The Role of Postoperative Radiotherapy in Carcinoma of the Endometrium

Clinical Oncology (2008) 20: 457e462 doi:10.1016/j.clon.2008.03.011

Overview

The Role of Postoperative Radiotherapy in Carcinoma of the Endometrium A. Kong*, M. Powelly, P. Blake* *Radiotherapy Department, Royal Marsden Hospital, London SW3 6JJ, UK; yRadiotherapy Department, St. Bartholomew’s Hospital, London EC1, UK

ABSTRACT: The role of adjuvant postoperative radiotherapy in endometrial carcinoma after surgery remains controversial. There is a great variation between centres in deciding when to give postoperative external beam radiotherapy and/or vaginal vault brachytherapy for patients with endometrial carcinoma. The role of pelvic and para-aortic lymphadenectomy as well as the need for postoperative radiotherapy after this type of surgical staging continue to be debated. Furthermore, the role of adjuvant chemotherapy either alone or in combination with adjuvant radiotherapy also remains to be determined. This overview discusses the role of postoperative radiotherapy in the context of surgery and other adjuvant treatments in carcinoma of the endometrium. Kong, A. et al. (2008). Clinical Oncology 20, 457—462 ª 2008 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Chemotherapy, endometrial carcinoma, external beam radiotherapy, lymphadenectomy, vaginal vault brachytherapy

Statement of Search Strategies Used and Sources of Information In collaboration with Cochrane Gynaecology Group, a systematic review and meta-analysis was previously carried out by the first author [17] and a highly sensitive search strategy described in the Cochrane handbook was used. The following electronic databases were searched: CENTRAL, MEDLINE, EMBASE, Physician Data Query (PDG), the Specialised Register of the Cochrane Gynaecological Cancer Review Group, as well as the reference lists of all the relevant papers. This overview used the sources of information from the systematic review [17] as well as the most recent publications found on PUBMED.

Introduction Endometrial carcinoma is the most common gynaecological cancer in the developed world [1]. Most patients are postmenopausal, with only 25% premenopausal and 3% under 40 years of age [2]. Risk factors for the development of endometrial cancer include obesity, nulliparity, late menopause, diabetes mellitus, unopposed oestrogens, tamoxifen therapy and use of the oral contraceptive pill [3]. Epithelial tumours comprise 97% of uterine malignancies and the remaining 3% are sarcomas [3]. Among the patients with epithelial tumours, most have endometrioid adenocarcinoma (or adenocarcinoma with squamous metaplasia or squamous differentiation). The remaining 10% include clear cell and papillary serous carcinomas [3]. 0936-6555/08/200457þ06 $35.00/0

Most women with endometrial cancer present with International Federation of Gynecology and Obstetrics (FIGO) stage I disease and have a good prognosis, with an overall survival of up to 90% [4]. Apart from women with locally advanced or metastatic disease, the definitive treatment for endometrial carcinoma is total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO) with or without pelvic and para-aortic lymphadenectomy [5]. The decision to give adjuvant treatments depends on the presence of certain risk factors [5]. These treatments include pelvic external beam radiotherapy and/or vaginal brachytherapy, chemotherapy and hormonal therapy. This overview will discuss the different treatment modalities as well as the management options for the different stages of endometrial carcinoma. The role of postoperative radiotherapy in carcinoma of the endometrium is discussed in the context of surgery and other adjuvant treatments, as all these treatment modalities are often used together in these patients. The management of uterine sarcoma will not be discussed here.

Staging System and Prognostic Factors Most endometrial cancers are confined to the uterus and the spread is usually lymphatic or by direct extension. Haematogenous spread (commonly to lungs) occurs late in the disease [6]. The prognosis of endometrial carcinoma is related to the stage of the disease as well as the presence of certain pathological risk factors [3]. FIGO uses both surgical and pathological staging for corpus uteri carcinoma and the stages are further subdivided by histological grade of

ª 2008 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

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tumour [7]. The definitions of the T categories of the TNM system correspond to the stages accepted by FIGO (Table 1) [7]. In the absence of any other distant metastasis, the presence of regional lymph node metastasis is the most important prognostic factor in endometrial carcinoma [7]. Other high risk factors in determining the recurrence and death rates of these patients include depth of myometrial invasion, grade of the tumour, lymphovascular space invasion (LVSI) and the histology subtypes (serous papillary and clear cell adenocarcinomas) [7,8]. Older patients tend to have worse survival compared with younger patients, although some studies suggest that age is not an independent risk factor after adjustment for tumour grade [3].

Treatment Modalities For localised disease, TAH and BSO is the gold standard treatment. There is debate about the role of pelvic and para-aortic lymphadenectomy as well as the extent of lymphadenectomy (sampling of suspicious nodes vs complete lymphadenectomy). The value of external beam Table 1 e TNM staging and International Federation of Gynecology and Oncology (FIGO) stage [7] TNM category

FIGO stage

Tx T0 Tis T1 T1a T1b

0 I IA IB

T1c

IC

T2

II

T2a

IIA

T2b

IIB

T3

III

T3a

IIIA

T3b T4

IIIB IVA

Nx N0 N1

IIIC

Mx M0 M1

IVB

Primary tumour cannot be assessed No evidence of primary tumour Carcinoma in situ Tumour confined to corpus uteri Tumour limited to endometrium Tumour invades less than one-half of the myometrium Tumour invades one-half or more of the myometrium Tumour invades cervix but does not extend beyond uterus Tumour limited to the glandular epithelium of the endocervix Invasion of the stromal connective tissue of the cervix Local and/or regional spread as defined below Tumour involves serosa and/or adnexa and/or cancer cells in ascites or peritoneal washings Vaginal involvement Tumour invades bladder mucosa and/or bowel mucosa (bullous oedema is not sufficient to classify a tumour as T4) Regional lymph nodes cannot be assessed No regional lymph node metastasis Regional lymph node metastasis to pelvic and/or para-aortic nodes Distant metastasis cannot be assessed No distant metastasis Distant metastasis

radiotherapy remains controversial, particularly in stage I disease in view of the excellent overall survival in these patients [9]. In addition, the use of vault brachytherapy in early disease remains unclear. Finally, the survival benefit of adjuvant chemotherapy in high risk patients is yet to be determined. The evidence for each treatment modality will be discussed here followed by the treatment options for different stages of endometrial carcinoma.

Surgery The primary modality for endometrial carcinoma involves TAH and BSO. A pelvic and/or para-aortic lymphadenectomy may be carried out to surgically stage patients, although the practice varies between centres and countries. Some gynaecological oncologists tend to rely on pelvic lymphadenectomy to exclude extrauterine disease and hence the need for adjuvant therapy and others will only do so for suspicious nodes. For example, all patients in GOG-99 underwent some form of lymphadenectomy [10], whereas in the PORTEC study only sampling of suspicious nodes was carried out [11]. The role of lymphadenectomy (either pelvic or para-aortic lymphadenectomy) in stage I endometrial carcinoma, the selection of patients, the extent of lymphadenectomy and the number of nodes to be removed will continue to be debated due to a lack of randomised data [12]. Diagnostic lymphadenectomy increases the risk of permanent lymphoedema and without a clear benefit it may be difficult to justify its use in all patients with stage I endometrial carcinoma. A randomised trial of lymphadenectomy and adjuvant external beam radiotherapy in the treatment of endometrial cancer (ASTEC study) has been conducted by the Medical Research Council (MRC) and the National Cancer Research Institute (NCRI) in the UK and the results will be published shortly. The preliminary reports from the UK ASTEC trial show eight treatment-related deaths in 704 women randomly allocated to lymphadenectomy compared with two out of 704 who did not have lymph node surgery [13]. There was no evidence that lymphadenectomy improves overall survival or disease specific survival in ASTEC surgical trial [13]. More recently, a small retrospective study of 63 patients had shown the number of positive pelvic nodes to be an independent prognostic factor in stage IIIC endometrial carcinoma [14]. It was shown in this study that para-aortic lymphadenectomy decreased the incidence of para-aortic recurrence and it may improve disease-related survival in patients with stage IIIC endometrial cancer with more than one pelvic lymph node [14].

Adjuvant Postoperative Radiotherapy Various randomised trials have shown that external beam radiotherapy decreases the risk of pelvic and local recurrence in stage I endometrial carcinoma patients [10,11,15,16]. However, there is uncertainty as to whether adjuvant radiotherapy improves overall survival. A systematic review and meta-analysis showed that adjuvant external

POSTOPERATIVE RADIOTHERAPY IN CARCINOMA OF THE ENDOMETRIUM

beam radiotherapy greatly reduced locoregional recurrence by a relative risk reduction of 72% in stage I endometrial cancer, although this did not translate into a reduction in the risk of death (from all causes), distant recurrence and endometrial cancer death [17]. However, the meta-analysis included a heterogeneous group of stage I patients with different prognostic factors. Although a subgroup analysis was carried out to analyse the survival benefit of external beam pelvic radiotherapy on the different subgroups of stage I endometrial cancer patients, it was limited by a lack of individual patient data [17]. Recent adjuvant radiotherapy studies from the National Cancer Institute of Canada Clinical Trials Group (CAN-NCIC-EN5) and the MRC/NCRI (UK) ASTEC trials will be published shortly. The preliminary data did not show a survival benefit for adjuvant radiotherapy in stage I endometrial carcinoma (2006 ASCO Meeting). The apparent lack of survival benefit from external beam radiotherapy in stage I endometrial carcinoma patients would not justify its use in these patients, despite the reduction in local recurrence, as that may be reduced by brachytherapy. In a prospective study by Piver et al. [18], patients with low risk endometrial cancer (stage I, grade 1e2 and less than 50% myometrial invasion) who were treated with postoperative vaginal brachytherapy alone without external beam pelvic radiotherapy had a 5-year disease-free survival of 99%. This is because most local recurrences in low risk endometrial carcinoma patients after surgery alone are due to vaginal vault recurrences [19,20]. These recurrences may be preventable by vaginal intracavity brachytherapy or be salvageable by surgery. In the PORTEC study, 75% of women with pelvic recurrence could be treated with curative intent and 85% of these achieved complete remission [11]. Thus, although prophylactic external beam radiotherapy reduces local recurrence, vaginal brachytherapy may be adequate prophylaxis for local recurrent disease for low risk patients and selective salvage therapy may be just as effective, as supported by multiple retrospective case series [19,20]. A Dutch multicentre randomised phase III trial (PORTEC 2 trial) is currently underway and aims to answer the question of whether postoperative vaginal vault brachytherapy is sufficient treatment to prevent vault recurrence. After surgery, patients with stage I disease are randomised to either external beam radiotherapy or vaginal vault brachytherapy. The trial includes patients with one high risk feature (stage IC, grade 3, stage IIA and age over 60 years).

Chemotherapy The role of adjuvant chemotherapy and the choice of chemotherapy remain unclear. There have been no published randomised trials looking solely at the role of adjuvant chemotherapy in endometrial carcinoma. A study comparing adjuvant chemotherapy alone with postoperative external beam radiotherapy in patients with high risk endometrial carcinoma (stage IC grade 3, stage II grade 3 and stage III) failed to showed a difference in either overall or progression-free survival [21]. However, the cumulative incidence of local recurrence was lower in patients

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receiving radiotherapy and conversely the distant relapses were lower in patients given adjuvant chemotherapy [21]. Therefore, there is a rationale to combine adjuvant chemotherapy and radiotherapy either concurrently or sequentially in high risk endometrial carcinoma patients. The EORTC 55991 trial, which is a randomised study of adjuvant radiation therapy with or without chemotherapy in high risk patients (stage IC or occult stage II and grade 3, clear cell, serous papillary, undifferentiated pathology), aims to answer the role of adjuvant chemotherapy in addition to external beam radiotherapy in these patients. The preliminary data from the trial showed that adjuvant chemotherapy given before or after radiotherapy increased the 5-year progression-free survival from 75e82% (2007 ASCO Annual Meeting). An intergroup trial of the Dutch Cooperative Gynaecologic Oncology Group and the UK NCRI will start recruiting patients for the PORTEC 3 study, a randomised trial comparing concurrent chemoradiation and adjuvant chemotherapy with pelvic radiation alone in high risk and advanced stage endometrial carcinoma (stage IB grade 3 with LVSI; stage IC or IIA grade 3; stage IIB; stage III; stage IB, IC, II or III with serous or clear cell pathology). The primary objective of this study is to assess the overall survival and disease-free survival of these patients treated after surgery with concurrent chemoradiation and adjuvant chemotherapy in comparison with patients treated with pelvic radiation alone. Various chemotherapy regimens have been used for endometrial carcinoma. The adjuvant chemotherapy used by Maggi et al. [21] consisted of cisplatin (50 mg/m2), doxorubicin (45 mg/m2), cyclophosphamide (600 mg/m2) every 28 days for five cycles, as this regimen had given an objective responses of about 45% for patients with advanced or recurrent endometrial carcinoma [22,23]. There were two randomised trials comparing the combination of doxorubicin and cisplatin with doxorubicin alone in patients with recurrent or advanced disease [24,25]. The combination chemotherapy was shown to produce a higher response rate (42e43%) compared with doxorubicin alone (17e25%), although combination chemotherapy produced more grade 3 and grade 4 haematological toxicities (up to 60% leucopenia in the combination arm compared with 40% in the doxorubicin alone arm) [24,25]. The PORTEC 3 study will use concurrent cisplatin 50 mg/m2 with pelvic radiotherapy on days 1 and 22, followed by adjuvant chemotherapy of carboplatin AUC 5 and paclitaxel 175 mg/m2 at 21 day intervals after the completion of radiotherapy for high risk and advanced stage endometrial carcinoma.

Hormonal Therapy The role of adjuvant medroxyprogesterone acetate (MPA) was assessed in a multicentre trial [26]. After surgery, patients with stage IB grade 1e2 tumours were randomised to no further treatment or MPA 100 mg twice a day for 12 months; patients with IB or IC or grade 3 tumours were randomised to external beam radiotherapy vs external beam radiotherapy and MPA; and patients with nodepositive disease were submitted to pelvic and para-aortic

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radiotherapy alone vs the same radiotherapy with MPA. The results of 856 randomised patients showed that there was no statistically significant difference in relapse-free survival between patients treated with MPA and patients treated without [26]. On the basis of this randomised trial, adjuvant MPA treatment cannot be recommended in patients with stage I endometrial carcinoma. For advanced or recurrent disease, oral MPA has been shown to have an overall response rate of 25% and 200 mg/ day is as good as 1000 mg/day [27]. Patients with welldifferentiated histology and positive progesterone receptor status have a higher response rate [27]. Tamoxifen (20 mg/ day), however, only has an overall response rate of 10% in patients with advanced or recurrent endometrial carcinoma [28]. Combining oral MPA 200 mg/day with tamoxifen 40 mg/ day has achieved a response rate of 33% for patients with advanced endometrial carcinoma in a phase II study [29].

The Role of Postoperative Radiotherapy and Proposed Management for Different Stages of Endometrial Carcinoma Patients We have discussed the available evidence for the treatment modalities of endometrial carcinoma, including surgery, radiotherapy, chemotherapy and hormonal therapy. From this current evidence, we propose the role of postoperative radiotherapy in carcinoma of the endometrium and the management options for different stages of endometrial carcinoma based on the risk factors (Table 2).

Early Endometrial Carcinoma, Stage I and IIA Low risk endometrial carcinoma with no high risk factors (stage IAeIB, grade 1e2) Radiotherapy may not be beneficial for this subgroup of patients who have well-differentiated tumours with minimal invasion and have a long-term survival of greater than 95% Table 2 e Treatment options Endometrial carcinoma Low risk stage IeIIA Intermediate risk stage IeIIA

Risk factors

Proposed treatment

IA/B grade 1/2

No further treatment

IA/B grade 3 IC grade 1/2 IIA grade 1/2 High risk stage IeIIA IC grade 3 Advanced IC LVSI disease Grade 3 LVSI stage IIBeIII IIA grade 3 IIB, all grades III, all grades IBeIII with clear cell or serous papillary histology LVSI, lymphovascular space invasion.

Vaginal vault brachytherapy External beam pelvic radiotherapy þ vaginal vault brachytherapy Consider concurrent chemoradiation and adjuvant chemotherapy in the context of the PORTEC 3 study

[9]. Indeed, the subgroup analysis from the systematic review of patients without high risk factors showed that external beam radiotherapy may cause additional treatment-related deaths [17]. The PORTEC 1 study recommended omitting adjuvant pelvic radiotherapy for stage I endometrial cancer patients below 60 years of age and patients with grade 2 tumours with superficial invasion because these patients have a low absolute risk of locoregional relapse [11]. Adjuvant external beam radiotherapy and vaginal vault brachytherapy should be omitted in this group of patients. Intermediate risk endometrial carcinoma with one high risk factor (grade 3 or stage IC or lymphovascular space invasion) The preliminary data from the ASTEC study did not show a survival benefit in these patients (2006 ASCO Meeting). The subgroup analysis from the systematic review on patients with one high risk factor (either grade 3 or stage IC) also failed to show that adjuvant radiotherapy reduced deaths from all causes or from endometrial cancer [17]. Vaginal vault brachytherapy alone may be adequate in these patients. If external beam radiotherapy is to be given to these patients, it should be given in the context of a trial, e.g. PORTEC 2, in view of the lack of survival benefit from the randomised trials and a systematic review [17]. High risk endometrial carcinoma with two or more high risk factors (stage IC grade 3, stage IC lymphovascular space invasion, grade 3 lymphovascular space invasion) Patients with stage IC grade 3 endometrial carcinoma were excluded from entry into the PORTEC 1 study as they have a high risk of recurrence [11]. However, Creutzberg et al. [30] carried out a separate analysis on patients with stage IC and grade 3 endometrial carcinoma co-registered with the PORTEC study (104 patients out of 715) and it was shown that these high risk patients had a 5-year locoregional recurrence rate of 14% and a 5-year distant metastasis rate of 31%, despite receiving external beam radiotherapy. The subgroup analysis of stage I endometrial cancer patients with at least two risk factors (most with grade 3 and stage IC) showed a trend for adjuvant radiotherapy to reduce death from all causes and endometrial cancer death although neither outcome was statistically significant (which may be due to the low number of patients) [17]. In view of the high rate of local and distant recurrence, external beam radiotherapy (with or without vaginal vault brachytherapy) may be offered in stage I endometrial cancer patients with multiple high risk features since in the systematic review adjuvant external beam radiotherapy was shown to reduce the local recurrence rate in these patients with a trend towards reducing the overall death rate [17]. The question also arises as to whether these patients should have adjuvant chemotherapy in addition to adjuvant radiotherapy, which may be answered by the EORTC 55991 trial when it is published. These patients

POSTOPERATIVE RADIOTHERAPY IN CARCINOMA OF THE ENDOMETRIUM

should be considered for inclusion in the PORTEC 3 study when the trial starts.

Advanced Endometrial Carcinoma, Stage IIB and III These patients should be considered for adjuvant external beam radiotherapy with or without vaginal vault brachytherapy as the evidence from a randomised trial by Maggi et al. [21] suggested that external beam radiotherapy would reduce local recurrence in these patients. It has also been shown that adjuvant chemotherapy may prevent distant recurrences in these patients [21]. Therefore, it is reasonable to consider adjuvant chemotherapy in these patients (particularly for patients with pelvic lymph node disease, stage IIIC), in addition to adjuvant radiotherapy. These patients should be considered for entry into the PORTEC 3 study.

Patients with Uterine Serous Papillary Carcinoma and Clear Cell Histology Patients with uterine serous papillary carcinoma and clear cell histology have a higher incidence of extrauterine disease at diagnosis and lower 5-year survival rates than patients with endometrioid carcinoma [3,7]. More recently, however, a prospective cohort study of 22 patients with these histologies was shown to have a 95% disease-free survival without adjuvant therapy [31]. However, the study was small and was not a randomised study. The investigators concluded that further prospective trials are needed to ascertain the role of adjuvant treatments in these patients [31]. In the ASTEC study, stage I endometrial carcinoma patients with these histologies were considered high risk and were recruited to assess the role of adjuvant radiotherapy. The EORTC 55991 trial and the PORTEC 3 study also included patients with these histologies to assess the role of adjuvant chemotherapy in addition to external beam radiotherapy. The role of adjuvant chemotherapy and radiotherapy in these patients will hopefully be answered by these randomised trials. Until then it is reasonable to consider adjuvant external beam radiotherapy in stage IB, IC, II or III patients with these high risk histologies and to consider entering these patients into the PORTEC 3 study.

Stage IV Endometrial Carcinoma and Recurrent Disease These patients should be treated with appropriate palliative treatments, but may be considered for systemic chemotherapy if they have a good performance status. For those patients who are not fit, single agent oral MPA 200 mg/day is superior to tamoxifen 20e40 mg/day [28].

Conclusion The management of endometrial carcinoma, especially in relation to adjuvant treatments, remains controversial. No

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further adjuvant treatment is needed for low risk endometrial carcinoma patients after surgery. Vaginal vault brachytherapy alone as adjuvant treatment may be adequate for intermediate risk stage I and IIA endometrial carcinoma patients. For patients with high risk stage IeIIA and more advanced endometrial carcinoma (stage IIB and III), the roles of pelvic external beam radiotherapy as well as concurrent chemoradiation and adjuvant chemotherapy remain to be determined. Acknowledgements. The authors wish to thank the Cochrane Gynaecological Oncology Group. Author for correspondence: P. Blake, Radiotherapy Department, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK; E-mail: [email protected] Received 21 February 2008; accepted 26 March 2008

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