Figure 1. Cancer-specific survival. Reprinted with permission from Gee et al, Int J Clin Oncol. 2021;6(3):125-129.4	Figure 2. Overall survival. Reprinted with permission from Gee et al, Int J Clin Oncol. 2021;6(3):125-129.4
Figure 3. Biochemical-free survival. Reprinted with permission from Gee et al, Int J Clin Oncol. 2021;6(3):125-129.4

The management of high-risk prostate cancer remains challenging. Up to 50% of patients experienced recurrent disease following radical surgery, underscoring a great need for better therapies in treating this disease. It is for this reason that we embarked on a new method of treatment for high-risk prostate cancer.

Multimodal therapy (MMT), a concept and term coined by the senior author (J.A.L.) in originating a novel, prospective, nonrandomized clinical trial of neoadjuvant androgen deprivation therapy, followed by radical surgery and postoperative radiation, was first used in 1990 to treat our initial patient with high-risk prostate cancer. This introduced MMT as a new treatment paradigm for high-risk prostate cancer management. High-risk prostate cancer has been associated with prostate cancer related death in 80%-90% of patients.^1-3 As a result of renewed interest in neoadjuvant therapy prior to radical surgery with short-term follow-up (3-4 years), we felt obligated to report our long-term experience with MMT (20 years).

From 1990-2012, 82 patients with clinically organ-confined prostate cancer and 10 years median follow-up underwent MMT consisting of neoadjuvant hormonal deprivation followed by radical retropubic prostatectomy and postoperative radiation. High-risk prostate cancer was defined preoperatively as Gleason Score 8-10 or PSA > 20. Patients with negative surgical margins were observed initially and treated with salvage radiation therapy in the instance of recurrence. The MMT protocol was well tolerated in all 82 patients with no treatment-related discontinuation of therapy. Final surgical pathology revealed stage pT3-T4 in 58/82 (71%) and nodal involvement in 7/82 (9%). Distant metastatic disease was identified in 10/82 patients (12%). For patients undergoing MMT at 10, 15, and 20 years, cancer-specific survival was 78/82 (95%), 77/82 (94%), and 77/82 (94%; Figure 1), overall survival was 68/82 (83%), 66/82 (80%), and 60/82 (73%; Figure 2), and biochemical recurrence was 61/82 (74%), 51/82 (62%), and 35/82 (43%; Figure 3).

These findings establish the MMT protocol as an effective treatment strategy for high-risk prostate cancer with excellent long-term cancer-specific survival. Recurrence occurring primarily as a rising PSA as opposed to distant metastatic disease suggests limited morbidity, as well, among patients treated with this protocol.

Cure remains the goal in cancer treatment. However, with high-risk prostate cancer, the risk of biochemical recurrence remains significant, even with the present multimodal treatment strategy. Nevertheless, cancer-specific survival and overall survival remain high with this strategy, and across studies appear to be higher at given intervals of follow-up than conventional treatment with androgen deprivation therapy and radiation therapy alone.

A secondary goal of our multimodal approach is to achieve lower local recurrence rates and as such fewer disease-related complications. Indeed, it appears that the incidence of local recurrence or symptomatic sequelae of cancer recurrence remains relatively low in our series. And now that we can utilize MRI for more accurate diagnosis and staging, we might expect our outcomes to be even better. For instance, we are now able to diagnose smaller volume cancers with MRI fusion biopsy which are more amenable to surgical removal. Another important difference with contemporary management is that prostate parametric MRI and PSMA PET-CT staging preoperatively enables more accurate staging of the local extent of disease, thereby affording better patient selection for surgical removal of the prostate, and better determination of duration of therapy and surgical timing following neoadjuvant treatment to optimize surgical outcomes.

For these reasons, with advancing therapies and more sophisticated tools in diagnosing and stratifying prostate cancers translating to earlier detection and longer lead time lending to longer overall survival with prostate cancer, it appears that the principles of treatment we have established with MMT will lead to even more successful future treatment strategies for high-risk prostate cancer.