ENDOMETRIAL CANCER Updated Apr 2017 by: Dr. Jenny Ko (Medical Oncologist, Abbotsford Cancer Centre)

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1 ENDOMETRIAL CANCER Updated Apr 2017 by: Dr. Jenny Ko (Medical Oncologist, Abbotsford Cancer Centre) Source: UpToDate 2017, ASCO/CCO/Alberta provincial guidelines, NCCN Reviewed by: Dr. Sarah Glaze (Gynecologic Oncologist, University of Calgary), Dr. Aalok Kumar (Gynecologic Oncologist, UBC), Dr. Stephanie Lhereux (Gynecologic Oncologist, University of Toronto) DISCLAIMER: The following are study notes compiled by the above PGY-5 medical oncology resident and reviewed by a staff gynecologic oncologist and medical oncologist. They reflect what we feel is relevant knowledge for graduating medical oncology residents preparing for their final examination. The information has not been surveyed or ratified by the Royal College. A) PUBLIC HEALTH EPIDEMIOLOGY - Worldwide, in 2008, 288,000 women were diagnosed with uterine cancer. Uterine cancer is the most common gynecologic malignancy in developed countries and is the second most common in developing countries. - The majority of women with uterine cancer are diagnosed at an early stage; distribution of stage at diagnosis is: confined to primary site (>80 percent), spread to regional organs and lymph nodes, and distant metastases. RISK FACTORS - Endometrioid cancer: excess of endogenous (obesity) or exogenous estrogen without adequate opposition by a progestin (eg, postmenopausal estrogen therapy without a progestin), tamoxifen therapy, obesity, nulliparity, diabetes mellitus, and hypertension, HNPCC, genetic predisposition (Lynch Syndrome) - Serous cancer: unclear PREVENTION & SCREENING: - None for general population - Women with Lynch syndrome: 27 to 71 percent lifetime risk of endometrial cancer and a 3 to 14 percent lifetime risk of ovarian cancer. - For women with Lynch syndrome who have completed childbearing, risk-reducing total hysterectomy is recommended. Endometrial cancer screening in asymptomatic women with Lynch syndrome consists primarily of annual endometrial sampling, starting at age 30 to 35 or five to ten years prior to the earliest age of Lynch-associated cancer of any kind in the family. For premenopausal women with Lynch syndrome, we suggest chemoprevention with oral contraceptive pills when used along with surveillance for either endometrial or ovarian cancer. B) PRESENTATION & DIAGNOSIS SYMPTOMS & SIGNS - Abnormal uterine bleeding, most common in women who are postmenopausal (>45) and with increasing age in premenopausal women - Occasionally, women with no abnormal uterine bleeding present with abnormal findings on cervical cytology - Even in younger women, abnormal uterine bleeding that is persistent, occurs in the setting of a history of unopposed estrogen exposure (obesity, chronic anovulation) or failed medical management of the bleeding, or in women at high risk of endometrial cancer (eg, Lynch syndrome) INVESTIGATIONS

2 - Laboratory: CBC, CA 125 (Ca 125 is useful only for monitoring clinical response. No indication for diagnosis) - Diagnostic Imaging: pelvic ultrasound or MR (MRI important role for defining myometrial infiltration) - Diagnostic Procedures: endometrial biopsy (can be done in the office). False negative rate 10%. If negative and patient symptomatic consider D&C. Biopsy is not useful for mesenchymal tumor Staging: chest xr, abdominal US, CT scan, PET (when indicated, non conventional) PATHOLOGY & MOLECULAR BIOLOGY - Common Histology: Ø Type I tumors include tumors of endometrioid histology that are grade 1 or 2; these comprise approximately 80 percent of endometrial carcinomas. These tumors typically have a favorable prognosis, are estrogen-responsive, and may be preceded by an intraepithelial neoplasm (atypical and/or complex endometrial hyperplasia). These tumors often have mutations in PTEN, KRAS, PI3K pathway, mismatch repair genes and microsatellite instability. Ø Type II tumors account for 10 to 20 percent of endometrial carcinomas. They include grade 3 endometrioid tumors as well as tumors of non-endometrioid histology: serous, clear cell, mucinous, squamous, transitional cell, mesonephric, and undifferentiated. These tumors are often high grade, have a poor prognosis, and are not clearly associated with estrogen stimulation. A precursor lesion is rarely identified. Other histologic types of uterine cancer are discussed separately. Type II tumors are more often described by p53 mutations, p16 inactivation or HER2 amplification. - Relevant Molecular Biology: MSI testing STAGING Primary tumor (T) (surgical-pathologic findings) TNM categories TX T0 Tis FIGO stages Definition Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ (preinvasive carcinoma) T1 I Tumor confined to corpus uteri T1a IA Tumor limited to endometrium or invades less than one-half of the myometrium T1b IB Tumor invades one-half or more of the myometrium T2 II Tumor invades stromal connective tissue of the cervix but does not extend beyond uterus Δ T3a IIIA Tumor involves serosa and/or adnexa (direct extension or metastasis) T3b IIIB Vaginal involvement (direct extension or metastasis) or parametrial involvement T4 IVA Tumor invades bladder mucosa and/or bowel mucosa (bullous edema is not sufficient to classify a tumor as T4)

3 Regional lymph nodes (N) TNM categories NX N0 FIGO stages Definition Regional lymph nodes cannot be assessed No regional lymph node metastasis N1 IIIC1 Regional lymph node metastasis to pelvic lymph nodes N2 IIIC2 Regional lymph node metastasis to para-aortic lymph nodes, with or without positive pelvic lymph nodes Distant metastasis (M) TNM categories M0 FIGO stages Definition No distant metastasis M1 IVB Distant metastasis (includes metastasis to inguinal lymph nodes intraperitoneal disease, or lung, liver, or bone. It excludes metastasis to para-aortic lymph nodes, vagina, pelvic serosa, or adnexa.) Anatomic stage/prognostic groups Carcinomas* Stage 0 Tis N0 M0 Stage I T1 N0 M0 Stage IA T1a N0 M0 Stage IB T1b N0 M0 Stage II T2 N0 M0 Stage III T3 N0 M0 Stage IIIA T3a N0 M0 Stage IIIB T3b N0 M0 Stage IIIC1 T1-T3 N1 M0 Stage IIIC2 T1-T3 N2 M0 Stage IVA T4 Any N M0 Stage IVB Any T Any N M1 NOTE: ctnm is the clinical classification, ptnm is the pathologic classification. * Carcinosarcomas should be staged as carcinoma. FIGO no longer includes Stage 0 (Tis). Δ Endocervical glandular involvement only should be considered as Stage I and not as Stage II. C) TREATMENT Slightly different from province to province, but in general

4 Low-risk endometrial cancer - Histologic grade 1 or 2 - Cancer limited to the endometrium (a subset of stage IA disease) - Cancer that is not a high-risk histologic type (eg, clear cell, serous, or carcinosarcoma) - Surgery is the standard treatment. Lymphoadenectomyto be discussed in low risk patients. Sentinel node mapping could be performed but it is not a standard of care. In this case, no chemo or RT improves OS and increases toxicity, therefore observation alone is appropriate after surgery. Progestin can be used if patient is not interested in surgery. Intermediate-risk endometrial cancer - Cancer confined to the uterus and invading the myometrium (a subset of stage IA or stage IB) or cancer that demonstrates occult cervical stromal invasion (stage II)- excludes women with serous or clear cell cancers, which are considered to be high-risk histologic types regardless of the stage at presentation. - A subset of women are considered to have high intermediate-risk based on certain pathologic criteria: Ø The Gynecologic Oncology Group (GOG) defines high intermediate-risk based on age and any of three pathologic factors: the presence of deep myometrial invasion, grade 2 or 3 histology, or the presence of lymphovascular space invasion (LVSI). Ø Women have high intermediate-risk disease if they are: 70 years with one risk factor, age 50 to 69 years with two risk factors, or age 18 years with all three risk factors Ø Post-Operative Radiation Therapy in Endometrial Cancer (PORTEC) trials define high intermediate-risk by two of three clinicopathologic factors present: age >60 years, outer half myometrial invasion, and grade 3 histology *** Brachy in earlier stage rather than pelvic RT; if pelvic RT done, brachy added only if margin + *** If endometrioid, consider chemo in all grades, stage II; grade 3, stage Ib. If serous/carcinosarcoma, stage Ia + myometrial invasion à chemo; if clear cell, Ibà chemotherapy (treat it like grade 3 endometrioid) PORTEC 1: Survival after relapse in patients with endometrial cancer: results from a randomized trial. (2003 Gynecol Oncol Creutzberg) Regimen After surgery, patients were randomized to receive pelvic RT (46 Gy) or no further treatment. Primary Endpoint Recurrence Inclusion/Exclusion Stage 1 endometrial cancer, either grade 1 or 2 with deep (>50%) myometrial invasion or grade 2 or 3 with<50% invasion. In all cases an abdominal hysterectomy was performed, without lymphadenectomy. Size (N) 715 Results 8-year actuarial locoregional recurrence rates were 4% in the RT group and 15% in the control group (P<0.0001). Eight-year rates of distant metastases were 10 and 6% (P = 0.20).The majority of the locoregional relapses were located in the vagina, mainly in the vaginal vault. Of the 39 patients with isolated vaginal relapse, 35 (87%) were treated with curative intent, usually with external RT and brachytherapy, and surgery in some. A complete remission (CR) was obtained in 31 of the 35 patients (89%), and 24 patients (77%) were still in CR after further follow-up. Five patients subsequently developed distant metastases, and 2 had a second vaginal recurrence. The 8-year actuarial overall survival rates were 71 (RT group) and 77% (control group, P = 0.18). The 3-year survival after first relapse was 51% for patients in the control group and 19% in the RT group (P = 0.004). The 3-year survival after vaginal relapse was 73%, in contrast to 8 and 14% after pelvic and distant relapse (P<0.001). At

5 5 years, the survival after vaginal relapse was 65% in the control group compared to 43% in the RT group. Conclusion Survival after relapse was significantly better in the patient group without previous RT. Treatment for vaginal relapse was effective, with 89% CR and 65% 5-year survival in the control group, while there was no difference in survival between patients with pelvic relapse and those with distant metastases. As pelvic RT was shown to improve locoregional control significantly, but without a survival benefit, its use should be limited to those patients at sufficiently high risk (15% or over) for recurrence in order to maximize local control and relapsefree survival. GOG 99: A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study. (2004 Gynec Oncol Keys) Regimen Randomized after surgery to either no additional therapy (NAT) or whole pelvic radiation therapy (RT) Primary Endpoint Recurrence Inclusion/Exclusion "Intermediate risk" endometrial adenocarcinoma (see above) Size (N) 448 Results 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). 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). Conclusion 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. Comments The treatment difference was particularly evident among the HIR subgroup (2-year CIR in NAT versus RT: 26% versus 6%; RH=0.42). PORTEC 2: Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, noninferiority, randomised trial. (2010 Lancet Nout) Regimen Pelvic EBRT (46 Gy in 23 fractions; n=214) or VBT (21 Gy high-dose rate in three fractions, or 30 Gy low-dose rate; n=213) Primary Endpoint Vaginal recurrence Inclusion/Exclusion Stage I or IIA endometrial carcinoma with features of highintermediate risk Size (N) 427 Results Estimated 5-year rates of vaginal recurrence were 1.8% (95% CI ) for VBT and 1.6% ( ) for EBRT (hazard ratio [HR]0.78, 95% CI ; p=0.74). 5-year rates of locoregional relapse (vaginal or pelvic recurrence, or both) were 5.1% ( ) for VBT and 2.1% ( ) for EBRT (HR 2.08, ; p=0.17). 1.5% ( ) versus 0.5% ( ) of patients presented with isolated pelvic recurrence (HR 3.10, ; p=0.30), and rates of distant metastases were similar (8.3% [ ]vs 5.7% [ ]; HR 1.32, ; p=0.46).

6 We recorded no differences in overall (84.8% [95% CI ]vs 79.6% [ ]; HR 1.17, ; p=0.57) or disease-free survival (82.7% [ ]vs 78.1% [ ]; HR 1.09, ; p=0.74). Toxicity Rates of acute grade 1-2 gastrointestinal toxicity were significantly lower in the VBT group than in the EBRT group at completion of radiotherapy (12.6% [27/215]vs 53.8% [112/208]). Conclusion VBT is effective in ensuring vaginal control, with fewer gastrointestinal toxic effects than with EBRT. VBT should be the adjuvant treatment of choice for patients with endometrial carcinoma of high-intermediate risk. High-risk endometrial cancer: serous or clear cell adenocarcinoma (any stage) or pathologic stage III disease 1) Stage I/II: Generally, if serous carcinoma or grade 3, consider adjuvant chemotherapy à radiation therapy.. 2) Stage III, adjuvant chemotherapy alone might be preferred (RT is associated with an increased risk of both acute (eg, myelosuppression) and late toxicities (eg, radiation enteritis) and has not been proven to extend survival in this setting). In Calgary, chemoàrt is standard except in 3B. There is no completed Phase 3 trial to guide this. Adjuvant chemotherapy is associated with improvement in both PFS and OS, regardless of whether RT is used. However, women with stage IIIA grade 1 endometrioid cancers appear to have a better prognosis compared with women with grade 2 or 3 cancers - Choice of chemotherapy is carboplatin and paclitaxel. - Treatment and the indication have to be evaluated in each patient after multidisciplinary discussion. - Current investigation (PORTEC 3 and GOG258) results pending Meta-analysis 2014 Galaal Cochrane database systematic review Regimen All participants received primary cytoreductive surgery. Two trials, evaluating 620 women (83% stage III, 17% stage IV), compared adjuvant chemotherapy with adjuvant radiotherapy (GOG 122); 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 (GOG 184); and one trial contributed no data. Primary Endpoint (e.g. OS, DFS, RR, QoL) Inclusion/Exclusion Women with FIGO stage III and IV endometrial cancer. Size (N) 4 RCT, n=1269 Results 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%). 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. Toxicity 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

7 between the chemotherapy and radiotherapy treatment arms (8/309 versus 5/311; Risk Ratio (RR) 1.67, 95% CI 0.55 to 5.00). Conclusion 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. Other Comments 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%). No trial comparing chemo vs chemort has resulted. GOG Miller SGO meeting Regimen Carboplatin plus paclitaxel or cisplatin, doxorubicin, and paclitaxel (TAP) Primary Endpoint PFS, OS Inclusion/Exclusion Women with chemotherapy-naïve or recurrent advanced endometrial cancer, including women with stage III disease Size (N) 1300 Results Similar ORR compared with TAP (51 percent in each arm) Similar PFS (median, 13 months in each arm, HR for recurrence 1.05) mos 37 vs 40m (NS) Toxicity A statistically significant reduction in the incidence of grade 2 or greater toxicity, including sensory neuropathy (19 versus 26 percent), thrombocytopenia (12 versus 23 percent), emesis (4 versus 7 percent), diarrhea (2 versus 6 percent), and metabolic derangements (8 versus 14 percent) with carbo/paclitaxel Conclusion Similar efficacy of TAP vs carbo/taxol, with favourable toxicities with carbo/taxol METASTATIC/RECURRENT DISEASE Newly diagnosed patients - For women with metastatic endometrial cancer (stage IVB), surgical cytoreduction is a reasonable treatment option, particularly if they are newly diagnosed and a complete resection appears feasible. Unfortunately, high quality data are lacking for cytoreduction for endometrial cancer. - For women who undergo surgical cytoreduction of metastatic disease, we administer first-line chemotherapy in the postoperative (or "adjuvant") setting. The administration of postoperative chemotherapy in this setting is extrapolated from the benefits of treatment for women with newly diagnosed, high-risk endometrial cancer. The preferred regimen is six cycles of carboplatin and paclitaxel. Patients who are not surgical candidates should be offered medical therapy, provided that they are candidates for treatment. - No benefit from triplet agents treatment (GOG 209) Hormone therapy is also options for first line treatment of metastatic endometrial cancer with: - Grade 1 or 2 endometrioid endometrial cancer. - Positive expression of estrogen (ER) and progesterone (PR) receptors - Asymptomatic or minimally symptomatic disease. - Progestin and tamoxifen, some evidence for the use of aromatase inhibitors

8 Second-line therapy - For women with a >6m treatment-free interval following platinum-based combination chemotherapy repeat treatment with a platinum-based combination is reasonable. - There are no standard of care for second line treatment. Agents that have same efficacy are others: single agents with doxorubicin, liposomal doxorubicin, weekly paclitaxel, etc. - Clinical trials ++ UTERINE SARCOMA - Stage I/II: observation - Stage III: chemotherapy (although no established survival benefit) - Stage IV: Doxorubicin is probably still first line. Gem + docetaxel, platinum/ifosfamide can be also considered.

Adjuvant Therapies in Endometrial Cancer. Emma Hudson

Adjuvant Therapies in Endometrial Cancer Emma Hudson Endometrial Cancer Most common gynaecological cancer Incidence increasing in Western world 1-2% cancer deaths 75% patients postmenopausal 97% epithelial