Don S. Dizon
INCIDENCE
Each year, over 49,000 women are diagnosed with uterine cancer, and approximately 8000 women succumb to the disease (1). The vast majority of uterine tumors are adenocarcinomas. Less than 5% of these are uterine sarcomas.
ENDOMETRIAL ADENOCARCINOMA
EPIDEMIOLOGY
Endometrial adenocarcinoma is more commonly diagnosed among older women with the peak incidence occurring in the sixth decade of life. It is also more commonly diagnosed in white women compared to non-white women. These cancers can be broadly categorized into two types based on clinical and pathologic factors (2):
• Type I endometrial carcinomas follow an estrogen-dependent pathway. The precursor lesion is atypical hyperplasia. These tumors comprise the majority of endometrial cancers, are limited to the uterus, and have a favorable prognosis.
• Type II endometrial carcinomas appear to develop independent of estrogen exposure. They occur more frequently among black women and arise in a background of atrophic endometrium. Compared to type I endometrial cancers, women tend to be diagnosed at an older age and at a later stage. They also confer a poorer overall prognosis.
RISK FACTORS
Risk factors for the development of type I endometrial cancer include states related to excess estrogen stimulation. This includes nulliparity, unopposed estrogen administration, tamoxifen exposure, polycystic ovarian syndrome, and obesity. Higher parity, smoking, and use of estrogen-progestin hormonal contraception are known to decrease risk. In contrast, specific risk factors for type II endometrial cancer have not been identified.
Genetic factors contribute to only about 10% of endometrial cancers, mostly due to hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, and, to a lesser degree, Cowden syndrome. Both of these genetic conditions follow autosomal dominant inheritance patterns. While it is not clear if individuals with BRCA 1 and 2 mutations have increased risk, there does seem to be higher risk for patients with breast cancer, perhaps because of shared risk factors.
PATHOGENESIS
There is no single molecular event that gives rise to endometrial cancer. However, type I and type II endometrial carcinomas are associated with distinct molecular changes: type I endometrial adenocarcinomas are associated with mutations involving the PTEN pathway or show evidence of microsatellite instability (3). Type II tumors are associated with p53 mutations and mutations involving HER2/neu (3, 4).
HISTOPATHOLOGY
The World Health Organization classifies endometrial adenocarcinoma into multiple types including endometrioid, serous, and clear cell, among the more common variants (5). Another variant of endometrial carcinoma is carcinosarcoma, which is considered a high-risk histology.
Endometrioid carcinoma is the most common endometrial cancer, comprising 75%–80% of all cases. These cancers occur with varying degrees of differentiation, characterized histologically by grade. Well (grade 1) to moderately (grade 2) differentiated endometrioid carcinomas are considered type I endometrial carcinomas. Under the microscope they may have varying degrees of complexity, such as back-to-back, cribiform, or confluent growth (5). In contrast, poorly differentiated (grade 3) endometrioid adenocarcinomas are more aggressive tumors and some experts classify them as a type II tumor. Grade 3 endometrioid adenocarcinomas are characterized by at least 50% of a solid growth pattern or prominent nuclear atypia (5).
Serous carcinomas (previously referred to as papillary serous) account for 5%–10% of endometrial cancer. These cancers are typically irregular in histologic appearance with branching papillae and single cells characterized by large prominent nucleoli (5). These tumors are characteristic of type II endometrial carcinoma. They are uniformly aggressive, regardless of stage.
Clear cell carcinomas are characterized by clear cytoplasm and are associated with a high degree of cytological atypia. Typical architectural patterns include solid, papillary, and tubolocystic variants. As with serous carcinomas, clear cell carcinomas are also considered a type II tumor. They are aggressive variants, which may not respond well to chemotherapy (6).
Undifferentiated carcinomas of the endometrium are characterized by specific findings, including: a predominantly noncohesive proliferative pattern, heterogeneously sized monotonous cells without marked nuclear pleomorphism, and lacking glandular differentiation (5). These tumors are also marked by brisk mitotic activity and extensive evidence of necrosis.
Carcinosarcomas are metaplastic carcinomas composed of epithelial (carcinomatous) and mesenchymal (sarcomatous) elements. The sarcomatous element is histologically defined as being either homologous (i.e., sarcoma arising from tissue native to the uterus) or heterologous (i.e., sarcoma element that is not native to the uterus). Metastatic lesions due to carcinosarcoma most commonly comprise of the epithelial element.
CLINICAL PRESENTATION
The classic presenting sign of endometrial cancer is abnormal uterine bleeding. However, other symptoms can be seen, including bloating, pelvic pain, or dyspareunia. However, type II endometrial cancers may not present with symptoms until advanced disease is present, at which time, systemic symptoms (nausea, vomiting, change in bowel habits, anorexia) may be present.
DIAGNOSIS
The diagnosis of endometrial cancer is usually made based on endometrial biopsy or dilation and curettage. If the sampling is negative but clinical suspicion of a malignancy is high, however, further evaluation is warranted. This can be performed by repeat endometrial sampling (preferably, biopsy), by diagnostic hysteroscopy, or with pelvic imaging (typically, ultrasound or MRI).
STAGING
Endometrial carcinoma, which includes carcinosarcoma, is surgically staged using the Federation of Gynecology and Obstetrics (FIGO) staging system. The staging technique requires total hysterectomy and bilateral salpingo-oophorectomy. Whether or not lymphadenectomy is required for all cases of endometrial adenocarcinoma remains controversial (7).
PROGNOSTIC FACTORS
The prognosis of newly diagnosed endometrial cancer are illustrated by the delineation of tumors into risk groups, used for both prognostication and for informing treatment decisions:
Low-risk—These include tumors with low-risk features including low to intermediate grade, minimal to no myometrial invasion, and absence of lymphovascular space invasion (LVSI). These patients have an excellent prognosis following surgery and expected survival is over 90%.
Intermediate-risk—These include cancers confined to the uterus with myometrial invasion (stage IA or IB) or occult cervical stromal invasion (stage II). These patients have approximately an 80% chance of overall survival. Additional factors further divide this group into high- and low-intermediate risk disease, including deep myometrial invasion, grade 2 or 3 differentiation, or the presence of lymphovascular invasion (LVSI).
High-intermediate risk criteria used by the Gynecologic Oncology Group for trial purposes include patients of any age with all three pathologic factors (grade 2 or 3, outer 1/3 invasion, LVSI), patients 50–69 years old with two factors, or patients who are 70 years or older with only one factor (8). In the absence of these additional risk factors, patients are considered to have low-intermediate risk.
High-risk—Women with clear cell or serous carcinomas and women with carcinosarcoma constitute the high-risk group, regardless of stage at diagnosis. This also includes women with stage III endometrial cancer that has been optimally resected. These patients are at an increased risk for both recurrence and death.
ADJUVANT TREATMENT
Low and low intermediate risk—Women with low- or low intermediate-risk endometrial cancer have an excellent prognosis following surgery alone. As such, the risks of adjuvant radiation therapy likely outweigh any benefit of treatment. In addition, adjuvant endocrine therapy is not indicated. A meta-analysis of adjuvant progestin therapy showed no benefit in the risk of mortality at 5 years compared with postoperative surveillance (9).
High intermediate-risk—Women with high intermediate-risk warrant adjuvant therapy due to an elevated risk of a local recurrence. For most patients, vaginal brachytherapy is sufficient. This was demonstrated in the Post Operative Radiation Therapy for Endometrial Cancer (PORTEC 2) trial, which compared pelvic to vaginal brachytherapy and showed that these treatments were equivalent and resulted in similar rates of locoregional or distant recurrence (10, 11).
There is no indication for adjuvant chemotherapy in this select group of women. However, a randomized trial being conducted by the Gynecologic Oncology Group (GOG 249) aims to characterize the benefit of combined modality treatment (vaginal brachytherapy plus carboplatin/paclitaxel chemotherapy) compared to whole pelvic radiation (12).
High-risk—Women with high-risk disease should be treated with adjuvant systemic chemotherapy, which has replaced the use of radiation therapy. This was based on the results of GOG 122, a randomized phase III trial that compared whole abdominal radiotherapy to 8 cycles of cisplatin and doxorubicin chemotherapy (AP) in stage III/IV disease with minimal residual tumor burden following surgery (13). Chemotherapy significantly increased progression-free (hazard ratio 0.71, 95% CI 0.55–0.91) and overall survival (HR 0.68, 95% CI 0.52–0.89). This translated to 5-year progression-free survival rates of 42% versus 38%, and overall survival rates of 53% and 42% for chemotherapy versus radiation, respectively.
Whether or not combining chemotherapy with adjuvant radiation therapy can improve outcomes is not known. This is being evaluated in GOG 258, which is open for women with high-risk endometrial cancer and compares concomitant cisplatin and tumor-directed irradiation followed by carboplatin and paclitaxel versus carboplatin and paclitaxel alone (14).
Approach to early stage serous or clear cell carcinoma—Regardless of stage, patients with serous or clear cell carcinoma are at an increased risk of relapse and death compared to those with similarly staged type I endometrioid cancers. Therefore, adjuvant therapy is generally warranted for stage I or II disease, although women with serous carcinoma limited to the endometrium may be appropriate candidates for surveillance (15). Clear cell carcinoma may be less sensitive to chemotherapy (6). Thus, it would be reasonable to treat clear cell cancers with local radiation therapy alone in an effort to reduce the risk of recurrence.
Carcinosarcoma—Adjuvant treatment is usually administered for carcinosarcoma. One exception may be for stage IA disease, in which the prognosis is good following surgical cytoreduction. However, for stage IB and higher disease, adjuvant chemotherapy is routinely administered. Based on GOG 232B, carboplatin and paclitaxel has largely replaced ifosfamide-based treatment in the adjuvant setting (16).
The benefit of chemotherapy rather than RT was demonstrated in GOG 150, in which 206 women with stage I–IV disease were randomized to whole abdominal irradiation (WAI) or to 3 cycles of ifosfamide plus cisplatin (17). Compared to WAI, chemotherapy resulted in a lower risk of death (HR 0.79, 95% CI 0.5–1.2) and a significantly lower risk of recurrence (HR 0.79, 95% CI 0.5–0.8).
METASTATIC DISEASE
There is no single paradigm for the approach to women with metastatic disease. The options depend on the extent of metastatic disease:
• Recurrence in the vaginal apex—Patients with endometrial cancer have a less than 10% risk for a local recurrence in the vaginal apex. However, these women are candidates for local therapy with radiation therapy (if not previously administered) or surgical excision. However, resection may require pelvic exenteration to ensure complete resection of disease.
• Recurrence in the pelvis—Patients with locally advanced recurrent disease may be candidates for cytoreduction or pelvic exenteration. However, a complete re-staging is important to ensure the extent of disease is identified and that complete resection is feasible.
• Extraabdominal metastatic disease—Patients with disease outside of the pelvis are best managed with chemotherapy. The approach to these patients depends on whether adjuvant chemotherapy was administered. There is no evidence of a platinum-free interval for patients with endometrial cancer.
MEDICAL TREATMENT OPTIONS
COMBINATION CHEMOTHERAPY
The standard combination regimen for the first-line treatment of metastatic disease was doxorubicin, cisplatin, and paclitaxel (TAP). This was shown on GOG 177, which compared TAP to AP among women with recurrent or metastatic endometrial carcinoma (18). Compared to AP, TAP resulted in a significant improvement in the overall response rate (57% vs. 34%), progression-free survival (8 vs. 5 months), and overall survival (15 vs. 12 months). However, it came at the expense of a higher rate of grade 3 neuropathy (12% vs. 1%).
More recently, the results of GOG 209, which compared carboplatin and paclitaxel to the TAP in patients with previously untreated, recurrent, advanced, or metastatic endometrial carcinoma (excluding carcinosarcoma), were reported (19). As presented at the 2012 Society for Gynecologic Oncology’s Annual Meeting, there was no significant difference in overall response rate (51% in both arms), progression-free survival (13 months in both arms), and overall survival (median, 37 vs. 40 months, respectively). We await longer follow-up of this trial.
SINGLE AGENT CHEMOTHERAPY
Multiple agents are active in previously treated endometrial carcinoma, although response durations are relatively short and median overall survival on clinical trials is typically less than 12 months. These include ixabepilone (20), ifosfamide (21), topotecan (22), and oxaliplatin (23). All patients with progressive endometrial cancer should consider enrollment in an appropriately designed randomized trial.
ENDOCRINE THERAPY
For patients with limited symptoms related to metastatic disease, endocrine therapy is a reasonable alternative to chemotherapy. While most studies suggest hormonal manipulation is effective in low-grade tumors, there is some evidence that higher grade cancers respond to treatment. For example, medroxyprogesterone (800 mg/day) results in a 40%, 15%, and 2% response rate in patients with grade 1, 2, or 3 cancer, respectively (24). However, the regimen of medroxyprogesterone (160 mg/day) alternating monthly with tamoxifen (40 mg/day) resulted in a 38%, 24%, and 22% response rate, respectively (25).
UTERINE SARCOMA
INCIDENCE AND EPIDEMIOLOGY
Uterine sarcoma comprises a heterogeneous group of tumors, including leiomyosarcoma, endometrial stromal sarcoma, and adenosarcoma among the more common variants. These tumors are rare with an incidence of 3%–7% per 100,000 in the United States (26).
As with carcinosarcoma, black women have an increased risk of leiomyosarcoma compared to white women. In addition, tamoxifen treatment appears to increase the risk of sarcoma, although the absolute risk is very small (17 per 100,000 women taking tamoxifen) (27).
CLINICAL PRESENTATION
Uterine sarcomas typically present due to pelvic pressure or vaginal bleeding. Women may also present due to a vaginal discharge or dyspareunia. Most cases do not present as a rapidly expanding uterine mass, despite common teachings. Endometrial stromal sarcomas typically affect women in their late 40s. Up to 30% have evidence of metastatic disease at presentation. Lung is the most common site of metastatic disease.
Adenosarcomas present in the same population as endometrial stromal sarcomas and are also hormone receptor positive in the vast majority. The recurrence risk is lower than that for endometrial stromal sarcoma.
Leiomyosarcomas typically are diagnosed in women in their 50s. Regardless of stage, the recurrence risk is uniformly high, ranging from 40% to 70% within 3 years of diagnosis.
DIAGNOSIS
The diagnosis of uterine sarcoma requires histological confirmation. It is not uncommon for the diagnosis to be made following a simple hysterectomy for a benign procedure.
HISTOLOGY
Endometrial stromal sarcoma—Histologically endometrial stromal sarcomas have a low mitotic rate and lack evidence of atypia or necrosis. Hormone receptors are positive in the vast majority (70%–95%) and approximately 70%–80% of endometrial stromal sarcomas are associated with a genetic mutation consisting of the JAZF1/JJAZ1 gene fusion encoding a product associated with cell survival and proliferation (28).
Adenosarcoma—Unlike endometrial stromal sarcoma, these sarcomas are associated with a benign epithelial component. Approximately 90% express hormone receptors. However, the presence of sarcomatous overgrowth typically signifies a more aggressive variant.
Leiomyosarcoma—The histologic appearance of leiomyosarcoma shows variably uniform bundles of smooth muscle cells exhibiting a high mitotic rate.
SURGICAL STAGING
For patients with histologically confirmed uterine sarcoma diagnosed by endometrial sampling, hysterectomy should be performed. The role of BSO is controversial and it is not clear if an oophorectomy improves survival, particularly in women with uterine confined endometrial stromal sarcoma or leiomyosarcoma (29–32). Lymphadenectomy should only be performed in patients with evidence of extrauterine involvement.
TREATMENT OF UTERINE SARCOMA
Adjuvant radiation therapy has no impact on survival outcomes. This was shown in a phase III study conducted by the European Organization for the Research and Treatment of Cancer (EORTC) in which 224 patients (103 with leiomyosarcoma, 91 with carcinosarcoma, and 28 with endometrial stromal sarcoma) were randomly assigned to RT vs. observation (33). Disease-free survival was similar (50% vs. 45% with RT vs. observation) as was overall survival (58% vs. 56%).
While chemotherapy has been shown to reduce the rate of recurrence, there is no evidence of a survival benefit with adjuvant administration (34). A large international phase II study (SARC 005) is evaluating a sequential treatment approach in uterine leiomyosarcoma (35). All patients get 4 cycles of docetaxel and gemcitabine followed by reimaging. Those patients without evidence of disease progression then proceed with doxorubicin for 4 cycles. As reported, the rate of progression-free survival at 3 years is 57%. Median progression-free survival and overall survival have not been reached.
RECURRENT UTERINE SARCOMA
For patients who present with a oligometastatic disease, surgical resection should be considered. Otherwise, systemic therapy is the only option for patients who desire further treatment. Active agents, which are used alone or as part of a combination regimen, include gemcitabine (with or without docetaxel) (36, 37), ifosfamide (38, 39), temazolamide (40), paclitaxel (41), and doxorubicin (42). There is some evidence that aromatase inhibitors may be active in leiomyosarcomas, although the evidence is fairly limited (43).
REFERENCES
1. Siegel R, Naishadham D, and Jemal A. Cancer Statistics, 2013. CA Cancer J Clin. 2013; 63: 11–30.
2. Bokham JV. Two pathologic types of endometrial carcinoma. Gynecol Oncol. 1983; 10: 237–246.
3. Cao QJ, Belbin T, Socci N, et al. Distinctive gene expression profiles by cDNA microarrays in endometrioid and serous carcinomas of the endometrium. Int J Gynecol Pathol. 2004; 23: 321–329.
4. Kovalev S, Marchenko ND, Gugliotta BG, et al. Loss of p53 function in uterine papillary serous carcinoma. Hum Pathol. 1998; 29: 613–619.
5. Bartosch C, Maneul Lopes J, Oliva E. Endometrial carcinomas: a review emphasizing overlapping and distinctive morphological and immunohistochemical features. Adv Anat Pathol. 2011; 18: 415–437.
6. Varughese J, Hui P, Lu Y, et al. Clear cell cancer of the uterine corpus: the association of clinicopathologic parameters and treatment on disease progression. J Clin Oncol. 2011; 200: 628084.
7. Dowdy SC, Borah BJ, Bakkum-Gamez JN, et al. Prospective assessment of cost, morbidity, and survival associated with lymphadenectomy in low risk endometrial cancer. J Clin Oncol. 2012; 30: abstr 5004.
8. Keys HM, Roberts JA, Brunetto VL, et al. A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: A Gynecologic Oncology Group Study. Gynecol Oncol. 2004; 92: 744–751.
9. Martin-Hirsch PP, Bryant A, Keep SL, et al. Adjuvant progestagens for endometrial cancer. Cochrane Database Syst Rev. 2011; 6:CD001040.
10. Nout RA, Smit VT, Putter H, et al. Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial. Lancet. 2010; 375: 816–823.
11. The ASTEC/EN.5 writing committee. Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-analysis. Lancet. 2009; 373: 137–146.
12. Pelvic Radiation Therapy or Vaginal Implant Radiation Therapy, Paclitaxel, and Carboplatin in Treating Patients With High-Risk Stage I or Stage II Endometrial Cancer. http://clinicaltrials.gov/show/NCT00807768. Accessed September 25, 2012.
13. 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. J Clin Oncol. 2006; 24: 36–44.
14. Carboplatin and Paclitaxel With or Without Cisplatin and Radiation Therapy in Treating Patients With Stage I, Stage II, Stage III, or Stage IVA Endometrial Cancer. http://clinicaltrials.gov/show/NCT00942357. Accessed September 25, 2012.
15. Kelly MG, O’Malley DM, Hui P, et al. Improved survival in surgical stage I patients with uterine papillary serous carcinoma (UPSC) treated with adjuvant platinum-based chemotherapy. Gynecol Oncol. 2005; 98: 353–359.
16. Powell MA, Fillaci VL, Rose PG, et al. Phase II evaluation of paclitaxel and carboplatin in the treatment of carcinosarcoma of the uterus: a Gynecologic Oncology Group Study. J Clin Oncol. 2010; 28: 2727–2731.
17. Wolfson AH, Brady MF, Rocereto T, et al. A gynecologic oncology group randomized phase III trial of whole abdominal irradiation (WAI) vs. cisplatin-ifosfamide and mesna (CIM) as post-surgical therapy in stage I-IV carcinosarcoma (CS) of the uterus. Gynecol Oncol. 2007; 107: 177–185.
18. Fleming, G, Brunetto, V, 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: 2159–2166.
19. Miller D, Filiaci V, Fleming G, et al. Randomized phase III noninferiority trial of first line chemotherapy for metastatic or recurrent endometrial carcinoma: a Gynecologic Oncology Group Study. Gynecol Oncol. 2012; 125: 771.
20. Dizon DS, Blessing JA, McMeekin DS, et al. Phase II trial of ixabepilone as second-line treatment in advanced endometrial cancer: gynecologic oncology group trial 129-P. J Clin Oncol. 2009; 27: 3104–3108.
21. Sutton GP, Blessing JA, DeMars LR, et al. A phase II Gynecologic Oncology Group trial of ifosfamide and mesna in advanced or recurrent adenocarcinoma of the endometrium. Gynecol Oncol. 1996; 63: 25–27.
22. Wadler S, Levy DE, Lincoln ST, et al. Topotecan is an active agent in the first-line treatment of metastatic or recurrent endometrial carcinoma: Eastern Cooperative Oncology Group Study E393. J Clin Oncol. 2003; 21: 2110–2114.
23. Fracasso PM, Blessing JA, Molpus KL, et al. Phase II study of oxaliplatin as second-line chemotherapy in endometrial carcinoma: a Gynecologic Oncology Group Study. Gynecol Oncol. 2006; 103: 523–526.
24. Podratz KC. Hormonal therapy in endometrial carcinoma. Recent Results Cancer Res. 1990; 118: 242–251.
25. Fiorica JV, Brunetto VL, Hanjani P, 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; 92: 10–14.
26. Brooks SE, Zhan M, Cote T, et al. Surveillance, epidemiology, and end results analysis of 2677 cases of uterine sarcoma 1989-1999. Gynecol Oncol. 2004; 93: 204–208.
27. Wickerham DL, Fisher B, Wolmark N, et al. Association of tamoxifen and uterine sarcoma. J Clin Oncol. 2002; 20: 2758–2760.
28. Chiang S, Oliva E. Cytogenetic and molecular aberrations in endometrial stromal tumors. Hum Pathol. 2011; 42: 609–617.
29. Shah JP, Bryant CS, Kumar S, et al. Lymphadenectomy and ovarian preservation in low-grade endometrial stromal sarcoma. Obstet Gynecol. 2008; 112: 1102–1108.
30. Kapp DS, Shin JY, Chan JK. Prognostic factors and survival in 1396 patients with uterine leiomyosarcomas: emphasis on impact of lymphadenectomy and oophorectomy. Cancer. 2008; 112: 820–830.
31. Dos Santos LA, Garg K, Diaz JP, et al. Incidence of lymph node and adnexal metastasis in endometrial stromal sarcoma. Gynecol Oncol. 2011; 121: 319–322.
32. Riopel J, Plante M, Renaud MC, et al. Lymph node metastases in low-grade endometrial stromal sarcoma. Gynecol Oncol. 2004; 96: 402–406.
33. Reed NS, Mangioni C, Malmström H, et al. Phase III randomised study to evaluate the role of adjuvant pelvic radiotherapy in the treatment of uterine sarcomas stages I and II: an European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group Study (protocol 55874). Eur J Cancer. 2008; 44: 808–818.
34. Omura GA, Blessing JA, Major F, et al. A randomized clinical trial of adjuvant adriamycin in uterine sarcomas: a Gynecologic Oncology Group Study. J Clin Oncol. 1985; 3: 1240–1245.
35. Hensley ML, Wathen K, Maki RG, et al. 3-year follow-up of SARC005: Adjuvant treatment of high risk primary uterine leiomyosarcoma with gemcitabine/docetaxel (GT), followed by Doxorubicin (D). Presented at the 2011 Connective Tissue Oncology Society Meeting, Chicago, IL. (Poster #78).
36. Hensley ML, Blessing JA, Mannel R, et al. Fixed-dose rate gemcitabine plus docetaxel as first-line therapy for metastatic uterine leiomyosarcoma: a Gynecologic Oncology Group phase II trial. Gynecol Oncol. 2008; 109: 329–334.
37. Look KY, Sandler A, Blessing JA, et al. Phase II trial of gemcitabine as second-line chemotherapy of uterine leiomyosarcoma: a Gynecologic Oncology Group (GOG) Study. Gynecol Oncol. 2004; 92: 644–647.
38. Homesley HD, Filiaci V, Markman M, et al. Phase III trial of ifosfamide with or without paclitaxel in advanced uterine carcinosarcoma: a Gynecologic Oncology Group Study. J Clin Oncol. 2007; 25: 526–531.
39. Sutton G, Kauderer J, Carson LF, et al. Adjuvant ifosfamide and cisplatin in patients with completely resected stage I or II carcinosarcomas (mixed mesodermal tumors) of the uterus: a Gynecologic Oncology Group study. Gynecol Oncol. 2005; 96: 630–634.
40. Talbot SM, Keohan ML, Hesdorffer M, et al. A phase II trial of temozolomide in patients with unresectable or metastatic soft tissue sarcoma. Cancer. 2003; 98: 1942–1946.
41. Gallup DG, Blessing JA, Andersen W, et al. Evaluation of paclitaxel in previously treated leiomyosarcoma of the uterus: a gynecologic oncology group study. Gynecol Oncol. 2003; 89: 48–51.
42. Judson I, Radford JA, Harris M, Blay JY, et al. Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2001; 37: 870–877.
43. O’Cearbhaill R, Zhou Q, Iasonos A, et al. Treatment of advanced uterine leiomyosarcoma with aromatase inhibitors. Gynecol Oncol. 2010; 116: 424–429.