Surveillance AFter Extremity Tumor surgerY

Study Overview
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Brief Summary
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Following treatment for a primary extremity sarcoma, patients remain at risk for the development of local and systemic disease recurrence. Metastasis (distant recurrence) to the lung is the most frequent single location of disease recurrence in sarcoma patients, occurring in almost half of all patients. Therefore, careful post-operative surveillance is an integral element of patient care. However, the detection of metastases does not necessarily affect long-term survival and may negatively impact quality of life. Surveillance strategies have not been well researched and have been identified as the top research priority in the extremity sarcoma field. Using a 2X2 factorial design to maximize efficiency and reduce overall trial costs, the SAFETY trial will randomize 830 extremity soft-tissue sarcoma (STS) patients to determine the effect of surveillance strategy on overall patient survival after surgery for a STS of the extremity by comparing the effectiveness of both surveillance frequency (every 3 vs. every 6 months) and imaging modality (CT scans vs. chest radiographs).

Detailed Description
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Post-treatment STS surveillance is an integral element of patient care. Although earlier detection of metastatic disease may improve long-term survival, no study has yet provided definitive evidence to support this assumption. A thorough systematic review of the literature has identified only a single limited randomized controlled trial (RCT) evaluating this clinical question, and surveys of sarcoma surgeons have determined that surgeons typically follow their patients based on the way in which they were trained. The orthopaedic oncology field has identified sarcoma surveillance strategy as the top research priority in the field. In order to fill the evidence gap in sarcoma surveillance, a large international RCT is required. The investigators, therefore, propose the Surveillance AFter Extremity Tumor surgerY (SAFETY) trial. In preparation for the SAFETY trial, the SAFETY investigators have completed the following preparatory work: A) establishment of a worldwide research collaborative group that spans 6 continents; B) collection of data from international sarcoma patients to determine their perceptions of sarcoma surveillance and their willingness to participate in a study in which randomization will determine their follow-up protocols; and C) the organization of a large Protocol Development Meeting with international and multidisciplinary participation, including sarcoma patient involvement, where critical aspects of the protocol were discussed and finalized. The international, multi-center SAFETY trial will determine the effect of surveillance strategy on overall patient survival after surgery for a STS of the extremity by comparing the effectiveness of both surveillance frequency (every 3 vs. every 6 months) and imaging modality (CT scans vs. chest radiographs). Ultimately, the SAFETY trial will provide the necessary evidence to develop evidence-based surveillance guidelines, and is poised to have a significant impact on the post-operative care and outcomes of extremity soft-tissue sarcoma patients.

Official Title
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Surveillance AFter Extremity Tumor surgerY (SAFETY) International Randomized Controlled Trial

Conditions
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Soft Tissue Sarcoma, Lung Metastases

Intervention / Treatment
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* Other: Frequency: Every 3 Months
* Other: Frequency: Every 6 Months
* Other: Imaging Modality: Chest Radiograph (CXR)
* Other: Imaging Modality: Chest CT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient is 18 years of age or older; The patient has been diagnosed with a primary extremity grade II or III soft-tissue sarcoma (STS); The patient has undergone surgical excision of the tumor with curative intent and with no evidence of gross residual disease based on the pathology report; The patient has completed all planned neoadjuvant or adjuvant radiation and / or chemotherapy, if applicable; The tumor size is greater than or equal to (≥) five centimeters according to the pathology report or based on the pre-treatment MRI if neoadjuvant radiation and / or chemotherapy are given; and The patient provides informed consent. Exclusion Criteria: The patient has metastases at initial presentation based on the radiology report of the initial thoracic imaging†; The patient has recently undergone surgical excision of a local recurrence; The patient has been diagnosed with one of the special sub-types, myxoid / round cell liposarcoma or extra-skeletal Ewing's sarcoma*; The patient has been previously diagnosed with a genetic syndrome with an elevated risk of malignancy, such as Li-Freumeni Syndrome‡; The patient has been previously diagnosed with a co-morbid condition that has a life expectancy of less than (<) one year; The site-specific surveillance protocol for the patient's disease is not compatible with the study protocol (i.e., regular planned whole-body imaging with positron emission tomography [PET] scans); Likely problems, in the judgment of the investigator, with the patient maintaining follow-up (with the specific reasoning requiring approval of the Methods Center); The patient is currently enrolled in a study that does not permit co-enrolment; and The patient has already been enrolled in the SAFETY trial. A second CT scan may be required to confirm that indeterminate nodules are false positives before the patient can be enrolled (provided that the second CT scan shows no evidence of metastatic disease); Myxoid liposarcoma and extra-skeletal Ewing's sarcoma have different metastatic patterns, which necessitate different surveillance protocols; Individuals with Li-Freumeni Syndrome, or other genetic syndromes with an elevated risk of malignancy, appear to be at an elevated risk for radiation-induced cancers, so the use of CT scans should be limited.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: 2 x 2 factorial superiority randomized controlled trial
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Surveillance Arm I<br>Clinical assessment and chest radiograph (CXR) every six months for two years | Other: Frequency: Every 6 Months<br>* every 6 months<br>Other: Imaging Modality: Chest Radiograph (CXR)<br>* Chest radiograph (CXR)<br>|
| Experimental: Surveillance Arm II<br>Clinical assessment and CXR every three months for two years | Other: Frequency: Every 3 Months<br>* every 3 months<br>Other: Imaging Modality: Chest Radiograph (CXR)<br>* Chest radiograph (CXR)<br>|
| Experimental: Surveillance Arm III<br>Clinical assessment and chest computed tomography (CT) every six months for two years | Other: Frequency: Every 6 Months<br>* every 6 months<br>Other: Imaging Modality: Chest CT<br>* Chest computed tomography (CT)<br>|
| Experimental: Surveillance Arm IV<br>Clinical assessment and chest CT every three months for two years | Other: Frequency: Every 3 Months<br>* every 3 months<br>Other: Imaging Modality: Chest CT<br>* Chest computed tomography (CT)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | as measured by death from any cause. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient Anxiety | The PROMIS® Cancer-Anxiety instrument assesses self-reported fear (fearfulness, panic), anxious misery (worry, dread), hyperarousal (tension, nervousness, restlessness), and somatic symptoms related to arousal (racing heart, dizziness). The PROMIS® Cancer-Anxiety instrument is a computer adaptive test. A minimum of 4 questions must be answered. One's responses will guide the system's choice of the next question. The test will continue until either the standard error drops below a specified level or the participant has answered the maximum number of 12 questions (whichever comes first). Each question has 5 response options ranging in value from 1 to 5. To find the raw score, sum the values of the response to each question. The lowest possible raw score is 4 and the highest is 60. The raw score will then be converted into a standardized T-score for each participant using the applicable conversion table. A higher T-score represents a higher degree of anxiety. | 5 years | 
| Patient Satisfaction | The PROMIS® Satisfaction with Social Roles & Activities instrument assesses satisfaction with performing one's usual social roles and activities (e.g., 'I am satisfied with my ability to participate in family activities'). This instrument is a computer adaptive test. A minimum of 4 questions must be answered. One's response will guide the system's choice of the next question. The test will continue until either the standard error drops below a specified level or the participant has answered the maximum number of 12 questions (whichever comes first). Each question has 5 response options ranging in value from 1 to 5. To find the raw score, sum the values of the response to each question. The lowest possible raw score is 4 and the highest possible raw score is 60. The raw score will then be converted into a standardized T-score for each participant using the applicable conversion table. A higher T-score represents a higher degree of satisfaction. | 5 years | 
| Patient Quality-of-Life | The validated EuroQol-5 Dimension 5-level (EQ-5D-5L) questionnaire measures generic health status and consists of 2 sections: the descriptive system and the Visual Analogue Scale (VAS). The descriptive system is comprised of 5 dimensions (mobility, self care, usual activities, pain / discomfort and anxiety / depression). Each question has 5 response options ranging in value from 1 to 5. To find the raw score, sum the values of the response to each question. The lowest possible raw score is 5 and the highest is 25. A lower raw score in the descriptive system represents fewer issues with each of the 5 domains. The VAS records a participant's self-rated health from 0 to 100 on a vertical VAS with endpoints labeled '100 - the best health you can imagine' and '0 - the worst health you can imagine'. The participant is asked to mark an 'X' on the scale and write the corresponding number, which is this section's raw score. | 5 years | 
| Local Recurrence-Free Survival | As measured by the length of time from the time of randomization that the participant survives with no detection of recurrent disease at the initial tumor site or operative field. | 5 years | 
| Metastasis-Free Survival | As measured by as the length of time from the time of randomization that the participant survives with no detection of systemic disease recurrence at any anatomic location. | 5 years | 
| Treatment-Related Complications | Will include both chemotherapy-related complications, such as febrile neutropenia, fungal infections or sepsis, and thoracotomy-related complications, such as pneumothorax or surgical site infections. | 5 years | 
| Net Healthcare Costs | Will include both the net costs of surveillance and costs incurred from metastasis treatment and metastasis treatment-related complications. | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Soft Tissue Sarcoma, Lung Metastases, Overall Survival, Surveillance, Randomized Controlled Trial