153Sm-EDTMP versus docetaxel for multiple painful osseous metastases in prostate cancer

Local radiotherapy, chemotherapy, and bisphosphonates were shown to provide
some pain relief and bone seeking intravenous radionuclide treatment is an
effective modality in these patients. Recently, docetaxel in a 3 weekly dosing
of 75 mg/m2 was shown to result in pain relief in up to 35% of patients. Pain
relief was experienced after the first two courses of docetaxel and pain relief
was sustained but not increased after the 2 initial courses [5]. Moreover, a
modest increase in overall survival was seen in patients receiving 3 weekly,
but not weekly docetaxel in 2 large randomized trials. The side-effects of
docetaxel chemotherapy prohibit its use in patients with a diminished
hematopoietic function. Moreover, toxicities of the agent such as asthenia,
nauseau and vomiting, and diarrhea led to withdrawal of treatment in 16% of the
patients receiving a combination of docetaxel and mitoxantrone. Second line
chemotherapy treatment with mitoxantrone after docetaxel was shown ineffective
suggesting that alternative palliative options after chemotherapy are required.

Recently, samarium-153 bound to lexidronam-pentanatrium (153Sm-EDTMP) became
available of radionuclide treatment of osseous metastases. The relatively short
radiation half-life of 153Sm-EDTMP (2 days) render it an interesting agent with
possibly less hematologic toxicity. 153Sm-EDTMP significantly reduced pain
compared to placebo within 2 weeks with mild bone marrow suppression. Repeated
dosing seemed feasible with clinically non-relevant changes in hematological
parametes. These initial clinical studies with 153Sm-EDTMP suggest that it
provides a relatively non-toxic alternative to chemotherapeutic regimens such
as docetaxel in patients with multiple osseous metastases.

Currently, several studies are evaluating the combined efficacy of radionuclide
therapy and docetaxel chemotherapy. Although the radiosensitizing effects of
docetaxel may potentiate efficacy, it may also increase toxicity in a
population already at risk for hematological problems due to bone marrow
suppression by osseous metastases. An important clinical question is the timing
and order of applicating the palliative treatment modalities in metastasized
prostate cancer. In the current study we want to evaluate the efficacy to
obtain pain relief in patients with painful osseous metastases from prostate
cancer for 3 weekly docetaxel and once 153Sm-EDTMP and evaluate possible
success predicting factors to aid in the selection of patients for specific
treatment sequelae.

The sequential application of chemotherapy and radionuclide treatment in
patients with symptomatic osseous metastasized prostate cancer. Patients with
more than one painful osseous metastasis will be randomized between 153Sm-EDTMP
or docetaxel 3 weekly 75mg/m2 (i.v.). Pain will be measured on a VAS of 10
points 3 times before treatment and again weekly until 6 weeks after start of
treatment using a pain diary. A pain response is defined as a two-point
reduction (20%) from baseline, without the need for palliative radiotherapy or
change in pain medication. In case pain response is not obtained after two
course of docetaxel or one dosing of 153Sm-EDTMP in the evaluation in week 5-6
patients receiving docetaxel will receive 153Sm-EDTMP or vice versa.

Patients with multiple osseous bone metastase from hormone refractory prostate
cacner are eligible.

inclusion criteria:
1. more than one painful osseous metastasis from prostate cancer
2. bone metastases with uptake at pre-treatment bone scintigraphy
3. serum testosterone at castrate levels
4. WHO performance status 0-2
5. Adequate bone marrow function (ANC> 1.5 109/l, Thr > 100 109/l)
6. creatinine clearance > 60 ml/min
7. Adequate hepatic function (bilirubin <= 1.5 UNL , SGOT/AST <= 2.5 UNL and
SGPT/ALT <= 2.5 UNL
8. Clinically normal cardiac function

exclusion criteria:
1. signs of myelumcompression due to spinal or epidural metastases.
2. earlier docetaxel chemotherapy for prostate cancer
3. earlier radionuclide treatment for prostate cancer
4. inability to sign informed consent or record VAS pain diary

After completion of VAS pain score and analgetic use documentation patients
will be randomized between once 150 Mbq or docetaxel 75mg/m2 every 3 weeks. At
6weeks the pain score will be assessed and compared for both arms. Patients
with insufficient pain relief will be offered the other treatment modality.

group 1: docetaxel 75mg/m2 every 3 weeks
group 2: 150 MBq 153Sm-EDTMP once

1. docetaxel:
Hematological toxicity grade 3 and 4 is expected in the following percentages
of patients and may be a reason to postpone docetaxel dosing: %
expected Grade 3 en 4
hematological toxicity:
- Anemia 5%
- Thrombocytopenia 1%
- Neutropenia 30-35%

Other toxicities observed in a comparable population were:
- alopecia 60-70%
- fatigue 50-55% (5% >grd2)
- nausea and vomiting 40-45%
- Diarrhea 30-35%
- Nail changes 30%
- Sensory neuropathy 30%
- Stomatitis 20%
- Peripheral edema 19%
- Changes in taste 18%
- Anorexia 17%
- Dyspnea 15%
- Myalgia 14%
- Tearing 10%
- Epistaxis 6%

In case of grade 3 and 4 toxicity it can be decided to postpone docetaxel
dosing for one week dependent on severity and to reduce the dose as follows: if
bilirubin/ASAT/ALAT or neutrophil count < 1.5 x10e9/L or platelet count < 100
x10e9/L delay dose one week; if grade IV hematotoxicity occurs (febrile
neutropenia and thrombocytopenia) 25% dose reduction.

2. 153Sm-EDTMP:A decrease in hematological parameters may occur 3 to 5 weeks
after radionuclide treatment. Hence, initial hematological parameters will be
monitored before initiation of the study. For 153Sm-EDTMP the observed
hematological toxicity consisted of a decrease of platelet count and white
blood cell count during the 3-5 weeks period after treatment. No significant
difference in grade 3 and 4 hematological toxicity was reported between placebo
and 153Sm-EDTMP in a randomized study [15]. The hematological parameters,
however, returned to normal by 6-8 weeks after treatment and no significant
effect on serum hemoglobin was reported [15]. Hence, we do not anticipate
hematological problems resulting in dose adaptations in the 153Sm-EDTMP. A
possible second dosing of 153Sm-EDTMP or subsequent docetaxel treatment,
however, should only be started after hematological changes due to the initial
treatment have weaned off after 6-8 weeks. A small number of patients (7%) may
report flare-up of pain several days after 153Sm-EDTMP administration [14].
This pain increase is over after several days and could always be managed with
analgesics. Other side-effects such as diarrhea, vomiting, nausea asthenia,
hypotension, peripheral edema, and headache have all been reported in
comparable rates in the placebo arm of randomized studies and thus seem to be
related to the stage of the disease the agent is given [14]. 153Sm-EDTMP is
rapidly cleared from the blood by the kidneys. Thirty minutes after injection
less than 10% of the initial dose was still presence in the plasma. After 4 and
24 hours after injection radioactivity in the plasma was reduced to 1,3 ± 0,7%
and 0,05 ± 0,03% of the initial doses. Urine secretion occurred mainly in the
first 4 hours after injection (30,3 ± 13,5%). After 12 hours 35,3 ± 13,6% of
the administered dose was secreted through the urine. Studies on a group of 453
patiënts with a wide range of osseous lesions showed that 65,5 ± 15,5% of the
total dose of 153Sm-EDTMP was bound to the skeleton.