Uterine Cancer Summary

Types

·         Endometrial cancers are classified as either type I or type II cancers

·         75% of women diagnosed with endometrial ca are postmenopausal, with an average age of 60.

·         Type I cancers comprise 85% of endometrial cancers and show endometrioid histology.

o   80% of patients presents with early stage, uterine confined disease.

o   Pathogenesis appears to be related to the effect of unopposed estrogen on the glandular cells of the endometrial lining of the uterus.

·         Type II cancer have non-emdometrioid histology (Serous, clear cell, mucinous, squamous, transitional cell, mesonephric, and undifferentiated)

o   Pathogenesis is less clear.

o   Account for 40 % of deaths from the disease.

o   70 % of patients with uterine serous cancer and 50 % with clear cell present with stage III or IV disease

o   The Median age of women with type II is > then that of women with type I

·         Women with simple endometrial hyperplasia have a low risk of developing invasive adenocarcinoma; however approximately 25% of women with complex endometrial hyperplasia with atypia will develop invasive cancer

·         The risk of endometrial ca in 40% lower for black women than for white in the US. The mortality rate for black women is approximately 50% higher.

Risk factors and disease presentation:

·         Estrogen replacement therapy after menopause without concomitant use of progestins, obesity, nulliparity, late menopause, complex atypical endometrial hyperplasia, and tamoxifen use.

·         Combined oral contraceptive use may decrease the risk of endometrial ca.

·         Smoking is associated with lower risk, likely through antiestrogenic effect.

·         The risk of endometrial cancer is 3 to 7 fold higher for women receiving tamoxifen than for women who do not take the drug.

·         Tamoxifen associated endometrial cancers are usually well differentiated and present at an early stage.

·         No clinical data justify routine screening for endometrial ca among women taking tamoxifen.

·         Women with hereditary non-polyposis colon cancer (HNPCC) syndrome carry a 20% to 60% lifetime risk of developing endometrial cancer. These women require annual transvaginal sonography with endometrial biopsy, even in the absence of symptoms or abnormal uterine bleeding.

·         15% of patients with postmenopausal bleeding will have endometrial cancer; thus all postmenopausal women with abnormal uterine bleeding require evaluation with endometrial sampling.

Prognosis:

SEER study of cases diagnosed from 1998 to 2001

5 yr survival	Serous	Clear cell	Endometrioid
Stage I	74 %	88 %	95 %
Stage II	56 %	67 %	86 %
Stage III	33 %	48 %	67 %
Stage IV	18 %	18 %	37 %

Staging and treatment:

·         Endometrial cancer is surgically staged

·         The standard surgical staging procedure includes hysterectomy, bilateral salpingo-oopherectomy, washings, pelvic and para-aortic lymph node dissection, and examination of the entire abdominal cavity.

Stage (FIGO 2009)	Definition	Treatment overview	5- yr overall survival
I	Tumor confined to the uterine corpus	Hysterectomy and complete surgical staging	83%
IA	Tumor confined to the endometrium or tumor invades < 50% of the myometrium	No adjuvant therapy for grade 1 & 2 cancers
IB	Tumor invades to > 50% of the myometrium	May consider postsurgical pelvic + intravaginal radiation or only intravaginal radiation. may consider adjuvant chemotherapy for high grade or high risk histologies and for patients meeting high intermediate risk criteria
II	Tumor invades the cervical stroma but does not invade beyond the uterus	May consider postsurgical pelvic and intravaginal radiation. May consider adjuvant chemotherapy for high grade or high risk histologies and for patients meeting high –intermediate risk criteria	73%
III	Locally and/or regional spread of tumor	Hysterectomy and complete surgical staging Adjuvant chemotherapy Or Combined radiation & chemotherapy	52%
IIIA	Tumor invades the uterine serosa and/or adnexa
IIIB	Vaginal and/or parametrial involvement
IIIC	Metastatic involvement of pelvic and/or para-aortic lymph nodes		30%
IIIC1	Positive pelvic lymph nodes
IIIC2	Positive para-aortic lymph nodes with or without positive pelvic lymph nodes
IV	Tumor involves bowel or bladder mucosa or distant metastatic disease	If patient underwent surgery and has no residual disease in peritoneal cavity > 2 cm, consider adjuvant chemotherapy	27%
IVA	Tumor involves bowel mucosa and/or bladder mucosa
IVB	Distant metastases, including intra-abdominal and/or inguinal lymph nodes	If not completely resectable, treatment is with palliative systemic therapy; Consider hormone treatments for low grade cancers; Combination chemotherapy for advanced, higher grade, disseminated disease.

·         80% of patients with endometrial cancer are stage I, 11% are stage II, 6% are stage III and only 2% are stage IV.

·         Low grade tumors are more likely to be estrogen and/or progesterone receptor positive.

·         GOG 99 study: (Gynecol Oncol; 2004;92;740)

o    All patients underwent TAH BSO, peritoneal cytology, and lymph node dissection.

o   Patients with 1998 FIGO stage IB or IC, or stage II endometrial ca (which is stage IA, IB &II with current FIGO), were randomly assigned to receive adjuvant radiation or to no additional treatment.

o   No significant difference in overall survival.

o   The risk of pelvic and/or vaginal recurrence was significantly lower in the pelvic radiation group compared with the no additional treatment group (12% vs 3%).

o   This trial was used to define low risk and high-intermediate risk groups

§  Low risk group:

·         Current FIGO stage IA ( 1998 FIGO stage IA, IB)

·         Grade 1 or 2 cancers

·         6% chance of local recurrence and surgery alone is adequate

§  High-intermediate group:

·         Patients > 70 yrs with 1 feature

·         Patients > 50 yrs with 2 features

·         Any age with all 3 features

·         Features (Grade 2 or 3 cancers, Outer third invasion of the myometrium & lymphovascualar invasion. (Current FIGO stage IB, II)

·         27% chance of recurrence with no treatment and only 13% with adjuvant radiation therapy.

·         PORTEC-2 trial: (Lancet 2010; 375; 816)

o   Adjuvant pelvic radiation compared with intravaginal brachytherapy for high-intermediate risk endometrial cancer suggested that outcomes are equivalent

o   Pelvic recurrence rates; 5.1% with vaginal brachytherapy vs. 2.1% with pelvic radiation

o   No difference in metastatic disease, relapse free survival, or overall survival

o   Less toxicity and superior quality of life in the adjuvant intravaginal brachytherapy group.

·         Patients with Current FIGO stage II disease is treated similarly to higher risk stage I cancers.

·         GOG 122 trial: (JCO; 2006; 24;36)

o   Phase III randomized trial. Patients with stage III & IV with no residual disease > 2 cm in the peritoneal cavity were randomly assigned to adjuvant whole abdomen radiation or to chemotherapy (Cisplatin + doxorubicin)

o   Chemotherapy significantly improved progression-free and overall survival (55% vs. 42%) compared with Radiation

·         GOG 184: (Gynecol. Oncol; 2009; 112: 543)

o   Phase III for completely resected stage III & IV

o   All received adjuvant radiation followed by doxorubicin/cisplatin with or w/o paclitaxel.

o   No difference in 3 yrs PFS between both arms (about 60% for both) but more toxicity in the paclitaxel arm.

·         Meta-analysis: (Cochrane syst. Review 2011 “adjuvant chemotherapy for endometrial ca after hysterectomy”)

o   9 randomized trials directly compared no further treatment following surgery for stage III endometrial cancer with adjuvant platinum based chemotherapy alone or adjuvant RT

o   The use of Platinum based chemotherapy resulted in:

§  Reduced risk of mortality (HR 0.74)

§  Reduced risk of disease progression (HR 0.75)

·         Patients with the rare, high risk histologies (papillary serous & clear cell) are at higher risk for recurrent disease. Data showing that combination chemotherapy improves survival for stage III disease suggest that adjuvant chemotherapy may be appropriate for these early stage, high risk histology tumors; however prospective data are lacking to define the optimal adjuvant treatment for these patients.

Metastatic or recurrent disease:

·         Type 1 endometrial cancer, is a hormonal sensitive malignant disease. Overall 10-30% of patients will have a response to hormonal agent but the likelihood of response is strongly influenced by tumor grade.

·         For local recurrence the data is limited.

o   For radiation therapy, there is two retrospective case series (n = 50 and 69) evaluated women with endometrial cancer, nearly all of whom had not received prior RT, following an isolated vaginal recurrence. Treatment with RT was associated with a five-year OS rate of 53 to 75 %.

o   The role of concurrent chemotherapy with RT is investigational

o   Data on the outcomes of women following surgery (pelvic exenteration) for recurrent endometrial cancer are limited as well.

o   The largest series included 44 women with recurrent endometrial cancer; the median OS after pelvic exenteration was 10.2 months and 5-year OS was 20 %

o   Obviously this is an extensive procedure with a substantial risk of short- and long-term morbidity

·         Multiple trials in advanced, metastatic & recurrent settings have shown improved RR, PFS and OS with chemotherapy as below;

·         GOG 107 trial: (JCO; 2004;22;3902)

o   The combination of cisplatin + doxorubicin produced higher objective response rates and limited improvement in PFS but no difference in OS when compared to doxorubicin alone.

·         GOG 177: (JCO; 2004;22;2159)

o   Phase III of women with advanced or metastatic endometrial ca, comparing Cisplatin + Doxorubicin with and without Paclitaxel

o   Improved objective response (57% vs 34%), improved PFS (8.3 months vs 5.3 months) and improved OS (15.3 months vs 12.3 months)

·         GOG 209 trial: (Gynecol Oncol; 2012; 125; 771):

o   1300 women with chemotherapy naive stage III, IV or recurrent endometrial carcinoma were randomly assigned to carboplatin/paclitaxel vs cisplatin/doxorubicin/paclitaxel.

o   Each regimen administered every 3 weeks for 6 cycles

o   Similar objective response rates (51% in each arm)

o   Similar PFS (13 months in each arm)

o   Similar OS ( 37 vs 40 months

o   Statistically significant reduction in the incidence of toxicities in the carbo/taxol arm.

·         GOG 229E: (JCO; 2011; 29;2259)

o   Phase II trial of Bevacizumab in 56 patients with persistent or recurrent endometrial cancer after receiving 1 or 2 prior cytotoxic regimens.

o   Bevacizumab acheived objective response in 13.5% of patients

o   40% of patients remained progression free at 6 months.

Uterine carcinosarcomas and sarcomas:

·         Uterine carcinosarcomas, leiomyosarcomas, endometrial stromal sarcomas, and adenosarcomas comprise 4% of uterine cancers

·         Carcinosarcomas (also called uterine mixed Mullerian tumors) make up about 50%, leiomyosarcomas about 40% and adenosarcomas and endometrial stromal sarcomas the remaining 10%.

·         Carcinosarcoma:

o   Carcinosarcomas are associated with high rates of recurrence, even among patients with early stage disease at diagnosis.

o   GOG 150 trial: (Gynecol Oncol; 2007; 107;177)

§  Phase III trial for women with stage I–IV uterine Carcinosarcoma, no more than 1 cm postsurgical residuum and/or no extraabdominal spread had their treatments randomly assigned as either whole abdominal irradiation (WAI) or three cycles of cisplatin, ifosfamide, and mesna.

§  Recurrence rate at 5 yrs were lower for patients in the chemotherapy arm (52% with chemotherapy vs 58% with radiation).

o   GOG 161 trial: (JCO; 2007; 25; 526)

§  Phase III trial in patients with advanced and recurrent carcinosarcoma.

§  The combination of paclitaxel + ifosfamide yielded higher response rates (45% vs 29%) and longer OS (13.5 months vs 8.4 months) than did ifosfamide alone.

o   GOG 232B trial: (JCO; 2010; 28; 2727)

§  Phase II trial of carboplatin/paclitaxel in 55 women with stage III, IV, Persistent or recurrent carcinosarcoma.

§  Overall response rate was 54% (13% CR & 41% PR)

o   Carboplatin/paclitaxel is being compared to paclitaxel/ifosfamide in an ongoing randomized phase III trial for patients with any stage carcinosarcoma.

·         Leiomyosarcoma:

o   High risk cancer of uterine smooth muscle

o   Propensity for early hematogenous dissemination

o   Patients with uterine-limited disease have a 50% to 70% risk of recurrence.

o   A phase III randomized trial comparing adjuvant pelvic radiation with observation for stage I or II uterine leiomyosarcoma didn’t show a benefit to adjuvant pelvic radiation.

o   The current standard of care after resection of uterus limited leiomyosarcoma is observation.

o   The role of adjuvant chemotherapy is being investigated in a prospective phase III trial.

o   Active agents for the treatment of advanced, metastatic disease include doxorubicin, ifosfamide and the combination of gemcitabine + docetaxel.

o   GOG 87L trial: (Gynecol Oncol; 2008; 109; 329)

§  Phase II trial of gemcitabine plus docetaxel as first-line therapy for metastatic uterine leiomyosarcoma

§  Overall objective response rates were 35.8% (CR 4.8%, PR 31%)

§  Stable disease in 26%

§  Median PFS was 4.4 months and median OS was 16 months.

·         True endometrial stromal sarcomas are low grade tumors that express estrogen and progesterone receptors.  Treatment with hormonal blockade may be effective in patients with recurrent disease.

·         High grade endometrial stromal sarcomas are now called high grade undifferentiated sarcomas. These tumors do not express estrogen or progesterone receptors.