According to recent WHO worldwide statistics, ovarian cancer incidence and mortality rates are second only to cervical cancer among female reproductive tract malignancies. In Western countries, the mortality rate of ovarian cancer is the first, even more than the total number of deaths from cervical cancer and endometrial cancer. Due to the lack of mature early diagnosis methods, 70% of ovarian cancers are late when detected, making treatment extremely difficult. Conventional surgery and chemotherapy are difficult to cure, and even temporary remission often recurs after 2-3 years, and repeated surgery and chemotherapy for this group of patients seriously affects their quality of life. It is not an exaggeration to say that ovarian cancer is the biggest challenge for gynecologic oncologists.
A review of the literature reveals that the five-year survival rate for ovarian cancer has improved somewhat in the last 20 years or so. From about 30% in the mid-1970s to 50% in the late 1990s. Longer-term remissions are achieved in about 25-35% of cases. This is mainly due to three major clinical advances in ovarian cancer, namely surgical pathological staging, tumor cytoreductive surgery, and paclitaxel + platinum as the first-line chemotherapy regimen for ovarian epithelial cancer. These diagnostic and therapeutic advances constitute the main strategies in the current diagnosis and treatment of ovarian cancer. From the perspective of experimental studies, the most notable ones are the series of studies on the early diagnosis of ovarian cancer.
I. Research strategies for early diagnosis of ovarian cancer.
We cannot talk about the diagnosis and treatment strategy without mentioning early diagnosis. The 5-year survival rate of advanced ovarian cancer is only 25%, while that of early-stage 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 have worked to find new, more sensitive serum markers. One of the more promising indicators is lysophosphatidic acid (LPA). It has been reported that 98% of ovarian cancer patients have elevated serum LPA concentrations, and the positive 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 than CA125 as a serological diagnostic indicator, 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 strategies for early-stage ovarian cancer.
The treatment strategy of 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 (3-6 courses) should be chosen.
1.Surgical treatment: It should be the first choice of treatment for early-stage ovarian cancer, and the opinions are more consistent. The purpose of surgery is to perform comprehensive surgical pathological staging while removing the lesion, so it is also called “staging surgery”.
This procedure is controversial because 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 stage, 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 as far as possible, with the same points and scope as above, to facilitate accurate judgment and improve prognosis and to help determine the appropriate treatment plan.
(2) Laparoscopic staging surgery: that is, the same range of surgery as the open staging surgery described above should be completed laparoscopically. Very skilled laparoscopic surgical skills and experience are required. It has been demonstrated 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 surgery to preserve reproductive function, 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, the surgery should be more aggressive and the principle of staged surgery should be strictly implemented. Patients with ovarian junctional tumors with fertility requirements usually undergo adnexal resection only on the affected side, 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 tumors like anaplastic cell tumors, which are very sensitive to radiotherapy, tend to prefer chemotherapy. 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 stage I and II, which are now advocated to be classified into two types: low-risk and high-risk.
The former includes those with stage IA or IB, grade 1 or 2 differentiation, with a recurrence rate of 5-10%; the latter includes all stage II, stage IC, all grade 3, and clear cell carcinoma, with a recurrence rate of 30-40%. It is now generally accepted 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 for ovarian epithelial cancer, 3-6 courses of treatment, usually no more than 6 courses. A randomized trial by the US GOG 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 randomized trial of ICON and ACTION 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 cases.
1, postoperative junctional tumors with residual tumor.
2, those with extra-ovarian lesions and confirmed infiltrative implantation;
3. Patients with DNA ploidy analysis of junctional tumor cells as aneuploidy.
III. 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 comprehensive treatment such as chemotherapy, radiotherapy, biological therapy and Chinese herbal 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 cell reduction surgery: Tumor cell reduction surgery is performed to clarify the diagnosis and stage of the tumor when the first open surgery is performed before the start of chemotherapy. The principle is to remove the primary foci and all metastases as much as possible. Clinical trials have confirmed that tumor cytoreductive surgery 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 residual cancer foci can be achieved for 6 months, classifying patients into platinum-sensitive and platinum-insensitive or drug-resistant types. 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. In the selection of second-line treatment regimen, the main consideration should be symptom control and maintaining quality of life, and the toxicity caused by the treatment is an important reference factor when weighing the pros and cons.
2. Neoadjuvant chemotherapy: It refers to several courses of chemotherapy when the experienced gynecologic oncologists judge that the initial tumor cytoreduction is difficult to achieve a satisfactory level of tumor cytoreduction. 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, this method should be used with caution because it may be more likely to induce the occurrence of tumor drug resistance and lose the chance of surgical treatment for those with primary drug resistance.
3.Radiotherapy: 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, to some extent, patients are effectively deprived of the opportunity to undergo surgery again and obtain remission through chemotherapy. Therefore, radiotherapy is mostly used for palliative or localized treatment of very advanced, locally recurrent, or refractory ovarian cancer.
4.Biological therapy: It is becoming one of the important adjuvant therapies. Most of the tumor biotherapy is 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.