- Email: [email protected]
Effects of bevacizumab and pegylated liposomal doxorubicin for the patients with recurrent or refractory ovarian cancers
Gynecologic Oncology 122 (2011) 233–237
Contents lists available at ScienceDirect
Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y g y n o
Effects of bevacizumab and pegylated liposomal doxorubicin for the patients with recurrent or refractory ovarian cancers Kazuya Kudoh a, b, 1, Masashi Takano a, c,⁎, 1, Hiroko Kouta a, Ryoko Kikuchi d, Tsunekazu Kita a, e, Morikazu Miyamoto c, Akio Watanabe c, Masafumi Kato c, Tomoko Goto c, Yoshihiro Kikuchi a a
Department of Gynecology, Ohki Memorial Kikuchi Cancer Clinic for Women, Tokorozawa, Saitama, Japan Department of Obstetrics and Gynecology, Nishisaitama-Chuo National Hospital, Tokorozawa, Saitama, Japan Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa, Saitama, Japan d Department of Basic Pathology, National Defense Medical College, Tokorozawa, Saitama, Japan e Department of Obstetrics and Gynecology, Nara Prefectural Nara Hospital, Nara, Nara, Japan b c
a r t i c l e
i n f o
Article history: Received 4 February 2011 Accepted 29 April 2011 Available online 23 May 2011 Keywords: Ovarian cancer Refractory Recurrent Bevacizumab Pegylated liposomal doxorubicin
a b s t r a c t Objectives. Currently, pegylated liposomal doxorubicin (PLD) is regarded as one of the standard treatment options in recurrent ovarian cancers (ROC). Bevacizumab has shown significant antitumor activity for ROC in single-agent or in combination with cytotoxic agents. We have conducted a preliminary study to investigate effects of combination of bevacizumab and PLD for heavily pretreated patients with ROC. Methods. Thirty patients with ROC were treated with combination therapy with weekly bevacizumab and PLD, 2 mg/kg of continuous weekly bevacizumab and 10 mg/m 2 of PLD (3 weeks on, 1 week off). The treatment was continued until development of disease progression, or unmanageable adverse effects. Response evaluation was based upon Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and Gynecologic Cancer Intergroup (GCIG) CA125 response criteria. Adverse effects were analyzed according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Results. Overall response rate was 33%, and clinical benefit rate (CR + PD + SD) was 73%. Median progression-free survival was 6 months (range: 2–20 months), and a 6-months progression-free survival was 47%. Any hematological toxicities more than grade 3 were not observed. Two cases developed nonhematologic toxicities more than grade 2; a case with grade 3 hand-foot syndrome, another with grade 3 gastrointestinal perforation (GIP). The case with GIP was conservatively treated and recovered after 2 months, and there was no case with treatment-related death. Conclusion. The present investigation suggested that combination therapy with bevacizumab and PLD was active and well tolerated for patients with ROC. We recommend the regimen be evaluated in further clinical studies. © 2011 Elsevier Inc. All rights reserved.
Introduction Ovarian cancer is the second most common gynecologic malignancy, but the most lethal gynecologic malignant tumor in the developed countries [1,2]. Combination chemotherapy with paclitaxel and platinum, recognized as ‘Gold standard’ regimen for ovarian cancer, has significantly improved the survival of the patients with advanced ovarian cancers [3,4]. More than half of the cases, however, will recur despite the treatment with maximal cytoreductive surgery followed by the chemotherapy [5]. For the treatment of platinumresistant or platinum-refractory ovarian cancers, non-platinum agents such as pegylated liposomal doxorubicin (PLD) and gemcitabine are
⁎ Corresponding author. Fax: + 81 4 2996 5213. E-mail address: [email protected] (M. Takano). 1 K. Kudoh and M. Takano contributed equally to this paper. 0090-8258/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2011.04.046
recommended as single-agent mono-therapy. However, these agents have limited effects for the patients with recurrent or refractory ovarian cancers, and new therapeutic agents including moleculartargeting agents are under investigation. Recently, bevacizumab, a humanized recombinant antibody binding to vascular endothelial growth factor (VEGF), has been recognized to harbor significant activity in recurrent or refractory epithelial ovarian cancers [6–9]. Additive effects of bevacizumab, in combination with paclitaxel and platinum, were also confirmed as the first-line chemotherapy for ovarian, tubal, and peritoneal cancers [10,11]. A report of combination with PLD and bevacizumab showed that standard dose of PLD (45 mg/m 2/4 weeks) and bevacizumab (5 mg/m 2/2 weeks) induced severe toxicities. But decreased dose of PLD (22.5 mg/m 2/2 weeks) significantly decreased toxicities [12]. So we attempted a weekly lowdose regimen for patients with recurrent or refractory ovarian cancers: PLD at a dose of 10 mg/m 2/week and bevacizumab at 2 mg/kg/m 2/week.
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Table 1 Patients characteristics (n = 30). Variables
Number (%)
Age, years Median FIGO stage I–II III IV Residual tumor at initial surgery Optimal Suboptimal Histological subtype Serous Clear cell Endometrioid Others Previous chemotherapy 1 regimen 2 regimen 3 regimen 4 regimen or more Previous chemotherapy with pegylated liposomal doxorubicin Yes No Previous chemotherapy with bevacizumab Yes No Previous radiotherapy Yes No Platinum-sensitivitya Platinum-sensitive Platinum-resistant a
55 (range: 34–69) 7 (23) 20 (67) 3 (10) 18 (60) 12 (40) 13 7 5 5
(43) (23) (17) (17)
3 6 10 11
(10) (20) (33) (37)
2 ( 7) 28 (93) 2 ( 7) 28 (93) 4 (13) 26 (87) 1 (3) 29 (97)
Platinum-sensitivity was evaluated by most recent platinum-based chemotherapy.
ment of disease progression or unmanageable adverse effects. Bevacizumab is not approved by Japanese Ministry of Health, Labour and Welfare for the treatment of ovarian cancers. So, the patients paid all the cost including drugs by themselves. The primary endpoint was response rate, and the second endpoints were progression-free survival and toxicities. Response evaluation was based upon Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. In the absence of measurable disease, CA125 level was used to evaluate response by Gynecologic Cancer Intergroup (GCIG) CA125 response criteria [13]. Complete response (CR) was defined as the disappearance of all target and non-target lesions, no evidence of new lesions and normalization of CA125. Partial response (PR) was defined as a 30% or greater reduction in the sum of the longest dimensions of all target lesions and no progression of non-target lesions, or N50% reduction of CA125 levels, lasting at least 4 weeks. Progressive disease (PD) was defined as a 20% or greater increase in the sum of the longest dimensions of target lesions, or the appearance of new lesions, or a doubling of CA125 levels within 8 weeks from the start of chemotherapy. Stable disease (SD) was defined as any condition which did not meet the above criteria. Clinical benefit rate (CBR) was estimated by the rate of the patients with CR, PR and SD. Adverse effects were analyzed according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. The time to progression was defined as the interval from the first date of the treatment with bevacizumab and PLD until the date of tumor progression or death due to any cause. Kaplan–Meier method was used for calculation of patient survival distribution. Six-month progression-free survival was estimated based on the Kaplan–Meier method. The chi-square test and Student t test for unpaired data were used for statistical analysis. A P value of b0.05 was considered statistically significant. The Stat View software ver.5.0 (SAS Institution Inc., Cary, NC, USA) was used to analyze the data.
Patients and methods
Results
During the period from 2006 until 2009, thirty patients with recurrent or refractory ovarian cancers were treated with bevacizumab and pegylated liposomal doxorubicin (PLD), weekly continuous administration of bevacizumab at a dose of 2 mg/kg and PLD at 10 mg/m 2 (3 weeks on, and 1 week off). Inclusion criteria of the patients were as follows: (1) patients whose tumor specimens were histologically confirmed as epithelial ovarian cancers; (2) patients who received one or more regimens of systemic chemotherapy as postoperative chemotherapy; (3) patients who were diagnosed to have recurrent or refractory tumor at the beginning of the present chemotherapy; (4) patients who received at least two cycles of chemotherapy with PLD and bevacizumab; (5) patients whose clinical information was assessable. Platinum-resistant disease was defined as progression during or within 6 months after completion of most recent platinumbased chemotherapy. The administration of weekly bevacizumab–PLD for recurrent ovarian carcinomas was reviewed and approved by institutional review board (IRB) of Ohki memorial Kikuchi cancer clinic for women. After receiving written informed consent from each patient, the therapy was initiated. The treatment was continued until develop-
Thirty patients with pretreated recurrent or refractory ovarian cancer (ROC) patients were enrolled in this exploratory study. The characteristics of the patients were summarized in Table 1. Median age of the cases was 55 years, ranging from 34 to 69. Seven patients (23%) with clear cell carcinoma and five cases with endometrioid histology were included. Twenty one patients (70%) had received three or more regimens of chemotherapy. Treatment-free interval from previous chemotherapy was less than three months in 24 (80%) cases, 3–6 months in 5 (17%) cases, and more than 6 months in only 1 (3%) patient. The patients included a case of platinum-sensitive disease and 29 cases of platinumresistant tumors. Four patients (13%) had received irradiation therapy for recurrent disease. Two cases (7%) received previous PLD regimen, and another two cases (7%) were treated with bevacizumab-containing chemotherapy. Response evaluation to weekly therapy with bevacizumab and PLD was shown in Table 2. The overall response rate was 33%. Complete response was observed in 7% and a partial response was noted in 27%. Overall CBR was 73% in all the patients. Response according to RECIST criteria was assessable in 25 cases with measurable disease, and 2 (8%)
Table 2 Response evaluation to weekly bevacizumab and pegylated liposomal doxorubicin according to Response Evaluation Criteria in Solid Tumors (RECIST). Response category
CR PR SD PD Response rate CBRa a
All patients (n = 30)
Histological subtype Serous (n = 13)
Clear cell (n = 7)
Endometrioid (n = 5)
Others (n = 5)
Sensitive (n = 1)
Resistant (n = 29)
2 (7%) 8 (27%) 12 (40%) 8 (27%) 33% 73%
1 (8%) 5 (38%) 4 (31%) 3 (23%) 46% 77%
1 (14%) 1 (14%) 3 (43%) 2 (29%) 29% 71%
0 (0%) 1 (20%) 2 (40%) 2 (40%) 20% 60%
0 (0%) 1 (20%) 3 (60%) 1 (20%) 20% 80%
0 (0%) 1 (100%) 0 (0%) 0 (0%) 100% 100%
2 (7%) 7 (24%) 12 (41%) 8 (28%) 31% 72%
CBR, Clinical Benefit rate = CR + PR + SD/all patients.
Platinum sensitivity
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Case presentation
Fig. 1. Progression-free survival of recurrent or refractory ovarian cancer patients treated with combination therapy using weekly bevacizumab and pegylated liposomal doxorubicin.
had a CR, 7 (28%) had a PR, and 10 (40%) had an SD. In five patients without measurable disease, a case had a PR, 2 had an SD, and 2 had a PD. Response rate was 46% in serous subtype, and 29% in clear cell subtype and 20% in endometrioid subtype, respectively. Response was observed in 31% of platinum-resistant disease. Partial response was observed in two cases previously treated with PLD. Progression-free survival curve was shown in Fig. 1. Median progression-free survival was 6 months (range: 2–20 months), and a 6-months progression-free survival was 47%. Hematological adverse effects more than grade 2 were not observed in the present study. A case developed grade 3 gastrointestinal perforation and needed hospitalization for conservative treatment. The patient recovered completely after 2 months; however, the patient did not wish to receive further chemotherapy. Although nasal bleeding was frequently observed, no treatment was required. Grade 1/2 induced hypertension was observed in 23% of the patients, however, it was manageable. Hand-foot syndrome was seen in 4 of 30 (13%) patients and treatment with ointment was required in one case (Table 3). In the present study, there were no patients with treatment-associated death. Discontinuation by toxicities occurred in only one patient (3%) that developed grade 3 gastrointestinal perforation.
Table 3 Adverse reactions evaluated by common terminology criteria for adverse events (CTCAE) v3.0 (n = 30). Adverse reaction
G1 (%)
G2 (%)
G3 (%)
G4 (%)
Leukopenia Neutropenia Thrombocytopenia Nausea Constipation Hyper pigmentation Hemorrhage, nose Stomatitis Neuropathy, sensory Vomiting Fatigue Hypertension Mucositis, oral cavity Diarrhea Rash Taste alteration Hand-foot syndrome Pain Gastrointestinal perforation
4 (13) 1 (3) 0 (0) 12 (40) 10 (33) 7 (23) 7 (23) 7 (23) 6 (20) 5 (17) 5 (17) 5 (17) 4 (13) 4 (13) 4 (13) 4 (13) 3 (10) 3 (10) 0 (0)
9 (30) 6 (20) 1 (3) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (7) 2 (7) 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 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (3) 0 (0) 1 (3)
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) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0)
Case 1 is a 47 year old patient with stage IIIc ovarian clear cell carcinoma was referred to our clinic because of refractory pelvic lymph node metastasis (Fig. 2A). Previous treatment using paclitaxel and carboplatin was not effective, and another regimen with irinotecan and cisplatin was also ineffective. After six cycles of weekly bevacizumab– PLD, complete response was achieved by CT images (Fig. 2B–C), and the patient received three more cycles of the therapy. Progression-free survival of the case was 10 months. Case 2: A 50 year old patients with stage IIIc ovarian serous cystadenocarcinoma was referred to our clinic because of refractory and recurrent disseminated disease located on liver surface and pelvic peritoneum (Fig. 3A). The patient underwent primary debulking surgery followed by 6 cycles of combination therapy with docetaxel plus carboplatin (DC) 5 years and 6 months ago. For the treatment of recurrent disease, she received two cycles of DC, however, the tumors increased in size. Subsequently, the patient was enrolled in the present study, and received weekly bevacizumab–PLD. Complete response was observed after 6 cycles of the therapy (Fig. 3B), another 6 cycles was administered with no toxicities more than grade 1. The patient obtained a progression-free survival of 20 months. Discussion For the treatment of platinum-resistant ovarian cancer, salvage chemotherapy with non-platinum agents yielded response rates of approximately 10% to 25% [14,15]. Non-platinum and non-taxane agents that are used for these patients include gemcitabine, pegylated liposomal doxorubicin (PLD), and topotecan. However, there was no significant difference in the efficacy of these drugs for platinumresistant ovarian cancers in large prospective clinical trials [16–18]. As a result, the aim of chemotherapy for these patients is mainly to maintain quality of life or to palliate complaints. PLD is often used among these agents, however, single-agent PLD induced significantly more cases of grade 3/4 hand-foot syndrome and mucositis in comparison with other agents, even when a dose of PLD was decreased at 40 mg/m2 [18]. Bevacizumab, a humanized monoclonal antibody binding to vascular endothelial growth factor (VEGF), showed activity for recurrent or refractory ovarian cancer patients in two phase II studies [8,19]. In a gynecologic oncology group study (GOG-0170), bevacizumab was administered at a dose of 15 mg/kg every 3 weeks to patients with recurrent ovarian cancers [19]. Overall response rate was 21%, however, responders were mainly in platinum-sensitive patients: 2 (6%) of 36 platinum-resistant and 11 (44%) of 25 platinumsensitive population. Another phase II study to evaluate single agent bevacizumab 15 mg/kg every 3 weeks for platinum-resistant recurrent ovarian cancers showed a response rate of 16% and a median progression-free survival of 4.4 months [8]. Although a higher incidence of gastrointestinal perforation (11%) was documented in this trial, all cases with intestinal perforation had platinum-resistant diseases and were heavily pretreated. A phase II study evaluating combination with bevacizumab 10 mg/kg every 2 weeks and oral cyclophosphamide 50 mg daily for recurrent ovarian cancers yielded a response rate of 24%; 12% in platinum-resistant and 33% in platinum-sensitive recurrent cancers [20]. There were three cases with toxicity-related death; one with pulmonary hypertension, another with thrombosis and embolism, and the other with gastrointestinal perforation. Another phase II study for recurrent ovarian cancers using the same regimen with bevacizumab and cyclophosphamide showed response rate of 41% with no event of grade 4 gastrointestinal perforation [21]. A combination with bevacizumab and weekly paclitaxel yielded a response rate of 60% (CR 25% and PR 35%) [22]. Although the trial yielded an extremely high response rate among the studies for platinum-resistant patients, response evaluation was judged by CA125 in 78% of the patients and
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Fig. 2. PET-CT images of metastatic pelvic lymph node in case 1 with platinum-resistant ovarian clear cell carcinoma. A. Image before combination therapy using weekly bevacizumab and pegylated liposomal doxorubicin (PLD) Metastatic tumor was shown by arrow. B. Image after three cycles of bevacizumab–PLD. C. Image after six cycles of bevacizumab–PLD. The patient obtained CR after six cycles of bevacizumab–PLD.
Fig. 3. CT images of liver metastasis in case 2 with platinum-resistant serous ovarian cancer. A. Image before combination therapy using weekly bevacizumab and pegylated liposomal doxorubicin (PLD). Liver metastasis was shown by arrow. B. Image after six cycles of bevacizumab–PLD. The tumor decreased in size, and only calcification was observed. The patient obtained a progression-free survival of 20 months.
by radiographic images in only 22%. Additionally, two cases developed toxicity-related deaths due to bowel perforation. So far, it could be concluded that gold-standard regimen for platinum-resistant ovarian cancers is not determined. Also, it is uncertain which agent is best drug in combination with bevacizumab for recurrent ovarian cancers. The response rates and frequencies of severe toxicities observed in these phase II/III studies were summarized in Table 4. In this cohort, twenty nine cases (97%) of the patients had platinumresistant recurrent ovarian cancers, and twenty one (70%) cases had previously received three or more chemotherapeutic regimens. Overall response rate was 33%, and clinical benefit rate (CR + PR + SD) was 73%. Notably, toxicity profile of weekly bevacizumab–PLD was also feasible, since no case developed grade 4 non-hematologic adverse reaction. A mean risk of gastrointestinal perforation was reported to be 5% (range; 0%–11%) [23]. Several possible risk factors include bowel thickness or rectovaginal nodularity by CT images and number of previous chemotherapy regimens [7,8,24]. In our preliminary series using weekly administration of low dose bevacizumab–PLD, it is presumed that
the treatment protocol could increase area under the curve (AUC) and decrease maximum dose of concentration (Cmax) of both drugs, leading to higher effects and tolerable toxicities. Although this is limited preliminary case series, the present encouraging findings warrant further investigation of the weekly bevacizumab–PLD for platinum-resistant or refractory ovarian cancers. We recommend the regimen be evaluated in prospective studies not only as salvage setting. Conflict of interest statement Kazuya Kudoh, MD, PhD declares no conflicts. Masashi Takano, MD, PhD declares no conflicts. Hiroko Kouta, PhD declares no conflicts. Ryoko Kikuchi, MD, PhD declares no conflicts. Tsunekazu Kita, MD, PhD declares no conflicts. Morikazu Miyamoto, MD declares no conflicts. Akio Watanabe, MD declares no conflicts. Masafumi Kato, MD declares no conflicts. Tomoko Goto, MD, PhD declares no conflicts. Yoshihiro Kikuchi, MD, PhD declares no conflicts.
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Table 4 Phase II/III studies using pegylated liposomal doxorubicine or bevacizumab for recurrent ovarian cancers. Drugs
Number of the patients
Response in platinum-sensitive cases
Response in platinum-resistant cases
Overall response rate
Adverse events, neutropenia (Ngrade 3/4)
Adverse events, PPE (Ngrade 3/4)
Adverse events, GIP (Ngrade 3/4)
PLD (50 mg/m2/4 weeks) [16] PLD (50 mg/m2/4 weeks) [17] PLD (40 mg/m2/4 weeks) [18] Topotecan [16] Gecitabine [17] Gecitabine [18] Bevacizumab (15 mg/kg/3 weeks) [19] Bevacizumab (15 mg/kg/3 weeks) [8] Bevacizumab (10 mg/kg/2 weeks) + oral cyclophosphamide [20] Bevacizumab (10 mg/kg/2 weeks) + oral cyclophosphamide [21] Bevacizumab (10–15 mg/kg/2 weeks) + paclitaxel (60–70 mg/m2,weekly) [22] The present study
239 96 76 235 99 77 62 44 70
31/109 (28%) – –/33 32/111 (29%) – –/34 11/25 (44%) – –/42
16/130 (12%) 8/96 (8%) –/43 8/124 (7%) 6/99 (6%) –/43 2/36 (7%) 7/39 (18%) –/24
47/239 (20%) 8/96 (8%) 11/70 (16%) 40/235 (17%) 6/99 (6%) 18/63 (29%) 13/61 (21%) 7/39 (18%) 17/70 (24%)
12% 19% 7% 81% 38% 23% 0% 0% 1%
23% 10% 6% 1% 0% 0% 0% 0% 0%
0% 0% 0% 0% 0% 0% 0% 11% (5/44) 3%
38
–/8
–/30
15/37(41%)
0%
0%
3%
55
–/1
–/54
60%
5%
0%
5%
30
1/1
9/29 (31%)
10/30 (33%)
0%
3%
3%
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Contents lists available at ScienceDirect
Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y g y n o
Effects of bevacizumab and pegylated liposomal doxorubicin for the patients with recurrent or refractory ovarian cancers Kazuya Kudoh a, b, 1, Masashi Takano a, c,⁎, 1, Hiroko Kouta a, Ryoko Kikuchi d, Tsunekazu Kita a, e, Morikazu Miyamoto c, Akio Watanabe c, Masafumi Kato c, Tomoko Goto c, Yoshihiro Kikuchi a a
Department of Gynecology, Ohki Memorial Kikuchi Cancer Clinic for Women, Tokorozawa, Saitama, Japan Department of Obstetrics and Gynecology, Nishisaitama-Chuo National Hospital, Tokorozawa, Saitama, Japan Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa, Saitama, Japan d Department of Basic Pathology, National Defense Medical College, Tokorozawa, Saitama, Japan e Department of Obstetrics and Gynecology, Nara Prefectural Nara Hospital, Nara, Nara, Japan b c
a r t i c l e
i n f o
Article history: Received 4 February 2011 Accepted 29 April 2011 Available online 23 May 2011 Keywords: Ovarian cancer Refractory Recurrent Bevacizumab Pegylated liposomal doxorubicin
a b s t r a c t Objectives. Currently, pegylated liposomal doxorubicin (PLD) is regarded as one of the standard treatment options in recurrent ovarian cancers (ROC). Bevacizumab has shown significant antitumor activity for ROC in single-agent or in combination with cytotoxic agents. We have conducted a preliminary study to investigate effects of combination of bevacizumab and PLD for heavily pretreated patients with ROC. Methods. Thirty patients with ROC were treated with combination therapy with weekly bevacizumab and PLD, 2 mg/kg of continuous weekly bevacizumab and 10 mg/m 2 of PLD (3 weeks on, 1 week off). The treatment was continued until development of disease progression, or unmanageable adverse effects. Response evaluation was based upon Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and Gynecologic Cancer Intergroup (GCIG) CA125 response criteria. Adverse effects were analyzed according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Results. Overall response rate was 33%, and clinical benefit rate (CR + PD + SD) was 73%. Median progression-free survival was 6 months (range: 2–20 months), and a 6-months progression-free survival was 47%. Any hematological toxicities more than grade 3 were not observed. Two cases developed nonhematologic toxicities more than grade 2; a case with grade 3 hand-foot syndrome, another with grade 3 gastrointestinal perforation (GIP). The case with GIP was conservatively treated and recovered after 2 months, and there was no case with treatment-related death. Conclusion. The present investigation suggested that combination therapy with bevacizumab and PLD was active and well tolerated for patients with ROC. We recommend the regimen be evaluated in further clinical studies. © 2011 Elsevier Inc. All rights reserved.
Introduction Ovarian cancer is the second most common gynecologic malignancy, but the most lethal gynecologic malignant tumor in the developed countries [1,2]. Combination chemotherapy with paclitaxel and platinum, recognized as ‘Gold standard’ regimen for ovarian cancer, has significantly improved the survival of the patients with advanced ovarian cancers [3,4]. More than half of the cases, however, will recur despite the treatment with maximal cytoreductive surgery followed by the chemotherapy [5]. For the treatment of platinumresistant or platinum-refractory ovarian cancers, non-platinum agents such as pegylated liposomal doxorubicin (PLD) and gemcitabine are
⁎ Corresponding author. Fax: + 81 4 2996 5213. E-mail address: [email protected] (M. Takano). 1 K. Kudoh and M. Takano contributed equally to this paper. 0090-8258/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2011.04.046
recommended as single-agent mono-therapy. However, these agents have limited effects for the patients with recurrent or refractory ovarian cancers, and new therapeutic agents including moleculartargeting agents are under investigation. Recently, bevacizumab, a humanized recombinant antibody binding to vascular endothelial growth factor (VEGF), has been recognized to harbor significant activity in recurrent or refractory epithelial ovarian cancers [6–9]. Additive effects of bevacizumab, in combination with paclitaxel and platinum, were also confirmed as the first-line chemotherapy for ovarian, tubal, and peritoneal cancers [10,11]. A report of combination with PLD and bevacizumab showed that standard dose of PLD (45 mg/m 2/4 weeks) and bevacizumab (5 mg/m 2/2 weeks) induced severe toxicities. But decreased dose of PLD (22.5 mg/m 2/2 weeks) significantly decreased toxicities [12]. So we attempted a weekly lowdose regimen for patients with recurrent or refractory ovarian cancers: PLD at a dose of 10 mg/m 2/week and bevacizumab at 2 mg/kg/m 2/week.
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Table 1 Patients characteristics (n = 30). Variables
Number (%)
Age, years Median FIGO stage I–II III IV Residual tumor at initial surgery Optimal Suboptimal Histological subtype Serous Clear cell Endometrioid Others Previous chemotherapy 1 regimen 2 regimen 3 regimen 4 regimen or more Previous chemotherapy with pegylated liposomal doxorubicin Yes No Previous chemotherapy with bevacizumab Yes No Previous radiotherapy Yes No Platinum-sensitivitya Platinum-sensitive Platinum-resistant a
55 (range: 34–69) 7 (23) 20 (67) 3 (10) 18 (60) 12 (40) 13 7 5 5
(43) (23) (17) (17)
3 6 10 11
(10) (20) (33) (37)
2 ( 7) 28 (93) 2 ( 7) 28 (93) 4 (13) 26 (87) 1 (3) 29 (97)
Platinum-sensitivity was evaluated by most recent platinum-based chemotherapy.
ment of disease progression or unmanageable adverse effects. Bevacizumab is not approved by Japanese Ministry of Health, Labour and Welfare for the treatment of ovarian cancers. So, the patients paid all the cost including drugs by themselves. The primary endpoint was response rate, and the second endpoints were progression-free survival and toxicities. Response evaluation was based upon Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. In the absence of measurable disease, CA125 level was used to evaluate response by Gynecologic Cancer Intergroup (GCIG) CA125 response criteria [13]. Complete response (CR) was defined as the disappearance of all target and non-target lesions, no evidence of new lesions and normalization of CA125. Partial response (PR) was defined as a 30% or greater reduction in the sum of the longest dimensions of all target lesions and no progression of non-target lesions, or N50% reduction of CA125 levels, lasting at least 4 weeks. Progressive disease (PD) was defined as a 20% or greater increase in the sum of the longest dimensions of target lesions, or the appearance of new lesions, or a doubling of CA125 levels within 8 weeks from the start of chemotherapy. Stable disease (SD) was defined as any condition which did not meet the above criteria. Clinical benefit rate (CBR) was estimated by the rate of the patients with CR, PR and SD. Adverse effects were analyzed according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. The time to progression was defined as the interval from the first date of the treatment with bevacizumab and PLD until the date of tumor progression or death due to any cause. Kaplan–Meier method was used for calculation of patient survival distribution. Six-month progression-free survival was estimated based on the Kaplan–Meier method. The chi-square test and Student t test for unpaired data were used for statistical analysis. A P value of b0.05 was considered statistically significant. The Stat View software ver.5.0 (SAS Institution Inc., Cary, NC, USA) was used to analyze the data.
Patients and methods
Results
During the period from 2006 until 2009, thirty patients with recurrent or refractory ovarian cancers were treated with bevacizumab and pegylated liposomal doxorubicin (PLD), weekly continuous administration of bevacizumab at a dose of 2 mg/kg and PLD at 10 mg/m 2 (3 weeks on, and 1 week off). Inclusion criteria of the patients were as follows: (1) patients whose tumor specimens were histologically confirmed as epithelial ovarian cancers; (2) patients who received one or more regimens of systemic chemotherapy as postoperative chemotherapy; (3) patients who were diagnosed to have recurrent or refractory tumor at the beginning of the present chemotherapy; (4) patients who received at least two cycles of chemotherapy with PLD and bevacizumab; (5) patients whose clinical information was assessable. Platinum-resistant disease was defined as progression during or within 6 months after completion of most recent platinumbased chemotherapy. The administration of weekly bevacizumab–PLD for recurrent ovarian carcinomas was reviewed and approved by institutional review board (IRB) of Ohki memorial Kikuchi cancer clinic for women. After receiving written informed consent from each patient, the therapy was initiated. The treatment was continued until develop-
Thirty patients with pretreated recurrent or refractory ovarian cancer (ROC) patients were enrolled in this exploratory study. The characteristics of the patients were summarized in Table 1. Median age of the cases was 55 years, ranging from 34 to 69. Seven patients (23%) with clear cell carcinoma and five cases with endometrioid histology were included. Twenty one patients (70%) had received three or more regimens of chemotherapy. Treatment-free interval from previous chemotherapy was less than three months in 24 (80%) cases, 3–6 months in 5 (17%) cases, and more than 6 months in only 1 (3%) patient. The patients included a case of platinum-sensitive disease and 29 cases of platinumresistant tumors. Four patients (13%) had received irradiation therapy for recurrent disease. Two cases (7%) received previous PLD regimen, and another two cases (7%) were treated with bevacizumab-containing chemotherapy. Response evaluation to weekly therapy with bevacizumab and PLD was shown in Table 2. The overall response rate was 33%. Complete response was observed in 7% and a partial response was noted in 27%. Overall CBR was 73% in all the patients. Response according to RECIST criteria was assessable in 25 cases with measurable disease, and 2 (8%)
Table 2 Response evaluation to weekly bevacizumab and pegylated liposomal doxorubicin according to Response Evaluation Criteria in Solid Tumors (RECIST). Response category
CR PR SD PD Response rate CBRa a
All patients (n = 30)
Histological subtype Serous (n = 13)
Clear cell (n = 7)
Endometrioid (n = 5)
Others (n = 5)
Sensitive (n = 1)
Resistant (n = 29)
2 (7%) 8 (27%) 12 (40%) 8 (27%) 33% 73%
1 (8%) 5 (38%) 4 (31%) 3 (23%) 46% 77%
1 (14%) 1 (14%) 3 (43%) 2 (29%) 29% 71%
0 (0%) 1 (20%) 2 (40%) 2 (40%) 20% 60%
0 (0%) 1 (20%) 3 (60%) 1 (20%) 20% 80%
0 (0%) 1 (100%) 0 (0%) 0 (0%) 100% 100%
2 (7%) 7 (24%) 12 (41%) 8 (28%) 31% 72%
CBR, Clinical Benefit rate = CR + PR + SD/all patients.
Platinum sensitivity
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Case presentation
Fig. 1. Progression-free survival of recurrent or refractory ovarian cancer patients treated with combination therapy using weekly bevacizumab and pegylated liposomal doxorubicin.
had a CR, 7 (28%) had a PR, and 10 (40%) had an SD. In five patients without measurable disease, a case had a PR, 2 had an SD, and 2 had a PD. Response rate was 46% in serous subtype, and 29% in clear cell subtype and 20% in endometrioid subtype, respectively. Response was observed in 31% of platinum-resistant disease. Partial response was observed in two cases previously treated with PLD. Progression-free survival curve was shown in Fig. 1. Median progression-free survival was 6 months (range: 2–20 months), and a 6-months progression-free survival was 47%. Hematological adverse effects more than grade 2 were not observed in the present study. A case developed grade 3 gastrointestinal perforation and needed hospitalization for conservative treatment. The patient recovered completely after 2 months; however, the patient did not wish to receive further chemotherapy. Although nasal bleeding was frequently observed, no treatment was required. Grade 1/2 induced hypertension was observed in 23% of the patients, however, it was manageable. Hand-foot syndrome was seen in 4 of 30 (13%) patients and treatment with ointment was required in one case (Table 3). In the present study, there were no patients with treatment-associated death. Discontinuation by toxicities occurred in only one patient (3%) that developed grade 3 gastrointestinal perforation.
Table 3 Adverse reactions evaluated by common terminology criteria for adverse events (CTCAE) v3.0 (n = 30). Adverse reaction
G1 (%)
G2 (%)
G3 (%)
G4 (%)
Leukopenia Neutropenia Thrombocytopenia Nausea Constipation Hyper pigmentation Hemorrhage, nose Stomatitis Neuropathy, sensory Vomiting Fatigue Hypertension Mucositis, oral cavity Diarrhea Rash Taste alteration Hand-foot syndrome Pain Gastrointestinal perforation
4 (13) 1 (3) 0 (0) 12 (40) 10 (33) 7 (23) 7 (23) 7 (23) 6 (20) 5 (17) 5 (17) 5 (17) 4 (13) 4 (13) 4 (13) 4 (13) 3 (10) 3 (10) 0 (0)
9 (30) 6 (20) 1 (3) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (7) 2 (7) 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 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (3) 0 (0) 1 (3)
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) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0)
Case 1 is a 47 year old patient with stage IIIc ovarian clear cell carcinoma was referred to our clinic because of refractory pelvic lymph node metastasis (Fig. 2A). Previous treatment using paclitaxel and carboplatin was not effective, and another regimen with irinotecan and cisplatin was also ineffective. After six cycles of weekly bevacizumab– PLD, complete response was achieved by CT images (Fig. 2B–C), and the patient received three more cycles of the therapy. Progression-free survival of the case was 10 months. Case 2: A 50 year old patients with stage IIIc ovarian serous cystadenocarcinoma was referred to our clinic because of refractory and recurrent disseminated disease located on liver surface and pelvic peritoneum (Fig. 3A). The patient underwent primary debulking surgery followed by 6 cycles of combination therapy with docetaxel plus carboplatin (DC) 5 years and 6 months ago. For the treatment of recurrent disease, she received two cycles of DC, however, the tumors increased in size. Subsequently, the patient was enrolled in the present study, and received weekly bevacizumab–PLD. Complete response was observed after 6 cycles of the therapy (Fig. 3B), another 6 cycles was administered with no toxicities more than grade 1. The patient obtained a progression-free survival of 20 months. Discussion For the treatment of platinum-resistant ovarian cancer, salvage chemotherapy with non-platinum agents yielded response rates of approximately 10% to 25% [14,15]. Non-platinum and non-taxane agents that are used for these patients include gemcitabine, pegylated liposomal doxorubicin (PLD), and topotecan. However, there was no significant difference in the efficacy of these drugs for platinumresistant ovarian cancers in large prospective clinical trials [16–18]. As a result, the aim of chemotherapy for these patients is mainly to maintain quality of life or to palliate complaints. PLD is often used among these agents, however, single-agent PLD induced significantly more cases of grade 3/4 hand-foot syndrome and mucositis in comparison with other agents, even when a dose of PLD was decreased at 40 mg/m2 [18]. Bevacizumab, a humanized monoclonal antibody binding to vascular endothelial growth factor (VEGF), showed activity for recurrent or refractory ovarian cancer patients in two phase II studies [8,19]. In a gynecologic oncology group study (GOG-0170), bevacizumab was administered at a dose of 15 mg/kg every 3 weeks to patients with recurrent ovarian cancers [19]. Overall response rate was 21%, however, responders were mainly in platinum-sensitive patients: 2 (6%) of 36 platinum-resistant and 11 (44%) of 25 platinumsensitive population. Another phase II study to evaluate single agent bevacizumab 15 mg/kg every 3 weeks for platinum-resistant recurrent ovarian cancers showed a response rate of 16% and a median progression-free survival of 4.4 months [8]. Although a higher incidence of gastrointestinal perforation (11%) was documented in this trial, all cases with intestinal perforation had platinum-resistant diseases and were heavily pretreated. A phase II study evaluating combination with bevacizumab 10 mg/kg every 2 weeks and oral cyclophosphamide 50 mg daily for recurrent ovarian cancers yielded a response rate of 24%; 12% in platinum-resistant and 33% in platinum-sensitive recurrent cancers [20]. There were three cases with toxicity-related death; one with pulmonary hypertension, another with thrombosis and embolism, and the other with gastrointestinal perforation. Another phase II study for recurrent ovarian cancers using the same regimen with bevacizumab and cyclophosphamide showed response rate of 41% with no event of grade 4 gastrointestinal perforation [21]. A combination with bevacizumab and weekly paclitaxel yielded a response rate of 60% (CR 25% and PR 35%) [22]. Although the trial yielded an extremely high response rate among the studies for platinum-resistant patients, response evaluation was judged by CA125 in 78% of the patients and
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Fig. 2. PET-CT images of metastatic pelvic lymph node in case 1 with platinum-resistant ovarian clear cell carcinoma. A. Image before combination therapy using weekly bevacizumab and pegylated liposomal doxorubicin (PLD) Metastatic tumor was shown by arrow. B. Image after three cycles of bevacizumab–PLD. C. Image after six cycles of bevacizumab–PLD. The patient obtained CR after six cycles of bevacizumab–PLD.
Fig. 3. CT images of liver metastasis in case 2 with platinum-resistant serous ovarian cancer. A. Image before combination therapy using weekly bevacizumab and pegylated liposomal doxorubicin (PLD). Liver metastasis was shown by arrow. B. Image after six cycles of bevacizumab–PLD. The tumor decreased in size, and only calcification was observed. The patient obtained a progression-free survival of 20 months.
by radiographic images in only 22%. Additionally, two cases developed toxicity-related deaths due to bowel perforation. So far, it could be concluded that gold-standard regimen for platinum-resistant ovarian cancers is not determined. Also, it is uncertain which agent is best drug in combination with bevacizumab for recurrent ovarian cancers. The response rates and frequencies of severe toxicities observed in these phase II/III studies were summarized in Table 4. In this cohort, twenty nine cases (97%) of the patients had platinumresistant recurrent ovarian cancers, and twenty one (70%) cases had previously received three or more chemotherapeutic regimens. Overall response rate was 33%, and clinical benefit rate (CR + PR + SD) was 73%. Notably, toxicity profile of weekly bevacizumab–PLD was also feasible, since no case developed grade 4 non-hematologic adverse reaction. A mean risk of gastrointestinal perforation was reported to be 5% (range; 0%–11%) [23]. Several possible risk factors include bowel thickness or rectovaginal nodularity by CT images and number of previous chemotherapy regimens [7,8,24]. In our preliminary series using weekly administration of low dose bevacizumab–PLD, it is presumed that
the treatment protocol could increase area under the curve (AUC) and decrease maximum dose of concentration (Cmax) of both drugs, leading to higher effects and tolerable toxicities. Although this is limited preliminary case series, the present encouraging findings warrant further investigation of the weekly bevacizumab–PLD for platinum-resistant or refractory ovarian cancers. We recommend the regimen be evaluated in prospective studies not only as salvage setting. Conflict of interest statement Kazuya Kudoh, MD, PhD declares no conflicts. Masashi Takano, MD, PhD declares no conflicts. Hiroko Kouta, PhD declares no conflicts. Ryoko Kikuchi, MD, PhD declares no conflicts. Tsunekazu Kita, MD, PhD declares no conflicts. Morikazu Miyamoto, MD declares no conflicts. Akio Watanabe, MD declares no conflicts. Masafumi Kato, MD declares no conflicts. Tomoko Goto, MD, PhD declares no conflicts. Yoshihiro Kikuchi, MD, PhD declares no conflicts.
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Table 4 Phase II/III studies using pegylated liposomal doxorubicine or bevacizumab for recurrent ovarian cancers. Drugs
Number of the patients
Response in platinum-sensitive cases
Response in platinum-resistant cases
Overall response rate
Adverse events, neutropenia (Ngrade 3/4)
Adverse events, PPE (Ngrade 3/4)
Adverse events, GIP (Ngrade 3/4)
PLD (50 mg/m2/4 weeks) [16] PLD (50 mg/m2/4 weeks) [17] PLD (40 mg/m2/4 weeks) [18] Topotecan [16] Gecitabine [17] Gecitabine [18] Bevacizumab (15 mg/kg/3 weeks) [19] Bevacizumab (15 mg/kg/3 weeks) [8] Bevacizumab (10 mg/kg/2 weeks) + oral cyclophosphamide [20] Bevacizumab (10 mg/kg/2 weeks) + oral cyclophosphamide [21] Bevacizumab (10–15 mg/kg/2 weeks) + paclitaxel (60–70 mg/m2,weekly) [22] The present study
239 96 76 235 99 77 62 44 70
31/109 (28%) – –/33 32/111 (29%) – –/34 11/25 (44%) – –/42
16/130 (12%) 8/96 (8%) –/43 8/124 (7%) 6/99 (6%) –/43 2/36 (7%) 7/39 (18%) –/24
47/239 (20%) 8/96 (8%) 11/70 (16%) 40/235 (17%) 6/99 (6%) 18/63 (29%) 13/61 (21%) 7/39 (18%) 17/70 (24%)
12% 19% 7% 81% 38% 23% 0% 0% 1%
23% 10% 6% 1% 0% 0% 0% 0% 0%
0% 0% 0% 0% 0% 0% 0% 11% (5/44) 3%
38
–/8
–/30
15/37(41%)
0%
0%
3%
55
–/1
–/54
60%
5%
0%
5%
30
1/1
9/29 (31%)
10/30 (33%)
0%
3%
3%
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