NOVEL APPROACHES TO BONE METASTASES
Oliver Sartor, MD
Dana Farber Cancer Institute,
Harvard Medical School,
Dr. Sartor is a regular presenter at prostate conferences arranged by Dr. Myers and UsToo. He had been at LSU but as a result of the destruction caused by Hurricane Katrina he left his research/teaching position there and joined the Dana Farber Cancer Institute earlier in 2006.
His area of specialization has been in dealing with bone metastases in advanced PCa. Some of his research has involved the use of Samarium-153, another radioactive element used to attack bone lesions in advanced PCa.
He started his lecture by pointing out the unique character of HRPC metastasis. Prostate cancer has an unusually high ratio of bone to soft tissue metastases compared to other solid tumors.
It is also exceptionally osteoblastic (as in creating new bone tissue). In the majority of PC patients, he reported, bone mets are the only detectable sites of metastases in advanced cases.
Bone seeking pharmaceuticals have been used in attempts to destroy such mets by having the radioactive element find its way to the bone met and destroy it via radiation in situ. He listed the elements that have been used to date:
Phosphorus-32, Strontium-89, Samarium-153 EDTMP (commercially available), Rhenium-186, Tin-117, and Radium-223
Strontium-89 is effective because it tracks the deposition of calcium in bone formation and delivers its cell killing radiation in situ. The action of Samarium-132, chelated with EDTMP, he reported, was via the attraction of the phosphonic group in the chelate to areas of newly deposited bone. The phosphorous -32 action results from its tracking of the action of the phosphorous in the body.
[Ed Note: All of these materials to-date have produced palliative reactions with no cures reported].
Use of radio-pharmaceuticals for pain reduction is one of its primary applications.
Because of potential toxicity of these materials, careful monitoring of patients using these materials is important. Since palliation, not cure, is the intended goal some disappointment may occur when the subject continues to experience pain and discomfort but at a “lover level”.
Patient pain perception is measured using different kinds of scales. In one, the pt is asked to rank his pain on a visual scale chart while in other studies a “pain descriptor scale” is used. In both cases, the study results will be affected by the subjective pt desire to report some beneficial results.
Consequently, great care is taken during these studies to generate statistically useful data.
Toxicity of these treatments is monitored by watching white blood cell counts, platelets and red cells. Because bone marrow is the major producer of blood radioactive pharmaceuticals that could impact this function have to be monitored carefully.
In one slide, Dr. Sartor showed reductions in platelets ranging from Grade 2 to Grade 4 from 10% to 28% vs. placebo results that ranged from 1.7% to 6.9% . The message of these data was to show some significant effects on blood platelets resulting from the use of Sr-89.
In some European data from 2003, he showed graphs comparing the difference in effectiveness between Sr-89 and local field radiotherapy on survival. There was a small advantage with the Sr-89 compared to the external beam radiation.
The two survival curves were quite close to one another however there was a statistically significant difference.
Following the practice of chemo cocktails to obtain synergism results from combinations of therapies, Dr. Sartor reported on such combinations as:
· Strontium 89/External Beam RT
· Strontium 89/Adriamycin
· Strontium 89/Cis-platinum
· Samarium 153/Docetaxel
Multiple trials started and in planning
He reported on the results of a Phase II trail involving Doxorubicin with and without Sr-89. The article reporting these results is Tu, et. al., Lancet 357: 336-41. It shows a significant advantage for the combination of Doxorubicin with Sr-89.
After 24 months a significantly higher % age of men were still alive compared to the chemo drug alone.
Dr. Sartor then discussed a trial involving the combination of Docetaxel and Quadramet® (commercial name for Samarium 153/phosphonate chelator). The reference for this trial is: Widmark, et. al. ASCO-Prostate 2006, #221. The trial involved a first cycle of 5 weeks of Docetaxel therapy with Quadramet introduced prior to week 4 Docetaxel.
The median PSA at the start of the trial was 838 (range 15 – 2330) indicating that this population of men were well along with advanced HRPC. Of the 29 pts who received the first course of tx only 17 went on to the second course. However, the median PSA was 200 prior to the start of the second course and that represented a major drop from the entering levels.
He reported that within 12 weeks of cycle 1, PSA declines of >50% and >75% were noted in 34 and 21% of pts respectively. The median time to response was 38 and 34 days respectively while the median time to PSA progression was 126 days and “clinical progression” in 108 days.
[Ed Note: clinical progression was not defined therefore one must research the original reference to find this].
Side effects reported in this trial included small numbers of Grade 3-4 neutropenia in cycle 1 and greater numbers following Cycle 2.
For men dealing with metastatic HRPC the results of this trial should be studied carefully to determine if it is applicable to their condition.
Another similar trial involving Quadramet and Docetaxel also utilized Emcyt in what oncologists call “induction therapy”. This trial used as endpoints Progression Free Survival (PFS) and survival at 1 year. The reference is: Laplanche et. al., ASCO 2006 #4608.
Almost 50% were PFS at 7 months and 71% had survived for one year! Also, they reported that 69% had an approximate 20% reduction in pain scores. Toxicity was reported as Grade 3-4 neutropenia in some 14% of pts and thrombocytopenia in some 5%.
Another Quadramet/Docetaxel trial was discussed: Mariani, SNM 2006 #135. This trial had only 23 pts with a Mean PSA of 105 and a Median of 171. Only 2/23 pts had a >50% PSA reduction, 5/23 had a 20-50% reduction and 6/23 <20% change.
In pain control, he reported that 15/23 showed partial to complete long lasting pain response, 6/23 with no significant response, and 1/23 with increasing pain.
Dr. Sartor closed his lecture by describing (briefly) what new trials are underway or planned with this combination approach of a chemo drug with Quadramet®.
[Ed Note: Because Quadramet® is a commercial product marketed by Cytogen, it is likely that Cytogen is funding these clinical trials. In order to make the studies more powerful statistically, larger sample sizes are required.
However, given the nature of the study population required and the number of sites that may be involved, it’s a reasonable guess that we will see smaller study populations and weaker statistics]
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