Prognostic Significance of Lymph Nodal Metastases in Prostate Cancer

0022-534 7/89/1422-0332$02.00/0 THE JOURNAL OF UROLOGY Copyright© 1989 by AMERICAN UROLOGICAL ASSOCIATION, INC.

Vol. 142, August

Printed in U.S.A.

PROGNOSTIC SIGNIFICANCE OF LYMPH NODAL METASTASES IN PROSTATE CANCER LAWRENCE A. GERVASI, JOHN MATA, JAMES D. EASLEY, JOHN H. WILBANKS, CARIE SEALEHAWKINS, C. EUGENE CARLTON, JR. AND PETER T. SCARDINO From the Scott Department of Urology and Department of Radiation Oncology, Baylor College of Medicine and The Methodist Hospital and St. Luke's Episcopal Hospital, Texas Medical Center, Houston, Texas

ABSTRACT

Pelvic lymph node metastases indicate a poor prognosis for patients with clinically localized prostate cancer but the significance of minimal nodal metastases still is debated. We determined the progression and cancer specific survival rates based on the extent of nodal metastases in 511 patients followed for a mean of 8_6 years (range 2.5 to 17.5 years) after bilateral pelvic lymph node dissection and irradiation therapy. The patients were divided into 4 groups based on the extent of nodal metastases: NO-negative nodes (359 patients), Nl-a single microscopic positive node (37), N2-multiple microscopic positive nodes (86) and N3-grossly positive or juxtaregional nodes (29). The risks of distant metastases and of dying of prostate cancer were much greater in the 152 · patients with positive nodes (N+) than in those with negative nodes (p less than 0.00005). The risk of metastatic disease at 10 years was only 31 ± 7 per cent for the NO patients compared to 83 ± 7 per cent for the N + patients, and the risk of dying of prostate cancer was only 17 ± 6 per cent at 10 years for the NO group and 57 ± 11 per cent for the N+ patients. Patients with a single microscopic node (Nl) had a pattern of progression and cancer specific mortality rate similar to patients with more extensive nodal metastases and markedly worse than patients with negative nodes_ The risk of distant metastases was 80 ± 15 per cent at 10 years for the Nl group, 84 ± 11 per cent for the N2 group and 88 ± 13 per cent for the N3 group, while the risk of dying of prostate cancer at 10 years was 40 ± 19, 66 ± 15 and 58 ± 24 per cent, respectively. The finding of a single pelvic lymph node containing microscopic metastatic disease markedly worsened the prognosis of our patients with prostate cancer_ Once prostate cancer is found within the pelvic lymph nodes the patient has systemic disease unlikely to be controlled by pelvic lymph node dissection and radiotherapy. (J_ Ural., 142: 332-336, 1989) Although the presence of extensive regional lymph node metastases at staging pelvic lymphadenectomy is recognized as a poor prognostic finding for patients with clinically localized prostate cancer, the significance of minimal nodal metastases has not been established. Some authorities argue that minimal nodal metastases, while associated with an unfavorable prognosis, sometimes can be treated effectively with regional therapy, such as pelvic lymph node dissection and radical prostatectomy or full pelvic radiotherapy. 1 - 5 Others contend that patients with regional nodal metastases, no matter how limited, have systemic disease and should not be subjected to the risks of local or regional therapy but should be treated systemically with immediate or delayed hormonal therapy. 6 - 12 Prostate cancer may progress slowly during many years. The eventual outcome of any local or regional treatment program can be affected profoundly by the concurrent administration of androgen deprivation therapy, which delays the appearance of metastases even further. 13 Few studies have reported the longterm outcome of local or regional therapy in patients with positive nodes who received no hormonal therapy before documented recurrence of tumor, and correlated these results with the extent of pelvic nodal metastases. We assessed the progression and cancer specific survival rates in 511 well characterized patients treated with pelvic lymph node dissection, radioactive gold seed implantation and external beam radiotherapy for clinically localized prostate cancer. 14- 16 None of the patients received hormonal therapy before documented recurrence of tumor. We then correlated Accepted for publication January 23, 1989. Read at annual meeting of American Urological Association, Atlanta, Georgia, May 12-16, 1985.

the progression and survival rates with the extent of nodal metastases to determine whether patients with a single microscopically positive node had a prognosis similar to patients with negative nodes or to those with more extensive nodal metastases. We found that a single microscopic positive node markedly reduced the prognosis of these patients, and was associated with a pattern of recurrence and mortality from cancer similar to patients with more extensive nodal disease. MATERIALS AND METHODS

Treatment protocol. Between 1966 and 1979 virtually all patients seen at our institution with clinical stage A2, B or Cl prostatic cancer were treated with a combination of radioactive gold seed implantation and external beam irradiation. 14- 16 Stag ing included history, physical examination in all patients, radioisotopic bone scan (in 92 per cent) or plain radiographs of the bones (in the remainder) and serum prostatic acid phosphatase determinations (in 90 per cent). At initial pelvic exploration, when grossly positive lymph nodes were found and verified by frozen section pathological study, a complete lymph node dissection was not performed and the patient was assigned to the N3 group (grossly positive or juxtaregional nodes). The remainder of the patients underwent bilateral pelvic lymph node dissection with removal of all tissue between the external and internal iliac arteries, from the bifurcation of the common iliac proximally to the circumflex iliac vein and endopelvic fascia distally. The tissue surrounding the obturator nerve was removed as well. Six to 10 radioactive gold (198Au) seeds then were implanted directly into the prostate gland for a dosage of 2,500 to 3,000 cGy. External beam irradiation was begun 2 to 3 weeks later with an 8 MeV. linear accelerator. If the pelvic

332

333

PROSTATE C.A.~JCER

lymph nodes were negative for n--ietastases a dose of 4,000 . was delivered to the prostate through a 6 X 6 cm. portal via a bilateral arch technique. However, if the nodes were positive for metastases opposing anterior and posterior 12 X 12 cm. portals were used to deliver 5,000 cGy. to the full pelvis. Therefore, the total dosage to the prostate was 6,500 to 8,000 cGy. and the actual dose delivered was 6,923 ± 841 (mean plus or minus standard deviation) cGy. Several recent reviews have described the over-all result of this treatment protocol in detail. 14: 16 Patient population. In a review of the records of the department of radiotherapy at Baylor College of Medicine and The Methodist Hospital, we identified 511 patients with biopsy proved adenocarcinoma of the prostate, clinical stages A2 through Cl, who underwent pelvic lymph node dissection and radioactive gold seed implantation, and who completed the course of external beam radiotherapy. None of these patients had evidence of distant metastases at treatment and none received systemic treatment (hormones or chemotherapy) before the documented tumor recurrence. The prostatic acid phosphatase level was elevated in approximately 9 per cent of the patient population before treatment. Of the 152 patients with positive lymph nodes (N+ group), 18 per cent had an elevated pre-treatment prostatic acid phosphatase. Clinical stage was assigned retrospectively after review of all recorded digital rectal examinations of the prostate. There were 130 patients with clinical stage A2 (no palpable_ tumor,. more than 3 microscopic foci or grade less than well differentiated), 25 with stage BIN (1.5 cm. or less, 1 lobe), 140 with stage Bl (more than 1.5 cm., l lobe), 100 with stage B2 (bot~ lobes) and 116 with stage Cl (extending into the lateral sulc1 or semmal vesicles but less than 6 cm.) disease. The grade of the tumor was determined by review of the original histological material when available, based upon the standard system used at our institution (grade I-well differentiated, grade II-moderately differentiated and grade HI-poorly differentiated). Recurrence. Local recurrence was defined as a clinical phenomenon with discrete signs or symptoms, such as bladder outlet obstruction, massive palpable local regrowth of tumor causing pain or hematuria, or ureteral obstruction evident on an excretory urogram and confirmed in each case a tissue diagnosis. A positive post-irradiation biopsy result or a pal~able abnormality on rectal examination alone did not constitute local recurrence. Distant recurrence was defined as a persistently elevated acid phosphatase, positive bone scan, blastic lesion seen on skeletal radiographs or biopsy proved soft tissue metastasis. An elevated prostatic acid phosphatase was the sole evidence of ~istant recurrence in only 5 pa-c1Emi:;s, The recurrence pattern m thrn analysis was defined as the site of first recurrence Patients who had local and distant recurrence within 3 months were considered to have local and distant recurrence simultaneously. Analysis. The clinical course of each patient was reviewed until death or for a mean of 8.6 years (range 2.5 to 17.5 years) after pelvic lymph node dissection for the surviving patients. Of the 511 patients 500 (98 per cent) have been followed for at least 5 years, 282 (55 per cent) for at least 10 years and 22? (44 per cent) for at least 15 years or until death. Only 14 patients (2.7 per cent) were lost to followup. Over-all, 43 per cent (220) of the patients have died and 49 per cent (251) have had recurrent tumor. The cause of death and presence of local or distant recurrence were determined by at least 2 independent reviewers. If a discrepancy existed a third reviewer was asked to resolve the difference. The results were analyzed by clinical stage, histological grade, and presence and extent of lymph node metastases. The significance of cross tabulations was tested with chi-square analysis. The actuarial rates of recurrence, local or distant or "any", and of death of all causes or of prostate cancer were determined by

life--table v.rith the Statistical Sciences. The mean ± 2 standard errors vvas at 5, 10 and 15 years after node UACM0'cc.•vu, and the significance of differences among various groups was determined the Lee-Desu statistic. 18

RESULTS

Patient age ranged from 43 to 82 years, with a mean age of 64 years, and they represented a wide range of clinical stages of localized prostate cancer. The incidence and extent of nodal metastases within each clinical stage are consistent with previous reports (table 1). Of the patients 152 (30 per cent) had positive nodes and 37 (24 per cent) of these had a single microscopic positive node. There was no significant difference in the extent of nodal metastases among the clinical stages, except that fixed or juxtaregional nodes (N3) were more common in the higher clinical stages. However, higher grade tumors were associated with more extensive nodal metastases (table 2, p <0.00005). Recurrence. The actuarial risks of local, distant and any (local or distant) recurrence at 5, 10 and 15 years are listed in table 3, which shows the per cent ± 2 standard errors and provides the 95 per cent confidence intervals of the results for each group of patients. Figures 1 and 2 show the actuarial curves for any recurrence and distant metastases, comparing the patients with negative nodes to all patients with positive nodes (N +) as well as to each subgroup of patients (Nl, N2 and N3). The risk of distant metastases was much greater for the 152 patients with ;::;cs,.t:\ nodes (N+) than for 2). The risk of those with negative nodes (p -,v.v,.,·vvv, metastatic disease was only 15 ± 4 per cent at 5 years and 31 ± 7 per cent at 10 years for patients with negative nodes, compared to 68 ± 8 per cent at 5 years and 83 ± 7 per cent at 10 years for the N+ patients. 0 ·:::

TABLE

1. Frequency and extent of lymph nodal metastases in each

clinical stage Extent of Nodal Metastases Clinical Stage

A2 BlN Bl B2

Cl Totals

Total No.

130 25 140 100

116 511

All Pts.

Pos. Nodes*'

NO No,(%)

N+ No.(%)

(78)t (92) (76) (63) (56) (70)

29 (22) 2 (8) 33 (24) 37

101 23 107 63 65 359

Nl No.(%)

N3 No.(%)

NO-negative pelvic lymph nodes. positive node. N2~multiple positive nod.es. taregional nodes. * The presence but not the extent of nodal metastasis correlated significantly vvi th stage. t Per cent of patients within each stage. :j: Per cent of patients with positive nodes within each stage.

TABLE 2.

Frequency and extent of nodal metastases within each grade Extent of Nodal Metastases

Grade*

Well Moderate Poor Totals

Total No.

196 177 84 457

All Pts. NO No.(%) 167 122 32 321

(85):j: (69) (38) (70)

Pas. Nodest

N+ No.(%)

Nl No.(%)

N2 No.(%)

N3 No.(%)

29 55 52 136

10 11 9 30

16 35 29 80

3 9 14 26

(15) (31) (62) (30)

(35)§ (20) (17) (22)

(55) (64) (56) (59)

(10) (16) (27) (19)

* Differentiation; 54 tumors were not graded. t The extent of nodal metastases correlated significantly with grade (p <0.00005). :j: Per cent of patients within each grade. § Per cent of patients with positive nodes within each grade.

334

GERVASI AND ASSOCIATES TABLE

3. Actuarial rate of recurrence at 5, 10 and 15 years by extent of nodal metastases (per cent± 2 standard errors) Local Recurrence*

Distant Recurrencet

Any Recurrencet

Nodal Group 5 Yrs. 13 52 38 56 62

NO N+ Nl N2 N3

± ± ± ± ±

10 Yrs.

15 Yrs.

± ± ± ± ±

41 ± 10

34 86 86 83 86

4 10 19

12 24

7 10 17 15 19

5 Yrs. 15 ± 68 ± 57 ± 69 ± 80 ±

10 Yrs.

15 Yrs.

± ± ± ± ±

34 ± 8

31 83 80 84 88

4 8 17 11 16

7 7 15 11 13

5 Yrs. 20 ± 78 ± 70 ± 79 ± 84 ±

4 7 16 9 14

10 Yrs.

15 Yrs.

± ± ± ± ±

47 ± 9

43 93 93 91 93

7 5 9 8 10

* With or without distant recurrence. t With or without local recurrence. t Local and/or distant recurrence. 0 20

>-

-. -....

ACTUARIAL SURVIVAL RATE BY EXTENT OF NOOAL METASTASES

'•. .i . .

·-.-....,.,._

40

C

<(

:5

60

i: .,

80

'i ~

.,

80

1-0-•...e---I

60

N, (n•359)

40 20 N, (n=:37) N, (nc:::86) N, (n,,,29)

N+ (n,,,152)

i:

W

~

0..

ACTUARIAL CANCER-SPECIFIC SURVIVAL RATE BY EXTENT OF NODAL METASTASES

1001'""",::""-""t!I:;::--------,

0.

100 5

10

15

5

10

15

80 60

Years

FIG. 1. Actuarial rate of any recurrence by presence and extent of pelvic lymph nodal metastases. Vertical bars indicate 95 per cent confidence intervals (mean ± 2 standard errors). While patients with 1 microscopic positive node, Nl, fared significantly better than patients with more extensive nodal metastases, N2 plus N3 (p = 0.03), by 8 years virtually all patients in each group had evidence of recurrent tumor. Only 1 patient with positive nodes followed more than 10 years remains free of recurrence.

40

20

p<.00005

10

5

15

10

5

15

Years

FIG. 3. Actuarial all cause and cancer specific survival rates by presence and extent of nodal metastases. Vertical bars indicate 95 per cent confidence intervals (mean ± 2 standard errors). Patients with positive nodes, regardless of extent, were far more likely to die of prostate cancer than of any other cause.

Actuarial all cause and cancer specific survival rates at 5, 10 and 15 years by extent of nodal metastases (per cent ± 2 standard errors)

TABLE 4.

N, (n=37)

All Cause Survival Rate

....

N, (n=86) N, (n,,29)

5

10

15

5

10

Ca Specific Survival Rate

Nodal Group 5 Yrs. 15

Years

FIG. 2. Actuarial rate of distant metastases by presence and extent

of nodal metastases. Vertical bars indicate 95 per cent confidence intervals (mean ± 2 standard errors). Although distant metastases appeared less rapidly in Nl subgroup, rate of development of distant metastases was parallel in each of 3 subgroups of N+ cancer patients.

Patients with a single microscopic positive node (Nl) had a pattern of progression similar to patients with more extensive nodal metastases (N2 and N3) and markedly worse than patients with negative nodes (NO). The risk of distant metastases for the Nl group was 57 ± 17 per cent at 5 years and 80 ± 15 per cent at 10 years. Patients in the N2 and N3 groups had metastases somewhat more rapidly (table 3 and fig. 2) but by 10 years the risk of metastases was comparable in the 3 subgroups of patients with positive nodes: 84 ± 11 per cent for the N2 and 88 ± 13 per cent for the N3 groups. The median interval to recurrence was only 33 months for the patients with positive nodes (N+ ), and 42, 30 and 27 months for the Nl, N2 and N3 groups, respectively. Of the entire group of 152 patients with positive nodes only 1 survived longer than 10 years without evidence of recurrence. Mortality. Table 3 and figure 3 show the all cause and cancer specific actuarial survival rates according to the presence and extent of nodal metastases. Of the patients with positive nodes

NO N+ Nl N2 N3

90 65 68 63 69

± ± ± ± ±

3 8 15 11 17

10 Yrs . 62 ± 32 ± 49 ± 22 ± 35 ±

6 9 17 11 22

15 Yrs. 36 ± 14 6 ± 10

5 Yrs. 98 75 82 72 75

± ± ± ± ±

2 7 13 10 17

10 Yrs.

15 Yrs.

±6 ± 11 ± 19 ± 15 ± 24

70 ± 13 21 ± 17

83 43 60 34 42

63 per cent had died by the time of the analysis, and prostate cancer accounted for the majority (71 per cent) of these deaths. Death of prostate cancer was much less common among patients with negative nodes: the risk of dying of prostate cancer was only 2 ± 2 per cent at 5 years and 17 ± 6 per cent at 10 years for patients with positive nodes (N+, p <0.00005). The cancer specific survival rate for patients with minimal nodal metastases (Nl) was similar to that for patients with more extensive nodal metastases (N2 and N3) and significantly worse than for patients with negative nodes (NO). At 10 years the cancer specific survival rate was 83 ± 6 per cent for patients with negative nodes (NO) but it decreased significantly (p <0.00005) to 60 ± 19 per cent for those with a single microscopic positive node (Nl). However, there was no significant difference between the cancer specific survival rates for Nl cancer patients and those with more extensive nodal metastases (N2 or N3, table 4 and fig. 3). DISCUSSION

Pelvic lymph node metastases indicate a poor prognosis for patients with clinically localized prostatic cancer but the significance of minimal nodal metastases still is debated. Some

PR.0Gl\10ST1C Sl(}l¾JiFICAI\JCE O:F LYiviPH NODAL IVlETA8TASE3 rN· PROS'i\b"-TE CAl\JCER TABLE

5. Nonprogression and mortality rates from prostate cancer at 5 years in patients with a single microscopically positive lymph node (NI) Reference

No. Pts.

Nonprogression Rate ( %)

Mortality from Prostate Ca ( %)

33

26

15

100

(18) (0)

Smith and Middleton 7

18

44

28

Present study

37

30

18

Zincke and Utz 22

Followup (yrs.)

t ?-5

8.6

Treatment* Radical prostatectomy alone Radical prostatectomy with immediate orchiectomy 50% had external beam irradiation, 50% had delayed hormonal therapy Combined gold seeds/external beam to prostate and full pelvis

Numbers in parentheses are all cause mortality rates.

* In addition to pelvic lymph node dissection. t Mean and range of followup not reported. Only 36 per cent of the patients were

argue that minimal lymph nodal metastases are not an unfavorable prognostic sign. 1- 3 Flocks, comparing patients with positive nodes to those with negative nodes, stated that the presence of positive regional nodes did not alter the incidence of local recurrence or the 5-year survival rate free of disease. 3 Barzell and associates quantified the volume of regional nodal metastases and reported that patients with minimal nodal metastases (less than 3 cc) have the same probability of being free of distant metastases at 5 years (74 per cent) as patients with negative nodes (71 per cent). 1 Prout and associates reported that the presence of a single metastasis was not an unfavorable prognostic sign but the small number of patients (11) with a solitary metastatic node in their series precluded definitive conclusions. 2 Other investigators suggested that even rn.inimal nodal metastasis indicates systemic disease. 6 - 12 Kramer and associates were unable to demonstrate greater control of disease in patients· who had only 1 positive node compared to those with multiple positive nodes, regardless of the therapeutic modality used. 9 Smith and Middleton reported on 18 patients with 1 positive node, of whom half were treated with external beam irradiation and half with immediate or delayed hormonal therapy. 7 At 5 years only 44 per cent of the patients were free of disease and 28 per cent had died of prostate cancer regardless of the treatment used. In most series, including our own, patients with positive nodes were treated with radiotherapy rather than radical prostatectomy after pelvic lymphadenectomy, Those who argue that radiotherapy is less effective than radical prostatectomy in eradicating the local tumor have questioned whether the high recurrence rate associated with nodes stems from inadequate control of the local tumor rather than from preexisting metastases outside of the field of treatment. "'~·s"'"H"' treatment encompassing the primary tumor and nodes 'Nill control 'Nho have testicular and some who have or renal2°· 21 tumors with regional nodal metastases. Can that is radical prostatectomy plus mJ)naaenecwimy cure some patients with minimal nodal metastases? Zincke and Utz reported the results of pelvic lymphadenectomy and radical retropubic prostatectomy in 52 patients with 1 lymph node.2 2 • 28 There were 33 patients who did not receive hormonal therapy until the tumor recurred. At 5 years only 26 per cent of the tumors had not progressed (table 5), a result similar to the 30 per cent nonprogression rate in our series and the 44 per cent nonprogression rate reported by Smith and Middleton. 7 In a subsequent report the nonprogression rate for patients with positive nodes decreased to zero 8 years after radical prostatectomy.23 In fact, Zincke and Utz concluded from the high relapse rate after radical prostatectomy alone for patients with even a single positive node that positive nodes indicate systemic disease and that adjunctive systemic treatment (in their series hormonal therapy) is indicated for such patients. 22 Recently, prostate specific antigen has proved to be particularly valuable to detect persistent tumor after radical prostatectomy. More

followed 5 years or longer.

than 85 per cent of the patients with positive pelvic lymph nodes (1 or more) had a measurably elevated prostate specific antigen level within 12 months after radical prostatectomy in the series at Washington University and the University of Minnesota (personal communication). In our study 37 patients had a single microscopically positive lymph node (Nl). Our hypothesis was that patients with minimally positive nodes, treated with bilateral pelvic lymphadenectomy and full pelvic radiotherapy, would have a prognosis more comparable to patients with negative nodes (NO) than to patients with multiple microscopic positive nodes (N2), or grossly positive or juxtaregional nodes (N3). However, we found that these patients (Nl) had a pattern of progression and cancer specific mortality similar to patients with more extensive nodal metastases and markedly worse than patients with negative nodes. For example, the risk of distant metastases at 10 years was 80 per cent for the Nl group, compared to only 31 per cent for the NO group and 84 to 88 per cent for the N2 and N3 groups, respectively. Similarly, the risk of dying of prostate cancer at 10 years was 40 per cent for the Nl group, compared to only 17 per cent for the NO group but 66 per cent for the N2 and 58 per cent for the N3 groups. An elevated pre-treatment prostatic acid phosphatase in patients with positive nodes was not a prognostic factor in interval to distant recurrence. At 5 years 33 per cent of the patients with a normal pre-treatment prostatic acid phosphatase were free of distant recurrence, compared to 32 per cent of those with an elevated pre-treatment prostatic acid phosphatase. At 10 years there also was no significant difference in per cent free of recurrence in the 2 groups. An elevated pretreatment n"'" 0 ' " 1·, acid phosphatase did not change the mortality rate. We conclude that the of a single microscopic focus of prostate cancer in a pelvic mJJhaa.enectoimy specimen usually indicates the presence of pre-existing metastases outside the field to which regional therapy can be directed practically. Patients with lymph nodes have a substantially reduced prognosis regardless of the mode of local or regional therapy they receive and they are appropriate candidates for systemic therapy, either alone or as an adjuvant. Ms. Carolyn Schum provided editorial assistance. REFERENCES

1. Barzell, W., Bean, N. 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. 2. Prout, G. R., Jr., Heaney, J. A., Griffin, P. P., Daly, J. J. and Shipley, W. U.: Nodal involvement as a prognostic indicator in patients with prostatic carcinoma. J. Urol., 124: 226, 1980. 3. Flocks, R. H.: The treatment of stage C prostatic cancer with special reference to combined surgical and radiation treatment. J. Urol., 109: 461, 1973. 4. Skinner, D. G. and Lieskovsky, G.: Management of invasive and high-grade bladder cancer. In: Diagnosis and Management of Genitourinary Cancer. Philadelphia: W. B. Saunders Co., chapt. 16,pp. 295-312, 1987.

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GERVASI AND ASSOCIATES

5. Smith, J. A., Jr., Haynes, T. H. and Middleton, R. G.: Impact of external irradiation on local symptoms and survival free of disease in patients with pelvic lymph node metastasis from adenocarcinoma of the prostate. J. Urol., 131: 705, 1984. 6. Johnson, D. E.: Cancer of the prostate: overview. In: Genitourinary Tumors: Fundamental Principles and Surgical Techniques. Edited by D. E. Johnson and M.A. Boileau. New York: Grune & Stratton, chapt. 1, p. 1, 1982. 7. Smith, J. A., Jr. and Middleton, R. G.: Implications of volume of nodal metastasis in patients with adenocarcinoma of the prostate. J. Urol., 133: 617, 1985. 8. W ajsman, Z.: Lymph node evaluation in prostatic cancer: is pelvic lymph node dissection necessary? Urology, suppl. 3, 17: 80, 1981. 9. Kramer, S. A., Cline, W. A., Jr., Farnham, R., Carson, C. C., Cox, E. B., Hinshaw, W. and Paulson, D. F.: Prognosis of patients with stage Dl prostatic adenocarcinoma. J. Urol., 125: 817, 1981. 10. Paulson, D. F.: Carcinoma of the prostate: the therapeutic dilemma. Ann. Rev. Med., 35: 341, 1984. 11. Bagshaw, M. A.: Radiation therapy for cancer of the prostate. In: Diagnosis and Management of Genitourinary Cancer. Edited by D. G. Skinner and G. Lieskovsky. Philadelphia: W. B. Saunders Co., chapt. 25, pp. 425-445, 1988. 12. Zincke, H. and Utz, D. C.: Radical surgery for stage Dl prostate cancer. Sem. Urol., 1: 253, 1983. 13. The Veterans Administration Cooperative Urological Research Group: Factors in the prognosis of carcinoma of the prostate: a cooperative study. J. Urol., 100: 59, 1968. 14. Scardino, P. T., Guerriero, W. G. and Carlton, C. E., Jr.: Surgical staging and combined therapy with radioactive gold grain implantation and external irradiation. In: Genitourinary Tumors: Fundamental Principles and Surgical Techniques. Edited by D. E. Johnson and M.A. Boileau. New York: Grune & Stratton, Inc., chapt. 6, p. 75, 1982. 15. Scardino, P. T. and Carlton, C. E., Jr.: Combined interstitial and external irradiation for prostatic cancer. In: Principles and Management ofUrologic Cancer. Edited by N. Javadpour. Baltimore: Williams & Wilkins, chapt. 22, p. 392, 1983. 16. Carlton, C. E., Jr. and Scardino, P. T.: Long-term results after combined radioactive gold seed implantation and external beam radiotherapy for localized prostatic cancer. In: A Multidisciplinary Analysis of Controversies in the Management of Prostate Cancer. Edited by D.S. Coffey, M. I. Resnick, F. A. Dorr and J. P. Karr. New York: Plenum Press, p. 109, 1988. 17. Berkson, J. and Gage, R.: Calculation of survival rates for cancer. Mayo Clin. Proc., 25: 270, 1950. 18. Lee, E. T. and Desu, M. M.: A computer program for comparing K samples with right-censored data. Comput. Programs Biomed., 2: 315, 1972. 19. Whitmore, W. F., Jr.: Surgical treatment of adult germinal testis tumors. Sem. Oncol., 6: 55, 1979. 20. Peters, P. C. and Brown, G. L.: The role of lymphadenectomy in the management of renal cell carcinoma. Urol. Clin. N. Amer., 7: 705, 1980. 21. Waters, W. B. and Richie, J. P.: Aggressive surgical approach to renal cell carcinoma: review of 130 cases. J. Urol., 122: 306, 1979. 22. Zincke, H. and Utz, D. C.: Observations on surgical management of carcinoma of the prostate with limited nodal metastases. Urology, 24: 137, 1984. 23. Utz, D. C.: Radical excision of adenocarcinoma of prostate with pelvic lymph node involvement: surgical gesture or curative procedure? Urology, suppl. 5, 24: 4, 1984.

EDITORIAL COMMENTS The authors present a retrospective analysis of more than 500 patients with stages A to C prostate cancer treated with bilateral pelvic lymphadenectomy, and combined external beam and interstitial radiation therapy with radioactive gold seeds. Virtually all of the patients were followed for a minimum of 5 years and long-term followup beyond 10 years is available in more than half of the patients. Less than 3 per cent of the entire group were lost to followup and no patient was treated with hormonal therapy until there was evidence of tumor recurrence. The authors convincingly demonstrate that patients who have any degree of lymph node metastases have more than an 80 per cent probability of recurrent tumor within 10 years and a 2 to 3-fold higher risk (40 to 66 per cent) of dying of prostate cancer within 10 years than those without nodal involvement. The results indicate that the prospects for cure are extremely poor in prostate cancer patients with lymph node metastases who are treated with pelvic lymphadenectomy and radioactive gold therapy. Whether these results can be extrapolated to patients treated with other regional forms of therapy, such as external beam radiation therapy or radical prostatectomy, remains to be demonstrated formally. However, I would be surprised if this were not the case. It is likely that the majority of prostate cancer patients with lymph node metastases also have occult distant metastases. In these patients any form of regional therapy directed at the primary tumor is likely to be of palliative benefit only. The decision about whether regional therapy should be applied in this clinical setting, therefore, must be based on estimates of the palliative efficacy and potential attendant adverse side effects of regional therapy, such as impotence, incontinence, other surgical complications and irradiation injury to the bladder, bowel, urethra, and urinary and anal sphincter mechanisms in relation to the palliative efficacy of hormonal therapy and its attendant morbidity. In my view most patients with lymph node metastases are treated best with early or delayed hormonal therapy. William J. Catalana Division of Urology Washington University Medical Center St. Louis, Missouri The authors provide information that strongly supports the position that node positive prostatic carcinoma represents systemic disease that cannot be controlled by local or regional therapy. The equivalent distant failure rate seen among patients with stages Nl, N2 and N3 disease parallels the observation of the Intergroup Testicular Study, which demonstrated that the rate of recurrence among patients with cleanly resected node positive retroperitoneal disease was independent of the number of positive nodes. These parallel observations strongly suggest that the appearance of malignant disease at a nodal site distant from the primary identifies a tumor that is capable biologically of seeding multiple sites and that the apparent appearance of stage N +MO disease reflects only the inability to detect the microscopic metastatic deposits. The increased death rate seen among patients with multiple nodal metastases most probably reflects the impact of large volume metastatic disease rather than any impact of surgical intervention on the nodal extension among the node positive group. The manuscript argues strongly for definition of node positive disease among all patients selected for a regional or local therapy and also provides information that the number of involved nodes may not be important as a stratification index in future prostate cancer trials. David F. Paulson Department of Urology Duke University School of Medicine Durham, North Carolina