苛原稔: PCOSの新しい新診断基準. 日産婦誌, 2008;60(9): N-185-190.
Kang S, Yoo HJ, Hwang JH, Lim MC, Seo SS, Park SY.
Sentinel lymph node biopsy in endometrial cancer: meta-analysis of 26 studies.
Gynecol Oncol. 2011 Dec;123(3):522-7. doi: 10.1016/j.ygyno.2011.08.034. Epub 2011 Sep 25.
Abstract/Text
OBJECTIVE: The validity of the sentinel lymph node (SLN) procedure for the assessment of nodal status in patients with endometrial cancer is unclear. We aimed to assess the diagnostic performance of this procedure.
METHODS: We searched the PubMed and Embase databases for studies published before June 1, 2011. Eligible studies had a sample size of at least 10 patients, and reported the detection rate and/or sensitivity of the SLN biopsy.
RESULTS: We identified 26 eligible studies, which included 1101 SLN procedures. The overall weighted-mean number of harvested SLNs was 2.6. The detection rate and the sensitivity were 78% (95% confidence interval [CI]=73%-84%) and 93% (95% CI=87%-100%), respectively. Significant between-study heterogeneity was observed in the analysis of the detection rate (I-squared statistic, 80%). The use of pericervical injection was correlated with the increase of the detection rate (P=0.031). The hysteroscopic injection technique was associated with the decrease of the detection rate (P=0.045) and the subserosal injection technique was associated with the decrease of the sensitivity (P=0.049), if they were not combined with other injection techniques. For the detection rate, significant small-study effects were noted (P<0.001).
CONCLUSIONS: Although SLN biopsy has shown good diagnostic performance in endometrial cancer, such performance should be interpreted with caution because of significant small study effects. Current evidence is not yet sufficient to establish the true performance of SLN biopsy in endometrial cancer.
Copyright © 2011 Elsevier Inc. All rights reserved.
Ballester M, Dubernard G, Lécuru F, Heitz D, Mathevet P, Marret H, Querleu D, Golfier F, Leblanc E, Rouzier R, Daraï E.
Detection rate and diagnostic accuracy of sentinel-node biopsy in early stage endometrial cancer: a prospective multicentre study (SENTI-ENDO).
Lancet Oncol. 2011 May;12(5):469-76. doi: 10.1016/S1470-2045(11)70070-5. Epub 2011 Apr 12.
Abstract/Text
BACKGROUND: Retrospective single-centre series have shown the feasibility of sentinel lymph-node (SLN) identification in endometrial cancer. We did a prospective, multicentre cohort study to assess the detection rate and diagnostic accuracy of the SLN procedure in predicting the pathological pelvic-node status in patients with early stage endometrial cancer.
METHODS: Patients with International Federation of Gynecology and Obstetrics (FIGO) stage I-II endometrial cancer had pelvic SLN assessment via cervical dual injection (with technetium and patent blue), and systematic pelvic-node dissection. All lymph nodes were histopathologically examined and SLNs were serial sectioned and examined by immunochemistry. The primary endpoint was estimation of the negative predictive value (NPV) of sentinel-node biopsy per hemipelvis. This is an ongoing study for which recruitment has ended. The study is registered with ClinicalTrials.gov, number NCT00987051.
FINDINGS: From July 5, 2007, to Aug 4, 2009, 133 patients were enrolled at nine centres in France. No complications occurred after injection of technetium colloid and no anaphylactic reactions were noted after patent blue injection. No surgical complications were reported during SLN biopsy, including procedures that involved conversion to open surgery. At least one SLN was detected in 111 of the 125 eligible patients. 19 of 111 (17%) had pelvic-lymph-node metastases. Five of 111 patients (5%) had an associated SLN in the para-aortic area. Considering the hemipelvis as the unit of analysis, NPV was 100% (95% CI 95-100) and sensitivity 100% (63-100). Considering the patient as the unit of analysis, three patients had false-negative results (two had metastatic nodes in the contralateral pelvic area and one in the para-aortic area), giving an NPV of 97% (95% CI 91-99) and sensitivity of 84% (62-95). All three of these patients had type 2 endometrial cancer. Immunohistochemistry and serial sectioning detected metastases undiagnosed by conventional histology in nine of 111 (8%) patients with detected SLNs, representing nine of the 19 patients (47%) with metastases. SLN biopsy upstaged 10% of patients with low-risk and 15% of those with intermediate-risk endometrial cancer.
INTERPRETATION: SLN biopsy with cervical dual labelling could be a trade-off between systematic lymphadenectomy and no dissection at all in patients with endometrial cancer of low or intermediate risk. Moreover, our study suggests that SLN biopsy could provide important data to tailor adjuvant therapy.
FUNDING: Direction Interrégionale de Recherche Clinique, Ile-de-France, Assistance Publique-Hôpitaux de Paris.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Gu Y, Cheng H, Zong L, Kong Y, Xiang Y.
Operative and Oncological Outcomes Comparing Sentinel Node Mapping and Systematic Lymphadenectomy in Endometrial Cancer Staging: Meta-Analysis With Trial Sequential Analysis.
Front Oncol. 2020;10:580128. doi: 10.3389/fonc.2020.580128. Epub 2021 Jan 13.
Abstract/Text
OBJECTIVE: To evaluate the utility of sentinel lymph node mapping (SLN) in endometrial cancer (EC) patients in comparison with lymphadenectomy (LND).
METHODS: Comprehensive search was performed in MEDLINE, EMBASE, CENTRAL, OVID, Web of science databases, and three clinical trials registration websites, from the database inception to September 2020. The primary outcomes covered operative outcomes, nodal assessment, and oncological outcomes. Software Revman 5.3 was used. Trial sequential analysis (TSA) and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) were performed.
RESULTS: Overall, 5,820 EC patients from 15 studies were pooled in the meta-analysis: SLN group (N = 2,152, 37.0%), LND group (N = 3,668, 63.0%). In meta-analysis of blood loss, SLN offered advantage over LND in reducing operation bleeding (I2 = 74%, P<0.01). Z-curve of blood loss crossed trial sequential monitoring boundaries though did not reach TSA sample size. There was no difference between SLN and LND in intra-operative complications (I2 = 7%, P = 0.12). SLN was superior to LND in detecting positive pelvic nodes (P-LN) (I2 = 36%, P<0.001), even in high risk patients (I2 = 36%, P = 0.001). While no difference was observed in detection of positive para-aortic nodes (PA-LN) (I2 = 47%, P = 0.76), even in high risk patients (I2 = 62%, P = 0.34). Analysis showed no difference between two groups in the number of resected pelvic nodes (I2 = 99%, P = 0.26). SLN was not associated with a statistically significant overall survival (I2 = 79%, P = 0.94). There was no difference in progression-free survival between SLN and LND (I2 = 52%, P = 0.31). No difference was observed in recurrence. Based on the GRADE assessment, we considered the quality of current evidence to be moderate for P-LN biopsy, low for items like blood loss, PA-LN positive.
CONCLUSION: The present meta-analysis underlines that SLN is capable of reducing blood loss during operation in regardless of surgical approach with firm evidence from TSA. SLN mapping is more targeted for less node dissection and more detection of positive lymph nodes even in high risk patients with conclusive evidence from TSA. Utility of SLN yields no survival detriment in EC patients.
Copyright © 2021 Gu, Cheng, Zong, Kong and Xiang.
Walker JL, Piedmonte MR, Spirtos NM, Eisenkop SM, Schlaerth JB, Mannel RS, Spiegel G, Barakat R, Pearl ML, Sharma SK.
Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2.
J Clin Oncol. 2009 Nov 10;27(32):5331-6. doi: 10.1200/JCO.2009.22.3248. Epub 2009 Oct 5.
Abstract/Text
PURPOSE: The objective was to compare laparoscopy versus laparotomy for comprehensive surgical staging of uterine cancer.
PATIENTS AND METHODS: Patients with clinical stage I to IIA uterine cancer were randomly assigned to laparoscopy (n = 1,696) or open laparotomy (n = 920), including hysterectomy, salpingo-oophorectomy, pelvic cytology, and pelvic and para-aortic lymphadenectomy. The main study end points were 6-week morbidity and mortality, hospital length of stay, conversion from laparoscopy to laparotomy, recurrence-free survival, site of recurrence, and patient-reported quality-of-life outcomes.
RESULTS: Laparoscopy was initiated in 1,682 patients and completed without conversion in 1,248 patients (74.2%). Conversion from laparoscopy to laparotomy was secondary to poor visibility in 246 patients (14.6%), metastatic cancer in 69 patients (4.1%), bleeding in 49 patients (2.9%), and other cause in 70 patients (4.2%). Laparoscopy had fewer moderate to severe postoperative adverse events than laparotomy (14% v 21%, respectively; P < .0001) but similar rates of intraoperative complications, despite having a significantly longer operative time (median, 204 v 130 minutes, respectively; P < .001). Hospitalization of more than 2 days was significantly lower in laparoscopy versus laparotomy patients (52% v 94%, respectively; P < .0001). Pelvic and para-aortic nodes were not removed in 8% of laparoscopy patients and 4% of laparotomy patients (P < .0001). No difference in overall detection of advanced stage (stage IIIA, IIIC, or IVB) was seen (17% of laparoscopy patients v 17% of laparotomy patients; P = .841).
CONCLUSION: Laparoscopic surgical staging for uterine cancer is feasible and safe in terms of short-term outcomes and results in fewer complications and shorter hospital stay. Follow-up of these patients will determine whether surgical technique impacts pattern of recurrence or disease-free survival.
Terai Y, Tanaka T, Sasaki H, Kawaguchi H, Fujiwara S, Yoo S, Tanaka Y, Tsunetoh S, Kanemura M, Ohmichi M.
Total laparoscopic modified radical hysterectomy with lymphadenectomy for endometrial cancer compared with laparotomy.
J Obstet Gynaecol Res. 2014 Feb;40(2):570-5. doi: 10.1111/jog.12194. Epub 2013 Oct 11.
Abstract/Text
AIM: This is the first report to determine the feasibility and safety of total laparoscopic modified radical hysterectomy (TLMRH) in the treatment of presumed stage I endometrial cancer.
METHODS: This was a retrospective study of 132 consecutive patients who underwent surgery for early endometrial cancer. Thirty-nine patients underwent TLMRH and bilateral salpingo-oophorectomy (BSO), and 93 had a total abdominal extrafascial hysterectomy and BSO. Lymphadenectomy was performed in 87 patients. The groups were compared for epidemiological and clinical characteristics, surgical outcomes, hospital stay, lymph nodes harvested, and intraoperative and postoperative complications.
RESULTS: The patients in the TLMRH group had less blood loss (42.9 ± 76.3 vs 236.8 ± 186.6 mL, P < 0.0001), a similar number of lymph nodes removed (32.3 ± 13.1 vs 28.0 ± 11.9, P = 0.15), less need for analgesia and a shorter hospital stay (9.3 ± 2.5 vs 14.6 ± 12.6 days, P = 0.009) but longer operations (321.1 ± 65.9 vs 262.6 ± 75.0 min, P < 0.0001) than those treated by laparotomy. In our study, we had no conversions from laparoscopy to laparotomy. No major complications occurred in the TLMRH group. The patients who underwent TLMRH had less intense postoperative pain than patients treated by laparotomy. The median length of vaginal cuff removed was 12.0 ± 4.1 mm in the TLMRH group, and was 5.6 ± 6.6 mm in the laparotomy group (P < 0.0001). No patients demonstrated recurrence in either of the groups after a median follow-up of 48.5 months (range, 1-84).
CONCLUSION: TLMRH is a safe and reliable alternative to open surgery in the management of early endometrial carcinoma, with a significantly reduced hospital stay and complications.
© 2013 The Authors. Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology.
Yaegashi N, Ito K, Niikura H.
Lymphadenectomy for endometrial cancer: is paraaortic lymphadenectomy necessary?
Int J Clin Oncol. 2007 Jun;12(3):176-80. doi: 10.1007/s10147-006-0621-2. Epub 2007 Jun 27.
Abstract/Text
Total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO) have been performed as a standard surgical treatment for endometrial cancer. Many studies have reported on issues such as whether retroperitoneal lymphadenectomy should also be performed with TAH+BSO, to what extent lymphadenectomy should be performed when TAH+BSO is performed, and in what type of patients should lymphadenectomy be performed. These issues have been actively discussed, but there has not been any consensus. In this review article, the benefits of retroperitoneal lymphadenectomy in the initial surgical treatment for endometrial cancer will be discussed in terms of patients with pelvic lymphadenectomy and those with paraaortic (PA) lymphadenectomy. From the previous data, the establishment of TAH+BSO plus pelvic lymphadenectomy as the standard surgical treatment for endometrial cancer is thought to be reasonable. In this situation, is there benefit in performing PA lymphadenectomy? A discussion will be provided by separating the diagnostic significance from the therapeutic significance of this treatment. At present, there are no established treatments for PA-lymph node-positive patients that can be recommended more than the adjuvant therapies that are already performed at various institutions. A scientific basis that clearly indicates the therapeutic effect of PA lymphadenectomy does not exist at the present time. Despite performing thorough PA lymphadenectomy, the route of progression to extrauterine sites cannot be completely controlled. The standard surgical procedure for endometrial cancer is TAH+BSO+pelvic lymphadenectomy, which is considered necessary and sufficient. At present, the addition of PA lymphadenectomy for endometrial cancer can be regarded as only an investigated protocol.
Abu-Rustum NR, Gomez JD, Alektiar KM, Soslow RA, Hensley ML, Leitao MM Jr, Gardner GJ, Sonoda Y, Chi DS, Barakat RR.
The incidence of isolated paraaortic nodal metastasis in surgically staged endometrial cancer patients with negative pelvic lymph nodes.
Gynecol Oncol. 2009 Nov;115(2):236-8. doi: 10.1016/j.ygyno.2009.07.016. Epub 2009 Aug 9.
Abstract/Text
OBJECTIVE: To describe the incidence of isolated paraaortic nodal metastasis in surgically staged endometrial cancer patients with negative pelvic lymph nodes.
METHODS: Using a prospectively maintained database we identified all cases of endometrial cancer that had both pelvic and aortic nodal dissection and determined the rate of isolated paraaortic nodal metastasis in the setting of negative pelvic nodes. For this report a satisfactory pelvic node dissection meant the identification of 8 or more pelvic nodes on final pathology.
RESULTS: 1942 endometrial cancer patients were surgically treated at our institution from 1/93 to 1/08. 847 had both pelvic and paraaortic nodes removed during surgery and identified by pathology. 734 had negative pelvic nodes with at least one paraaortic node identified. Only 12 (1.6%) had positive paraaortic nodes with negative pelvic nodes. Seven (1%) of 640 cases with 8 or more negative pelvic nodes had positive paraaortic nodes. Final grade for these cases included: G1 (2), G2 (2), G3 (1), papillary serous (1), and undifferentiated (1). Of the 570 cases with a final diagnosis of grade 1 endometrial cancer, 187 had both pelvic and aortic node dissection during the same operation, and 2/187 (1%) had a positive paraaortic node with negative pelvic nodes.
CONCLUSIONS: Isolated paraaortic nodal metastasis in the setting of negative pelvic nodes occurs in approximately 1% of surgically staged endometrial cancer cases. This low rate seems consistent for low- and high-grade lesions. Future studies looking at the incidence of isolated paraaortic nodal metastasis in the setting of negative sentinel pelvic nodes are warranted.
Todo Y, Kato H, Kaneuchi M, Watari H, Takeda M, Sakuragi N.
Survival effect of para-aortic lymphadenectomy in endometrial cancer (SEPAL study): a retrospective cohort analysis.
Lancet. 2010 Apr 3;375(9721):1165-72. doi: 10.1016/S0140-6736(09)62002-X. Epub 2010 Feb 24.
Abstract/Text
BACKGROUND: In response to findings that pelvic lymphadenectomy does not have any therapeutic benefit for endometrial cancer, we aimed to establish whether complete, systematic lymphadenectomy, including the para-aortic lymph nodes, should be part of surgical therapy for patients at intermediate and high risk of recurrence.
METHODS: We selected 671 patients with endometrial carcinoma who had been treated with complete, systematic pelvic lymphadenectomy (n=325 patients) or combined pelvic and para-aortic lymphadenectomy (n=346) at two tertiary centres in Japan (January, 1986-June, 2004). Patients at intermediate or high risk of recurrence were offered adjuvant radiotherapy or chemotherapy. The primary outcome measure was overall survival.
FINDINGS: Overall survival was significantly longer in the pelvic and para-aortic lymphadenectomy group than in the pelvic lymphadenectomy group (HR 0.53, 95% CI 0.38-0.76; p=0.0005). This association was also recorded in 407 patients at intermediate or high risk (p=0.0009), but overall survival was not related to lymphadenectomy type in low-risk patients. Multivariate analysis of prognostic factors showed that in patients with intermediate or high risk of recurrence, pelvic and para-aortic lymphadenectomy reduced the risk of death compared with pelvic lymphadenectomy (0.44, 0.30-0.64; p<0.0001). Analysis of 328 patients with intermediate or high risk who were treated with adjuvant radiotherapy or chemotherapy showed that patient survival improved with pelvic and para-aortic lymphadenectomy (0.48, 0.29-0.83; p=0.0049) and with adjuvant chemotherapy (0.59, 0.37-1.00; p=0.0465) independently of one another.
INTERPRETATION: Combined pelvic and para-aortic lymphadenectomy is recommended as treatment for patients with endometrial carcinoma of intermediate or high risk of recurrence. If a prospective randomised or comparative cohort study is planned to validate the therapeutic effect of lymphadenectomy, it should include both pelvic and para-aortic lymphadenectomy in patients of intermediate or high risk of recurrence.
FUNDING: Japanese Foundation for Multidisciplinary Treatment of Cancer, and the Japan Society for the Promotion of Science.
Copyright 2010 Elsevier Ltd. All rights reserved.
Gunderson CC, Fader AN, Carson KA, Bristow RE.
Oncologic and reproductive outcomes with progestin therapy in women with endometrial hyperplasia and grade 1 adenocarcinoma: a systematic review.
Gynecol Oncol. 2012 May;125(2):477-82. doi: 10.1016/j.ygyno.2012.01.003. Epub 2012 Jan 11.
Abstract/Text
OBJECTIVE: The objective of this review was to analyze published contemporary oncologic and reproductive outcomes in women with endometrial hyperplasia or cancer undergoing medical management with progestin therapy.
METHODS: A systematic review of oncologic and pregnancy outcomes in women with complex atypical hyperplasia or grade 1 adenocarcinoma was performed using a comprehensive search of the MEDLINE literature. English language studies published from 2004 to 2011 which utilized hormonal therapy were identified using key words endometrial hyperplasia, endometrial cancer, fertility preservation, hormone and progestin therapy. Fisher's exact test was used to calculate statistical differences.
RESULTS: Forty-five studies with 391 study subjects were identified. The median age was 31.7 years. Therapies included medroxyprogesterone (49%), megestrol acetate (25%), levonorgestrel intrauterine device (19%), hydroxyprogesterone caproate (0.8%), and unspecified/miscellaneous progestins (13.5%). Overall, 344 women (77.7%) demonstrated a response to hormonal therapy. After a median follow up period of 39 months, a durable complete response was noted in 53.2%. The complete response rate was significantly higher for those with hyperplasia than for women with carcinoma (65.8% vs. 48.2%, p=.002). The median time to complete response was 6 months (range, 1-18 months). Recurrence after an initial response was noted in 23.2% with hyperplasia and 35.4% with carcinoma during the study periods (p=.03). Persistent disease was observed in 14.4% of women with hyperplasia and 25.4% of women with carcinoma (p=.02). During the respective study periods, 41.2% of those with hyperplasia and 34.8% with a history of carcinoma became pregnant (p=.39), with 117 live births reported.
CONCLUSION: Based on this systematic review of the contemporary literature, endometrial hyperplasia has a significantly higher likelihood of response (66%) to hormonal therapy than grade 1 endometrial carcinoma (48%). Disease persistence is more common in women with carcinoma (25%) compared to hyperplasia (14%). Reproductive outcomes do not seem to differ between the cohorts.
Copyright © 2012 Elsevier Inc. All rights reserved.
Randall ME, Filiaci VL, Muss H, Spirtos NM, Mannel RS, Fowler J, Thigpen JT, Benda JA; Gynecologic Oncology Group Study.
Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group Study.
J Clin Oncol. 2006 Jan 1;24(1):36-44. doi: 10.1200/JCO.2004.00.7617. Epub 2005 Dec 5.
Abstract/Text
PURPOSE: To compare whole-abdominal irradiation (WAI) and doxorubicin-cisplatin (AP) chemotherapy in women with stage III or IV endometrial carcinoma having a maximum of 2 cm of postoperative residual disease.
PATIENTS AND METHODS: Four hundred twenty-two patients were entered onto this trial. Of 396 assessable patients, 202 were randomly allocated to receive WAI, and 194 were allocated to receive AP. Irradiation dosage was 30 Gy in 20 fractions, with a 15-Gy boost. Chemotherapy consisted of doxorubicin 60 mg/m2 and cisplatin 50 mg/m2 every 3 weeks for seven cycles, followed by one cycle of cisplatin.
RESULTS: Most patient and tumor characteristics were well balanced. The median patient age was 63 years; 50% had endometrioid tumors. Median follow-up time was 74 months. The hazard ratio for progression adjusted for stage was 0.71 favoring AP (95% CI, 0.55 to 0.91; P < .01). At 60 months, 50% of patients receiving AP were predicted to be alive and disease free when adjusting for stage compared with 38% of patients receiving WAI. The stage-adjusted death hazard ratio was 0.68 (95% CI, 0.52 to 0.89; P < .01) favoring AP. Moreover, at 60 months and adjusting for stage, 55% of AP patients were predicted to be alive compared with 42% of WAI patients. Greater acute toxicity was seen with AP. Treatment probably contributed to the deaths of eight patients (4%) on the AP arm and five patients (2%) on the WAI arm.
CONCLUSION: Chemotherapy with AP significantly improved progression-free and overall survival compared with WAI. Nevertheless, further advances in efficacy and reduction in toxicity are clearly needed.
Susumu N, Sagae S, Udagawa Y, Niwa K, Kuramoto H, Satoh S, Kudo R; Japanese Gynecologic Oncology Group.
Randomized phase III trial of pelvic radiotherapy versus cisplatin-based combined chemotherapy in patients with intermediate- and high-risk endometrial cancer: a Japanese Gynecologic Oncology Group study.
Gynecol Oncol. 2008 Jan;108(1):226-33. doi: 10.1016/j.ygyno.2007.09.029. Epub 2007 Nov 9.
Abstract/Text
OBJECTIVE: To establish an optimal adjuvant therapy for intermediate- and high-risk endometrial cancer patients, we conducted a multi-center randomized phase III trial of adjuvant pelvic radiation therapy (PRT) versus cyclophosphamide-doxorubicin-cisplatin (CAP) chemotherapy in women with endometrioid adenocarcinoma with deeper than 50% myometrial invasion.
METHODS: Among 385 evaluated patients, 193 patients received PRT and 192 received CAP. The PRT group received at least 40 Gy. The CAP group received cyclophosphamide (333 mg/m2), doxorubicin (40 mg/m2) and cisplatin (50 mg/m2) every 4 weeks for 3 or more courses.
RESULTS: No statistically significant differences in progression-free survival (PFS) and overall survival (OS) were observed. The 5-year PFS rates in the PRT and CAP groups were 83.5% and 81.8% respectively, while the 5-year OS rates were 85.3% and 86.7% respectively. These rates were also not significantly different in a low- to intermediate-risk group defined as stage IC patients under 70 years old with G1/2 endometrioid adenocarcinoma. However, among 120 patients in a high- to intermediate-risk group defined as (1) stage IC in patients over 70 years old or with G3 endometrioid adenocarcinoma or (2) stage II or IIIA (positive cytology), the CAP group had a significantly higher PFS rate (83.8% vs. 66.2%, log-rank test P=0.024, hazard ratio 0.44) and higher OS rate (89.7% vs. 73.6%, log-rank test P=0.006, hazard ratio 0.24). Adverse effects were not significantly increased in the CAP group versus the PRT group.
CONCLUSION: Adjuvant chemotherapy may be a useful alternative to radiotherapy for intermediate-risk endometrial cancer.
Galaal K, Al Moundhri M, Bryant A, Lopes AD, Lawrie TA.
Adjuvant chemotherapy for advanced endometrial cancer.
Cochrane Database Syst Rev. 2014 May 15;2014(5):CD010681. doi: 10.1002/14651858.CD010681.pub2. Epub 2014 May 15.
Abstract/Text
BACKGROUND: Approximately 13% of women diagnosed with endometrial cancer present with advanced stage disease (International Federation of Gynecology and Obstetrics (FIGO) stage III/IV). The standard treatment of advanced endometrial cancer consists of cytoreductive surgery followed by radiation therapy, or chemotherapy, or both. There is currently little agreement about which adjuvant treatment is the safest and most effective.
OBJECTIVES: To evaluate the effectiveness and safety of adjuvant chemotherapy compared with radiotherapy or chemoradiation, and to determine which chemotherapy agents are most effective in women presenting with advanced endometrial cancer (FIGO stage III/IV).
SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Collaborative Review Group's Trial Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 10 2013), MEDLINE and EMBASE up to November 2013. Also we searched electronic clinical trial registries for ongoing trials.
SELECTION CRITERIA: Randomised controlled trials (RCTs) of adjuvant chemotherapy compared with radiotherapy or chemoradiation in women with FIGO stage III and IV endometrial cancer.
DATA COLLECTION AND ANALYSIS: Two review authors selected trials, extracted data, and assessed trials for risk of bias. Where necessary, we contacted trial investigators for relevant, unpublished data. We pooled data using the random-effects model in Review Manager (RevMan) software.
MAIN RESULTS: We included four multicentre RCTs involving 1269 women with primary FIGO stage III/IV endometrial cancer. We considered the trials to be at low to moderate risk of bias. All participants received primary cytoreductive surgery. Two trials, evaluating 620 women (83% stage III, 17% stage IV), compared adjuvant chemotherapy with adjuvant radiotherapy; one trial evaluating 552 women (88% stage III, 12% stage IV) compared two chemotherapy regimens (cisplatin/doxorubicin/paclitaxel (CDP) versus cisplatin/doxorubicin (CD) treatment) in women who had all undergone adjuvant radiotherapy; and one trial contributed no data.Overall survival (OS) and progression-free survival (PFS) was longer with adjuvant chemotherapy compared with adjuvant radiotherapy (OS: hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.57 to 0.99, I² = 22%; and PFS: HR 0.74, 95% CI 0.59 to 0.92, I² = 0%). Sensitivity analysis using adjusted and unadjusted OS data, gave similar results. In subgroup analyses, the effects on survival in favour of chemotherapy were not different for stage III and IV, or stage IIIA and IIIC (tests for subgroup differences were not significant and I² = 0%). This evidence was of moderate quality. Data from one trial showed that women receiving adjuvant chemotherapy were more likely to experience haematological and neurological adverse events and alopecia, and more likely to discontinue treatment (33/194 versus 6/202; RR 5.73, 95% CI 2.45 to 13.36), than those receiving adjuvant radiotherapy. There was no statistically significant difference in treatment-related deaths between the chemotherapy and radiotherapy treatment arms (8/309 versus 5/311; Risk Ratio (RR) 1.67, 95% CI 0.55 to 5.00).There was no clear difference in PFS between intervention groups in the one trial that compared CDP versus CD (552 women; HR 0.90, 95% CI 0.69 to 1.17). We considered this evidence to be of moderate quality. Mature OS data from this trial were not yet available. Severe haematological and neurological adverse events occurred more frequently with CDP than CD.We found no trials to include of adjuvant chemotherapy versus chemoradiation in advanced endometrial cancer; however we identified one ongoing trial of this comparison.
AUTHORS' CONCLUSIONS: There is moderate quality evidence that chemotherapy increases survival time after primary surgery by approximately 25% relative to radiotherapy in stage III and IV endometrial cancer. There is limited evidence that it is associated with more adverse effects. There is some uncertainty as to whether triplet regimens offer similar survival benefits over doublet regimens in the long-term. Further research is needed to determine which chemotherapy regimen(s) are the most effective and least toxic, and whether the addition of radiotherapy further improves outcomes. A large trial evaluating the benefits and risks of adjuvant chemoradiation versus chemotherapy in advanced endometrial cancer is ongoing.
Nomura H, Aoki D, Michimae H, Mizuno M, Nakai H, Arai M, Sasagawa M, Ushijima K, Sugiyama T, Saito M, Tokunaga H, Matoda M, Nakanishi T, Watanabe Y, Takahashi F, Saito T, Yaegashi N; Japanese Gynecologic Oncology Group.
Effect of Taxane Plus Platinum Regimens vs Doxorubicin Plus Cisplatin as Adjuvant Chemotherapy for Endometrial Cancer at a High Risk of Progression: A Randomized Clinical Trial.
JAMA Oncol. 2019 Jun 1;5(6):833-840. doi: 10.1001/jamaoncol.2019.0001.
Abstract/Text
IMPORTANCE: The efficacy of taxane plus platinum regimens has been demonstrated for advanced or recurrent endometrial cancer; however, it has not been assessed in postoperative adjuvant chemotherapy for endometrial cancer.
OBJECTIVE: To evaluate the clinical benefit of taxane plus platinum compared with standard doxorubicin plus cisplatin as postoperative adjuvant chemotherapy in endometrial cancer.
DESIGN, SETTING, AND PARTICIPANTS: In this multicenter, open-label, phase 3 randomized clinical trial, patients with endometrial cancer at high-risk stage I or II or stage III or IV that did not extend beyond the abdominal cavity and had 2 cm or greater residual tumor were included from 118 institutions in Japan from November 24, 2006, to January 7, 2011. Data was analyzed from March 15, 2017, to June 30, 2017.
INTERVENTIONS: Eligible patients were randomly assigned (1:1:1) to receive 6 cycles of doxorubicin, 60 mg/m2, plus cisplatin, 50 mg/m2, on day 1; docetaxel, 70 mg/m2, plus cisplatin, 60 mg/m2, on day 1; or paclitaxel, 180 mg/m2, plus carboplatin (area under the curve, 6.0 mg/mL × min) on day 1 every 3 weeks.
MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival. Secondary end points were overall survival, occurrence of adverse events, tolerability, and status of lymph node dissection.
RESULTS: Among 788 eligible patients, the median (SD) age was 59 (22-74) years; 263 patients were assigned to doxorubicin plus cisplatin treatment, 263 patients to docetaxel plus cisplatin treatment, and 262 patients to paclitaxel plus carboplatin treatment. The number of patients who did not complete 6 cycles was 53 (20.1%) for the doxorubicin plus cisplatin group, 45 (17.1%) for the docetaxel plus cisplatin group, and 63 (24.0%) for the paclitaxel plus carboplatin group. Tolerability of these regimens were not statistically different. After a median follow-up period of 7 years, there was no statistical difference of progression-free survival (doxorubicin plus cisplatin, 191; docetaxel plus cisplatin, 208; paclitaxel plus carboplatin, 187; P = .12) or overall survival (doxorubicin plus cisplatin, 217; docetaxel plus cisplatin, 223; paclitaxel plus carboplatin, 215; P = .67) among the 3 groups. The 5-year progression-free survival rate was 73.3% for the doxorubicin plus cisplatin group, 79.0% for the docetaxel plus cisplatin group, and 73.9% for the paclitaxel plus carboplatin group, while the 5-year overall survival rates were 82.7%, 88.1%, and 86.1%, respectively.
CONCLUSIONS AND RELEVANCE: There was no significant difference of survival among patients receiving doxorubicin plus cisplatin, docetaxel plus cisplatin, or paclitaxel plus carboplatin as postoperative adjuvant chemotherapy for endometrial cancer. Because each regimen showed adequate tolerability but different toxic effects, taxane plus platinum regimens may be a reasonable alternative to treatment with doxorubicin plus cisplatin.
TRIAL REGISTRATION: UMIN-CTR identifier: UMIN000000522.
Creutzberg CL, Nout RA, Lybeert ML, Wárlám-Rodenhuis CC, Jobsen JJ, Mens JW, Lutgens LC, Pras E, van de Poll-Franse LV, van Putten WL; PORTEC Study Group.
Fifteen-year radiotherapy outcomes of the randomized PORTEC-1 trial for endometrial carcinoma.
Int J Radiat Oncol Biol Phys. 2011 Nov 15;81(4):e631-8. doi: 10.1016/j.ijrobp.2011.04.013. Epub 2011 Jun 2.
Abstract/Text
PURPOSE: To evaluate the very long-term results of the randomized Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC)-1 trial for patients with Stage I endometrial carcinoma (EC), focusing on the role of prognostic factors for treatment selection and the long-term risk of second cancers.
PATIENTS AND METHODS: The PORTEC trial (1990-1997) included 714 patients with Stage IC Grade 1-2 or Stage IB Grade 2-3 EC. After surgery, patients were randomly allocated to external-beam pelvic radiotherapy (EBRT) or no additional treatment (NAT). Analysis was by intention to treat.
RESULTS: 426 patients were alive at the date of analysis. The median follow-up time was 13.3 years. The 15-year actuarial locoregional recurrence (LRR) rates were 6% for EBRT vs. 15.5% for NAT (p < 0.0001). The 15-year overall survival was 52% vs. 60% (p = 0.14), and the failure-free survival was 50% vs. 54% (p = 0.94). For patients with high-intermediate risk criteria, the 15-year overall survival was 41% vs. 48% (p = 0.51), and the 15-year EC-related death was 14% vs. 13%. Most LRR in the NAT group were vaginal recurrences (11.0% of 15.5%). The 15-year rates of distant metastases were 9% vs. 7% (p = 0.25). Second primary cancers had been diagnosed over 15 years in 19% of all patients, 22% vs. 16% for EBRT vs. NAT (p = 0.10), with observed vs. expected ratios of 1.6 (EBRT) and 1.2 (NAT) compared with a matched population (p = NS). Multivariate analysis confirmed the prognostic significance of Grade 3 for LRR (hazard ratio [HR] 3.4, p = 0.0003) and for EC death (HR 7.3, p < 0.0001), of age >60 (HR 3.9, p = 0.002 for LRR and 2.7, p = 0.01 for EC death) and myometrial invasion >50% (HR 1.9, p = 0.03 and HR 1.9, p = 0.02).
CONCLUSIONS: The 15-year outcomes of PORTEC-1 confirm the relevance of HIR criteria for treatment selection, and a trend for long-term risk of second cancers. EBRT should be avoided in patients with low- and intermediate-risk EC.
Copyright © 2011 Elsevier Inc. All rights reserved.
Keys HM, Roberts JA, Brunetto VL, Zaino RJ, Spirtos NM, Bloss JD, Pearlman A, Maiman MA, Bell JG; Gynecologic Oncology Group.
A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study.
Gynecol Oncol. 2004 Mar;92(3):744-51. doi: 10.1016/j.ygyno.2003.11.048.
Abstract/Text
BACKGROUND: Despite their low risk for recurrence, many women with endometrial adenocarcinoma receive postoperative radiation therapy (RT). This study was developed to determine if adjunctive external beam irradiation lowers the risk of recurrence and death in women with endometrial cancer International Federation of Gynaecology and Obstetrics (FIGO) stages IB, IC, and II (occult disease).
METHODS: Four hundred forty-eight consenting patients with "intermediate risk" endometrial adenocarcinoma were randomized after surgery to either no additional therapy (NAT) or whole pelvic radiation therapy (RT). They were followed to determine toxicity, date and location of recurrence, and overall survival. A high intermediate risk (HIR) subgroup of patients was defined as those with (1) moderate to poorly differentiated tumor, presence of lymphovascular invasion, and outer third myometrial invasion; (2) age 50 or greater with any two risk factors listed above; or (3) age of at least 70 with any risk factor listed above. All other eligible participants were considered to be in a low intermediate risk (LIR) subgroup.
RESULTS: Three hundred ninety-two women met all eligibility requirements (202 NAT, 190 RT). Median follow-up was 69 months. In the entire study population, there were 44 recurrences and 66 deaths (32 disease or treatment-related deaths), and the estimated 2-year cumulative incidence of recurrence (CIR) was 12% in the NAT arm and 3% in the RT arm (relative hazard (RH): 0.42; P=0.007). The treatment difference was particularly evident among the HIR subgroup (2-year CIR in NAT versus RT: 26% versus 6%; RH=0.42). Overall, radiation had a substantial impact on pelvic and vaginal recurrences (18 in NAT and 3 in RT). The estimated 4-year survival was 86% in the NAT arm and 92% for the RT arm, not significantly different (RH: 0.86; P=0.557).
CONCLUSIONS: Adjunctive RT in early stage intermediate risk endometrial carcinoma decreases the risk of recurrence, but should be limited to patients whose risk factors fit a high intermediate risk definition.
ASTEC/EN.5 Study Group; Blake P, Swart AM, Orton J, Kitchener H, Whelan T, Lukka H, Eisenhauer E, Bacon M, Tu D, Parmar MK, Amos C, Murray C, Qian W.
Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-analysis.
Lancet. 2009 Jan 10;373(9658):137-46. doi: 10.1016/S0140-6736(08)61767-5. Epub 2008 Dec 16.
Abstract/Text
BACKGROUND: Early endometrial cancer with low-risk pathological features can be successfully treated by surgery alone. External beam radiotherapy added to surgery has been investigated in several small trials, which have mainly included women at intermediate risk of recurrence. In these trials, postoperative radiotherapy has been shown to reduce the risk of isolated local recurrence but there is no evidence that it improves recurrence-free or overall survival. We report the findings from the ASTEC and EN.5 trials, which investigated adjuvant external beam radiotherapy in women with early-stage disease and pathological features suggestive of intermediate or high risk of recurrence and death from endometrial cancer.
METHODS: Between July, 1996, and March, 2005, 905 (789 ASTEC, 116 EN.5) women with intermediate-risk or high-risk early-stage disease from 112 centres in seven countries (UK, Canada, Poland, Norway, New Zealand, Australia, USA) were randomly assigned after surgery to observation (453) or to external beam radiotherapy (452). A target dose of 40-46 Gy in 20-25 daily fractions to the pelvis, treating five times a week, was specified. Primary outcome measure was overall survival, and all analyses were by intention to treat. These trials were registered ISRCTN 16571884 (ASTEC) and NCT 00002807 (EN.5).
FINDINGS: After a median follow-up of 58 months, 135 women (68 observation, 67 external beam radiotherapy) had died. There was no evidence that overall survival with external beam radiotherapy was better than observation, hazard ratio 1.05 (95% CI 0.75-1.48; p=0.77). 5-year overall survival was 84% in both groups. Combining data from ASTEC and EN.5 in a meta-analysis of trials confirmed that there was no benefit in terms of overall survival (hazard ratio 1.04; 95% CI 0.84-1.29) and can reliably exclude an absolute benefit of external beam radiotherapy at 5 years of more than 3%. With brachytherapy used in 53% of women in ASTEC/EN.5, the local recurrence rate in the observation group at 5 years was 6.1%.
INTERPRETATION: Adjuvant external beam radiotherapy cannot be recommended as part of routine treatment for women with intermediate-risk or high-risk early-stage endometrial cancer with the aim of improving survival. The absolute benefit of external beam radiotherapy in preventing isolated local recurrence is small and is not without toxicity.
Makker V, Colombo N, Casado Herráez A, Monk BJ, Mackay H, Santin AD, Miller DS, Moore RG, Baron-Hay S, Ray-Coquard I, Ushijima K, Yonemori K, Kim YM, Guerra Alia EM, Sanli UA, Bird S, Orlowski R, McKenzie J, Okpara C, Barresi G, Lorusso D.
Lenvatinib Plus Pembrolizumab in Previously Treated Advanced Endometrial Cancer: Updated Efficacy and Safety From the Randomized Phase III Study 309/KEYNOTE-775.
J Clin Oncol. 2023 Jun 1;41(16):2904-2910. doi: 10.1200/JCO.22.02152. Epub 2023 Apr 14.
Abstract/Text
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We report the final prespecified analysis for overall survival (OS), along with updated progression-free survival (PFS) and objective response rate (ORR), and safety from the open-label, randomized, phase III Study 309/KEYNOTE-775. In total, 827 patients with advanced, recurrent, or metastatic endometrial cancer (EC) were randomly assigned to receive lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously once every 3 weeks (n = 411) or chemotherapy of the treating physician's choice (doxorubicin 60 mg/m2 intravenously once every 3 weeks or paclitaxel 80 mg/m2 intravenously once weekly [3 weeks on; 1 week off] [n = 416]). Efficacy was reported for patients with mismatch repair proficient (pMMR) tumors and all-comers, and by subgroups (histology, prior therapy, MMR status). Updated safety was also reported.Lenvatinib plus pembrolizumab showed benefits in OS (pMMR HR, 0.70; 95% CI, 0.58 to 0.83; all-comer HR, 0.65; 95% CI, 0.55 to 0.77), PFS (pMMR HR, 0.60; 95% CI, 0.50 to 0.72; all-comer HR, 0.56; 95% CI, 0.48 to 0.66), and ORR (pMMR patients, 32.4% v 15.1%; all-comers, 33.8% v 14.7%) versus chemotherapy. OS, PFS, and ORR favored lenvatinib plus pembrolizumab in all subgroups of interest. No new safety signals were observed. Lenvatinib plus pembrolizumab continued to show improved efficacy versus chemotherapy and manageable safety in patients with previously treated advanced EC.
O'Malley DM, Bariani GM, Cassier PA, Marabelle A, Hansen AR, De Jesus Acosta A, Miller WH Jr, Safra T, Italiano A, Mileshkin L, Xu L, Jin F, Norwood K, Maio M.
Pembrolizumab in Patients With Microsatellite Instability-High Advanced Endometrial Cancer: Results From the KEYNOTE-158 Study.
J Clin Oncol. 2022 Mar 1;40(7):752-761. doi: 10.1200/JCO.21.01874. Epub 2022 Jan 6.
Abstract/Text
PURPOSE: Pembrolizumab demonstrated durable antitumor activity in patients with previously treated, advanced microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR) tumors, including endometrial cancer, in the nonrandomized, open-label, multicohort, phase II KEYNOTE-158 study (NCT02628067). We report efficacy and safety outcomes for patients with MSI-H/dMMR endometrial cancer enrolled in KEYNOTE-158.
METHODS: Eligible patients from cohorts D (endometrial cancer, regardless of MSI-H/dMMR status) and K (any MSI-H/dMMR solid tumor, except colorectal) with previously treated, advanced MSI-H/dMMR endometrial cancer received pembrolizumab 200 mg once every 3 weeks for 35 cycles. The primary end point was objective response rate per RECIST version 1.1 by independent central radiologic review. Secondary end points included duration of response, progression-free survival, overall survival, and safety.
RESULTS: As of October 5, 2020, 18 of 90 treated patients (20%) had completed 35 cycles of pembrolizumab and 52 (58%) had discontinued treatment. In the efficacy population (patients who received ≥ 1 dose of pembrolizumab and had ≥ 26 weeks of follow-up; N = 79), the median time from first dose to data cutoff was 42.6 (range, 6.4-56.1) months. The objective response rate was 48% (95% CI, 37 to 60), and median duration of response was not reached (2.9-49.7+ months). Median progression-free survival was 13.1 (95% CI, 4.3 to 34.4) months, and median overall survival was not reached (95% CI, 27.2 months to not reached). Among all treated patients, 76% had ≥ 1 treatment-related adverse event (grades 3-4, 12%). There were no fatal treatment-related events. Immune-mediated adverse events or infusion reactions occurred in 28% of patients (grades 3-4, 7%; no fatal events).
CONCLUSION: Pembrolizumab demonstrated robust and durable antitumor activity and encouraging survival outcomes with manageable toxicity in patients with previously treated, advanced MSI-H/dMMR endometrial cancer.
