- Email: [email protected]
A phase II trial (AGO 2.11) in platinum-resistant ovarian cancer: a randomized multicenter trial with sunitinib (SU11248) to evaluate dosage, schedule, tolerability, toxicity and effectiveness of a multitargeted receptor tyrosine kinase inhibitor monotherapy
original articles
Annals of Oncology
Annals of Oncology 23: 2265–2271, 2012 doi:10.1093/annonc/mds003 Published online 29 February 2012
K. H. Baumann1*, A. du Bois2, W. Meier3, J. Rau4, P. Wimberger5, J. Sehouli6, C. Kurzeder7, F. Hilpert8, A. Hasenburg9, U. Canzler10, L. C. Hanker11, P. Hillemanns12, B. Richter13, K. Wollschlaeger14, T. Dewitz15, D. Bauerschlag16 & U. Wagner1 1 Department of Gynaecology, University of Marburg, Marburg; 2Department of Gynaecology and Gynaecological Oncology, HSK Wiesbaden and Kliniken Essen Mitte, Essen; 3Department of Gynaecology and Obstetrics, Evangelic Hospital, Duesseldorf; 4Coordinating Centre for Clinical Trials, University of Marburg, Marburg; 5 Department of Gynaecology and Obstetrics, University of Duisburg-Essen, Essen; 6Department of Gynaecology, Charité, Berlin; 7Department of Gynaecology and Obstetrics, University of Ulm, Ulm; 8Department of Gynaecology and Obstetrics, University of Kiel, Kiel; 9Department of Gynaecology and Obstetrics, University of Freiburg, Freiburg; 10Department of Gynaecology and Obstetrics, University of Dresden, Dresden; 11Department of Gynaecology and Obstetrics, University of Frankfurt am Main, Frankfurt am Main; 12Department of Gynaecology and Obstetrics, Medical School Hannover, Hannover; 13Department of Gynaecology and Obstetrics, Elbland Hospital, Radebeul; 14Department of Gynaecology and Obstetrics, University of Magdeburg, Magdeburg; 15Department of Gynaecology and Obstetrics, Hospital of Gifhorn, Gifhorn; 16Department of Gynaecology and Obstetrics, University Medical Center Aachen RWTH, Aachen, Germany
Received 20 August 2011; revised 25 December 2011; accepted 27 December 2011
Background: Recurrent platinum-resistant ovarian cancer usually has a poor outcome with conventional chemotherapeutic therapy and new treatment modalities are warranted. This phase II study was conducted to evaluate sunitinib, an oral antiangiogenic multitargeted tyrosin kinase inhibitor, in this setting. Material and methods: The primary end point of this randomized phase II trial was the objective response rate according to RECIST criteria and/or Gynecologic Cancer InterGroup CA125 response criteria to sunitinib in patients with recurrent platinum-resistant ovarian cancer who were pretreated with up to three chemotherapies. A selection design was employed to compare two schedules of sunitinib (arm 1: 50 mg sunitinib daily orally for 28 days followed by 14 days off drug; and arm 2: 37.5 mg sunitinib administered daily continuously). Results: Of 73 patients enrolled, 36 patients were randomly allocated to the noncontinuous treatment arm (arm 1) and 37 patients were randomly allocated to the continuous treatment arm (arm 2). The mean age was 58.8 and 58.5 years, respectively. We observed six responders (complete response + partial response) in arm 1 (16.7%) and 2 responders in arm 2 (5.4%). The median progression-free survival (arm 1: 4.8 [2.9–8.1] months; arm 2: 2.9 [2.9–5.1] months) and the median overall survival (arm 1: 13.6 [7.0–23.2] months; arm 2: 13.7 [8.4–25.6] months) revealed no significant difference. Adverse events included fatigue as well as cardiovascular, gastrointestinal and abdominal symptoms, hematologic and hepatic laboratory abnormalities. Pattern and frequency of adverse events revealed no substantial differences between both treatment groups. Conclusions: Sunitinib treatment is feasible and moderately active in relapsed platinum-resistant ovarian cancer. The noncontinuous treatment schedule should be chosen for further studies in ovarian cancer. Key words: angiogenesis inhibitor, ovarian cancer, platinum resistant, sunitinib
introduction Ovarian cancer ranks fifth as the cause of female cancer death [1, 2]. In 2007, > 8000 new cases of ovarian cancer were *Correspondence to: Dr K. H. Baumann, Department of Gynaecology, Gyn. Endocrinology and Oncology, University Hospital of Gießen and Marburg, Baldingerstraße, 35043 Marburg, Germany. Telephone: + 49-6421-5866491; Fax: + 49-6421-5866587; E-mail: [email protected]
diagnosed in Germany, with a mortality rate of 14.5 per 100 000 women [3]. Consequently, the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) Study Group is committed to improve surgical and systemic treatment strategies for ovarian cancer [4, 5]. Approximately 70% of patients are presenting with advanced disease [International Federation of Gynecology and Obstetrics (FIGO) stage III/IV] [6]. The frontline treatment usually
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A phase II trial (AGO 2.11) in platinum-resistant ovarian cancer: a randomized multicenter trial with sunitinib (SU11248) to evaluate dosage, schedule, tolerability, toxicity and effectiveness of a multitargeted receptor tyrosine kinase inhibitor monotherapy
original articles
| Baumann et al.
day) or repeated 6-week cycles of daily oral therapy (50.0 mg/ day sunitinib) for 28 days followed by 2 weeks off treatment. The results of the AGO-Ovar 2.11 trial provides information on the safety and antitumor activity of a sunitinib monotherapy in patients with platinum-resistant ovarian cancer.
material and methods patients The study was conducted by the AGO Ovarian Cancer Study Group in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Patients with platinum-resistant epithelial ovarian cancer or primary peritoneum or the fallopian tube cancer who were ≥18 years and suitable for study participation according to the inclusion and exclusion criteria were enrolled after they had signed informed consent. The study protocol was reviewed and approved by an independent ethics committee at each study center. The study was designed in accordance with the European Medicines Agency (EMA) recommendations for clinical studies in cancer patients [21]. The inclusion criteria were as follows: histologically confirmed epithelial ovarian cancer, primary cancer of the fallopian tube or peritoneum; up to three prior chemotherapies including at least one platinum-based chemotherapy; platinum-refractory or platinum-resistant disease defined as either SD or PD during platinum-based chemotherapy, or within the treatment-free interval <6 months following the last platinum dose; measurable or nonmeasurable disease; thyroid-stimulating hormone within the normal range; Eastern Cooperative Oncology Group (ECOG) performance status of zero to two. Among others, exclusion criteria included any of the following within the 12 months before study drug administration: myocardial infarction, severe/unstable angina, coronary/ peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis or other thromboembolic events; patients with ileus within the last 28 days before randomization; current treatment with CYP3A4 inhibitors or inducers; hypertension that could not be controlled with medication ( >150/100 mmHg despite optimal medical therapy); left ventricular ejection fraction ≤50% as measured by echocardiogram; ongoing cardiac dysrhythmias of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grade ≥2, atrial fibrillation of any grade or prolongation of the QTc interval to >470 ms.
treatment plan, response evaluation and patient monitoring Patients were randomly allocated to receive either 50 mg sunitinib once daily orally for 4 weeks in a 6-week cycle ( = noncontinuous group, arm 1) or 37.5 mg sunitinib p.o. once daily continuously ( = continuous group, arm 2). Side-effects were classified according to the NCI CTCAE (Version 3.0) criteria. Doses were reduced in case of grade 3 and 4 nonhematologic and hematologic adverse events. In arm 1, sunitinib could be reduced by one dose level from 50 mg once daily to 37.5 mg once daily maintaining the same treatment schedule; in arm 2 sunitinib could be reduced by one dose level from 37.5 mg once daily to 25 mg once daily maintaining the same treatment schedule. No further dose reductions were admitted. Treatment discontinuation was not to exceed 28 days. Doses reduced following drug-related toxicity were not reescalated. Responses were evaluated based on the RECIST criteria [22] in patients with measurable disease. In patients without measurable lesions, response rate was evaluated
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includes optimal surgical debulking, followed by a combination chemotherapy with platinum and paclitaxel [7, 8]. Despite all treatment efforts, the prognosis is still poor, with a 5-year survival rate of <30% in advanced stages and of ∼40% for all stages combined [9]. Patients initially refractory to chemotherapy have the worst prognosis and the lowest chances of responding to any salvage therapy, while a longer ‘treatment-free interval’ is generally associated with higher response rates and longer progressionfree survival (PFS) [10]. Patients with resistant tumors (e.g. with a treatment-free interval of <6 months) or refractory tumors [ progressive (PD) or stable disease (SD) after first-line therapy] require alternative approaches. Current research focuses on improving chemotherapeutic approaches and includes new compounds like immunologicals or signal transduction modifiers [10]. Sunitinib (SU11248) is an orally administered multi-tyrosine kinase inhibitor targeting platelet-derived growth factor (PDGF) receptors, vascular endothelial growth factor (VEGF) receptors, Flt3 and c-Kit [11, 12]. The regression of a variety of tumor xenografts in mice has been observed [13, 14]. PDGF and VEGF receptors have been shown to be expressed in ovarian cancer, as well as c-Kit [15]. Blood vessels express PDGF and VEGF receptors [15]. Thus, sunitinib targets both tumor cells and endothelial cells, providing evidence for the regulatory and increased inhibitory effects on cell growth and (neo)angiogenesis [15, 16]. Sunitinib has been administered in clinical studies [16–18] carried out in gastrointestinal stromal cancer (GIST) and metastatic renal cell cancer on a 4 weeks on/2 weeks off schedule. In GIST trials, signs of interval tumor progression in the ‘off’ period have been observed by using regular positron emission tomography scanning to assess patients. Preclinical investigations indicate that a total drug (sunitinib or of its analog SU012662) concentration of 50 ng/ml or higher is required to achieve the inhibition of receptor phosphorylation [16]. At a 50 mg daily dose, a mean steady-state plasma trough concentration of 80 ng/ml can be achieved; pharmacokinetic modeling of a once-daily 37.5-mg dose indicates that the steady-state trough concentrations of total drug will be in the level of 60 ng/ml. Based on the large amount of experience using sunitinib in cycles composed of 4 weeks of daily dosing at 50 mg followed by 2 weeks of treatment rest, it is of interest to gain more experience with continuous dosing beyond 4 weeks. These different dosing schedules of sunitinib were also used in a recently published trial in recurrent ovarian cancer [19]. Some responses were seen in a clinical phase II trial using sunitinib as a single agent in recurrent ovarian cancer; the aforementioned trial showed some evidence of tumor response in platinum-sensitive ovarian cancer, whereas no objective response was observed in patients with platinum-resistant ovarian cancer [19]. Additionally, an experimental in vivo ovarian cancer model supports the potential of sunitinib monotherapy in ovarian cancer [20]. This trial was designed to evaluate the antitumor activity, tolerability, toxicity, safety and an improved dose and treatment schedule of sunitinib monotherapy in platinumresistant recurrent ovarian cancer. Patients were randomly allocated to receive a continuous sunitinib therapy (37.5 mg/
Annals of Oncology
original articles
Annals of Oncology using the concentration profiles of serum tumor marker CA 125 according to the recommendations by the Gynecologic Cancer InterGroup (GCIG) [23, 24]. While on therapy, the patients were monitored including blood pressure, hematology, biochemistry, CA 125 levels, urine analysis, thyroid function, electrocardiography, cardiac ultrasound. Adverse events were documented. Imaging (computer tomography or magnetic resonance imaging) was carried out at baseline and was subsequently repeated at 12-week intervals. Additional investigations were carried out as clinically indicated.
The AGO-Ovar 2.11 trial was a randomized multicenter, two-schedule and dose level, open-label phase II study in patients with ovarian cancer resistant or refractory to platinum-based chemotherapy. Treatment was to be given for up to 1 year (therapy could be continued in case of tumor response and benefit for the patient for >1 year). In order to determine time to progression and overall survival (OS), at the end of the study patients were followed up every 2 months until death. The treatment had to be terminated in case of progressive disease. Treatment was terminated prematurely in cases in which the patients withdrew informed consent, or because of unacceptable toxicity (not manageable by supportive care, dose reduction and/or dose delay) or at the discretion of the investigator. The primary objective was to determine the objective response rate [complete response (CR) and partial response (PR) per treatment schedule] according to RECIST criteria for patients with measurable disease, and additionally by tumor marker (CA 125) for patients with nonmeasurable disease. Secondary objectives included tolerability, toxicity, time to progression and OS. The statistical analysis of the primary end point was based on the intention-to-treat population. The phase II selection design proposed by Simon [25] was employed to identify the better treatment arm. In order to achieve a 90% probability of correctly selecting the better treatment schedule, with at least an 11% better
results patients and treatment Seventy-three patients were recruited in 14 trial centers across Germany from September 2007 to July 2008. Thirty-six patients were randomly assigned into the noncontinuous treatment arm and 37 patients to the continuous treatment arm. Baseline patient characteristics were well balanced (Table 1). The two treatment groups were not significantly different with respect to number of patients with platinumresistant or platinum-refractory disease, and most had serous histology. Eight patients had one prior chemotherapy, while the remaining 65 patients had more than one prior chemotherapy. All patients were assessable for efficacy and toxicity analysis. Only 5.6% of patients in the noncontinuous therapy group completed the treatment as planned, whereas none in the other group did. The reasons for treatment discontinuation included disease progression (52.8%; 75.7%), death (8.3%; 0.0%), toxicity (16.7%; 5.4%), the patient’s decision (8.3%; 5.4%), lost to follow-up (2.8%; 0.0%) and other reasons (5.6%; 13.5%) for the noncontinuous and the continuous treatment arms, respectively. The reported deaths were not related to the treatment but to disease progression. Dose reduction was documented in 19.4% and 13.5% for noncontinuous and continuous treatment arms, respectively.
Table 1. Baseline characteristics of patients Parameter Age mean (years) Performance status ECOG 0/1 (%) FIGO stage primary disease (%) I–IIA IIB–III IV Histology (%) Serous Endometroid Muscinous Remaining tumor after surgery for primary disease (%) Microscopically/0 cm 0.1–1 cm > 1 cm Prior chemotherapies (%) 1 >1 Measurable disease (n, %) Tumor burden (RECIST sums in mm: mean, standard deviation, median) Patients with CA 125 values assessable according to GCIG criteria (n) CA 125 at baseline (mean, standard deviation; median, interquartile range; kU/l) Time since original diagnosis (mean and standard deviation, months)
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Non-continuous (n = 36)
Continuous (n = 37)
58.8 97.2
58.5 100.0
5.6 77.8 16.7
5.4 73.0 21.6
83.3 0.0 2.8
73.0 13.5 5.4
36.1 33.3 19.4
32.4 35.1 27.0
5.6 94.2 30 (83.3) 73.7, 66.9, 56.5 36 655.3 (1159.5); 302 (71.7–677.8) 31.99 (19.63)
16.2 83.7 28 (75.7) 72.1, 55.5, 61.0 37 1009.6 (1520.4); 444 (129.5–1016.0) 28.83 (23.9)
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design, sample size considerations and statistical analyses
response rate than the other treatment schedule, 36 patients per arm were needed. Hence, a total sample size of 72 patients was required. OS and PFS were estimated using the Kaplan–Meier method and analyzed by log-rank tests with 95% confidence intervals (CIs).
original articles
Annals of Oncology
Table 2. NCI–CTC grade 3 and 4 hematologic and biochemical toxic effects (% of all reported adverse events) Toxicity
Noncontinuous (%)
Continuous (%)
Hemoglobin Platelets White blood cells Neutrophils Sodium Potassium Calcium γ-GT ALT AST
0.6 1.6 1.9 3.9 0.6 0.6 1.0 4.5 1.0 0.3
0.0 4.3 2.3 3.3 1.6 0.8 0.0 6.1 1.2 0.8
Table 3. NCI–CTC grade 3 and 4 nonhematologic toxic effects (% of all reported adverse events) Adverse event
Non-continuous (%)
Continuous (%)
Gastrointestinal Syndrome Hematologic aberrations Hepatic laboratory findings Abdominal symptoms Infection Pulmonary symptoms Edema Fatigue and reduced general condition Skin symptoms Cardiovascular symptoms Pain Urological symptoms ENT symptoms, mucositis
3.0 2.8 1.1 1.1 0.6 0.4 0.2 0.6
1.5 2.3 2.0 2.0 0.3 0.8 0.3 0.5
0.0 0.9 0.2 0.4 0.0
0.3 0.8 0.3 0.5 0.3
| Baumann et al.
the noncontinuous schedule (Table 5). Both treatment schedules resulted in similar median PFS (Figure 1) and median OS (Figure 2). Median PFS (arm 1: 4.8 [2.9–8.1] months; arm 2: 2.9 [2.9–5.1] months) and median OS (arm 1: 13.6 [7.0–23.2] months; arm 2: 13.7 [8.4–25.6] months) revealed no significant differences.
discussion The selection design allowed us to identify the noncontinuous schedule as the more efficacious. The response rate (CR and PR) in the noncontinuous arm was 16.7% and therefore higher than in the continuous treatment group (5.4%), even though the wide confidence limits indicate that these estimates have low precision. However, the sample size was planned for the purpose of the selection of the more promising schedule in this phase II study. Overall, these results support the report of Biagi et al. [19] demonstrating a modest activity of sunitinib monotherapy in ovarian cancer, especially with the 50 mg intermittent dose schedule. Therapy responders of aforementioned study had platinum-sensitive relapsed disease and the number of patients with platinum-resistant ovarian cancer was low [19]. Thus far, we investigated the largest group of patients with platinum-resistant ovarian cancer treated with sunitinib. The data provides, in addition to the report by Biagi et al. [19] about platinum-sensitive patients, some evidence of therapeutic activity of sunitinib monotherapy in platinumresistant ovarian cancer. Table 4. Best reported response according to RECIST criteria (in patients without measurable lesions response rate was evaluated according to GCIG criteria) Best reported response Lesion CR PR SD PD Total CR + PR
Noncontinuous, n (%) Measurable All 1 (3.3) 5 (16.7) 7 (23.3) 17 (56.7) 30 6 (20.0)
1 (2.8) 5 (13.9) 8 (22.2) 22 (61.1) >36 6 (16.7)
Continuous, n (%) Measurable All 0 (0.0) 2 (7.1) 7 (25) 19 (67.9) 28 2 (7.1)
0 (0.0) 2 (5.4) 7 (18.9) 28 (75.7) 37 2 (5.4)
CR, complete response; GCIG, Gynecologic Cancer InterGroup; PD, progressive disease; PR, partial response; SD, stable disease.
Table 5. Best reported response according to GCIG criteria Best reported response Lesion CR PR SD PD Total CR + PR
Noncontinuous, n (%) Measurable All 1 (3.3) 4 (13.2) 5 (16.7) 20 (66.7) 30 5 (16.7)
1 (2.8) 4 (11.1) 6 (16.7) 25 (69.4) 36 5 (13.9)
Continuous, n (%) Measurable All 0 (0.0) 2 (7.1) 5 (16.7) 21 (75.0) 28 2
0 (0.0) 2 (5.4) 5 (13.5) 30 (81.1) 37 2 (5.4)
CR, complete response; GCIG, Gynecologic Cancer InterGroup; PD, progressive disease; PR, partial response; SD, stable disease.
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In the continuous treatment arm, 46 adverse events grade 3 and 4 occurred in 22 patients, whereas in the noncontinuous arm, 60 adverse events grade 3 and 4 were reported of 25 patients. Of all adverse events in the noncontinuous group and in the continuous group, 88.8% and 88.4%, respectively, were classified as grade 1 and 2. There were no substantial differences between both treatment arms. NCI–CTC grade 3 and 4 adverse events are listed in Tables 2 and 3. There were no unexpected serious adverse events in both treatment groups. We observed six (16.7%) objective responses (CR or PR) in the noncontinuous group (exact 95% CI of 6.4%–32.8%), and two (5.4%) in the continuous treatment group (exact 95% CI 0.7%–18.1%) (Table 4). The same pattern was observed on the basis of the GCIG CA125 response criteria. Therefore, the absolute difference of response rates between both schedules was 11.3%. According to the selection design, the noncontinuous treatment arm, which had the better objective response rate (P ≥ 0.11), could be considered as an option for further clinical studies. Best overall response of GCIG CA 125 criteria in case of nonmeasurable disease showed a slightly smaller difference of 8.9% of CR and PR, but likewise favoring
original articles
Annals of Oncology
Figure 2. Overall survival. CI, confidence interval; evts, events; HR, hazard ratio; pts, patients.
The maximum therapeutical activity of sunitinib as observed in the noncontinuous schedule achieved an objective response rate of 16.7%, an encouraging result. This result is also within the range of bevacizumab therapy resulting in 16% response rate in platinum-resistant ovarian cancer [26] and is even higher than the objective response rate of topotecan or pegylated liposomal doxorubicin [27]. A median PFS of 4.8 months (95% CI 2.9%–8.1%) and a median OS of 13.6 months (95% CI 7.0%–23.2%) for the noncontinuous treatment arm were still in line with the expectations for antiangiogenic monotherapy [26]. It is noteworthy, that despite a lower response rate and a shorter PFS time in the continuous treatment group, the median OS time was not different from that in the noncontinuous group. Some case reports on sunitinib in relapsed ovarian cancer show conflicting results [28]. A recently published two-stage
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trial of sunitinib in recurrent ovarian cancer including platinum-sensitive and platinum-resistant patients provided evidence for clinical efficacy at least in platinum-sensitive patients [19]. In that study, sunitinib was given 50 mg/day p.o. to some patients for 4 weeks of a 6-week cycle, while others received 37.5 mg/d p.o. continuously; the comparison between both treatment arms was not an objective in that trial [19]. In this randomized phase II trial, a selection design was used [25] to compare two different doses and schedules of sunitinib monotherapy. In the noncontinuous arm, sunitinib was given at 50.0 mg p.o. daily for 4 weeks of a 6-week cycle that included 2 weeks off-treatment period. In the continuous arm, 37.5 mg p.o. sunitinib was given daily without off-treatment periods. Both treatment modalities are feasible and well tolerated. Dose reductions and early treatment termination were similar for both treatment groups. The occurrence and
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Figure 1. Progression-free survival. CI, confidence interval; evts, events; HR, hazard ratio pts, patients.
original articles
funding Pfizer Deutschland GmbH.
disclosure AdB serves on advisory boards and gives educational lectures and has received honoraria from Amgen, Roche, PharmaMar, Schering Plough, Jansen, Astra Zeneca and Glaxo-Smith-Kline. The remaining authors have declared no conflict of interest.
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quality of adverse events was, compared with other trials, within expectation [17–19]. Abdominal, gastrointestinal cardiovascular symptoms including hypertension and fatigue were reported. None of the reported deaths was related to the treatment. Laboratory evaluations included abnormal hematological and biochemical findings. These observations are within the range of adverse events and toxic effects caused by antiangiogenic therapy [17–19]. Toxic effects and adverse events found in this trial of patients with relapsed ovarian cancer match the side-effects associated with sunitinib therapy in patients with renal cell cancer [17], GIST [18] and ovarian cancer [19]. Overall, sunitinib monotherapy was well tolerated in patients with platinum-resistant ovarian cancer patients, which applies to both treatment arms in this trial. Targeted therapy has become a focus of interest in cancer research. The inhibition of angiogenesis is an emerging treatment option for a range of malignant tumors including ovarian cancer. Bevacizumab combined with nab-paclitaxel achieved a response rate of 46% and a median OS time of 16.5 months in platinum-resistant ovarian cancer providing important evidence to support chemotherapy and targeted agents combinations, especially with antiangiogenic therapy [29]. So far, there has been no reported trial combining sunitinib with chemotherapy in patients with ovarian cancer. However, feasibility studies combining sunitinib with irinotecan, pemetrexed, docetaxel or capecitabin in patients with solid tumors indicate the safety and tolerability of this approach [30, 31]. The evidence of some activity of the noncontinuous sunitinib monotherapy in platinum-resistant ovarian cancer found in our trial, together with findings by Biagi et al. [19] indicate that suntinib may be an interesting compound for further trials in ovarian cancer.
Annals of Oncology
original articles
Annals of Oncology 25. Simon R, Wittes RE, Ellenberg SS.Randomized phase II clinical trials. Cancer Treat Rep 1985; 69(12): 1375–1381. 26. Cannistra S, Matulonis UA, Penson RT et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer. J Clin Oncol 2007; 25(33): 5180–5186. 27. Gordon AN, Fleagle JT, Guthrie D et al. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 2001; 19(14): 3312–3322. 28. Taran A, Ignatov A, Smith B et al. Acute hepatic failure following monotherapy with sunitinib for ovarian cancer. Cancer Chemother Pharmacol 2009; 63(5): 971–972.
29. Tillmanns TD, Lowe MP, Schwartzberg LS et al. A phase II study of bevacizumab with nab-paclitaxel in patients with recurrent, platinum-resistant primary epithelial ovarian or primary peritoneal carcinoma. J Clin Oncol 2010; 28: 15s. (Abstr 5009). 30. Sweeney C, Chiorean EG, Verschraegen CF et al. A phase I study of sunitinib plus capecitabine in patients with advanced solid. J Clin Oncol 2010; 28(29): 4513–4520. 31. Robert F, Sandler A, Schiller JH et al. Sunitinib in combination with docetaxel in patients with advanced solid tumors: a phase I dose-escalation study. Cancer Chemother Pharmacol 2009; 66(4): 669–680.
Influence of zoledronic acid on disseminated tumor cells in primary breast cancer patients E.-F. Solomayer1*, G. Gebauer2, P. Hirnle3, W. Janni4, H.-J. Lück5, S. Becker1, J. Huober6, B. Krämer1, B. Wackwitz7, D. Wallwiener8 & T. Fehm1 1 Department of Obstetrics, Gynecology, and Reproductive Medicine, University of Saarland, Homburg; 2Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg; 3Department of Radiation Oncology, Central Academic Hospital, Bielefeld; 4Department of Gynecology and Obstetrics, Heinrich-Heine University, Düsseldorf; 5Department of Gynecologic Oncology, Hannover Medical School, Hannover, Germany; 6Breast Center, Department of Senologie, Kantonsspital St. Gallen, St. Gallen, Switzerland; 7Norvartis Oncology, Department of Medical Affairs, Nuremberg; 8Department of Obstetrics and Gynecology, University of Tuebingen, Tuebingen, Germany
Received 10 August 2011; revised 5 December 2011; accepted 12 December 2011
Background: The presence of disseminated tumor cells (DTCs) in bone marrow of patients with early breast cancer (EBC) has been correlated with increased risk of metastatic disease or locoregional relapse. Zoledronic acid (ZOL) treatment has reduced DTCs in the bone marrow of patients with EBC in several studies. This controlled study sought to confirm these observations. Patients and methods: Patients with EBC and DTC-positive bone marrow were randomized (N = 96) to treatment with ZOL plus adjuvant systemic therapy or adjuvant systemic therapy alone. The change in DTC numbers at 12 months versus baseline was measured. Results: DTC-positive patients treated with ZOL were more likely to become DTC-negative after 12 months of treatment compared with the controls (67% versus 35%; P = 0.009). At 12 months, DTC counts decreased to a mean of 0.5 ± 0.8 DTCs in the ZOL group and to 0.9 ± 0.8 DTCs in the control group. In addition, ZOL was generally well tolerated. Conclusions: Treatment with ZOL improves elimination of DTCs. Further studies are needed to determine whether the reduction in DTCs by ZOL provides clinical benefit. Key words: breast cancer, disseminated tumor cells, metastasis, recurrence, zoledronic acid
introduction Breast cancer (BC) is the most common solid tumor in women [1]. Metastatic disease is the predominant cause of death in the ∼465 000 patients who succumb to this disease [1]. Despite therapeutic interventions, ∼15% develop distant metastases within 3 years [2]. Furthermore, patients may have late
*Correspondence to: Prof. Dr E.-F. Solomayer, Department of Obstetrics, Gynecology, and Reproductive Medicine, University of Saarland, Kirrberger Strasse, 66421 Homburg/Saar, Germany. Tel: + 49-6841-162-8100; Fax: + 49-6841-162-8110; E-mail: [email protected]
recurrence (‘metastatic dormancy’) ≥10 years after initial diagnosis [2]. Common sites of BC metastasis include bone, lung, and brain [2, 3], of which bone is the most common site (∼75% of cases) [4]. Distant metastasis is associated with poor prognosis [4, 5]. The hypothesis that recurrent/metastatic disease is initiated by micrometastases has gained wide acceptance. Disseminated tumor cells (DTCs) can be sequestered in a dormant state in the bone marrow for several years before reactivating to cause disease recurrence [6]. The most compelling clinical evidence comes from a retrospective pooled analysis of patients with BC (N = 4703) wherein patients with DTC-positive bone marrow
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Annals of Oncology 23: 2271–2277, 2012 doi:10.1093/annonc/mdr612 Published online 1 March 2012
Annals of Oncology
Annals of Oncology 23: 2265–2271, 2012 doi:10.1093/annonc/mds003 Published online 29 February 2012
K. H. Baumann1*, A. du Bois2, W. Meier3, J. Rau4, P. Wimberger5, J. Sehouli6, C. Kurzeder7, F. Hilpert8, A. Hasenburg9, U. Canzler10, L. C. Hanker11, P. Hillemanns12, B. Richter13, K. Wollschlaeger14, T. Dewitz15, D. Bauerschlag16 & U. Wagner1 1 Department of Gynaecology, University of Marburg, Marburg; 2Department of Gynaecology and Gynaecological Oncology, HSK Wiesbaden and Kliniken Essen Mitte, Essen; 3Department of Gynaecology and Obstetrics, Evangelic Hospital, Duesseldorf; 4Coordinating Centre for Clinical Trials, University of Marburg, Marburg; 5 Department of Gynaecology and Obstetrics, University of Duisburg-Essen, Essen; 6Department of Gynaecology, Charité, Berlin; 7Department of Gynaecology and Obstetrics, University of Ulm, Ulm; 8Department of Gynaecology and Obstetrics, University of Kiel, Kiel; 9Department of Gynaecology and Obstetrics, University of Freiburg, Freiburg; 10Department of Gynaecology and Obstetrics, University of Dresden, Dresden; 11Department of Gynaecology and Obstetrics, University of Frankfurt am Main, Frankfurt am Main; 12Department of Gynaecology and Obstetrics, Medical School Hannover, Hannover; 13Department of Gynaecology and Obstetrics, Elbland Hospital, Radebeul; 14Department of Gynaecology and Obstetrics, University of Magdeburg, Magdeburg; 15Department of Gynaecology and Obstetrics, Hospital of Gifhorn, Gifhorn; 16Department of Gynaecology and Obstetrics, University Medical Center Aachen RWTH, Aachen, Germany
Received 20 August 2011; revised 25 December 2011; accepted 27 December 2011
Background: Recurrent platinum-resistant ovarian cancer usually has a poor outcome with conventional chemotherapeutic therapy and new treatment modalities are warranted. This phase II study was conducted to evaluate sunitinib, an oral antiangiogenic multitargeted tyrosin kinase inhibitor, in this setting. Material and methods: The primary end point of this randomized phase II trial was the objective response rate according to RECIST criteria and/or Gynecologic Cancer InterGroup CA125 response criteria to sunitinib in patients with recurrent platinum-resistant ovarian cancer who were pretreated with up to three chemotherapies. A selection design was employed to compare two schedules of sunitinib (arm 1: 50 mg sunitinib daily orally for 28 days followed by 14 days off drug; and arm 2: 37.5 mg sunitinib administered daily continuously). Results: Of 73 patients enrolled, 36 patients were randomly allocated to the noncontinuous treatment arm (arm 1) and 37 patients were randomly allocated to the continuous treatment arm (arm 2). The mean age was 58.8 and 58.5 years, respectively. We observed six responders (complete response + partial response) in arm 1 (16.7%) and 2 responders in arm 2 (5.4%). The median progression-free survival (arm 1: 4.8 [2.9–8.1] months; arm 2: 2.9 [2.9–5.1] months) and the median overall survival (arm 1: 13.6 [7.0–23.2] months; arm 2: 13.7 [8.4–25.6] months) revealed no significant difference. Adverse events included fatigue as well as cardiovascular, gastrointestinal and abdominal symptoms, hematologic and hepatic laboratory abnormalities. Pattern and frequency of adverse events revealed no substantial differences between both treatment groups. Conclusions: Sunitinib treatment is feasible and moderately active in relapsed platinum-resistant ovarian cancer. The noncontinuous treatment schedule should be chosen for further studies in ovarian cancer. Key words: angiogenesis inhibitor, ovarian cancer, platinum resistant, sunitinib
introduction Ovarian cancer ranks fifth as the cause of female cancer death [1, 2]. In 2007, > 8000 new cases of ovarian cancer were *Correspondence to: Dr K. H. Baumann, Department of Gynaecology, Gyn. Endocrinology and Oncology, University Hospital of Gießen and Marburg, Baldingerstraße, 35043 Marburg, Germany. Telephone: + 49-6421-5866491; Fax: + 49-6421-5866587; E-mail: [email protected]
diagnosed in Germany, with a mortality rate of 14.5 per 100 000 women [3]. Consequently, the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) Study Group is committed to improve surgical and systemic treatment strategies for ovarian cancer [4, 5]. Approximately 70% of patients are presenting with advanced disease [International Federation of Gynecology and Obstetrics (FIGO) stage III/IV] [6]. The frontline treatment usually
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A phase II trial (AGO 2.11) in platinum-resistant ovarian cancer: a randomized multicenter trial with sunitinib (SU11248) to evaluate dosage, schedule, tolerability, toxicity and effectiveness of a multitargeted receptor tyrosine kinase inhibitor monotherapy
original articles
| Baumann et al.
day) or repeated 6-week cycles of daily oral therapy (50.0 mg/ day sunitinib) for 28 days followed by 2 weeks off treatment. The results of the AGO-Ovar 2.11 trial provides information on the safety and antitumor activity of a sunitinib monotherapy in patients with platinum-resistant ovarian cancer.
material and methods patients The study was conducted by the AGO Ovarian Cancer Study Group in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Patients with platinum-resistant epithelial ovarian cancer or primary peritoneum or the fallopian tube cancer who were ≥18 years and suitable for study participation according to the inclusion and exclusion criteria were enrolled after they had signed informed consent. The study protocol was reviewed and approved by an independent ethics committee at each study center. The study was designed in accordance with the European Medicines Agency (EMA) recommendations for clinical studies in cancer patients [21]. The inclusion criteria were as follows: histologically confirmed epithelial ovarian cancer, primary cancer of the fallopian tube or peritoneum; up to three prior chemotherapies including at least one platinum-based chemotherapy; platinum-refractory or platinum-resistant disease defined as either SD or PD during platinum-based chemotherapy, or within the treatment-free interval <6 months following the last platinum dose; measurable or nonmeasurable disease; thyroid-stimulating hormone within the normal range; Eastern Cooperative Oncology Group (ECOG) performance status of zero to two. Among others, exclusion criteria included any of the following within the 12 months before study drug administration: myocardial infarction, severe/unstable angina, coronary/ peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis or other thromboembolic events; patients with ileus within the last 28 days before randomization; current treatment with CYP3A4 inhibitors or inducers; hypertension that could not be controlled with medication ( >150/100 mmHg despite optimal medical therapy); left ventricular ejection fraction ≤50% as measured by echocardiogram; ongoing cardiac dysrhythmias of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grade ≥2, atrial fibrillation of any grade or prolongation of the QTc interval to >470 ms.
treatment plan, response evaluation and patient monitoring Patients were randomly allocated to receive either 50 mg sunitinib once daily orally for 4 weeks in a 6-week cycle ( = noncontinuous group, arm 1) or 37.5 mg sunitinib p.o. once daily continuously ( = continuous group, arm 2). Side-effects were classified according to the NCI CTCAE (Version 3.0) criteria. Doses were reduced in case of grade 3 and 4 nonhematologic and hematologic adverse events. In arm 1, sunitinib could be reduced by one dose level from 50 mg once daily to 37.5 mg once daily maintaining the same treatment schedule; in arm 2 sunitinib could be reduced by one dose level from 37.5 mg once daily to 25 mg once daily maintaining the same treatment schedule. No further dose reductions were admitted. Treatment discontinuation was not to exceed 28 days. Doses reduced following drug-related toxicity were not reescalated. Responses were evaluated based on the RECIST criteria [22] in patients with measurable disease. In patients without measurable lesions, response rate was evaluated
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includes optimal surgical debulking, followed by a combination chemotherapy with platinum and paclitaxel [7, 8]. Despite all treatment efforts, the prognosis is still poor, with a 5-year survival rate of <30% in advanced stages and of ∼40% for all stages combined [9]. Patients initially refractory to chemotherapy have the worst prognosis and the lowest chances of responding to any salvage therapy, while a longer ‘treatment-free interval’ is generally associated with higher response rates and longer progressionfree survival (PFS) [10]. Patients with resistant tumors (e.g. with a treatment-free interval of <6 months) or refractory tumors [ progressive (PD) or stable disease (SD) after first-line therapy] require alternative approaches. Current research focuses on improving chemotherapeutic approaches and includes new compounds like immunologicals or signal transduction modifiers [10]. Sunitinib (SU11248) is an orally administered multi-tyrosine kinase inhibitor targeting platelet-derived growth factor (PDGF) receptors, vascular endothelial growth factor (VEGF) receptors, Flt3 and c-Kit [11, 12]. The regression of a variety of tumor xenografts in mice has been observed [13, 14]. PDGF and VEGF receptors have been shown to be expressed in ovarian cancer, as well as c-Kit [15]. Blood vessels express PDGF and VEGF receptors [15]. Thus, sunitinib targets both tumor cells and endothelial cells, providing evidence for the regulatory and increased inhibitory effects on cell growth and (neo)angiogenesis [15, 16]. Sunitinib has been administered in clinical studies [16–18] carried out in gastrointestinal stromal cancer (GIST) and metastatic renal cell cancer on a 4 weeks on/2 weeks off schedule. In GIST trials, signs of interval tumor progression in the ‘off’ period have been observed by using regular positron emission tomography scanning to assess patients. Preclinical investigations indicate that a total drug (sunitinib or of its analog SU012662) concentration of 50 ng/ml or higher is required to achieve the inhibition of receptor phosphorylation [16]. At a 50 mg daily dose, a mean steady-state plasma trough concentration of 80 ng/ml can be achieved; pharmacokinetic modeling of a once-daily 37.5-mg dose indicates that the steady-state trough concentrations of total drug will be in the level of 60 ng/ml. Based on the large amount of experience using sunitinib in cycles composed of 4 weeks of daily dosing at 50 mg followed by 2 weeks of treatment rest, it is of interest to gain more experience with continuous dosing beyond 4 weeks. These different dosing schedules of sunitinib were also used in a recently published trial in recurrent ovarian cancer [19]. Some responses were seen in a clinical phase II trial using sunitinib as a single agent in recurrent ovarian cancer; the aforementioned trial showed some evidence of tumor response in platinum-sensitive ovarian cancer, whereas no objective response was observed in patients with platinum-resistant ovarian cancer [19]. Additionally, an experimental in vivo ovarian cancer model supports the potential of sunitinib monotherapy in ovarian cancer [20]. This trial was designed to evaluate the antitumor activity, tolerability, toxicity, safety and an improved dose and treatment schedule of sunitinib monotherapy in platinumresistant recurrent ovarian cancer. Patients were randomly allocated to receive a continuous sunitinib therapy (37.5 mg/
Annals of Oncology
original articles
Annals of Oncology using the concentration profiles of serum tumor marker CA 125 according to the recommendations by the Gynecologic Cancer InterGroup (GCIG) [23, 24]. While on therapy, the patients were monitored including blood pressure, hematology, biochemistry, CA 125 levels, urine analysis, thyroid function, electrocardiography, cardiac ultrasound. Adverse events were documented. Imaging (computer tomography or magnetic resonance imaging) was carried out at baseline and was subsequently repeated at 12-week intervals. Additional investigations were carried out as clinically indicated.
The AGO-Ovar 2.11 trial was a randomized multicenter, two-schedule and dose level, open-label phase II study in patients with ovarian cancer resistant or refractory to platinum-based chemotherapy. Treatment was to be given for up to 1 year (therapy could be continued in case of tumor response and benefit for the patient for >1 year). In order to determine time to progression and overall survival (OS), at the end of the study patients were followed up every 2 months until death. The treatment had to be terminated in case of progressive disease. Treatment was terminated prematurely in cases in which the patients withdrew informed consent, or because of unacceptable toxicity (not manageable by supportive care, dose reduction and/or dose delay) or at the discretion of the investigator. The primary objective was to determine the objective response rate [complete response (CR) and partial response (PR) per treatment schedule] according to RECIST criteria for patients with measurable disease, and additionally by tumor marker (CA 125) for patients with nonmeasurable disease. Secondary objectives included tolerability, toxicity, time to progression and OS. The statistical analysis of the primary end point was based on the intention-to-treat population. The phase II selection design proposed by Simon [25] was employed to identify the better treatment arm. In order to achieve a 90% probability of correctly selecting the better treatment schedule, with at least an 11% better
results patients and treatment Seventy-three patients were recruited in 14 trial centers across Germany from September 2007 to July 2008. Thirty-six patients were randomly assigned into the noncontinuous treatment arm and 37 patients to the continuous treatment arm. Baseline patient characteristics were well balanced (Table 1). The two treatment groups were not significantly different with respect to number of patients with platinumresistant or platinum-refractory disease, and most had serous histology. Eight patients had one prior chemotherapy, while the remaining 65 patients had more than one prior chemotherapy. All patients were assessable for efficacy and toxicity analysis. Only 5.6% of patients in the noncontinuous therapy group completed the treatment as planned, whereas none in the other group did. The reasons for treatment discontinuation included disease progression (52.8%; 75.7%), death (8.3%; 0.0%), toxicity (16.7%; 5.4%), the patient’s decision (8.3%; 5.4%), lost to follow-up (2.8%; 0.0%) and other reasons (5.6%; 13.5%) for the noncontinuous and the continuous treatment arms, respectively. The reported deaths were not related to the treatment but to disease progression. Dose reduction was documented in 19.4% and 13.5% for noncontinuous and continuous treatment arms, respectively.
Table 1. Baseline characteristics of patients Parameter Age mean (years) Performance status ECOG 0/1 (%) FIGO stage primary disease (%) I–IIA IIB–III IV Histology (%) Serous Endometroid Muscinous Remaining tumor after surgery for primary disease (%) Microscopically/0 cm 0.1–1 cm > 1 cm Prior chemotherapies (%) 1 >1 Measurable disease (n, %) Tumor burden (RECIST sums in mm: mean, standard deviation, median) Patients with CA 125 values assessable according to GCIG criteria (n) CA 125 at baseline (mean, standard deviation; median, interquartile range; kU/l) Time since original diagnosis (mean and standard deviation, months)
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Non-continuous (n = 36)
Continuous (n = 37)
58.8 97.2
58.5 100.0
5.6 77.8 16.7
5.4 73.0 21.6
83.3 0.0 2.8
73.0 13.5 5.4
36.1 33.3 19.4
32.4 35.1 27.0
5.6 94.2 30 (83.3) 73.7, 66.9, 56.5 36 655.3 (1159.5); 302 (71.7–677.8) 31.99 (19.63)
16.2 83.7 28 (75.7) 72.1, 55.5, 61.0 37 1009.6 (1520.4); 444 (129.5–1016.0) 28.83 (23.9)
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design, sample size considerations and statistical analyses
response rate than the other treatment schedule, 36 patients per arm were needed. Hence, a total sample size of 72 patients was required. OS and PFS were estimated using the Kaplan–Meier method and analyzed by log-rank tests with 95% confidence intervals (CIs).
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Annals of Oncology
Table 2. NCI–CTC grade 3 and 4 hematologic and biochemical toxic effects (% of all reported adverse events) Toxicity
Noncontinuous (%)
Continuous (%)
Hemoglobin Platelets White blood cells Neutrophils Sodium Potassium Calcium γ-GT ALT AST
0.6 1.6 1.9 3.9 0.6 0.6 1.0 4.5 1.0 0.3
0.0 4.3 2.3 3.3 1.6 0.8 0.0 6.1 1.2 0.8
Table 3. NCI–CTC grade 3 and 4 nonhematologic toxic effects (% of all reported adverse events) Adverse event
Non-continuous (%)
Continuous (%)
Gastrointestinal Syndrome Hematologic aberrations Hepatic laboratory findings Abdominal symptoms Infection Pulmonary symptoms Edema Fatigue and reduced general condition Skin symptoms Cardiovascular symptoms Pain Urological symptoms ENT symptoms, mucositis
3.0 2.8 1.1 1.1 0.6 0.4 0.2 0.6
1.5 2.3 2.0 2.0 0.3 0.8 0.3 0.5
0.0 0.9 0.2 0.4 0.0
0.3 0.8 0.3 0.5 0.3
| Baumann et al.
the noncontinuous schedule (Table 5). Both treatment schedules resulted in similar median PFS (Figure 1) and median OS (Figure 2). Median PFS (arm 1: 4.8 [2.9–8.1] months; arm 2: 2.9 [2.9–5.1] months) and median OS (arm 1: 13.6 [7.0–23.2] months; arm 2: 13.7 [8.4–25.6] months) revealed no significant differences.
discussion The selection design allowed us to identify the noncontinuous schedule as the more efficacious. The response rate (CR and PR) in the noncontinuous arm was 16.7% and therefore higher than in the continuous treatment group (5.4%), even though the wide confidence limits indicate that these estimates have low precision. However, the sample size was planned for the purpose of the selection of the more promising schedule in this phase II study. Overall, these results support the report of Biagi et al. [19] demonstrating a modest activity of sunitinib monotherapy in ovarian cancer, especially with the 50 mg intermittent dose schedule. Therapy responders of aforementioned study had platinum-sensitive relapsed disease and the number of patients with platinum-resistant ovarian cancer was low [19]. Thus far, we investigated the largest group of patients with platinum-resistant ovarian cancer treated with sunitinib. The data provides, in addition to the report by Biagi et al. [19] about platinum-sensitive patients, some evidence of therapeutic activity of sunitinib monotherapy in platinumresistant ovarian cancer. Table 4. Best reported response according to RECIST criteria (in patients without measurable lesions response rate was evaluated according to GCIG criteria) Best reported response Lesion CR PR SD PD Total CR + PR
Noncontinuous, n (%) Measurable All 1 (3.3) 5 (16.7) 7 (23.3) 17 (56.7) 30 6 (20.0)
1 (2.8) 5 (13.9) 8 (22.2) 22 (61.1) >36 6 (16.7)
Continuous, n (%) Measurable All 0 (0.0) 2 (7.1) 7 (25) 19 (67.9) 28 2 (7.1)
0 (0.0) 2 (5.4) 7 (18.9) 28 (75.7) 37 2 (5.4)
CR, complete response; GCIG, Gynecologic Cancer InterGroup; PD, progressive disease; PR, partial response; SD, stable disease.
Table 5. Best reported response according to GCIG criteria Best reported response Lesion CR PR SD PD Total CR + PR
Noncontinuous, n (%) Measurable All 1 (3.3) 4 (13.2) 5 (16.7) 20 (66.7) 30 5 (16.7)
1 (2.8) 4 (11.1) 6 (16.7) 25 (69.4) 36 5 (13.9)
Continuous, n (%) Measurable All 0 (0.0) 2 (7.1) 5 (16.7) 21 (75.0) 28 2
0 (0.0) 2 (5.4) 5 (13.5) 30 (81.1) 37 2 (5.4)
CR, complete response; GCIG, Gynecologic Cancer InterGroup; PD, progressive disease; PR, partial response; SD, stable disease.
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In the continuous treatment arm, 46 adverse events grade 3 and 4 occurred in 22 patients, whereas in the noncontinuous arm, 60 adverse events grade 3 and 4 were reported of 25 patients. Of all adverse events in the noncontinuous group and in the continuous group, 88.8% and 88.4%, respectively, were classified as grade 1 and 2. There were no substantial differences between both treatment arms. NCI–CTC grade 3 and 4 adverse events are listed in Tables 2 and 3. There were no unexpected serious adverse events in both treatment groups. We observed six (16.7%) objective responses (CR or PR) in the noncontinuous group (exact 95% CI of 6.4%–32.8%), and two (5.4%) in the continuous treatment group (exact 95% CI 0.7%–18.1%) (Table 4). The same pattern was observed on the basis of the GCIG CA125 response criteria. Therefore, the absolute difference of response rates between both schedules was 11.3%. According to the selection design, the noncontinuous treatment arm, which had the better objective response rate (P ≥ 0.11), could be considered as an option for further clinical studies. Best overall response of GCIG CA 125 criteria in case of nonmeasurable disease showed a slightly smaller difference of 8.9% of CR and PR, but likewise favoring
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Annals of Oncology
Figure 2. Overall survival. CI, confidence interval; evts, events; HR, hazard ratio; pts, patients.
The maximum therapeutical activity of sunitinib as observed in the noncontinuous schedule achieved an objective response rate of 16.7%, an encouraging result. This result is also within the range of bevacizumab therapy resulting in 16% response rate in platinum-resistant ovarian cancer [26] and is even higher than the objective response rate of topotecan or pegylated liposomal doxorubicin [27]. A median PFS of 4.8 months (95% CI 2.9%–8.1%) and a median OS of 13.6 months (95% CI 7.0%–23.2%) for the noncontinuous treatment arm were still in line with the expectations for antiangiogenic monotherapy [26]. It is noteworthy, that despite a lower response rate and a shorter PFS time in the continuous treatment group, the median OS time was not different from that in the noncontinuous group. Some case reports on sunitinib in relapsed ovarian cancer show conflicting results [28]. A recently published two-stage
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trial of sunitinib in recurrent ovarian cancer including platinum-sensitive and platinum-resistant patients provided evidence for clinical efficacy at least in platinum-sensitive patients [19]. In that study, sunitinib was given 50 mg/day p.o. to some patients for 4 weeks of a 6-week cycle, while others received 37.5 mg/d p.o. continuously; the comparison between both treatment arms was not an objective in that trial [19]. In this randomized phase II trial, a selection design was used [25] to compare two different doses and schedules of sunitinib monotherapy. In the noncontinuous arm, sunitinib was given at 50.0 mg p.o. daily for 4 weeks of a 6-week cycle that included 2 weeks off-treatment period. In the continuous arm, 37.5 mg p.o. sunitinib was given daily without off-treatment periods. Both treatment modalities are feasible and well tolerated. Dose reductions and early treatment termination were similar for both treatment groups. The occurrence and
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Figure 1. Progression-free survival. CI, confidence interval; evts, events; HR, hazard ratio pts, patients.
original articles
funding Pfizer Deutschland GmbH.
disclosure AdB serves on advisory boards and gives educational lectures and has received honoraria from Amgen, Roche, PharmaMar, Schering Plough, Jansen, Astra Zeneca and Glaxo-Smith-Kline. The remaining authors have declared no conflict of interest.
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| Baumann et al.
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quality of adverse events was, compared with other trials, within expectation [17–19]. Abdominal, gastrointestinal cardiovascular symptoms including hypertension and fatigue were reported. None of the reported deaths was related to the treatment. Laboratory evaluations included abnormal hematological and biochemical findings. These observations are within the range of adverse events and toxic effects caused by antiangiogenic therapy [17–19]. Toxic effects and adverse events found in this trial of patients with relapsed ovarian cancer match the side-effects associated with sunitinib therapy in patients with renal cell cancer [17], GIST [18] and ovarian cancer [19]. Overall, sunitinib monotherapy was well tolerated in patients with platinum-resistant ovarian cancer patients, which applies to both treatment arms in this trial. Targeted therapy has become a focus of interest in cancer research. The inhibition of angiogenesis is an emerging treatment option for a range of malignant tumors including ovarian cancer. Bevacizumab combined with nab-paclitaxel achieved a response rate of 46% and a median OS time of 16.5 months in platinum-resistant ovarian cancer providing important evidence to support chemotherapy and targeted agents combinations, especially with antiangiogenic therapy [29]. So far, there has been no reported trial combining sunitinib with chemotherapy in patients with ovarian cancer. However, feasibility studies combining sunitinib with irinotecan, pemetrexed, docetaxel or capecitabin in patients with solid tumors indicate the safety and tolerability of this approach [30, 31]. The evidence of some activity of the noncontinuous sunitinib monotherapy in platinum-resistant ovarian cancer found in our trial, together with findings by Biagi et al. [19] indicate that suntinib may be an interesting compound for further trials in ovarian cancer.
Annals of Oncology
original articles
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Influence of zoledronic acid on disseminated tumor cells in primary breast cancer patients E.-F. Solomayer1*, G. Gebauer2, P. Hirnle3, W. Janni4, H.-J. Lück5, S. Becker1, J. Huober6, B. Krämer1, B. Wackwitz7, D. Wallwiener8 & T. Fehm1 1 Department of Obstetrics, Gynecology, and Reproductive Medicine, University of Saarland, Homburg; 2Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg; 3Department of Radiation Oncology, Central Academic Hospital, Bielefeld; 4Department of Gynecology and Obstetrics, Heinrich-Heine University, Düsseldorf; 5Department of Gynecologic Oncology, Hannover Medical School, Hannover, Germany; 6Breast Center, Department of Senologie, Kantonsspital St. Gallen, St. Gallen, Switzerland; 7Norvartis Oncology, Department of Medical Affairs, Nuremberg; 8Department of Obstetrics and Gynecology, University of Tuebingen, Tuebingen, Germany
Received 10 August 2011; revised 5 December 2011; accepted 12 December 2011
Background: The presence of disseminated tumor cells (DTCs) in bone marrow of patients with early breast cancer (EBC) has been correlated with increased risk of metastatic disease or locoregional relapse. Zoledronic acid (ZOL) treatment has reduced DTCs in the bone marrow of patients with EBC in several studies. This controlled study sought to confirm these observations. Patients and methods: Patients with EBC and DTC-positive bone marrow were randomized (N = 96) to treatment with ZOL plus adjuvant systemic therapy or adjuvant systemic therapy alone. The change in DTC numbers at 12 months versus baseline was measured. Results: DTC-positive patients treated with ZOL were more likely to become DTC-negative after 12 months of treatment compared with the controls (67% versus 35%; P = 0.009). At 12 months, DTC counts decreased to a mean of 0.5 ± 0.8 DTCs in the ZOL group and to 0.9 ± 0.8 DTCs in the control group. In addition, ZOL was generally well tolerated. Conclusions: Treatment with ZOL improves elimination of DTCs. Further studies are needed to determine whether the reduction in DTCs by ZOL provides clinical benefit. Key words: breast cancer, disseminated tumor cells, metastasis, recurrence, zoledronic acid
introduction Breast cancer (BC) is the most common solid tumor in women [1]. Metastatic disease is the predominant cause of death in the ∼465 000 patients who succumb to this disease [1]. Despite therapeutic interventions, ∼15% develop distant metastases within 3 years [2]. Furthermore, patients may have late
*Correspondence to: Prof. Dr E.-F. Solomayer, Department of Obstetrics, Gynecology, and Reproductive Medicine, University of Saarland, Kirrberger Strasse, 66421 Homburg/Saar, Germany. Tel: + 49-6841-162-8100; Fax: + 49-6841-162-8110; E-mail: [email protected]
recurrence (‘metastatic dormancy’) ≥10 years after initial diagnosis [2]. Common sites of BC metastasis include bone, lung, and brain [2, 3], of which bone is the most common site (∼75% of cases) [4]. Distant metastasis is associated with poor prognosis [4, 5]. The hypothesis that recurrent/metastatic disease is initiated by micrometastases has gained wide acceptance. Disseminated tumor cells (DTCs) can be sequestered in a dormant state in the bone marrow for several years before reactivating to cause disease recurrence [6]. The most compelling clinical evidence comes from a retrospective pooled analysis of patients with BC (N = 4703) wherein patients with DTC-positive bone marrow
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Annals of Oncology 23: 2271–2277, 2012 doi:10.1093/annonc/mdr612 Published online 1 March 2012