Comparative Therapeutic Efficacy of 153Sm-EDTMP and 177Lu-EDTMP for Bone Pain Palliation in Patients with Skeletal Metastases: Patients’ Pain Score Analysis and Personalized Dosimetry

Introduction The aim of the present study was to compare the therapeutic efficacy of 153Sm-EDTMP and 177Lu-EDTMP in pain palliation in cancer patients with skeletal metastases. Materials and methods Thirty patients (25 M:5 F, mean age: 66.0 ± 14.7 years) of breast/prostate cancer with documented skeletal metastases were recruited prospectively. Twenty patients were considered randomly for treatment with 153Sm-EDTMP and with 177Lu-EDTMP in 10 patients, respectively. Using fixed dose of 37.0 MBq/kg body weight of each, the mean administered doses of 153Sm-EDTMP and 177Lu-EDTMP were 2,155.2 ± 419.6 MBq (1,347–2,857) and 1,935.1 ± 559.4 MBq (1,073–2,627), respectively. Anterior and posterior whole body images were acquired at different time points following radioactivity administration. The first data set of pre-void images (acquired at 0.5 h) representing the total activity of either of 153Sm-EDTMP or 177Lu-EDTMP was considered as reference images. All the serial images were used for patients’ dosimetry analysis by using organ level internal dosimetry assessment algorithm. Reduction in pain scoring was assessed clinically over 8 weeks by using appropriate WHO criteria and correlated with the absorbed dose to the metastatic sites. Results A total of 86 metastatic lesions clearly visualized on post-therapy serial images (matching on bone scans) were evaluated for absorbed dose calculations. Both 153Sm-EDTMP and 177Lu-EDTMP delivered similar absorbed dose to the metastatic sites, i.e., 6.22 ± 4.21 and 6.92 ± 3.92 mSv/MBq, respectively. The mean absorbed doses to various other organs were found to be comparable and within the safe limits. A complete response (CR) for each radionuclide was evaluated as 80.0%. No significant alternation in blood parameters and no untoward reaction were observed. However, a mild to severe toxicity was observed in two patients (1 each with 153Sm-EDTMP and 177Lu-EDTMP). Kaplan–Meier survival analysis demonstrated that 27/30 patients had pain-free survival (CR) up to the observational period of 8 weeks. However, no statistically significant correlation could be established between the pain scoring and absorbed dose to metastatic sites. Conclusion Both the radionuclides thus offer an effective and comparable therapeutic efficacy for bone pain palliation at an affordable cost and can be used interchangeably as per the availability.

Materials and methods: Thirty patients (25 M:5 F, mean age: 66.0 ± 14.7 years) of breast/prostate cancer with documented skeletal metastases were recruited prospectively. Twenty patients were considered randomly for treatment with 153 Sm-EDTMP and with 177 Lu-EDTMP in 10 patients, respectively. Using fixed dose of 37.0 MBq/kg body weight of each, the mean administered doses of 153 Sm-EDTMP and 177 Lu-EDTMP were 2,155.2 ± 419.6 MBq (1,347-2,857) and 1,935.1 ± 559.4 MBq (1,073-2,627), respectively. Anterior and posterior whole body images were acquired at different time points following radioactivity administration. The first data set of pre-void images (acquired at 0.5 h) representing the total activity of either of 153 Sm-EDTMP or 177 Lu-EDTMP was considered as reference images. All the serial images were used for patients' dosimetry analysis by using organ level internal dosimetry assessment algorithm. Reduction in pain scoring was assessed clinically over 8 weeks by using appropriate WHO criteria and correlated with the absorbed dose to the metastatic sites.
results: A total of 86 metastatic lesions clearly visualized on post-therapy serial images (matching on bone scans) were evaluated for absorbed dose calculations. Both 153 Sm-EDTMP and 177 Lu-EDTMP delivered similar absorbed dose to the metastatic sites, i.e., 6.22 ± 4.21 and 6.92 ± 3.92 mSv/MBq, respectively. The mean absorbed doses to various other organs were found to be comparable and within the safe limits. A complete response (CR) for each radionuclide was evaluated as 80.0%. No significant alternation in blood parameters and no untoward reaction were observed. However, a mild to severe toxicity was observed in two patients (1 each with 153 Sm-EDTMP and 177 Lu-EDTMP). Kaplan-Meier survival analysis demonstrated that 27/30 patients had pain-free survival (CR) up to the observational period of 8 weeks. However, no statistically significant correlation could be established between the pain scoring and absorbed dose to metastatic sites. conclusion: Both the radionuclides thus offer an effective and comparable therapeutic efficacy for bone pain palliation at an affordable cost and can be used interchangeably as per the availability.
Keywords: 153 sm-eDTMP, 177 lu-eDTMP, prostate/breast cancer, skeletal metastases, bone pain palliation, pain scoring, patients' dosimetry inTrODUcTiOn Skeletal metastases remain a major cause of morbidity and mor tality in 65-75% of the patients with advanced breast and pro state cancer (1)(2)(3). The consequences of bone metastases include pathologic fractures, lifethreatening hypercalcemia, spinal cord compression, and other nervecompression complications asso ciated with severe and persisting pain. Often, the management of pain due to wide spread skeletal metastases is not only a challenge to the treating oncologists but also adds to the financial and social burden on the family of such patients (4)(5)(6). The palliative care does not provide any survival benefits but it improves the quality of life by pain reduction (7). The spectrum of palliative treatment ranges from nonsteroidal analgesics to opioids, chemotherapy or hormonal therapy, as well as radiation treatment using external beam irradiation or systemic radionu clide therapy (6,(8)(9)(10)(11). However, after the initial standard pallia tive treatment, about 50% of these patients still continue to have substantial bone pain (12). Pain due to bone metastases is usually the first clinical symptom of the disease which increases in sever ity with advancing disease stage and duration (13). Therefore, bone pain palliation requires appropriate therapies for improving the quality of life in these patients (14,15).
Radionuclide therapy has the advantage of targeting all the involved osseous sites simultaneously. The selective absorption/ uptake of these bone seeking therapeutic radio pharmaceuticals provides high target to nontarget (T/NT) ratio to achieve best possible palliation effects (9,16). Multidentate polyaminophos phonic acids have been demonstrated as potential molecules for labeling with radiolanthanides and with other +3 metal ions for developing agents suitable for bone pain palliation (17). 153 SmEDTMP which localizes preferentially in areas of increased osteoblastic activity has been approved by FDA for bone pain palliation secondary to metastases (18). It possesses ideal physi cal properties, i.e., mediumenergy βparticles ranging between 640 and 810 keV limiting the tissue range to 3.0 mm, halflife of 1.95 days and has ɤemission of 103 keV which permits imaging of its skeletal distribution with conventional gamma cameras. Also, 177 LuEDTMP is considered as an excellent radionuclide for bone pain palliation owing to its favorable physical (T1/2 = 6.73 days; Eβmax = 497 keV; Eɤ = 113, 208 keV) characteristics suitable both for treatment and scintigraphic localization of the bone meta static sites. And an indigenous largescale production of both 177 Lu and 153 Sm in adequate specific activities is feasible in India using moderate flux research reactor to provide treatment to the patients at an affordable cost (19)(20)(21).
In the present study, we evaluated the comparative therapeu tic efficacy of 153 SmEDTMP and 177 LuEDTMP for bone pain palliation in prostate and breast cancer patients with multiple skeletal metastases. The absorbed dose to the metastatic lesions was evaluated using organ level internal dosimetry assessment (OLINDA) approach (22,23). The outcome of the therapeutic efficacy of both the therapeutic radionuclides was measured as a function of decrease in pain following appropriate clinical criteria for pain assessment.

Patients' selection
Thirty patients (25 M:5 F, mean age: 66.0 ± 14.7 years) of breast/ prostate cancer with documented skeletal metastases were recruited during the study period (January, 2012-January, 2015) prospectively. The patients were randomly divided into two groups. The first group (n = 20) was considered for radionuclide therapy with 153 SmEDTMP and the second group (n = 10) with 177 LuEDTMP. The patients were kept blinded to the treatment received. Prior to administration of radionuclide, each patient underwent a detailed history, clinical examination, 99m Tcmeth ylelene diphosponate ( 99m TcMDP) bone scanning, and various blood investigations.
Only the patients with positive 99m TcMDP bone scanning (within the last 8 weeks) as evidence of multiple skeletal metas tases, having severe bone pain despite receiving analgesics, not candidates for local external beam radiation therapy and who had given a written and informed consent were included in the study. The other inclusion criteria were patients not having received any chemotherapy or external beam therapy during the last 4-12 weeks and with normal hematological/renal parameters. And patients with absolute contraindications for pregnancy/ lactation, preexisting cytopenia, super "bone scan appearance" and having any previous documented history of hypersensitivity or reaction to radionuclide/radiopharmaceutical administration were excluded from the study. Mumbai, India). Prior to use, radiolabeled product from each consignment was subjected to routine quality checks. The patients were administered intravenously either with 153 SmEDTMP or 177 LuEDTMP at a dose rate of 37.0 MBq/kg body weight. The safety of the radionuclide treatment was assessed using the Common Terminology Criteria for Adverse Events criteria, version 4.0 (24). All the patients were treated on an Out Patient Department basis.
Imaging was performed by using two gamma cameras (either Symbia T16, Siemens, Erlangen, Germany or Infinia Hawkeye4, GE, Milwaukee, WI, USA) fitted with lowenergy high resolution collimator. Each gamma camera was peaked to the energy of the respective radionuclide. The sensitivity or calibration factor (fac tor for converting counts per minute per cm to MBq) for each gamma camera and the dose calibrators used in the study were calculated for both the radionuclides by using a standard method (25,26). This calibration factor was used for patients' dosimetry calculations.
The patients lied in supine position on the imaging table. The whole body (anterior and posterior) images were acquired in 1,024 × 256 matrix at a scan speed of 10.0 cm/min. The imaging in each patient was performed at 0.5 h, 3 h, 6 h, 24 h, 48 h, 96 h, and 5-6 days post radioactivity administration. The first data set of anterior and posterior images acquired at 0.5 h (without allow ing the patients to void) represented 100.0% of the administered activity of either of 153 SmEDTMP or 177 LuEDTMP. This data set of images was considered as reference images for patients' dosimetry analysis.

Data analysis
All the lesions/organs which were clearly visualized (and had higher tracer uptake than the background) on 0.5 h whole body anterior and posterior reference images were identified. A region of interest (ROI) on each of the identified lesion/organ was drawn on the reference 0.5 h whole body anterior and posterior images. Exactly the same sized ROIs were then replicated on the cor responding regions on the serial delayed images of each patient. The background corrected counts for each organ were divided by the number of pixels within the ROI. In each patient, a total of seven regions (whole body, brain, bladder, right kidney, left kidney, thigh muscles, and normal femur bone) each on anterior and posterior images were included for this semiquantitative analysis.
The geometric means of the background corrected counts/ pixel calculated for each lesion/organ were converted into percent fraction of the total injected activity. The following formula was used to calculate the %ID: where % IDuncorrected = uncorrected percentage of injected activity (later corrected for decay factor), CROI/pixel = counts per pixel in the ROI, and CWB/pixel = counts per pixel in the whole body ROI. The % ID values calculated for various regions including the skeletal metastatic sites on the serial set of anterior and posterior whole body images were analyzed using the OLINDA software (version 1.0) for absorbed dose estimates. The %ID values were plotted against time for each organ. Area under the curve analysis of the time activity curve of an organ/lesion represented the num ber of disintegrations or cumulative activity of the representative organ. The number of disintegrations for the source organ was obtained using the OLINDA/EXM kinetic input model, applying a mono or biexponential fit to the data of each source region/ organ. The radiation absorbed dose in mSv/MBq in the target organs and the metastatic lesions was estimated by inserting the corresponding number of disintegrations and dose factors of source organ (derived from OLINDA) for each of the organs. Residence time was calculated by dividing number of disintegra tions with injected activity. The whole body effective dose and effective dose equivalents were also evaluated by this data analysis.
Pain relief assessment Following radionuclide Therapy The therapeutic efficacy of each of the two radionuclides at post therapy periods of 1, 3, 6, and 8 weeks was evaluated by using standard pain scoring assessment criteria (8). Based upon this assessment, the response was labeled as (a) complete response when the pain score was <3.0, (b) partial response when the pain score ranged between 4 and 8, and (c) no response when the pain score was >8.0 and had no change from the baseline score.

statistical analysis
The quantitative data evaluated as mean ± SD for the mean absorbed dose (for different lesions/organs) obtained for two different radiopharmaceuticals in two groups of patients was compared using the independent student "t" test. The pain scores among responders and nonresponders within the two groups were compared using paired Student "t" test. The p value of <0.05 was considered significant for all tests at 95% confidence interval. The data were analyzed using Statistical Package for the Social Sciences (27).

resUlTs
The mean administered doses of 153 SmEDTMP and 177 LuEDTMP did not differ significantly (as we used 37.0 MBq/Kg body weight for both the radiopharmaceuticals) and were 2,155.2 ± 419.6 (range 1,347-2,857) MBq and 1,935.1 ± 559.4 (range 1,073-2,627) MBq, respectively. No significant alternation in the blood param eters was observed (in comparison with the baseline values) at posttherapy followup periods of 1, 3, 6, and 8 weeks with either of the two radiopharmaceuticals (Tables 1 and 2).
Following intravenous administration, both 153 SmEDTMP and 177 LuEDTMP cleared rapidly from blood with less than 5.0% of the injected dose remaining in the blood by 6 h (Figures 1A,B  and 2A,B). About 20.0-25.0% of the administered activity of both the radiopharmaceuticals excreted in the urine within the first 3 h. A negligible amount of the activity was observed thereafter over the next 24 h (Figures 3A,B).
The serial imaging data demonstrated that both 153 SmEDTMP and 177 LuEDTMP exhibited a rapid blood and soft tissue clear ance. The skeletal metastatic lesions showed increased uptake of    the radiopharmaceuticals which remained consistent throughout the imaging sequences (Figures 4 and 5 LuEDTMP are presented in Table 3. The mean absorbed dose  to bone from 177 LuEDTMP was observed to be 5.26 ± 1.40 mSv/ MBq which was slightly higher than (4.04 ± 2.47 mSv/MBq) that observed from 153 SmEDTMP. However, the difference was not sig nificant. The mean absorbed dose to kidneys from 153 SmEDTMP treatment was 0.124 ± 0.20 mSv/MBq which was significantly higher (p < 0.001) than that observed (0.06 ± 0.04 mSv/MBq) with 177 LuEDTMP treatment. On the contrary, the mean absorbed dose to the urinary bladder was significantly (p < 0.001) higher (1.35 ± 1.05 mSv/MBq) in 177 LuEDTMP treated patients than (0.64 ± 0.34 mSv/MBq) in 153 SmEDTMP treated patients. The mean absorbed dose to testes in 177 LuEDTMP patients was sig nificantly (p < 0.001) lower (0.05 ± 0.04 mSv/MBq) as compared with 153 SmEDTMP patients. The statistical analysis using two tailed unpaired "t" test indicated that no significant (p > 0.05) difference was observed in the mean absorbed dose, total body dose, effective dose to various organs in the two groups of patients treated with 153 SmEDTMP and 177 LuEDTMP.

Pain assessment: Pain scoring
In 153 SmEDTMPtreated patients, 16 (16/20) patients were responders and the remaining 4 patients were nonresponders. In responders, the mean pain score values were 5.75 ± 0.7, 4.31 ± 0.09, 2.4 ± 0.51, and 1.31 ± 0.5 at 1, 3, 6, and 8 weeks after the treat ment ( Table 4). The mean pain score in responders declined to 1.31 ± 0.48 at 8 weeks from the baseline score of 7.2 ± 1.72. Likewise, in 177 LuEDTMP patients, 8 (8/10) were responders and the remain ing 2/10 were nonresponders. In responders, the mean pain score values were 5.25 ± 1.04, 4.38 ± 1.06, 2.63 ± 0.52, and 1.63 ± 0.5 at 1, 3, 6, and 8 weeks after the treatment. The mean pain score in responders declined to 1.63 ± 0.52 at 8 weeks from the baseline score of 7.9 ± 1.55. The statistical analysis of the pain score data demonstrated that a significant (p < 0.0001) decrease in pain score was noted at each posttherapy (with both the radiopharmaceuti cals) assessment period when compared with the baseline value.
The response rate for each radionuclide in terms of a signifi cant reduction in pain score was evaluated as about 80.0%. A sta tistical analysis using chisquare test did not show any statistical significant association (χ 2 = 1 and p = 0.317) in pain relief among responders and nonresponders in these two group of patients. No statistically significant correlation was observed between the absorbed dose to the metastatic sites and pain score.

Toxicity assessment and survival analysis
A mild to severe toxicity was observed in one patient each treated with 153 SmEDTMP and 177 LuEDTMP, respectively. These find ings suggest that either of the two therapeutic radiopharmaceuti cals can be used safely and confidently for achieving comparable therapeutic efficacy. Twentyseven (27/30)    LuEDTMP is presented in Figure 6.

DiscUssiOn
An irradiation of the bone metastatic lesions with minimal radia tion effect on the surrounding normal tissue with the use of short tissue range beta emitters provides a significant bone pain pallia tion in patients with multiple skeletal metastases. In the present study, we treated 20 patients with 153 SmEDTMP and 10 patients with 177 LuEDTMP using a fixed dose protocol of 37.0 MBq/kg body weight of each of the two radiopharmaceuticals. The bone metastatic lesions seen on bone scanning were matched with the corresponding lesions on serial 153 SmEDTMP and 177 LuEDTMP images. The accurate mapping is necessary to ensure a significant dose delivery to the bony metastatic sites to achieve the predicted therapeutic outcome of RN therapy in these patients (28). The comparative dosimetry data analysis revealed that the mean absorbed doses to the bony metastatic lesions in 153 Sm EDTMP and 177 LuEDTMPtreated patients were 6.22 ± 4.21 and 6.92 ± 3.92 mGy/MBq, respectively. These values were not significantly different from each other. We could not find the reference absorbed dose data to the metastatic lesions in con text with either 153 SmEDTMP or 177 LuEDTMP. However, the mean absorbed dose values to the metastatic lesions have been reported for 186 ReHEDP and 188 ReHEDP (29,30) previously. These authors reported that the median and mean absorbed dose values were 26.0 and 12.4 ± 6.2 Gy for 186 ReHEDP (85.0 mCi) and 188 ReHEDP, respectively. In our study, an administra tion of mean dose of 2220 MBq either of 153 SmEDTMP and 177 LuEDTMP to a patient will deliver a mean absorbed dose of about 14.0 Gy to the bone metastases which is comparable with the absorbed dose estimates with 186 ReHEDP or 188 ReHEDP as reported by these authors. These results therefore suggest an adequate cumulative absorbed dose delivery to the metastatic lesions for sustained pain relief palliation effect over an extended period.
Further, in the present study, both the radiopharmaceuticals, i.e., 153 SmEDTMP and 177 LuEDTMP exhibited a similar response (bone pain reduction) rate (80.0%) and painfree survival period. Our results for 153 SmEDTMP are in agreement with the previous studies which have shown response rate ranging between 65 and 86% (21,31,32).
In a recent study, Shinto et al. (33) used the same indigenous production 177 LuEDTMP at a fixed dose of 3,700.0 MBq and reported a complete pain relief at 12 weeks in their patients. Further, Yuan et al. (34) reported that a fixed dose of 2,590 MBq of 177 LuEDTMP exhibited a response rate of 80.0%. However, these authors reported a lower response rate of 55.0% while using a lower dose of 1,295 MBq as a part of their comparative analysis. Recently, Agarwal et al. (35) in a group of 44 patients treated with 177 LuEDTMP reported an overall response rate of 86%. They further observed that complete, partial, and minimal response rate was seen in 13, 48, and 25% patients, respectively. These results are comparable with 89 SrCl2 which has been the most extensively used radiopharmaceuticals for bone pain palliation especially in the western countries. However, 89 SrCl2 has to be imported at an exorbitant cost and has been reported to cause a significant myelo toxicity (36). Therefore, we need to use the indigenously developed therapeutic agents with least myelotoxicity and which can be made available to the patients at an affordable cost in our country.
We observed that both the indigenously produced radiopharma ceuticals are very safe for human administration with observation of no untoward incidence, pain flare, or change in hematological parameters. However, one patient each in the two groups of patients treated with 153 SmEDTMP and 177 LuEDTMP developed grade III/IV and I/II toxicity, respectively. There are varied reports on toxicity with the use of these therapeutic radionuclides (21,32). However, Shinto et al. reported no incidence of any toxicity in their preliminary study using 3,700.0 MBq dose of 177 LuEDTMP (33).
The results of our study demonstrates that 177 LuEDTMP delivers lesser (0.83 ± 0.21 mSv/MBq) red marrow absorbed dose than (1.41 ± 0.61 mSv/MBq) that observed with 153 SmEDTMP treatment. The mean absorbed dose to the lesions following RN therapy with both 153 SmEDTMP and 177 LuEDTMP was similar and was six to seven times higher than the bone marrow absorbed dose and thereby offering high target to nontarget ratio. The bone marrow absorbed dose from 177 LuEDTMP treatment in a recently published Indian study has been reported to be 0.8 mGy/ MBq, which is similar to our results (37). Therefore, 177 LuEDTMP seems to be a promising alternative for bone pain palliation therapy. The bone marrow absorbed dose from 153 SmEDTMP treatment in previous studies has been reported to be ranging between 0.89 and 1.86 mGy/MBq (38)(39)(40). This difference in bone marrow absorbed dose could be due to the lower beta energy of 177 Lu as compared to that of 153 Sm. However, it has been reported that the lower βenergy of 177 Lu and relatively longer halflife will allow the deposition of an adequate tumor irradiation dose at a constant rate (41). However, the mean absorbed doses to the bone (target organ) following 153 SmEDTMP (4.04 ± 2.47 mSv/MBq) and 177 LuEDTMP (5.26 ± 1.40 mSv/MBq) were comparable.
In the present study, the mean absorbed radiation doses to the kidneys and urinary bladder were 0.124 ± 0.20 and 0.64 ± 0.34 mSv/MBq and 0.06 ± 0.04 and 1.35 ± 1.05 mSv/MBq, respectively, in 153 Sm and 177 Lutreated patients. With the use of either of these two radiopharmaceuticals, the kidney and bladder absorbed doses are well below the maximum permissible dose limits of 23.0 and 2.0 Gy, respectively.
Both 153 SmEDTMP and 177 LuEDTMP offered good image quality for performing individualized patients' dosimetry. The statistical analysis indicated that no significant (p > 0.05) differ ence was observed in the mean absorbed dose, total body dose, effective dose to various lesions/organs in patients treated with 153 SmEDTMP and 177 LuEDTMP. These results indicated that both the radionuclides have the similar normal human bio distribution and deliver the same radiation dose to the various metastatic lesions and body organs and therefore can be used interchangeably depending upon the availability in a given setting.
The present study thus highlights that both 177 LuEDTMP and 153 SmEDTMP provide competitive therapeutic efficacy for achieving bone pain palliation, but the same needs to be estab lished in a large number of cancer patients through multicentric trials prospectively.

eThics sTaTeMenT
This study was carried out in accordance with the recommenda tions of "the guidelines of the Institute Ethics committee"IEC with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the "IEC and IBC. "

aUThOr cOnTriBUTiOns
Study design, experimental work, imaging and data analysis, and manuscript writing: all authors. reFerences