Palliative Treatment of Painful Disseminated Bone Metastases With ^Sup 186^Rhenium-HEDP in Patients With Lung Cancer

November 25, 2004

Aim. The aim of this study was to determine if patients with lung cancer and metastatic bone pain due to disseminated secondary bone disease, can benefit from the treatment with ^sup 186^Re-HEDP and to discuss the criteria useful for selecting those patients.

Methods. Twenty-four patients were included in this study and they received 1 295 MBq ^sup 186^Re-HEDP. All patients underwent ^sup 99m^Tc-MDP bone scan before treatment from which the bone scan index (BSI) was determined (mean=18.717.1%). Most patients underwent CT scan of the painful areas from which the osteolytic element of their bone lesions as well as possible infiltration of the soft tissues was determined. Patients with predominantly osteolytic metastases at the sites considered to be the origin of pain in the CT scan, were excluded. All patients were under analgesic therapy, 22/24 were taking opiates. Pain was estimated by the visual analogue scale (VAS) before the application of ^sup 186^Re-HEDP and over the following 8 weeks. The possible myelotoxicity of ^sup 186^Re was assessed.

Results. The mean VAS score was 6.92.5 before the application and 3.22.6 after therapy. Pain relief was obtained in 23/24 patients. Sixty-two percent of the patients exhibited clinically significant pain relief of at least 3 VAS score. The dosage of opiates was decreased in 77% of the patients and could be discontinued in 4 of them. Myelotoxicity was observed in 1 patient. Ninety-one percent of our patients showed improvement in the parameters that assess the quality of life.

Conclusion, The application of a standard dose of ^sup 186^Re- HEDP in patients with lung cancer and painful disseminated bone metastases has a satisfactory pain alleviating effect. The easy application and very low myelotoxicity are important factors in this group of patients. A better analgesic effect of the ^sup 186^Re- HEDP application can be expected if combined estimation of the ^sup 99m^Tc-MDP bone scan and the CT scan is used.

KEY WORDS: Radiopharmaceuticals * Lung neoplasms, radionuclide imaging * Radiotherapy * Bone neoplasms, secondary.

Metastatic bone disease is one of the commonest cause of cancer pain, ancl is frequently difficult to manage effectively.1 Targeted radiotherapy using bone-seeking, β-emitting ractiopharmaceuticals has proved to be an effective systemic pain- palliative treatment in patients with disseminated bone metastases due to prostate or breast cancer.2,3

In patients suffering from lung cancer, bone metastases have a mixed osteoblastic and osteolytic pattern. They occur in 80% of these patients. Osseous metastases can cause pain, hypercalcemia, loss of function after pathologic fractures and neurological symptoms from nerve compression that severely influence the quality of life. A significant proportion of patients with bone metastases will have their performance level reduced both by the pain and. the side effects of the analgesics required (especially opiates) to treat the pain.4 The overall goal of therapy for these patients is to improve their quality of life, not only by reducing pain but, if possible, by reducing narcotic use and, in turn, increasing functional status.

Single-site pain responds to local field radiotherapy, which is the therapy of choice in this case. This approach becomes less effective in malignancy associated with extensive skeletal involvement. As the skeletal tumor burden increases, pain becomes typically multifocal and has a tendency to move from one site to another. Hemibocly radiotherapy is of value in this context but is associated with significant morbidity, particularly affecting the gastro-intestinal tract and the bone marrow.5

186-Rhenium hyclroxy-ethylene-diphosphonate (^sup 186^Re-HEDP) has been used for pain palliation in bone metastases for more than a decade.6-8 Its uptake is similar to that of ^sup 99m^fc labelled methylne diphosphonate (MDP) bound to technetium-99m (^sup 99m^Tc), which is used for routine bone scintigraphy. A bone scan can thus be used to demonstrate the extent and degree of concentration of therapeutic ^sup 186^Re-HEDP prior to its administration. ^sup 186^Re emits β radiation (1.07 MeV Emax) with an average range of 0.5 mm in bone of density p=1.85 g/cm^sup 3^ and a γ emission of 137 KeV (9%), so that its distribution can be imaged with a γ camera 9 after administration.

The mixed osteoblastic-osteolytic nature of the bone metastases of lung cancer patients discourages physicians from applying ^sup 186^Re-HEDP for palliative purposes to those patients presumably on the principle that osteolytic lesions are more often the cause of pain and therefore administration of radiotherapeutic agents such as ^sup 186^Re-HEDP will not result in satisfactory irradiation of these lesions. In patients who do not respond, the treatment is without clinical benefit, prolongs the time the patient remains without specific analgesia and is also unnecessarily expensive. There is no study, to the best of our knowledge, which investigates the efficacy of ^sup 186^Re-HEDP in a group of lung cancer patients with metastatic bone pain. The patients included in this study represent a group, in which efficient analgesia is difficult. The chemotherapy treatment they had received did not result in relieving pain, they were not on bisphosphonates, and because of the disseminated nature of their bony metastases they could not undergo external radiotherapy. The vast majority of them were under opiate treatment. A special characteristic, essential for inclusion in the study, was that the bone lesion, which produced the bone pain, had a predominantly osteoblastic element. Our aim was to determine if these patients can benefit from the treatment with a bone-seeking β-emitting radiopharmaceutical.

Materials and methods

Twenty-four patients (7 women, 17 men; mean age: 62.67.3 years) with pain associated with bone metastases from lung cancer were included in the study (Table I). They received an intravenous injection of 1 295 MBq (35 mCi) ^sup 186^Re_HEDP followed by a slow i.v. infusion of 0.5 L 0.9% NaCl and were encouraged to drink water for hyclration purposes. Between 1/2 and 4 hour after treatment the patients underwent a post-treatment scintigram to verify the uptake of the radiopharmaceutical in the lesions. After voiding they were allowed to leave the hospital.

The primary histologically proved malignancy was lung cancer of different histological types: 18 patients with adenocarcinoma, acanthocarcinoma or squamous-cell carcinoma of the lung, and 6 patients with small cell lung cancer (SLC).

All patients underwent a diagnostic whole-body ^sup 99m^Tc-MDP bone scintigraphy within the 2 weeks before treatment. Nineteen out of 24 patients were referred to our department from the same centre and a CT-scan had been performed on those patients to assess the osteolytic element of those bone lesions which produced the pain the patients were suffering from. Although in the rest of the patients we have no information about the CT-findings, they had bone lesions which were markedly osteoblastic, as shown in their bone-scan, coinciding with sites of pain.

The patients included in this study had received chemotherapy treatment according to the therapeutic protocol followed for treatment of metastatic carcinoma of the lung (docetaxel, cisplatin and hydrocortisone or docetaxel, gemcitabine and hyclrocortisone for patients with non-small cell lung cancer [NSCLC], cisplatin, etoposide and a corticosteroid [hydrocortisone] for patients with SCLC), which was repeated in cycles every 21 days for 6 months. The chemotherapy didn’t have any evident analgesic effect and the patients required opiates or other analgesics for pain relief. This was the reason that they were referred for ^sup 186^Re-HEDP therapy. External beam radiotherapy for palliative purposes was not applied, because of the presence of multiple, or a few but disseminated, foci in the bone scintigram with ^sup 99m^MDP (mean bone scan index, BSI=18.7%).

TABLE I.-Overview of the age, the histological lung cancer type, the BSI, the evaluation of the lesions with a CT scan, the changes in the VAS score and in the opiate treatment of the patients with NSCLC and SCLC treated with ^sup 186^Re-HEDP.

All patients included in this study had pain arising from bone metastases with increased ^sup 9mm^Tc-MDP uptake, resistant to chronic analgesic therapy (including the use of opiates in most of them). The patients in this study were not on bisphosphonate treatment.

There was a baseline requirement of a total white blood cells (WBC) of 4 000 ml or more, baseline total platelet count of at least 125 000 ml and serum creatinine levels of 1.5 mg/dl or less.

Patients were excluded from the study and did not receive treatment if:

* The CT-scan revealed predominantly osteolytic bone metastases.

* The pain was originating from a pathological fracture.

* There were signs of spinal cord compression.

* They had metastatic foci in the upper cervical spine.

* Their pain was originating from soft tissue or nerve plexus infiltration by the tumor.

* They had signs of disseminated intravascular coagulation.

* They had a life expectancy of less than 2 months.

Determination of the BSI

The BSI was determined 10 using the pret\reatment ^sup 99m^Tc- MDP whole body scintigram in order to get an estimation of the possible myelotoxicity.11 This method divides the skeleton into 4 anatomical regions, spine/skull, shoulder girdle/ribs, pelvis, extremities. Each region is scored visually for the apparent proportion of skeleton involved. Scores for each region are summed and the sum renormalized to a scale of O to 100 as an index for the extent of skeletal involvement. The range of the BSI determined in our patients was 5-60% (2 patients with a super scan, Table I), the mean BSI was 18.717.1% and the median BSI was 10%.

TABLE II.-Descriptive data of the BSI, the VAS score before therapy (VAS pre), the VAS score after therapy (VAS post) and the difference in pain relief after treatment (DVAS) of all patients treated, of the BSI and DVAS of the patients with NSCLC and SCLC and of the BSI and the DVAS of the patients with a DVAS score ≥3 and of those with a DVAS score

Pain assessment

All patients were under analgesic therapy, in 22/24 of the patients the therapy included opiates. The pain and the analgesic therapy were assessed immediately before ^sup 186^Re-HEDP treatment and at the follow-up at 6 weeks. For pain estimation we used the visual analogue scale (VAS). In brief each patient was asked to score his pain according to a score system from 0-10 (O: no pain, 10: unbearable pain). The mean VAS score before treatment in our patients was 6.92.5 (15/24 patients VAS 7-10). Parameters, which give information about the quality of life (sleep duration, mobility, communication with the social environment, mood, daily activities) were assessed before and after treatment. The analgesic therapy was modified according to the patient’s response to the treatment with 186ReHEDP.

We considered that there was a clinically evident palliative effect if the pain decreased 3 VAS. The discontinuation or the reduction of the opiate dosage was also considered as a successful palliative result of the treatment with 186Re-HEDP.


After the treatment the patients were followed clinically at weekly intervals for 8 weeks. The response to the treatment was assessed using the VAS and the analgesic therapy was adjusted accordingly. Six weeks after the treatment a full blood count was determined to assess the condition of the bone marrow.


The lesions, which were considered responsible for the bone pain showed a satisfactory uptake of the radiopharmaceutical in the post- treatment scintigram.

Analgesic effect

The mean BSI of all patients was 18.717.1% and the median BSI was 10% (Table II). Pain relief occurred in 23/24 patients (Table I). The mean VAS score was 6.92.5 before the application and 3.22.6 after therapy. The difference in pain relief after treatment (DVAS) was mean=3.72.5 and the median DVAS was 3 (Table II). In 9/24 patients complete pain relief was observed (post-therapy VAS O or 1). One patient did not experience any pain relief at all.

Clinically significant pain relief of at least 3 VAS was observed in 15/24 (62%) patients and it started between 24 hours and 1 week after receiving the treatment. The duration of pain relief was from 20 days to 2 months (mean duration 1.5 months). There was no statistically significant correlation between the BSI and the degree of pain relief after treatment (p=ns) and the BSI and the decrease of the opiates. The mean BSI of the patients with a DVAS score >3 (n=15) was 18.517.3 and the median BSI is 10%. Their mean DVAS is 52.39 and their median DVAS=4. The mean BSI of the patients with a DVAS score

The mean BSI of the patients with NSCLC was 19.818.42 (median BSI=12.5), the mean VAS before therapy was 7.42.3 and after therapy 3-92.6. DVAS was 3.52.5 in this group of patients (Table II). The mean BSI of the patients with SCLC was 15.313.5 (median BSI=S.5), the mean VAS before therapy was 5.72.8 and after therapy 1.31.2 and the mean (DVAS) was 4.32.7 in this group of patients (Table II).

Opiate reduction

The dosage of the opiates was decreased in 17 of the 22 patients (77%), who were on opiate treatment before therapy with 186Re-HEDP. In 4 of those patients the opiate treatment was discontinued. The mean DVAS score of the patients who reduced or discontinued the opiate dosage they were receiving (n=17) was 4.22.7, the median DVAS=4. The mean DVAS score of the patients with no effect of the 186Re-HEDP treatment on their opiate therapy (n=5) was 1.8+1.1 and the median DVAS=2. Of the 5 patients who did not reduce the opiates they were receiving 4 had a DVAS

A pain flare reaction occurred in 2 patients and lasted for 2 days. Myelotoxicity was observed during the follow-up in 1 patient (patient 11 in Table I) 6 weeks after the treatment. His platelet count and WBC dropped (PLT from 300 000 l to 195 000 l, WBC from 4 000 l to 3000 l). This patient, for reasons unknown to us, underwent local field radiotherapy to the spine 10 days after the treatment with ^sup 186^Re-HEDP. In all other patients platelet and leucocyte counts were at baseline levels 6 weeks after ^sup 186^Re-HEDP administration. No other adverse effect was observed (including changes in the serum creatinine levels indicating nephrotoxicity) in any of our patients.

TADLE III.-The decrease in the VAS score and the changes in the opiate treatment of the patients who were on opiates (n=22).

Quality of life

The communication ability, sleep, mobility and the mood improved in 22/24 (91%) of our patients and some daily activities could be resumed.


The pathogenesis of metastatic bone pain and its alleviation by radiation are poorly understood. The mechanism could be a combined action of different factors as it is thought to be in palliative external radiotherapy.

Due to the mixed osteoblastic-osteolytic nature of the osseous metastases bone seeking fadiopharmaceuticals have been empirically applied to patients with lung cancer and painful bone metastases. Our study shows that a careful estimation of the osteoblastic and osteolytic element of the metastatic lesion and the soft-tissue involvement could help select the patients who would profit from treatment with 186ReHEDP. By applying the selection criteria described above to the patients with lung cancer and painful disseminated bone metastases about 40% ware eligible for inclusion in this study. The CT scan helped us to exclude the patients with predominantly osteolytic lesions and to gain an estimation of the effect of ^sup 186^Re-HEDP treatment and of the remaining analgesic treatment needed. We could achieve a good estimation by comparing the lesions (on the MDP-bone scan and the CT) from which pain was originating. This comparison provided the information we needed to distinguish the predominantly osteolytic lesions from the osteoblastic lesions and the osteolytic lesions with a significant osteoblastic reaction at the periphery (positive MDP-scan). The estimation of the extent of the metastatic disease in the skeleton and of the pattern of the metastatic lesions only by the MDP-scan leads to an underestimation of the osteolytic element and might lead to failure of the treatment. Small osteolytic lesions surrounded by significant osteoblastic activity may be irradiated by the ^sup 186^Re-HEDP deposited in surrounding tissue and result in relief of pain caused by the osteolytic component of these metastatic deposits, whereas large osteolytic lesions with or without an osteoblastic reaction will not be adequately irradiated. The CT- scan also provided information about soft tissue infiltration by the tumor and about existence of neural compression, and helped in that way to assess the origin of the pain and to choose the appropriate treatment.

Briefly the following mechanisms of action of 186ReHEDP could account for the pain alleviation effect in our patients:

1. The etiology of metastatic bone pain is likely to involve both mechanical and humoral factors.12 Pain relief occurred in our patients up to 1 week, usually 2-4 days, after treatment. It is unreasonable to believe that tumor shrinkage has taken place so soon after treatment. Humoral factors which could be involved in metastatic bone pain modulation include the production of several cytokines and interferones in cells of the immune system which are present in the tumor microenvironment (.e.g. lymphocytes), – radiation emitted from 186Re could damage those cells and in that way halt the production of the mentioned humoral factors.13

2. The analgesic effect of targeted radiotherapy could also be mediated via early response gene (ERG) induction, which occurs after exposure to ionizing radiation.14 It is suggested that the products of ERGs regulate downstream genes that in turn modify the cellular adaptation to ionizing radiation stress.15 Possible downstream targets for proteins encoded by ERGs include genes for DNA repair and cell cycle regulation and those for cytokine and growth factor production. A dose rate such as that of 186Re may influence ERG induction.5

3. It is reasonable to assume that there is a psychological- placebo component in the pain relief our patients experienced. In a recent study, Han et al.16 reported a statistically significant shorter duration of pain relief in patients treated with placebo compared to patients treated with ^sup 186^Re-HEDP. We consider that the duration of the analgesiceffect in our study (mean duration 1.5 months), which is in agreement with other studies applying ^sup 186^Re-HEDP,5-17 indicates that this effect could not be attributed to placebo. The analgesic effect of ^sup 186^Re-HEDP is established in patients with osteoblastic metastases, and we considered it unethical to treat a similar group of patients with placebo.

Successful pain management is notoriously difficult to achieve on a consistent basis because of the large interpatient variability in the efficacy of analgesics and because of the multidimensional and subjective nature of pain.18 The determination of the palliative effect of the treatment with bone-seeking radiopharmaceuticals is very complex and responses are hard to objectify, as illustrated by studies using 89Srchloricle ” or ^sup 186^Re-HEDRW The VAS is probably the most convenient and accurate method to measure pain intensity but it is difficult to use it in the elderly and in patients with poor compliance, who represent the majority in the palliative care setting.20 The patients in this study were not on bisphosphonate treatment, and the chemotherapy treatment they received did not interfere with the analgesic effect of our treatment because it was completed before that and the patients continued receiving strong analgesic therapy and were referred to us because they continued to suffer from bone pain. This facilitated the estimation of the analgesic result of ^sup 186^Re-HEDP.

To determine the effect of ^sup 186^Re-HEDP in our study, we used a rather strict decision rule. Only a reduction in pain intensity of at least 30% as compared to the pretherapy base line status was considered to be clinically significant and related to ^sup 186^Re- HEDP therapy. At the same time the influence of ^sup 186^Re-HEDP on the use of analgesics and specifically in the use of opiates and in resuming daily activities was taken into account. Applying these criteria, 15/24 (62%) of our patients with lung cancer and painful disseminated bone metastases, had a clinically evident pain relief of at least 3 VAS. A VAS score ≥7 was reported by 15/24 (62.5%) patients before treatment and by only 1 after treatment, 2/ 24 (8.3 %) of the patients reported a pretherapy VAS score ≤3, while post-therapy 13/24 (54.2%) had a VAS score of ≤3.

Two patients (12 and 15 in Table I) had low pretherapy VAS score (VASPRE=I and. 3, respectively) but this low score was achieved using opiates, with side effects, which were affecting their life quality. Due to their low VAS score before therapy, these patients fall into the group of patients with no clinically significant pain relief, although they have a posttherapy VAS score of O and 1, respectively. In 1 patient the opiate treatment could be discontinued after the application of ^sup 186^Re-HEDP and the other one did decrease the opiate dosage he was receiving. In our opinion the ^sup 186^Re-HEDP treatment should be considered as effective in those 2 cases.

The dosage of opiate analgesics was decreased in 77% of the patients who were using them. In 4 of them the opiate treatment could be discontinued. In 12/22 (55%) patients there was a clinical significant pain relief and a decrease or a discontinuation of the opiate treatment observed after the application of ^sup 186^Re- HEDP. On the other side, 4/22 (18%) had no clinical significant pain relief and no decrease of the opiate dosage they were receiving (Table III).

One patient (6 in Table I) did not experience any pain relief at all, although his bone lesions were positive on the MDP scan and there was no osteolytic element seen on the CT scan. It is possible that the neuralgic component of this patient’s pain was such that ^sup 186^Re-HEDP treatment did not result in any pain relief. In 5/ 22 patients no decrease in opiate dosage could be achieved. This result can be explained by the nature of the main illness of our patients. The metastases tend to infiltrate soft tissue and compress neural plexus. The physical evolution of the disease is such, that in case of application of a bone seeking radiopharmaceutical, it is difficult to isolate the relief from the originally assessed osseous pain in the long term. Therefore the effect of the treatment with ^sup 186^Re-HEDP is difficult to evaluate precisely.

Bisphosphonates on the other hand act by reducing bone resorption and promoting recalcification of destructive lesions.21 Adding bisphosphonates to the treatment of the patients could therefore add to its analgesic effect, because this substance would act on the osteolytic part of the metastases.

The patients with SCLC had mean pretherapy VAS 5.72.8 (median pretherapy VAS=6.5), the patients with NSCLC had a mean pretherapy VAS 7.4+2.3 (median pretherapy VAS=S). The group of patients with SCLC does tend to have a lower BSI and an increased DVAS in comparison to the group of patients with NSCLC (Table II). All patients with SCLC did reduce the dosage of the opiates they were receiving. Due to the small number of patients with SCLC we cannot formulate any statistical conclusions from the above. In view of the different biological behaviour of the 2 lung cancer types further investigation is needed to see if the tendencies described above are of any significance.

The patients of this study (except 3 and 16, Table I) didn’t experience pain flare after ^sup 186^Re-HEDP administration. Patient 3 had a mild pain flare reaction at the left hip soon after he had the ^sup 186^Re-HEDP injection. The duration was 24 hour and it disappeared without any special treatment. Patient 16 had a severe pain flare reaction 48 hour after the injection of ^sup 186^Re- HEDP, which lasted for 48 hour. This reaction was treated with NSAID. The pain flare phenomenon has been attributed to radiation induced endosseous edema.22 The pain flare phenomenon can be avoided in our experience by administration of 16 mg methylprednisolone, from 2 days before until 2 days after ^sup 186^ReHEDP therapy. The patients included in this study did not receive this kind of preventive therapy because this would have a potential additional analgesic effect making the origin of the pain relief unclear.

The bone marrow is the dose limiting organ when bone-seeking radiopharmaceuticals are used.3 Our study, in which patients were treated with a single dose of 1 295 MBq of ^sup 186^Re-HEDP, did not show any evidence of myelotoxicity as a side effect of the treatment in the vast majority of the patients, which is very important for this group of patients considering the severity of their disease and the side effects of the main therapeutic efforts (chemotherapy). The drop of the platelet (PLT) ancl WBC of patient 11 (Table I) can’t be attributed solely to 186Re-HEDP, because of the local field radiotherapy to the spine he received 10 days after our treatment.

^sup 186^Re-HEDP myelotoxicity in escalating dosage protocols has been studied by a number of authors.8, 23-24 BSI cannot be directly related to marrow toxicity as metastases in peripheral bones will add to BSI but not affect marrow toxicity.

Although our patients exhibited a broad scale of BSI (5-60%), we used the same standard dose of ^sup 186^ReHEDP in all patients. This decision was clue to the experience reported5 about the absence of a dose-response relationship both for external radiotherapy and for unsealed source therapy. In a recent study 25 a threshold for therapeutic efficacy of 2.1 Gy has been suggested. De Klerk etal.11 found an excellent correlation between the BSI and the amount of ^sup 186^Re-HEDP retained in the skeleton. In patients with a high BSI a greater fraction of the administered dose is retained and less is excreted in the urine than in patients with a low BSI. This explains why patients with a high BSI still respond to the administered standard dose. On the other hand, Quirijnen et al.8 found an increase in response to the treatment with ^sup 186^Re- HEDP in patients suffering from prostate cancer and receiving an escalated dose. They report that this increase in response did not reach statistical significance due to the small number of patients. It remains to be clarified in the future if lung cancer patients would benefit from an escalating dosage protocol treatment. Studies 9,23 assessing myelotoxicity in escalating dosage protocols agree that the administered close should not exceed 2960 MBq (80 mCi).

Retreatments have shown to be helpful in patients who respond after the first treatment. For reasons unrelated to the response of patients to the ^sup 186^Re-HEDP treatment in our series there was no application of a second treatment.

The patients included in this study represent a group in which efficient analgesia is difficult. ^sup 186^Re-HEDP treatment was, in fact, the last resort for pain relief, opiate treatment reduction and improvement of the quality of their life. If we take that into account the result of 62% for clinically significant pain relief and 55% for clinically significant pain relief plus decrease or discontinuation of the opiate treatment indicate that patients with lung cancer and painful disseminated bone metastases can benefit from treatment with ^sup 186^Re-HEDP.

Some recent developments suggest that bone-seeking, β- emitting racliopharmaceuticals have a role in the prolongation of life in metastatic prostate cancer (pure osteoblastic metastases).26 To improve the therapeutic efficacy of the treatment, a variety of approaches are discussed, including increasing the local dose to the metastases, changing the close rate, using prior or concomitant chemotherapy and induction of cell cycle perturbations, with the latter 2 resulting in increased tissue sensitivity to radiation.27’28 It needs to be investigated if patients with lung cancer can benefit from such applications.

Up to date no reliable prognostic indicators have been identified, with respect to targeted radiotherapy. Detai\led analysis of factors such as tumor histology, differentiation, cell cycle, cytochemistry and metabolism would be invaluable to compare with clinical response, particularly for the identification of prognostic indicators.5 These data would also establish whether knowledge of specific tumor characteristics could influence the selection of radionuclides, enabling treatment to be tailored more accurately to an individual patient.


Our study shows that the application of a standard dose of ^sup 186^Re-HEDP (independently of the BSI), to patients with lung cancer and painful disseminated bone metastases, has a significant pain alleviating effect. The treatment is easy to apply and has a very low myelotoxicity, which is very important for this group of patients considering the severity of their disease and the side effects of the main therapeutic efforts (chemotherapy).

A combined treatment with analgesic drugs, ^sup 186^Re-HEDP or other bone seeking radiopharmaceuticals, bisphosphonates and localized external radiotherapy could be appropriate for the majority of patients. The proper combination mode in order to achieve the maximum in analgesic relief and the minimum in side effects remains to be identified.

A careful selection of the patients, according to their MDP-bone scan and their CT, to estimate as precisely as possible the osteoblastic and osteolytic element of the metastases and soft tissue infiltration, is very important in order to achieve the optimum analgesic effect. This helps to avoid unnecessary application of ^sup 186^Re-HEDP and to choose the individual analgesic therapy for each patient.

This paper was accepted at the EANM Congress 2003, 23-27 August, Amsterdam, The Netherlands.


1. Twyerors RG, Fairfield S. Pain in far advanced cancer. Pain 1982;14:303-10.

2. McEwan AJB. Unsealed source therapy of painful bone metastases: an update. Semin Nucl Med 1997;27:165-82.

3. Lewington VJ. Targeted radionuclide therapy for bone metastases. Eur J Nucl Med 1993;20:66-74.

4. Silberstein EB. Painful osteoblastic metastases: the role of nuclear medicine. Oncology 2001;15:157-63.

5. Lewington VJ. Cancer therapy using bone-seeking isotopes. Phys MedBiol 1996;4l:2027-42.

6. Maxon HR, Deutch EA, Thomas SR, Libson K, Lukes SJ, Williams CC et al. Re-ISo(Sn)HEDP for treatment of multiple metastatic foci in bone: human biodistribution and dosimetric studies. Radiology 1988;l66:501-7.

7. Maxon HR, Schroeder LE, Hertzberg VS, Thomas SR, Englaro EE, Samaratunga R et al. Rhenium-186(Sn)HEDP for treatment of painful osseous metastases: results of a double-blind crossover comparison with placebo. J Nucl Med 1991;32:1877-81.

8. Quirijnen JMSP, Han SH, Zonnenberg BA, de Klerk JM, van het Schip AD, van DiJk A et al. Efficacy of Rhenium-186-etidronate in prostate cancer patients with metastatic bone pain. J Nucl Med 1996;37:1511-5.

9. Graham MC, Scher HI, Liu GB, Yeh SD, Curley T, Daghighian F et ClI. Rhenium-186-labeled hydroxyethylidene diphosphonate dosimetry and dosing guidelines for the palliation of skeletal metastases from androgen-independent prostate cancer. Clin Cancer Res 1999;5:1307- 18.

10. Blake GM, Zivanovic MA, McEwan AJ, Ackery DM. Strontium-89 therapy: strontium kinetics in disseminated carcinoma of the prostate. Eur J Nucl Meet 1986;12:447-54.

11. de Klerk JM, van DiJk A, van het Schip AD, Zonnenberg BA, van RiJk PP. Pharmacokinetics of rhenium-186 after administration of rhenium-186-HEDP to patients with bone metastases. J Nucl Med 1992;33:646-51.

12. Ventafridda V, Sbanotto A, de Conno F. Pain in prostate cancer. PaIl Med 1990;4:173-84.

13. Silberstein EB. Racliopharmaceutical therapy of osseous metastatic disease. In: Khalkhali I, Maublant JC, Goldsmith SJ, editors. Nuclear oncology diagnosis and therapy. Philadelphia: Lippincott Williams and Wilkins; 2000.p.l04.

14. Roche E, Prentki M. Calcium regulation of immediate early response genes. Cell Calcium 1994;l6:331-8.

15. Hellman S, Weichselbaum RR. Radiation oncology. JAMA 1994; 271:1712-4.

16. Han SH, de Klerk JM, Tan S, van het Schip AD, Derksen BH, van DiJk A et al. The PLACORHEN study: a double blind, placebo controlled, randomised radionuclide study with ^sup 186^Re- etidronate in hormone resistant prostate cancer patients with painful bone metastases. Placebo Controlled Rhenium Study. J Nucl Med 2002;43:1150-6.

17. Quilty PM, Kirk D, Boiger JJ, Dearnaley DP, Lewington VJ, Mason MD et al. A comparison of the palliative effects of Strontium- 89 and external beam radiotherapy in metastatic prostate cancer. Radiother Oncol 1994;31:33-40.

18. Rowbotham DJ. Endogenous opioids, placebo response and pain. Lancet 2001;357:1901-2.

19. Maxon HR 3rd, Thomas SR, Hertzberg VS, Schroder LE, Englaro EE, Samaratunga R et al. Rhenium-186-hydroxyethylidene diphosphonate for the treatment of painful bone metastases. Semin Nucl Med 1992;22:33-40.

20. Price DD, Bush FM, Long S, Harkins SW. A comparison of pain measurement characteristics of mechanical visual analogue and simple numerical rating scales. Pain 1994;56:217-26.

21. Mertens WC. Radionuclide therapy of bone metastases: prospects for enhancement of therapeutic efficacy. Semin Oncol 1993;20 Suppl 2:49-55.

22. de Klerk JM, Zonnenberg BA, Quirijnen JM, van net Schip AD, van DiJk A, van RiJk PP. Re-186-PIEDP palliation of painful bone metastases. Fetten: Mallinckroclt Medical BV; 1992.

23. de Klerk JM1 Zonnenberg BA, van het Schip AD, van DiJk A, Man SH, Quirijnen JM et al. Dose escalation study of rhenium-186 hydroxyethylidene diphosphonate in patients with metastatic prostate cancer. Eur J Nucl Mecl 1994;21:1114-20.

24. Silberstein EB. Dosage and response in radiopharmaceutical therapy of painful osseous metastases. J Nucl Mecl 1996;37:249-52.

25. Israel O, Keidar Z, Rubinov R, losilevski G, Frenkel A, Kuten A et al. Quantitative bone SPECT for prediction of pain relief in metastatic bone disease treated with Rhenium-186 Etidronate. J Clin Oncol 2000;18:2747-54.

26. Tu SM, Milikan RE, Mengistu B, Amato RJ, Pagliaro LC, Daliani D etal. Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomized phase II trial. Lancet 2001;357:336-41.

27. McCready VR, O’Sullivan JM. Future directions for unsealed source radionuclicle therapy for bone metastases. Eur J Nucl Med 2002;29:1271-5.

28. Geldof A, Plaizier M, Duivenvoorden I, Ringelberg M, Versteegh R, Newling D et al. Cell cycle perturbations and radiosensitization effects in a human prostate cancer cell line. J Cancer Res Clin Oncol 2003;129:175-82.


1 Department of Nuclear Medicine Alexandra Hospital, Athens, Greece

2 Eigbth Department of Chest Diseases Sotiria Hospital, Athens, Greece

3 pain Clinic, Alexandra Hospital, Athens, Greece

Address reprint requests to: A. Leondi, A. Papanastasiou str. 142, 10445 Athens, Greece. E-mail: msouvatz@bel.gr

Copyright Edizioni Minerva Medica Sep 2004

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