Success has often eluded doctors in the treatment of unresectable or metastatic medullary thyroid cancers. Results with chemotherapy have been limited, and external beam radiation may control only local disease. However, a new study reported in the Journal of Nuclear Medicine (January 2000, Vol. 41:1, pp. 93-103) shows promising initial results with a third technique: high-dose radioimmunotherapy of cancer sites with anti-carcinoembryonic antigen monoclonal antibodies.
Because high radiation doses are accompanied by myelotoxicity and potential bone marrow ablation, the antigen therapy was combined with autologous hematopoietic stem cell rescue (AHSCR). The study marks the first known use of the combined technique with metastatic medullary thyroid cancer, and is one of only a few studies involving solid tumors, according to the authors.
The phase I study, conducted at the Garden State Cancer Center in Belleville, NJ, and at St. Joseph's Hospital in Paterson, NJ, sought to assess the toxicity and therapeutic potential of targeting cancer cells with high-dose 131I-MN-14 F(ab)2 with anti-carcinoembryonic antigen monoclonal antibodies (MAbs). This antigen, manufactured by Immunomedics of Morris Plains, NJ, appeared to be the best available choice for the study due to its high affinity to cancer cells and its imaging sensitivity of 99%.
The 12 patients chosen for the study all had clear evidence of rapidly progressing metastatic medullary thyroid cancer, or unresectable gross primary or locoregional disease. All but two of them (three women and nine men aged 20-64) had undergone total thyroidectomy, and nine had also undergone unilateral radical or modified radical neck dissection. All patients scored at least 70 on the Karnofsky scale, and had a minimum life expectancy of at least three months. The trial was conducted under an investigational new drug application from the Food and Drug Administration.
Before receiving therapy, autologous hematopoietic stem cells were harvested from all the patients, and reinfused 1-2 weeks after therapy, when total body radiation exposure had returned to safe levels. The researchers used a dose escalation protocol based on dose estimates to critical organs, including the kidneys, liver and lungs, based on a diagnostic-dosimetric study performed a week before the therapy infusion. Because the high radiation doses were intended to be myoablative, the authors wrote, only nonhematologic grade 3 or 4 toxicity was determined to be dose-limiting. Doses were increased to the next level when three patients completed eight weeks of therapy without dose-limiting toxicity.
The starting dose was set at 900 cGy for the kidneys, and did not exceed 1200 cGy for the lungs and liver. Because the absorbed radiation dose to the kidneys was set lower than for the other organs, and the kidneys usually had the highest absorbed dose estimates, the kidney dose determined the radiation doses in 11 of 12 patients. The antibody infusions were given intravenously, and patients received potassium perchlorate in advance to decrease gastric uptake of radioiodine. Lugol's solution, or SSKI, was also given to minimize radiation uptake in the GI tract resulting from MAb breakdown, the authors wrote.
Results
Following treatment, the authors reported that the MAb scans of all patients showed positive findings. Except for one instance of grade 3 gastrointestinal toxicity seen in a patient who had been treated at the 900-cGy dose level, nonhematologic toxicity was fairly mild, and did not exceed level 2 in nine patients.
One patient had partial remission for a year, which was significant considering that he had rapidly progressing disease before therapy and a massive liver tumor burden, the authors wrote. One patient had a minor response for three months: a regression of diffuse pulmonary metastases accompanied by a significant decrease in plasma calcitonin levels. In 10 patients, radiologic follow-up, primarily with CT, showed that the disease had stabilized for periods ranging from 1-16 months. Of these 10 patients, four remained stable after 10 months, while the disease progressed again in six.
Conclusions
The authors concluded that even though the patient sample was relatively small, it was clear that dose escalation of radioimmunotherapy with AHSCR is feasible in patients with medullary thyroid cancer, and that the technique produced encouraging antitumor effects with only moderate nonhematologic toxicity. Nevertheless, they urged special caution in using the technique because "the nonhematologic toxicity observed is clearly more frequent and more intense than that seen in nonmyeloablative radioimmunotherapy trials, with the potential for delayed or more chronic toxicity...."
The authors elected to discontinue the trial when a new humanized form of MN-14 became available which offered the advantage of reduced immunogenicity compared with the murine form used in the trial.
"As the doses are escalated further, using this radiolabeled humanized MAb, either alone or in combination with chemotherapy, the prospects of achieving better antitumor effects will increase," the authors wrote. At that point "the role of high-dose radioimmunotherapy in the management of patients with metastatic medullary thyroid cancer and other solid tumors may then be defined."
By Eric Barnes
AuntMinnie.com staff writer
February 21, 2000
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