Locally advanced prostate cancer - Treatment

Locally advanced prostate cancer is cancer (T3) that has spread beyond the prostate capsule with invasion of the paresis, bladder neck, seminal vesicles, but without lymph node involvement or distant metastasis.

Numerous studies show that the treatment results for patients with locally advanced prostate cancer are inferior to those in the group of patients with localized risk. However, the imperfection of prostate cancer staging methods at this stage of diagnosis rarely leads to an overestimation of the clinical stage of the disease, and more often to an underestimation.

When talking about patients with stage T3 prostate cancer, it is important to remember that they represent a fairly diverse group, with different pathohistological criteria that seriously affect the choice of treatment method and life expectancy. To date, the optimal method for this category of patients has not yet been determined.

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Locally advanced prostate cancer cancer: operations

According to the guidelines of the European Association of Urologists, prostate resection in patients with locally advanced prostate cancer is considered possible (PSA less than 20 ng/ml; stage T3a: G equal to 8 or less). At the same time, the work of a number of specialists has shown that surgery (as myotherapy) is most effective in the group of patients with stage T3a with a PSA level of less than 10 ng/ml. Thus, 60% of patients did not experience relapses of the disease within 5 years, and the overall survival rate within 6-8 months of observation was 97.6%.

Performing prostate resection in patients with PSA less than 20 ng/ml and G equal to 8 or less may be beneficial, but the likelihood of using adjuvant treatment (hormonal, radiation) is extremely high.

Surgical treatment of patients with stage T3a includes prostate removal with extended lymph node dissection, thorough apical dissection, complete removal of the seminal vesicles, resection of the vascular-nerve bundles and the neck of the bladder.

The incidence of postoperative complications in prostate resection in patients with T3 prostate cancer, such as impotence and urinary incontinence, is higher than in surgical treatment of localized forms.

For patients with well, moderately, and poorly differentiated tumors (pT3), cancer-specific survival for 10 years is 73, 67, and 29%, respectively. The attitude towards the use of neoadjuvant treatment is ambiguous. Despite the fact that its use reduces the frequency of positive surgical margins by 50%, the survival times of patients in this group do not significantly differ from those who underwent surgical treatment alone. Studies are underway on the effectiveness of a combination of chemotherapy drugs as neoadjuvant treatment, as well as on increasing its duration to 9-12 months.

The use of adjuvant (hormonal, chemo- or radiation therapy) therapy, especially in the high-risk group of patients (G equals 8 or less), stage T3a can significantly improve treatment outcomes. According to recent studies, 56-78% of patients with prostate cancer at stage T3a require adjuvant treatment after prostate resection; with 5- and 10-year cancer-specific survival rates of 95-98 and 90-91%, respectively.

Indications for adjuvant treatment:

• extended surgical margin;
• identified metastases in the lymph nodes;
• high risk group (G equals 8 and less);
• tumor invasion of the seminal vesicles.

Currently, there are studies in which prostate resection in combination with adjuvant therapy is considered as an alternative to non-invasive multimodal treatment (a combination of radiation and hormonal therapy) in patients at stage T3a.

Thus, prostate resection is an effective method of treating patients with locally advanced prostate cancer. The best candidates for prostate resection are patients with an elevated stage of the local process, non-extended extracapsular extension, highly or moderately differentiated tumors. PSA less than 10 ng/ml.

In young patients, a poorly differentiated tumor or invasion into the seminal vesicles may not be a contraindication to prostate resection.

Locally advanced prostate cancer: other treatments

Radiologists prefer radiation therapy as the main method of treating patients with locally advanced prostate cancer. At the same time, many specialists offer a multimodal approach, i.e. a combination of radiation and hormonal treatment.

Thus, a balanced approach is needed to treat patients with stage T3a prostate cancer. The doctor must compare such criteria as the patient's age, examination data, indications for choosing a particular treatment method, possible complications, and only then, taking into account the patient's wishes and informed consent, begin treatment.

Radiation therapy for prostate cancer

External beam radiation therapy for prostate cancer involves the use of γ-rays (usually photons) directed at the prostate and surrounding tissues through multiple beam fields. Three-dimensional conformal radiation therapy, in which the beam fields are focused on the prostate, has been developed to minimize radiation damage to the bladder and rectum. The most effective form of three-dimensional conformal radiation therapy is intensity modulation. Intensity modulated radiation therapy provides localization of radiation in geometrically complex fields. Intensity modulation of radiation is possible on a linear accelerator equipped with a modern multi-leaf collimator and a special program: the movement of the collimator flaps evenly distributes the dose in the beam field, creating concave isodose curves. Heavy particle radiation therapy, carried out with high-energy protons or neutrons, is also used to treat prostate cancer.

Indications for radiotherapy: localized and locally advanced prostate cancer. Palliative therapy is used for bone metastases, spinal cord compression, and brain metastases. Radionuclide therapy Str is used for palliative treatment of hormone-refractory prostate cancer.

Contraindications to radiation therapy: general severe condition of the patient, cancer cachexia, severe cystitis and pyelonephritis, chronic urinary retention, chronic renal failure. Relative contraindications to radiation therapy: previous TUR of the prostate, severe obstructive symptoms, inflammatory bowel disease.

There are significant differences in the approaches to radiation therapy among the authors, concerning the technique and methods of irradiation, the volume of radiation exposure and the total focal doses.

The main serious side effects of radiation therapy are associated with damage to the microcirculation of the bladder, rectum and its sphincter, and urethra. About one third of patients have symptoms of acute proctitis and cystitis during the course of radiation therapy. 5-10% have persistent symptoms (irritable bowel syndrome, periodic rectal bleeding, symptoms of bladder irritation, and periodic macrohematuria). The incidence of late complications after radiation therapy, according to the European Organization for Research and Treatment of Cancer: cystitis - 5.3%, hematuria - 4.7%, urethral strictures - 7.1%, urinary incontinence - 5.3%, proctitis - 8.2%, chronic diarrhea - 3.7%, small bowel obstruction - 0.5%, lower limb lymphostasis - 1.5%. Impotence occurs in about half of the patients, which usually develops approximately 1 year after completion of treatment. This occurs due to damage to the blood supply to the cavernous nerves and cavernous bodies of the penis.

Localized Prostate Cancer: Radiation Therapy

For patients with Tl-2aN0M0 tumors, Gleason score of 6 or less, and PSA less than 10 ng/mL (low-risk group), radiation therapy at a dose of 72 Gy is recommended. Relapse-free survival has been shown to be higher with a dose of 72 Gy or more compared with a dose of less than 72 Gy.

According to a number of studies, with a T2b tumor or a PSA level of 10-20 ng/ml or a Gleason sum of 7 (medium risk group), increasing the dose to 76-81 Gy significantly improves 5-year relapse-free survival without causing severe complications. A dose of 78 Gy is used for everyday practice.

For T2c tumors or PSA >20 ng/mL or Gleason score >7 (high-risk group), escalation of radiation dose increases recurrence-free survival but does not prevent recurrence outside the pelvis. One randomized trial from France showed an advantage of 80 Gy compared with 70 Gy.

For conformal radiation therapy with dose escalation, impressive results have been obtained, indicating an increase in 5-year relapse-free survival from 43 to 62% with an increase in the radiation dose from 70 to 78 Gy for patients with intermediate- and high-risk prostate cancer. With a primary tumor invasion depth of T1 or T2, a Gleason score of 7 or less, and a PSA level of 10 ng/mL or less, the relapse-free survival is 75%.

There are no completed randomized trials demonstrating that adding antiandrogen therapy to radiation therapy is beneficial in high-risk patients with localized prostate cancer. However, based on studies in locally advanced prostate cancer, the use of hormonal therapy with radiation therapy is supported in high-risk patients with localized prostate cancer.

Antiandrogen therapy for 6 months (2 months before, 2 months during, and 2 months after radiotherapy) improves treatment outcomes in patients with intermediate-risk prostate cancer. Radiation therapy for locally advanced prostate cancer Antiandrogen therapy for 3 years, administered together with radiotherapy, improves survival in patients with locally advanced prostate cancer. A combination of antiandrogen therapy before, during, and after radiotherapy for 28 months compared with 4 months of hormone therapy before and during irradiation has better oncological treatment efficacy rates, with the exception of overall survival. The overall survival benefit of longer-term hormone therapy in combination with radiotherapy has been demonstrated for patients with locally advanced prostate cancer with a Gleason score of 8-10.

Evaluating the results of radiation therapy is not an easy task because cancer cells do not die immediately after irradiation. Their DNA is lethally damaged, and the cells do not die until they attempt to divide again. Thus, the PSA level gradually decreases over 2-3 years after completion of radiation therapy. Accordingly, the PSA level is examined every 6 months until it reaches its lowest value (nadir). In patients undergoing radiation therapy, the prostate is not completely destroyed, and the remaining epithelium continues to produce PSA. In addition, inflammation of the prostate can cause a transient increase in PSA, called a PSA "surge".

The biochemical cutoff point used to define treatment success after external beam radiotherapy is controversial. Optimally, a PSA level of less than 0.5 ng/mL is considered to be predictive of a favorable outcome after irradiation. The American Society of Therapeutic Radiology and Oncology defines biochemical relapse after radiation therapy as a PSA level of more than 2 ng/mL, provided that this PSA level is greater than the minimum (nadir) level. The PSA level after radiation therapy can predict the nature of relapse. In patients with local relapse, the PSA doubling time is 13 months; in patients with systemic relapse, it is 3 months. Radiation Therapy After Radical Prostatectomy The need for adjuvant radiation therapy or watchful waiting with salvage radiation therapy in the case of relapse after RP is currently under debate. There are no randomized trials comparing adjuvant radiation with early salvage radiation therapy after surgery. There is only evidence to support a survival advantage with adjuvant radiotherapy compared with observation in patients with positive surgical margins, extracalsular extension, and seminal vesicle invasion. Salvage external beam radiotherapy is used for relapse until the PSA level reaches 1-1.5 ng/mL.

In high-risk patients with localized prostate cancer, brachytherapy may be combined with external beam radiotherapy. Brachytherapy is then performed first.

Recently, external beam radiation therapy with heavy particles (high-energy photons and neutrons) has been positioned as a more effective method of conformal irradiation, but there is no convincing evidence of an advantage over standard photon irradiation. Moreover, a higher incidence of urethral strictures has been noted after the use of heavy particles.

Modern research is exploring the possibility of using higher doses of radiation in more metabolically active foci, as determined by magnetic resonance spectroscopy.

It should be noted that the main point of application of radiation therapy for prostate cancer is a localized tumor. The advent of three-dimensional conformal radiation therapy and modulation of radiation intensity, as one of its perfect forms, has made it possible to increase the radiation dose, reduce complications of traditional radiation therapy, and obtain oncological results that compete with radical surgical treatment.