Nucleaire behandeling
Uitgangsvraag
Wat is de plaats van (botzoekende) radionuclidetherapie ter pijnbestrijding bij patiënten met osteoblastische metastasen?
Aanbeveling
Symptomatische botmetastasen bij prostaatkanker:
Volg hierbij de richtlijn prostaatkanker.
Symptomatische botmetastasen bij andere primaire tumoren:
Overweeg radionuclide behandeling met samarium-153 bij patiënten met multifocale pijnklachten van botmetastasen, waarbij uitwendige radiotherapie geen uitkomst lijkt te bieden.
Voorafgaand aan behandeling dient de osteoblastische component van de metastasen aangetoond te worden met botscan.
Combineer radionuclide behandeling niet met andere systemische antitumortherapie.
Overwegingen
Voor- en nadelen van de interventie en de kwaliteit van het bewijs
Effect op pijnvermindering
Therapie met radionucliden bij symptomatische ossale metastasen geeft een relevante afname van pijn bij de grote meerderheid van de patiënten. Met name de radionucliden met een korte halfwaardetijd geven een snel effect binnen enkele weken. Het is wisselend hoe lang het effect van pijnreductie aanhoudt.
Er lijkt een kleine reductie te zijn in het optreden van pathologische fracturen, echter gezien kleine aantallen is dit effect waarschijnlijk niet klinisch relevant. Ook is het aannemelijk dat er een afname is van opioïdengebruik en ook een lagere kans op aanvullende uitwendige radiotherapie ter palliatie.
Er zijn enkele studies die suggereren dat er een positief effect is op de survival. Dit blijkt met name uit de ALSYMPCA-trial naar het effect van Radium-223. Mediane overall survival verbeterde van 11 naar 15 maanden na Radium-223 behandeling. Buiten de scope van de huidige literatuursearch toont de VISION trial, die de (niet specifiek botzoekende) radioligand Lutetium-177-PSMA vergelijkt met placebo, een positief effect op survival, op kwaliteit van leven en op pijn (Sartor 2021; Fizazi 2023).
De belangrijkste bijwerking van radionuclidentherapie is beenmerg toxiciteit, dit is over het algemeen mild (graad 1 of 2) en leidt niet tot aanvullende behandeling. Lange-termijn effecten met als gevolg hematologische maligniteit worden een enkele keer beschreven en zijn zeer zeldzaam.
De bewijskracht ten aanzien van pijnreductie is over het algemeen laag. Gerandomiseerde studies met pijn als primaire uitkomstmaat zijn schaars. Pijn als uitkomstmaat kent beperkingen en vaak zijn grote studies nodig om significant effect aan te tonen, zeker als pijn bij aanvang van behandeling beperkt is of reeds adequaat behandeling wordt met opioïden. Er is een veelvoud aan publicaties van observationele of niet vergelijkende studies die bij herhaling een positief effect laten zijn als het gaat om pijnbeleving en afname van opioïde gebruik.
Radionuclidetherapie wordt in de praktijk ingezet als uitwendige radiotherapie, een behandeling waar ruime ervaring mee bestaat en waar veel wetenschappelijk bewijskracht voor is, geen uitkomst lijkt te bieden. Dit is meestal het geval als er sprake is van multifocale pijn of er geen ruimte meer is voor bestraling na eerdere behandelingen.
Middel keuze
Literatuur toont een vergelijkbare effectiviteit wanneer gekeken wordt naar het effect van de verschillende beta-stralende radionucliden in het algemeen. Hierbij treedt het effect van pijnreductie eerder op bij samarium-153 of rhenium 186/188 dan bij strontium-89. Ook wordt een lagere mate van beenmergtoxiciteit beschreven bij deze radionucliden (sm153m/Rh-186/188) met een kortere halfwaardetijd.
Studies naar alpha-stralende radionucliden zoals radium-223 zijn veelal opgezet om het antitumor effect te bepalen met overall survival als primaire uitkomstmaat. Subanalyses als het gaat om kwaliteit van leven, opioidegebruik en noodzaak tot uitwendige radiotherapie laten hier ook een positief effect zien. Daarnaast zijn er meerdere observationele studies die een positief effect op pijn, opioid gebruik en kwaliteit leven zeer waarschijnlijk maken (Badrising 2022, Higano 2023).
Inzet bij patiënten met niet-symptomatische metastasen
Er is beperkt bewijs voor behandeling met botzoekende radionucliden wanneer de ossale metastasen niet symptomatisch zijn. Mogelijk zou pijn of medicatiegebruik in de toekomst uitgesteld of voorkomen kunnen worden, dit is onvoldoende onderzocht.
Wanneer er reeds een andere systemische behandeling gegeven wordt (chemotherapie, anti hormonale therapie) wordt niet aangeraden om dit te combineren met radionuclidenbehandeling. Er is een variëteit aan studies die verschillende combinaties toetst, echter zonder eenduidig positief resultaat.
Waarden en voorkeuren van patiënten (en evt. hun naasten)
Radionucliden behandelingen zijn weinig belastend voor de patiënt en kunnen daarom in de palliatieve setting de voorkeur hebben boven andere behandelingen. Dit komt zowel door de kortdurende weinig frequente toediening als zeer beperkte impact van bijwerkingen.
Een eventueel nadeel van de behandeling is dat het soms noodzakelijk is om gedurende een korte periode afstand (2 meter) te houden tot naasten vanwege stralingshygienische factoren. Ook is het onwenselijk als bij overlijden de patiënt recent een radionuclidebehandeling heeft ondergaan met oog op het voorkomen van blootstelling aan straling van populatie en milieu.
Het belangrijkste doel van de radionuclidebehandeling is verbeteren van kwaliteit van leven. Hierbij gaat het om verminderen van pijn, verminderen van opioïden gebruik, en voorkomen van andere meer invasieve behandelingen. Het merendeel van de patiënten ervaart deze verbetering zonder veel bijwerkingen.
Kosten (middelenbeslag)
Radionucliden zijn een kostbare behandeling van enkele duizenden euro’s per gift. Gezien beperkte indicatiestelling is het totale gebruik van radionucliden beperkt en zijn de totale kosten voor de maatschappij laag. Internationale studies naar kosteneffectiviteit laten veelal een positief effect zien ten aanzien van radionuclide behandeling. Het is echter de vraag hoe goed de kwaliteit is van deze studies en in hoeverre deze uitkomsten te extrapoleren zijn naar de Nederlandse praktijk.
Aanvaardbaarheid, haalbaarheid en implementatie
In Nederland zijn radionuclidenbehandelingen niet in elk ziekenhuis beschikbaar, mogelijk is verwijzing binnen de regio noodzakelijk naar een ziekenhuis met nucleaire afdeling die deze behandeling faciliteert.
In Nederland zijn slechts een beperkt aantal therapeutische radionucliden geregistreerd.
Samarium-153 is geregistreerd in de vorm van Quadramet (Samarium (153Sm) lexidronam pentanatrium). Dit middel kan ter palliatie van pijn ten gevolge van osteoblastische metastasen (aangetoond met botscan) aan iedere patiënt met voldoende beenmergreserve worden voorgeschreven, tumortype onafhankelijk. Dit middel kan dus breed worden toegepast.
Daarnaast is radium-223 geregistreerd voor symptomatische patienten met ossaal gemetastaseerd hormoon refractair prostaatcarcinoom (mCRPC), zonder viscerale metastasen. Dit middel volgt na tenminste twee voorafgaande systemische therapielijnen voor mCRPC (andere dan LHRH-analogen), of die niet in aanmerking komen voor een beschikbare systemische mCRPC behandeling. Lutetium-177-PSMA is momenteel beperkt beschikbaar in Nederland voor patienten met prostaatkanker, dit gaat naar verwachting veranderen als er meer duidelijk is over Nederlandse registratie en vergoeding door zorgverzekeraars.
Rationale van de aanbeveling: weging van argumenten voor en tegen de interventie
De literatuur geeft ondanks matige bewijskracht eenduidig aan dat radionuclidetherapie zorgt voor pijnreductie danwel minder gebruik van opioïden bij de patiënt met ossale metastasen
Bij de meeste patienten heeft een locale behandeling met radiotherapie de voorkeur voor de behandeling van pijn. Dit geldt zeker als er sprake is van neurologische uitval of dreigende myelumcompressie. Overweeg bij patiënten met multifocale pijnklachten op basis van uitgebreide osteoblastische botmetastasering een behandeling met een radionuclide.
Er is onvoldoende bewijs over effectiviteit om een radionuclidenbehandeling te combineren met andere systemische antitumortherapie.
Om discrepanties te voorkomen met de meer tumorspecifieke richtlijn voor prostaatkanker is ervoor gekozen om voor patiënten met prostaatkanker naar deze richtlijn te verwijzen in de aanbeveling.
Onderbouwing
Achtergrond
Behandelen van pijnlijke ossale metastasen met radionucliden is een mogelijkheid in de palliatieve setting. Deze weinig invasieve behandeling kan worden ingezet bij patiënten met overwegend osteoblastische metastasen en kan bij hen op korte termijn zorgen voor effectieve pijnbestrijding. Er zijn verschillende keuzes voor radionucliden waarbij radium-223, samarium-153, strontium-89 en rhenium-186/188 het meest worden toegepast. Mogelijke bijwerkingen zijn beperkt, voornamelijk beenmergdepressie. Het is gewenst om de wetenschappelijke publicaties betreffende dit onderwerp samen te vatten met betrekking tot indicatiestelling, effectiviteit en bijwerkingen, en te vergelijken met andere pijnbehandelingen zoals radiotherapie.
Conclusies
Low GRADE |
The evidence suggests nuclear treatment reduces pain on the short and medium term when compared to placebo. No conclusions can be drawn about long-term effects of nuclear treatment on pain response.
Source: Buchali 1988; Porter 1993; Serafini 1998; Han 2002; Smeland 2003; Sartor 2004. |
Very low GRADE |
No conclusions can be drawn about the effects on nuclear treatment on quality of life. The certainty of the evidence is very low due to paucity of data. Source: Smeland 2003; Nilsson 2016 |
Samenvatting literatuur
Summary of literature
We summarized the results of studies that compared:
- Nuclear treatment versus placebo among patients with bone metastases;
- Nuclear treatment (with or without another pain intervention) versus another pain intervention (such as: radiotherapy, zoledronic acid) among patients with bone metastases.
Secondary to the studies relevant for the PICO, we summarized studies that compared:
- One radionuclide compared to another;
- Dosage studies
For the comparisons 1 and 2 we assessed the certainty of the evidence by applying GRADE in line with Murad (2017).
Table 1. Overview of studies comparing nuclear treatment versus placebo among patients with bone metastases.
Author year |
Study design |
Patients |
Intervention |
Control |
Outcomes |
||
Strontium versus placebo |
|||||||
Buchali 1988 |
RCT
|
I: 25 C: unclear |
89-SR |
Placebo |
pain response (best response), survival |
||
Porter 1993 |
RCT All patients received RT for pain |
I: 68 C: 58 |
89-SR
|
Placebo |
pain response, analgesic use, QoL using unvalidated scales |
||
Smeland 2003 |
RCT All patients received RT for pain |
I: 46 C: 49 |
89-SR |
Placebo |
Pain response, QoL |
||
Samarium versus placebo |
|||||||
Sartor 2004 |
RCT |
I: 101 C: 51 |
153-SM |
Placebo (nonradioactive 152Sm) |
pain response (4-wk), WBC or ANC, PC, pain flare, survival |
||
Serafini 1998 |
RCT |
I: 23 (18,5 MBq/kg) I: 28 (37 MBq/kg) C: 29 (placebo) |
153-SM (two different doses) |
Placebo |
pain response (AUC 16 wk), WBC or ANC, PC, pain flare |
||
Rhenium versus placebo |
|||||||
Han 2002 |
RCT |
I: 66 C: 65 |
186-Re |
Placebo |
pain response (12 wk), survival |
||
Radium versus placebo |
|||||||
Nilsson 2007 |
RCT Phase II |
I: 33 C: 31 |
223RaCl2 |
Placebo |
Toxicity, bone ALP, SRE, OS |
||
Parker 2013 (primary paper ALSYMPCA trial) |
RCT ALSYMPCA |
I: 614 C: 307 |
223RaCl2 |
Placebo |
OS, SRE, ALP, PSA, adverse events |
||
Publications of subgroup and secondary analyses of ALSYMPCA trial (for specification: see grey column) |
|||||||
Sartor 2014
|
RCT ALSYMPCA |
I: 614 C: 307 |
223RaCl2 |
Placebo |
SRE, external beam radiation, spinal cord compression |
||
Sartor 2017 |
RCT ALSYMPCA |
I: 614 C: 307 |
223RaCl2 |
Placebo |
ALP, LDH, PSA |
||
Parker 2017 |
RCT ALSYMPCA |
I: 578-589 C: 287-298 |
223RaCl2 |
Placebo |
Hospitalization events, hospitalization days |
||
Parker 2016 |
RCT ALSYMPCA |
I: 269+345 C: 139+168 |
223RaCl2 (no opioid group and opioid group) |
Placebo (no opioid group and opioid group) |
OS, SRE, adverse events |
||
Hoskin 2014 |
RCT ALSYMPCA |
I: 352+174 C: 174+133 |
223RaCl2 (prior docetaxel group and no prior docetaxel group) |
Placebo (prior docetaxel group and no prior docetaxel group) |
OS, adverse events, |
||
Sartor 2016 |
RCT ALSYMPCA |
I: 142 C: 64 |
223RaCl2 |
Placebo |
Chemotherapy use, haemotologic values, OS |
||
Vogelzang 2017 |
RCT ALSYMPCA |
I: 614 C: 307 |
223RaCl2 |
Placebo |
Haematologic safety |
||
Nilsson 2016 |
RCT ALSYMPCA |
I: 614 C: 307 |
223RaCl2 |
Placebo |
QoL |
||
Parker 2018 |
RCT ALSYMPCA |
I: 600 C: 301 |
223RaCl2 |
Placebo |
Long term (3 yr) safety ALSYMPCA-trial: TEAE, haematologic TEAE |
||
AE: Adverse events; ALP: bone-alkaline phosphatase concentration; LDH: lactate dehydrogenase; OS: Overall survival; PSA: prostate-specific antigen; QoL: quality of life; RCT: Randomized Controlled Trial; RT: Radiotherapy; SRE: skeletal-related events; TEAE: treatment emergent adverse events.
Table 2. Overview of studies comparing nuclear treatment (with or without another pain intervention) versus another pain intervention or no treatment among patients with bone metastases.
Author year |
Study design |
Patients |
Intervention |
Control |
Outcomes |
|
Strontium (with or without another pain intervention) versus another pain intervention or no additional treatment |
||||||
Bilen 2015 |
RCT All patients received ADT, doxorubicin, and zoledronic acid |
I:39 C: 40 |
89-SR |
No additional treatment |
Pain |
|
Wang 2013 |
RCT |
Ia: 45 Ib: 45 Ic: 45 Id: 45 |
Ia: ZA + 89-SR Ib: ZA Ic: 89-SR |
Other intervention arms and 1d: No treatment |
OS, SRE |
|
Seider 2018 |
RCT All patients received zoledronic acid |
I: C: |
89-SR or Sm-153
|
No additional treatment |
Pain, QoL |
|
Li 2018 |
RCT
|
Ia: 35 Ib: 35 Ic: 35 |
Ia: 89-SR Ib: Sr-89 + zoledronic acid |
Ic: Zoledronic acid |
OS, SRE |
|
Oosterhof 2003 |
RCT |
I: 101 C: 102 |
89-SR |
Local field radiotherapy |
pain response (4-wk), white blood cell count (WBC) or absolute neutrophil count (ANC), platelet count (PC), pain flare, survival. |
|
Quilty 1994 |
RCT |
I: 153 C: ? |
89-SR |
Local field radiotherapy or hemibody radiotherapy |
Pain response (12-wk), WBC or ANC, PC, survival |
|
Samarium (with or without another pain intervention) versus another pain intervention |
None (up-to-date till July 2022) |
Rhenium (with or without another pain intervention) versus another pain intervention |
None (up-to-date till July 2022) |
Radium (with or without another pain intervention) versus another pain intervention |
None (up-to-date till February 2019) |
OS: Overall survival; QoL: quality of life; RCT: Randomized Controlled Trial; SRE: skeletal-related events.
1. Nuclear treatment versus placebo among patients with bone metastases
Strontium vs placebo
Smeland (2003) randomized 95 patients (93 eligible patients: 64 prostate, 19 breast, 10 other cancers) to radiotherapy combined with Sr-89 150 MBq (46 patients) or radiotherapy combined with placebo (saline) (49 patients). Pain response after 3 months was 30% in the Sr-89 group and 20% in the placebo group (p = n.s.). No significant differences were seen in quality of life. Adverse effects: leukocytopenia (grade I/II) 35% in the Sr-89 group and 12% in the placebo group (p = 0.02), thrombocytopenia 15 vs 4% (p not reported) not). The study planned to include 140 patients but was closed early because of slow recruitment.
Porter (1993) randomized 126 prostate cancer patients to local field radiotherapy combined with Sr-89 (400 MBq) or local field radiotherapy with placebo. No significant differences were seen in survival or in relief of pain at the index site. Intake of analgesics over time demonstrated a significant reduction in the Sr-98 group. Progression of pain as measured by sites of new pain or the requirement for radiotherapy showed statistically significant differences between the arms in favor of strontium-89. A QoL analysis was performed as a multivariate data set and demonstrated an overall superiority of Sr-89 with alleviation of pain and improvement in physical activity being statistically significant. Toxicity was evaluated and demonstrated increased hematological toxicity in the group receiving Sr-89.
Buchali (1988) treated 49 prostate cancer patients with either 3 x 75 MBq Sr-89 (25 patients) or placebo (saline) (24 patients). Pain relief was assessed 1-3 years after treatment and showed no significant difference. A higher survival rate was found in the Sr-89 group (46% vs 4% after 2 years). In the Sr-89 group thrombopenia was seen in 50% and neutropenia in 14%. In the placebo group thrombopenia was seen in 24% and neutropenia in 6%.
Samarium vs placebo
Sartor (2004) randomized 152 prostate cancer patients to either Sm-153 or nonradioactive Sm-152 (2:1). Pain and analgesic use were recorded in diaries for 16 weeks. Non-responders were informed of the treatment received after 4 weeks of treatment and, if initially treated with placebo, were allowed to receive 153Sm-lexidronam in an open-label fashion. 153Sm-lexidronam had positive effects on measures of pain relief compared with placebo within 1 to 2 weeks. Reductions in opioid use were recorded at weeks 3 and 4. Mild, transient bone marrow suppression was the only adverse event associated with 153Sm-lexidronam administration.
Serafini (1998) randomized 118 patients with bone metastases from various primary tumours between 1.0 mCi/kg (37 MBq/kg), 0.5 mCi/kg (18 MBq/kg) and placebo. Treatment was unblinded for patients who did not respond by week 4, with those who had received placebo eligible to receive 1.0 mCi/kg of active drug in an open-label manner. Patient and physician evaluations were used to assess pain relief, as was concurrent change in opioid analgesia. Patients who received 1.0 mCi/kg had significant reductions in pain during the first 4 weeks. Pain relief was observed in 62% to 72% of those who received the 1.O-mCi/kg dose during the first 4 weeks, with marked or complete relief noted in 31% by week 4. Persistence of pain relief was seen through week 16 in 43% of patients who received 1.0 mCi/kg. Bone marrow suppression was mild, reversible, and not associated with grade 4 toxicity.
Rhenium vs placebo
Han (2002) included 111 prostate cancer patients who were randomized to either Re-186 (43 evaluable patients) or placebo (36 evaluable patients). Pain response was determined using a specific decision rule in which pain intensity, medication index, and daily activities were the core determinants. The total response of the patients treated with 186Re-etidronate varied from 0% to 96% (mean, 27%, or 23/84 d). In the placebo group, the total response varied from 0% to 80% (mean, 13%, or 11/84 d; Mann-Whitney U test, P < 0.05). The number of patients who requested radiotherapy was higher in the placebo group (67%) than in the 186Re-etidronate group (44%) (relative risk, 1.51; Fisher’s exact test, P = 0.069).
Radium vs placebo
Parker (2013) describes the ALSYMPCA-trial, a phase III randomized double-blind, placebo-controlled study in which 921 prostate cancer patients who had received, were not eligible to receive, or declined docetaxel, were randomized in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223. At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval [CI], 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Time to first skeletal related event results were in favour of radium-223 (median, 15.6 months vs. 9.8 months; hazard ratio 0.66; 95%CI 0.52-0.83; P<0.001). Assessments of all other main biochemical secondary end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events. The study was terminated for efficacy at the prespecified interim analysis.
Nilsson (2016) reported QoL and pain data of the ALSYMPCA-trial. They used two validated instruments: the general EuroQoL 5D (EQ-5D) and the disease-specific Functional Assessment of Cancer Therapy-Prostate (FACT-P). Outcomes were the percentage of patients experiencing improvement, percentage of patients experiencing worsening, and mean QOL scores.
Pain-related questions from the subscale prostate cancer symptoms were used to estimate a pain-related score. Both groups had a relatively low meaningful improvement in pain (radium-223: 30.2%; placebo: 20.1%; p = 0.010). Pain was in this study not measured conform the predefined criteria of the guideline working group.
Radium-223 was associated with higher QoL scores versus placebo (0.56 versus 0.50; p = 0.002). The mean change from baseline was -0.10 with radium-223 and -0.16 with placebo (P = 0.002). For FACT-P total score, radium-223 was associated with a higher score (99.08 versus 95.22; p = 0.004) and a significantly smaller decrease from baseline versus placebo (-4.83 versus -8.69; p = 0.004). Nilsson (2016) found that the higher QoL observed with radium-223 patients was a direct consequence of a slower rate of decline in QoL with radium-223 versus placebo.
Subanalyses of ALSYMPCA trial
Parker (2016) reported a subanalysis of the ALSYMPCA-trial. Outcome measures were compared between of baseline opiod and a non-opiod use group. At baseline, 408 (44%) patients had no pain and no analgesic use or mild pain with nonopioid therapy (World Health Organization ladder pain score 0–1 [non-opioid subgroup]), and 513 (56%) had moderate pain with occasional opioids or severe pain with regular daily opioids (World Health Organization ladder pain score 2–3 [opioid sub-group]). Time to first opioid use for bone pain was assessed in patients not receiving baseline opioids (ie, nonopioid subgroup) and was significantly delayed with radium-223 versus placebo (HR = 0.62, 95% CI:0.46–0.85, p = 0.002; median not estimable vs 6.9 mo, respectively). During the study, opioids were required by 36% (96/269) of radium-223 patients versus 50% (70/139) of placebo patients. During the study, 30% (186/614) of radium-223 patients and 34% (105/307) of placebo patients received EBRT for bone pain. Radium-223 significantly reduced the risk of needing
EBRT for bone pain by 33% versus placebo (HR = 0.67, 95% CI:0.53–0.85, p = 0.001.
Sartor (2014) reported a subanalysis of the ALSYMPCA-trial the time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention. All events were required to be clinically apparent and were not assessed by periodic
radiological review. Time to fi rst symptomatic skeletal event was longer with radium-223 than with placebo (median 15·6 months [95% CI 13·5–18·0] vs 9·8 months [7·3–23·7]; hazard ratio [HR]=0·66, 95% CI 0·52–0·83; p=0·00037). The risks of external beam radiation therapy for bone pain (HR 0·67, 95% CI 0·53–0·85) and spinal cord compression (HR=0·52, 95% CI 0·29–0·93) were reduced with radium-233 compared with placebo. Radium-223 treatment did not seem to signifi cantly reduce the risk of symptomatic pathological bone fracture (HR 0·62, 95% CI 0·35–1·09), or the need for tumour-related orthopaedic surgical intervention (HR 0·72, 95% CI 0·28–1·82).
Level of evidence of the literature
1. Nuclear treatment versus placebo among patients with bone metastases
The level of evidence regarding the outcome measure pain response was downgraded by two levels to low because of serious study limitations (risk of bias); serious indirectness in terms of population, interventions and outcomes across studies and serious imprecision, i.e. optimal information size not met or the CIs of all the studies or of the largest studies include no effect and clinically meaningful benefits or harms.
No conclusions could be drawn about the effects on nuclear treatment on quality of life. The certainty of the evidence is very low due to paucity of data. We’re uncertain if nuclear treatment has a similar effect or perhaps may lead to a slower rate of decline in QoL when compared to placebo.
Table 3. Effect of nuclear treatment versus placebo on pain response and analgesics use among patients with bone metastases
|
Pain response |
Analgesics use |
||||
|
Short term (<12 weeks) |
Medium term |
Long term |
Short term |
Medium term |
Long term (>12 months) |
Strontium
|
||||||
Smeland 2003 |
|
+ (NT) |
|
|
|
|
Porter 1993 |
|
+ (NT) |
|
|
++ (NT) |
|
Buchali 1988 |
|
|
- |
|
|
|
Samarium |
||||||
Sartor 2004 |
++ (NT) |
|
|
++ (NT) |
|
|
Serafini 1998 |
++ (NT) |
|
|
++ (NT) |
|
|
Rhenium |
||||||
Han 2002 |
++ (NT) |
|
|
|
|
|
Radium |
||||||
Nillson 2016 Parker 2016 Sartor 2014 |
|
* (NT)
* (NT) |
|
|
* (NT)
|
|
Conclusions overall effect nuclear treatment |
The evidence suggests nuclear treatment reduces pain on the short and medium term when compared to placebo.1,2,3 No conclusions can be drawn about long-term effects of nuclear treatment on pain response. |
Grey: no information available
NT: in favour of nuclear treatment
P: in favour of placebo
++: clinically relevant effect, confidence interval does not include “no clinically relevant effect”
+ : clinically relevant effect, confidence interval does not include “no effect”
*: clinically relevant effect, not in accordance with our predefined pain response conditions
- : no clinically relevant effect
GRADE (meta-analysis not possible)
1 Serious methodological limitations of the studies, i.e. risk of bias
2 Serious indirectness in terms of population, interventions and outcomes across studies
3 Serious imprecision, i.e. optimal information size not met or the CIs of all the studies or of the largest studies include no effect and clinically meaningful benefits or harms
4 Serious inconsistency of the direction and the magnitude of effects across studies
5 Likelihood of publication bias
2. Nuclear treatment (with or without another intervention) versus another intervention among patients with bone metastases.
Strontium vs radiotherapy
Oosterhof (2003) randomized 203 prostate cancer patients to a single intravenous injection of 150 MBq Sr-89 (101 patients) or palliative local field radiotherapy (102 patients). There was no difference in pain response or in adverse effects between both groups. Median overall survival was better in the radiotherapy group (11.0 months) than in the Sr-89 group (7.2 months, p<0.05).
Quilty (1994) included 305 prostate cancer patients who were first stratified according to suitability for local or hemibody radiotherapy, then randomly allocated that form of treatment or Sr-89 (i.v. injection). Pain relief after three months was not different between the Sr-89 groups and the radiotherapy groups (Sr vs local radiotherapy 66 vs 61%; Sr-89 vs hemibody radiotherapy 66 vs 64%). After 80% of the patients had died, median survival was 33 weeks in the Sr-89 group and 28 weeks in the radiotherapy group (p=0.10). Fewer patients reported new pain sites after Sr-89 than after local or hemibody radiotherapy (p < 0.05). Platelets and leukocytes fell by an average 30–40% after strontium-89.
Strontium + doxorubicin vs doxorubicin alone
Tu (2001) randomized 72 prostate cancer patients to Sr-89 plus doxorubicin (36 patients) or doxorubicin alone (36 patients) after two or three cycles of induction chemotherapy, consisting of ketoconazole and doxorubicin alternating with estramustine and vinblastine. For the whole study population, pain resolution was seen in 52%, pain improvement in 81%. Median overall survival was 28 months in the Sr-89 + doxorubicin group and 17 months in the patients who received doxorubicin alone (HR = 2.8, p=0.001). Adverse effects >= grade 2: in the Sr-89 + doxorubicin group neutropenia was seen in 45%, anemia in 3% and nausea and vomiting in 8%; in the doxorubicin group neutropenia was seen in 22%, anemia in 8% and nausea and vomiting in 17%. More data on treatment groups was not available.
Docetaxel (D) vs docetaxel + zoledronic acid (DZA) vs docetaxel + Sr-89 (DSr89) vs docetaxel + Sr-89 + ZA (DSZ)
James (2016) randomized 757 prostate cancer patients to each of four arms: docetaxel (D) vs docetaxel plus zoledronic acid (DZA) vs docetaxel plus Sr-89 (DSr89) vs docetaxel plus Sr-89 and ZA (DSZ). The primary phase 3 analysis compared ZA vs no ZA (stratified for Sr89 use) and Sr-89 vs no Sr-89 (stratified for ZA use) in terms of clinical progression free survival (CPFS), pain progression, or death. Secondary outcome measures were symptomatic SRE-free interval, pain progression–free interval, overall survival, and numbers of SREs.
Results for Sr-89 vs no Sr-89: CPFS showed evidence of a moderate effect (HR 0.85; 95% CI, 0.73-0.99; P = 0.03). There were no statistically significant differences in pain progression free interval and median overall survival. Sr-89 did not significantly prolong the SRE-free interval (HR 0.88; 95% CI, 0.73-1.06; P=0.17), though the median SRE-free interval did increase from 11.7 to 13.0 months.
Strontium vs zoledronic acid
Li (2018) randomized 105 lung cancer patients into three groups of 35 patients: Sr-89 + ZA, Sr-89 alone and ZA alone. Wang (2013) randomized 180 lung cancer patients into four groups of 45 patients: Sr-89 + ZA, ZA alone, Sr-89 alone and no treatment. Hu (2020) performed a meta-analysis of the results of LI and Wang which suggests that ZA + strontium-89 and ZA obtained a significant improvement in the 1-year survival rate (RR = 2.1, 95% CI 1.63-2.81) and 2-year survival rate (RR = 1.8, 95% CI 1.33-2.38) compared with strontium- 89. The use of ZA + Sr-89 was associated with a higher 1-year survival rate (RR = 1.2, 95% CI 1.04 to 1.40) than that of ZA alone. Hu also did a network meta-analysis which showed that ZA + strontium-89 showed a better 1- year survival rate than the other therapeutic options. Strontium-89 alone seemingly did not significantly increase the 1-year survival rate (RR = 0.82, 95% CI 0.57, 1.19) and 2-year survival rate (RR = 1.3, 95% CI 0.45 to 3.75) compared with placebo. In comparison with Sr-89, ZA alone harbored a better 1-year survival rate (RR = 1.8, 95% CI 1.32 to 2.35), but had no significant difference in the 2-year survival rate (RR = 1.8, 95% CI 0.77 to 4.21). The network meta-analysis for NSCLC patients with bone metastases showed that ZA + strontium-89, among all the therapeutic options, displayed the highest clinical benefit of SREs. The effects of strontium-89 alone were not more favorable than those of placebo in terms of SREs (RR = 0.92, 95% CI 0.70 to 1.20)
Wang 2013 found that ZA + Sr-89 vs. ZA vs. Sr-89 harbored similar toxicity profiles. On the other hand, Li 2018 found that, compared with ZA, Sr-89 decreased the counts of leukocytes and platelets. ZA + Sr-89 was associated with more reduction of leukocytes and platelets than ZA and Sr-89. ZA seemingly had no impact on leukocytes and platelets.
Zoledronic acid with Strontium or Samarium vs zoledronic acid without Strontium or Samarium
Seider (2018) included 261 patients with prostate, breast or long cancer and bone metastases. Those patients were randomized to either zoledronate alone or zoledronate plus radiopharmaceuticals (Sr-89 or Sm-153). The primary endpoint was time to development of SREs. Secondary objectives included quality of life, pain control, overall survival (OS) and toxicity. Patients were stratified by site of primary cancer (lung vs. breast, vs. prostate) and number of bone metastases (≤2 vs. > 2). All patients received supplemental Vitamin D and Calcium.
Seider 2018 reported about a total of 248 patients with follow-up information after one year: 52 patients (42%) in the zoledronate group and 49 (40%) in the zoledronate and radiopharmaceuticals arm experienced a SRE (HR 1.04, 95% CI 0.70 to 1.54).
After one year, Seider 2018 did not find a difference between the groups with respect to pain scores or quality of life measures. Seider 2018 reported that the radiopharmaceuticals were well tolerated.
Rhenium + docetaxel vs docetaxel
Van Dodewaard-de Jong (2017) randomised patients with progressive prostate cancer and bone metastases for first-line docetaxel 75 mg/m2 3-weekly plus prednisone with or without 2 injections of rhenium-188-HEDP after the third (40 MBq/kg) and after the sixth (20 MBq/kg) cycle of docetaxel. Primary endpoint was progression-free survival (PFS), defined as either PSA, radiographic or clinical progression. Patients were stratified by extent of bone metastases and hospital. Forty-two patients were randomised for standard treatment and 46 patients for combination therapy. Median follow-up was 18.4 months. In the intention to treat analysis no differences in survival and PSA became apparent between the two groups. In an exploratory per-protocol analysis median overall survival was significantly longer in the experimental group (34 months (95%CI 31.8 to 35.9)) than in the control group (21 months (95%CI 13.6 to 28.4); p 0.01).
No differences in VAS scores for pain assessment were seen, but the VAS-scores were already low at the start of the intervention.
3. One radionuclide compared to another
Strontium vs Rhenium
Sciuto (2001) randomized 50 breast cancer patients to either Sr-89 (25 patients) or Re-186 (25 patients). Pain response was similar in both groups. Median onset of pain relief was 21 days with Sr-89 and 4 days with Re-186. Performance status (Karnofsky score) was not different between the groups. No grade 3–4 hematological toxicity (WHO criteria) was seen.
Strontium vs Samarium
Baczyk (2007) randomized 100 patients (mixed population, of which 40 breast cancer patients) to either Sr-89 150 MBq/kg (50 patients) or Sm-153 37 MBq/kg (50 patients). Pain response was comparable between the groups: change from baseline for Sr-89 was -3 (-5 ± 2) and for Sm-153 -4 (-8 ± 2). In the Sr-89 group 25% had a VAS <2, in the Sm-153 group it was 40%. Performance status: change from baseline for Sr-89 was +10 (-20 ± 20) and for Sm-153 +20 (-30 ± 30). Toxicity data were not reported.
Sharma 2017 randomized 30 patients with breast/prostate cancer and skeletal metastases. Twenty patients were considered for treatment with 153Sm-EDTMP and with 177Lu-EDTMP in 10 patients, respectively. Using fixed dose of 37.0 MBq/kg body weight of each, the mean administered doses of 153Sm-EDTMP and 177Lu-EDTMP were 2,155.2 +/- 419.6 MBq (1,347-2,857) and 1,935.1 +/- 559.4 MBq (1,073-2,627), respectively. Reduction in pain scoring was assessed clinically over 8 weeks by using WHO criteria and correlated with the absorbed dose to the metastatic sites.
In 153Sm-EDTMP-treated patients, 16 (16/20) patients were responders and the remaining 4 patients were non-responders. In 177Lu-EDTMP patients, 8 (8/10) were responders and the remaining 2/10 were non-responders. The response rate for each radionuclide in terms of a significant reduction in pain score was evaluated as about 80.0%. A mild to severe toxicity was observed in one patient each treated with 153Sm-EDTMP and 177Lu-EDTMP, respectively. These findings suggest that either of the two therapeutic radiopharmaceuticals can be used safely.
4. Dosage studies
Samarium
Tian (1999) randomized 105 patients with bone metastases from various primary tumours between single doses of 37 MBq/kg (n=70) and 18.5 MBq/kg (n=35). The effects were evaluated according to change in daily analgesic consumption, pain score, sum of effect product (SEP), Physician’s Global Assessment (PGA), blood counts, and organ function tests conducted regularly for 16 weeks. Fifty-eight of 70 patients in group I and 30 of 35 in group II had a positive response, with SEPs of 22.29±14.47 and 20.13±13.90 respectively. Of 72 patients who had been receiving analgesics, 63 reduced their consumption. PGA showed that the Karnofsky score (KS) increased from 58.54±25.90 to 71.67±26.53, indicating improved general condition, but the difference was not significant. Response and side-effects were both independent of dose.
Resche (1997) randomized 114 patients with bone metastases from various primary tumours between 1.0 mCi/kg (37 MBq/kg, n=59) and 0.5 mCi/kg (18 MBq/kg, n=55). During the first 4 weeks after dose administration, there were statistically significant changes from baseline with the 1.0 mCi/kg dose but not with the 0.5 mCi/kg dose. The difference between doses in visual analogue pain scores was statistically significant at week 4 (P = 0.0476). Among subsets of patients examined, female patients with breast cancer receiving 1.0 mCi/kg had the most noticeable improvement. The physicians judged that approximately half of the patients in each dose group were experiencing some degree of pain relief by week 2. This value increased to 55% for the 0.5 mCi/kg group and 70% for the 1.0 mCi/kg group at week 4. More patients in the higher dose group (54%) than in the lower dose group (44%) completed the 16-week study. A predictable level of dose-related marrow suppression was the only toxicity associated with 153Sm-EDTMP treatment. Values for platelets and WBCs reached nadirs at 3 or 4 weeks with both doses and recovered by 8 weeks. Long-term follow-up revealed longer survival among breast cancer patients who had received the higher dose than among those who had received the lower dose. The results suggest that the 1.0 mCi/kg dose of 153Sm-EDTMP is safe and effective for the treatment of painful bone metastases.
Rhenium
Palmedo (2003) randomized 64 prostate cancer patients to either one or two injections (with an interval of 8 weeks) of Re-188. The effectiveness of Re-188 HEDP for pain palliation was better in the repeated treatment group (group B), with a response rate and time of response of 92% and 5.66 months, respectively (P = .006 and P = .001). In group B, 11 (39%) of 28 patients had a prostate-specific antigen decrease of more than 50% for at least 8 weeks, compared with two (7%) of 30 patients in the single-injection group (group A). The median times to progression of group A and group B were 2.3 months (range, 0 to 12.2 months) and 7.0 months (range, 0 to 24.1 months), respectively (P = .0013), and the median overall survival times were 7.0 months (range, 1.3 to 36.7 months) and 12.7 months (range, 4.1 to 32.2 months), respectively (P = .043). In both groups, toxicity was low, with moderate thrombopenia and leukopenia (maximum common toxicity criteria grade of 2).
177Lu-EDTMP
Agarwal 2015 included 44 patients with breast cancer (12 patients) or castration-resistant prostate cancer (32 patients) and skeletal metastases. Patients were randomized into two equal groups treated with 177Lu-EDTMP intravenously at a dose of 1,295 MBq (group A) or 2,590 MBq (group B). Pain palliation was evaluated using a visual analogue score (VAS), analgesic score (AS) and Karnofsky performance score (KPS) up to 16 weeks. The overall response rate (in all 44 patients) was 86 %. Complete, partial and minimal responses were seen in 6 patients (13 %), 21 patients (48 %) and 11 patients (25 %), respectively. A favourable response was seen in 27 patients (84 %) with prostate cancer and in 11 patients (92 %) with breast cancer. There was a progressive decrease in the VAS from baseline up to 4 weeks (p < 0.05). Also, AS decreased significantly from 1.8 ± 0.7 to 1.2 ± 0.9 (p < 0.0001). There was an improvement in quality of life of the patients as reflected by an increase in mean KPS from 56 ± 5 to 75 ± 7 (p < 0.0001). The overall response rate in group A was 77 % compared to 95 % in group B (p = 0.188). Nonserious haematological toxicity (grade I/II) was observed in 15 patients (34 %) and serious toxicity (grade III/IV) occurred in 10 patients (23 %). There was no statistically significant difference in haematological toxicity between the groups.
223-Radium
Parker (2013) prospectively evaluated the efficacy and safety of three different doses of
radium chloride (Ra 223) in patients with CRPC and bone metastases; 25 kBq/kg (n = 41), 50 kBq/kg (n = 39), or 80 kBq/kg (n = 42). Ra 223 had a dose-dependent effect on serum markers of CRPC activity.
The most common treatment-related AEs (≥10%) occurring up to week 24 across all dose groups were diarrhea (21%), nausea (16%), and anemia (14%). No difference in incidence of hematologic events was seen among dose groups. No notable between-group differences in nature or number of reported SREs occurred. The most frequent SREs (≥10% of patients in any dose group; n = 112) were pain increase (13%), analgesic consumption increase (18%), and external radiotherapy administration (11%).
Pain index data were available for 86 of 112 patients (77%) in the PP population, of whom 66 patients (77%) had baseline pain (ie, score ≥2 on BPI item 3). Percentage of pain responders did not significantly differ between groups and was approximately 50% (extracted from figure).
Discussion of findings
The evidence suggests comparable effects of beta-emitting radionuclides such as strontium-89, samarium 153m and rhenium-186. Time to pain response following samarium was shorter than after strontium.
Evidence with respect to alpha-emitting radionuclides (Radium-223) for pain reduction is scarce but suggests positive effects as well with regard to reduction in opioid use and need for external beam radiation. Also, some positive effects with regard to quality of life were found.
Several therapeutical bone seeking radionuclides have been compared or added to some form of chemotherapy, external radiotherapy or bisphosphonate therapy. No conclusions with regard to pain response or quality of life can be drawn from these studies because of great diversity in study set up and selected outcome parameters.
No added relevant side effects or negative outcome were observed in most studies.
Zoeken en selecteren
A systematic review of the literature was performed to answer the following question: What are the effects of bone seeking radionuclide therapy compared to placebo or another pain intervention on pain in patients with osteoblastic metastases?
P: patients with osteoblastic bone metastases
I: samarium-153, strontium-89, radium-223, rhenium-186/188, or treatment with other bone-seeking radionuclide (with or without another pain intervention)
C: placebo or other pain intervention (eg. pain medication, radiotherapy, chemotherapy), denosumab, bisphosphonates
O: pain, quality of life, bone marrow suppression (need for transfusion), fracture risk, skeletal related events (SRE: pathological fractures), need for surgery or radiotherapy, bone necrosis, jaw and dental problems, hypercalcemia, neurological complaints, neurological deficit, nausea, feeling full, overall survival
Relevant outcome measures
The guideline development group considered pain and quality of life as a critical outcome measure for decision making; and bone marrow suppression and fractures as an important outcome measure for decision making. Following international criteria (Chow 2012), a clinically important pain response was defined as:
- a decrease in the initial pain score by at least 2 points (on a Visual Analogue Scale (VAS) from 0-10), without analgesic increase
or
- an analgesic decrease of ≥25% without an increase in pain score.
The working group considered comparable effects on pain and quality of life (QoL) as clinically relevant when nuclear treatment was compared to another pain intervention, considering that the burden of the treatment itself is low and is associated with few complications/adverse effects.
Search and select (Methods)
The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms until 19th of July 2022. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 12111 hits. Because of the large number of hits the working group initially focused on systematic reviews. Studies were thus selected based on the following criteria:
- Systematic review;
- Includes patients with bone metastases;
- Intervention is nuclear treatment (samarium, strontium, radium, rhenium-188, or other);
- Comparator is placebo or another pain intervention (eg. Pain medication, radiotherapy, denosumab or bisphosphonates);
- Pain is operationalized as a score on a VAS or as analgesic use.
Sixteen systematic reviews were initially selected based on title and abstract screening. After reading the full text, six reviews were excluded (see the table with reasons for exclusion under the tab Methods), and ten review studies were included. Since the systematic reviews partly included the same RCTs and because of the heterogeneity of reporting of the results, it was decided to describe the RCTs individually.
Table of included studies
Reference SR (search date) |
Radionuclide |
Included studies |
Terrisse 2020 (Jun 2013) |
Several |
Oosterhof 2003, Tu 2001, Smeland 2003, Nilsson 2007, James 2016, Parker 2013 |
Hu 2020 (Mrt 2019) |
Strontium |
Wang 2013, Li 2018 |
Dizdarevic 2020 (Feb 2019) |
Radium |
Nilsson 2007, Nilsson 2012, Parker 2013, Sartor 2014, Sartor 2017, Parker 2017, Parker 2016, Hoskin 2014, Sartor 2016, Vogelzang 2017, Nilsson 2016, Parker 2018. |
Tassinari 2018 (Feb 2018)
|
Radium |
Parker 2013 |
Zacho 2017 (Apr 2015) |
Several |
Tian 1999 |
van Dodewaard-de Jong 2016 (Nov 2014) |
Several |
Oosterhof 2003, Quilty 1994, Lewington 1991, Buchali 1988, Baczyk 2013, Sartor 2004, Serafini 1998, Resche 1997, Han 2002, Palmedo 2003, Parker 2012, Nilsson 2012, Baczyk 2007 |
Hendriks 2016 (Jan 2015) |
Samarium |
Serafini 1998, Tian 1999 |
Tunio 2015 (Search date not reported) |
Several |
Porter 1993, Buchali 1988, Quilty 1994, Oosterhof 2003, Lewington 1991, Sartor 2004, Han 2002, Parker 2013, Sartor 2014 |
Christensen 2012 (Sept 2009) |
Several |
Resche 1997, Sciuto 2001, Baczyk 2007 |
Bauman 2005 (Jan 2004) |
Strontium |
Porter 1993, Smeland 2003, Oosterhof 2003, Quilty 1994, Buchali 1988, Sciuto 2001, Tu 2001, Lewington 1991 |
The working group considered radium, strontium, samarium and rhenium the most important. The search output was screened for additional RCTs studying strontium, samarium, rhenium or another radionuclide. Seven additional RCTs (Bilen 2015; Agarwal 2015; Heery 2018; Seider 2018; Sharma 2017; van Dodewaard-de Jong 2017; Van Winter 2022) were derived from the search results that were not included in one of the systematic reviews. Survival benefits (Overall survival, OS) were of secondary interest, but several studies were included because of additional results regarding pain and quality of life.
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- 23 - Palmedo H, Manka-Waluch A, Albers P, Schmidt-Wolf IG, Reinhardt M, Ezziddin S, Joe A, Roedel R, Fimmers R, Knapp FF Jr, Guhlke S, Biersack HJ. Repeated bone-targeted therapy for hormone-refractory prostate carcinoma: tandomized phase II trial with the new, high-energy radiopharmaceutical rhenium-188 hydroxyethylidenediphosphonate. J Clin Oncol. 2003 Aug 1;21(15):2869-75. doi: 10.1200/JCO.2003.12.060. PMID: 12885803.
- 24 - Parker CC, Coleman RE, Sartor O, Vogelzang NJ, Bottomley D, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, Chodacki A, Wiechno P, Logue J, Seke M, Widmark A, Johannessen DC, Hoskin P, James ND, Solberg A, Syndikus I, Kliment J, Wedel S, Boehmer S, Dall'Oglio M, Franzén L, Bruland ØS, Petrenciuc O, Staudacher K, Li R, Nilsson S. Three-year Safety of Radium-223 Dichloride in Patients with Castration-resistant Prostate Cancer and Symptomatic Bone Metastases from Phase 3 Randomized Alpharadin in Symptomatic Prostate Cancer Trial. Eur Urol. 2018 Mar;73(3):427-435. doi: 10.1016/j.eururo.2017.06.021. Epub 2017 Jul 11. PMID: 28705540.
- 25 - Parker C, Finkelstein SE, Michalski JM, O'Sullivan JM, Bruland Ø, Vogelzang NJ, Coleman RE, Nilsson S, Sartor O, Li R, Seger MA, Bottomley D. Efficacy and Safety of Radium-223 Dichloride in Symptomatic Castration-resistant Prostate Cancer Patients With or Without Baseline Opioid Use From the Phase 3 ALSYMPCA Trial. Eur Urol. 2016 Nov;70(5):875-883. doi: 10.1016/j.eururo.2016.06.002. Epub 2016 Jun 22. PMID: 27344296
- 26 - Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, Chodacki A, Wiechno P, Logue J, Seke M, Widmark A, Johannessen DC, Hoskin P, Bottomley D, James ND, Solberg A, Syndikus I, Kliment J, Wedel S, Boehmer S, Dall'Oglio M, Franzén L, Coleman R, Vogelzang NJ, O'Bryan-Tear CG, Staudacher K, Garcia-Vargas J, Shan M, Bruland ØS, Sartor O; ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013 Jul 18;369(3):213-23. doi: 10.1056/NEJMoa1213755. PMID: 23863050.
- 27 - Parker C, Zhan L, Cislo P, Reuning-Scherer J, Vogelzang NJ, Nilsson S, Sartor O, O'Sullivan JM, Coleman RE. Effect of radium-223 dichloride (Ra-223) on hospitalisation: An analysis from the phase 3 randomised Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial. Eur J Cancer. 2017 Jan;71:1-6. doi: 10.1016/j.ejca.2016.10.020. Epub 2016 Dec 6. PMID: 27930924.
- 28 - Porter AT, McEwan AJ, Powe JE, Reid R, McGowan DG, Lukka H, Sathyanarayana JR, Yakemchuk VN, Thomas GM, Erlich LE, et al. Results of a randomized phase-III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Int J Radiat Oncol Biol Phys. 1993 Apr 2;25(5):805-13. doi: 10.1016/0360-3016(93)90309-j. PMID: 8478230.
- 29 - Quilty PM, Kirk D, Bolger JJ, Dearnaley DP, Lewington VJ, Mason MD, Reed NS, Russell JM, Yardley J. A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer. Radiother Oncol. 1994 Apr;31(1):33-40. doi: 10.1016/0167-8140(94)90411-1. PMID: 7518932.
- 30 - Resche I, Chatal JF, Pecking A, Ell P, Duchesne G, Rubens R, Fogelman I, Houston S, Fauser A, Fischer M, Wilkins D. A dose-controlled study of 153Sm-ethylenediaminetetramethylenephosphonate (EDTMP) in the treatment of patients with painful bone metastases. Eur J Cancer. 1997 Sep;33(10):1583-91. doi: 10.1016/s0959-8049(97)00155-x. PMID: 9389919.
- 31 - Sartor O, de Bono J, Chi KN, Fizazi K, Herrmann K, Rahbar K, Tagawa ST, Nordquist LT, Vaishampayan N, El-Haddad G, Park CH, Beer TM, Armour A, Pérez-Contreras WJ, DeSilvio M, Kpamegan E, Gericke G, Messmann RA, Morris MJ, Krause BJ, for the VISION Investigators. Lutetium-177PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021;385:1091-1103 DOI: 10.1056/NEJMoa2107322.
- 32 - Sartor O, Coleman R, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, Chodacki A, Wiechno P, Logue J, Widmark A, Johannessen DC, Hoskin P, James ND, Solberg A, Syndikus I, Vogelzang NJ, O'Bryan-Tear CG, Shan M, Bruland ØS, Parker C. 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 Jun;15(7):738-46. doi: 10.1016/S1470-2045(14)70183-4. Epub 2014 May 13. PMID: 24836273.
- 33 - Sartor O, Coleman RE, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Vogelzang NJ, Bruland Ø, Kobina S, Wilhelm S, Xu L, Shan M, Kattan MW, Parker C. An exploratory analysis of alkaline phosphatase, lactate dehydrogenase, and prostate-specific antigen dynamics in the phase 3 ALSYMPCA trial with radium-223. Ann Oncol. 2017 May 1;28(5):1090-1097. doi: 10.1093/annonc/mdx044. PMID: 28453701.
- 34 - Sartor O, Hoskin P, Coleman RE, Nilsson S, Vogelzang NJ, Petrenciuc O, Staudacher K, Thuresson M, Parker C. Chemotherapy following radium-223 dichloride treatment in ALSYMPCA. Prostate. 2016 Jul;76(10):905-16. doi: 10.1002/pros.23180. Epub 2016 Mar 23. PMID: 27004570.
- 35 - Sartor O, Reid RH, Hoskin PJ, Quick DP, Ell PJ, Coleman RE, Kotler JA, Freeman LM, Olivier P; Quadramet 424Sm10/11 Study Group. Samarium-153-Lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer. Urology. 2004 May;63(5):940-5. doi: 10.1016/j.urology.2004.01.034. PMID: 15134985.
- 36 - Sciuto R, Festa A, Pasqualoni R, Semprebene A, Rea S, Bergomi S, Maini CL. Metastatic bone pain palliation with 89-Sr and 186-Re-HEDP in breast cancer patients. Breast Cancer Res Treat. 2001 Mar;66(2):101-9. doi: 10.1023/a:1010658522847. PMID: 11437096.
- 37 - Seider MJ, Pugh SL, Langer C, Wyatt G, Demas W, Rashtian A, Clausen CL, Derdel JD, Cleary SF, Peters CA, Ramalingam A, Clarkson JE, Tomblyn M, Rabinovitch RA, Kachnic LA, Berk LB; NRG Oncology. Randomized phase III trial to evaluate radiopharmaceuticals and zoledronic acid in the palliation of osteoblastic metastases from lung, breast, and prostate cancer: report of the NRG Oncology RTOG 0517 trial. Ann Nucl Med. 2018 Oct;32(8):553-560. doi: 10.1007/s12149-018-1278-4. Epub 2018 Aug 9. PMID: 30094545.
- 38 - Serafini AN, Houston SJ, Resche I, Quick DP, Grund FM, Ell PJ, Bertrand A, Ahmann FR, Orihuela E, Reid RH, Lerski RA, Collier BD, McKillop JH, Purnell GL, Pecking AP, Thomas FD, Harrison KA. Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial. J Clin Oncol. 1998 Apr;16(4):1574-81. doi: 10.1200/JCO.1998.16.4.1574. PMID: 9552068.
- 39 - Sharma 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' Pain Score Analysis and Personalized Dosimetry. Front Med (Lausanne). 2017 May 1:4:46. doi: 10.3389/fmed.2017.00046. eCollection 2017. PMID: 28507988 PMCID: PMC5410571.
- 40 - Smeland S, Erikstein B, Aas M, Skovlund E, Hess SL, Fosså SD. Role of strontium-89 as adjuvant to palliative external beam radiotherapy is questionable:resultsofadouble-blindrandomized study. Int J Radiat Oncol Biol Phys. 2003;56(5): 1397-1404. doi:10.1016/S0360-3016(03)00274-8. PMID: 12873686.
- 41 - Tassinari D, Cherubini C, Roudnas B, Tamburini E, Drudi F, Bianchi E, Fantini M, Montanari F, Sartori S. Treatment of Metastatic, Castration-resistant, Docetaxel-resistant Prostate Cancer: A Systematic Review of Literature With a Network Meta-analysis of Randomized Clinical Trials. Rev Recent Clin Trials. 2018;13(3):226-237. doi: 10.2174/1574887113666180404120540. PMID: 29623850.
- 42 - Terrisse S, Karamouza E, Parker CC, Sartor AO, James ND, Pirrie S, Collette L, Tombal BF, Chahoud J, Smeland S, Erikstein B, Pignon JP, Fizazi K, Le Teuff G; MORPHEP Collaborative Group. Overall Survival in Men With Bone Metastases From Castration-Resistant Prostate Cancer Treated With Bone-Targeting Radioisotopes: A Meta-analysis of Individual Patient Data From Randomized Clinical Trials. JAMA Oncol. 2020 Feb 1;6(2):206-216. doi: 10.1001/jamaoncol.2019.4097. PMID: 31830233.
- 43 - Tian JH, Zhang JM, Hou QT, Oyang QH, Wang JM, Luan ZS, Chuan L, He YJ. 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 Jan;26(1):2-7. doi: 10.1007/s002590050351. PMID: 9933654.
- 44 - Tu SM, Millikan RE, Mengistu B, Delpassand ES, Amato RJ, Pagliaro LC, Daliani D, Papandreou CN, Smith TL, Kim J, Podoloff DA, Logothetis CJ. Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial. Lancet. 2001 Feb 3;357(9253):336-41. doi: 10.1016/S0140-6736(00)03639-4. PMID: 11210994. Erratum in Lancet 2001 Apr 14;357(9263):1210.
- 45 - Tunio M, Al Asiri M, Al Hadab A, Bayoumi Y. Comparative efficacy, tolerability, and survival outcomes of various radiopharmaceuticals in castration-resistant prostate cancer with bone metastasis: a meta-analysis of randomized controlled trials. Drug Des Devel Ther. 2015 Sep 21;9:5291-9. doi: 10.2147/DDDT.S87304. eCollection 2015. PMID: 26451085.
- 46 - Vogelzang NJ, Coleman RE, Michalski JM, Nilsson S, O'Sullivan JM, Parker C, Widmark A, Thuresson M, Xu L, Germino J, Sartor O. Hematologic Safety of Radium-223 Dichloride: Baseline Prognostic Factors Associated With Myelosuppression in the ALSYMPCA Trial. Clin Genitourin Cancer. 2017 Feb;15(1):42-52.e8. doi: 10.1016/j.clgc.2016.07.027. Epub 2016 Aug 8. PMID: 27613490.
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Evidence tabellen
Evidence tables
RCTs not included in a systematic review
Research question: What are the effects of radionuclide therapy compared to placebo or another pain intervention on pain in patients with osteoblastic metastases?
Study reference |
Study characteristics |
Patient characteristics 2 |
Intervention (I) |
Comparison / control (C) 3
|
Follow-up |
Outcome measures and effect size 4 |
Comments |
Bilen, 2015 |
Type of study: Multicenter randomized phase II study (Strontium)
Setting and country: Advanced castrate-sensitive prostate cancer
USA
Funding and conflicts of interest: This study was conducted as a collaborative trial of the MD Anderson Cancer Center Community Clinical Oncology Program Research Base and MD Anderson Cancer Center. The study was supported in part by NCI grant U10 CA045809. MD Anderson is supported in part by the National Institutes of Health through Cancer Center Support Grant, CA016672
The authors made no disclosures. |
Inclusion criteria:
Exclusion criteria:
N total at baseline: Intervention: 39 Control: 40
Important prognostic factors2: Age, range (median): I: 46-77 (62) C:46-82 (63)
Groups comparable at baseline? Yes
|
Standard therapy:
+
1 dose of Sr-89 (4 mCi total dose) administered intravenously on the first day of treatment
|
Standard therapy:
+
no Sr-89 |
Length of follow-up: Median follow-up for the patients alive at the last follow-up: 76.9 (range: 0.07 – 103.4 months)
Loss-to-follow-up: Intervention: 2 (5.1%) Reason: not described
Control: 1 (2.5%) Reason: not described
Incomplete outcome data: Intervention: None
Control: 4 (10%) Reasons: Myelosuppression prior to treatment (n=1)
|
Outcome measures and effect size (include 95%CI and p-value if available):
Pain Not reported
Treatment-related toxicity (Grade 3 or 4) C: 3 (7.5%) I: 3 (7.6%)
Quality of life Not reported |
|
Agarwal, 2015 |
Type of study: Randomized phase II study
Setting and country: Palliation of pain from bone metastases in patients with prostate and breast cancer
India (Mumbai)
Funding and conflicts of interest: No funding received from any organization for this study. The authors declare no conflict of interest. |
Inclusion criteria:
Exclusion criteria:
N total at baseline: Intervention: 22 Control: 22
Important prognostic factors2: Age, mean (SD): I: 61 (14) C:60 (13)
Primary (prostate/breast), n I: 17/5 C: 15/7
Groups comparable at baseline? Yes
|
Group A received a low dose (1,295 MBq).
|
Group B received a high dose (2,590 MBq) |
Length of follow-up: 16 weeks
Loss-to-follow-up: Not reported
Incomplete outcome data: Not reported
|
Outcome measures and effect size (include 95%CI and p-value if available):
Pain VAS decrease* (mean, SD) I: Baseline: 6.5 (1.6) 16 weeks: 3.8 (2.1) P<0.001 C: Baseline:: 7.0 (1.3) 16 weeks:3.3 (1.2) P<0.001
No group differences (p value not reported)
Quality of life Karnofsky performance score (mean, SD) I: Baseline: 56.5 (5) 16 weeks: 73 (9) P<0.001
C: Baseline: 57 (5) 16 weeks: 76 (5) P<0.001
No group differences (p=0.498) |
Pain relief was assessed in terms of changes in the average baseline VAS in comparison with the average VAS at 1, 2, 4, 6, 8, 12 and 16 weeks after injection.
*The VAS in 32 prostate cancer patients decreased from 6.9±1.5 to 3.4±1.8. Similarly, the VAS in 12 breast cancer patients decreased from 6.5±1.1 to 3.7±1.3.
|
Heery, 2018 |
Type of study: Randomized phase III study
Setting and country: Palliation of osteoblastic metastases from lung, breast, and prostate cancer USA
Funding and conflicts of interest: This project was supported by RTOG grant U10 CA21661 and CCOP grant U10 CA37422 from the National Cancer Institute (NCI). Additional support was provided by Novartis. Conflicts of interest not reported. |
Inclusion criteria:
Exclusion criteria:
N total at baseline: Intervention: 22 Control: 22
Important prognostic factors2: Age, mean (range): I: 69.2 (52-86) C:64.5 (50-80) Groups comparable at baseline? Yes
|
Sm-153-EDTMP plus vaccine
|
Sm-153-EDTMP |
Length of follow-up: Not reported
Loss-to-follow-up: Not reported
Incomplete outcome data: Intervention: 1 (4.%) Reasons: Did not progress, refused further treatment on day 70 due to toxicity (n=1)
Control: 4 (18.2%) Reasons: Refused treatment after randomization (n=3) Did not progress,, refused further treatment on day 70 due to toxicity (n=1)
|
Outcome measures and effect size (include 95%CI and p-value if available):
Pain Subjects requiring narcotic pain: I: 8/22 (36%) C: 11/19 (58%) P=0.22
Quality of life Not reported |
Although the trial was designed to enroll 68 patients, the study was ended early due to poor accrual.
|
Seider, 2018 |
Type of study: Randomized phase III study
Setting and country: Metastatic castration-resistant prostate cancer
USA
Funding and conflicts of interest: Funding for this study was provided through the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health, and the Cancer Therapy Evaluation Program (CTEP), National Cancer Institute, National Institutes of Health. The authors declare no conflict of interest. |
Inclusion criteria:
Exclusion criteria:
N total at baseline: Intervention: 132 Control: 129
Important prognostic factors2: Age, median (range): I: 68 (32-90) C:67.5 (25-88)
Primary disease: Breast/Lung/Prostate I: 44/12/68 C: 42/14/68
Groups comparable at baseline? Yes
|
Standard therapy: Patients received ZA 4 mg IV monthly |
Standard therapy:
|
Length of follow-up: Not reported
Loss-to-follow-up: Not reported
Incomplete outcome data: Intervention: 8 (6.1%) Reasons: Invalid bone scan date (n=3) Unstable bone metastases (n=2) Dental disease (n=1) Institution registration error (n=1) Radiation out of time frame (n=1)
Control: 5 (3.9%) Reasons: Invalid bone scan date (n=2) ANC levels (n=2) Unstable bone metastases (n=1)
|
Outcome measures and effect size (include 95%CI and p-value if available):
Pain & Quality of life* No quantitative data was presented
Description of the author: “The addition of radiopharmaceuticals to ZA led to a significant reduction in pain at one month based on BPI* worst score (p=0.02). No other group differences were noted for QOL or toxicity.”
*Brief Pain Inventory |
*Differences in QOL and pain control between treatment arms were examined using the mean FACT-G scores (total score as well as the four subscale scores) and mean BPI score from baseline to each follow-up assessment time. |
Sharma, 2017 |
Type of study: Randomized study
Setting and country: Pain palliation in patients with skeletal metastases (breast/prostate cancer)
India
Funding and conflicts of interest: Funding not reported
The authors declare no conflict of interest. |
Inclusion criteria:
Exclusion criteria:
N total at baseline: Intervention: 20 Control: 10
Important prognostic factors2: Demographic characteristics were not reported/stratified for both groups. Thirty patients (25 M:5 F, mean age: 66.0 ± 14.7 years) of breast/ prostate cancer with documented skeletal metastases were recruited.
Primary disease was not stratified for both groups.
Groups comparable at baseline? Unable to make a judgement.
|
153Sm-EDTMP Radiopharmaceuticals were given at a dose of 37.0 MBq / kg body weight in both groups |
177Lu-EDTMP Radiopharmaceuticals were given at a dose of 37.0 MBq / kg body weight in both groups |
Length of follow-up: 8 weeks
Loss-to-follow-up: Not reported
Incomplete outcome data: Not reported
|
Outcome measures and effect size (include 95%CI and p-value if available):
Pain* Responders I: 16/20 (80%) C: 8/10 (80%)
Pain change (8 weeks from baseline) I: 1.31 ± 0.48 C: 1.63 ± 0.52
Quality of life Not reported |
*The therapeutic efficacy of each of the two radionuclides at post-therapy periods of 1, 3, 6, and 8 weeks was evaluated by using WHO-standard pain scoring assessment criteria. Based upon this assessment, the response was labelled as (a) complete response when the pain score was <3.0, (b) partial response when the pain score ranged between 4 and 8, and (c) no response when the pain score was >8.0 and had no change from baseline score.
|
Van Dodewaard-de Jong , 2018 |
Type of study: Randomized phase II study
Setting and country: Castration-resistant prostate cancer (CRPC) metastatic to bone
The Netherlands
Funding and conflicts of interest: Funding for this study was provided by KWF kankerbestrijding with. The authors transparently provided their conflict of interests. |
Inclusion criteria:
Exclusion criteria:
N total at baseline: Intervention: 46 Control: 42
Important prognostic factors2: Age, median (range): I: 70.5 (54.1-84.9) C:71.4 (64.1-84.9)
Groups comparable at baseline? Yes
|
Docetaxel and rhenium-188-HED |
Docetaxel |
Length of follow-up: Median follow-up 18.4 months
Loss-to-follow-up: Not reported
Incomplete outcome data: Eight patients in the experimental group did not receive rhenium-188-HEDP at all, whereas in the standard group three patients dropped out before the fourth cycle of docetaxel.
.
|
Outcome measures and effect size (include 95%CI and p-value if available):
Pain & Quality of life* Data was visualised with box plots
“At baseline, VAS-scores for pain assessment were available for 83 patients. After five cycles data on pain were available for 64 patients (31 in the control group and 34 in the experimental group) and after 10 cycles only for 43 patients (20 in the control group and 23 in the experimental group). In both groups median VAS-scores were already low”
“There was no significant change in global quality of life during the whole treatment period.” |
*Patients completed a visual analogue scale (VAS) pain assessment and the EORTC-Quality of Life Questionnaire-30 before each treatment cycle until disease progression |
Van Winter, 2022 |
Type of study: Randomized phase IB and IIA study
Setting and country: Breast cancer patients with bone metastases
UK
Funding and conflicts of interest: The study was funded by Bayer Healthcare, supported by Yorkshire Cancer Research (YCR) through the YCR Centre for Early Phase Clinical Trials, and sponsored by the University of Sheffield. Additional support was also provided by the National Institute for Health Research (NIHR) through the use of the Clinical Research Network (CRN).
The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report
The authors transparently provided their conflict of interests. |
Inclusion criteria:
denosumab for ≥ 6 weeks;
Exclusion criteria:
N total at baseline: Intervention: 25 Control: 6
Important prognostic factors2: Age, median (range): I: 58 (34-75) C:55 (45-85)
Groups comparable at baseline? Yes
|
Capecitabine + Ra223 |
Capecitabine |
Length of follow-up: Median follow-up, months I: 11.5 (3.4-23.3) C: 13.5 (3.4-21.1)
Loss-to-follow-up & incompete outcome data: I: 15/23 (65.2%) Reasons: Disease progression (n=13) Intolerability due to toxicities (n=2)
C: -
|
Outcome measures and effect size (include 95%CI and p-value if available):
Pain
Quality of life QLQ-C30 at end of cyclus 6* I: 82.1 (79.2-85.1) C: 67.6 (55.6-79.7)
“The mean QLQ-C30 global health status was similar between the arms at baseline and end of study visit, but slightly increased in the capecitabine alone arm at cycle 6 (mean [95% CI]: 67.6 [55.6–79.7] combination arm and 82.1 [79.2–85.1] capecitabine alone arm), although numbers are small (combination = 17 capecitabine alone = 7).” |
*Baseline QLQ-C30 global health status was not reported. |
Notes:
- Prognostic balance between treatment groups is usually guaranteed in randomized studies, but non-randomized (observational) studies require matching of patients between treatment groups (case-control studies) or multivariate adjustment for prognostic factors (confounders) (cohort studies); the evidence table should contain sufficient details on these procedures
- Provide data per treatment group on the most important prognostic factors [(potential) confounders]
- For case-control studies, provide sufficient detail on the procedure used to match cases and controls
- For cohort studies, provide sufficient detail on the (multivariate) analyses used to adjust for (potential) confounders
Risk of bias table
RCTs not included in a systematic review
Research question: What are the effects of radionuclide therapy compared to placebo or another pain intervention on pain in patients with osteoblastic metastases?
Study reference
(first author, publication year) |
Was the allocation sequence adequately generated?
Definitely yes Probably yes Probably no Definitely no |
Was the allocation adequately concealed?
Definitely yes Probably yes Probably no Definitely no |
Blinding: Was knowledge of the allocated interventions adequately prevented?
Were patients blinded?
Were healthcare providers blinded?
Were data collectors blinded?
Were outcome assessors blinded?
Were data analysts blinded?
Definitely yes Probably yes Probably no Definitely no |
Was loss to follow-up (missing outcome data) infrequent?
Definitely yes Probably yes Probably no Definitely no |
Are reports of the study free of selective outcome reporting?
Definitely yes Probably yes Probably no Definitely no |
Was the study apparently free of other problems that could put it at a risk of bias?
Definitely yes Probably yes Probably no Definitely no |
Overall risk of bias If applicable/necessary, per outcome measure
LOW Some concerns HIGH
|
Bilen, 2015 |
Probably no; Reason: Study-eligible patients were randomized immediately upon entry to the trial |
Probably no; Reason: Study-eligible patients were randomized immediately upon entry to the trial to receive either (sequentially numbered) |
Definitely no;
Reason: Open-label trial |
Probably yes;
Reason: Loss to follow-up was infrequent in intervention and control group. |
Definitely yes;
Reason: All relevant outcomes were reported |
Definitely yes;
Reason: No other problems noted |
Some concerns |
Agarwal, 2014 |
Probably no; Reason: Patients were randomly assigned to two groups based on administered radioactivity. |
Probably no; Reason: Patients were randomly assigned to two groups based on administered radioactivity (sequentially numbered). |
Definitely no;
Reason: Open-label trial. |
Probably yes;
Reason: Loss to follow-up was not reported. |
Definitely yes;
Reason: All relevant outcomes were reported. |
Definitely yes;
Reason: No other problems noted. |
Some concerns |
Heery, 2016 |
Definitely yes;
Reason: Patients were randomized centrally, without stratification, using a locally-written SAS software program to generate a random 1:1 sequence of assignments to treatment, using variable block sizes (2 or 4).
|
Probably yes
Reason: Central allocation. |
Definitely no;
Reason: Open-label trial. |
Probably no
Reason: Loss to follow-up was higher in the control group. |
Definitely yes;
Reason: All relevant outcomes were reported. |
Definitely no;
Reason: Although the trial was designed to enroll 68 patients, the study was ended early due to poor accrual.
|
HIGH
|
Seider, 2018 |
Definitely yes;
Reason: Patients were stratified by site of primary cancer (lung vs. breast, vs. prostate) and number of bone mets (≤2 vs. > 2) and randomized 1:1 using a treatment allocation scheme. |
Probably yes
Reason: Central allocation. |
Definitely no;
Reason: Open-label trial. |
Probably no;
Reason: Loss to follow-up was not reported |
Probably yes;
Reason: All relevant outcomes were reported.
|
Probably yes;
Reason: The patient population in this study was somewhat different from previous trials in that blastic metastases from three different primary disease sites (prostate, breast and lung) were included.
The secondary outcomes were not quantitively reported. |
HIGH |
Sharma, 2017 |
Definitely no;
Reason: Randomization method not described. |
Definitely no:
Reason: Allocation was based on open random allocation schedule. |
Probably no;
Reason: Only patients were blinded to treatment. |
Probably no;
Reason: Loss to follow-up was not reported. |
Definitely yes;
Reason: All relevant outcomes were reported. |
Probably no;
Reason: Demographics were not reported, funding was not reported. |
HIGH |
van Dodewaard-de Jong, 2018 |
Definitely no;
Reason: Randomization method not described. |
Definitely no:
Reason: Patients were centrally randomly assigned. |
Definitely no;
Reason: Open-label trial. |
Probably no;
Reason: Loss to follow-up was infrequent. A high percentage in the experimental group did not receive the treatment at all. |
Definitely yes;
Reason: All relevant outcomes were reported. |
Probably no;
Reason: The outcomes pain and quality of life were not reported quantitively. |
HIGH |
Winter, 2022 |
Probably yes;
Reason: Participants were randomised 2:1 to the combination and single agent capecitabine using the CTRU 9-to-5 randomisation service, via permuted blocks. |
Definitely no:
Reason: Patients were allocated via permuted blocks. |
Definitely no;
Reason: Open-label trial. |
Definitely no;
Reason: A high percentage in the experimental group were lost-to-follow up due to disease progression or toxicities. |
Probably yes;
Reason: All relevant outcomes were reported, but no baseline values of quality of life were reported. |
Probably no;
Reason: The baseline values of quality of life were not reported quantitively. |
HIGH |
Table of excluded studies
Excluded SR |
Reason for exclusion |
Nuhn P, De Bono JS, Fizazi K, Freedland SJ, Grilli M, Kantoff PW, Sonpavde G, Sternberg CN, Yegnasubramanian S, Antonarakis ES. Update on Systemic Prostate Cancer Therapies: Management of Metastatic Castration-resistant Prostate Cancer in the Era of Precision Oncology. Eur Urol. 2019 Jan;75(1):88-99. doi: 10.1016/j.eururo.2018.03.028. Epub 2018 Apr 16. PMID: 29673712 |
No systematic review |
Unda-Urzaiz M, Sousa-Campo R, Rodríguez-Antolín A, Silva-Marins C, Juárez-Soto A, Miñana-López B, Figueiredo-de Castro A, Cozar-Olmos JM. Radium-223 in the therapeutic sequence of metastatic castration-resistant prostate cancer. Actas Urol Esp (Engl Ed). 2018 May;42(4):227-237. doi: 10.1016/j.acuro.2017.05.005. Epub 2017 Jul 12. PMID: 28711312 |
No systematic review |
Pang X, Zhou L, Niu S, Sun R, Chen Y, Xu L, Li S. Efficacy and safety of strontium chloride for bone metastases from prostate cancer: A systematic review. |
Chinese language |
Humm JL, Sartor O, Parker C, Bruland OS, Macklis R. Radium-223 in the treatment of osteoblastic metastases: a critical clinical review. Int J Radiat Oncol Biol Phys. 2015 Apr 1;91(5):898-906. doi: 10.1016/j.ijrobp.2014.12.061. PMID: 25832684. |
No systematic review |
Ryan CJ, Saylor PJ, Everly JJ, Sartor O. Bone-targeting radiopharmaceuticals for the treatment of bone-metastatic castration-resistant prostate cancer: exploring the implications of new data. Oncologist. 2014 Oct;19(10):1012-8. doi: 10.1634/theoncologist.2013-0472. Epub 2014 Sep 17. PMID: 25232039 PMCID: PMC4200991 |
No systematic review |
D'angelo G, Sciuto R, Salvatori M, Sperduti I, Mantini G, Maini CL, Mariani G. Targeted "bone-seeking" radiopharmaceuticals for palliative treatment of bone metastases: a systematic review and meta-analysis. Q J Nucl Med Mol Imaging. 2012 Dec;56(6):538-43. PMID: 23358407 |
Unclear reporting of incuded studies |
Excluded RCT |
|
Heery CR, Madan RA, Stein MN, Stadler WM, Di Paola RS, Rauckhorst M, Steinberg SM, Marté JL, Chen CC, Grenga I, Donahue RN, Jochems C, Dahut WL, Schlom J, Gulley JL. Samarium-153-EDTMP (Quadramet®) with or without vaccine in metastatic castration-resistant prostate cancer: A randomized Phase 2 trial. Oncotarget. 2016 Oct 18;7(42):69014-69023. doi: 10.18632/oncotarget.10883. PMID: 27486817 |
Wrong comparison |
Baczyk M, Milecki P, Pisarek M, Gut P, Antczak A, Hrab M. A prospective randomized trial: a comparison of the analgesic effect and toxicity of 153Sm radioisotope treatment in monotherapy and combined therapy including local external beam radiotherapy (EBRT) among metastatic castrate resistance prostate cancer (mCRPC) patients with painful bone metastases. Neoplasma. 2013;60(3):328-33. doi: 10.4149/neo_2013_044. PMID: 23374004 |
Wrong comparison |
Wang F, Chen W, Chen H, Mo L, Jin H, Yu Z, Li C, Liu Q, Duan F, Weng Z. Comparison between zoledronic acid and clodronate in the treatment of prostate cancer patients with bone metastases. Med Oncol. 2013;30(3):657. doi: 10.1007/s12032-013-0657-x. Epub 2013 Jul 18. PMID: 23864249 |
Wrong comparison |
Lewington VJ, McEwan AJ, Ackery DM, Bayly RJ, Keeling DH, Macleod PM, Porter AT, Zivanovic MA. A prospective, randomised double-blind crossover study to examine the efficacy of strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to bone. Eur J Cancer. 1991;27(8):954-8. doi: 10.1016/0277-5379(91)90257-e. PMID: 1716935 |
Wrong outcome measurement instrument |
Verantwoording
Autorisatiedatum en geldigheid
Laatst beoordeeld : 10-10-2024
Laatst geautoriseerd : 10-10-2024
Geplande herbeoordeling : 10-10-2029
Algemene gegevens
De ontwikkeling/herziening van deze richtlijnmodule werd ondersteund door het Kennisinstituut van de Federatie Medisch Specialisten (www.demedischspecialist.nl/kennisinstituut) en werd gefinancierd uit de Kwaliteitsgelden Medisch Specialisten (SKMS). De financier heeft geen enkele invloed gehad op de inhoud van de richtlijnmodule.
Samenstelling werkgroep
Het initiatief voor deze richtlijn is afkomstig van Nederlandse Orthopaedische Vereniging (NOV). De richtlijn is opgesteld door een multidisciplinaire commissie met vertegenwoordigers vanuit de orthopedisch chirurgen, radiotherapeuten, radiologen, nucleair geneeskundigen, internist-oncologen, en chirurgen/traumatologen.
Het perspectief van patiënten werd ingebracht door een vertegenwoordiger van de Nederlandse Federatie van Kankerpatiëntenorganisaties (NFK) samen met een aantal patiënten. Zie hiervoor ook de samenstelling van de werkgroep.
Werkgroep
- Dr. J.J.W. Ploegmakers, orthopedisch chirurg, Universitair Medisch Centrum Groningen, NOV (voorzitter)
- Dr. P.G. Westhoff, radiotherapeut-oncoloog, Radboud UMC Nijmegen, NVRO (vice-voorzitter)
- Dr. E.F. Dierselhuis, orthopedisch chirurg, Radboud UMC Nijmegen, NOV
- Drs. B. Meesters, traumachirurg, Zuyderland Medisch Centrum, NVVH NVT
- Dr. C.S.P. van Rijswijk, interventieradioloog, Leids Universitair Medisch Centrum, NVVR
- Dr. F. Intema, nucleair geneeskundige, Rijnstate Ziekenhuis, NVNG
- Prof. Dr. Y.M. van der Linden, radiotherapeut-oncoloog, Leids Universitair Medisch Centrum, NVRO
- Dr. mr. J.J. de Haan, internist-oncoloog, Universitair Medisch Centrum Groningen, NIV
- W. van der Veen, namens Borstkankervereniging Nederland (BVN) (tot juni 2023)
- E. Walrave, namens Longkanker Nederland (tot januari 2022)
- J. Rijlaarsdam, namens Longkanker Nederland (van februari 2022 tot september 2022)
- Dr. K.M. Holtzer, Nederlandse Federatie van Kankerpatiëntenorganisaties (vanaf september 2022)
Met ondersteuning van
- Dr. M.A. Pols, senior adviseur, Kennisinstituut van de Federatie Medisch Specialisten
- Drs M. Oerbekke, adviseur, Kennisinstituut van de Federatie Medisch Specialisten (tot september 2022)
- Dr. J. Boschman, senior adviseur (vanaf september 2022)
- I. van Dusseldorp, senior informatiespecialist, Kennisinstituut van de Federatie Medisch Specialisten
Wilma van der Veen heeft namens de NFK/BVN een waardevolle bijdrage geleverd aan de totstandkoming van deze richtlijnmodules. Helaas heeft zij de afronding van de richtlijn niet meer mee mogen maken. De werkgroep is Wilma dankbaar voor de prettige en open samenwerking en heeft bewondering voor de manier waarop zij zich heeft ingezet voor huidige en toekomstige patiënten.
Belangenverklaringen
De Code ter voorkoming van oneigenlijke beïnvloeding door belangenverstrengeling is gevolgd. Alle werkgroepleden hebben schriftelijk verklaard of zij in de laatste drie jaar directe financiële belangen (betrekking bij een commercieel bedrijf, persoonlijke financiële belangen, onderzoeksfinanciering) of indirecte belangen (persoonlijke relaties, reputatiemanagement) hebben gehad. Gedurende de ontwikkeling of herziening van een module worden wijzigingen in belangen aan de voorzitter doorgegeven. De belangenverklaring wordt opnieuw bevestigd tijdens de commentaarfase.
Een overzicht van de belangen van werkgroepleden en het oordeel over het omgaan met eventuele belangen vindt u in onderstaande tabel. De ondertekende belangenverklaringen zijn op te vragen bij het secretariaat van het Kennisinstituut van de Federatie Medisch Specialisten.
Werkgroeplid |
Functie |
Nevenfuncties |
Gemelde belangen |
Ondernomen actie |
E. Dierselhuis
|
Orthopedisch chirurg |
Opleidingscommissie Nederlandse Orthopedische Vereniging (onbetaald) |
Betrokken bij onderzoek naar BOS-score (niet commercieel)
|
Geen restricties |
J. de Haan
|
Internist-oncoloog |
Geen |
Betrokken bij onderzoek van Astellas, Boehringer, Cogent, Incyte, Inhibrx, Zentalis, Zymeworks (geen relatie met onderwerp richtlijn, geen persoonlijke vergoeding) |
Geen restricties |
F. Intema |
Nucleair geneeskundige |
Geen |
Geen |
Geen restricties |
Y. van der Linden
|
Radiotherapeut-oncoloog. Hoofd expertisecentrum palliatieve zorg. |
Course director ESTRO cursus Palliative Care and Radiotherapy |
Betrokken bij onderzoek naar BOS-score (niet commercieel) AlpduZes UL 2013-6286 OPTIMAL study |
Geen restricties |
B. Meesters
|
Traumachirurg |
Bestuurslid Nederlandse Vereniging voor Trauma Chirurgie |
Geen |
Geen restricties |
J. Ploegmakers |
Orthopedisch chirurg |
Geen |
Stryker, 3M: honorarium dienstverlening (2020, 2021, geen relatie met onderwerp richtlijn)
|
Geen restricties |
J. Rijlaarsdam
|
Panellid Longkanker Nederland. Onbezoldigd |
Geen |
Geen |
Geen restricties |
C. van Rijswijk |
Interventieradioloog |
Geen |
PI van FLOW-project (met Philips): geen relatie met botmetastasen. W.L. Gore & Associates: honorarium dienstverlening (2021, 2022, geen relatie met onderwerp richtlijn Cordis Netherlands: honorarium dienstverlening (2022, geen relatie met onderwerp richtlijn) |
Geen restricties |
W. van der Veen |
Patient advocate Borstkankervereniging Nederland, onbetaald |
Vrijwilliger Abrona, dagbesteding, onbetaald |
Geen |
Geen restricties |
P. Westhoff |
Radiotherapeut-oncoloog |
Geen |
Betrokken bij onderzoek naar BOS-score (niet commercieel) |
Geen restricties |
Inbreng patiëntenperspectief
Er werd aandacht besteed aan het patiëntenperspectief door deelname in de werkgroep van vertegenwoordigers vanuit patiëntenverenigingen en van de Nederlandse Federatie van Kankerpatiëntenorganisaties. De vertegenwoordigers zijn betrokken bij het opstellen van de uitgangsvragen, de keuze voor de uitkomstmaten en bij het opstellen van de overwegingen en aanbevelingen. De conceptrichtlijn is tevens voor commentaar voorgelegd aan betrokken patiëntenverenigingen en de eventueel aangeleverde commentaren zijn besproken en verwerkt.
Kwalitatieve raming van mogelijke financiële gevolgen in het kader van de Wkkgz
Bij de richtlijn is conform de Wet kwaliteit, klachten en geschillen zorg (Wkkgz) een kwalitatieve raming uitgevoerd om te beoordelen of de aanbevelingen mogelijk leiden tot substantiële financiële gevolgen. Bij het uitvoeren van deze beoordeling is de richtlijnmodule op verschillende domeinen getoetst (zie het stroomschema op de Richtlijnendatabase).
Module |
Uitkomst raming |
Toelichting |
Module Nucleaire behandeling |
Geen financiële gevolgen |
Uit de toetsing volgt dat de aanbeveling(en) niet breed toepasbaar zijn (<5.000 patiënten) en daarom naar verwachting geen substantiële financiële gevolgen zal hebben voor de collectieve uitgaven. |
Werkwijze
AGREE
Deze richtlijn is opgesteld conform de eisen vermeld in het rapport Medisch Specialistische Richtlijnen 2.0 van de adviescommissie Richtlijnen van de Raad Kwaliteit. Dit rapport is gebaseerd op het AGREE II instrument (Appraisal of Guidelines for Research & Evaluation II; Brouwers, 2010).
Knelpuntenanalyse en uitgangsvragen
Tijdens de voorbereidende fase inventariseerde de werkgroep de knelpunten in de zorg voor patiënten met botmetastasen door middel van een schriftelijke knelpuntenanalyse. De werkgroep beoordeelde de aanbeveling(en) uit de eerdere richtlijn Botmetastasen (IKNL, 2010) op noodzaak tot revisie. Tevens zijn er knelpunten aangedragen door de NVRO, IGJ, KNGF, NVKF, NVRO, NVKG. Een verslag hiervan is opgenomen onder aanverwante producten.
Op basis van de uitkomsten van de knelpuntenanalyse zijn door de werkgroep concept-uitgangsvragen opgesteld en definitief vastgesteld.
Uitkomstmaten
Na het opstellen van de zoekvraag behorende bij de uitgangsvraag inventariseerde de werkgroep welke uitkomstmaten voor de patiënt relevant zijn, waarbij zowel naar gewenste als ongewenste effecten werd gekeken. Hierbij werd een maximum van acht uitkomstmaten gehanteerd. De werkgroep waardeerde deze uitkomstmaten volgens hun relatieve belang bij de besluitvorming rondom aanbevelingen, als cruciaal (kritiek voor de besluitvorming), belangrijk (maar niet cruciaal) en onbelangrijk. Tevens definieerde de werkgroep tenminste voor de cruciale uitkomstmaten welke verschillen zij klinisch (patiënt) relevant vonden.
Methode literatuursamenvatting
Een uitgebreide beschrijving van de strategie voor zoeken en selecteren van literatuur is te vinden onder ‘Zoeken en selecteren’ onder Onderbouwing. Indien mogelijk werd de data uit verschillende studies gepoold in een random-effects model. Review Manager 5.4 werd gebruikt voor de statistische analyses. De beoordeling van de kracht van het wetenschappelijke bewijs wordt hieronder toegelicht.
Beoordelen van de kracht van het wetenschappelijke bewijs
De kracht van het wetenschappelijke bewijs werd bepaald volgens de GRADE-methode. GRADE staat voor ‘Grading Recommendations Assessment, Development and Evaluation’ (zie http://www.gradeworkinggroup.org/). De basisprincipes van de GRADE-methodiek zijn: het benoemen en prioriteren van de klinisch (patiënt) relevante uitkomstmaten, een systematische review per uitkomstmaat, en een beoordeling van de bewijskracht per uitkomstmaat op basis van de acht GRADE-domeinen (domeinen voor downgraden: risk of bias, inconsistentie, indirectheid, imprecisie, en publicatiebias; domeinen voor upgraden: dosis-effect relatie, groot effect, en residuele plausibele confounding).
GRADE onderscheidt vier gradaties voor de kwaliteit van het wetenschappelijk bewijs: hoog, redelijk, laag en zeer laag. Deze gradaties verwijzen naar de mate van zekerheid die er bestaat over de literatuurconclusie, in het bijzonder de mate van zekerheid dat de literatuurconclusie de aanbeveling adequaat ondersteunt (Schünemann, 2013; Hultcrantz, 2017).
GRADE |
Definitie |
Hoog |
|
Redelijk |
|
Laag |
|
Zeer laag |
|
Bij het beoordelen (graderen) van de kracht van het wetenschappelijk bewijs in richtlijnen volgens de GRADE-methodiek spelen grenzen voor klinische besluitvorming een belangrijke rol (Hultcrantz, 2017). Dit zijn de grenzen die bij overschrijding aanleiding zouden geven tot een aanpassing van de aanbeveling. Om de grenzen voor klinische besluitvorming te bepalen moeten alle relevante uitkomstmaten en overwegingen worden meegewogen. De grenzen voor klinische besluitvorming zijn daarmee niet één op één vergelijkbaar met het minimaal klinisch relevant verschil (Minimal Clinically Important Difference, MCID). Met name in situaties waarin een interventie geen belangrijke nadelen heeft en de kosten relatief laag zijn, kan de grens voor klinische besluitvorming met betrekking tot de effectiviteit van de interventie bij een lagere waarde (dichter bij het nuleffect) liggen dan de MCID (Hultcrantz, 2017).
Overwegingen (van bewijs naar aanbeveling)
Om te komen tot een aanbeveling zijn naast (de kwaliteit van) het wetenschappelijke bewijs ook andere aspecten belangrijk en worden meegewogen, zoals aanvullende argumenten uit bijvoorbeeld de biomechanica of fysiologie, waarden en voorkeuren van patiënten, kosten (middelenbeslag), aanvaardbaarheid, haalbaarheid en implementatie. Deze aspecten zijn systematisch vermeld en beoordeeld (gewogen) onder het kopje ‘Overwegingen’ en kunnen (mede) gebaseerd zijn op expert opinion. Hierbij is gebruik gemaakt van een gestructureerd format gebaseerd op het evidence-to-decision framework van de internationale GRADE Working Group (Alonso-Coello, 2016a; Alonso-Coello 2016b). Dit evidence-to-decision framework is een integraal onderdeel van de GRADE methodiek.
Formuleren van aanbevelingen
De aanbevelingen geven antwoord op de uitgangsvraag en zijn gebaseerd op het beschikbare wetenschappelijke bewijs en de belangrijkste overwegingen, en een weging van de gunstige en ongunstige effecten van de relevante interventies. De kracht van het wetenschappelijk bewijs en het gewicht dat door de werkgroep wordt toegekend aan de overwegingen, bepalen samen de sterkte van de aanbeveling. Conform de GRADE-methodiek sluit een lage bewijskracht van conclusies in de systematische literatuuranalyse een sterke aanbeveling niet a priori uit, en zijn bij een hoge bewijskracht ook zwakke aanbevelingen mogelijk (Agoritsas, 2017; Neumann, 2016). De sterkte van de aanbeveling wordt altijd bepaald door weging van alle relevante argumenten tezamen. De werkgroep heeft bij elke aanbeveling opgenomen hoe zij tot de richting en sterkte van de aanbeveling zijn gekomen.
In de GRADE-methodiek wordt onderscheid gemaakt tussen sterke en zwakke (of conditionele) aanbevelingen. De sterkte van een aanbeveling verwijst naar de mate van zekerheid dat de voordelen van de interventie opwegen tegen de nadelen (of vice versa), gezien over het hele spectrum van patiënten waarvoor de aanbeveling is bedoeld. De sterkte van een aanbeveling heeft duidelijke implicaties voor patiënten, behandelaars en beleidsmakers (zie onderstaande tabel). Een aanbeveling is geen dictaat, zelfs een sterke aanbeveling gebaseerd op bewijs van hoge kwaliteit (GRADE gradering HOOG) zal niet altijd van toepassing zijn, onder alle mogelijke omstandigheden en voor elke individuele patiënt.
Implicaties van sterke en zwakke aanbevelingen voor verschillende richtlijngebruikers |
||
|
||
|
Sterke aanbeveling |
Zwakke (conditionele) aanbeveling |
Voor patiënten |
De meeste patiënten zouden de aanbevolen interventie of aanpak kiezen en slechts een klein aantal niet. |
Een aanzienlijk deel van de patiënten zouden de aanbevolen interventie of aanpak kiezen, maar veel patiënten ook niet. |
Voor behandelaars |
De meeste patiënten zouden de aanbevolen interventie of aanpak moeten ontvangen. |
Er zijn meerdere geschikte interventies of aanpakken. De patiënt moet worden ondersteund bij de keuze voor de interventie of aanpak die het beste aansluit bij zijn of haar waarden en voorkeuren. |
Voor beleidsmakers |
De aanbevolen interventie of aanpak kan worden gezien als standaardbeleid. |
Beleidsbepaling vereist uitvoerige discussie met betrokkenheid van veel stakeholders. Er is een grotere kans op lokale beleidsverschillen. |
Organisatie van zorg
In de knelpuntenanalyse en bij de ontwikkeling van de richtlijn is expliciet aandacht geweest voor de organisatie van zorg: alle aspecten die randvoorwaardelijk zijn voor het verlenen van zorg (zoals coördinatie, communicatie, (financiële) middelen, mankracht en infrastructuur). Randvoorwaarden die relevant zijn voor het beantwoorden van de specifieke uitgangsvraag zijn genoemd bij de overwegingen. Een aantal bijkomende aspecten van de organisatie van zorg worden behandeld in de modules Ondersteunende zorg en Multidisciplinaire zorg.
Commentaar- en autorisatiefase
De conceptrichtlijn werd aan de betrokken (wetenschappelijke) verenigingen en (patiënt) organisaties voorgelegd ter commentaar. De commentaren werden verzameld en besproken met de werkgroep. Naar aanleiding van de commentaren werd de conceptrichtlijn aangepast en definitief vastgesteld door de werkgroep. De definitieve richtlijn werd aan de deelnemende (wetenschappelijke) verenigingen en (patiënten)organisaties voorgelegd voor autorisatie en door hen geautoriseerd dan wel geaccordeerd.
Literatuur
Agoritsas T, Merglen A, Heen AF, Kristiansen A, Neumann I, Brito JP, Brignardello-Petersen R, Alexander PE, Rind DM, Vandvik PO, Guyatt GH. UpToDate adherence to GRADE criteria for strong recommendations: an analytical survey. BMJ Open. 2017 Nov 16;7(11):e018593. doi: 10.1136/bmjopen-2017-018593. PubMed PMID: 29150475; PubMed Central PMCID: PMC5701989.
Alonso-Coello P, Schünemann HJ, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Rada G, Rosenbaum S, Morelli A, Guyatt GH, Oxman AD; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction. BMJ. 2016 Jun 28;353:i2016. doi: 10.1136/bmj.i2016. PubMed PMID: 27353417.
Alonso-Coello P, Oxman AD, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Vandvik PO, Meerpohl J, Guyatt GH, Schünemann HJ; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 2: Clinical practice guidelines. BMJ. 2016 Jun 30;353:i2089. doi: 10.1136/bmj.i2089. PubMed PMID: 27365494.
Brouwers MC, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, Fervers B, Graham ID, Grimshaw J, Hanna SE, Littlejohns P, Makarski J, Zitzelsberger L; AGREE Next Steps Consortium. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ. 2010 Dec 14;182(18):E839-42. doi: 10.1503/cmaj.090449. Epub 2010 Jul 5. Review. PubMed PMID: 20603348; PubMed Central PMCID: PMC3001530.
Hultcrantz M, Rind D, Akl EA, Treweek S, Mustafa RA, Iorio A, Alper BS, Meerpohl JJ, Murad MH, Ansari MT, Katikireddi SV, Östlund P, Tranæus S, Christensen R, Gartlehner G, Brozek J, Izcovich A, Schünemann H, Guyatt G. The GRADE Working Group clarifies the construct of certainty of evidence. J Clin Epidemiol. 2017 Jul;87:4-13. doi: 10.1016/j.jclinepi.2017.05.006. Epub 2017 May 18. PubMed PMID: 28529184; PubMed Central PMCID: PMC6542664.
Medisch Specialistische Richtlijnen 2.0 (2012). Adviescommissie Richtlijnen van de Raad Kwalitieit. http://richtlijnendatabase.nl/over_deze_site/over_richtlijnontwikkeling.html
Neumann I, Santesso N, Akl EA, Rind DM, Vandvik PO, Alonso-Coello P, Agoritsas T, Mustafa RA, Alexander PE, Schünemann H, Guyatt GH. A guide for health professionals to interpret and use recommendations in guidelines developed with the GRADE approach. J Clin Epidemiol. 2016 Apr;72:45-55. doi: 10.1016/j.jclinepi.2015.11.017. Epub 2016 Jan 6. Review. PubMed PMID: 26772609.
Schünemann H, Brożek J, Guyatt G, et al. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The GRADE Working Group, 2013. Available from http://gdt.guidelinedevelopment.org/central_prod/_design/client/handbook/handbook.html.
Zoekverantwoording
Zoekacties zijn opvraagbaar. Neem hiervoor contact op met de Richtlijnendatabase.