Tamoxifen has a variety of bothersome side effects, related mostly to forced early menopause.
In addition, a rare complication of tamoxifen is uterine lining overgrowth, which can proceed to endometrial bleeding. Abnormal uterine bleeding occurs in more than 50% of premenopausal women taking tamoxife and in this group of women, up to 23% will have an underlying endometrial abnormality such as polyps, hyperplasia, or EC. However, the incidence of endometrial disease is not markedly different compared with that in premenopausal women with breast cancer and AUB who are not taking tamoxifen. However, two meta-analyses found the risk of uterine/endometrial cancer nearly doubled with tamoxifen use. In the great majority of the cases, these are early stage cancers that are curable with hysterectomy. Unfortunately, there are no effective or generally accepted ways to monitor endometrial overgrowth. Given the higher rate of endometrial disease in premenopausal women taking tamoxifen who have development of  uterine bleeding, further evaluation is warranted via endometrial sampling with an office biopsy or with operative curettage (with or without hysteroscopy). There are no guidelines that recommend preventative hysterectomy or cystoscopy.

Recently, USPTF recommended ten years of adjuvant tamoxifen instead of five. This greatly increases concern for the development of endometrial caner over this longer period. The ASCO guideline* (Visvanathan et al) has this to say: “Follow-up should include a baseline gynecologic examination before initiation of treatment and annually thereafter, with a timely work-up for abnormal vaginal bleeding.”
H.F. Kennecke,New guidelines for treatment of early hormone-positive breast cancer with tamoxifen and aromatase inhibitors, BCMJ, Vol. 48, No. 3, April 2006,  121-126

Kala Visvanathanet al, American Society of Clinical Oncology Clinical Practice Guideline Update on the Use of Pharmacologic Interventions Including Tamoxifen, Raloxifene, and Aromatase Inhibition for Breast Cancer Risk Reduction, JCO July 1, 2009 vol. 27 no. 19 3235-3258

Bushnell CD wt al, (2004) Risk of ischemic stroke with tamoxifen treatment for breast cancer: A meta-analysis. Neurology 63:12301233.

Jamie N. Bakkum-Gamez et al, Challenges in the Gynecologic Care of Premenopausal Women With Breast Cancer, Mayo Clin Proc. 2011 March; 86(3): 229–240.

For the Lay version see here

Restaging is an integral part of treatment for metastatic disease. The issue is whether PET/CT is a SOC restaging modality for endometrial cancer. PET scan is coming into wider use for endometrial cancer, either for diagnosis, staging or restaging. It has been shown that endometrial cancer is generally highly FDG-avid and that it is feasible to detect the primary tumor, as well as regional nodal and distant metastases, with FDG-PET. As with other types of malignancies, FDG-PET is unable to detect small tumor volumes, and the sensitivity of tumor detection by FDG-PET is reduced in poorly controlled hyperglycemia. The intense activity of FDG excreted in the urinary bladder may impair visualization of adjacent FDG-avid disease, such as primary endometrial cancer or locoregional nodal metastases. Bladder irrigation has been suggested as one method of overcoming this potential problem.

NCCN on p. ENDO-3 says MRI/ CT/PET for initial staging , and there is literature that suggests that PET is useful in post-therapy surveillance for localizing suspected recurrences. A study showed that in the detection of recurrence and the evaluation of treatment response, FDG-PET, implemented by CT and/or MRI, performed better (sensitivity 100%, specificity 88.2%, and accuracy 93.3%) than CT and/or MRI (sensitivity 84.6%, specificity 85.7%, and accuracy 85%) and tumor markers, ie, CA125, CA19-9, CEA, and sialyl TN antigen (sensitivity 100%, specificity 70.6%, and accuracy 83.3%). The results of FDG-PET correlated well with the clinical outcome of the patients, with patients having negative PET results tending to show disease-free courses.

A recent review by Must et al concludes: “ we may highlight that in “T” staging of uterine malignancies FDG PET/CT is a secondary technique compared with CECT and MRI. In some series, FDG PET/CT results have matched MRI. The most promising role of metabolic imaging may be its ability to quantitatively predict DFS, OS, and TTR by assessing “N” status with SUVmax, MTV, and TLG.

For endometrial cancer, these techniques could be used to select patients who do not require surgical staging, thus sparing unhelpful lymphadenectomies. There is an important limitation regarding the staging of very small lymph nodes (<0.5 cm). FDG PET/CT is generally superior to CECT and MRI for detecting distant metastasis in advanced stage patients. PET/CT is recommended for detecting distal metastases in current clinical practice guidelines.^4,5 PET/CT may change the management in a significant percentage of patients regarding recurrence monitoring and follow up, resolving uncertain findings of CECT and MRI. In addition, there is growing interest in PET and MRI fusion imaging for the evaluation and follow-up of uterine and cervical cancers“.

Chung HH, Kang WJ, Kim JW, et al. The clinical impact of [(18)F]FDG PET/CT for the management of recurrent endometrial cancer: correlation with clinical and histological findings. European Journal of Nuclear Medicine & Molecular Imaging 2008; 35(6):1081-1088.

ACR Appropriateness Criteria ® 8 Endometrial Cancer of the Uterus 2010
Kitajima K, Murakami K, Yamasaki E, et al. Performance of FDGPET/ CT in the diagnosis of recurrent endometrial cancer. Annals of Nuclear Medicine 2008; 22(2):103-109.

Park JY, Kim EN, Kim DY, et al. Clinical impact of positron emission tomography or positron emission tomography/computed tomography in the posttherapy surveillance of endometrial carcinoma: evaluation of 88 patients. International Journal of Gynecological Cancer 2008; 18(6):1332-1338.

Koyama K, Okamura T, Kawabe J, et al. Evaluation of 18F-FDG PET with bladder irrigation in patients with uterine and ovarian tumors. J Nucl Med. 2003;44:353-358

Alessandra Musto et al, Role of 18F-FDG PET/CT in the Carcinoma of the Uterus: A Review of Literature. Yonsei Med J. 2014 Nov 1; 55(6): 1467–1472.

Kitajima K¹, Murakami K, Kaji Y, Sakamoto S, Sugimura K.

Established, emerging and future applications of FDG-PET/CT in the uterine cancer. Clin Radiol. 2011 Apr;66(4):297-307

Doxorubicin is the most active anticancer agent employed, with useful but temporary responses obtained in as many as 33% of patients with metastatic disease. Paclitaxel also has significant activity.

The combination of doxorubicin plus cisplatin (AP) has produced RRs of 40% to 46%, with reported median progression-free survival (PFS) ranging from 5.2 to 7.2 months in the three most recent Gynecologic Oncology Group (GOG) randomized trials. Most recently, the GOG compared AP with doxorubicin plus paclitaxel 150 mg/m2 as a 24-hour continuous infusion with filgrastim support, and there was no statistically significant improvement in objective RR, PFS, or overall survival (OS) between the regimens. The most recent randomized study found that TAP significantly improves RR, PFS, and OS compared with AP. What this suggested is that riplet therapy is superior to doublets. I elaborate. In 2001, the GOG published the results of a dose-finding trial that combined cisplatin, doxorubicin, and a 3-hour infusion of paclitaxel (TAP) in chemotherapy-naïve patients with advanced endometrial carcinoma and other gynecologic malignancies. In that trial, doxorubicin and cisplatin were administered on day 1, and paclitaxel, on day 2 because of previous reports suggesting that the cardiotoxicity associated with the paclitaxel + doxorubicin combination was decreased when these agents were administered 16 to 24 hours apart.12 Even when low doses of the combination of TAP were used, filgrastim was required for hematopoietic support, and neurotoxicity became the dose-limiting toxicity. The recommended phase II doses were doxorubicin 45 mg/m2, cisplatin 60 mg/m2, and paclitaxel 160 mg/m2 intravenously over 3 hours, with filgrastim 5 µg/kg given on days 3 to 12. Of 20 patients treated at this dose level, two (10%) developed grade 3 peripheral neuropathy Next GOG did a phase III trial compared cisplatin plus doxorubicin to doxorubicin, cisplatin, and paclitaxel with granulocyte colony-stimulating factor (G-CSF) support. The three-drug arm produced more objective responses than the two-drug arm (57% vs 34%, P < .01). Progression-free survival was extended to 8.3 months compared with 5.3 months in the control arm (P < .01); and overall survival reached a median of 15.3 months compared with 12.3 months (P < .037). Patients who received doxorubicin plus cisplatin on this trial were not likely to receive paclitaxel as first salvage therapy, which might account for the survival advantage for the three-drug combination. As seen in previous trials, increasing efficacy with more chemotherapy also led to increasing toxicity; patients receiving the three-drug combination were more likely to suffer thrombocytopenia and grade 3 and 4 neurotoxicity. The current GOG phase III trial compares the three-drug regimen of cisplatin, doxorubicin, and paclitaxel with G-CSF support to carboplatin combined with paclitaxel. Phase II trials testing the combination of carboplatin and paclitaxel in advanced, recurrent, or metastatic endometrial cancer have shown response rates of 46% to 78%. A Cochrane review recently attempted to address the issue of whether more chemotherapy is better in the case of treating advanced, recurrent, or metastatic endometrial cancer. Eleven randomized clinical trials were identified that included a total of 2,288 patients. A meta-analysis of six trials showed improved progression-free survival with more intensive chemotherapy compared with less intense chemotherapy (hazard ratio [HR] = 0.80, 95% confidence interval [CI] = 0.71–0.90; P = .004) but a comparable overall survival (HR = 0.90, 95% CI = 0.80–1.03; P = .12). Grade 3 and 4 toxicity, particularly in the form of myelosuppression and gastrointestinal toxicity, was higher in patients receiving more intense chemotherapy regimens. The NCCN lists carboplatin, cisplatin and palcitaxel as options for metastatic or advanced endometrial carcinoma, as single agents or combined. For clinical use, carboplatin is interchangeable with cisplatin by general consensus because of their similarity and trial evidence in a a number of cancer sites (although not in all and not in endometrial cancer). NCCN cites a variety of regimens, including ifosfamide/paclitaxel, doxorubicin/cisplatin/paclitaxel, cisplatin/dosorubicin and the single agents: cisplatin, doxorubicin, paclitaxel and ifosfamide. Cisplatin, etoposide, adriamycin is an older regimen that was found in 1995 to be superior to a melphalan based regimen. It is not currently in any trial for endometrial cancer as per clinicaltrials.gov.

NCCN, Endometrial ENDO-B, 2019

Samarnthai N, Hall K, Yeh IT. Molecular profiling of endometrial malignancies. Obstet Gynecol Int. 2010;2010:162363.

Urick, M.E., Bell, D.W. Clinical actionability of molecular targets in endometrial cancer. Nat Rev Cancer 19, 510–521 (2019)

Sarah M. Temkin, MD, Gini Fleming, MD Current Treatment of Metastatic Endometrial Cancer
Cancer Control. 2009;16(1):38-45.

Fleming GF, Brunetto VL, Cella D, et al. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2004;22(11):2159-2166.

Humber CE, Tierney JF, Symonds RP, et al. Chemotherapy for advanced, recurrent or metastatic endometrial cancer: a systematic review of Cochrane collaboration. Ann Oncol. 2007;18(3):409-420.

Wolf K, Slomovitz BM. Novel biologic therapies for the treatment of endometrial cancer. Int J Gynecol Cancer. 2005;15(2):411.

J. T. Thigpen, M. F. Brady, H. D. Homesley, J. Malfetano, B. DuBeshter, R. A. Burger, and S. Liao Phase III Trial of Doxorubicin With or Without Cisplatin in Advanced Endometrial Carcinoma: A Gynecologic Oncology Group Study J. Clin. Oncol., October 1, 2004; 22(19): 3902 – 3908.

G. F. Fleming, V. L. Filiaci, R. C. Bentley, T. Herzog, J. Sorosky, L. Vaccarello, and H. Gallion Phase III randomized trial of doxorubicin + cisplatin versus doxorubicin + 24-h paclitaxel + filgrastim in endometrial carcinoma: a Gynecologic Oncology Group study Ann. Onc., August 1, 2004; 15(8): 1173 – 1178

Cornelison TL, Baker TR, Piver MS, Driscoll DL..Cisplatin, adriamycin, etoposide, megestrol acetate versus melphalan, 5-fluorouracil, medroxyprogesterone acetate in the treatment of endometrial carcinoma.: Gynecol Oncol. 1995 Nov;59(2):243-8

Data from randomized studies such as PORTEC-1 (Postoperative Radiation Therapy in Endometrial Carcinoma), the GOG-99 (Gynecologic Oncology Group) and the recent ASTEC/EN.5 trial have shown a reduction in locoregional disease recurrence but not benefit in overall survival. Those studies have shown that the majority of the initial recurrences for patients with disease limited to the uterus were limited to the vagina, suggesting that vaginal vault brachytherapy alone could be used as an adjuvant treatment. To compare adjuvant pelvic RT with vaginal BT alone in uterine-confined disease, the PORTEC-2 study randomized patients between those two modalities and showed very satisfactory vaginal and pelvic control rates and equal survival with both modalities.

Another option under discussion is chemoradiation. In the EORTC 55991 trial (abstract only), patients with stages I, II, IIIA (positive cytology only), and IIIC (excluding para-aortic metastases) and clear, serous, and anaplastic cell types were enrolled. Most patients had two or more risk factors including G3, deep myometrial invasion, or DNA nondiploidy. Enrolled patients were randomized to RT (EBRT ± VBT) or combined chemoradiotherapy. The chemotherapy regimen before August 2004 was cisplatin-doxorubicin or -epirubicin; thereafter, it was changed to cisplatin-doxorubicin or -epirubicin, paclitaxel-epirubicin-carboplatin, or paclitaxel- carboplatin. The hazard ratio for PFS was 0.58 in favor of the combined chemoradiotherapy group, and a 7% difference in estimated 5-year PFS was found. There is also an ongoing PORTEC-3 trial in which high-intermediate and high risk patients (stage IB with LVSI and G3, stage II and G3, stage IIIA or IIIC, and stage IB-III and serous or clear cell type) were randomized to pelvic EBRT (48.6 Gy) alone or concurrent chemoradiotherapy (EBRT and two courses of cisplatin) followed by adjuvant CT (carboplatin and paclitaxel for four courses). Results are awaited. Additionally, there is an ongoing GOG 258 trial in which patients (stages I and II with serous or clear cell type and positive cytology, stage III-IVA) were randomized to receive carboplatin and paclitaxel for six courses or concurrent chemoradiotherapy (EBRT ± VBT and two courses of cisplatin) followed by four courses of carboplatin and paclitaxel

Randall ME, Filiaci VL, Muss H, et al. Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: A Gynecologic Oncology Group Study. Journal of Clinical Oncology . 2006;24:36-44.

Sheng-Mou Hsiao and Lin-Hung Wei Controversies in the Adjuvant Therapy of Endometrial Cancer ISRN Obstetrics and Gynecology Volume 2011 (2011), Article ID 724649

T Dell’Anna, A Buda, I Floriani Adjuvant chemotherapy for endometrial cancer Cochrane Database of Systematic Reviews 2008 Issue 1

nccn.org, endometrial cancer, ENDO-5 and ENDO-B, 2012

There is a statement of NCCN on p.32 of the text that accompanies the guideline: ” For medically inoperable patients… radiation therapy has been demonstrated as a well tolerated and effective treatment that can provide some measure of pelvic control and long-term progression free survival”.

B. Anderson, S. Bentzen, R. Das, M. Straub, K. Bradley
Single Institution Experience Treating Medically Inoperable Stage I Endometrial Cancer with High-dose Rate Intracavitary Brachytherapy
International Journal of Radiation Oncology*Biology*Physics, Volume 72, Issue 1, Supplement 1, 1 September 2008, Page S370
Jiade J. Lu and Luther W. Brady
Endometrial Cancer
Book Series Medical Radiology
ISSN 0942-5373
Radiation Oncology
An Evidence-Based Approach