ANTI-TUMOUR TREATMENT
Systemic therapy in metastatic or recurrent endometrial cancer

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Summary

Endometrial cancer is one of the most common gynecologic malignancies. In patients with advanced or recurrent endometrial cancer survival is greatly diminished. Hormonal therapy and chemotherapy play a major role in the management of advanced or recurrent endometrial cancer. Endocrine therapy provides a 10–20% response rate (RR) and survival of less than 1 year. Combination chemotherapy offers a RR of 40–60%, but the survival is still less than 1 year. The combination of cisplatin plus doxorubicin is the most commonly used regimen, but carboplatin plus paclitaxel represents an efficacious, low toxicity regimen in advanced or recurrent endometrial cancer. The addition of paclitaxel to cisplatin plus doxorubicin appears to improve response rates, progression-free survival and overall survival, but to worsen toxicity profile. At this time the focus of future research should be on the use of novel targeted agents, since it is unlikely that further significant advances could be made with chemotherapy and endocrine therapy. mTOR inhibitors represent a promising therapeutic strategy for endometrial cancer. Anti-HER-2/neu targeted therapy might be a novel and attractive therapeutic option in patients with biologically aggressive variants (uterine serous papillary carcinoma, clear cell carcinoma) of endometrial cancer. Research in better understanding the signal transduction pathways in endometrial carcinogenesis will allow the development of specific and selective molecularly targeted inhibitors.

Introduction

Endometrial carcinoma is the most common gynecological cancer, having an incidence in western countries of 15–20 per 100000 women per year.1 The American Cancer Society estimated that there were 40800 new cases of endometrial carcinoma and 7310 deaths in the United Stages in 2005.2 Endometrial carcinoma is the fourth most common cancer in females with approximately 7000 deaths each year, making it the 7th leading cause of death from malignancy in women. It is a disease of postmenopausal women, although 25% of the cases occur in premenopausal patients, with 5% occurring in patients younger than 40 years of age.3

At presentation, 75% of cases are stage I and an additional 13% are stage II. Most patients with stage I or II achieve cure with surgical resection or radiotherapy or a combination of two.4 Radiation, the standard modality along with surgery, for treatment of early disease5, 6, 7, 8 and local or regional recurrences,9 has no clear benefit in advanced stage patients or patients with non-localized recurrent disease.10, 11, 12 Chemotherapy and/or hormonal therapy are often considered to be the only active treatments in advanced disease.13 Many different chemotherapy and hormonal therapy agents have been tested in this setting. The most common regimens in clinical practice include doxorubicin (ADR), cisplatin (CDDP) and paclitaxel (Tx) (either as single agents or in combination), and progestins (megestrol acetate, medroxyprogesterone (MPA)).13 Response rates (RRs) to systemic therapy reported in the literature vary considerable, ranging from 10% to 78%, due to marked differences in the studied patient populations.14 Reported median survival times in patients with advanced or recurrent disease treated with chemotherapy is rarely more than 1 year. The activity of hormonal regimens, mainly progestins, is thought to be influenced by certain prognostic factors, such as receptor content.15 However, RRs are unlikely to be high and the exact impact on survival is uncertain.15, 16, 17 Several phase I and II trials have been conducted to evaluate the efficacy of the most commonly used regimens either as single agents18 or as combinations19, 20, 21, 22, 23 in an effort to identify better treatments.

This review was conducted in an attempt to evaluate the chemotherapeutic and hormonal therapy options for women with advanced or recurrent adenocarcinoma of the endometrium.

Section snippets

Prognostic factors

Surgical stage is strongly prognostic factor of the outcome for women with endometrial adenocarcinoma.24, 25, 26, 27, 28 Patients with stage I have 5-year survival rate of 88% compared with 55% for those with stage III.29 Histology has been recognized as being important in predicting survival in patients with endometrial carcinoma. Women with tumors of serous histology have a poor 5-year survival rate compared with that for tumors of endometrioid histology.30, 31, 32 This is related in large

Treatment

Once endometrial carcinoma is diagnosed, the treatment is total abdominal hysterectomy, bilateral salpingo-oophorectomy, with pelvic and/or para-aortic lymph nodes and peritoneal washings assessment with or without pelvic radiotherapy. The use of external pelvic radiotherapy for patients with poor prognosis disease is an accepted standard of care to decrease the risk of recurrent pelvic disease. Patients with recurrent endometrial cancer may be treated, depending on the sites of the recurrence

Endocrine therapy

Hormonal agents have been evaluated in patients with advanced or recurrent endometrial carcinoma. Since many patients with advanced or recurrent endometrial carcinoma present at an advanced age with other co-morbidities, endocrine therapy may be a therapeutic alternative for those with well-differentiated tumors or a long disease-free interval. In the 1970s, both parenteral and oral progestins yielded similar serum levels and RRs, which ranged from 18% to 34% in patients with advanced or

Chemotherapy

Chemotherapy has typically been reserved for patients with disseminated primary or recurrent disease. Several single agents and combination chemotherapy regimens have been evaluated in advanced or recurrent endometrial cancer. Chemotherapy is capable of inducing overall survival <12 months in patients with metastatic uterine cancer. In patients with recurrent disease responses to treatment are in the majority of cases partial, ranging 3–6 months, the time to tumor progression 4–6 months and the

Molecularly targeted therapy

Novel molecularly targeted therapies are currently under evaluation in endometrial carcinoma and in uterine serous papillary carcinoma (Table 5).

Recently, it has been shown that uterine serous papillary carcinoma (USPC) overexpresses HER-2/neu in 60–80% of the tested samples.110, 111 Uterine papillary serous carcinoma has similar histological findings but a more aggressive biological behaviour with respect to high-grade serous epithelial ovarian cancer (EOC). HER-2/neu is the most overexpressed

Conclusions

Progestins and combination chemotherapy are the most commonly used therapies for women with advanced or recurrent endometrial cancer. Patients with long disease-free interval, not candidates for chemotherapy and well differentiated or progesterone positive tumors should be treated with endocrine therapy (progestins). Systemic chemotherapy should be used in patients with rapidly progressive disease, poorly differentiated tumors and serous papillary and clear cell histology. Systemic chemotherapy

References (130)

  • M.L. Carcangiu et al.

    Uterine papillary serous carcinoma: a study on 108 cases with emphasis on the prognostic significance of associated endometrioid carcinoma, absence of invasion, and concomitant ovarian carcinoma

    Gynecol Oncol

    (1992)
  • B.G. Ward et al.

    Papillary carcinomas of the endometrium

    Gynecol Oncol

    (1990)
  • J.K. Chan et al.

    Significance of comprehensive surgical staging in noninvasive papillary serous carcinoma of the endometrium

    Gynecol Oncol

    (2003)
  • G.A. Webb et al.

    Clear cell carcinoma of the endometrium

    Am J Obstet Gynecol

    (1987)
  • K.M. Alektiar et al.

    Is there a difference in outcome between stage I–II endometrial cancer of papillary serous/clear cell and endometrioid FIGO Grade 3 cancer?

    Int J Radiat Oncol Biol Phys

    (2002)
  • C. Aquino-Parsons et al.

    Papillary serous and clear cell carcinoma limited to endometrial curettings in FIGO stage 1a and 1b endometrial adenocarcinoma: treatment implications

    Gynecol Oncol

    (1998)
  • G.S. Bucy et al.

    Clinical stage I and II endometrial carcinoma treated with surgery and/or radiation therapy: analysis of prognostic and treatment-related factors

    Gynecol Oncol

    (1989)
  • D. Gal et al.

    Lymphvascular space involvement—a prognostic indicator in endometrial adenocarcinoma

    Gynecol Oncol

    (1991)
  • R.N. Grimshaw et al.

    Prognostic value of peritoneal cytology in endometrial carcinoma

    Gynecol Oncol

    (1990)
  • N. Kadar et al.

    Positive peritoneal cytology is an adverse factor in endometrial carcinoma only if there is other evidence of extrauterine disease

    Gynecol Oncol

    (1992)
  • G.M. Rendina et al.

    Tamoxifen and medroxyprogesterone therapy for advanced endometrial carcinoma

    Eur J Obstet Gynecol Reprod Biol

    (1984)
  • J.V. Fiorica et al.

    Phase II trial of alternating courses of megestrol acetate and tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study

    Gynecol Oncol

    (2004)
  • C.W. Whitney et al.

    Phase II study of medroxyprogesterone acetate plus tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study

    Gynecol Oncol

    (2004)
  • D.S. McMeekin et al.

    A phase II trial of arzoxifene, a selective estrogen response modulator, in patients with recurrent or advanced endometrial cancer

    Gynecol Oncol

    (2003)
  • P.G. Rose et al.

    A phase II trial of anastrozole in advanced recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study

    Gynecol Oncol

    (2000)
  • F. Calero et al.

    Epirubicin in advanced endometrial adenocarcinoma: a phase II study of the Grupo Ginecologico Espanol para el Tratamiento Oncologico (GGETO)

    Eur J Cancer

    (1991)
  • H.D. Homesley et al.

    Phase II trial of liposomal doxorubicin at 40 mg/m2 every 4 weeks in endometrial carcinoma: a Gynecologic Oncology Group Study

    Gynecol Oncol

    (2005)
  • J.T. Thigpen et al.

    Phase II trial of cisplatin as first-line chemotherapy in patients with advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group Study

    Gynecol Oncol

    (1989)
  • T.W. Burke et al.

    Treatment of advanced or recurrent endometrial carcinoma with single-agent carboplatin

    Gynecol Oncol

    (1993)
  • F.H. van Wijk et al.

    Phase II study of carboplatin in patients with advanced or recurrent endometrial carcinoma. A trial of the EORTC Gynaecological Cancer Group

    Eur J Cancer

    (2003)
  • S. Lincoln et al.

    Activity of paclitaxel as second-line chemotherapy in endometrial carcinoma: a Gynecologic Oncology Group study

    Gynecol Oncol

    (2003)
  • H.G. Ball et al.

    A phase II trial of paclitaxel in patients with advanced or recurrent adenocarcinoma of the endometrium: a Gynecologic Oncology Group study

    Gynecol Oncol

    (1996)
  • D.S. Miller et al.

    A phase II trial of topotecan in patients with advanced, persistent, or recurrent endometrial carcinoma: a gynecologic oncology group study

    Gynecol Oncol

    (2002)
  • P.G. Rose et al.

    A phase II and pharmacokinetic study of weekly 72-h topotecan infusion in patients with platinum-resistant and paclitaxel-resistant ovarian carcinoma

    Gynecol Oncol

    (2000)
  • T.A. Traina et al.

    Weekly topotecan for recurrent endometrial cancer: a case series and review of the literature

    Gynecol Oncol

    (2004)
  • F.M. Muggia et al.

    Doxorubicin–cyclophosphamide: effective chemotherapy for advanced endometrial adenocarcinoma

    Am J Obstet Gynecol

    (1977)
  • V. Seltzer et al.

    Adriamycin and cis-diamminedichloroplatinum in the treatment of metastatic endometrial adenocarcinoma

    Gynecol Oncol

    (1984)
  • C. Trope et al.

    Treatment of recurrent endometrial adenocarcinoma with a combination of doxorubicin and cisplatin

    Am J Obstet Gynecol

    (1984)
  • J.H. Edmonson et al.

    Randomized phase II studies of cisplatin and a combination of cyclophosphamide–doxorubicin–cisplatin (CAP) in patients with progestin-refractory advanced endometrial carcinoma

    Gynecol Oncol

    (1987)
  • C.J. Dunton et al.

    Treatment of advanced and recurrent endometrial cancer with cisplatin, doxorubicin, and cyclophosphamide

    Gynecol Oncol

    (1991)
  • M.S. Aapro et al.

    Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomised study (55872) by the EORTC Gynaecological Cancer Group

    Ann Oncol

    (2003)
  • T. Akram et al.

    Carboplatin and paclitaxel for the treatment of advanced or recurrent endometrial cancer

    Am J Obstet Gynecol

    (2005)
  • G.F. Fleming et al.

    Phase III randomized trial of doxorubicin + cisplatin versus doxorubicin + 24-h paclitaxel + filgrastim in endometrial carcinoma: a Gynecologic Oncology Group study

    Ann Oncol

    (2004)
  • O. Viser et al.

    Incidence of cancer in the Netherlands 1995

    (1998)
  • A. Jemal et al.

    Cancer statistics, 2005

    CA Cancer J Clin

    (2005)
  • D.G. Gallup et al.

    Adenocarcinoma of the endometrium in women 40 years of age or younger

    Obstet Gynecol

    (1984)
  • J.R. Glassburn

    Carcinoma of the endometrium

    Cancer

    (1981)
  • M.S. Piver et al.

    A prospective trial of postoperative vaginal radium/cesium for grade 1–2 less than 50% myometrial invasion and pelvic radiation therapy for grade 3 or deep myometrial invasion in surgical stage I endometrial adenocarcinoma

    Cancer

    (1990)
  • J.A. Stryker et al.

    Adjuvant external beam therapy for pathologic stage I and occult stage II endometrial carcinoma

    Cancer

    (1991)
  • M.E. Randall et al.

    Whole abdominal radiotherapy versus combination chemotherapy with doxorubicin and cisplatin in advanced endometrial carcinoma (phase III): Gynecologic Oncology Group Study No. 122

    J Natl Cancer Inst Monogr

    (1995)
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