Advances in the treatment of endometrial cancer

Review Advances in the treatment of endometrial cancer Martin K. Oehler, Alison Fung and Thomas W. Jobling Department of Gynaecological Oncology, Mon...
Author: Jessie Cameron
14 downloads 3 Views 100KB Size
Review

Advances in the treatment of endometrial cancer Martin K. Oehler, Alison Fung and Thomas W. Jobling Department of Gynaecological Oncology, Monash Medical Centre, Melbourne, Australia

Abstract

Endometrial cancer (EC) most commonly affects postmenopausal women. It is curable if treated early, but tumours with adverse histopathological features or at an advanced stage are associated with a high mortality rate. These cancers require a complex therapeutic approach, consisting of surgery, radiotherapy, chemotherapy and/or hormonal therapy. As one of the leading causes of death from malignancy in women, EC has been subject to intense clinical investigation. This article examines recent advances in the surgical treatment of the disease, such as sentinel lymph node sampling and total laparoscopic hysterectomy, as well as topics such as conservative treatment of EC for fertility preservation. Furthermore, new agents for EC treatment are presented, for example inhibitors of the mTOR pathway and the angiogenesisinhibitor VEGF-trap.

Keywords: Endometrial cancer, mTOR, sentinel lymph node, trastuzumab, VEGF-trap

Introduction Endometrial cancer (EC) is the most common gynaecological cancer in the industrialized world; in 2003 there were an estimated 40,100 new cases and 6800 deaths in the USA from the disease. EC is typically a disease of postmenopausal women, as the incidence is highly age dependent: there are about 5 cases per 100,000 women under 50 years of age and about 76 cases per 100,000 women over that age.1 There are two types of EC. Type I is the oestrogendependent cancer that tends to be endometrioid in cell type, is oestrogen and progesterone receptor positive, and presents with a lower histological grade. Type II occurs mainly in postmenopausal women and is not oestrogen dependent. It tends to be of serous papillary or clear cell type, is more aggressive, lacks oestrogen and progesterone Correspondence: Dr Martin K. Oehler, Clinical Fellow, Department of Gynaecological Oncology, Monash Medical Centre, Moorabbin Campus, PO Box 72, East Bentleigh 3165, Victoria, Australia. Email: [email protected]

18

receptors and presents with a higher histological grade. Genetic factors are involved in both types of EC. These include mutations in DNA-mismatch repair genes in type I cancers, and p53 mutations and HER2/neu amplification in type II cancers.2

Surgery Laparotomy, total hysterectomy and bilateral salpingooophorectomy is the standard surgical therapy for EC. In addition, pelvic and para-aortic lymphadenectomy are advocated by many for both therapeutic and prognostic purposes. The benefits of lymphadenectomy remain contentious, as full-pelvic and para-aortic dissection adds to the duration as well as the morbidity of surgery. Several parameters are assessed intraoperatively to distinguish which patients are at high risk of extrauterine spread and therefore in need of lymphadenectomy. These include the size of the primary lesion, depth of myometrial invasion (DMI), involvement of the cervix and enlargement of the lymph nodes. As the accuracy rate for determining the DMI by gross visual examination has been reported to be only about 90%, some authors recommend that an intraoperative frozen section is examined.3 The preparation of a frozen section, however, is time consuming and susceptible to errors. One study reported suboptimal management in about 5% of cases when DMI was assessed by frozen section.4 Intraoperative lymph node assessment (to determine lymph node enlargement by 1 cm or more) has been shown to have a high false-negative rate – more than 25% – and is therefore inadequate.5 The poor ability to determine intraoperatively the need for lymphadenectomy has led to an interest in the preoperative assessment of lymph node involvement, in order to inform the planning of surgery. The use of imaging to estimate the DMI before surgery has been examined. The most encouraging of these modalities is magnetic resonance imaging (MRI). The main benefit of MRI is its excellent capacity for soft-tissue contrast resolution.6 The reported overall staging accuracy of MRI in EC is up to 92%, with up to 91% accuracy for differentiating superficial from deep EC.7 A recent meta-analysis comparing computerized tomography (CT), transvaginal ultrasound

Journal of the British Menopause Society Vol. 11 No. 1 March 2005

M K Oehler et al.

and MRI found that contrast-enhanced MRI performed the best in the assessment of DMI.8 A further method to assess lymph node status in EC is by sentinel lymph node sampling. The sentinel lymph node procedure is established in the management of breast cancer and is under evaluation for vulvar and cervical malignancies.9 There is, though, relatively little experience with sentinel lymph node procedures in EC.10,11 In most studies the endometrial tumour is visualized by hysteroscopy and tracers (99mTc and/or blue dye) injected around the lesion. The sentinel lymph node is then detected during laparoscopy or laparotomy as a hot spot with a gamma-counter or by its blue staining. With this method the sentinel node detection rate varies from 62% to 100%.12,13 Thus, although the sentinel node has been reported to be accurate in prediction of lymph node status in EC, many questions remain open, such as the sites and numbers of injections and volume of tracers. Moreover, the complex and extensive uterine lymphatic network may be a disadvantage for sentinel lymph node interpretation in EC. Larger clinical studies are therefore warranted. With respect to the operative approach, there has been a recent trend towards laparoscopic management of early EC. Techniques include total laparoscopic hysterectomy (TLH) and laparoscopically assisted vaginal hysterectomy. The reputed benefits of laparoscopic surgery are the reduced morbidity, recovery time and hospital stay.14 Laparoscopically assisted vaginal hysterectomy usually involves laparoscopic securing of the ovarian pedicles and reflection of the bladder, and may or may not include laparoscopic division of the uterine vessels before completion of the rest of the procedure through the vagina. In contrast, TLH involves performing the entire operation laparoscopically. A specially designed tube, such as the McCartney tube, is inserted into the vagina against the vault during TLH. It stabilizes the vagina and thereby allows easier dissection of the bladder and exposure of the cervico-vaginal junction. The tube also helps to identify a safe point for division of the uterine vessels and permits maintenance of the pneumoperitoneum once the vagina is opened.15,16 A prerequisite for the laparoscopic approach is that staging and the extent of surgery are not compromised. Studies published to date indicate no difference in prognosis whether EC is operated on laparoscopically or by open surgery. A retrospective study comparing EC patients treated either by TLH or open hysterectomy showed no differences in disease-free and overall survival after a median follow-up of 29 months. Patterns of recurrence were similar in the two groups and no port-site metastasis (a reported complication of laparoscopy in malignancies) occurred in the TLH group.17 However, laparoscopic surgery is currently restricted to early-stage cancers and may be performed only on suitable patients. Factors such as body mass index and previous surgery can be limiting factors. The technique also requires operator proficiency in order for the procedure to be accomplished entirely laparoscopically. As the studies to date have relatively short follow-up and tend to include small numbers of women, additional research is required to determine whether outcome is indeed uncompromised by this technique. The US Gynecologic Oncology Group (GOG) study ‘Laparoscopic Surgery or Standard Surgery in Treating Patients with Endometrial Cancer or Cancer of the Uterus’ (GOG-LAP2) is currently examining the potential role of laparoscopic surgery in EC.

Advances in endometrial cancer treatment

Radiotherapy Radiation in EC is usually given as an adjuvant treatment. Preoperative radiotherapy, often recommended in earlier times, lost favour because of the potential loss of pathological information and inability to tailor adjuvant treatment according to surgico-pathological findings.18 Adjuvant radiotherapy has been shown to reduce the incidence of both pelvic and vaginal recurrence significantly. Nevertheless, evidence in support of survival benefit from adjuvant radiotherapy is unsatisfactory, mainly because of the insufficient numbers of prospective randomized studies. The role of radiation in the adjuvant setting is therefore controversial. The GOG-99 trial investigated the use of postoperative pelvic radiotherapy compared with no additional treatment in women with FIGO stage IB, IC, IIA occult disease or IIB occult disease.19 Whole-pelvic radiation resulted in a highly significant reduction in loco-regional recurrence (3% versus 12% two-year vaginal or pelvic failure) but only a negligible effect on overall survival. Unfortunately, the study was unable to examine the effect on survival in high-risk groups. The Post-Operative Radiation Therapy in Endometrial Carcinoma (PORTEC) trial included women with intermediate-risk disease (stage I, grade 1, with deep myometrial invasion; stage I, grade 2, with any invasion; or stage I, grade 3, with superficial invasion).20 It had comparable results to the GOG-99 trial, with a significant reduction in loco-regional recurrence but no overall survival benefit with radiotherapy. The conclusion that can be drawn from both studies is that adjuvant radiotherapy improves loco-regional control but does not affect survival in low- and intermediate-risk EC. However, as both studies decreased vaginal recurrence, suggestions have been made that vaginal vault radiation be substituted for pelvic radiation for intermediate-risk disease.21,22 This question is being addressed prospectively in the PORTEC-2 study (a multicentre, randomized phase III trial comparing external-beam irradiation with vaginal brachytherapy).23 Unlike early-stage disease, there is consensus that patients whose tumours possess high-risk features such as positive lymph nodes have a significant risk of relapse after surgery alone and postoperative radiotherapy improves their prognosis. What remains unclear is what represents the optimal radiotherapy, and many patients receive a highly individualized approach owing to the widely varying manifestations of extrauterine spread. Patients with positive pelvic lymph nodes as their only risk factor are usually given adjuvant whole-pelvis or extended-field radiation. Radiation management of patients with involvement of the adnexa (stage IIIa) or other intraperitoneal structures (stage IVb) is also controversial. For those with completely excised cancers, whole-abdomen radiation appears a reasonable option, but there is potential for significant toxicity. The results of the GOG-122 trial comparing patients with stage III or IV disease treated with whole-abdomen radiation versus chemotherapy are pending.

Hormonal therapy Larger trials have been unable to show a significant survival benefit with adjuvant progestogens in stage I

Journal of the British Menopause Society Vol. 11 No. 1 March 2005

19

M K Oehler et al.

Advances in endometrial cancer treatment

disease. A recent Cochrane analysis concluded that there appears to be no indication for adjuvant progestogens after surgery for early EC.24 However, progestogens have a definite role in advanced or recurrent EC. The overall response in advanced EC is approximately 25%. The average time to progression for all patients is approximately four months but patients who have a complete or partial response may have durable remissions lasting up to several years. Overall survival with progestogen treatment is about one year. A long disease-free interval (exceeding two or three years), well differentiated histological types and positive oestrogen or progesterone receptor status have all been associated with response to treatment. The route of administration does not appear to be of importance, as both parenteral and oral progestogens yield similar serum levels and response rates. Primary hormonal therapy with progestogens was suggested as an alternative treatment to surgery in an attempt to preserve fertility in young patients. A recent review analysed all reported cases of grade 1 endometrial adenocarcinoma conservatively managed with hormonal therapy in the literature (81 patients in 27 articles). The majority of patients (76%) responded and 20 were able to become pregnant at least once after completing treatment. When an initial response was not achieved or in case of disease recurrence, extension of the disease beyond the uterus was rare.25 Although promising, the reports have to be interpreted with caution because of small case numbers and publication bias. Furthermore, the main problem of how to select patients for conservative treatment is unsolved. Only patients with early-stage disease and good prognostic criteria are eligible. Accurate staging – which may have to include imaging (e.g. MRI and/or positron emission tomography) – is vital but may not be possible in many cases. In patients with early-stage EC and a high risk of perioperative complications (American Society for Anesthesiology class 3 and 4), progestogen administration via the levonorgestrel intrauterine system Mirena® may be an option. Using this approach, a potential therapeutic effect with eradication of the disease was observed in a small case series.26 Tamoxifen has been applied with modest results as salvage therapy in EC. A meta-analysis showed a pooled response rate of 22% for tamoxifen alone.27 The potential of combined tamoxifen–progestogen therapy has also been evaluated. A recent study of tamoxifen alternating with megestrol acetate in recurrent or advanced EC in women who had not had previous chemotherapy or hormonal therapy has shown a response rate of 31% in those with extra-pelvic disease and 14% in those with pelvic or vaginal disease.28 A GOG trial of tamoxifen combined with medroxyprogresterone acetate reported a response rate of 33%.29 Fulvestrant (Faslodex®) is another anti-oestrogen with potential for use in EC. A phase II trial entitled ‘Fulvestrant in Treating Patients with Recurrent, Persistent, or Metastatic Endometrial Cancer’ is currently recruiting subjects (GOG-188).30 Anastrozole (Arimidex®) is an oral non-steroidal aromatase inhibitor that has become an established treatment for breast cancer. However, in a phase II trial with advanced recurrent or persistent EC, performed by the GOG, it showed only limited activity.31 Whether more

20

potent aromatase inhibitors such as letrozole are more active in EC remains to be examined. Analogues of gonadotrophin-releasing hormone (GnRH) down-regulate receptors in the pituitary, leading to subsequent decline of gonadotrophin and oestrogen levels. Initial results from small case series treated with GnRH analogues in EC have been promising, but larger studies have demonstrated only limited activity.32,33

Chemotherapy Cytotoxic chemotherapy has no proven role in the management of early-stage EC but is used in patients with primary advanced or recurrent EC. Many agents have been studied in the treatment of EC, but few have shown significant single-agent activity. The most active single agents are doxorubicin and cisplatin, which give response rates of 20–40%. Given the activity demonstrated by these two agents, studies have investigated combination treatment with doxorubicin and cisplatin. A GOG study showed a response rate of 45% with this combination, compared with 27% for doxorubicin alone, but no survival benefit. 34 A recent randomized study conducted by the European Organization for Research and Treatment of Cancer (EORTC) confirmed the activity of doxorubicin–cisplatin in advanced and recurrent EC and even observed a survival benefit for patients treated with this combination when compared with those treated with doxorubicin only. 35 Doxorubicin has been recently repackaged in a pegylated liposome (Caelix®, Doxil®), which reduces its cardiac and myelotoxicity. The GOG tested its activity in patients with metastatic EC who had failed other chemotherapy, including unpegylated doxorubicin.36 Although only limited activity was demonstrated in this study, the effect of pegylated doxorubicin in chemotherapy-naïve patients remains to be assessed. Given the reduced toxicity, pegylated doxorubicin may have potential in combination with other myelosuppressive agents. Paclitaxel has also been studied as a single agent for the treatment of advanced or recurrent EC. An overall response rate of 30% was obtained, with manageable adverse reactions. 37 Because of the significant activity of paclitaxel, studies are now investigating whether combination therapy increases survival. A recent phase III trial demonstrated a statistically significant increase in response with the addition of paclitaxel to doxorubicin and cisplatin (57% versus 34%), improved progressionfree survival (67% versus 50%), but only a modest improvement in overall survival (58% versus 50%). 38 Several studies have focused on the use of chemotherapy with radiotherapy. In combination, chemotherapy is used as a radiation sensitizer; in a sequential setting, it is used to address distant metastases. Studies have suffered methodological problems but the GOG is conducting a phase III trial comparing pelvic radiotherapy with or without para-aortic radiotherapy followed by cisplatin– doxorubicin or cisplatin– doxorubicin– paclitaxel in stage III EC (GOG 184). The concurrent use of paclitaxel and cisplatin as radiosensitizers during radiotherapy for stage III or IV EC is being evaluated in the GOG 9907 phase I study. In addition, a study examining

Journal of the British Menopause Society Vol. 11 No. 1 March 2005

M K Oehler et al.

radiotherapy with or without cisplatin and doxorubicin– epirubicin chemotherapy (EORTC-55991) is in progress. Because of the lack of overlapping toxicity and the efficacy of progestogens in advanced EC, the combination of chemotherapy with progestin therapy has also been examined. Responses range between 15% and 74%, but the limited data available do not show an improvement in survival.39,40 Currently, there appears to be no evidence in support of concurrent chemotherapy and hormonal treatment of EC. There have been suggestions that chemotherapy may be combined with hyperthermia in the treatment of EC. Hyperthermia kills tumour cells by heating them to several degrees above body temperature, usually with minimal injury to normal tissues. Hyperthermia in combination with chemotherapy has its biological rationale based on thermal enhancement of cytotoxicity and partial circumvention of resistance. Results of feasibility studies with a small number of patients are promising.41,42 The combination of fluorouracil and liposomal doxorubicin with systemic hyperthermia in treating patients with metastatic EC is currently being tested in a phase II study (UTHSCMS-96205).43

New agents Trastuzumab (Herceptin®), a humanized murine monoclonal antibody directed against the extracellular domain of the HER2/neu protein, is known to prolong the survival of people with solid tumours such as breast cancer. However, in advanced or recurrent EC a phase II trial of trastuzumab showed only limited activity. This may be explained by the fact that only 13% of the treated tumours over-expressed HER2/neu.44 The GOG-0181-B phase II trial is now exploring ‘Trastuzumab in Treating Patients with Stage III, Stage IV, or Recurrent Endometrial Cancer’. It is noteworthy that recent studies have shown that type II EC (papillary serous carcinomas) may express significantly higher levels of HER2/neu than type I endometrial tumours. Results from a small case series in which patients with advanced papillary serous carcinomas responded to trastuzumab treatment are encouraging.45 Anti-HER2/neu therapy may therefore be a new treatment strategy in type II EC. The mammalian target of rapamycin (mTOR) is a serine-threonine kinase member of the phosphatidylinositol 3-kinase (PI3K) pathway, which is involved in multiple biological functions, including cell growth and proliferation. Inhibiting mTOR results in cell cycle arrest and specific blockers of mTOR act in a cytostatic way. Rapamycin is a macrolide that acts as a specific inhibitor of mTOR down-stream signalling. It is a specific cell inhibitor and induces apoptosis.46 CCI779, a pro-drug of rapamycin, has been investigated as a cytostatic agent. Data from current phase II trials of CCI779 in breast carcinoma and renal cell carcinoma reveal anti-tumour activity and good tolerability. Its value in recurrent EC is being evaluated in a phase II study (CAN-NCICIND160).43 Everolimus (RAD001) is an oral rapamycin analogue. No studies concerning the effect of everolimus in solid tumours have yet been published but it is currently being examined in a phase I clinical trial ‘RAD001 in Recurrent Endometrial Cancer’ (NCT00087685).43

Advances in endometrial cancer treatment

Angiogenesis, the development of new blood vessels from the existing vasculature, is an essential component of solid tumour growth and metastasis. Despite initial setbacks, clinical research is focusing on anti-angiogenic therapy more than ever. Vascular endothelial growth factor (VEGF) is one of the principal angiogenic factors in solid tumours such as EC and is a potential target for anti-angiogenic treatment. The relevance of this strategy was first successfully demonstrated in human clinical trials using a monoclonal antibody against VEGF. VEGF-Trap is a newly designed high-affinity decoy for the VEGF receptor; it possesses an affinity for VEGF that is significantly higher than that of the monoclonal antibody. VEGF-Trap has demonstrated marked efficacy in halting angiogenesis and shrinking tumours in preclinical animal models.47 Recruitment of patients for a phase I study of VEGF-Trap in patients with relapsed or refractory advanced solid tumours, including EC, is now in progress (REGENERON-VGFT-ST-0304).43

Conclusion The treatment of EC has seen many advances in recent years and ongoing clinical studies are likely to result in further progress. While the roles of well established treatments such as surgery, radiotherapy, chemotherapy and hormonal therapy are being further defined, greater effort should be put in the understanding of the molecular biology and the mechanisms controlling the growth and metastasis of EC. This is the basis for the design of new therapeutics directed against specific molecular targets, which, in theory, should be more effective than the conventional treatment options. Competing interests: None declared.

References 1 Ries L, Eisner M, Kosary C, et al. SEER Cancer Statistics Review, 1975–2000. Bethesda, MD: NCI, 2003. See http://seer.cancer. gov/csr/1975_2000. Last accessed 10 November 2004 2 Oehler MK, Brand A, Wain GV. Molecular genetics and endometrial cancer. J Br Menopause Soc 2003;9:27–31 3 Franchi M, Ghezzi F, Melpignano M, et al. Clinical value of intraoperative gross examination in endometrial cancer. Gynecol Oncol 2000;76:357–61 4 Quinlivan JA, Petersen RW, Nicklin JL. Accuracy of frozen section for the operative management of endometrial cancer. Br J Obstet Gynaecol 2001;108:798–803 5 Eltabbakh GH. Intraoperative clinical evaluation of lymph nodes in women with gynecologic cancer. Am J Obstet Gynecol 2001;184:1177–81 6 Ben-Shachar I, Vitellas KM, Cohn DE. The role of MRI in the conservative management of endometrial cancer. Gynecol Oncol 2004;93:233–7 7 Ascher SM, Reinhold C. Imaging of cancer of the endometrium. Radiol Clin North Am 2002;40:563–76 8 Kinkel K, Kaji Y, Yu KK, et al. Radiologic staging in patients with endometrial cancer: a meta-analysis. Radiology 1999;212:711–18 9 Barranger E, Darai E. Lymphatic mapping for gynecologic malignancies. Semin Oncol 2004;31:394–402 10 Raspagliesi F, Ditto A, Kusamura S, et al. Hysteroscopic injection of tracers in sentinel node detection of endometrial cancer: a feasibility study. Am J Obstet Gynecol 2004;191:435–9

Journal of the British Menopause Society Vol. 11 No. 1 March 2005

21

M K Oehler et al.

Advances in endometrial cancer treatment

11 Niikura H, Okamura C, Utsunomiya H, et al. Sentinel lymph node detection in patients with endometrial cancer. Gynecol Oncol 2004;92:669–74 12 Pelosi E, Arena V, Baudino B, et al. Preliminary study of sentinel node identification with 99mTc colloid and blue dye in patients with endometrial cancer. Tumori 2002;88:S9–10 13 Barranger E, Cortez A, Grahek D, et al. Laparoscopic sentinel node procedure using a combination of patent blue and radiocolloid in women with endometrial cancer. Ann Surg Oncol 2004; 11:344–9 14 Querleu D, Leblanc E. Laparoscopic surgery for gynaecological oncology. Curr Opin Obstet Gynecol 2003;15:309–14 15 McCartney AJ, Johnson N. Using a vaginal tube to separate the uterus from the vagina during laparoscopic hysterectomy. Obstet Gynecol 1995;85:293–6 16 McCartney AJ, Obermair A. Total laparoscopic hysterectomy with a transvaginal tube. J Am Assoc Gynecol Laparosc 2004;11:79–82 17 Obermair A, Manolitsas TP, Leung Y, et al. Total laparoscopic hysterectomy for endometrial cancer: patterns of recurrence and survival. Gynecol Oncol 2004;92:789–93 18 Koh WJ, Tran AB, Douglas JG, Stelzer KJ. Radiation therapy in endometrial cancer. Best Pract Res Clin Obstet Gynaecol 2001;15:417–32 19 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;92:744–51 20 Creutzberg CL, van Putten WL, Koper PC, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet 2000;355:1404–11 21 Rittenberg PV, Lotocki RJ, Heywood MS, et al. High-risk surgical stage 1 endometrial cancer: outcomes with vault brachytherapy alone. Gynecol Oncol 2003;89:288–94 22 Horowitz NS, Peters WA, 3rd, Smith MR, et al. Adjuvant high dose rate vaginal brachytherapy as treatment of stage I and II endometrial carcinoma. Obstet Gynecol 2002;99:235–40 23 Cardenes H, Randall ME. Is observation and salvage (when necessary) an appropriate approach to intermediate risk endometrial cancer? Gynecol Oncol 2003;89:199–200 24 Martin-Hirsch PL, Jarvis G, Kitchener H, Lilford R. Progestagens for endometrial cancer. Cochrane Database Syst Rev 2000: CD001040 25 Ramirez PT, Frumovitz M, Bodurka DC, et al. Hormonal therapy for the management of grade 1 endometrial adenocarcinoma: a literature review. Gynecol Oncol 2004;95:133–8 26 Montz FJ, Bristow RE, Bovicelli A, et al. Intrauterine progesterone treatment of early endometrial cancer. Am J Obstet Gynecol 2002;186:651–7 27 Moore TD, Phillips PH, Nerenstone SR, Cheson BD. Systemic treatment of advanced and recurrent endometrial carcinoma: current status and future directions. J Clin Oncol 1991;9:1071–88 28 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 29 Whitney CW, Brunetto VL, Zaino RJ, et al. Phase II study of medroxyprogesterone acetate plus tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2004;92:4–9 30 Addo S, Yates RA, Laight A. A phase I trial to assess the pharmacology of the new oestrogen receptor antagonist fulvestrant on the

22

31

32 33 34

35

36

37 38

39

40

41 42

43 44

45 46 47

endometrium in healthy postmenopausal volunteers. Br J Cancer 2002;87:1354–9 Rose PG, Brunetto VL, VanLe L, et al. Phase II trial of anastrozole in advanced recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2000;78:212–16 Gallagher CJ, Oliver RT, Oram DH, et al. A new treatment for endometrial cancer with gonadotrophin releasing-hormone analogue. Br J Obstet Gynaecol 1991;98:1037–41 Asbury RF, Brunetto VL, Lee RB, et al. Goserelin acetate as treatment for recurrent endometrial carcinoma: a Gynecologic Oncology Group study. Am J Clin Oncol 2002;25:557–60 Thigpen J, Blessing H, Homesley H, et al. Phase III trial of doxorubicin +/– cisplatin in advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group (GOG) study. Proceedings of the American Society for Clinical Oncology 1993;12:261 Aapro MS, Van Wijk FH, Bolis G, 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;14:441–8 Muggia FM, Blessing JA, Sorosky J, Reid GC. Phase II trial of the pegylated liposomal doxorubicin in previously treated metastatic endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol 2002;20:2360–4 Hirai Y, Hasumi K, Onose R, et al. Phase II trial of 3-h infusion of paclitaxel in patients with adenocarcinoma of endometrium: Japanese Multicenter Study Group. Gynecol Oncol 2004;94:471–6 Fleming GF, Filiaci VL, Bentley RC, 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;15:1173–8 Ayoub J, Audet-Lapointe P, Methot Y, et al. Efficacy of sequential cyclical hormone therapy in endometrial cancer and the correlation with steroid hormone receptor status. Gynecol Oncol 1988;31:327–37 Bafaloukos D, Aravantinos G, Samonis G, et al. Carboplatin, methotrexate and 5-fluorouracil in combination with medroxyprogesterone acetate (JMF-M) in the treatment of advanced or recurrent endometrial carcinoma: a Hellenic cooperative oncology group study. Oncology 1999;56:198–201 Rietbroek RC, Schilthuis MS, van der Zee J, Gonzalez D. Hyperthermia in combination with chemotherapy in gynecological cancers. Ned Tijdschr Geneeskd 1999;143:85–8 [Dutch] Piotrkowicz N, Zielinski J, Jonska J, et al. Intracavitary 500 kHz hyperthermia treatment of patients with endometrial and cervical cancer – preliminary clinical and pathological results. Ginekol Pol 2003;74:824–9 [Polish] National Institutes of Health. www.clinicaltrials.gov. Last accessed 10 November 2004 Fleming G, Sill M, Thigpen J, et al. Phase II evaluation of trastuzumab in patients with advanced or recurrent endometrial carcinoma: a report on GOG 181B. 39th Meeting of the American Society of Clinical Oncology, 2003: abstract 1821 Villella J, Cohen S, Tiersten A, et al. HER2/neu expression in uterine papillary serous cancers. 39th Meeting of the American Society of Clinical Oncology 2003: abstract 1870 Carraway H, Hidalgo M. New targets for therapy in breast cancer: mammalian target of rapamycin (mTOR) antagonists. Breast Cancer Res 2004;6:219–24 Byrne AT, Ross L, Holash J, et al. Vascular endothelial growth factor-trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model. Clin Cancer Res 2003;9:5721–8

Journal of the British Menopause Society Vol. 11 No. 1 March 2005

Suggest Documents