Invest New Drugs (2010) 28:887–894 DOI 10.1007/s10637-009-9351-4
SHORT REPORT
Complete remission of ovarian cancer induced intractable malignant ascites with intraperitoneal bevacizumab. Immunological observations and a literature review Filippo Bellati & Chiara Napoletano & Ilary Ruscito & Maria Pastore & Milena Pernice & Morena Antonilli & Marianna Nuti & Pierluigi Benedetti Panici
Received: 23 September 2009 / Accepted: 28 October 2009 / Published online: 24 November 2009 # Springer Science + Business Media, LLC 2009
Summary Malignant ascites resistant to conventional drugs frequently affects ovarian cancer patients at the end of life. Here we report the case of a patient who benefited from complete resolution of ascites after low dose intraperitoneal administration of bevacizumab. Immunological analyses showed an initial increase in proportion and function of CD8+ effector T cells and a reduction of circulating Treg cells. A review of the current literature regarding bevacizumab in ovarian cancer is reported. Bevacizumab has shown a high efficacy in the treatment of ovarian cancer. Intraperitoneal administration induces an immune activation and appears promising in the treatment of malignant ascites.
Condensation Intraperitoneal Bevacizumab induces an immune activation and is highly effective in the treatment of refractory malignant ascites in ovarian cancer. Filippo Bellati and Chiara Napoletano have contributed equally to this work. F. Bellati : M. Pastore : M. Pernice : M. Antonilli : P. Benedetti Panici Institute of Gynecology and Obstetrics, Sapienza University, Rome, Italy F. Bellati : C. Napoletano : I. Ruscito : M. Nuti Department of Experimental Medicine, Sapienza University, Rome, Italy F. Bellati (*) Department of Gynecology and Obstetrics, University of Rome Sapienza, viale del Policlinico, Rome 155-00161, Italy e-mail:
[email protected]
Keywords Ascites . Bevacizumab . Intraperitoneal . Lymphocyte . Ovarian Cancer
Introduction Patients affected by platinum refractory ovarian cancer remain the greatest problem faced by Gynecologic Oncologists in developed countries [1]. These women suffer from a dismal prognosis associated with severely impaired quality of life. In their last period of life, malignant ascites resistant to conventional drugs affects 28% of these patients. Symptoms include abdominal swelling (55%), abdominal pain (53%), nausea (37%), anorexia (36%), vomiting (25%), and fatigue (17%) [2, 3]. Several medical strategies can be attempted, but most patients will in any case require repeated paracentesis or permanent drains. Drugs that have been investigated and that are commonly adopted in the treatment of malignant ascites include diuretics, cytokines and cytotoxic agents administered intraperitoneally (ip). Diuretics have demonstrated to achieve high response rates in particular subsets of oncology patients, although their efficacy in women with peritoneal carcinomatosis has been questioned [4]. Intraperitoneal administration of Interferonalpha 2b has been attempted by a series of authors with complete response rates ranging from 10% to 30% [5–7]. This treatment requires frequent repeated administrations [7] and is associated with nausea, dyspepsia, abdominal distension and flu like symptoms. Intraperitoneal chemotherapy has been used for the treatment of malignant ascites and recent randomized studies have demonstrated its superiority in terms of survival to conventional intravenous administration as primary treatment of ovarian cancer [8]. This
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therapeutic strategy yields its best results in patients in whom tumor has shown to be responsive to earlier systemic therapies [9] and nodules have greatest size inferior to 1 cm. Bevacizumab is a dimeric monoclonal antibody directed against Vascular Endothelial Growth Factor (VEGF), currently under evaluation in ovarian cancer by several international gynecologic oncology groups. Intravenous administration has been shown to induce chylous ascites in some patients, although the precise mechanism that justifies this side effect remains unknown [10]. Some authors have reported a high efficacy of intraperitoneal bevacizumab for the treatment of malignant ascites [11, 12]. We report the third case of a platinum refractory ovarian cancer patient, who experienced a complete resolution of malignant ascites, after intraperitoneal administration of bevacizumab. Since recent evidence has demonstrated that the therapeutic effect of oncology treatments can be greatly ascribed to an immune activation [13, 14], we also describe the immunological changes induced by this monoclonal antibody. A review of the literature about the role of bevacizumab in ovarian cancer is presented.
Patient’s history In 2005, after two years of negative follow up, a 55 years old women with a history of stage IIIC serous G3 ovarian cancer came at our institution with CA125 of 234 UI/mL and a CT scan showing a single hepatic recurrence. The patient had been previously treated with primary cytoreduction with no residual disease and adjuvant carboplatin and paclitaxel. She was subjected to a diagnostic laparoscopy which confirmed the superficial hepatic lesion, but showed carcinomatosis not amenable of optimal debulking. Consequently, she was addressed to six cycles of platinum and taxane chemotherapy. At the end of treatment, the patient showed a complete clinical response, but 5 months later CA125 increased again. She underwent six subsequent cycles of III line chemotherapy with doxil, which was successively switched to topotecan for disease progression. After the third cycles of the latter treatment, she started complaining abdominal distension and dyspnea. Trans-abdominal ultrasound showed ascites and different abdomino-pelvic lesions. A paracentesis was carried out removing 5 litres. It was decided to attempt palliative care of ascites with the administration of intraperitoneal cisplatin 75 mg/mq. The patient benefited from a 3-week period without ascites, after which she complained abdominal bloating. Treatment with intraperitoneal cisplatin was repeated after ascites removal for six cycles and additional paracentesis were carried in between cycles on patient’s need. At the end of the sixth cycle, she started complaining weekly severe abdominal bloating, with partial gastrointestinal occlusion and dyspnea, which rapidly improved after peritoneal drainage. Each paracentesis removed between 3 and 5 litres of volume.
Invest New Drugs (2010) 28:887–894 Fig. 1 Lymphocyte subset and IFNγ production analyses. Panel a shows the percentage of CD4 and CD8 effector T cells in ascites and blood reported as CCR7-CD45RA+ cells (at the top) and the cytofluorimetric analysis of CD45RA and CCR7 in CD4 and CD8 T cells (below). Panel b represents the intracellular staining of IFNγ produced by T cells purified from ascites and peripheral blood after the addition of PMA and Ionomycin. Results are reported as percentage of IFNγ. Panel c depicts the percentage of Treg cells isolated from ascites and peripheral blood of at different time points. Treg cells were marked using anti-CD4, anti-CD25 and anti-FOXP3 antibodies
After a careful counselling and patient’s refusal of intraperitoneal indwelling catheter, it was decided to begin treatment with intraperitoneal bevacizumab at 5 mg/kg every three weeks [12]. The patient was subjected to paracentesis with removal of 5 litres of ascites and intraperitoneal infusion of bevacizumab diluted in 250 ml of saline solution. After the first administration, she benefited from a general clinical improvement without any complaint or side effect. Treatment was repeated four times with the patient reporting a highly improved quality of life. Throughout treatment CA125 levels remained high showing a stable disease [15], but she deceased before the fifth administration. The family reported that, for a few days before exitus, the patient had suffered from a progressive loss of appetite and fatigue. The patient’s family informed us that she had died during the night for respiratory failure.
Immunological changes during intraperitoneal bevacizumab In order to evaluate if the beneficial effects of bevacizumab could be partially ascribed to an immune effect, changes in the different lymphocyte subsets were analyzed in peripheral blood and ascite before treatment (time 0) and only in peripheral blood after 21 days before three successive administrations (time 1, time 2 and time 3). Due to the complete remission of the peritoneal effusion, a more accurate analysis of the local effect of bevacizumab was not possible. CD4+ and CD8+ lymphocyte subsets were analyzed by cytofluorimetry for the expression of CD45RA and CCR7 markers. The percentage of CD8 + effector T cells (CD45RA+CCR7-) in peripheral blood and ascites was comparable at time 0. In peripheral blood, the first administration of bevacizumab increased the amount of CD8+ effector cells from 42% (time 0) to 57% (time 1), but this effect did not persist in successive administrations (time 2: 48%, time 3: 34,5%). Different results were obtained in the CD4+ effector T cells. The percentage of CD4+ effector lymphocytes in peripheral blood was 21%, while in ascites was 0,5% at time 0. Drug administrations reduced the amount of CD4+ effector T cells from 21% to 9% at time 3 (Fig. 1a).
Invest New Drugs (2010) 28:887–894
Effector T cells
100
CD8
60
%CCR7-CD45RA+
a
889
CD4
40
20
0
Ascites
Time 0
Time 1
Time 2
Time 3
CD45RA
CD4
CD8
CCR7
b
c
IFN-gamma production 50
1.2
%CD4+CD25+FOXP3+
%IFN-gamma
40
30
20
10
0
Regulatory T cells 1.5
0.9
0.6
0.3
Ascites
Time 0
Time 1
Time 2
Time 3
0
Ascites
Time 0
Time 1
Time 2
Time 3
890
Invest New Drugs (2010) 28:887–894
In order to study the lymphocyte polarization (TH1, TH2, TH17), T cells were stimulated with PMA (25 ng/ml) and Ionomycin (250 ng/ml) in presence of Brefeldin (10 μg/ml) for 16 hours and the release of IFNγ, IL-4 and IL-17 was analyzed by cytofluorimetry. Results showed a prevalence of IFNγ producing cells in both blood and ascites. In particular, the amount of IFNγ in the blood was 28,7% at time 0, while in ascites was 11,3%. The percentage of this cytokine increased after the first dose of bevacizumab (41,5%) and remained stable during the other administrations (time 2: 42%, time 3: 40%) (Fig. 1b). IL-4 was not produced, while IL-17 was present only in ascites (3,3%). Regulatory T cells (Treg) (CD4+CD25+FOXP3+) were also analyzed in blood and ascites. The level of this lymphocyte subset was similar in peripheral blood and ascites at time 0. Bevacizumab decreased the percentage of circulating Treg cells from 1% (time 0) to 0,5% (time 1). This reduction remained stable after each administration (Fig. 1c). Finally, the levels of NK (CD3-CD16+CD56+) and NKT (CD3+CD16+CD56+) cells were analyzed. The amount of
NK and NKT cells in peripheral blood was higher compared to that analyzed in the ascites (NK: blood 18% vs ascites 6,3%; NKT: blood 22% vs ascites 3,1%). The percentage of these two populations did not change during treatment.
Comment Ascites represents a major issue in patients affected by recurrent ovarian cancer. Ascites has an important effect on women’s quality of life [16] and survival [17]. The direct correlation between the presence of ascites and advanced and/or disseminated intraperitoneal disease can partially justify the dismal prognosis observed in these patients, although ascites itself could play a direct role on the history of the disease. Ascites contains elevated concentration of several growth factors and immunosuppressive cytokines, such as VEGF, IL-10 and TNFα [18, 19]. The feeling of mechanical distension and abdominal bloating reduces appetite and can cause partial bowel obstruction. On the
Table 1 Pilot studies on single agent bevacizumab in recurrent ovarian cancer iv single agent bevacizumab in progressive or recurrent ovarian cancer No of patients
Treatment schedule
median n. of cycles
Monk et al. [36] Monk et al. [37]
1 30
Bev 15 mg/m2 q 3 wks Bev 15 mg/m2 q 3 wks
7 6
Bidus et al. [38]
3
Bev 15 mg/m2 q 3 wks
20
Grade III-IV toxicity
Clinical response
Asscites remission
Hypertension 3
PR CR PR SD Prog na CR
Complete nr
none
Numnum et al. [39] Cannistra et al. [28]
4 44
Bev 15 mg/m2 q 3 wks Bev 15 mg/kg q 3 wks
7 5
none 18§ § 3 drug related deaths
Burger et al. [29]
62
Bev 15 mg/kg q 3 wks
7
24
Aroraa et al. [40] 1 Bev 15 mg/m2 q 3 wks ip bevacizumab for ascites palliation in ovarian cancer Hamilton et al. [12] 1 5 mg/kg Current case 1 5 mg/kg q 3 wks
26
none
PR SD PR SD Prog CR PR SD Prog na CR
2 4
none none
nr SD
a
Recurrent faloppian tube neopalsm
CR complete response, na not available, PR partial response, Prog progressive disease, SD stable disease
1 1 4 20 4 1
3% 13% 67% 13% 1
7 27 5 2 11 31 16 2 1
2 4 16% 61% 12% 3% 18% 50% 26%
nr All complete nr
Complete Complete Complete
23
Wright et al. [41]
13
13
70
Azad et al. [34]
Nimeiri et al. [35]
Schultheis et al. [33]
Bev 10 mg/kg q 1 or 2 wks + Cyclo 50 mg/day
Bev 15 mg/kg q 3 wks + Erlotinib 150 mg/day
Bev 5–10 mg/kg q 3 wks + Sorafenib 200 mg twice daily
Bev 15 mg/kg q 3 wks + paclitaxel 80 mg/m2 plq7 Bev 10 mg/kg q 2 wks + Cyclo 50 mg/day
Bev 5 mg/kg q 1 or 2 wks with
Bev 15 mg/m2 q 3 wks + 5FU/leu + Oxal or Bev 15 mg/m2 q 3 wks + Cyclo Bev 10 mg/kg q 2 wks + Taxane 40–70 mg/m2 p1q7
Treatment schedule
Bev 15 mg/kg q 3 wks + paclitaxel 175 mg/m2 + carboplatin (AUC=5) plq21
6 (26%) 1 (4%) 1 (4%)
5FU Gem + Doxil Doce
6
nr
6
4ç
5
8
7
1
na
8 17
Prog na
1 2
PR SD nr
2 hypetension 1 Neurological toxicity
Recurrent fallopian tube neoplasm
10
CR
6
33
SD
4 12
PR
Prog
1 7
PR SD
1
7 CR
SD
9 6
Prog PR
17 44
PR
1
5
10
SD
CR
Prog
SD
8
1
SD PR
8
PR
2
18 neutopenia
nr
2 drug related deaths due to bowel perforation
§
10§
2
83
none
2 drug related deaths due to bowel perforation
§
11§
none
4
Prog
6%
55%
33%
12%
47%
175
3%
54%
7%
7%
54%
46%
13%
63%
24%
22%
44%
35%
11%
89%
Clinical response
study also included patients subjected to bevacizumab single agent followed by the other drugs in combination. These patients have been dscribed in Table 1
20 primary neoplasm
15 (65%)
Cyclo
none
Grade III–IV toxicity
6
Median n. of cycles
nr
nr
nr
nr
nr
Cr
nr
2 Pr
2 Cr
nr
Ascites remission
Bev Bevacizumab, CR complete response, Cyclo Cyclophosphamide, Doce Docetaxel, 5 FU 5-fluorouracil, Gem gemcitabine, Leu lecovorin, na not available, nr not reported, Oxal Oxaliplatine, PR parial response, Prog progressive disease, SD stable disease
b
a
Micha et al. [43]
Combination therapies with bevacizumab in primary ovarian cancer
70
Garcia et al. [32]
1
10
Cohn et al. [31]
Kesterson et al. [42]
2
Monk et al. [37a]
No of patients
Combination therapies with bevacizumab in progressive or recurrent ovarian cancer
Table 2 Pilot studies on combination treatments with bevacizumab in ovarian cancer
Invest New Drugs (2010) 28:887–894 891
892
Invest New Drugs (2010) 28:887–894
other hand, ascites contains high concentrations of nutrient such as proteins [20], fat-soluble vitamins and carotenoids [21], which are lost during paracentesis or permanent drainage thereby contributing to cachexia. Neoplastic ascites contains, in addition to malignant cells, a great variety of immune cells including NK, Cytotoxic T Lymphocytes (CTL) and regulatory T cells, which are selectively recruited in the peritoneal cavity [22]. Intraperitoneal administration of monoclonal antibodies has not yet been thoroughly investigated, but preliminary studies have mostly given promising results. Excluding intraperitoneal radioimmunotherapy [23], some clinical studies have been conducted on trifunctional antibodies. Catumaxomab, a rat/murine hybrid, trifunctional, bispecific antibody (anti-epithelial cell adhesion molecule, antiEpCAM, and anti-CD3) has been adopted for the treatment of ascites. Intraperitoneal catumaxomab has a systemic effect on tumor cells [24] and enhances antitumor immunity [25]. Bevacizumab has given important results in colorectal cancer [26, 27] and is currently under thorough investigation in women affected by ovarian neoplasms. In patients with platinum resistant chemotherapy, who had failed at least two lines of chemotherapy, iv bevacizumab as single agent achieved response rates ranging from 16% to 21% [28, 29]. In an important study in mice models, bevacizumab showed to have a strong synergic effect with cisplatin, possibly due to a re-establishment of sensitivity to platinum agents [30]. Higher response rates were observed in combination regimens with metronomic administration of traditional drugs [31–33] and novel target therapies [34, 35], but frequent severe side effects including bowel perforation, hypertension and fatigue [28, 29] have been reported. The Medical Research Council has recently launched a large phase III trial with the objective of evaluating the possible addition of bevacizumab to standard first line chemotherapy (NCT00483782). A review of available data and ongoing
phase III randomized trials on bevacizumab in ovarian cancer patients are shown in Tables 1, 2 and 3. The primary intention of blocking VEGF is to inhibit tumour vasculogenesis [44, 45] although new mechanism through which this cytokine can favour cancer progression are being found. Recently, it has been shown that VEGF is able to induce a immunosuppressive milieu. It has been demonstrated that VEGF interferes with dendritic cells maturation [46] and can induce and/or maintain Tregs in cancer patients [47, 48]. Intraperitoneal therapy with bevacizumab has been recently suggested as treatment of malignant ascites [11, 12]. El-Shami et al. [11] reported nine patients, one affected by ovarian cancer, in whom ascites resolved with low dose bevacizumab administered monthly. Accurate data regarding this initial experience are currently unavailable. Hamilton et al. [12], reported a case of an elderly patient with platinum refractory ovarian cancer who refused surgery, second line therapy and consequently addressed to palliative care. After a three month interval, the patient suffered from ascites and lower limbs edema which rapidly recurred after an initial paracentesis. Treatment with bevacizumab 5 mg/kg repeated after 24 days was able to resolve ascites and correlated symptoms and the patient deceased peacefully in her sleep. It is unknown if traditional second line cytotoxic drugs could have achieved a palliative beneficial effect. In this case, the patient had been subjected to multiple lines of chemotherapy including rechallenging with platinum regimens, pegilated liposomal doxorubicin and topotecan. Furthermore, attempts of palliation with intraperitoneal cisplatin had been carried out. After paracentesis and a single administration of intraperitoneal low dose bevacizumab, the patient benefited from a complete resolution of ascites and correlated symptoms. The patient referred a great improvement in her quality of life. This clinical and symptomatic improvement supported our decision to continue treatment for
Table 3 Ongoing phase III randomized trials Sponsor and collaborators Study chair
Protocol ID
Treatment
N. of patients
FIGO disease stage
Estimated date of closure
Gynecologic oncology group Burger RA Genetech Hua M.
NCT00262847
Bev iv Carboplatin iv + Paclitaxel iv
2000
Stage III–IV
Closed
NCT00434642
Bev iv Carboplatin + Gemcitabine
450
Platinum sensitive recurrence
June 2010
NCT00565851
Bev iv Carboplatin + Taxane
660
December 2009
NCT00483782 NCT00951496
Bev iv Carboplatin + Paclitaxane Bev iv + Paclitaxel iv (paclitaxel ip, Carboplatin iv or ip, Cispatin ip.)
Platinum sensitive recurrence Stage I–IV Stage II–III
Gynecologic oncology group Coleman RL. Medical research council Gynecologic oncology group Walker JL
Bev Bevacizumab, ip intraperitoneal, iv intravenous, na not applicable Data collected from NCI (cancer.gov, August 2009)
1,520 1,100
na January 2016
Invest New Drugs (2010) 28:887–894
successive cycles. The patient deceased at home in the absence of pain, several weeks after the last drug administration for respiratory arrest. This time interval between the last drug administration and death makes the hypothesis of a iatrogenic side effect extremely unlikely. The extent of the disease and the compromised clinical conditions of the patient before the beginning of treatment makes any conclusion on an effect on the history of the disease speculative. Recent findings have shown that treatment with bevacizumab is associated with a reduction in VEGF levels, but this change does not correlate with clinical outcome [32]. In this patient, we investigated the role that ip bevacizumab had on the immune system. It is not possible to draw conclusions on a single case, but some preliminary observations can be drawn. Studies on other monoclonal antibodies adopted in oncology have shown that the immune system gives a crucial contribution to the antitumour effects [49]. Circulating lymphocytes were able to secrete IFNγ in a higher proportion as compared to lymphocytes recruited in ascitic fluid. In peripheral blood, this capability increased and remained high during treatment with bevacizumab. Ip bevacizumab temporarily increased effector CD8+ cells, whereas CD4+ effector cells remained low. In vivo, CD4+ effector cells are pivotal for maintaining an adequate number and function of cytotoxic T lymphocytes by cytokine secretion. Circulating Tregs halfened after drug administration and remained low. NK and NKT proportion were not influenced by the ip administration of bevacizumab. Overall, the early cellular changes show the beginning of an activation of the immune system. This positive initial effect gradually aborted with treatment continuation. Possible explanations could be an immunological impairment due to several previous lines of chemotherapy and the high tumor burden or alternatively the induction of human anti-mouse antibodies. Future biological studies on larger number of patients will be necessary to confirm these immunological observations and better understand the complex mechanism that underlays the therapeutic effect of bevacizumab. Analyses on less heavily pre-treated women will show if bevacizumab is able to induce a more prolonged immune activation. In conclusion, although only few cases have been reported, the exceptional results and the complete absence of side effects observed in this and other reported cases strongly warrant future trials to investigate the role that intraperitoneal bevacizumab can have both as palliative treatment of refractory ascites and as salvage therapy in ovarian cancer. Acknowledgements This work was supported by Associazione Italiana Ricerca contro il Cancro, Ministero della Salute/Regione Lazio, Ministero dell’Istruzione dell’Università e della Ricerca. Chiara Napoletano was supported by Associazione Italiana Ricerca contro il Cancro.
893
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