Ovarian malignancy is one of the common malignant tumors of female reproductive organs, ranking third in incidence after cervical cancer and uterine corpus cancer. However, the mortality rate of ovarian epithelial cancer is the first among all kinds of gynecological tumors, posing a serious threat to women’s lives.
Diagnosis and treatment of ovarian cancer
I. Research strategies for early diagnosis of ovarian cancer
Early diagnosis cannot be mentioned in the diagnosis and treatment strategy. The 5-year survival rate of advanced ovarian cancer is only 25%, while that of early ovarian cancer can be more than 85%. Therefore, it can be said that early diagnosis is the most important part of ovarian cancer diagnosis and treatment strategy, and only early diagnosis can fundamentally change the situation of high mortality rate of ovarian cancer. However, early diagnosis has always been the most challenging topic in ovarian cancer research. There is no mature method to achieve true early diagnosis.
The most commonly used basic diagnostic methods for ovarian cancer include: gynecological triage, negative color ultrasound and serum CA125 test. The combined application of these three methods is also the current ovarian cancer screening method recommended by experts. Due to the low incidence of ovarian cancer in the population, the positive predictive value is still very low even with the application of highly specific tests, so it is difficult to implement screening in the general population yet. Currently, the target population for ovarian cancer screening is mainly the high-risk group of hereditary ovarian cancer families and menopausal women over 50 years of age. Screening in high-risk groups has been shown to be an effective means of early diagnosis of ovarian cancer, and the survival of ovarian cancer patients in the screened group is significantly longer. Dynamic monitoring of serum CA125 levels during the screening process is important and can significantly improve the outcome of screening.
Although CA125 is the most widely used serum tumor marker for ovarian cancer, its most useful value is to monitor the recurrence of ovarian cancer. Serum CA125 levels can be elevated in 1% of healthy women, 3% of benign ovarian tumors, and 6% of non-ovarian related benign diseases. Therefore, many investigators are working to find new and more sensitive serum markers. Lysophosphatidic acid (LPA) is one of the more promising indicators. It has been reported that 98% of ovarian cancer patients have elevated serum LPA concentrations, and the positivity rate can be as high as 90% in stage I patients. HE4 is a newly discovered ovarian cancer antigen that is overexpressed in certain ovarian epithelial and junctional tumors but not in normal ovarian epithelial tissues, and is more sensitive and specific as a serological diagnostic indicator than CA125, which is a promising direction for early diagnosis. Currently, diagnostic kits for detecting HE4 are available in China.
In 1999, Brown et al. first used protein microarray technology for ovarian cancer research, and Petricoin et al. applied SELDI-TOF and MALDI-TOF protein microarray systems to obtain specific serum profiles for ovarian cancer and performed blinded detection. The sensitivity, specificity and positive predictive value for ovarian cancer diagnosis were 100%, 95% and 94%, respectively, while the corresponding positive predictive value for serum CA125 was only 35%. In an article published in Lancet, Beverly said that Petricoin et al. had overestimated the positive predictive value of the method. The main reason is that this method can only detect small molecular weight peptides and has poor stability.
Treatment strategy for early-stage ovarian cancer
The treatment strategy for early-stage ovarian cancer can be summarized as follows: surgery is preferred, chemotherapy is the only adjuvant treatment, and a simple plan (try not to use three-drug combination chemotherapy plan) and a limited course of treatment (3 to 6 courses) should be chosen.
1.Surgical treatment
There is a consensus that surgery should be the first choice of treatment for early-stage ovarian cancer. The purpose of surgery is to perform comprehensive surgical pathological staging while removing the lesion, so it is also called “staging surgery”.
The controversial aspect of this procedure is that some physicians believe that early-stage ovarian cancer does not warrant the risk of major surgery and that lymphatic dissection is not necessary; however, studies have found that the rate of lymph node metastasis in patients with visual inspection of clinical stage I can be as high as 24%. A nationwide collaborative study found that 28% of patients originally considered to be in clinical stage I had increased stage after complete staging surgery. According to the internationally accepted FIGO staging, a positive lymph node is stage IIIc, and how do you know early or late stage without lymphatic clearance! Inadequate staging is often the main reason for inappropriate postoperative treatment and poor prognosis. Therefore, we advocate that “the earlier the lymph node, the greater the staging”.
There are 2 variants of this procedure.
(1) Open re-staging surgery: Patients referred from primary care or emergency (lack of freezing conditions) after initial surgery, but without precise surgical staging and before starting chemotherapy, should be reopened or staged laparoscopically if possible, with the same points and scope as above, in order to facilitate accurate judgment and improve prognosis and to help determine the appropriate treatment plan.
(2) Laparoscopic staging surgery: i.e., the same scope of surgery as the above-mentioned open staging surgery should be completed laparoscopically. Very skilled laparoscopic surgical skills and experience are required. It has been proven that laparoscopic staging is feasible for patients with largely early-stage ovarian cancer and tumors of a size that can be removed vaginally. However, to say with certainty that laparoscopic staging of early-stage ovarian cancer is superior, large studies are needed to examine disease-free survival and overall survival rates in these patients.
Conservative surgery for early-stage ovarian cancer is also known as fertility-preserving surgery, i.e., preservation of the uterus and contralateral adnexa, and the rest of the surgical scope is the same as staging surgery. Patients should be selected strictly and carefully for epithelial ovarian cancer. This procedure is also suitable for stage Ia mesenchymal tumors and malignant germ cell tumors of all stages that require fertility. A second operation to remove the uterus and the contralateral adnexa can be performed after the completion of childbirth, depending on the situation.
For surgical treatment of ovarian junctional tumors, according to the FIGO staging principle, patients with ovarian junctional tumors without fertility requirements should also undergo the same open staging surgery as early stage ovarian cancer. However, in recent years, surgery for junctional tumors has become more conservative. For young patients, only unilateral adnexal resection can be considered for unilateral junctional tumors after careful exploration and pathological confirmation by ice; for bilateral tumors, total hysterectomy + bilateral adnexal resection can be performed. However, for patients with micropapillary junctional plasmacytoma and extra-ovarian implants, especially those with infiltrative implants, surgery should be more aggressive and the principle of staged surgery should be strictly implemented. For patients with ovarian junctional tumors with fertility requirements, only the affected adnexal resection is usually performed, but careful confirmation of normal contralateral ovaries and fallopian tubes is required, and long-term postoperative follow-up is warranted.
2.Chemotherapy
Chemotherapy is the only adjuvant treatment for early-stage ovarian cancer, or it can be said that chemotherapy is the only adjuvant treatment for ovarian cancer. Even for tumors like asexual cell tumors, which are very sensitive to radiotherapy, chemotherapy is often preferred. Because tumors that are sensitive to radiotherapy are also very sensitive to chemotherapy, and chemotherapy is not only effective for local tumors, but can also control possible distant metastases. The toxic side effects are not as long-lasting as those of radiotherapy.
Early-stage ovarian cancer includes FIGO stages I and II, which are now advocated to be divided into 2 types: low-risk and high-risk. The former includes those with stage IA or IB and grade 1 or 2 differentiation, with a recurrence rate of 5% to 10%; the latter includes all stage II, stage IC, all grade 3, and clear cell carcinoma, with a recurrence rate of 30% to 40%. It is now generally believed that low-risk patients do not need adjuvant therapy, while high-risk patients need chemotherapy, but unlike chemotherapy for advanced ovarian cancer, simple regimens with limited courses are generally chosen. That is, single drug or combination chemotherapy with 2 drugs is selected according to the patient’s condition, such as TC or CP regimen is selected for ovarian epithelial cancer with 3% to 6% course of treatment, generally not more than 6 courses of treatment. The US GOG randomized trial showed that 6 courses of TC regimen chemotherapy reduced the risk of disease progression by 31% compared to the 3-course group, but there was no improvement in overall survival. Chemotherapy should be administered immediately after surgery. The European ICON and ACTION randomized trial showed an 8% improvement in recurrence rate in the immediate chemotherapy group compared to the non-immediate chemotherapy group (74% vs. 82%). However, patients who are of poor tissue type, such as clear cell carcinoma, should be treated according to the principles of advanced ovarian cancer, i.e., early as late, for complete control in a single visit. PEB or PVB regimens are preferred for germ cell tumors and interstitial tumors of the sex cord.
Chemotherapy for ovarian junctional tumors: adjuvant therapy is generally not required for ovarian junctional tumors, but should be closely followed up. Chemotherapy may be considered only in the following three situations.
(1) postoperative junctional tumors with residual tumor.
(2) Those with extra-ovarian lesions with proven infiltrative implantation.
(3) Patients with aneuploidy in DNA ploidy analysis of junctional tumor cells.
3. Treatment strategies for advanced and recurrent ovarian cancer
In principle, surgery is still the first choice for the treatment of advanced ovarian cancer, supplemented by a combination of chemotherapy, radiotherapy, biological therapy and traditional Chinese medicine. For advanced ovarian cancer, there is no exact surgical procedure available. The value, indications and timing of surgical treatment for recurrent ovarian cancer are still controversial. Attention should be paid to combining general principles with individualized principles.
(1) Initial tumor cytoreductive surgery
Tumor cytoreductive surgery is performed to clarify the diagnosis and stage of the tumor during the first open surgery before the start of chemotherapy. The principle is to remove the primary site and all metastases as much as possible. Clinical trials have confirmed that tumor cytoreduction can clarify tumor stage, reduce cancer tumor, increase chemotherapy sensitivity, improve nutritional status and quality of life, and increase five-year survival rate, which is the basic treatment for ovarian cancer.
The scope of primary tumor cytoreductive surgery depends on whether the residual cancer foci <1cm can be achieved. As long as satisfactory tumor cytoreductive surgery can be achieved and tolerated by the patient, it should be resolutely resected, including partial bowel resection and partial cystectomy, and lymphatic dissection; if satisfactory tumor cytoreductive surgery cannot be achieved, the principle is whether it is conducive to tumor reduction, while minimizing trauma and facilitating postoperative recovery and early initiation of chemotherapy. If it is not possible to achieve satisfactory tumor cell reduction, the principle is whether it is conducive to tumor reduction while minimizing trauma, facilitating postoperative recovery and starting chemotherapy as early as possible. The residual cancer foci, unresected uterus, lymph nodes and other organs can be considered for intermediate tumor cytoreduction after chemotherapy.
(2) Secondary tumor cytoreductive surgery
If a patient achieves complete clinical remission after the first treatment and then relapses, the second surgical treatment is called secondary tumor cytoreduction. There are no randomized controlled clinical trials to confirm the effectiveness of surgery for recurrent ovarian cancer; secondary surgery does not improve the survival of patients with tumor progression and stable status during chemotherapy; some patients do have prolonged survival after secondary surgery, and the majority of these patients have been in remission for more than 1 year after initial surgery and adjuvant chemotherapy. Therefore, it is believed that although secondary surgery has not been shown to improve prognosis and survival is the same as chemotherapy alone, the surgery itself is reasonable and it is important to carefully screen appropriate patients for secondary surgical treatment.
Reasonable selection should be for patients who are young, in good physical condition, with residual foci <1 cm from the initial surgery, isolated and resectable lesions from this recurrence; complete clinical remission for more than 6 to 12 months after chemotherapy, and with effective second-line chemotherapy. Sometimes a second surgery is also necessary to relieve intestinal obstruction, etc., but the purpose of the surgery may change accordingly. Surgery is contraindicated if the lesions are multiple or not completely resectable. For example, large, or multiple lesions in liver parenchyma; multiple and extensive implantation metastases in mesentery and intestinal canal, extensive cancerous adhesions that make the intestinal canal stiff and rigid, etc.
(3) Intermediate tumor cytoreductive surgery
It refers to the second tumor cytoreduction procedure after 3 courses of chemotherapy for patients who are not satisfied with the initial tumor cytoreduction (residual cancer >2cm). The European RCT study confirmed that this procedure was an independent prognostic factor (p=0.012); the results of long-term trials also showed that intermediate tumor cytoreduction improved the survival rate and prolonged the survival time of patients with advanced epithelial ovarian cancer. However, the US GOG concluded that intermediate tumor cell reduction had no significant improvement in patient survival by clinical RCT study. The author believes that there is also a problem of selecting the indications for intermediate tumor cell reduction, and as long as the selection is correct, i.e., no visual residue can be achieved by intermediate tumor cell reduction, it will help to prolong the survival of patients.
(4) Chemotherapy
Chemotherapy is the most important adjuvant treatment for advanced ovarian cancer. In the past 30 years, the preferred chemotherapy regimen for ovarian cancer has changed from FAC to CAP to CP to the current paclitaxel+carboplatin (TC) regimen. Since 1997, many new drugs have been introduced and many advances have been made in the drug treatment of ovarian cancer. The availability of new sensitive drugs has given us a variety of options in the treatment of ovarian cancer. However, the more drugs are available, the more it means that no one drug is outstandingly effective. How to use these drugs to design combination chemotherapy regimens with the best anti-tumor activity and the least toxicity and resistance, so as to improve the survival rate and quality of life of ovarian cancer patients while minimizing the price/effectiveness ratio, is still the focus of our future in-depth research.
The adjuvant treatment of advanced ovarian cancer emphasizes the combination of chemotherapy, radiotherapy, biological therapy and Chinese herbal medicine treatment. Chemotherapy is the most important and essential adjuvant treatment. Timely, adequate, on-time, and multiple courses of treatment are the main principles of drug administration. The first-line preferred regimen (or standard regimen) is now internationally recognized as the combination chemotherapy with Tysol and carboplatin/cisplatin, with a response rate of 70% to 80%. To date, randomized clinical trials of new drug combination chemotherapy regimens have not found which regimen is more advantageous than the TC regimen. However, CP or CAP is also often used as the first choice in China due to the economic constraints of patients, with a response rate of 60% to 65%.
In advanced ovarian cancer, if the residual foci of initial tumor cytoreduction are less than 1 cm, 6 to 8 courses of chemotherapy are generally preferred, and chemotherapy is discontinued after achieving complete remission with regular follow-up. If there is no measurable lesion after the initial tumor cytoreductive surgery, it is recommended to perform intermediate tumor cytoreductive surgery after 3 courses. If there is no measurable lesion after the intermediate tumor cytoreductive surgery, another 6 courses of chemotherapy should be applied to the original regimen and regular follow-up afterwards; if there is still a measurable lesion, the number of courses of chemotherapy should be increased or the drug should be changed in time according to the tumor regression.
For patients in complete remission after initial surgery and chemotherapy no consolidation therapy has been found to improve survival. With regard to intraperitoneal chemotherapy, three randomized trials have been conducted to confirm the prolonged survival of patients with residual cancer foci less than 1 cm after initial tumor cytoreductive surgery.
The toxicity is increased but still within the tolerable range. Although the clinical benefits of intraperitoneal chemotherapy are well established, there is no recommended drug dose or optimal regimen for intraperitoneal therapy based on toxicity, and clinical caution is warranted.
Chemotherapy for recurrent ovarian cancer: The purpose of treatment for recurrent ovarian cancer is different from that for patients with initial treatment. It is based on the premise of controlling symptoms and maintaining a certain quality of life, prolonging the progression-free interval as much as possible, and taking into account the overall survival rate. Patients are generally classified as platinum-sensitive and platinum-insensitive or resistant according to whether they achieve complete remission clinically and whether the time between complete remission and reappearance of lesions is >6 months.
For platinum-sensitive patients in remission for more than 1 year, paclitaxel + carboplatin can still be considered and has been reported to improve progression-free survival by at least 3 months compared with other regimens; carboplatin combination chemotherapy is superior to carboplatin monotherapy in platinum-sensitive recurrent ovarian cancer. Chemotherapy for platinum-resistant ovarian cancer is now mostly advocated to first extend the interval of platinum-free therapy for more than 1 year, and monotherapy such as liposomal adriamycin, gemcitabine, topotecan and oral pedialyte glycosides can be considered, followed by a platinum-containing combination chemotherapy regimen. At this point, the patient is likely to be re-sensitized to platinum drugs, thereby enhancing the role of chemotherapy. When choosing a second-line regimen, the main consideration should be symptom control and maintaining quality of life, and treatment-induced toxicity is an important reference factor when weighing the pros and cons.
(5) Neoadjuvant chemotherapy
It refers to several courses of chemotherapy after the initial tumor cytoreduction is judged by experienced gynecologic oncologists to be difficult to achieve a satisfactory level of tumor cytoreduction, and then perform satisfactory tumor cytoreduction after the tumor has partially regressed. There is preliminary clinical evidence that this approach is an alternative treatment modality for ovarian cancer with distant metastases and extensive pelvic and abdominal metastases. However, it should be used with caution because it may be more likely to induce the development of tumor resistance and lose the chance of surgical treatment for those with primary drug resistance.
(6) Radiation therapy
Due to the introduction of new chemical drugs, especially the improved effect after the combined use of multiple drugs, and the fact that radiotherapy requires some special equipment and has long-lasting toxic side effects, even for life, not many surgeries are supplemented with radiotherapy recently. In addition, ovarian cancer often requires repeated surgery and chemotherapy, while radiotherapy increases the difficulty of surgery and complications; occlusion of local blood vessels reduces the local concentration of chemotherapy drugs in the tumor. Once radiotherapy is applied, it actually deprives the patient of the opportunity to have another surgery and to obtain another remission through chemotherapy to some extent. Therefore, radiotherapy is mostly used for palliative or localized treatment of very advanced, locally recurrent, or refractory ovarian cancer.
(7) Biological therapy
Biological therapy is becoming one of the important adjuvant therapies. Most of the tumor biotherapies are still in the laboratory and clinical research stage, and it will take a long time and great efforts to be applied in the clinic, and even some technical breakthroughs are still needed. Biological tumor therapy will play an increasingly important role as a supplement to traditional treatments such as surgery, chemotherapy and radiotherapy in controlling small residual cancer foci, delaying the recurrence of cancer, and improving survival and quality of life.