Efficacy and safety profile of 177-Lu-EDTMP for bone pain palliation in patients with metastatic bone pain.

Efficacy and safety profile of 177-Lu-EDTMP for bone pain palliation in patients with metastatic bone pain. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy and safety profile of 177-Lu-EDTMP for bone pain palliation in patients with metastatic bone pain. Rakesh Ramprakash Pandey, Rajesh Kumar, Sameer Taywade This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8053922/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: The most common symptom of patients with bone metastasis is bone pain which leads to decrease in quality of life of patients. Many different therapies are available for relief of bone pain, amongst which bone targeted radionuclide therapy is preferred in those with relapse after an initial line of treatment or those who have received maximum limit of irradiation. Various radionuclides have been previously used for bone pain palliation. Due to its medium range energy, long half-life, good binding properties, availability of gamma emissions for imaging, 177 Lutetium appears useful for pain palliation. Result: 13 patients with metastatic bone pain recieved 177- Lu EDTMP. There was significant decrease in Visual Analogue Score (VAS) (p < 0.001) and Analgesic Score (AS) (p ~ 0.001) from baseline till 3 months’ post-therapy. There was improvement in Quality of life in most of the patients responding to the therapy. Overall response rate (ORR) was 76.9%. There was transient decrease in haemoglobin, WBCs and platelets post treatment. Conclusion: This study concludes that use of 177Lu-EDTMP as a systemic radionuclide therapy for pain palliation in patients with metastatic bone pain is a safe, effective and feasible alternative to conventional therapy options and other radiopharmaceuticals for pain palliation. Clinical Trial Registration : It was registered under CTRI (Clinical Trial Registry - India), Reference number: REF/2021/04/042801, Registered on 23 April 2021. URL: https://ctri.nic.in/Clinicaltrials/regtrial.php?modid=1&compid=19&EncHid=38227.67491 177-Lu EDTMP metastatic bone pain palliation therapy prostate cancer breast cancer lung cancer Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Bony metastasis is most common type of metastasis( 1 ). The incidence of bony metastasis varies among different cancers like myeloma (90–100%), prostate (65–75%), breast (65–75%), lung (30–40%), renal (20–25%), thyroid (60%), melanoma (14–45%) depending on the advanced state of disease( 1 ). Skeletal metastatic disease leads to considerably increased morbidity and mortality in cancer patients. Most patients usually present with pain, which develops slowly over weeks to months, and it increases in intensity with time. The pain can be due to inflammatory mediators or mechanical factors. The inflammatory pain is due to local release of cytokines and chemical mediators from cancer cell and periosteal irritation( 2 ). It is important to differentiate nociception pain with neuropathic pain as the management of both is varied. Nociceptive pain is a result of activity in the neural pathways caused by actual tissue damage or any stimuli which could potentially damage tissue( 3 ) while neuropathic pain is caused due to lesion or disease in the somatosensory nervous system( 4 ). Bone targeted radionuclide therapy has been used since many decades. Various radiotracers have been used over time like P-32, Sr- 89, Sm-153, Re-186, Re-188, Ra-223, Lu-177 and Sn-117. The common indications of radionuclide bone pain palliation therapy include: 1. Painful metastatic bone lesions with intense uptake in osteoblastic lesions seen on radionuclide bone scans. 2. Primary painful bone tumours with osteoblastic lesion showing intense uptake on radionuclide bone scan( 5 ). The mechanism of action for pain reduction may involve reduction in pain mediators (histamine, prostaglandin E, interleukin, substance P) produced by the tumour and radiation induced mechanical factors like reduction of periosteal reaction( 6 ). The target of radionuclide therapy is to administer sufficient dose to the metastatic foci while minimising the dose to the normal tissue. Properties of individual radionuclide like half-life, particle energy plays important role in clinical characteristic, onset and duration of palliative effect and also on the toxic effect of the therapy. The particle emission energy of 32P and 89Sr is high, so they are associated with greater marrow toxicity. Samarium-153 has short physical half-life of 1.9 days resulting in more rapid delivery of radiation( 7 ). The physical half-life of Lutetium-177 is 6.73 days. It is a β and γ emitter. The γ emitting property can be used to acquire scintigraphic images. The absorbed dose coefficient for endosteum is 4 + 2.5 mGy/MBq, for red bone marrow is 1.4 + 0.6 mGy/MBq, and for urinary bladder wall is 0.644 + 0.334 mGy/MBq( 8 ). Due to long half-life and low beta energy, the tumour cells are irradiated by 177Lu-EDTMP at a slower rate with relatively lower dose per cycle. Also 177Lu-EDTMP can be supplied to regions far from the site of production. In terms of its physical and biological properties 177Lu-EDTMP appears to be a good agent for palliation therapy in the patients of bone pain due to metastasis( 9 ). Materials and Methods Patients: Patients of either sex, greater than 18 years of age who were diagnosed to have bone pain due to metastatic lesion of bone were approached for participating in the study, which was progressive even with pain medication. were included in the study. The patient was primed about the study procedure, the possible benefits, and any adverse outcomes. Bone scan was done using 99mTc-MDP, for all the patients within a span of 8 weeks from therapy to document multiple osteoblastic lesions. Patients having pain at multiple location that corresponded to increased radiotracer uptake in the bone scan were considered for enrolment in the study. Routine blood workup including haemoglobin, WBCs, platelets and KFT was performed within 1 week prior to therapy. Patients with haemoglobin < 9 g/dL, total white cell count < 3000/µL, platelet count < 60000/µL and eGFR 4, and interval between prior chemotherapy and radiotherapy > 4 weeks. Protocol and data tools: The eligible patients were administered 18.5–37 MBq/kg of 177-Lu EDTMP by slow iv infusion over 2–3 minutes via indwelling cannula. Planar anterior and posterior images were acquires after 3 hour of dose administration using gamma camera. The change in pain was documented by assessing VAS score at 15 days, 1 month, 2 months and 3 months post treatment. It is scale ranging from 0 to 10 where 0 is no pain and which increases with increase in intensity of pain to reach 10 which is the maximum pain that the patient can have. The percentage decrease in VAS score was calculated from the base line at each point of follow-up and the response was categorised according to decrease in VAS/NRS score; complete response decrease > 70%, partial response decrease in VAS > 50% but 20% but < 50% and no response for decrease in VAS < 20%. Analgesic score was assessed at each follow-up. It is a graded from 1 to 6 according to the dose and type of analgesics administered by the patient for pain relief where 1 corresponds to no pain and no use of analgesics, 2 – using non-narcotic analgesic, 3 – occasional oral narcotics, 4 – Regular oral narcotics, 5 – parenteral narcotics and 6 – uncontrollable with parenteral narcotics. ECOG and Karnofsky Performance Status (KPS) score were calculated to assess the quality of life of the patients pre and post therapy. Bone lesion score was calculated on the basis of extent and number of lesions on the basis of bone scan. The entire skeleton was divided into five anatomical regions, namely skull, spine, thorax, extremities and pelvis. The grading of 1 to 4 was done on the basis of number of lesions for skull, thorax extremities and spine and percentage of bone involvement for the pelvis. The side effect to the therapy were assessed using CTCAE Version 5. Statistical analysis: Descriptive statistics including mean, median, range, standard deviation were calculated for the baseline and follow-up data. Normality of distribution for continuous variables was assessed using Kolmogirov-smirnov test. Difference between pre-therapy and post-therapy VAS, AS, serum haematological values were analysed by paired sample t-test. Pre-therapy and post-therapy difference in ECOG and Karnofsky Performance Status (KPS) were evaluated by Friedman’s test. Results Between March 2021 to December 2022, 15 patients were recruited for the study. The follow-up of two patients was not available. Thirteen patients who fulfilled all the inclusion criteria and were considered for the study. There were 8 patients of prostate cancer, 2 patients of carcinoma breast and 3 patients of carcinoma lung. The mean age of patients was 62. 42 + 13.57 and the mean bone lesion score was 12.37 + 4.24. The baseline characteristics of all 13 patients is described in Table 1 . Table 1 Baseline characteristics of all patients: Variable Patients, n 13 Primary (Prostate/breast/lung), n 8/2/3 Age (years) 62.42 ± 13.57 Bone lesion Score, mean ± SD 12.37 ± 4.24 Latency time from diagnosis (months), median (range) 15 (4–72) Previous Radiotherapy (yes/no), n 7/6 Previous Chemotherapy (yes/no), n 10/3 Previous Hormonal therapy (yes/no), n 7/6 Baseline Visual Analogue Score (VAS), mean + SD 8.15 ± 1.28 Baseline Analgesic score (AS), mean + SD 3.31 ± 0.75 Baseline ECOG, median (range) 1 ( 1 – 3 ) Baseline Karnofsky performance score (KFS), median (range) 80 (50–90) Baseline Hemoglobin (g/dL), mean ± SD 11.85 ± 1.52 Baseline WBC (per microlitre), mean ± SD 8750.00 ± 2788.26 Baseline Platelets (per microlitre), mean ± SD 324846.15 ± 136531.34 Pain Relief: There was statistically significant decrease in mean VAS score from baseline to each point time at follow-up. The mean VAS score came down from 8.15 + 1.28 at baseline to 2.31 + 3.01 at 3 months (p < 0.001). Similarly, the mean AS came down from 3.31 + 0.751 in baseline to 1.62 + 1.66 at 3 months (p < 0.001). There was progressive decrease in VAS from baseline till 3-month follow-up. There was statistically significant difference between VAS score at each follow-up in comparison to baseline (Table 2 ). The percentage decrease in mean VAS score was 42% at 15 days, 51% at 1 month, 67% at 2 months and 72% at 3 months (Fig. 1 ). There was progressive decrease in analgesic score in each follow-up. There was statistically significant difference between AS score at each follow-up in comparison to baseline (Table 3 ). Table 2 Decrease in mean VAS from baseline in follow-up: Time period VAS, mean + SD p-Value Baseline 8.15 + 1.28 15 days 4.85 + 3.05 0.001 1 Month 4.15 + 2.82 < 0.001 2 Month 2.85 + 3.36 < 0.001 3 Month 2.31 + 3.01 < 0.001 Table 3 Decrease in mean AS from baseline in follow-up: Time period AS, mean ± SD p-Value Baseline 3.31 ± 0.751 15 days 2.15 ± 1.59 0.012 1 Month 2.15 ± 1.34 0.005 2 Month 1.69 ± 1.60 0.001 3 Month 1.62 ± 1.66 0.001 Quality of life assessment: Both ECOG and Karnofsky Performance Status (KPS) did not have Gaussian distribution and therefore their median were calculated and compared. There was improvement in Quality of life in most of the patients responding to the therapy however there was no significant difference in the median Karnofsky Performance Status (KPS) and median ECOG at baseline as compared to medians at subsequent follow-ups (Tables 4 & 5 ). Table 4 Change in median Karnofsky Performance Status (KPS) from baseline in follow-up: Time period KPS, median (Range) p-Value Baseline 80 (50–90) 15 days 80 (50–100) 0.785 1 Month 80 (60–100) 0.279 2 Month 80 (60–100) 0.068 3 Month 80 (50–100) 0.103 Table 5 Change in median ECOG from baseline in follow-up: Time period ECOG, median (Range) p-Value Baseline 1 ( 1 – 3 ) 15 days 1 ( 1 – 3 ) 0.317 1 Month 1 ( 1 – 2 ) 0.564 2 Month 1 ( 1 – 2 ) 0.180 3 Month 1 ( 1 – 3 ) 0.414 Overall Response rates: Overall response rate (ORR) was calculated by including patients showing complete response, partial response and minimal response. Ten among the thirteen patients showed response i.e ORR was 76.9%. The baseline characteristics including, VAS, AS, ECOG, Karnofsky Performance Status (KPS) and haematological parameters among the responders and non-responders were comparable (Table 6 ). The VAS in responders came down from 8.20 + 1.3 to 0.9 + 1.52 while in non-responders it came from 8.0 + 1.0 to 7.00 + 1.00. The difference in VAS score between responders and non-responders at 12 weeks was statistically significant (p < 0.01). Similarly, the Analgesic score in responders came down from 3.3 + 0.58 to 1.1 + 1.52 while in non-responders it did not change much, from 3.3 + 0.82 in baseline to 3.3 + 0.57 at 12 weeks. The difference in AS score between responders and non-responders at 12 weeks was statistically significant (p < 0.03). Reference: Handkiewicz-Junak et al., Eur J Nucl Med Mol Imaging. 2018. Table 6 Baseline characteristics between responders and non-responders Variable Responders Non Responders p-value Patients, n 10 3 Primary (Prostate/breast/lung), n 8/1/1 0/1/2 0.04 Age (years) 60.4 ± 12.43 50.00 ± 14.17 0.33 Bone lesion Score, mean ± SD 15.33 ± 2.08 11.8 ± 3.93 0.081 Latency time from diagnosis (months), median (range) 6 (4–23) 15 (7–72) Previous Radiotherapy (yes/no), n 4/6 3/0 0.067 Previous Chemotherapy (yes/no), n 7/3 3/0 0.279 Previous Hormonal therapy (yes/no), n 7/3 0/3 0.03 Baseline Visual Analogue Score (VAS), mean + SD 8.20 ± 1.3 8.0 ± 1.0 0.747 Baseline Analgesic score (AS), mean + SD 3.3 ± 0.58 3.33 ± 0.82 0.278 Baseline ECOG, median (range) 1 ( 1 – 3 ) 1 ( 1 – 2 ) 1 Baseline Karnofsky performance score (KFS), median (range) 80 (50–90) 80 (60–80) 1 Hemoglobin (g/dL), mean ± SD 11.80 ± 1.68 12.00 ± 1.00 0.875 Response in different cancers group: In the patients with prostate cancer, 8/8 showed favourable response, 1 of the 2 breast cancer patients had no response (ORR = 50%) while 2 of the 3 lung cancer patients showed no response (ORR = 33.33%) (Fig. 2 , 3 ). The mean VAS in patients with prostate cancer came down from 8.63 + 0.916 to 1.13 + 1.64 and in non-prostate cancer patients came down from 7.4 + 1.51 to 4.2 + 3.99. There was no statistically significant difference between them (p = 0.07) (Fig. 4 ). Time to maximum pain relief: The maximum pain relief was achieved at 15 days in 1 patient (10%), 30 days in 2 patients (20%), at 60 days in 5 patients (50%) and at 90 days in 2 patients (20%). The median being 60 days (Fig. 5 ). Haematological Toxicity: The haematological parameters including mean haemoglobin, WBC and platelets decreased significantly from baseline post administration of 177Lu-EDTMP. However, statistically significant difference from the previous value was seen for haemoglobin and WBC at 15 days’ follow-up (p = 0.012, p = 0.013). For platelet counts statistically significant decline from previous value was seen at each follow-up at 15 days and subsequently at 1,2 and 3 months. According to Common Terminology Criteria for Adverse Events (CTCAE) grading, 2/13 patients had grade III anaemia, 3/13 had grade II anaemia and 3/13 patients experienced grade I anaemia. 3/13 patients had grade I leukopenia, while 1/13 experienced grade II leukopenia. 4/13 patients had grade I thrombocytopenia while 1/13 patient experienced grade II thrombocytopenia. None of the patient developed life threatening complications or required blood transfusion. Different haematological toxicities experienced by the patients are categorised according to CTCAE in Table 7 . Table 7 CTCAE grading of Haematological toxicities in all patients: CTCAE grade: Anaemia Leukopenia Thrombocytopenia Grade I 3 3 4 Grade II 3 1 1 Grade III 2 0 0 Grade IV 0 0 0 Total 8 4 5 Discussion Patients with cancer spread to bones usually presents with pain of intense severity. Most of them are on chronic pain medication, which not only adds to the economic burden of the patients but also have their unique toxicities affecting other organs of the body. Similarly, pain affects the quality of life in these patients and often it hinders the routine activities of self-care. Radionuclide therapy for bone pain palliation is considered as a potent alternative in patients with multiple sites of bone metastasis with bone pain. Radionuclides including, P-32, Sr- 89, Sm-153, Re-186, Re-188, Ra-223, Lu-177 and Sn-117have been used for bone pain palliation resulting from osteoblastic metastatic bone cancer. 89-Sr is not readily available and therefore is not widely used. It also does not allow for post therapy imaging in the patients as it does not emit any gamma photon which can be used for imaging. The half-life of 153Sm-EDTMP and 186Re-HEDP are1.9 days and 3.7 days, respectively and maximal beta-energy of 0.81 MeV and 1.07 MeV, respectively. These properties pose challenges like increased radiation exposure to surrounding bone, short duration of exposure and transport to farther areas. 177Lu has a low electron energy, βmax 0.497 MeV, which ensures a low tissue penetration, thus ensuring minimal radiation exposure to surrounding tissue and effectively less bone marrow suppression compared to other bone palliation radionuclides. 177Lu is a β as well as γ emitter. γ ray emission allows post-therapy imaging as well as makes dosimetry possible( 10 ). 177Lu-EDTMP has a longer half-life 6.73 days and lower maximum electron energy, βmax 0.497 MeV. Due to longer effective half-life 177Lu-EDTMP irradiates tumor cells at a low dose rate, with a relatively low dose per cycle for a longer duration as compared to other radiopharmaceuticals with shorter half-life which deliver radiation at high dose rate. Another advantage of longer half-life, it provides the ability to deliver the radiopharmaceutical to farther locations from the reactor. Other advantages of 177Lu-EDTMP, include the feasibility of large scale production and radionuclide purity can be determined using a moderate flux reactor that produces sufficiently high specific activity. In our study the mean VAS of all patients came down from 7.2 + 2.7 in baseline to 2.3 + 2.8 at 12-week follow-up (p < 0.001). Our results were consistent with the existing literature. In a study by Shinto et. al. the mean VAS score significantly came down from 8.4 + 1 to 1.7 + 0.44 (p < 0.001) in 10 patients after administration of 177Lu-EDTMP( 11 ). Similarly, Bal et. al in a study reported fall in mean VAS score from 6.6 + 2.4 in baseline to 3.6 + 3.1 (p < 0.0001)( 12 ). In this study, we found overall response of 76.9% while complete response was seen in 69.2% of all the patients. Our results on overall efficacy are consistent with the previously reported literature. In a comparative study of 153-Sm-EDTMP and 177Lu-EDTMP, Sharma et. al. reported a response rate of 80% for both the pharmaceuticals( 13 ). In a study, Mehrosadat Alavi et. al. showed overall response of 96% with 72% patients showing complete response( 14 ). In the only meta-analysis on 177Lu-EDTMP, Emran Askari et. al. showed a pooled overall response of 84% with 32% patients showing complete response( 15 ). Reference: Handkiewicz-Junak et al., Eur J Nucl Med Mol Imaging. 2018. In different cancer type, our study showed 100% overall response in prostate cancer patients, 50% in breast cancer patients and 33% in lung cancer patients. Agarwal et al. showed overall response of 84% in patients of prostate cancer while it was 92% in patients of breast cancer. Similarly, the reduction in mean VAS score was comparable between both the cancer types( 16 ). Carlo et. al. reviewed studies of 153-Sm-EDTMP in breast cancer patient and found response rate of 75–90%( 17 ). The reason for the difference in our study may be due to heterogeneous type of bone lesions seen in different cancer groups. Where most of the prostate cancer patients produce osteoblastic metastasis to bone, breast and lung cancer osseous metastasis is of mixed type. Also the number of patients of breast and lung cancer recruited in the study were significantly low. An analysis on subgroups of prostate versus non-prostate cancer we found that the mean VAS in patients with prostate cancer came down from 8.63 + 0.916 to 1.13 + 1.64. While in non-prostate cancer patients it came down from 7.4 + 1.51 to 4.2 + 3.99. There was no statistically significant difference between them (p = 0.07). Reference: Handkiewicz-Junak et al., Eur J Nucl Med Mol Imaging. 2018. The mean bone lesion score for responders was 15.33 + 2.08 while it was 11.8 + 3.93 in the non-responders which was comparable among both the groups (p = 0.081) and hence the probability of response was not dependent on the baseline number of osteoblastic lesions in the patients. Previous treatment like radiotherapy and chemotherapy did not show any effect on the outcome. Seven out of ten responders had received hormonal therapy while none of the non-responders had received hormonal therapy (p = 0.03). Various studies have used different performance scales for evaluation of improvement in quality of life due to reduction in pain among the patients. Karnofsky Performance Status (KPS) and ECOG scores were used in our study. In our study, there was improvement in performance score in patients who responded to treatment however no statistically significant change could be noted. Shinto et. al. reported significant increase in mean Karnofsky Performance Status (KPS) of patients after administration of 177Lu-EDTMP from 45 in baseline to 69 in follow-up( 11 ). In a study by Tripathi et. al. on 153-Sm-EDTMP, the mean Karnofsky Performance Status (KPS) increased from 70 .83 in baseline to 79.16 in follow-up( 18 ). The reason for the difference in findings of our study was that most of the patients recruited had baseline scores close to normal (Median Karnofsky Performance Status (KPS) 80 and Median ECOG 1) and therefore no much difference was seen between the baseline value and the subsequent follow-up values. Also the total number of patients recruited were less, so the data on ECOG and Karnofsky Performance Status (KPS) score did not follow normal distribution. The major limiting factor in therapy using bone-seeking radiopharmaceuticals is bone marrow toxicity leading to significant bone marrow suppression and thereby decrease in the peripheral blood counts. In our study, 10 events of CTCAE grade I haematological toxicity were observed, among which 3 were Grade I anaemia, 3 were Grade I leukopenia and 4 were grade I thrombocytopenia. 5 events of CTCAE grade II haematological toxicity were seen, among which 3 were grade II anaemia, 1 was grade II leukopenia and 1 was grade II thrombocytopenia. 2 events of CTCAE grade III haematological toxicity were seen, both of which were grade III anaemia. Overall 5 patients (38.5%) showed grade I haematological toxicity, 3 patients (23%) showed grade II haematological toxicity and 2 patients (15.4%) showed grade III haematological toxicity. None of the patients experienced any serious toxicity. There was decrease in mean haemoglobin, leukocytes and platelets from baseline in most of the follow-up visit. The percentage decrease from baseline was significant for platelets in most of the follow-up visits up to 12 weeks. Other studies have reported similar haematological toxicity rates. In a study by Dolezal et. al. using 153Sm-EDTMP in 32 patients, none of the patient had grade IV hematologic toxicity, 2 patients (6.25%) showed grade III toxicity and most of the patient showed grade I or grade II haematological toxicity( 19 ). In the study by Thapa et. al. nonserious hematologic toxicity (grade I/II) was observed in 53.33% patients and serious toxicity (grade III/IV) in 26.67% patients in patients administered 177Lu-EDTMP. While in patients receiving 153Sm-EDTMP, nonserious hematologic toxicity (grade I/II) was observed in 10 (62.5%) and serious toxicity (grade III/IV) in 3 (18.75%)( 20 ). Our study is limited by a small sample size. Secondly, most of our patients were of prostate cancer. Other types of cancer were few in number. A data with equal number of different cancer types would have helped in better commenting the response in each cancer. Additionally, long term follow-up of the patients was not available, considering the limited time period of study and thus survival curves could not be derived. Conclusion This study concludes that use of 177Lu-EDTMP as a systemic radionuclide therapy for pain palliation in patients with metastatic bone pain is a safe, effective and feasible alternative to conventional therapy options and other radiopharmaceuticals for pain palliation. It is an easy to administer, simple OPD based therapy and a single dose provides good pain palliation. It is also well tolerated by the patients. Declarations Competing Interests The authors have no relevant financial or non-financial interests to disclose neither any other competing interests. Ethical Approval This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of All India Institute of Medical Sciences, Jodhpur. Consent to participate Informed consent was obtained from all individual participants included in the study. Consent to publication No patient identity or images displayed in the manuscript. Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Authors contribution RRP has worked in conceptualisation of the study, collecting data, assessment of data and writing of the manuscript. RK helped in conceptualisation of the study, making of study protocol and final proofreading. ST helped in conceptualisation of the study, interpretation of patient data and final proofreading. Acknowledgements Not applicable. Availability of data and material Data is available with the author and can be shared on request. References Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev. 2001;27(3):165–76. Macedo F, Ladeira K, Pinho F, Saraiva N, Bonito N, Pinto L, et al. 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Pandey","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-0711-2553","institution":"National Cancer Institute","correspondingAuthor":true,"prefix":"","firstName":"Rakesh","middleName":"Ramprakash","lastName":"Pandey","suffix":""},{"id":543744341,"identity":"4525135a-1f2a-4968-94d7-95f5d47d7104","order_by":1,"name":"Rajesh Kumar","email":"","orcid":"","institution":"All India Institute of Medical Sciences - Jodhpur","correspondingAuthor":false,"prefix":"","firstName":"Rajesh","middleName":"","lastName":"Kumar","suffix":""},{"id":543744342,"identity":"6865fde1-788f-4d0a-bdd8-cfec8fca30cf","order_by":2,"name":"Sameer Taywade","email":"","orcid":"","institution":"All India Institute of Medical Sciences - Jodhpur","correspondingAuthor":false,"prefix":"","firstName":"Sameer","middleName":"","lastName":"Taywade","suffix":""}],"badges":[],"createdAt":"2025-11-07 06:54:30","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8053922/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8053922/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":96616082,"identity":"0f35fe36-0ebf-4a1e-b440-c0444cc0e6dd","added_by":"auto","created_at":"2025-11-24 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1","display":"","copyAsset":false,"role":"figure","size":24080,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePercentage change in mean VAS score in follow-up.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8053922/v1/860aca233987cd1d004af3b7.jpg"},{"id":96708525,"identity":"2d15e3da-d12f-46fc-a9e5-831f16b1a80e","added_by":"auto","created_at":"2025-11-25 10:04:15","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":50711,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eResponse rates in all the patients:\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8053922/v1/c1e393bbc8131633b1cabe03.jpg"},{"id":96616081,"identity":"8953c6b0-854c-4ebf-8e74-3c427b9aaff1","added_by":"auto","created_at":"2025-11-24 10:21:58","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":10978,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eResponse rate in prostate cancer patients\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Picture3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8053922/v1/a031a2aba1ebb030446393f6.jpg"},{"id":96616101,"identity":"352ae0f5-b4e9-49ea-abb6-92727952ed37","added_by":"auto","created_at":"2025-11-24 10:21:59","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":13164,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDecrease in mean VAS from baseline to 3 months in prostate cancer versus other cancers\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Picture4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8053922/v1/52b8270e69a75bdb4109ea4d.jpg"},{"id":96708632,"identity":"68afd6c8-41e1-4a5b-bafc-2f54d6293033","added_by":"auto","created_at":"2025-11-25 10:04:53","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":74719,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTime to maximum pain relief\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Picture5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8053922/v1/3958b9362a3d553d9eadf8cd.jpg"},{"id":97369322,"identity":"0a439808-e5a4-4ba8-a5a0-8c26ac4fdf39","added_by":"auto","created_at":"2025-12-03 16:24:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1006472,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8053922/v1/20b69539-4943-4deb-bcbe-bffa6ece2475.pdf"}],"financialInterests":"","formattedTitle":"Efficacy and safety profile of 177-Lu-EDTMP for bone pain palliation in patients with metastatic bone pain.","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBony metastasis is most common type of metastasis(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). The incidence of bony metastasis varies among different cancers like myeloma (90\u0026ndash;100%), prostate (65\u0026ndash;75%), breast (65\u0026ndash;75%), lung (30\u0026ndash;40%), renal (20\u0026ndash;25%), thyroid (60%), melanoma (14\u0026ndash;45%) depending on the advanced state of disease(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Skeletal metastatic disease leads to considerably increased morbidity and mortality in cancer patients. Most patients usually present with pain, which develops slowly over weeks to months, and it increases in intensity with time. The pain can be due to inflammatory mediators or mechanical factors. The inflammatory pain is due to local release of cytokines and chemical mediators from cancer cell and periosteal irritation(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). It is important to differentiate nociception pain with neuropathic pain as the management of both is varied. Nociceptive pain is a result of activity in the neural pathways caused by actual tissue damage or any stimuli which could potentially damage tissue(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) while neuropathic pain is caused due to lesion or disease in the somatosensory nervous system(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eBone targeted radionuclide therapy has been used since many decades. Various radiotracers have been used over time like P-32, Sr- 89, Sm-153, Re-186, Re-188, Ra-223, Lu-177 and Sn-117. The common indications of radionuclide bone pain palliation therapy include: 1. Painful metastatic bone lesions with intense uptake in osteoblastic lesions seen on radionuclide bone scans. 2. Primary painful bone tumours with osteoblastic lesion showing intense uptake on radionuclide bone scan(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). The mechanism of action for pain reduction may involve reduction in pain mediators (histamine, prostaglandin E, interleukin, substance P) produced by the tumour and radiation induced mechanical factors like reduction of periosteal reaction(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). The target of radionuclide therapy is to administer sufficient dose to the metastatic foci while minimising the dose to the normal tissue. Properties of individual radionuclide like half-life, particle energy plays important role in clinical characteristic, onset and duration of palliative effect and also on the toxic effect of the therapy. The particle emission energy of 32P and 89Sr is high, so they are associated with greater marrow toxicity. Samarium-153 has short physical half-life of 1.9 days resulting in more rapid delivery of radiation(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe physical half-life of Lutetium-177 is 6.73 days. It is a β and γ emitter. The γ emitting property can be used to acquire scintigraphic images. The absorbed dose coefficient for endosteum is 4\u0026thinsp;+\u0026thinsp;2.5 mGy/MBq, for red bone marrow is 1.4\u0026thinsp;+\u0026thinsp;0.6 mGy/MBq, and for urinary bladder wall is 0.644\u0026thinsp;+\u0026thinsp;0.334 mGy/MBq(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Due to long half-life and low beta energy, the tumour cells are irradiated by 177Lu-EDTMP at a slower rate with relatively lower dose per cycle. Also 177Lu-EDTMP can be supplied to regions far from the site of production. In terms of its physical and biological properties 177Lu-EDTMP appears to be a good agent for palliation therapy in the patients of bone pain due to metastasis(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003ePatients:\u003c/p\u003e\u003cp\u003ePatients of either sex, greater than 18 years of age who were diagnosed to have bone pain due to metastatic lesion of bone were approached for participating in the study, which was progressive even with pain medication. were included in the study. The patient was primed about the study procedure, the possible benefits, and any adverse outcomes.\u003c/p\u003e\u003cp\u003eBone scan was done using 99mTc-MDP, for all the patients within a span of 8 weeks from therapy to document multiple osteoblastic lesions. Patients having pain at multiple location that corresponded to increased radiotracer uptake in the bone scan were considered for enrolment in the study. Routine blood workup including haemoglobin, WBCs, platelets and KFT was performed within 1 week prior to therapy. Patients with haemoglobin\u0026thinsp;\u0026lt;\u0026thinsp;9 g/dL, total white cell count\u0026thinsp;\u0026lt;\u0026thinsp;3000/\u0026micro;L, platelet count\u0026thinsp;\u0026lt;\u0026thinsp;60000/\u0026micro;L and eGFR\u0026thinsp;\u0026lt;\u0026thinsp;30 mL/min were excluded from the study. Other inclusion criterias included, minimum VAS score\u0026thinsp;\u0026gt;\u0026thinsp;4, and interval between prior chemotherapy and radiotherapy\u0026thinsp;\u0026gt;\u0026thinsp;4 weeks.\u003c/p\u003e\u003cp\u003eProtocol and data tools:\u003c/p\u003e\u003cp\u003eThe eligible patients were administered 18.5\u0026ndash;37 MBq/kg of 177-Lu EDTMP by slow iv infusion over 2\u0026ndash;3 minutes via indwelling cannula. Planar anterior and posterior images were acquires after 3 hour of dose administration using gamma camera. The change in pain was documented by assessing VAS score at 15 days, 1 month, 2 months and 3 months post treatment. It is scale ranging from 0 to 10 where 0 is no pain and which increases with increase in intensity of pain to reach 10 which is the maximum pain that the patient can have. The percentage decrease in VAS score was calculated from the base line at each point of follow-up and the response was categorised according to decrease in VAS/NRS score; complete response decrease\u0026thinsp;\u0026gt;\u0026thinsp;70%, partial response decrease in VAS\u0026thinsp;\u0026gt;\u0026thinsp;50% but \u0026lt;\u0026thinsp;70%, Minimal response decrease in VAS\u0026thinsp;\u0026gt;\u0026thinsp;20% but \u0026lt;\u0026thinsp;50% and no response for decrease in VAS\u0026thinsp;\u0026lt;\u0026thinsp;20%.\u003c/p\u003e\u003cp\u003eAnalgesic score was assessed at each follow-up. It is a graded from 1 to 6 according to the dose and type of analgesics administered by the patient for pain relief where 1 corresponds to no pain and no use of analgesics, 2 \u0026ndash; using non-narcotic analgesic, 3 \u0026ndash; occasional oral narcotics, 4 \u0026ndash; Regular oral narcotics, 5 \u0026ndash; parenteral narcotics and 6 \u0026ndash; uncontrollable with parenteral narcotics. ECOG and Karnofsky Performance Status (KPS) score were calculated to assess the quality of life of the patients pre and post therapy. Bone lesion score was calculated on the basis of extent and number of lesions on the basis of bone scan. The entire skeleton was divided into five anatomical regions, namely skull, spine, thorax, extremities and pelvis. The grading of 1 to 4 was done on the basis of number of lesions for skull, thorax extremities and spine and percentage of bone involvement for the pelvis. The side effect to the therapy were assessed using CTCAE Version 5.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis:\u003c/h2\u003e\u003cp\u003eDescriptive statistics including mean, median, range, standard deviation were calculated for the baseline and follow-up data. Normality of distribution for continuous variables was assessed using Kolmogirov-smirnov test. Difference between pre-therapy and post-therapy VAS, AS, serum haematological values were analysed by paired sample t-test. Pre-therapy and post-therapy difference in ECOG and Karnofsky Performance Status (KPS) were evaluated by Friedman\u0026rsquo;s test.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eBetween March 2021 to December 2022, 15 patients were recruited for the study. The follow-up of two patients was not available. Thirteen patients who fulfilled all the inclusion criteria and were considered for the study. There were 8 patients of prostate cancer, 2 patients of carcinoma breast and 3 patients of carcinoma lung. The mean age of patients was 62. 42\u0026thinsp;+\u0026thinsp;13.57 and the mean bone lesion score was 12.37\u0026thinsp;+\u0026thinsp;4.24. The baseline characteristics of all 13 patients is described in Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline characteristics of all patients:\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePatients, \u003cem\u003en\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrimary (Prostate/breast/lung), \u003cem\u003en\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8/2/3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e62.42\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;13.57\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBone lesion Score, mean\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12.37\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;4.24\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLatency time from diagnosis (months), median (range)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15 (4\u0026ndash;72)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevious Radiotherapy (yes/no), \u003cem\u003en\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7/6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevious Chemotherapy (yes/no), \u003cem\u003en\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10/3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevious Hormonal therapy (yes/no), \u003cem\u003en\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7/6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBaseline Visual Analogue Score (VAS), mean\u0026thinsp;+\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8.15\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;1.28\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBaseline Analgesic score (AS), mean\u0026thinsp;+\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.31\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;0.75\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBaseline ECOG, median (range)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBaseline Karnofsky performance score (KFS), median (range)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e80 (50\u0026ndash;90)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBaseline Hemoglobin (g/dL), mean\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11.85\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;1.52\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBaseline WBC (per microlitre), mean\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8750.00\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;2788.26\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBaseline Platelets (per microlitre), mean\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e324846.15\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;136531.34\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003ePain Relief:\u003c/h3\u003e\n\u003cp\u003eThere was statistically significant decrease in mean VAS score from baseline to each point time at follow-up. The mean VAS score came down from 8.15\u0026thinsp;+\u0026thinsp;1.28 at baseline to 2.31\u0026thinsp;+\u0026thinsp;3.01 at 3 months (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Similarly, the mean AS came down from 3.31\u0026thinsp;+\u0026thinsp;0.751 in baseline to 1.62\u0026thinsp;+\u0026thinsp;1.66 at 3 months (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). There was progressive decrease in VAS from baseline till 3-month follow-up. There was statistically significant difference between VAS score at each follow-up in comparison to baseline (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The percentage decrease in mean VAS score was 42% at 15 days, 51% at 1 month, 67% at 2 months and 72% at 3 months (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). There was progressive decrease in analgesic score in each follow-up. There was statistically significant difference between AS score at each follow-up in comparison to baseline (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDecrease in mean VAS from baseline in follow-up:\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"+\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTime period\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eVAS, mean\u0026thinsp;+\u0026thinsp;SD\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep-Value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBaseline\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"+\" colname=\"c2\"\u003e\u003cp\u003e8.15\u0026thinsp;+\u0026thinsp;1.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e15 days\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"+\" colname=\"c2\"\u003e\u003cp\u003e4.85\u0026thinsp;+\u0026thinsp;3.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1 Month\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"+\" colname=\"c2\"\u003e\u003cp\u003e4.15\u0026thinsp;+\u0026thinsp;2.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2 Month\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"+\" colname=\"c2\"\u003e\u003cp\u003e2.85\u0026thinsp;+\u0026thinsp;3.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3 Month\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"+\" colname=\"c2\"\u003e\u003cp\u003e2.31\u0026thinsp;+\u0026thinsp;3.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDecrease in mean AS from baseline in follow-up:\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTime period\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAS, mean\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;SD\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep-Value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBaseline\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e3.31\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;0.751\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e15 days\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e2.15\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;1.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.012\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1 Month\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e2.15\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;1.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.005\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2 Month\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e1.69\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;1.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3 Month\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e1.62\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;1.66\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003eQuality of life assessment:\u003c/h3\u003e\n\u003cp\u003eBoth ECOG and Karnofsky Performance Status (KPS) did not have Gaussian distribution and therefore their median were calculated and compared. There was improvement in Quality of life in most of the patients responding to the therapy however there was no significant difference in the median Karnofsky Performance Status (KPS) and median ECOG at baseline as compared to medians at subsequent follow-ups (Tables\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e \u0026amp; \u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eChange in median Karnofsky Performance Status (KPS) from baseline in follow-up:\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTime period\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eKPS, median (Range)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep-Value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBaseline\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e80 (50\u0026ndash;90)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e15 days\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e80 (50\u0026ndash;100)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.785\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1 Month\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e80 (60\u0026ndash;100)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.279\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2 Month\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e80 (60\u0026ndash;100)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.068\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3 Month\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e80 (50\u0026ndash;100)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.103\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eChange in median ECOG from baseline in follow-up:\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTime period\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eECOG, median (Range)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep-Value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBaseline\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e15 days\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.317\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1 Month\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.564\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2 Month\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.180\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3 Month\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.414\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003eOverall Response rates:\u003c/h3\u003e\n\u003cp\u003eOverall response rate (ORR) was calculated by including patients showing complete response, partial response and minimal response. Ten among the thirteen patients showed response i.e ORR was 76.9%. The baseline characteristics including, VAS, AS, ECOG, Karnofsky Performance Status (KPS) and haematological parameters among the responders and non-responders were comparable (Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). The VAS in responders came down from 8.20\u0026thinsp;+\u0026thinsp;1.3 to 0.9\u0026thinsp;+\u0026thinsp;1.52 while in non-responders it came from 8.0\u0026thinsp;+\u0026thinsp;1.0 to 7.00\u0026thinsp;+\u0026thinsp;1.00. The difference in VAS score between responders and non-responders at 12 weeks was statistically significant (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Similarly, the Analgesic score in responders came down from 3.3\u0026thinsp;+\u0026thinsp;0.58 to 1.1\u0026thinsp;+\u0026thinsp;1.52 while in non-responders it did not change much, from 3.3\u0026thinsp;+\u0026thinsp;0.82 in baseline to 3.3\u0026thinsp;+\u0026thinsp;0.57 at 12 weeks. The difference in AS score between responders and non-responders at 12 weeks was statistically significant (p\u0026thinsp;\u0026lt;\u0026thinsp;0.03). Reference: Handkiewicz-Junak et al., Eur J Nucl Med Mol Imaging. 2018.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline characteristics between responders and non-responders\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eResponders\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNon Responders\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePatients, \u003cem\u003en\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrimary (Prostate/breast/lung), \u003cem\u003en\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8/1/1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0/1/2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.04\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e60.4\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;12.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e50.00\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;14.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.33\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBone lesion Score, mean\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15.33\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;2.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11.8\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;3.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.081\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLatency time from diagnosis (months), median (range)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 (4\u0026ndash;23)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15 (7\u0026ndash;72)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevious Radiotherapy (yes/no), \u003cem\u003en\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4/6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3/0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.067\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevious Chemotherapy (yes/no), \u003cem\u003en\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7/3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3/0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.279\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevious Hormonal therapy (yes/no), \u003cem\u003en\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7/3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0/3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.03\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBaseline Visual Analogue Score (VAS), mean\u0026thinsp;+\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8.20\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;1.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8.0\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;1.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.747\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBaseline Analgesic score (AS), mean\u0026thinsp;+\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.3\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;0.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.33\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;0.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.278\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBaseline ECOG, median (range)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBaseline Karnofsky performance score (KFS), median (range)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e80 (50\u0026ndash;90)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e80 (60\u0026ndash;80)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHemoglobin (g/dL), mean\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11.80\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;1.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12.00\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.875\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eResponse in different cancers group:\u003c/h2\u003e\u003cp\u003eIn the patients with prostate cancer, 8/8 showed favourable response, 1 of the 2 breast cancer patients had no response (ORR\u0026thinsp;=\u0026thinsp;50%) while 2 of the 3 lung cancer patients showed no response (ORR\u0026thinsp;=\u0026thinsp;33.33%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e,\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The mean VAS in patients with prostate cancer came down from 8.63\u0026thinsp;+\u0026thinsp;0.916 to 1.13\u0026thinsp;+\u0026thinsp;1.64 and in non-prostate cancer patients came down from 7.4\u0026thinsp;+\u0026thinsp;1.51 to 4.2\u0026thinsp;+\u0026thinsp;3.99. There was no statistically significant difference between them (p\u0026thinsp;=\u0026thinsp;0.07) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eTime to maximum pain relief:\u003c/h3\u003e\n\u003cp\u003eThe maximum pain relief was achieved at 15 days in 1 patient (10%), 30 days in 2 patients (20%), at 60 days in 5 patients (50%) and at 90 days in 2 patients (20%). The median being 60 days (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eHaematological Toxicity:\u003c/h3\u003e\n\u003cp\u003eThe haematological parameters including mean haemoglobin, WBC and platelets decreased significantly from baseline post administration of 177Lu-EDTMP. However, statistically significant difference from the previous value was seen for haemoglobin and WBC at 15 days\u0026rsquo; follow-up (p\u0026thinsp;=\u0026thinsp;0.012, p\u0026thinsp;=\u0026thinsp;0.013). For platelet counts statistically significant decline from previous value was seen at each follow-up at 15 days and subsequently at 1,2 and 3 months. According to Common Terminology Criteria for Adverse Events (CTCAE) grading, 2/13 patients had grade III anaemia, 3/13 had grade II anaemia and 3/13 patients experienced grade I anaemia. 3/13 patients had grade I leukopenia, while 1/13 experienced grade II leukopenia. 4/13 patients had grade I thrombocytopenia while 1/13 patient experienced grade II thrombocytopenia. None of the patient developed life threatening complications or required blood transfusion. Different haematological toxicities experienced by the patients are categorised according to CTCAE in Table \u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab7\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 7\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCTCAE grading of Haematological toxicities in all patients:\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCTCAE grade:\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAnaemia\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLeukopenia\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eThrombocytopenia\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGrade I\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGrade II\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGrade III\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGrade IV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePatients with cancer spread to bones usually presents with pain of intense severity. Most of them are on chronic pain medication, which not only adds to the economic burden of the patients but also have their unique toxicities affecting other organs of the body. Similarly, pain affects the quality of life in these patients and often it hinders the routine activities of self-care. Radionuclide therapy for bone pain palliation is considered as a potent alternative in patients with multiple sites of bone metastasis with bone pain.\u003c/p\u003e\u003cp\u003eRadionuclides including, P-32, Sr- 89, Sm-153, Re-186, Re-188, Ra-223, Lu-177 and Sn-117have been used for bone pain palliation resulting from osteoblastic metastatic bone cancer. 89-Sr is not readily available and therefore is not widely used. It also does not allow for post therapy imaging in the patients as it does not emit any gamma photon which can be used for imaging. The half-life of 153Sm-EDTMP and 186Re-HEDP are1.9 days and 3.7 days, respectively and maximal beta-energy of 0.81 MeV and 1.07 MeV, respectively. These properties pose challenges like increased radiation exposure to surrounding bone, short duration of exposure and transport to farther areas. 177Lu has a low electron energy, βmax 0.497 MeV, which ensures a low tissue penetration, thus ensuring minimal radiation exposure to surrounding tissue and effectively less bone marrow suppression compared to other bone palliation radionuclides. 177Lu is a β as well as γ emitter. γ ray emission allows post-therapy imaging as well as makes dosimetry possible(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). 177Lu-EDTMP has a longer half-life 6.73 days and lower maximum electron energy, βmax 0.497 MeV. Due to longer effective half-life 177Lu-EDTMP irradiates tumor cells at a low dose rate, with a relatively low dose per cycle for a longer duration as compared to other radiopharmaceuticals with shorter half-life which deliver radiation at high dose rate. Another advantage of longer half-life, it provides the ability to deliver the radiopharmaceutical to farther locations from the reactor. Other advantages of 177Lu-EDTMP, include the feasibility of large scale production and radionuclide purity can be determined using a moderate flux reactor that produces sufficiently high specific activity.\u003c/p\u003e\u003cp\u003eIn our study the mean VAS of all patients came down from 7.2\u0026thinsp;+\u0026thinsp;2.7 in baseline to 2.3\u0026thinsp;+\u0026thinsp;2.8 at 12-week follow-up (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Our results were consistent with the existing literature. In a study by Shinto et. al. the mean VAS score significantly came down from 8.4\u0026thinsp;+\u0026thinsp;1 to 1.7\u0026thinsp;+\u0026thinsp;0.44 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) in 10 patients after administration of 177Lu-EDTMP(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Similarly, Bal et. al in a study reported fall in mean VAS score from 6.6\u0026thinsp;+\u0026thinsp;2.4 in baseline to 3.6\u0026thinsp;+\u0026thinsp;3.1 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn this study, we found overall response of 76.9% while complete response was seen in 69.2% of all the patients. Our results on overall efficacy are consistent with the previously reported literature. In a comparative study of 153-Sm-EDTMP and 177Lu-EDTMP, Sharma et. al. reported a response rate of 80% for both the pharmaceuticals(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). In a study, Mehrosadat Alavi et. al. showed overall response of 96% with 72% patients showing complete response(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). In the only meta-analysis on 177Lu-EDTMP, Emran Askari et. al. showed a pooled overall response of 84% with 32% patients showing complete response(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Reference: Handkiewicz-Junak et al., Eur J Nucl Med Mol Imaging. 2018.\u003c/p\u003e\u003cp\u003eIn different cancer type, our study showed 100% overall response in prostate cancer patients, 50% in breast cancer patients and 33% in lung cancer patients. Agarwal et al. showed overall response of 84% in patients of prostate cancer while it was 92% in patients of breast cancer. Similarly, the reduction in mean VAS score was comparable between both the cancer types(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Carlo et. al. reviewed studies of 153-Sm-EDTMP in breast cancer patient and found response rate of 75\u0026ndash;90%(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). The reason for the difference in our study may be due to heterogeneous type of bone lesions seen in different cancer groups. Where most of the prostate cancer patients produce osteoblastic metastasis to bone, breast and lung cancer osseous metastasis is of mixed type. Also the number of patients of breast and lung cancer recruited in the study were significantly low. An analysis on subgroups of prostate versus non-prostate cancer we found that the mean VAS in patients with prostate cancer came down from 8.63\u0026thinsp;+\u0026thinsp;0.916 to 1.13\u0026thinsp;+\u0026thinsp;1.64. While in non-prostate cancer patients it came down from 7.4\u0026thinsp;+\u0026thinsp;1.51 to 4.2\u0026thinsp;+\u0026thinsp;3.99. There was no statistically significant difference between them (p\u0026thinsp;=\u0026thinsp;0.07). Reference: Handkiewicz-Junak et al., Eur J Nucl Med Mol Imaging. 2018.\u003c/p\u003e\u003cp\u003eThe mean bone lesion score for responders was 15.33\u0026thinsp;+\u0026thinsp;2.08 while it was 11.8\u0026thinsp;+\u0026thinsp;3.93 in the non-responders which was comparable among both the groups (p\u0026thinsp;=\u0026thinsp;0.081) and hence the probability of response was not dependent on the baseline number of osteoblastic lesions in the patients. Previous treatment like radiotherapy and chemotherapy did not show any effect on the outcome. Seven out of ten responders had received hormonal therapy while none of the non-responders had received hormonal therapy (p\u0026thinsp;=\u0026thinsp;0.03).\u003c/p\u003e\u003cp\u003eVarious studies have used different performance scales for evaluation of improvement in quality of life due to reduction in pain among the patients. Karnofsky Performance Status (KPS) and ECOG scores were used in our study. In our study, there was improvement in performance score in patients who responded to treatment however no statistically significant change could be noted. Shinto et. al. reported significant increase in mean Karnofsky Performance Status (KPS) of patients after administration of 177Lu-EDTMP from 45 in baseline to 69 in follow-up(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). In a study by Tripathi et. al. on 153-Sm-EDTMP, the mean Karnofsky Performance Status (KPS) increased from 70 .83 in baseline to 79.16 in follow-up(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). The reason for the difference in findings of our study was that most of the patients recruited had baseline scores close to normal (Median Karnofsky Performance Status (KPS) 80 and Median ECOG 1) and therefore no much difference was seen between the baseline value and the subsequent follow-up values. Also the total number of patients recruited were less, so the data on ECOG and Karnofsky Performance Status (KPS) score did not follow normal distribution.\u003c/p\u003e\u003cp\u003eThe major limiting factor in therapy using bone-seeking radiopharmaceuticals is bone marrow toxicity leading to significant bone marrow suppression and thereby decrease in the peripheral blood counts. In our study, 10 events of CTCAE grade I haematological toxicity were observed, among which 3 were Grade I anaemia, 3 were Grade I leukopenia and 4 were grade I thrombocytopenia. 5 events of CTCAE grade II haematological toxicity were seen, among which 3 were grade II anaemia, 1 was grade II leukopenia and 1 was grade II thrombocytopenia. 2 events of CTCAE grade III haematological toxicity were seen, both of which were grade III anaemia. Overall 5 patients (38.5%) showed grade I haematological toxicity, 3 patients (23%) showed grade II haematological toxicity and 2 patients (15.4%) showed grade III haematological toxicity. None of the patients experienced any serious toxicity. There was decrease in mean haemoglobin, leukocytes and platelets from baseline in most of the follow-up visit. The percentage decrease from baseline was significant for platelets in most of the follow-up visits up to 12 weeks.\u003c/p\u003e\u003cp\u003eOther studies have reported similar haematological toxicity rates. In a study by Dolezal et. al. using 153Sm-EDTMP in 32 patients, none of the patient had grade IV hematologic toxicity, 2 patients (6.25%) showed grade III toxicity and most of the patient showed grade I or grade II haematological toxicity(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). In the study by Thapa et. al. nonserious hematologic toxicity (grade I/II) was observed in 53.33% patients and serious toxicity (grade III/IV) in 26.67% patients in patients administered 177Lu-EDTMP. While in patients receiving 153Sm-EDTMP, nonserious hematologic toxicity (grade I/II) was observed in 10 (62.5%) and serious toxicity (grade III/IV) in 3 (18.75%)(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eOur study is limited by a small sample size. Secondly, most of our patients were of prostate cancer. Other types of cancer were few in number. A data with equal number of different cancer types would have helped in better commenting the response in each cancer. Additionally, long term follow-up of the patients was not available, considering the limited time period of study and thus survival curves could not be derived.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study concludes that use of 177Lu-EDTMP as a systemic radionuclide therapy for pain palliation in patients with metastatic bone pain is a safe, effective and feasible alternative to conventional therapy options and other radiopharmaceuticals for pain palliation. It is an easy to administer, simple OPD based therapy and a single dose provides good pain palliation. It is also well tolerated by the patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eCompeting Interests\u003c/h2\u003e\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose neither any other competing interests.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003cp\u003e This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of All India Institute of Medical Sciences, Jodhpur.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003cp\u003e Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent to publication\u003c/strong\u003e\u003cp\u003eNo patient identity or images displayed in the manuscript.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\u003ch2\u003eAuthors contribution\u003c/h2\u003e\u003cp\u003eRRP has worked in conceptualisation of the study, collecting data, assessment of data and writing of the manuscript. RK helped in conceptualisation of the study, making of study protocol and final proofreading. ST helped in conceptualisation of the study, interpretation of patient data and final proofreading.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eAvailability of data and material\u003c/h2\u003e\u003cp\u003eData is available with the author and can be shared on request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eColeman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev. 2001;27(3):165\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMacedo F, Ladeira K, Pinho F, Saraiva N, Bonito N, Pinto L, et al. Bone Metastases: An Overview. Oncol Rev. 2017;11(1):321.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNicholson B. Differential diagnosis: nociceptive and neuropathic pain. Am J Manag Care. 2006;12(9 Suppl):S256\u0026ndash;262.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSt John Smith E. Advances in understanding nociception and neuropathic pain. J Neurol. 2018;265(2):231\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHandkiewicz-Junak D, Poeppel TD, Bodei L, Aktolun C, Ezziddin S, Giammarile F, et al. EANM guidelines for radionuclide therapy of bone metastases with beta-emitting radionuclides. Eur J Nucl Med Mol Imaging. 2018;45(5):846\u0026ndash;59.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKrishnamurthy GT, Krishnamurthy S. Radionuclides for metastatic bone pain palliation: a need for rational re-evaluation in the new millennium. J Nucl Med Off Publ Soc Nucl Med. 2000;41(4):688\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSartor O. Overview of samarium sm 153 lexidronam in the treatment of painful metastatic bone disease. Rev Urol. 2004;6(Suppl 10):S3\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMostafa MYA, Zakaly HMH, Tekin HO, Issa SAM, Erdemir RU, Zhukovsky M. Assessment of absorbed dose for Zr-89, Sm-153 and Lu-177 medical radioisotopes: IDAC-Dose2.1 and OLINDA experience. Appl Radiat Isot Data Instrum Methods Use Agric Ind Med. 2021;176:109841.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAlavi M, Omidvari S, Mehdizadeh A, Jalilian AR, Bahrami-Samani A. Metastatic Bone Pain Palliation using (177)Lu-Ethylenediaminetetramethylene Phosphonic Acid. World J Nucl Med. 2015;14(2):109\u0026ndash;15.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eM\u0026aacute;th\u0026eacute; D, Balogh L, Poly\u0026aacute;k A, Kir\u0026aacute;ly R, M\u0026aacute;ri\u0026aacute;n T, Pawlak D, et al. Multispecies animal investigation on biodistribution, pharmacokinetics and toxicity of 177Lu-EDTMP, a potential bone pain palliation agent. Nucl Med Biol. 2010;37(2):215\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShinto AS, Shibu D, Kamaleshwaran KK, Das T, Chakraborty S, Banerjee S, et al. 177Lu-EDTMP for treatment of bone pain in patients with disseminated skeletal metastases. J Nucl Med Technol. 2014;42(1):55\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBal C, Arora G, Kumar P, Damle N, Das T, Chakraborty S, et al. Pharmacokinetic, Dosimetry and Toxicity Study of 177Lu-EDTMP in Patients: Phase 0/I study. Curr Radiopharm. 2016;9(1):71\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSharma S, Singh B, Koul A, Mittal BR. Comparative Therapeutic Efficacy of 153Sm-EDTMP and 177Lu-EDTMP for Bone Pain Palliation in Patients with Skeletal Metastases: Patients\u0026rsquo; Pain Score Analysis and Personalized Dosimetry. Front Med. 2017;4:46.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAlavi M, Khajeh-Rahimi F, Yousefnia H, Mohammadianpanah M, Zolghadri S, Bahrami-Samani A, et al. 177Lu/153Sm-Ethylenediamine Tetramethylene Phosphonic Acid Cocktail: A Novel Palliative Treatment for Patients with Bone Metastases. Cancer Biother Radiopharm. 2019;34(5):280\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAskari E, Harsini S, Vahidfar N, Divband G, Sadeghi R. 177Lu-EDTMP for Metastatic Bone Pain Palliation: A Systematic Review and Meta-Analysis. Cancer Biother Radiopharm. 2021;36(5):383\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAgarwal KK, Singla S, Arora G, Bal C. (177)Lu-EDTMP for palliation of pain from bone metastases in patients with prostate and breast cancer: a phase II study. Eur J Nucl Med Mol Imaging. 2015;42(1):79\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMaini CL, Bergomi S, Romano L, Sciuto R. 153Sm-EDTMP for bone pain palliation in skeletal metastases. Eur J Nucl Med Mol Imaging. 2004;31(Suppl 1):S171\u0026ndash;178.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTripathi M, Singhal T, Chandrasekhar N, Kumar P, Bal C, Jhulka PK, et al. Samarium-153 ethylenediamine tetramethylene phosphonate therapy for bone pain palliation in skeletal metastases. Indian J Cancer. 2006;43(2):86\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDolezal J. Systemic radionuclide therapy with Samarium-153-EDTMP for painful bone metastases. Nucl Med Rev Cent East Eur. 2000;3(2):161\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eThapa P, Nikam D, Das T, Sonawane G, Agarwal JP, Basu S. Clinical Efficacy and Safety Comparison of 177Lu-EDTMP with 153Sm-EDTMP on an Equidose Basis in Patients with Painful Skeletal Metastases. J Nucl Med. 2015;56(10):1513\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"177-Lu EDTMP, metastatic bone pain palliation therapy, prostate cancer, breast cancer, lung cancer","lastPublishedDoi":"10.21203/rs.3.rs-8053922/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8053922/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe most common symptom of patients with bone metastasis is bone pain which leads to decrease in quality of life of patients. Many different therapies are available for relief of bone pain, amongst which bone targeted radionuclide therapy is preferred in those with relapse after an initial line of treatment or those who have received maximum limit of irradiation. Various radionuclides have been previously used for bone pain palliation. Due to its medium range energy, long half-life, good binding properties, availability of gamma emissions for imaging, \u003csup\u003e177\u003c/sup\u003eLutetium appears useful for pain palliation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResult:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e13 patients with metastatic bone pain recieved 177- Lu EDTMP. There was significant decrease in Visual Analogue Score (VAS) (p \u0026lt; 0.001) and Analgesic Score (AS) (p ~ 0.001) from baseline till 3 months’ post-therapy. There was improvement in Quality of life in most of the patients responding to the therapy. Overall response rate (ORR) was 76.9%. There was transient decrease in haemoglobin, WBCs and platelets post treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study concludes that use of 177Lu-EDTMP as a systemic radionuclide therapy for pain palliation in patients with metastatic bone pain is a safe, effective and feasible alternative to conventional therapy options and other radiopharmaceuticals for pain palliation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Registration\u003c/strong\u003e: It was registered under CTRI (Clinical Trial Registry - India), Reference number: REF/2021/04/042801, Registered on 23 April 2021. URL: https://ctri.nic.in/Clinicaltrials/regtrial.php?modid=1\u0026amp;compid=19\u0026amp;EncHid=38227.67491\u003c/p\u003e","manuscriptTitle":"Efficacy and safety profile of 177-Lu-EDTMP for bone pain palliation in patients with metastatic bone pain.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-24 10:21:54","doi":"10.21203/rs.3.rs-8053922/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fdcbf328-8568-4512-9fab-a64c80de5156","owner":[],"postedDate":"November 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-03T07:36:13+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-24 10:21:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8053922","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8053922","identity":"rs-8053922","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}