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Keywords:

  • sunitinib;
  • radiation therapy;
  • central nervous system;
  • antiangiogenesis;
  • brain metastases

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

BACKGROUND:

In this phase 1 trial, the authors evaluated sunitinib combined with radiation therapy (RT) for the treatment of primary or metastatic central nervous system (CNS) malignancies.

METHODS:

Eligible patients had CNS malignancies that required a (minimum) 2-week course of RT. Sunitinib (37.5 mg) was administered daily for the duration of RT with optional treatment extension of 1 month. Urine was collected at 3 time points for correlative biomarker studies. The primary endpoint was acute toxicity defined according to Common Toxicity Criteria version 3.

RESULTS:

Fifteen patients were enrolled (12 with CNS metastasis and 3 with primary tumors). RT doses ranged from 14 Gray (Gy) to 70 Gy (1.8-3.5 Gy per fraction). Acute toxicities included hematologic, nausea, hyperglycemia, fatigue, hypocalcemia, and diarrhea. Six patients (40%) developed grade ≤2 toxicities. Grade 3 toxicities occurred in 7 patients (47%) and included hematologic toxicity, fatigue, deep vein thrombosis, dysphasia, hyperglycemia, and hyponatremia. No grade 3 through 5 hypertensive events or intracerebral hemorrhages occurred. Two grade 5 adverse events attributed to disease progression occurred. The median follow-up was 34.2 months. Two patients (13%) achieved a partial response, 9 patients (60%) had stable disease, and 2 patients (13%) patients had progressive disease. The 6-month progression-free survival rate for patients who had brain metastasis was 58%. Grade 3 hematologic toxicity was correlated with greater changes in vascular endothelial growth factor levels changes between baseline and the completion of RT.

CONCLUSIONS:

Continuous 37.5-mg sunitinib combined with RT in patients who had CNS malignancies yielded acceptable toxicities and adverse events. The current results indicated that changes in urine vascular endothelial growth factor levels are associated with hematologic toxicity, and this association should be analyzed in a larger cohort. The feasibility, safety, and early response results warrant a phase 2 trial. Cancer 2011;. © 2011 American Cancer Society.

Preclinical studies suggest that the combination of angiogenic blockade and radiotherapy (RT) can enhance the therapeutic ratio of ionizing radiation through the phenomenon of vascular normalization.1, 2 Although it is counterintuitive and poorly understood, combining ionizing RT and antiangiogenic agents may cause aberrant tumor vessels to regress,3, 4 thereby increasing tumor oxygen concentration and acting as a potential radiosensitizing agent. Antiangiogenic agents also may decrease interstitial fluid pressure within tumors, allowing improved oxygen delivery to hypoxic tissues.5, 6

Furthermore, antiangiogenic agents have multiple other effects on the tumor microenvironment which may impact the tumor response to radiation therapy. Agents that disrupt the phosphoinositol-3 kinase/protein kinase B/mammalian target of rapamycin (PI3K-Akt-mTOR) signaling pathway may radiosensitize the vascular endothelium.7 The ability of endothelial progenitor stem cells, which contribute to tumor angiogenesis and growth, to mobilize and recruit can be impaired by agents that disrupt the PI3K-Akt-mTOR pathway.8-10 Preclinical studies in glioma11 and meningioma12 suggest that antiangiogenic agents may have an enhanced radiosensitizing effect in central nervous system (CNS) tumors.

SU11248 (sunitinib) is an orally active, indolinone-based, multitargeted receptor tyrosine kinase inhibitor that selectively targets vascular endothelial growth factor receptors 1 through 3 (VEGFR1, VEGFR2, VEGFR3), platelet-derived growth factor receptors α and β (PDGFRα, PDGFRβ), stem cell factor receptor (c-KIT), neurotropic factor receptor (rearranged during transfection [RET]), FMS-like tyrosine kinase-3 (FLT3), and colony-stimulating factor 1R (CSF-1R).13-22 Sunitinib is approved by the US Food and Drug Administration as monotherapy in metastatic renal cell carcinoma and imatinib-refractory gastrointestinal stromal tumor (GIST).

Despite an array of tumor markers currently in use, none serve as general predictors of outcome after therapy. In theory, angiogenic factors can identify patients who are at risk for recurrent disease regardless of tumor type, because the process of angiogenesis is ubiquitous to cancer. Urine biomarkers provide a noninvasive platform to interrogate disease status and tumor biology. On the basis of this information, we hypothesized that urine VEGF measured at baseline, at the end of RT, and at 1 month after RT may be predictive of treatment response.

The combination of RT and VEGF pathway-targeting antiangiogenic agents has demonstrated tumor growth delay and tumor cell killing in preclinical studies.23-27 In addition, preclinical models with sunitinib and ionizing radiation have demonstrated a more than additive effect on tumor growth delay compared with either treatment alone.3, 28, 29

We evaluated the safety and toxicity profile of 37.5 mg of oral sunitinib administered daily to patients undergoing RT for primary or metastatic central nervous system malignancies. In addition, we evaluated correlative urine biomarker results and early response rates for this regimen.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Patient Selection

This study received approval of the Kimmel Cancer Center Research Review Committee and Thomas Jefferson University Institutional Review Board (IRB) (IRB 06C.549) before patient recruitment and accrual. Patients with histologically confirmed primary or metastatic CNS malignancies whose treatment involved a minimum 2-week course of RT were eligible. Patients who had widely metastatic disease with brain metastases did not have biopsy confirmation of their brain metastases if they had magnetic resonance imaging (MRI) findings that were characteristic of brain metastases. Other eligibility requirements included age ≥18 years, a World Health Organization performance status between 0 and 2,30 and a life expectancy >3 months. Prior surgery, chemotherapy, and/or RT (including RT to the CNS) were allowed provided there was resolution of all acute toxic effects of prior therapies (grade ≤1 according to National Cancer Institute Common Toxicity Criteria version 3 [CTCv3]).31 Adequate hematologic, hepatic, and renal function (defined as hemoglobin >9 g/dL, platelet count >100,000, absolute neutrophil count >1500/μL, aspartate and alanine aminotransferase levels <2.5 times the upper limit of normal [ULN], total serum bilirubin <1.5 times the ULN, serum calcium <12 mg/dL, and serum creatinine <1.5 times the ULN) was required.

Study Design

The study involved a baseline screening assessment period, treatment, and an observation period. During treatment, sunitinib 37.5 mg was given orally starting the first day of RT and was taken daily throughout the RT course, including weekends. This regimen was chosen based on multiple phase 1 and 2 studies in metastatic renal cell carcinoma,32, 33 GIST,34 and soft tissue sarcoma,35 which demonstrated that this schedule was well tolerated and had a manageable toxicity profile. In addition, we hypothesized that a continuous daily regimen would maximize the potential radiosensitizing effect. The total dose and fractionation of RT varied depending on tumor type, prior RT doses, and physician preference. Dose-limiting toxicities (DLTs) were defined as any grade 3 through 5 toxicity attributable to sunitinib, excluding grade 3 hematologic toxicity unless it clearly was dose limiting. Early termination of the study was stipulated if the DLT rate exceeded 50%. A provision for de-escalation to sunitinib 25 mg using the standard 3 + 3 phase 1 trial design (Design 1 described by Simon et al36) was permitted if >33% of patients enrolled experienced a DLT. Patients who experienced minimal toxicity were given the option to continue sunitinib for an additional 30 days after the completion of RT. All patients had weekly hematology and chemistry panels. Corticosteroid use before treatment, during treatment, and at 1-month follow-up was documented. Corticosteroids were not required but were used as necessary at the discretion of the treating physicians.

The primary endpoint of this study was to evaluate the toxicity and safety profile of combining sunitinib and RT. Secondary endpoints included assessment of radiographic tumor response at 1 month and urine biomarker changes.

Toxicity Grading and Evaluation of Response

All toxicities were documented according to CTCv3 criteria,31 and patients were evaluated for potential DLT weekly during treatment and 4 weeks after the completion of treatment. Pertinent history, physical examinations, and hematology and chemistry studies were completed weekly during treatment and 1 month after the completion of treatment. MRI studies or computed tomography scans were completed approximately 1 month after study completion and at regular follow-up appointments thereafter, depending on the diagnosis, to assess early response. Formal neurocognitive functional assessments were not performed. Early imaging response was assessed using the criteria described by Macdonald et al.37

Patients, Urine Collection, and Processing

Urine was collected from all study patients at baseline, at the completion of RT, and 1-month post-treatment. Urine was stored at −20°C before evaluation and then centrifuged at 3000 revolutions per minute for 10 minutes at 4°C. The supernatant was used for subsequent assays. Urinary creatinine levels were obtained on the Bayer DCA 2000+ Analyzer (Bayer HealthCare, Elkhart, Ind) according to the manufacturer's protocol. All samples were normalized by creatinine level. Urine samples were assayed for VEGF, the met proto-oncogene (MET), matrix metalloproteinase-1 (MMP-2), and MMP-9. These biomarkers were chosen for analysis, because previously published data suggested an association between these biomarkers and brain tumors.38, 39

Electrochemiluminescence Immunoassays

MET, MMP-2, MMP-9, and VEGF were measured in urine specimens using an electrochemiluminescence immunoassay (Meso Scale Discovery, Gaithersburg, Md). All samples were thawed at room temperature for 4 hours before evaluation. MMP-2, MMP-9, and VEGF assays were performed according to the manufacturer's protocol. MET levels were detected according to a previously published protocol.40

Statistical Methods

To assess clinical efficacy, the neurologic progression-free survival (PFS) and overall survival (OS) rates were calculated from the time of enrollment using the Kaplan-Meier method.41 Median urinary VEGF levels over time were compared using the Friedman chi-square test based on ranks. Median levels of VEGF fold-change were compared based on the development of hematologic toxicity using the exact Wilcoxon rank-sum test. All statistical tests were 2-sided, and P values ≤ .05 were considered significant.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Patient Characteristics and Treatment

Fifteen patients were accrued between April 16, 2007 and January 7, 2008. Table 1 displays patient characteristics and total RT dose and fraction size. Two patients had received previously RT to the brain. The median total dose was 37.5 Gy (range, 14-70 Gy), including 5 patients who received >50 Gy. The median dose per fraction was 2.5 Gy (range, 1.8-3.5 Gy). Thirteen patients completed the prescribed treatment. One patient died during treatment, and another patient chose to discontinue sunitinib secondary to decreased blood counts, vomiting, and fatigue. Seven patients (47%) chose to continue daily sunitinib for 30 days after the completion of RT.

Table 1. Patient and Treatment Characteristics
 No. of Patients
CharacteristicAll PatientsMetastatic DiseasePrimary Tumor
  1. Abbreviations: CNS, central nervous system; Gy, grays; HNSCC, head and neck squamous cell carcinoma; NSCLC, nonsmall cell lung cancer; RT, radiotherapy; WHO, World Health Organization.

No. of patients15123
Histology   
 Melanoma440
 NSCLC330
 Adenoid cystic220
 HNSCC110
 Chordoma110
 Anaplastic meningioma101
 CNS sarcoma101
 WHO grade II astrocytoma101
Prior RT220
Median age (range), y58.7 (31-77)54.4 (37-77)50.7 (31-76)
Age, y   
 <45211
 45-54321
 55-64550
 65-74330
 ≥75211
Sex   
 Men1293
 Women330
Race   
 Caucasian1091
 African American330
 Asian American202
WHO performance status   
 0321
 112102
RT target   
 Whole brain990
 Partial brain633
Median RT dose (range), Gy37.5 (14-70)37.5 (14-59.4)60.0 (50.4-70)
RT dose per fraction, Gy   
 1.8211
 2.0202
 2.5880
 3.0110
 3.5220
Total RT dose, Gy   
 <25110
 25-30220
 35-45770
 >45523
Median duration of sunitinib treatment (range), wk5 (0.6-10.8)4.7 (0.6-10.8)6.4 (2.6-8.8)

Toxicity Evaluation

Six patients (40%) had grade 1 or 2 toxicities, including fatigue, hyperglycemia, nausea, hypocalcemia, and diarrhea. Hematologic toxicities were most common, and nearly all patients had at least grade 1 anemia, leukopenia, or thrombocytopenia. Toxicities are listed according to grade in Table 2.

Table 2. Toxicity Profile
 No. of Episodes
ToxicitiesGrade 1Grade 2Grade 3Grade 4Grade 5Any
  1. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; DVT, deep vein thrombosis.

Hematologic      
 Leukopenia222  6
 Thrombocytopenia311  5
 Anemia22   4
 Lymphopenia  1  1
 Neutropenia  1  1
Metabolic      
 Hyponatremia3 1  4
 Hyperglycemia3 1  4
 Hypocalcemia11   2
 Hypercarbia1    1
 Hyperuremia1    1
 Hypokalemia1    1
 Elevated creatinine1    1
Hepatic      
 Hyperbilirubinemia11   2
 Hypoproteinemia1    1
 Hypoalbuminemia1    1
 Elevated alkaline phosphatase1    1
 Elevated ALT1    1
 Elevated AST1    1
Constitutional      
 Fatigue332  8
 Pain 2   2
 Dermatitis11   2
 Chest pain11   2
 Alopecia11   2
 Edema1    1
Gastrointestinal      
 Nausea31   4
 Anorexia3    3
 Diarrhea11   2
 Dyspepsia11   2
 Emesis 1   1
 Mucositis 1   1
Neurologic      
 Seizure 1  12
 Dysphasia  1  1
 Drooling/difficulty chewing  1  1
 Headache1    1
 Motor neuropathy1    1
Vascular      
 DVT 11  2
 Pulmonary embolism    11
 Dyspnea1    1
 Epistaxis 1   1
 Vaginal bleeding1    1
 Hypertension0    0
All4323120280

Grade 3 toxicities occurred in 7 patients (47%). Two (13%) grade 3 toxicities met the criteria for DLT. The other grade 3 toxicities were considered attributable to the combination of sunitinib with RT and were not dose limiting. Of the 12 grade 3 toxicities, 7 were considered attributable to sunitinib (including neutropenia, leukopenia, thrombocytopenia, hyponatremia, and hyperglycemia), 2 were attributed to RT (dysphasia, difficulty chewing), 2 were attributed to the combination (fatigue), and 1 DVT was attributed to the prevalent coagulation abnormalities among patients with brain tumors. No difference in toxicity was observed between patients who received whole-brain RT (WBRT) versus partial-brain RT. No difference in toxicity was observed based on RT fraction size or total dose administered. There was no observed difference in skin toxicity or toxicity of other tissues within the radiation portal. No grade 4 or 5 hypertensive events or intracerebral hemorrhages occurred. Two grade 5 adverse events (status epilepticus and pulmonary embolism) occurred, and the medical monitor determined that these events were related to disease progression. One patient with metastatic melanoma who was retreated with WBRT after previous WBRT and stereotactic radiosurgery died on Day 4 of treatment from uncontrolled status epilepticus, which was attributed to multiple brain metastases. A second patient with multiple brain metastases from nonsmall cell lung cancer died 6 days after study completion from a presumed pulmonary embolism.

Early Response

Thirteen patients had follow-up MRI imaging to assess 1-month tumor response. Two patients (15%) achieved a partial response, 9 patients (70%) patients had stable disease, and 2 patients (15%) had disease progression. All 3 patients with primary CNS tumors had stable disease. Among the patients with metastatic disease, 2 (20%) had a partial response, 6 (60%) had stable disease, and 2 (20%) had progressive disease (Table 3). Before the initiation of treatment, 5 patients (33%) were receiving high-dose corticosteroids. At 1-month follow-up, none of the patients required corticosteroids. Three patients (20%) initiated corticosteroid therapy during RT, and all were tapered off corticosteroids within 1 month after RT.

Table 3. Early Treatment Response as Determined by Gadolinium-Enhanced Magnetic Resonance Imaging 1 Month After Treatment, 6-Month Progression-Free Survival, and Median Overall Survival
 No. of Patients (%)
VariableAll PatientsMetastatic DiseaseCNS Primary
  1. Abbreviations: CNS, central nervous system; OS, overall survival; PFS, progression-free survival.

Partial response2 (15)2 (20)0 (0)
Stable disease9 (70)6 (60)3 (100)
Progressive disease2 (15)2 (20)0 (0)
6-mo PFS9 (60)8 (67)1 (33)
Median OS, mo8.87.6Not reached

One patient initially presented with multiple, small, parenchymal, metastatic brain lesions from adenoid cystic carcinoma, the largest of which was located in the right parietal lobe and measured 14 × 10 mm with an additional 12 × 8 mm lesion in the right frontal lobe. After finishing RT and continuing sunitinib for 1 month, an MRI revealed an interval decrease in the size of all previous parenchymal enhancing lesions. Another patient with metastatic renal cell carcinoma presented with a 4.6-cm, dural-based mass involving the sphenoid sinus, sella, suprasellar cistern, clivus, and cribriform plate with residual tumor after transphenoidal resection. A 1-month follow-up MRI revealed a significant decrease in the size of the skull base lesion with no enhancement and no metabolic activity on a positron emission tomography.

Survival

At a median follow-up of 34.2 months, 6 patients continued to have stable disease, and 7 patients had disease progression. The PFS rate at 6 months was 60%, and 9 patients had stable disease (Fig. 1). Four of the original 15 patients (27%) remained alive at the time of this report. The median survival was 8.8 months (Table 4). Eleven patients (73%) remained alive 6 months after treatment, and survival for all patients ranged from 0.1 months to 39.9 months. Among those with brain metastases, 2 of 12 patients (18%) remained alive (range, 0.1-39.9 months). Seven patients (58%) who had brain metastases were progression-free for 6 months.

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Figure 1. These Kaplan-Meier curves illustrate (Top) overall survival and (Bottom) neurologic progression-free survival.

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Table 4. Histology, Response, Neurologic Progression-Free Survival and Overall Survival
PatientHistologyResponseNeurologic PFS, moOS, mo
  1. Abbreviations: CNS; central nervous system; HNSCC, head and neck squamous cell carcinoma; NA, not available; NSCLC, nonsmall cell lung cancer; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.

1Adenoid cysticPD7.47.4
2NSCLCNA0.70.7
3MelanomaNA0.40.4
4AstrocytomaSD19.820.9
5NSCLCSD4.94.9
6HNSCCSD15.739.9
7ChordomaSD7.87.8
8Atypical meningiomaSD11.511.5
9NSCLCSD28.928.9
10MelanomaSD20.820.8
11MelanomaSD3.26.0
12Adenoid cysticPR6.08.8
13MelanomaPD4.35.4
14Renal cellPR18.320.0
15CNS sarcomaSD7.816.7

Urine VEGF

Urine samples were collected from 13 of the 15 patients enrolled on this study. Samples were collected from 12 of 13 patients at baseline, from 10 of 13 patients at the end of RT, and from 5 of 13 patients 1 month after RT. Urine VEGF levels were detectable in 24 of 27 samples (89%). The median VEGF concentration for at time points for patients who had detectable levels was 336 pg/mg (range, 53-1153 pg/mg). There were no statistically significant differences in VEGF levels between any of the 3 time points (Friedman chi-square test; P = .87) (see Fig. 2).

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Figure 2. Urinary vascular endothelial growth factor (VEGF) levels were measured at baseline, at the end of radiotherapy (RT), and 1 month post-RT. It was assumed that patients with undetectable VEGF levels had a VEGF value of 24 pg/mg, which was the lowest detectable level. Solid squares indicate median values, and error bars represent 95% confidence intervals.

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Only 10 patients had paired baseline and end-of-RT samples. For the current analysis, we assumed that patients who had undetectable VEGF levels had values of 24 pg/mg, which was the lowest detectable level of VEGF for our assay. Four of 10 patients (40%) had an increase >3-fold (relative to baseline) in their urine VEGF level. This is similar to the >3-fold increase in plasma VEGF levels reported in 44% of patients with metastatic renal cell cancer who received sunitinib.42

Paired samples between baseline and 1 month after RT were available for 4 patients. We were unable to correlate changes in urinary VEGF levels and RT response because of the lack of paired samples. Of the paired samples, 2 of patients had metastatic melanoma and continued on sunitinib after RT. One patient had a >2 fold increase in VEGF from baseline to 1 month after RT and developed progressive disease, and the other patient had a 72% reduction in VEGF between the same time points and had stable disease. We also analyzed changes in VEGF levels between baseline and the end of RT in patients who did and did not develop grade 3 hematologic toxicities. Three of 5 patients who developed grade 3 hematologic toxicities had paired urine samples between baseline and the end of RT, whereas 5 of 5 patients who did not develop grade 3 hematologic toxicity had paired samples. The median fold change in VEGF levels (end of RT/baseline) between patients with versus without a grade 3 hematologic toxicity was 5.0 versus 0.75, respectively (P = .036) (see Fig. 3). The median RT dose delivered to these 2 groups did not differ significantly (P = .39).

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Figure 3. Urinary vascular endothelial growth factor (VEGF) fold changes (fc) (in pg/mg) between baseline and the end of radiation therapy are illustrated for patients who did not (n = 5) and did (n = 3) develop grade 3 or 4 hematologic toxicity during treatment. Median values for those who did not develop toxicity and those who did develop toxicity differed significantly (0.8 pg/mg [range, 0.4-2.2 pg/mg] vs 5.0 pg/mg [range, 4.1-17.8 pg/mg], respectively; P = .037; Wilcoxon rank-sum exact test). Wilcoxon scores are plotted and were based on the ranks in the original data.

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Urine MMP-9

Urine MMP-9 was detectable in 21 of 27 samples (78%). All 6 undetectable samples were from patients with metastatic melanoma and were over various time points (3 at baseline, 2 at the end of RT, 1 at 1 month after RT). The median MMP-9 concentration over all 3 time points for those with detectable levels was 2095 pg/mg (range 80-804,101 pg/mg), and there was no significant difference between time points. To determine the median fold change for patients who had paired samples (baseline and the end of RT) available, we assumed that the MMP-9 levels in undetectable samples were 72 pg/mg, which was the lowest detectable level of MMP-9 for our assay. An increase in MMP-9 from baseline to the end of RT was observed in 6 of 10 patients, and the median fold increase was 21 pg/mg (range, 2-227 pg/mg).

Urine MET

Urine MET was detectable in 27 of 27 samples (100%). The median MET concentration overall all 3 time points was 324 pg/mg (range, 44-1109 pg/mg), and there was no significant difference between time points. An increase in MET from baseline to the end of RT was observed in 5 of 10 patients, and the median fold increase was 1.8 pg/mg (range, 1.7-21 pg/mg).

Urine MMP-2

Urine MMP-2 was detectable in 11 of 27 samples (41%). The median MMP-2 concentration over all 3 time points for those with had detectable levels was 878 pg/mg (range, 199-10,359 pg/mg). Given the high number of samples with undetectable MMP-2 levels, further analysis was not carried out for this biomarker.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

In this trial, we sought to assess the safety and tolerability of combining RT to intracranial tumors with continuously dosed sunitinib. Overall, the combination of sunitinib and RT was well tolerated. Most toxicities were not severe and did not limit the patient's ability to complete the combined course. Toxicity was limited to grade 1/2 in 40% of the patients in this study. Forty-seven percent of the patients in this study had grade 3 toxicities, which most commonly were hematologic and were without significant clinical consequences. We were particularly interested in differentiating toxicity that occurred as a result of sunitinib, RT, or the combination to assess the potential for a more than additive toxicity profile. Among the 14 grade ≥3 toxicities, 7 hematologic and metabolic toxicities were attributed to sunitinib, 2 were attributed to RT, 2 were attributed to the combination, 1 was attributed to disease progression, and 2 venous thromboembolic events occurred that may have been related to sunitinib or to the underlying procoagulant status of patients with brain tumors. The grade 3 toxicity rate did not increase with increasing RT dose.

Comparing the experience from this trial with the known toxicity data on WBRT is possible in a limited manner. Over the past decade, 4 prominent phase 3 trials have included a WBRT-alone control arm: Radiation Therapy Oncology Group (RTOG) trial 0118,43 a trial of efaproxiral (RSR-13),44 RTOG 9508,45 and motexafin gadolinium.46 Compared with these historic controls, the rate of treatment-related adverse events from continuously dosed sunitinib and intracranial RT may be modestly higher than the toxicity of WBRT alone (see Table 5).

Table 5. Comparison of Toxicities Reported in Trials That Used Whole-Brain Radiotherapy Compared With the Toxicity of Radiotherapy Combined With Continuously Dosed 37.5-mg Sunitinib
 Percentage of Patients
ToxicityWBRT and SunitinibRTOG 9508RTOG 0118Motexafin GadoliniumEfaproxiral
  1. Abbreviations: GI, gastrointestinal; NR, not reported; RTOG, Radiation Therapy Oncology Group; WBRT, whole-brain radiotherapy.

StudyCurrent studySmith 200838Simon 199736Chan 200439Macdonald 199037
No. of patients916793208250
Acute toxicity     
 Grade 1-2406266NRNR
 Grade 347027NRNR
 Grade 4005NR11
 Grade 51302NRNR
All grades     
 Nausea27NRNR24NR
 Diarrhea13NRNR2NR
 Paresthesia13NRNR11NR
 Pain27NRNR8NR
 Rash13NRNR14NR
 Tachycardia0NRNR2NR
 Peripheral edema0NRNR11NR
Hematologic, grade ≥320NRNRNRNR
Neurologic, grade ≥320NR12NR3
GI, grade ≥30NR6NR6
 Nausea0NRNRNR2
 Vomiting0NRNRNR2
 Constipation0NRNRNR2
Vascular, grade ≥313NR4NRNR
Constitutional, grade ≥313NR5NRNR
Metabolic, grade ≥313NR3NRNR

To our knowledge, only 1 other study has evaluated the toxicity of continuously dosed sunitinib and RT: Kao et al47 recently published their experience treating 21 patients to 36 non-CNS oligometastatic sites with a combination of sunitinib and hypofractionated, image-guided RT. Those authors reported a 57% response rate and 28% rate of stable disease; and they described a DLT in 1 of 10 patients when sunitinib 37.5 mg was combined with 10 Gy × 5 fractions. In that trial, 2 of 5 patients had a DLT with sunitinib 50 mg combined with 10 Gy × 5 fractions. The 1-year local control, PFS, and OS rates were 85%, 44%, and 75%, respectively. The authors concluded that the combination of sunitinib (25-37.5 mg) plus image-guided RT was tolerable in patients with oligometastatic disease without potentiation of RT-related toxicity. The rate of grade 3 through 5 toxicities from continuously dosed sunitinib and intracranial RT is similar to the rates reported from other larger studies that used continuous daily dosing with sunitinib 37.5 mg alone. However, comparisons are difficult, because patients on continuously dosed sunitinib trials may have received a greater number of previous therapies and/or a longer duration of exposure to sunitinib.

A debate remains about the optimal timing of antiangiogenic therapies and RT. Preclinical studies on the inhibition of VEGF2 and the window of vascular normalization and radiosensitization by Winkler et al48 suggested an open window for maximum radiosensitivity in the range of 4 to 6 days after the initiation of anti-VEGF2 therapies. In the clinical setting of glioblastoma multiforme, Batchelor et al49 described imaging techniques for detecting vascular normalization after antiangiogenic therapy. They discovered that vascular normalization may begin immediately upon antiangiogenic therapy and has a window that lasts approximately 28 days. The scheme for RTOG 0825, a phase 3 study testing RT and temozolomide with or without bevacizumab, starts bevacizumab after 30 Gy of the planned 60 Gy of RT have been delivered. Future clinic trials in this arena should use advanced imaging techniques like diffusion-weighted MRI or permeability mapping through dynamic contrast-enhanced MRI to determine the optimal timing of concurrent antiangiogenic therapy and RT. Alternately, the development of blood-based or urine-based biomarkers of vascular normalization could be developed to guide the optimal timing of these therapies.

Concern about using antiangiogenic agents in patients with brain metastases has been raised by Pouessel and Culine50; however, no patients in our current study experienced intracranial hemorrhage. Similarly, there were no episodes of intracranial hemorrhage reported in 15 patients with recurrent malignant glioma who received bevacizumab and RT in a pilot study conducted at the Memorial Sloan-Kettering Cancer Center.51

When antiangiogenic drugs alter vascular permeability, they may change the apparent size of tumors without affecting the underlying tumor mass, compromising our ability to observe these tumors on MRI studies. Therefore, response rates as an indication of treatment efficacy should be interpreted with caution when antiangiogenic agents are used.

Over all time points, our patients had a median urine VEGF level of 336 pg/mg. This is similar to the mean urine VEGF level of 317 pg/mg reported at baseline for a cohort of patients with prostate, breast, brain, and hematologic malignancies.39 However, other studies have reported median urine VEGF levels of 753 pg/mL at presentation in a cohort of pediatric and adult patients with brain tumors and 101 pg/mL at baseline in patients with advanced soft tissue sarcomas.38, 52 These results emphasize the wide range of baseline urine VEGF levels observed for different histologies and stages of disease. It also suggests that looking at trends between different time points is likely to be more fruitful as a predictive marker than using absolute cutoff values. However, given the limited number of patients with complete urine sets, we were unable to determine which comparisons between time points may be most predictive of response.

We observed a correlation between grade 3 hematologic toxicity and higher VEGF fold changes between baseline and the end of RT. Significant changes in white blood cell counts during sunitinib treatment have been reported in patients with GIST.53 The largest proportional decrease was noted in monocytes, which may reflect the finding that monocytes have higher expression of VEGF receptor 1 relative to other peripheral blood mononuclear cells.53 Sunitinib-related peripheral blood mononuclear cell changes also may be related to “off-target” inhibition of KIT and FLT-3. Given the small dataset, this finding is hypothesis-generating and merits evaluation in future studies.

We are encouraged in this limited study by the responses observed. The 58% 6-month PFS rate in patients with brain metastases is higher than that reported historically.54-56 The RTOG reported that brain metastases were the cause of death in 33% to 50% of patients who were enrolled on studies 7916, 8528, and 8905.54 The 13% rate of neurologic death in our study also compares favorably with historic data. We are aware that patient selection can bias small studies, and this improvement will have to be validated by a larger study.

In conclusion, 37.5-mg daily dosing of sunitinib combined with cranial RT yielded acceptable toxicities and adverse events. This unique combination also produced intriguing responses. A phase 2 study further evaluating the use of sunitinib as a radiosensitizing agent in the setting of brain metastases is being planned by the RTOG.

FUNDING SOURCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

This study was supported by the P30 CA056036-08 Kimmel Cancer Center grant and in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Dr. Adam P. Dicker received an unrestricted grant from Pfizer Incorporated in association with this trial.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES
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