Pediatr Radiol (1992) 22:93--98

Pediatric Radiology 9 Springer-Verlag 1992

Phase III clinical evaluation of gadoteridol injection: experience in pediatric neuro-oncologic MR imaging J. F. D e b a t i n I , S . N . N a d e l 1, L. G r a y 1, H . S. F r i e d m a n 2, P. Trotter t , B. H o c k e n b e r g e r 2, a n d W . J . O a k e s 3

Department of Radiology, 2Department of Pediatrics and 3 Department of Neurosurgery, Duke University Medicat Center, Durham, North Carolina, USA Received: 20 October 1991; accepted: 20 December 1991

A b s t r a c t . Twenty-two pediatric patients with known CNS

neoplasms underwent magnetic resonance (MR) imaging before and after intravenous injection of 0.1 mmol/kg gadoteridol injection as part of a Phase IIIB open label multicenter clinical trial. Intravenous administration of this neutral, nonionic contrast agent was found to be safe in children. No clinically relevant changes in vital signs or laboratory values (including complete blood count, blood chemistry, serum electrolytes, thyroid and metabolic panel and clotting function) were attributed to the administration of gadoteridol injection. There were no systemic complaints. The imaging characteristics of gadoteridol in pediatric CNS disease appeared similar to those of gadopentetate dimeglumine. Contrast enhancement was present in 17 of 22 patients (77%). The administration of gadoteridol injection provided additional clinically relevant information including improved visualization and delineation of the primary lesion, detection of additional lesions, determination o f tumor recurrence and narrowing the list of differential considerations in all 17 enhancing studies as well as in 2 of 5 studies without signal intensity enhancement. The very low toxicity, inherent to this nonionic low osmolal paramagnetic contrast formulation may allow administration of increased doses at increased infusion rates for an increased number of indications with improved sensitivity.

cal practice [2]. The safety and efficacy of this compound has been extensively documented [3-10]. It is administered intravenously, rapidly distributes throughout the extracellular spaces and is excreted primarily by the kidneys. Gadopentetate possesses a net charge of -2 and thus can be administered only as a dimeglumine salt which yields an osmolality of 1820 mOsmol/kg in the standard half molar preparation. Recent developments have focused on the formulation and preliminary evaluation of nonionic, neutral paramagnetic M R contrast agents. Unlike gadopentetate dimeglumine, these agents are neutral in aqueous solutions. Their lower osmolality and greater in vitro chelate stability [11, 12] may further improve safety and patient tolerance. The improved safety profile of these nonionic contrast agents may allow imaging at increased doses [11-14], at increased rates of administration and potentially for an increased number of indications. As part of an open label, multicenter clinical study we investigated the safety and efficacy of a low osmolal, nonionic paramagnetic metal ion chelate for pediatric, neurooncologic M R imaging: Gadoteridol injection, gadolinium 1,4,7-tris (carboxymethyl)-10-(2'-hydroxypropyl)-l, 4,7,10-tetraazacyclodode-cane (gadoteridol [Gd-HPDO3A]) (ProHance; Squibb Diagnostics, Princeton, NJ). Materials and methods

The diagnostic information of Magnetic Resonance (MR) images is improved with the application of exogenous pharmaceutical compounds which change M R signal behavior by altering longitudinal (T1) and transverse (T2) relaxation times in the tissues in which they accumulate. These substances will frequently increase the already vast intrinsic soft tissue contrast, thus enabling detection of smaller and less conspicuous lesions. These potential gains, however, must be balanced against the added cost and inconvenience of drug administration and the potential for pharmacologic toxicity [1]. Gadopentetate dimeglumine, a paramagnetic metal ion chelate, has become indispensible in neuroradiologi-

Twenty-two pediatric patients (13 female and 9 male) with known, surgically proven CNS neoplasms were enrolled in the study. Ages ranged from 4 months to 17 years. All patients had been scheduled for routine neurologic MR imaging. The study was approved by our Institutional Review Board and informed parental consent was obtained in each case. Twenty-one patients underwent MR evaluation of the brain and one patient of the spine. Gadoteridol was administered intravenously at a dose of 0.1 mmol/kg. Provided as a clear aqueous solution at a concentration of 0.5 mol/1between 1.0 and 20 ml of the contrast agent were injected rapidly (approximately 1-2 ml/s. All patients had been diagnosed with primary neurologic neoplasms prior to enrollment in the study. Surgically proven diagnoses included ependymoma (n = 4), glioma (n = 3), astrocytoma (n = 5), oligodendroglioma (n = 2), medulloblastoma (n = 4), pineal tumor (n = 2), neuroblastoma (n -- 1) and

94 pontine glioma (n = 1). Twelve of the 22 patients were undergoing treatment with chemotherapeutic agents at the time of the MR exam. Table 1 summarizes the individual patients' age, sex, weight, amount of contrast agent injected and the diagnosis. Within 24 h preceeding the MR exam, a medical history was obtained and each patient subjected to an extensive laboratory analysis which was repeated 24 h after the contrast enhanced MR exam. Blood evaluation included a complete blood count (hemoglobin, hematocrit, mean corpuscular volume, total red cell count, total white cell count with differential, and platelet count), blood chemistry (glucose, creatinine, urea nitrogen, calcium, phosphorus, uric acid, total cholesterol, total protein, albumin, total bilirubin, alkaline phosphatase, lactic dehydrogenese, serum glutamic pyruvic transaminase, serum glutamic oxaloacetic transaminase, and gamma glutamic transaminase), serum electrolytes (sodium, potassium and chloride), iron metabolic panel (transferrin, serum iron, serum iron binding capacity and serum ferritin) and a clotting function panel (prothrombin time and partial prothrombine time). Vital signs, including heart rate, blood pressure, respiratory rate and body temperature, acquired either orally or rectally, were determined in all patients 24 h and immediately before the MR examination, and repeated immediately, as well as 2 and 24 h after the contrast material had been administered intravenously. Imaging studies were performed on a 1.5 Tesla MR imaging system (Signa, GE, Milwaukee, WI). To enhance the signal-to-noise ratio all examinations were performed in a quadrature transmission and reception surface head coil. Following a localizing sequence, dual-echo T2-weighted (TR/TE =2000-3000/30 and 70) images were acquired in the axial and the most appropriate orthogonal plane. Tl-weighted images (TR/TE = 500/20) were acquired both immediately before and following the administration of the contrast agent usually in the axial plane for head studies (with exception of pineal tumors where images were performed in the coronal plane) and sagittal plane for spine studies. The sequences were supplemented by pre- and post-contrast Tl-weighted images in a perpendicular plane (sagittal or coronal for brain studies and axial for spine studies). First order motion gradient nulling was applied to the T2weighted sequences. An acquisition matrix of 256 x 128 with i excitation, field of view of 20 cm 2for the axial brain images (larger for the orthogonal plane) with a section thickness of 5 mm for axial and 3 mm for sagittal and coronal images was used. Anterior spatial saturation was implemented for the spine study. The images were objectively evaluated for the presence of contrast enhancement by means of region of interest (ROI) (0.4 mm 2) signal intensity measurements, obtained by computer analysis, with percentage enhancement calculated as follows: % enhancement = SI postcontrast- SI precontrast where SI SI precontrast denotes signal intensity. Signal intensity enhancement of more than 50% was characterized as "marked" and less than 50% as "slight". Subsequently two radiologists subjectively judged the efficacy of the agent by determining whether the administration of contrast material provided additional information not contained in the precontrast T1- and T2-weighted sequences. Criteria in this evaluation included: (a) detection of the lesion itself, (b) detection of additional lesions not otherwise visible, (c) improved visualization of the lesion with determination of the borders and distinction of edema from lesion, (d) determination of tumor recurrence, and (e) aid in disease classification. In those cases that did not show abnormal enhancement, a judgement was made as to whether the agent was helpful in excluding suspected disease. Results

Clinical and laboratory evaluation T h e r e w e r e no s e v e r e a d v e r s e r e a c t i o n s following t h e int r a v e n o u s a d m i n i s t r a t i o n of g a d o t e r i d o l at 0.1 m m o l / k g . C h a n g e s in vital signs w e r e n o t clinically significant. F r o m

i m m e d i a t e l y p r i o r to the M R e x a m i n a t i o n to i m m e d i a t e l y a f t e r t h e p o s t c o n t r a s t s e q u e n c e the a v e r a g e c h a n g e in h e a r t r a t e was 7 b e a t s / m i n , in systolic b l o o d p r e s s u r e 5 m m H g , in diastolic b l o o d p r e s s u r e 7 m m H g a n d in t h e respiratory rate 3 breaths/min. M i n o r r e d n e s s at the injection site d u e to m i n o r e x t r a v a s a t i o n was n o t e d in o n e patient. A single p a t i e n t d e v e l o p e d a f e v e r with a m a x i m u m t e m p e r a t u r e of 37.8~ 24 h a f t e r a d m i n i s t r a t i o n of the c o n t r a s t agent. This was felt to b e d u e to c o n c u r r e n t a d m i n i s t r a t i o n of b l o o d p r o d u c t s . L a b o r a t o r y analysis, p r e - a n d p o s t - a d m i n i s t r a t i o n of c o n t r a s t m a t e r i a l d e m o n s t r a t e d clinically significant c h a n g e s in eight p a t i e n t s . In 5 p a t i e n t s w o r s e n i n g a n e m i a was n o t e d a n d felt to b e s e c o n d a r y to t h e r e c e n t administ r a t i o n of c h e m o t h e r a p e u t i c agents c o u p l e d w i t h v i g o r o u s i n t r a v e n o u s h y d r a t i o n . I n two p a t i e n t s , a l r e a d y l e u k o p e n i c f r o m r e c e n t c h e m o t h e r a p y , a f u r t h e r d r o p in t h e white cell c o u n t was n o t e d 24 h after t h e M R exam. This t o o was a t t r i b u t e d to c h e m o t h e r a p e u t i c side effects. In the final p a t i e n t w h o was also u n d e r g o i n g c h e m o t h e r a p e u t i c t r e a t m e n t at t h e t i m e of t h e M R e v a l u a t i o n , a p r e c i p i t o u s d r o p in s e r u m i r o n f r o m 127 to 36 mg/dl was n o t e d . R e p e a t d e t e r m i n a t i o n 48 h l a t e r s h o w e d s e r u m i r o n level to b e in the n o r m a l r a n g e again. Transferrin, i r o n b i n d i n g cap a c i t y a n d s e r u m ferritin r e m a i n e d within n o r m a l limits. This i s o l a t e d c h a n g e in s e r u m i r o n r e m a i n e d u n e x p l a i n e d a n d was m o s t l i k e l y d u e to a s p u r i o u s l a b value.

Image evaluation C o n t r a s t e n h a n c e m e n t was p r e s e n t in 17 of 22 e v a l u a t e d patients. It was m a r k e d ( g r e a t e r t h a n 50% i n c r e a s e in sign a l intensity) in 10 e x a m s a n d slight (less t h a n 50% inc r e a s e in signal intensity) in 7 exams. In t h e r e m a i n i n g 5 p a t i e n t s no c h a n g e in signal i n t e n s i t y was n o t e d after the a d m i n i s t r a t i o n of c o n t r a s t m a t e r i a l . L e s i o n s n o t exhibiting c o n t r a s t e n h a n c e m e n t i n c l u d e d p o s t e r i o r fossa e p e n -

Table 1. Patient data

Age 2Y 9M 7Y 4M 6Y 11M 9M 6M 2Y 10M 11Y 9M 12Y 5M 21M 12Y l l Y 9M 7Y 18M 15M 4M l l Y 4M 4Y 6M 2Y 6M 17Y l l Y 2M 13Y 6Y l l M

Sex F F M F F M F F F F M M F F F M M M M M F F

Dose 2 cc 4 cc 4.4 cc 1.6 cc 1.4 cc 2.8 cc 10 cc 20 cc 2 cc 10 cc 10.4 cc 7.2 cc 2 cc 1.8 cc 1.0 cc 6.2 cc 3.4 cc 2 cc 15.2 cc 7.0 cc 9.6 cc 7 cc

Tumor type Ependymoma Oligodendroglioma Neuroblastoma Oligodendroglioma Medulloblastoma Ependymoma Ependymoma Astrocytoma Pilocytic astrocytoma Pilocytic astrocytoma Medulloblastoma Optic glioma Spinal ependymoma Glioblastoma Glioblastoma Medulloblastoma Glioma Medulloblastoma Pineal tumor Pineal germinoma Astrocytoma Pontine glioma

95

Fig.la-c. Seventeen-year-old patient with pineal tumor. T1weighted axial image (TR/TE 500/20) (a) demonstrates postoperative changes in the left parietal lobe region. No abnormalities are identified in the brain stem. Axial T2-weighted image (TR/TE 2100/80) (b) also demonstrates postoperative changes in the left parietal lobe. Small focus of increased signal is identified adjacent to the cerebellar vermis representing fluid. No abnormalities identified within the pineal region. Axial contrast-enhanced image (TR/TE 500/20) (c) shows distinct contrast enhancement in the pineal region consistent with residual tumor

Fig.2a-c. Recurrent medulloblastomain a two-year-old boy. Axial Tl-weighted image (TR/TE 500/20) (a) demonstrates postsurgical changes in the right posterior fossa region. A mass, characterized by heterogeneous signal intensity is identified to the right of midline. Axial T2-weighted image (TR/TE 2500/80) (b) also demonstrates postsurgical changes. The previously described mass is largely isointense with cerebral cortex with central hyperintense component most likely representing necrosis. Contrast enhanced axial image (TR/TE 500/20) (e) demonstrates enhancement of this mass lesion consistent with recurrent medulloblastoma

d y m o m a (n = 1), spinal e p e n d y m o m a (n = 1), glioblastoma (n = 1), medulloblastoma (n = 1) and glioma (n = 1). The administration of gadoteridol provided additional information in all 17 enhancing studies, improving visualization of primary lesions by better defining their margins in 9 cases and permitting distinction of lesion f r o m surrounding e d e m a in 6. In 7 patients contrast administration was useful in the determination of t u m o r recurrence. Additional small lesions, which had not b e e n seen on precontrast images were identified on the contrast enhanced images in 4 patients. Lack of e n h a n c e m e n t aided in nar-

rowing the differential diagnosis in 2 of 5 patients without signal intensity enhancement. Clinically relevant information was thus provided by the administration of gadoteridol injection in 19 (83 %) of the 22 exams included in this study.

Discussion The imaging effects of extracellular M R contrast agents (leading to improved lesion detection) are similar to those of iodinated contrast media. The agents are rapidly redis-

96 Fig.3a, b. Twenty-one-month-oldpatient

with pyelocyticastrocytoma.Axial T1weightedimage (TR/TE 500/20)(a) demonstrates heterogeneousmidhnemass. Contrast enhanced axialTl-weighted image (TtVTE 500/20) (h) demonstrates homogeneous enhancementof central part of the mass with rim enhancement surroundingthe areas of necrosis Fig. 4 a-c. Seven-year-oldgirlwith oligendroglioma. Axial Tl-weighted image (TR/TE 500/20) (a) demonstratesmass lesion in left basal ganglia region.There is dilatation of the posterior horns of the lateral ventricles.Axial T2-weightedimage (TR/TE 2000/80)(b) shows this lesionto be characterizedby a diffuselyincreasedsignal intensity. Axial contrast enhanced image (TR/TE 500/20) (c) demonstratesrim enhancement of the mass aiding in lesiondelineation and differentiationfrom surrounding edema

tributed from the vascular compartment into the extracellular space and undergo renal elimination by passive glomerular filtration. On Tl-weighted images, enhancement is due to multiple factors, primarily perfusion in peripheral tissues and contrast accumulation in areas of breakdown of blood brain barrier [2] in the central nervous system. Although greater blood brain barrier breakdown is needed for leakage of contrast material than alterations of brain water content [9] the sensitivity and specificity of M R imaging has been improved over conventional spin echo imaging with the introduction of paramagnetic contrast agents [3-10]. In addition, paramagnetic contrast enhanced imaging has improved the delineation, and aided in the temporal characterization of processes which actively destroy the blood brain barrier [15]. In the evaluation of 20 pediatric patients with intracranial mass lesions, dramatic enhancement after administration of gadolinium-DPTA was demonstrated in eleven, improving definition of presence and extent of disease in 6 patients [16].

Similar to other gadolinium compounds, gadoteridol injection has unpaired electrons, resulting in paramagnetism that reduce the T1- and T2 relaxation time of protons [17]. Its relaxivity in water at 10 MHz is 4.6 m m for T1 and 5.1 mm -1 s -1 for T2, which is slightly greater than that of gadolinium-DPTA [18]. The agent therefore increases MR signal intensity on Tl-weighted images at sites in the central nervous system where it accumulates due to lesion vascularity or breakdown of the blood brain barrier. The imaging characteristics of gadoteridol in pediatric CNS disease appear similar to those of gadopentetate dimeglumine. Contrast enhancement was demonstrated in 17 of 22 patients with CNS tumors. It provided additional information with respect to lesion detection, disease classification, distinction of lesion from edema, definition of lesion margins and determination of recurrent tumor. In two patients lack of enhancement narrowed the list of differential diagnosis. Similar results have been reported by other investigators in evaluating the utility of gadoteridol in MR imaging of adults [11-14, 19].

97 Tl-weighted images obtained after the injection of GdHP-DO3A significantly influenced the interpretation of the MR study in 19 of 22 cases (83%). This high percentage which contrasts with results reported by Moody et al. [20], showing that administration of gadopentetate dimeglumine was helpful in only 37% of 500 evaluated cases, is a reflection of the patient population enrolled in the study. All 22 patients in our study had known CNS neoplasms, whose identification and delineation would likely benefit from contrast enhancement. Our findings indicate that the intravenous administration of gadoteridol at a dose of 0.1 mmol/kg is safe in children. No clinically relevant changes in vital signs were attributed to the administration of the nonionic contrast agent in this clinical trial involving 22 pediatric patients with known CNS tumors, the majority of whom were undergoing chemotherapy treatment at the time of the evaluation. There were no systemic complaints. None of the eight clinically significant laboratory changes should be contributed to the administration of gadoteridol. Worsening of underlying anemia in five patients and leukopenia in two patients reflected adjuvant chemotherapy with vigorous intravenous hydration regimens. The contrast agent could have caused these changes in hematocrit only via hemolysis. Absence of serum iron increases in these patients confirms that these changes were unrelated to the gadoteridol administration. One patient experienced a transient decrease in serum iron within 24 h after administration of gadoteridol. In view of the return to normal 48 h later and the absence of concomittant laboratory abnormalities this must be interpreted as a spurious lab value. No other clinically relevant laboratory changes were noted. A similarly low incidence of adverse clinical events was reported in a recently published multicenter study evaluating gadoteridol in 411 adult patients [21]. In that study 18 patients (4.4%) complained of transient dysgeusia or nausea. No clinically significant changes in laboratory values were noted [21]. Unlike gadopentetate dimeglumine, gadoteridol injection is a neutral nonionic agent, demonstrating a substantially lower osmolarity of 0.63 osmol-kg in water as compared with 1.96 osmol-kg for gadopentetate dimeglumine, and sfightly higher complex formation constants at 25~ 22.7 log Keg for gadoteridol versus 22.2 of log Keg for gadopentetate dimeglumine [22]. It has been suggested that certain adverse reactions and laboratory anomalies encountered with gadopentetate dimeglumine injection, such as reproducible mild elevation of serum iron and total bilirubin levels, presumably due to hemolysis [23, 24] may be caused by the hyperosmolarity of the contrast solution. Such changes have not been reported with low-osmolar gadoteridol [11-14, 19], and were not evident in the evaluated very volatile pediatric population. Other, possible safety related advantages of this nonionic paramagnetic contrast formulation, include less extravascular toxicity from accidental subcutaneous extravasation [25]. Increased safety through reduced toxicity may permit administration of paramagnetic contrast agents at increased doses, at increased rates to an increased number of patients. In addition it may enhance

the use of the paramagnetic contrast agents to include even those patients with renal insufficiency and hemolytic anemia, currently considered relative contraindications for the administration of gadolinium-DPTA. The utility of imaging CNS lesions with higher doses of gadoteridol (0.2 and 0.3 mmol/kg) was demonstrated in a recent report by Yuh et al. [13]. Greater enhancement of lesions was noted after administration of gadoteridol at concentrations of 0.2 and 0.3 mmol/kg as compared to lesions imaged with the standard dose of 0.1 mmol/kg of gadopentetate dimeglumine [13]. In a second study Yuh et al. [26] reported improved visualization of 70 of 71 lesions and identification of 44 new lesions after administration of 0.2 mmol/kg gadoteridol compared to a preceding study with 0.1 mmol/kg [26]. We have shown gadoteridol injection at a dose of 0.1 mmol/kg to be a safe and efficacious MR contrast agent in a very volatile pediatric patient population. While a direct comparison of gadopentetate dimeglumine and gadoteridol injection is not possible on the basis of the data presented, the pattern of contrast enhancement following administration of gadoteridol was very similar to that anticipated for gadopentetate dimeglumine. The nonionic low osmolal formulation of this gadoliniurn-based paramagnetic contrast agent appears to reduce toxicity and enhance the agent's safety. This may allow the administration of increased doses of paramagnetic contrast, enhancing its diagnostic effectiveness in the pediatric patient population. Acknowledgements. The authors are indebted to Jacqueline Wright for her masterful preparation of the manuscript.

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Dr. J. E Debatin Department of Radiology Duke University Medical Center Box 3808 Durham, NC 27710 USA

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