Lymph Node–Positive Prostate Cancer: The Benefit of Local Therapy

In this issue of ONCOLOGY, Dr. Mitin and colleagues provide a comprehensive review of the limited literature on management of men with prostate cancer who have pelvic lymph node involvement but no known distant metastatic disease at diagnosis.[1] Although these men are often written off as “incurable” and managed with androgen deprivation therapy alone, there are several reasons to consider local treatment with prostatectomy, radiation therapy, or both prostatectomy and radiation.

First, local treatment can prevent symptomatic local progression. Multiple retrospective studies demonstrate that in men with lymph node–positive prostate cancer (LN+ PCa), prostatectomy decreases the risk of developing local symptoms, including urinary obstruction, hematuria, and pain.[2-4] There are less data for men with LN+ PCa who receive radiation therapy; however, administration of prostate radiation therapy to men with LN+ PCa improves local control, thereby decreasing the risk of developing local symptoms.[5]

Second, administration of local therapy may delay disease progression. Retrospective studies suggest that both prostatectomy and radiation therapy improve both freedom from the development of metastatic disease and disease-free survival in men with LN+ PCa.[5-8] Targeting the bulk of the disease with local therapy may reduce cancer clonogens, extend the androgen deprivation therapy–free interval, and potentially prolong the time to development of castrate-resistant disease. In a prospective study evaluating systemic therapy, men who received prior definitive local therapy had a longer time to development of castrate-resistant disease than men who had not received local therapy.[9] Therefore, local therapy may make systemic therapy more effective.

Third, for select patients, administration of local therapy may actually lengthen survival. Retrospective studies suggest that both prostatectomy and radiation therapy may improve overall survival in men with LN+ PCa.[5-8] In order for local therapy to confer a survival benefit, either the patient must have no micrometastatic disease outside the treatment field or the micrometastatic disease must be controlled by systemic therapy. If the patient has uncontrolled micrometastatic disease, the distant metastasis will drive the clinical course and survival. The recent development of more effective systemic agents for prostate cancer, which are better able to control micrometastases, may well enhance the impact of local therapy on prostate cancer survival in men with node-positive disease. This phenomenon has occurred in other diseases. For example, the link between improved local-regional control and overall survival for node-positive breast cancer was not established until better systemic agents were developed that could eradicate micrometastatic disease.[10]

Clinically, men with incidental lymph node involvement found at the time of prostatectomy are approached differently from men with gross nodal involvement visualized on staging imaging. Some men who undergo prostatectomy and are found to have incidental small-volume nodal disease are cured of their cancer and do not require any adjuvant therapy.[11] Others found to have incidental nodal disease at resection are harboring residual microscopic local-regional disease and/or microscopic metastatic disease. Based on our current understanding of incidentally found nodal disease, it is challenging to identify which men with undetectable prostate-specific antigen (PSA) after surgery need adjuvant androgen deprivation or radiation therapy, and which men should be monitored with serial PSA tests, with consideration of androgen deprivation or radiation therapy at time of PSA recurrence. It is our practice to more strongly consider adjuvant radiation therapy for men with pathologic features that place them at risk for harboring microscopic residual disease in the prostate resection bed (pathologic T3 or margin-positive disease) in addition to the nodal disease found at surgery. A small number of lymph nodes (≤ 3) is also an important consideration, since this is the group whose disease is most likely local-regional. For men found to have incidental nodal involvement at prostatectomy who have persistent PSA after surgery or who develop PSA recurrence, we similarly consider salvage radiation therapy if the pathologic features of their disease are more strongly predictive of persistent or recurrent local-regional disease than systemic disease. Radiation to the prostatic fossa and lymph node drainage areas is combined with androgen deprivation therapy.

When considering local therapy for men with gross nodal involvement visualized on initial staging evaluation, it is important to understand the extent of nodal involvement. Men with gross nodal involvement are a heterogeneous group. Some have involvement of only one low-level node, while others have bulky bilateral disease that extends up to the aortic bifurcation. If the nodal disease is low, small, and away from the small bowel (which is the dose-limiting organ for pelvic radiation therapy), it is possible that the radiation dose that can be safely delivered to the gross disease will be high enough to eradicate the tumor, especially when combined with androgen deprivation. If, however, the patient has extensive bulky disease in close proximity to the small bowel, it is unlikely that high-dose radiation can be safely delivered to all of the gross disease. Additionally, this presentation is quite likely to portend more extensive micrometastases. For men with gross nodal disease, it is our practice to initially administer androgen deprivation therapy and monitor disease response with PSA testing and repeat imaging. Administration of 6 to 12 months of androgen deprivation therapy prior to local therapy significantly decreases the disease burden, and also identifies patients who develop early castrate-resistant disease and are unlikely to benefit from aggressive local therapy. After maximal disease response to androgen deprivation therapy, consolidative local treatment, either radiation therapy or surgical resection, is considered based on the patient’s overall health and preference.

Although high-level evidence is lacking, the existing literature indicates that select men with lymph node–positive prostate cancer benefit from local therapy. Local therapy has the potential to prevent symptomatic local progression, extend androgen deprivation therapy–free intervals, prolong the time to the development of castrate-resistant disease, delay the development of metastatic disease, and lengthen disease survival. As new systemic agents are developed that better address micrometastatic disease, local-regional therapy is expected to play an increasingly important role in the management of LN+ PCa, and internationally, treatment paradigms have already begun to shift toward an integrated strategy.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

REFERENCES

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3. Frohmuller HG, Theiss M, Manseck A, et al. Survival and quality of life of patients with stage D1 (T1-3 pN1-2 M0) prostate cancer. Radical prostatectomy plus androgen deprivation versus androgen deprivation alone. Eur Urol. 1995;27:202-6.

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8. 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. 1999;161:1223-7.

9. Millikan RE, Wen S, Pagliaro LC, et al. Phase III trial of androgen ablation with or without three cycles of systemic chemotherapy for advanced prostate cancer. J Clin Oncol. 2008;26:5936-42.

10. Punglia RS, Morrow M, Winer EP, et al. Local therapy and survival in breast cancer. N Engl J Med. 2007;356:2399-405.

11. Boorjian SA, Thompson RH, Siddiqui S, et al. Long-term outcome after radical prostatectomy for patients with lymph node positive prostate cancer in the prostate specific antigen era. J Urol. 2007;178:864-70.