Bone Metastases of Bone Metastases

Radionuclide Therapy of Radionuclide Therapy of Bone MetastasesBone Metastases

Presented by Presented by EKKASIT SRITHAMMASIT, MD.EKKASIT SRITHAMMASIT, MD.

H. Palmedo

• Radionuclide therapy of bone metastasesRadionuclide therapy of bone metastases : a systemic therapy with IV administration of : a systemic therapy with IV administration of

open radioactive agents. open radioactive agents.

• AimAim : maximal dose to the target. : maximal dose to the target. : minimal dose to the rest of the body.: minimal dose to the rest of the body.

IntroductionIntroduction

Bone metastasesBone metastases – Breast cancer (60%)Breast cancer (60%)– Prostate cancer (50%) Prostate cancer (50%) – Lung cancer(30%)Lung cancer(30%)


• Once bone Once bone metastases are metastases are diagnosed, the diagnosed, the disease must be disease must be classified asclassified as incurableincurable. .


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


• Although bone metastases are rarely the Although bone metastases are rarely the cause of cancer-related death, they lead to cause of cancer-related death, they lead to serious complicationsserious 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.


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

““These patients represent the These patients represent the main indication for radionuclide main indication for radionuclide

therapy”therapy”


“Radionuclide therapy is useful in Radionuclide therapy is useful in nociceptor pain patientsnociceptor pain patients

but not for neuropathy painbut 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.


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.


[ prostaglandin E, bradykinin, histamine, and interleukin ]

Table of contentTable of content

Radiopharmaceuticals Methodology

Dosimetry Pain Documentation

Clinical Indications Pain Palliation Progression Free Interval and

Survival Side EffectsNew Treatment Strategies

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

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

RadiopharmaceuticRadiopharmaceuticalsals

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


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


• Strontium-89Strontium-89– Excreted renally to 70–90% Excreted renally to 70–90% – Eliminated from the vascular compartment within the first Eliminated from the vascular compartment within the first

few hours.few hours.– Except for the bone uptake and the excretion via the urinary Except for the bone uptake and the excretion via the urinary

system, there is no accumulation in any organ system. system, there is no accumulation in any organ system. – The tracer uptake in the skeletal system ranges between The tracer uptake in the skeletal system ranges between

12% and 90% of the administered activity. 12% and 90% of the administered activity. – The accumulation of strontium-89 chloride in metastatic The accumulation of strontium-89 chloride in metastatic

lesions is 5–20 times as high as the accumulation in normal lesions is 5–20 times as high as the accumulation in normal bone tissue. bone tissue.

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







Survival Side EffectsNew Treatment Strategies

MethodologyMethodology

DosimetryDosimetry• 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.


DosimetryDosimetry• 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 .


DosimetryDosimetry

The radiation dose to bone metastasesThe 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 Normal bone tissue receives a dose between 1 and 2.5 Gy that below of metastatic lesions2.5 Gy that below of metastatic lesions


DosimetryDosimetry• 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.


Pain DocumentationPain 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.”


Pain DocumentationPain 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.





survival Side Effects New Treatment Strategies

Clinical IndicationsClinical Indications

Pain PalliationPain 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.


Pain PalliationPain PalliationStrontium-89 chlorideStrontium-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.


Pain PalliationPain Palliation• 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.


Pain PalliationPain Palliation

• 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 .


Pain PalliationPain Palliation• 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.


Pain PalliationPain Palliation• 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.


Pain PalliationPain Palliation• 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%.


Pain PalliationPain Palliation• 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 summaryIn summary, also in breast cancer patients, there is evidence that radionuclide therapy is effective in palliating painful bone metastases.


Progression Free Interval and Progression Free Interval and SurvivalSurvival

• Porter et al. (1993):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):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 palliationpure pain palliation

and certainly has a tumoricidal effecttumoricidal effect..


Side EffectsSide 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 89Laing 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)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 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.


Side EffectsSide Effects• 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.



1.1. Bone marrow suppressionBone marrow suppression2. Flare effect


New Treatment New Treatment StrategiesStrategies

• 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 chemotherapyCombined radionuclide and chemotherapy

• Exponentially increased cell killing => higher tumoricidal effect.

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



• Mertens et al 1992: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):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):Sciuto et al. (2002):– 70 patients with painful bone metastases either to a group

A receiving 148 MBq Sr-89 and 50 mg/m2 cisplatin or to a group B receiving 148 MBq Sr-89 plus placebo.

Arm A Arm B

Overall pain relief 91% 63%

New painful sites on previously asymptomatic bone metastases 14% 30%

The median survival without new painful sites 4 mo 2 mo

progression of bone disease 27% 64%



• Sciuto et al. (2002):Sciuto et al. (2002):– Between both arms of the cited study, there was no

significant difference with regard to side effects.

Arm A Arm B

Overall pain relief 91% 63%

New painful sites on previously asymptomatic bone metastases 14% 30%

The median survival without new painful sites 4 mo 2 mo

progression of bone disease 27% 64%



• Akerley et al. (2002) :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.



• Another new approach to enhancing efficacy of radionuclide therapy is to repeat the injection, aiming at a higher radiation dose.



• Palmedo et al. 2003 :Palmedo et al. 2003 :– Group A received a single injection of Re-188

HEDP, and patients of group B received two injections

– In both groups, toxicity was low with moderate thrombo- and leukopenia.

A B

PSA decrease 7% 39%

Median overall survivals 7 mo 12.7 mo



• A third new approach is the application of high dose radionuclide therapy necessitating bone marrow support.



• Anderson et al. (2002):Anderson et al. (2002):– Administered different doses of Sm-153

EDTMP in 30 patients with locally recurrent or metastatic osteosarcoma or skeletal metastases.

– High dose irradiation (39–241 Gy) by bone-targeted therapy with Sm-153 EDTMP is feasible and that non-hematologic side effects are minimal.

The end….The end….

Education

Bone Metastases of Bone Metastases