Phase III Randomized Trial for High-risk Asymptomatic or Minimally Symptomatic Bone Metastases: Early Radiotherapy Versus Observation
Phase III Randomized Trial for High-risk Asymptomatic or Minimally Symptomatic Bone Metastases: Early Radiotherapy Versus Observation
The goal of this clinical trial is to learn whether radiotherapy (i.e. treatment with ionizing radiation to destroy cancer cells) can prevent symptoms in patients with metastatic cancer, having high-risk bone metastases that currently result in no or only mild symptoms. High-risk bone metastases are bone metastases at high-risk of developing bone complications, such as fractures or myelum compression.
The main questions this study aims to answer are:
Researchers will compare 2 treatment groups in order to answer the questions listed above: 1 group treated with medication or observation alone (group A) and 1 group treated with medication or observation and preventive radiotherapy (group B).
Participants will
It is estimated that two out of three patients with advanced cancer will develop metastases in the bones (i.e. bone metastases). Any type of cancer can spread to the bone, but the types of cancer in which the likelihood of spreading to the bone is greatest include prostate cancer, breast cancer, lung cancer, kidney cancer and skin cancer. The development of bone metastases is a serious complication of cancer that greatly affect quality of life. A large proportion of patients experience bone pain and associated reduced mobility. Bone metastases can also cause bone fractures. The growth of bone metastases in the vertebrae can lead to entrapment of the spinal cord. This is called spinal cord compression. The symptoms can range from mild (pain and a tingling sensation) to very severe (paralysis). In the English-language literature, these bone complications due to bone metastases are often indicated as skeletal-related events ("skeletal-related events"; SREs) or symptomatic skeletal-related events ("symptomatic skeletal-related events"; SSEs) when they also cause symptoms.
SSEs are defined as:
When SSE occur that have a negative impact on the quality of life, these can be treated with systemic therapy, surgery or radiotherapy (RT). Scientific evidence is already available for radiotherapy as an effective treatment for patients with bone metastases causing symptoms. Recent data from an American trial suggest that also preventive radiotherapy of high-risk asymptomatic bone metastases may have a favorable effect. Hence, the aim of the HERMES study is to investigate if early preventive radiation of high-risk asymptomatic or minimally symptomatic bone metastases in patients with metastatic cancer can decrease the number of symptomatic skeletal events (SSEs) in a multi-centric randomized phase 3 trial.
A potential participant needs to sign an informed consent form before participating in the HERMES study. Participation in the HERMES study will comprise a screening period, during which the screening assessments must be completed, a treatment phase and a follow-up phase.
During the screening phase, eligibility of the patient to participate in the study will be assessed. Demographics data, Karnofsky performance score, information regarding medical history, prior medications and adverse events will be recorded. Moreover, the potential participant needs to complete questionnaires regarding his/her quality of life, characteristics of the high-risk metastases will be recorded based on imaging and a pain score will be determined for each lesion.
Eligible, consenting subjects will then be randomized (1:1) into one of two treatment arms: an observational arm (arm A) receiving systemic therapy / observation or an upfront RT arm (arm B) receiving upfront RT plus systemic therapy / observation.
During the treatment phase, RT should take place within 21 days after date of randomization for subjects in arm B. Participants of both study arms receive either systemic therapy or observation, according to the standard of care guidelines.
The follow-up phase consists of 6 follow-up visits which will take place at 1, 3, 6, 12, 18 and 24 months after date of randomization and during which safety and efficacy are monitored. More specifically, the Karnofsky performance score, concomitant medications and adverse events will be recorded at each visit. Moreover, the potential participant needs to complete questionnaires regarding his/her quality of life. Note that patients in arm B are strongly advised to receive additional preventive radiotherapy in case of appearance of new asymptomatic or minimally symptomatic high-risk bone metastases during follow-up. A maximum of 5 high-risk asymptomatic or minimally symptomatic bone metastases can be irradiated at once.
In case an SSE would occur, the assessments that should take place during the next follow-up visit, should be completed at that time point, preferably within one week. Afterwards, only survival data will be recorded on the planned FU visits until 24 months after the randomization date as well as possible occurrence of another SSE and hospitalizations related to the high-risk bone metastasis(es) until 24 months after the randomization date.
Inclusion Criteria:
I1: Histologically confirmed solid tumor malignancy (with polymetastastic spread (≥ 3 metastases))
I2: High-risk bone metastasis(es) that is (are) asymptomatic or minimally symptomatic:
*Asymptomatic or minimally symptomatic is defined as follows: O Numeric Pain Rating Scale (NRS) score ≤2 for the specific lesion(s)
*High-risk is defined as follows (i.e. at least one of the following points must be applicable): O Bulky site of disease in bone (diameter ≥ 2 cm) O Disease involving the hip (acetabulum, femoral head, femoral neck), shoulder (acromion, glenoid, humeral head), or sacroiliac joints O Disease in long bones with cortical involvement of >1/3 in proportion to the diameter of the bone (humerus, radius, ulna, clavicle, femur, tibia, fibula, metacarpals, phalanges) O Disease in vertebrae of the junctional spine (C1-2, C7- T1, T12-L1, L5-S1) and/or disease with posterior element involvement or epidural extension (Bilsky epidural compression score 1a-3) [Bilsky et al]. The posterior elements of the spine consist of the pedicles, laminae, facets (articular processes), transverse processes, and the spinous process.
I3: Number of Risk Factors (NRF) prognostic score 0-2
I4: Age ≥ 18 years
I5: Ability to provide informed consent (either by the patient or by a legally authorized representative)
I6: A female participant is eligible to participate if she confirms not to be pregnant at screening, and one of the following conditions applies:
Is not a woman of child bearing potential or A woman of child bearing potential must confirm that she is not pregnant at screening and must agree to use a very effective method of birth control
Exclusion Criteria:
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