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(Radiology. 1999;212:755-759.)
© RSNA, 1999

Radiation Oncology

Phases IB and II Multidose Trial of Gadolinium Texaphyrin, a Radiation Sensitizer Detectable at MR Imaging: Preliminary Results in Brain Metastases1

Juliette Viala, MD, Daniel Vanel, MD, Philippe Meingan, MD, Eric Lartigau, MD, Patrice Carde, MD and Markus Renschler, MD

1 From the Departments of Radiology (J.V., D.V., P.M.) and Medicine (E.L., P.C.), Institut Gustave-Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France; and Pharmacyclics, Sunnyvale, Calif (M.R.). From the 1997 RSNA scientific assembly. Received May 27, 1998; revision requested July 30; final revision received December 30; accepted March 26, 1999. Supported by Pharmacyclics. Address reprint requests to J.V. (e-mail: vanel@igr.fr).


   Abstract
TOP
 Abstract
Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
PURPOSE: To evaluate magnetic resonance (MR) imaging results after administration of gadolinium texaphyrin, a tumor-selective radiation sensitizer that is detectable at MR imaging, and to determine an appropriate intravenous dose of gadolinium texaphyrin for repeated injections during radiation therapy, the dose-limiting toxicity of reiterated doses of gadolinium texaphyrin, the maximal tolerated dose, the biolocalization of gadolinium texaphyrin (as assessed at MR examinations), and the response to treatment.

MATERIALS AND METHODS: Ten daily intravenous injections of gadolinium texaphyrin, each followed by whole-brain radiation therapy (total of 10 fractions, 30 Gy), were administered to patients with brain metastases in a multicenter study. At the study institution, 11 patients underwent MR imaging before and after the first injection, after the 10th injection, and 8 weeks after entry into the study.

RESULTS: MR imaging revealed selective drug uptake in metastases, without enhancement of normal brain tissue. In 10 patients, tumor uptake was higher after the 10th injection than after the first injection, which indicated accumulation of gadolinium texaphyrin in metastases. One lesion was visible only after the 10th injection and not at the pretherapeutic MR examination with injection of conventional gadolinium-based contrast material. Response to treatment was defined as a reduction in the size of the metastases between the preinjection MR study and the last MR study; seven patients achieved partial remission with tumor regression exceeding 50% of the initial size, and four achieved a minor response with less than 50% tumor regression.

CONCLUSION: These preliminary results indicate that gadolinium texaphyrin is tumor selective and that brain metastases can be depicted at MR imaging long after the administration of gadolinium texaphyrin.

Index terms: Brain neoplasms, MR, 10.121412, 10.30 • Brain neoplasms, secondary, 10.33 • Brain neoplasms, therapeutic radiology, 10.1299, 10.33 • Contrast media , 10.12143, 10.1299 • Texaphyrins, 10.33, 10.1299


   Introduction
TOP
 Abstract
 Introduction
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Radiation therapy is an important treatment for localized cancers. Unfortunately, the radiation dose is often too limited because of injury to normal surrounding tissue. A radiation-sensitizing agent capable of maximizing the cytotoxic effect of radiation delivered to the tumor while minimizing exposure of surrounding tissue would improve the chances of achieving local control.

Gadolinium texaphyrin is the prototype of a new class of compounds, the texaphyrins, which are expanded porphyrins. Several models have been used to demonstrate the radiation-sensitizing effect of gadolinium texaphyrin in studies carried out with HT29 cells in vitro and experimentally in single and multifraction irradiation studies with a murine model (mammary carcinoma) in vivo (1). Findings from a phase IA study, in which 38 patients were enrolled, demonstrated very good tolerance and a maximal tolerated dose of 19.4 µmol per kilogram of body weight in a single bolus (2).

The present study is part of a multicenter phase IB study (establishment of the maximal tolerated dose in patients with brain metastases requiring palliative therapy) in which gadolinium texaphyrin and standard radiation therapy are being used in patients with brain metastases. Magnetic resonance (MR) imaging was used exclusively for the follow-up of these patients in our institution, Institut Gustave-Roussy. We report the preliminary results of our participation in the phase IB study in which MR imaging is being used.

The primary objectives of the multicenter phase IB study were to determine an appropriate intravenous dose of gadolinium texaphyrin for repeated injections during radiation therapy, the dose-limiting toxicity of reiterated doses of gadolinium texaphyrin, the maximal tolerated dose, the biolocalization of gadolinium texaphyrin (as assessed at MR examinations), and the response to treatment.

Texaphyrins are expanded porphyrins that are capable of binding lanthanide metals such as lutetium or gadolinium (Fig 1) (3). Gadolinium texaphyrin captures x rays that are delivered in radiation treatment and can be activated by radio-frequency pulses, such as those used in MR imaging (Fig 2) (4).



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  		Figure 1. Diagram of the gadolinium texaphyrin molecule. Ac = acetyl, Gd = gadolinium, H = hydrogen, Me = methyl, N = nitrogen, O = oxygen.

 


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  		Figure 2. Diagram demonstrates the mechanism of action of gadolinium texaphyrin (Gd-Tex).

 
Gadolinium texaphyrin is water soluble and kinetically stable and is not dependent on tumor oxygenation or on cell-cycle phases. The radiation-sensitizing property of texaphyrins is not dependent on the inserted metal and is exclusively a function of the ligand. Porphyrins localize selectively in tumors; this prompted the simultaneous use of gadolinium texaphyrin as a selective radiosensitizer and as a contrast agent for MR imaging.


   MATERIALS AND METHODS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
This phase IB and II study, initiated in September 1996 and ended in May 1998, is a multidose trial. The study protocol was approved by the institutional review board of the University of Bicelie, Paris, France.

All patients older than 18 years with brain metastases requiring palliative radiation therapy were eligible, providing the following other criteria were met: a baseline World Health Organization (5) performance status of 0–2 (ambulatory and capable of all self-care but unable to carry out any work activities, ambulatory more than 50% of waking hours); neurologic function less than 2 (able to carry out normal activities with minimal difficulties, neurologic impairment does not require nursing care or hospitalization); and a life expectancy of at least 2 months.

Patients had a hematologic profile with a white blood cell count greater than 3,000 per cubic millimeter (0.003 x 109 per liter), an absolute granulocyte count greater than 1,500 per cubic millimeter (0.0015 x 109 per liter), platelets greater than 100,000 per cubic millimeter (0.1 x 109 per liter); hepatic and renal functions with bilirubin level less than 2 mg/dL (34.2 µmol/L); aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels less than 2 times the upper normal limit; prothrombin time and activated partial thromboplastin time less than 1.5 times the upper normal limit; and serum creatinine level less than 1.5 mg/dL (132.6 µmol/L).

Patients had no concomitant chemotherapy during the 14-day follow-up observation period after the end of treatment; no prior surgical resection of metastases; and no medical or psychiatric condition likely to compromise their ability to give informed consent. They were fully informed of the type of disease diagnosed, the objectives, and the experimental nature of the study and were able to return to the study site for treatment and follow-up visits, as defined in the protocol.

Eleven patients (six women, five men), aged 41–82 years, were enrolled in this study. Ten patients had already undergone treatment for a tumor: three for breast cancer, five for lung cancer, one for thyroid cancer, and one for skin cancer (melanoma). One patient had brain metastases, which revealed a lung cancer.

Each patient received 10 daily intravenous injections of gadolinium texaphyrin (Xcytrin; Pharmacyclics, Sunnyvale, Calif), except during weekends and on public holidays, followed within 2–5 hours with whole-brain radiation therapy. Radiation therapy was delivered in 10 fractions of 3 Gy, for a total of 30 Gy.

The gadolinium texaphyrin doses injected were as follows: 0.25 µmol/kg (no patients), 0.50 µmol/kg (one patient), 0.80 µmol/kg (one patient), 1.30 µmol/kg (two patients), 1.80 µmol/kg (one patient), 2.30 µmol/kg (one patient), 3.10 µmol/kg (three patients), and 4.10 µmol/kg (two patients).

A modified Fibonacci system (with modifications imposed by the manufacturer) was used for dose escalation of gadolinium texaphyrin injections in subsequent cohorts of treated patients (Table).


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  		Dose of Gadolinium Texaphyrin Injection
 
Three patients were evaluated at each nontoxic dose. The second patient in a cohort must have completed a 7-day follow-up period (after the last injection and irradiation), and the third patient in a cohort must have completed at least the 10-day therapy course before the next cohort was initiated.

If the maximal tolerated dose was not reached by group 8, additional cohorts of three patients were to have been enrolled and were to have received incremental increases of 33% in relation to the previous dose level until the maximal tolerated dose was reached. Three patients were required per cohort, which could have been increased to five patients if grade 3 or 4 toxic reactions had been observed. Data in patients with toxic reactions attributable to radiation therapy were excluded from the determination of the maximal tolerated dose (no patients in our institution, Institut Gustave-Roussy).

Timing of MR Studies
In our institution, Institut Gustave-Roussy, each patient underwent at least four brain MR imaging examinations. The first MR study was performed before the first injection (pretherapeutic) without or with intravenous injection of gadoterate meglumine (0.1 mmol per kilogram of body weight; Dotarem; Guerbet, Roissy, France). The second study was performed after the first injection of gadolinium texaphyrin and before radiation therapy. The third study was performed after the last injection of gadolinium texaphyrin and before the last radiation therapy session, and the fourth was performed 56 days after the beginning of the treatment. Two patients underwent an extra MR examination 3–4 months after the beginning of the treatment. One patient underwent two additional MR examinations 6 and 9 months after the beginning of the treatment.

A 1.5-T magnet (Signa; GE Medical Systems, Milwaukee, Wis) and a T1-weighted spoiled gradient-recalled-echo pulse sequence (35/4 [repetition time msec/echo time msec], 40° flip angle) were used. Images were acquired in axial, coronal, and sagittal planes. A maximum of three studies were graded for each patient per target lesion. Two radiologists (J.V., D.V.) evaluated together, by consensus, enhancement of signal intensity after the first and last injections and 56 days later. This enhancement was graded 0–3, where 0 was no enhancement, 1 was moderate enhancement, 2 was fully visible enhancement, and 3 was high enhancement.

Evaluation of Response
Response to the treatment was assessed between the pretherapeutic MR study and the MR study performed 56 days after the beginning of the treatment. Response was based on World Health Organization criteria (the product of the two largest perpendicular diameters of measurable lesions).


   RESULTS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Treatment was very well tolerated. There was no nausea or vomiting after administration of gadolinium texaphyrin. A single incident of considerably increased intracranial pressure occurred in one patient on the day of the first injection and treatment. Gradual yellow-green discoloration of urine was noted from the fourth dose level (1.30 µmol/kg) upward, and discoloration of skin was noted by the seventh level (3.10 µmol/kg). Biologic functions, in particular, liver or kidney functions, were normal.

During the months following treatment, five patients died; one died of massive pulmonary embolism, one died of septic shock (which was probably pulmonary in origin), and three died of tumor progression. The maximal tolerated dose had not been reached in our center.

Results of Brain MR Examinations
Enhancement of signal intensity.—In the patient with a melanoma, signal intensity was high in brain metastases before injection of any contrast agent; this patient was excluded from the evaluation of enhancement. Therefore, signal intensity was evaluated in 10 patients (Figs 3, 4).



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  		Figure 3a. Axial T1-weighted spoiled gradient-recalled-echo MR images (35/4, 40° flip angle) in a 54-year-old woman, treated 18 months previously for a bronchial cancer, with cerebellar metastases. (a) Pretherapeutic non-enhanced MR image shows the target lesion (arrowheads) in the left cerebellum is hypointense. (b) Pretherapeutic MR image after injection of gadoterate meglumine (11-mL intravenous injection). Target lesion shows peripheral enhancement (arrowheads). (c) MR image after the first injection of gadolinium texaphyrin (1.30 µmol/kg). Enhancement (arrowheads) is localized in the target and is grade 2 (completely visible enhancement). (d) MR image after the 10th injection of gadolinium texaphyrin. Enhancement (arrowheads) is higher and is grade 3 (high enhancement). 1 and 2 are the two largest perpendicular diameters of the lesion. (e) MR image 56 days after the first gadolinium texaphyrin injection, without injection of contrast agent. Enhancement (arrowheads) is still well visible and is grade 2. Tumor decreased to 65% of initial size.

 


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  		Figure 3b. Axial T1-weighted spoiled gradient-recalled-echo MR images (35/4, 40° flip angle) in a 54-year-old woman, treated 18 months previously for a bronchial cancer, with cerebellar metastases. (a) Pretherapeutic non-enhanced MR image shows the target lesion (arrowheads) in the left cerebellum is hypointense. (b) Pretherapeutic MR image after injection of gadoterate meglumine (11-mL intravenous injection). Target lesion shows peripheral enhancement (arrowheads). (c) MR image after the first injection of gadolinium texaphyrin (1.30 µmol/kg). Enhancement (arrowheads) is localized in the target and is grade 2 (completely visible enhancement). (d) MR image after the 10th injection of gadolinium texaphyrin. Enhancement (arrowheads) is higher and is grade 3 (high enhancement). 1 and 2 are the two largest perpendicular diameters of the lesion. (e) MR image 56 days after the first gadolinium texaphyrin injection, without injection of contrast agent. Enhancement (arrowheads) is still well visible and is grade 2. Tumor decreased to 65% of initial size.

 


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  		Figure 3c. Axial T1-weighted spoiled gradient-recalled-echo MR images (35/4, 40° flip angle) in a 54-year-old woman, treated 18 months previously for a bronchial cancer, with cerebellar metastases. (a) Pretherapeutic non-enhanced MR image shows the target lesion (arrowheads) in the left cerebellum is hypointense. (b) Pretherapeutic MR image after injection of gadoterate meglumine (11-mL intravenous injection). Target lesion shows peripheral enhancement (arrowheads). (c) MR image after the first injection of gadolinium texaphyrin (1.30 µmol/kg). Enhancement (arrowheads) is localized in the target and is grade 2 (completely visible enhancement). (d) MR image after the 10th injection of gadolinium texaphyrin. Enhancement (arrowheads) is higher and is grade 3 (high enhancement). 1 and 2 are the two largest perpendicular diameters of the lesion. (e) MR image 56 days after the first gadolinium texaphyrin injection, without injection of contrast agent. Enhancement (arrowheads) is still well visible and is grade 2. Tumor decreased to 65% of initial size.

 


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  		Figure 3d. Axial T1-weighted spoiled gradient-recalled-echo MR images (35/4, 40° flip angle) in a 54-year-old woman, treated 18 months previously for a bronchial cancer, with cerebellar metastases. (a) Pretherapeutic non-enhanced MR image shows the target lesion (arrowheads) in the left cerebellum is hypointense. (b) Pretherapeutic MR image after injection of gadoterate meglumine (11-mL intravenous injection). Target lesion shows peripheral enhancement (arrowheads). (c) MR image after the first injection of gadolinium texaphyrin (1.30 µmol/kg). Enhancement (arrowheads) is localized in the target and is grade 2 (completely visible enhancement). (d) MR image after the 10th injection of gadolinium texaphyrin. Enhancement (arrowheads) is higher and is grade 3 (high enhancement). 1 and 2 are the two largest perpendicular diameters of the lesion. (e) MR image 56 days after the first gadolinium texaphyrin injection, without injection of contrast agent. Enhancement (arrowheads) is still well visible and is grade 2. Tumor decreased to 65% of initial size.

 


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  		Figure 3e. Axial T1-weighted spoiled gradient-recalled-echo MR images (35/4, 40° flip angle) in a 54-year-old woman, treated 18 months previously for a bronchial cancer, with cerebellar metastases. (a) Pretherapeutic non-enhanced MR image shows the target lesion (arrowheads) in the left cerebellum is hypointense. (b) Pretherapeutic MR image after injection of gadoterate meglumine (11-mL intravenous injection). Target lesion shows peripheral enhancement (arrowheads). (c) MR image after the first injection of gadolinium texaphyrin (1.30 µmol/kg). Enhancement (arrowheads) is localized in the target and is grade 2 (completely visible enhancement). (d) MR image after the 10th injection of gadolinium texaphyrin. Enhancement (arrowheads) is higher and is grade 3 (high enhancement). 1 and 2 are the two largest perpendicular diameters of the lesion. (e) MR image 56 days after the first gadolinium texaphyrin injection, without injection of contrast agent. Enhancement (arrowheads) is still well visible and is grade 2. Tumor decreased to 65% of initial size.

 


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  		Figure 4a. Coronal T1-weighted spoiled gradient-recalled-echo MR images (35/4, 40° flip angle) in a 41-year-old woman with brain metastases from a breast cancer. (a) Pretherapeutic MR image after injection of 16 mL of gadoterate meglumine. Target lesions (arrowheads) localized in the caudate nucleus show fully visible signal intensity enhancement. 1 and 2 are the two largest perpendicular diameters of the lesion. (b) MR image after the first injection of gadolinium texaphyrin (2.30 µmol/kg). No enhancement in the target lesions. (c) MR image after the 10th injection of gadolinium texaphyrin. Enhancement is localized in the target lesions (arrowheads) and is grade 3 (high enhancement). (d) MR image 56 days after the first gadolinium texaphyrin injection. Enhancement (arrowheads) is still visible and is grade 3. Tumor decreased to 68% of initial size. (e) MR image 16 weeks after the first gadolinium texaphyrin injection. Enhancement (arrowheads) is still visible and is grade 1 (moderate enhancement).

 


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  		Figure 4b. Coronal T1-weighted spoiled gradient-recalled-echo MR images (35/4, 40° flip angle) in a 41-year-old woman with brain metastases from a breast cancer. (a) Pretherapeutic MR image after injection of 16 mL of gadoterate meglumine. Target lesions (arrowheads) localized in the caudate nucleus show fully visible signal intensity enhancement. 1 and 2 are the two largest perpendicular diameters of the lesion. (b) MR image after the first injection of gadolinium texaphyrin (2.30 µmol/kg). No enhancement in the target lesions. (c) MR image after the 10th injection of gadolinium texaphyrin. Enhancement is localized in the target lesions (arrowheads) and is grade 3 (high enhancement). (d) MR image 56 days after the first gadolinium texaphyrin injection. Enhancement (arrowheads) is still visible and is grade 3. Tumor decreased to 68% of initial size. (e) MR image 16 weeks after the first gadolinium texaphyrin injection. Enhancement (arrowheads) is still visible and is grade 1 (moderate enhancement).

 


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  		Figure 4c. Coronal T1-weighted spoiled gradient-recalled-echo MR images (35/4, 40° flip angle) in a 41-year-old woman with brain metastases from a breast cancer. (a) Pretherapeutic MR image after injection of 16 mL of gadoterate meglumine. Target lesions (arrowheads) localized in the caudate nucleus show fully visible signal intensity enhancement. 1 and 2 are the two largest perpendicular diameters of the lesion. (b) MR image after the first injection of gadolinium texaphyrin (2.30 µmol/kg). No enhancement in the target lesions. (c) MR image after the 10th injection of gadolinium texaphyrin. Enhancement is localized in the target lesions (arrowheads) and is grade 3 (high enhancement). (d) MR image 56 days after the first gadolinium texaphyrin injection. Enhancement (arrowheads) is still visible and is grade 3. Tumor decreased to 68% of initial size. (e) MR image 16 weeks after the first gadolinium texaphyrin injection. Enhancement (arrowheads) is still visible and is grade 1 (moderate enhancement).

 


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  		Figure 4d. Coronal T1-weighted spoiled gradient-recalled-echo MR images (35/4, 40° flip angle) in a 41-year-old woman with brain metastases from a breast cancer. (a) Pretherapeutic MR image after injection of 16 mL of gadoterate meglumine. Target lesions (arrowheads) localized in the caudate nucleus show fully visible signal intensity enhancement. 1 and 2 are the two largest perpendicular diameters of the lesion. (b) MR image after the first injection of gadolinium texaphyrin (2.30 µmol/kg). No enhancement in the target lesions. (c) MR image after the 10th injection of gadolinium texaphyrin. Enhancement is localized in the target lesions (arrowheads) and is grade 3 (high enhancement). (d) MR image 56 days after the first gadolinium texaphyrin injection. Enhancement (arrowheads) is still visible and is grade 3. Tumor decreased to 68% of initial size. (e) MR image 16 weeks after the first gadolinium texaphyrin injection. Enhancement (arrowheads) is still visible and is grade 1 (moderate enhancement).

 


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  		Figure 4e. Coronal T1-weighted spoiled gradient-recalled-echo MR images (35/4, 40° flip angle) in a 41-year-old woman with brain metastases from a breast cancer. (a) Pretherapeutic MR image after injection of 16 mL of gadoterate meglumine. Target lesions (arrowheads) localized in the caudate nucleus show fully visible signal intensity enhancement. 1 and 2 are the two largest perpendicular diameters of the lesion. (b) MR image after the first injection of gadolinium texaphyrin (2.30 µmol/kg). No enhancement in the target lesions. (c) MR image after the 10th injection of gadolinium texaphyrin. Enhancement is localized in the target lesions (arrowheads) and is grade 3 (high enhancement). (d) MR image 56 days after the first gadolinium texaphyrin injection. Enhancement (arrowheads) is still visible and is grade 3. Tumor decreased to 68% of initial size. (e) MR image 16 weeks after the first gadolinium texaphyrin injection. Enhancement (arrowheads) is still visible and is grade 1 (moderate enhancement).

 
On MR images acquired after the first injection, enhanced signal intensity was visible in five patients. No enhancement was observed when the dose injected was below or equal to 0.80 µmol/kg. On MR images obtained after the last injection, enhanced signal intensity was visible in nine patients. The patient with no enhancement had received a dose of 0.80 µmol/kg. The patient who had received a dose of 0.50 µmol/kg per injection had no enhancement of signal intensity in the target lesion on the MR image obtained after the first injection of gadolinium texaphyrin. However, after the 10th injection, there was enhanced signal intensity, which was grade 2. One lesion was visible on the MR study acquired after the 10th injection of gadolinium texaphyrin (1.80 µmol/kg per injection), but it had not been visible on the first MR image obtained after injection with conventional gadolinium-based contrast material.

MR images obtained 56 days after the beginning of treatment showed persistent enhancement of signal intensity in seven patients. The patient who had received the dose of 0.80 µmol/kg per injection had images that showed enhanced signal intensity in the three grade 1 target lesions that had become visible only on the fourth MR study.

Additional MR studies were obtained in two patients 3–4 months after the beginning of treatment; the high level of signal intensity was still visible and was of a magnitude comparable to that of the fourth MR studies.

In a patient who received a dose of 1.30 µmol/kg per injection, the MR images acquired after the beginning of treatment showed enhancement of signal intensity, which had been grade 3 on the fourth MR image and was still fully visible at 6 months (grade 2) and moderate at 9 months (grade 1).

Localization of enhanced signal intensity.—Enhancement of signal intensity was noted only in target lesions, never in normal brain tissue or the mucous membrane.

Appearance of enhanced signal intensity.—There was no remarkable modification in the appearance of the signal intensity noted on successive MR images, which means enhancement was not due to hemorrhage in metastases.

Response to Treatment
Response was evaluated according to World Health Organization criteria. Seven patients achieved a partial remission, with tumor regression greater than or equal to 50%. One patient achieved a minor response with a tumor regression of 25%–49% of the initial size, and in three patients the disease stabilized, with tumor regression of 1%–24% of the initial size. One patient had new brain metastases 2 months after the end of the treatment.


   DISCUSSION
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
Radiation therapy is an important treatment for localized cancers. Unfortunately, the radiation dose is often too limited because of injury to normal surrounding tissue. An ideal radiosensitizer would exert its effect only when administered in the appropriate sequence with radiation therapy, with no direct toxic reaction.

Metronidazole, which was used as a radiation sensitizer in the treatment of supratentorial glioblastomas 20 years ago, achieved a notable positive effect (6). A few years later, nimorazole was used as a hypoxic radiation sensitizer in the treatment of supraglottic laryngeal and pharyngeal carcinoma; the study findings (7) revealed an apparent independent and additive relationship between the hemoglobin concentration and the use of the hypoxic radiosensitizer, and the tumor response was better in patients randomly assigned to the nimorazole group than in patients in the placebo group.

Unfortunately, most radiation sensitizers do not show any differential therapeutic index between tumor and surrounding normal tissues. The use of a tumor-selective radiation sensitizer could help maximize tumor exposure to ionizing radiation and could help improve the chances of obtaining tumor control. Furthermore, a tumor-selective radiation sensitizer that is detectable at MR imaging could help in the appreciation of response to radiation therapy. Such was the case with gadolinium texaphyrin, the prototype of a new class of compounds.

These preliminary results based on limited findings in 11 patients indicate that gadolinium texaphyrin is safe and tumor selective, since enhancement of signal intensity was detected only in target lesions and never in normal brain tissue. Uptake in target lesions was higher after 10 daily injections of gadolinium texaphyrin than after the first one, which indicated the accumulation of gadolinium texaphyrin in brain metastases and its persistence several months later in metastases, as revealed at additional MR examinations. The lesion that was visible only after the 10th injection of gadolinium texaphyrin was either a new metastasis or a lesion that was undetectable with conventional gadolinium-based contrast material.

It is possible not only to depict brain metastases at MR imaging with gadolinium texaphyrin but also to evaluate response to treatment at successive MR imaging examinations, since gadolinium texaphyrin remains in tumors for several months. Injection of a paramagnetic contrast agent for the follow-up MR examinations would be redundant.

These preliminary results do not reflect the radiation-sensitizing effect of gadolinium texaphyrin, which requires further investigation.

Findings of this phase IB and phase II study indicate that gadolinium texaphyrin is tumor selective. The accumulation of gadolinium texaphyrin in metastases over several months as revealed at brain MR studies should permit imaging of brain metastases after radiation therapy and, therefore, evaluation of response to the treatment. A further study in more patients is necessary to appreciate the radiation-sensitizing effect of gadolinium texaphyrin.


   Footnotes
 
Dr Carde and Dr Renschler each has a financial interest through ownership of stock or stock options in the company developing gadolinium texaphyrin, Pharmacyclics. Dr Carde also serves as a consultant to the company. Dr Renschler is the senior director of clinical research and is an employee of the company.

Author contributions: Guarantor of integrity of entire study, D.V.; study concepts, M.R.; study design, P.C.; definition of intellectual content, D.V.; literature research, J.V.; clinical studies, E.L.; data acquisition and analysis, P.M., J.V.; manuscript preparation and editing, J.V.; manuscript review, D.V.


   References
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

  1. Young S, Qing F, Harriman A, et al. Gadolinium(III) texaphyrin: a tumor selective radiation sensitizer that is detectable by MRI. Proc Natl Acad Sci USA 1996; 93:6610-6615.[Abstract/Free Full Text]
  2. Rosenthal DI, Nurenberg P, Becerra CR, et al. A phase I single-dose trial of gadolinium texaphyrin (Gd-Tex), a tumor selective radiation sensitizer detectable by magnetic resonance imaging. Clin Cancer Res 1999; 5:739-745.[Abstract/Free Full Text]
  3. Young SW, Sidhu MK, Qing F, et al. Preclinical evaluation of gadolinium (III) texaphyrin complex: a new paramagnetic contrast agent for magnetic resonance imaging. Invest Radiol 1994; 29:330-338.[Medline]
  4. Sessler JL, Hemmi G, Mody TD, Murai T, Burrell A, Young SA. Texaphyrins: synthesis and applications. Accounts Chem Res 1994; 27:43-50.
  5. Borgelt B, Gelber R, Kramer S, et al. The palliation of brain metastases: final results of the first two studies by the Radiation Therapy Oncology Group. Int J Rad Oncol Biol Phys 1980; 6:1-9.[Medline]
  6. Urtasun R, Band P, Chapman JD, Feldstein ML, Mielke B, Fryer C. Radiation and high-dose metronidazole in supratentorial glioblastomas. N Engl J Med 1976; 294:1364-1367.[Abstract]
  7. Overgaard J, Sand Hansen H, Lindelov B, et al. Nimorazole as a hypoxic radiosensitizer in the treatment of supraglottic larynx and pharynx carcinoma: first report from the Danish Head and Neck Cancer Study (DAHANCA) protocol 5-85. Radiother Oncol 1991; (suppl 1):143-149.



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Neurocognitive Function and Progression in Patients With Brain Metastases Treated With Whole-Brain Radiation and Motexafin Gadolinium: Results of a Randomized Phase III Trial
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M. P. Mehta, P. Rodrigus, C.H.J. Terhaard, A. Rao, J. Suh, W. Roa, L. Souhami, A. Bezjak, M. Leibenhaut, R. Komaki, et al.
Survival and Neurologic Outcomes in a Randomized Trial of Motexafin Gadolinium and Whole-Brain Radiation Therapy in Brain Metastases
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M. P. Mehta, W. R. Shapiro, M. J. Glantz, R. A. Patchell, M. A. Weitzner, C. A. Meyers, C. J. Schultz, W. H. Roa, M. Leibenhaut, J. Ford, et al.
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R. A. Miller, K. W. Woodburn, Q. Fan, I. Lee, D. Miles, G. Duran, B. Sikic, and D. Magda
Motexafin Gadolinium: A Redox Active Drug That Enhances the Efficacy of Bleomycin and Doxorubicin
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