Currently, systemic therapy of prostate cancer is limited to various forms of androgen deprivation. While approximately 80% of patients will demonstrate clinical improvement, objective tumor regression is seen in only 2-3%. Almost inevitably, an androgen independent clone will appear, and time to progression of disease is a median of 12-18 months (15). Once this occurs, there is no standard therapy and the median duration of survival approximates one year. Endocrine therapy is palliative, not curative, and while it improves quality of life, the data suggests that it does not extend the quantity of life (16). Cytotoxic chemotherapy is poorly tolerated in this age group and generally considered ineffective and/or impractical. Biological response modifiers, such as suramin, are under active investigation.
A parallel line of investigation has relavence for mAb based therapy. Local-field radiation therapy (RT) has proven very effective at controlling pain due to bony metastasis from prostate cancer. Local-field RT, however, is compromised by the later appearance of other sites requiring treatment. Hemibody RT, while also relatively effective, is compromised by significant gastrointestinal and hematologic morbidity. For these reasons, bone-seeking radiopharmaceuticals have been undergoing study in this setting. 89Strontium (Sr) exchanges with the calcium component of hydroxyapatite and concentrates in osteoblastic bone lesions where it may remain for 100 days (17). It is calculated that the dose to metastatic bone sites is 10-fold the dose to the red marrow (17). This agent provides palliation of prostate cancer bone pain in 75-80% of hormone-refractory patients (18). In a randomized trial comparing 89Sr to either local-field or hemi-body RT, the efficacy of 89Sr was comparable to either conventional form of radiotherapy. 89Sr, however, was associated with less morbidity and with a longer interval to the onset of new bone pain, presumably due to irradiation of sites which were asymptomatic at the time of therapy (19). 89Sr also proved to be an effective adjuvant when combined with local-field RT. The combination prolonged the interval to further radiotherapy from 23 to 51 weeks. Beyond palliating pain, 89Sr has some anti-tumor effect as measured by a >50% decline in PSA (20). Other radionuclides such as 186Rh and 153Sm, conjugated to ligands with affinity to bone, are currently undergoing study. It is significant that 89Sr which is targetted to bone rather than the cancer per se, and which has a ratio of absorbed dose of 10:1 (bone:red marrow; and presumably less than 10:1 for cancer to marrow), has an anti-tumor effect measured by both pain relief and PSA decline. It is interesting to contemplate what one might be able to accomplish with a more cancer-specific targetting modality.
CYT-356, conjugated with 90yttrium, is currently in a phase I trial to define the maximum tolerated dose with this beta-emitter. Eligible patients must have hormone-refractory disease, a Karnofsky performance status greater than 60, and have disease documented to be immunoreactive with CYT-356. Patients who have received prior radiotherapy will be escalated independently from those without prior RT. No data are as yet available.
