- Email: [email protected]
Chemotherapy for advanced, recurrent or metastatic endometrial cancer: a systematic review of Cochrane collaboration
Annals of Oncology 18: 409–420, 2007 doi:10.1093/annonc/mdl417 Published online 5 December 2006
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Chemotherapy for advanced, recurrent or metastatic endometrial cancer: a systematic review of Cochrane collaboration C. E. Humber1*, J. F. Tierney2, R. P. Symonds3, M. Collingwood4, J. Kirwan5, C. Williams6 & J. A. Green7 1
Department of Oncology, University Hospitals of Coventry and Warwickshire, Coventry; 2Meta-analysis Group, MRC Clinical Trials Unit, London; University Department of Cancer Studies and Molecular Medicine, Leicester Royal Infirmary, Leicester; 4Department of Radiotherapy, Churchill Hospital, Oxford; 5Liverpool Women’s Hospital, Liverpool; 6Bristol Haematology and Oncology Centre, Bristol; 7Department of Clinical Science, Division of Clinical Medicine, University of Liverpool, Liverpool, UK 3
cancer. Commonly used agents include cisplatin and doxorubicin, but the side-effect profile may be unacceptable for many patients. The feasibility of administration of combination chemotherapy is limited in many patients on account of significant co-morbidity. While early-stage endometrial adenocarcinoma is a common gynaecological cancer with a favourable prognosis, advanced or recurrent disease presents a difficult management problem. The platinum and anthracycline compounds have been widely used for many years, but their impact on progression-free survival (PFS) and overall survival (OS) is not clear. This systematic review aimed to evaluate both the benefits and adverse effects of cytotoxic chemotherapy in these women. Patients and methods: We carried out systematic searches for randomised controlled trials (RCTs) comparing chemotherapy with another intervention. Data were extracted from trial reports or supplied by investigators. Where possible, hazard ratios (HRs) were calculated for OS and PFS and odds ratios (ORs) were calculated for acute toxicity. The impact of more versus less intensive chemotherapy on OS, PFS and acute toxicity was assessed in a metaanalysis. Results: Eleven eligible RCTs were identified that recruited 2288 patients. A meta-analysis of six of these trials found that PFS [HR = 0.80, 95% confidence interval (CI) 0.71–0.90; P = 0.004], but not OS (HR = 0.90, 95% CI 0.80–1.03; P = 0.12), was significantly improved when more intensive chemotherapy was compared with less intensive chemotherapy. OS was improved when doxorubicin, cisplatin and other drugs were compared with doxorubicin and cisplatin. Toxicity was generally higher with more chemotherapy. There was insufficient evidence to assess the effect of chemotherapy on symptom control or quality of life (QoL). Platinums, anthracyclines and taxanes were the most studied in phase II trials and combinations gave the best responses, but patient selection and pretreatment was very variable. Conclusions: More intense combination chemotherapy significantly improves the disease-free survival and the data indicate a modest improvement in OS. The addition of anthracyclines (e.g. doxorubicin) or the taxanes [e.g. paclitaxel (Taxol)] to cisplatin increases the response rate. More intensive regimens are associated with the gain in survival. However, grade 3 and 4 myelosuppression and gastrointestinal toxicity are also increased. Future developments are likely to exploit specific molecular characteristics of endometrial cancers, including their hormone dependence, growth factor target overexpression and PTEN loss. While no one drug or regimen offers a clear benefit for women with advanced endometrial cancer, platinum drugs, anthracyclines and paclitaxel seem the most promising agents. Future trials should address the impact of such agents on QoL and symptom control in addition to survival. Chemotherapy and endocrine therapy need to be compared directly in an RCT. Key words: cytotoxic chemotherapy, endometrial cancer, meta-analysis, randomized controlled trials, review
background *Correspondence to: Dr C. E. Humber, Department of Oncology, University Hospitals of Coventry and Warwickshire, Clifford Bridge Road, Coventry, CV2 2DX, UK. Tel: +44-2476-967478; Fax: +44-2476-538900; E-mail: [email protected]
ª 2006 European Society for Medical Oncology
There were 200 000 cases of endometrial adenocarcinoma worldwide in 2005 with 50 000 deaths [1]. There is, however, wide geographical variation in disease incidence with the
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Background: Cytotoxic chemotherapy has a limited place in the management of advanced or recurrent endometrial
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Received 18 May 2006; revised 20 September 2006; accepted 22 September 2006
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patients and methods Randomised controlled trials (RCTs) were sought by a systematic search of major bibliographic databases, trial registers and by hand searching the reference lists of studies identified. The amount of randomised evidence found was limited and so we extended our searches to include nonrandomised phase II studies of the response to chemotherapy updated at the end of 2005. For the meta-analysis, only RCTs that compared cytotoxic chemotherapy (single agent or combination) versus placebo, best supportive care, alternative chemotherapy or endocrine (hormonal) therapy were considered. They should have aimed to randomly assign women with advanced, recurrent or metastatic endometrial adenocarcinoma that was not amenable to potentially curative surgery or radical radiotherapy. Trials of adjuvant chemotherapy or which included women with uterine carcinosarcoma or sarcoma were excluded. Data on trial design, participants, treatments, relevant outcomes and analyses were extracted from the reports of each included trial by two authors independently. The outcomes of interest were OS, PFS, QoL measured on a validated QoL instrument, acute and late toxicity grade on a validated scoring system and any measure of symptom control. OS and
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PFS were considered the primary outcomes. Authors were contacted for extra information and updated outcome data. Meta-analyses of single-agent chemotherapy versus the same drug in combination, and two-drug chemotherapy versus the same two drugs in combination with other drugs were considered feasible and are combined to give an overall comparison of more versus less chemotherapy. Hazard ratios (HRs) were used directly in meta-analyses if provided in the trial report or by the investigators. Where they were not provided, they were estimated indirectly from other summary statistics or from the data extracted from published Kaplan–Meier curves [3]. These were then combined across all trials using the fixed-effect model to give a pooled HR [4], which represents the overall risk of an event on the research treatment versus control. Absolute differences in median PFS and OS were estimated using the HR and average median control group PFS and OS [(median/HR) ÿ median]. Scales, grades and sites of acute toxicity were extracted from the text and grouped into common subtypes: nausea and vomiting, diarrhoea/other gastrointestinal (GI), leucopenia, thrombocytopenia, fever/infection, renal/ genitourinary, neurological, alopecia, anaemia, cardiotoxicity, fever/ infection and stomatitis/mucositis. A meta-analysis was carried out to compare the toxicity of less versus more chemotherapy using odds ratios (ORs) to calculate the total number of grade 3 and 4 events for each subtype. Where more than one type of toxicity was reported in a category (e.g. nausea reported separately from vomiting), the most frequent was used. These ORs were combined across all trials, using the fixed-effect model, to give the odds of any toxic event or severe toxic event for each type of toxicity in the treatment arm (more chemotherapy) versus the control arm (less chemotherapy). Differences between trial results were assessed using the I2 for inconsistency [5], which gives values between 0% and 100%. Low values (25%) indicated a low level of inconsistency, high values (75%) a high level of inconsistency and intermediate values (50%) moderate level of inconsistency. All P values quoted are two-sided.
results RCTs of chemotherapy Eleven eligible RCTs were identified. All trials compared one form of chemotherapy with another. No trials compared chemotherapy with best supportive care or hormone therapy. Of these reports, three gave only limited data on the primary end points of PFS and OS [6–8]. The toxicity scales used varied from trial to trial, but grouping of toxicity data as described in the Materials and methods section was feasible. No trials collected QoL data or objective measures of symptoms. Further information was requested from all authors but updated data were only obtained for three trials [7, 9, 10]. Characteristics of the included trials are given in Table 1. Only four trials gave details of the method of randomisation [10–13], although some details of stratification were given for three others [6, 9, 14]. Five reports indicated that randomisation was carried out by a central office [6, 12, 13, 15, 16]. Six studies described how the sample size was determined [8, 10, 12, 13, 15, 16]. Three trials randomly assigned <50 patients [6, 7, 9] and because of this would only be sufficiently powered to detect a very large difference in the effectiveness of the two arms. Two studies were stopped prematurely [7, 10]. Eight of 11 eligible trials excluded patients after randomisation [6, 8, 11–16] mainly for reasons of ineligibility or because they were deemed inassessable. Sometimes, more patients were excluded from one arm than the other, as shown
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highest in North America (22.0 per 100 000 per year) and Europe (11.8–12.5 per 100 000 per year) [1]. Most women present with early disease and are treated with surgery, giving 5-year survival rates of >70%. Women with certain histological subtypes, high-grade lesions, deep invasion of the uterus, tumour extending to the cervix, spread to lymphatic or blood vessels or outside the uterus are at high risk of recurrence [2] and may be offered adjuvant radiotherapy. Only a small proportion of women present with advanced disease at diagnosis. If the tumour is not amenable to surgery or radical radiotherapy, then women are considered for systemic endocrine therapy or cytotoxic chemotherapy, with the aim of palliating symptoms, improving quality of life (QoL), delaying progression of disease and extending overall survival (OS). Moreover, many patients with endometrial cancer are obese with significant co-morbidity such as diabetes mellitus and ischaemic heart disease, which can restrict treatment options. Cytotoxic chemotherapy has been used for advanced disease. Commonly used regimens incorporate the platinum agents and anthracyclines, on the basis of phase II and limited phase III data. Cross-resistance between the taxanes and anthracyclines, however, is also incomplete in many tumour types in vitro and phase II studies. Early studies used single agents with modest response rates and remission durations of 4–6 months were seen. Combinations of two or more drugs have been employed, but the general perception is that these patients tolerate chemotherapy less well than comparable patients with breast or ovarian cancers. Furthermore, cross-resistance between different groups of agents is common and responses in chemotherapy-pre-treated patients are low. Debate over the role of pelvic radiotherapy has further complicated the use of chemotherapy as prior radiotherapy compromises both the activity and assessment of subsequent chemotherapy. The aim of this review is to evaluate the impact of cytotoxic chemotherapy on progression-free survival (PFS), OS, QoL and symptom relief, as well as to assess the toxicity of such treatment.
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Table 1. Characteristics of randomised controlled trials of chemotherapy Accrual period
Patients randomly assigned (and excluded)
Chemotherapy
Overall response rate (%)
Median PFS (months)
Median OS (months)
Edmonson et al. [7]
1980–1983
30 (no patients excluded)
Arm 1: cisplatin 60 mg/m2 i.v. every 21 days until progression Arm 2: cyclophosphamide 400 mg/m2 i.v., doxorubicin 40 mg/m2 i.v., cisplatin 40 mg/m2 i.v., cisplatin every 28 days until progression Arm 1: doxorubicin 60 mg/m2 i.v. every 28 days Arm 2: doxorubicin 60 mg/m2 i.v., cisplatin 50 mg/m2 i.v. every 28 days
Arm 1: 21
Arm 1: 1.8
Arm 1: 4.1
Arm 2: 31
Arm 2: 2.9
Arm 2: 6.6
Arm 1: 17
Arm 1: 7
Arm 1: 7
Arm 2: 43
Arm 2: 8
Arm 2: 9
Arm 1: doxorubicin 60 mg/m2 i.v. every 21 days Arm 2: doxorubicin 60 mg/m2 i.v., cyclophosphamide 500 mg/m2 i.v. every 21 days Arm 1: doxorubicin 60 mg/m2 i.v. every 21 days Arm 2: doxorubicin 60 mg/m2, cisplatin 50 mg/m2 i.v. every 21 days
Arm 1: 22
Arm 1: 3.2
Arm 1: 6.9
Arm 2: 30
Arm 2: 3.9
Arm 2: 7.3
Arm 1: 25
Not stated
Not stated
Arm 1: 27
Arm 1: 6.2
Arm 1: 15
Arm 2: 69
Arm 2: 6.9
Arm 2: 15
Arm 1: 34
Arm 1: 5.3
Arm 1: 12.3
Arm 2: 57
Arm 2: 8.3
Arm 2: 15.3
Arm 1: 19
NR
NR
Arm 1: 7
Arm 1: 1.6
NR
Arm 2: 12
Arm 2: 1.8
Aapro et al. [8]
Thigpen et al. [9]
Thigpen et al. [14]
Long et al. [5]
Fleming et al. [13]
Horton et al. [4]
Pawinski et al. [6]
1988–1994
1979–1985
1988–1992
Not stated
1998–2000
Not stated
1987–1994
177 (12 patients ineligible and five without follow-up data, but all patients analysed for efficacy; 12 patients receiving one cycle of chemotherapy excluded from toxicity analyses) 387 (31 ineligible patients excluded from the analyses due to ineligibility; 80 more patients not assessable for response) 299 (18 ineligible patients excluded from the analyses due to ineligibility, uncertain eligibility or inadequate; three more patients not receiving chemotherapy excluded from toxicity analyses) 28 (no patients excluded)
273 (10 patients excluded from analyses due to ineligibility; three more patients receiving one cycle of chemotherapy excluded from toxicity analysis)
47 (seven patients excluded from analyses due to protocol violations or unavailability of data)
74 (13 ineligible patients excluded from analysis due to of ineligibility; patients dying of non-malignant disease before evaluation were considered inassessable)
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Arm 1: doxorubicin plus cyclophosphamide every 28 days until progression Arm 2: methotrexate, vinblastine, doxorubicin, cisplatin every 28 days until progression Arm 1: doxorubicin 60 mg/m2 i.v., cisplatin 50 mg/m2 i.v. every 21 days for seven cycles Arm 2: doxorubicin 45 mg/m2 i.v., cisplatin 50 mg/m2 i.v., paclitaxel 160 mg/m2 i.v. every 21 days for seven cycles plus G-CSF support Arm 1: doxorubicin 50 mg/m2 i.v. bolus every 21 days until progression Arm 2: cyclophosphamide 666 mg/m2 i.v. bolus every 21 days until progression Arm 1: cyclophosphamide 1200 mg/m2 i.v. infusion every 21 days until progression Arm 2: ifosfamide 5 g/m2 i.v. Infusion every 21 days until progression
Arm 2: 42
Arm 2: 0
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Table 1. (Continued) Accrual period
Patients randomly assigned (and excluded)
Chemotherapy
Overall response rate (%)
Median PFS (months)
Median OS (months)
Fleming et al. [11]
1996–1998
328 (11 patients excluded from the analyses due to ineligibility or withdrawn patient consent; four more receiving less than one cycle of chemotherapy excluded from toxicity analyses)
Arm 1: doxorubicin 60 mg/m2 i.v., cisplatin 50 mg/m2 i.v. every 21 days for seven cycles or until progression or unacceptable toxicity Arm 2: doxorubicin 50 mg/m2 i.v., paclitaxel 150 mg/m2 i.v., filgrastim 5 mcg/kg d3-12 every 21 days for seven cycles or until progression or unacceptable toxicity Arm 1: doxorubicin 60 mg/m2 i.v., cisplatin 60 mg/m2 i.v. every 21 days for eight cycles Arm 2: doxorubicin 60 mg/m2 i.v. at 6 am, cisplatin 60 mg/m2 i.v. at 6 pm every 21 days for eight cycles Arm 1: melphalan 7 mg/m2/day p.o. for 4 days, 5-FU 525 mg/m2/day i.v. for 4 days repeated every 28 days, megace 180 mg/day orally for 8 weeks Arm 2: doxorubicin 40 mg/m2 i.v. bolus, cyclophosphamide 400 mg/m2 i.v. bolus, 5-FU 400 mg/m2 i.v. bolus every 21days plus megace as for arm 1
Arm 1: 40
Arm 1: 7.2
Arm 1: 12.6
Arm 2: 43
Arm 2: 6.0
Arm 2: 13.6
Arm 1: 46
Arm 1: 6.5
Arm 1: 11.2
Arm 2: 49
Arm 2: 5.9
Arm 2: 13.2
Arm 1: 38
Arm 1: 6.1
Arm 1: 10.6
Arm 2: 36
Arm 2: 5.2
Arm 2: 10.1
Gallion et al. [10]
Cohen et al. [12]
1993–1996
1977–1979
352 (10 patients excluded from the analyses because of ineligibility)
295 (25 patients excluded from analysis due to ineligibility and 13 excluded because they were inassessable)
5-FU, 5-fluorouracil; G-CSF, granulocyte colony-stimulating factor; NR, not recorded; OS, overall survival; PFS, progression-free survival.
in Table 1. There was variability in statistical analysis between these studies, with some providing much clearer definitions of outcomes and information on how the analysis was carried out than others and the duration of follow-up was not always well documented.
meta-analysis of RCTs of more versus less intense chemotherapy Four trials were identified that compared a single agent with the same agent in combination [9–11, 16] (Table 1). Two further trials compared doxorubicin and cisplatin with doxorubicin and cisplatin combined with other drugs [7, 15] (Table 1). The reported response rates, median PFS and median OS for each trial are listed in Table 1. Six trials were included in the meta-analysis of less chemotherapy versus more chemotherapy [7, 9–11, 15, 16]. Despite the exclusion of patients, the trials of more versus less chemotherapy were well balanced with respect to well-known prognostic factors such as age, stage and performance status. In
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the study of cyclophosphamide, doxorubicin and cisplatin (CAP) versus cisplatin [9], however, a slightly higher proportion had received prior radiation in the CAP arm. In another trial of doxorubicin and cyclophosphamide versus doxorubicin [11], there was a higher proportion of patients with grade 3 tumours in the doxorubicin arm. In all six trials, the objective response rate (ORR) appeared greater when more was compared with less chemotherapy (30%–69% versus 17%–34%, Table 2). These differences were statistically significant in only two of the trials [15, 16]. Progression data were available for these six trials (1132 patients and 1014 events), although only as time to progression in two of these [7, 10]. Across all included trials, the results show a moderate degree of consistency, irrespective of the regimens being compared (I2 = 38.9%), and overall, the results favoured more rather than less chemotherapy. The pooled HR of 0.80 [95% confidence interval (CI) 0.71–0.90] shows a highly significant 20% relative improvement in PFS (P = 0.0004) with more intensive regimens (Figure 1) which translates into an absolute improvement in the median PFS of 1 month.
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Table 2. Characteristics of phase II trials of chemotherapy: cisplatin-containing regimens Trial ID
Patients recruited (and having prior chemotherapy) 26 31 56 33 19 19 16 15
Turbow et al. [25]
21 (0)
Hancock et al. [26]
18 (0)
Hoffman 1989 [57]
15 (NR)
Burke et al. [27]
(5) (24) (0) (0) (NR) (0) (4) (0)
102 (0)
Pietrzak et al. [28]
41 (NR)
Alberts et al. [30]
64 (0)
Piver et al. [31]
20 (2)
Cornelison et al. [32]
50 (0)
Long et al. [33]
30 (0)
Pierga et al. [34]
20 (0)
Lissoni et al. [35]
30 (0)
Dimopoulos et al. [36] Sorbe et al. [37]
24 (0) 44 (0)
Gebbia et al. [38] Pierga et al. [39]
35 (0) 49 (2)
Overall response rate (%)
Median PFS (months)
Median OS (months)
Cisplatin 50–100 mg/m2 Cisplatin 50 mg/m2 Cisplatin 50 mg/m2 Cisplatin 60 mg/m2, doxorubicin 60 mg/m2 Cisplatin 50 mg/m2, Doxorubicin 50 mg/m2 Cisplatin 50 mg/m2, doxorubicin 50 mg/m2 Cisplatin 60 mg/m2, doxorubicin 60 mg/m2 Cisplatin 50 mg/m2, doxorubicin 30 mg/m2, cyclophosphamide 300 mg/m2, megace 120 mg/day Cisplatin 60 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 600 mg/m2 Cisplatin 50 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 Cisplatin 50 mg/m2, doxorubicin 30 mg/m2, cyclophosphamide 500 mg/m2, megace 160 mg/day Cisplatin 50 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 Cisplatin 50 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 Cisplatin 50 mg/m2, doxorubicin 30 mg/m2, vinblastine 0.15 mg/m2 Cisplatin 60 mg/m2, doxorubicin 40 mg/m2, etoposide 225 mg/m2, megace 160 mg/day Cisplatin 60 mg/m2, doxorubicin 40 mg/m2, etoposide 225 mg/m2, megace 160 mg/day Cisplatin 70 mg/m2, doxorubicin 40 mg/m2, vinblastine 9 mg/m2, methotrexate 90 mg/m2 Cisplatin 105 mg/m2, doxorubicin 30 mg/m2, etoposide 240 mg/m2, 5-FU 1800 mg/m2 Cisplatin 50 mg/m2, paclitaxel 175 mg/m2, epirubicin 70 mg/m2 Cisplatin 75 mg/m2, paclitaxel 175 mg/m2 Cisplatin 60 mg/m2, vincristine 1.5 mg/m2, VM-26 100 mg/m2, megace 500 mg/day Cisplatin 80 mg/m2, vinorelbine 50 mg/m2 5-FU 1800 mg/m2
42 4 20 60 37 60 81 60
5 NR 2.9 7.5 NR NR NR NR
NR NR 8.2 14 NR NR 10 NR
47
NR
10
56
NR
NR
33
3.9
1.2
45
NR
NR
12
NR
NR
31
NR
75
NR
6.5 15
54
11.9
16.4
67
7.2
9.9
45
8
17
73
NR
NR
67 52
8.4 NR
17.6 7
57 41
NR NR
7.9 14
5-FU, 5-fluorouracil; NR, not recorded; OS, overall survival; PFS, progression-free survival.
The effect is more pronounced in the group of trials that compared doxorubicin and cisplatin plus other drugs with doxorubicin and cisplatin alone [7, 15], with a HR of 0.64 (95% CI 0.49–0.82, P = 0.0004). The Fleming et al. trial [13] had an individual result that was significantly in favour of more chemotherapy, the additional drug being paclitaxel (Taxol). Data on OS were available for six trials, including 1135 patients and 1034 events and the results of these trials of various types of chemotherapy are very consistent (I2 = 18.6%). There is no OS benefit for more compared with less chemotherapy (HR = 0.91, 95% CI 0.80–1.03; P = 0.12) (Figure 2). Doxorubicin and cisplatin in combination with other drugs, however, do offer a survival benefit when compared with doxorubicin and cisplatin alone [7, 15]. The HR of 0.75 (95% CI 0.58–0.97)
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indicates a 25% reduction in the relative risk of death with more intense chemotherapy equivalent to a 3-month improvement in survival. These results are largely driven by the results of the one trial evaluating the addition of paclitaxel [15] that individually had a statistically significant result (HR = 0.75, 95% CI 0.57–0.988; P = 0.037, adjusted for performance status). Data on grade 3 or 4 nausea and vomiting, diarrhoea/other GI toxicity, leucopenia, thrombocytopenia and neurological toxicity were available in sufficient detail for five out of six trials, including 761 patients. To assess toxicity, two trials used the National Cancer Institute Common Toxicity Criteria (CTC) [7, 9], one used the CTC criteria version 2 [15], one used the World Health Organisation (WHO) criteria [10] and two the Gynaecologic Oncology Group (GOG) criteria [11, 16]. Across
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Seski et al. [17] Thigpen et al. [18] Thigpen et al. [19] Barrett et al. [20] Deppe et al. [21] Trope et al. [22] Pasmantier et al. [23] Lovecchio et al. [24]
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trials, serious nausea and vomiting was increased almost threefold with the more intense regimens (OR = 2.73, 95% CI 1.76– 4.23; P < 0.00001) and the results appeared consistent across trials (I2 = 15.1%). Although there were few grade 3 or 4 diarrhoea/other GI events overall (29), there still seemed to be an excess with more compared with less chemotherapy (OR = 2.48, 95% CI 1.19–5.17; Figure 3). Results for serious leucopenia were much more variable from trial to trial (I2 = 89.5%), with no statistically significant increase with more intense chemotherapy (OR = 1.30, 95% CI 0.98–1.73; P = 0.07). Grade 3 or 4 thrombocytopenia was increased more than four-fold with more chemotherapy (OR = 4.44, 95% CI 2.67–7.38; P < 0.00001) and this result was consistent across trials (I2 = 19.2%). Serious neurological toxicity was very rare, except in the trial of doxorubicin, cisplatin and paclitaxel versus doxorubicin and cisplatin [15], where it was significantly increased in the arm including paclitaxel (P = 0.0004). Grade 3–4 alopecia, anaemia, cardiotoxicity, fever/infection, stomatitis/mucositis and renal/genitourinary toxicity were reported for fewer trials and also tended to be less frequent. Thus, the results of the formal analyses of these types of toxicity are less reliable. The overall tendency for these types of toxicity, however, was to be more frequent when more chemotherapy was given. There were seven possible treatment-related deaths (1.8%) in one trial [11], but it is not clear whether these relate to one or
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other treatment. In another trial [15], five treatment-related deaths were attributable to the doxorubicin, cisplatin and paclitaxel arm but there were none on the doxorubicin and cisplatin arm. Aapro et al. [8] found that 10% of patients stopped treatment in the doxorubicin and cisplatin arm compared with 2% of patients receiving cisplatin alone.
other RCTs of chemotherapy The other five trials addressed different chemotherapy questions and could not be combined for meta-analysis [6, 8, 12–14] (Table 1). There were no clear differences in response rates in all but two of these trials [6, 8]. There were no significant differences in PFS or OS for any of these trials (Table 1). The acute toxic effects reported were mainly haematological and GI, but tended to be similar irrespective of treatment regimen. Gallion et al. [10], however, found that grade 3 or 4 WBC toxicity (as per GOG scale) was significantly greater with standard-timed doxorubicin and cisplatin (75%) compared with circadian-timed doxorubicin and cisplatin (65%, P = 0.04). Other toxic effects did not appear to vary by treatment allocation. phase II trials of chemotherapy Eighty phase II non-randomised trials of the use of cytotoxic chemotherapy in advanced or recurrent endometrial carcinoma
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Figure 1. Progression free survival meta-analysis for six trials (1132 patients) comparing more intensive with less intensive combination regimens in advanced endometrial carcinoma.
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were identified, and 12 studies [17, 18] containing <15 patients were excluded. All studies included response rates, and 34 reported PFS, OS or both. Studies were divided up according to five broad categories of chemotherapy: cisplatin-containing regimens, carboplatin-containing regimens, paclitaxel-containing regimens (without platinum), anthracycline-containing regimens (without platinum) and miscellaneous single agents. cisplatin-containing regimens. The 23 studies addressing the use of cisplatin alone or in combination are described in Table 2. Three studies (113 patients) assessed the response to singleagent cisplatin [19–21]. One only included chemotherapy-naive patients [21]. Response was evaluated clinically or radiologically and varied from 4% to 42.3%. The lowest response rate was observed in women who had received previous chemotherapy [20]. Only one study reported survival, with a median of 8.2 months [21]. In all three studies, nausea and vomiting were the major toxic effects, but nephrotoxicity, neurotoxicity and mild myelosuppression were also common. Four studies (involving 87 patients) assessed the response to combined cisplatin and doxorubicin [22–25] (Table 2). Two studies treated only chemotherapy-naive patients [22, 24], in one study it was not stated [23] and one study allowed prior chemotherapy [25]. Where stated, response was evaluated clinically or radiologically, and ranged from 36.8% to 81.2% (Table 2). Six phase II trials of the CAP regimen were identified, involving 212 patients [26–30]. In two of these, megestrol
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acetate was also given [26, 31]. Response rates varied from 12.2% to 60%; in four studies, the response rate was >40%. Five studies (involving 184 patients) assessed response to cisplatin and doxorubicin in combination with other cytotoxic drugs [32–36] (Table 2). Prior progestogen use was permitted in all studies, but prior chemotherapy in only one [33]. Three studies assessed response radiologically [33, 34, 36]; while in the other studies, the method of assessment was not reported. Response rates varied from 30.9% to 75%, but no one regimen was consistently better than another (Table 2). Median survival ranged from 6.5 months [32] to 17 months [36]. Common toxic effects included myelosuppression and nausea and vomiting, with peripheral neuropathy, cardiotoxicity and stomatitis, also being reported. Two studies (involving 54 patients) addressed the response to cisplatin in combination with a taxane in chemotherapy-naive patients [37, 38]. One [38] recruited patients who had progressed on progestogens or rapidly advancing disease not amenable to hormonal therapy. Both used the WHO criteria for assessing response and toxicity. The response rates were 73% [37] and 67% [38]. Median OS was 17.6 months in one study [38] and not stated for the other. In both studies, myelosuppression was a common toxic effect, as was mild neuropathy, and haematological toxicity was very frequent without the routine use of granulocyte colony-stimulating factor. In one study [38], 14 of 24 patients had improvements in their performance status and six in their pain score.
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Figure 2. Survival meta-analysis for six trials (1135 patients) comparing more intensive with less intensive combination regimens in advanced endometrial carcinoma.
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Three studies involving 128 patients investigated the use of cisplatin in combination with other cytotoxics. One study [39] gave cisplatin in combination with vincristine, megestrol acetate and the podophyllotoxin VM-26 (teniposide), another study [40] gave cisplatin in combination with vinorelbine and in the third study [41] cisplatin was combined with etoposide and 5-fluorouracil (5-FU). carboplatin-containing regimens. Five studies addressed the use of carboplatin (Table 3); three of these used carboplatin as a single agent [42–44] and two used carboplatin in combination with one or more drugs [45, 46]. In total, 180 patients were enrolled in phase II trials of carboplatin-based chemotherapy and none. These patients had received prior chemotherapy. In all studies, response to treatment was assessed radiologically. Single-agent carboplatin resulted in overall response rates varying from 28% [43] to 33% [44], and median survival ranged from 7.1 months [43] to 10 months [44]. Toxicity was mainly grade 1 and 2 haematological. Carboplatin in combination with methotrexate, 5-FU and megestrol acetate resulted in an ORR of 74% and a median
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survival of 16 months with only mild haematological and GI toxicity [45], and carboplatin in combination with paclitaxel resulted in an ORR of 60.9% [46]. anthracycline-containing regimens. Five studies involving 183 patients addressed the use of anthracyclines (Table 4), either alone or in combination with non-platinum drugs [47–51]. In two of these studies, prior chemotherapy was permitted [47, 50], while in the other three studies prior treatments were not reported. In two studies, it was not clear how assessment of response was made [47, 48]; in the other three studies, assessment was radiological. Single-agent doxorubicin resulted in an ORR of 37.2% and a median survival of 6.8 months [47]. Toxicity was mainly haematological, but cardiac toxicity and nausea and vomiting were also reported. Pegylated doxorubicin resulted in an ORR of 9.5% and a median survival of 8.2 months in heavily pre-treated patients [50]. Toxicity was mainly haematological and was mild. Single-agent epirubicin resulted in an ORR of 25.9%, with median survival of 9.5 months [51]. The most frequent sideeffect was nausea and vomiting and cardiac toxicity was not
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Figure 3. Meta-analysis of Grade 3 and 4 toxicity combined (761 patients) for more intensive regimens compared to less intensive combination chemotherapy regimens for five of the six trials in advanced endometrial carcinoma analysed in Figures 1 and 2.
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Annals of Oncology
Table 3. Characteristics of phase II trials of chemotherapy: carboplatin-containing regimens Trial ID
Patients recruited (and having prior chemotherapy)
Chemotherapy
Overall response rate (%)
Median PFS (months)
Median OS (months)
Long et al. [41] Green et al. [40] Burke et al. [42] Bafaloukos et al. [43]
25 32 33 23
28 30 33 74
3.8 NR 4–5 NR
7.1 9.3 8–10 16
Hoskins et al. [44]
67 (0)
Carboplatin 400 mg/m2 Carboplatin 400 mg/m2 Carboplatin 360–450 mg/m2 Carboplatin 300 mg/m2, methotrexate 30 mg/m2, 5-FU 500 mg/m2, megace 300 mg/day Carboplatin AUC 5–7, paclitaxel 175 mg/m2
61
NR
15–26
(0) (0) (0) (0)
AUC, area under the curve; 5-FU, 5-fluorouracil; NR, not recorded; OS, overall survival; PFS, progression-free survival.
Trial ID
Patients recruited (and having prior chemotherapy)
Chemotherapy
Overall response rate (%)
Median PFS (months)
Median OS (months)
Thigpen et al. [45] Seski et al. [46]
55 (2) 26 (NR)
37 30
NR NR
6.8 NR
Deppe et al. [47]
29 (NR)
45
NR
6.7–12.5
Muggia et al. [48] Calero et al. [49]
46 (40) 27 (0)
Doxorubicin 60 mg/m2 Doxorubicin 40–50 mg/m2, cyclophosphamide 500–600 mg/m2 Doxorubicin 40 mg/m2, cyclophosphamide 400 mg/m2, 5-FU 400 mg/m2, megace 160 mg/day Pegylated liposomal, doxorubicin 50 mg/m2 Epirubicin 80 mg/m2
9 26
NR 6
8.2 9.5
5-FU, 5-fluorouracil; NR, not recorded; OS, overall survival; PFS, progression-free survival.
seen. Doxorubicin in combination with cyclophosphamide (oral or i.v.) resulted in an ORR of 30.7%; median survival was not reported [48]. Nausea and vomiting was the most frequently reported toxicity and admission to hospital for febrile neutropenia was required in five of 26 patients. Doxorubicin in combination with cyclophosphamide, 5-FU and megestrol acetate resulted in an ORR of 44.9% [49]. Median survival was not reported for the whole group. taxane-containing regimens. Four studies involving 89 patients addressed the use of paclitaxel (Table 5), either alone or in combination with a non-platinum-based drug [52–55]. One of these studies only recruited patients with uterine papillary serous carcinoma, including both advanced disease and adjuvant therapy [54]. Another recruited patients with both advanced endometrial carcinoma and uterine sarcoma [55]. Radiological imaging was carried out regularly in two studies [53, 54]. In three studies, no prior chemotherapy was allowed [52, 54, 55] while in the fourth study, prior chemotherapy with cisplatin, cyclophosphamide and doxorubicin was one of the criteria for eligibility [53]. Single-agent paclitaxel achieved response rates of 35.7% [52] to 77% [54]. The response rate to paclitaxel in patients previously treated with chemotherapy was 37%, and 47% of these patients were considered to have platinum-resistant disease [53]. Median survival was only reported in one study at 9.5 months [52]. Myelosuppression was common, although it was milder in the study using lower dose paclitaxel [53]. Arthralgia, myalgia and neuropathy were
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also reported. Paclitaxel in combination with liposomal doxorubicin resulted in an ORR of 40.7% but survival was not reported [55]. The most frequently reported toxic effects were myelosuppression and plantar–palmar erythema. miscellaneous single agents and combinations. A further 28 phase II trials involving 789 patients of single agents not included in the above categories were identified and there is one further study of melphalan, 5-FU and a progestogen containing 11 assessable patients (data not shown).
discussion Phase II data show that a number of drugs have some activity in advanced endometrial cancer. The most commonly investigated drugs include platinums, anthracyclines and taxanes, either alone or in combination. The patients, however, were selected according to different criteria and some were variously pretreated. Therefore, in the absence of a randomised control group, it is not possible to tell whether any of the combinations are superior in terms of PFS, OS, palliation of symptoms or effects on QoL. In total, 778 women participated in phase II trials of cisplatinbased chemotherapy with response rates ranging from 4% to 81.2%. Median survival was not reported for all studies but varied from 6.5 months [32] to 17.6 months [38], and higher response rates did not always correlate with longer survival. The combination of cisplatin with paclitaxel resulted in an
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Table 4. Characteristics of phase II trials of chemotherapy: anthracycline-containing regimens
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Table 5. Characteristics of phase II trials of chemotherapy: taxane-containing regimens Trial ID
Patients recruited (and having prior chemotherapy)
Chemotherapy
Overall response rate (%)
Median PFS (months)
Median OS (months)
Ball et al. [50] Lissoni et al. [51] Ramondetta et al. [52] Hornreich et al. [53]
30 19 13 27
Paclitaxel 250 mg/m2 Paclitaxel 175 mg/m2 Paclitaxel 200 mg/m2 Paclitaxel 225 mg/m2, liposomal doxorubicin 30 mg/m2
36 37 77 41
3.8 NR NR NR
9.5 NR NR NR
(0) (19) (0) (0)
NR, not recorded; OS, overall survival; PFS, progression-free survival.
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and no one regimen appears superior to another in improving PFS and OS. The only RCT that reported a significant improvement in PFS and OS was that of doxorubicin, cisplatin and paclitaxel versus doxorubicin and cisplatin [15] with the benefit associated with the paclitaxel-containing arm. Grade 3 or 4 thrombocytopenia and neurological toxicity, however, were also significantly greater and there were five treatment-related deaths with the paclitaxel arm. There was no clear evidence from the RCTs comparing other miscellaneous chemotherapy regimens or schedules that any were superior in terms of OS and PFS and/or reduced toxicity. The median survival varied from 7 to 15 months and median PFS varied from 2.5 to 8 months. These may reflect prior treatments and stage of disease, as well as the effect of any particular regimen. One additional trial compared doxorubicin and cisplatin chemotherapy with whole-abdominal radiotherapy (WAR), and showed a survival gain for the cytotoxic chemotherapy arm [54]. While it did not meet the inclusion criteria for this review, if the assumption is made that WAR does not adversely affect survival, then this is indirect evidence that combination chemotherapy improves survival in endometrial cancer. Conclusions on the potential of chemotherapy to palliate symptoms and improve QoL are limited given the modest potential impact of chemotherapy on PFS and OS, and collection of such patient-reported data should be a priority in future research. Response rates up to 75% were, however, reported and response may be regarded as a crude surrogate for palliation if maintained for several months. Clinicians may consider chemotherapy for patients with more aggressive disease or visceral disease, or may offer it to younger patients of good performance status. The RCTs enrolled a heterogeneous group of patients in terms of prior therapies with hormonal agents or cytotoxic agents. The phase II data show a lack of cross-resistance between cisplatin and paclitaxel and that response rates for doxorubicin/cisplatin combinations are much higher than those for single agents. Performance status was not reported in all studies, yet may have a significant impact on how much benefit a patient obtains from treatment. The data indicate that the increased toxicity associated with the use of more than two drugs is not justified by the slight improvement in outcome. There is no data regarding correlation between sites of metastatic disease and benefit. The effect of co-morbidity is also difficult to establish and may vary with ethnic background and socioecomonic group.
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impressive response rate and the longest median survival in a small group of heavily pre-treated patients [38]. A total of 180 patients were enrolled in phase II studies of carboplatin-based chemotherapy. The response rates and median OS from these studies do not indicate that carboplatin is inferior to cisplatin in the therapy of advanced endometrial cancer. Myelosuppression may be more frequent but nephrotoxicity, neurotoxicity and emesis were all less frequently reported and were milder than those in cisplatin-based regimens. Carboplatin in combination with paclitaxel appears as active as cisplatin in combination with paclitaxel [46]. A total of 183 patients were enrolled in phase II studies of anthracyclines, either alone or in combination with nonplatinum drugs. Response rates varied from 9.5% (60) with pegylated doxorubicin in heavily pre-treated patients to 44.9% (49). The response rates for doxorubicin in combination with non-platinum drugs were similar to the response rates achieved by single-agent, non-pegylated doxorubicin. The response rates for single-agent anthracyclines compare quite favourably with those for single-agent platinum. A total of 89 patients were enrolled in phase II studies of paclitaxel, either alone or in combination with a non-platinum drug. Single-agent response rates appear similar to anthracyclines and platinum drugs used alone. The response rates reported in one small trial [53] seem impressive given that all patients in this study had received prior chemotherapy and just under half had disease described as platinum resistant. The quality of the 11 identified RCTs of cytotoxic chemotherapy in advanced or recurrent endometrial adenocarcinoma randomly assigning 2288 women was somewhat variable. Response rates varied between RCTs, with the worst rates in the most heavily pre-treated patients [8, 9]. In a number of trials, combination therapy led to a higher response than single-agent treatment or other combinations [7, 10, 11], but with the exception of Fleming et al. [13], this better response rate did not translate into better PFS or OS, at least at the individual trial level. A meta-analysis of the six trials that compared more intense chemotherapy combinations indicates that more intense chemotherapy significantly improves the median PFS, but not OS. This is, however, at the expense of increased grade 3/4 toxicity. It should be noted that a number of these trials pre-date the routine use of the type 3 serotonin receptor (5-HT3) antagonists and the rate of grade 3 and 4 vomiting may be higher than what one would expect in current practice. Across these six trials, the results are fairly consistent
Annals of Oncology
conclusions
acknowledgements The authors would like to thank Vivien Garner for obtaining papers for the background section and Aapro and Long for providing further information on trials included in this review. The authors declare no potential financial conflicts of interest.
references 1. Parkin DM, Bray F, Ferlay J et al. Global cancer statistics, 2002. CA Cancer J Clin 2005; 55: 74–108. 2. Bremond A, Bataillard A, Thomas L et al. Cancer of the endometrium. Br J Cancer 2001; 84: 31–36. 3. Higgins JPT, Thompson SG, Deeks JJ et al. Measuring inconsistency in metaanalyses. BMJ 2003; 327: 557–560. 4. Horton J, Begg CB, Bruckner H et al. Comparison of adriamycin with cyclophosphamide in patients with advanced endometrial cancer. Cancer Treat Rep 1978; 62: 159–161. 5. Long HJ, Nelimark RA, Cha SS. Comparison of methotrexate, vinblastine, doxorubucin and cipslatin (MVAC) vs doxorubicin and cisplatin (AC) in advanced endometrial carcinoma. Proc Am Soc Clin Oncol 1995; 14: 282 (Abstr 797). 6. Pawinski A, Tumolo S, Hoesel G et al. Cyclophosphamide or ifosfamide in patients with advanced and/or recurrent endometrial carcinoma: a randomized phase II study of the EORTC Gynecological Cancer Cooperative Group. Eur J Obstet Gynecol Reprod Biol 1999; 86: 179–183.
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7. Edmonson JH, Krook JE, Hilton JF et al. Randomized phase II studies of cisplatin and a combination of cyclophosphamide-doxorubicin-cisplatin (CAP) in patients with progestin-refractory advanced endometrial carcinoma. Gynecol Oncol 1987; 28: 20–24. 8. 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: 441–448. 9. Thigpen JT, Blessing JA, DiSaia PJ et al. A randomized comparison of doxorubicin alone versus doxorubicin plus cyclophosphamide in the management of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 1994; 12: 1408–1414. 10. Gallion HH, Brunetto VL, Cibull M et al. Randomized phase III trial of standard timed doxorubicin plus cisplatin versus circadian timed doxorubicin plus cisplatin in stage III or IV recurrent endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol 2003; 21: 3808–3813. 11. 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: 1173–1178. 12. Cohen CJ, Bruckner HW, Deppe G et al. Multidrug treatment of advanced and recurrent endometrial carcinoma: a Gynecologic Oncology Group study. Obstet Gynecol 1984; 63: 719–726. 13. Fleming GF, Brunetto VL, 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. 14. Thigpen JT, Brady MF, Homesley HD et al. Phase III trial of doxorubicin with or without cisplatin in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 2004; 22: 3902–3908. 15. Boadle DJ, Tattersall MHN. Phase II study of mitoxantrone in advanced or metastatic endometrial carcinoma. Aust N Z J Obstet Gynaecol 1987; 27: 341–342. 16. Runge HM, Meerpohl HG, Pfeiderer A. Mitoxantrone therapy of advanced adenocarcinoma of the endometrium. A phase II trial. Onkologie 1989; 12: 102–103. 17. Seski JC, Edwards CL, Hersen J et al. Cisplatin chemotherapy for disseminated endometrial cancer. Obstet Gynecol 1982; 59: 225–228. 18. Thigpen JT, Blessing JA, Lagasse LD. Phase II trial of cisplatin as second-line chemotherapy in patients with advanced or recurrent endometrial carcinoma. Am J Clin Oncol 1984; 7: 253–256. 19. Thigpen JT, Blessing JA, Homesley H et al. Phase II trial of cisplatin as first line chemotherapy in patients with advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 1989; 33: 68–70. 20. Barrett RJ, Blessing JA, Homesley HD et al. Circadian-timed combination doxorubicin-cisplatin chemotherapy for advanced endometrial carcinoma. Am J Clin Oncol 1993; 16: 494–496. 21. Deppe G, Malviya VK, Malone JM et al. Treatment of recurrent and metastatic endometrial carcinoma with cisplatin and doxorubicin. Eur J Gynaecol Oncol 1994; 15: 263–266. 22. Trope C, Johnsson JE, Simonsen E et al. Treatment of recurrent endometrial adenocarcinoma with a combination of doxorubicin and cisplatin. Am J Obstet Gynecol 1984; 149: 379–381. 23. Pasmantier MW, Coleman M, Silver RT et al. Treatment of advanced endometrial carcinoma with doxorubicin and cisplatin: effects on both untreated and previously treated patients. Cancer Treat Rep 1985; 69: 539–542. 24. Lovecchio JL, Averette HE, Lichtinger M et al. Treatment of advanced or recurrent endometrial adenocarcinoma with cyclophosphamide, doxorubicin, cis-platinum and megestrol acetate. Obstet Gynecol 1984; 63: 557–560. 25. Turbow MM, Ballon SC, Sikic BI et al. Cisplatin, doxorubicin and cyclophosphamide for advanced endometrial carcinoma. Cancer Treat Rep 1985; 69: 465–467. 26. Hancock KC, Freedman RS, Edwards CL et al. Use of cisplatin, doxorubicin and cyclophosphamide to treat advanced and recurrent adenocarcinoma of the endometrium. Cancer Treat Rep 1986; 70: 789–791. 27. Burke TW, Stringer CA, Morris M et al. Prospective treatment of advanced or recurrent endometrial carcinoma with cisplatin, doxorubicin and cyclophosphamide. Gynecol Oncol 1991; 40: 264–267.
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There is a need for a trial that randomly assigns women with advanced disease and no prior treatment with endocrine or cytotoxic therapy to receive chemotherapy or endocrine therapy. GOG 189 attempted this but failed to recruit. European Organisation for Research and Treatment of Cancer (EORTC 55984) randomly assigned patients between cisplatin and doxorubicin with or without paclitaxel and also had difficulty in recruitment for reasons which included concerns over the toxicity of both arms [55]. Clinicians therefore have to consider whether the modest survival gain of the order of 3 months justifies the toxicity of a three-drug combination in the individual patient. Assessment of baseline and on-treatment QoL and symptom scores should supplement primary outcomes such as PFS and OS. The optimum chemotherapy regimen to be used is not established, but there is wide experience in other tumours with the use of carboplatin and paclitaxel together, and this combination merits consideration in endometrial cancer as well as carboplatin and liposomal doxorubicin for which more limited data exist [56]. Future trials may also clarify which groups of patients would benefit from which treatment by stratifying patients at trial entry for tumour grade, prior therapies, performance status, site of disease and co-morbidity. Molecular parameters such as hormone receptor status, topoisomerase IIa and possibly growth factor pathway activation status need to be evaluated for their prognostic value and ability to predict sensitivity to the anthracyclines, platinums and taxanes. These factors are likely to be even more important in evaluating novel agents such as the mTOR inhibitors, which is in order to design adjuvant chemotherapy trials for high-risk stage 1 patients (such as the PORTEC 3 study); it is also vital that good quality data be acquired from the treatment of patients with advanced disease.
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44.
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treatment of advanced or recurrent endometrial carcinoma: a Hellenic Cooperative Oncology Group Study. Oncology 1999; 56: 198–201. Hoskins PJ, Swenerton KD, Pike JA et al. Paclitaxel and carboplatin, alone or with irradiation, in advanced or recurrent endometrial cancer: a phase II study. J Clin Oncol 2001; 19: 4048–4053. Thigpen JT, Buchsbaum HJ, Mangan C et al. Phase II trial of adriamycin in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. Cancer Treat Rep 1979; 63: 21–27. Seski JC, Edwards CL, Gershenson DM et al. Doxorubicin and cyclophosphamide chemotherapy for disseminated endometrial cancer. Obstet Gynecol 1981; 58: 88–91. Deppe G, Jacobs AJ, Bruckner H et al. Chemotherapy of advanced and recurrent endometrial carcinoma with cyclophosphamide, doxorubicin, 5-fluorouracil and megestrol acetate. Am J Obstet Gynecol 1981; 140: 313–316. Muggia FM, Blessing JA, Sorosky J et al. Phase II trial of the pegylated liposomal doxorubicin in previously treated metastatic endometrial cancer: a Gynecological Oncology group study. J Clin Oncol 2002; 20: 2360–2364. Calero F, Asins-Codoner E, Jimeno J et al. Epirubicin in advanced endometrial adenocarcinoma: a phase II study of the Grupo Ginecologico Espanol para el Tratamiento Oncologico (GGETO). Eur J Cancer 1991; 27: 864–866. Ball HG, Blessing JA, Lentz SS et al. A phase II trial of paclitaxel in patients with advanced or recurrent adenocarcinoma of the endometrium: a Gynecologic Oncology Group study. Gynecol Oncol 1996; 62: 278–281. Lissoni A, Zanetta G, Losa GA et al. Phase II study of paclitaxel as salvage treatment in advanced endometrial cancer. Ann Oncol 1996; 7: 861–863. Ramondetta L, Burke TW, Levenback C et al. Treatment of uterine papillary serous carcinoma with paclitaxel. Gynecol Oncol 2001; 82: 156–161. Hornreich G, Muggia FM, Wadler S et al. Phase II combination doxil-paclitaxel (PacliDox) in uterine carcinomas and sarcomas an active regimen. Gynecol Oncol 2000; 76: 265. Carey MS, Gawlik C, Fung-Kee-Fung M et al. Systematic review of systemic therapy for advanced or recurrent endometrial cancer. Gynecol Oncol 2006; 101: 158–167. Randall ME, Filiacia VL, Muss H et al. Whole abdominal radiotherapy versus combination doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a randomised phase 111 trial of the Gynecologic Oncology group. J Clin Oncol 2006; 24: 36–44 du Bois A, Burges A, Meier W et al. Pegylated liposomal doxorubicin and carboplatin in advanced gynecologic tumors: a prospective phase I/II study of the AGO-OVAR Group. Ann Oncol 2006; 17: 93–96. Hoffman MS, Roberts WS, Cavanagh D, Praphat H, Solomon P, Lyman GH. Treatment of recurrent and metastatic endometrial cancer with cisplatin, doxorubicin, cyclophosphamide and megestrol acetate. Gynecol Oncol 1989; 35: 75–77.
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28. Pietrzak K, Zielinski J, Borowial J et al. Assessment of chemotherapy results in advanced and recurring endometrial cancer. G Ital Oncol 1995; 1: 61–64. 29. Vokes EE, Bitran JD, Hoffman PC et al. Neoadjuvant vindesine, etoposide and cisplatin for locally advanced non-small cell lung cancer: final report of a phase 2 study. Chest 1989; 96: 110–113. 30. Alberts DS, Mason NL, O’Toole RV et al. Doxorubicin cisplatin vinblastine combination chemotherapy of advanced endometrial carcinoma: a Southwest Oncology Group study. Gynecol Oncol 1987; 26: 193–201. 31. Piver MS, Fanning J, Baker TR. Phase II trial of cisplatin, adriamycin and etoposide for metastatic endometrial adenocarcinoma. Am J Clin Oncol 1991; 14: 200–202. 32. Cornelison TL, Baket TR, Piver MS et al. Cisplatin, adriamycin, etoposide, megestrol acetate versus melphalan, 5-flourouracil, medroxyprogesterone acetate in the treatment of endometrial carcinoma. Gynecol Oncol 1995; 59: 243–248. 33. Long HJ, Langdon RM, Cha SS et al. Phase II trial of methotrexate, vinblastine, doxorubicin, and cisplatin in advanced/recurrent endometrial carcinoma. Gynecol Oncol 1995; 58: 240–243. 34. Pierga J-Y, Die´ras V, Beuzeboc P et al. Phase II trial of doxorubicin, 5fluorouracil, etoposide, and cisplatin in advanced or recurrent endometrial carcinoma. Gynecol Oncol 1997; 66: 246–249. 35. Lissoni A, Gabriele A, Gorga G et al. Cisplatin-, epirubicin- and paclitaxel-containing chemotherapy in uterine adenocarcinoma. Ann Oncol 1997; 8: 969–972. 36. Dimopoulos MA, Papadimitriou CA, Georgoulias V et al. Paclitaxel and cisplatin in advanced or recurrent carcinoma of the endometrium: long-term results of a phase II multicenter study. Gynecol Oncol 2000; 78: 52–57. 37. Sorbe B, Wolmesjo E, Frankendal B. VM-26 vincristine-cisplatin combination chemotherapy in the treatment of primary advanced and recurrent endometrial carcinoma. Obstet Gynecol 1989; 73: 343–348. 38. Gebbia V, Testa A, Borsellino N et al. Cisplatin and vinorelbine in advanced and/or metastatic adenocarcinoma of the endometrium: a new highly active chemotherapeutic regimen. Ann Oncol 2001; 12: 767–772. 39. Pierga J-Y, Dieras V, Paraiso D et al. Treatment of advanced or recurrent endometrial carcinoma with combination of etoposide, cisplatin, and 5fluorouracil: a phase II study. Gynecol Oncol 1996; 60: 59–63. 40. Green JB, Green S, Alberts DS et al. Carboplatin therapy in advanced endometrial cancer. Obstet Gynecol 1990; 75: 696–699. 41. Long HJ, Pfeifle DM, Wieand HS et al. Phase II evaluation of carboplatin in advanced endometrial carcinoma. J Natl Cancer Inst 1988; 80: 276–278. 42. Burke TW, Munkarah A, Kavanagh JJ et al. Treatment of advanced or recurrent endometrial carcinoma with single agent carboplatin. Gynecol Oncol 1993; 51: 397–400. 43. Bafaloukos D, Aravantinos G, Samonis G et al. Carboplatin, methotrexate and 5-fluorouracil in combination with medroxyprogeterone acetate (JMF-M) in the
Annals of Oncology
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Chemotherapy for advanced, recurrent or metastatic endometrial cancer: a systematic review of Cochrane collaboration C. E. Humber1*, J. F. Tierney2, R. P. Symonds3, M. Collingwood4, J. Kirwan5, C. Williams6 & J. A. Green7 1
Department of Oncology, University Hospitals of Coventry and Warwickshire, Coventry; 2Meta-analysis Group, MRC Clinical Trials Unit, London; University Department of Cancer Studies and Molecular Medicine, Leicester Royal Infirmary, Leicester; 4Department of Radiotherapy, Churchill Hospital, Oxford; 5Liverpool Women’s Hospital, Liverpool; 6Bristol Haematology and Oncology Centre, Bristol; 7Department of Clinical Science, Division of Clinical Medicine, University of Liverpool, Liverpool, UK 3
cancer. Commonly used agents include cisplatin and doxorubicin, but the side-effect profile may be unacceptable for many patients. The feasibility of administration of combination chemotherapy is limited in many patients on account of significant co-morbidity. While early-stage endometrial adenocarcinoma is a common gynaecological cancer with a favourable prognosis, advanced or recurrent disease presents a difficult management problem. The platinum and anthracycline compounds have been widely used for many years, but their impact on progression-free survival (PFS) and overall survival (OS) is not clear. This systematic review aimed to evaluate both the benefits and adverse effects of cytotoxic chemotherapy in these women. Patients and methods: We carried out systematic searches for randomised controlled trials (RCTs) comparing chemotherapy with another intervention. Data were extracted from trial reports or supplied by investigators. Where possible, hazard ratios (HRs) were calculated for OS and PFS and odds ratios (ORs) were calculated for acute toxicity. The impact of more versus less intensive chemotherapy on OS, PFS and acute toxicity was assessed in a metaanalysis. Results: Eleven eligible RCTs were identified that recruited 2288 patients. A meta-analysis of six of these trials found that PFS [HR = 0.80, 95% confidence interval (CI) 0.71–0.90; P = 0.004], but not OS (HR = 0.90, 95% CI 0.80–1.03; P = 0.12), was significantly improved when more intensive chemotherapy was compared with less intensive chemotherapy. OS was improved when doxorubicin, cisplatin and other drugs were compared with doxorubicin and cisplatin. Toxicity was generally higher with more chemotherapy. There was insufficient evidence to assess the effect of chemotherapy on symptom control or quality of life (QoL). Platinums, anthracyclines and taxanes were the most studied in phase II trials and combinations gave the best responses, but patient selection and pretreatment was very variable. Conclusions: More intense combination chemotherapy significantly improves the disease-free survival and the data indicate a modest improvement in OS. The addition of anthracyclines (e.g. doxorubicin) or the taxanes [e.g. paclitaxel (Taxol)] to cisplatin increases the response rate. More intensive regimens are associated with the gain in survival. However, grade 3 and 4 myelosuppression and gastrointestinal toxicity are also increased. Future developments are likely to exploit specific molecular characteristics of endometrial cancers, including their hormone dependence, growth factor target overexpression and PTEN loss. While no one drug or regimen offers a clear benefit for women with advanced endometrial cancer, platinum drugs, anthracyclines and paclitaxel seem the most promising agents. Future trials should address the impact of such agents on QoL and symptom control in addition to survival. Chemotherapy and endocrine therapy need to be compared directly in an RCT. Key words: cytotoxic chemotherapy, endometrial cancer, meta-analysis, randomized controlled trials, review
background *Correspondence to: Dr C. E. Humber, Department of Oncology, University Hospitals of Coventry and Warwickshire, Clifford Bridge Road, Coventry, CV2 2DX, UK. Tel: +44-2476-967478; Fax: +44-2476-538900; E-mail: [email protected]
ª 2006 European Society for Medical Oncology
There were 200 000 cases of endometrial adenocarcinoma worldwide in 2005 with 50 000 deaths [1]. There is, however, wide geographical variation in disease incidence with the
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Background: Cytotoxic chemotherapy has a limited place in the management of advanced or recurrent endometrial
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Received 18 May 2006; revised 20 September 2006; accepted 22 September 2006
review
patients and methods Randomised controlled trials (RCTs) were sought by a systematic search of major bibliographic databases, trial registers and by hand searching the reference lists of studies identified. The amount of randomised evidence found was limited and so we extended our searches to include nonrandomised phase II studies of the response to chemotherapy updated at the end of 2005. For the meta-analysis, only RCTs that compared cytotoxic chemotherapy (single agent or combination) versus placebo, best supportive care, alternative chemotherapy or endocrine (hormonal) therapy were considered. They should have aimed to randomly assign women with advanced, recurrent or metastatic endometrial adenocarcinoma that was not amenable to potentially curative surgery or radical radiotherapy. Trials of adjuvant chemotherapy or which included women with uterine carcinosarcoma or sarcoma were excluded. Data on trial design, participants, treatments, relevant outcomes and analyses were extracted from the reports of each included trial by two authors independently. The outcomes of interest were OS, PFS, QoL measured on a validated QoL instrument, acute and late toxicity grade on a validated scoring system and any measure of symptom control. OS and
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PFS were considered the primary outcomes. Authors were contacted for extra information and updated outcome data. Meta-analyses of single-agent chemotherapy versus the same drug in combination, and two-drug chemotherapy versus the same two drugs in combination with other drugs were considered feasible and are combined to give an overall comparison of more versus less chemotherapy. Hazard ratios (HRs) were used directly in meta-analyses if provided in the trial report or by the investigators. Where they were not provided, they were estimated indirectly from other summary statistics or from the data extracted from published Kaplan–Meier curves [3]. These were then combined across all trials using the fixed-effect model to give a pooled HR [4], which represents the overall risk of an event on the research treatment versus control. Absolute differences in median PFS and OS were estimated using the HR and average median control group PFS and OS [(median/HR) ÿ median]. Scales, grades and sites of acute toxicity were extracted from the text and grouped into common subtypes: nausea and vomiting, diarrhoea/other gastrointestinal (GI), leucopenia, thrombocytopenia, fever/infection, renal/ genitourinary, neurological, alopecia, anaemia, cardiotoxicity, fever/ infection and stomatitis/mucositis. A meta-analysis was carried out to compare the toxicity of less versus more chemotherapy using odds ratios (ORs) to calculate the total number of grade 3 and 4 events for each subtype. Where more than one type of toxicity was reported in a category (e.g. nausea reported separately from vomiting), the most frequent was used. These ORs were combined across all trials, using the fixed-effect model, to give the odds of any toxic event or severe toxic event for each type of toxicity in the treatment arm (more chemotherapy) versus the control arm (less chemotherapy). Differences between trial results were assessed using the I2 for inconsistency [5], which gives values between 0% and 100%. Low values (25%) indicated a low level of inconsistency, high values (75%) a high level of inconsistency and intermediate values (50%) moderate level of inconsistency. All P values quoted are two-sided.
results RCTs of chemotherapy Eleven eligible RCTs were identified. All trials compared one form of chemotherapy with another. No trials compared chemotherapy with best supportive care or hormone therapy. Of these reports, three gave only limited data on the primary end points of PFS and OS [6–8]. The toxicity scales used varied from trial to trial, but grouping of toxicity data as described in the Materials and methods section was feasible. No trials collected QoL data or objective measures of symptoms. Further information was requested from all authors but updated data were only obtained for three trials [7, 9, 10]. Characteristics of the included trials are given in Table 1. Only four trials gave details of the method of randomisation [10–13], although some details of stratification were given for three others [6, 9, 14]. Five reports indicated that randomisation was carried out by a central office [6, 12, 13, 15, 16]. Six studies described how the sample size was determined [8, 10, 12, 13, 15, 16]. Three trials randomly assigned <50 patients [6, 7, 9] and because of this would only be sufficiently powered to detect a very large difference in the effectiveness of the two arms. Two studies were stopped prematurely [7, 10]. Eight of 11 eligible trials excluded patients after randomisation [6, 8, 11–16] mainly for reasons of ineligibility or because they were deemed inassessable. Sometimes, more patients were excluded from one arm than the other, as shown
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highest in North America (22.0 per 100 000 per year) and Europe (11.8–12.5 per 100 000 per year) [1]. Most women present with early disease and are treated with surgery, giving 5-year survival rates of >70%. Women with certain histological subtypes, high-grade lesions, deep invasion of the uterus, tumour extending to the cervix, spread to lymphatic or blood vessels or outside the uterus are at high risk of recurrence [2] and may be offered adjuvant radiotherapy. Only a small proportion of women present with advanced disease at diagnosis. If the tumour is not amenable to surgery or radical radiotherapy, then women are considered for systemic endocrine therapy or cytotoxic chemotherapy, with the aim of palliating symptoms, improving quality of life (QoL), delaying progression of disease and extending overall survival (OS). Moreover, many patients with endometrial cancer are obese with significant co-morbidity such as diabetes mellitus and ischaemic heart disease, which can restrict treatment options. Cytotoxic chemotherapy has been used for advanced disease. Commonly used regimens incorporate the platinum agents and anthracyclines, on the basis of phase II and limited phase III data. Cross-resistance between the taxanes and anthracyclines, however, is also incomplete in many tumour types in vitro and phase II studies. Early studies used single agents with modest response rates and remission durations of 4–6 months were seen. Combinations of two or more drugs have been employed, but the general perception is that these patients tolerate chemotherapy less well than comparable patients with breast or ovarian cancers. Furthermore, cross-resistance between different groups of agents is common and responses in chemotherapy-pre-treated patients are low. Debate over the role of pelvic radiotherapy has further complicated the use of chemotherapy as prior radiotherapy compromises both the activity and assessment of subsequent chemotherapy. The aim of this review is to evaluate the impact of cytotoxic chemotherapy on progression-free survival (PFS), OS, QoL and symptom relief, as well as to assess the toxicity of such treatment.
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Table 1. Characteristics of randomised controlled trials of chemotherapy Accrual period
Patients randomly assigned (and excluded)
Chemotherapy
Overall response rate (%)
Median PFS (months)
Median OS (months)
Edmonson et al. [7]
1980–1983
30 (no patients excluded)
Arm 1: cisplatin 60 mg/m2 i.v. every 21 days until progression Arm 2: cyclophosphamide 400 mg/m2 i.v., doxorubicin 40 mg/m2 i.v., cisplatin 40 mg/m2 i.v., cisplatin every 28 days until progression Arm 1: doxorubicin 60 mg/m2 i.v. every 28 days Arm 2: doxorubicin 60 mg/m2 i.v., cisplatin 50 mg/m2 i.v. every 28 days
Arm 1: 21
Arm 1: 1.8
Arm 1: 4.1
Arm 2: 31
Arm 2: 2.9
Arm 2: 6.6
Arm 1: 17
Arm 1: 7
Arm 1: 7
Arm 2: 43
Arm 2: 8
Arm 2: 9
Arm 1: doxorubicin 60 mg/m2 i.v. every 21 days Arm 2: doxorubicin 60 mg/m2 i.v., cyclophosphamide 500 mg/m2 i.v. every 21 days Arm 1: doxorubicin 60 mg/m2 i.v. every 21 days Arm 2: doxorubicin 60 mg/m2, cisplatin 50 mg/m2 i.v. every 21 days
Arm 1: 22
Arm 1: 3.2
Arm 1: 6.9
Arm 2: 30
Arm 2: 3.9
Arm 2: 7.3
Arm 1: 25
Not stated
Not stated
Arm 1: 27
Arm 1: 6.2
Arm 1: 15
Arm 2: 69
Arm 2: 6.9
Arm 2: 15
Arm 1: 34
Arm 1: 5.3
Arm 1: 12.3
Arm 2: 57
Arm 2: 8.3
Arm 2: 15.3
Arm 1: 19
NR
NR
Arm 1: 7
Arm 1: 1.6
NR
Arm 2: 12
Arm 2: 1.8
Aapro et al. [8]
Thigpen et al. [9]
Thigpen et al. [14]
Long et al. [5]
Fleming et al. [13]
Horton et al. [4]
Pawinski et al. [6]
1988–1994
1979–1985
1988–1992
Not stated
1998–2000
Not stated
1987–1994
177 (12 patients ineligible and five without follow-up data, but all patients analysed for efficacy; 12 patients receiving one cycle of chemotherapy excluded from toxicity analyses) 387 (31 ineligible patients excluded from the analyses due to ineligibility; 80 more patients not assessable for response) 299 (18 ineligible patients excluded from the analyses due to ineligibility, uncertain eligibility or inadequate; three more patients not receiving chemotherapy excluded from toxicity analyses) 28 (no patients excluded)
273 (10 patients excluded from analyses due to ineligibility; three more patients receiving one cycle of chemotherapy excluded from toxicity analysis)
47 (seven patients excluded from analyses due to protocol violations or unavailability of data)
74 (13 ineligible patients excluded from analysis due to of ineligibility; patients dying of non-malignant disease before evaluation were considered inassessable)
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Arm 1: doxorubicin plus cyclophosphamide every 28 days until progression Arm 2: methotrexate, vinblastine, doxorubicin, cisplatin every 28 days until progression Arm 1: doxorubicin 60 mg/m2 i.v., cisplatin 50 mg/m2 i.v. every 21 days for seven cycles Arm 2: doxorubicin 45 mg/m2 i.v., cisplatin 50 mg/m2 i.v., paclitaxel 160 mg/m2 i.v. every 21 days for seven cycles plus G-CSF support Arm 1: doxorubicin 50 mg/m2 i.v. bolus every 21 days until progression Arm 2: cyclophosphamide 666 mg/m2 i.v. bolus every 21 days until progression Arm 1: cyclophosphamide 1200 mg/m2 i.v. infusion every 21 days until progression Arm 2: ifosfamide 5 g/m2 i.v. Infusion every 21 days until progression
Arm 2: 42
Arm 2: 0
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Table 1. (Continued) Accrual period
Patients randomly assigned (and excluded)
Chemotherapy
Overall response rate (%)
Median PFS (months)
Median OS (months)
Fleming et al. [11]
1996–1998
328 (11 patients excluded from the analyses due to ineligibility or withdrawn patient consent; four more receiving less than one cycle of chemotherapy excluded from toxicity analyses)
Arm 1: doxorubicin 60 mg/m2 i.v., cisplatin 50 mg/m2 i.v. every 21 days for seven cycles or until progression or unacceptable toxicity Arm 2: doxorubicin 50 mg/m2 i.v., paclitaxel 150 mg/m2 i.v., filgrastim 5 mcg/kg d3-12 every 21 days for seven cycles or until progression or unacceptable toxicity Arm 1: doxorubicin 60 mg/m2 i.v., cisplatin 60 mg/m2 i.v. every 21 days for eight cycles Arm 2: doxorubicin 60 mg/m2 i.v. at 6 am, cisplatin 60 mg/m2 i.v. at 6 pm every 21 days for eight cycles Arm 1: melphalan 7 mg/m2/day p.o. for 4 days, 5-FU 525 mg/m2/day i.v. for 4 days repeated every 28 days, megace 180 mg/day orally for 8 weeks Arm 2: doxorubicin 40 mg/m2 i.v. bolus, cyclophosphamide 400 mg/m2 i.v. bolus, 5-FU 400 mg/m2 i.v. bolus every 21days plus megace as for arm 1
Arm 1: 40
Arm 1: 7.2
Arm 1: 12.6
Arm 2: 43
Arm 2: 6.0
Arm 2: 13.6
Arm 1: 46
Arm 1: 6.5
Arm 1: 11.2
Arm 2: 49
Arm 2: 5.9
Arm 2: 13.2
Arm 1: 38
Arm 1: 6.1
Arm 1: 10.6
Arm 2: 36
Arm 2: 5.2
Arm 2: 10.1
Gallion et al. [10]
Cohen et al. [12]
1993–1996
1977–1979
352 (10 patients excluded from the analyses because of ineligibility)
295 (25 patients excluded from analysis due to ineligibility and 13 excluded because they were inassessable)
5-FU, 5-fluorouracil; G-CSF, granulocyte colony-stimulating factor; NR, not recorded; OS, overall survival; PFS, progression-free survival.
in Table 1. There was variability in statistical analysis between these studies, with some providing much clearer definitions of outcomes and information on how the analysis was carried out than others and the duration of follow-up was not always well documented.
meta-analysis of RCTs of more versus less intense chemotherapy Four trials were identified that compared a single agent with the same agent in combination [9–11, 16] (Table 1). Two further trials compared doxorubicin and cisplatin with doxorubicin and cisplatin combined with other drugs [7, 15] (Table 1). The reported response rates, median PFS and median OS for each trial are listed in Table 1. Six trials were included in the meta-analysis of less chemotherapy versus more chemotherapy [7, 9–11, 15, 16]. Despite the exclusion of patients, the trials of more versus less chemotherapy were well balanced with respect to well-known prognostic factors such as age, stage and performance status. In
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the study of cyclophosphamide, doxorubicin and cisplatin (CAP) versus cisplatin [9], however, a slightly higher proportion had received prior radiation in the CAP arm. In another trial of doxorubicin and cyclophosphamide versus doxorubicin [11], there was a higher proportion of patients with grade 3 tumours in the doxorubicin arm. In all six trials, the objective response rate (ORR) appeared greater when more was compared with less chemotherapy (30%–69% versus 17%–34%, Table 2). These differences were statistically significant in only two of the trials [15, 16]. Progression data were available for these six trials (1132 patients and 1014 events), although only as time to progression in two of these [7, 10]. Across all included trials, the results show a moderate degree of consistency, irrespective of the regimens being compared (I2 = 38.9%), and overall, the results favoured more rather than less chemotherapy. The pooled HR of 0.80 [95% confidence interval (CI) 0.71–0.90] shows a highly significant 20% relative improvement in PFS (P = 0.0004) with more intensive regimens (Figure 1) which translates into an absolute improvement in the median PFS of 1 month.
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Table 2. Characteristics of phase II trials of chemotherapy: cisplatin-containing regimens Trial ID
Patients recruited (and having prior chemotherapy) 26 31 56 33 19 19 16 15
Turbow et al. [25]
21 (0)
Hancock et al. [26]
18 (0)
Hoffman 1989 [57]
15 (NR)
Burke et al. [27]
(5) (24) (0) (0) (NR) (0) (4) (0)
102 (0)
Pietrzak et al. [28]
41 (NR)
Alberts et al. [30]
64 (0)
Piver et al. [31]
20 (2)
Cornelison et al. [32]
50 (0)
Long et al. [33]
30 (0)
Pierga et al. [34]
20 (0)
Lissoni et al. [35]
30 (0)
Dimopoulos et al. [36] Sorbe et al. [37]
24 (0) 44 (0)
Gebbia et al. [38] Pierga et al. [39]
35 (0) 49 (2)
Overall response rate (%)
Median PFS (months)
Median OS (months)
Cisplatin 50–100 mg/m2 Cisplatin 50 mg/m2 Cisplatin 50 mg/m2 Cisplatin 60 mg/m2, doxorubicin 60 mg/m2 Cisplatin 50 mg/m2, Doxorubicin 50 mg/m2 Cisplatin 50 mg/m2, doxorubicin 50 mg/m2 Cisplatin 60 mg/m2, doxorubicin 60 mg/m2 Cisplatin 50 mg/m2, doxorubicin 30 mg/m2, cyclophosphamide 300 mg/m2, megace 120 mg/day Cisplatin 60 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 600 mg/m2 Cisplatin 50 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 Cisplatin 50 mg/m2, doxorubicin 30 mg/m2, cyclophosphamide 500 mg/m2, megace 160 mg/day Cisplatin 50 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 Cisplatin 50 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 Cisplatin 50 mg/m2, doxorubicin 30 mg/m2, vinblastine 0.15 mg/m2 Cisplatin 60 mg/m2, doxorubicin 40 mg/m2, etoposide 225 mg/m2, megace 160 mg/day Cisplatin 60 mg/m2, doxorubicin 40 mg/m2, etoposide 225 mg/m2, megace 160 mg/day Cisplatin 70 mg/m2, doxorubicin 40 mg/m2, vinblastine 9 mg/m2, methotrexate 90 mg/m2 Cisplatin 105 mg/m2, doxorubicin 30 mg/m2, etoposide 240 mg/m2, 5-FU 1800 mg/m2 Cisplatin 50 mg/m2, paclitaxel 175 mg/m2, epirubicin 70 mg/m2 Cisplatin 75 mg/m2, paclitaxel 175 mg/m2 Cisplatin 60 mg/m2, vincristine 1.5 mg/m2, VM-26 100 mg/m2, megace 500 mg/day Cisplatin 80 mg/m2, vinorelbine 50 mg/m2 5-FU 1800 mg/m2
42 4 20 60 37 60 81 60
5 NR 2.9 7.5 NR NR NR NR
NR NR 8.2 14 NR NR 10 NR
47
NR
10
56
NR
NR
33
3.9
1.2
45
NR
NR
12
NR
NR
31
NR
75
NR
6.5 15
54
11.9
16.4
67
7.2
9.9
45
8
17
73
NR
NR
67 52
8.4 NR
17.6 7
57 41
NR NR
7.9 14
5-FU, 5-fluorouracil; NR, not recorded; OS, overall survival; PFS, progression-free survival.
The effect is more pronounced in the group of trials that compared doxorubicin and cisplatin plus other drugs with doxorubicin and cisplatin alone [7, 15], with a HR of 0.64 (95% CI 0.49–0.82, P = 0.0004). The Fleming et al. trial [13] had an individual result that was significantly in favour of more chemotherapy, the additional drug being paclitaxel (Taxol). Data on OS were available for six trials, including 1135 patients and 1034 events and the results of these trials of various types of chemotherapy are very consistent (I2 = 18.6%). There is no OS benefit for more compared with less chemotherapy (HR = 0.91, 95% CI 0.80–1.03; P = 0.12) (Figure 2). Doxorubicin and cisplatin in combination with other drugs, however, do offer a survival benefit when compared with doxorubicin and cisplatin alone [7, 15]. The HR of 0.75 (95% CI 0.58–0.97)
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indicates a 25% reduction in the relative risk of death with more intense chemotherapy equivalent to a 3-month improvement in survival. These results are largely driven by the results of the one trial evaluating the addition of paclitaxel [15] that individually had a statistically significant result (HR = 0.75, 95% CI 0.57–0.988; P = 0.037, adjusted for performance status). Data on grade 3 or 4 nausea and vomiting, diarrhoea/other GI toxicity, leucopenia, thrombocytopenia and neurological toxicity were available in sufficient detail for five out of six trials, including 761 patients. To assess toxicity, two trials used the National Cancer Institute Common Toxicity Criteria (CTC) [7, 9], one used the CTC criteria version 2 [15], one used the World Health Organisation (WHO) criteria [10] and two the Gynaecologic Oncology Group (GOG) criteria [11, 16]. Across
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Seski et al. [17] Thigpen et al. [18] Thigpen et al. [19] Barrett et al. [20] Deppe et al. [21] Trope et al. [22] Pasmantier et al. [23] Lovecchio et al. [24]
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trials, serious nausea and vomiting was increased almost threefold with the more intense regimens (OR = 2.73, 95% CI 1.76– 4.23; P < 0.00001) and the results appeared consistent across trials (I2 = 15.1%). Although there were few grade 3 or 4 diarrhoea/other GI events overall (29), there still seemed to be an excess with more compared with less chemotherapy (OR = 2.48, 95% CI 1.19–5.17; Figure 3). Results for serious leucopenia were much more variable from trial to trial (I2 = 89.5%), with no statistically significant increase with more intense chemotherapy (OR = 1.30, 95% CI 0.98–1.73; P = 0.07). Grade 3 or 4 thrombocytopenia was increased more than four-fold with more chemotherapy (OR = 4.44, 95% CI 2.67–7.38; P < 0.00001) and this result was consistent across trials (I2 = 19.2%). Serious neurological toxicity was very rare, except in the trial of doxorubicin, cisplatin and paclitaxel versus doxorubicin and cisplatin [15], where it was significantly increased in the arm including paclitaxel (P = 0.0004). Grade 3–4 alopecia, anaemia, cardiotoxicity, fever/infection, stomatitis/mucositis and renal/genitourinary toxicity were reported for fewer trials and also tended to be less frequent. Thus, the results of the formal analyses of these types of toxicity are less reliable. The overall tendency for these types of toxicity, however, was to be more frequent when more chemotherapy was given. There were seven possible treatment-related deaths (1.8%) in one trial [11], but it is not clear whether these relate to one or
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other treatment. In another trial [15], five treatment-related deaths were attributable to the doxorubicin, cisplatin and paclitaxel arm but there were none on the doxorubicin and cisplatin arm. Aapro et al. [8] found that 10% of patients stopped treatment in the doxorubicin and cisplatin arm compared with 2% of patients receiving cisplatin alone.
other RCTs of chemotherapy The other five trials addressed different chemotherapy questions and could not be combined for meta-analysis [6, 8, 12–14] (Table 1). There were no clear differences in response rates in all but two of these trials [6, 8]. There were no significant differences in PFS or OS for any of these trials (Table 1). The acute toxic effects reported were mainly haematological and GI, but tended to be similar irrespective of treatment regimen. Gallion et al. [10], however, found that grade 3 or 4 WBC toxicity (as per GOG scale) was significantly greater with standard-timed doxorubicin and cisplatin (75%) compared with circadian-timed doxorubicin and cisplatin (65%, P = 0.04). Other toxic effects did not appear to vary by treatment allocation. phase II trials of chemotherapy Eighty phase II non-randomised trials of the use of cytotoxic chemotherapy in advanced or recurrent endometrial carcinoma
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Figure 1. Progression free survival meta-analysis for six trials (1132 patients) comparing more intensive with less intensive combination regimens in advanced endometrial carcinoma.
Annals of Oncology
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were identified, and 12 studies [17, 18] containing <15 patients were excluded. All studies included response rates, and 34 reported PFS, OS or both. Studies were divided up according to five broad categories of chemotherapy: cisplatin-containing regimens, carboplatin-containing regimens, paclitaxel-containing regimens (without platinum), anthracycline-containing regimens (without platinum) and miscellaneous single agents. cisplatin-containing regimens. The 23 studies addressing the use of cisplatin alone or in combination are described in Table 2. Three studies (113 patients) assessed the response to singleagent cisplatin [19–21]. One only included chemotherapy-naive patients [21]. Response was evaluated clinically or radiologically and varied from 4% to 42.3%. The lowest response rate was observed in women who had received previous chemotherapy [20]. Only one study reported survival, with a median of 8.2 months [21]. In all three studies, nausea and vomiting were the major toxic effects, but nephrotoxicity, neurotoxicity and mild myelosuppression were also common. Four studies (involving 87 patients) assessed the response to combined cisplatin and doxorubicin [22–25] (Table 2). Two studies treated only chemotherapy-naive patients [22, 24], in one study it was not stated [23] and one study allowed prior chemotherapy [25]. Where stated, response was evaluated clinically or radiologically, and ranged from 36.8% to 81.2% (Table 2). Six phase II trials of the CAP regimen were identified, involving 212 patients [26–30]. In two of these, megestrol
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acetate was also given [26, 31]. Response rates varied from 12.2% to 60%; in four studies, the response rate was >40%. Five studies (involving 184 patients) assessed response to cisplatin and doxorubicin in combination with other cytotoxic drugs [32–36] (Table 2). Prior progestogen use was permitted in all studies, but prior chemotherapy in only one [33]. Three studies assessed response radiologically [33, 34, 36]; while in the other studies, the method of assessment was not reported. Response rates varied from 30.9% to 75%, but no one regimen was consistently better than another (Table 2). Median survival ranged from 6.5 months [32] to 17 months [36]. Common toxic effects included myelosuppression and nausea and vomiting, with peripheral neuropathy, cardiotoxicity and stomatitis, also being reported. Two studies (involving 54 patients) addressed the response to cisplatin in combination with a taxane in chemotherapy-naive patients [37, 38]. One [38] recruited patients who had progressed on progestogens or rapidly advancing disease not amenable to hormonal therapy. Both used the WHO criteria for assessing response and toxicity. The response rates were 73% [37] and 67% [38]. Median OS was 17.6 months in one study [38] and not stated for the other. In both studies, myelosuppression was a common toxic effect, as was mild neuropathy, and haematological toxicity was very frequent without the routine use of granulocyte colony-stimulating factor. In one study [38], 14 of 24 patients had improvements in their performance status and six in their pain score.
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Figure 2. Survival meta-analysis for six trials (1135 patients) comparing more intensive with less intensive combination regimens in advanced endometrial carcinoma.
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Three studies involving 128 patients investigated the use of cisplatin in combination with other cytotoxics. One study [39] gave cisplatin in combination with vincristine, megestrol acetate and the podophyllotoxin VM-26 (teniposide), another study [40] gave cisplatin in combination with vinorelbine and in the third study [41] cisplatin was combined with etoposide and 5-fluorouracil (5-FU). carboplatin-containing regimens. Five studies addressed the use of carboplatin (Table 3); three of these used carboplatin as a single agent [42–44] and two used carboplatin in combination with one or more drugs [45, 46]. In total, 180 patients were enrolled in phase II trials of carboplatin-based chemotherapy and none. These patients had received prior chemotherapy. In all studies, response to treatment was assessed radiologically. Single-agent carboplatin resulted in overall response rates varying from 28% [43] to 33% [44], and median survival ranged from 7.1 months [43] to 10 months [44]. Toxicity was mainly grade 1 and 2 haematological. Carboplatin in combination with methotrexate, 5-FU and megestrol acetate resulted in an ORR of 74% and a median
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survival of 16 months with only mild haematological and GI toxicity [45], and carboplatin in combination with paclitaxel resulted in an ORR of 60.9% [46]. anthracycline-containing regimens. Five studies involving 183 patients addressed the use of anthracyclines (Table 4), either alone or in combination with non-platinum drugs [47–51]. In two of these studies, prior chemotherapy was permitted [47, 50], while in the other three studies prior treatments were not reported. In two studies, it was not clear how assessment of response was made [47, 48]; in the other three studies, assessment was radiological. Single-agent doxorubicin resulted in an ORR of 37.2% and a median survival of 6.8 months [47]. Toxicity was mainly haematological, but cardiac toxicity and nausea and vomiting were also reported. Pegylated doxorubicin resulted in an ORR of 9.5% and a median survival of 8.2 months in heavily pre-treated patients [50]. Toxicity was mainly haematological and was mild. Single-agent epirubicin resulted in an ORR of 25.9%, with median survival of 9.5 months [51]. The most frequent sideeffect was nausea and vomiting and cardiac toxicity was not
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Figure 3. Meta-analysis of Grade 3 and 4 toxicity combined (761 patients) for more intensive regimens compared to less intensive combination chemotherapy regimens for five of the six trials in advanced endometrial carcinoma analysed in Figures 1 and 2.
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Table 3. Characteristics of phase II trials of chemotherapy: carboplatin-containing regimens Trial ID
Patients recruited (and having prior chemotherapy)
Chemotherapy
Overall response rate (%)
Median PFS (months)
Median OS (months)
Long et al. [41] Green et al. [40] Burke et al. [42] Bafaloukos et al. [43]
25 32 33 23
28 30 33 74
3.8 NR 4–5 NR
7.1 9.3 8–10 16
Hoskins et al. [44]
67 (0)
Carboplatin 400 mg/m2 Carboplatin 400 mg/m2 Carboplatin 360–450 mg/m2 Carboplatin 300 mg/m2, methotrexate 30 mg/m2, 5-FU 500 mg/m2, megace 300 mg/day Carboplatin AUC 5–7, paclitaxel 175 mg/m2
61
NR
15–26
(0) (0) (0) (0)
AUC, area under the curve; 5-FU, 5-fluorouracil; NR, not recorded; OS, overall survival; PFS, progression-free survival.
Trial ID
Patients recruited (and having prior chemotherapy)
Chemotherapy
Overall response rate (%)
Median PFS (months)
Median OS (months)
Thigpen et al. [45] Seski et al. [46]
55 (2) 26 (NR)
37 30
NR NR
6.8 NR
Deppe et al. [47]
29 (NR)
45
NR
6.7–12.5
Muggia et al. [48] Calero et al. [49]
46 (40) 27 (0)
Doxorubicin 60 mg/m2 Doxorubicin 40–50 mg/m2, cyclophosphamide 500–600 mg/m2 Doxorubicin 40 mg/m2, cyclophosphamide 400 mg/m2, 5-FU 400 mg/m2, megace 160 mg/day Pegylated liposomal, doxorubicin 50 mg/m2 Epirubicin 80 mg/m2
9 26
NR 6
8.2 9.5
5-FU, 5-fluorouracil; NR, not recorded; OS, overall survival; PFS, progression-free survival.
seen. Doxorubicin in combination with cyclophosphamide (oral or i.v.) resulted in an ORR of 30.7%; median survival was not reported [48]. Nausea and vomiting was the most frequently reported toxicity and admission to hospital for febrile neutropenia was required in five of 26 patients. Doxorubicin in combination with cyclophosphamide, 5-FU and megestrol acetate resulted in an ORR of 44.9% [49]. Median survival was not reported for the whole group. taxane-containing regimens. Four studies involving 89 patients addressed the use of paclitaxel (Table 5), either alone or in combination with a non-platinum-based drug [52–55]. One of these studies only recruited patients with uterine papillary serous carcinoma, including both advanced disease and adjuvant therapy [54]. Another recruited patients with both advanced endometrial carcinoma and uterine sarcoma [55]. Radiological imaging was carried out regularly in two studies [53, 54]. In three studies, no prior chemotherapy was allowed [52, 54, 55] while in the fourth study, prior chemotherapy with cisplatin, cyclophosphamide and doxorubicin was one of the criteria for eligibility [53]. Single-agent paclitaxel achieved response rates of 35.7% [52] to 77% [54]. The response rate to paclitaxel in patients previously treated with chemotherapy was 37%, and 47% of these patients were considered to have platinum-resistant disease [53]. Median survival was only reported in one study at 9.5 months [52]. Myelosuppression was common, although it was milder in the study using lower dose paclitaxel [53]. Arthralgia, myalgia and neuropathy were
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also reported. Paclitaxel in combination with liposomal doxorubicin resulted in an ORR of 40.7% but survival was not reported [55]. The most frequently reported toxic effects were myelosuppression and plantar–palmar erythema. miscellaneous single agents and combinations. A further 28 phase II trials involving 789 patients of single agents not included in the above categories were identified and there is one further study of melphalan, 5-FU and a progestogen containing 11 assessable patients (data not shown).
discussion Phase II data show that a number of drugs have some activity in advanced endometrial cancer. The most commonly investigated drugs include platinums, anthracyclines and taxanes, either alone or in combination. The patients, however, were selected according to different criteria and some were variously pretreated. Therefore, in the absence of a randomised control group, it is not possible to tell whether any of the combinations are superior in terms of PFS, OS, palliation of symptoms or effects on QoL. In total, 778 women participated in phase II trials of cisplatinbased chemotherapy with response rates ranging from 4% to 81.2%. Median survival was not reported for all studies but varied from 6.5 months [32] to 17.6 months [38], and higher response rates did not always correlate with longer survival. The combination of cisplatin with paclitaxel resulted in an
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Table 4. Characteristics of phase II trials of chemotherapy: anthracycline-containing regimens
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Table 5. Characteristics of phase II trials of chemotherapy: taxane-containing regimens Trial ID
Patients recruited (and having prior chemotherapy)
Chemotherapy
Overall response rate (%)
Median PFS (months)
Median OS (months)
Ball et al. [50] Lissoni et al. [51] Ramondetta et al. [52] Hornreich et al. [53]
30 19 13 27
Paclitaxel 250 mg/m2 Paclitaxel 175 mg/m2 Paclitaxel 200 mg/m2 Paclitaxel 225 mg/m2, liposomal doxorubicin 30 mg/m2
36 37 77 41
3.8 NR NR NR
9.5 NR NR NR
(0) (19) (0) (0)
NR, not recorded; OS, overall survival; PFS, progression-free survival.
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and no one regimen appears superior to another in improving PFS and OS. The only RCT that reported a significant improvement in PFS and OS was that of doxorubicin, cisplatin and paclitaxel versus doxorubicin and cisplatin [15] with the benefit associated with the paclitaxel-containing arm. Grade 3 or 4 thrombocytopenia and neurological toxicity, however, were also significantly greater and there were five treatment-related deaths with the paclitaxel arm. There was no clear evidence from the RCTs comparing other miscellaneous chemotherapy regimens or schedules that any were superior in terms of OS and PFS and/or reduced toxicity. The median survival varied from 7 to 15 months and median PFS varied from 2.5 to 8 months. These may reflect prior treatments and stage of disease, as well as the effect of any particular regimen. One additional trial compared doxorubicin and cisplatin chemotherapy with whole-abdominal radiotherapy (WAR), and showed a survival gain for the cytotoxic chemotherapy arm [54]. While it did not meet the inclusion criteria for this review, if the assumption is made that WAR does not adversely affect survival, then this is indirect evidence that combination chemotherapy improves survival in endometrial cancer. Conclusions on the potential of chemotherapy to palliate symptoms and improve QoL are limited given the modest potential impact of chemotherapy on PFS and OS, and collection of such patient-reported data should be a priority in future research. Response rates up to 75% were, however, reported and response may be regarded as a crude surrogate for palliation if maintained for several months. Clinicians may consider chemotherapy for patients with more aggressive disease or visceral disease, or may offer it to younger patients of good performance status. The RCTs enrolled a heterogeneous group of patients in terms of prior therapies with hormonal agents or cytotoxic agents. The phase II data show a lack of cross-resistance between cisplatin and paclitaxel and that response rates for doxorubicin/cisplatin combinations are much higher than those for single agents. Performance status was not reported in all studies, yet may have a significant impact on how much benefit a patient obtains from treatment. The data indicate that the increased toxicity associated with the use of more than two drugs is not justified by the slight improvement in outcome. There is no data regarding correlation between sites of metastatic disease and benefit. The effect of co-morbidity is also difficult to establish and may vary with ethnic background and socioecomonic group.
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impressive response rate and the longest median survival in a small group of heavily pre-treated patients [38]. A total of 180 patients were enrolled in phase II studies of carboplatin-based chemotherapy. The response rates and median OS from these studies do not indicate that carboplatin is inferior to cisplatin in the therapy of advanced endometrial cancer. Myelosuppression may be more frequent but nephrotoxicity, neurotoxicity and emesis were all less frequently reported and were milder than those in cisplatin-based regimens. Carboplatin in combination with paclitaxel appears as active as cisplatin in combination with paclitaxel [46]. A total of 183 patients were enrolled in phase II studies of anthracyclines, either alone or in combination with nonplatinum drugs. Response rates varied from 9.5% (60) with pegylated doxorubicin in heavily pre-treated patients to 44.9% (49). The response rates for doxorubicin in combination with non-platinum drugs were similar to the response rates achieved by single-agent, non-pegylated doxorubicin. The response rates for single-agent anthracyclines compare quite favourably with those for single-agent platinum. A total of 89 patients were enrolled in phase II studies of paclitaxel, either alone or in combination with a non-platinum drug. Single-agent response rates appear similar to anthracyclines and platinum drugs used alone. The response rates reported in one small trial [53] seem impressive given that all patients in this study had received prior chemotherapy and just under half had disease described as platinum resistant. The quality of the 11 identified RCTs of cytotoxic chemotherapy in advanced or recurrent endometrial adenocarcinoma randomly assigning 2288 women was somewhat variable. Response rates varied between RCTs, with the worst rates in the most heavily pre-treated patients [8, 9]. In a number of trials, combination therapy led to a higher response than single-agent treatment or other combinations [7, 10, 11], but with the exception of Fleming et al. [13], this better response rate did not translate into better PFS or OS, at least at the individual trial level. A meta-analysis of the six trials that compared more intense chemotherapy combinations indicates that more intense chemotherapy significantly improves the median PFS, but not OS. This is, however, at the expense of increased grade 3/4 toxicity. It should be noted that a number of these trials pre-date the routine use of the type 3 serotonin receptor (5-HT3) antagonists and the rate of grade 3 and 4 vomiting may be higher than what one would expect in current practice. Across these six trials, the results are fairly consistent
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conclusions
acknowledgements The authors would like to thank Vivien Garner for obtaining papers for the background section and Aapro and Long for providing further information on trials included in this review. The authors declare no potential financial conflicts of interest.
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There is a need for a trial that randomly assigns women with advanced disease and no prior treatment with endocrine or cytotoxic therapy to receive chemotherapy or endocrine therapy. GOG 189 attempted this but failed to recruit. European Organisation for Research and Treatment of Cancer (EORTC 55984) randomly assigned patients between cisplatin and doxorubicin with or without paclitaxel and also had difficulty in recruitment for reasons which included concerns over the toxicity of both arms [55]. Clinicians therefore have to consider whether the modest survival gain of the order of 3 months justifies the toxicity of a three-drug combination in the individual patient. Assessment of baseline and on-treatment QoL and symptom scores should supplement primary outcomes such as PFS and OS. The optimum chemotherapy regimen to be used is not established, but there is wide experience in other tumours with the use of carboplatin and paclitaxel together, and this combination merits consideration in endometrial cancer as well as carboplatin and liposomal doxorubicin for which more limited data exist [56]. Future trials may also clarify which groups of patients would benefit from which treatment by stratifying patients at trial entry for tumour grade, prior therapies, performance status, site of disease and co-morbidity. Molecular parameters such as hormone receptor status, topoisomerase IIa and possibly growth factor pathway activation status need to be evaluated for their prognostic value and ability to predict sensitivity to the anthracyclines, platinums and taxanes. These factors are likely to be even more important in evaluating novel agents such as the mTOR inhibitors, which is in order to design adjuvant chemotherapy trials for high-risk stage 1 patients (such as the PORTEC 3 study); it is also vital that good quality data be acquired from the treatment of patients with advanced disease.
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