Annals of Oncology Advance Access originally published online on December 3, 2007
Annals of Oncology 2008 19(4):807-813; doi:10.1093/annonc/mdm510
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pediatric malignancies |
Compassionate use of bevacizumab (Avastin®) in children and young adults with refractory or recurrent solid tumors
1 Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Austria
2 Division of Pediatric Hematology and Oncology, Children's Hospital Medical Centre, Bonn, Germany
3 St Anna Children's Hospital Vienna, Austria
* Correspondence to: Dr M. Benesch, Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Auenbruggerplatz 30, A-8036 Graz, Austria. Tel: +43-316-38580427; Fax: +43-316-3853450; E-mail: martin.benesch{at}klinikum-graz.at
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Abstract |
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Background: The aim of this study was to evaluate feasibility and toxicity of bevacizumab (Avastin®), a monoclonal antibody directed against the vascular endothelial growth factor in children and young adults.
Patients and methods: Fifteen patients (male: n = 8; female: n = 7; median age, 14.6 years) received bevacizumab for recurrent or progressive solid tumors (carcinoma: n = 3; neuroblastoma: n = 2; astrocytoma grade III: n = 2; rhabdomyosarcoma: n = 2; nephroblastoma: n = 2; benign vascular tumors: n = 2; synovial sarcoma: n = 1; and malignant hemangiopericytoma: n = 1) on a compassionate basis. Bevacizumab was administered at 5–10 mg/kg body weight intravenously every 2–3 weeks. Most patients received chemotherapy in addition to bevacizumab. Duration of bevacizumab therapy ranged from 1.5 to 23 months.
Results: Bevacizumab-related side-effects were mild and included hypertonia (n = 2), proteinuria/hematuria (n = 2), epistaxis (n = 2), local erythema (n = 1), and defective wound healing and ascites (n = 1). Radiographic objective responses (partial responses) were observed in two patients with astrocytoma grade III and in one patient each with neuroblastoma and pleomorphic rhabdomyosarcoma, respectively.
Conclusions: Bevacizumab seems to have a good acute safety profile and some antitumor activity in heavily pretreated children and young adults with recurrent solid tumors. Prospective clinical trials are urgently needed to further evaluate the safety and efficacy of bevacizumab in pediatric patients.
Key words: angiogenesis, bevacizumab, children, refractory solid tumors
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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During the past decades prognosis of almost all types of childhood cancer has dramatically improved. In European countries survival at 5 years increased from 54% in patients diagnosed between 1978 and 1982 to 75% in patients diagnosed between 1993 and 1997 [1]. However, outcome is poor in case of refractory or recurrent solid tumors and only about 25% of patients who relapse after discontinuation of treatment will ultimately remain disease free at 10–15 years [2–4]. For some subtypes of cancer, the overall survival after relapse or progression is 5% or less [5, 6].
Targeted therapies for the most common adult malignancies became available during the past decade [7–9]. In contrast, little progress has been made towards the introduction of such therapies for children with malignant solid tumors. Thus, treatment of relapse in childhood malignancies is still on the basis of surgery, irradiation, and cytotoxic chemotherapy. Angiogenesis is a crucial step in the growth and metastatic spread of solid tumors. Several factors are involved in the regulation of both normal and abnormal angiogenesis. Among them the vascular endothelial growth factor (VEGF) exerts a number of different proangiogenic properties by binding to their respective receptors. VEGF was found to be overexpressed in various malignancies [10, 11]. Bevacizumab (Avastin®; Genentech Inc., San Francisco, CA) is a humanized antibody against VEGF [12]. By specific binding to VEGF-A and its isoforms, this compound counteracts angiogenic effects induced by VEGF and allows for a normalization of tumor vasculature [13]. In 2004, the USA Food and Drug Administration approved bevacizumab as a first-line treatment of patients with metastatic colorectal cancer [14]. The drug is currently being tested for various other adult malignancies such as renal cell carcinoma, metastatic breast cancer, or advanced pancreatic cancer [15–17]. Clinical experiences with bevacizumab in pediatric patients are limited. The current report describes the compassionate use of bevacizumab in children with recurrent or refractory solid tumors.
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patients and methods |
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The primary goal of the present retrospective study was to report on the safety profile and toxicity of bevacizumab in a cohort of children and young adults with refractory or recurrent solid tumors. Between 2004 and 2006, 15 patients [male: n = 8; female: n = 7; median age at diagnosis, 12.5 (range 0–22) years; median age at initiation of bevacizumab therapy, 14.6 (range 0.9–30) years] received treatment with bevacizumab at three different tertiary care institutions. Thirteen patients had malignant underlying diseases. Basic clinical characteristics and treatment before bevacizumab are summarized in Tables 1 and 2. Characteristics of the administration of bevacizumab are shown in Table 3.
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In three patients initial diagnosis was made before 2000 (1988: n = 1; 1993: n = 1; and 1997: n = 1), whereas the remaining 10 patients had their malignancy diagnosed in 2000 or thereafter (2000: n = 1; 2001: n = 1; 2003: n = 4; and 2004: n = 2; and 2005: n = 2). Except for the three patients with primary intracranial tumors and one patient with synovial sarcoma, all other patients initially presented with metastatic disease (metastases at multiple sites: n = 4; lung metastases: n = 2, peritoneal carcinosis: n = 1; peritoneal carcinosis and liver metastases: n = 1; and bone marrow metastases: n = 1). In two other patients with benign vascular tumors (congenital giant lymphangioma of the head, neck, and thorax: n = 1; von Hippel–Lindau disease with multiple hemangioblastomas of the right eye, cerebellum, and spinal cord: n = 1) treatment with bevacizumab was initiated due to the potentially life-threatening site of the tumor.
In nine out of 13 patients (patients 6–13, 15) with malignant diseases, initial therapies were carried out according to prospective multi-institutional trials active at the time of diagnosis (Table 2). Following progression or relapse, patients proceeded to different salvage therapies including surgery, radiotherapy, and conventional chemotherapy. A total of eight patients (neuroblastoma: n = 2; nephroblastoma: n = 2; rhabdomyosarcoma: n = 2; malignant intracranial hemangiopericytoma: n = 1; and pancreatic acinar cell carcinoma: n = 1) underwent high-dose chemotherapy with autologous stem cell support also.
Bevacizumab was administered on a compassionate basis out of a specific protocol assuming that the potential benefits and toxicity would compare favorably with other conventional cytotoxic drugs in these heavily pretreated patients. In the majority of patients, bevacizumab was given as third- or fourth-line therapy following failure to previous relapse therapies. The drug dose and intervals of administration were on the basis of the currently available clinical studies in adult patients [12, 14–17]. Bevacizumab was administered at 5–10 mg/kg body weight (BW) intravenously every 2–3 weeks. Patients and/or their legal guardians were informed about the potential benefits and side-effects of this experimental approach and gave their informed consent before the initiation of bevacizumab administration. During administration of bevacizumab, patients were monitored according to center guidelines for side-effects with special emphasis on hypertension, proteinuria, bleeding, thromboembolic complications, and delays in wound healing. Assessment of response was done using clinical and radiographic evaluations at regular intervals. The total duration of bevacizumab treatment was on the basis of the decision of the treating physician.
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results |
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intracranial tumors (patients 1–3)
Three patients with intracranial tumors received bevacizumab. One girl, initially diagnosed with hypothalamic pilocytic astrocytoma World Health Organization (WHO) grade I, had to undergo irradiation due to tumor progression. A continuous increase in tumor size necessitated two partial resections with subsequent regrowth of the tumor (Figure 1A). Centrally reviewed histopathology now disclosed pleomorphic xanthoastrocytoma grade III. Administration of bevacizumab and concomitant temozolomide (TMZ) was started 2 years and 8 months after diagnosis, leading to a 50% reduction of the tumor volume (Figure 1B). This patient is still under bevacizumab/TMZ therapy. The second patient in this group was diagnosed with hemispheric anaplastic astrocytoma grade III and progressed following subtotal resection and simultaneous radiochemotherapy. As treatment with numerous other cytotoxic drugs failed in this patient (Table 2), bevacizumab treatment was initiated 5
years after diagnosis. A remarkable, but short-lasting partial remission (Figure 2A, B) could be achieved, but was followed by clinical deterioration and death. The third patient, a 13-year-old boy who had been diagnosed with malignant hemangiopericytoma in 1988, developed liver and multiple skeletal metastases almost 10 years later. A number of antiangiogenic drugs were administered for a period of 6 years in addition to local surgery and irradiation. Since he did not respond, bevacizumab was initiated and given for a period of almost 2 years. The clinical course could be stabilized, but metastases progressed slowly during bevacizumab treatment. The patient was then changed to other antiangiogenic therapies.
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carcinomas (patients 4–6)
Bevacizumab was administered in three patients with carcinomas of different sites (Table 1) and extensive disease at diagnosis. Whereas one patient, a 15-year-old female with renal cell carcinoma, received bevacizumab immediately following diagnosis concomitant to other biologicals, in two other patients bevacizumab was started 2 years after diagnosis. No durable stabilization was observed. Two patients are alive with progressive disease and one of them died.
pediatric solid tumors (neuroblastoma; patients 7 and 8)
A 4-year-old boy developed local relapse after multimodality treatment of metastatic neuroblastoma according to the European high-risk neuroblastoma protocol. Two of the metastatic lesions decreased in size on bevacizumab and concomitant carboplatin and irinotecan, another suspicious lesion showed decreased enhancement intensity. All lesions were resected. At last follow-up the patient was in complete remission. In the second patient with neuroblastoma, a late relapse involving bone and bone marrow occurred >13 years after diagnosis. He was treated with conventional chemotherapy and cis-retinoic acid for 1 year, but progressed and subsequently received a short course of bevacizumab. The patient, however, died before the evaluation of response.
pediatric solid tumors (nephroblastoma; patients 9 and 10)
Multiple slowly progressing lung metastases from the date of diagnosis complicated the clinical course in a girl who was diagnosed with nephroblastoma in 1997. During treatment with bevacizumab which was started at the end of 2005, lung metastases were stable for 7 months and then slightly progressed for another 6 months. The patient is alive with progressive disease. Similarly disease stabilization for 6 months could be achieved in a 13-year-old boy with (second) abdominal and mediastinal relapse by concomitant administration of bevacizumab and topotecan (Hycamtin; GlaxoSmithKline, Philadelphia, PA). The patient subsequently developed refractory ascites, most probably as a consequence of tumor progression. To prevent possible hepatic thromboembolic events, however, treatment with both bevacizumab and topotecan was stopped. He died 3 months later of progressive disease.
pediatric solid tumors (sarcoma; patients 11–13)
Treatment with bevacizumab and concomitant topotecan was given also in two patients with multifocal relapse of alveolar rhabdomyosarcoma and pleomorphic rhabdomyosarcoma, respectively. In the first patient this therapy was stopped after 6 weeks due to progression. The second patient, however, achieved a partial remission with complete disappearance of left supraclavicular and regression of prevertebral lymph node metastases (Figure 3A, B). While on therapy he tragically committed suicide 9 months following diagnosis of relapse.
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A 19-year-old female patient with parathyroidal synovial sarcoma developed late distant recurrence with lung metastases 7 years after diagnosis. She received conventional chemotherapy with subsequent resection of lung metastases. Postoperative consolidation included bevacizumab and cyclophosphamide for 4 months. The patient, however, developed second recurrence and died shortly thereafter.
nonmalignant tumors (von Hippel–Lindau disease, lymphangioma; patients 14 and 15)
Two patients received bevacizumab for treatment of nonmalignant diseases. The first patient was diagnosed with von Hippel–Lindau disease at the age of 16. Whereas the cerebellar mass was completely removed, this was not possible for a solid, contrast-enhancing lesion located in the cervical spinal cord at the level of C4. The patient was put on interferon 
2a. Since the spinal cord mass increased in size on magnetic resonance imaging, antiangiogenetic therapy was intensified by adding bevacizumab to interferon. Bevacizumab was given for 12 months without further progression. Presently, the patient is neurologically asymptomatic with stable disease (less than a 50% reduction and less than a 25% increase of the tumor volume).
A giant congenital lymphangioma involving the head, neck, and thorax was partially resected and treated with low-dose conventional chemotherapy including ifosfamide and etoposide. Due to progression, chemotherapy was changed to trofosfamide supplemented with bevacizumab. Although further growth of the tumor did not occur, treatment of bevacizumab was not continued after three doses in this patient due to concerns about possible side-effects in very young children.
side-effects
Side-effects of bevacizumab are summarized in Table 3. Bevacizumab was well tolerated, even in patients who received this drug over a prolonged period of time. None of the patients required dose reduction or termination of administration due to side-effects.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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When added to standard chemotherapy, bevacizumab has been shown to significantly increase survival of patients with metastatic colorectal cancer [14]. In patients with metastatic renal cell carcinoma, bevacizumab at both 3 mg/kg and 10 mg/kg BW was able to prolong time to progression, but not overall survival [15]. Encouraging results with bevacizumab have also been reported in patients with advanced pancreatic and hepatocellular carcinoma [17, 18]. In contrast, studies on the administration of bevacizumab in patients with metastatic breast cancer have yielded controversial results [16, 19].
Although it is difficult to predict clinical effectiveness to antiangiogenetic drugs such as bevacizumab on the basis of the expression pattern of angiogenic factors and their corresponding receptors, growing preclinical evidence indicates that these factors also play an important role in the development and progression of solid tumors of childhood including high-grade glioma, rhabdomyosarcoma, nephroblastoma, neuroblastoma or Ewing's sarcoma [20–25]. Intraperitoneal administration of bevacizumab in a mouse xenograft model of neuroblastoma has recently been shown to significantly reduce tumor growth in vivo [26]. So far the clinical use of bevacizumab in younger patients has been reported only sporadically [27, 28]. A phase I dose-escalating study in 20 patients aged 1–21 years with refractory solid tumors was presented at the American Society of Clinical Oncology 2006 meeting [28]. The authors found no dose-limiting toxicity. No partial or complete responses were observed. In five patients disease could be stabilized for >3 months.
In the present retrospective study bevacizumab was used on a compassionate basis in 13 heavily pretreated patients with progressing malignant diseases and in two patients with nonmalignant angiomatous tumors. Although assessment of the efficacy of bevacizumab was not the primary goal of the present report, we did observe objective radiographic responses in patients who received bevacizumab in combination with other cytotoxic drugs. In two female patients with astrocytoma WHO grade III bevacizumab was combined with TMZ according to a preliminary cases series presented at the same meeting [29]. In accordance with this report, the tumor volume and contrast enhancement decreased in both patients (Figures 1 and 2), indicating that bevacizumab with concomitant TMZ is effective even in extensively pretreated patients with high-grade gliomas. These encouraging preliminary results might argue for the use of bevacizumab earlier in the clinical course of patients with high-grade gliomas who generally have a poor prognosis. Interestingly, no radiographic response was observed in the patient with intracranial hemangiopericytoma and multiple liver and skeletal metastases. Three patients with carcinomas at different sites were also treated with bevacizumab combined with other cytotoxic drugs, but none of them showed regression of metastases. Among patients with other solid tumors of childhood, one patient with pleomorphic rhabdomyosarcoma unequivocally achieved a remarkable regression of lymph node metastases; one patient with recurrent neuroblastoma showed a decrease in tumor size radiographically. Disease stabilization was achieved for about 6 months in two patients with nephroblastoma. Whether or not bevacizumab added to disease stabilization in the two patients with von Hippel–Lindau disease [30] and a giant congenital lymphangioma, respectively, is difficult to answer. Whereas in the first of these two patients bevacizumab was given for a period of 12 months without significant side-effects, therapy with bevacizumab was stopped in the second patient because of the very young age and the underlying benign tumor to avoid possible side-effects related to VEGF inhibition at this age [12].
As already highlighted in the study by Glade Bender et al. [28], bevacizumab was well tolerated in all patients. This also applies for the four patients (patients 3, 5, 9, and 12) who received bevacizumab over a prolonged period of time (
10 months). Overall, two patients developed hypertension which, however, did not cause any symptoms nor necessitated antihypertensive medication. Epistaxis and proteinuria were observed in two patients each. Local erythema and defective wound healing was observed in one patient each. In the latter patient bevacizumab was not continued in order to avoid hepatic thromboembolic complications which possibly might have increased preexisting ascites formation.
The ‘off-label’ use of a new drug such as bevacizumab in children and young adults out of a specifically designed protocol might raise some ethical concerns. It is, however, well known that carrying out clinical studies in children is nowadays hampered by many factors. First the pharmaceutical industry is generally very reluctant to carry out studies on new drugs in children, because the commercial profit can be expected to be conceivably small compared with the adult population. The imminent high legal risks further prevent many pharmaceutical companies from carrying out clinical studies in children. Secondly, the new EU Clinical Trials Directive to be included in the national legislation by May 2004 hinders the conduct particularly of investigator-initiated trials by a dramatic increase of legal regulations, administrative work and stringent responsibilities for investigators [31,32]. Adherence with these legal regulations significantly increases the costs for the development and conduct of clinical trials, mainly attributable to additional personnel required. So far pediatric hematologists/oncologists are faced with a tremendous ethical dilemma, when they have to decide whether or not to use new drugs off-label for the treatment of children with progressive malignant diseases. As all our patients with malignant diseases would have died before a possible approval of bevacizumab in pediatric cancer patients, we decided to use this drug off-label on a compassionate basis, particularly because the toxicity and safety was expected to be favorable compared with other cytotoxic drug combinations. As our and other investigators' experiences indicate that bevacizumab has activity in pediatric malignancies, large multicenter trials are needed without delay to rapidly assess the clinical value of this drug in childhood malignancies.
Received for publication September 18, 2007. Revision received October 1, 2007. Accepted for publication October 1, 2007.
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