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Quality of Life

Patients with bone metastases of the long bone(s) receiving surgical stabilisation of a pathologic or impending fracture or receiving radiotherapy for a painful metastasis.

Stabilisation of pathological fracture or impending fracture with prosthesis, plate, intramedullary nail, cement, or other stabilisation method

Stabilisation of (impending) pathological fracture

Radiotherapy of bone metastasis, single or multi-fractionated

Radiotherapy of bone metastasis

Julie J Willeumier, MD

Gerco van der Wal, MD

Sander Dijkstra, MD PhD

Yvette van der Linden, MD PhD

Rationale: Bone metastases arise in 50% of all patients dying from carcinoma, increasing up to 70% in patients with breast and prostate cancer. The lesions can cause pain and fractures, leading to diminished quality of life and poorer survival. Current knowledge concerning adequate, personalized treatment of metastatic lesions of the long bones in patients with disseminated cancer is insufficient and inconclusive due to lack of large, prospective series with patient reported outcome measures.

Objective: The OPTIMAL cohort aims to describe the quality of life and pain perception of patients after local treatment (radiotherapy and/or surgery) of metastases of the long bones, for both the entire cohort as well as for specific treatments separately. With this a more personalized treatment for metastases in the long bones based on expected survival and impending fracture risk can be provided in order to improve functioning and the quality of life for the remaining lifetime in patients with disseminated cancer.

Study design: Observational, prospective, multicentre cohort study.

Study population: All patients with metastases of the long bones visiting a radiation oncologist or orthopaedic surgeon.

Main study parameters/endpoints: Primary endpoints are patient reported quality of life (including functioning) and pain levels. Complications and survival are secondary endpoints.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Patients in the OPTIMAL cohort will perhaps not directly benefit from their participation. Participation will contribute to deriving patient-specific treatment modalities for future patients with bone metastases of the long bones. Risks associated with participation in the prospective cohort are considered negligible due to the observational nature of the study. The burden for the patients lies in completion of questionnaires, which is considered to be in proportion with the potential value of this research.

The OPTIMAL Study in its entirety aims to provide a more personalized treatment for metastases in the long bones based on expected survival and impending fracture risk in order to improve functioning and the quality of life for the remaining lifetime in patients with disseminated cancer. The OPTIMAL Study will provide the infrastructure for a prospective cohort (OPTIMAL cohort) and multiple independent trials. The specific aims of the cohort are discussed in this protocol. The objectives and plan of the first trial (Post-Operative Radiotherapy; PORT study) are discussed in a separate protocol.

The primary aim of the cohort is to describe the quality of life and pain perception of patients after local treatment (radiotherapy and/or surgery) of metastases of the long bones, for both the entire cohort as well as for specific treatments separately.

Secondary aims are to describe the complication rate and survival of patients after local treatment (radiotherapy and/or surgery) of metastases of the long bones.

The specific aims of further future individual trials will be described in separate protocols and submitted to the medical research ethics committee (METC) independently. In general however, all trials will be pragmatic research trials in search of answers to which treatment (radiotherapy or surgery) fits specific patients (categorised by metastasis location, expected survival and fracture risk) best.

STUDY DESIGN The cohort will be prospectively collected and multicentre, including all consecutive patients with bone metastases of the long bones (BMLB) who have signed informed consent. These patients will be followed prospectively, and data concerning patient and treatment characteristics as well as patient reported outcomes on quality of life will be collected. Baseline data will be collected by the physician and entered into the OPTIMAL database. These baseline data match the information that is obtained for standard care. For the assessment of patient reported outcomes a set of internationally and nationally validated questionnaires will be used.

At moment of inclusion baseline patient data will be collected for the OPTIMAL cohort, which will also be used for the Post-Operative RadioTherapy (PORT) study. Data will comprehend information concerning demographics, medical history, and clinical status and functioning. Details concerning the treatment(s) will be reported when relevant.

Patients will be invited to fill out questionnaires about quality of life (QoL) at baseline (pre-treatment; if possible), and 4, 8, 12, and 24 weeks after initial treatment, then every six months for minimal two years or until death. All subsequently or concomitantly symptomatic metastases will be registered (including treatment and follow-up), but a new course of questionnaires will generally not be initiated. These outcome measures will be applied in the entire OPTIMAL cohort.

Pain:

Pain has been chosen as primary endpoint because it can act as a proxy for mechanical complications (i.e. loosening). Mechanical complications are only relevant for these patients if they give clinical complaints needing treatment.

To measure the primary endpoint patients will be asked to score the worst pain in the past 24 hours on a numeric rating scale (NRS) from 0-10. In addition, patients will be asked to list their usual pain medication and the escape medication they used the previous 24 hours. These questions are derived from the Brief Pain Intervention (BPI) score, which is advised by the International Consensus Statement for Bone Metastasis Research. The BPI is a pain assessment tool for use with cancer patients developed by the Pain Research Group of the World Health Organization (WHO) Collaborating Centre for Symptom Evaluation in Cancer Care and is also available in Dutch. However, multiple questions are similar to questions in the European Organization for Research and Treatment of Cancer (EORTC) Quality of life questionnaire for palliation (QLQ-PAL15) and EORTC Quality of life questionnaire for bone metastases (QLQBM-22) (described below). Thus to spare patients answering the same questions twice, the investigators have selected only 2 questions from the BPI.

Quality of life:

For longitudinal assessment of quality of life after treatment, the investigators will use nationally and internationally used, validated and recommended questionnaires: European Organization for Research and Treatment of Cancer (EORTC) QLQ-C15-PAL and EORTC QLQ-BM22. In addition, the EQ-5D (5 dimension) questionnaire will be conducted. The EORTC is currently developing a utility scoring instrument for the EORTC QLQ-C30 (from which the QLQ-C15-PAL originates). The investigators expect this scoring instrument will also be applicable for the QLQ-C15-PAL. After validation of this scoring instrument has taken place, the investigators plan to apply it to the data. This would make the addition of the EQ-5D questionnaire redundant and it will then be withdrawn.

Function:

For assessing improvements in functional outcomes after treatment, the Toronto Extremity Salvage Score (TESS) for upper and lower extremities will be used.

Observational clinical data will be collected at baseline (pre-treatment; if possible) and at first, and possibly second, post-operative follow-up (generally, patients are subsequently only seen if there are complications or new complaints):

Complications:

For complication rate, the Henderson classification of complications will be applied. This classification identifies five primary modes of endoprosthetic failure: soft tissue failure (type 1), aseptic loosening (type 2), structural failure (type 3), infection (type 4), and tumour progression (type 5). Wound complications with clinical consequences will be registered separately. Re-operations due to complications will be registered as such in the treatment field as a new operation.

Radiological status:

Progression of BMLB will be monitored with conventional radiography and on indication with CT scan. This is according to usual care, generally at six weeks and 3 months. No additional outpatient visits or imaging will be requested for study purposes only. The radiological images will be used to place the subjective reports of pain (as reported by the patient on a numeric rating scale) into perspective.

Survival:

Dates of death will be derived from the Hospital Electronic Patient Registry, which is linked to the Municipal Personal Records Database. If this is not possible or not up to date, data will be derived from the general practitioner. The utmost will be tried to prevent sending questionnaires to deceased patients.

The OPTIMAL Study - A Prospective Cohort of Patients With Bone Metastases of the Long Bones

The influence on the quality of life of a treatment will be measured by several patient reported outcome scores (EQ-5D, EORTC BM-22, and EORTC PAL-15) at several time points after treatment. These will be used to calculate the changes shortly and longer after treatment.

The influence of a treatment on the pain will be measured by a reported outcome score (NRS) at several time points after treatment. These will be used to calculate the changes shortly and longer after treatment.

The influence of a treatment on the function will be measured by a patient reported outcome scores (TESS) at several time points after treatment. These will be used to calculate the changes shortly and longer after treatment.

For complication rate, the Henderson classification of complications will be applied. This classification identifies five primary modes of endoprosthetic failure: soft tissue failure (type 1), aseptic loosening (type 2), structural failure (type 3), infection (type 4), and tumour progression (type 5). Wound complications with clinical consequences will be registered separately. Re-operations due to complications will be registered as such in the treatment field as a new operation.

Leiden University Medical Center

MD PhD

Multifractionated post-operative radiotherapy, several weeks after surgery

Radiotherapy

Julie Willeumier, MD

Rationale: Bone metastases arise in 50% of all patients dying of cancer, increasing up to 70% in patients with breast and prostate cancer. The lesions can cause pain and fractures, leading to diminished quality of life and poorer survival. Current knowledge concerning adequate, personalized treatment of metastatic lesions of the long bones in patients with disseminated cancer is insufficient and inconclusive due to lack of large, prospective series with patient reported outcome measures. One of the debatable issues is the effectiveness of postoperative radiotherapy. It has become common practise due to professional opinion, but research evidence is lacking. It is thought that adjuvant radiotherapy improves the durability of an implant, prevents progression of the lesion, promotes bone healing, improves limb function, minimises pain and reduces the need for reoperations, however none of these are certain. Moreover, it is a burden on patient's quality of life (e.g. multiple extra hospital visits) causing toxicity and possible side effects (e.g. skin irritation). The true beneficial effect, weighing up the possible pros and certain cons, of adjuvant radiotherapy is thus unknown.

Objective: The PORT study aims to demonstrate the non-inferiority of 'surgery only' compared to surgery with adjuvant radiotherapy as treatment of impending and actual pathological fractures on the pain experienced by patients.

Study design: A multicentre, prospective, randomised non-inferiority trial nested within the OPTIMAL study.

Study population: All patients with metastases of the long bones undergoing surgery for a(n) (impending) pathologic fracture in the participating centres.

Study intervention: One study arm (A) will receive surgery with adjuvant radiotherapy; the other study arm (B) will receive surgery only.

Main study parameters/endpoints: Primary endpoint is patient reported pain according to a numeric rating scale (NRS). Clinical functioning, radiological status, complications and survival are secondary endpoints.

The PORT study aims to demonstrate the non-inferiority of 'surgery only' compared to 'surgery with adjuvant radiotherapy' for the fixation of impending and actual pathological fractures of the long bones. We hypothesize that patients without post-operative radiotherapy will not have more pain than those receiving post-operative radiotherapy. The primary efficacy endpoint will be the pain level (as measured by an eleven point numeric rating scale (NRS)) 12 weeks after treatment. Pain has been chosen as primary endpoint because it can be interpreted as a "proxy" for mechanical loosening or other complications. It was undesirable to select revision surgery as endpoint, because the number of revision surgeries will be very low in this patient population. A revision will only be performed for serious complications with large effects on the quality of life. In other cases, conservative options will be chosen over revision surgery.

Secondary endpoints are complications, quality of life and overall survival.

A secondary objective is to conduct cost-effectiveness and costs-utility analyses.

This study is a multicentre, prospective, randomised non-inferiority trial nested within the OPTIMAL study. The OPTIMAL study is the backbone of the (OPTIMAL-) PORT study, encompassing the prospective cohort and providing the infrastructure for collection patient reported outcome measures. If patients do not have an indication for surgery, they can only be included in the OPTIMAL study. If patients have an indication for surgery, they are recruited for the OPTIMAL-PORT study. However, if patients do not give consent for randomisation for radiotherapy, they can give partial consent and participate in the prospective cohort and complete questionnaires. This data will contribute to the OPTIMAL study. Details concerning the OPTIMAL study are described in the respective protocol.

The PORT trial is a non-inferiority trial between ' surgery with post-operative radiotherapy' (Arm A) with 'surgery only (no post-operative radiotherapy)' (Arm B). A non-inferiority design is appropriate for this study because we expect that the clinical outcomes with surgery only are not worse than with post-operative radiotherapy. 'Surgery only' however has evident advantages, as it will lessen the burden on patients of visiting the hospital, prevent toxicity and cost less. Furthermore, as mentioned in the introduction, the focus of treatment is on maintaining and improving quality of life. The goal is to do what is right, safe, and efficient and not to provide more care than is needed. Rethinking whether we need post-operative radiotherapy is part of achieving that goal.

All patients with (impending) fractures of the long bones due to bone metastases and an operation indication will be asked to participate in the OPTIMAL cohort and provide patient reported outcomes. In addition, they will be informed about the PORT trial. Post-operatively, shortly before discharge from the hospital, they will be asked for informed consent for the PORT trial by the treating physician or a researcher. This assures a waiting period of 3-7 days between information and consent. Patients are informed that they are free to decide whether they wish to participate in the trial and will receive written information in addition to oral information. If patients do not wish to participate in the trial, they will receive standard care (which is post-operative radiotherapy in most cases). The first post-operative questionnaire will be sent 4 weeks after surgery.

Statistical analysis: To describe patient characteristics and outcomes, descriptive statistics (mean, median, standard deviation, and proportions) will be used. For univariate testing, p-values will be one tailed and considered significant if less than 0.05.

The primary endpoint of this study is pain response after surgery with or without post-operative radiotherapy. This will be expressed in absolute numbers (difference in NRS). A linear regression model to adjust for patients' characteristics will be used to compare the difference in mean pain level between the two arms with the centre from which the patient originates as a random effect.

For the analysis of non-inferiority primarily an intention to treat (ITT) will be performed. However, an ITT analysis is more likely to narrow the difference between treatments in a non-inferiority trial and yield a non-inferior result, thus a per protocol (PP) analysis is needed to cross-validate the ITT analysis.

Differences in the occurrence of complications will be compared by Fisher's exact test or chi-square test.

The QoL will be analysed using the EORTC QLQ-C15-PAL and EORTC QLQ-BM22. A comparison will be made between the baseline QoL and at predefined intervals after treatment (at 4 and 8 weeks, 3, 6 and 12 months following radiotherapy). A change of 10% of the scale width will be considered a clinically relevant change of QoL (Osoba 2005). The data will be presented as stable, worsened (≥ 10% decrease in QoL) or improved (≥ 10%increase in QOL). These time points will be compared using a Chi square test with a conservative p-value of 0.01 to correct for multiple testing. We will also evaluate the pattern of QoL as a continuous outcome over time during follow up with the mixed models approach.

Overall survival and progression free survival will be estimated by applying Kaplan-Meier's methodology analysis. Time to event will be measured from time of treatment to death or to progression of the disease. Comparisons in outcomes between treatment groups will be performed by Log Rank test.

Post-operative RadioTherapy for Patients With Metastases of the Long Bones

Post-operative RadioTherapy for Patients With Metastases of the Long Bones: a Randomised Controlled Trial

Pain will measured before treatment and after treatment on an 11-point numeric rating scale for pain. If the score differs more than 2 points between those measuring moments the change in pain is reported as significant. The number of patients in each group with a significant change in pain score will be measured.

Complications such as loosening of implant

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
The OPTIMAL Study - A Prospective Cohort of Patients With Bone Metastases of the Long Bones	NCT02705157	Bone Metastasis	Stabilisation o... Radiotherapy of...	18 Years -	Leiden University Medical Center
Post-operative RadioTherapy for Patients With Metastases of the Long Bones	NCT02705183	Metastasis to B...	Radiotherapy	18 Years -	Leiden University Medical Center
The OPTIMAL Study - A Prospective Cohort of Patients With Bone Metastases of the Long Bones	NCT02705157	Bone Metastasis	Stabilisation o... Radiotherapy of...	18 Years -	Leiden University Medical Center

Spots Global Cancer Trial Database for long bones

Every month we try and update this database with for long bones cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for long bones

Every month we try and update this database with for long bones cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for long bones cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.