Adjuvant Chemotherapy For Endometrial Cancer Research Articles

The role of adjuvant chemotherapy in endometrial cancer following pre-operative neoadjuvant chemoradiation therapy (1137)

The role of adjuvant chemotherapy in endometrial cancer following pre-operative neoadjuvant chemoradiation therapy (1137)

PS-BPR02-1: A CASE OF ADVANCED ENDOMETRIAL CANCER AFTER NEPHRECTOMY FOR RENAL CELL CANCER WITH HYPERTENSION AND PROTEINURIA INDUCED BY LENVATINIB

Background: The combination of pembrolizumab plus lenvatinib is approved for advanced endometrial cancer that is not MSI-H or dMMR, is progressive on prior systemic therapy, and is not amenable to curative surgery or radiation. Lenvatinib is an oral, multi-targeted tyrosine kinase inhibitor (TKI) that exerts anti-malignant effects by inhibiting many tyrosine kinase receptors, such as VEGF receptors 1, 2, and 3, fibroblast growth factor receptors 1 through 4, platelet-derived growth factor receptor α, rearranged during transfection (RET), and stem cell factor receptor (KIT) signaling networks. Although lenvatinib's usefulness has been demonstrated, adverse effects such as hypertension and proteinuria often necessitate the discontinuation of administration. We encountered a patient with advanced endometrial cancer after nephrectomy for renal cell cancer who developed hypertension and proteinuria due to lenvatinib. We discussed TKI induced hypertension and proteinuria in patients on pre-existing eGFR decline. Case presentation: A 65-year-old Japanese female was diagnosed in 2011 with concurrent endometrial cancer and right renal cell cancer. She underwent total hysterectomy, bilateral salpingo oophorectomy, and right nephrectomy. She received 6 courses of CAP (cyclophosphamide, epirubicin and cisplatin) therapy as adjuvant chemotherapy for endometrial cancer. More than 7 years later, the patient presented with a vaginal cuff recurrence that was histologically confirmed and radiotherapy was indicated. In 2019, there was a recurrence in pelvic lymph nodes. Between 2019 and 2021, she underwent 9 cycles of chemotherapy with carboplatin plus paclitaxel, however the cancer progression was observed. In February 2021, the patient was started on pembrolizumab and Lenvatinib (20 mg/day) combination therapy. Her creatinine was 0.85 mg/dL, with an eGFR of 52 mL/min/1.73m2 before the administration of lenvatinib. The patient experienced continuous grade 3 hypertension (systolic blood pressure Hiragino Sans 160 mmHg or diastolic blood pressure ≧ 100 mmHg), and 2 antihypertensive agents(amlodipine and ormesartan) were required to control hypertension. Despite lenvatinib dose reduction and the aggressive use of antihypertensive agents, grade 3 hypertension had recurred several times, and then proteinuria gradually increased to 3.0 g/day. Lenvatinib was decreased to 10 mg/day (2 steps of dose reduction) within 2 months of treatment initiation, and finally, hypertention and proteinuria were ameliorated. Conclusion: A history of nephrectomy, pre-existing eGFR decline and hypertension are associated with developing TKI induced proteinuria. These patients should be monitored carefully, and appropriate measures for the early control of hypertension and proteinuria may result in higher-dose treatment with lenvatinib, thereby maximizing its therapeutic effect.

Adjuvant chemotherapy in endometrial cancer.

The role of adjuvant chemotherapy (CT) is controversial in endometrial carcinoma (EC). Surgery alone is usually curative for women who are at a low risk of disease recurrence. The treatment of EC following surgical staging is based on the risk of relapse, which is defined by the cancer stage at diagnosis, histology of the tumor and other prognostic factors such as grade differentiation, the presence of substantial lymphovascular invasion (LVSI), or depth of myometrial invasion (MI). External beam radiotherapy (EBRT) and/or vaginal brachytherapy (VBT) improved local control and are used as adjuvant treatment for early-stage disease. The role of adjuvant CT is controversial in early-stage EC, and there is no uniform approach to the treatment of women with stage III EC or early-staged non-endometrioid EC. Available evidence did not support the indication of adjuvant CT in stage I-II endometroid EC. In those cases at higher risk of relapse, defined as grade 3 tumors with substantial (no focal) LVSI, specifically with deep MI or cervical involvement, could be considered. Adjuvant CT should be administered to stage III EC patients. When RT is indicated (extensive lymph node involvement or deep MI), sequential treatment with RT or "sandwich" regimen may be considered rather than concurrent CRT. The patients with stage IA MI or IB USC may be offered adjuvant CT alone or in combination with VBT, whereas in stage II uterine serous carcinoma patients adding EBRT may be reasonable. Management approach for patients with stage IA without MI USC who underwent a comprehensive surgery remains controversial, and surveillance alone or CT plus VBT is an appropriate option. Early-stage clear-cell carcinoma patients might not benefit for adjuvant CT, but stage III patients might benefit from the combination of CT and EBRT. Stage I-III uterine carcinosarcoma patients might be offered adjuvant CT followed by RT or as a "sandwich" régimen.

Analysis of the relapse patterns and risk factors of endometrial cancer following postoperative adjuvant chemotherapy in a phase III randomized clinical trial

ObjectiveThis study was to analyze patterns and risk factors of relapse after postoperative adjuvant chemotherapy for endometrial cancer. MethodsAmong patients enrolled in a randomized phase III trial (JGOG2043) investigating the efficacy of adjuvant chemotherapy for endometrial cancer at a high risk of progression, the recurrent patients were studied. Clinical information were collected, and correlation between relapse-related factors and clinicopathological factors were analyzed. ResultsAmong 193 patients analyzed, 50% had local relapse and 63% had distant relapse. Local relapse involved regional lymph nodes in 30%, while distant relapse involved the abdominal cavity in 42%. Imaging was used to confirm relapse in 83%, and the median disease-free interval (DFI) was 11.5 months. Factors showing a significant correlation with DFI ≤12 months were residual tumor at surgery (p < 0.01), Grade 3 histology (p < 0.01), and lymph node metastasis (p = 0.03). In contrast, treatment with paclitaxel and carboplatin showed a significant correlation with DFI >12 months (p = 0.04). The median post-relapse overall survival (RS) was 23.9 months. In multivariate analysis, CA125 ≥ 100 U/mL prior to relapse (p < 0.01), distant metastasis (p < 0.01), DFI ≤ 12 months (p = 0.02), and not performing para-aortic lymphadenectomy (p = 0.01) were independently related to poor RS. ConclusionsRelapse of endometrial cancer following adjuvant chemotherapy often occurs by 1 year after treatment, with common relapse sites of the abdominal cavity and regional lymph nodes. Among treatment-related factors, RS was correlated with DFI and para-aortic lymphadenectomy.

Effect of Taxane Plus Platinum Regimens vs Doxorubicin Plus Cisplatin as Adjuvant Chemotherapy for Endometrial Cancer at a High Risk of Progression

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. To evaluate the clinical benefit of taxane plus platinum compared with standard doxorubicin plus cisplatin as postoperative adjuvant chemotherapy in endometrial cancer. 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. 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. 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. 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. 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. UMIN-CTR identifier: UMIN000000522.

A randomized phase III trial of docetaxel plus cisplatin or paclitaxel plus carboplatin compared with doxorubicin plus cisplatin as adjuvant chemotherapy for endometrial cancer at high risk of recurrence: Japanese Gynecologic Oncology Group study (JGOG2043).

5503 Background: The superiority of chemotherapy regimens employing a taxane plus a platinum agent over standard therapy with doxorubicin plus cisplatin (AP) was recently demonstrated for advanced or recurrent endometrial cancer. This multicenter phase III trial evaluated the clinical benefit of taxane plus platinum agent regimens as adjuvant chemotherapy compared with AP for endometrial cancer patients at high risk of recurrence after surgery. Methods: Endometrial cancer patients having a high risk of recurrence and postoperative residual disease &lt; 2 cm were randomly assigned (1:1:1) with stratification by FIGO stage and histologic grade to receive 6 cycles of doxorubicin (60 mg/m2) plus cisplatin (50 mg/m2) on day 1 (AP), docetaxel (70 mg/m2) plus cisplatin (60 mg/m2) on day 1 (DP) or paclitaxel (180 mg/m2) plus carboplatin (AUC 6.0 mg/mL x minute) on day 1 (TC) every 3 weeks as adjuvant chemotherapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), adverse events, and tolerability. Results: From November 2006 to January 2011, 788 patients were enrolled from 118 institutions in Japan and were eligible for evaluation. The proportion of patients receiving 6 cycles was 80% for AP, 83% for DP, and 76% for TC, and tolerability of the regimens showed no significant difference. After a median follow-up period of 7.0 years, there was no statistical difference of PFS (P=0.1246) or OS (P=0.6734) among the 3 groups. The 5-year PFS rate was 74.9% for AP, 80.9% for DP, and 74.7% for TC, while the 5-year OS rates were 84.3%, 89.3%, and 88.4%, respectively. Conclusions: There was no significant difference of survival among patients receiving AP, DP, or TC as adjuvant chemotherapy for endometrial cancer. Since each regimen showed adequate tolerability, taxane plus platinum agent regimens may be a reasonable alternative to AP. Clinical trial information: UMIN000000522.

Patients' and clinicians' preferences for adjuvant chemotherapy in endometrial cancer: an ANZGOG substudy of the PORTEC-3 intergroup randomised trial.

Background:To determine the minimum survival benefits that patients, and their clinicians, judged sufficient to make adjuvant chemotherapy (ACT) worthwhile, in addition to pelvic radiotherapy, for women with high risk and advanced stage endometrial cancer.Methods:Eighty-three participants in the PORTEC-3 trial completed a time trade-off questionnaire before and after adjuvant therapy; 44 of their clinicians completed it once only. The questionnaire used four hypothetical scenarios including baseline survival times without ACT of 5 and 8 years, and baseline survival rates at 5 years without ACT of 50 and 65%.Results:Over 50% of patients judged an extra 1 year of survival time or an extra 5% in survival rate sufficient to make ACT worthwhile. Over 50% of clinicians judged an extra 1 year of survival time, or an extra 10% in survival rate, sufficient to make ACT worthwhile. Compared with patients, clinicians required similar survival time benefits (medians both 1 year, P=0.4), but larger survival rate benefits (medians 8.5% vs 5%, P=0.03), and clinicians' preferences varied less (IQR 0.5–1.5 years vs 0.4–2 years, P=0.0007; 5–10% vs 1–13%, P=0.004). Patients' preferences changed over time for the survival rate scenarios depending on whether they had ACT or not (change in median benefit - 3 months vs 2.5 months respectively, P=0.028). There were no strong predictors of patients' or clinicians' preferences.Conclusions:Patients and clinicians judged moderate survival benefits sufficient to make ACT worthwhile after pelvic radiotherapy for endometrial cancer. These benefits are larger than those judged sufficient by patients with breast or colon cancers, but similar to those judged sufficient by patients with lung or ovarian cancers.

Update on chemotherapy in gynaecological cancers

Key content Ovarian cancer requires multidisciplinary management, usually with postoperative adjuvant chemotherapy. In some cases, however, neo‐adjuvant chemotherapy and delayed surgery may be offered. Recurrent ovarian cancer management is usually treated with chemotherapy, with drug choice often influenced by the platinum‐free interval. The role of adjuvant chemotherapy for endometrial cancer remains open to debate. Adjuvant chemotherapy is increasingly offered for high‐risk cases with lymphovascular space invasion. Carboplatin and paclitaxel are the most effective drugs in adjuvant and recurrent settings. Concomitant cisplatin with radiation therapy is the standard of care for locally advanced cervical cancer; recent studies have shown that the addition of bevacizumab to carboplatin and paclitaxel leads to improved response rates in the recurrent, metastatic setting. There are many rare gynaecological cancers that require multidisciplinary management, and entry into clinical trials should be strongly supported. Learning objectives To understand the role and scheduling of chemotherapy in both newly diagnosed and recurrent epithelial ovarian cancer. To understand when chemotherapy should be offered in cervical and endometrial cancers. To be able to seek information sources for the management of rare and uncommon gynaecological cancers. Ethical issues The question of systemic lymphadenectomy remains controversial and should be carefully discussed with the patient. Women should be encouraged to participate in clinical trials to help address some of the controversies in endometrial cancer management.

Evaluation of TOP2A as a Predictive Marker for Endometrial Cancer With Taxane-Containing Adjuvant Chemotherapy.

Paclitaxel plus carboplatin and doxorubicin plus cisplatin are usually selected as adjuvant chemotherapy for endometrial cancer. However, biomarkers that can determine the appropriate chemotherapy regimen are not known. In the present study, we performed a retrospective investigation of the association between TOP2A, HER2 overexpression, and disease-free and overall survival in patients with endometrial cancer receiving taxane and platinum. Eligible patients had a diagnosis of endometrial cancer based on histology and treated with an adjuvant chemotherapy regimen comprising taxane-platinum after surgery, and the HER2 and TOP2A status of the endometrial cancer regions was determined. Overall survival and disease-free survival between HER2 status and TOP2A status were estimated by the Kaplan-Meier method and compared using the log-rank test. We identified 56 patients who fulfilled the previously described criteria. Median follow-up was 49 months (range, 18-110 months). HER2-positive tumors were detected in 11 patients (19.6%), and TOP2A-positive tumors were detected in 7 patients (12.5%). Overall survival was not significantly different between patients with HER2-positive tumors and those with HER2-negative tumors, although disease-free survival for patients with HER2-positive tumors was significantly lower than disease-free survival for patients with HER2-negative tumors (P = 0.049). In contrast, patients with TOP2A-positive tumors had significantly lower overall survival than did patients with TOP2A-negative tumors (P = 0.020), and disease-free survival for patients with TOP2A-positive tumors tended to be shorter than for those with TOP2A-negative tumors. Patients with TOP2A overexpression have a worse prognosis compared with those with TOP2A nonexpression, and TOP2A may be a useful biomarker in patients receiving adjuvant taxane-platinum regimens with moderate- to high-risk endometrial cancer.

Adjuvant chemotherapy for endometrial cancer after hysterectomy.

Endometrial adenocarcinoma (womb cancer) is a malignant growth of the lining (endometrium) of the womb (uterus). It is distinct from sarcomas (tumours of the uterine muscle). Survival depends the risk of microscopic metastases after surgery. Adjuvant (postoperative) chemotherapy improves survival from some other adenocarcinomas, and there is evidence that endometrial cancer is sensitive to cytotoxic therapy. This systematic review examines the effect of chemotherapy on survival after hysterectomy for endometrial cancer. To assess efficacy of adjuvant (postoperative) chemotherapy for endometrial cancer. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2010, Issue 3), MEDLINE and EMBASE up to August 2010, registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. Randomised controlled trials (RCTs) comparing adjuvant chemotherapy with any other adjuvant treatment or no other treatment. We used a random-effects meta-analysis to assess hazard ratios (HR) for overall and progression-free survival and risk ratios (RR) to compare death rates and site of initial relapse. Five RCTs compared no additional treatment with additional chemotherapy after hysterectomy and radiotherapy. Four trials compared platinum based combination chemotherapy directly with radiotherapy. Indiscriminate pooling of survival data from 2197 women shows a significant overall survival advantage from adjuvant chemotherapy (RR (95% CI) = 0.88 (0.79 to 0.99)). Sensitivity analysis focused on trials of modern platinum based chemotherapy regimens and found the relative risk of death to be 0.85 ((0.76 to 0.96); number needed to treat for an additional beneficial outcome (NNT) = 25; absolute risk reduction = 4% (1% to 8%)). The HR for overall survival is 0.74 (0.64 to 0.89), significantly favouring the addition of postoperative platinum based chemotherapy. The HR for progression-free survival is 0.75 (0.64 to 0.89). This means that chemotherapy reduces the risk of being dead at any censorship by a quarter. Chemotherapy reduces the risk of developing the first recurrence outside the pelvis (RR = 0.79 (0.68 to 0.92), 5% absolute risk reduction; NNT = 20). The analysis of pelvic recurrence rates is underpowered but the trend suggests that chemotherapy may be less effective than radiotherapy in a direct comparison (RR = 1.28 (0.97 to 1.68)) but it may have added value when used with radiotherapy (RR = 0.48 (0.20 to 1.18)). Postoperative platinum based chemotherapy is associated with a small benefit in progression-free survival and overall survival irrespective of radiotherapy treatment. It reduces the risk of developing a metastasis, could be an alternative to radiotherapy and has added value when used with radiotherapy.

Adjuvant Chemotherapy for Endometrial Cancer

To review the role of adjuvant chemotherapy in endometrial cancer and to identify the groups of patients who were most likely to have benefit from adjuvant chemotherapy. Bibliographic search was conducted for randomized trials involving chemotherapy given in an adjuvant setting for early stage endometrial cancer or advanced stage with minimal residual disease after surgery. The search included the National Library of Medicine's MEDLINE/PubMed database, studies cited in the reports, proceedings of international conferences, and registered clinical trials. Details of each trial were explored and summarized. Seven reports from 8 randomized trials were identified. Two trials were reported together with separate and combined statistical analyses. Characteristic features of the patients and diseases, details of surgical treatment including lymph node resection, types and pattern of radiation and chemotherapy, and the results from each trial varied. Only 2 trials showed significant survival improvement in patients who had adjuvant chemotherapy alone or chemotherapy after radiation compared with radiation alone. Data from these trials showed that the patients who were likely to have survival benefit from adjuvant chemotherapy were those with the following high risk features: did not have or had limited lymph node surgical evaluation, metastatic nodal involvement, tumors of high-grade or aggressive histology, stage IC, stage II or IIIA with 50% or greater myometrial invasion, and stage IIIC to IV. The results from trials were inconsistent regarding a survival benefit of adjuvant chemotherapy in comparison to radiation alone or in addition to radiation. Only certain groups of patients with high risk features were likely to gain survival advantage from adjuvant chemotherapy. The physician must carefully evaluate risk features of each patient and her disease to select one who is most likely to gain advantage from chemotherapy.

Adjuvant Chemotherapy in Endometrial Cancer

The indications for adjuvant therapy in endometrial cancer are briefly reviewed. The importance of systemic adjuvant therapy is emphasized. A short summary of randomized studies on adjuvant chemotherapy versus radiotherapy and on adjuvant sequential chemotherapy plus radiotherapy versus radiotherapy alone is given. On the basis of the present results from randomized trials, a combination of adjuvant radiotherapy and platinum-based chemotherapy seems to be most effective.