Node-Positive Prostate Cancer: A Call for Level 1 Evidence

Baker et al have nicely reviewed the possible therapeutic options for men with node-positive prostate cancer.[1] In recent years, several well-designed studies have clarified the role of combined treatment modalities in men with locally advanced prostate cancer.[2-6] However, none specifically focused on men with node-positive disease. This was likely due to two assumptions: (1) node dissemination indicates the presence of systemic disease; and (2) lymph node metastases from prostate cancer are uncommon in today’s patients. However, both these assumptions have proven to be wrong.

Therefore, virtually all data that are useful for the management of pathologically node-positive patients derive from retrospective studies or unpowered/exploratory analyses of randomized controlled trials, so they still need appropriate validation. More importantly, we do not yet have sufficient knowledge of the mechanisms regulating prostate cancer nodal spread. Do lymph nodes represent the door to hematogeneous dissemination, or are they instead the route to separate pathways of metastatic spread? Unfortunately, these questions are still largely unanswered. Given the complexity of this condition, individual study of disease biology should, ideally, drive optimal treatment in the future. Meanwhile, some key points in the management of pathologically node-positive prostate cancer deserve attention.

Key Considerations in the Management of Pathologically Node-Positive Prostate Cancer

Importance of local disease control

Despite the lack of level 1 evidence, retrospective studies support the need for appropriate local treatment, even in the context of node-positive disease. Using both radiotherapy and radical prostatectomy cohorts, previous studies have shown that addition of appropriate local treatment may improve the oncologic outcome of patients with pathologically node-positive prostate cancer.[7-9] In this context, adequate local therapy should aim at maximizing cancer control, not only in the prostate but also in all pelvic lymphatic landing sites. There is, indeed, no adjuvant or salvage therapy that can overcome suboptimal treatments performed upfront.

Importance of multimodal treatment: which one for which patients?

Previous studies have shown that a multimodal approach is key to obtain appropriate cancer control in prostate cancer patients with pathologically node-positive disease.[10-12]

However, the optimal strategy to use is still under debate. In the surgical setting, there is only a single prospective randomized study that showed that the addition of androgen deprivation therapy (ADT) after radical prostatectomy improved survival.[10] Although this trial was well conducted, it has several limitations that seriously hinder the applicability of its results to contemporary patients. These include the low number of men enrolled, lack of standardized extent of pelvic lymph node dissection, lack of patient stratification according to the extent of nodal invasion, and the absence of data regarding early postoperative prostate-specific antigen (PSA) levels at initiation of ADT. Such shortcomings may be justified by the fact that this trial was designed and performed well before the release of the major (retrospective) data on the natural history of pathologically node-positive prostate cancer.[13,14] Given current knowledge regarding the heterogeneous outcomes of these patients after radical prostatectomy, it is indeed at least questionable whether immediate ADT should be applied to all patients, even in those, for example, with low volume of nodal invasion and undetectable postoperative PSA. A wait-and-see policy is indeed often chosen in this setting. However, although one may argue that cancer control may not be compromised using an early salvage treatment, this approach still needs to be properly tested. For all these reasons, there is an urgent need for a similar study in the contemporary setting, with patients properly selected prior to randomization according to the extent of nodal disease invasion, cancer aggressiveness, and early postoperative PSA values. Recently, the role of adjuvant radiotherapy in combination with ADT has also been explored in pathologically node-positive disease, albeit in a retrospective fashion.[11,12] Supporting the notion of high heterogeneity of this population, adjuvant radiotherapy was found to be beneficial in some of these patients,[12] namely those in whom prostate cancer was locally advanced but not yet systemic. However, prospective randomized trials are still awaited to confirm these findings. In addition, provided that adjuvant radiotherapy will eventually be shown to be beneficial in properly conducted clinical trials, studies will also be needed to determine whether early salvage radiotherapy can be as effective as adjuvant radiotherapy. This would further decrease possible overtreatment of patients. Furthermore, we do not yet have enough evidence to determine the optimal radiotherapy regimen to use after radical prostatectomy, or to determine whether concomitant use of ADT is always needed in this setting. Finally, it is likely that the optimal postoperative treatment will be based not only on clinical parameters but also on the biological profile of the individual patient. Therefore, novel biomarkers and genomic tests need to be tested in men with pathologically node-positive disease, with the aim of identifying the right treatment for the right patient.

Heterogeneity of node-positsive disease: clinical implications for future trials

As discussed, patients with pathologically node-positive prostate cancer have heterogeneous outcomes. Up to 30% of men with low volume of nodal invasion may even be free from biochemical recurrence at long-term follow-up.[14] On the other hand, the vast majority of men with aggressive disease and high volume of nodal invasion will invariably experience disease recurrence if left untreated after radical prostatectomy.[13,14] Therefore, if a trial testing the role of any postoperative treatment is planned, it should be focused on the appropriate subgroup of node-positive men. For example, if adjuvant ADT is tested in men with more favorable cancer features, any positive effect associated with this treatment would likely be diluted by the favorable outcomes obtained by surgery alone. Similarly, it is possible that combining surgery with adjuvant radiotherapy is not beneficial for systemic disease. Thus, the success of any trial testing multimodality treatments in node-positive disease depends upon appropriate patient selection.

Clinical node-positive disease

The optimal treatment of clinically node-positive prostate cancer is currently unknown. Given the low sensitivity of conventional imaging for detection of nodal metastases, even in contemporary patients,[15] the vast majority of node-positive patients are indeed found to have nodal invasion at extended pelvic lymph node dissection. It is not yet clear whether men with grossly enlarged lymph nodes at pretreatment imaging may benefit from accurate pelvic debulking. Moreover, it is currently unknown which multimodal approach (if any) is more efficacious. Again, this will need to be tested in appropriate studies.

In conclusion, there is an urgent need for a high level of evidence in the setting of node-positive prostate cancer. As a result of several wrong assumptions, these patients have previously been excluded from virtually all major clinical trials of combination treatments. However, given the heterogeneity of this patient group, all future studies will need to be based on accurate patient selection. We hope that in the future, a “one size fits all” approach will be avoided in the management of men with pathologically node-positive disease.

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:

1. Baker BR, Mohiuddin JJ, Chen RC. The role of radiotherapy in node-positive prostate cancer. Oncology (Williston Park). 2015;29:108-16.

2. Widmark A, Klepp O, Solberg A, et al. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet. 2009;373:301-8.

3. Warde P, Mason M, Ding K, et al. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet. 2011;378:2104-11.

4. Bolla M, van Poppel H, Tombal B, et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet. 2012;380:2018-27.

5. Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J Urol. 2009;181:956-62.

6. Wiegel T, Bottke D, Steiner U, et al. Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative undetectable prostate-specific antigen: ARO 96-02/AUO AP 09/95. J Clin Oncol. 2009;27:2924-30.

7. Zagars GK, Pollack A, von Eschenbach AC. Addition of radiation therapy to androgen ablation improves outcome for subclinically node-positive prostate cancer. Urology. 2001;58:233-9.

8. Tward JD, Kokeny KE, Shrieve DC. Radiation therapy for clinically node-positive prostate adenocarcinoma is correlated with improved overall and prostate cancer-specific survival. Pract Radiat Oncol. 2013;3:234-40.

9. Engel J, Bastian PJ, Baur H, et al. Survival benefit of radical prostatectomy in lymph node-positive patients with prostate cancer. Eur Urol. 2010;57:754-61.

10. Messing EM, Manola J, Yao J, et al. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol. 2006;7:472-9.

11. Briganti A, Karnes RJ, Da Pozzo LF, et al. Combination of adjuvant hormonal and radiation therapy significantly prolongs survival of patients with pT2-4 pN+ prostate cancer: results of a matched analysis. Eur Urol. 2011;59:832-40.

12. Abdollah F, Karnes RJ, Suardi N, et al. Impact of adjuvant radiotherapy on survival of patients with node-positive prostate cancer. J Clin Oncol. 2014;32:3939-47.

13. Seiler R, Studer UE, Tschan K, et al. Removal of limited nodal disease in patients undergoing radical prostatectomy: long-term results confirm a chance for cure. J Urol. 2014;191:1280-5.

14. Touijer KA, Mazzola CR, Sjoberg DD, et al. Long-term outcomes of patients with lymph node metastasis treated with radical prostatectomy without adjuvant androgen-deprivation therapy. Eur Urol. 2014;65:20-5.

15. Briganti A, Abdollah F, Nini A, et al. Performance characteristics of computed tomography in detecting lymph node metastases in contemporary patients with prostate cancer treated with extended pelvic lymph node dissection. Eur Urol. 2012;61:1132-8.