Surveillance AFter Extremity Tumor surgerY (SAFETY)

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

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 randomized 310 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).

Study Overview

• Status: Active, not recruiting
• Conditions: Soft Tissue Sarcoma; Lung Metastases
• Intervention / Treatment: Other: Frequency: Every 6 Months; Other: Imaging Modality: Chest Radiograph (CXR); Other: Frequency: Every 3 Months; Other: Imaging Modality: Chest CT

Detailed Description

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 patient-important outcomes 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 STS patients.

• Study Type: Interventional
• Enrollment (Actual): 310
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Hospital Universitario Austral
• Australia
  • Melbourne
    • Fitzroy, Melbourne, Australia, 3065
      • St. Vincent's Hospital Melbourne
• Austria
  • Graz, Austria, 8036
    • LKH - Universitätsklinikum Graz
• Belgium
  • Brussels, Belgium
    • Cliniques Universitaires Saint-luc
• Brazil
  • Porto Alegre, Brazil
    • Hospital de Clínicas de Porto Alegre
• Canada
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 3A7
      • Nova Scotia Health
  • Ontario
    • Hamilton, Ontario, Canada, L8V1C3
      • Juravinski Hospital and Cancer Centre
    • Ottawa, Ontario, Canada
      • The Ottawa Hospital
    • Toronto, Ontario, Canada, M5G 1X5
      • Mount Sinai Hospital
  • Quebec
    • Montréal, Quebec, Canada, H1T 2M4
      • Hôpital Maisonneuve-Rosemont
    • Montréal, Quebec, Canada, H4A 3J1
      • McGill University Health Centre
    • Québec, Quebec, Canada, G1R 2J6
      • Hôtel Dieu du Quebec
• Germany
  • Berlin, Germany
    • Helios Klinikum Berlin
• Italy
  • Turin, Italy
    • Centro Traumatologico Ortopedico Hospital
• Malaysia
  • Kuala Lumpur, Malaysia
    • University Malaya Kuala Lumpur
• Netherlands
  • Leiden, Netherlands
    • Leiden University Medical Center
• Portugal
  • Coimbra, Portugal
    • Centro Hospitalar e Universitario de Coimbra
• Spain
  • Barcelona, Spain
    • Hospital Vall d'Hebron
• Sweden
  • Stockholm, Sweden
    • Karolinska University Hospital
• United States
  • California
    • Sacramento, California, United States, 95817
      • University of California Davis Medical Center
  • Connecticut
    • Hartford, Connecticut, United States, 06102
      • Hartford Healthcare
  • Florida
    • Gainesville, Florida, United States, 32608
      • University of Florida Health Shands Hospital
  • Illinois
    • Chicago, Illinois, United States, 60637
      • UChicago Medicine
  • Indiana
    • Fort Wayne, Indiana, United States, 46845
      • Parkview Cancer Institute
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Holden Comprehensive Cancer Center
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical Center
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • New York, New York, United States, 10010
      • NYU Langone Orthopaedic Hospital/Perlmutter Cancer Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University Hospital
  • Pennsylvania
    • Monroeville, Pennsylvania, United States, 15212
      • Allegheny Health Network Research Institute
  • Texas
    • El Paso, Texas, United States, 79905
      • Texas Tech Health Sciences Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hierarchal Composite Outcome of Patient-Important Outcomes	The composite outcome consists of overall survival, serious adverse events, and patient-reported cancer-related anxiety	3 years post randomization

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.	3 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.	3 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.	3 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.	3 years
Metastasis-Free Survival	As measured by the length of time from the time of randomization that the participant survives with no detection of systemic disease recurrence at any anatomic location.	3 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.	3 years
Net Healthcare Costs	Will include both the net costs of surveillance and costs incurred from metastasis treatment and metastasis treatment-related complications.	3 years

Collaborators and Investigators

• Sponsor: McMaster University
• Collaborators: Canadian Institutes of Health Research (CIHR); Canadian Cancer Society (CCS); Hamilton Academic Health Sciences Organization; Musculoskeletal Tumor Society; American Academy of Orthopaedic Surgeons
• Investigators: Principal Investigator: Michelle Ghert, MD, McMaster University

Publications and helpful links

General Publications

• SAFETY Investigators. The Surveillance After Extremity Tumor Surgery (SAFETY) trial: protocol for a pilot study to determine the feasibility of a multi-centre randomised controlled trial. BMJ Open. 2019 Sep 18;9(9):e029054. doi: 10.1136/bmjopen-2019-029054.

Helpful Links

• Optimal surveillance strategies following curative surgery for extremity sarcoma: A systematic review of Randomized Control Trials [published in pre-print].
• Surveillance AFter Extremity Tumor surgerY (SAFETY): A Protocol for an International Randomized Controlled Trial [published in pre-print].
• The Surveillance After Extremity Tumor Surgery (SAFETY) Pilot International Multi-Center Randomized Controlled Trial

Study record dates

Study Major Dates

• Study Start (Actual): November 19, 2019
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: May 7, 2019
• First Submitted That Met QC Criteria: May 8, 2019
• First Posted (Actual): May 10, 2019

Study Record Updates

• Last Update Posted (Estimated): November 22, 2024
• Last Update Submitted That Met QC Criteria: November 20, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Randomized Controlled Trial; Surveillance; Soft Tissue Sarcoma; Overall Survival; Lung Metastases; Serious Adverse Events; Patient Anxiety
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplasms by Histologic Type; Neoplastic Processes; Neoplasms, Connective and Soft Tissue; Neoplasm Metastasis; Sarcoma
• Other Study ID Numbers: GHRT02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No