Bevacizumab and weekly taxane chemotherapy demonstrates activity in refractory ovarian cancer

Gynecologic Oncology 102 (2006) 134 – 139 www.elsevier.com/locate/ygyno

Bevacizumab and weekly taxane chemotherapy demonstrates activity in refractory ovarian cancer David E. Cohn ⁎, Sue Valmadre, Kimberly E. Resnick, Lynne A. Eaton, Larry J. Copeland, Jeffrey M. Fowler Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, The Ohio State University College of Medicine and Comprehensive Cancer Center, 320 West 10th Avenue, M-210 Starling Loving Hall, Columbus, OH 43210, USA Received 21 October 2005 Available online 9 March 2006

Abstract Objective. To determine the ability of patients to be treated with biweekly bevacizumab and weekly taxane chemotherapy in women with advanced, refractory ovarian cancer. Methods. Ten patients with advanced, recurrent, and refractory ovarian cancer who were treated with biweekly bevacizumab (10 mg/kg) and weekly taxane (paclitaxel or docetaxel) chemotherapy days 1, 8, 15, and 22 every 28 days were identified retrospectively. All patients were followed with serial CA125 measurements prior to each cycle of therapy; cross-sectional imaging was not used to follow response to therapy. Toxicities were assessed prior to each cycle of treatment. Results. Of the 10 patients treated with weekly taxane and biweekly bevacizumab therapy, all 9 that were evaluable had a decrease in CA125. Five patients have had an increase in CA125 after therapy after a median of three cycles (range 1–4), while 3 patients experienced normalization of CA125 and another with continued improvement in CA125. All symptomatic patients experienced rapid palliation of pain, nausea, and ascites. Side effects have been mild, with no grade 3 or 4 toxicities noted. No treatment delays or discontinuations have been necessary. Conclusion. Treatment of advanced, recurrent, refractory epithelial ovarian cancer with bevacizumab and weekly taxane chemotherapy leads to significant, albeit temporary, improvement in the cancer-related symptoms in women treated on this regimen, and short-term exposure to these agents is not associated with significant toxicity. Thus, continued investigation of bevacizumab with weekly scheduling of cytotoxic chemotherapy is imperative. © 2006 Elsevier Inc. All rights reserved. Keywords: Ovarian cancer; Bevacizumab; Taxane; Recurrence; Angiogenesis

Epithelial ovarian cancer is the most lethal gynecologic malignancy in the United States [1] due to the high rate of recurrence and the development of chemotherapy-resistant disease. Although there are a number of chemotherapeutic agents used for recurrent ovarian cancer, response rates are generally reported to be no more than 30% for most drugs and lower in women who become refractory to platinum and platinum analogues generally used for primary therapy of ovarian cancer. Vascular endothelial growth factor (VEGF) is the most potent mediator of angiogenesis and is often overexpressed in ovarian cancers [2]. In February 2004, a

⁎ Corresponding author. Fax: +614 293 3078. E-mail address: [email protected] (D.E. Cohn). 0090-8258/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2006.01.030

humanized murine monoclonal antibody against VEGF (bevacizumab) was FDA-approved for adjuvant therapy in colorectal cancer in combination with 5-fluorouracil [3], and activity has been reported in renal cell carcinoma [4] and lung cancer [5]. A search of Medline through July 2005 using the terms ovarian cancer, VEGF, and bevacizumab revealed only one case report of a woman with recurrent, progressive ovarian cancer who responded to single-agent bevacizumab after failing multiple other therapies [6]. Recently, preliminary results of a phase II study of bevacizumab in women with recurrent or refractory epithelial ovarian cancer demonstrated a 17.7% objective response rate [7]. In the United States, paclitaxel (in combination with carboplatin on an every 21-day cycle) is the standard of care for the primary treatment of ovarian cancer. At doses lower than

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the cytotoxic doses used in the primary treatment for ovarian cancer, paclitaxel has been suggested to demonstrate antiangiogenic (rather than cytotoxic) anti-tumor efficacy [8]. As a single agent, weekly paclitaxel has been demonstrated to have significant efficacy (25% objective response rate) in the treatment of platinum-resistant disease [9]. The ability of weekly paclitaxel to prevent recurrence of early ovarian cancer is currently being tested in a phase III setting [Gynecologic Oncology Group (GOG) trial 175]. Importantly, the combination of paclitaxel and bevacizumab has demonstrated improved survival compared with paclitaxel alone in a phase III randomized trial in patients with metastatic breast cancer [10]. In ovarian cancer, preclinical studies have shown that paclitaxel with an antiVEGF antibody reduces ovarian tumor xenograft burden and ascites volume [11]. Recently, the preclinical concept of anti-VEGF therapy with low-dose chemotherapy was applied to 29 women with recurrent ovarian cancer. In the preliminary results from a study of bevacizumab with lowdose metronomic cyclophosphamide, high rates of response and disease stabilization were reported [12]. Because of the biologic relevance of VEGF in ovarian cancer and the suggestion of anti-angiogenic synergy between paclitaxel and anti-VEGF antibody therapy, we have treated patients with refractory ovarian cancer with weekly taxane chemotherapy and biweekly bevacizumab. Methods Treatment with weekly taxanes and biweekly bevacizumab was not administered as a clinical trial, but rather as palliative therapy for refractory disease after counseling regarding the current state of knowledge regarding bevacizumab and taxanes in recurrent ovarian cancer. Details of the specific doses and schedules are described in the individual case descriptions. Bevacizumab was generally given over 30 min immediately following taxane administration without premedications. Vital signs (including blood pressure) were taken prior to, during, and 15 min following bevacizumab. A urine sample for dipstick analysis was obtained prior to bevacizumab to ensure urine protein less than 2+. CA125 was recorded prior to each 28-day cycle; this value was used to evaluate response to therapy, as is generally done as standard clinical practice in our Division of Gynecologic Oncology. Cross-sectional imaging was performed at the discretion of the attending physician. Symptoms were recorded prior to each cycle. For this study, CA125 responses and relief of cancer-related symptoms were considered to be evidence of clinical benefit of this regimen. No specific criterion for objective responses (such as decrease tumor size by cross-sectional imaging or Rustin criteria for response by CA125) was applied to this population given the retrospective nature of this report.

Cases Patient 1 This 39-year-old underwent an exploratory laparotomy for uterine fibroids and ovarian cysts in 2001. Intraoperatively, masses were noted throughout the pelvis and abdomen; an optimal cytoreduction of a stage IIIB serous carcinoma of the ovary was performed. Initial chemotherapy with 6 cycles of paclitaxel and carboplatin led to a pathologically negative second look laparoscopy at the time of cholecystectomy.

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After a platinum-free interval of 18 months, recurrent disease was noted, and she was treated with 6 cycles of paclitaxel and carboplatinum. Her CA125 rose during therapy, and she was treated with multiple other regimens (Table 1). She was started on weekly paclitaxel (60 mg/m2 days 1, 8, 15, and 22 every 28 days) but continued to require twice weekly paracentesis due to symptomatic recurrent ascites. Bevacizumab (10 mg/kg days 1 and 15 every 28 days) was added to the weekly paclitaxel regimen. Within 2 days of the first cycle of therapy, her ascites diminished, and she had not required any further paracentesis. Her CA125 decreased from 4022 to 1216 after 1 cycle and continued to decrease until cycle 4, at which time it began rising, commensurate with increasingly symptomatic ascites and measurable disease. Treatment was complicated by grade 1 diarrhea. Patient 2 This 66-year-old underwent a suboptimal cytoreduction of a stage IIIC ovarian serous adenocarcinoma in 2002. On Gynecologic Oncology Group (GOG) trial 182, she received carboplatin and topotecan for 4 cycles followed by paclitaxel and carboplatin for 4 cycles. After her initial therapy, she had a radiographic complete response, but her CA125 began rising at the end of treatment. She was then treated with thalidomide on GOG 198 until radiographic disease was documented. She was then treated with a variety of other regimens (Table 1). Recently, when her CA125 was continuing to rise she was started on weekly paclitaxel (60 mg/m2 days 1, 8, 15, and 22) and bevacizumab (10 mg/kg days 8 and 22) every 28 days. Her CA125 decreased from 748 to 65 after the first cycle of treatment and normalized after 2 cycles of therapy. She had no symptoms related to disease prior to initiation of paclitaxel and bevacizumab. To date, her 8 cycles of therapy have been tolerated well without any significant toxicity. Patient 3 In 2001, this 48-year-old woman was diagnosed with stage IIIC serous adenocarcinoma of the peritoneum at the time of optimal cytoreduction. She was then treated with 8 cycles of carboplatin, paclitaxel, and liposomal doxorubicin (every other cycle) on GOG 182. She had a complete clinical response to therapy. After a platinum-free interval of 12 months, she had an elevation of her CA125 and a CT demonstrated carcinomatosis; she was treated with a variety of regimens for her recurrent disease (Table 1). Most recently, she was treated with weekly paclitaxel (70 mg/m2 days 1, 8, 15, and 22 every 28 days), leading to an initial clinical improvement; after 5 cycles, however, she began having an increasing CA125 and worsening symptomatic ascites. Bevacizumab (10 mg/kg days 1 and 15 every 28 days) was added to the paclitaxel. She experienced a decreasing CA125 from 227 to 58 after the first cycle and felt clinical improvement for 2 cycles with decreased abdominal distension and pressure. Her CA125 has continued to decrease

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Table 1 Diagnosis, treatment history, and response to biweekly bevacizumab and weekly taxane chemotherapy in 10 women with recurrent, refractory ovarian cancer Patient

Year of diagnosis

Stage

Best response to platinum– taxane

Platinum-free interval

Subsequent treatment

Disease status prior to bevacizumab

CA125 response to bevacizumab

1

2001

IIIB

Complete

18 months

Carcinomatosis; increasing CA125

Decreased for 4 cycles then increased

2

2002

IIIC

Complete

6 months

6× carboplatin/paclitaxel 5× liposomal doxorubicin 4× gemcitabine/cisplatin 2× topotecan (weekly) 3× paclitaxel (weekly) Thalidomide (GOG 198) 5× gemcitabine/cisplatin 3× liposomal doxorubicin 4× topotecan (weekly)

Paraaortic lymphadenopathy; increasing CA125

3

2001

IIIC

Complete

12 months

Carcinomatosis; increasing CA125

4

1997

IIIB

Complete

18 months

5

2003

IIIC

Complete

3 months

6× gemcitabine/cisplatin 3× topotecan (weekly) 3× paclitaxel (weekly) 6× carboplatin/paclitaxel 3× gemcitabine/cisplatin 6× paclitaxel (weekly) 5× liposomal doxorubicin 7× topotecan (weekly) 3× gemcitabine/carboplatin 3× hexamethylmelamine 10× gemcitabine/cisplatin

Normal at 2 cycles, continues on treatment at 8 cycles Continues to decrease at 3 cycles Decreased for 2 cycles then increased

6

2004

IIIC

Partial

N/A

3× gemcitabine/cisplatin 5× topotecan (weekly)

Carcinomatosis; increasing CA125

7

2002

IIIC

Complete

6 months

Carcinomatosis; increasing CA125

8

2004

IIIC

Partial

2 months

4× liposomal doxorubicin 7× gemcitabine/cisplatin 1× topotecan (weekly) 2× gemcitabine/cisplatin

9

2000

IV

Complete

15 months

8× carboplatin/paclitaxel 3× docetaxel 12× gemcitabine/cisplatin

Carcinomatosis; increasing CA125

10

1997

IIIC

Complete

4 years

6× carboplatin/paclitaxel 1× gemcitabine/cisplatin 3× gemcitabine 15× liposomal doxorubicin 4× topotecan (weekly)

Carcinomatosis; increasing CA125

CA125 response (evaluable patients)

after 3 cycles of this regimen. She experienced grade 1 diarrhea and a grade 1 rash (thought not to be related to therapy). Patient 4 In July of 1997, this 47-year-old woman had a diagnosis of a stage IB1 squamous cell carcinoma. Concurrently, a CT demonstrated septated adnexal masses and omental caking. She underwent radical hysterectomy, lymphadenectomy, and a suboptimal cytoreduction of her stage IIIC serous ovarian cancer and stage IB1 cervical cancer (without intermediate or high risk features). She was treated with paclitaxel and cisplatin

Carcinomatosis; increasing CA125; small intestinal obstruction

Increasing CA125

Carcinomatosis; increasing CA125

Decreased for 3 cycles then increased Decreased for 3 cycles then increased Not evaluated (stopped after 1 cycle) Decreased for 2 cycles then increased Normal at 2 cycles, continues on treatment at 4 cycles Normal at 2 cycles, continues on treatment at 6 cycles 9/9 (100%)

for 6 cycles with a complete clinical response. After a platinumfree interval of 18 months, a colonoscopy showed recurrent ovarian cancer, for which she underwent secondary cytoreduction. She then received 6 cycles of carboplatin and paclitaxel leading to a partial response. For the next 4 years, she received numerous chemotherapy regimens (Table 1) yet continued to have refractory disease. In May 2005, she had progressive disease, a rising CA125, and a small intestinal obstruction. She was then treated with weekly paclitaxel (60 mg/m2 days 1, 8, 15, and 22) and bevacizumab (10 mg/kg days 8 and 22) every 28 days. After her first cycle of therapy, her CA125 had decreased from 1091 to 403. Despite initial symptomatic improvement with decreased abdominal distension and

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pressure, her CA125 began rising to 680 after her second cycle of paclitaxel and bevacizumab. Treatment was complicated by transient grade 2 proteinuria. Patient 5 This 70-year-old woman presented in 2003 with left lower quadrant pain and abdominal distension. Imaging demonstrated a complex ovarian mass; a CA125 was 4630. She underwent optimal cytoreduction of a stage IIIC serous ovarian adenocarcinoma with metastasis to the large intestine and retroperitoneal lymph nodes. She received 8 cycles of paclitaxel, carboplatin, and liposomal doxorubicin (every other cycle) on GOG 182. After a complete clinical response, she had a platinum-free interval of 3 months and was then treated with gemcitabine and cisplatin for 10 cycles (Table 1). When her CA125 began rising, she began treatment with weekly paclitaxel (70 mg/m2 days 1, 8, 15, and 22) and bevacizumab (10 mg/kg days 1 and 15) every 28 days. She experienced a decrease in her CA125 from 444 to 177 after the first cycle and to 44 after 3 cycles of paclitaxel and bevacizumab. There were no symptoms prior to initiation of paclitaxel and bevacizumab. An increasing CA125 after her fourth cycle led to discontinuation of this regimen. Toxicity included transient fever without neutropenia.

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planned treatment on days 8 and 22 every 28 days). When her performance status continued to decline through the first 20 days of her first cycle of paclitaxel and bevacizumab, treatment was discontinued, and the patient is not evaluable for response. She did not experience any significant toxicity related to the paclitaxel and bevacizumab. Patient 8 This 60-year-old was diagnosed with a suboptimally cytoreduced stage IIIC serous adenocarcinoma of the ovary in 2004. She was then treated with 4 cycles of gemcitabine and carboplatin followed by an optimal interval cytoreduction. She then underwent treatment with 3 of a planned 4 cycles of carboplatin and paclitaxel (due to hematologic toxicity), achieving a partial response on GOG 182. When her CA125 plateaued and then began rising, she was started on weekly docetaxel (40 mg/m2 days 1, 8, 15, and 22) and bevacizumab (10 mg/kg days 1 and 15) every 28 days. She had experienced a decrease in her CA125 from 548 to 326 after 1 cycle of therapy. However, her CA125 began rising after her second cycle, and therapy was changed. She had no cancer-related symptoms prior to initiation of docetaxel and bevacizumab. She experienced grade 1 nausea controlled with oral antiemetics while on this regimen.

Patient 6 Patient 9 This 68-year-old presented with ascites, a pelvic mass, an omental cake, and bilateral pleural effusions in 2004. A biopsy of the omental tumor revealed a metastatic serous adenocarcinoma. Due to her poor performance status, she was treated with 6 cycles of neoadjuvant carboplatin and paclitaxel. After a partial response to therapy, she underwent a suboptimal interval cytoreduction due to the volume of her persistent upper abdominal disease. She was then treated with 2 other regimens without a response (Table 1). Due to persistent bulky disease and elevated CA125, she was treated with weekly paclitaxel (50 mg/m2 days 1, 8, 15, and 22) and bevacizumab (10 mg/kg days 1 and 15) every 28 days, leading to symptomatic improvement in abdominal pressure and a slightly decreased CA125. After 3 cycles, her CA125 began rising, symptoms recurred, and therapy was discontinued. She had grade 1 nausea, effectively treated with oral antiemetics. Patient 7 In 2002, this 53-year-old underwent suboptimal cytoreduction for a stage IIIC serous ovarian adenocarcinoma with bulky disease in the small intestinal lymph nodes. She was then treated with 10 cycles of carboplatin and paclitaxel leading to a complete clinical response. After a platinum-free interval of 3 months, her CA125 began rising. Therapy was initiated with a variety of regimens when her disease became measurable (6 months later, Table 1). She was most recently treated with weekly topotecan, but this was discontinued due to worsening functional status. She was then switched to weekly paclitaxel (60 mg/m2 days 1, 8, 15, and 22) and bevacizumab (10 mg/kg,

This 69-year-old experienced upper respiratory complaints in 2000, and a chest radiograph demonstrated a right pleural effusion. A CT scan demonstrated ascites, carcinomatosis, and a pelvic mass; her CA125 was elevated. She underwent an optimal cytoreduction of a stage IV serous ovarian adenocarcinoma and was then treated with 6 cycles of carboplatin and paclitaxel followed by 3 months of paclitaxel. She experienced a complete clinical response and a platinum-free interval of 15 months until recurrent, measurable disease was noted. She was then treated with numerous regimens (Table 1). Due to increasing CA125 and radiographic evidence of carcinomatosis, she was treated with weekly paclitaxel (70 mg/m2 days 1, 8, 15, and 22) and bevacizumab (10 mg/kg days 8 and 22) every 28 days. Her CA125 decreased from 1738 prior to this regimen to 18 prior to her fourth cycle. No cancer-related symptoms were present prior to paclitaxel and bevacizumab. Therapy has been tolerated without significant toxicity. Patient 10 In 1997, this 45-year-old underwent cholecystectomy, at which time omental caking, a pelvic mass, and carcinomatosis were discovered. She underwent optimal cytoreduction followed by 6 cycles of cisplatin and paclitaxel on GOG 158. After a complete response, she was without recurrence for the next 4 years, at which time an elevated CA125 was noted. Radiography was without measurable disease. She was then treated with numerous regimens (Table 1). Recently, carcinomatosis, an elevated CA125, and symptomatic ascites were recognized. She

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was started on weekly paclitaxel (70 mg/m2 days 1, 8, 15, and 22) and bevacizumab (10 mg/kg days 1 and 15) every 28 days. Her slightly elevated CA125 (which is a marker for her disease) of 37 has decreased to 11 prior to her fourth cycle of treatment and continues to be normal after 6 cycles of therapy. Symptomatic ascites has resolved. Therapy has been tolerated without significant toxicity. Discussion We have demonstrated that treatment of advanced, recurrent, refractory epithelial ovarian cancer with bevacizumab and weekly taxane chemotherapy leads to improvement of cancerrelated symptoms and does so without significant toxicity. In this series of 10 patients treated with a regimen of weekly taxanes and biweekly bevacizumab, all evaluable patients experienced a decrease in CA125 within one treatment cycle; furthermore, all symptomatic patients reported palliation of ascites or improvement of gastrointestinal function. Importantly, therapy was well tolerated with no grade 3 toxicities. Interestingly, we did not see any grade 2 or 3 hypertension, as has been reported in most other series investigating bevacizumab. Like most chemotherapy regimens in this heavily pretreated, chemotherapy refractory patient population, however, most patients evaluable for response experienced disease progression after 3 cycles of therapy. Given that all patients in this series have CA125 as a tumor marker, cross-sectional radiography was not used to evaluate objective responses to therapy. Although this fact does not allow us to make the statement that bevacizumab is efficacious in this population, it should not overshadow the ability of this regimen to provide significant, although sometimes transient, improvement in cancer-related symptoms and decreases in CA125. Although weekly paclitaxel alone has demonstrated activity in patients with refractory ovarian cancer [9], we have demonstrated that, in two patients who experienced elevating CA125s while being treated with weekly paclitaxel alone (Patient 1 and Patient 3), the addition of biweekly bevacizumab to the paclitaxel led to a decrease in CA125; this observation suggests that at least some of the response to this combination therapy is related to the bevacizumab and not alone to the weekly taxanes. It is well known that tumor growth depends upon angiogenesis and cancer cells begin to promote this process early in tumorigenesis. Angiogenesis is dependent upon oncogene-driven tumor expression of proangiogenic proteins including VEGF, interleukin-8, basic fibroblast growth factor, TGF-beta, platelet-derived growth factor, and placenta-like growth factor, among others [13]. VEGF is considered to be a central mediator of angiogenesis, and its gene expression is regulated by several mechanisms and in normal physiologic conditions; it is upregulated only after episodes of hypoxia [14]. VEGF in tumor tissues, however, is consistently overexpressed independent of the environmental oxygen tension. The potential of VEGF as a target for cancer therapy was supported by in vitro and in vivo preclinical studies demonstrating that murine antiVEGF antibodies inhibited tumor xenografts in animal models

[15]. In humans, the anti-VEGF monoclonal antibody bevacizumab has been demonstrated with cytotoxic chemotherapy to be effective in the treatment of cancers of the colon [3], kidney [4], lung [5], and breast [10], with a low incidence of significant toxicity. A query of MEDLINE (1966–July 2005 using the terms ovarian cancer, VEGF, and bevacizumab) revealed only one case of a patient with epithelial ovarian cancer being treated with bevacizumab [6]. This patient, like those described in the current investigation, was heavily pretreated and had a platinumresistant, refractory ovarian cancer. She experienced a rapid response to bevacizumab and symptomatic improvement. There have been 2 studies of the use of bevacizumab in women with ovarian cancer recently reported in abstract form [7,12]. In a phase II study by the GOG, bevacizumab 15 mg/kg every 21 days was used as a single agent in the treatment of 62 patients with recurrent or persistent ovarian cancer [7]. An overall response rate of 17.7% (4.8% complete and 12.9% partial) was seen. In this pretreated population, an additional 55% of patients experienced disease stabilization. The median response duration was approximately 10 months, and 24 patients (38.7%) were progression-free at 6 months. Based on these encouraging results, the GOG is developing a phase III trial evaluating the use of bevacizumab along with standard cytotoxic chemotherapy in the front line treatment of advanced ovarian cancer. Another study conducted by the California Cancer Consortium examined the use of bevacizumab (10 mg/kg days 1 and 15) in recurrent ovarian cancer by combining the drug with oral cyclophosphamide (50 mg daily). The goal of this study was to determine whether low-dose metronomic chemotherapy would be an effective anti-angiogenic therapy when combined with bevacizumab. Of the 29 patients enrolled in this study, 28% had an objective response; 62% experienced stabilization of their disease. The most common adverse side effects were pain and hypertension [12]. These data suggest that bevacizumab is an effective treatment for recurrent ovarian cancer and that combination with low-dose metronomic cytotoxic chemotherapy may be synergistic in the treatment of this disease. In this study, we demonstrate that treatment of advanced, recurrent, refractory epithelial ovarian cancer with bevacizumab and weekly taxane chemotherapy leads to a rapid decrease in CA125 and significant palliation of cancer-related symptoms in women treated on this regimen. As such, continued investigation of bevacizumab with weekly scheduling of cytotoxic chemotherapy is imperative. References [1] Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, et al. Cancer Statistics, 2005. CA Cancer J Clin 2005;55:10–30. [2] Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Science 1989;246:1306–9. [3] Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003;21:60–5. [4] Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, et al. A randomized trial of bevacizumab, and anti-vascular endothelial

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