Treatment of prostate cancer with regional lymph node (N1) metastasis

Treatment of Prostate Cancer With Regional Lymph Node (N1) Metastasis Alan Pollack, Eric M. Horwitz, and Ben Movsas Prostate cancer with pathologically documented regional lymph node positive disease has been associated with a dismal prognosis in the past. Clinical and/or biochemical progression is evident within 5 years in over 50% treated with external-beam radiotherapy (EBRT) alone, radical prostatectomy (RP) alone, or androgen deprivation (AD) alone. By 10 years after treatment, greater than 75% progress and over half succumb to prostate cancer. In contrast, the results with

the combination of EBRT ⴙ AD or RP ⴙ AD have been very promising. Ten-year biochemical progression and overall survival rates are roughly 20% and 70%, respectively, for patients with subclinical lymph node involvement. Patients with a 10-year life expectancy should be treated aggressively with long-term AD combined with either EBRT or RP. © 2003 Elsevier Inc. All rights reserved.

O

phangiogram fared better than those with a negative CT scan. Although adjustment for the possible uneven distribution of other prognostic factors was not done, the findings were similar for T2b and T3/T4 patients. Despite these encouraging results, lymphangiogram is not considered adequate for the determination of lymph node status because the internal iliac and sacral lymph nodes are not reliably visualized.11 Along these lines, Hanks et al10 showed that lymph node negative status as determined by lymphadenectomy was associated with lower treatment failure rates after radiotherapy compared with negative lymph node status by clinical parameters (CT pelvis or lymphangiogram.). The ProstaScint scan (Cytogen Corporation, Princeton, NJ) is based on imaging using a radiolabeled PSA-membrane antigen antibody and shows promise in high-risk patients.12,13 Optimal use of indium-111 capromab pendetide involves coregistration with CT scan14 and considerable expertise on the part of the radiologist. The results have not always been straightforward.15 Lymphadenectomy is the most reliable method for determining lymphatic involvement. The standard procedure involves en bloc resection of the lymph node bed between the internal and external iliac vessels. The borders are the anteromedial surface of the hypogastric artery medially, the external iliac artery laterally, the pelvic floor and obturator foramen inferiorly, and the bifurcation of the iliac arteries superiorly.16 Lymphadenectomy is a diagnostic procedure that is not considered therapeutic. At one time, it was relatively common before external-beam radiotherapy (EBRT). High-risk patients had lymphadenectomy because when N1 disease was identified treatment took a dramatically different

ne of the major routes of prostate cancer spread is to the draining lymphatics in the pelvis. Prostate cancer spreads to the obturator, external iliac, internal iliac, presacral, and lateral sacral (presciatic) lymph nodes.1-4 This pattern of lymph node spread combined with the typical pattern of microscopic involvement makes visualization by imaging insensitive. Pelvic computed tomography (CT) scan requires lymph node enlargement to over 1.0 cm, and most would concur that a threshold of 1.5 cm improves specificity. Although we routinely obtain a pelvic CT scan for patients with high-risk features (prostate-specific antigen [PSA] ⬎20 ng/mL, stage ⱖT3, or Gleason score 8-10), the yield is still relatively low.5,6 Whenever possible, enlarged lymph nodes seen on CT scan should be biopsied by fine-needle aspiration to establish the diagnosis.7 Lymphoid malignancies are sometimes diagnosed when enlarged lymph nodes are found in the staging workup for prostate cancer.8 The most common type is chronic lymphocytic lymphoma, which usually would not influence the decision to proceed with treatment of the prostate cancer with definitive radiotherapy. Hanks et al9,10 found that the prognosis of patients who underwent lymphangiogram for staging was better than for patients who underwent pelvic CT scan. Those with a negative lym-

From the Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA. Address reprint requests to Alan Pollack, MD, PhD, Department of Radiation Oncology, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111. © 2003 Elsevier Inc. All rights reserved. 1053-4296/03/1302-0005$30.00/0 doi:10.1053/srao.2003.50011

Seminars in Radiation Oncology, Vol 13, No 2 (April), 2003: pp 121-129

121

122

Pollack, Horwitz, and Movsas

Figure 1. Schematic representation of prognostic groups based on clinical or biochemical relapse hazard indices using the factors of T-stage category, pretreatment PSA, and Gleason score. (Reprinted with permission.21)

course. Those found to be lymph node positive (LN⫹) were treated with androgen deprivation (AD) alone, whereas lymph node negative (LN⫺) patients received definitive EBRT alone. Since the treatment of clinically staged patients with high-risk features is now typically EBRT plus 2.5 to 3.0 years of AD,17,18 a regimen amenable for N1 disease, the rationale for lymphadenectomy is far less. Some would contend that permanent AD should be used in N1 disease; however, there may be a fraction of these patients who are cured, and intermittent AD19 is a practical, albeit unproven, approach. Stopping AD after 2 to 3 years will permit an assessment of cure, and if biochemical failure is later manifest, AD may be reinstituted with probably little, if any, negative effect. Other data from Zagars et al20 indicate that the prognosis of LN⫺ patients, established via lymphadenectomy, is about the same as undissected patients when stratified by clinical prognostic factors. Based on hazard indices for relapse or a rising PSA,21 clinically staged prostate cancer patients treated with radiotherapy alone were classified into 6 prognostic groups (Fig 1). This prognostic grouping was associated with 6 year failure rates of 6% for group I, 30% for group II, 40% for group III, 46% for group IV, 57% for group V, and 88% for unfavorable. This grouping also correlated with the risk of distant metastasis in this primarily clinically staged cohort21 and with the risk of lymph node involvement in patients who underwent pelvic lymphadenectomy (Fig 2).20 When patients in categories 4, 5, and unfavorable were subdivided by whether they

were LN⫺ (based on pelvic lymph node dissection) or did not undergo lymphadenectomy,20 no difference in the incidence of relapse or a rising PSA was observed (Fig 3). Although lymph node status is clearly prognostic, the current combination of clinical risk factors (PSA, Gleason score, and stage) appear to be equally so.

Rationale for Combined Modality Therapy Prostate cancer with pathologically confirmed regional LN⫹ disease has been associated with a dismal prognosis in the past. Clinical and/or bio-

Figure 2. Incidence of lymph node involvement by the MD Anderson prognostic groups depicted in Figure 4. (Reprinted with permission.20)

Treatment of Prostate Cancer

123

Table 2. Regional Lymph Node Positive (N1) Disease Treated With Radical Prostatectomy Ref

Year

N

F/U (mo)

Dekernion30 Myers31 Zincke32 Sgrignoli33 Messing34

1990 1992 1992 1994 1999

35 34 77 113 51

72 54 60 — 85

DF (%)

OS (%)

⬃30 ⬃55 (5 yr)* 29 — (5 yr) 24 71 (10 yr)* ⬃20 — (5 yr) — ⬃58 (10 yr)

Abbreviations: DF, disease freedom (time of analysis as indicated for OS); OS, overall survival at time indicated. *Cause-specific survival. Modified with permission.29

Figure 3. Kaplan-Meier survival curves for freedom from relapse or a rising PSA for patients that were pelvic lymph node dissection negative and for those who never had a pelvic lymph node dissection. Patients were stratified by risk categories IV, V, and unfavorable, as depicted in Figure 1. (Reprinted with permission.20)

chemical progression is evident within 5 years in over 50% of patients treated with external-beam radiotherapy alone, radical prostatectomy (RP) alone, or androgen deprivation alone. By 10 years after diagnosis, greater than 75% progress and over half succumb to prostate cancer.22-39 Tables 1 through 3 display the failure rates after singlemodality therapy for N1 prostate cancer. Time to progression after starting AD alone appears to be slightly longer than for either EBRT or RP alone. Although the results with EBRT alone have in general been poor, there are reports of freedom from failure rates of 61% long-term with irradiation of the pelvic lymph nodes.25 Standard practice is to irradiate the pelvic lymph nodes to

Table 3. Regional lymph node positive (N1) disease treated with immediate androgen deprivation

Table 1. Regional Lymph Node Positive (N1) Disease Treated With EBRT Ref Bagshaw Smith23 Gervasi24 Lawton25 Hanks26 Leibel27 Lawton28

22

Year

N

F/U (mo)

1984 1984 1989 1992 1993 1994 1997

60 46 152 56 — 345 75

⬎60 ⬎60 103 108 — 105 59

about 45 Gy, but some have questioned whether pelvic lymph node irradiation, even in N1 patients, is a significant determinant of outcome.27 The debate concerning pelvic lymph node irradiation has revolved mostly around patients with high-risk disease who have not had a lymphadenectomy.40 Because the results with EBRT and RP have overall been poor and most cases eventually require AD for distant metastasis, primary treatment historically has predominantly been AD alone. Zagars et al35 described the results of 179 patients diagnosed with regional lymph node involvement via lymphadenectomy and treated with AD alone at MD Anderson Cancer Center (MDACC). Biochemical and/or disease failure occurred in ⬃55% by 5 years, which is in agreement with others (Table 3). They also reported that local progression at 8 years was evident in over half of the patients (Fig 4). Local progression was more common than distant metastasis (44% at 8 years). Lymph node progression was

DF (%)

OS (%)

⬃15 17 22 61 ⬃30 ⬃35* 11

⬃45 60 65 76 64 ⬃70 65

Abbreviations: EBRT, external beam radiotherapy; DF, disease freedom at 5 years; OS, overall survival at 5 years. *Distant metastasis free. Modified with permission.29

Ref Zagars35 van Aubel36 Kramolowsky37 Cadeddu38‡ Ghavamian39

F/U Year N (mo) 1994 1985 1988 1997 1999

DF (%)

179 43 25 30 34 55 30 ⬎60 100 mo* 41 62 — 79 ⬎60 —

OS (%) 57 (8 yr) — (5 yr) 150 mo* 45 (10 yr)† 28 (10 yr)

Abbreviations: DF, disease freedom (time of analysis as indicated for OS); OS, overall survival at time indicated. *Median value. †Cause-specific survival. ‡Seventy-one percent received immediate AD after lymph node dissection. Modified with permission.29

124

Pollack, Horwitz, and Movsas

Figure 4. The Kaplan-Meier local and distant progression survival curves for stage N1 patients treated with AD alone at MDACC. (Reprinted with permission.35)

only seen in 2 patients (1%). Another significant finding was that the post-AD PSA response was highly predictive of relapse. Failure to achieve an undetectable PSA was tantamount to failure, whereas only 5% of those attaining an undetectable PSA progressed by 8 years. These data in combination with encouraging results with RP and AD30,41 led these investigators and others to explore the combination of EBRT and AD.

EBRT Plus AD for N1 Prostate Cancer Even though the incidence of patients presenting with regional metastasis is waning,42,43 emerging data have shown that management considerations are crucial to prolonging time to progression and survival. All radiation oncologists in general practice will be asked to contemplate treatment for N1 disease, as well as for those at a high risk of harboring lymph node metastasis. More recent results indicate that appropriate management should include combination therapy with a local treatment (EBRT or RP) plus AD. There have not been any randomized trials of EBRT ⫹ AD that were limited solely to N1 patients, although there are subset analyses of trials that included such patients. A Swedish randomized trial44 comparing EBRT alone with permanent AD ⫹ EBRT was closed early because of a survival benefit favoring the combined modality arm. Permanent AD was begun about 3 weeks before EBRT (65 Gy). At last report44 with a median follow-up of 9.3 years, 50% of those with

N1 disease who received EBRT ⫹ AD were alive, whereas none of those treated with EBRT alone (delayed AD was used for salvage) were alive. Combined EBRT ⫹ AD profoundly prolonged survival, far beyond that ever documented for early AD alone versus delayed AD alone.45-47 In another subset analysis of a randomized trial, Lawton et al28 examined the LN⫹ patients in Radiation Therapy Oncology Group (RTOG) protocol 85-31. In this trial, patients with paraaortic lymph node involvement (M1 disease) were included. The randomization was also permanent EBRT ⫹ AD (started at the end of EBRT) with EBRT alone. As displayed in Table 428,48-50 the freedom from biochemical failure (bNED) rate at 5 years was 55% for those treated with EBRT ⫹ AD. The rate for patients treated with EBRT alone was 11% (P ⫽ .0001). No difference in overall survival was observed (73% v 65% for EBRT⫹AD v EBRT alone). Recently updated retrospective findings from MDACC49 revealed a significant improvement in freedom from clinical and/or biochemical failure (FFF), freedom from distant metastasis, and overall survival, when the combination of long term EBRT ⫹ AD was used over that of AD alone. The AD alone cohort was comprised of 183 patients treated earlier historically, with a median follow-up from the date of lymphadenectomy of 9.4 years (Fig 5). There were 77 patients treated with the combination, with a median EBRT dose of 70 Gy and postlymphadenectomy follow-up of 5.9 years (Fig 6). Patients who received AD alone had slightly worse prognostic features, but the advantage of AD ⫹ EBRT held up in multivariate analyses of all endpoints using Cox proportional hazards regression. Other EBRT ⫹ AD series, as depicted in Table 4, also have shown very favorable freedom from progression and survival rates for patients treated with Table 4. Regional Lymph Node Positive (N1) Disease Treated With EBRT ⫹ AD Ref

Year

N

F/U (mo)

bNED (%)

OS (%)

Whittington52 Lawton28 Zagars53 Buskirk54

1997 1997 2001 2001

66 98 72 60

49 59 74 101

47 55 80 82

84 (8 yr) 73 (5 yr) 67 (10 yr) 76 (5 yr)

Abbreviation: OS, overall survival at time indicated. Modified with permission.29

Treatment of Prostate Cancer

125

Figure 5. Updated MDACC Kaplan-Meier freedom from relapse or a rising PSA and overall survival curves for stage N1 patients treated with AD alone. Expected survival for a cancerfree population of similar age is also shown. (Reprinted with permission.49)

EBRT ⫹ AD when compared with the outcome from single-modality treatment (Tables 1-3). Whittington et al48 described the results of 66 patients treated with EBRT ⫹ AD. They observed a steep drop in the freedom from clinical disease survival curves between 5 and 8 years (85% to 67%) that was not seen in the cohort studied by Zagars et al.49 Likewise, Lawton et al28

found lower disease-free rates than that of Zagars et al.49 These differences are probably related to the characteristics of the populations reviewed. The majority of those treated with EBRT ⫹ AD in the MDACC group were defined as LN⫹ at attempted radical prostatectomy; the patients had a relatively low risk of lymph node involvement and lymph node extent was usually

Figure 6. Updated MDACC Kaplan-Meier freedom from relapse or a rising PSA and overall survival curves for stage N1 patients treated with EBRT ⫹ long-term AD. Expected survival for a cancer-free population of similar age is also shown. (Reprinted with permission.49)

126

Pollack, Horwitz, and Movsas

microscopic (would not have been seen on pelvic CT scan). The patients in the University of Pennsylvania48 and RTOG28 series included patients with much more advanced local-regional disease. In summary, the results with the combination of EBRT ⫹ AD have been very promising. The published series have dealt with small patient numbers, and so specifics concerning prognostic factors and patient selection are not available. Some factors that may have an effect on outcome may be inferred from the available data. The extent of nodal involvement, such as N1 versus N2-3 using the 1992 American Joint Committee on Cancer (AJCC) staging system48 or regional versus metastatic (para-aortic) lymph node involvement,28 may be a factor.

EBRT Treatment Considerations Whether the whole pelvis should be treated in patients receiving EBRT for prostate cancer with a high risk of lymph node involvement has long been debated.40 The threshold for treating regional lymph nodal areas at risk for most sites is about 15%. For prostate cancer conclusive documentation that there will be an improvement in outcome for a nodal risk of 30 to 50% has not been shown. One could argue from these data that either nodal involvement is a surrogate for systemic spread, that insufficient RT doses were used to eradicate the primary tumor in the prostate, and/or that insufficient doses were used to eradicate lymph node micrometastasis. The latter is unlikely given the lack of recurrence and symptoms from nodal metastasis. Lymph node recurrence in other pelvic malignancies, such as squamous cell carcinoma of the cervix, more often are grossly apparent and cause symptoms, such as pelvic pain or lower-extremity edema. For prostate cancer, symptomatic nodal progression is rarer, particularly once AD is instituted. Progression in the prostate and bone are much more common. In the normal prostate, stromal-epithelial cell (paracrine) interactions maintain a balance between cell proliferation and death.51,52 Likewise, the proliferation of malignant prostate cells is strongly influenced by stromal cell growth factors.51,53 Such interactions are prevalent in the prostate and in bone and are probably much less a factor in lymph nodes. Tumor-stromal cell interactions may be responsible in part for tumor-cell survival and resistance to

AD. Because the prostate is a major site of recurrence in regional lymph node positive patients and nodal recurrence is extremely low, we reasoned that treatment of the prostate was of greater importance. Hence, at MDACC beginning in the late 1980s, the prostate and periprostatic tissues were irradiated using 4-field technique with approximately 11 ⫻ 11 cm anterior-posterior fields and 11 ⫻ 9 cm lateral fields. No attempt was made to comprehensively cover the prostatic lymph nodes, although periprostatic and periseminal vesicle lymph nodes would have been included.54 The administration of long-term AD was hypothesized to secure control of the lymph nodes and inhibit distant micrometastatic deposits, whereas prostate EBRT would prolong disease progression via local effects. Recent data from RTOG protocol 94-1355 suggest that, contrary to the argument mentioned earlier, pelvic EBRT in combination with neoadjuvant/adjuvant short-term AD affords an advantage in terms of freedom from failure over pelvic or prostate only EBRT given with short-term AD applied after EBRT or neoadjuvant/adjuvant AD given with prostate only EBRT (61% v ⬃47% for the other 3 treatment combinations at 4 years). No survival difference was evident with a median follow-up of 59.3 months. The patients in this trial had a greater than 15% risk of lymph node involvement. It would appear that treatment with neoadjuvant and concurrent AD increased the eradication of subclinical nodal disease when combined with pelvic radiotherapy and that this translated into improved outcome. One explanation for the excellent results in the MDACC N1 disease series, which did not involve whole-pelvic EBRT, is that with concurrent and extended long-term AD the need for complete pelvic coverage may not be warranted. As mentioned earlier, the standard is for pelvic EBRT in patients pathologically defined as having regional lymph node metastasis. Nodal burden is another variable that has been associated with outcome. In the 1992 AJCC staging system, nodal stage was divided into N1, microscopic involvement of a single lymph node ⱕ2 cm; N2, a single lymph node ⬎2 cm and ⱕ5 cm or multiple lymph nodes ⱕ5 cm; and N3, a ⬎5 cm lymph node. The 1997 and 2002 AJCC staging systems have only 1 regional nodal metastasis category, N1, which does not address the extent of nodal involvement. There is no consensus on

Treatment of Prostate Cancer

Table 5. Regional Lymph Node Positive (N1) Disease Treated With RP ⫹ AD Author (Ref) Dekernion(30)† Zincke(32)† Schmeller(65)‡ Messing(34)†

Year

N

1990 21 1992 243 1997 39 1999 47

F/U DF (mo) (%) 72 60 46 85

OS (%)

⬃70 ⬃85 (10 yr)* 76 80 (10 yr)* ⬃45 ⬃85 (5 yr) ⬃85 ⬃83 (10 yr)

DF, disease freedom (time of analysis as indicated for OS); OS, overall survival at time indicated. *Cause-specific survival. †Suggested an advantage compared with radical prostatectomy alone. ‡Suggested not different from AA alone.

the prognostic value of the extent of lymph node involvement. There are studies that show improved outcome with a lower nodal burden41,56-59 and others that have not.24 This debate is unsettled. The current staging system ignores extent of nodal involvement, but the best reported results have been in those with microscopic involvement limited to a single lymph node. Evaluation of the efficacy of EBRT ⫹ AD is not possible until AD is stopped. Permanent AD is the standard for N1 disease; however, it is possible that some patients are cured after 3 years of AD. Prime candidates for temporary AD are those in whom the nodal burden was low and the PSA rapidly (⬍6 months) became undetectable. The latter is an extrapolation from patients treated with AD alone.35

127

the combination was indeed superior to singlemodality therapy (Table 5).34,65 The largest experience has been at the Mayo clinic,32 where the best results for AD ⫹ RP were seen when the prostate tumor was diploid. More recently, Messing and colleagues34 reported a survival advantage for RP ⫹ AD over RP alone (delayed AD) in a randomized trial of 100 men with N1 disease. After a median follow-up of 7.1 years, the 10 year overall survival rate was about 83% for those who received RP ⫹ AD versus 57% for those who received RP alone (P ⫽ .02). A complementary matched pair analysis of 158 patients by Ghavamian et al39 showed a survival advantage for RP ⫹ AD over AD alone (66% v 28% at 10 years). In summary, the diagnosis of lymph node positive disease has become much rarer than it once was, making it difficult to accrue the numbers needed for the design of decisive randomized trials. The Eastern Cooperative Oncology Group trial reported by Messing et al34 was 120 patients short of the accrual target when published, and during the period of this trial (1988-1993), there were many more patients with N1 disease. Although the available studies may be viewed as suboptimal because of low patient numbers and the paucity of randomized trials, virtually all show a benefit for combining local therapy with long-term AD. Patients with a life expectancy of 10 years should receive combined modality therapy.

RP Plus AD for N1 Prostate Cancer The mechanism of the effects from EBRT ⫹ AD are uncertain. Some evidence suggests a supraadditive interaction,60,61 but the main effect may be additivity in cell killing.62 Additivity as the predominant mechanism of cell killing with EBRT ⫹ AD, combined with the observations that few prostate cancer patients progress in the lymph nodes and failure after AD alone is often seen locally in the prostate, suggests that local therapy of any type combined with AD may benefit patients with N1 disease. Further justification for early AD plus local therapy is that early AD may be more effective at slowing tumor growth and prolonging survival when contrasted with delayed AD; animal63,64 and clinical data45-47 corroborate this concept. The initial retrospective reports of permanent AD ⫹ RP30,32 indicated that

References 1. Golimbu M, Morales P, Al-Askari S, et al: Extended pelvic lymphadenectomy in prostatic cancer. J Urol 121:617-620, 1979 2. Heidenreich A, Varga Z, Von Knobloch R: Extended pelvic lymphadenectomy in patients undergoing radical prostatectomy: High incidence of lymph node metastasis. J Urol 167:1681-1686, 2002 3. Brossner C, Ringhofer H, Hernady T, et al: Lymphatic drainage of prostatic transition and peripheral zones visualized on a three-dimensional workstation. Urology 2001;57:389-393, 2001 4. Wawroschek F, Vogt H, Weckermann D, et al: Radioisotope guided pelvic lymph node dissection for prostate cancer. J Urol 166:1715-1719, 2001 5. Albertsen PC, Hanley JA, Harlan LC, et al: The positive yield of imaging studies in the evaluation of men with newly diagnosed prostate cancer: a population based analysis. J Urol 163:1138-1143, 2000

128

Pollack, Horwitz, and Movsas

6. Sandler HM, Ohl DA, Quint LE, et al: Determining local-regional extension of prostate cancer. Semin Radiat Oncol 3:169-178, 1993 7. Oyen RH, Van Poppel HP, Ameye FE, et al: Lymph node staging of localized prostatic carcinoma with CT and CT-guided fine-needle aspiration biopsy: Prospective study of 285 patients. Radiology 190:315-322, 1994 8. Terris MK, Hausdorff J, Freiha FS: Hematolymphoid malignancies diagnosed at the time of radical prostatectomy. J Urol 158:1457-1459, 1997 9. Hanks GE, Krall JM, Pilepich MV, et al: Comparison of pathologic and clinical evaluation of lymph nodes in prostate cancer: implications of RTOG data for patient management and trial design and stratification. Int J Radiat Oncol Biol Phys 23:293-298, 1992 10. Hanks GE, Krall JM, Pilepich MV, et al: Comparison of pathologic and clinical evaluation of lymph nodes in prostate cancer: implications of RTOG data for patient management and trial design and stratification. Int J Radiat Oncol Biol Phys 23:293-298, 1992 11. Castellino RA: Lymphography in clinically localized prostate cancer. NCI Monogr 7:37-39, 1988 12. Polascik TJ, Manyak MJ, Haseman MK, et al: Comparison of clinical staging algorithms and 111indium-capromab pendetide immunoscintigraphy in the prediction of lymph node involvement in high risk prostate carcinoma patients. Cancer 85:1586-1592, 1999 13. Manyak MJ, Hinkle GH, Olsen JO, et al: Immunoscintigraphy with indium-111-capromab pendetide: Evaluation before definitive therapy in patients with prostate cancer. Urology 54:1058-1063, 1999 14. Raj GV, Partin AW, Polascik TJ: Clinical utility of indium 111-capromab pendetide immunoscintigraphy in the detection of early, recurrent prostate carcinoma after radical prostatectomy. Cancer 94:987-996, 2002 15. Seltzer MA, Barbaric Z, Belldegrun A, et al: Comparison of helical computerized tomography, positron emission tomography and monoclonal antibody scans for evaluation of lymph node metastases in patients with prostate specific antigen relapse after treatment for localized prostate cancer. J Urol 162:1322-1328, 1999 16. McDowell GC 2nd, Johnson JW, Tenney DM, et al: Pelvic lymphadenectomy for staging clinically localized prostate cancer. Indications, complications, and results in 217 cases. Urology 35:476-482, 1990 17. Hanks G, Lu J, Machtay M, et al: RTOG Protocol 92-02: A Phase III trial of the use of long-term total androgen suppression following neoadjuvant cytoreduction and radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 48:112, 2000 18. Bolla M, Gonzalez D, Warde P, et al: Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 337:295300, 1997 19. Grossfeld GD, Chaudhary UB, Reese DM, et al: Intermittent androgen deprivation: Update of cycling characteristics in patients without clinically apparent metastatic prostate cancer. Urology 58:240-245, 2001 20. Zagars GK, Pollack A, von Eschenbach AC: Management of unfavorable locoregional prostate carcinoma with radiation and androgen ablation. Cancer 80:764-775, 1997

21. Zagars GK, Pollack A, von Eschenbach AC: Prognostic factors for clinically localized prostate carcinoma: Analysis of 938 patients irradiated in the prostate specific antigen era. Cancer 79:1370-1380, 1997 22. Bagshaw MA: Radiotherapeutic treatment of prostatic carcinoma with pelvic node involvement. Urol Clin North Am 11:297-304, 1984 23. Smith JA Jr, Haynes TH, Middleton RG: 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 131:705-707, 1984 24. Gervasi LA, Mata J, Easley JD, et al: Prognostic significance of lymph nodal metastases in prostate cancer. J Urol 142:332-336, 1989 25. Lawton CA, Cox JD, Glisch C, et al: Is long-term survival possible with external beam irradiation for stage D1 adenocarcinoma of the prostate? Cancer 69:2761-2766, 1992 26. Hanks GE: The challenge of treating node-positive prostate cancer. An approach to resolving the questions. Cancer 1993;71:1014-1018, 1993 27. Leibel S, Fuks Z, Zelefsky M: The effects of local and regional treatment on the metastatic outcome in prostatic carcinoma with pelvis lymph node involvement. Int J Radiat Oncol Biol Phys 28:7-16, 1994 28. Lawton C, Winter K, Byhardt R, et al: Androgen suppression plus radiation vs. radiation alone for patients with D1 (pN⫹) adenocarcinoma of the prostate (results based on a national prospective randomized trial RTOG 85-31). Int J Radiat Oncol Biol Phys 38:931-939, 1997 29. Pollack A: The prostate, in Cox J, Ang K (eds): Moss’ Radiation Oncology, 8th Edition: Rationale, Technique, Results. St Louis, MO, 2002, pp 629-680 30. DeKernion JB, Neuwirth H, Stein A, et al: Prognosis of patients with stage D1 prostate carcinoma following radical prostatectomy with and without early endocrine therapy. J Urol 144:700-703, 1990 31. Myers RP, Larson-Keller JJ, Bergstralh EJ, et al: Hormonal treatment at time of radical retropubic prostatectomy for stage D1 prostate cancer: Results of long-term followup. J Urol 147:910-915, 1992 32. Zincke H, Bergstralh EJ, Larson-Keller JJ, et al: Stage D1 prostate cancer treated by radical prostatectomy and adjuvant hormonal treatment. Evidence for favorable survival in patients with DNA diploid tumors. Cancer 70:311323, 1992 33. Sgrignoli AR, Walsh PC, Steinberg GD, et al: Prognostic factors in men with stage D1 prostate cancer: Identification of patients less likely to have prolonged survival after radical prostatectomy. J Urol 152:1077-1081, 1994 34. Messing EM, Manola J, Sarosdy M, et al: Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 341: 1781-1788, 1999 35. Zagars GK, Sands ME, Pollack A, et al: Early androgen ablation for stage D1 (N1 to N3, M0) prostate cancer: Prognostic variables and outcome. J Urol 151:1330-1333, 1994 36. van Aubel OG, Hoekstra WJ, Schroder FH: Early orchiectomy for patients with stage D1 prostatic carcinoma. J Urol 134:292-294, 1985

Treatment of Prostate Cancer

37. Kramolowsky EV: The value of testosterone deprivation in stage D1 carcinoma of the prostate. J Urol 139:12421244, 1988 38. Cadeddu JA, Partin AW, Epstein JI, et al: Stage D1 (T1-3, N1-3, M0) prostate cancer: A case-controlled comparison of conservative treatment versus radical prostatectomy. Urology 50:251-255, 1997 39. Ghavamian R, Bergstralh EJ, Blute ML, et al: Radical retropubic prostatectomy plus orchiectomy versus orchiectomy alone for pTxN⫹ prostate cancer: a matched comparison. J Urol 161:1223-1227, 1999; discussion 12271228. 40. Stock RG, Ferrari AC, Stone NN: Does pelvic irradiation play a role in the management of prostate cancer? Oncology (Huntingt) 12:1467-1472, 1998; discussion 1472, 1475-1466 41. Cheng L, Bergstralh EJ, Cheville JC, et al: Cancer volume of lymph node metastasis predicts progression in prostate cancer. Am J Surg Pathol 22:1491-1500, 1998 42. Arai Y, Kanamaru H, Yoshimura K, et al: Incidence of lymph node metastasis and its impact on long-term prognosis in clinically localized prostate cancer. Int J Urol 5:459-465, 1998 43. Amling CL, Blute ML, Lerner SE, et al: Influence of prostate-specific antigen testing on the spectrum of patients with prostate cancer undergoing radical prostatectomy at a large referral practice. Mayo Clin Proc 73:401406, 1998 44. Granfors T, Modig H, Damber J, et al: Combined orchiectomy and external radiotherapy versus radiotherapy alone for nonmetastatic prostate cancer with or without pelvic lymph node involvement: A prospective randomized study. J Urol 159:2030-2034, 1998 45. Byar DP, Green SB: The choice of treatment for cancer patients based on covariate information: application to prostate cancer. Bull Cancer 67:477-490, 1988 46. Byar DP, Corle DK: Hormone therapy for prostate cancer: results of the Veterans Administration Cooperative Urological Research Group studies. NCI Monogr 7:165170, 1988 47. Immediate versus deferred treatment for advanced prostatic cancer: Initial results of the Medical Research Council Trial. The Medical Research Council Prostate Cancer Working Party Investigators Group. Br J Urol 79:235-246, 1997 48. Whittington R, Malkowicz SB, Machtay M, et al: The use of combined radiation therapy and hormonal therapy in the management of lymph node-positive prostate cancer. Int J Radiat Oncol Biol Phys 39:673-680, 1997 49. Zagars GK, Pollack A, von Eschenbach AC: Addition of radiation therapy to androgen ablation improves outcome for subclinically node-positive prostate cancer. Urol 58: 233-239, 2001 50. Buskirk SJ, Pisansky TM, Atkinson EJ, et al: Lymph nodepositive prostate cancer: Evaluation of the results of the combination of androgen deprivation therapy and radiation therapy. Mayo Clin Proc 76:702-706, 2001

129

51. Chung LW, Cunha GR: Stromal-epithelial interactions: II. Regulation of prostatic growth by embryonic urogenital sinus mesenchyme. Prostate 4:503-511, 1983 52. Planz B, Wang Q, Kirley SD, et al: Androgen responsiveness of stromal cells of the human prostate: regulation of cell proliferation and keratinocyte growth factor by androgen. J Urol 160:1850-1855, 1998 53. Gleave ME, Hsieh JT, von Eschenbach AC, et al: Prostate and bone fibroblasts induce human prostate cancer growth in vivo: Implications for bidirectional tumor-stromal cell interaction in prostate carcinoma growth and metastasis. J Urol 147:1151-1159, 1992 54. Kothari PS, Scardino PT, Ohori M, et al: Incidence, location, and significance of periprostatic and periseminal vesicle lymph nodes in prostate cancer. Am J Surg Pathol 25:1429-1432, 2001 55. Roach III M, Lu J, Lawton C: A Phase III trial comparing whole pelvis (WP) to prostate only (PO) radiotherapy and neoadjuvant to adjuvant total of androgen suppression (TAS): Preliminary analysis of RTOG 9413. Int J Radiat Oncol Biol Phys 51:3, 2001 56. Smith JA Jr, Middleton RG: Implications of volume of nodal metastasis in patients with adenocarcinoma of the prostate. J Urol 133:617-619, 1985 57. Golimbu M, Provet J, Al-Askari S, et al: Radical prostatectomy for stage D1 prostate cancer. Prognostic variables and results of treatment. Urology 30:427-435, 1987 58. Ferrari AC, Stone NN, Eyler JN, et al: Prospective analysis of prostate-specific markers in pelvic lymph nodes of patients with high-risk prostate cancer. J Natl Cancer Inst 89:1498-1504, 1997 59. Anscher MS, Prosnitz LR: Prognostic significance of extent of nodal involvement in stage D1 prostate cancer treated with radiotherapy. Urology 39:39-43, 1992 60. Joon DL, Hasegawa M, Sikes C, et al: Supraadditive apoptotic response of R3327-G rat prostate tumors to androgen ablation and radiation. Int J Radiat Oncol Biol Phys 38:1071-1077, 1997 61. Zietman AL, Prince EA, Nakfoor BM, et al: Androgen deprivation and radiation therapy: sequencing studies using the Shionogi in vivo tumor system. Int J Radiat Oncol Biol Phys 38:1067-1070, 1997 62. Pollack A, Salem N, Ashoori F, et al: Lack of prostate cancer radiosensitization by androgen deprivation. Int J Radiat Oncol Biol Phys 51:1002-1007, 2001 63. Isaacs JT, Coffey DS: Adaptation versus selection as the mechanism responsible for the relapse of prostatic cancer to androgen ablation therapy as studied in the Dunning R-3327-H adenocarcinoma. Cancer Res 41:5070-5075, 1981 64. Pollack A, Block NL, Stover BJ, et al: Tumor progression in serial passages of the Dunning R3327-G rat prostatic adenocarcinoma: Growth rate response to endocrine manipulation. Cancer Res 45:1052-1057, 1985 65. Schmeller N, Lubos W: Early endocrine therapy versus radical prostatectomy combined with early endocrine therapy for stage D1 prostate cancer. Br J Urol 79:226234, 1997