Med Oncol (2014) 31:930 DOI 10.1007/s12032-014-0930-7
ORIGINAL PAPER
A pilot study of combination intraperitoneal recombinant human endostatin and chemotherapy for refractory malignant ascites secondary to ovarian cancer Jing Zhao • Xinxiao Chen • Aimu Zhang Feng Xu • Meilong Hu • Congying Xie • Shengliu Xue
•
Received: 11 February 2014 / Accepted: 14 March 2014 / Published online: 22 March 2014 Ó Springer Science+Business Media New York 2014
Abstract The management of refractory malignant ascites (MA) due to ovarian cancer (OC) remains a difficult clinical problem. A total of 23 eligible patients with refractory MA due to OC were treated with combined intraperitoneal therapy repeated 4 weeks, which consisted of paclitaxel 100 mg m-2 (over 3 h) on day 1, 5-FU 600 mg m-2 on day 1–3 followed by recombinant human endostatin 60 mg on day 4. The objective response rate was 60.9 % (14/23). The median time to progression and overall survival was 5.8 and 12.9 months, respectively. Treatment-related toxicities were uncommon and manageable without therapy-associated deaths. The mean Karnofsky performance status score was significantly improved from 60.0 ± 1.89 at enrollment to 70.0 ± 2.59 at 2 weeks after the first cycle of therapy (P = 0.000). Moreover, the mean score of overall ascites-associated symptoms was also increased significantly from 5.1 ± 0.32 to 4.0 ± 0.20 (P = 0.002). There were remarkable improvements in 7 out of 9 individual ascites-associated symptoms including well being, anxiety, abdominal distention, vomiting, anorexia, fatigue, and dyspnea as well (all P \ 0.05). These results suggest that combination Jing Zhao and Xinxiao Chen have contributed equally to this study, and both should be considered first author. J. Zhao X. Chen A. Zhang F. Xu Department of Obstetrics and Gynecology, Wenzhou Central Hospital, Wenzhou 325002, Zhejiang, People’s Republic of China M. Hu C. Xie S. Xue (&) Department of Radiation Oncology and Chemotherapy, The First Affiliated Hospital of Wenzhou Medical University, 2 Fuxuexiang Road, Wenzhou 325002, Zhejiang, People’s Republic of China e-mail: [email protected]
intraperitoneal recombinant human endostatin and chemotherapy is effective and safe in patients with refractory MA secondary to OC and significantly improves patients’ quality of life with encouraging survival, which might highlight more effective treatment for this challenging disease and merits further investigation. Keywords Combination therapy Recombinant human endostatin Intraperitoneal chemotherapy Ovarian cancer Refractory malignant ascites
Introduction Ovarian cancer (OC) remains the leading cause of death from gynecological cancer and is the fourth most common cause of cancer mortality in women [1]. Although better results have been reported due to the advances both in surgery and chemotherapy for OC, nearly all patients with OC will develop malignant ascites (MA) during or after tumor progression, which is a major source of morbidity and mortality [2]. In these patients, MA is essentially treated through the treatment of the underlying disease; that is, using platinum-based systemic chemotherapy. However, once chemoresistant disease has developed, refractory or intractable ascites can be a difficult problem, which has been a significant challenge in the gynecologic oncology since the past decades [3]. MA can cause series of distressing symptoms such as abdominal distention, abdominal pain, nausea, anorexia, vomiting, fatigue, and dyspnea, thus significantly deteriorates patient’s quality of life (QOL). Current treatment options for MA include fluid restriction, parecentesis, peritoneovenous shunts, and medical treatments. However, all of these approaches have limitations in terms of efficacy and/or tolerability. There
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are no established optimal treatment modalities or widely accepted guidelines for MA so far [2, 4]. Therefore, novel and more effective treatment approaches for this challenging disease are urgently needed in the clinical setting. Recent advances in the research of the pathogenesis of MA have promoted the developments on the treatment for it. Results from many studies addressing the pathogenesis of MA have demonstrated that vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) are the two key factors in the formation of MA and both of them contribute significantly to this process. MMPs contribute to the formation of ascites through the release of VEGF [5, 6]. Thus, both of VEGF and MMPs can serve as therapeutic targets, and targeting VEGF and/or MMPs has provided a new therapeutic approach for the treatment of MA. Encouraging clinical results had been reported with bevacizumab (a monoclonal antibody to VEGF) [5, 7], aflibercept (a VEGF-trap) [8], and batimastat (a MMPs inhibitor) [9]. A novel recombinant human endostatin was approved by the Chinese State Food and Drug Administration in 2005 for the treatment of non-small-cell lung cancer as a broad spectrum targeted angiogenesis inhibitor. Recombinant human endostatin exerts its anti-angiogenic effect via blocking the VEGF-induced tyrosine phosphorylation of KDR/Flk-1(VEGFR-2) as well as the overall VEGFR-2 expression and the activation of ERK, p38 MAPK, and AKT [10, 11]. Additionally, it can inhibit tumor invasion through downregulating the expression of MMP-2 and MMP-9 [11]. Therefore, recombinant human endostatin can target both VEGF and MMPs simultaneously. Given the prominent role of VEGF and MMPs in ascites formation, these data indicate that recombinant human endostatin may have a potential role in the treatment of MA. Mouse model bearing MA showed that intraperitoneal recombinant human endostatin could obviously reduce ascites accumulation, peritoneal capillary permeability, and the count of tumor cells in ascites. The mice received intraperitoneal recombinant human endostatin injection also showed longer survival [12]. Intraperitoneal chemotherapy has been used for the treatment of MA, and recent randomized studies have demonstrated its superiority in terms of survival to intravenous administration as primary treatment of OC [13]. In addition, pre-clinical studies [14] and several clinical trials have shown that the combination of recombinant human endostatin with chemotherapy can enhance anti-tumor effects [15]. Collectively, it would be rational and interesting to establish an additional benefit if intraperitoneal recombinant human endostatin and chemotherapy are used concurrently in the treatment of MA due to OC. Herein, we present the results of a pilot study evaluating the efficacy, safety, and consequent impact on QOL of
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combination intraperitoneal recombinant human endostatin and chemotherapy in patients with refractory MA due to OC.
Materials and methods Patient eligibility All patients enrolled were required to have cytologically confirmed diagnosis of MA caused by pre-treated epithelial OC (relapse or progression during or after treatment) with at least two lines of previous chemotherapy (at least one with platinum based). MA must be measurable on ultrasonographic examination and/or computed tomography (CT) with maximal depth or thickness C3.0 cm. In addition, the interval for previous chemotherapy must be C4 weeks, and patients had recovered from any toxic effects. Additional requirements for eligibility were as follows: age 18–75 years; an Karnofsky performance status (KPS) score C40; predicted survival C3 months; adequate hematological, hepatic, renal, and cardiac functions. Main exclusion criteria included previous treatment with recombinant human endostatin, anti-VEGF treatment, MMPs inhibitors, and paclitaxel within the past 6 months; more than 50 % tumor infiltration of the liver or portal vein obstruction; loculated ascites, concurrent uncontrolled infective ascites, or central nervous system metastasis. All patients provided written informed consent. The present study was approved by the ethical committees of the First Affiliated Hospital of Wenzhou Medical University. Administration and treatment plan Before every intraperitoneal therapy, a single lumen central venous catheter (produced by Arrow Raulerson Syring, USA) was inserted into the peritoneal cavity using the Seldinger technique blindly under local anesthesia based on previous ultrasonographic localization of ascites. After peritoneal catheterization, paracentesis was continued until flow of ascites fluid ended to remove as much of the ascites as possible, during which concurrent intravenous infusions were administered if clinically indicated. Intraperitoneal drug delivery was conducted through the catheter following paracentesis. The combined intraperitoneal therapy consisted of paclitaxel 100 mg m-2 (over 3 h) on day 1, 5-FU 600 mg m-2 on day 1 to day 3 followed by recombinant human endostatin 60 mg on day 4. All patients were pre-medicated with standard anti-emetic and anti-hypersensitivity therapeutics before 5-FU and paclitaxel intraperitoneal delivery. At the beginning of 4-day treatment course, 100 ml 0.9 % normal saline with 10 mg dexamethasone was instilled into the peritoneal cavity daily. Paclitaxel and 5-FU were diluted in 1,000 ml 5 % glucose
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and 500 ml 0.9 % normal saline, respectively, and recombinant human endostatin was diluted in 250 ml 0.9 % normal saline. Patients were asked to change their body position every 30 min for 2 h after the intraperitoneal administration. The fluid was left in the abdominal cavity until the next infusion. The catheter was removed 48 h after the last infusion. The course of treatment was repeated every 4 weeks for up to 4 cycles. If grade 3–4 toxicities occurred, the doses of intraperitoneal therapy (chemotherapy and/or recombinant human endostatin, according to clinical judgment) were decreased by 20 %. Treatment was discontinued if disease progression or intolerable toxicities were confirmed or the patient refused further treatment. Follow-up evaluation Comprehensive baseline assessments, including a complete medical history, KPS score, ascites-associated symptoms, routine blood examination, serum concentration of cancer antigen 125 (CA-125), electrocardiogram (ECG), abdominal ultrasonography and CT, were conducted at the enrollment. During the treatment, patients were checked and assessed weekly by complete blood cell count, blood chemistries, ECG, and toxicity assessment. Abdominal ultrasonography and CT were repeated prior to each cycle of therapy. Patients were followed up monthly for 6 months, then every 2 months till death after treatment. Follow-up examinations consisted of physical examination, complete blood cell count, blood chemistries, serum CA125, ECG, abdominal ultrasonography, and CT. Toxicities were evaluated following the National Cancer Institute Common Toxicity Criteria, version 3.0. Response assessment Response assessment was performed 3 weeks after 2 cycles of therapy or sooner in the event that there were evidences of any clinical deterioration, according to WHO criteria: (1) Complete remission (CR): ascites disappears or less than 100 ml in the peritoneal cavity, persisting for at least 4 weeks. (2) Partial remission (PR): volume of ascites decreases C50 %, persisting for at least 4 weeks. (3) Stable disease (SD): volume of ascites decreases B50 % or increases B25 %. (4) Progressive disease (PD): volume of ascites increases C25 %. The percentage changes in the volume of ascites were based on the percentage changes in the maximum depth of ascites serially measured by abdominal ultrasonography and/or the maximum thickness measured by abdominal CT. CR plus PR was defined as objective response rate. CR plus PR and SD was defined as MA controlled rate.
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QOL assessment Patient’s QOL was assessed with KPS scale (100-point) and patient self-reported ascites-associated symptoms questionnaire (PSRASQ) by investigators and patients themselves at enrollment (pre-treatment) and at 2 weeks after the first cycle of therapy (post-treatment), respectively. The PSRASQ included 9 individual symptom categories: well being, anxiety, abdominal distention, abdominal pain, nausea, vomiting, anorexia, fatigue, and dyspnea on a scale of increasing severity from 0 to 10. Then the mean KPS score, the mean score of overall ascites-associated symptoms, and 9 individual ascitesassociated symptoms, as measured by PSRASQ, were calculated and compared between pre- and post-treatment. Statistical analysis Statistical analysis was performed by SPSS 16.0 software (SPSS, Inc., Chicago, IL, USA). Time to progression (TTP) was defined as time from treatment to PD or death due to any cause. Overall survival (OS) was defined as time from treatment to death due to any cause. TTP and OS were estimated using Kaplan–Meier method. QOL scores were all presented as mean ± standard error. Pre- and posttreatment QOL scores were compared using paired t test, and statistical significance was demonstrated by P \ 0.05.
Results Patients From January 2009 to October 2012, a total of 25 patients were enrolled. Two patients were excluded from all analyses due to major protocol violation. Twenty-three patients were eligible, with a median age of 61 years (range 24–72). Eighteen patients (78.3 %) had a KPS score less than or equal to 60 when they were enrolled. Patients most commonly had serous adenocarcinoma. Most patients had undergone previous debulking surgery. Moreover, all patients were pre-treated with a median of 3 previous lines of chemotherapy, and they all had platinum resistant disease (Table 1). Response According to the response criteria subscribed above, the objective response rate was 60.9 % (14/23), with a CR of 26.1 % (6/23) and a PR of 34.8 % (8/23). SD was observed in 5 patients (21.7 %), and 4 patients (17.4 %) presented PD. The MA controlled rate (CR ? PR ? SD) was 82.6 % (19/23).
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Table 1 Patient characteristics (n = 23) Characteristic
No. of patients (%)
Age (years) Median (range)
61 (24–72)
Time since initial OC diagnosis (years) Median (range)
2.5 (0.9–8.2)
KPS score 40
1 (4.3)
50
6 (26.1)
60
11 (47.8)
70
3 (13.0)
80
2 (8.7)
Histology Serous adenocarcinoma
19 (82.6)
Endometrioid adenocarcinoma
2 (8.7)
Clear cell carcinoma
1 (4.3)
Mixed epithelial tumor
1 (4.3)
Fig. 1 Kaplan–Meier curve for time to progression (TTP). The median TTP was 5.8 months (95 % CI 3.59–7.98)
Histology grade Moderately differentiated Poorly differentiated Unknown Previous debulking surgery
1 (4.3) 21 (91.3) 1 (4.3) 22 (95.7)
Number of lines of previous chemotherapy Median (range)
3 (2–6)
Previous platinum
23 (100.0)
Higher KPS scores indicate better performance status OC ovarian cancer, KPS Karnofsky performance status
Survival With a median follow-up time of 9.9 months (range 5.9–35.2), 6 patients are still alive at the time of survival analysis. The median TTP was 5.8 months [95 % confidence interval (CI) 3.59–7.98] (Fig. 1), and the median OS was 12.9 months (95 % CI 9.25–16.56) (Fig. 2).
Fig. 2 Kaplan–Meier curve for overall survival (OS). The median OS was 12.9 months (95 % CI 9.25–16.56)
Qol Toxicity and tolerability Fifteen patients (65.2 %) received all 4 cycles of therapy, and all patients completed at least 2 cycles. The grade 3–4 toxicities observed included neutropenia (13.0 %), abdominal pain (8.7 %), thrombocytopenia (4.3 %), fatigue (4.3 %), and diarrhea (4.3 %). Three patients discontinued their treatments due to intolerable toxicities after 2 cycles of therapy. Grade 2 tachycardia was observed in 1 patient and was considered to be recombinant human endostatin related. There were no cases of severe recombinant human endostatin-related toxicities or catheterrelated complications. There were no treatment-related deaths (Table 2).
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All patients were evaluable for QOL assessment. The mean KPS score was 60.0 ± 1.89 at enrollment, which was improved significantly to 70.0 ± 2.59 at 2 weeks after the first cycle of therapy (P = 0.000). The mean score of overall ascites-associated symptoms was also improved significantly from 5.1 ± 0.32 to 4.0 ± 0.20 (P = 0.002). Improvements of all 9 individual ascites-associated symptoms were observed, with 7 of them, including well being, anxiety, abdominal distention, vomiting, anorexia, fatigue, and dyspnea had statistical significance (all P \ 0.05). The improvements of other two individual symptoms: abdominal pain and nausea were not statistically significant (both P [ 0.05) (Fig. 3).
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Discussion
Table 2 Treatment-related toxicities (n = 23) Toxicity
Grade 1–2 n (%)
Grade 3–4 n (%)
All n (%)
Hematological Neutropenia
4 (17.4)
3 (13.0)
7 (30.4)
Anemia
2 (8.7)
0
2 (8.7)
Thrombocytopenia
2 (8.7)
1 (4.3)
3 (13.0)
Abdominal pain
4 (17.4)
2 (8.7)
6 (26.1)
Alopecia Myalgia and arthralgia
3 (13.0) 2 (8.7)
0 0
3 (13.0) 2 (8.7)
Peripheral neuropathy
2 (8.7)
0
2 (8.7)
Fatigue
3 (13.0)
1 (4.3)
4 (17.4)
Diarrhea
1 (4.3)
1 (4.3)
2 (8.7)
Non-hematological
Nausea
4 (17.4)
0
4 (17.4)
Vomiting
3 (13.0)
0
3 (13.0)
Abdominal distention
3 (13.0)
0
3 (13.0)
Impaired liver function
2 (8.7)
0
2 (8.7)
Impaired renal function
1 (4.3)
0
1 (4.3)
Tachycardia
1 (4.3)
0
1 (4.3)
Fig. 3 Comparison of ascites-associated symptoms severity between pre-treatment (at enrollment; black and white square bars) and posttreatment (at 2 weeks after the first cycle of therapy; light bars). Each symptom was graded on a scale of increasing severity from 0 (absent) to 10 (worst). Bars represent mean scores of corresponding symptoms, and error bars represent standard errors. Higher scores indicated more severe symptoms. There were statistically significant (indicated by asterisk) improvements in the mean scores of overall ascites-associated symptoms and 7 individual ascites-associated symptoms including well being, anxiety, abdominal distention, vomiting, anorexia, fatigue, and dyspnea (all P \ 0.05 using a paired t test)
Given expected poor prognosis of all patients who had failed at least two lines of previous chemotherapy in the present study, the combination intraperitoneal recombinant human endostatin and chemotherapy showed encouraging clinical activity in these patients. The objective response rate was 60.9 % (14/23), and refractory MA was controlled in 82.6 % (19/23) of patients, which seems to be better than that of intraperitoneal chemotherapy alone [16]. The median OS was 12.9 months, which is much better than that of recurrent MA due to OC treated with catumaxomab alone: 110 days [17]. Furthermore, the mean score of KPS and overall ascites-associated symptoms were both significantly improved from enrollment to 2 weeks after the first cycle of therapy, and remarkable improvements in 7 out of 9 individual ascites-associated symptoms were also observed. Therefore, the encouraging efficacy recorded in the present study indicated that this combined modality might have a role in the treatment of refractory MA secondary to pre-treated OC. The encouraging efficacy of this combination therapy could be probably related in one hand to the advantage of targeting VEGF, MMPs, and cancer cells in the abdominal cavity simultaneously, which provides the rationale for the treatment regimen. The mechanism for the formation of MA is multifactorial and complicated. Currently, tumorinduced cytokines that promote angiogenesis and augment the permeability of microvasculature and cancer cells spread into draining lymph vessels that cause lymphatic obstruction are thought to be the two leading factors involved into the pathogenesis of MA [18]. Increasing findings have confirmed that local VEGF secretion is responsible, in a large part, for initiating and maintaining the ascites pattern of tumor growth. Although the role of MMPs in the mechanism of MA formation is not as clear cut as for VEGF, it contributes significantly to the process also [5]. From a theoretical point of view, the use of a combined modality that targets both tumor-induced cytokines such as VEGF and MMPs and the cancer cells in the peritoneal cavity simultaneously will be more effective than a single mode of treatment modality. In the present study, patients were treated with a combined modality using intraperitoneal recombinant human endostatin and chemotherapy, while the former has the ability to target both VEGF and MMPs, and the latter is capable of eradicating free cancer cells in the peritoneal cavity. Therefore, the advantage of targeting VEGF, MMPs, and the cancer cells in the peritoneal cavity simultaneously could facilitate the acquisition of encouraging efficacy for this combined modality. On the other hand, the promising efficacy of this combined modality could be probably related to the synergistic anti-tumor effect between intraperitoneal
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recombinant human endostatin and chemotherapy. Preclinical researches have shown that the combination of recombinant human endostatin with chemotherapy can enhance anti-tumor and anti-angiogenic effects [14]. Correspondingly, a growing body of clinical dada have demonstrated that the efficacy of recombinant human endostatin combined with chemotherapy is better than that of chemotherapy alone in non-small cell lung cancer [15]. These studies have suggested that there is a synergistic effect between recombinant human endostatin and chemotherapy. Therefore, it is conceivable to hypothesize that recombinant human endostatin combined with chemotherapy used intraperitoneally has synergistic effect in the treatment of MA. Finally, the encouraging efficacy of this combination therapy may be also related to dexamethasone with a total dose of 40 mg instilled into the peritoneal cavity during the treatment, which has synergistic antiangiogenesis and anti-cancer effects in combination with recombinant human endostatin [19] and chemotherapeutic agents [20], respectively. Currently, dexamethasone has been identified as an anti-angiogenesis agent [21]. In a recent study by Li et al. [19], synergistic anti-angiogenesis effects of the combined recombinant human endostatin and dexamethasone were observed. They demonstrated that dexamethasone plus recombinant human endostatin presented more potent efficacy in anti-angiogenesis and tumor growth suppression than the single-drug treatment. However, these explanations aforementioned need to be verified in future confirmatory studies. Patient tolerance in the present study was well, suggesting a favorable toxicity profile for this combined modality. On the whole, adverse effects were uncommon, and they were generally mild to moderate. Although grade 3 or 4 toxicities caused discontinuation of treatment in 3 patients, they were reversible after appropriate management. As noted, all patients in this study had been pretreated; therefore, careful monitoring of toxicities and the use of appropriate supportive care measures were necessary to improve patients’ tolerance. Irrefutably, issues relating to QOL are immensely important to patients with refractory MA and their caregivers. This is especially important in relation to new treatments in refractory MA that do not yet have evidence supporting their contribution to extended survival but may significantly improve the expected QOL deterioration occurring after failure of previous therapies. Patient perspective, as measured by patient-reported outcomes questionnaires, can provide valuable information on the efficacy of an intervention and its possible detrimental effects [22]. In the present study, patients’ QOL was assessed by PSRASQ. Results of the QOL assessment demonstrate that combination intraperitoneal recombinant human endostatin and chemotherapy can significantly improve patients’ QOL
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at 2 weeks following the first cycle of therapy. Palliating ascites-related symptoms as the greatest extent as possible is an extremely important goal of the treatment for refractory MA due to pre-treated OC, which will certainly improve the patient’s QOL and may even prolong survival. With the emerging of novel agents for the management of MA, such as bevacizumab, catumaxomab, aflibercept, and recombinant human endostatin reported by us, patients with refractory MA secondary to pre-treated OC might look at the future with hope and growing optimism in the near future. Besides, the present study has limitations. The first one is its small sample size. Results of this study should be confirmed in prospective randomized controlled trials with larger study population. The second one is that all patients in this study had ascites-associated symptoms such as abdominal pain, fatigue, nausea, vomiting, and abdominal distention, which were the same as treatment-related toxicities. Thus, these ascites-associated symptoms would complicate and affect the accuracy of toxicity assessment to some extent. In conclusion, our results indicate that combination intraperitoneal recombinant human endostatin and chemotherapy is effective and safe in patients with refractory MA due to pre-treated OC and significantly improves patients’ QOL with encouraging survival. The novel approach might highlight the better management of this distressing disease and merits further investigation. Conflict of interest peting interests.
The authors declare that they have no com-
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ORIGINAL PAPER
A pilot study of combination intraperitoneal recombinant human endostatin and chemotherapy for refractory malignant ascites secondary to ovarian cancer Jing Zhao • Xinxiao Chen • Aimu Zhang Feng Xu • Meilong Hu • Congying Xie • Shengliu Xue
•
Received: 11 February 2014 / Accepted: 14 March 2014 / Published online: 22 March 2014 Ó Springer Science+Business Media New York 2014
Abstract The management of refractory malignant ascites (MA) due to ovarian cancer (OC) remains a difficult clinical problem. A total of 23 eligible patients with refractory MA due to OC were treated with combined intraperitoneal therapy repeated 4 weeks, which consisted of paclitaxel 100 mg m-2 (over 3 h) on day 1, 5-FU 600 mg m-2 on day 1–3 followed by recombinant human endostatin 60 mg on day 4. The objective response rate was 60.9 % (14/23). The median time to progression and overall survival was 5.8 and 12.9 months, respectively. Treatment-related toxicities were uncommon and manageable without therapy-associated deaths. The mean Karnofsky performance status score was significantly improved from 60.0 ± 1.89 at enrollment to 70.0 ± 2.59 at 2 weeks after the first cycle of therapy (P = 0.000). Moreover, the mean score of overall ascites-associated symptoms was also increased significantly from 5.1 ± 0.32 to 4.0 ± 0.20 (P = 0.002). There were remarkable improvements in 7 out of 9 individual ascites-associated symptoms including well being, anxiety, abdominal distention, vomiting, anorexia, fatigue, and dyspnea as well (all P \ 0.05). These results suggest that combination Jing Zhao and Xinxiao Chen have contributed equally to this study, and both should be considered first author. J. Zhao X. Chen A. Zhang F. Xu Department of Obstetrics and Gynecology, Wenzhou Central Hospital, Wenzhou 325002, Zhejiang, People’s Republic of China M. Hu C. Xie S. Xue (&) Department of Radiation Oncology and Chemotherapy, The First Affiliated Hospital of Wenzhou Medical University, 2 Fuxuexiang Road, Wenzhou 325002, Zhejiang, People’s Republic of China e-mail: [email protected]
intraperitoneal recombinant human endostatin and chemotherapy is effective and safe in patients with refractory MA secondary to OC and significantly improves patients’ quality of life with encouraging survival, which might highlight more effective treatment for this challenging disease and merits further investigation. Keywords Combination therapy Recombinant human endostatin Intraperitoneal chemotherapy Ovarian cancer Refractory malignant ascites
Introduction Ovarian cancer (OC) remains the leading cause of death from gynecological cancer and is the fourth most common cause of cancer mortality in women [1]. Although better results have been reported due to the advances both in surgery and chemotherapy for OC, nearly all patients with OC will develop malignant ascites (MA) during or after tumor progression, which is a major source of morbidity and mortality [2]. In these patients, MA is essentially treated through the treatment of the underlying disease; that is, using platinum-based systemic chemotherapy. However, once chemoresistant disease has developed, refractory or intractable ascites can be a difficult problem, which has been a significant challenge in the gynecologic oncology since the past decades [3]. MA can cause series of distressing symptoms such as abdominal distention, abdominal pain, nausea, anorexia, vomiting, fatigue, and dyspnea, thus significantly deteriorates patient’s quality of life (QOL). Current treatment options for MA include fluid restriction, parecentesis, peritoneovenous shunts, and medical treatments. However, all of these approaches have limitations in terms of efficacy and/or tolerability. There
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are no established optimal treatment modalities or widely accepted guidelines for MA so far [2, 4]. Therefore, novel and more effective treatment approaches for this challenging disease are urgently needed in the clinical setting. Recent advances in the research of the pathogenesis of MA have promoted the developments on the treatment for it. Results from many studies addressing the pathogenesis of MA have demonstrated that vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) are the two key factors in the formation of MA and both of them contribute significantly to this process. MMPs contribute to the formation of ascites through the release of VEGF [5, 6]. Thus, both of VEGF and MMPs can serve as therapeutic targets, and targeting VEGF and/or MMPs has provided a new therapeutic approach for the treatment of MA. Encouraging clinical results had been reported with bevacizumab (a monoclonal antibody to VEGF) [5, 7], aflibercept (a VEGF-trap) [8], and batimastat (a MMPs inhibitor) [9]. A novel recombinant human endostatin was approved by the Chinese State Food and Drug Administration in 2005 for the treatment of non-small-cell lung cancer as a broad spectrum targeted angiogenesis inhibitor. Recombinant human endostatin exerts its anti-angiogenic effect via blocking the VEGF-induced tyrosine phosphorylation of KDR/Flk-1(VEGFR-2) as well as the overall VEGFR-2 expression and the activation of ERK, p38 MAPK, and AKT [10, 11]. Additionally, it can inhibit tumor invasion through downregulating the expression of MMP-2 and MMP-9 [11]. Therefore, recombinant human endostatin can target both VEGF and MMPs simultaneously. Given the prominent role of VEGF and MMPs in ascites formation, these data indicate that recombinant human endostatin may have a potential role in the treatment of MA. Mouse model bearing MA showed that intraperitoneal recombinant human endostatin could obviously reduce ascites accumulation, peritoneal capillary permeability, and the count of tumor cells in ascites. The mice received intraperitoneal recombinant human endostatin injection also showed longer survival [12]. Intraperitoneal chemotherapy has been used for the treatment of MA, and recent randomized studies have demonstrated its superiority in terms of survival to intravenous administration as primary treatment of OC [13]. In addition, pre-clinical studies [14] and several clinical trials have shown that the combination of recombinant human endostatin with chemotherapy can enhance anti-tumor effects [15]. Collectively, it would be rational and interesting to establish an additional benefit if intraperitoneal recombinant human endostatin and chemotherapy are used concurrently in the treatment of MA due to OC. Herein, we present the results of a pilot study evaluating the efficacy, safety, and consequent impact on QOL of
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combination intraperitoneal recombinant human endostatin and chemotherapy in patients with refractory MA due to OC.
Materials and methods Patient eligibility All patients enrolled were required to have cytologically confirmed diagnosis of MA caused by pre-treated epithelial OC (relapse or progression during or after treatment) with at least two lines of previous chemotherapy (at least one with platinum based). MA must be measurable on ultrasonographic examination and/or computed tomography (CT) with maximal depth or thickness C3.0 cm. In addition, the interval for previous chemotherapy must be C4 weeks, and patients had recovered from any toxic effects. Additional requirements for eligibility were as follows: age 18–75 years; an Karnofsky performance status (KPS) score C40; predicted survival C3 months; adequate hematological, hepatic, renal, and cardiac functions. Main exclusion criteria included previous treatment with recombinant human endostatin, anti-VEGF treatment, MMPs inhibitors, and paclitaxel within the past 6 months; more than 50 % tumor infiltration of the liver or portal vein obstruction; loculated ascites, concurrent uncontrolled infective ascites, or central nervous system metastasis. All patients provided written informed consent. The present study was approved by the ethical committees of the First Affiliated Hospital of Wenzhou Medical University. Administration and treatment plan Before every intraperitoneal therapy, a single lumen central venous catheter (produced by Arrow Raulerson Syring, USA) was inserted into the peritoneal cavity using the Seldinger technique blindly under local anesthesia based on previous ultrasonographic localization of ascites. After peritoneal catheterization, paracentesis was continued until flow of ascites fluid ended to remove as much of the ascites as possible, during which concurrent intravenous infusions were administered if clinically indicated. Intraperitoneal drug delivery was conducted through the catheter following paracentesis. The combined intraperitoneal therapy consisted of paclitaxel 100 mg m-2 (over 3 h) on day 1, 5-FU 600 mg m-2 on day 1 to day 3 followed by recombinant human endostatin 60 mg on day 4. All patients were pre-medicated with standard anti-emetic and anti-hypersensitivity therapeutics before 5-FU and paclitaxel intraperitoneal delivery. At the beginning of 4-day treatment course, 100 ml 0.9 % normal saline with 10 mg dexamethasone was instilled into the peritoneal cavity daily. Paclitaxel and 5-FU were diluted in 1,000 ml 5 % glucose
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and 500 ml 0.9 % normal saline, respectively, and recombinant human endostatin was diluted in 250 ml 0.9 % normal saline. Patients were asked to change their body position every 30 min for 2 h after the intraperitoneal administration. The fluid was left in the abdominal cavity until the next infusion. The catheter was removed 48 h after the last infusion. The course of treatment was repeated every 4 weeks for up to 4 cycles. If grade 3–4 toxicities occurred, the doses of intraperitoneal therapy (chemotherapy and/or recombinant human endostatin, according to clinical judgment) were decreased by 20 %. Treatment was discontinued if disease progression or intolerable toxicities were confirmed or the patient refused further treatment. Follow-up evaluation Comprehensive baseline assessments, including a complete medical history, KPS score, ascites-associated symptoms, routine blood examination, serum concentration of cancer antigen 125 (CA-125), electrocardiogram (ECG), abdominal ultrasonography and CT, were conducted at the enrollment. During the treatment, patients were checked and assessed weekly by complete blood cell count, blood chemistries, ECG, and toxicity assessment. Abdominal ultrasonography and CT were repeated prior to each cycle of therapy. Patients were followed up monthly for 6 months, then every 2 months till death after treatment. Follow-up examinations consisted of physical examination, complete blood cell count, blood chemistries, serum CA125, ECG, abdominal ultrasonography, and CT. Toxicities were evaluated following the National Cancer Institute Common Toxicity Criteria, version 3.0. Response assessment Response assessment was performed 3 weeks after 2 cycles of therapy or sooner in the event that there were evidences of any clinical deterioration, according to WHO criteria: (1) Complete remission (CR): ascites disappears or less than 100 ml in the peritoneal cavity, persisting for at least 4 weeks. (2) Partial remission (PR): volume of ascites decreases C50 %, persisting for at least 4 weeks. (3) Stable disease (SD): volume of ascites decreases B50 % or increases B25 %. (4) Progressive disease (PD): volume of ascites increases C25 %. The percentage changes in the volume of ascites were based on the percentage changes in the maximum depth of ascites serially measured by abdominal ultrasonography and/or the maximum thickness measured by abdominal CT. CR plus PR was defined as objective response rate. CR plus PR and SD was defined as MA controlled rate.
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QOL assessment Patient’s QOL was assessed with KPS scale (100-point) and patient self-reported ascites-associated symptoms questionnaire (PSRASQ) by investigators and patients themselves at enrollment (pre-treatment) and at 2 weeks after the first cycle of therapy (post-treatment), respectively. The PSRASQ included 9 individual symptom categories: well being, anxiety, abdominal distention, abdominal pain, nausea, vomiting, anorexia, fatigue, and dyspnea on a scale of increasing severity from 0 to 10. Then the mean KPS score, the mean score of overall ascites-associated symptoms, and 9 individual ascitesassociated symptoms, as measured by PSRASQ, were calculated and compared between pre- and post-treatment. Statistical analysis Statistical analysis was performed by SPSS 16.0 software (SPSS, Inc., Chicago, IL, USA). Time to progression (TTP) was defined as time from treatment to PD or death due to any cause. Overall survival (OS) was defined as time from treatment to death due to any cause. TTP and OS were estimated using Kaplan–Meier method. QOL scores were all presented as mean ± standard error. Pre- and posttreatment QOL scores were compared using paired t test, and statistical significance was demonstrated by P \ 0.05.
Results Patients From January 2009 to October 2012, a total of 25 patients were enrolled. Two patients were excluded from all analyses due to major protocol violation. Twenty-three patients were eligible, with a median age of 61 years (range 24–72). Eighteen patients (78.3 %) had a KPS score less than or equal to 60 when they were enrolled. Patients most commonly had serous adenocarcinoma. Most patients had undergone previous debulking surgery. Moreover, all patients were pre-treated with a median of 3 previous lines of chemotherapy, and they all had platinum resistant disease (Table 1). Response According to the response criteria subscribed above, the objective response rate was 60.9 % (14/23), with a CR of 26.1 % (6/23) and a PR of 34.8 % (8/23). SD was observed in 5 patients (21.7 %), and 4 patients (17.4 %) presented PD. The MA controlled rate (CR ? PR ? SD) was 82.6 % (19/23).
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Table 1 Patient characteristics (n = 23) Characteristic
No. of patients (%)
Age (years) Median (range)
61 (24–72)
Time since initial OC diagnosis (years) Median (range)
2.5 (0.9–8.2)
KPS score 40
1 (4.3)
50
6 (26.1)
60
11 (47.8)
70
3 (13.0)
80
2 (8.7)
Histology Serous adenocarcinoma
19 (82.6)
Endometrioid adenocarcinoma
2 (8.7)
Clear cell carcinoma
1 (4.3)
Mixed epithelial tumor
1 (4.3)
Fig. 1 Kaplan–Meier curve for time to progression (TTP). The median TTP was 5.8 months (95 % CI 3.59–7.98)
Histology grade Moderately differentiated Poorly differentiated Unknown Previous debulking surgery
1 (4.3) 21 (91.3) 1 (4.3) 22 (95.7)
Number of lines of previous chemotherapy Median (range)
3 (2–6)
Previous platinum
23 (100.0)
Higher KPS scores indicate better performance status OC ovarian cancer, KPS Karnofsky performance status
Survival With a median follow-up time of 9.9 months (range 5.9–35.2), 6 patients are still alive at the time of survival analysis. The median TTP was 5.8 months [95 % confidence interval (CI) 3.59–7.98] (Fig. 1), and the median OS was 12.9 months (95 % CI 9.25–16.56) (Fig. 2).
Fig. 2 Kaplan–Meier curve for overall survival (OS). The median OS was 12.9 months (95 % CI 9.25–16.56)
Qol Toxicity and tolerability Fifteen patients (65.2 %) received all 4 cycles of therapy, and all patients completed at least 2 cycles. The grade 3–4 toxicities observed included neutropenia (13.0 %), abdominal pain (8.7 %), thrombocytopenia (4.3 %), fatigue (4.3 %), and diarrhea (4.3 %). Three patients discontinued their treatments due to intolerable toxicities after 2 cycles of therapy. Grade 2 tachycardia was observed in 1 patient and was considered to be recombinant human endostatin related. There were no cases of severe recombinant human endostatin-related toxicities or catheterrelated complications. There were no treatment-related deaths (Table 2).
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All patients were evaluable for QOL assessment. The mean KPS score was 60.0 ± 1.89 at enrollment, which was improved significantly to 70.0 ± 2.59 at 2 weeks after the first cycle of therapy (P = 0.000). The mean score of overall ascites-associated symptoms was also improved significantly from 5.1 ± 0.32 to 4.0 ± 0.20 (P = 0.002). Improvements of all 9 individual ascites-associated symptoms were observed, with 7 of them, including well being, anxiety, abdominal distention, vomiting, anorexia, fatigue, and dyspnea had statistical significance (all P \ 0.05). The improvements of other two individual symptoms: abdominal pain and nausea were not statistically significant (both P [ 0.05) (Fig. 3).
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Discussion
Table 2 Treatment-related toxicities (n = 23) Toxicity
Grade 1–2 n (%)
Grade 3–4 n (%)
All n (%)
Hematological Neutropenia
4 (17.4)
3 (13.0)
7 (30.4)
Anemia
2 (8.7)
0
2 (8.7)
Thrombocytopenia
2 (8.7)
1 (4.3)
3 (13.0)
Abdominal pain
4 (17.4)
2 (8.7)
6 (26.1)
Alopecia Myalgia and arthralgia
3 (13.0) 2 (8.7)
0 0
3 (13.0) 2 (8.7)
Peripheral neuropathy
2 (8.7)
0
2 (8.7)
Fatigue
3 (13.0)
1 (4.3)
4 (17.4)
Diarrhea
1 (4.3)
1 (4.3)
2 (8.7)
Non-hematological
Nausea
4 (17.4)
0
4 (17.4)
Vomiting
3 (13.0)
0
3 (13.0)
Abdominal distention
3 (13.0)
0
3 (13.0)
Impaired liver function
2 (8.7)
0
2 (8.7)
Impaired renal function
1 (4.3)
0
1 (4.3)
Tachycardia
1 (4.3)
0
1 (4.3)
Fig. 3 Comparison of ascites-associated symptoms severity between pre-treatment (at enrollment; black and white square bars) and posttreatment (at 2 weeks after the first cycle of therapy; light bars). Each symptom was graded on a scale of increasing severity from 0 (absent) to 10 (worst). Bars represent mean scores of corresponding symptoms, and error bars represent standard errors. Higher scores indicated more severe symptoms. There were statistically significant (indicated by asterisk) improvements in the mean scores of overall ascites-associated symptoms and 7 individual ascites-associated symptoms including well being, anxiety, abdominal distention, vomiting, anorexia, fatigue, and dyspnea (all P \ 0.05 using a paired t test)
Given expected poor prognosis of all patients who had failed at least two lines of previous chemotherapy in the present study, the combination intraperitoneal recombinant human endostatin and chemotherapy showed encouraging clinical activity in these patients. The objective response rate was 60.9 % (14/23), and refractory MA was controlled in 82.6 % (19/23) of patients, which seems to be better than that of intraperitoneal chemotherapy alone [16]. The median OS was 12.9 months, which is much better than that of recurrent MA due to OC treated with catumaxomab alone: 110 days [17]. Furthermore, the mean score of KPS and overall ascites-associated symptoms were both significantly improved from enrollment to 2 weeks after the first cycle of therapy, and remarkable improvements in 7 out of 9 individual ascites-associated symptoms were also observed. Therefore, the encouraging efficacy recorded in the present study indicated that this combined modality might have a role in the treatment of refractory MA secondary to pre-treated OC. The encouraging efficacy of this combination therapy could be probably related in one hand to the advantage of targeting VEGF, MMPs, and cancer cells in the abdominal cavity simultaneously, which provides the rationale for the treatment regimen. The mechanism for the formation of MA is multifactorial and complicated. Currently, tumorinduced cytokines that promote angiogenesis and augment the permeability of microvasculature and cancer cells spread into draining lymph vessels that cause lymphatic obstruction are thought to be the two leading factors involved into the pathogenesis of MA [18]. Increasing findings have confirmed that local VEGF secretion is responsible, in a large part, for initiating and maintaining the ascites pattern of tumor growth. Although the role of MMPs in the mechanism of MA formation is not as clear cut as for VEGF, it contributes significantly to the process also [5]. From a theoretical point of view, the use of a combined modality that targets both tumor-induced cytokines such as VEGF and MMPs and the cancer cells in the peritoneal cavity simultaneously will be more effective than a single mode of treatment modality. In the present study, patients were treated with a combined modality using intraperitoneal recombinant human endostatin and chemotherapy, while the former has the ability to target both VEGF and MMPs, and the latter is capable of eradicating free cancer cells in the peritoneal cavity. Therefore, the advantage of targeting VEGF, MMPs, and the cancer cells in the peritoneal cavity simultaneously could facilitate the acquisition of encouraging efficacy for this combined modality. On the other hand, the promising efficacy of this combined modality could be probably related to the synergistic anti-tumor effect between intraperitoneal
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recombinant human endostatin and chemotherapy. Preclinical researches have shown that the combination of recombinant human endostatin with chemotherapy can enhance anti-tumor and anti-angiogenic effects [14]. Correspondingly, a growing body of clinical dada have demonstrated that the efficacy of recombinant human endostatin combined with chemotherapy is better than that of chemotherapy alone in non-small cell lung cancer [15]. These studies have suggested that there is a synergistic effect between recombinant human endostatin and chemotherapy. Therefore, it is conceivable to hypothesize that recombinant human endostatin combined with chemotherapy used intraperitoneally has synergistic effect in the treatment of MA. Finally, the encouraging efficacy of this combination therapy may be also related to dexamethasone with a total dose of 40 mg instilled into the peritoneal cavity during the treatment, which has synergistic antiangiogenesis and anti-cancer effects in combination with recombinant human endostatin [19] and chemotherapeutic agents [20], respectively. Currently, dexamethasone has been identified as an anti-angiogenesis agent [21]. In a recent study by Li et al. [19], synergistic anti-angiogenesis effects of the combined recombinant human endostatin and dexamethasone were observed. They demonstrated that dexamethasone plus recombinant human endostatin presented more potent efficacy in anti-angiogenesis and tumor growth suppression than the single-drug treatment. However, these explanations aforementioned need to be verified in future confirmatory studies. Patient tolerance in the present study was well, suggesting a favorable toxicity profile for this combined modality. On the whole, adverse effects were uncommon, and they were generally mild to moderate. Although grade 3 or 4 toxicities caused discontinuation of treatment in 3 patients, they were reversible after appropriate management. As noted, all patients in this study had been pretreated; therefore, careful monitoring of toxicities and the use of appropriate supportive care measures were necessary to improve patients’ tolerance. Irrefutably, issues relating to QOL are immensely important to patients with refractory MA and their caregivers. This is especially important in relation to new treatments in refractory MA that do not yet have evidence supporting their contribution to extended survival but may significantly improve the expected QOL deterioration occurring after failure of previous therapies. Patient perspective, as measured by patient-reported outcomes questionnaires, can provide valuable information on the efficacy of an intervention and its possible detrimental effects [22]. In the present study, patients’ QOL was assessed by PSRASQ. Results of the QOL assessment demonstrate that combination intraperitoneal recombinant human endostatin and chemotherapy can significantly improve patients’ QOL
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at 2 weeks following the first cycle of therapy. Palliating ascites-related symptoms as the greatest extent as possible is an extremely important goal of the treatment for refractory MA due to pre-treated OC, which will certainly improve the patient’s QOL and may even prolong survival. With the emerging of novel agents for the management of MA, such as bevacizumab, catumaxomab, aflibercept, and recombinant human endostatin reported by us, patients with refractory MA secondary to pre-treated OC might look at the future with hope and growing optimism in the near future. Besides, the present study has limitations. The first one is its small sample size. Results of this study should be confirmed in prospective randomized controlled trials with larger study population. The second one is that all patients in this study had ascites-associated symptoms such as abdominal pain, fatigue, nausea, vomiting, and abdominal distention, which were the same as treatment-related toxicities. Thus, these ascites-associated symptoms would complicate and affect the accuracy of toxicity assessment to some extent. In conclusion, our results indicate that combination intraperitoneal recombinant human endostatin and chemotherapy is effective and safe in patients with refractory MA due to pre-treated OC and significantly improves patients’ QOL with encouraging survival. The novel approach might highlight the better management of this distressing disease and merits further investigation. Conflict of interest peting interests.
The authors declare that they have no com-
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