Ignite Creation Date:
2024-05-06 @ 2:30 PM
Last Modification Date:
2024-10-26 @ 1:32 PM
Study NCT ID:
NCT04338867
Status:
COMPLETED
Last Update Posted:
2020-04-22
First Post:
2020-03-05
Brief Title:
Nitroglycerin Plus Intracranial Radiotherapy for Brain Metastases in NSCLC Patients
Sponsor:
Instituto Nacional de Cancerologia de Mexico
Organization:
Instituto Nacional de Cancerologia de Mexico
Study Overview
Official Title:
Nitroglycerin Plus Whole Intracranial Radiotherapy for Brain Metastases in Non-small Cell Lung Cancer Patients a Phase II Open Randomized Clinical Trial
Status:
COMPLETED
Status Verified Date:
2020-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Background Whole-brain radiotherapy WBRT is the standard treatment for multiple brain metastases BM in NSCLC patients who are not candidates for treatment with stereotactic radiation body therapy Hypoxia has been associated with chemo-radioresistance secondary to Vascular Endothelial Growth Factor Receptor VEGFR induced by Hypoxia Induced Factor HIF Nitroglycerin NTG can reduce HIF-1 alfa in tissues and this may have anti-angiogenic pro-apoptotic and anti-efflux effects In this phase II study we evaluated the effect of transdermal nitroglycerin TN on intracranial progression-free survival ICPFS objective response rate ORR and overall survival OS of NSCLC patients with BM
Material and methods We performed an open-label phase II clinical trial among ninety-six histologically confirmed NSCLC patients with BM Patients were randomized 11 to receive NTG plus WBRT or WBRT alone ORR and ICPFS were evaluated by MRI by two independent blinded radio-oncologists
Material and methods We performed an open-label phase II clinical trial among ninety-six histologically confirmed NSCLC patients with BM Patients were randomized 11 to receive NTG plus WBRT or WBRT alone ORR and ICPFS were evaluated by MRI by two independent blinded radio-oncologists
Detailed Description:
Non-small cell Lung cancer NSCLC is the most frequent type of lung cancer worldwide Brain metastases BM are the most frequent neurological complications related to NSCLC and it is estimated that 20 to 40 of these patients will present them at some point during the progression of their disease leading to a poor prognosis
As only a selected group of NSCLC patients with single metastases or small lesions are candidates for surgical resection or SBRT the standard treatment for multiple BM is whole-brain radiation therapy WBRT Although 80 of the patients who receive WRBT can initially respond to treatment 50 of these patients will have disease progression This further has been related to genetic and environmental factors that may lead to radio-resistance which is the capacity of a cell to stand the effects of radiant energy To face this problem other options such as chemotherapy or radio-sensitizers have shown slight benefit in terms of progression-free survival PFS but not in overall survival OS
Different studies have suggested tumor microenvironment TME has an important role in treatment response of BM-derived from melanoma and NSCLC The demand for O2 by tumors during cancer is an unsteady phenomenon caused by continuous metabolic profile changes immune response activity and TME interactions Hypoxia occurs in most tumors and plays an important role in tumor progression In NSCLC exists a clear relationship between hypoxia and radioresistance Hence there is interest into modulate TME hypoxia to improve treatment response Hypoxia regulates the expression of genes that encode growth factors such as endothelin-1 ET-1 growth factor-derived platelets-B PDGF and vascular endothelial growth factor VEGF as well as genes that regulate the production of gas molecules such as nitric oxide NO and carbon monoxide CO The hypoxia-inducible factor HIF is a transcription factor that regulates the cellular response to hypoxia functioning as a regulator of oxygen homeostasis Several studies have shown that over-expression of HIF-1α is capable of inducing resistance to chemotherapy radiotherapy and decreasing overall survival in NSCLC primary tumors
The administration of nitric oxide donors such as nitroglycerin reduces the tumor resistance related to hypoxia by inducing the direct proteolysis of HIF-1α In tumor cells increases oxygen pressure increased blood flow activation of p53 and apoptosis have shown a synergistic effect with ionizing irradiation in an experimental model According to several randomized phase II studies the addition of transdermal nitroglycerin to vinorelbine and cisplatin treatment can significantly improve the OS and time to progression in patients with locally advanced non-small cell lung cancer However in phase III the addition of nitroglycerin to carboplatin-based did not show benefit in PFS OS and health-related quality of life PMID 26347110 Therefore the aim of this study was to assess if the addition of transdermal NTG to standard WRBT treatment among stage IV NSCLC patients with BM could have a significant impact in PFS and OS as primary end-point and disease control rate DCR and overall response rate ORR as secondary endpoints
METHODS Experimental design We conducted a phase II clinical trial with a parallel design study among patients treated at the Instituto Nacional de Cancerología from January 2014 to May 2017 The Median follows up was 18 months Patients with histologically confirmed NSCLC and documented BM defined as the presence of one or more intra-axial enhancing lesions on gadolinium-enhanced brain magnetic resonance imaging MRI were included Candidate patients who underwent radiosurgery or surgical resection were excluded
Sample size The sample size calculation was estimated for a two-sample proportion difference in ORR for NSCLC patients who received WBRT plus TN Although in one of our previous studies we found a difference of 40 in ORR among locally advanced NSCLC patients 30 we prefer to be more conservative in our estimations taking into account our different study populations Thus our sample estimation assumptions were performed for a difference in ORR delta of 30 between population p1 25 vs p2 65 with a study power was set at 080 and the two-sided type I error alpha was set as 005 Therefore the estimated sample number is 108 54 per group We also add a 5 of extra patients to prevent the possible loss of patients due to the progression of the disease
Endpoints The primary outcome was overall response rate ORR Secondary endpoints were disease control rate DCR intracranial progression-free survival ICPFS and overall survival OS The radiographic response was assessed by two independent blinded radiologists according to the Response Evaluation Criteria in Solid Tumors RECIST guideline version 11 by comparing the pre-and post-treatment images Any in-field tumor progression or the appearance of new malignant lesions denoted progressive disease ORR was defined as the sum of complete and partial response whereas DCR was defined as the sum of ORR and stable disease For PFS time to event was defined and calculated from the date of randomization until radiographic disease progression treatment discontinuation due to either unacceptable toxicity death by any cause For OS time-to-event was defined as time from randomization until death by any cause or loss to follow-up Observations for patients who did not experience the event were censored at patient-specific last follow-up Finally treatment toxicity was evaluated with CTCAE criteria
Intervention assignment and informed consent Patients were randomized 11 and allocated to either the control arm who received whole-brain radiotherapy WBRT 30 Gy in 10 fractions in 10 days of treatment or the experimental arm who received WBRT and the addition 36 mg of transdermal nitroglycerin TN with release of 10 mg in 24 hours for 24 hours with a 12-hour rest interval to avoid saturation of receptors All patients signed the informed consent letter prior to any procedure The project was approved by the local scientific and bioethics committee number Further details can be found in clinicaltrialsgov NCT Patients received chemotherapy CT platinum-based or TKI according to mutation status
Response assessment BM was documented among all patients at NSCLC diagnosis and staging by either computed tomography CT of the head gadolinium-enhanced brain magnetic resonance imaging MRI at baseline Then all patients underwent an MRI prior to treatment and at the end of treatment median 15 days The imaging studies were carried out in a Signa HDxt 15 T scanner GE Healthcare They include conventional sequences in multiple planes T1 T2 T2 Flair Echo gradient Diffusion volumetric acquisition in axial plane T1 Spoiled Gradient recalled SPGR without contrast and after this Gadolinium Cerebral perfusion was evaluated by echo-planar sequence with the following parameters multiphase 25 - 45 phases with an acquisition time of 110 with a PSI of 5 and a flow rate of 5 with a volume of 15ml of gadolinium 20ml of saline at a speed of 5mlsecond
The radiographic response of intracranial tumors was assessed by two blinded and independent blinded radio-oncologist MY FM according to the Response Evaluation Criteria in Solid Tumors RECIST guideline version 11 by comparing the pre-and post-treatment intracranial images 15 Any in-field tumor progression or the appearance of new malignant lesions denoted progressive disease Objective response was defined as the sum of complete and partial response
DNA Extraction Biopsies were taken using CT-guided tru-cut or bronchoscopy and were analyzed by the pathology department for their histologic diagnosis and neoplastic cellularity quantification 50 they were later embedded in paraffin until processed for DNA extraction Genomic DNA was extracted from the areas of paraffin slides using a standard procedure and a QIAamp DNA FFPE tissue kit TMQIAGEN following manufacturers instructions
Determination of EGFR and KRAS mutational status EGFR exon 19 exon 20 and exon 21 gene mutations were detected using the Therascreen RGQ PCR kit TMQIAGEN Scorpions ARMS method which combines both the ARMS and Scorpions technologies for detecting the mutations by real-time polymerase chain reactions PCR Real-time PCR was performed using a Rotor-Gene Q 5plex HRM TMQIAGEN following manufacturers instructions
Statistical analysis Continuous variables were summarized as arithmetic means or medians with standard deviation or interquartile range for descriptive purposes according to normal data distribution assessed by means of the Shapiro-Swilk test Meanwhile categorical variables were summarized as frequencies and percentages For dichotomous outcomes eg objective response rate ORR disease control rate DCR the percentage incidence rate and 95 CI are presented Inferential comparisons were made using the T-test or two-way ANOVA for continuous variables and with either Mann-Whitney U test or Kruskall-Wallis test conforming to the data distribution and a number of groups The χ2 test or Fisher exact test was used for assessing the statistical significance of categorical variables To address the effect of treatment of secondary outcomes eg OS ICPFS we performed univariate survival analysis Time-to-event was estimated using the Kaplan-Meier method and comparisons among the subgroups were analyzed using the log-rank test For survival curve analysis all the variables were dichotomized according to their median After we performed a forward stepwise Multivariable Cox regression model and hazard ratios HR were calculated along with their corresponding 95 CIs as a measure of association Statistically and clinically significant and borderline significant variables p 10 were included for the adjustment in the multivariate Cox regression model Significantly Kaplan-Meir curves were plotted Statistical significance was determined as P 005 using a 2-tailed test Stata software version 14 was used for all statistical analyses
As only a selected group of NSCLC patients with single metastases or small lesions are candidates for surgical resection or SBRT the standard treatment for multiple BM is whole-brain radiation therapy WBRT Although 80 of the patients who receive WRBT can initially respond to treatment 50 of these patients will have disease progression This further has been related to genetic and environmental factors that may lead to radio-resistance which is the capacity of a cell to stand the effects of radiant energy To face this problem other options such as chemotherapy or radio-sensitizers have shown slight benefit in terms of progression-free survival PFS but not in overall survival OS
Different studies have suggested tumor microenvironment TME has an important role in treatment response of BM-derived from melanoma and NSCLC The demand for O2 by tumors during cancer is an unsteady phenomenon caused by continuous metabolic profile changes immune response activity and TME interactions Hypoxia occurs in most tumors and plays an important role in tumor progression In NSCLC exists a clear relationship between hypoxia and radioresistance Hence there is interest into modulate TME hypoxia to improve treatment response Hypoxia regulates the expression of genes that encode growth factors such as endothelin-1 ET-1 growth factor-derived platelets-B PDGF and vascular endothelial growth factor VEGF as well as genes that regulate the production of gas molecules such as nitric oxide NO and carbon monoxide CO The hypoxia-inducible factor HIF is a transcription factor that regulates the cellular response to hypoxia functioning as a regulator of oxygen homeostasis Several studies have shown that over-expression of HIF-1α is capable of inducing resistance to chemotherapy radiotherapy and decreasing overall survival in NSCLC primary tumors
The administration of nitric oxide donors such as nitroglycerin reduces the tumor resistance related to hypoxia by inducing the direct proteolysis of HIF-1α In tumor cells increases oxygen pressure increased blood flow activation of p53 and apoptosis have shown a synergistic effect with ionizing irradiation in an experimental model According to several randomized phase II studies the addition of transdermal nitroglycerin to vinorelbine and cisplatin treatment can significantly improve the OS and time to progression in patients with locally advanced non-small cell lung cancer However in phase III the addition of nitroglycerin to carboplatin-based did not show benefit in PFS OS and health-related quality of life PMID 26347110 Therefore the aim of this study was to assess if the addition of transdermal NTG to standard WRBT treatment among stage IV NSCLC patients with BM could have a significant impact in PFS and OS as primary end-point and disease control rate DCR and overall response rate ORR as secondary endpoints
METHODS Experimental design We conducted a phase II clinical trial with a parallel design study among patients treated at the Instituto Nacional de Cancerología from January 2014 to May 2017 The Median follows up was 18 months Patients with histologically confirmed NSCLC and documented BM defined as the presence of one or more intra-axial enhancing lesions on gadolinium-enhanced brain magnetic resonance imaging MRI were included Candidate patients who underwent radiosurgery or surgical resection were excluded
Sample size The sample size calculation was estimated for a two-sample proportion difference in ORR for NSCLC patients who received WBRT plus TN Although in one of our previous studies we found a difference of 40 in ORR among locally advanced NSCLC patients 30 we prefer to be more conservative in our estimations taking into account our different study populations Thus our sample estimation assumptions were performed for a difference in ORR delta of 30 between population p1 25 vs p2 65 with a study power was set at 080 and the two-sided type I error alpha was set as 005 Therefore the estimated sample number is 108 54 per group We also add a 5 of extra patients to prevent the possible loss of patients due to the progression of the disease
Endpoints The primary outcome was overall response rate ORR Secondary endpoints were disease control rate DCR intracranial progression-free survival ICPFS and overall survival OS The radiographic response was assessed by two independent blinded radiologists according to the Response Evaluation Criteria in Solid Tumors RECIST guideline version 11 by comparing the pre-and post-treatment images Any in-field tumor progression or the appearance of new malignant lesions denoted progressive disease ORR was defined as the sum of complete and partial response whereas DCR was defined as the sum of ORR and stable disease For PFS time to event was defined and calculated from the date of randomization until radiographic disease progression treatment discontinuation due to either unacceptable toxicity death by any cause For OS time-to-event was defined as time from randomization until death by any cause or loss to follow-up Observations for patients who did not experience the event were censored at patient-specific last follow-up Finally treatment toxicity was evaluated with CTCAE criteria
Intervention assignment and informed consent Patients were randomized 11 and allocated to either the control arm who received whole-brain radiotherapy WBRT 30 Gy in 10 fractions in 10 days of treatment or the experimental arm who received WBRT and the addition 36 mg of transdermal nitroglycerin TN with release of 10 mg in 24 hours for 24 hours with a 12-hour rest interval to avoid saturation of receptors All patients signed the informed consent letter prior to any procedure The project was approved by the local scientific and bioethics committee number Further details can be found in clinicaltrialsgov NCT Patients received chemotherapy CT platinum-based or TKI according to mutation status
Response assessment BM was documented among all patients at NSCLC diagnosis and staging by either computed tomography CT of the head gadolinium-enhanced brain magnetic resonance imaging MRI at baseline Then all patients underwent an MRI prior to treatment and at the end of treatment median 15 days The imaging studies were carried out in a Signa HDxt 15 T scanner GE Healthcare They include conventional sequences in multiple planes T1 T2 T2 Flair Echo gradient Diffusion volumetric acquisition in axial plane T1 Spoiled Gradient recalled SPGR without contrast and after this Gadolinium Cerebral perfusion was evaluated by echo-planar sequence with the following parameters multiphase 25 - 45 phases with an acquisition time of 110 with a PSI of 5 and a flow rate of 5 with a volume of 15ml of gadolinium 20ml of saline at a speed of 5mlsecond
The radiographic response of intracranial tumors was assessed by two blinded and independent blinded radio-oncologist MY FM according to the Response Evaluation Criteria in Solid Tumors RECIST guideline version 11 by comparing the pre-and post-treatment intracranial images 15 Any in-field tumor progression or the appearance of new malignant lesions denoted progressive disease Objective response was defined as the sum of complete and partial response
DNA Extraction Biopsies were taken using CT-guided tru-cut or bronchoscopy and were analyzed by the pathology department for their histologic diagnosis and neoplastic cellularity quantification 50 they were later embedded in paraffin until processed for DNA extraction Genomic DNA was extracted from the areas of paraffin slides using a standard procedure and a QIAamp DNA FFPE tissue kit TMQIAGEN following manufacturers instructions
Determination of EGFR and KRAS mutational status EGFR exon 19 exon 20 and exon 21 gene mutations were detected using the Therascreen RGQ PCR kit TMQIAGEN Scorpions ARMS method which combines both the ARMS and Scorpions technologies for detecting the mutations by real-time polymerase chain reactions PCR Real-time PCR was performed using a Rotor-Gene Q 5plex HRM TMQIAGEN following manufacturers instructions
Statistical analysis Continuous variables were summarized as arithmetic means or medians with standard deviation or interquartile range for descriptive purposes according to normal data distribution assessed by means of the Shapiro-Swilk test Meanwhile categorical variables were summarized as frequencies and percentages For dichotomous outcomes eg objective response rate ORR disease control rate DCR the percentage incidence rate and 95 CI are presented Inferential comparisons were made using the T-test or two-way ANOVA for continuous variables and with either Mann-Whitney U test or Kruskall-Wallis test conforming to the data distribution and a number of groups The χ2 test or Fisher exact test was used for assessing the statistical significance of categorical variables To address the effect of treatment of secondary outcomes eg OS ICPFS we performed univariate survival analysis Time-to-event was estimated using the Kaplan-Meier method and comparisons among the subgroups were analyzed using the log-rank test For survival curve analysis all the variables were dichotomized according to their median After we performed a forward stepwise Multivariable Cox regression model and hazard ratios HR were calculated along with their corresponding 95 CIs as a measure of association Statistically and clinically significant and borderline significant variables p 10 were included for the adjustment in the multivariate Cox regression model Significantly Kaplan-Meir curves were plotted Statistical significance was determined as P 005 using a 2-tailed test Stata software version 14 was used for all statistical analyses
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None