- Email: [email protected]
Treatment Results for Non-Small Cell Lung Cancer Patients Presenting With Brain Metastases
I. J. Radiation Oncology d Biology d Physics
S512
Volume 69, Number 3, Supplement, 2007
First, we carried out two univariate analysis as to determine whether OPN level is a significant predictor for survival: (a) the Kaplan-Meier method was used to calculate overall survival for the whole group (n = 94), as well as for patients with ‘‘high’’ and ‘‘low’’ osteopontin levels (above or below the group’s median). (b) using the continuous values of the OPN levels, we applied the log-transform as to make its distribution Gaussian in good approximation; then we carried out a correlation analysis w.r.t. 1-year survival (n = 89 patients). Second, we calculated creatinine clearance (Cockcroft-Gault formula) from gender, age, weight and serum creatinine levels, and considered the product of OPN level and creatinine clearance (i.e., its log-transform), which we correlated with 1-year survival. Results: Overall 1-year survival for the whole group (n = 94) was 56%, calculated using the Kaplan Meier method. The median survival was 14.5 months. In both univariate analyses of OPN levels, no significant relationship to survival was found: (a) median survival times of patients with high or low osteopontin levels were 10.0 and 16.1 months, respectively; the log-rank test applied to the Kaplan-Meier curves resulted in a statistically insignificant p-value of 0.11. (b) the correlation analysis with 1-year survival (n = 89 patients) also resulted in an insignificant p-value, namely 0.18. However, the product of OPN level and creatinine clearance showed a negative correlation with 1-year-survival, with a significant p-value of 0.03, confirming our hypothesis. Conclusions: OPN level together with creatinine clearance is a significant predictor for 1-year survival. Elevated OPN levels do not necessarily reduce the probability of 1-year survival, especially when creatinine clearance is low. Conversely, low OPN levels do not necessarily promise high probability of 1-year survival, particularly when creatinine clearance is high. The underlying biological mechanism may be that OPN accumulates in the blood due to slow clearance by the kidneys, even if it is created at a low rate in the tumor, leading to high OPN levels despite an only slightly hypoxic tumor. This approach is potentially useful for any biomarkers with urinary excretion. Author Disclosure: H. Steck, None; C. Dehing, None; H. van der Weide, None; D. De Ruysscher, None; B. Nijsten, None; S. Wanders, None; L. Boersma, None; S. Krishnan, None; R.B. Rao, None; P. Lambin, None.
2556
Intensity Modulated Radiation Therapy for the Treatment of Malignant Mesothelioma
K. L. Du, S. Both, S. M. Hahn Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA Purpose/Objective(s): Radiation therapy improves local control of lung cancer at the cost of increased treatment toxicities to critical organs in the thorax and upper abdomen. Recently IMRT has been used to limit the dose to these organs while treating large target volumes. Here we describe our experience with IMRT for the treatment of patients with malignant mesothelioma. Materials/Methods: Patient medical records were reviewed retrospectively. CT simulation was performed (AcQSim PQ5000, Marconi). Target volumes were outlined based on preoperative imaging, 18F-FDG PET, intraoperative findings and planning CT data. Organs at risk (contralateral lung, heart, liver, spinal cord and kidneys) were outlined. Oncentra TPS (Nucletron) was used for treatment planning. Treatment plan validation was performed using a water equivalent phantom (MedTec) ion chamber and film dosimetry. Treatment delivery was performed on an Oncor Linac (Siemens) using an automated step-and-shoot MLC approach. Orthogonal portal images were compared to digitally reconstructed radiographs generated by the TPS. TLD measurements were performed at the surgical scar level to verify the delivered dose. Results: Patient Information From 2004–2005, 10 patients with malignant mesothelioma underwent hemithorax IMRT in our department. Their ages ranged from 55–74 years old. 9 were male and 1 was female. 2 patients had Stage I disease, 2 had Stage II disease and 6 had Stage III disease. 9 patients underwent pre-IMRT extrapleural pneumonectomy, 1 patient underwent pre-IMRT radical pleurectomy. 5 patients additionally underwent intraoperative PDT. 1 patient received additional systemic therapy with pemetrexed and cisplatin. 1 patient did not complete the course of IMRT secondary to disease progression through treatment. Dosimetry Median CTV ranged from 45.4–54.2 Gy. Target dose was achieved in .95% of the CTV. Minimum doses typically occurred at clinically nonsignificant locations. Radiation doses to critical organs at risk met the prescribed constraints. For the contralateral lung, V20 ranged from 6.7–25%, V5 from 68.2–100%, and MLD from 10.1–16.5 Gy. Toxicities The most common toxicities were fatigue, shortness of breath, cough, decreased appetite, weight loss, nausea, skin erythema and desquamation, and pain at the surgical site. These symptoms were managed supportively and did not require treatment breaks. In this series, 1 patient experienced respiratory failure, while on treatment, secondary to radiation pneumonitis, and another patient experienced respiratory failure 8 months after completion of radiation therapy, secondary to progression of disease. Conclusions: Traditional radiation delivery to the hemithorax is poorly tolerated by patients, resulting in subtherapeutic dosing for many tumors. IMRT enables increased radiation dose delivery while reducing toxicities. Here we describe the treatment of patients with combined EPP, PDT with IMRT. Patients undergoing this therapy generally tolerate it well. Multimodality therapy combining EPP with increased doses of radiation, using IMRT, and newer treatment modalities such as PDT, may improve local control and is a viable tool in the treatment of malignant mesothelioma. Efforts to reduce lung toxicity and improve dose delivery are needed and provide the promise of improved local control and quality of life with a carefully chosen multidisciplinary approach. Author Disclosure: K.L. Du, None; S. Both, None; S.M. Hahn, None.
2557
Treatment Results for Non-Small Cell Lung Cancer Patients Presenting With Brain Metastases 1
A. Shapiro , H. A. Gay2, S. S. Hahn1, J. A. Bogart1, H. Shah1, C. T. Chung1 1
Upstate Medical University, Syracuse, NY, 2East Carolina University, Greenville, NC
Background: To determine effective treatment plan for patients presenting with brain metastases by conducting retrospective analysis of treatment results according to simple palliative and aggressive palliative treatments. Purpose/Objective(s): Brain is a common site of metastases and frequently the first site of treatment failure for non-small cell lung cancer (NSCLC) patients. Even though most of brain metastases occur some time after the initial diagnosis of NSCLC, occasionally patients present with symptoms of brain metastases prior to or at the time of diagnosis. There are no established treatment guidelines
Proceedings of the 49th Annual ASTRO Meeting
S513
for these patients. They are generally treated by simple palliative techniques; whole brain XRT and chemotherapy with or without chest XRT. Considering the possibility of less advanced disease and better performance status of this group of NSCLC patients compared to those who develop brain metastases after their initial diagnosis, we performed a retrospective study to determine whether aggressive treatments to brain, lung or both is beneficial in disease control and/or survival. Materials/Methods: The cases of 75 patients presenting with non-small cell lung carcinoma with synchronous brain metastases treated between 1998-2002 were reviewed at Upstate Medical University at Syracuse. Patients were assessed for aggressive treatment to the brain with either craniotomy or gamma knife radiosurgery and aggressive treatment to the primary lung cancer with surgery, chemoradiation therapy or both. Results: Median follow-up was 15 months. 43 patients received aggressive treatment to brain, 20 received aggressive treatment to lung and 45 patients had palliative treatment. 21 patients recurred in the brain, (10/43 in aggressive treatment group, 11/36 palliative group). 9 patients recurred or demonstrated progressive disease in the lung (1/12 aggressive treatment group, 8/63 in nonaggressive group). The median survival was 7.9 months for the entire cohort, 8.4 months in the aggressive treatment group and 7.7 months in the non-aggressive treatment group (p = 0.44). There were 10 long-term survivors living more than 2 years. 2 of them were treated by aggressive treatment overall (7 with aggressive treatment to the brain and 3 with aggressive treatment to the thorax). 5/6 patients who developed intracranial recurrences were salvaged with radiosurgery. Median disease free survival in this subgroup of patients was 22.6 months. Median overall survival was 48.7 months. None of the prognostic factors analyzed including performance status, number of intracranial lesions, presence of extracranial metastases or treatment approach influenced survival significantly. Only variable found the play a significant role in prolonging overall survival was aggressive salvage treatment with gamma knife radiosurgery. (Median survival 15.2 mo after salvage radiosurgery, 8.2 mo following palliative whole brain radiation therapy. p = 0.03). Conclusions: Majority of patients who present with synchronous brain metastases also have extracranial disease. Their prognosis is poor. In our study, median survival was 7.9 months, similar to survival in patients developing brain metastases following diagnosis of NSCLC. Our data suggests that there is a definite subgroup of patients who could be long-term survivors if treated aggressively for intracranial disease. Author Disclosure: A. Shapiro, None; H.A. Gay, None; S.S. Hahn, None; J.A. Bogart, None; H. Shah, None; C.T. Chung, None.
2558
Moderate Dose IMRT for Resected Mesothelioma
N. A. Larrier, E. Miles, J. Hubbs, J. Ma, S. Yoo, L. Marks Duke University Medical Center, Durham, NC Purpose/Objective(s): To determine the pulmonary toxicity and local control associated with moderate dose (z45 Gy) comprehensive pleural space IMRT after extrapleural pneumonectomy for mesothelioma. Materials/Methods: 10 patients received IMRT after extrapleural pneumonectomy with curative intent between 7/05 and 12/06 at Duke University. The clinical target volume (CTV) was defined as the entire ipisilateral hemithorax, chest wall incisions including drain sites, and involved nodal stations. The dose prescribed to the clinical target volume (CTV) was 40–50 Gy (mean 45 Gy). Records were reviewed to determine acute and late toxicity, and local control. Toxicity was graded using the RTOG grading scale. Dosimetric parameters from subgroups experiencing pneumonitis and those that did not were compared using a two-tailed T-test. Results: The 10 patients included in the study had Stage I to IV disease; six were left-sided, four were right-sided. Histology was epithelioid in 8 patients; biphasic in 2. Eight received chemotherapy; 2 preoperatively and 6 postoperatively. Median follow up from diagnosis was 12 months, and 6 months from completion of RT. All patients experienced grade 1–2 nausea/vomiting or esophagitis acutely; 4 described grade 1–2 fatigue. Three patients experienced early (within 3 months) grade $3 pulmonary toxicity, including one patient who later died z6 months after RT, likely due, in part, to lung injury. One patient developed a local recurrence in the chest wall, followed by peritoneal carcinomatosis. One patient developed an ipsilateral brachial plexus injury at 3 months after RT that has persisted. The mean lung dose (MLD) was similar to those with and without symptomatic pneumonitis (8.9 vs 8.1 Gy). There was a trend towards a lower lung V20 (2.3 vs 5.5%) and higher V5 (80 vs 64.2%) in those that developed pneumonitis. Population average dose volume histograms (DVH) constructed from individual patient DVH’s confirmed these results. The single pulmonary fatality had a higher MLD than those not experiencing fatality (11.4 vs 8.0 Gy). The lung V20 (6.8 vs 4.3%) and V5 (92 vs 66%) were similarly increased in the case of suspected fatal pneumonitis. Calculation of a p-value is not possible for comparison between a group and a single data point. Serial LFT’s monitored in a subset of patients revealed no episodes of enzyme elevation beyond the normal range (mean liver dose 28.6–30.7 Gy) (Table). Conclusions: Moderate dose IMRT provides good local control in mesothelioma, albeit with limited follow-up. Treatment related pulmonary toxicity remains a concern. Our data are consistent with other published data and suggest that the MLD be kept below 8–10 Gy, V20 below z4–10%, and V5 below z70%. Dosimetric Parameters in Those With and Without Fatality
Author, Institution
Fatality rate
Mean RT dose
Allen, Harvard (1) Rice, MDAH (2) Larrier, Duke
6/13 6/63 1/10
54 Gy 45 Gy 45 Gy
MLD (Gy) V20 (%) V5 (%) (Median dose/volume with fatality vs not, p-value) 15 vs 13, p = 0.07 11 vs 8, p = 0.003 11 vs 8, not sig.
18 vs 11, p = 0.08 11 vs 4, p = \0.001 7 vs 4, not sig.
99 vs 90, p = 0.20 88 vs 72, p = 0.054 92 vs 66, not sig
(1) Allen AM et al, Int J Radiat Oncol Biol Phys 2006;65:640–645. (2) Rice DC et al, ASTRO Proceedings 2006, Abstract #111.
Author Disclosure: N.A. Larrier, None; E. Miles, None; J. Hubbs, None; J. Ma, None; S. Yoo, None; L. Marks, Lance Armstrong Foundation, B. Research Grant.
S512
Volume 69, Number 3, Supplement, 2007
First, we carried out two univariate analysis as to determine whether OPN level is a significant predictor for survival: (a) the Kaplan-Meier method was used to calculate overall survival for the whole group (n = 94), as well as for patients with ‘‘high’’ and ‘‘low’’ osteopontin levels (above or below the group’s median). (b) using the continuous values of the OPN levels, we applied the log-transform as to make its distribution Gaussian in good approximation; then we carried out a correlation analysis w.r.t. 1-year survival (n = 89 patients). Second, we calculated creatinine clearance (Cockcroft-Gault formula) from gender, age, weight and serum creatinine levels, and considered the product of OPN level and creatinine clearance (i.e., its log-transform), which we correlated with 1-year survival. Results: Overall 1-year survival for the whole group (n = 94) was 56%, calculated using the Kaplan Meier method. The median survival was 14.5 months. In both univariate analyses of OPN levels, no significant relationship to survival was found: (a) median survival times of patients with high or low osteopontin levels were 10.0 and 16.1 months, respectively; the log-rank test applied to the Kaplan-Meier curves resulted in a statistically insignificant p-value of 0.11. (b) the correlation analysis with 1-year survival (n = 89 patients) also resulted in an insignificant p-value, namely 0.18. However, the product of OPN level and creatinine clearance showed a negative correlation with 1-year-survival, with a significant p-value of 0.03, confirming our hypothesis. Conclusions: OPN level together with creatinine clearance is a significant predictor for 1-year survival. Elevated OPN levels do not necessarily reduce the probability of 1-year survival, especially when creatinine clearance is low. Conversely, low OPN levels do not necessarily promise high probability of 1-year survival, particularly when creatinine clearance is high. The underlying biological mechanism may be that OPN accumulates in the blood due to slow clearance by the kidneys, even if it is created at a low rate in the tumor, leading to high OPN levels despite an only slightly hypoxic tumor. This approach is potentially useful for any biomarkers with urinary excretion. Author Disclosure: H. Steck, None; C. Dehing, None; H. van der Weide, None; D. De Ruysscher, None; B. Nijsten, None; S. Wanders, None; L. Boersma, None; S. Krishnan, None; R.B. Rao, None; P. Lambin, None.
2556
Intensity Modulated Radiation Therapy for the Treatment of Malignant Mesothelioma
K. L. Du, S. Both, S. M. Hahn Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA Purpose/Objective(s): Radiation therapy improves local control of lung cancer at the cost of increased treatment toxicities to critical organs in the thorax and upper abdomen. Recently IMRT has been used to limit the dose to these organs while treating large target volumes. Here we describe our experience with IMRT for the treatment of patients with malignant mesothelioma. Materials/Methods: Patient medical records were reviewed retrospectively. CT simulation was performed (AcQSim PQ5000, Marconi). Target volumes were outlined based on preoperative imaging, 18F-FDG PET, intraoperative findings and planning CT data. Organs at risk (contralateral lung, heart, liver, spinal cord and kidneys) were outlined. Oncentra TPS (Nucletron) was used for treatment planning. Treatment plan validation was performed using a water equivalent phantom (MedTec) ion chamber and film dosimetry. Treatment delivery was performed on an Oncor Linac (Siemens) using an automated step-and-shoot MLC approach. Orthogonal portal images were compared to digitally reconstructed radiographs generated by the TPS. TLD measurements were performed at the surgical scar level to verify the delivered dose. Results: Patient Information From 2004–2005, 10 patients with malignant mesothelioma underwent hemithorax IMRT in our department. Their ages ranged from 55–74 years old. 9 were male and 1 was female. 2 patients had Stage I disease, 2 had Stage II disease and 6 had Stage III disease. 9 patients underwent pre-IMRT extrapleural pneumonectomy, 1 patient underwent pre-IMRT radical pleurectomy. 5 patients additionally underwent intraoperative PDT. 1 patient received additional systemic therapy with pemetrexed and cisplatin. 1 patient did not complete the course of IMRT secondary to disease progression through treatment. Dosimetry Median CTV ranged from 45.4–54.2 Gy. Target dose was achieved in .95% of the CTV. Minimum doses typically occurred at clinically nonsignificant locations. Radiation doses to critical organs at risk met the prescribed constraints. For the contralateral lung, V20 ranged from 6.7–25%, V5 from 68.2–100%, and MLD from 10.1–16.5 Gy. Toxicities The most common toxicities were fatigue, shortness of breath, cough, decreased appetite, weight loss, nausea, skin erythema and desquamation, and pain at the surgical site. These symptoms were managed supportively and did not require treatment breaks. In this series, 1 patient experienced respiratory failure, while on treatment, secondary to radiation pneumonitis, and another patient experienced respiratory failure 8 months after completion of radiation therapy, secondary to progression of disease. Conclusions: Traditional radiation delivery to the hemithorax is poorly tolerated by patients, resulting in subtherapeutic dosing for many tumors. IMRT enables increased radiation dose delivery while reducing toxicities. Here we describe the treatment of patients with combined EPP, PDT with IMRT. Patients undergoing this therapy generally tolerate it well. Multimodality therapy combining EPP with increased doses of radiation, using IMRT, and newer treatment modalities such as PDT, may improve local control and is a viable tool in the treatment of malignant mesothelioma. Efforts to reduce lung toxicity and improve dose delivery are needed and provide the promise of improved local control and quality of life with a carefully chosen multidisciplinary approach. Author Disclosure: K.L. Du, None; S. Both, None; S.M. Hahn, None.
2557
Treatment Results for Non-Small Cell Lung Cancer Patients Presenting With Brain Metastases 1
A. Shapiro , H. A. Gay2, S. S. Hahn1, J. A. Bogart1, H. Shah1, C. T. Chung1 1
Upstate Medical University, Syracuse, NY, 2East Carolina University, Greenville, NC
Background: To determine effective treatment plan for patients presenting with brain metastases by conducting retrospective analysis of treatment results according to simple palliative and aggressive palliative treatments. Purpose/Objective(s): Brain is a common site of metastases and frequently the first site of treatment failure for non-small cell lung cancer (NSCLC) patients. Even though most of brain metastases occur some time after the initial diagnosis of NSCLC, occasionally patients present with symptoms of brain metastases prior to or at the time of diagnosis. There are no established treatment guidelines
Proceedings of the 49th Annual ASTRO Meeting
S513
for these patients. They are generally treated by simple palliative techniques; whole brain XRT and chemotherapy with or without chest XRT. Considering the possibility of less advanced disease and better performance status of this group of NSCLC patients compared to those who develop brain metastases after their initial diagnosis, we performed a retrospective study to determine whether aggressive treatments to brain, lung or both is beneficial in disease control and/or survival. Materials/Methods: The cases of 75 patients presenting with non-small cell lung carcinoma with synchronous brain metastases treated between 1998-2002 were reviewed at Upstate Medical University at Syracuse. Patients were assessed for aggressive treatment to the brain with either craniotomy or gamma knife radiosurgery and aggressive treatment to the primary lung cancer with surgery, chemoradiation therapy or both. Results: Median follow-up was 15 months. 43 patients received aggressive treatment to brain, 20 received aggressive treatment to lung and 45 patients had palliative treatment. 21 patients recurred in the brain, (10/43 in aggressive treatment group, 11/36 palliative group). 9 patients recurred or demonstrated progressive disease in the lung (1/12 aggressive treatment group, 8/63 in nonaggressive group). The median survival was 7.9 months for the entire cohort, 8.4 months in the aggressive treatment group and 7.7 months in the non-aggressive treatment group (p = 0.44). There were 10 long-term survivors living more than 2 years. 2 of them were treated by aggressive treatment overall (7 with aggressive treatment to the brain and 3 with aggressive treatment to the thorax). 5/6 patients who developed intracranial recurrences were salvaged with radiosurgery. Median disease free survival in this subgroup of patients was 22.6 months. Median overall survival was 48.7 months. None of the prognostic factors analyzed including performance status, number of intracranial lesions, presence of extracranial metastases or treatment approach influenced survival significantly. Only variable found the play a significant role in prolonging overall survival was aggressive salvage treatment with gamma knife radiosurgery. (Median survival 15.2 mo after salvage radiosurgery, 8.2 mo following palliative whole brain radiation therapy. p = 0.03). Conclusions: Majority of patients who present with synchronous brain metastases also have extracranial disease. Their prognosis is poor. In our study, median survival was 7.9 months, similar to survival in patients developing brain metastases following diagnosis of NSCLC. Our data suggests that there is a definite subgroup of patients who could be long-term survivors if treated aggressively for intracranial disease. Author Disclosure: A. Shapiro, None; H.A. Gay, None; S.S. Hahn, None; J.A. Bogart, None; H. Shah, None; C.T. Chung, None.
2558
Moderate Dose IMRT for Resected Mesothelioma
N. A. Larrier, E. Miles, J. Hubbs, J. Ma, S. Yoo, L. Marks Duke University Medical Center, Durham, NC Purpose/Objective(s): To determine the pulmonary toxicity and local control associated with moderate dose (z45 Gy) comprehensive pleural space IMRT after extrapleural pneumonectomy for mesothelioma. Materials/Methods: 10 patients received IMRT after extrapleural pneumonectomy with curative intent between 7/05 and 12/06 at Duke University. The clinical target volume (CTV) was defined as the entire ipisilateral hemithorax, chest wall incisions including drain sites, and involved nodal stations. The dose prescribed to the clinical target volume (CTV) was 40–50 Gy (mean 45 Gy). Records were reviewed to determine acute and late toxicity, and local control. Toxicity was graded using the RTOG grading scale. Dosimetric parameters from subgroups experiencing pneumonitis and those that did not were compared using a two-tailed T-test. Results: The 10 patients included in the study had Stage I to IV disease; six were left-sided, four were right-sided. Histology was epithelioid in 8 patients; biphasic in 2. Eight received chemotherapy; 2 preoperatively and 6 postoperatively. Median follow up from diagnosis was 12 months, and 6 months from completion of RT. All patients experienced grade 1–2 nausea/vomiting or esophagitis acutely; 4 described grade 1–2 fatigue. Three patients experienced early (within 3 months) grade $3 pulmonary toxicity, including one patient who later died z6 months after RT, likely due, in part, to lung injury. One patient developed a local recurrence in the chest wall, followed by peritoneal carcinomatosis. One patient developed an ipsilateral brachial plexus injury at 3 months after RT that has persisted. The mean lung dose (MLD) was similar to those with and without symptomatic pneumonitis (8.9 vs 8.1 Gy). There was a trend towards a lower lung V20 (2.3 vs 5.5%) and higher V5 (80 vs 64.2%) in those that developed pneumonitis. Population average dose volume histograms (DVH) constructed from individual patient DVH’s confirmed these results. The single pulmonary fatality had a higher MLD than those not experiencing fatality (11.4 vs 8.0 Gy). The lung V20 (6.8 vs 4.3%) and V5 (92 vs 66%) were similarly increased in the case of suspected fatal pneumonitis. Calculation of a p-value is not possible for comparison between a group and a single data point. Serial LFT’s monitored in a subset of patients revealed no episodes of enzyme elevation beyond the normal range (mean liver dose 28.6–30.7 Gy) (Table). Conclusions: Moderate dose IMRT provides good local control in mesothelioma, albeit with limited follow-up. Treatment related pulmonary toxicity remains a concern. Our data are consistent with other published data and suggest that the MLD be kept below 8–10 Gy, V20 below z4–10%, and V5 below z70%. Dosimetric Parameters in Those With and Without Fatality
Author, Institution
Fatality rate
Mean RT dose
Allen, Harvard (1) Rice, MDAH (2) Larrier, Duke
6/13 6/63 1/10
54 Gy 45 Gy 45 Gy
MLD (Gy) V20 (%) V5 (%) (Median dose/volume with fatality vs not, p-value) 15 vs 13, p = 0.07 11 vs 8, p = 0.003 11 vs 8, not sig.
18 vs 11, p = 0.08 11 vs 4, p = \0.001 7 vs 4, not sig.
99 vs 90, p = 0.20 88 vs 72, p = 0.054 92 vs 66, not sig
(1) Allen AM et al, Int J Radiat Oncol Biol Phys 2006;65:640–645. (2) Rice DC et al, ASTRO Proceedings 2006, Abstract #111.
Author Disclosure: N.A. Larrier, None; E. Miles, None; J. Hubbs, None; J. Ma, None; S. Yoo, None; L. Marks, Lance Armstrong Foundation, B. Research Grant.