Motexafin Gadolinium (MGd) and Concurrent Chemoradiation in Head and Neck Cancer

Ryan Smith, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 13, 2003

Faculty Disclosure: David M. Brizel, MD
In this presentation Dr. Brizel discusses the use of Motexafin Gadolinium (MGd)in the treatment of head and neck cancer which has not been approved by the FDA.

Presenter: David M. Brizel, MD
Affiliation: Duke University Medical Center

Approximately 60% of those patients diagnosed with head and neck cancer have locally advanced but non-metastatic disease. In these patients, local and regional failures continue to predominate and are the most likely causes of death. Recently, advances have been made in terms of controlling these diseases. Hyperfractionated radiation regimens and the use of concurrent chemoradiation regimens have increased not only local control, but also survival. However, even with these advancements, there is still a need for even more efficacious regimens.

Motexafin Gadolinium (MGd) is a radiosensitizing compound currently being investigated in the treatment of head and neck cancer. MGd is a texaphyrin (from the porphyrin family of compounds) that forms large complexes with cations, which have been shown to be selectively taken up into tumor tissues compared with normal tissues. MGd works as a radiosensitizer by two different mechanisms. First, it has favorable electron transfer properties that contribute to the disruption of cellular respiration. This is thought to increase the oxygen levels in tumors. Also, MGd catalyzes reactions that deplete the intracellular stores of NADPH, ascorbate, and glutathione. These are all well-known oxygen free radical scavengers that would normally serve to protect against radiation damage. Hence, by these processes MGd increases the susceptibility of these tumor cells to the effects of radiation therapy. This trial was performed to establish the maximally tolerated dose of MGd in a treatment regimen for locally advanced head and neck cancer.

Patients had locally advanced oropharynx, hypopharynx, or larynx cancer. All were required to have a primary tumor of >4cm (T3 or greater). They were treated with 125 cGy BID of radiation to a total dose of 72 Gy with a planned break at week 4. During weeks 1 and 5, concurrent chemotherapy was delivered. This consisted of 5-FU 600 mg/m2/d x 5 days and cisplatin 12 mg/m2/d x 5 days, given after the MGd. The initial dose of MGd (obtained from a different trial in metastatic brain tumors treated with radiation therapy alone) was 2.5 mg/kg/d during weeks 1 and 5 with additional doses of 2.5 mg/kg on Monday, Wednesday, and Fridays in the weeks where radiation was given without chemotherapy. However, in the original cohort of four patients, two had dose limiting toxicities consisting of mucositis and radiation dermatitis. Therefore, a dose reduction to 1.0 mg/kg/d during weeks 1 and 5 only (no doses without chemotherapy) was performed. In five patients, there were no dose limiting toxicities noted, though there were significant mucositis and radiation dermatitis reactions noted. Eight out of nine patients had a complete response to therapy and at a median follow up of nine months, only 2 treatment failures have been noted. Oxygen measurements were done in one patient and this patient was noted to have a four fold increase in tumor oxygenation after the administration of MGd.

This study indicates that MGd can be safely administered with chemoradiation in the treatment of head and neck cancers. No new toxicities were noted, though there appeared to be an amplification of known toxicities (mucositis, dermatitis), keeping in mind however that this is in an already aggressive treatment regimen. This trial also presented evidence that MGd may have efficacy in head and neck cancers, perhaps by increasing tumor oxygenation. Regardless, locally advanced head and neck cancer continues to present a problem to physicians in terms of attempting to control the disease. MGd may assist in treating these patients, though it should be kept in mind that patient selection is the key in using this aggressive treatment regimen. Furhter studies of this agent in the head and neck cancer patient population should be encouraged.