Update of the International Consensus on Palliative Radiotherapy Endpoints for Future Clinical Trials in Bone Metastases

doi:10.1016/j.ijrobp.2011.02.008

International Journal of Radiation OncologyBiologyPhysics

Volume 82, Issue 5, 1 April 2012, Pages 1730-1737

https://doi.org/10.1016/j.ijrobp.2011.02.008 Get rights and content

Purpose

To update the international consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases by surveying international experts regarding previous uncertainties within the 2002 consensus, changes that may be necessary based on practice pattern changes and research findings since that time.

Methods and Materials

A two-phase survey was used to determine revisions and new additions to the 2002 consensus. A total of 49 experts from the American Society for Radiation Oncology, the European Society for Therapeutic Radiology and Oncology, the Faculty of Radiation Oncology of the Royal Australian and New Zealand College of Radiologists, and the Canadian Association of Radiation Oncology who are directly involved in the care of patients with bone metastases participated in this survey.

Results

Consensus was established in areas involving response definitions, eligibility criteria for future trials, reirradiation, changes in systemic therapy, radiation techniques, parameters at follow-up, and timing of assessments.

Conclusion

An outline for trials in bone metastases was updated based on survey and consensus. Investigators leading trials in bone metastases are encouraged to adopt the revised guideline to promote consistent reporting. Areas for future research were identified. It is intended for the consensus to be re-examined in the future on a regular basis.

Introduction

External beam radiotherapy (RT) is a well-established and efficacious method of palliating painful bone metastases (1). Numerous randomized trials have evaluated the potential benefits of certain dose fractionations of external beam RT 1, 2, 3, 4, 5, 6, 7. However, because of the varying endpoints used, different results can be obtained from each trial, making comparisons among trials extremely difficult.

In 2002, the International Bone Metastases Consensus Working Party published its first consensus on palliative RT in an attempt to encourage investigators to adopt a common set of endpoints for future clinical trials in bone metastases (8). This initiative involved an international faculty representing the American Society for Radiation Oncology (ASTRO), the European Society for Therapeutic Radiology and Oncology (ESTRO), the Faculty of Radiation Oncology of the Royal Australian and New Zealand College of Radiologists (RANZCR), and the Canadian Association of Radiation Oncology (CARO). The participating members from these groups collaboratively formulated a framework for palliative RT trials in patients with bone metastases.

The following items were discussed in the first consensus (Appendix 1) (8):

1.
Eligibility criteria for future trials
2.
Pain and analgesic assessments
3.
Radiation techniques
4.
Follow-up and timing of assessments
5.
Parameters at follow-up
6.
Endpoints
7.
Reirradiation
8.
Statistical analysis

It is important that radiation oncologists worldwide conducting clinical trials with patients with bone metastases continually ensure consistency in the endpoints used for RT trials in this group of patients. As a way of updating and refining the previous recommendations, and to better represent current practice, the Working Party aimed to revisit and to re-examine the published consensus. The purpose of this study was to report the consensus results.

Section snippets

Methods and Materials

A two-phase electronic survey was used to identify both new areas requiring consensus and aspects of the previous consensus needing to be updated. A secure Web site with password protection was used to create and distribute online surveys. Previous participants, investigators, and others with a recognized interest in bone metastases were identified globally and invited to participate. Representation from four major membership/credentialing radiotherapy organizations were included in this update

Results

A total of 80 participants were invited to take part in the consensus work, of whom 49 (61%) responded and completed the surveys. Items for which more than 50% of participants believed that at least some change was necessary in Phase I and their suggested changes can be found in Appendix 3. Results of the Phase II are categorized as those with >80% agreement, 70% to 80% agreement, and <70% agreement. Overall, 5 of 15 statements had agreement >80% and 6 of 15 had agreement between 70% and 80%.

Discussion

The purpose of this survey was to update the international consensus endpoints for RT trials in bone metastases. The Working Party acknowledges that specific studies may choose to measure additional endpoints beyond those described here, and that the goal of this update is to describe the minimum features that should be incorporated into bone metastases trials.

Since the publication of the initial consensus recommendations, several authors have used these endpoints to evaluate the response to RT

Acknowledgments

The authors thank American Society for Radiation Oncology (ASTRO), the European Society for Therapeutic Radiology and Oncology (ESTRO), the Faculty of Radiation Oncology of the Royal Australian and New Zealand College of Radiologists (RANZCR) and the Canadian Association of Radiation Oncology (CARO) for supporting the consensus work, especially Carol A. Hahn and Shari Siuta from ASTRO. The authors sincerely appreciate the valuable time and comments shared by the participants in our consensus

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Practice and principles of stereotactic body radiation therapy for spine and non-spine bone metastases
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Radiotherapy is the dominant treatment modality for painful spine and non-spine bone metastases (NSBM). Historically, this was achieved with conventional low dose external beam radiotherapy, however, stereotactic body radiotherapy (SBRT) is increasingly applied for these indications. Meta-analyses and randomized clinical trials have demonstrated improved pain response and more durable tumor control with SBRT for spine metastases. However, in the setting of NSBM, there is limited evidence supporting global adoption and large scale randomized clinical trials are in need. SBRT is technically demanding requiring careful consideration of organ at risk tolerance, and strict adherence to technical requirements including immobilization, simulation, contouring and image-guidance procedures. Additional considerations include follow up practices after SBRT, with appropriate imaging playing a critical role in response assessment. Finally, there is renewed research into promising new technologies that may further refine the use of SBRT in both spinal and NSBM in the years to come.
Impact of Short-Course Palliative Radiation Therapy on Pancreatic Cancer-Related Pain: Prospective Phase 2 Nonrandomized PAINPANC Trial
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Clinical evidence is limited regarding palliative radiation therapy for relieving pancreatic cancer-related pain. We prospectively investigated pain response after short-course palliative radiation therapy in patients with moderate-to-severe pancreatic cancer-related pain.
In this prospective phase 2 single center nonrandomized trial, 30 patients with moderate-to-severe pain (5-10, on a 0-10 scale) of pancreatic cancer refractory to pain medication, were treated with a short-course palliative radiation therapy; 24 Gy in 3 weekly fractions (2015-2018). Primary endpoint was defined as a clinically relevant average decrease of ≥2 points in pain severity, compared with baseline, within 7 weeks after the start of treatment. Secondary endpoint was global quality of life (QoL), with a clinically relevant increase of 5 to 10 points (0-100 scale). Pain severity reduction and QoL were assessed 9 times using the Brief Pain Inventory and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C15-PAL, respectively. Both outcomes were analyzed using joint modeling. In addition, acute toxicity based on clinician reporting and overall survival (OS) were assessed.
Overall, 29 of 30 patients (96.7%) received palliative radiation therapy. At baseline, the median oral morphine equivalent daily dose was 129.5 mg (range, 20.0-540.0 mg), which decreased to 75.0 mg (range, 15.0-360.0 mg) after radiation (P = .021). Pain decreased on average 3.15 points from baseline to 7 weeks (one-sided P = .045). Patients reported a clinically relevant mean pain severity reduction from 5.9 to 3.8 points (P = .011) during the first 3 weeks, which further decreased to 3.2 until week 11, ending at 3.4 (P = .006) in week 21 after the first radiation therapy fraction. Global QoL significantly improved from 50.5 to 60.8 during the follow-up period (P = .001). Grade 3 acute toxicity occurred in 3 patients and no grade 4 to 5 toxicity was observed. Median OS was 11.8 weeks, with a 13.3% 1-year actuarial OS rate.
Short-course palliative radiation therapy for pancreatic cancer-related pain was associated with rapid, clinically relevant reduction in pain severity, and clinically relevant improvement in global QoL, with mostly mild toxicity.
MR-guided Focused Ultrasound for Musculoskeletal Applications
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Treatment outcomes of radiotherapy for malignant psoas syndrome: A single-center retrospective study
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The efficacy of radiotherapy for symptomatic relief of malignant psoas syndrome (MPS) remains unknown because there are limited publications with high level evidence, including analyses with sufficient number of cases, clinical trials, and systematic reviews about radiotherapy for MPS. We aimed to investigate the characteristics of and symptom relief rates in patients treated with radiotherapy for MPS in palliative intent.
In this single-center retrospective study, we analyzed data of 22 consecutive patients treated with radiotherapy for MPS at our institution in Japan between 2012 and 2022. We recorded patient characteristics, including primary site, invasion pattern, recognition of MPS by the attending physician, radiation regimen, biological effective dose with α/β = 10 Gy (BED₁₀), and adverse events. Since no objective evaluation index for palliative radiotherapy for non-bone metastases has been established, we modified and used an International Consensus on Palliative Radiotherapy Endpoint, which was originally used for bone metastases, to evaluate symptom relief in the present retrospective study. “Response” was defined as symptom relief described in medical records or the use of analgesic medications reduced by ≥25% within 3 months post-initiation of radiotherapy.
Genitourinary organs (41%) were the most common primary-tumor sites. MPS was caused by metastasis in the iliopsoas muscle in 14 patients (64%) and by direct invasion of the primary tumor in eight patients (36%). Since the optimal radiation dose for MPS has not been established, the radiation dose varied from low dose, which are used in palliative radiotherapy for painful bone metastases, to high dose with conventional fraction using 1.8 to 2 Gy per fraction, with a median BED₁₀ of 48 Gy (range, 10.6–79.2 Gy). Fifteen patients (68%) achieved a response. No acute nor late adverse events of grade 2 or higher, according to Common Terminology Criteria for Adverse Events version 5.0, were reported during the observation period.
Radiotherapy for symptomatic MPS might be an effective treatment option with a high response rate (68%) and minimal adverse events. Since the present study is a retrospective study with small number of cases, a prospective study with a larger sample size is required.
L'efficacité de la radiothérapie pour le soulagement des symptômes du syndrome malin du psoas (SMP) reste inconnue car il y a peu de publications avec des preuves de haut niveau, y compris des analyses avec un nombre suffisant de cas, des essais cliniques et des revues systématiques sur la radiothérapie pour le SMP. Nous avons cherché à étudier les caractéristiques et les taux de soulagement des symptômes chez les patients traités par radiothérapie pour le syndrome du psoas malin dans une intention palliative.
Dans cette étude rétrospective monocentrique, nous avons analysé les données de 22 patients consécutifs traités par radiothérapie pour le SMP dans notre institution au Japon entre 2012 et 2022. Nous avons enregistré les caractéristiques des patients, y compris le site primaire, le schéma d'invasion, la reconnaissance du SMP par le médecin traitant, le régime d'irradiation, la dose efficace biologique avec α/β = 10 Gy (BED10) et les effets indésirables. Comme aucun indice d'évaluation objective de la radiothérapie palliative pour les métastases non osseuses n'a été établi, nous avons modifié et utilisé un critère d'évaluation du Consensus international sur la radiothérapie palliative, qui a été initialement utilisé pour les métastases osseuses, pour évaluer le soulagement des symptômes dans la présente étude rétrospective. La « réponse » a été définie comme un soulagement des symptômes décrit dans les dossiers médicaux ou une réduction de ≥25 % de la consommation d'analgésiques dans les trois mois suivant le début de la radiothérapie.
Les organes génito-urinaires (41 %) étaient les sites de tumeur primaire les plus fréquents. Le SMP a été causé par des métastases dans le muscle iliopsoas chez 14 patients (64 %) et par invasion directe de la tumeur primaire chez huit patients (36 %). La dose de radiation optimale pour le SMP n'ayant pas été établie, la dose de radiation variait d'une faible dose, utilisée en radiothérapie palliative pour les métastases osseuses douloureuses, à une dose élevée avec un fractionnement conventionnel utilisant 1,8 à 2 Gy par fraction, avec un BED10 médian de 48 Gy (intervalle, 10,6-79,2 Gy). Une réponse a été obtenue chez 15 patients (68 %). Aucun événement indésirable aigu ou tardif de grade 2 ou supérieur, selon la version 5.0 des Critères de terminologie communs pour les événements indésirables, n'a été signalé pendant la période d'observation.
La radiothérapie pour le SMP symptomatique pourrait être une option thérapeutique efficace avec un taux de réponse élevé (68 %) et des effets indésirables minimes. Étant donné que la présente étude est une étude rétrospective avec un petit nombre de cas, une étude prospective avec un nombre suffisant de cas est nécessaire.
Incidence, characteristics, management and outcome of patients with follicular lymphoma with tumor epidural compression, a study on 22 cases
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Follicular lymphoma (FL) is one of the most common lymphoma. Occasionally, FL is associated with tumoral epidural compression and management of these patients remain poorly codified. This study aims to report incidence, clinical characteristics, management and outcomes of patients with FL and tumoral epidural compression.
Observational, retrospective cohort study of adult patients with FL and epidural tumor compression, treated in a French Institute over the last 20 years (2000–2021).
Between 2000 and 2021, 1382 patients with FL were followed by the haematological department. Of them, 22 (1.6%) patients (16 men and 6 women) had follicular lymphoma with epidural tumor compression. At epidural tumor compression occurrence, 8/22 (36%) patients had a neurological clinical deficit (motor, sensory or sphincter function) and 14/22 (64%) had tumor pain. All patients were treated with immuno-chemotherapy; the main regimen being used was R-CHOP plus high dose IV methotrexate in 16/22 (73%) patients. Radiotherapy for tumor epidural compression was performed in 19/22 (86%) patients. With a median follow-up of 60 months (range = [1–216]), 5 year local tumor relapse free survival was achieved in 65% (95% CI 47–90%) of patients. The median PFS was of 36 months (95% CI 24–NA) and 5 years OS estimate was 79% (95% CI 62–100%). Two patients developed a relapse at a second epidural site.
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Le lymphome folliculaire est l’un des lymphomes les plus fréquents. Il occasionne parfois une épidurite, dont la prise en charge est mal codifiée. Cette étude visait à décrire rétrospectivement l’incidence, les caractéristiques cliniques et la prise en charge de ces patients.
Nous avons mené une étude monocentrique de cohorte observationnelle sur des patients adultes traités entre 2000 et 2021.
Entre 2000 et 2021, 1382 patients atteints d’un lymphome folliculaire ont été suivis dans le service. Au total, 22 d’entre eux (1,6 %) (16 hommes et 6 femmes) ont souffert d’une épidurite. Lors de l’évènement, 8/22 (36 %) patients avaient un déficit clinique (moteur, sensitif ou sphinctérien) et 14/22 (64 %) étaient douloureux. Tous les patients ont été pris en charge par une l’immuno-chimiothérapie, par du R-CHOP (rituximab, cyclophosphamide; chlorhydrate de doxorubicine, vincristine, prednisone) associé à du méthotrexate haute dose chez 16/22 (73 %) des patients. Une radiothérapie a été délivrée chez 19/22 (86 %) patients. Avec un suivi médian de 60 [1–216] mois, le contrôle local a été obtenu à cinq ans chez 65 % (IC 95 % (intervalle de confiance à 95 %) = 47–90 %) des patients. La survie sans progression était de 36 mois (IC 95 % = 24–NA) et l’estimation de la probabilité de survie globale à 5 ans était de 79 % (IC 95 % = 62–100 %). Deux lymphomes ont récidivé sous la forme d’une épidurite.
L’épidurite a été retrouvée chez 1,6 % des patients atteints de lymphome folliculaire. Sa prise en charge, basée sur l’immuno-chimiothérapie et la radiothérapie, a donné des résultats similaires à celle de la population des patients atteints de lymphome folliculaire dans son ensemble.
Randomized controlled study of pain education in patients receiving radiotherapy for painful bone metastases
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Although short-course radiotherapy is an effective treatment for patients with painful bone metastases, pain is not always sufficiently controlled. We therefore investigated the additional effect of a nurse-led pain education program on pain control and quality of life (QoL).
In this multicenter study, patients with solid tumor bone metastases and a worst pain intensity of ≥5 on a 0–10 numeric rating scale (NRS) were randomized between care as usual (control-group) and care as usual plus the Pain Education Program (PEP-group). PEP consisted of a structured interview and personalized education with follow-up phone calls. Patients completed the Brief Pain Inventory, EORTC QLQ-C15-PAL and BM22 at week 0, 1, 4, 8 and 12. The primary outcome was pain control, defined as the number of patients whose worst pain intensity was <5 on a 0–10 NRS after 12 weeks. Secondary outcomes were time to reach control of pain (NRS < 5), mean worst pain and average pain, and QoL at weeks 1, 4, 8 and 12.
Of 308 included patients, 182 (92 PEP-group) completed 12 weeks follow-up. At 12 weeks, more patients in the PEP-group (71%) compared to the control-group (52%) reported pain control (P =.008). In the PEP-group, pain control was reached earlier than in the control-group (median 29 days versus 56 days; P =.003). Mean worst and average pain decreased in both groups but decreased more in the PEP-group. QoL did not differ between the groups.
The addition of PEP to care as usual for patients treated with radiotherapy for painful bone metastases resulted in less pain and faster pain control.

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: Note—An online CME test for this article can be taken at http://astro.org/MOC.

: Conflict of interest: none.

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Clinical InvestigationUpdate of the International Consensus on Palliative Radiotherapy Endpoints for Future Clinical Trials in Bone Metastases

Purpose

Methods and Materials

Results

Conclusion

Introduction

Section snippets

Methods and Materials

Results

Discussion

Acknowledgments

Clin Oncol (R Coll Radiol)

Radiother Oncol

Radiother Oncol

Radiother Oncol

Clin Oncol (R Coll Radiol)

Int J Radiat Oncol Biol Phys

Radiother Oncol

Support Cancer Ther

Int J Radiat Oncol Biol Phys

Contemp Clin Trials

Respir Med

Eur J Cancer

Eur J Cancer

Clinical Investigation
Update of the International Consensus on Palliative Radiotherapy Endpoints for Future Clinical Trials in Bone Metastases