Does Pelvic Irradiation Play a Role in the Management of Prostate Cancer?

Introduction

Recent advances in the radiotherapeutic management of localized prostate cancer have focused on methods of improving local control with the use of brachytherapy and conformal dose escalation. In addition, androgen suppression has been used to enhance cytoreduction prior to and induce synergistic cell kill during radiation therapy, as well as to address microscopically disseminated disease.

The implications and treatment of regional lymph node metastases in patients with prostate cancer have not received as much attention. The optimal treatment approach for these patients remains controversial. Most patients undergoing radiation therapy are not surgically staged. Therefore, an important unresolved issue is whether prophylactic pelvic irradiation is beneficial in patients at high risk for lymph node involvement. In order to help clarify these issues, the following questions need to be addressed:

• With the trend toward the diagnosis of earlier-stage prostate cancer, has the incidence of lymph node metastases changed? Also, what is the current percentage of patients harboring lymph node metastases who potentially could benefit most from prophylactic pelvic irradiation?

• What is the natural history of lymph node-positive prostate cancer, and is node positivity synonymous with systemic disease ?

• Is there a subset of patients with apparently pathologically negative lymph nodes who have occult nodal disease that could be eradicated by prophylactic pelvic irradiation?

• What do both prospective and retrospective clinical studies examining the effect of pelvic irradiation on nodepositive prostate cancer reveal about the behavioral patterns of this disease and the efficacy of pelvic irradiation?

• Does pelvic irradiation improve outcome over prostate-alone irradiation in comparative series?

Changing Incidence of Pelvic Lymph Node Metastases

The presentation of prostate cancer has shifted to earlier stages with lower tumor volumes. This shift is due to the widespread use of prostate-specific antigen (PSA) as a detection tool.

Paralleling the change to earlier-stage disease at presentation has been a decrease in the incidence of pelvic lymph node metastases. In a 1959 study by Flocks et al, of 411 patients undergoing pelvic lymph node dissection, 146 (36%) had lymph node metastases.[1] Reporting on 511 patients who underwent lymph node dissection prior to receiving radiation therapy from 1966 to 1979, Gervasi et al found that 152 (30%) had lymph node metastases.[2]

In the 1970s, radical prostatectomy series revealed node-positive disease in approximately 35% of patients.[3-5] A review of lymphadenectomy series from that time found that, overall, 30% (726/2,458) of men had lymph node metastases.[6]

Few data were published on this topic in the early to mid-1980s. In the late 1980s and early ’90s, however, data emerged revealing a lower yield of positive lymph nodes. Reports showed rates of node positivity ranging from 3.7% to 7.7% in patients undergoing radical prostatectomy.[7,8] In a series published by Stock et al, 10% of patients undergoing laparoscopic pelvic lymph node dissection prior to external-beam irradiation or brachytherapy were found to have positive lymph nodes.[9]

In a recent series by Partin et al, only 5% of 4,133 patients undergoing radical prostatectomy had lymph node involvement.[10] These data demonstrate that, currently, 5% to 10% of patients with newly diagnosed prostate cancer harbor pathologically positive lymph node nodes, depending on the risk features of the study population.

Natural History of Node-Positive Prostate Cancer

The natural history of lymph node-positive disease is difficult to define. Most of the data on node-positive patients reveal a high propensity toward the development of metastatic disease.

In a series of 1,078 patients treated with iodine-125 prostate implants reported by Leibel et al, the rate of freedom from distant metastases at 15 years ranged from 4% to 8%, depending on the extent of nodal disease. In this analysis, local control of the primary tumor had no effect on the development of distant metastases in patients with node-positive disease. This led the authors to conclude that distant micrometastatic dissemination already exists at the time of initial diagnosis in these patients.[11]

Similar conclusions were reached by Gervasi et al, who showed that the risk of developing distant metastases at 10 years was 83% in patients with node-positive disease vs 31% in those with node-negative disease.[2] Other studies have supported the theory that nodal disease is synonymous with microscopic distant disease.[12-15]

Other investigators suggest the existence of a subset of node-positive prostate cancer patients who have locoregional disease without distant dissemination at presentation. This subset of early node-positive patients includes those with a single lymph node metastasis, low- to moderate-grade tumors, or diploid tumors.[16-19]

In a study of 42 patients with node-positive prostate cancer treated with radical prostatectomy, Golimbu et al found that 50% of patients with only one node involved were alive at 10 years, as compared with no patient with metastases in more than one node.[18] Davidson et al examined 61 patients with lymph node metastases who remained untreated until disease progression. They found that 36% of patients with grade 1 or 2 disease were free of disease progression at 5 years, as opposed to 0% of those with grade 3 disease (P < .001).[17]

Zincke et al studied 370 patients with stage D1 disease treated with radical prostatectomy and hormonal therapy. Their analysis revealed that 72% of patients with diploid tumors were free of systemic progression at 10 years, as compared with 45% of those with aneuploid tumors (P < .0001).[19]

A subset of node-positive patients with locoregional, nonmetastatic disease has also been shown to exist among patients with cervical, breast, or head and neck cancers.[20-22] With respect to prostate cancer, it is this subgroup of node-positive patients with locoregional disease only who could potentially benefit most from prophylactic pelvic irradiation.

Occult Pelvic Lymph Node Metastases

The detection of prostate cancer cells by the expression of prostate-specific genes at the messenger RNA (mRNA) level has opened up the possibility of detecting metastases at the molecular stage.[23,24] Using the reverse transcription-polymerase chain reaction for PSA (RTPCR-PSA) and prostate-specific membrane antigen (RTPCR-PSM), we tested whether tumor spread could be detected in the pelvic lymph nodes of 33 patients with high-risk prostate cancer undergoing laparoscopic lymph node dissection prior to radiation therapy. Overall, four patients (12%) had pathologically positive lymph nodes. Of the 29 patients with pathologically negative nodes, 15 (52%) were positive for RTPCR-PSA.[25]

An update of these data found that patients with high-grade cancers were at highest risk for having RTPSR-PSA-positive nodes. Of 72 patients, 56 had Gleason scores ³ 7 and 15 had scores £ 6. Nodes were RTPCR-PSA-positive in 49% of patients with high-grade cancers vs 20% of those with low-grade cancers (P = .04).

The prognostic significance of lymph node RTPCR-PSA positivity was suggested by Edelstein et al, who tested archived lymph node specimens from patients who had undergone radical prostatectomy for the presence of RTPCR-PSA. In this series, 88% of patients whose lymph nodes were positive for RTPCR-PSA experienced disease recurrence, as compared with 33% of patients with RTPCR-PSA-negative nodes.[26]

These studies suggest that there may be a subgroup of pathologic lymph node-negative patients who harbor occult lymph node disease, which can be detected by a highly sensitive assay. Furthermore, as demonstrated by the study of Edelstein et al, these patients may develop disseminated disease if left untreated. This subset of patients may benefit from pelvic irradiation.