| Cervical cancer is one of the common gynecological malignant tumors,and surgical treatment is the main treatment method for early-stage cervical cancer.The 2018 version of the FIGO cancer report recommends Q-M type B radical hysterectomy(RH)for patients with stage IA1(LVSI+)and IA2 cervical cancer who don’t have the desire of fertility sparing,and Q-M type C RH for patients with stageⅠB 1,ⅠB2 and selected patients with stage ⅡA.The main difference between these two different radical hysterectomy procedures is the resection extent of the cardinal ligment and uterosacral ligament of the uterus.During Q-M type B RH,half of the cardinal ligament and uterosacral ligament need to be removed,while during Q-M type C RH,doctors need to transect the whole cardinal ligament to the pelvic side wall inside the iliac vessels and the uterosacral ligament close to the sacrum.However,preliminary analysis of the types of hysterectomy based on the large database of clinical diagnosis and treatment of cervical cancer in China reveals that,in China,59.22%of cervical cancer patients who underwent surgical treatment didn’t receive Q-M type C RH,but Q-M type B RH.So,what is the outcome of Q-M type B RH when applied to the surgical treatment of early-stage cervical cancer?Will the different resection extents of cardinal ligament and uterosacral ligament affect the oncological prognosis of early-stage cervical cancer patients?The most important clinical evaluation of cervical cancer oncology prognosis is oncology outcomes,namely 5-year overall survival(OS)and 5-year tumor-free survival(DFS).A comparative study of the oncological outcomes of two types of hysterectomy in the previous literature found that Q-M type B RH can achieve similar oncology outcomes compared to Q-M type C RH in patients with cervical squamous cell carcinoma with a tumor size less than 2 cm and high differentiation.(OS:100.0%vs.100%,DFS:98.33%vs.97.92%,P=0.736).Subsequent studies also found that even in locally advanced cervical cancer patients,after receiving effective neoadjuvant chemotherapy,Q-M type B RH can still achieve an oncological outcome similar to Q-M type C RH group(OS:93.0%vs.96.7%,P=0.42;DFS:88.6%vs.85.5%,P=0.77).A study that included patients with stage ⅠA2,ⅠB1,and ⅡA1 cervical cancer comparing the oncology outcomes of Q-M type B and type C RH found that the 5-year OS in the Q-M type B group was higher than that in the Q-M type C RH group(95.2%vs.86.8%,P=0.0156),and there was no difference in DFS between the two groups after 5 years(91.2%vs.82.9%,P=0.0677).Cox analysis also showed that the type of hysterectomy was the independent risk factor that affecting the postoperative mortality and recurrence,and the Q-M type B RH group had a lower risk of death and recurrence compared with type C RH group.Similar findings in prospective studies support the conclusion that Q-M type B and Q-M type C RH have similar oncological outcomes.However,at present,whether Q-M type B RH could be used in the surgical treatment of early cervical cancer has not yet given a definitive conclusion,and some previous studies have not considered the high-risk factors in pathology and the impact of postoperative adjuvant therapy on the oncology outcome.On the other hand,for the oncological prognosis of cervical cancer,we are also concerning about complications or dysfunctions besides the oncology outcomes.There have been few literatures comparing the complications after Q-M type B and Q-M type C RH.The postoperative complications are more common in urinary tract injury,with an incidence of about 0.4%to 3.7%,which is often related to the intraoperative management of ureteral tunnels.But the sample size of such literature is relatively small.The two different radical hysterectomy surgical procedures have difference scopes of cardinal and uterosacral ligament resection,which leads to different incidence and severity of postoperative bladder,rectum,and sexual dysfunction.Taking bladder dysfunction as an example,the bladder dysfunction after Q-M type B RH is not obvious,and could basically recover within 3 months after surgery,while there is serious bladder dysfunction after Q-M type C RH and long-term use of abdominal pressure to compensate for urination exists.Therefore,in order to avoid serious postoperative dysfunction or complications,many doctors intentionally or unintentionally narrow the scope of surgery,which has also been reported abroad.However,there is no definite conclusion on the efficacy and safety of Q-M type B RH for the surgical treatment of early stage cervical cancer.For the range of cardinal and uterosacral ligaments resection,the Q-M classification,which is simple and universal,is currently used to define different types of hysterectomy.Research on the quantification of the excision length of the cardinal and uterosacral ligaments of the uterus is rare.The concensus range of resection in tumor treatment is 3 cm adjacent to the cancer lesion.For cervical cancer patients with different depths of cervical stromal invasion,the resection lengths of the cardinal and uterosacral ligament resection might be different.According to the current research at home and abroad,the length of resection of the cardinal and uterosacral ligaments in cervical cancer is still defined by different types of hysterectomy.Therefore,we attempt to use the data of Q-M type B and type C RH to preliminarily explore the impact of different resection extent of the cardinal and uterosacral ligaments on the oncological outcome of cervical cancer.We have achieved the three-dimenstional reconstruction and measurement of pericervical ligament in the early stage cervical cancer using CTA or MRI data sets to get quantitative indicators of lesion and ligaments.It is possible to measure the length of the resection lengths of the cardinal and uterosacral ligament directly after surgery to know whether the resection is "enough",so as to realize the individualized decision of the surgical scope of different cervical cancer patients.Therefore,in order to explore the impact of different resection scopes of the cardinal and uterosacral ligament on the oncology prognosis of early-stage cervical cancer,this study intends to compare the oncolologic outcomes,causes of recurrence and death,and severe surgical complications of patients with early-stage cervical cancer who underwent Q-M typeB and type C RH,based on the data of the multi-center retrospective cohort study of cervical cancer clinical diagnosis and treatment in China and the data of the single-center prospective cohort study of Nanfang Hospital,Southern Medical University,and to do the 3D measurement and evaluate the safe resection range of cervical cancer patients,based on the reconstruction of preoperative CTA or MRI data sets.Chapter 1:Comparison of Abdominal type B vs.type C Radical Hysterectomy in Early-stage Cervical Cancer:Based on the Clinical Diagnosis and Treatment for Cervical Cancer in China DatabaseObjective:Based on the clinical diagnosis and treatment for cervical cancer in China database(Four C database),the survival outcomes of Q-M type B and type C RH for patients with early-stage cervical cancer were compared.And the incidence of surgical complications was compared to explore the feasibility of abdominal Q-M type B RH for early stage cervical cancer patients.Material and methods:1.Patients Source:Based on the clinical diagnosis and treatment for cervical cancer in China database and the database of serious surgical complications of cervical cancer,patients’ general information,preoperative laboratory examinations and biopsy pathological results,surgical related information,preoperative and postoperative adjuvant treatment strategies,postoperative pathological data,follow-up data,and information related to serious surgical complications were collected and compared for oncology outcomes and complications.2.Inclusion criteria:2.1 The inclusion criteria of first level:① patients who underwent laparotomy;②underwent Q-M type B or type C RH;③ whose survival outcome was intact.2.2 The inclusion criteria of second level:① patients whose age was over 18 years old;②whose FIGO stage was ⅠA1 with positive LVSI to ⅡA2;③whose histological type was squamous cell carcinoma,adenocarcinoma or adenosquamous cell carcinoma;④ whose the initial treatment was surgery without any preoperative adjuvant therapy;⑤ who underwent open Q-M type B or type C RH with pelvic lymphadenectomy with or without para-aortic lymph node resection;⑥whose survival outcome was intact.2.3 The inclusion criteria of third level:① patients who met the inclusion criteria of the second level;② who received standardized adjuvant treatment after surgery.3.Comparison of oncology outcomes:The 5-year OS and DFS of patients underwent abdominal Q-M type B and type C RH were compared under different levels of inclusion criteria by propensity scores matching.Cox proportional hazard model was adopted to assess whether the type of hysterectomy is an independent risk factor of patients’ prognosis.4.Comparison of postoperative recurrence and causes of death:Based on the aforementioned inclusion criteria,cases with recurrence and cases with tumor death within 5 years after surgery were selected to compare the recurrence patterns and causes of relapse risk factors for death from tumor deaths.5.Comparison of postoperative serious surgical complications:From the database of cervical cancer serious surgical complications,according to the aforementioned second-level inclusion criteria,cases with serious surgical complications were selected,and the incidence and risk factors of severe surgical complications of Q-M type B and type C RH type were analyzed.Results:1.Under the first level of inclusion criteria,before matching,15471 cases were included in the Q-M type B RH group and 4547 cases were in the type C RH group.The 5-year OS difference between the two groups was not statistically significant(90.1%vs 88.7%,P=0.087).The 5-year DFS of the type C RH group was lower than that of the type B group(82.1%vs 84.8%,P=0.002).The risk of relapse or death in the type C RH group was 1.159 times that of the type B group.After the 1:4 matching,10694 cases were included in the type B RH group and 2947 cases in the type C RH group.The 5-year OS difference between the two groups was not statistically significant(90.2%vs 88.7%,P=0.067).The 5-year DFS of the type C RH group was lower than the type B RH group(82.1%vs 84.9%,P=0.002).The risk of recurrence or death in the type C RH group was 1.170 times that of the type B RH group.2.Under the second-level inclusion criteria,before matching,7316 patients in the type B RH group and 1814 patients in the type C RH group were included.5 years OS in the type C RH group(89.5%vs 92.0%,P=0.003),5 years DFS(84.4%vs 87.4%,P<0.001)was lower than that of type B RH group.The risk of death and the risk of recurrence/death in type C RH group were 1.378 times and 1.333 times of those in type B RH group,respectively.After 1:4 matching,6452 cases were included in the type B RH group and 1813 cases in the type C RH group.5-year OS(89.5%vs 92.3%,P=0.001),5-year DFS(84.3%vs 87.9%,P<0.001)in the type C RH group were lower than the type B RH group,the risk of death and the risk of recurrence/death in the Q-M type C RH group are 1.376 times and 1.345 times that of the type B RH group,respectively.3.Under the third-level inclusion criteria,4091 cases in the type B RH group and 971 cases in the type C RH group were included before matching.The differences between 5-year OS(91.7%vs 90.1%,P=0.113)and 5-year DFS(86.8%vs 84.8%,P=0.064)were not statistically significant.The risk of death and the risk of recurrence/death in type C RH group were 1.333 times and 1.267 times of those in type B RH group.After 1:4 matching,3386 cases were included in the type B RH group and 967 cases in the type C RH group.The 5-year OS(90.1%vs 92.2%,P=0.045)and 5-year DFS(84.7%vs 87.1%,P=0.032)in the type C RH group were lower than type B RH group.The risk of death and the risk of recurrence/death in the type C RH group are 1.312 times and 1.261 times that of the type B RH group,respectively.4.Before and after matching,there is no statistical difference between the type B RH group and type C RH group whether it is single site recurrence,organ metastasis,pelvic recurrence or central recurrence and the recurrence site(P>0.05).5.Under the second-level inclusion criteria,182 patients who had serious surgical complications were included.The incidence of serious surgical complications in the type B RH group was lower than that in the type C RH group(1.68%vs 3.25%,P<0.001).Among all the types of serious surgical complications,the most common intraoperative complication was ureteral injury,and the most common postsurgery complication was venous thrombosis.After adjustment,the incidence of severe surgical complications,intraoperative complications and postoperative complications occurred in the type C RH group were 1.564 times,2.024 times,and 1.516 times of the type B RH group,respectively.Conclusion:Through multi-angle and multi-level comparison of early-stage cervical cancer prognosis between Q-M type B and type C RH,the 5-year oncological outcome of the type B RH group was found superior to the type C RH group.The Q-M type B RH group had a lower risk of serious surgical complications than the type C RH group.Q-M type B RH might be safe and effective for surgical treatment of early-stage cervical cancer.Chapter 2:Comparison of Oncology Prognosis between abdominal Q-M type B vs.Type C Radical Hysterectomy in Early-stage Cervical Cancer:A Single Centre Cohort ReportObjective:Based on single-center cohort data,the comparison between Q-M type B and type C RH were conducted,and methods of intraoperative photographs,immediate postoperative questionnaire and specimen measurements were used to accurately determine the extensive of surgery,providing evidence for the possibility of Q-M type B RH in early-stage cervical cancer surgery.Material and methods:426 cervical cancer patients who underwent abdominal Q-M type B or type C RH were enrolled in Nanfang Hospital,Southern Medical University.Patients’ general data,preoperative examination and treatment,surgical data,postoperative pathology,postoperative adjuvant therapy and prognostic data were used to stratify the oncological outcomes of patients in Q-M type B RH group and type C RH group.Inclusion criteria:The first-level inclusion criteria:①age≥18 years old;②FIGO stage ⅠA2-ⅠB1 andⅡA1;③ underwent open Q-M type B or type C RH and pelvic lymphadenectomy with or without para-aortic lymphadenectomy;④ whose survival outcome was intact.The inclusion criteria of second level:① Same as the first level;② The histological type was squamous cell carcinoma,adenocarcinoma or adenosquamous carcinoma;③The initial treatment was direct surgery without preoperative treatment.The inclusion criteria of third level:① Same as the second level;② who received standardized adjuvant treatment after surgery.Results:1.Under the first-level inclusion criteria,278 patients in the Q-M type B RH group and 148 patients in the type C RH group were included before matching.The differences in 5-year OS(88.6%vs 88.6%,P=0.802)and 5-year DFS(85.5%vs 85.0%,P=0.694)were not statistically significant.No statistically significant differences were found in death,recurrence/death risk between the two groups(P>0.05).After 1:2 matching,226 cases in type B RH group and 138 cases in type C RH group were included.The differences in 5-year OS(87.8%vs 89.4%,P=0.814)and 5-year DFS(84.9%vs 85.6%,P=0.898)were not statistically significant.There were no statistically significant differences in death,recurrence/death risk between the two groups(P>0.05).2.Under the second-level inclusion criteria,181 cases in type B RH group and 84 cases in type C RH group were included before matching.The differences in 5-year OS(91.4%vs 93.5%,P=0.990)and 5-year DFS(88.1%vs 89.1%,P=0.735)were not statistically significant.There was no statistically significant difference in death,recurrence/death risk between the two groups(P>0.05).After 1:2 matching,128 cases in the type B RH group and 77 cases in the type C RH group were included.No statistically significant differences were found in 5-year OS(88.7%vs 97.1%,P=0.250),5-year DFS(84.7%vs 92.3%,P=0.541),death risk and recurrence/death risk between the two groups(P>0.05).3.Under the third-level inclusion criteria,94 cases in the type B RH group and 52 cases in the type C RH group were included before matching.The two groups had similar 5-year OS(92.7%vs 92.3%,P=0.674)and 5-year DFS(90.3%vs 87.9%,P=0.426).The differences in death risk and recurrence/death risk were not statistically significant between the two groups(P>0.05).After 1:2 matching,68 cases in the type B RH group and 40 cases in the type C RH group were included.The differences in 5-year OS(96.0%vs 97.4%,P=0.903),5-year DFS(92.4%vs 91.9%,P=0.531)were not statistically significant.There was no statistically significant difference in death,recurrence/death risk between the two groups(P>0.05).Conclusion:Single-center prospective cohort data suggest that Q-M type B RH could achieve similar oncological outcomes compared to Q-M type C RH.Chapter 3:Comparison of Oncology Outcomes between Q-M type B and type C RH in Early-stage Cervical Cancer patients with Different Depths of Cervical Stromal InvasionObjective:Based on the Four C database and the single-center prospective cohort study data,the depth of cervical muscular infiltration was distinguished,and the oncological outcomes after Q-M type B and type C RH were stratified and compared,to providing new ideas for the scope of excision of the cardinal the uterosacral ligaments.Material and methods:Based on the Four C database and single-center prospective cohort study data,we included patients with early-stage cervical cancer who underwent open Q-M type B or type C RH and standard postoperative adjuvant therapy to compare the oncological outcomes.Inclusion criteria:Screened from the Four C database:①age≥18 years old;②whose clinical stage was ⅠA1(with positive LVSI)to ⅡA2;③whose histological type was squamous cell carcinoma,adenocarcinoma or adenosquamous carcinoma;④whose initial treatment was surgery without any adjuvant treatment before surgery;⑤ who underwent open Q-M type B or type C RH and pelvic lymphadenectomy with or without para-aortic lymphadenectomy;⑥ who had definitive survival outcome;⑦ and who received standard adjuvant therapy after surgery.Screened from the single-center cohort database:①Age ≥18 years old;②FIGO stage IA2-IIA2;③whose histological type was squamous cell carcinoma,adenocarcinoma or adenosquamous carcinoma;④whose initial treatment was direct surgery without any preoperative treatment;⑤ who underwent open type B or type C RH and pelvic lymphadenectomy with or without para-aortic lymphadenectomy;⑥ who had definitive survival outcome;⑦ and who received standard adjuvant treatment after surgery.Patients who had cervical stromal invasion≤1/2 depth were considered the superficial cervical stromal invasion group,and who had cervical stromal invasion>1/2 depth were considered the deep cervical stromal invasion group.Results:1.In total,4678 patients in the Four C database were included,including 2062 patients in the superficial cervical stromal invasion group and 2616 patients in the deep cervical stromal invasion group.Before matching,for the superficial cervical stromal invasion group,1630 cases in the Q-M type B RH group and 432 cases in the type C RH group were included.The differences in 5-year OS and DFS between the two groups were not statistically significant(OS:97.5%vs 95.9%,P=0.074;DFS:94.1%vs 92.3%,P=0.111).There was no statistically significant difference in death,recurrence/death risk between the two groups(P>0.05).After 1:4 matching,1461 cases in the type B RH group and 431 cases in the type C RH group were included.There were no statistically significant differences in OS and DFS between the two groups(OS:97.4%vs 95.9%,P=0.102;DFS:93.7%vs 92.3%,P=0.182).No statistically significant differences were found in death and recurrence/death risk between the two groups(P>0.05).Before matching,for the deep cervical stromal invasion group,2179 cases in the type B RH group and 437 cases in the type C RH group were included.The differences in 5-year OS between the two groups were not statistically significant(86.8%vs 83.0%,P=0.051).The 5-year DFS of the type C RH was lower than that of the type B RH group(76.2%vs 80.4%,P=0.027).There was no significant difference in risk of death,recurrence/death between the two groups(P>0.05).After 1:4 matching,1575 cases in type B RH group and 435 cases in type C RH group were included.The 5-year OS and DFS of type C RH group were lower than those of type B RH group(OS:82.9%vs.88.4%,P=0.007;DFS:76.1%vs.82,1%,P=0.006),the risk of death and the risk of recurrence/death in Q-M type C RH group were 1.454 times and 1.334 times of those in Q-M type B group,respectively.2.We further included 1567 patients without any high-risk factors in the superficial cervical stromal invasion group,including 1247 cases in the Q-M type B RH group and 320 cases in the type C RH group.There were no statistical significant differences in 5-year OS and DFS between the two groups(OS:97.8%vs 96.7%,P=0.162;DFS:94.6%vs 92.4%,P=0.106).No statistically significant differences were found in death,recurrence/death risk between the two groups(P>0.05).After 1:4 matching,there were 1149 cases in the type B RH group and 320 cases in the type C RH group.The differences in 5-year OS and DFS between the two groups were not statistically significant(OS:97.8%vs 96.7%,P=0.191;DFS:94.3%vs 92.4%,P=0.170),there was no statistically significant difference in risk of death,recurrence/death between the two groups(P>0.05).Then,450 patients without any high-risk factors in the deep cervical stromal invasion group were included in further analysis,including 361 patients in type B RH group and 89 in type C RH group.No significant differences in OS and DFS between the two groups at 5 years were found(OS:92.6%vs 86.3%,P=0.101;DFS:88.8%vs 81.5%,P=0.069).There were no statistically significant differences in risk of death and recurrence/death between the two groups(P>0.05).3.A total of 133 patients who met the third level inclusion criteria in the single-centre cohort were included,including 73 cases in the superficial cervical stromal invasion group and 60 in the deep cervical stromal invasion group.In the superficial cervical stromal invasion group,52 cases of the type B RH group and 21 cases of the type C RH group were included.The differences in 5-year OS and DFS between the two groups were not statistically significant(OS:91.9%vs 95.0%,P=0.856;DFS:89.0%vs 85.0%,P=0.375)and there were no statistically significant differences in the risk of death and recurrence/death between the two groups(P>0.05).In the deep cervical stromal invasion group,we included 35 cases in the type B RH group and 25 cases in the type C RH group.The differences in 5-year OS and DFS between the two groups were not statistically significant(OS:92.8%vs 89.1%,P=0.481;DFS:90.2%vs 89.1%,P=0.829)and there were no statistically significant differences in risk of death and recurrence/death between the two groups(P>0.05).Conclusion:According to further analyses of different depths of cervical stromal invasion,Q-M type B RH could achieve similar oncological outcomes to type C RH.Chapter 4:Evaluation of individualized resection of the cardinal ligament in cervical cancer patients based on three-dimensional reconstructionObjective:Using a digital three-dimensional(3D)model of peri-cervical ligaments in women based on preoperative CTA/MRI data sets of cervical cancer patients,we explored the possibility of individualized ligament resection,through the evaluation of 3D measurements,matched postoperative specimen measurements and oncology outcomes.Material and methods:A total of 374 patients who were diagnosed with cervical cancer by pretreatment biopsy in our hospital,and received CTA/MRI scan followed by surgery conducted by the same group of doctors were included.Postoperative specimen measurement were finished right after surgery.Three-dimensional models of pelvic structures such as the pelvis,uterus,cervix,primary lesion,cardinal ligament,uterosacral ligament,pelvic vessels and ureter were reconstructed based on the CTA or MRI T2W sequence data sets.Mimics and UG software were utilized to reconstruct and measure the relative parameters.Results:1.The consistency test of the 3D measurement based on CTA or MRI datasets:The intra-group correlation coefficient(ICC)of the measured lengths of the cardinal and uterosacral ligaments based on the digital 3D reconstruction of the CTA and MRI data sets showed that the correlation of average measurement was 0.834(P<0.001)and the consistency of the two sets of data was acceptable.2.The consistency test of surgical resection length of the specimens and the length of the ligaments in vivo:there is a conversion scale between the surgical resection length of the specimens and the length of the ligaments in vivo.The conversion between din vivo and din vitro was eventually defined as din vitro equals to din vivo/1.13,3.Evaluation of the safe resection range of the cardinal ligament of patients with cervical cancer:We established a conception of para-tumor resection range(PRR)and defined the 3D PRR as the sum of the conversional resection length of the CL and the distance from the tumor border to the edge of the cervix.The cut-off value of PRR related to survival was 32.35 mm(POS=0.024,PDFS=0.027).For the 171 patients with stromal invasion<1/2 depth,patients with a PRR over 32.35 mm had a lower risk of death and higher 5-year overall survival(OS)than that in the≤32.35 mm group(HR=0.110,95%CI:0.012-0.988,P=0.046;OS:98.8%vs.86.8%P=0.012).No significant differences were found in 5-year disease-free survival(DFS)between the two groups(92.2%vs.84.4%,P=0.115).For the 178 cases with stromal invasion≥1/2 depth,no significant differences were found in 5-year OS and DFS between groups(≤32.35 mm group vs.>32.35 mm group,OS:71.0%vs.83.0%,P=0.413;DFS:65.7%vs.80.4%,P=0.207).Conclusion:In patients with stromal invasion<1/2 depth,the PRR should reach 32.35 mm to get more survival benefit and the removal of the cardinal ligament should be at least(32.35-distance from tumor edge to cervical edge/1.13)mm. |
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