Prostate cancer (PCa) is one of the most common malignant tumors in men, ranking as the second leading cause of cancer death in men in the United States in 2006, and is rapidly increasing in China. The main modalities of radiation therapy are conventional external irradiation, neutron irradiation, and short or permanent tissue interposition radiotherapy. Currently, the definitive treatment for PCa is radical prostatectomy, external radiation therapy, and permanent radioisotope insertion therapy. According to the available data, there is no statistically significant difference in PSA recurrence-free survival and disease-free survival among patients with similar prognostic factors obtained with the three treatments [1].1 Radical prostatectomy.
1,1 Indications for surgery
According to the TNM staging system of AJ CC and UICC, prostate tumors can be classified as limited early stage, locally advanced stage and advanced stage. The early stage PCa (T1 to T2) is the absolute indication for radical prostatectomy. There is controversy as to whether patients with stage T3 (tumors that have penetrated the envelope, have seminal vesicles or local invasion) should undergo radical PCa. It has been suggested that the incidence of positive margins, lymph node metastasis or distant metastasis after surgery is higher than that of early local PCa, and therefore, many patients with stage T3 receive endocrine therapy or radiation + endocrine therapy. However, Ward et al [2] looked at 842 patients with stage T3 who underwent radical PCa, with survival rates of 90 and 79% at 10 and 15 years, respectively, and it should be noted that one half of this group received adjuvant endocrine therapy. The median time to progression to biochemical recurrence was 416 years. The mortality rate for PCa at 5, 10, and 15 years was 6%, 15%, and 24%, respectively. step hen et al [4] reported a long-term tumor control rate of approximately 50% and a cancer-related survival rate of 84% after radical PCa surgery alone. In the long-term follow-up, short-term neoadjuvant therapy was found to reduce the rate of positive margins but did not significantly improve the long-term prognosis of patients, and neoadjuvant therapy has the adverse effects of hormonal therapy and increases the cost of patients. In patients who underwent bilateral surgery with preservation of the vascular nerve bundle, complete resection of the tumor was achieved by removing the Diaphragm including the fat of the anterior rectal wall. > The tumor was found to be invasive of the vascular nerve bundle. Although there is no reliable diagnostic tool for the extent of prostate invasion, preoperative MRI is particularly important for the surgeon to decide on a treatment plan. Adjuvant endocrine therapy and radiotherapy after radical surgery for stage T3 patients may be indicated in high-risk patients and in those with positive margins or lymphatic invasion of the prostate envelope or seminal vesicles after surgery. Most scholars recommend early postoperative endocrine therapy, but early endocrine therapy has not been shown to improve survival. Postoperative radiotherapy may improve progression-free survival and reduce local recurrence, but there is no evidence to suggest that radiotherapy improves long-term survival. It has been reported that postoperative radiotherapy for stage C lesions with positive margins, tumor penetration of the envelope, and seminal vesicle invasion resulted in a 5-year local control rate of 80% and a 10-year rate of 72%. The local control rate is 80% at 5 years and 72% at 10 years. Radical prostatectomy with recurrence can also be well controlled with radiotherapy. Although there is no strict age limit for radical PCa surgery, the incidence of complications increases significantly with age, especially in patients >70 years of age, who are at increased risk of death.
1,2 Lymph node dissection
Pelvic lymph node dissection is the most accurate means of determining lymph node metastasis and staging, as well as providing a basis for postoperative adjuvant therapy and prognosis. Patients with high-risk limited PCa and minimal focal metastases have the greatest benefit from pelvic lymph node dissection, whereas patients with extensive lymph node metastases may benefit from androgen stripping therapy [6 ]. It is currently believed that a positive lymph node means systemic metastasis, suggesting a poor prognosis and the need for systemic therapy, but unfortunately there is no specific test to determine lymph node metastasis. Currently, most scholars believe that the incidence of lymph node metastasis in patients with PSA < 10 ng/ mL and Gleason score < 7 is low, and lymph node dissection is not recommended, but this may underestimate the incidence of lymph node metastasis. For patients with PSA < 10 ng/ mL and Gleason score > 7, the positive rate of lymph node metastasis is 25%, and lymph node dissection is recommended. Lymph node imaging shows that prostate lymphatic drainage is not limited to the foramen ovale and external iliac vessels, but also includes the internal iliac and presacral lymph nodes. In extensive lymph node dissection (LND), there are usually more than 20 lymph nodes, while in limited LND, there are only 8-10 lymph nodes on average. However, compared with limited lymph node dissection, extensive lymph node dissection has an increased incidence of complications, such as lymphocysts, lymphoedema, and deep vein thrombosis.
1.3 New surgical approaches
Open PCa radical surgery, laparoscopic PCa radical surgery, and robotic-assisted PCa radical surgery do not differ significantly in terms of intraoperative and postoperative complication rates; laparoscopic PCa radical surgery and robotic-assisted PCa radical surgery also have advantages in terms of blood loss and length of stay [7 ]. Robotic-assisted PCa radical surgery has the advantages of being minimally invasive and having a short learning curve, and a center in the United Kingdom reported that the average time for robotic-assisted PCa radical surgery was 355 min for the first 15 cases and only 256 min for the second 15 cases [8]. The learning curves for laparoscopic PCa and robotic-assisted PCa radical surgery are slightly different, and there is a trend to gradually replace laparoscopic PCa radical surgery in North America.
1,4 Neoadjuvant endocrine therapy and radical PCa surgery Accurate preoperative clinical staging of PCa patients is difficult, and the literature reports that preoperative staging is underestimated in 42% to 50% of patients, and the rate of positive surgical margins and extraperitoneal invasion after radical prostatectomy is as high as 25%. Therefore, some scholars have proposed the concept of neoadjuvant therapy to reduce tumor size, decrease tumor stage and suppress potential metastases, in order to achieve complete surgical resection and improve the cure rate. Neoadjuvant endocrine therapy cannot improve the overall survival rate of PCa radical surgery, cannot prolong the disease-free survival, and may delay the optimal time of surgical treatment. Its long-term efficacy needs to be further studied.
2.Extracorporeal radiation therapy
The advantages of radiotherapy are less invasive compared with radical surgery, and the incidence of postoperative urinary incontinence and erectile dysfunction is low. For early tumors, the treatment effect is similar to radical surgery, so that 80% to 90% of T1 and T2 stage PCa can be controlled. However, because the prostate remains in the body, it increases the likelihood of tumor recurrence. Despite protection of the surrounding normal tissues, patients may also experience intestinal, urethral and genital damage. The rate of local control after radiation therapy depends on the clinical stage of the tumor, the degree of differentiation, the size of the tumor, the radiation dose, and the size of the irradiated field. EBRT alone has a 5-year recurrence-free survival rate of 30%-50%, which increases to 50%-85% when combined with anti-androgen therapy. EBRT has no anatomical limitations compared to PCa radical surgery and internal radiation, and has a larger treatment range. For low-risk patients, radiation treatment with >70 Gy reduces the risk of PSA recurrence but has no significant effect on survival; for high-risk patients, external radiation therapy plus hormonal therapy (>3 years) can prolong survival. The RTOG 85231 trial reported a median follow-up of 716 years for 977 patients with clinical stage T3 or lymph node metastases, and only < 25% of patients died of PCa after combined therapy (radiotherapy + chemotherapy) [9 ].
Short-term endocrine therapy can improve the radiological outcome. Endocrine therapy has a clear efficacy in most patients with intermediate to advanced PCa, and the combination of endocrine therapy with radiation therapy can improve the control rate of intermediate to advanced PCa. RTOG conducted a prospective randomized clinical study in stage IIB and C PCa patients to determine the efficacy of endocrine therapy and ex vivo radiotherapy.
The results showed that the combined treatment group showed significant advantages over the radiotherapy alone in terms of 4-year local failure rate, distant metastasis rate, disease-free survival rate and biochemical disease-free rate. New radiation techniques such as 3D conformal radiotherapy and intensity-modulated techniques are gradually being applied in clinical practice. Retrospective studies have shown that increasing the dose of PCa radiation not only improves the biochemical recurrence-free survival rate, but also increases the overall survival rate. The three-dimensional conformal radiotherapy (3DCRT) technique developed in the 1990s can increase the target dose to 78 Gy or even >80 Gy, which can reduce the positive rate of PCa biopsy after radiotherapy and improve the local control rate.
At the same time, the 3DCRT technique significantly reduces the volume of surrounding normal tissues and organs, and does not increase rectal and bladder adverse effects while increasing the radiation dose. Protons and heavy ions have a better dose distribution than conventional photons (X-rays) and better conformability of the target area, which can better protect the rectum and reduce rectal injury. In a clinical phase III randomized controlled trial, 5014 Gy of photon conformal irradiation and 6715 Gy of proton dosing were used in the test group (103 cases) and conventional radiotherapy techniques in the control group (99 cases). The results showed that the 5 and 8-year local control rates were 94% and 84% in the test group and 64% and 19% in the control group, respectively. 32% of rectal bleeding was observed in the test group and 12% in the control group at 8 years after treatment, but the bleeding in both groups was mild and there were no serious sequelae. The treatment effect was better than photon stereotactic radiotherapy, even better than surgery, and the post-radiation complications were not serious. Loma Linda’s experience with proton radiotherapy for PCa is as follows: for high-risk metastases (Partinogram, ≥ 15% DM), 45 Gy of photons (primary foci + lymphatic drainage areas at stations 1 and 2), 30 CGE/15f x dosed primary foci; for low-risk metastases, 74 CGE/37f x 714wks (prostate, seminal vesicles) 5 mm border of protons. The technique of carbon ion radiotherapy has been applied to patients with PCa (T1b to T3) with excellent efficacy and no significant toxic side effects, but further studies are needed to confirm [11].
3.Interstitial radiotherapy
In 1981, Holm et al. used transrectal ultrasound-guided trans-perineal prostate puncture to implant radionuclide 125I particles into the prostate gland for the treatment of PCa. Since brachytherapy can achieve a high dose of localized tumor irradiation with less impact on the surrounding normal tissues, it obviously improves the clinical effect and reduces the incidence of complications, and has become one of the important tools for the treatment of limited PCa in foreign countries. The indications are similar to those of radical surgery, mainly for early-stage limited PCa; for mid- to late-stage PCa, the combination of external radiotherapy and endocrine therapy is required. After endocrine therapy, 82% of the patients’ prostate volume was reduced to less than 50 cm3, and the average reduction in prostate volume was 33% after an average of 319 months, in which the volume of the prostate before hormone blockade and the duration of treatment were two important factors in the degree of volume reduction.
The efficacy of radiotherapy for PCa needs to be further improved. In the literature, it has been reported that secondary tumors have appeared in other areas after PCa radiotherapy, which indicates that the current radiotherapy measures need to be studied more thoroughly. With the rapid development of molecular biology technology and a deeper understanding of the mechanism of radiation-induced cell damage, radiation therapy combined with molecular biology technology will certainly lead to new effective therapeutic techniques, such as gene replacement therapy and immunotherapy.
The immediate complications of PCa radiation therapy are mainly rectal and urinary side effects, and the long-term complications are rectal and bladder side effects, including rectal bleeding, prostatitis, rectal or anal stricture, radiation cystitis, urethral stricture and bladder contracture. Urethral stricture occurs mainly in patients after transurethral resection of the prostate. Some patients experience sexual dysfunction after radiation therapy, especially with near-implantation radiation therapy, but sildenafil is usually effective. At conventional external radiation doses of 70 Gy, 60% of patients will experience recent rectal and urinary grade ≥2 side effects. Conformal radiotherapy can better protect normal tissues and reduce the side effects in the rectum or bladder.
4.Comparison of the three treatment methods
At present, there are no clinical studies to compare the three treatment options for definitive PCa treatment, one of the reasons is the continuous progress of radiotherapy and surgical treatment methods. Proponents of radical PCa surgery believe that surgery can improve the patient’s local symptoms, including bleeding, pain and urinary tract obstruction, and improve the patient’s quality of life. Therefore, adverse effects and patient intention are the main factors in deciding the protocol. A retrospective study reported that 60,000 patients with limited PCa treated with RP, EBRT, or observation therapy showed better 10-year disease-related survival for advanced PCa. Since most locally advanced PCa are high-grade tumors (> 60%), this study also suggests that surgical treatment may be a definitive treatment option for high-risk groups. Radiotherapy (> 70 Gy) or radiotherapy + endocrine therapy (if tolerated) is recommended. In case of perineural invasion, radical PCa surgery
However, if only a small amount of tumor protrudes outside the prostate envelope, radical PCa surgery is recommended.
5. Outlook
Looking back at the history of PCa treatment in the last half century, the following phenomena can be observed: due to the application of PSA, definitive treatment of early PCa has become the mainstay of treatment; due to new technologies such as robotic surgery and proton radiotherapy, the surgical treatment of PCa has entered a new phase. However, there is a lack of “head-to-head” comparison of several definitive treatments, and there are still controversies regarding some treatments such as T3 stage PCa. As PCa research progresses, these questions will be better answered.