Distribution Pattern Of Lymph Node Metastases And Its Implication In Personalized Radiotherapeutic Clinical Target Volume Delineation Of Regional Lymph Nodes In Early Stage Cervical Cancer

Cervical cancer is the most common gynecological malignancy in Chinese women. Radical hysterectomy and pelvic lymphadenectomy are the standard therapy for early stage cervical cancer. Postoperative radiotherapy is an important component of multimodality treatments for patients with high-risk factors. Generally, patients with risk factors, such as positive pelvic nodes, invasion of parametric, lymph vascular space invasion or a positive vaginal margin, are regarded as being at high risk recurrence.Although the status of pelvic lymph nodes is not included in International Federation Gynecology and Obstetrics (FIGO) stage, it is one of the most important prognostic factors and also an indicator for postoperative radiotherapy. In a report, recurrences are much more frequent in cervical cancer patients with lymph node involvement. Pelvic irradiation combined with cisplatin-based chemotherapy (with or without 5-fluorouracil) is superior to radiation alone in improving patients’progression-free and overall survival. Nevertheless, some studies have shown that patients benefited a lot from pelvic radiotherapy with concurrent cisplatin, but they also suffered from therapeutic toxicities. Acute grade 3-4 nonhematologic toxicity was present in 23.4% and chronic grade 4 toxicity was present in 5% patients with postoperative chemo-radiation therapy. In a study of stage IIB-IVA cervical cancer with negative para-aortic lymph nodes, it pointed out that the late grade 3-4 complication rate is up to 16.2% with cisplatin-based chemotherapy at 3 years. These toxicity rates increase when chemotherapy and extended field radiotherapy are combined, and the rate of acute grade 3-4 nonhematologic toxicity was 81%, while chronic grade 3-4 toxicity was 40% with follow-up up to 38 months. Despite the already high toxicity, the situation might worsen with time. Grade 3 toxicity rates at 3 and 5 years were 7.7% and 9.3%, but the rate increased approximately 0.34% per year through 10-20 years in a retrospective analysis from 1,784 cervical cancer patients who underwent radiation. These situations underline the need for improvements in radiotherapy delivery. One way to accomplish this is with the application of intensity-modulated radiotherapy (IMRT) particularly suitable for cervical cancer with irregular irradiation field. IMRT has been shown to reduce the incidence of acute and late toxicities and has been associated with low rates of in-field failures. Another way to achieve this task is with accurate delineation for the target volume. Accurate target delineation is very important to avoid over-treatment. An over-treated target can increase the doses of normal tissues and result in more complications. That inclusion of all pelvic lymph nodes in the clinical target volume (CTV) may not be necessary for all patients was mentioned in a review. Although the National Comprehensive Cancer Network (NCCN; 2013) and the Radiation Therapy Oncology Group (RTOG; 2008) achieved some consensus guidelines on a CTV definition for intensity-modulated pelvic radiotherapy for postoperative cervical cancer, they mainly defined margins and rarely mentioned how to perform selective regional irradiation with different risk factors. In the present study, we retrospectively examined 665 cervical cancer patients who had undergone radical hysterectomy and lymphadenectomy, and analyzed patterns of lymph node metastases. The study of risk factors related to lymph node metastases can help identify patients who are more likely to have involved lymph nodes and guide personalized radiotherapy.Objectives:To study the distribution pattern of lymph node metastases of stage ⅠA1～ⅡA2 cervical cancer and clarify the personalized clinical target volume delineation of regional lymph nodes (CTVn).Methods:A total of 665 cases with International Federation Gynecology and Obstetrics stage ⅠA1～ ⅡA2 cervical cancer who underwent radical hysterectomy and pelvic lymphadenectomy were retrospectively reviewed. The clinicopathological factors related to lymph node metastases were analyzed using logistic regression analysis.Results:Pelvic lymph node metastases were found in 168 of 665 patients, resulting in a metastasis rate of 25.3%. The most common site for pelvic lymph node metastases was the obturator nodes (17.6%; 117 of 665 patients), followed by the external iliac and internal iliac nodes (13.4%; 89 of 665 patients), the common iliac nodes (3.6%; 24 of 665 patients), the circumflex iliac nodes distal to the external iliac nodes (CINDEIN; 2.6%,17 of 665 patients), and the parametrial nodes (1.8%; 12 of 665 patients). Metastases to the para-aortic nodes (1.7%; 11 of 665 patients) and the sacral nodes (0.6%; 4 of 665 patients) were relatively rare. Binary logistic regression analysis showed that age, lymph vascular space involvement (LVSI) and deep stromal invasion statistically influenced pelvic lymph node metastases (p=0.017, <0.001,<0.001, respectively; OR=0.975,2.930,3.967, respectively; 95%CI=0.955-0.996, 2.006～4.280,2.358-6.674, respectively). Pathological morphology type, lymph node metastases of the obturator, the external iliac and internal iliac, and the para-aortic had a strong influence on lymph node metastases of the common iliac (p=0.022,0.003,<0.001, 0.009, respectively; OR=5.572,1.667,1.858,3.215, respectively; 95%CI=1.285-24.16, 1.185～2.345,1.345～2.566,1.343～7.695, respectively). Tumor size and lymph node metastases of the common iliac were significantly related to lymph node metastases of the para-aortic (p=0.045,<0.001, respectively; OR=5.165,1.593, respectively; 95%CI=1.036～25.76,1.277～1.988, respectively). Lymph node metastases of the obturator, the external iliac and internal iliac were strongly correlated to lymph node metastases of CINDEIN (p=0.027,0.024, respectively; OR=1.419,1.403, respectively; 95%CI=1.041～1.934,1.046～1.882, respectively).Conclusions:CTVn must be customized by experienced oncologists according to the various clinical factors that influence lymph node metastasis. Irradiation of selective regional lymph nodes and their correlated lymphatic drainage regions should be performed according to clinical and pathological factors, such as deep stromal invasion and LVSI. For large and endophytic tumors, the irradiation field should be enlarged appropriately. CINDEIN is not suggested in CTV with negative obturator, internal and external iliac lymph nodes, especially with no lymph node involvement. Our results can improve the accuracy of postoperative radiotherapy and allow a more personalized treatment for cervical cancer patients.