Dietary Flaxseed in Non-Small Cell Lung Cancer Patients Receiving Chemoradiation
Dietary Flaxseed in Non-Small Cell Lung Cancer Patients Receiving Chemoradiation
Year: 2013
Authors: Berman, A.T. Turowski, J. Mick, R. Cengel, K. Farnese, N. Basel-Brown, L. Mesaros, C. Blair, I.
Publication Name: J. Pulm. Resp. Med.
Publication Details: Volume 3; Issue 4; Page 154
Abstract:
The standard of care in Locally Advanced Non Small Cell Lung Cancer (LANSCLC) is chemotherapy and radiation; however, Radiation Induced Lung Injury (RILI), which may be prevented by the anti inflammatory and anti oxidant properties of Flaxseed (FS), impedes its maximum benefit. Patients with LA NSCLC requiring definitive RT were randomized to one FS or control muffin daily from start to 2 weeks after RT. Blood and urine were collected to quantify plasma FS metabolites, Enterodione (ED) and Enterolactone (EL), and urinary oxidative stress biomarkers, 8, 12 iso iPF2a VI (isoprostane) and 8 oxo 7,8 dihydro 2 deoxyguanosine (8 oxo dGuo). Tolerability was defined as consuming less than or equal to 75 per cent of the intended muffins and no more than grade 3 gastrointestinal toxicities. Fourteen patients (control, 7; FS, 7) were enrolled. The tolerability rates were 42.9 versus 71.4 per cent for FS and control, respectively. Mean percentages of intended number of muffins consumed were 37 per cent versus 73 per cent. ED and EL increased at onset of FS and decreased with discontinuation, confirming bioavailability. Isoprostane and 8 oxo dGuo were detectable. There was a trend towards decreased rates of pneumonitis in FS. This is the first study to report FS bioavailability and quantify oxidative stress markers in NSCLC patients. FS in the administered muffin formulation did not meet tolerability criteria. Given the promising mechanism of FS as a radioprotectant, further investigations should focus on the optimal method for administration of FS. (Authors abstract)
The standard of care for patients with unresectable, locally-advanced Non-Small Cell Lung Cancer (NSCLC) is definitive Radiation Therapy (RT) given with or without chemotherapy. A major barrier to improved outcomes is the development of Radiation Induced Lung Injury (RILI). RILI manifests on a spectrum from acute radiation pneumonitis, an inflammatory state occurring within weeks to 6 months of RT, to chronic radiation fibrosis, characterized by replacement of functional lung parenchyma with fibrotic tissue usually occurring months to years following therapy. Reducing oxidative stress would hypothetically prevent RILI and improve the therapeutic index of radiotherapy in lung cancer.
In this study, two urinary biomarkers of systemic oxidative stress, 8, 12 iso iPF2a VI isoprostane and 8 oxo 7, 8 dihydro 2 deoxyguanosine (8 oxo dGuo), were investigated. Isoprostanes, oxidative stress biomarkers, are prostaglandin like compounds formed by the peroxidation of arachidonic acid by free radicals. Flaxseed (FS) lignan complex (FLC) has potent anti inflammatory, antioxidant and antifibrotic properties. The primary objective of this study was to ascertain the feasibility of incorporating a validated radioprotector, FS, in the treatment regimen of patients with advanced NSCLC receiving chemotherapy and thoracic radiation. The study focused on whether flaxseed muffins would have a reasonable toxicity and tolerability index for patients receiving chemoradiation and to validate FS bioavailability by quantifying serum markers of metabolism and quantifying urinary markers of systemic oxidative stress before, during, and after RT in the presence and absence of concurrent FS supplementation. An additional component of the study aimed to establish if serum lignan levels and or urinary markers of systemic oxidative stress demonstrated a dose response relationship with 20 versus 40 grams of flaxseed.
Adherence to the flaxseed diet in the baked muffin formulation was below required levels for the study and therefore the trial was terminated after the first dose level. Initial analysis of the patients enrolled is presented. Markers of flaxseed metabolism, enterodione and enterolactone, were detected in the sera of the flaxseed group undergoing therapy. Urinary biomarkers of systemic oxidative stress (isoprostane and 8 oxo D guo) increased in response to radiotherapy. Trends toward reduced rates of pneumonitis were seen in FS fed patients. More patients in the FS arm received concurrent chemotherapy than in the control arm; and despite this difference, pneumonitis rates were lower in the FS arm.
The standard of care for patients with unresectable, locally-advanced Non-Small Cell Lung Cancer (NSCLC) is definitive Radiation Therapy (RT) given with or without chemotherapy. A major barrier to improved outcomes is the development of Radiation Induced Lung Injury (RILI). RILI manifests on a spectrum from acute radiation pneumonitis, an inflammatory state occurring within weeks to 6 months of RT, to chronic radiation fibrosis, characterized by replacement of functional lung parenchyma with fibrotic tissue usually occurring months to years following therapy. Reducing oxidative stress would hypothetically prevent RILI and improve the therapeutic index of radiotherapy in lung cancer.
In this study, two urinary biomarkers of systemic oxidative stress, 8, 12 iso iPF2a VI isoprostane and 8 oxo 7, 8 dihydro 2 deoxyguanosine (8 oxo dGuo), were investigated. Isoprostanes, oxidative stress biomarkers, are prostaglandin like compounds formed by the peroxidation of arachidonic acid by free radicals. Flaxseed (FS) lignan complex (FLC) has potent anti inflammatory, antioxidant and antifibrotic properties. The primary objective of this study was to ascertain the feasibility of incorporating a validated radioprotector, FS, in the treatment regimen of patients with advanced NSCLC receiving chemotherapy and thoracic radiation. The study focused on whether flaxseed muffins would have a reasonable toxicity and tolerability index for patients receiving chemoradiation and to validate FS bioavailability by quantifying serum markers of metabolism and quantifying urinary markers of systemic oxidative stress before, during, and after RT in the presence and absence of concurrent FS supplementation. An additional component of the study aimed to establish if serum lignan levels and or urinary markers of systemic oxidative stress demonstrated a dose response relationship with 20 versus 40 grams of flaxseed.
Adherence to the flaxseed diet in the baked muffin formulation was below required levels for the study and therefore the trial was terminated after the first dose level. Initial analysis of the patients enrolled is presented. Markers of flaxseed metabolism, enterodione and enterolactone, were detected in the sera of the flaxseed group undergoing therapy. Urinary biomarkers of systemic oxidative stress (isoprostane and 8 oxo D guo) increased in response to radiotherapy. Trends toward reduced rates of pneumonitis were seen in FS fed patients. More patients in the FS arm received concurrent chemotherapy than in the control arm; and despite this difference, pneumonitis rates were lower in the FS arm.
The antioxidant mechanism of flaxseed is either by direct hydroxyl radical scavenging or by counteracting lipid peroxidation. ED and EL plasma concentration were quantifiable in the flaxseed group with the ED and EL levels at or greater than seen previously. A response in two urinary markers of systemic oxidative stress, isoprostane and and 8 oxo dGuo were noted.
Given that this is a pilot study and therefore would only have adequate power to identify large differences between groups, no definitive conclusions can be made regarding the difference in oxidative stress levels between the flaxseed and control groups. There were no cases of pneumonitis in the flaxseed arm, which was encouraging. In addition, there were fewer cases of radiation induced esophagitis. Again, these were very important findings but need to be assessed in a randomized study with adequate power. Flaxseed administration in the muffin formulation was not feasible due to a range of factors including patient anorexia, odynophagia and tolerability of the flaxseed muffin formulation. However, quantification of flaxseed bioavailability and urinary markers of systemic oxidative stress could be achieved. There was a trend towards decreased rates of pneumonitis in FS versus control. Dietary flaxseed may be clinically useful as an agent to increase the therapeutic index of thoracic RT by increasing the radiation tolerance of organs at risk including the esophagus and lungs. Based on this preliminary data, further clinical trials investigating different formulations of flaxseed which are now available are warranted. (Editors comments)
Given that this is a pilot study and therefore would only have adequate power to identify large differences between groups, no definitive conclusions can be made regarding the difference in oxidative stress levels between the flaxseed and control groups. There were no cases of pneumonitis in the flaxseed arm, which was encouraging. In addition, there were fewer cases of radiation induced esophagitis. Again, these were very important findings but need to be assessed in a randomized study with adequate power. Flaxseed administration in the muffin formulation was not feasible due to a range of factors including patient anorexia, odynophagia and tolerability of the flaxseed muffin formulation. However, quantification of flaxseed bioavailability and urinary markers of systemic oxidative stress could be achieved. There was a trend towards decreased rates of pneumonitis in FS versus control. Dietary flaxseed may be clinically useful as an agent to increase the therapeutic index of thoracic RT by increasing the radiation tolerance of organs at risk including the esophagus and lungs. Based on this preliminary data, further clinical trials investigating different formulations of flaxseed which are now available are warranted. (Editors comments)
