Non-small Cell Lung Cancer, Renal Cell Carcinoma
Conditions
Keywords
Surgery
Brief summary
This is a pilot study of biomarker evaluation and safety of pre-incisional ketorolac for patients undergoing surgical resection for non-small cell lung cancer and renal cell carcinoma. There is significant promise in the use of preoperative ketorolac to decrease the inflammatory response after surgical resection of tumors, thereby potentially reducing the risk of distant metastatic tumor spread and improving survival. This research will advance scientific knowledge by studying the safety of a preoperative dose of ketorolac prior to major surgical resection, which needs to be assessed prior to proceeding with a larger phase II study designed to evaluate traditional efficacy endpoints such as recurrence and overall survival.
Detailed description
Surgical resection is a cornerstone of standard-of-care treatment for early-stage non-small cell lung carcinoma (NSCLC) and renal cell carcinoma (RCC). Yet despite optimal treatment, many of these patients will develop cancer recurrence within the first few years. For example, the 5-year survival rate for patients with stage I/II NSCLC is only around 55%. As a result, more effective treatments that decrease cancer recurrence and increase survival are still needed. Surgery induces inflammation, immunosuppression and angiogenesis. Although these processes are important for wound healing in response to tissue injury caused by surgery, they also support the survival, growth and dissemination of any remaining cancer cells and can lead to systemic recurrence soon after surgery. Surgical trauma increases the production of prostaglandins and thromboxanes, which have tumor-promoting and immunosuppressive activities, and reduces the activity of natural killer cells, which impairs the ability of the immune system to keep cancer cells in check. However, if given just before tissue injury, non-steroidal anti-inflammatory drugs (NSAIDs) may be able to block the production of prostaglandins/thromboxanes and boost the activity of natural killer cells, and thereby decrease the risk of cancer recurrence. NSAIDs such as ketorolac are already routinely given to cancer patients postoperatively for pain management and are sometimes given intraoperatively (immediately before or during surgery) to prevent postoperative pain. A retrospective clinical analysis found that intraoperative intravenous ketorolac or diclofenac (another NSAID), when added to standard of care for patients with stage I/II NSCLC, was associated with decreased risks of distant recurrence and mortality. In this study, patients with NSCLC or RCC will be screened and recruited during the preoperative period by the responsible medical and surgical team. Participants will be randomized on the day of surgery to either the preoperative ketorolac group or a concurrent control group who will not receive preincisional ketorolac. Participants will be followed for 28 days.
Interventions
DRUGPreoperative Ketorolac
30 mg ketorolac will be administered intravenously 30 minutes prior to incision.
Sponsors
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Pathology-proven or suspected stage 1 or 2 NSCLC and Stage 3 tumor stage 3, node stage 0 (T3N0) RCC, that require surgical resection as the treatment of choice * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 * Ability to understand and the willingness to sign an informed written consent
Exclusion criteria
* Individuals with pure lung ground-glass opacity (GGO) lesions or mixed GGO with \<50% solid component * Patients undergoing pneumonectomy * History of cancer in the 3 years prior to surgery (except for basal-cell carcinoma of the skin or cervical neoplasia). * Contraindication for NSAIDs, including peptic ulcer disease, preoperative chronic kidney disease with estimated glomerular filtration rate (eGFR) \<45, allergies or intolerance to NSAIDs, coagulation disorder, or age \> 80 years * Having taken an NSAID within 5 days prior to surgery * Immunocompromised status * Refusal or inability to understand the protocol and consent form or to receive follow-up in line with the recommendations * Preoperative hemoglobin \< 9.0
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Receiving a Blood Transfusion | Prior to Hospital Discharge (up to 13 days post surgery) | Hemorrhagic side effects among participants receiving ketorolac preoperatively will be assessed as the need for blood transfusions before being discharged from the hospital after surgery. The need for a blood transfusion is defined as needing two or more units of blood, which are not related to vascular injury due to technical considerations or complications, as determined by the operating surgeon. |
| Number of Participants Experiencing Clinically Significant Hematoma Development | Prior to Hospital Discharge (up to 13 days post surgery) | Post-surgical significant hematoma development is assessed as the number of participants experiencing a hematoma prior to hospital discharge. |
| Number of Participants Returning to the Operating Room for Bleeding | Prior to Hospital Discharge (up to 13 days post surgery) | Post-operative bleeding is assessed at the number of participants needing to return to the operating room for bleeding, as determined by the treating surgeon. |
| Number of Participants Experiencing Postoperative Renal Failure | Prior to Hospital Discharge (up to 13 days post surgery) | Postoperative renal failure is assessed as the number of participants experiencing renal failure prior to hospital discharge. |
| Number of Participants Experiencing Postoperative Morbidity | Prior to Hospital Discharge (up to 13 days post surgery) | Postoperative morbidity is assessed as the count of participants experiencing at least one adverse event or serious adverse event from surgery to hospital discharge. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Interleukin-1beta (IL-1β) Levels | Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28 | IL-1beta levels will be compared between study arms. |
| Interleukin-2 (IL-2) Levels | Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28 | IL-2 levels will be compared between study arms. |
| Interleukin-6 (IL-6) Levels | Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28 | IL-6 levels will be compared between study arms. |
| Interleukin-8 (IL-8) Levels | Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28 | IL-8 levels will be compared between study arms. |
| Interleukin-10 (IL-10) Levels | Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28 | IL-10 levels will be compared between study arms. |
| Transcriptome Analysis | Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28 | Transcriptome analysis will be performed to evaluate the effects of ketorolac on immune response pathways. |
| Tumor Necrosis Factor-alpha (TNF-alpha) Levels | Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28 | TNF-alpha levels will be compared between study arms. |
| Interferon (INF)-Gamma Levels | Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28 | INF-gamma levels will be compared between study arms. |
| Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) Levels | Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28 | GM-CSF levels will be compared between study arms. |
| Monocyte Chemotactic and Activating Factor (MCAF) Levels | Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28 | MCAF levels will be compared between study arms. |
| Interleukin-12p70 (IL-12p70) Levels | Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28 | IL-12p70 levels will be compared between study arms. |
| Flow Cytometry | Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28 | Flow Cytometry will be performed to evaluate the effects of ketorolac on immune response pathways. |
| T-Cell Receptor (TCR) Sequencing | Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28 | T-Cell receptor (TCR) sequencing will be performed to evaluate the effects of ketorolac on immune response pathways. |
| Single Cell RNA Sequencing | Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28 | Single cell RNA sequencing will be performed to evaluate the effects of ketorolac on immune response pathways. |
| Interleukin-1 Alpha (IL-1alpha) Levels | Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28 | IL-1alpha levels will be compared between study arms. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from the Emory Clinic, Emory University Hospital Midtown, Emory University Hospital, and the Winship Cancer Institute in Atlanta, Georgia, USA. Participant enrollment began August 24, 2020 the final study assessment occurred February 1, 2024.
Participants by arm
| Arm | Count |
|---|---|
| Preoperative Ketorolac For Participants With Non-small Cell Lung Carcinoma (NSCLC) Participants randomized to receive ketorolac prior to surgery for stage I/II non-small cell lung carcinoma (NSCLC). Participants receive standard-of-care surgery. Open, video-assisted thoracic surgery, laparoscopy, or robotic surgery are allowed. Standard anesthesia is administered.
Preoperative Ketorolac: 30 mg ketorolac will be administered intravenously 30 minutes prior to incision. | 14 |
| Control Group For Participants With Non-small Cell Lung Carcinoma (NSCLC) Participants randomized to the control group receiving the standard of care during surgery for stage I/II non-small cell lung carcinoma (NSCLC). Open, video-assisted thoracic surgery, laparoscopy, or robotic surgery are allowed. Standard anesthesia is administered. The concurrent control group is to obtain untreated biologic samples for biologic correlative studies and secondary endpoints. | 6 |
| Preoperative Ketorolac For Participants With Renal Cell Carcinoma (RCC) Participants randomized to receive ketorolac prior to surgery for stage III renal cell carcinoma (RCC). Participants receive standard-of-care surgery. Open, video-assisted thoracic surgery, laparoscopy, or robotic surgery are allowed. Standard anesthesia is administered.
Preoperative Ketorolac: 30 mg ketorolac will be administered intravenously 30 minutes prior to incision. | 28 |
| Control Group For Participants With Renal Cell Carcinoma (RCC) Participants randomized to the control group receiving the standard of care during surgery for stage III renal cell carcinoma (RCC). Open, video-assisted thoracic surgery, laparoscopy, or robotic surgery are allowed. Standard anesthesia is administered. The concurrent control group is to obtain untreated biologic samples for biologic correlative studies and secondary endpoints. | 10 |
| Total | 58 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Early termination | 0 | 0 | 3 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 2 | 3 |
Baseline characteristics
| Characteristic | Preoperative Ketorolac For Participants With Non-small Cell Lung Carcinoma (NSCLC) | Total | Control Group For Participants With Renal Cell Carcinoma (RCC) | Preoperative Ketorolac For Participants With Renal Cell Carcinoma (RCC) | Control Group For Participants With Non-small Cell Lung Carcinoma (NSCLC) |
|---|---|---|---|---|---|
| Age, Continuous | 67.2 years STANDARD_DEVIATION 6.2 | 62.2 years STANDARD_DEVIATION 12.1 | 62.2 years STANDARD_DEVIATION 13.6 | 59.9 years STANDARD_DEVIATION 13.9 | 61.2 years STANDARD_DEVIATION 8.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 45 Participants | 8 Participants | 17 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 12 Participants | 2 Participants | 10 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 10 Participants | 3 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 7 Participants | 1 Participants | 6 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 39 Participants | 6 Participants | 17 Participants | 4 Participants |
| Region of Enrollment United States | 14 Participants | 58 Participants | 10 Participants | 28 Participants | 6 Participants |
| Sex: Female, Male Female | 9 Participants | 26 Participants | 2 Participants | 10 Participants | 5 Participants |
| Sex: Female, Male Male | 5 Participants | 32 Participants | 8 Participants | 18 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 6 | 0 / 28 | 0 / 10 |
| other Total, other adverse events | 6 / 14 | 1 / 6 | 16 / 28 | 6 / 10 |
| serious Total, serious adverse events | 2 / 14 | 0 / 6 | 1 / 28 | 2 / 10 |
Outcome results
Primary
Number of Participants Experiencing Clinically Significant Hematoma Development
Post-surgical significant hematoma development is assessed as the number of participants experiencing a hematoma prior to hospital discharge.
Time frame: Prior to Hospital Discharge (up to 13 days post surgery)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Preoperative Ketorolac For Participants With Non-small Cell Lung Carcinoma (NSCLC) | Number of Participants Experiencing Clinically Significant Hematoma Development | 0 Participants |
| Control Group For Participants With Non-small Cell Lung Carcinoma (NSCLC) | Number of Participants Experiencing Clinically Significant Hematoma Development | 0 Participants |
| Preoperative Ketorolac For Participants With Renal Cell Carcinoma (RCC) | Number of Participants Experiencing Clinically Significant Hematoma Development | 1 Participants |
| Control Group For Participants With Renal Cell Carcinoma (RCC) | Number of Participants Experiencing Clinically Significant Hematoma Development | 0 Participants |
Primary
Number of Participants Experiencing Postoperative Morbidity
Postoperative morbidity is assessed as the count of participants experiencing at least one adverse event or serious adverse event from surgery to hospital discharge.
Time frame: Prior to Hospital Discharge (up to 13 days post surgery)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Preoperative Ketorolac For Participants With Non-small Cell Lung Carcinoma (NSCLC) | Number of Participants Experiencing Postoperative Morbidity | 6 Participants |
| Control Group For Participants With Non-small Cell Lung Carcinoma (NSCLC) | Number of Participants Experiencing Postoperative Morbidity | 1 Participants |
| Preoperative Ketorolac For Participants With Renal Cell Carcinoma (RCC) | Number of Participants Experiencing Postoperative Morbidity | 14 Participants |
| Control Group For Participants With Renal Cell Carcinoma (RCC) | Number of Participants Experiencing Postoperative Morbidity | 6 Participants |
Primary
Number of Participants Experiencing Postoperative Renal Failure
Postoperative renal failure is assessed as the number of participants experiencing renal failure prior to hospital discharge.
Time frame: Prior to Hospital Discharge (up to 13 days post surgery)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Preoperative Ketorolac For Participants With Non-small Cell Lung Carcinoma (NSCLC) | Number of Participants Experiencing Postoperative Renal Failure | 0 Participants |
| Control Group For Participants With Non-small Cell Lung Carcinoma (NSCLC) | Number of Participants Experiencing Postoperative Renal Failure | 0 Participants |
| Preoperative Ketorolac For Participants With Renal Cell Carcinoma (RCC) | Number of Participants Experiencing Postoperative Renal Failure | 0 Participants |
| Control Group For Participants With Renal Cell Carcinoma (RCC) | Number of Participants Experiencing Postoperative Renal Failure | 1 Participants |
Primary
Number of Participants Receiving a Blood Transfusion
Hemorrhagic side effects among participants receiving ketorolac preoperatively will be assessed as the need for blood transfusions before being discharged from the hospital after surgery. The need for a blood transfusion is defined as needing two or more units of blood, which are not related to vascular injury due to technical considerations or complications, as determined by the operating surgeon.
Time frame: Prior to Hospital Discharge (up to 13 days post surgery)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Preoperative Ketorolac For Participants With Non-small Cell Lung Carcinoma (NSCLC) | Number of Participants Receiving a Blood Transfusion | 0 Participants |
| Control Group For Participants With Non-small Cell Lung Carcinoma (NSCLC) | Number of Participants Receiving a Blood Transfusion | 0 Participants |
| Preoperative Ketorolac For Participants With Renal Cell Carcinoma (RCC) | Number of Participants Receiving a Blood Transfusion | 2 Participants |
| Control Group For Participants With Renal Cell Carcinoma (RCC) | Number of Participants Receiving a Blood Transfusion | 2 Participants |
Primary
Number of Participants Returning to the Operating Room for Bleeding
Post-operative bleeding is assessed at the number of participants needing to return to the operating room for bleeding, as determined by the treating surgeon.
Time frame: Prior to Hospital Discharge (up to 13 days post surgery)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Preoperative Ketorolac For Participants With Non-small Cell Lung Carcinoma (NSCLC) | Number of Participants Returning to the Operating Room for Bleeding | 0 Participants |
| Control Group For Participants With Non-small Cell Lung Carcinoma (NSCLC) | Number of Participants Returning to the Operating Room for Bleeding | 0 Participants |
| Preoperative Ketorolac For Participants With Renal Cell Carcinoma (RCC) | Number of Participants Returning to the Operating Room for Bleeding | 0 Participants |
| Control Group For Participants With Renal Cell Carcinoma (RCC) | Number of Participants Returning to the Operating Room for Bleeding | 0 Participants |
Other Pre-specified
Flow Cytometry
Flow Cytometry will be performed to evaluate the effects of ketorolac on immune response pathways.
Time frame: Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Other Pre-specified
Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) Levels
GM-CSF levels will be compared between study arms.
Time frame: Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Other Pre-specified
Interferon (INF)-Gamma Levels
INF-gamma levels will be compared between study arms.
Time frame: Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Other Pre-specified
Interleukin-10 (IL-10) Levels
IL-10 levels will be compared between study arms.
Time frame: Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Other Pre-specified
Interleukin-12p70 (IL-12p70) Levels
IL-12p70 levels will be compared between study arms.
Time frame: Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Other Pre-specified
Interleukin-1 Alpha (IL-1alpha) Levels
IL-1alpha levels will be compared between study arms.
Time frame: Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Other Pre-specified
Interleukin-1beta (IL-1β) Levels
IL-1beta levels will be compared between study arms.
Time frame: Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Other Pre-specified
Interleukin-2 (IL-2) Levels
IL-2 levels will be compared between study arms.
Time frame: Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Other Pre-specified
Interleukin-6 (IL-6) Levels
IL-6 levels will be compared between study arms.
Time frame: Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Other Pre-specified
Interleukin-8 (IL-8) Levels
IL-8 levels will be compared between study arms.
Time frame: Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Other Pre-specified
Monocyte Chemotactic and Activating Factor (MCAF) Levels
MCAF levels will be compared between study arms.
Time frame: Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Other Pre-specified
Single Cell RNA Sequencing
Single cell RNA sequencing will be performed to evaluate the effects of ketorolac on immune response pathways.
Time frame: Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Other Pre-specified
T-Cell Receptor (TCR) Sequencing
T-Cell receptor (TCR) sequencing will be performed to evaluate the effects of ketorolac on immune response pathways.
Time frame: Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Other Pre-specified
Transcriptome Analysis
Transcriptome analysis will be performed to evaluate the effects of ketorolac on immune response pathways.
Time frame: Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Other Pre-specified
Tumor Necrosis Factor-alpha (TNF-alpha) Levels
TNF-alpha levels will be compared between study arms.
Time frame: Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28