Stage T3a prostate cancer is classified as locally progressive prostate cancer, which pathologically presents as extra envelope invasion (ECE) of the prostate. However, not all high-risk prostate cancers are locally progressive, and the definition of high-risk needs to be combined with the Gleason score and PSA level. The ideal treatment plan for locally progressive prostate cancer has long been controversial. In the past, patients diagnosed with locally progressive prostate cancer were mostly treated with combination therapy (endocrine therapy + radiotherapy).
In recent years, as clinical treatment modalities for prostate cancer have been studied, there is increasing evidence that radical prostatectomy (RP) is beneficial for the treatment of locally progressive prostate cancer, and that radical prostatectomy is an important part of multimodal treatment options for locally progressive prostate cancer. Radical prostate cancer surgery is used in cT3a patients with life expectancy greater than 10 years.
I. Radical prostate cancer surgery can provide accurate T and N staging, thus providing a basis for further treatment and prognosis.
At present, the clinical staging of prostate cancer is mainly based on the results of anal finger examination (DRE), and TURS is not superior to DRE in determining whether there is extraperitoneal invasion and seminal vesicle invasion. recent years, prostate MR has become an important method to determine whether there is extraperitoneal invasion of the prostate before surgery. The sensitivity and specificity of endorectal MR are 70% and 90%, respectively, for extraprostatic lesions of 1 mm or more. However, for smaller lesions, MR is still not ideal for determining prostate cancer staging.
There are no reliable imaging examinations that can determine the presence or absence of extraperitoneal invasion. Therefore, there is some error between the preoperative clinical staging and the postoperative pathological staging of patients.
This error is manifested by the tendency to preoperatively overstage tumors with pT2 and understage tumors with pT3. Ouden et al. found that 43-75% of cT2 stage tumors were postoperatively confirmed as pT3, whereas 17-30% of cT3 stage tumors were postoperatively pathologically confirmed as pT2 [7]. In contrast, in a large European study (EORTC 30001), 43.8% of patients with a preoperative diagnosis of stage cT3 had postoperative pathology confirmed as stage pT2. This has caused a proportion of patients with limited prostate cancer to forgo radical surgical treatment due to an overstaging diagnosis of stage cT3 based on traditional treatment concepts, thus losing the opportunity to obtain a cure surgically.
The preoperative use of a scale to predict the histopathological type of the tumor has been applied in limited prostate cancer (Partin tables), which provides a reference basis on the selection of different treatment options for prostate cancer patients. van Poppel et al. also proposed a scale for the analysis of stage T3a by analyzing the clinical data of 200 cases of radical cT3a prostate cancer, and the postoperative histopathological type and Gleason and PSA levels were linked to compare the preoperative multi-degree staging and multi-low staging ratios, and they concluded that a predictive scale could help in the assessment of locally progressive prostate cancer and the selection of radical surgery.
Pelvic lymph node dissection during radical prostate cancer surgery can accurately determine whether a patient has lymph node metastasis, and postoperative antiandrogenic therapy can be used promptly for patients with positive lymph nodes, while blood PSA levels can be closely monitored for patients with negative lymph nodes, and the timing of adjuvant or salvage therapy can be decided based on PSA. Therefore, one advantage of radical prostate cancer surgery is that it can provide accurate information about lymph node metastasis, which provides an important basis for the decision of postoperative treatment plan.
Second, radical surgery for stage T3a prostate cancer can achieve oncologic outcomes without an increased complication rate with surgery.
In a Johns Hopkins study, a mean 10.3-year follow-up study of 58 patients with stage T3a prostate cancer who underwent radical surgery found that pathology confirmed the presence of extraperitoneal invasion in 91% of patients, 22% had positive margins, and none of the patients were treated with adjuvant or neoadjuvant therapy. The prostate cancer-specific survival rates at 5, 10, and 15 years after surgery were 98%, 91%, and 84%, respectively. Nearly 75% of patients in this study had no PSA recurrence or only a slow increase in PSA levels. They concluded that radical prostatectomy alone was adequate for the treatment of 75% of appropriately selected patients with T3a prostate cancer.
Saito et al. compared 209 treatment options for locally progressive prostate cancer divided into RP+ADT, RT+ADT, and ADT alone groups and found that overall survival (OS) was better in both the RP+ADT and RT+ADT groups than in the ADT alone group, and tumor-specific survival (CSS) between RP+ADT and RT+ADT and between RP+ADT and ADT alone did not differ significantly.
Akakura et al. compared the effects of radical treatment + adjuvant endocrine therapy and radiotherapy + endocrine therapy in 95 patients with locally progressive prostate cancer, and the follow-up showed that the 5-year progression-free survival (PFS) and tumor-specific survival (CSS) rates were 90.5% and 96.6% in the former and 81.2% and 84.6% in the latter. Patients in the radical group had an advantage over the radiotherapy group in both PFS and CSS. 10-year follow-up showed that the radical group remained superior to the radiotherapy group with biochemical progression-free survival (BPFS): 76.2% vs. 71.1%, clinical progression-free survival (CPFS): 83.5% vs. 66.1%, CSS: 85.7% vs. 77.1%, and OS: 67.9% vs. 60.9% [ 12].
Hsu et al. 164 cases with clinical stage cT3 prostate cancer underwent radical prostatectomy with 5-year, 10-year and 15-year BPFS of 50.4%, 43.0% and 38.3%, CPFS of 79.7%, 68.7% and 63.5%, CSS of 93.4%, 80.3% and 66.3%, and OS of 87.1%, 67.2% and The results showed that radical prostatectomy for locally progressive prostate cancer and radiotherapy plus endocrine therapy regimens were comparable for patients with long-term BPFS [13].
Regarding the safety of radical surgery for locally progressive prostate cancer, Ward et al. found in a large follow-up study of 842 radical surgery for cT3 stage prostate cancer that 79% of patients had satisfactory urinary control at 1 year after surgery and only 6% had significant urinary incontinence, and the rate of surgical complications and urinary control was not significantly different from that of radical surgery for cT2 stage prostate cancer. In another study, in 34 cases of radical T3 prostate cancer, 96% of patients had satisfactory postoperative urinary control and 46% had postoperative erectile dysfunction, and there was no significant difference in urinary control and sexual function when comparing cT2 and cT3 radical surgery.
Third, radical surgery for lymph node positive prostate cancer still helps patients’ prognosis.
An important reason for avoiding radical prostate cancer treatment is the possible presence of pelvic lymph node metastases in patients with prostate cancer diagnosed by physicians. In the 1980s, radical prostatectomy was introduced for the treatment of limited prostate cancer, whereas for lymph node positive prostate cancer, it was considered that the tumor had developed into a systemic disease and that local removal of the prostate would not help the patient’s prognosis. Based on this philosophy, for patients with positive intraoperative lymph node dissection, many hospitals have adopted the option of discontinuing radical surgery and switching to combination therapy.
In recent years, as treatment approaches have changed, more physicians have found that radical prostate cancer with pelvic lymph node dissection is more helpful for tumor-specific survival in prostate cancer patients with lymph node metastases, and have recommended extended pelvic lymph node dissection.
Engel et al. compared the prognostic analysis of patients with positive lymph nodes with or without radical prostate cancer and found that overall survival (OS) and tumor-related survival (RS) were higher in patients with positive intraoperative lymph node findings who went on to radical prostate cancer than in patients who had positive intraoperative lymph node biopsies and discontinued radical surgery. The study included 35629 patients with a total of 1413 positive lymph nodes. 5-year and 10-year OS was 84% and 64% in the RP group, compared with 60% and 28% in the no RP group. 5-year and 10-year RS was 95% and 86% in the RP group, compared with 70% and 40% in the no RP group, respectively.
A possible mechanism for the improved prognosis of patients with lymph node-positive prostate cancer by resection of the primary tumor is that resection of the primary site reduces the risk of tumor dissemination and metastasis, and the primary tumor growth process produces multiple growth factors, and tumor arrival at distant sites is accompanied by early changes in the local microenvironment, suggesting the type of metastatic dissemination. A better understanding of this mechanism could help the emergence of new therapeutic tools, such as blocking the lymphatic angiogenesis axis.
IV. Treatment of locally progressive prostate cancer after radical prostatectomy
Adjuvant therapy is recommended for locally progressive prostate cancer after radical surgery.
The results of an EORTC study of 1005 pT3N0 prostate cancer patients comparing postoperative adjuvant radiotherapy at 60 Gy to salvage radiotherapy at 70 Gy showed that adjuvant radiotherapy was better tolerated, with no significant difference in complications such as postoperative urinary incontinence and anastomotic stricture, while adjuvant radiotherapy improved the 5-year progression-free survival rate. The results of EORCT were confirmed in the ARO study in 385 patients with pT3 prostate cancer at 54 months of follow-up, and a long-term follow-up study in 425 patients with pT3 prostate cancer at 11.5 years in SWOG showed that adjuvant radiotherapy improved not only metastasis-free survival but also overall survival.