The OPTIMAL Study - A Prospective Cohort of Patients With Bone Metastases of the Long Bones
The OPTIMAL Study - A Prospective Cohort of Patients With Bone Metastases of the Long Bones
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.
Inclusion Criteria:

 -  Aged 18 or older

 -  Radiographic or histologic proof of metastatic bone disease

 -  Histologic diagnosis of the primary tumour or - if the diagnosis is unknown - at least
 adequate diagnostic investigations into the origin of the metastasis (e.g.
 dissemination imaging, histology, biopsy)

 -  Bone metastasis deriving from the bones of the extremities

 Exclusion Criteria:

 -  Primary bone tumours (benign and/or malignant)

 -  No informed consent signed

 -  Communication with patient is hampered (e.g. language barrier, severe cognitive
 impairment, dementia)