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ABSTRACT & COMMENTARY
Synopsis: For patients with advanced, hormone refractory prostate cancer, metastatic disease in bone is a prominent cause of increased morbidity and shortened survival. Researchers from M.D. Anderson report their institution’s randomized phase II trial of bone targeted consolidation therapy combining chemotherapy with strontium-89. A subset of patients (those who had responded to induction chemotherapy) was shown to have better survival if consolidation included Sr-89 plus chemotherapy when compared to chemotherapy alone. This report strengthens the rationale for bone targeted therapy in the management of prostate cancer and provides additional impetus for a large, multi-institutional phase III investigation.
Source: Tu S-M, et al. Lancet 2001;357:336-341.
Prostate cancer has a predisposition to spread to bone and this leads to significant morbidity and increased mortality.1 Specific interactions with the bone microenvironment have been implicated in this pattern and the complications that develop from progressive skeletal metastases dominate the clinical picture of advanced prostate cancer.2 Thus, Tu and colleagues from the M.D. Anderson Cancer Center in Houston, Tex, performed a randomized trial to assess the potential role of bone-targeted therapy in patients with progressive, androgen-independent prostate cancer.
There were 105 patients included in this analysis. Two patients were enrolled but declined therapy after signing informed consent. The remaining 103 patients received induction chemotherapy consisting of doxorubicin (20 mg/m2) as a 24-hour infusion on the first day of weeks one, three, and five and ketokonazole (400 mg) administered three times daily during those same weeks. In weeks two, four, and six, treatment consisted of vinblastine (4 mg/m2) intravenously on the first day of the week in combination with estramustine (140 mg) orally three times daily during those same weeks. All patients also received hydrocortisone 30 mg orally in divided doses each day. Weeks seven and eight were "rest" weeks and no drugs were administered during this time. Upon completion of either two or three eight-week cycles, patients with stable or responding disease were randomized to consolidation therapy with either doxorubicin alone (at the same dose, once weekly for 6 weeks), or doxorubicin (same dose) with a single dose of strontium-89 (Sr-89); 2.035 MBq per kg body weight), given during the first week after the doxorubicin injection.
The induction chemotherapy resulted in responses (as indicated by a reduction of 50% or more in PSA concentration that persisted ³ 8 weeks) in 62 of the 103 patients. The toxicities associated with therapy included deep vein thrombosis in 11 patients (thought to be related to indwelling venous catheters), grade 4 neutropenia in 11 patients, and grade 3 anemia in seven. Two patients died during therapy, one of a myocardial infarction and another with neutropenic sepsis.
Of the 72 patients who were considered to have either responding or stable disease after the induction chemotherapy, 36 were randomized to receive doxorubicin alone and 36 were randomized to receive doxorubicin and Sr-89. The remaining 31 patients had either progressive disease during induction therapy (n = 16), intolerable side effects (n = 9), or were lost to follow-up (n = 6). The estimated median survival for the entire group of 103 patients was 17.5 months (range, 0.5-37.7). For those that received Sr-89 and doxorubicin, the median survival was 27.7 months (4.9-37.7) and for those that received consolidation with doxorubicin alone it was 16.8 months (range, 4.4-34.2; P = 0.0014).
Tu et al concluded that bone-targeted consolidation therapy (with Sr-89) and continued chemotherapy offered a survival advantage for those patients with either stable or responding disease after induction chemotherapy.
COMMENT by William B. Ershler, MD
Organ directed therapy makes inherent sense for certain tumors that have a proclivity to spread predominantly to that organ. Such is the case for prostate cancer. The great majority of patients who die with prostate cancer have metastases in bone, and for most, bone is the only organ to which the disease has spread.1 Thus, treatment that might influence tumor growth in bone is a logical therapeutic question in the management of prostate cancer. Sr-89, a bone-homing radioisotope, had already been shown to be a feasible approach and was a reasonable choice for this trial.3
Indeed, the patients randomized to receive Sr-89 had significantly longer time to progression and overall survival than those who did not receive Sr-89. However, as Tu et al point out, this was a relatively small, single institution study with results that might lend themselves to over interpretation. Certainly, the findings are encouraging and warrant a larger, multi-institution Phase III trial.
The mechanism of Sr-89 activity is unclear and may be related to alterations in the bone microenvironment rather than direct prostate cancer cytotoxicity.4 In this light, perhaps pamidronate or other bisphosphonates will also be shown to have the same effect on survival in this setting.
1. McRea LE, Karafin L. Int Coll Surg J 1958;29:723-728.
2. Sabbatini P, et al. J Clin Oncol 1999;17:948-957.
3. Tu S-M, et al. Urol Ocnol 1996:2:191-197.
4. Jacobsson H, et al. Int J Radiat Oncol Biol Phys 1991;20:1297-1303.