT consisted of limited pelvic irradiation with the exception of four patients who, early in the study, received whole pelvic RT. The beams of radiation used for the treatment of these patients included 7 (9%) 10 MV, 6 (8%) 4 MV, and in 65 (83%) patients 23 MV X ray beam was used. All treatments were given at 100 cm TAD or TSD using a fourfield (“box”) technique with all fields treated daily. The average AP portal dimension was 11 x 11 cm. All portals were shaped using custom shields to optimize protection of normal tissues not suspected of tumor involvement (Figs. 1 and 2). The total tumor dose was 45 Gy in patients with microscopic disease and 55 Gy in patients with macroscopic residual disease. These tumor doses were to encompass the volume of interest and were defined to 90 or 95% isodose line. All patients were treated 5 days a week at 180 cGy daily increments. RT was begun 6 to 12 weeks postoperatively. In addition to RT, 20 (26%) patients received cyclophosphamide (CTX). CTX was given intravenously (IV) at 1 grn/m* per month. CTX combined with 5Fluorouracil(l

Table 3. Status of lymph nodes (path) Lymph nodes Primary site

A2 R, B, C, C2 C, Total

Positive

Negative

Total

%

1 1 1 2 1 22 28

0 0 0 16 19 15 50

1 1 1 18 20 37 78

1.3 1.3 1.3 28.1 25.6 47.4 100

Postoperative radiotherapy for prostatic carcinoma 0 Z.

Fig. 1. Anterior portal in a patient treated with postoperative

gm) was given intravenously to 4 (5%) patients and 4 (5%) patients received DES. The indication for this systemic treatment was the presence of pelvic lymph node invasion. This systemic treatment was given for 4 to 8 months and was begun 1 month following completion of irradiation or

radiotherapy

PETROVICH

951

et al.

with superimposed

radiation dose

4 to 5 months post-radical prostatectomy. Patients receiving CTX-SFU combination were given each drug on alternating months. The patients were followed regularly at 3-month intervals for the first post-treatment year, twice per year for the second year and annually thereafter. No patient was lost to follow-up. The follow-up extended from 4 to 16 years with a mean of 5.5 years and a median of 5 years. At each follow-up visit, patients had a detailed interval history and physical examination, serum acid and alkaline phosphatase, prostatic specific antigen. Signs, symptoms, or laboratory studies suggestive of recurrent disease required additional detailed studies. Local and distant failure were diagnosed using all of the available clinical, laboratory, and imaging data. Recurrent disease was histologically confirmed with the use of a needle biopsy. Survival was calculated from diagnosis using the actuarial method (11). RESULTS

Fig. 2. Lateral portal in the same patient as in Figure 1.

The 5- and lo-year actuarial survival for the 78 treated patients was 95 and 77%, respectively (Fig. 3) (Table 4). The 5- and lo-year disease-free actuarial survival was 58 and 43%, respectively, and the median disease-free survival was 83 months. The presence of tumor in pelvic lymph nodes had a significant influence on disease-free survival. The lo-year disease-free actuarial survival for the 50 lymph node negative patients was 51%, whereas it was 28% for those 28 patients who had pelvic lymph node metastases, p = 0.001, Log rank test (Table 5). Of the 78 patients treated, 34 (44%) developed recurrent

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1

I

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I

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2

4

6

6

10

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14

0

2

4

6

Ynra

6

10

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Y4U4

Fig. 3. The overall actuarial survival for the 78 treated patients.

Fig. 4. Probability

tumor. The probability of recurrence is shown in Figure 4. The 2- and 5-year actuarial survival from recurrence in the 34 patients was 86 and 64%, respectively. Note that only 2 (3%) patients developed pelvic recurrence, whereas 32 (41%) had evidence of metastatic disease (Table 6). The first evidence of tumor recurrence was: elevated PSA in 20 (59%), bone pain and pathological bone scintigraphy in 5 (15%), other clinical evidence of distant metastases in 5 (15%), elevated PAP in 3 (9%), and digital examination in 3% patients. The presence of lymph node metastases, clinical stage, tumor grade, and Gleason’s grade were important parameters predicting tumor recurrence. Of the 50 patients without nodal metastases, 14 (28%) developed recurrent tumor, while of the 28 patients with such metastases, 19 (68%) had evidence of tumor recurrence, p = 0.002, Fisher’s 2 sided exact test (6). In the group of 63 patients with clinical Stage A,, B,, and B,, 23 (36%) developed recurrent tumor, and in the group of 15 patients with clinical stage C and D,, 11 (73%) developed recurrent tumor, p = 0.018, Fisher’s 2-sided exact test. Of the 19 patients with well differentiated tumors, 6 (32%) had recurrent tumors. This compared with 12 (46%) of the 26 patients with moderately well differentiated tumors, 6 (100%) of the 6 with poorly differentiated tumors and 10 (37%) of the 27 patients in whom tumor grade was not available, p = 0.013, test for trend. Tumor recurrence developed in patients with Gleason’s grade as follows: 1 and 2-2/17, 3-9/17, 4 and 5 -4/4 and in 19/40 patients in whom Gleason’s grade was not available, p = 0.002.

tions in 5 (6.4%) patients. Urinary continence was carefully evaluated. At 1 year after surgery, 60 (77%) patients were fully continent, mild stress incontinence was present in 8 (lo%), 9 (12%) were incontinent, and in 1 (1%) patient the information on continence was not available. Of the 9 patients who were incontinent, 4 required 2 pads or less daily, 2 required 3 to 4 pads, and 3 required more than 5 pads a day. Pelvic irradiation was very well tolerated with 45 (59%) patients experiencing no treatment toxicity. Mild diarrhea in the final 2 weeks of RT was noted in 30 (38%) patients. This diarrhea responded well to medical management and did not persist following the completion of RT. Severe complications were seen in 2 (3%) patients who developed scrotal and lower extremity edema several months following the completion of radiation treatment. The above problem occurred early in the series and it was probably related to the use of whole pelvic irradiation and perhaps to the more complete pelvic lymph node dissection. Chemotherapy was also very well tolerated. Of the 24 patients treated, 1 (4%) developed neutropenic sepsis following the administration of the third cycle of CTX-5-FU combination. This patient required hospitalization. At the last follow-up, 72 (92%) patients were alive and 6 (8%) patients were known to have died. Of these 6 patients, 4 died of disseminated Cap, 2 had pelvic lymph node metastases, and 2 had no pelvic lymph node metastases. These 4 patients died at 23, 26, 42, and 86 months, respectively. The remaining 2 patients died without evidence of persistent or recurrent CaP at 50 and 80 months after diagnosis. Patient 1 died of primary lung cancer and Patient 2 died of cholangiocarcinoma. Of the 72 patients who were alive at the last follow-up, 42 had no evidence of tumor and 30 had recurrent CaP, including 2 with local and 28 with metastatic cancer. Treatment for recurrent tumor was: orchiectomy in 11

Treatment complications There was no mortality among the 78 radical prostatectomy patients and 68 (87%) had no complications. Minor complications were seen in 5 (6.4%) and major complica-

Overall Disease free

2 yrs

5 yrs

10 yrs

14 yrs

.97 .92

.95 .58

.77 .43

.77

in 34 patients who had relapse.

Table 5. A comparison of disease-free lymph node status

Table 4. Actuarial survival for all patients

Survival

of recurrence

Median (mos)

N

83

78 78

survival by

Lymph nodes

2 yrs

5 yrs

10 yrs

Median (mos)

N

Not involved Involved Total

.96 .85 .92

.72 .33 .58

Sl .25 .43

50 83

50 28 78

Postoperative radiotherapy for prostatic carcinoma ??Z. Table 6. Tumor recurrence

Site

N

%

Local Distant PSA elevation No recurrence Total

2 17 15 44 78

3 22 19 56 100

(32%), LHRH agonist in 2 (6%), RT to control bone pain in 1 (3%), other treatment to control symptoms of disease in 2 (6%), and in 18 (53%) patients who had no symptoms of recurrent tumor, no treatment was given. The 5-year actuarial survival of the 34 recurrent disease patients was 64%. DISCUSSION This study has again demonstrated the efficacy of pelvic irradiation in patients with microscopic or macroscopic residual disease following radical prostatectomy for localized adenocarcinoma of the prostate. The results, in terms of low incidence of treatment complications and excellent (97%) local tumor control rate, are in keeping with other published data (3, 7, 9, 12, 19, 20). The survival rates, as obtained in this study, are difficult to compare with other reports. This is primarily due to the possibility of selection bias favoring our patients. The 160 patients treated with radical prostatectomy and pelvic lymphadenectomy were

hTROVICH

et al.

953

selected for radical surgery if, in the judgement of the surgeons, the expected survival was 10 years or longer. In spite of this, the overall 5- and IO-year actuarial survival of 95 and 77% is very good. The main difference between this study and other reports in the literature is the radiation dose. Our patients have consistently received 45 Gy at the standard daily fractions for patients with microscopic residual disease and a dose of 55 Gy for patients with macroscopic residual disease. Both groups were treated with the exception of a few patients early in the study using a limited (less than whole pelvis) target volume. This volume included prostatic fossa and its immediate vicinity. Special care was taken to exclude from the treatment volume structures considered not likely to be involved by the tumor. Post radical prostatectomy radiotherapy has strongly been recommended by several investigators (3, 7, 9, 12, 19, 20). They recommended, however, a substantially higher radiation dose which ranged from 60 to 70 Gy, as compared to 45 to 55 Gy as used in this study. In spite of the lack of a prospective randomized trial comparing radical prostatectomy alone with the same S followed by postoperative RT one has to assume, based on the available data, that the addition of RT to S is beneficial in selected patients. This benefit is primarily a tenfold reduction in the incidence of pelvic relapse. There is also a probable survival benefit experienced by these patients. In view of the above, we recommend the routine use of postoperative RT following radical prostatectomy in patients with microscopic or macroscopic residual disease in the pelvis.

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