Ovarian malignant tumor is one of the common malignant tumors of female reproductive organs, and its incidence ranks third after cervical cancer and endometrial cancer. Among them, epithelial tumors account for 50%-70% of primary ovarian tumors, and their malignant types account for 85%-90% of ovarian malignant tumors.
Surgery and chemotherapy can cure most patients in the initial stage, but cannot save the lives of many advanced patients. Ovarian cancer is more sensitive to cisplatin. Targeted therapies (such as anti-angiogenic drugs or poly ADP-ribose polymerase inhibitors) can also improve patient survival.
Globally, 220,000 women suffer from epithelial ovarian cancer each year. In the United Kingdom, 7,000 women develop the disease each year (4,200 deaths); in the United States, 22,500 women develop the disease each year (14,000 deaths). Epidemiological findings show a significantly lower incidence of ovarian cancer in women in a non-ovulatory state (e.g., oral contraceptives).
Histopathology and molecular pathology
The main types of ovarian cancer tissues are junctional tumors, plasmacytoma, endometrioid carcinoma, clear cell carcinoma, and mucinous carcinoma. In the last decade, in order to improve the cure rate of ovarian cancer, a new classification has been proposed to divide ovarian cancer into type I and type II.
Type I is a low-grade tumor containing BRAF, KRAS, and PTEN mutations in endometrioid, mucinous, and clear cell carcinomas. type II tumors are high-grade plasmacytoma and carcinosarcoma containing p53, BRCA1, and BRCA2 gene mutations. Also, NOTCH and FOXM1 signaling pathways are associated with the pathophysiological mechanisms of ovarian plasmacytoma.
The majority of patients with epithelial ovarian cancer are high-grade plasmacytoma, endometrioid carcinoma and other high-grade undifferentiated types, which are often associated with abnormal p53 gene expression.
Although all of these tumors develop from the ovarian surface epithelium, almost all ovarian cancers with BRCA1 and BRCA2 mutations are high-grade plasmacytotic carcinomas. However, this classification has not yet been applied clinically.
Some studies have found that low-grade plasmacytotic ovarian cancer has low responsiveness to cytotoxic drugs and hormonal agents. Mutations in BRAF, KRAS, and PI3KCA genes are very common in these tumors, but these mutations are frequently missing in effectively treated patients. Therefore, these molecular biomarkers cannot be used to guide therapy.
One study found frequent mutations in the ARID1A gene in clear cell and low-grade endothelial-like epithelial ovarian cancer. And in 1/3 of cases, the PIK3 gene was mutated.
Mucinous carcinoma can usually be diagnosed in the early stages of the disease. With the application of immunohistochemistry for cytokeratin CK7 and CK20, researchers found a significant reduction in the incidence of advanced mucinous carcinoma. At the same time, KRAS mutations with HER2 gene amplification were found in almost all mucinous carcinomas.
Current status
Patients with ovarian cancer who present with abdominal pain and bloating are easily misdiagnosed as irritable bowel syndrome. The National Institute for Health and Clinical Excellence (NICE) in the UK recommends that such women (especially those over 50 years of age) should have a serum cancer antigen 125 (CA-125) test to exclude the possibility of ovarian cancer. When CA-125 is increased, patients should undergo further pelvic ultrasound.
The incidence of epithelial ovarian cancer in women with BRCA1 or BRCA2 mutations is 40C60 %. Therefore, if a woman with BRCA mutation has no need for fertility, tubo-ovarian resection is a better option.
Surgical procedures
Ovarian cancer surgery is performed to establish a histopathological diagnosis, eliminate as much cancerous tissue as possible, and establish FIGO staging. Surgery includes hysterectomy, bilateral tubo-oophorectomy, tumor and omentectomy.
Based on surgical staging, lymph node dissection is necessary, but there are no trials showing that extensive retroperitoneal lymph node dissection improves patient survival.
Cytotoxic chemotherapy
Cytotoxic chemotherapy in early stage ovarian cancer (which includes about 20% of epithelial ovarian cancer) improves patient survival. However, based on long-term follow-up of patients with stage I ovarian cancer, researchers have found that cytotoxic chemotherapy regimens should also be used in the treatment of patients with grade 3 or clear cell carcinoma; grade 2/ 3, stage IB; grade 1C3, stage 1C ovarian cancer.
Worldwide, cisplatin-containing chemotherapy regimens have been used for nearly 40 years. One study found that when paclitaxel was combined with cisplatin, patient survival was also significantly improved. Therefore, carboplatin in combination with paclitaxel is also used in the treatment of patients with ovarian cancer.
Recurrence
There are several ways to detect whether ovarian cancer has recurred. Early stages of recurrent ovarian cancer typically present with CA-125 concentrations twice the upper limit of normal without imaging or other clinical evidence. a CT scan may detect an ovarian mass.
Therefore, physicians should follow up patients with ovarian cancer. After recurrence, most patients will receive second-line chemotherapy regimens and may also be considered for secondary surgery.
In the study of second-line chemotherapy timing, researchers randomized patients with recurrence who had only elevated CA-125 or clinical symptoms to chemotherapy. The study found that early intervention due to elevated CA-125 concentrations not only failed to improve patient survival, but also affected patients’ quality of life.
The average progression-free survival (PFS) for patients with advanced ovarian cancer is 18 months. Most recurrent ovarian cancers are sensitive to cisplatin. Some studies have shown that platinum-sensitive recurrent patients should choose platinum-based drugs (e.g., carboplatin in combination with paclitaxel, gemcitabine, or polyethylene glycol liposomal adriamycin).
In contrast, for cisplatin-resistant patients, physicians generally use polyethylene glycol liposomal adriamycin or topotecan to control the disease.
New treatment strategies
BRCA mutations and poly ADP-ribose polymerase (PARP) inhibitors
Approximately 15% of ovarian cancers (mostly plasmacytosis) are associated with mutations in the BRCA1 or BRCA2 genes. Recent evidence suggests that up to 50% of high-grade plasmacytotic cancers present with a lack of homologous recombination due to BRCA gene mutations, epigenetic silencing, or other mutations affecting homologous recombination. In contrast, patients with BRCA mutations are more sensitive to cisplatin and have longer survival.
Clinical studies of PARP inhibitors in patients with high-grade plasmacytoma and BRCA-mutated recurrent tumors have found that PARP inhibitors are generally used alone for maintenance therapy. In addition to BRCA mutations, other biomarkers of ovarian cancer are important for patient drug selection.
Anti-angiogenic therapy and effective maintenance therapy
Angiogenesis is the basis of tumor growth and tumor metastasis. Inhibition of angiogenesis can inhibit tumor growth and stop tumor metastasis. Vascular endothelial growth factor (VEGF) can be targeted to inhibit neovascularization.
Most of the cytokines are inhibited by anti-VEGF antibodies and VEGF receptor tyrosine kinase inhibitors. In the future, more and more anti-vascular drugs will be discovered.
New drugs
With the advent of molecularly targeted therapies, the molecular biological mechanisms of ovarian cancer are increasingly understood. Mitogen-activated protein kinases (MAPK), located downstream of PI3K/Akt and Ras/Raf and other major signaling pathways, are activated in ovarian cancer.
Meanwhile, angiogenesis and cell proliferation have many common ligands, including fibroblast growth factors (FGFs), platelet-derived growth factors (PDGFs) and HGF / c-Met. these molecular targets may become ovarian cancer biomarkers.
Endocrine therapy and hormone replacement therapy
One study found that estrogen receptors were detected in about 60% of ovarian cancer samples, but the disease is not estrogen-sensitive. In contrast, endocrine drugs (such as tamoxifen or letrozole) are occasionally effective.
Hormone replacement therapy for patients with gynecologic malignancies is a second important issue. Hormone replacement therapy is generally safe in young patients younger than 50 years of age because of their exposure to estrogen.
Younger patients with longer-term survival who have undergone bilateral oophorectomy should receive bone densitometry every 2C3 years and receive appropriate therapy.
Prognosis
The prognosis of ovarian cancer is related to surgery, FIGO staging, and postoperative residual tumor volume. Recent data suggest that thrombocytosis is associated with advanced disease and shorter survival. 50% of patients with FIGO stage III have more than 5 years of survival after effective surgery and chemotherapy. In contrast, the average survival of recurrent cisplatin-sensitive patients is about 3 years; while the average survival of cisplatin-resistant patients is about 1 year.
Symptom remission and causes of death
In general, physicians should use palliative care in conjunction with specialist treatment advice to try to control nausea, vomiting, abdominal cramps, and constipation. A low residue diet will help to relieve the condition. Patients may often develop excretable ascites. And most patients with ovarian cancer die from malignant intestinal obstruction
Screening
Successful screening for ovarian cancer requires a highly sensitive and specific test. Serum CA-125 test, pelvic ultrasound, abdominal and vaginal ultrasonography can be used for ovarian cancer screening. Meanwhile, CT and MR scans can be used to estimate the degree and site of tumor differentiation.
Future outlook
The therapeutic effect of cytotoxicity has been improved by adjusting the drug dose and is used as a first-line treatment modality. The combination of VEGF pathway inhibitors with traditional cytotoxic drugs can improve the sensitivity of patients to the drugs and prolong disease control compared to drug maintenance therapy.
Over the next decade, other new drugs will emerge and clinicians will need to select the right drug at the appropriate stage based on the underlying tumor phenotype and genotype. This is a great challenge for effective treatment of ovarian cancer.