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Metastatic prostate cancer seriously affects the survival prognosis of patients, in European and American populations, metastatic prostate cancer accounts for only 5%~6% of new prostate cancer, while in China, this proportion is as high as 54%1
.
For patients with metastatic castration-resistant prostate cancer (mCRPC), abiraterone is the first-line treatment
recommended by domestic and international guidelines.
In recent years, the rapid development of new endocrine therapy (NHT) represented by abiraterone acetate has provided accurate and individualized treatment strategies for castration resistant patients of specific molecular or pathological classification, which is the general trend
of modern urological oncology medical research.
In this issue of the "Practice Progland" column, Yimaitong invited Professor Liu Zihao of the Second Hospital of Tianjin Medical University to provide mCRPC cases, and invited Professor Wang Yong of the Second Hospital of Tianjin Medical University to comment on the readers
.
medical history
Male, 54 years old
.
Complaint: He was admitted to our hospital in August 2018 due to
"frequent urination, urgency, and painful urination".
Ancillary examination
Laboratory tests: tPSA: 100.
08 ng/ml
.
MRI showed that prostate cancer was considered, involving the bladder and bilateral seminal vesicles, pelvic and bilateral iliac paravascular lymph nodes, partial enlargement, left epididymal cyst, and no obvious abnormalities
on systemic bone scintigraphy.
Pathological findings of puncture biopsy: prostate adenocarcinoma, Gleason score 4+4=8 points
.
Diagnostic results
Prostate cancer (cT4N1M0).
After the treatment
Figure 1: Follow-up of PSA throughout treatment
Phase I: 2018-08, patients were given the regimen of "Bicalutamide 50mg + goserelin + docetaxel 6 cycles
".
After 6 months of treatment, PSA dropped to less than
0.
2 ng/ml.
After continuing treatment, the patient's PSA gradually increased to 0.
36 ng/ml
.
Phase II: 2019-08, patients switched to flutamide + androgen deprivation therapy (ADT).
After 1 month of treatment, the patient's PSA gradually increased to 3.
63ng/ml
.
Phase III: 2019-09, combined with imaging/laboratory/gene sequencing test results, diagnosed the patient as mCRPC
.
After the regimen was changed to "abiraterone + prednisone + goserelin", the patient's PSA was quickly controlled
.
The results of the examination are as follows:
2019-09-03, MRI showed that the central area and peripheral band were still poorly demarcated, the diffuse signal on T2WI was reduced, multiple divergent hypersignal opacities could be seen on DWI, and multiple lymph node opacities
could be seen next to pelvic and bilateral iliac vessels.
2019-09-12, PSMA-PET/CT showed that there were multiple lymph nodes of different sizes in the body, abnormal high uptake of PSMA and CHO, and the possibility of lymph node metastasis was considered in combination with the medical history
.
Fig.
2 PSMA-PET/CT results
2019-09-23, laboratory tests: PSA: 3.
63ng/ml, testosterone: 0.
21ng/ml
.
2019-09-25, the patient underwent transrectal prostate biopsy under local anesthesia, and underwent pathological and gene sequencing examination
.
Fig.
3 Results of transrectal prostate biopsy after surgery
Case analysis
The patient was first diagnosed with prostate cancer (cT4N1M0) in August 2018, combined with PSA of 100.
08ng/ml, Gleason score of 4+4=8, and imaging showed regional lymph node metastasis, which was metastatic prostate cancer
.
Since lesions are no longer limited, reducing tumor recurrence, controlling disease progression, and improving patient survival are more important considerations
.
ADT is the cornerstone of metastatic prostate cancer, the basis of a variety of combination regimens, and needs to be used throughout the patient's systemic treatment2
.
In addition, patients are younger, have better physical fitness, have a longer life expectancy, and need to take active comprehensive treatment
.
Based on the conclusions of the three major studies of GETUG-AFU 15, CHAARTED and STAMPEDE, docetaxel chemotherapy for mHSPC patients has been written into NCCN, AUA, EUA and other major guidelines
.
IN 2016 STAMPEDE STUDY, DOCETAXEL IN COMBINATION WITH ADT HAD OVERALL SURVIVAL UP TO 65 MONTHS AND A 27% REDUCED RISK OF DEATH, AND IN THE 2018 CHAARTED STUDY DOCETAXEL IN COMBINATION WITH ADT, OVERALL SURVIVAL WAS 57.
6 MONTHS AND A 28% LOWER RISK OF DEATH.
3,4
。 Therefore, with "bicalutamide 50mg" + "goserelin" + "docetaxel 6 cycles" treatment, after 6 months of treatment, PSA decreased to less than 0.
2ng/ml, which is undoubtedly a good prognosis
.
After continued treatment, the patient's PSA gradually increased to 3.
63 ng/ml, and PSMA-PETCT showed distant lymph node metastases, so mCRPC
was diagnosed.
The pathogenic mechanism of CRPC is unknown, the related molecular network is complex, and multiple signaling pathways synergize to cause disease, and change with the development of the disease.
CRPC is not "a disease" but a "disease state.
"
Its pathogenesis involves a variety of complex mechanisms, and there is a heterogeneity in sensitivity to ADT treatment, histopathological type, and genotype
.
Because of this heterogeneity, there is no theoretical support for the clinical use of a unified treatment method for CRPC, and it is difficult to achieve the desired effect
.
Therefore, in order to have a better treatment effect, it is necessary to first reveal the pathogenesis of mCRPC, classify mCRPC from the pathogenesis, and then adopt targeted individualized treatment plans according to their respective characteristics to achieve the ideal efficacy
.
Combined with the three theories of the current pathogenesis of CRPC: overactivation of androgen receptor signaling pathway, neuroendocrine transdifferentiation and stem/progenitor cell abnormal proliferation, as well as molecular markers determined by the basic experiments of our central laboratory, the etiological classification of CRPC is given individualized precision treatment
.
Type I: AR-dependent, positive for FKBP5 and AKR1C3; Type III: neuroendocrine type, positive for NTS, NSE, Syn, CgA; Type II: stem cell type, positive for Yap1 and CD44 but negative for neuroendocrine molecular markers
.
Therefore, patients are advised to undergo a secondary needle biopsy
.
The pathological results showed that AKRIC3 was positive and other molecular markers were negative
.
Combined with our center's classification and treatment strategy for CRPC, this patient belongs to type I, and we performed blood and tissue gene sequencing, and the result was AR gene wild type, indicating that abiraterone has a good
prognosis.
Therefore, in September 2019, the patient began to receive abiraterone treatment, the patient's PSA was quickly controlled, the follow-up is stable, the treatment effect is obvious, and there are no adverse events
.
Fig.
4 Treatment strategies for CRPC typing
Zihao Liu
Professor Liu Zihao
Department of Urology, Second Hospital of Tianjin Medical University
M.
D.
Attending physician
In his clinical work, he is mainly engaged in the diagnosis and treatment of prostate cancer and the comprehensive treatment of castration-resistant prostate cancer, and has certain insights into the precise needle biopsy of primary and metastases in mCRPC patients and the molecular typing treatment of CRPC
He has participated in 2 National Natural Science Foundation of China, 2 provincial and ministerial projects, 2 clinical research projects, 4 papers indexed by SCI and 1 paper published in the Chinese Journal of Urology
After 13 months of comprehensive treatment, PSA was further elevated to more than 2 ng/ml and PSMA-PETCT showed distant lymph node metastasis, and mCRPC
was diagnosed.
Our center has formulated the "4W1H" secondary puncture biopsy principle to guide the secondary needle biopsy of mCRPC patients5
.
However, the metastatic lymph nodes in this patient were small and it was difficult to obtain metastatic soft tissue, so the prostate was selected as the secondary puncture lesion, and immunohistochemical staining and next-generation gene sequencing were performed
.
Based on years of basic research and clinical research on prostate cancer, we classify CRPC from the etiology according to the heterogeneity, diversity and multiple formation mechanisms of CRPC, combined with next-generation sequencing technology, and adopt precision medical methods for clinical individualized treatment of CRPC
for different classifications 。 The immunohistochemistry results of this patient showed that AKR1C3 was positive, AKR1C3 was highly expressed in human prostate cancer and its cancerous tissues, and participated in the synthesis of androgens such as testosterone and 5α-dihydrotestosterone, which is still AR signal-dependent, combined with mCRPC based on etiological classification and treatment strategy, using abiraterone combined with prednisone treatment
.
In addition, the results of next-generation gene sequencing (ctDNA, tissue) all showed that the AR gene was wild-type, suggesting that the prognosis of abiraterone was good
.
After treatment with abiraterone plus prednisone, the patient now has stable PSA control and significant reduction of lymph nodes on imaging
.
At present, the formulation of major guidelines at home and abroad is not based on the etiology of CRPC, but according to the severity of disease symptoms to classify, so as to give corresponding treatment options, but the effect is very little
.
Therefore, new treatment strategies are needed to improve the efficacy
of CRPC.
The transformation process of tumor treatment strategy can be divided into the era of local treatment, the era of chemotherapy, and the era
of precision medicine individualized treatment after the emergence of molecular diagnostic technology.
The classification precision treatment of CRPC at home and abroad is still in the clinical research stage, and its focus is on exploring the selection of CRPC treatment methods and prognostic markers
.
It is believed that in the near future, with the deepening of research, it will provide more theoretical basis
for the treatment of CRPC.
Patients with CRPC will receive individualized, precise and more effective treatment
.
Professor Wang Yong
M.
D.
Chief physician
Associate Professor, Master Supervisor
Deputy Director of the Medical Department of the Second Hospital of Tianjin Medical University
Member of the Youth Group of the Urology Branch of the Chinese Medical Association
Youth member of the Urogenital Tumor Professional Committee of the Chinese Anti-Cancer Association
Youth member of the Urology Professional Committee of the Chinese Research Hospital Association
Member and Secretary of the Urology Professional Committee of Tianjin Association of Integrative Medicine
Tianjin Young Medical Cutting-edge, Tianjin Specially Appointed Young Scholar
Although there are still many difficulties in the diagnosis and treatment of prostate cancer, it is believed that in the future, more and more castration-resistant prostate cancer patients will benefit from NHT combined with ADT treatment represented by abiraterone acetate and obtain long-term survival
.
The pioneer opens up a unique way, the persistent one goes forward bravely, chooses the power that "Ze" belongs to you, crosses adversity, and is born to the sun!
References:
1.
HUANG Jian, WANG Jianye, KONG Chuze, et al.
Chinese Guidelines for the Diagnosis and Treatment of Urology and Andrology Diseases, 2019.
Science Press.
2.
Huggins C.
Effect of Orchiectomy and Irradiation on Cancer of the Prostate[J].
Ann Surg.
1942,115(6):1192-1200.
3.
Sweeney C J, Chen Y, Carducci M, et al.
Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer[J].
The New England journal of medicine,2015,373(8):737-746.
4.
Kyriakopoulos C E, Chen Y H, Carducci M A, et al.
Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer: Long-Term Survival Analysis of the Randomized Phase III E3805 CHAARTED Trial[J].
Journal of Clinical Oncology, 2018, 36(11):JCO2017753657.
5.
Liu Z, Wang L, Zhou Y, et al.
Application of metastatic biopsy based on "When, Who, Why, Where, How (4W1H)" principle in diagnosis and treatment of metastatic castration-resistance prostate cancer[J].
Translational Andrology and Urology, 2021(4).
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