Bone Metastases of Bone Metastases

Radionuclide Therapy of Bone Metastases Presented by EKKASIT SRITHAMMASIT, MD. H. Palmedo

Radionuclide therapy of bone metastases

: a systemic therapy with IV administration of open radioactive agents.

Aim

: maximal dose to the target.

: minimal dose to the rest of the body.

Introduction

Bone metastases

Breast cancer (60%)

Prostate cancer (50%)

Lung cancer(30%)

Introduction

Once bone metastases are diagnosed, the disease must be classified as incurable .

Introduction

At this stage, quality of life and prolongation of survival are the important parameters that form the basis for further medical decision making.

Introduction

Although bone metastases are rarely the cause of cancer-related death, they lead to serious complications :

Pain symptoms of varying intensity.

Fractures resulting in considerable morbidity

Hypercalcemic syndrome due to increased bone resorption of osteolytic metastases - paraneoplastic syndrome .

Destroyed and clinically relevant alterations of the blood counts .

Introduction

Chronic pain syndrome is the most important complication of bone metastases and has a negative impact on quality of life and the social environment of the patient.

“ These patients represent the main indication for radionuclide therapy”

Introduction

“ Radionuclide therapy is useful in nociceptor pain patients

but not for neuropathy pain ”

Nociceptor pain : patient as being of a stinging, gnawing or dull character gnawing or dull character.

Neuropathic pain : burning and appearing suddenly.

Introduction

Bone metastases can generate pain by

A strong mechanical impact to the nociceptor.

An osteoblastic (and osteoclastic) induced excretion of pain mediators that result in sensitization of the nociceptor.

Introduction [ prostaglandin E, bradykinin, histamine, and interleukin ]

Table of content

Radiopharmaceuticals

Methodology

Dosimetry

Pain Documentation

Clinical Indications

Pain Palliation

Progression Free Interval and Survival

Side Effects

New Treatment Strategies

Radionuclide therapy of bone metastases was started decades ago with the administration of phosphorus-32 .

This inappropriate ratio and the frequently observed strong myelosuppression were the reasons for abandoning phosphorus-32.

Since that time a variety of β -emitters have been investigated for therapy of bone metastases.

Principally, the radiation dose can be applied over a very short period, necessitating a high dose rate, or over a longer time period administering a radionuclide with a low dose rate.

Strontium-89

Excreted renally to 70–90%

Eliminated from the vascular compartment within the first few hours.

Except for the bone uptake and the excretion via the urinary system, there is no accumulation in any organ system.

The tracer uptake in the skeletal system ranges between 12% and 90% of the administered activity.

The accumulation of strontium-89 chloride in metastatic lesions is 5–20 times as high as the accumulation in normal bone tissue.

The effective half-life = over 50 days and thus strontium-89 chloride delivers a low dose rate radiation.

A different radiopharmaceutical option is to label radionuclides to phosphonates that are known to have a high osteoaffinity .

Sm-153 EDTMP:

samarium-153 ethylenediaminetetramethylenephosphonate

Re-186 HEDP:

rhenium-186 hydroxyethylidenediphosphonate

Sm-153 EDTMP and Re-186 HEDP

Excreted mainly by the kidneys and they disappear rapidly from the vascular compartment.

The uptake in the skeleton ranges between 20–30% and 30–50% of the injected dose for Re-186 HEDP and Sm-153 EDTMP, respectively.

The accumulation in the metastatic lesions is between 3 and 20 times as high as normal bone.

The effective half-life of Re-186 HEDP and Sm-153 EDTMP lies in the range of 2–3 days.

Table of content

Methodology

Dosimetry

Pain Documentation

Pain Palliation

Progression Free Interval and Survival

Side Effects

Methodology Dosimetry

The accumulation of radiopharmaceuticals is much higher in osteoblastic than in osteolytic metastases , with ratios of 1:15 and 1:3, respectively.

The uptake of the radionuclide determines the therapeutic dose in the bone metastases.

The predictive value of bone scintigraphy previous to treatment is indispensable even if osseous metastases have already been diagnosed by other imaging modalities.

To calculate the radiation dose to apply to tumor tissue and organs, different methods are used, showing a deviation of the calculated to the real dose of up to 50%.

Generally, a time-activity curve is generated over the region of interest by ROI analysis of multiple whole-body scintigrams.

The area under the curve represents the accumulated activity and must be multiplied by the S-value .

The S-value contains nuclide and tissue specific parameters .

The radiation dose to bone metastases

4 mCi Sr-89 chloride : 8 and 90 Gy.

70 mCi Sm-153 EDTMP : 10 and 70 Gy.

35 mCi Re-186 HEDP : 14 and 140 Gy.

Normal bone tissue receives a dose between 1 and 2.5 Gy that below of metastatic lesions

The organ doses demonstrating that kidneys and bladder receive uncritical doses.

Obviously, the critical organ is the bone marrow, which is exposed to doses between 1 and 1.5 Gy.

At this level, the first alterations of blood counts can be expected .

Methodology Pain Documentation

Documentation of pain is difficult because large inter and intra individual variations exist for the parameter “pain”.

It is recommended to use standardized questionnaires for pain documentation to evaluate the success of the treatment.

For the daily routine, such a questionnaire must be short but comprehensive enough to include the fields “ pain ,” “ activity of patient ” and “ consumption of analgesics .”

Methodology Pain Documentation

There are a variety of different pain scores and questionnaires that supply these items of information adequately.

The reader’s attention is drawn to the well evaluated and widely used visual analog scale(VAS) and the scoring of analgesic consumption using Foley’s score .

Table of content

Methodology

Dosimetry

Pain Documentation

Pain Palliation

Progression Free Interval and survival

Side Effects

Clinical Indications Pain Palliation

The application of radionuclides for treatment of painful bone metastases has been investigated for several decades.

Beginning in the 1960s, the first nuclide administered for pain therapy of multiple osseous metastases was phosphorus-32.

Since that time many different radiopharmaceuticals such as strontium-89 chloride , yttrium-90 citrate, rhenium-186 HEDP , samarium-153 EDTMP , tin-177m DTPA, and rhenium-188 HEDP have been investigated.

This list is not complete and therefore this chapter can only concern itself with the most important agents.

Strontium-89 chloride

Laing et al. (1991) :

A total of 75% of the prostate cancer with painful metastatic patients demonstrated a marked improvement of the pain status and every 5 patient was almost completely painfree.

The effect of Sr-89 treatment began 10–20 days postinjection and reached a maximum after 6 weeks.

Recommended dose of 150 MBq or 4 mCi of Sr-89 . ( standard dosage since that time.)

Lewington et al. (1991) :

The patients treated with Sr-89 showed a significantly better pain reduction than the patients in the placebo group.

In the group of new radiopharmaceuticals, Sm-153 EDTMP and Re-186 HEDP are the best studied and also commercially available agents.

Serafini et al. (1998) : double blind and placebo-controlled study

The response rate of the Sm-153 group was significantly better than that of the placebo group, which showed response rates of 40% and 2% after 4 weeks and 4 months, respectively.

Furthermore, the study delivered evidence that a dose of 1.0 mCi/kg body weight results more frequently and for a longer period in pain reduction than a dose of 0.5 mCi/kg body weight.

Tian et al. (1999):

were not able to confirm in their multicenter trial that the two different dose groups of Sm-153 have a different effect on pain palliation.

Maxon et al. (1988):

demonstrated in a group of 20 patients that a significant improvement of pain can be achieved in 80% of the cases after a single injection of Re-186.

Palmedo 1996 :

a response rate of 70% and an average time of 4 weeks for pain relief beginning 1 week after injection of Re-186 .

Han et al. (1999):

The total response of patients treated with Re-186 was statistically significantly better than that of the placebo group.

Also the rate of patients requesting additional radiotherapy was lower in the Re-186 group at 44% than in the placebo group at 67%.

Amazingly, the overall response rate of Re-186 was only 30% on average.

In summary, there is sufficient evidence-based data that confirm the benefit of radionuclide therapy as an effective treatment modality of painful osseous metastases in hormone-refractory prostate cancer patients.

Robinson (1993):

A responded rate 81% in breast cancer patients with multiple bone metastases after injection of Sr-89.

Baziotis et al. (1998): 64 breast cancer patients by a single injection with 2 MBq/kg body weight of Sr-89.

They found an improvement of the pain situation in 80% of the cases including 35% of patients demonstrating almost complete pain relief.

The average time of response was 3 months.

Serafini et al. and Tian et al.: Sm-153 EDTMP for breast cancer patients.

They reported effective pain therapy in 72–85% of metastatic bone disease with a mean duration of 1–2 months.

After 4 months, the response rate was still at the level of 43%.

Hauswirth et al. (1998): prospectively 17 breast cancer patients receiving 35 mCi Re-186

a response rate of 60% and a mean duration of response of 5 weeks.

Palmedo et al. 1999: confirmed these data .

Han et al. (1999):

They also found a response rate of 60% and a mean duration of 1 month.

In summary , also in breast cancer patients, there is evidence that radionuclide therapy is effective in palliating painful bone metastases.

Clinical Indications Progression Free Interval and Survival

Porter et al. (1993):

Efficacy of Sr-89 treatment for hormone-refractory prostate cancer patients as an adjunct to radiation therapy.

Three months after radiation therapy, the rates of new osseous metastases were 66% and 41% in the placebo group and the Sr-89 group, respectively .

This difference was statistically significant.

More patients in the Sr-89 group demonstrated a reduction of serum PSA and alkaline phosphatase over 50% within the first 4 months after treatment.

Quilty et al. (1993):

284 prostate cancer patients with bone metastasis. ( Radiotherapy VS Sr-89)

Pain reduction was equivalent.

However, new pain foci were significantly less frequent in the Sr-89 group, even when compared to irradiation group .

Both studies cited give evidence that radionuclide therapy with Sr-89 is more than pure pain palliation and certainly has a tumoricidal effect .

Clinical Indications Side Effects

Clinical Indications Side Effects Blood cell counts can change if a dose of 1 Gy or more is applied.

the most relevant side effect of radionuclide therapy of bone metastases is a thrombo- and leukopenia.

Laing et al.(1991) : Sr 89

the main side effect was a thrombocytopenia with an average decrease of 25% and a nadir at week 6.

No patient showed a toxicity of more than grade II.

Quilty et al. (1993)

leuko- and thrombocyte counts demonstrate an average decrease of 30–40% compared to baseline values after the injection of Sr-89 200 MBq.

Nadir of thrombo- and leukocytes was 6 weeks.

Significant toxicity (WHO grade III and IV) of blood counts was observed in only 7% of patients.

Hemoglobin levels were not altered by radionuclide therapy.

Hemibody irradiation necessitated twice as many blood transfusions. Also nausea, vomiting and diarrhea were observed four times more frequently after hemibody irradiation.

Sm-153 EDTMP and Re-186 HEDP

Lead to a mild hematotoxicity if a dose of 1.0 mCi/kg body weight and of 35 mCi are administered, respectively.

The nadir of the 20–30% decrease of thrombo- and leukocytes was found to be at week 4–5.

If higher doses of Sm-153 EDTMP (>2.0 mCi/kg BW) and Re-186 HEDP (>70 mCi) are used, grade III or higher toxicity can occur.

The patient must be informed that pain syndromes might be aggravating for some days ( flare-effect ) and go back to the initial level afterwards.

Rarely is it necessary to increase the pain medication in this situation.

There are some case reports in the literature describing temporary paresis and paresthesia for Re-186 HEDP in patients with extensive metastatic disease of the skull base and of the vertebral column.

However, this might also be caused by progressive bone metastases.

After more than 400 treatments with rhenium-188 HEDP, we were unable to observe any patient who had developed temporary paresis and paresthesia due to radionuclide therapy.

Conversely, one patient with pretherapeutic, unilateral hypoglossus paresis showed significant improvement of tongue movement after Re-188 HEDP treatment.

Eight weeks after radionuclide therapy, paresis had completely disappeared.

Bone marrow suppression

Flare effect

Clinical Indications New Treatment Strategies

To enhance the effect of radionuclide therapy on the cancer cells, the following new strategies have been recently investigated:

combined radionuclide and chemotherapy.

high dose radionuclide therapy.

repeated radionuclide therapy.

Combined radionuclide and chemotherapy

Exponentially increased cell killing => higher tumoricidal effect.

Reduced-dosage protocol for chemotherapy => decrease side effects of chemotherapy.

Mertens et al 1992:

18 hormone-refractory prostate cancer patients who received a combination of 4 mCi Sr-89 and a low-dose cisplatin infusion (35 mg/m2).

They observed good pain palliation and an improvement in hemoglobin, tumor markers and bone scans in some patients.

Tu et al. (2001):

103 patients with advanced, hormone-refractory prostate cancer.

Overall survival can be improved by combined chemo- and radionuclide therapy.

The median survival of patients also increased from 16.8 months (chemotherapy alone) to 27.7months after additional injection of Sr-89.

Sciuto et al. (2002):

70 patients with painful bone metastases either to a group A receiving 148 MBq Sr-89 and 50 mg/m 2 cisplatin or to a group B receiving 148 MBq Sr-89 plus placebo.

64% 27% progression of bone disease 2 mo 4 mo The median survival without new painful sites 30% 14% New painful sites on previously asymptomatic bone metastases 63% 91% Overall pain relief Arm B Arm A

Sciuto et al. (2002):

Between both arms of the cited study, there was no significant difference with regard to side effects.

64% 27% progression of bone disease 2 mo 4 mo The median survival without new painful sites 30% 14% New painful sites on previously asymptomatic bone metastases 63% 91% Overall pain relief Arm B Arm A

Akerley et al. (2002) :

Hormone-refractory prostate cancer patients using estramustine and vinblastine combined with Sr-89

The addition of Sr-89 to chemotherapy and its repeated administration is safe and effective .

Repeated injections of radionuclides seem to enhance the treatment efficacy.

However, clinicians are often concerned about hematological toxicity when radionuclide therapy is repeated or administered simultaneously with chemotherapy.