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Review
Treatment with bone-seeking radionuclides for painful bone metastases in patients with lung cancer: a systematic review Helle D Zacho,1,2 Nita N Karthigaseu,1 Randi F Fonager,1 Lars J Petersen1,2
▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ bmjspcare-2015-000957). 1
Department of Nuclear Medicine, Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark 2 Department of Clinical Medicine, Aalborg University, Aalborg, Denmark Correspondence to Dr Helle D Zacho, Department of Nuclear Medicine, Aalborg University Hospital, Hobrovej 18-22, Postboks 365, Aalborg DK-9000, Denmark; [email protected] Received 19 June 2015 Accepted 5 January 2016
To cite: Zacho HD, Karthigaseu NN, Fonager RF, et al. BMJ Supportive & Palliative Care Published Online First: [ please include Day Month Year] doi:10.1136/bmjspcare-2015000957
ABSTRACT Treatment with bone-seeking radionuclides may provide palliation from pain originating from bone metastases. However, most studies have been conducted in patients with prostate cancer and patients with breast cancer. We aimed to perform a systematic review of the use of radionuclide treatment in lung cancer in accordance with the PRISMA guidelines. In the eligible trials, pain relief was reported in 75% of the patients included in the studies. The onset of pain relief was seen within 1–5 weeks after treatment, lasting up to 6 months. However, the methodology in the included trials was poor— only two randomised trials were eligible, and none of them compared radionuclide treatments with placebo or best standard of care. The remaining trials were case series with inherent problems of methodology reporting. Particularly challenging was the lack of reporting of baseline disease status and use of prior/concomitant analgaesics. Large randomised controlled trials are needed to clarify the efficacy of radionuclide treatment in lung cancer.
INTRODUCTION Bone metastasis is a common complication of advanced-stage cancer. Particularly, prostate, breast and lung cancers frequently metastasise to the bone.1 Patients with bone metastases often experience a reduced quality of life due to severe pain, and an increased incidence of skeletalrelated events, including pathological fractures, spinal cord compression and hypercalcaemia. Treatment of pain related to osseous metastases includes common analgaesics, opiates and external beam radiation.2 However, external radiation is unsuitable if painful osseous metastases are present in multiple anatomical regions and may
be limited by cumulative radiation toxicity on repeated treatments. Systemic internal radiotherapy using radioisotopelabelled bone-seeking tracers is an alternative treatment modality, particularly for patients with wide-spread metastatic disease. It is a well-established treatment for prostate cancer, with high tolerability and a rather low toxicity.3–6 However, for other cancer types, the evidence of a treatment benefit is rather sparse.7 Several radionuclides have been evaluated in clinical trials, but only a few have gained regulatory approval. These are strontium-89 hydrochloride (Sr-89) (Metastron; GE Healthcare, Amersham, England) and samarium-153 lexidronam (Sm-153) (Quadramet; Iba Molecular Imaging, Gif-sur-Yvette, France), which have obtained marketing approval in many European countries, the USA and other countries, and rhenium-186 hydroxyethylidene diphosphonate (Re-186) (Re-Bone; Covidien, Minneapolis, Minnesota, USA), which has been approved in some European countries. Recently, the α-emitter radium-223 dichloride (Xofigo; Bayer) was approved only for the treatment of castrationresistant metastatic prostate cancer in numerous countries worldwide. The use of systemic radionuclides is recommended by international guidelines in prostate cancer for the treatment of painful osseous metastases.2 8 9 Although evidence of their benefit has been investigated predominantly in patients with prostate cancer,10–12 a Cochrane review has provided evidence for pain relief without limitations to specific cancer types.13 The role and efficacy of radionuclide treatment in painful osseous
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Review metastases in lung cancer remain unclear. Thus, the aim of the present work was to perform a systematic review of the evidence for systemic treatment with bone-seeking radionuclides in patients with osseous metastasis from lung cancer. MATERIALS AND METHODS Ethics
No public protocol has been registered for the present systematic review. This study complied with the Helsinki-II declaration and, according to Danish legislation, systematic reviews of the existing literature do not require ethical approval by the local ethical committee. Search strategy for the literature
Three online databases were searched for relevant articles. The search was customised for each of the following databases: MEDLINE (PubMed), EMBASE (Ovid) and Web of Science, as shown in online supplementary appendix A. The terms used were lung cancer, bone metastasis, radionuclides (strontium-89, samarium-153 and rhenium-186) and pain. The search period spanned from 1974 to April 30, 2015. Ra-223 (Xofigo) has been approved for the treatment of prostate cancer only and, therefore, was not included in the search. The search retrieved 192 references, of which 27 were retrieved from MEDLINE, 116 from EMBASE and 49 from Web of Science, as shown in figure 1. All citations were entered into Reference Manager, V.12 (Thomson Reuters, USA), and 47 duplicate citations were identified and deleted (figure 1). Selection criteria
Abstracts of the 145 eligible papers were read and evaluated independently by two observers for inclusion in the review. Papers were excluded only if there was consensus that the reference did not fulfil the eligible criteria. Eligibility criteria for the present systematic review were as follows: the radionuclide dose had to be within the recommended dose range according to the European Association of Nuclear Medicine procedure guideline for the use of radionuclides for the treatment of bone pain, with a variance of ±30%, which is consistent with the product summary for Quadramet, Metastron and Re-Bone. A minimum of six patients with lung cancer was included in each trial. If the trial consisted of mixed cancer types, data from patients with lung cancer were reported separately. Finally, the end point had to include the reporting of pain, performance status and/or quality of life. No criterion for the length of follow-up was applied. Eighty-eight papers were excluded based on the abstract alone. One paper could not be retrieved in full text regardless of a search through Scandinavian and British libraries.14 Thus, 56 full-text references were retrieved. There were notable numbers of 2
Figure 1 Flowchart for the selection of the eligible studies.
non-English papers. Nine papers were written in Chinese, two were written in Japanese, one was written in German and one paper was written in French. The Chinese and Japanese references were translated into English by two PhD students whose native languages were Chinese and Japanese, respectively. The German and French papers were read by physicians with German/French as their primary foreign language. Furthermore, reviews included in the initial search as well as eligible full-text references were hand searched for additional publications not identified in the original literature search. No additional eligible references were found. The full-text articles were read independently by two of the authors, and eligibility was defined in consensus. A total of 12 papers met the eligibility criteria and were included in the review,
Zacho HD, et al. BMJ Supportive & Palliative Care 2016;0:1–8. doi:10.1136/bmjspcare-2015-000957
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Review details of the included papers are provided in online supplementary appendix B. Figure 1 shows the consort diagram for the selection process. The reasons for excluding papers were primarily (1) a lack of original data (reviews), (2) fewer than six patients with lung cancer, (3) no separate reporting of data in lung cancer in studies with mixed types of cancer and (4) the dose of the radioisotope was outside the recommended clinical interval. Two Chinese papers including 65 and 126 patients with lung cancer, respectively, were from the same institution, published the same year, and overlapped among authors (two of three authors were identical).15 16 One paper addressed the outcome among different pathological lung cancer types, whereas the second paper addressed the relationship between serum tumour markers and the response to radionuclide treatment. It remained unknown if the studies comprised separate populations. An attempt to clarify this issue was hampered by the lack of response from the corresponding author to several electronic mails. We included both papers in this systematic review. The corresponding author of one randomised controlled trial (RCT) was unsuccessfully contacted by electronic mail to obtain additional information regarding the dose of the additional treatment in one of the treatment arms.17 Data from the 12 included papers were extracted by two independent readers and discussed until consensus. There was no need for a third-party arbitrator.
prospective only if the word ‘prospective’ was used or if the treatment was assigned in a random manner. An unbiased inclusion of patients was noted if the word ‘consecutive’ was used or if all eligible patients during a specific time frame were included in the trial. The reporting of previous therapies was expected, but they were not required to be documented in detail. A major concern was the use of medical pain control using opioids and non-opioids, including any change in medication during the follow-up period. Because some trials included patients receiving more than one treatment cycle with radionuclide therapy, the outcome after every treatment was reported separately. Patients lost to follow-up for both efficacy and safety were investigated. Thus, clear criteria for grading a response by the authors were examined as either a binary outcome (responder vs non-responder) or a graded response (eg, no, mild, substantial or dramatic response). We assessed the onset and duration of pain relief and the criteria for pain relapse. It was noted whether safety was reported and graded in accordance with standardised criteria—for example, WHO or Common Terminology Criteria for Adverse Events (CTCAE), particularly for haematological side effects. In general, the evaluation of the used trial methodology was based on data presented for the entire study population, including mixed trials. Assessment of efficacy
Research methodology of the eligible studies
The Jadad score was used for the evaluation of RCT. This score evaluates blinding, randomisation and the description of dropouts, with each giving one point. Additionally, two points can be given if the method of randomisation and blinding were thoroughly described and considered appropriate (similarly, points for blinding and randomisation can be subtracted if the methods were clearly inappropriate). Thus, the Jadad score may range from 0 to 5.18 The Oxford University (UK) Centre for Evidencebased Medicine (CEBM) grading of therapeutic trials ( http://www.cebm.net/) was used, in addition, to assess the level of evidence among the eligible papers. We found no tools designed for the assessment of the quality of non-randomised controlled trials or case series. Thus, we implemented key elements from the CONSORT statement,19 20 as we had done previously in systematic reviews when reporting trial methodology in case series.7 Additionally, parts of the STROBE checklist available for observational studies were employed.21 The extracted information is shown in table 1. The trial methodology was based uniquely on the actual reporting. Thus, if an item was not described at all, this item was classified as missing in the evaluation of methodology. Specifically, a trial was considered
To provide an overall treatment effect across different outcome measures, we defined minimum criteria for a successful outcome (binary outcome) after radionuclide treatment as follows: (1) a decrease in pain by one class for semiquantitative data, (2) a 3 cm decrease in a 10 cm VAS or three points on an 11-item numerical rating scale (0–10) score, or (3) an increase in Karnofsky’s performance score of 10 or an improvement of 1 using the Eastern Cooperative Oncology Group (ECOG) performance score. RESULTS Trial overview
Eligibility criteria were met by 12 studies as shown in figure 1. Two of the 12 trials were RCTs. One RCT assigned patients to three different active therapy regimes.17 One RCT examined two different doses of Sm-153.22 Nine of 12 studies were case series (uncontrolled trials) and one study was a non-RCT comparing three groups of patients with lung cancer receiving either Sr-89, Sr-89 in combination with clodronate or clodronate alone. Patients were enrolled for 7 years without description of whether it was an analysis of a change in patient management over time or if it was randomised or blinded.23 Six studies included patients with lung cancer only. In trials with mixed populations, lung cancer
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Review Table 1 Reporting of trial methodology. The numbers (proportions) represent reporting of the individual items if identified in the individual trials for the entire study population
Prospective design Consecutive patients Minimum life expectancy Clinical variables Imaging performed at baseline Extend of metastases reported at baseline Performance status reported at baseline Grading of pain at baseline Use of analgaesics reported at baseline Prior therapy reported Treatment More than one treatment per patient Results from multiple treatments reported separately Concomitant medical treatment Follow-up Stating whether patients lost to follow-up If lost to follow-up, reason described Efficacy Clear definition of clinical benefit Efficacy graded by response Onset of pain release described Duration of pain relief described Safety Haematological toxicity reported Standardised grading system (WHO/CTCAE) toxicity criteria CTCAE, Common Terminology Criteria for Adverse Events.
Randomised controlled trials n=2
Uncontrolled trials, lung cancer only n=4
Uncontrolled trials mixed cancers n=6
2 (100%) 0 (0%) 1 (50%)
0 (0%) 1 (25%) 1 (25%)
0 (0%) 0 (0%) 4 (67%)
2 0 1 0 0 0
4 2 1 4 2 3
6 (100%) 0 (0%) 2 (33%) 1 (17%) 0 (0%) 2 (33%)
(100%) (0%) (50%) (0%) (0%) (0%)
0 (0%) – 1 (50%)
1 (25%) 0 2 (50%)
3 (50%) 2 0 (0%)
0 (0%) –
1 (25%) 1
3 (50%) 1
2 2 1 1
2 0 3 2
5 (83%) 5 (83%) 4 (67%) 4 (67%)
(100%) (100%) (50%) (50%)
2 (100%) 1
represented 22–46% of the study population with a median number of patients with lung cancer of 31 patients (range: 14–41). In trials with patients with lung cancer only, the median number was 65 patients (range: 6–126). A total of 517 patients were included in these trials. It could not be clarified whether partly duplicate data were included in the two Chinese papers including 65 and 126 patients with lung cancer, respectively.15 16 All studies used pain relief as the primary end point. In addition, two trials included performance score and change in lesion appearance on bone scintigraphy as independent outcomes,17 24 a change in performance score was a secondary end point in two trials22 25 and a change in bone scintigraphy was used as an independent outcome in an additional four trials.15 16 23 26 Table 2 presents an overview of the eligible trials, including the number of patients and type of radionuclide used. Randomised controlled trials
There were two RCTs, one including lung cancer patients only (table 3). None of the RCTs were placebo controlled. One trial compared two different doses of Sm-153.22 The second RCT compared Sr-89 4
(100%) (50%) (25%) (100%) (50%) (75%)
(50%) (0%) (75%) (50%)
3 (75%) 1
6 (100%) 1
with Sr-89 and Tc-99-methylene diphosphonate, versus Sr-89 and zoledronic acid.17 The RCT comparing two doses of Sm-153 used pain relief (calculated as a Sum of Effect Product consisting of the extent of pain relief and duration of pain relief ) and performance score as outcomes. For baseline status, only the performance score was available—neither pain score nor extent of metastatic disease was provided. No description of prior therapy was available. A total of 72 of 105 patients used analgaesics for pain relief at the time of enrolment. It is worth noting that 160 patients were enlisted in the study, but only 105 completed the 16-week follow-up and, thus, were included in the analysis. The trial reported no significant difference between the two doses of Sm-153 in terms of pain relief calculated as the Sum of Effect Product, performance score, or onset or duration of pain relief. The trial included a mixed population; patients with lung cancer showed the lowest response rate, although not significantly lower than the other tumour types (breast, prostate and oesophagus). Irrespective of cancer type and dose of samarium, the response rate was 84% (88/105). Among the 17 patients not responding to 153-Sm treatment, 10 had
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Review Table 2
Overview of the trials included in the review
Author (publication year) Kasalicky and Krajska (1998) Fang et al (1998) Tian et al (1999) Lou et al (2001) Su et al (2002) Fan et al (2004)* Leondi et al (2004) Zheng et al (2004)* Chen et al (2005) Ratsimanohatra et al (2005) Minutoli et al (2006) Dong et al (2012) *Probable inclusion of the same patients RCT, randomised controlled trial.
Trial design Case series Case series RCT Case series Non-randomised controlled trial Case series Case series Case series Case series Case series Case series RCT in both trials.
lung cancer; accordingly, the response rate for lung cancer was 76% (31/41). The RCT by Dong et al included 95 patients with lung cancer randomly assigned to either Sr-89 alone or to a combination of Sr-89 with either Tc-99-MDP given daily for 15 days (25 mg, the radioactive dose was not specified) or zoledronic acid (the dose was not specified). No baseline data concerning the status of pain, performance score, prior therapy or use of analgaesics were presented. Additionally, the extent of metastatic disease was not reported. The criteria were defined for success in terms of pain relief, Karnofsky performance score and change in bone scintigraphy.
Radionuclide
Patients with lung cancer /total study population (proportion) (%)
Sr-89 Sr-89 Sm-153 Sr-89 Sr-89 Sr-89 Re-186 Sr-89 Sm-153 Sm-153 Re-186 Sr-89
31/118 (26) 14/42 (33) 41/105 (39) 22/56 (39) 39/39 (100) 65/65 (100) 24/24 (100) 126/126 (100) 35/158 (22) 6/6 (100) 19/41 (46) 95/95 (100)
Patients were followed for 3 months, and no difference was found between combining Sr-89 with Tc-99 or zoledronic acid. Both treatment regimens were superior to Sr-89 therapy alone regarding pain relief, increase in Karnofsky performance score and change in bone scintigraphy. The onset and duration of pain relief were not assessed. None of the RCTs reported any serious adverse events. Haematological toxicity was reported, and one study used WHO criteria for the grading of toxicity. Both trials had a Jadad score of 1, and the score was given based on randomisation; no points were
Table 3 Efficacy and safety data from two randomised controlled trials regarding the use of radionuclides to treat bone pain in patients with metastatic lung cancer Author
Treatment groups
Tian et al
Sm-153, 37 MBq/kg (70 patients; 31 lung cancer) vs Sm-153, 18.5 MBq/kg (35 patients; 10 lung cancer)
Baseline clinical data Baseline pain score: not reported Karnofsky score 62.7±22.4 (the entire population)
Pain response
Performance status
Toxicity
Change from baseline at 16 weeks Pain was assessed semiquantitatively using sum of effect product (SEP), SEP >3 considered successful. The SEP was 18.5±14 in high-dose group and 13.4±12 in low-dose group. Response rates for the entire population: High dose group: 58/70 (83%) Low dose group: 30/35 (86%) Change in pain (grade 1–4) at 3 months. Response: At least one class improvement. Response rates: Control group: 19/33 (58%) Group A: 25/30 (83%) Group B: 26/32 (81%)
Change from baseline at 16 weeks Improvement of Karnofsky score 8.2±14
No separate data for lung cancer No reporting of group toxicity data by standard criteria
Proportion of patients with at least 10 point improvement of Karnofsky score at 3 months: Control group: 17/33 (52%) Group A: 24/30 (80%) Group B: 23/32 (72%)
No grade 3–4 haematological toxicity (WHO criteria) 1 month after treatment
Baseline pain Control-group: score: not Sr-89, 1.48 MBq/kg (n=33) reported vs Baseline Group A: Sr-89, 1.48 MBq/ performance kg+25 mg of Tc-99 MDP/ score: not daily for 15 days(n=30) reported vs Group B: Sr-89, 1.48 MBq/ kg+intravenous zoledronic acid (dose not specified) repeated three times at 4 weeks interval (n=32) Data are shown for patients with lung cancer if not otherwise mentioned. Dong et al
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Review given for (appropriate) blinding or a description of withdrawals or dropouts. Case series
Six of nine case series had defined criteria for successful outcome after radionuclide treatment either regarding pain, performance score, change in bone scintigraphy or a combination of these. However, quantitative baseline data were reported only in four of the case series. As shown in table 1, the methodology for reporting patient enrolment, baseline values, definition of response criteria, assessing the use of analgaesics and reasons for dropout was deficient. Consequently, the efficacy of treatment was difficult to assess. Generally, most patients were available for the analysis of efficacy; the onset and duration of pain relief were reported in six of nine uncontrolled trials, but none of the trials reported how pain relapse was defined. Five of nine uncontrolled trials reported the grading of pain at baseline; however, the concomitant use of analgaesics and change in analgaesics were reported in two uncontrolled trials, whereas previous therapies were reported in five trials. The use of more than one treatment session per patient was conducted in four uncontrolled trials, but only two trials reported the outcome separately for each cycle of treatment.25 27 A non-randomised controlled trial included 67 patients with lung cancer. The patients received either Sr-89, Sr-89 in combination with clodronate, or clodronate alone. Every patient had received prior chemotherapy without a sufficient effect on pain management, but no information regarding the baseline status of pain, use of analgaesics or performance score was available. Patients were followed for 3 months, and the outcome after therapy was based on pain relief, performance score and change in bone scintigraphy. No difference was found between the treatment groups in terms of pain relief or increase in Karnofsky performance score; however, the combination of Sr-89 and clodronate was superior to the single-drug groups in terms of a change in bone scintigraphy. No serious adverse events were reported. Level of evidence
The level of evidence for the use of radioisotopes for pain relief in bone metastasis in lung cancer was low. None of the trials compared radionuclide treatment with placebo or standard oncological care, including external palliative radiotherapy. According to the Oxford Centre for Evidence, the level of evidence of these studies was level 4 (due to case series and RCTs with neither proper blinding nor placebo control). The RCT included in the trial had a Jadad score of 1. Efficacy
The success rate of radionuclide treatment in lung cancer was reported by the included trials to have a 6
median of 79% (range: 0–100%). However, the definition of effect varied among the included studies; one study used a significant decrease in the mean score of the visual analogue scale (VAS) as a definition of successful treatment, whereas other studies used the improvement in pain score, change in bone scintigraphy, performance score or a combination of these for the individual patient and calculated the proportion of patients with improvement. Using our defined criteria for success, 383 of 511 patients (75%) from 11 studies experienced a positive effect by radionuclide treatment. It was not possible to extract efficacy data on a patient level from one study with lung cancer only (n=6).28 Eight of 12 trials reported the onset of pain relief ranging from 2 to 35 days with a duration (reported in seven trials) of 1.5 to 6 months. Safety
A minority of the trials reported whether patients were available for sufficient follow-up, and even fewer reported reasons for dropout. In one trial, two patients died without any assessment of the causality regarding radionuclide treatment. Haematological toxicity was assessed in the two RCTs, the non-RCT and in eight of nine uncontrolled trials, of which one RCT and one case series used standardised methods for grading toxicity. WHO criteria for haematological toxicity were used in both trials. DISCUSSION The role of radionuclide treatment of bone metastases in lung cancer has not yet been established. Our review of the existing literature indicates that approximately 75% of patients may benefit from treatment in terms of pain reduction. Nevertheless, the reported efficacy should be interpreted considering the low level of evidence of the eligible trials. Most of the included trials were uncontrolled case series. The inadequacy of information is an inherent problem of retrospective trials. Despite the low level of evidence in this design, a few of them described the clinical variables at baseline, and during treatment and follow-up, in a detailed manner.24 25 Accordingly, important information may be obtained from these studies. Regrettably, the reporting of methodology was deficient in the remaining trials, particularly the reporting of the baseline disease status such as pain and performance score and, importantly, the lack of reporting of analgaesic use. Radionuclide treatment is not considered a first-line treatment for pain caused by bone metastases. Other means of therapy should be tried initially such as common analgaesics, opiates, bisphosphonates or external radiotherapy, if the bone metastases are confined to a few regions. This idea emphasises the need for thorough information concerning the use of analgaesics before and after radionuclide treatment. Nevertheless, in one RCT, approximately one-third of
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Review the patients did not use any analgaesics at the time of enrolment in the trial.22 The reason for not using analgaesics was not described, making it impossible to distinguish between opiate-intolerant or NSAID-intolerant patients and patients with no need for analgaesics. The inclusion of patients without the need for analgaesics may bias the outcome after radionuclide treatment; it could be speculated that their pain might be reduced or dissolved more easily than patients with opiate-resistant pain. The patients lost to follow-up and dropouts were only reported in a minority of trials. A total of 160 patients were included in one RCT, but only 105 patients completed the follow-up—without any explanation for the loss to follow-up.22 Thus, patients were lost for both efficacy and safety evaluation. Except for in one trial, haematological toxicity was described in all trials; however, other adverse events were not reported. In the study by Lou et al,26 two patients died after treatment; whether this was related to the disease or to treatment was not described. Several studies have evaluated the efficacy of radionuclide treatment for painful bone metastases in prostate and breast cancer. Particularly, the number of trials in prostate cancer is large and includes many RCTs.29 The use of radionuclide therapy in prostate cancer has proven to be efficient for pain reduction.30 To what extent radionuclides improve overall survival is controversial.3 4 Owing to disease-specific tumour biology, if the bone metastases are predominantly osteosclerotic or osteolytic, caution should be exercised to directly apply the efficacy data of radionuclide therapy in prostate cancer to other cancer types. This notion is emphasised by a study analysing a group of patients who did not respond to radionuclide treatment. In that group, lung cancer represented a comparatively larger proportion than other cancer types.31 We aimed to evaluate the clinical effect of radionuclide treatment; thus, we only included radiopharmaceuticals with regulatory approval that were used in clinically relevant doses, in our search. The radiopharmaceutical, phosphorous-32, was not included because it has not gained regulatory approval. Radium-223 was also excluded because it was approved in the USA, the EU and several other countries for castration-resistant prostate cancer only. In the present systematic review, we have included trials published within the past 40 years. No trials were excluded due to language. More than 50% of the eligible trials were published in non-English language, six papers were published in Chinese and one eligible paper was published in French. Trials published in English included 129 patients, corresponding to less than one-fourth of the patients included by all trials, independent of language. These findings emphasise the need to include all papers, irrespective of language, in a systematic review.
Lung cancer is one of the most common cancers worldwide. A large proportion of patients present with disseminated disease or may develop painful bone metastases during the course of disease. Nevertheless, we could not identify any randomised phase II or III trials with radionuclide treatment for painful bone metastases in lung cancer. We identified two RCTs, of which one included patients with lung cancer only. All RCTs included variations of radionuclide therapy; there was no comparison with placebo nor with established therapy such as external radiation therapy. Furthermore, the methodological framework for efficacy and safety was poor. In addition, neither pain grading at baseline nor the use of analgaesics was described. In conclusion, it seems that patients with lung cancer may benefit in terms of pain relief from radionuclide treatment. However, the level of evidence supporting this statement is low. Only a transnational or multinational effort to conduct a large well-designed trial comparing radionuclide treatment versus existing standard of care in patients with lung cancer with bone metastases will provide us with the evidence of such treatment. Acknowledgements The authors thank the librarians Conni Skrubbeltrang and Pernille Gaardsted Rasmussen from Aalborg University Hospital for assistance with the literature search. Contributors HDZ and LJP were involved in the conception and design. HDZ, NNK and RFF were involved in the acquisition of data. HDZ, NNK, RFF and LJP were involved in the analysis/interpretation of data. HDZ was involved in the drafting the manuscript. Critically revising the manuscript: All the authors discussed the results and implications, and commented on the manuscript at all stages. HDZ, NNK, RFF and LJP were involved in the final approval of the manuscript. Competing interests None declared. Provenance and peer review Not commissioned; externally peer reviewed.
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Review 6 Brady D, Parker CC, O’sullivan JM. Bone-targeting radiopharmaceuticals including radium-223. Cancer J 2013;19:71–8. 7 Christensen MH, Petersen LJ. Radionuclide treatment of painful bone metastases in patients with breast cancer: a systematic review. Cancer Treat Rev 2012;38:164–71. 8 Heidenreich A, Bastian PJ, Bellmunt J, et al. Eau guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol 2014;65:467–79. 9 Mohler J, Armstrong AJ, Bahnson RR, et al. Prostate cancer, version 3.2012 featured update to the NCCN guidelines. J Natl Compr Canc Netw 2012;10:1081–7. 10 Sartor O, Coleman R, Nilsson S, et al. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol 2014;15:738–46. 11 Shapiro D, Tareen B. Current and emerging treatments in the management of castration-resistant prostate cancer. Expert Rev Anticancer Ther 2012;12:951–64. 12 Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013;369:213–23. 13 Roque IF, Martinez-Zapata MJ, Scott-Brown M, et al. Radioisotopes for metastatic bone pain. Cochrane Database Syst Rev 2011;(7):CD003347. 14 Montesano T, Giacomobono S, Acqualagna G, et al. Our experience on pain palliation of bone metastasis with Sr-89 or Sm-153 in cancer patients resistant to a conventional analgesic therapy. A Retrospective Study. Clin Ter 2009;160:193–9. 15 Fan Y-X, Luo R-C, Li G-P, et al. Antalgic effects of strontium-89 therapy on bone metastases in 65 patients with lung cancer. Chin J Clin Rehabil 2004;8:812–13. 16 Zheng H, Luo RC, Fan YX. Therapeutic effects of strontium-89 against osseous metastases of lung cancer: analysis of 126 cases. Di Yi Jun Yi Da Xue Xue Bao 2004;24:1194–6. 17 Dong Z, Qing Y, Wang X. Clinical observation of internal radiotherapy using 89sr 99tc-Mdp and zoledronic acid in the treatment and pain relief of lung cancer patients with bone metastasis. Chin L Clin Oncol 2012;39:1660–2. 18 Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1–12. 19 Calvert M, Blazeby J, Altman DG, et al. Reporting of patient-reported outcomes in randomized trials: the consort pro extension. JAMA 2013;309:814–22.
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20 Moher D, Hopewell S, Schulz KF, et al. Consort 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. Int J Surg 2012;10:28–55. 21 Von EE, Altman DG, Egger M, et al. The strengthening the reporting of observational studies in epidemiology (Strobe) statement: guidelines for reporting observational studies. Int J Surg 2014;12:1495–9. 22 Tian JH, Zhang JM, Hou QT, et al. Multicentre trial on the efficacy and toxicity of single-dose samarium-153-ethylene diamine tetramethylene phosphonate as a palliative treatment for painful skeletal metastases in China. Eur J Nucl Med 1999;26:2–7. 23 Su J, You C, Cai S, et al. 89srcl2, And/Or Bonefos in the treatment of bone metastasis from pulmonary carcinoma. Chin J Lung Cancer 2002;5:357–9. 24 Leondi AH, Souvatzoglou MA, Rapti AS, et al. Palliative treatment of painful disseminated bone metastases with 186Rhenium-hedp in patients with lung cancer. Q J Nucl Med Mol Imaging 2004;48:211–19. 25 Kasalicky J, Krajska V. The effect of repeated strontium-89 chloride therapy on bone pain palliation in patients with skeletal cancer metastases. Eur J Nucl Med 1998;25: 1362–7. 26 Lou C, Zhang D, Yu L. [Internal strontium-89 radiotherapy for malignant bony metastasis]. Zhonghua Zhong Liu Za Zhi 2001;23:507–9. 27 Minutoli F, Herberg A, Spadaro P, et al. 186re]Hedp in the palliation of painful bone metastases from cancers other than prostate and breast. Q J Nucl Med Mol Imaging 2006;50:355–62. 28 Ratsimanohatra H, Barlesi F, Doddoli C, et al. Use of 153Sm-EDTMP to relieve pain from bone metastasis in lung cancer. Rev Mal Respir 2005;22(2 Pt 1):317–20. 29 Han SH, De Klerk JM, Tan S, et al. The PLACORHEN study: a double-blind, placebo-controlled, randomized radionuclide study with (186)Re-etidronate in hormone-resistant prostate cancer patients with painful bone metastases. Placebo Controlled Rhenium Study. J Nucl Med 2002;43:1150–6. 30 Lawrentschuk N, Davis ID, Bolton DM, et al. Diagnostic and therapeutic use of radioisotopes for bony disease in prostate cancer: current practice. Int J Urol 2007;14:89–95. 31 Tian J, Cao L, Zhang J, et al. Comparative analysis of patients not responding to a single dose of 153Sm-EDTMP palliative treatment for painful skeletal metastases. Chin Med J (Engl) 2002;115:824–8.
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Treatment with bone-seeking radionuclides for painful bone metastases in patients with lung cancer: a systematic review Helle D Zacho, Nita N Karthigaseu, Randi F Fonager and Lars J Petersen BMJ Support Palliat Care published online January 27, 2016
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References
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Review
Treatment with bone-seeking radionuclides for painful bone metastases in patients with lung cancer: a systematic review Helle D Zacho,1,2 Nita N Karthigaseu,1 Randi F Fonager,1 Lars J Petersen1,2
▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ bmjspcare-2015-000957). 1
Department of Nuclear Medicine, Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark 2 Department of Clinical Medicine, Aalborg University, Aalborg, Denmark Correspondence to Dr Helle D Zacho, Department of Nuclear Medicine, Aalborg University Hospital, Hobrovej 18-22, Postboks 365, Aalborg DK-9000, Denmark; [email protected] Received 19 June 2015 Accepted 5 January 2016
To cite: Zacho HD, Karthigaseu NN, Fonager RF, et al. BMJ Supportive & Palliative Care Published Online First: [ please include Day Month Year] doi:10.1136/bmjspcare-2015000957
ABSTRACT Treatment with bone-seeking radionuclides may provide palliation from pain originating from bone metastases. However, most studies have been conducted in patients with prostate cancer and patients with breast cancer. We aimed to perform a systematic review of the use of radionuclide treatment in lung cancer in accordance with the PRISMA guidelines. In the eligible trials, pain relief was reported in 75% of the patients included in the studies. The onset of pain relief was seen within 1–5 weeks after treatment, lasting up to 6 months. However, the methodology in the included trials was poor— only two randomised trials were eligible, and none of them compared radionuclide treatments with placebo or best standard of care. The remaining trials were case series with inherent problems of methodology reporting. Particularly challenging was the lack of reporting of baseline disease status and use of prior/concomitant analgaesics. Large randomised controlled trials are needed to clarify the efficacy of radionuclide treatment in lung cancer.
INTRODUCTION Bone metastasis is a common complication of advanced-stage cancer. Particularly, prostate, breast and lung cancers frequently metastasise to the bone.1 Patients with bone metastases often experience a reduced quality of life due to severe pain, and an increased incidence of skeletalrelated events, including pathological fractures, spinal cord compression and hypercalcaemia. Treatment of pain related to osseous metastases includes common analgaesics, opiates and external beam radiation.2 However, external radiation is unsuitable if painful osseous metastases are present in multiple anatomical regions and may
be limited by cumulative radiation toxicity on repeated treatments. Systemic internal radiotherapy using radioisotopelabelled bone-seeking tracers is an alternative treatment modality, particularly for patients with wide-spread metastatic disease. It is a well-established treatment for prostate cancer, with high tolerability and a rather low toxicity.3–6 However, for other cancer types, the evidence of a treatment benefit is rather sparse.7 Several radionuclides have been evaluated in clinical trials, but only a few have gained regulatory approval. These are strontium-89 hydrochloride (Sr-89) (Metastron; GE Healthcare, Amersham, England) and samarium-153 lexidronam (Sm-153) (Quadramet; Iba Molecular Imaging, Gif-sur-Yvette, France), which have obtained marketing approval in many European countries, the USA and other countries, and rhenium-186 hydroxyethylidene diphosphonate (Re-186) (Re-Bone; Covidien, Minneapolis, Minnesota, USA), which has been approved in some European countries. Recently, the α-emitter radium-223 dichloride (Xofigo; Bayer) was approved only for the treatment of castrationresistant metastatic prostate cancer in numerous countries worldwide. The use of systemic radionuclides is recommended by international guidelines in prostate cancer for the treatment of painful osseous metastases.2 8 9 Although evidence of their benefit has been investigated predominantly in patients with prostate cancer,10–12 a Cochrane review has provided evidence for pain relief without limitations to specific cancer types.13 The role and efficacy of radionuclide treatment in painful osseous
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Review metastases in lung cancer remain unclear. Thus, the aim of the present work was to perform a systematic review of the evidence for systemic treatment with bone-seeking radionuclides in patients with osseous metastasis from lung cancer. MATERIALS AND METHODS Ethics
No public protocol has been registered for the present systematic review. This study complied with the Helsinki-II declaration and, according to Danish legislation, systematic reviews of the existing literature do not require ethical approval by the local ethical committee. Search strategy for the literature
Three online databases were searched for relevant articles. The search was customised for each of the following databases: MEDLINE (PubMed), EMBASE (Ovid) and Web of Science, as shown in online supplementary appendix A. The terms used were lung cancer, bone metastasis, radionuclides (strontium-89, samarium-153 and rhenium-186) and pain. The search period spanned from 1974 to April 30, 2015. Ra-223 (Xofigo) has been approved for the treatment of prostate cancer only and, therefore, was not included in the search. The search retrieved 192 references, of which 27 were retrieved from MEDLINE, 116 from EMBASE and 49 from Web of Science, as shown in figure 1. All citations were entered into Reference Manager, V.12 (Thomson Reuters, USA), and 47 duplicate citations were identified and deleted (figure 1). Selection criteria
Abstracts of the 145 eligible papers were read and evaluated independently by two observers for inclusion in the review. Papers were excluded only if there was consensus that the reference did not fulfil the eligible criteria. Eligibility criteria for the present systematic review were as follows: the radionuclide dose had to be within the recommended dose range according to the European Association of Nuclear Medicine procedure guideline for the use of radionuclides for the treatment of bone pain, with a variance of ±30%, which is consistent with the product summary for Quadramet, Metastron and Re-Bone. A minimum of six patients with lung cancer was included in each trial. If the trial consisted of mixed cancer types, data from patients with lung cancer were reported separately. Finally, the end point had to include the reporting of pain, performance status and/or quality of life. No criterion for the length of follow-up was applied. Eighty-eight papers were excluded based on the abstract alone. One paper could not be retrieved in full text regardless of a search through Scandinavian and British libraries.14 Thus, 56 full-text references were retrieved. There were notable numbers of 2
Figure 1 Flowchart for the selection of the eligible studies.
non-English papers. Nine papers were written in Chinese, two were written in Japanese, one was written in German and one paper was written in French. The Chinese and Japanese references were translated into English by two PhD students whose native languages were Chinese and Japanese, respectively. The German and French papers were read by physicians with German/French as their primary foreign language. Furthermore, reviews included in the initial search as well as eligible full-text references were hand searched for additional publications not identified in the original literature search. No additional eligible references were found. The full-text articles were read independently by two of the authors, and eligibility was defined in consensus. A total of 12 papers met the eligibility criteria and were included in the review,
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Review details of the included papers are provided in online supplementary appendix B. Figure 1 shows the consort diagram for the selection process. The reasons for excluding papers were primarily (1) a lack of original data (reviews), (2) fewer than six patients with lung cancer, (3) no separate reporting of data in lung cancer in studies with mixed types of cancer and (4) the dose of the radioisotope was outside the recommended clinical interval. Two Chinese papers including 65 and 126 patients with lung cancer, respectively, were from the same institution, published the same year, and overlapped among authors (two of three authors were identical).15 16 One paper addressed the outcome among different pathological lung cancer types, whereas the second paper addressed the relationship between serum tumour markers and the response to radionuclide treatment. It remained unknown if the studies comprised separate populations. An attempt to clarify this issue was hampered by the lack of response from the corresponding author to several electronic mails. We included both papers in this systematic review. The corresponding author of one randomised controlled trial (RCT) was unsuccessfully contacted by electronic mail to obtain additional information regarding the dose of the additional treatment in one of the treatment arms.17 Data from the 12 included papers were extracted by two independent readers and discussed until consensus. There was no need for a third-party arbitrator.
prospective only if the word ‘prospective’ was used or if the treatment was assigned in a random manner. An unbiased inclusion of patients was noted if the word ‘consecutive’ was used or if all eligible patients during a specific time frame were included in the trial. The reporting of previous therapies was expected, but they were not required to be documented in detail. A major concern was the use of medical pain control using opioids and non-opioids, including any change in medication during the follow-up period. Because some trials included patients receiving more than one treatment cycle with radionuclide therapy, the outcome after every treatment was reported separately. Patients lost to follow-up for both efficacy and safety were investigated. Thus, clear criteria for grading a response by the authors were examined as either a binary outcome (responder vs non-responder) or a graded response (eg, no, mild, substantial or dramatic response). We assessed the onset and duration of pain relief and the criteria for pain relapse. It was noted whether safety was reported and graded in accordance with standardised criteria—for example, WHO or Common Terminology Criteria for Adverse Events (CTCAE), particularly for haematological side effects. In general, the evaluation of the used trial methodology was based on data presented for the entire study population, including mixed trials. Assessment of efficacy
Research methodology of the eligible studies
The Jadad score was used for the evaluation of RCT. This score evaluates blinding, randomisation and the description of dropouts, with each giving one point. Additionally, two points can be given if the method of randomisation and blinding were thoroughly described and considered appropriate (similarly, points for blinding and randomisation can be subtracted if the methods were clearly inappropriate). Thus, the Jadad score may range from 0 to 5.18 The Oxford University (UK) Centre for Evidencebased Medicine (CEBM) grading of therapeutic trials ( http://www.cebm.net/) was used, in addition, to assess the level of evidence among the eligible papers. We found no tools designed for the assessment of the quality of non-randomised controlled trials or case series. Thus, we implemented key elements from the CONSORT statement,19 20 as we had done previously in systematic reviews when reporting trial methodology in case series.7 Additionally, parts of the STROBE checklist available for observational studies were employed.21 The extracted information is shown in table 1. The trial methodology was based uniquely on the actual reporting. Thus, if an item was not described at all, this item was classified as missing in the evaluation of methodology. Specifically, a trial was considered
To provide an overall treatment effect across different outcome measures, we defined minimum criteria for a successful outcome (binary outcome) after radionuclide treatment as follows: (1) a decrease in pain by one class for semiquantitative data, (2) a 3 cm decrease in a 10 cm VAS or three points on an 11-item numerical rating scale (0–10) score, or (3) an increase in Karnofsky’s performance score of 10 or an improvement of 1 using the Eastern Cooperative Oncology Group (ECOG) performance score. RESULTS Trial overview
Eligibility criteria were met by 12 studies as shown in figure 1. Two of the 12 trials were RCTs. One RCT assigned patients to three different active therapy regimes.17 One RCT examined two different doses of Sm-153.22 Nine of 12 studies were case series (uncontrolled trials) and one study was a non-RCT comparing three groups of patients with lung cancer receiving either Sr-89, Sr-89 in combination with clodronate or clodronate alone. Patients were enrolled for 7 years without description of whether it was an analysis of a change in patient management over time or if it was randomised or blinded.23 Six studies included patients with lung cancer only. In trials with mixed populations, lung cancer
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Review Table 1 Reporting of trial methodology. The numbers (proportions) represent reporting of the individual items if identified in the individual trials for the entire study population
Prospective design Consecutive patients Minimum life expectancy Clinical variables Imaging performed at baseline Extend of metastases reported at baseline Performance status reported at baseline Grading of pain at baseline Use of analgaesics reported at baseline Prior therapy reported Treatment More than one treatment per patient Results from multiple treatments reported separately Concomitant medical treatment Follow-up Stating whether patients lost to follow-up If lost to follow-up, reason described Efficacy Clear definition of clinical benefit Efficacy graded by response Onset of pain release described Duration of pain relief described Safety Haematological toxicity reported Standardised grading system (WHO/CTCAE) toxicity criteria CTCAE, Common Terminology Criteria for Adverse Events.
Randomised controlled trials n=2
Uncontrolled trials, lung cancer only n=4
Uncontrolled trials mixed cancers n=6
2 (100%) 0 (0%) 1 (50%)
0 (0%) 1 (25%) 1 (25%)
0 (0%) 0 (0%) 4 (67%)
2 0 1 0 0 0
4 2 1 4 2 3
6 (100%) 0 (0%) 2 (33%) 1 (17%) 0 (0%) 2 (33%)
(100%) (0%) (50%) (0%) (0%) (0%)
0 (0%) – 1 (50%)
1 (25%) 0 2 (50%)
3 (50%) 2 0 (0%)
0 (0%) –
1 (25%) 1
3 (50%) 1
2 2 1 1
2 0 3 2
5 (83%) 5 (83%) 4 (67%) 4 (67%)
(100%) (100%) (50%) (50%)
2 (100%) 1
represented 22–46% of the study population with a median number of patients with lung cancer of 31 patients (range: 14–41). In trials with patients with lung cancer only, the median number was 65 patients (range: 6–126). A total of 517 patients were included in these trials. It could not be clarified whether partly duplicate data were included in the two Chinese papers including 65 and 126 patients with lung cancer, respectively.15 16 All studies used pain relief as the primary end point. In addition, two trials included performance score and change in lesion appearance on bone scintigraphy as independent outcomes,17 24 a change in performance score was a secondary end point in two trials22 25 and a change in bone scintigraphy was used as an independent outcome in an additional four trials.15 16 23 26 Table 2 presents an overview of the eligible trials, including the number of patients and type of radionuclide used. Randomised controlled trials
There were two RCTs, one including lung cancer patients only (table 3). None of the RCTs were placebo controlled. One trial compared two different doses of Sm-153.22 The second RCT compared Sr-89 4
(100%) (50%) (25%) (100%) (50%) (75%)
(50%) (0%) (75%) (50%)
3 (75%) 1
6 (100%) 1
with Sr-89 and Tc-99-methylene diphosphonate, versus Sr-89 and zoledronic acid.17 The RCT comparing two doses of Sm-153 used pain relief (calculated as a Sum of Effect Product consisting of the extent of pain relief and duration of pain relief ) and performance score as outcomes. For baseline status, only the performance score was available—neither pain score nor extent of metastatic disease was provided. No description of prior therapy was available. A total of 72 of 105 patients used analgaesics for pain relief at the time of enrolment. It is worth noting that 160 patients were enlisted in the study, but only 105 completed the 16-week follow-up and, thus, were included in the analysis. The trial reported no significant difference between the two doses of Sm-153 in terms of pain relief calculated as the Sum of Effect Product, performance score, or onset or duration of pain relief. The trial included a mixed population; patients with lung cancer showed the lowest response rate, although not significantly lower than the other tumour types (breast, prostate and oesophagus). Irrespective of cancer type and dose of samarium, the response rate was 84% (88/105). Among the 17 patients not responding to 153-Sm treatment, 10 had
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Review Table 2
Overview of the trials included in the review
Author (publication year) Kasalicky and Krajska (1998) Fang et al (1998) Tian et al (1999) Lou et al (2001) Su et al (2002) Fan et al (2004)* Leondi et al (2004) Zheng et al (2004)* Chen et al (2005) Ratsimanohatra et al (2005) Minutoli et al (2006) Dong et al (2012) *Probable inclusion of the same patients RCT, randomised controlled trial.
Trial design Case series Case series RCT Case series Non-randomised controlled trial Case series Case series Case series Case series Case series Case series RCT in both trials.
lung cancer; accordingly, the response rate for lung cancer was 76% (31/41). The RCT by Dong et al included 95 patients with lung cancer randomly assigned to either Sr-89 alone or to a combination of Sr-89 with either Tc-99-MDP given daily for 15 days (25 mg, the radioactive dose was not specified) or zoledronic acid (the dose was not specified). No baseline data concerning the status of pain, performance score, prior therapy or use of analgaesics were presented. Additionally, the extent of metastatic disease was not reported. The criteria were defined for success in terms of pain relief, Karnofsky performance score and change in bone scintigraphy.
Radionuclide
Patients with lung cancer /total study population (proportion) (%)
Sr-89 Sr-89 Sm-153 Sr-89 Sr-89 Sr-89 Re-186 Sr-89 Sm-153 Sm-153 Re-186 Sr-89
31/118 (26) 14/42 (33) 41/105 (39) 22/56 (39) 39/39 (100) 65/65 (100) 24/24 (100) 126/126 (100) 35/158 (22) 6/6 (100) 19/41 (46) 95/95 (100)
Patients were followed for 3 months, and no difference was found between combining Sr-89 with Tc-99 or zoledronic acid. Both treatment regimens were superior to Sr-89 therapy alone regarding pain relief, increase in Karnofsky performance score and change in bone scintigraphy. The onset and duration of pain relief were not assessed. None of the RCTs reported any serious adverse events. Haematological toxicity was reported, and one study used WHO criteria for the grading of toxicity. Both trials had a Jadad score of 1, and the score was given based on randomisation; no points were
Table 3 Efficacy and safety data from two randomised controlled trials regarding the use of radionuclides to treat bone pain in patients with metastatic lung cancer Author
Treatment groups
Tian et al
Sm-153, 37 MBq/kg (70 patients; 31 lung cancer) vs Sm-153, 18.5 MBq/kg (35 patients; 10 lung cancer)
Baseline clinical data Baseline pain score: not reported Karnofsky score 62.7±22.4 (the entire population)
Pain response
Performance status
Toxicity
Change from baseline at 16 weeks Pain was assessed semiquantitatively using sum of effect product (SEP), SEP >3 considered successful. The SEP was 18.5±14 in high-dose group and 13.4±12 in low-dose group. Response rates for the entire population: High dose group: 58/70 (83%) Low dose group: 30/35 (86%) Change in pain (grade 1–4) at 3 months. Response: At least one class improvement. Response rates: Control group: 19/33 (58%) Group A: 25/30 (83%) Group B: 26/32 (81%)
Change from baseline at 16 weeks Improvement of Karnofsky score 8.2±14
No separate data for lung cancer No reporting of group toxicity data by standard criteria
Proportion of patients with at least 10 point improvement of Karnofsky score at 3 months: Control group: 17/33 (52%) Group A: 24/30 (80%) Group B: 23/32 (72%)
No grade 3–4 haematological toxicity (WHO criteria) 1 month after treatment
Baseline pain Control-group: score: not Sr-89, 1.48 MBq/kg (n=33) reported vs Baseline Group A: Sr-89, 1.48 MBq/ performance kg+25 mg of Tc-99 MDP/ score: not daily for 15 days(n=30) reported vs Group B: Sr-89, 1.48 MBq/ kg+intravenous zoledronic acid (dose not specified) repeated three times at 4 weeks interval (n=32) Data are shown for patients with lung cancer if not otherwise mentioned. Dong et al
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Review given for (appropriate) blinding or a description of withdrawals or dropouts. Case series
Six of nine case series had defined criteria for successful outcome after radionuclide treatment either regarding pain, performance score, change in bone scintigraphy or a combination of these. However, quantitative baseline data were reported only in four of the case series. As shown in table 1, the methodology for reporting patient enrolment, baseline values, definition of response criteria, assessing the use of analgaesics and reasons for dropout was deficient. Consequently, the efficacy of treatment was difficult to assess. Generally, most patients were available for the analysis of efficacy; the onset and duration of pain relief were reported in six of nine uncontrolled trials, but none of the trials reported how pain relapse was defined. Five of nine uncontrolled trials reported the grading of pain at baseline; however, the concomitant use of analgaesics and change in analgaesics were reported in two uncontrolled trials, whereas previous therapies were reported in five trials. The use of more than one treatment session per patient was conducted in four uncontrolled trials, but only two trials reported the outcome separately for each cycle of treatment.25 27 A non-randomised controlled trial included 67 patients with lung cancer. The patients received either Sr-89, Sr-89 in combination with clodronate, or clodronate alone. Every patient had received prior chemotherapy without a sufficient effect on pain management, but no information regarding the baseline status of pain, use of analgaesics or performance score was available. Patients were followed for 3 months, and the outcome after therapy was based on pain relief, performance score and change in bone scintigraphy. No difference was found between the treatment groups in terms of pain relief or increase in Karnofsky performance score; however, the combination of Sr-89 and clodronate was superior to the single-drug groups in terms of a change in bone scintigraphy. No serious adverse events were reported. Level of evidence
The level of evidence for the use of radioisotopes for pain relief in bone metastasis in lung cancer was low. None of the trials compared radionuclide treatment with placebo or standard oncological care, including external palliative radiotherapy. According to the Oxford Centre for Evidence, the level of evidence of these studies was level 4 (due to case series and RCTs with neither proper blinding nor placebo control). The RCT included in the trial had a Jadad score of 1. Efficacy
The success rate of radionuclide treatment in lung cancer was reported by the included trials to have a 6
median of 79% (range: 0–100%). However, the definition of effect varied among the included studies; one study used a significant decrease in the mean score of the visual analogue scale (VAS) as a definition of successful treatment, whereas other studies used the improvement in pain score, change in bone scintigraphy, performance score or a combination of these for the individual patient and calculated the proportion of patients with improvement. Using our defined criteria for success, 383 of 511 patients (75%) from 11 studies experienced a positive effect by radionuclide treatment. It was not possible to extract efficacy data on a patient level from one study with lung cancer only (n=6).28 Eight of 12 trials reported the onset of pain relief ranging from 2 to 35 days with a duration (reported in seven trials) of 1.5 to 6 months. Safety
A minority of the trials reported whether patients were available for sufficient follow-up, and even fewer reported reasons for dropout. In one trial, two patients died without any assessment of the causality regarding radionuclide treatment. Haematological toxicity was assessed in the two RCTs, the non-RCT and in eight of nine uncontrolled trials, of which one RCT and one case series used standardised methods for grading toxicity. WHO criteria for haematological toxicity were used in both trials. DISCUSSION The role of radionuclide treatment of bone metastases in lung cancer has not yet been established. Our review of the existing literature indicates that approximately 75% of patients may benefit from treatment in terms of pain reduction. Nevertheless, the reported efficacy should be interpreted considering the low level of evidence of the eligible trials. Most of the included trials were uncontrolled case series. The inadequacy of information is an inherent problem of retrospective trials. Despite the low level of evidence in this design, a few of them described the clinical variables at baseline, and during treatment and follow-up, in a detailed manner.24 25 Accordingly, important information may be obtained from these studies. Regrettably, the reporting of methodology was deficient in the remaining trials, particularly the reporting of the baseline disease status such as pain and performance score and, importantly, the lack of reporting of analgaesic use. Radionuclide treatment is not considered a first-line treatment for pain caused by bone metastases. Other means of therapy should be tried initially such as common analgaesics, opiates, bisphosphonates or external radiotherapy, if the bone metastases are confined to a few regions. This idea emphasises the need for thorough information concerning the use of analgaesics before and after radionuclide treatment. Nevertheless, in one RCT, approximately one-third of
Zacho HD, et al. BMJ Supportive & Palliative Care 2016;0:1–8. doi:10.1136/bmjspcare-2015-000957
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Review the patients did not use any analgaesics at the time of enrolment in the trial.22 The reason for not using analgaesics was not described, making it impossible to distinguish between opiate-intolerant or NSAID-intolerant patients and patients with no need for analgaesics. The inclusion of patients without the need for analgaesics may bias the outcome after radionuclide treatment; it could be speculated that their pain might be reduced or dissolved more easily than patients with opiate-resistant pain. The patients lost to follow-up and dropouts were only reported in a minority of trials. A total of 160 patients were included in one RCT, but only 105 patients completed the follow-up—without any explanation for the loss to follow-up.22 Thus, patients were lost for both efficacy and safety evaluation. Except for in one trial, haematological toxicity was described in all trials; however, other adverse events were not reported. In the study by Lou et al,26 two patients died after treatment; whether this was related to the disease or to treatment was not described. Several studies have evaluated the efficacy of radionuclide treatment for painful bone metastases in prostate and breast cancer. Particularly, the number of trials in prostate cancer is large and includes many RCTs.29 The use of radionuclide therapy in prostate cancer has proven to be efficient for pain reduction.30 To what extent radionuclides improve overall survival is controversial.3 4 Owing to disease-specific tumour biology, if the bone metastases are predominantly osteosclerotic or osteolytic, caution should be exercised to directly apply the efficacy data of radionuclide therapy in prostate cancer to other cancer types. This notion is emphasised by a study analysing a group of patients who did not respond to radionuclide treatment. In that group, lung cancer represented a comparatively larger proportion than other cancer types.31 We aimed to evaluate the clinical effect of radionuclide treatment; thus, we only included radiopharmaceuticals with regulatory approval that were used in clinically relevant doses, in our search. The radiopharmaceutical, phosphorous-32, was not included because it has not gained regulatory approval. Radium-223 was also excluded because it was approved in the USA, the EU and several other countries for castration-resistant prostate cancer only. In the present systematic review, we have included trials published within the past 40 years. No trials were excluded due to language. More than 50% of the eligible trials were published in non-English language, six papers were published in Chinese and one eligible paper was published in French. Trials published in English included 129 patients, corresponding to less than one-fourth of the patients included by all trials, independent of language. These findings emphasise the need to include all papers, irrespective of language, in a systematic review.
Lung cancer is one of the most common cancers worldwide. A large proportion of patients present with disseminated disease or may develop painful bone metastases during the course of disease. Nevertheless, we could not identify any randomised phase II or III trials with radionuclide treatment for painful bone metastases in lung cancer. We identified two RCTs, of which one included patients with lung cancer only. All RCTs included variations of radionuclide therapy; there was no comparison with placebo nor with established therapy such as external radiation therapy. Furthermore, the methodological framework for efficacy and safety was poor. In addition, neither pain grading at baseline nor the use of analgaesics was described. In conclusion, it seems that patients with lung cancer may benefit in terms of pain relief from radionuclide treatment. However, the level of evidence supporting this statement is low. Only a transnational or multinational effort to conduct a large well-designed trial comparing radionuclide treatment versus existing standard of care in patients with lung cancer with bone metastases will provide us with the evidence of such treatment. Acknowledgements The authors thank the librarians Conni Skrubbeltrang and Pernille Gaardsted Rasmussen from Aalborg University Hospital for assistance with the literature search. Contributors HDZ and LJP were involved in the conception and design. HDZ, NNK and RFF were involved in the acquisition of data. HDZ, NNK, RFF and LJP were involved in the analysis/interpretation of data. HDZ was involved in the drafting the manuscript. Critically revising the manuscript: All the authors discussed the results and implications, and commented on the manuscript at all stages. HDZ, NNK, RFF and LJP were involved in the final approval of the manuscript. Competing interests None declared. Provenance and peer review Not commissioned; externally peer reviewed.
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Zacho HD, et al. BMJ Supportive & Palliative Care 2016;0:1–8. doi:10.1136/bmjspcare-2015-000957
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Treatment with bone-seeking radionuclides for painful bone metastases in patients with lung cancer: a systematic review Helle D Zacho, Nita N Karthigaseu, Randi F Fonager and Lars J Petersen BMJ Support Palliat Care published online January 27, 2016
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