Endometrial cancer is the second most common gynecological malignancy after cervical cancer, accounting for approximately 20% -30% of gynecological malignancies. According to the statistics of the National Cancer Center in 2015, the incidence rate of endometrial cancer in China was 63.4/100000, and the mortality rate was 21.8/100000. Surgery is a necessary treatment for endometrial cancer, but due to the risk of tumor recurrence and persistence in some patients after surgery, comprehensive treatment such as radiotherapy, chemotherapy, and steroids is needed. At present, the scope and clinical management of high-risk populations for postoperative recurrence of endometrial cancer and factors affecting prognosis vary among different guidelines. This article summarizes the postoperative adjuvant treatment strategies for endometrial cancer by organizing common problems and guidelines, hoping to be helpful for our clinical work.
Question 1: Risk stratification of endometrial cancer
At present, different clinical trials or guidelines have formed their own risk factors and corresponding risk stratification based on the recurrence or persistent risk of endometrial cancer, such as the PORTEC trial, GOG trial, SEPAL, ESMO risk stratification, etc. Among them, the risk stratification proposed by ESMO at the 2015 European Oncology Annual Conference is more widely used in clinical practice, and lymphatic vessel infiltration LVSI is an important risk factor for this risk stratification. The specific stratification is as follows:
Question 2: The role of postoperative adjuvant radiotherapy in the treatment of endometrial cancer
Radiotherapy is one of the main methods for treating endometrial cancer, which can be divided into external radiation therapy and intracavitary radiation therapy. one External radiation therapy (EBRT): mainly targeting the treatment of tumor spread and metastasis areas, the irradiation range includes gross lesions, lower common iliac region, outer iliac region, inner iliac region, parametrial region, upper vaginal region, and sacral anterior region (when cervical invasion occurs). Extended field irradiation should include the iliac and abdominal active lymph node regions, with an upper boundary at least reaching the level of renal vessels. Three dimensional conformal or intensity-modulated radiation therapy is currently the main recommended extracorporeal irradiation technique, especially intensity-modulated technology. Due to the low incidence of acute and chronic toxic reactions, it has been widely used in clinical practice. The typical irradiation dose is 45-50.4 Gy, 1.8-2.0 Gy per session, for a course of 5-6 weeks. Treatment usually begins 4 weeks after surgery to allow the wound to fully heal. two Intravaginal radiation therapy (VBT): mainly used for the irradiation of vaginal stump and partial upper vaginal segment, usually completed in 3-5 times, 2-3 times a week, and can use vaginal oval or vaginal cylindrical applicator. NCCN guidelines recommend a dosage of 7 Gy x 3 times or 6 Gy x 5 times for intracavitary brachytherapy alone; If intracavitary close range therapy combined with extracorporeal irradiation is applied, 4-6 Gy x (2-3) times. In recent years, internal irradiation has gradually entered the era of three-dimensional and personalized treatment, and image-guided three-dimensional close range therapy technology has also gradually increased in the treatment of endometrial cancer.
Question 3: The role of postoperative adjuvant chemotherapy in the treatment of endometrial cancer
The adjuvant therapy for endometrial cancer after surgery is still mainly radiotherapy, which is beneficial for controlling local recurrence. However, if there is a risk of distant recurrence, systemic chemotherapy treatment still needs to be considered. Chemotherapy is mainly used for advanced (stage III-IV) or recurrent patients, as well as patients with type II endometrial cancer.
Question 4: Postoperative adjuvant therapy for low-risk endometrial cancer
The main risk for low-risk endometrial cancer patients after surgery is local recurrence (such as recurrence at the vaginal fornix), but this risk is ≤ 5%. The risk of radiotherapy for this group of patients outweighs the benefits, therefore postoperative adjuvant therapy is not recommended.
Question 5: Postoperative adjuvant therapy for moderate risk endometrial cancer
These patients usually undergo close range vaginal radiation therapy to reduce vaginal recurrence rates. However, the overall prognosis of such patients after surgery is good, and postoperative adjuvant radiotherapy does not improve overall survival rate. Therefore, choosing adjuvant therapy is also acceptable, especially for patients under the age of 60. The GOG 99 trial showed that compared with the postoperative observation group, there was no significant difference in the recurrence rate, distant recurrence rate, and mortality rate of the postoperative adjuvant pelvic radiotherapy group. However, the proportion of patients with moderate to severe toxic reactions was significantly increased, including hematological toxicity (14% vs 5%), gastrointestinal toxicity (64% vs 5%), and skin toxicity (15% vs 9%). Six patients who received radiotherapy also experienced severe gastrointestinal obstruction, while only one patient in the observation group experienced this condition.
Question 6: Postoperative adjuvant therapy for medium to high risk endometrial cancer
For patients with medium to high-risk endometrial cancer, the recurrence risk ranges from 5% (with adjuvant radiotherapy) to 30% (without adjuvant therapy after surgery). But regardless of whether radiotherapy is used or not, the expected survival rate for patients can be over 80%. Research shows that although adjuvant radiation therapy does not seem to improve overall survival, it can reduce pelvic recurrence. For patients who have not undergone systematic lymph node dissection during surgery, if LVSI is clearly positive, pelvic external irradiation is recommended without the need for further surgery to complete staging. Based on the research findings of PORTEC-2, vaginal brachytherapy has a good vaginal control rate, mild side effects, and significantly better quality of life than pelvic external irradiation. Therefore, for medium to high-risk patients who have completed comprehensive staged surgery, vaginal brachytherapy has replaced pelvic external irradiation as the standard adjuvant therapy. At present, there is no clear benefit shown from chemotherapy and immunotherapy.
Question 7: Postoperative adjuvant therapy for high-risk endometrial cancer
Due to the higher rates of distant metastasis and tumor related mortality in high-risk patients, pelvic external irradiation remains the standard treatment. In recent years, postoperative adjuvant therapy decision-making for this group of patients has been a hot research topic. There is no unified answer on whether adjuvant radiotherapy, chemotherapy, or radiotherapy combined with chemotherapy should be used for high-risk endometrial cancer after surgery, whether external irradiation or vaginal brachytherapy should be used for radiotherapy, the chemotherapy regimen, and the number of treatment courses. The PORTEC-3 study shows that sequential radiotherapy and chemotherapy have significant advantages in tumor control compared to pelvic external irradiation, especially for patients with stage III and serous endometrial cancer who benefit better. The GOG-258 trial also showed that the survival rate of endometrial cancer treated with radiotherapy and sequential chemotherapy is comparable to that of chemotherapy alone, but the recurrence rate of local and pelvic abdominal lymph nodes is low. The combination of radiotherapy and chemotherapy includes sandwich therapy (3 courses of chemotherapy → radiotherapy → 3 courses of chemotherapy) and sequential therapy (such as concurrent radiotherapy and chemotherapy → TC × 4 courses in the PORTEC-3 trial), and there is currently no consensus on which is better or worse. ESMO has made corresponding recommendations based on the different situations of high-risk endometrial cancer: 1. Stage I endometrioid adenocarcinoma, G3， Muscle infiltration>50%, regardless of LVSI positive/negative (1) lymph node dissection has been performed and negative: pelvic external radiation (Level I evidence)/vaginal close range radiation therapy (Level III evidence) can be considered, and whether chemotherapy should be added remains to be studied. (2) No lymph node resection: Pelvic external irradiation reduces local recurrence, sequential chemotherapy prolongs PFS and cancer-related survival. Pelvic external irradiation+chemotherapy (3-4 cycles of carboplatin+paclitaxel) is recommended. 2. Stage II endometrial like (1) simple hysterectomy, lymph node dissection, and negative results: G1-G2, LVSI negative, recommended vaginal brachytherapy; G3 or LVSI positive, pelvic external radiation/vaginal close range radiation therapy. (2) Simple hysterectomy without lymph node dissection: it is recommended to use pelvic external irradiation as an adjunct, and vaginal brachytherapy may be considered; G3 or LVSI positive, consider adjuvant chemotherapy. (3) The 2019 NCCN guidelines state that if the surgical margin is negative after extensive total hysterectomy, observation or close vaginal radiation therapy can be chosen. 3. Stage III endometrial like (1) pelvic external radiation is recommended for reducing pelvic recurrence rate, prolonging PFS, and prolonging survival. (2) Recommend using chemotherapy to prolong PFS and OS. 4. Type II endometrial cancer: serous/clear, carcinosarcoma, undifferentiated (1) serous and clear cell carcinoma, fully staged postoperative: consider chemotherapy, encourage participation in clinical trials; IA and LVSI negative results suggest vaginal close range irradiation as a substitute for chemotherapy; ≥ IB stage pelvic external irradiation+chemotherapy. (2) Cancer sarcoma and undifferentiated tumors: chemotherapy is recommended; Consider pelvic external irradiation and encourage participation in clinical trials.
Question 8: Other prognostic factors for endometrial cancer
In addition to histological type and staging, other factors can also be utilized after risk stratification to further predict the effect of adjuvant therapy.
These factors include: 1 Patient age: According to the GOG report of the American Gynecological Oncology Group, the 5-year survival rate of endometrial cancer gradually decreases with age. Retrospective studies have found that age is an independent prognostic factor for patients with medium to low-risk endometrial cancer, with poor prognosis for those aged 60 years or older. two Positive ascites cytology: About 11% of patients with surgical staging have positive ascites cytology examination results, which is common in late stage patients. Although it does not affect staging, the prognostic significance of single positive ascites cytology without extrauterine metastasis is still controversial. three Lower uterine involvement: Studies have shown that if there is lower uterine involvement, the risk of lymph node metastasis increases in patients. However, it is currently unclear whether involvement of the lower segment of the uterus is an independent risk factor for patient prognosis. four Widespread tumor lesions: lesion size is another possible important prognostic factor for endometrial cancer. Research on clinical stage I endometrial cancer shows that for tumors with a diameter of ≤ 2 cm, the lymph node metastasis rate is 4%; For those with a diameter greater than 2 cm, the lymph node metastasis rate is 15%; For tumors that involve the entire uterine cavity, the lymph node metastasis rate is 35%. The 5-year survival rates of patients were 98%, 84%, and 64%, respectively. If the above risk factors exist, there is still significant controversy over how to supplement adjuvant therapy for endometrial cancer patients after surgery. The attending physician needs to make personalized decisions and treatments based on the patient's condition and personal experience.
