Thoracotomy Versus Thoracoscopic Management of Pulmonary Metastases in Patients With Osteosarcoma

• ClinicalTrials.gov Identifier: NCT05235165
• Recruitment Status: Recruiting
• First Posted: February 11, 2022
• Last Update Posted: May 23, 2023
• Sponsor: Children's Oncology Group
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Children's Oncology Group

Tracking Information

• First Submitted Date: January 19, 2022
• First Posted Date: February 11, 2022
• Last Update Posted Date: May 23, 2023
• Actual Study Start Date: February 15, 2022
• Estimated Primary Completion Date: March 31, 2031 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 18, 2022)

Thoracic event-free survival (tEFS) [ Time Frame: Four years after enrollment ]

Estimated four year thoracic event free survival (tEFS) where tEFS is calculated as the time from study enrollment. Any recurrence within the pulmonary parenchyma, involving the pleural surface or the drain/surgical site wound will be considered an event. A death that results from the procedure, as confirmed by the treating physician, will be considered an event. Patients with recurrences arising outside the thoracic region, the diagnosis of a malignancy that is not osteosarcoma (SMN) or death considered unrelated to the study surgical procedure, as confirmed by the treating physician will be considered competing events provided these occur prior to a thoracic cavity event as defined above. Patients without an event of any kind at last contact are considered censored.

Original Primary Outcome Measures (submitted: January 31, 2022)

Thoracic event-free survival (tEFS) [ Time Frame: Number of days from randomization until the ascertainment of a tEFS-event, a competing event or last patient contact without an event, assessed up to 12 months after last patient is enrolled ]

A 1-sided log rank test of size 0.05 will be used to test the null hypothesis H0: the cause-specific relative risk of a thoracic event associated with a thoracotomy is 1; with the alternative hypothesis H1: the cause-specific relative risk of a thoracic event associated with a thoracotomy is less than 1.

Current Secondary Outcome Measures (submitted: May 18, 2022)

• Event free survival (EFS) [ Time Frame: Four years after enrollment ]
  Estimated four year EFS where EFS is calculated as the time from study enrollment to disease progression, disease relapse, occurrence of a second malignant neoplasm, death from any cause or last follow-up whichever occurs first. Patients without an event at last contact are considered censored.
• Overall survival (OS) [ Time Frame: Four years after enrollment ]
  Time from study enrollment to death or last patient contact. Patients alive at last contact are considered censored.
• Post operative pain interference at time point 3, 7-14 days after surgical intervention [ Time Frame: 7-14 days after surgical intervention ]
  Total PROMIS pain interference score from the 8 item PROMIS pain interference short form.
• Post operative pain interference at time point 4, 4-6 weeks after surgical intervention [ Time Frame: 4-6 weeks after surgical intervention ]
  Total PROMIS pain interference score from the 8 item PROMIS pain interference short form.

Original Secondary Outcome Measures (submitted: January 31, 2022)

• Event free survival (EFS) [ Time Frame: From randomization until disease progression or recurrence at any site, diagnosis of an malignancy that is not osteosarcoma (SMN), death or last follow-up whichever is first observed, assessed up to 12 months after last patient is enrolled ]
  A patient who experiences disease progression or recurrence, is diagnosed with an SMN or dies will be considered to have experienced and EFS-event; otherwise the patient will be censored at last contact. The proportion of patients alive and the proportion considered EFS-event-free as a function of time since randomization will be estimated by the method of Kaplan and Meier.
• Overall survival (OS) [ Time Frame: From randomization until death or last follow-up, assessed up to 12 months after last patient is enrolled ]
  The proportion of patients alive as a function of time since randomization will be estimated by the method of Kaplan and Meier. Pointwise confidence intervals will be calculated using the complementary log-log transformation of the Kaplan-Meier estimate.
• Post operative pain interference at time point 3, 7-14 days after surgical intervention [ Time Frame: 7-14 days after surgical intervention ]
  Total PROMIS pain interference score from the 8 item PROMIS pain interference short form
• Post operative pain interference at time point 4, 4-6 weeks after surgical intervention [ Time Frame: 4-6 weeks after surgical intervention ]
  Total PROMIS pain interference score from the 8 item PROMIS pain interference short form

Current Other Pre-specified Outcome Measures (submitted: May 18, 2022)

• Perioperative surgical complications [ Time Frame: At 30 days post-op ]
  The descriptions and grading scales found in the revised National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 will be utilized for AE reporting.
• Mode of tEFS event [ Time Frame: Four years after enrollment ]
  Classified as: (1) ipsilateral recurrence site; (2) contralateral recurrence site; or (3) ipsilateral and contralateral recurrence site. The analysis will be restricted to patients with unilateral disease at enrollment.
• Use of localization techniques [ Time Frame: 12 months after enrollment ]
  Data collection will include a description of all localization methods used.
• Decision to change the post-operative treatment plan [ Time Frame: 12 months after enrollment ]
  Whether the investigator adhered to the post-thoracic surgery plan for systemic therapy.
• Radiological features to the presence of viable tumor [ Time Frame: 12 months after enrollment ]
  Radiological features and pathological characteristics of lung nodules contributed by the same patient.
• Post operative upper extremity function at time point 2, 24-48 hours after surgical intervention [ Time Frame: 24-48 hours after surgical intervention ]
  Total PROMIS upper extremity score from the 8 item PROMIS upper extremity short form.
• Post operative upper extremity function at time point 3, 7-14 days after surgical intervention [ Time Frame: 7-14 days after surgical intervention ]
  Total PROMIS upper extremity score from the 8 item PROMIS upper extremity short form.
• Post operative pain intensity at time point 2, 24-48 hours after surgical intervention [ Time Frame: 24-48 hours after surgical intervention ]
  NRS 11 single item pain intensity score.
• Post operative pain intensity at time point 3, 7-14 days after surgical intervention [ Time Frame: 7-14 days after surgical intervention ]
  NRS 11 single item pain intensity score.
• Frequency of obtaining quality tumor tissue for biological analysis [ Time Frame: 1 month after surgical intervention ]
  Tumor samples obtained from the surgical procedure that are submitted to the COG tissue bank and subjected to dual nucleic acid extraction will be classified by central review as to whether sufficient tumor content was obtained for ultra low passage whole genome sequencing.

Original Other Pre-specified Outcome Measures (submitted: January 31, 2022)

• Perioperative surgical complications [ Time Frame: At 30 days post-op ]
  The descriptions and grading scales found in the revised National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 will be utilized for AE reporting.
• Mode of tEFS event [ Time Frame: Up to 12 months after last patient is enrolled ]
  Classified as: (1) ipsilateral recurrence site; (2) contralateral recurrence site; or (3) ipsilateral and contralateral recurrence site. The analysis will be restricted to patients with unilateral disease at enrollment. The proportional hazards regression model will be used to evaluate each type of recurrence where all other recurrence modes and non-relapse EFS-events will be considered censoring events
• Use of localization techniques [ Time Frame: Up to 12 months after last patient is enrolled ]
  Data collection will include a description of all localization methods used and the analysis techniques described subsequently will be applied if sufficient instances of any other technique are observed. Will present Kaplan-Meier estimates of tEFS, EFS, and OS outcomes according to randomized surgical procedure in groups defined by each of the localization techniques used.
• Prognostic significance of a decision to change the post-operative treatment plan [ Time Frame: Up to 12 months after last patient is enrolled ]
  Will be conducted using comparing the cause-specific risk for tEFS-event and the risk for an EFS event between patient groups defined by whether the investigator adhered to the post-thoracic surgery plan for systemic therapy. For these analyses a landmark analysis will be conducted; tEFS and EFS time will be modified to count the number of days starting two weeks after the surgery is completed. The power associated with such analyses to differences in risk for tEFS and EFS event will be limited.
• Comparing radiological features to the presence of viable tumor [ Time Frame: Up to 12 months after last patient is enrolled ]
  Statistical assessment of the relationship between radiological features and pathological characteristics will be done acknowledging that lung nodules contributed by the same patient likely are correlated using a population average model fitted by generalized estimating equations. Statistical significance will be assessed using the asymptotic distribution of the coefficient of the characteristic of interest. Will control the false discovery rate at 0.05 in the same manner as with the principal analysis for this aim.
• Post operative upper extremity function at time point 2, 24-48 hours after surgical intervention [ Time Frame: 24-48 hours after surgical intervention ]
  Total PROMIS upper extremity score from the 8 item PROMIS upper extremity short form
• Post operative upper extremity function at time point 3, 7-14 days after surgical intervention [ Time Frame: 7-14 days after surgical intervention ]
  Total PROMIS upper extremity score from the 8 item PROMIS upper extremity short form
• Post operative pain intensity at time point 2, 24-48 hours after surgical intervention [ Time Frame: 24-48 hours after surgical intervention ]
  NRS 11 single item pain intensity score
• Post operative pain intensity at time point 3, 7-14 days after surgical intervention [ Time Frame: 7-14 days after surgical intervention ]
  NRS 11 single item pain intensity score
• Frequency of obtaining quality tumor tissue for biological analysis [ Time Frame: 1 month after surgical intervention ]
  Tumor samples obtained from the surgical procedure that are submitted to the COG tissue bank and subjected to dual nucleic acid extraction will be classified by central review as to whether sufficient tumor content was obtained for ultra low passage whole genome sequencing

Descriptive Information

• Brief Title: Thoracotomy Versus Thoracoscopic Management of Pulmonary Metastases in Patients With Osteosarcoma
• Official Title: A Phase 3 Randomized Controlled Trial Comparing Open vs Thoracoscopic Management of Pulmonary Metastases in Patients With Osteosarcoma
• Brief Summary: This phase III trial compares the effect of open thoracic surgery (thoracotomy) to thoracoscopic surgery (video-assisted thoracoscopic surgery or VATS) in treating patients with osteosarcoma that has spread to the lung (pulmonary metastases). Open thoracic surgery is a type of surgery done through a single larger incision (like a large cut) that goes between the ribs, opens up the chest, and removes the cancer. Thoracoscopy is a type of chest surgery where the doctor makes several small incisions and uses a small camera to help with removing the cancer. This trial is being done evaluate the two different surgery methods for patients with osteosarcoma that has spread to the lung to find out which is better.

Detailed Description

PRIMARY OBJECTIVE:

I. To determine if open surgical resection is superior to thoracoscopic resection for thoracic event-free survival (tEFS) in patients with resectable oligometastatic pulmonary osteosarcoma.

SECONDARY OBJECTIVES:

I. To determine if open surgical resection is superior to thoracoscopy for event free survival (EFS) in patients with resectable oligometastatic pulmonary osteosarcoma.

II. To determine if open surgical resection is superior to thoracoscopy for overall survival (OS) in patients with resectable oligometastatic pulmonary osteosarcoma.

III. To determine if thoracoscopy is superior to open surgical resection for post-operative pain interference in patients with resectable oligometastatic pulmonary osteosarcoma.

EXPLORATORY OBJECTIVES:

I. To compare 30-day rates of perioperative surgical complications for both open surgical resection and thoracoscopy.

II. To compare patterns of recurrence (ipsilateral and/or contralateral) in patients who undergo open or thoracoscopic resection for unilateral or bilateral pulmonary metastases.

III. To describe the use of localization techniques and its relationship with both surgical approach and pathologic findings.

IV. To assess the prognostic significance of a decision to change the post-operative treatment plan.

V. To describe the relationship between the preoperative chest computed tomography (CT) imaging, intraoperative surgical findings, and pathologic results, comparing radiological features to the presence of viable tumor.

VI. To prospectively compare between treatment arms the relationship between surgical approach and patient-reported outcomes (PROs), specifically patient functional impairment of the upper extremities, pain intensity, and health-related quality of life (HRQoL).

VII. To generate well-characterized, clinically-annotated, distributable models of metastatic osteosarcoma.

VIII. To collect and bank pulmonary metastatic lesions (including frozen tissues and paired metastatic lesions coming from the same patient) to facilitate study of metastatic disease and serial blood samples for future tumor profiling, germline and circulating tumor deoxyribonucleic acid (DNA) studies.

OUTLINE: Patients are randomized into 1 of 2 arms.

ARM A: Patients undergo open thoracic surgery (thoracotomy).

ARM B: Patients undergo thoracoscopy (video-assisted thoracoscopic surgery or VATS).

All patients undergo computed tomography (CT) throughout the trial. Patients may also undergo collection of tissue on study and blood throughout the trial.

After completion of study treatment, patients are followed up at 7-14 days, 4-6 weeks, and 3 months post-surgery and then every 3 months for up to 2 years.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Metastatic Malignant Neoplasm in the Lung
• Metastatic Osteosarcoma
• Osteosarcoma

Intervention

• Procedure: Biospecimen Collection
  Undergo collection of tissue and blood
  Other Names:

  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection
• Procedure: Computed Tomography
  Undergo CT
  Other Names:

  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized axial tomography (procedure)
  • Computerized Tomography
  • CT
  • CT Scan
  • tomography
• Other: Questionnaire Administration
  Ancillary studies
• Procedure: Thoracoscopy
  Undergo video-assisted thoracoscopic surgery or VATS
  Other Name: Pleuroscopy
• Procedure: Thoracotomy
  Undergo open thoracic surgery
  Other Names:

  • incision of Chest Wall
  • Incision of Thorax

Study Arms

• Experimental: Arm A (thoracotomy)
  Patients undergo open thoracic surgery (thoracotomy). Patients undergo CT throughout the trial. Patients may also undergo collection of tissue on study and blood throughout the trial.
  Interventions:

  • Procedure: Biospecimen Collection
  • Procedure: Computed Tomography
  • Other: Questionnaire Administration
  • Procedure: Thoracotomy
• Experimental: Arm B (thoracoscopy)
  Patients undergo thoracoscopy (video-assisted thoracoscopic surgery or VATS). Patients undergo CT throughout the trial. Patients may also undergo collection of tissue on study and blood throughout the trial.
  Interventions:

  • Procedure: Biospecimen Collection
  • Other: Questionnaire Administration
  • Procedure: Thoracoscopy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: January 31, 2022): 250
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 31, 2031
• Estimated Primary Completion Date: March 31, 2031 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patients must be < 50 years at the time of enrollment.

• Patients must have =< 4 nodules per lung consistent with or suspicious for metastases, with at least one of which being >= 3 mm and all of which must be =< 3 cm size.

  • Note: Patient must have eligibility confirmed by rapid central imaging review.
• Lung nodules must be considered resectable by either open thoracotomy or thoracoscopic surgery. Determination of resectability is made by the institutional surgeon.
• Patients must have a histological diagnosis of osteosarcoma.
• Patients must have evidence of metastatic lung disease at the time of initial diagnosis, or at time of 1st recurrence following completion of therapy for initially localized disease.
• Patients with newly diagnosed disease must have completed successful gross tumor resection for their primary tumor or surgical local control of primary tumor must be planned to be performed simultaneously with thoracic surgery.
• Newly diagnosed patients must be receiving systemic therapy considered by the treating physician as at least equivalent to methotrexate, doxorubicin and cisplatin (MAP) at the time of enrollment on this study.
• Patients at time of 1st recurrence must have previously completed initial systemic therapy for their primary tumor, considered by the treating physician as at least equivalent to MAP.

Exclusion Criteria:

• Patients with unresectable primary tumor.
• Patients with pulmonary metastatic lesions that would require anatomic resection (lobectomy or pneumonectomy) or lesions that are defined as "central" (i.e., central lesion involves or is proximal to segmental bronchi and peripheral is lesion distal to segmental bronchi).
• Patients with pleural or mediastinal based metastatic lesions, or with pleural effusion.
• Patients with disease progression at either the primary or pulmonary metastatic site while on initial therapy. Note: Once the patient has been enrolled on the study, additional computed tomography (CT) scans are not anticipated prior to thoracic surgery. Note: Some variation in nodule size measurements over the course of pre-operative therapy is anticipated and does not qualify for exclusion unless deemed true disease progression by the primary treatment team.
• Patients with evidence of extrapulmonary metastatic disease.
• Patients who received therapeutic pulmonary surgery for lung metastasis prior to enrollment.
• All patients and/or their parents or legal guardians must sign a written informed consent.
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 50 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: Australia, Canada, New Zealand, Puerto Rico, United States

Administrative Information

• NCT Number: NCT05235165
• Other Study ID Numbers: AOST2031; NCI-2021-14237 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); AOST2031 ( Other Identifier: Children's Oncology Group ); AOST2031 ( Other Identifier: CTEP ); U10CA180886 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Children's Oncology Group
• Original Responsible Party: Same as current
• Current Study Sponsor: Children's Oncology Group
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: John J Doski; Children's Oncology Group

• PRS Account: Children's Oncology Group
• Verification Date: May 2023