Targeted Radiotherapy to the Skeleton Using 166Ho-DOTMP with Autologous Stem Cell Transplantation for Patients with Bone-Only Metastatic Breast Cancer.

The skeleton is the most frequent site of metastatic disease in breast cancer, involving cortical and trabecular bone with or without extension into adjacent bone marrow. A subset of breast cancer patients develop bone dominant disease without metastases to other organs over a prolonged period of time. An attractive strategy is to utilize bone targeted radiotherapy to address this site of disease with minimal systemic toxicity. This study was designed to determine the safety and preliminary efficacy of 166Ho-DOTMP, which localizes to bone providing radiation to adjacent marrow and malignant cells. The limiting toxicity is myelosuppression, which can be overcome by autologous stem cell transplantation. We studied this strategy in subjects with breast cancer metastatic to confined to the bone.

Treatment occurred between 1997 and 1999. Subjects were eligible if they were <65 years of age, had bone only disease, had an estrogen receptor negative tumor or had failed hormonal therapy. A 30 mCi tracer dose was administered to assess targeting and to allow the therapeutic dose to be calculated.

If uptake was adequate, a therapeutic dose was to be administered in one of 2 dose levels, receiving 22 Gy (n=3) or 28 Gy (n=3). Treatment was followed by autologous stem cell transplantation when the ongoing radiation dose to marrow was <1 cGy/hour. The 6 subjects received a median of 1548 mCi (range 870 2065 mCi) of 166Ho DOTMP. There was selective uptake in the bone, particularly in sites of osteoblastic metastases, with unbound drug cleared into the urine. The most common toxicities seen during active treatment were mild nausea and vomiting. None of the patients experienced grade >3 acute toxicity aside from the expected profound myelosuppression. All subjects treated in the trial had prompt trilineage hematologic recovery post transplant. Two patients developed hemorrhagic cystitis at approximately two years following therapy which resolved in both patients. One of these patients also had GI bleeding and pseudomembranous colitis unrelated to the 166Ho DOTMP treatment. One subject developed MDS, but was found to have a pre-existing trisomy 8 by FISH analysis from the peripheral blood stem cell product collected prior to treatment on this study. Two patients achieved complete remission and remain progression-free over 5 years following study entry. Four relapsed and died of progressive disease; all recurred in extraosseous sites with two also having disease in the bone marrow. Median time to progression was 10 months.

Conclusions: Treatment with 166Ho DOTMP delivers targeted radiotherapy to the skeleton with an acceptable toxicity profile. Two of 6 patients with bone-only metastases achieved sustained complete responses. Further studies are warranted to evaluate this strategy for treatment of bone metastases.