Post-operative RadioTherapy for Patients With Metastases of the Long Bones
Post-operative RadioTherapy for Patients With Metastases of the Long Bones
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.
Inclusion Criteria:

 -  Aged 18 or older

 -  Bone metastasis deriving from the following bones:

 -  humerus, ulna, radius

 -  femur, tibia, fibula

 -  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)

 -  Receive surgical treatment with palliative intent for a pathologic fracture or
 impending pathologic fracture

 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)

 -  Lesions in the small bones of the extremities

 -  (Surgical) treatment with curative intent