Nodal Involvement as A Prognostic Indicator in Patients with Prostatic Carcinoma

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Vol. 124, August Printed in U.S.A.

THE JOURNAL OF UROLOGY

Copyright© 1980 by The Williams & Wilkins Co.

NODAL INVOLVEMENT AS A PROGNOSTIC INDICATOR IN PATIENTS WITH PROSTATIC CARCINOMA GEORGE R. PROUT, JR.,* JOHN A. HEANEY, PAMELA P. GRIFFIN, JAMES J. DALY WILLIAM U. SHIPLEY

AND

From the Urological Service and the Department of Radiation Medicine, Massachusetts General Hospital and the Departments of Surgery and Radiation Therapy, Harvard Medical School, Boston, Massachusetts

ABSTRACT

Between 1969 and 1976, 92 patients with proved prostatic carcinoma in stages TO to T4 underwent pelvic lymphadenectomy. Median followup has been 43 months. All patients had normal serum acid phosphatase levels and no clinical evidence of metastases as determined by physical examination, bone scans and metastatic bone surveys. Pelvic lymph node metastases were noted in 32 cases. Radical prostatectomy was done in 34 cases and 45 patients received radiotherapy, 11 of whom had 125iodine seeds implanted. Progression of the neoplastic process, almost exclusively in the form of bony metastases, occurred in 18 of the 32 patients who had positive pelvic nodes and in 6 of the 60 patients with negative nodes (p less than 0.001). Patients with poorly differentiated carcinoma were more likely to have progression of the disease than those with moderately differentiated carcinoma (p less than 0.01) and no patient with a well differentiated carcinoma had disease progression. Prostatic adenocarcinoma displays great variability in its growth characteristics and biological potential. In the past perineal prostatectomy was done for patients with apparently localized disease. Therefore, while information about local extent and its relationship to survival was available 1 there were scant data concerning metastatic nodes. This is in sharp contrast to many other neoplastic processes, for example tumors of the breast, stomach, bowel and bladder, in which cases nodal involvement has been used for decades as a means to assess the potential of the tumor and the prognosis for the patient. 2- 5 Not until the retropubic approach was used were data regarding metastatic nodes from prostatic carcinoma collected. While Flocks and associates, 6 and Arduino and Glucksman 7 were among the first to record their observations in this regard there are now several reports that establish a relationship among grade, extent of the primary tumor and the incidence of positive nodes. 8 - 11 We herein investigate further the prognostic significance of lymph node metastases relative to systemic disease progression. METHODS AND MATERIALS

Between September 1, 1969 and December 31, 1976, 92 men underwent pelvic lymphadenectomy. Followup has been from 5 to 96 months, with a mean of 43 months. Patients ranged in age from 48 to 81 years, with an average of 64.7 years. The anticipated 5-year survival rate of American white men at this age is 81 per cent. Each of the patients studied had normal serum acid and alkaline phosphatase determinations, normal bone roentgenograms, and 99mtechnetuim diphosphonate bone scans. Preoperatively, an estimate of the size and extent of the total disease was done in each case and, in most circumstances, line drawings of the prostate also were made. All patients were assigned a T stage (table 1, fig. 1) according to the tumor, node and metastases (TNM) system of the American Joint Committee for Cancer Staging and End Results Reporting (fig. 2). Lymphangiography was not used routinely. Two patients were exduded in retrospect with bony changes, considered inconseAccepted for publication September 14, 1979. Supported by grants from the United States Public Health Service, National Cancer Institute, CA 15944 and CA 15284 and by a grant from the Skerryvore Foundation, New York, New York. * Requests for reprints: Urological Service, Massachusetts General Hospital, Boston, Massachusetts 02114.

quential hefore pelvic lymphadenectomy, proved on followup to be metastases. One of these patients had multiple pelvic nodal metastases and both have died of prostatic carcinoma, 1 within 24 months and 1 within 36 months. The curves of the likelihood of progression according to tumor histology, metastatic nodes and rad.iotherapy were generated by the life-table method (fig. 3). Operative staging. The operation usually was performed through a midline, suprapubic incision so that bilateral lymphadenectomy could be done from just above the bifurcation of the common iliac vessels to the inguinal canal. Additionally, the obturator and hypogastric spaces were dissected bilaterally. On occasion, multiple positive nodes were identified upon performing the dissection and 1 or 2 nodes were removed in these cases only. Rarely, only a single side was dissected. This occurred early in the series when it was conceived that unilateral extension evident on rectal examination indicated that if nodes were to be involved they would be on the ipsilateral side. (This belief may be erroneous since multiple nodes may be involved bilaterally and unilateral dissection may lead to incorrect estimation of the total nodal involvement.) Non-lethal complications have included wound infection, ileus, and penile and lower extremity lymphedema. One patient died postoperatively of pulmonary embolism. Treatment (table 2). Initial treatment, whether done along with or after staging lymphadenectomy, included prostatoseminal vesiculectomy alone in 34 patients, definitive radiotherapy using 1251 and external beam alone or in combination in 45 patients, and a combination of a radical operation and radiotherapy in 3 patients. No initial local treatment was used in the remaining 10 patients. Prostatoseminal vesiculectomy or interstitial radiotherapy alone with 1251 needles (9 cases) was used mainly in patients with intracapsular lesions, and external beam radiotherapy (alone or in combination) was used mainly in patients with extracapsular lesions or in the presence of positive nodes. Of the 10 patients who did not receive local therapy 8 had extracapsular tumor and/ or positive nodes. Pathology. All pathological material from prostatic and nodal sites was re-examined blind (J. J. D. and J. A.H.). The tumors designated as well differentiated were those composed of circumscribed collections of acini that were packed closely and variably devoid of intervening stroma propria with back-toback configuration. The constituent cells only rarely could be 226

227

NODAL INVOLVEMENT AS PROGNOSTIC INDICATOR OF PROSTATIC CARCINOMA

l. Distribution of 92 patients with prostatic adenocarcinoma who underwent staging pelvic lymphadenectomy according to T stage, tumor differentiation, presence of nodal metastases and later disease progression

TABLE

Pos. Nodes No. Pts. No. Well differentiated Moderately differentiated Poorly differentiated Totals

Progression

ProNo. gres-

8

'TOT

=

11r::1

PCOR

E:'.:2Z!

= 'TOTAL

SlOll

51 25

0 18 14

0 9

16 33

9

11

3 3

92

32

Tii

60

6

3

1 0

0 0 0

16

KL'/ -WELL

Neg. Nodes

0 17

Stage TOb: Well differentiated Moderately differentiated Poorly differentiated Totals

3 2 1

0 1

1

0 0 1

6

2

T

4

0

Tla: Well differentiated Moderately differentiated Poorly differentiated

2 3 0

0 0

2 3

0

0 0 0

0

0 0 0

5

0

0

5

0

3 7

0 0 0

3

2

0 0 0

0 0 2

12

0

0

1 3 2

0 2 1

0 0

1

0

6

3

T

3

0

Totals

Tlb: Well differentiated Moderately differentiated Poorly differentiated Totals Tlc: Well differentiated Moderately differentiated Poorly differentiated Totals T2: Well differentiated Moderately differentiated Poorly differentiated Totals -

--

-

-

-

-

7 2 12

2 0

0

I

T4: Well differentiated Moderately differentiated Poorly differentiated Totals

Extracapsular: Well differentiated Moderately differentiated Poorly differentiated Totals

0 TO,

11,

LI TOT 6

TOb

N1-

2

70T

5 Tl,

\!)

"'0

TOT

,,

i 6

12 Tlb

I Ll

N'I-

TOT

th

TOT

N~

2

21

4

J4

16

TOT

Tlo

T 2

T 3

TOT

ti•

8

T '

FiG. 1. Distribution of 92 patients with prostatic adenocarcinoma

according to stage, tumor differentiation and presence of pelvic lymph node metastases. (fig. 4, C). Some moderately and poorly differentiated tumors exhibited cribriform architecture (fig. 4, D).

3

0

0 1 0

3

0

RESULTS

3 1

10

4

0 0

21

4

T

17

0

0

0 2

0 0 2

Table 1 demonstrates the distribution of the 92 according to 1) T stage, 2) tumor differentiation, 3) presence of metastatic nodes at pelvic lymphadenectorny and 4) disease progression with disseminated metastases. Well differentiated tumors comprised 24 per cent of the intra capsular tumors, while less well differentiated tumors comprised >90 per cent of the extracapsular tumors. Thirty-two patients (35 per cent) had positive nodes. Only 9 of 50 patients (18 per cent) with intracapsular tumors had nodal metastases compared to 23 of 42 (55 per cent) of patients with extracapsular tumors (p <0.01). No patient with a well differentiated tumor had nodal metastases (table 3); lack of tumor differentiation was related directly to the presence of nodal metastases. Poor histological differentiation in an extracapsular tumor was associated with nodal metastases in 11 of 15 cases (73 per cent). Half of the tumors that exhibited cribriform architecture were associated with nodal metastases (table 4). A solitary lymph node metastasis was detected in 11 patients. Bilateral involvement was present in 14 of 24 patients having > 1 metastatic node. Poor histological differentiation was more likely to be found in patients with multiple node involvement (13 of 21 patients) than when a solitary node was present (5 of 11 patients). Table 5 demonstrates the correlation between the histological differentiation of primary tumors and that of nodal metastases. Of the 18 patients with moderately differentiated primary tumors 4 showed poorer differentiation in the lymph nodes. Tumor progression was noted at followup in 24 patients (26 per cent) and was almost invariably in the form of bony metastases distributed among the pelvis, lumbar spine, ribs and skull. Pulmonary metastases were the first evidence of progression in 2 patients, 1 of these being confirmed by immunochemical methods. The mean time from the pelvic lymphadenectomy to the discovery of distant metastases was 31 months. The primary tumor was extracapsular in 19 of 24 patients (79

12 28 10

6 3

I

12 22 7

50

9

3

41

2

4 17 13

0 7 9

0

4

0

4

10 4

2 1

34

1!

1o

0 6

0 3 2

0 1

2

0 5 2

0

0 I 0

8

7

5

T

T

4 23 15

0

0

4

12 11

7 8

11

4

0 3 1

42

23

15~

To

4

- - - - - - -

T3: Well differentiated Moderately differentiated Poorly differentiated Totals

TOT

~y~

fit

t7

13 5

- - - -

Intracapsular: Well differentiated Moderately differentiated Poorly differentiated Totals

't)f

6

"

~

3

~

considered malignant on an individual basis (fig. 4, A). Tumors lacking demarcation by tissue planes with infiltration through the fibromuscular stroma of malignant acini, either singly or on broad fronts, were designated moderately differentiated (fig. 4, B). Gland formation in the moderately differentiated group was sometimes rudimentary and cytological anaplasia was frequent. Poorly differentiated tumors were those that failed to form acini focally or throughout the lesion with consequent appearance of malignant cells invading singly, in strands or in sheets

228

PROUT AND ASSOCIATES

Tla

TO a

TOb

Tlb

Tlc

T2

T4

T3

FIG. 2. Clinical extent of tumor according to American Joint Committee for Cancer Staging and End Results Reporting Classification. T, primary tumor. TX, minimum requirements cannot be met. TOa, no tumor palpable, not >3 high power fields of tumor and/or needle biopsy positive from 1 lobe only. TOb, no tumor palpable, >3 high power fields of tumor and/or needle biopsy positive from both lobes. Tia, l cm. nodule confined to prostate, surrounded by normal gland. Tl b, nodule/induration > 1 cm. confined to gland occupying any part of 1 lobe. Tl c, nodule/ induration involving both lobes but apparently confined to gland. T2, tumor confined to gland, deforming contour and invading capsule but lateral sulci and seminal vesicles are not involved. T3, tumor extends beyond capsule with or without involvement of lateral sulci and/ or seminal vesicles. T4, tumor fixed or involving neighboring structures.

per cent) who had disease progression (table 1). Only 1 of 21 patients originally with T2 tumors had distant metastases. The probability of survival for 3 years without having clinical evidence of progressive carcinoma in patients with moderately differentiated tumors (85 per cent) was significantly greater than that for patients with poorly differentiated tumors (55 per cent) (p <0.01) (fig. 3, A). This trend continued through 5 years but since numbers were small the trend did not retain statistical significance. The probability of survival without progressive carcinoma at 5 years for patients without nodal disease (84 per cent) was significantly greater than that for patients with nodal disease (34 per cent) (p <0.001) (fig. 3, B). The combination of lymph node metastases with poorly differentiated tumor implies a 64 per cent risk of progression within 2 years. The presence of a single nodal metastasis was not an unfavorable sign (table 6). Progression occurred only in 2 of 11 cases (18 per cent) with a solitary metastatic node compared to 16 of 21 cases (76 per cent) with multiple (either bilateral or unilateral) nodal involvement (p <0.05), both groups being followed for a similar period. Thirty-three patients died during the study and 9 patients died of causes other than prostatic carcinoma before development of distant metastases. Of 24 patients who had distant metastases 11 (46 per cent) died of the disease within 3 to 80 months (mean 22 months). Ten patients (42 per cent) were alive with distant metastases 4 to 65 months (mean 20 months) after detection of metastases, while the remaining 3 patients with distant metastases were lost to followup within 6 months of the detection of progressive disease. Neither T stage, N stage, histological differentiation nor initial therapy appeared to affect the disease course once distant metastases were established. One patient who did not have distant metastases had progressive local disease despite external beam radiation. Recurrent hemorrhage necessitated cystoprostatectomy and the patient died postoperatively of hepatorenal failure.

Table 2 illustrates therapies used relative to T stage and presence of positive pelvic lymph nodes. Only 3 of 27 patients without nodal disease who underwent radical prostatectomy had distant metastases. In contrast, 3 of 7 patients with nodal disease progressed after the same procedure. External beam radiation was associated with a similar low progression rate in patients with negative nodes (3 of 28 patients). In patients with nodal disease those selected for external beam radiation had an equivalent incidence of progression as TABLE

2. Progression of disease relative to grade and stage, lymphatic involvement and 2 treatments Radical Prostatectomy No.

Definitive Radiotherapy

ProgresSl0Il

No.

Progression

Neg. nodes Intra capsular: Well differentiated Moderately differentiated Poorly differentiated Totals Extracapsular: Well differentiated Moderately differentiated Poorly differentiated Totals

4 7

23

0 0 2

2

14

2

0 1 0 1

7 13

3

.! 4

3

2

0 0 0 0

10

0 2

2

.!

14

3

Pas. nodes Intracapsular: Moderately differentiated Poorly differentiated Totals

2 0

0

2

Extracapsular: Moderately differentiated Poorly differentiated Totals

5 0 5

2

2 0

0

6

2

3

4 7

3

3

il

4

4

7

Excludes 10 patients treated with hormonal therapy alone and 3 patients with radical prostatectomy and radiotherapy combined.

NODAL INVOLVEMENT AS PROGNOSTIC INDICATOR OF PROSTATIC CARCINOMA 100

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30 Nffi. t-ODES (n=60) POS. ITTDES (n=32)

20

----- POOR (n•25)

10

10

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lB

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--- >O XRr (n=16)

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FIG. 3. Probability of survival without progression of clinical prostatic adenocarcinoma related to A, differentiation of primary tumor, B, presence of pelvic lymph node metastases and C, external beam radiation therapy in patients with pelvic lymph node metastases.

those not irradiated (fig. 3, C). The group of patients receiving radiation therapy did not differ significantly from those patients not receiving radiation relative to tumor stage, differentiation or number of positive nodes present. DISCUSSION

This study was designed to relate the factors of grade and stage of the primary tumor, the presence of nodal metastases and the kinds of therapy selected to each other and to the clinical progression of the neoplastic process. The presence of metastases to the regional pelvic lymph nodes was evaluated especially as an indicator of later progression. Eligibility was based on clinical features that signified that the tumor was localized to the prostate and/or periprostatic tissues, and no patient with elevated serum acid phosphatase, or a suspicious bone scan or metastatic series was included. A particular group, having apparently localized disease that might be arrested or cured by appropriate therapy, was selected from the entire population of patients presenting to the hospital with prostatic carcinoma. It was not necessarily representative of a large segment of the population and might best be considered as a group picked because of disease characteristics that

suited our diagnostic capabilities and our therapeutic aspirations, matters common to nearly all studies of this type. Two subgroups emerged: 1 with and 1 without metastatic pelvic nodes. Since progression, almost universally in the form of bony metastases, occurred largely in those patients with positive lymph nodes it is reasonable to hypothesize that the bony metastases already were present at the time of lymphadenectomy and the election of the treatment to be used. Possibly, failure to control the primary carcinoma created or added to the bony metastases but we have no way of detecting this event. With this caveat the data, consistent with that of other investigators, 9 • 11- 13 indicate that as with many other neoplastic states positive regional nodes, especially when multiple, are strong predictors that the disease had spread elseTABLE

3. Relationship of histologic appearance to nodal metastases

and disease progression Histologic Appearance

No. Pta.

Well differentiated Moderately differentiated Poorly differentiated Cribriform architecture

16 51 25

22

Pos. Nodes No.(%)

Progression No.(%)

0 (0) 18 (35) 14 (56) 11 (50)

0 (0) 12 (24) 12 (48) 8 (36)

230

PROUT AND ASSOCIATES

FIG. 4. A, well differentiated tumor with small acini demarcated by stroma from benign hypertrophy. B, moderately differentiated tumor with acini infiltrating fibromuscular stroma. C, poorly differentiated tumor failing to form acini and infiltrating as single cells or in strands or sheets. D, tumor in lymph node demonstrating cribriform architecture. TABLE 4.

Relationship between appearance of cribriform pattern and nodal disease

Primary Tumor Well differentiated: No cribriform Cribriform Moderately differentiated: No cribriform Cribriform Poorly differentiated: No cribriform Cribriform TABLE

No. Pts.

Neg. Nodes

16

16

34

25

17

8

20

8 3

5

Pos. Nodes

9 9

12 2

5. Differentiation of primary tumor and nodal metastases Nodes

Primary Tumor

No. Pts.

Moderately Differentiated

Poorly Differentiated

Moderately differentiated Poorly differentiated

18 14

14

4 14

TABLE 6.

Relationship of progression of disease and solitary or multiple metastatic nodes

Single pos. node Multiple pos. nodes p <0.05.

0

No. Pts.

Progressed

11

2 16

21

where-such metastases being silent and undetectable at the time of diagnoses and operation. This is in keeping with the concept that prostatic carcinoma metastasizes first to bone and then elsewhere. 14 Continued followup of the 60 patients who had negative pelvic nodes will be important in this regard. Of these patients 6 have suffered bony metastases to date, which raises the question of the adequacy of lymphadenectomy. We never considered it a therapeutic measure and have serious reservations about discussing cure as a result of the operation, although this is not to set aside experiences that may tend to prove the case. 15• 16 The difference in progression between the groups (positive or negative nodes, vide infra) is so great that it seems quite unlikely that we overlooked nodal metastases in more than a few patients. We were unable to duplicate the experience of Barzell and associates in estimating the volume of tumor in metastatic nodes. 11 A single nodal metastasis was found in 11 patients and in 2 cases the patient was treated with irradiation but progressed. This is in striking contrast to the experience of the 16 of 21 patients with multiple positive nodes who had progression of the disease (table 6). The data in table 2 tend to confirm that already noted and add another dimension regarding treatment.' Progression was much less likely to occur in the patients with negative nodes whether they received radical prostatectomy (3 of 27 patients) or definitive radiotherapy (3 of 28 patients). The corresponding therapeutic groups that had positive nodes consisted of fewer

NODAL INVOLVEMENT AS PROGNOSTIC INDICATOR OF PROSTATIC CARCINOMA

patients but, respectively, progression occurred in 3 of 7 patients for the former and 9 of 17 for the latter. These groups are far too small to allow any conclusions to be drawn but the trend clearly is towards progression if the patient has positive nodes. Furthermore, extracapsular disease (in the radical prostatectomy groups the stage is pathological p) was more likely to be associated in patients with positive nodes, as one would expect. It may be misleading to put these groups side by side or make any comparisons because there was no attempt to control, standardize or randomize therapy. The patients fulfilled the protocol criteria and underwent the treatment elected by the responsible clinicians. Thus, any comparisons made must be with these qualifications. The histological configuration of the tumors introduces a subjective component to the analyses. We may be using more rigid criteria for well differentiated than other groups since we have not found positive nodes in patients with this degree of differentiation, while others have. 10' 11 ' 17 However, comments about the kind of nodal metastases are lacking in many reports and it is possible that disparity existed between the histological features of the primary tumor and at least some of the nodal metastases. Cribriform architecture (tables 3 and 4) was found more commonly in patients with moderately differentiated adenocarcinomas and was proportionately more likely to be associated with positive nodes than in those patients without cribriform architecture. Again, no statistically significant difference exists but these observations concerning cribriform carcinoma make its presence important. The data in figure 3, A and B are consistent with the previous analyses. Patients with positive nodes are much more likely to have progression of the disease. The data in figure 3, C indicate that treatment with radiotherapy did not prevent progression in the group of patients with positive nodes. This experience is similar to reports of others. 17• 18 Lastly, all of the foregoing data are within a specified time limit and any conclusions must be within this reference. The fate of this population of patients must await further followup. The dismal outlook for the patient with extracapsular, moderately or poorly differentiated carcinoma with positive pelvic nodes indicates the continuing need for the assignment of a high priority for the search for chemotherapeutic and immunotherapeutic agents that will alter the course of these unfortunate patients. Furthermore, urologists and radiotherapists may be overzealous in some settings. It may be unnecessary to perform pelvic lymphadenectomy in patients for whom radical prostatectomy or 1251 seed implantation is planned when the lesion is TO or Tl and well differentiated. Likewise, full pelvic irradiation may be unwarranted in patients with multiple nodal

231

metastases. Additional followup may clarify this circumstance further. REFERENCES

1. Whitmore, W. F., Jr.: Proceedings: the natural history of prostatic cancer. Cancer, 32: 1104, 1973. 2. Berg, J. W. and Robbins, G. F.: Factors influencing short and long term survival of breast cancer patients. Surg., Gynec. & Obst., 122: 1311, 1966. 3. Goldsmith, H. S. and Ghosh, B. L.: Carcinoma of the stomach. Amer. J. Surg., 120: 317, 1970. 4. Bussey, H. J. R., Dukes, C. E. and Lockhart-Mummery, H. E.: Results of the surgical treatment of rectal cancer. In: Cancer of the Rectum. Edited by C. E. Dukes. London: E. S. Livingstone, p. 267, 1960. 5. Laplante, M. and Brice, M., II: The upper limits of hopeful application of radical cystectomy for vesical carcinoma: does nodal metastases always indicate incurability? J. Urol., 109: 261, 1973. 6. Flocks, R. H., Culp, D. and Porto, R.: Lymphatic spread from prostatic cancer. J. Urol., 81: 194, 1959. 7. Arduino, L. J. and Glucksman, M. A.: Lymph node metastases in early carcinoma of the prostate. J. Urol., 88: 91, 1962. 8. McCullough, D. L., Prout, G. R., Jr. and Daly, J. J.: Carcinoma of the prostate and lymphatic metastases. J. Urol., 111: 65, 1974. 9. Varkarakis, M. J., Murphy, G. P., Nelson, C. M. K., Cheval, M., Moore, R. H. and Flocks, R. H.: Lymph node involvement in prostatic carcinoma. Urol. Clin. N. Amer., 2: 197, 1975. 10. McLaughlin, A. P., Saltzstein, S. L., McCullough, D. L. and Gittes, R. F.: Prostatic carcinoma: incidence and location of unsuspected lymphatic metastases. J. Urol., 115: 89, 1976. 11. Barzell, W., Bean, M. A., Hilaris, B. S. and Whitmore, W. F., Jr.: Prostatic adenocarcinoma: relationship of grade and local extent to the pattern of metastases. J. Urol., 118: 278, 1977. 12. Flocks, R. H.: The treatment of stage C prostatic cancer with special reference to combined surgical and radiation therapy. J. Urol., 109: 461, 1973. 13. Bagshaw, M. A., Ray, G. R., Pistenma, D. A., Castellino, R. A. and Meares, E. M., Jr.: External beam radiation therapy of primary carcinoma of the prostate. Cancer, 36: 723, 1975. 14. Viadana, E., Bross, I. D. and Pickren, J. W.: The metastatic spread of kidney and prostatic cancers in man. Neoplasms, 23: 323, 1976. 15. McCullough, D. L. and Leadbetter, W. F.: Radical pelvic surgery for locally extensive carcinoma of the prostate. J. Urol., 108: 939, 1972. 16. Spaulding, J. T. and Whitmore, W. F., Jr.: Extended total excision of prostatic adenocarcinoma. J. Urol., 120: 188, 1978. 17. Bagshaw, M. A., Pistenma, D. A., Ray, G. R., Freiha, F. S. and Kempson, R. L.: Evaluation of extended-field radiotherapy for prostatic neoplasm: 1976 progress report. Cancer Treatm. Rep., 61: 297, 1977. 18. Hill, D.R., Crews, Q. E., Jr. and Walsh, P. C.: Prostate carcinoma: radiation treatment of the primary and regional lymphatics. Cancer, 34: 156, 1974.