Evidence-based, evidence-based-the current status of diagnosis and treatment of bone metastases from prostate cancer

According to the editors, bone metastasis of prostate cancer is very common in clinical practice, with an incidence rate of >80%, and there is usually no clinical symptoms in the early stage, and it is often in the advanced stage when the diagnosis is made
.

The prognosis of prostate cancer patients with bone metastasis is poor, the survival period is significantly shortened, and bone-related events (SRE) are prone to occur
.

SRE is the general term for a series of events caused by tumor bone metastasis, including fractures, bone surgery, bone radiotherapy, spinal cord compression, and hypercalcemia, which seriously damage the quality of life of patients
.

Six months, one year, and two years after prostate cancer patients were diagnosed with bone metastasis, the cumulative incidence of SRE was 21.
5%, 30.
4%, and 41.
9%, respectively
.

Therefore, how to prevent and treat bone metastasis and SRE is particularly important
.

This article will outline the pathogenesis and treatment progress of prostate cancer bone metastasis for readers
.

Pathogenesis Under physiological conditions, osteoblasts and osteolytic cells interact to maintain bone remodeling together
.

Once the disseminated tumor cells enter the bone marrow environment, they will interfere with this interaction and cause osteogenic or osteolytic bone destruction
.

The mutual feedback between tumor cells, osteoblasts and osteolytic cells will form a "vicious circle", which is considered to be the main mechanism of bone metastasis
.

The bone metastases of prostate cancer are mainly osteogenic lesions
.

Moreover, the osteogenic lesions are dominated by structural disorder and unstable osteogenic changes, and osteogenic changes and osteolytic changes exist at the same time
.

At present, it is believed that there are two main theories in the pathogenesis of prostate cancer bone metastasis
.

Transfer to the spine through the Baston vertebral venous plexus.
This theory mainly believes that the vertebral venous plexus has no venous valves, and that the vertebral venous plexus communicates with the thoracic venous plexus, abdominal venous plexus, and intercostal venous plexus.
The pressure of this vein is low.
When the pressure increases due to various reasons, the tumor cells in the vein can directly enter the Baston vertebral venous plexus without passing through the liver and lungs, and then transfer to the spine and pelvis
.

Based on Paget's seed and soil theory, this theory believes that seeds are prostate cancer cells and soil is bone
.

Prostate cancer cells and bones are in a microenvironment.
The inherent biological characteristics of the bone microenvironment provide conditions for implantation of prostate cancer cells.
At the same time, prostate cancer cells destroy the bone matrix and release cytokines, which in turn regulate the bone microenvironment.
, Stimulates the growth of prostate cancer cells
.

In recent years, studies have also shown that the primary foci can promote the formation and development of metastatic foci.
The cytokines secreted by the primary foci may directly affect the growth of metastatic clones in distant metastatic foci, but the specific mechanism of action is still being explored and studied
.

The clinical manifestations of prostate cancer bone metastasis are more common in the pelvis, followed by the spine.
Skull metastasis is rare.
Among the peripheral bones, it is most likely to metastasize to the limb bones, of which the femur is the most common
.

Bone metastases can cause pathological fractures and spinal cord compression
.

Patients with extensive bone metastases are prone to symptoms such as fatigue, weight loss, and anemia.
In severe cases, systemic organ failure may occur
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Treatment methods With the continuous development of medical technology, treatment methods for bone metastasis of prostate cancer emerge in endlessly.
At present, it mainly includes systemic treatments based on endocrine therapy and chemotherapy, as well as local treatments for bone metastases, such as surgery, radiotherapy, and bone targeting.
treatment
.

Endocrine therapy Endocrine therapy is the most common treatment for prostate cancer bone metastases, and androgen deprivation therapy (ADT) is the most basic and most common endocrine therapy
.

Endocrine therapy is mainly divided into the following categories: 1.
Surgery or drug-only castration, such as leuprolide, goserelin, triptorelin, and gonadotropin releasing hormone (GnRH) antagonist degarelix and so on
.

2.
New endocrine therapy for apatamide: The SPARTAN study showed that compared with placebo, apatamide can significantly prolong the metastasis-free survival (MFS) of patients with non-metastatic castration-resistant prostate cancer (nmCRPC) (40.
5 vs 16.
2 months) )
.

Enzalutamide: It is a non-steroidal androgen receptor inhibitor, and its binding force to androgen receptor is 5 to 8 times that of bicalutamide
.

The PREVAIL study showed that compared with placebo, enzalutamide can significantly prolong the median overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) who have not been chemotherapy before (36 vs 31) Month, HR=0.
83, 95%CI 0.
75-0.
93, P=0.
0008), which significantly reduced the patient’s risk of death by 17%
.

The PROSPER study showed that in the treatment of high-risk nmCRPC patients with enzalutamide, the median OS was 67.
0 months, which was 10.
7 months longer than the placebo group, and the risk of death was reduced by 27% (HR=0.
73, 95% CI 0.
61-0.
89, P =0.
001)
.

Abiraterone acetate: By inhibiting the key enzyme CYP17 in the androgen synthesis pathway, it inhibits the androgen synthesis of testis, adrenal glands, and prostate cancer cells
.

The COU-AA-301 study showed that for mCRPC patients who progressed after docetaxel chemotherapy, the abiraterone acetate group prolonged the median OS (15.
8 vs 11.
2 months) compared with the placebo group
.

The COU-AA-302 study showed that the abiraterone acetate group significantly prolonged the median OS of mCRPC patients (34.
7 vs 30.
3 months) compared with the placebo group
.

Currently, enzalutamide and abiraterone are recommended for patients with castration-resistant bone metastases with mild symptoms or obvious pain
.

Chemotherapy is also one of the main treatments for bone metastasis of prostate cancer
.

Currently, based on the results of clinical trials of TAX327 and SWOG9916, docetaxel is approved for the standard treatment of mCRPC
.

Targeted therapy olaparib as a PARP inhibitor, for mCRPC patients who have been treated with docetaxel, cabazitaxel, abiraterone acetate, and enzalutamide and have progressed after treatment with BRCA and ATM gene mutations, there are Very good treatment effect
.

A large number of clinical studies on bisphosphonates have shown that bisphosphonates can delay and reduce the occurrence of SRE
.

Bisphosphonates are currently the most widely used anti-bone metastasis treatment
.

Clinically, in most cases, as long as bone metastasis is found, bisphosphonates will be added for anti-bone metastasis treatment
.

Whether it is used for preventive use, when bone metastasis is found, or when there are clinical symptoms, there is still no consensus, and a large number of clinical trials are still needed to verify it
.

In addition, the use of bisphosphonates may also cause adverse reactions such as hypocalcemia, hypophosphatemia, and osteonecrosis of the mandible.
Therefore, it is necessary to monitor changes in the patient's condition during use and give symptomatic treatment at the same time
.

Desulumab is the first approved monoclonal antibody specifically targeting nuclear factor kappa B receptor activator ligand (RANKL), which can inhibit the activation of osteoclasts, reduce bone resorption, and promote bone Reconstruction, reduce the incidence of fractures
.

In reducing and delaying the occurrence of bone-related events in patients with mCRPC bone metastases, desulumab is superior to zoledronic acid
.

Common adverse reactions of desulumab include hypocalcemia and osteonecrosis of the mandible
.

Radionuclide therapy 89SrCl2 and radium-223 are currently more commonly used drugs for radionuclide therapy
.

The results of a randomized, double-blind phase three trial showed that radium-223 can not only delay the appearance of first SRE in patients with castration-resistant prostate cancer and bone metastases, but also improve OS
.

Orthopedic surgery For patients who meet the surgical indications for bone metastases and do not have relative surgical contraindications, orthopedic surgery can be selected to obtain tumor tissue pathological specimens, relieve pain, and improve the quality of life of patients
.

Multidisciplinary treatment (MDT) At present, all hospitals in our country are actively developing their own MDT team.
Under the MDT treatment mode, an individualized comprehensive treatment mode of surgical treatment combined with chemotherapy, radiotherapy, targeted therapy, and interventional therapy has been formed
.

The editor's handbook of prostate cancer bone metastasis and complications such as bone pain, pathological fractures and metastatic epidural spinal cord compression accompanied by bone metastasis seriously affect the quality of life of prostate cancer patients, shorten the overall survival of the patients, and increase the patient's life.
Economic burden
.

Therefore, only effective systemic therapy combined with targeted anti-bone metastasis therapy can prolong the overall survival of patients
.

References: 1.
Prostate Cancer Group of the Professional Committee of Urinary and Male Reproductive Tumors of the Chinese Anti-Cancer Association.
Expert consensus on multidisciplinary diagnosis and treatment of bone metastases in prostate cancer (2020 edition)[J].
Cancer Research on Prevention and Treatment,2020,47(7):479 -486.
2.
Dong Shiqiang, Liu Qing, Xu Zihan, Yang Zhikai, Connectivity, Li Bowen, Wang Haitao.
The treatment progress and efficacy evaluation of bone metastases in prostate cancer[J].
Tumor,2019,39(7):573-581.
3.
Liu Pan, Jiang Rui .
Progress in diagnosis and treatment of bone disease in prostate cancer[J].
Journal of Clinical Urology,2016,31(8):762-766.
4.
Andrew J Armstrong, et al.
Eur Urol.
2020 Jun 9;S0302-2838(20) 30329-8.
5.
Sternberg CN, et al.
N Engl J Med.
2020 Jun 4;382(23) 2197-2206.
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