Abstract
Background
Cervical cancer is still present a major public health problem, especially in developing countries. In International Federation of Gynaecology and Obstetrics 2018, allowing assessment of retroperitoneal lymph nodes by imaging and/or pathological findings and, if deemed metastatic, the case is designated as stage IIIC (with r and p notations). Patients with lymph node metastases have lower overall survival (OS), progression free survival (PFS), and survival after recurrence, especially those who have unresectable macroscopical positive lymph nodes. Retrospective analysis suggests that there may be a benefit to debulking macroscopic nodes that would be otherwise difficult to sterilize with standard doses of radiation therapy. However, there are no prospective study reporting that resecting macroscopic nodes before concurrent chemoradiation therapy (CCRT) would improve PFS or OS of cervical cancer and no guidelines for surgical resection of bulky lymph nodes. The CQGOG0103 study is a prospective, multicenter and randomized controlled trial (RCT) evaluating lymph node dissection on stage IIICr of cervical cancer.
Methods
Eligible patients are histologically confirmed cervical squamous cell carcinoma, adenocarcinoma, adeno-squamous cell carcinoma. Stage IIICr (confirmed by computed tomography [CT]/magnetic resonance imaging/positron emission tomography/CT) and the short diameter of image-positive lymph node ≥15 mm. 452 patients will be equally randomized to receive either CCRT (pelvic external-beam radiotherapy [EBRT]/extended-field EBRT + cisplatin [40 mg/m2] or carboplatin [the area under curve=2] every week for 5 cycles + brachytherapy) or open/minimally invasive pelvic and para-aortic lymph node dissection followed by CCRT. Randomization is stratified by status of para-aortic lymph node. The primary endpoint is PFS. Secondary endpoints are OS and surgical complications. A total of 452 patients will be enrolled from multiple hospitals in China within 4 years and followed up for 5 years.
Trial Registration
ClinicalTrials.gov Identifier: NCT04555226
Keywords: Lymph Node Dissection, Stage IIICr, Cervical Cancer, RCT
INTRODUCTION
Cervical cancer is one of the most common malignancies of the female reproductive system. It is a major cause of morbidity and mortality from cancer and presents a serious threat to women’s health. In 2020, there were an estimated 604,127 new cases of cervical cancer in worldwide. More than 85% of these cases occur in developing countries due to a late popularization of human papilloma virus (HPV) vaccines [1,2]. Of the cervical cancer, approximately 53.5% were diagnosed with locally advanced disease, defined as International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IB3, IIA2–IVA, with 5-year relative survival rates range from 24.0% to 76.1% [3]. As has been proven, the number, size, and affected region of lymph nodal metastases are key prognostic factor which have led to the addition of two new subgroups to the FIGO classification in 2018 [4,5,6]. According to the revised FIGO 2018 staging of cervical cancer, imaging and/or pathological findings were incorporated into the staging to assess the lymph nodes. Only pelvic lymph node metastasis is diagnosed stage IIIC1, and the presence of para-abdominal aortic lymph node metastasis is diagnosed stage IIIC2. The staging should also indicate the method of diagnosis, with remarks (r) for diagnosis by imaging and remarks (p) for diagnosis by pathological [7].
Apparently, lymph node metastasis indicates a worse survival prognosis in cervical cancer, with a 3-year survival rate of only 64% compared with 94% of those with negative metastasis [8]. The patients with unresectable macroscopical lymph nodes have a poorer prognosis. Macroscopical lymph nodes also as known as bulky lymph nodes and there is no unambiguous definition, it generally refers to a short axis of ≥15 or 20 mm on imaging [9,10,11]. The 2022 National Comprehensive Cancer Network (NCCN) guidelines also recommend concurrent chemoradiation therapy (CCRT) for stage IIIC, the standard dose of conventional external-beam radiotherapy (EBRT) involves 50–60 Gy which sufficient to control a single, small lymph node metastasis, but it is insufficient for sterilizing the bulky lymph nodes [12,13,14,15]. The management of patients with bulky lymph nodes who may not candidates for radical surgery and not response to CCRT has unmet clinical need for years.
At present, high-dose boosted EBRT and nodal resection are main strategies for bulky lymph nodes [16]. However, higher doses are limited by the risk of serious or fatal toxicities to adjacent organs, such as bladder, rectum and intestine. Removing the bulky lymph nodes might improve the chance of completely sterilizing by CCRT and reduce the toxicity caused by higher dose of radiation. Some studies demonstrated improved survival after bulky nodal resecting [9,17], while others showed no survival benefit from nodal resection in cervical cancer with bulky lymph node [18,19,20]. However, almost of the studies are retrospective with the limitations, such as without unified action protocol for nodal surgery and boosting, enrollment spanned long time and insufficient quantity. Therefore, whether pretreatment resection of the bulky lymph nodes prolonging patient prognosis has always been a controversial issue. A randomized controlled trial might overcome bias related to retrospective study designs.
Thus, it is necessary to conduct a prospective randomized controlled trial, to assess whether resecting bulky lymph nodes before CCRT can achieve a superior prognosis on Stage IIICr of Cervical Cancer. The CQGOG0103 study is a prospective, multicenter and randomized clinical study evaluating bulky lymph nodes dissection on stage IIICr of cervical cancer. The findings of this trial will improve to assess the impact of bulky lymph nodes dissection on stage IIICr of cervical cancer and to examine the specific complications of this therapy, while providing robust data for clinical guidance. The trial was registered with ClinicalTrials.gov (NCT04555226) and initiated on 11th January 2021.
MATERIALS AND METHODS
1. Objectives
The primary aim of this trial is to investigate the effect of lymph node dissection in patients on stage IIICr cervical cancer before CCRT. The secondary aims are to explore the benefit population of lymph node dissection, screen out the relevant factors and assist in the accurate selection of target population of lymph node dissection.
2. End points
The primary end point is the PFS. The 3 years and 5 years OS, surgery complications and quality of life (QOL) are secondary end points.
PFS is defined as the time interval between the date of randomization and radiographic evidence of recurrence (local/distant) or second cancer or death (all causes). OS is defined as the time interval between the date of randomization and death (all causes). The clinical efficacy was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Surgical complications within 12 weeks after surgery will be assessed according to the Clavien-Dindo classification [21]. Health-related quality of life assessed before treatment, 4 weeks and 24 weeks after treatment, through a total score of using the European Organization for Research and Treatment of Cancer questionnaires, specifically core module C30 (V3.0) and cervical cancer module CX24 (EORTC QLQ-C30[V3.0]/CX24), with 54 endpoints in total [22,23].
3. Trial design and patients
The efficacy of lymph node dissection for stage IIICr of cervical cancer (CQGOG0103) is a national, prospective, multicenter and randomized clinical trial (NCT04555226). It will conduct in the leading center, Chongqing University Cancer Hospital, Chongqing, and multiple participating centers which have high volume of gynecologic cancers and high quality of surgery in China.
Eligible patients are histologically confirmed cervical squamous cell carcinoma, adenocarcinoma, adeno-squamous cell carcinoma. Stage IIICr (confirmed by computed tomography [CT]/magnetic resonance imaging [MRI]/positron emission tomography [PET]/CT) and the short diameter of image-positive lymph node ≥15 mm. 452 patients will be equally randomized to receive either CCRT (pelvic EBRT/extended-field EBRT + cisplatin [40 mg/m2] or carboplatin [area under curve {AUC}=2] every week for 5 cycles + brachytherapy) or open/minimally invasive pelvic and para-aortic lymph node dissection followed by CCRT. Randomization is stratified by status of para-aortic lymph node. The trial schema is shown in Fig. 1.
Fig. 1. Trial design.
CCRT, concurrent chemoradiation therapy; CT, computed tomography; MRI, magnetic resonance imaging; OS, overall survival; PALN, para-aortic lymph node; PET, positron emission tomography; PFS, progression free survival.
4. Eligibility criteria
Eligible patients
1) Age: 18–75 years
2) Histopathology: Squamous cell carcinoma, adenocarcinoma, adeno-squamous cell carcinoma
3) Cervical cancer stage IIICr (confirmed by CT/MRI/PET/CT) and the short diameter of image-positive lymph node ≥15 mm
4) Eastern Cooperative Oncology Group score 0–1
5) Expected survival over 6 months
6) The serum or urine pregnancy test must be negative within 7 days before enrollment for the women of childbearing age who should agree that contraception must be used during the trial
7) No surgical contraindication
Exclusion criteria
1) Activity or uncontrol severe infection
2) Liver cirrhosis, Decompensated liver disease
3) History of immune deficiency, including HIV positive or suffering from congenital immunodeficiency disease
4) Chronic renal insufficiency or renal failure
5) Has combined with other malignant tumor which diagnosed within 5 years and/or needed to be treated
6) Myocardial infarction, severe arrhythmia and New York heart association ≥2 for congestive heart failure
7) A history of pelvic artery embolization
8) A history of pelvic radiotherapy
9) A history of partial hysterectomy or radical hysterectomy
10) A history of severe allergic reaction to platinum drugs
11) During the treatment for complications, the drugs which lead to serious liver and/or kidney function impairment need to be used, such as tuberculosis
5. Randomization and masking
Randomization will be done individually at each center. Using a central stratified randomization protocol, in a 1:1 ratio, the computer-based eRand Clinical Trials Central Randomization System (https://erand.odtech.info/) was used for participant registration and randomization, with the Patients were randomly assigned to standard care or experimental groups. The leading center (Chongqing University Cancer Hospital) is the data center. The leading center applies for an account for each participating center through the eRand system. After obtaining the informed consent of the eligible patients, randomization of enrolled patients was performed independently at each participating center. Before an individual is successfully enrolled, her treatment assignment will remain concealed. This trial will be open label: patients and study physicians were aware of treatment assignment. All data will be entered into a database system (dCap, https://dcap.odtech.info/user/login), managed by a specific statistician to ensure the accuracy and completeness of the data.
6. Treatment
All eligible patients will be randomly assigned in a 1:1 ratio to standard treatment group which receive CCRT or surgery group which receive total pelvic and para-aortic lymph node dissection followed by CCRT. The surgical approaches can be either open laparotomy or minimally invasive surgeries (including conventional laparoscopy or robotic laparoscopy). The total pelvic lymph node tissue included in the procedure is the obturator fossa, internal iliac, external iliac regions and common iliac vessels. Para-aortic lymphadenectomy is typically done to the level of the inferior mesenteric artery. The cephalad extent of dissection can be modified based on radiologic or intraoperative findings if the enlarged lymph node extends beyond the inferior mesenteric artery, but not above the renal vein. CCRT will be started postoperatively within 28 days. The details for CCRT are as below:
1) Pelvic EBRT/extended-field EBRT combines with cisplatin (40 mg/m2) or carboplatin (AUC=2, if patient is cisplatin intolerant) every week for 5 cycles, and combines with brachytherapy. For total point A. dose or minimum dose delivered to 90% of high-risk clinical target volume (HR-CTV D90) ≥80 Gy, but no more than 96 Gy. CCRT need to be completed within 56 days.
2) Extended-field EBRT should be carried out for the patients who have image-positive of common iliac lymph nodes (short diameter ≥10 mm) and/or image-positive of para-aortic lymph nodes in the standard treatment group or have para-aortic lymph node pathologic positive in the surgery group.
3) Target dose for image-positive lymph nodes should be reached at least to 55 Gy and the short diameter ≥15 mm should be reached at least to 60 Gy in the standard treatment group. Coverage of surgical cleaned lymph node drainage area requires a dose of 45 Gy. In the surgery group, grossly involved unresected lymph node should be labeled by silver or peptide clips and reference to the lymph node thrust standard of the standard treatment group. The treatment protocol of EBRT is intensity-modulated radiotherapy and the dose constraints to the organ at risks in EBRT + brachytherapy are bladder D2cc ≤80–90 Gy (EQD2), rectum D2cc ≤65–75 Gy (EQD2), sigmoid D2cc ≤70–75 Gy (EQD2), bowel D2cc ≤65-75Gy (EQD2).
4) The adjuvant chemotherapy (ACT) (paclitaxel 135 mg/m2, cisplatin 50 mg/m2, every 3 weeks for 3 cycles; If cisplatin intolerant, paclitaxel 135 mg/m2, carboplatin AUC=4 will be performed) ± brachytherapy (point A dose or HR-CTV D90 is no more than 96 Gy) should be performed for the patients with residual disease confirmed by cervical biopsy and/or image-positive lymph nodes (short diameter ≥15 mm) within 4 weeks after CCRT.
7. Statistical analysis
The aim of the trial is to estimate the difference in PFS with CCRT between lymph node dissection followed by CCRT. With a hazard ratio of 0.7273, power of 0.8, level for alpha error of 0.05, dropout of 20%, and an increase in PFS of 9 months, the target size is 226 cases per group. A total of 452 patients will be enrolled from multiple hospitals in China within 4 years and followed up for 5 years. Time-to-event analyses will be done with Cox proportional hazards regression models with date of operation as starting point. The PFS, 3 years OS and 5 years OS will be compared between each group by log-rank test. The rates of each surgery complication event will be compared by χ2 test or Fisher’s exact test. The t-test or Mann-Whitney U test will be used to compare the scores of life quality before treatment, 4 weeks and 24 weeks after treatment between each group. A value of p=0.05 will be used as the limit of statistical significance in all of the analyses performed. All statistical analyses will be done with latest version of SPSS.
8. Ethics and dissemination
The protocol has been approved by the Ethics Committees of Chongqing University Cancer Hospital. The informed consent was acquired from each enrolled patient. The trial will be conducted according to the principles of the World Medical Association’s Declaration of Helsinki and in accordance with Good Clinical Practice (GCP) standards. The findings of this trial will be presented at international congress and published in a peer-reviewed journal.
9. Patient and public involvement
Patients and the public were not involved in the design of this trial.
DISCUSSION
The CQGOG0103 trial aims to assess whether resecting bulky nodes before CCRT can achieve a better PFS on stage IIICr of cervical cancer. Also, the surgery complications, quality of life and OS will be evaluated. The early stage of cervical cancer can be cured with radical surgery, and most local advanced stages may be cured with CCRT. However, the management of patients with bulky positive lymph nodes who may not candidates for radical surgery and not response to CCRT has unmet clinical need for years. Recently, more and more surgical staging clinical trials [24,25,26] shown pretreatment surgical staging lymphadenectomy for locally advanced cervical cancer allows the adaption of radiotherapy fields to avoid false-positive and false-negative imaging results. Meanwhile surgical staging provides a survival benefit without increasing complications and delaying initiation of CCRT. The lasted NCCN guideline recommend surgical staging for some patients, especially stage IIIC1r. But there are still no guidelines for deal with the bulky lymph nodes. Thus, if our hypothesis is proven, our data will provide strong evidences for resecting bulky lymph nodes before CCRT being accepted as a standard treatment, in order to improve the well-being for such patients.
In CQGOG0103 we only focus on the patients with the bulky lymph nodes (short axis of ≥15 mm). Although, there is lacking of clearly definition of bulky lymph nodes. Song et al classified 268 patients with cervical cancer into three groups: the negative lymphadenopathy (group N), the small (<15 mm) lymphadenopathy (group SP), and the large (≥15 mm) lymphadenopathy (group LP). The result shown that the group LP showed significantly lower survival rates than the groups N and SP (5-year OS rates of 89%, 82%, and 58%, for groups N, SP, and LP, respectively, p<0.001; 5-year DFS rates of 80%, 67%, and 50%, respectively, p<0.001) [10]. Olthof et al indicated that Subgroup analysis for bulky nodes ≥20 mm demonstrated similar survival results among the treatment groups (boosting, debulking, and neither treatment groups) [19]. Moreover, according to RECIST version 1.1 [27], the lymph node with short axis ≥15 mm is considered measurable and assessable as target lesions. Therefore, in our trial we not only choose the stage IIICr, but also demand the short axis of image-positive lymph node ≥15 mm.
The ACT should be performed for the patients with residual disease confirmed by cervical biopsy and/or image-positive lymph nodes (short diameter ≥15 mm) in our trial. Despite the OUTBACK trial shown negative result on ACT, the efficacy of ACT of LACC after CCRT were inconsistent [28,29]. The experts of our trial consider the residual disease after CCRT as the possible helpful factor in identifying subtype that could derive benefit from ACT. So, in our trial only suggested the patients with residual disease after CCRT should be following the ACT as it may provide the most benefit for patients.
Generally, between 5,500 to 6,500 cGy is delivered to involved nodes based on size, location, contribution from brachytherapy, and dose per fraction. If there are still residual lesions in pelvic and abdominal lymph nodes, the radiotherapy dose cannot be further increased due to the limitation of surrounding organs at risk, which is one of the important reasons for tumor treatment failure. In a retrospective analysis [17], 266 patients with cervical cancer who underwent extraperitoneal pelvic and para-aortic lymphadenectomy before radiotherapy were grouped according to lymph node status. The 5 years and 10 years DFS were similar in the endoscopic/visual lymph node metastasis resection group, while all patients in the visual lymph node metastasis unresectable group relapsed. These results suggest that surgical resection of visible and/or large metastatic lymph nodes before concurrent chemoradiotherapy can improve prognosis. Therefore, extraperitoneal pelvic and para-aortic lymphadenectomy before radiotherapy can not only accurately assess abdominal lymph node status, provide information for subsequent radiation field and auxiliary treatment options, but also through the removal of the visible metastasis lymph nodes, increase the radiation and chemotherapy curative effect, which is expected to improve the overall prognosis of patients.
Our prospective and randomized controlled trial requires a large sample size and collaboration with multiple centers. All centers have their high volume of gynecologic cancers and high quality of surgery. The CQGOG0103 trial has registered in ClinicalTrials.gov (NCT04555226) for better multi-center cooperation. The accrual in the lead center (Chongqing University Cancer Hospital, Chongqing) has started in January 2021. Up to October 26th, 2022, 72 patients have been enrolled, with 35 in standard treatment group, 37 in surgery group. The removal of such large lymph nodes is quite difficult, but there are still some tips to share. Although the no-touch method cannot be done for these patients, but unilateral reverse exposure of blood vessels and lymph nodes suggested to be use. To prevent potential tumor spread and vessel damage when the metastases lymph nodes tightly attach to vital blood vessels such as the abdominal aorta, inferior vena cava and iliac vessel, try to avoid holding the lymph nodes and minimize the use of electric equipment throughout the procedure. In this way, the lymph nodes can be completely and safely cut off. So far, there were no surgery-related complications and no serious adverse event.
ACKNOWLEDGEMENTS
We thank Dr. Bairong Xia, Dr. Xiaoying Xie, Dr. Jiaying Bai, Dr. Ge Lou, Dr. Ling Li, Dr. Xinfeng Yang, Dr. Yunyan Ouyang, Dr. Kun Song, Dr. Guonan Zhang, Dr. Ying Zheng, Dr. Li Li, Dr. Zheng Li, Dr. He Huang, Dr. Huanwu Lu, Dr. Jun Wang for their efforts on this study.
Footnotes
Funding: This work was supported by: 1) Misi He: Chongqing Science and Technology Commission (cstc2020jxjl130019); 2) Dongling Zou: National Natural Science Foundation of China (82073129); 3) Dongling Zou: Chongqing Municipal Public Health Bureau, Chongqing People's Municipal Government (2021jstg001); 4) Lin Zhong: Shapingba Science and Technology Committee of Chongqing (Jcd202116); 5) Lin Li: Chongqing Science and Health Committee joint medical research project (2021MSXM295).
Conflict of Interest: No potential conflict of interest relevant to this article was reported.
- Conceptualization: H.M., G.M., T.Y., Z.D.
- Formal analysis: H.M., Z.D.
- Methodology: H.M., G.M., Z.Q., T.Y., Z.L., L.Q., F.X., Z.X., Z.X., C.G., S.Y., X.Q., C.X., L.Y., Z.D.
- Project administration: H.M., G.M., T.Y., Z.L., L.Q., F.X., Z.X., Z.X., C.G., S.Y., X.Q., C.X., L.Y., Z.D.
- Supervision: Z.Q.
- Writing - original draft: H.M., G.M.
- Writing - review & editing: Z.D.
References
- 1.Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–249. doi: 10.3322/caac.21660. [DOI] [PubMed] [Google Scholar]
- 2.Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66:115–132. doi: 10.3322/caac.21338. [DOI] [PubMed] [Google Scholar]
- 3.Wright JD, Matsuo K, Huang Y, Tergas AI, Hou JY, Khoury-Collado F, et al. Prognostic performance of the 2018 International Federation of Gynecology and Obstetrics cervical cancer staging guidelines. Obstet Gynecol. 2019;134:49–57. doi: 10.1097/AOG.0000000000003311. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Ditto A, Martinelli F, Lo Vullo S, Reato C, Solima E, Carcangiu M, et al. The role of lymphadenectomy in cervical cancer patients: the significance of the number and the status of lymph nodes removed in 526 cases treated in a single institution. Ann Surg Oncol. 2013;20:3948–3954. doi: 10.1245/s10434-013-3067-6. [DOI] [PubMed] [Google Scholar]
- 5.Cibula D, Planchamp F, Fischerova D, Fotopoulou C, Kohler C, Landoni F, et al. European Society of Gynaecological Oncology quality indicators for surgical treatment of cervical cancer. Int J Gynecol Cancer. 2020;30:3–14. doi: 10.1136/ijgc-2019-000878. [DOI] [PubMed] [Google Scholar]
- 6.Gouy S, Morice P, Narducci F, Uzan C, Martinez A, Rey A, et al. Prospective multicenter study evaluating the survival of patients with locally advanced cervical cancer undergoing laparoscopic para-aortic lymphadenectomy before chemoradiotherapy in the era of positron emission tomography imaging. J Clin Oncol. 2013;31:3026–3033. doi: 10.1200/JCO.2012.47.3520. [DOI] [PubMed] [Google Scholar]
- 7.Bhatla N, Berek JS, Cuello Fredes M, Denny LA, Grenman S, Karunaratne K, et al. Revised FIGO staging for carcinoma of the cervix uteri. Int J Gynaecol Obstet. 2019;145:129–135. doi: 10.1002/ijgo.12749. [DOI] [PubMed] [Google Scholar]
- 8.Morice P, Castaigne D, Pautier P, Rey A, Haie-Meder C, Leblanc M, et al. Interest of pelvic and paraaortic lymphadenectomy in patients with stage IB and II cervical carcinoma. Gynecol Oncol. 1999;73:106–110. doi: 10.1006/gyno.1998.5308. [DOI] [PubMed] [Google Scholar]
- 9.Hacker NF, Wain GV, Nicklin JL. Resection of bulky positive lymph nodes in patients with cervical carcinoma. Int J Gynecol Cancer. 1995;5:250–256. doi: 10.1046/j.1525-1438.1995.05040250.x. [DOI] [PubMed] [Google Scholar]
- 10.Song S, Kim JY, Kim YJ, Yoo HJ, Kim SH, Kim SK, et al. The size of the metastatic lymph node is an independent prognostic factor for the patients with cervical cancer treated by definitive radiotherapy. Radiother Oncol. 2013;108:168–173. doi: 10.1016/j.radonc.2013.04.015. [DOI] [PubMed] [Google Scholar]
- 11.Choi KH, Kim JY, Lee DS, Lee YH, Lee SW, Sung S, et al. Clinical impact of boost irradiation to pelvic lymph node in uterine cervical cancer treated with definitive chemoradiotherapy. Medicine (Baltimore) 2018;97:e0517. doi: 10.1097/MD.0000000000010517. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Japan Clinical Oncology Group. Toita T, Ohno T, Kaneyasu Y, Uno T, Yoshimura R, et al. A consensus-based guideline defining the clinical target volume for pelvic lymph nodes in external beam radiotherapy for uterine cervical cancer. Jpn J Clin Oncol. 2010;40:456–463. doi: 10.1093/jjco/hyp191. [DOI] [PubMed] [Google Scholar]
- 13.Oh J, Seol KH, Choi YS, Lee JW, Bae JY. Clinical significance of lymph node size in locally advanced cervical cancer treated with concurrent chemoradiotherapy. Yeungnam Univ J Med. 2019;36:115–123. doi: 10.12701/yujm.2019.00143. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Jürgenliemk-Schulz IM, Beriwal S, de Leeuw AA, Lindegaard JC, Nomden CN, Pötter R, et al. Management of nodal disease in advanced cervical cancer. Semin Radiat Oncol. 2019;29:158–165. doi: 10.1016/j.semradonc.2018.11.002. [DOI] [PubMed] [Google Scholar]
- 15.Bacorro W, Dumas I, Escande A, Gouy S, Bentivegna E, Morice P, et al. Dose-volume effects in pathologic lymph nodes in locally advanced cervical cancer. Gynecol Oncol. 2018;148:461–467. doi: 10.1016/j.ygyno.2017.12.028. [DOI] [PubMed] [Google Scholar]
- 16.Cibula D, Pötter R, Planchamp F, Avall-Lundqvist E, Fischerova D, Haie Meder C, et al. The European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology guidelines for the management of patients with cervical cancer. Radiother Oncol. 2018;127:404–416. doi: 10.1016/j.radonc.2018.03.003. [DOI] [PubMed] [Google Scholar]
- 17.Cosin JA, Fowler JM, Chen MD, Paley PJ, Carson LF, Twiggs LB. Pretreatment surgical staging of patients with cervical carcinoma: the case for lymph node debulking. Cancer. 1998;82:2241–2248. doi: 10.1002/(sici)1097-0142(19980601)82:11<2241::aid-cncr20>3.0.co;2-t. [DOI] [PubMed] [Google Scholar]
- 18.Marnitz S, Tsunoda AT, Martus P, Vieira M, Affonso Junior RJ, Nunes J, et al. Surgical versus clinical staging prior to primary chemoradiation in patients with cervical cancer FIGO stages IIB-IVA: oncologic results of a prospective randomized international multicenter (Uterus-11) intergroup study. Int J Gynecol Cancer. 2020;30:1855–1861. doi: 10.1136/ijgc-2020-001973. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Olthof EP, Wenzel H, van der Velden J, Spijkerboer AM, Bekkers R, Beltman JJ, et al. Treatment of bulky lymph nodes in locally advanced cervical cancer: boosting versus debulking. Int J Gynecol Cancer. 2022;32:861–868. doi: 10.1136/ijgc-2022-003357. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Díaz-Feijoó B, Acosta Ú, Torné A, Gil-Ibáñez B, Hernández A, Domingo S, et al. Surgical outcomes of laparoscopic pelvic lymph node debulking during staging aortic lymphadenectomy in locally advanced cervical cancer: a multicenter study. Cancers (Basel) 2022;14:1974. doi: 10.3390/cancers14081974. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Clavien PA, Barkun J, de Oliveira ML, Vauthey JN, Dindo D, Schulick RD, et al. The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg. 2009;250:187–196. doi: 10.1097/SLA.0b013e3181b13ca2. [DOI] [PubMed] [Google Scholar]
- 22.Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365–376. doi: 10.1093/jnci/85.5.365. [DOI] [PubMed] [Google Scholar]
- 23.Greimel ER, Kuljanic Vlasic K, Waldenstrom AC, Duric VM, Jensen PT, Singer S, et al. The European Organization for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire cervical cancer module: EORTC QLQ-CX24. Cancer. 2006;107:1812–1822. doi: 10.1002/cncr.22217. [DOI] [PubMed] [Google Scholar]
- 24.Frumovitz M, Querleu D, Gil-Moreno A, Morice P, Jhingran A, Munsell MF, et al. Lymphadenectomy in locally advanced cervical cancer study (LiLACS): phase III clinical trial comparing surgical with radiologic staging in patients with stages IB2-IVA cervical cancer. J Minim Invasive Gynecol. 2014;21:3–8. doi: 10.1016/j.jmig.2013.07.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Gold MA, Tian C, Whitney CW, Rose PG, Lanciano R. Surgical versus radiographic determination of para-aortic lymph node metastases before chemoradiation for locally advanced cervical carcinoma: a Gynecologic Oncology Group Study. Cancer. 2008;112:1954–1963. doi: 10.1002/cncr.23400. [DOI] [PubMed] [Google Scholar]
- 26.Cho WK, Kim YI, Park W, Yang K, Kim H, Cha H. Para-aortic lymph node recurrence after curative radiotherapy for cervical cancer. Int J Gynecol Cancer. 2019;29:1116–1120. doi: 10.1136/ijgc-2019-000615. [DOI] [PubMed] [Google Scholar]
- 27.Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45:228–247. doi: 10.1016/j.ejca.2008.10.026. [DOI] [PubMed] [Google Scholar]
- 28.Dueñas-González A, Zarbá JJ, Patel F, Alcedo JC, Beslija S, Casanova L, et al. Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the cervix. J Clin Oncol. 2011;29:1678–1685. doi: 10.1200/JCO.2009.25.9663. [DOI] [PubMed] [Google Scholar]
- 29.Čerina D, Boraska Jelavić T, Buljubašić Franić M, Tomić K, Bajić Ž, Vrdoljak E. Is there a place for adjuvant chemotherapy in the treatment of locally advanced cervical cancer? Curr Oncol. 2022;29:5223–5237. doi: 10.3390/curroncol29080415. [DOI] [PMC free article] [PubMed] [Google Scholar]