Gynecologic Oncology 136 (2015) 240–245
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
A phase II trial of paclitaxel, carboplatin, and bevacizumab in advanced and recurrent endometrial carcinoma (EMCA) Fiona Simpkins a, Richard Drake b, Pedro F. Escobar b, Benjamin Nutter c, Nabila Rasool b, Peter G. Rose b,⁎ a b c
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA, United States Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cleveland Clinic Foundation, Cleveland, OH, United States Quantitative Health Sciences, Cleveland Clinic Foundation, Cleveland, OH, United States
H I G H L I G H T S • Bevacizumab, carboplatin and paclitaxel plus bevacizumab maintenance was evaluated in endometrial cancer with measurable disease. • This regimen was well tolerated with acceptable toxicity despite prior radiation therapy in 36% of patients. • This prospective trial provides preliminary evidence of significant durable anti-tumor activity.
a r t i c l e
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Article history: Received 13 July 2014 Accepted 2 December 2014 Available online 6 December 2014 Keywords: Advanced stage endometrial cancer Chemotherapy Bevacizumab
a b s t r a c t Objective. To evaluate the effect of adding bevacizumab to adjuvant paclitaxel and carboplatin and as maintenance on progression-free survival (PFS) in advanced or recurrent endometrial carcinoma (EMCA). Methods. A phase II trial was conducted in patients with measurable disease. Paclitaxel (175 mg/m2/3 h), carboplatin (AUC 5) and bevacizumab (15 mg/kg) were administered q 21 days. Patients with a complete response after 6–8 cycles received maintenance therapy with bevacizumab 15 mg/kg q 21 days for 16 cycles. Based on GOG 177 which had a 6-month PFS rate of 59%, an increase in 6-month PFS to 72% with the treatment regimen was considered of clinical interest. Results. 15 patients were enrolled on protocol when accrual to the study was discontinued due to the initiation of a national randomized phase II trial. A total of 127 courses (median 8, range 1–20) of carboplatin, paclitaxel, and bevacizumab combination therapy were administered. One patient suffered a bowel perforation after her first course of therapy and was inevaluable for response. Fourteen of the 15 patients (93%, 95% CI: 82–100) were progression free at 6 months. The median follow-up was 36 months (7–58+). The median PFS was 18 months (CI: 11–25). Five complete responses and 6 partial responses were seen for an overall response rate of 73% (CI: 45–91). The median overall survival was 58 months (CI: 48–68). Conclusions. The bevacizumab, paclitaxel, and carboplatin regimen is active and tolerable in advanced and recurrent EMCA. Its impact awaits results of the recently completed randomized phase II trial. © 2014 Elsevier Inc. All rights reserved.
Introduction Endometrial cancer is the most common gynecologic cancer in the United States with an estimated 52,630 cases occurring in the United States in 2014 with an estimated 8590 deaths [1]. Endometrial carcinoma can be subdivided into type I and type II. Type I tumors associated with obesity or exogenous estrogen use, present at early stage and
⁎ Corresponding author at: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cleveland Clinic Foundation, A81, 9500 Euclid Avenue, Cleveland, OH 44195, United States. Fax: +1 216 444 8551. E-mail address: [email protected] (P.G. Rose).
http://dx.doi.org/10.1016/j.ygyno.2014.12.004 0090-8258/© 2014 Elsevier Inc. All rights reserved.
have an excellent prognosis. These tumors histologically comprise of well to moderately differentiated endometrioid adenocarcinomas which typically have minimal invasion, and infrequent nodal metastasis. Type II tumors are not classically associated with obesity or exogenous estrogen use. Histologically, these tumors are poorly differentiated endometrioid adenocarcinomas, serous papillary or clear cell carcinomas [2]. Estrogen and progesterone receptors are commonly expressed in low grade type I tumors but not type II tumors. Therefore, for the majority of patients who develop metastatic or recurrent disease systemic hormonal therapy is not effective and chemotherapy is utilized. The Gynecologic Oncology Group (GOG) has conducted studies systematically evaluating the addition or substitution of new agents for the treatment of advanced and recurrent endometrial cancer.
F. Simpkins et al. / Gynecologic Oncology 136 (2015) 240–245
Fleming et al. reported the results of GOG protocol #177 that evaluated the combination of paclitaxel (Taxol), doxorubicin (Adriamycin) and cisplatin (Platinol) (TAP) [3]. The TAP combination demonstrated improvements in response rate, progression-free survival and overall survival compared to cisplatin and doxorubicin. However, the toxicity of this regimen is significant with grade 2 or greater neuropathy occurring in 46% of patients. Numerous phase II trials have demonstrated significant activity with the combination of paclitaxel and carboplatin [4–6] however, phase III data with this combination was lacking. Therefore, the GOG performed a randomized phase III trial in an effort to evaluate the relative activity and toxicity of TAP compared to paclitaxel and carboplatin [7]. An interim analysis of this trial demonstrated that carboplatin and paclitaxel regimen was non-inferior to TAP with a more favorable toxicity profile. Vascular endothelial growth factor (VEGF) expression, increased in endometrial cancer, is associated with a higher histological grade and myometrial invasion. VEGF has also been shown to be associated with poor patient prognosis in endometrial cancer [8–11]. Bevacizumab, a recombinant humanized monoclonal antibody to VEGF, has been evaluated in combination with carboplatin in lung cancer [12]. In ECOG 4599, a phase III randomized trial for non-small cell lung carcinoma, the addition of bevacizumab to carboplatin and paclitaxel increased the PFS and OS. In view that angiogenesis plays a role in endometrial cancer progression and the encouraging data of bevacizumab in combination with platinum/taxane chemotherapy in other cancers, we elected to perform an investigator-initiated phase II trial of paclitaxel, carboplatin and bevacizumab with bevacizumab maintenance in patients with advanced and recurrent endometrial carcinoma. Genentech provided bevacizumab and Cleveland Clinic Foundation provided the remaining support to conduct this single institution study. Patients and methods This trial concept was developed by the primary author while a gynecologic oncology fellow in 2006. The concept was accepted and the protocol was written with the assistance of ASCO clinical trial experts including biostatisticians at the ASCO Clinical Trial Writing Workshop. Genentech also approved the protocol and supplied the bevacizumab for this trial. The trial was registered with clinicaltrials.gov (NCT00879359).
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Treatment Chemotherapy The clinical trial design is shown in Table 1. Treatment consisted of paclitaxel at a dose of 175 mg/m2 (135 mg/m2 if prior radiation therapy to greater than 25% of bone marrow), administered as a 3-hour infusion, Day 1, q 21 days. Standard pre-medications included dexamethasone, and anti-histamine H1 and H2 blockers. In the event of Grade 2 (or greater) peripheral neuropathy, docetaxel at a dose of 75 mg/m2 (60 mg/m2 if prior radiation therapy to greater than 25% of bone marrow), was substituted for paclitaxel Day 1, q 21 days. Carboplatin, dosed to an AUC of 5.0, Day 1, q 21 days, was administered directly following completion of the taxane therapy. Bevacizumab Bevacizumab was given at a dose of 15 mg/kg Day 1, every q 21 days for 16 cycles. No maximum bevacizumab dose was prescribed. There were no dose reductions for bevacizumab. The initial doses of bevacizumab were administered over 90, 60 and 30 min and if well tolerated delivered over 30 min with all subsequent courses. For uncontrolled hypertension (systolic N 150 mm Hg or diastolic N 90) or symptomatic hypertension less than CTCAE Grade 4, bevacizumab treatment was withheld until blood pressure was controlled with anti-hypertensive therapy. Bevacizumab was also temporarily discontinued in the event of severe proteinuria defined as a urine protein:creatinine (UPC) ratio N 3.5. Bevacizumab could be restarted if the UPC ratio recovered to b3.5 within 8 weeks of discontinuation. Bevacizumab was to be permanently discontinued if the following criteria were met: grade 4 hypertension, reversible posterior leukoencephalopathy syndrome or hypertensive encephalopathy, grade 4 nephritic syndrome, arterial thrombosis, symptomatic grade 4 or recurrent/worsening venous thromboembolic events after resumption of bevacizumab treatment, grade 3 hemorrhage, bowel perforation or fistula and any complete wound disruption.
Table 1 Clinical trial design. Endometrial Cancer (measurable disease)
Patient selection Eligibility criteria Eligible patients had histologically confirmed primary stage III or IV or recurrent endometrial carcinoma with measurable disease by RECIST criteria version 1.0 whose potential for cure by radiation therapy or surgery alone or in combination was very poor. Recurrent disease was biopsy confirmed when possible. Patients may have received prior radiation therapy. Patients may have received one prior cytotoxic chemotherapy regimen excluding a platinum/taxane and patients may have received prior hormonal or biologic therapy. Patients were required to have normal blood counts, and adequate renal and hepatic function. Patients required a GOG performance status of 0–2. Exclusion criteria Patients were ineligible if they met any of the following criteria: history of concomitant malignancy or prior malignancy other than non-melanoma skin cancer, brain metastasis, bleeding diathesis or coagulopathy, clinically significant CDV disease, history of abdominal fistula or gastrointestinal perforation or intraabdominal abscess within 6 months prior to study enrollment. Also, patients with clinical symptoms or signs of gastrointestinal obstruction or those who required parenteral hydration and/or nutrition were excluded.
Regimen Carboplatin AUC 5 IV day 1 Paclitaxel 175 mg/m2 IV day 1 Bevacizumab 15 mg/kg IV day 1 Triplet every 21 days Follow-up after every 3 cycles (PFS, RR, toxicity)
Continue triplet regimen until disease progression or unacceptable drug toxicity
Cancer progression: off study
Complete response: 2 additional cycles of triplet regimen Consolidation: Bevacizumab 15 mg/kg Q 21 days x 16 cycles
Cancer Progression: Carboplatin and paclitaxel ONLY
Cancer progression: off study regimen
Partial response: continue triplet
Cancer progression: off study
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Subsequent cycles were delayed up to 3 weeks if pretreatment ANC was b 1500 cells/mm3 or if the platelet count was b100,000/mm3. Patients who failed to recover adequate counts within a three-week delay were to discontinue cytotoxic chemotherapy, but continue bevacizumab alone.
Table 2 Patient demographics (n = 15). Age in years Median Range
63 32–88
Performance status
Assessment of toxicity and anti-tumor activity
0 1 2
Patients were evaluated for toxicity and by physical and pelvic exam before each treatment cycle. Radiographical studies were obtained after every 3 cycles. If patients achieved a complete response, they were to receive 2 additional cycles of carbo/taxol/bevacizumab and then continue only on bevacizumab 15 mg/kg every 21 days for consolidation for a maximum of 16 cycles (Table 1). Patients with a partial response or stable disease were to continue on the triplet regimen until progression of disease or unacceptable toxicity. If progression occurred while on consolidation, patients were to receive carboplatin and paclitaxel without bevacizumab every 21 days. If the patient continued to progress, the patient was taken off protocol. Serum VEGF levels were drawn prior to treatment and after every 3 cycles of therapy. VEGF levels were quantified using ELISA performed by Quest Diagnostics which was funded by Cleveland Clinic.
9 6 0
Stage (FIGO 2009) IA IB IIB IIIC1 IIIC2 IVB
4 1 1 1 1 7
Tumor histology and grade 6a 5 3 1
Serous papillary Endometrioid grade 2 Endometrioid grade 3 Clear cell Prior treatment Pelvic radiation +/− Brachytherapy Brachytherapy Chemotherapy Hormonal therapy
Statistical design
Fourteen of the 15 evaluable patients (93% CI: 82–100) were progression free at 6 months. The median progression-free survival was 18 months (95% CI: 11–25) (Fig. 1). A total of 99 courses of maintenance bevacizumab therapy were administered to 7/15 evaluable patients (47% of enrolled patients). Only four (27% of enrolled patients) were
0.4
0.6
0.8
1.0
Progression Free Survival Estimates
Probability of Remaining Progression Free
Fifteen patients were enrolled on protocol from 12/28/2007–11/23/ 2010. Accrual to the study was discontinued by the sponsor in February 2011 due to the initiation of a competing randomized phase II trial, GOG 86P evaluating paclitaxel, carboplatin and bevacizumab versus paclitaxel, carboplatin, and temsirolimus versus ixabepilone, carboplatin, and bevacizumab. The demographics of the patients enrolled on this study are listed in Table 2. Two thirds (n = 10/15) of the patients entered on this trial had type II endometrial cancer (papillary serous, clear cell or poorly differentiated endometrioid adenocarcinoma) and 60% had advanced stages (stage III/IV) of disease at diagnosis. Sixty percent of enrolled patients had a performance status of 0 and the remaining had a performance status of 1. The median follow-up was 36 months (7–58+ months).
Anti-tumor activity
0.2
Results
a One patient had a mixed tumor with 10% serous and 90% endometrioid but all metastatic sites were serous carcinoma.
0.0
The primary end point of this study was to determine the six-month progression-free survival of the triplet bevacizumab, carboplatin and paclitaxel in advanced/recurrent endometrial cancer. Sample size analysis was based on the GOG 177 trial, which had a 6-month PFS rate of 59% (CI: 52%–69%) given that GOG 209 data was unavailable at the time this trial was designed. The median PFS for recurrent endometrial cancer patients treated with standard chemotherapy TAP from GOG 177 was approximately 8 months which translates into a 6-month PFS rate of 59%, assuming that PFS follows an exponential distribution. A clinically relevant effect was deemed as a 20% absolute increase in PFS above the lower bound of the GOG 177 observed PFS, or 72%. Using 85% power, a one-side 10% significance level, and based on a chi-square test of a single proportion, it was determined that a total of 31 patients would be necessary to adequately evaluate the study objectives. However, given the opening of a competing GOG trial, the trial was terminated after 15 patients were enrolled. Secondary end points of the study were response rate, treatment-related toxicity, overall survival, and to determine the relationship of VEGF serum and tissue levels with outcome. Serial VEGF assays obtained on patients were summarized by median and quartile. VEGF levels were quantified by Quest Diagnostics. The first VEGF for each patient was used. A comparison between the responsive and non-responsive patients was performed by a Mann–Whitney test.
4 1 0 2
Median PFS: 18 months 0
6
12
18
24
8 8
5 11
Months From Start of Chemotherapy N At Risk N Events
15 0
15 1
11 5
Fig. 1. Progression free survival estimates.
F. Simpkins et al. / Gynecologic Oncology 136 (2015) 240–245
able to complete all of their intended maintenance bevacizumab. One patient who achieved a complete response to chemotherapy with bevacizumab did not receive maintenance therapy with bevacizumab because of the development of a non-healing skin ulcer. Five complete responses and 6 partial responses were seen for a total response rate of 73% (95% CI: 45–91) among the 15 evaluable patients. The median duration of response was 20 months (range 13–46+ months) for complete responders and 10–22 months (range 9–35 months) for partial responders. Adverse effects A total of 127 courses (median 8, range 1–20) of carboplatin, paclitaxel, and bevacizumab combination therapy were administered. One patient suffered a bowel perforation after her first course of therapy and subsequently received only carboplatin and paclitaxel. No other GI perforations or fistulas occurred. One patient who developed a hypersensitivity to carboplatin after 12 cycles went on to receive 36 additional cycles of paclitaxel and bevacizumab. One patient had paclitaxel substituted with abraxane for a severe hypersensitivity to paclitaxel. Neulasta was added to one patient after cycle 4 for a 2 week delay for neutropenia. Subsequent therapy and survival Three patients who progressed were retreated with paclitaxel and carboplatin with one complete response. Doxorubicin was subsequently administered in 7 patients as second (n = 4), fourth (n = 2) or fifth (n = 1) line therapy with no objective responses. The median overall survival was 58 months (95% CI: 48–68) (Fig. 2). VEGF assays A total of 46 VEGF assays were obtained on 11 patients. The median VEGF value was 57 (range 31–318). Only 46 of 615 planned VEGF assays (7.4%) were drawn. VEGF assays were obtained from 3 responding patients, 2 patients with stable disease and 1 with progressive disease. No trend in VEGF level was noted between responding vs nonresponding patients in this small sample size (p = 0.58).
0.6 0.4 0.0
0.2
Probability of Survival
0.8
1.0
Survival Estimates
Median Survival: 58 months 0
12
24
36
48
60
5 5
2 6
Months From Start of Chemotherapy N At Risk N Events
14 0
13 2
11 3
7 5
Fig. 2. Survival estimates.
243
Discussion The incidence of both type I and type II carcinomas is increasing proportionally likely due to the increased incidence of obesity and increased longevity of the population, respectively [13]. Death rates for endometrial cancer have increased over 100% in the last 2 decades [14]. For patients with recurrent or advanced disease systemic chemotherapy with paclitaxel, cisplatin and doxorubicin (TAP) is effective with a 57% response rate [3]. However, this regimen is associated with significant toxicity, only a 10% cure rate, a median progression free survival of only 8.3 months, and a median survival of only 15.3 months. As noted previously, GOG 209 compared TAP to carboplatin and paclitaxel in patients with both measurable and non-measurable advanced stage disease. On interim analysis, the median progression free survival was 14 months for both regimens with a HR = 1.03. The median overall survival was 38 and 32 months for TAP and carboplatin and paclitaxel, respectively with HR = 1.01. The authors concluded that carboplatin and paclitaxel are non-inferior and associated with less toxicity compared to TAP in a similar patient population [7]. However, it is important to note that the progression free and overall survival is significantly longer by approximately 100% in GOG 209 when non-measurable disease patients are included in the study compared to GOG 177 which only included measurable disease patients. The authors further concluded that carboplatin and paclitaxel is an acceptable backbone for further trials in combination with “targeted” therapies. Final results and manuscript are however, not yet published. We designed this clinical trial to include endometrial cancer patients with measurable disease, similar to the GOG 177 patient population so the endpoints were comparable. GOG 209 included a heterogenous population of both patients with and without measurable disease making comparison to this trial difficult. In addition, GOG 209 interim analysis had not yet been published upon design of this trial. Angiogenesis has been shown to be a driver of endometrial carcinogenesis [8,9]. During this study, results of GOG 229E were published Table 3 Adverse events* (N = 15). AE category Hematologic Leukopenia Neutropenia Thrombocytopenia Anemia Non-hematologic Allergy/immunology Alopecia Anorexia Cough Depression Diarrhea Dyspnea Epistaxis Fatigue Gastrointestinal Hemorrhage Hoarseness Hypercalcemia Infection Lymphatics Nausea Neurosensory Ocular/visual Pain Rash Rhinitis Tinnitus Vomiting
0
1
2
3
4
5
Total
2 3 6 0
1 1 4 7
5 1 2 7
7 2 2 1
0 8 1 0
0 0 0 0
15 15 15 15
13 5 7 11 13 10 12 14 3 6 14 13 14 13 14 9 9 14 10 12 14 14 12
1 3 3 4 2 3 2 1 8 6 1 2 1 2 1 5 5 1 3 3 1 0 1
0 7 4 0 0 1 1 0 3 1 0 0 0 0 0 1 1 0 1 0 0 1 2
0 0 1 0 0 1 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0
1a 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 1 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15
*The maximum severity of each adverse event per patient, graded according to Common Terminology Criteria for Adverse Events v3.0 (CTCAE). a Hypersensitivity to carboplatin.
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showing single agent activity of bevacizumab in recurrent endometrial cancer [15]. This was a phase II trial of bevacizumab following one or two chemotherapy regimens in 33 (63.5%) and 19 (36.5%) patients, respectively. Twenty-nine of these patients (55.8%) received prior radiation. Among 52 eligible patients, seven patients (13.5%) experienced clinical responses (one complete response and six partial responses; median response duration, 6.0 months), and 21 patients (40.4%) survived progression free for at least 6 months. Adverse events were consistent with those expected of bevacizumab treatment. Additionally, no GI perforations or fistulae were seen (Table 3). The first study comparing the addition of bevacizumab to platinum/taxane chemotherapy vs platinum/taxane chemotherapy alone was in non-small cell lung cancer [12]. The bevacizumab plus chemotherapy group showed a significant increase in progression free survival and overall survival compared to the chemotherapy only treated group. Since our study was designed, the results of GOG 218 became available which compared three arms: chemotherapy alone, chemotherapy with bevacizumab during chemotherapy and chemotherapy with bevacizumab during chemotherapy and as maintenance [16]. This study demonstrated that the addition of bevacizumab during chemotherapy administration and as maintenance therapy improved the progression free survival, but the addition of bevacizumab therapy only during chemotherapy was not more effective than chemotherapy alone. Given that angiogenesis is a driver of endometrial cancer, and the favorable results of bevacizumab in combination with chemotherapy, the purpose of this current study was to determine if the addition of bevacizumab to carboplatin and paclitaxel during chemotherapy and bevacizumab as maintenance therapy could increase progression-free survival for patients with recurrent or advanced stage endometrial cancer. The primary end point of this study was to determine the six-month progression-free survival. The six-month progression-free survival of 93% (95% CI: 82–100) compares favorably to the 59% reported in GOG 177 for TAP. The response rate in this trial of 73% (95% CI: 45–91) compares favorably to the 57% response rate reported in GOG 177 for TAP and 50% response rate for carboplatin and paclitaxel in GOG 209 (D. Miller, GOG 209 Metastatic Cancer Update from SGO 2013, March 13, 2013; www.oncologytube.com). The median overall survival of 58 months (95% CI: 48–68) compares favorably to 15.3 months reported in GOG 177 for TAP and 32 months for carboplatin and paclitaxel in GOG 209. The current study demonstrates that the combination of bevacizumab, carboplatin and paclitaxel was well tolerated in advanced/recurrent endometrial cancer (Table 4). While this might be an expected finding based on our experience with ovarian cancer, 36% of this patient population had received prior radiation therapy. This trial was closed before its planned accrual was reached due to the opening of GOG 86P. Based on the results of large clinical trials, the use of adjuvant chemotherapy has become common practice in advanced and high risk endometrial cancer. In advanced stage disease, GOG 122 demonstrated that chemotherapy was superior to whole abdominal radiation therapy in optimal residual stage III and IV disease [17]. Even in early stage disease, chemotherapy is being used more frequently. Portec I demonstrated a 29% rate of extra-pelvic failure following pelvic radiation therapy for poorly differentiated endometrial carcinoma [18]. Hogberg et al. demonstrated that radiation with chemotherapy was superior to pelvic radiation alone in high risk early stage disease [19]. Retrospective data support the use of chemotherapy in uterine papillary
Table 4 Response to taxol/carboplatin/bevacizumab. Response
Number
Percent of patients
Complete response Partial response Stable Progression
5 6 3 1
33 40 20 7
serous carcinoma [20]. Additionally, chemotherapy is being utilized in cases with vascular lymphatic invasion [21]. Collectively, this results in a diminution of patients with chemotherapy-naive recurrent endometrial cancer. This issue was addressed during the design of the trial but to be comparable to GOG 177, we only enrolled patients with measurable disease and no prior chemotherapy. However, in our trial the planned accrual was never reached and as a consequence the results obtained in this study have wide confidence intervals and lack power. There are a limited number of active chemotherapy or biologic agents in endometrial cancer. Therefore, optimizing first-line therapy in advanced and recurrent endometrial carcinoma is a logical treatment strategy. Unfortunately, second-line chemotherapy options for recurrent endometrial carcinoma are extremely limited. Planned retreatment with paclitaxel and carboplatin was incorporated in the design of this trial based on the results from Hoskins et al. with response rates of 45% [22]. While only a small number of patients were treated with this regimen, a complete response was noted. None of the patients who subsequently received doxorubicin responded. This lack of significant activity with doxorubicin following prior exposure to taxane and platinum therapy has been demonstrated in a prospective Italian trial in which there were no objective responses [23]. To date the mechanism of this cross-resistance is unexplained. Serial VEGF assays were obtained in this study. Previous studies have demonstrated inconsistent results between VEGF assays and clinical outcome [24]. Biomarkers to predict patient response to antiangiogenesis drugs are lacking. No association between VEGF levels and clinical response was noted in our study but the patient sample was very small and not collected uniformly across all participating centers. Furthermore, scarcity of data in the responsive group renders conclusions from these comparisons unreliable. There are a number of limitations to this study. First based on the truncated sample size of 14 patients, the expected power from this sample is only 44%. Secondly, the study design was non-randomized which limits comparative conclusions. Additionally, the optimal use of bevacizumab either concurrently with chemotherapy or as maintenance or the combination has not been evaluated in endometrial cancer. The optimal duration of bevacizumab maintenance has not been established. Lastly, the biologic correlates to identify which patients are most likely to benefit for chemotherapy with bevacizumab have not been demonstrated. The availability of VEGF levels for evaluation as a biomarker is also a limitation of this study. In conclusion, the current study demonstrates that the combination of bevacizumab, paclitaxel, and carboplatin is active and tolerable in advanced and recurrent endometrial carcinoma. Its impact awaits results of the recently completed randomized phase II trial Gynecologic Oncology Group trial (GOG 86 P) comparing this combination to other chemotherapy and biologic combinations. Hopefully GOG 86 P will provide important information regarding future direction in the treatment of advanced and recurrent endometrial carcinoma. We hope the authors of GOG 86P will address response rates between patient subgroups with measurable vs non-measurable disease. Conflict of interest statement The authors of this manuscript, Fiona Simpkins, Richard Drake, Pedro F. Escobar, Benjamin Nutter, Nabila Rasool, and Peter G. Rose, have no conflicts of interest to disclose.
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Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
A phase II trial of paclitaxel, carboplatin, and bevacizumab in advanced and recurrent endometrial carcinoma (EMCA) Fiona Simpkins a, Richard Drake b, Pedro F. Escobar b, Benjamin Nutter c, Nabila Rasool b, Peter G. Rose b,⁎ a b c
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA, United States Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cleveland Clinic Foundation, Cleveland, OH, United States Quantitative Health Sciences, Cleveland Clinic Foundation, Cleveland, OH, United States
H I G H L I G H T S • Bevacizumab, carboplatin and paclitaxel plus bevacizumab maintenance was evaluated in endometrial cancer with measurable disease. • This regimen was well tolerated with acceptable toxicity despite prior radiation therapy in 36% of patients. • This prospective trial provides preliminary evidence of significant durable anti-tumor activity.
a r t i c l e
i n f o
Article history: Received 13 July 2014 Accepted 2 December 2014 Available online 6 December 2014 Keywords: Advanced stage endometrial cancer Chemotherapy Bevacizumab
a b s t r a c t Objective. To evaluate the effect of adding bevacizumab to adjuvant paclitaxel and carboplatin and as maintenance on progression-free survival (PFS) in advanced or recurrent endometrial carcinoma (EMCA). Methods. A phase II trial was conducted in patients with measurable disease. Paclitaxel (175 mg/m2/3 h), carboplatin (AUC 5) and bevacizumab (15 mg/kg) were administered q 21 days. Patients with a complete response after 6–8 cycles received maintenance therapy with bevacizumab 15 mg/kg q 21 days for 16 cycles. Based on GOG 177 which had a 6-month PFS rate of 59%, an increase in 6-month PFS to 72% with the treatment regimen was considered of clinical interest. Results. 15 patients were enrolled on protocol when accrual to the study was discontinued due to the initiation of a national randomized phase II trial. A total of 127 courses (median 8, range 1–20) of carboplatin, paclitaxel, and bevacizumab combination therapy were administered. One patient suffered a bowel perforation after her first course of therapy and was inevaluable for response. Fourteen of the 15 patients (93%, 95% CI: 82–100) were progression free at 6 months. The median follow-up was 36 months (7–58+). The median PFS was 18 months (CI: 11–25). Five complete responses and 6 partial responses were seen for an overall response rate of 73% (CI: 45–91). The median overall survival was 58 months (CI: 48–68). Conclusions. The bevacizumab, paclitaxel, and carboplatin regimen is active and tolerable in advanced and recurrent EMCA. Its impact awaits results of the recently completed randomized phase II trial. © 2014 Elsevier Inc. All rights reserved.
Introduction Endometrial cancer is the most common gynecologic cancer in the United States with an estimated 52,630 cases occurring in the United States in 2014 with an estimated 8590 deaths [1]. Endometrial carcinoma can be subdivided into type I and type II. Type I tumors associated with obesity or exogenous estrogen use, present at early stage and
⁎ Corresponding author at: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cleveland Clinic Foundation, A81, 9500 Euclid Avenue, Cleveland, OH 44195, United States. Fax: +1 216 444 8551. E-mail address: [email protected] (P.G. Rose).
http://dx.doi.org/10.1016/j.ygyno.2014.12.004 0090-8258/© 2014 Elsevier Inc. All rights reserved.
have an excellent prognosis. These tumors histologically comprise of well to moderately differentiated endometrioid adenocarcinomas which typically have minimal invasion, and infrequent nodal metastasis. Type II tumors are not classically associated with obesity or exogenous estrogen use. Histologically, these tumors are poorly differentiated endometrioid adenocarcinomas, serous papillary or clear cell carcinomas [2]. Estrogen and progesterone receptors are commonly expressed in low grade type I tumors but not type II tumors. Therefore, for the majority of patients who develop metastatic or recurrent disease systemic hormonal therapy is not effective and chemotherapy is utilized. The Gynecologic Oncology Group (GOG) has conducted studies systematically evaluating the addition or substitution of new agents for the treatment of advanced and recurrent endometrial cancer.
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Fleming et al. reported the results of GOG protocol #177 that evaluated the combination of paclitaxel (Taxol), doxorubicin (Adriamycin) and cisplatin (Platinol) (TAP) [3]. The TAP combination demonstrated improvements in response rate, progression-free survival and overall survival compared to cisplatin and doxorubicin. However, the toxicity of this regimen is significant with grade 2 or greater neuropathy occurring in 46% of patients. Numerous phase II trials have demonstrated significant activity with the combination of paclitaxel and carboplatin [4–6] however, phase III data with this combination was lacking. Therefore, the GOG performed a randomized phase III trial in an effort to evaluate the relative activity and toxicity of TAP compared to paclitaxel and carboplatin [7]. An interim analysis of this trial demonstrated that carboplatin and paclitaxel regimen was non-inferior to TAP with a more favorable toxicity profile. Vascular endothelial growth factor (VEGF) expression, increased in endometrial cancer, is associated with a higher histological grade and myometrial invasion. VEGF has also been shown to be associated with poor patient prognosis in endometrial cancer [8–11]. Bevacizumab, a recombinant humanized monoclonal antibody to VEGF, has been evaluated in combination with carboplatin in lung cancer [12]. In ECOG 4599, a phase III randomized trial for non-small cell lung carcinoma, the addition of bevacizumab to carboplatin and paclitaxel increased the PFS and OS. In view that angiogenesis plays a role in endometrial cancer progression and the encouraging data of bevacizumab in combination with platinum/taxane chemotherapy in other cancers, we elected to perform an investigator-initiated phase II trial of paclitaxel, carboplatin and bevacizumab with bevacizumab maintenance in patients with advanced and recurrent endometrial carcinoma. Genentech provided bevacizumab and Cleveland Clinic Foundation provided the remaining support to conduct this single institution study. Patients and methods This trial concept was developed by the primary author while a gynecologic oncology fellow in 2006. The concept was accepted and the protocol was written with the assistance of ASCO clinical trial experts including biostatisticians at the ASCO Clinical Trial Writing Workshop. Genentech also approved the protocol and supplied the bevacizumab for this trial. The trial was registered with clinicaltrials.gov (NCT00879359).
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Treatment Chemotherapy The clinical trial design is shown in Table 1. Treatment consisted of paclitaxel at a dose of 175 mg/m2 (135 mg/m2 if prior radiation therapy to greater than 25% of bone marrow), administered as a 3-hour infusion, Day 1, q 21 days. Standard pre-medications included dexamethasone, and anti-histamine H1 and H2 blockers. In the event of Grade 2 (or greater) peripheral neuropathy, docetaxel at a dose of 75 mg/m2 (60 mg/m2 if prior radiation therapy to greater than 25% of bone marrow), was substituted for paclitaxel Day 1, q 21 days. Carboplatin, dosed to an AUC of 5.0, Day 1, q 21 days, was administered directly following completion of the taxane therapy. Bevacizumab Bevacizumab was given at a dose of 15 mg/kg Day 1, every q 21 days for 16 cycles. No maximum bevacizumab dose was prescribed. There were no dose reductions for bevacizumab. The initial doses of bevacizumab were administered over 90, 60 and 30 min and if well tolerated delivered over 30 min with all subsequent courses. For uncontrolled hypertension (systolic N 150 mm Hg or diastolic N 90) or symptomatic hypertension less than CTCAE Grade 4, bevacizumab treatment was withheld until blood pressure was controlled with anti-hypertensive therapy. Bevacizumab was also temporarily discontinued in the event of severe proteinuria defined as a urine protein:creatinine (UPC) ratio N 3.5. Bevacizumab could be restarted if the UPC ratio recovered to b3.5 within 8 weeks of discontinuation. Bevacizumab was to be permanently discontinued if the following criteria were met: grade 4 hypertension, reversible posterior leukoencephalopathy syndrome or hypertensive encephalopathy, grade 4 nephritic syndrome, arterial thrombosis, symptomatic grade 4 or recurrent/worsening venous thromboembolic events after resumption of bevacizumab treatment, grade 3 hemorrhage, bowel perforation or fistula and any complete wound disruption.
Table 1 Clinical trial design. Endometrial Cancer (measurable disease)
Patient selection Eligibility criteria Eligible patients had histologically confirmed primary stage III or IV or recurrent endometrial carcinoma with measurable disease by RECIST criteria version 1.0 whose potential for cure by radiation therapy or surgery alone or in combination was very poor. Recurrent disease was biopsy confirmed when possible. Patients may have received prior radiation therapy. Patients may have received one prior cytotoxic chemotherapy regimen excluding a platinum/taxane and patients may have received prior hormonal or biologic therapy. Patients were required to have normal blood counts, and adequate renal and hepatic function. Patients required a GOG performance status of 0–2. Exclusion criteria Patients were ineligible if they met any of the following criteria: history of concomitant malignancy or prior malignancy other than non-melanoma skin cancer, brain metastasis, bleeding diathesis or coagulopathy, clinically significant CDV disease, history of abdominal fistula or gastrointestinal perforation or intraabdominal abscess within 6 months prior to study enrollment. Also, patients with clinical symptoms or signs of gastrointestinal obstruction or those who required parenteral hydration and/or nutrition were excluded.
Regimen Carboplatin AUC 5 IV day 1 Paclitaxel 175 mg/m2 IV day 1 Bevacizumab 15 mg/kg IV day 1 Triplet every 21 days Follow-up after every 3 cycles (PFS, RR, toxicity)
Continue triplet regimen until disease progression or unacceptable drug toxicity
Cancer progression: off study
Complete response: 2 additional cycles of triplet regimen Consolidation: Bevacizumab 15 mg/kg Q 21 days x 16 cycles
Cancer Progression: Carboplatin and paclitaxel ONLY
Cancer progression: off study regimen
Partial response: continue triplet
Cancer progression: off study
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Subsequent cycles were delayed up to 3 weeks if pretreatment ANC was b 1500 cells/mm3 or if the platelet count was b100,000/mm3. Patients who failed to recover adequate counts within a three-week delay were to discontinue cytotoxic chemotherapy, but continue bevacizumab alone.
Table 2 Patient demographics (n = 15). Age in years Median Range
63 32–88
Performance status
Assessment of toxicity and anti-tumor activity
0 1 2
Patients were evaluated for toxicity and by physical and pelvic exam before each treatment cycle. Radiographical studies were obtained after every 3 cycles. If patients achieved a complete response, they were to receive 2 additional cycles of carbo/taxol/bevacizumab and then continue only on bevacizumab 15 mg/kg every 21 days for consolidation for a maximum of 16 cycles (Table 1). Patients with a partial response or stable disease were to continue on the triplet regimen until progression of disease or unacceptable toxicity. If progression occurred while on consolidation, patients were to receive carboplatin and paclitaxel without bevacizumab every 21 days. If the patient continued to progress, the patient was taken off protocol. Serum VEGF levels were drawn prior to treatment and after every 3 cycles of therapy. VEGF levels were quantified using ELISA performed by Quest Diagnostics which was funded by Cleveland Clinic.
9 6 0
Stage (FIGO 2009) IA IB IIB IIIC1 IIIC2 IVB
4 1 1 1 1 7
Tumor histology and grade 6a 5 3 1
Serous papillary Endometrioid grade 2 Endometrioid grade 3 Clear cell Prior treatment Pelvic radiation +/− Brachytherapy Brachytherapy Chemotherapy Hormonal therapy
Statistical design
Fourteen of the 15 evaluable patients (93% CI: 82–100) were progression free at 6 months. The median progression-free survival was 18 months (95% CI: 11–25) (Fig. 1). A total of 99 courses of maintenance bevacizumab therapy were administered to 7/15 evaluable patients (47% of enrolled patients). Only four (27% of enrolled patients) were
0.4
0.6
0.8
1.0
Progression Free Survival Estimates
Probability of Remaining Progression Free
Fifteen patients were enrolled on protocol from 12/28/2007–11/23/ 2010. Accrual to the study was discontinued by the sponsor in February 2011 due to the initiation of a competing randomized phase II trial, GOG 86P evaluating paclitaxel, carboplatin and bevacizumab versus paclitaxel, carboplatin, and temsirolimus versus ixabepilone, carboplatin, and bevacizumab. The demographics of the patients enrolled on this study are listed in Table 2. Two thirds (n = 10/15) of the patients entered on this trial had type II endometrial cancer (papillary serous, clear cell or poorly differentiated endometrioid adenocarcinoma) and 60% had advanced stages (stage III/IV) of disease at diagnosis. Sixty percent of enrolled patients had a performance status of 0 and the remaining had a performance status of 1. The median follow-up was 36 months (7–58+ months).
Anti-tumor activity
0.2
Results
a One patient had a mixed tumor with 10% serous and 90% endometrioid but all metastatic sites were serous carcinoma.
0.0
The primary end point of this study was to determine the six-month progression-free survival of the triplet bevacizumab, carboplatin and paclitaxel in advanced/recurrent endometrial cancer. Sample size analysis was based on the GOG 177 trial, which had a 6-month PFS rate of 59% (CI: 52%–69%) given that GOG 209 data was unavailable at the time this trial was designed. The median PFS for recurrent endometrial cancer patients treated with standard chemotherapy TAP from GOG 177 was approximately 8 months which translates into a 6-month PFS rate of 59%, assuming that PFS follows an exponential distribution. A clinically relevant effect was deemed as a 20% absolute increase in PFS above the lower bound of the GOG 177 observed PFS, or 72%. Using 85% power, a one-side 10% significance level, and based on a chi-square test of a single proportion, it was determined that a total of 31 patients would be necessary to adequately evaluate the study objectives. However, given the opening of a competing GOG trial, the trial was terminated after 15 patients were enrolled. Secondary end points of the study were response rate, treatment-related toxicity, overall survival, and to determine the relationship of VEGF serum and tissue levels with outcome. Serial VEGF assays obtained on patients were summarized by median and quartile. VEGF levels were quantified by Quest Diagnostics. The first VEGF for each patient was used. A comparison between the responsive and non-responsive patients was performed by a Mann–Whitney test.
4 1 0 2
Median PFS: 18 months 0
6
12
18
24
8 8
5 11
Months From Start of Chemotherapy N At Risk N Events
15 0
15 1
11 5
Fig. 1. Progression free survival estimates.
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able to complete all of their intended maintenance bevacizumab. One patient who achieved a complete response to chemotherapy with bevacizumab did not receive maintenance therapy with bevacizumab because of the development of a non-healing skin ulcer. Five complete responses and 6 partial responses were seen for a total response rate of 73% (95% CI: 45–91) among the 15 evaluable patients. The median duration of response was 20 months (range 13–46+ months) for complete responders and 10–22 months (range 9–35 months) for partial responders. Adverse effects A total of 127 courses (median 8, range 1–20) of carboplatin, paclitaxel, and bevacizumab combination therapy were administered. One patient suffered a bowel perforation after her first course of therapy and subsequently received only carboplatin and paclitaxel. No other GI perforations or fistulas occurred. One patient who developed a hypersensitivity to carboplatin after 12 cycles went on to receive 36 additional cycles of paclitaxel and bevacizumab. One patient had paclitaxel substituted with abraxane for a severe hypersensitivity to paclitaxel. Neulasta was added to one patient after cycle 4 for a 2 week delay for neutropenia. Subsequent therapy and survival Three patients who progressed were retreated with paclitaxel and carboplatin with one complete response. Doxorubicin was subsequently administered in 7 patients as second (n = 4), fourth (n = 2) or fifth (n = 1) line therapy with no objective responses. The median overall survival was 58 months (95% CI: 48–68) (Fig. 2). VEGF assays A total of 46 VEGF assays were obtained on 11 patients. The median VEGF value was 57 (range 31–318). Only 46 of 615 planned VEGF assays (7.4%) were drawn. VEGF assays were obtained from 3 responding patients, 2 patients with stable disease and 1 with progressive disease. No trend in VEGF level was noted between responding vs nonresponding patients in this small sample size (p = 0.58).
0.6 0.4 0.0
0.2
Probability of Survival
0.8
1.0
Survival Estimates
Median Survival: 58 months 0
12
24
36
48
60
5 5
2 6
Months From Start of Chemotherapy N At Risk N Events
14 0
13 2
11 3
7 5
Fig. 2. Survival estimates.
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Discussion The incidence of both type I and type II carcinomas is increasing proportionally likely due to the increased incidence of obesity and increased longevity of the population, respectively [13]. Death rates for endometrial cancer have increased over 100% in the last 2 decades [14]. For patients with recurrent or advanced disease systemic chemotherapy with paclitaxel, cisplatin and doxorubicin (TAP) is effective with a 57% response rate [3]. However, this regimen is associated with significant toxicity, only a 10% cure rate, a median progression free survival of only 8.3 months, and a median survival of only 15.3 months. As noted previously, GOG 209 compared TAP to carboplatin and paclitaxel in patients with both measurable and non-measurable advanced stage disease. On interim analysis, the median progression free survival was 14 months for both regimens with a HR = 1.03. The median overall survival was 38 and 32 months for TAP and carboplatin and paclitaxel, respectively with HR = 1.01. The authors concluded that carboplatin and paclitaxel are non-inferior and associated with less toxicity compared to TAP in a similar patient population [7]. However, it is important to note that the progression free and overall survival is significantly longer by approximately 100% in GOG 209 when non-measurable disease patients are included in the study compared to GOG 177 which only included measurable disease patients. The authors further concluded that carboplatin and paclitaxel is an acceptable backbone for further trials in combination with “targeted” therapies. Final results and manuscript are however, not yet published. We designed this clinical trial to include endometrial cancer patients with measurable disease, similar to the GOG 177 patient population so the endpoints were comparable. GOG 209 included a heterogenous population of both patients with and without measurable disease making comparison to this trial difficult. In addition, GOG 209 interim analysis had not yet been published upon design of this trial. Angiogenesis has been shown to be a driver of endometrial carcinogenesis [8,9]. During this study, results of GOG 229E were published Table 3 Adverse events* (N = 15). AE category Hematologic Leukopenia Neutropenia Thrombocytopenia Anemia Non-hematologic Allergy/immunology Alopecia Anorexia Cough Depression Diarrhea Dyspnea Epistaxis Fatigue Gastrointestinal Hemorrhage Hoarseness Hypercalcemia Infection Lymphatics Nausea Neurosensory Ocular/visual Pain Rash Rhinitis Tinnitus Vomiting
0
1
2
3
4
5
Total
2 3 6 0
1 1 4 7
5 1 2 7
7 2 2 1
0 8 1 0
0 0 0 0
15 15 15 15
13 5 7 11 13 10 12 14 3 6 14 13 14 13 14 9 9 14 10 12 14 14 12
1 3 3 4 2 3 2 1 8 6 1 2 1 2 1 5 5 1 3 3 1 0 1
0 7 4 0 0 1 1 0 3 1 0 0 0 0 0 1 1 0 1 0 0 1 2
0 0 1 0 0 1 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0
1a 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 1 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15
*The maximum severity of each adverse event per patient, graded according to Common Terminology Criteria for Adverse Events v3.0 (CTCAE). a Hypersensitivity to carboplatin.
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showing single agent activity of bevacizumab in recurrent endometrial cancer [15]. This was a phase II trial of bevacizumab following one or two chemotherapy regimens in 33 (63.5%) and 19 (36.5%) patients, respectively. Twenty-nine of these patients (55.8%) received prior radiation. Among 52 eligible patients, seven patients (13.5%) experienced clinical responses (one complete response and six partial responses; median response duration, 6.0 months), and 21 patients (40.4%) survived progression free for at least 6 months. Adverse events were consistent with those expected of bevacizumab treatment. Additionally, no GI perforations or fistulae were seen (Table 3). The first study comparing the addition of bevacizumab to platinum/taxane chemotherapy vs platinum/taxane chemotherapy alone was in non-small cell lung cancer [12]. The bevacizumab plus chemotherapy group showed a significant increase in progression free survival and overall survival compared to the chemotherapy only treated group. Since our study was designed, the results of GOG 218 became available which compared three arms: chemotherapy alone, chemotherapy with bevacizumab during chemotherapy and chemotherapy with bevacizumab during chemotherapy and as maintenance [16]. This study demonstrated that the addition of bevacizumab during chemotherapy administration and as maintenance therapy improved the progression free survival, but the addition of bevacizumab therapy only during chemotherapy was not more effective than chemotherapy alone. Given that angiogenesis is a driver of endometrial cancer, and the favorable results of bevacizumab in combination with chemotherapy, the purpose of this current study was to determine if the addition of bevacizumab to carboplatin and paclitaxel during chemotherapy and bevacizumab as maintenance therapy could increase progression-free survival for patients with recurrent or advanced stage endometrial cancer. The primary end point of this study was to determine the six-month progression-free survival. The six-month progression-free survival of 93% (95% CI: 82–100) compares favorably to the 59% reported in GOG 177 for TAP. The response rate in this trial of 73% (95% CI: 45–91) compares favorably to the 57% response rate reported in GOG 177 for TAP and 50% response rate for carboplatin and paclitaxel in GOG 209 (D. Miller, GOG 209 Metastatic Cancer Update from SGO 2013, March 13, 2013; www.oncologytube.com). The median overall survival of 58 months (95% CI: 48–68) compares favorably to 15.3 months reported in GOG 177 for TAP and 32 months for carboplatin and paclitaxel in GOG 209. The current study demonstrates that the combination of bevacizumab, carboplatin and paclitaxel was well tolerated in advanced/recurrent endometrial cancer (Table 4). While this might be an expected finding based on our experience with ovarian cancer, 36% of this patient population had received prior radiation therapy. This trial was closed before its planned accrual was reached due to the opening of GOG 86P. Based on the results of large clinical trials, the use of adjuvant chemotherapy has become common practice in advanced and high risk endometrial cancer. In advanced stage disease, GOG 122 demonstrated that chemotherapy was superior to whole abdominal radiation therapy in optimal residual stage III and IV disease [17]. Even in early stage disease, chemotherapy is being used more frequently. Portec I demonstrated a 29% rate of extra-pelvic failure following pelvic radiation therapy for poorly differentiated endometrial carcinoma [18]. Hogberg et al. demonstrated that radiation with chemotherapy was superior to pelvic radiation alone in high risk early stage disease [19]. Retrospective data support the use of chemotherapy in uterine papillary
Table 4 Response to taxol/carboplatin/bevacizumab. Response
Number
Percent of patients
Complete response Partial response Stable Progression
5 6 3 1
33 40 20 7
serous carcinoma [20]. Additionally, chemotherapy is being utilized in cases with vascular lymphatic invasion [21]. Collectively, this results in a diminution of patients with chemotherapy-naive recurrent endometrial cancer. This issue was addressed during the design of the trial but to be comparable to GOG 177, we only enrolled patients with measurable disease and no prior chemotherapy. However, in our trial the planned accrual was never reached and as a consequence the results obtained in this study have wide confidence intervals and lack power. There are a limited number of active chemotherapy or biologic agents in endometrial cancer. Therefore, optimizing first-line therapy in advanced and recurrent endometrial carcinoma is a logical treatment strategy. Unfortunately, second-line chemotherapy options for recurrent endometrial carcinoma are extremely limited. Planned retreatment with paclitaxel and carboplatin was incorporated in the design of this trial based on the results from Hoskins et al. with response rates of 45% [22]. While only a small number of patients were treated with this regimen, a complete response was noted. None of the patients who subsequently received doxorubicin responded. This lack of significant activity with doxorubicin following prior exposure to taxane and platinum therapy has been demonstrated in a prospective Italian trial in which there were no objective responses [23]. To date the mechanism of this cross-resistance is unexplained. Serial VEGF assays were obtained in this study. Previous studies have demonstrated inconsistent results between VEGF assays and clinical outcome [24]. Biomarkers to predict patient response to antiangiogenesis drugs are lacking. No association between VEGF levels and clinical response was noted in our study but the patient sample was very small and not collected uniformly across all participating centers. Furthermore, scarcity of data in the responsive group renders conclusions from these comparisons unreliable. There are a number of limitations to this study. First based on the truncated sample size of 14 patients, the expected power from this sample is only 44%. Secondly, the study design was non-randomized which limits comparative conclusions. Additionally, the optimal use of bevacizumab either concurrently with chemotherapy or as maintenance or the combination has not been evaluated in endometrial cancer. The optimal duration of bevacizumab maintenance has not been established. Lastly, the biologic correlates to identify which patients are most likely to benefit for chemotherapy with bevacizumab have not been demonstrated. The availability of VEGF levels for evaluation as a biomarker is also a limitation of this study. In conclusion, the current study demonstrates that the combination of bevacizumab, paclitaxel, and carboplatin is active and tolerable in advanced and recurrent endometrial carcinoma. Its impact awaits results of the recently completed randomized phase II trial Gynecologic Oncology Group trial (GOG 86 P) comparing this combination to other chemotherapy and biologic combinations. Hopefully GOG 86 P will provide important information regarding future direction in the treatment of advanced and recurrent endometrial carcinoma. We hope the authors of GOG 86P will address response rates between patient subgroups with measurable vs non-measurable disease. Conflict of interest statement The authors of this manuscript, Fiona Simpkins, Richard Drake, Pedro F. Escobar, Benjamin Nutter, Nabila Rasool, and Peter G. Rose, have no conflicts of interest to disclose.
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