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I. J. Radiation Oncology
48
● Biology ● Physics
Volume 66, Number 3, Supplement, 2006
The Maximum Uptake of 18F-deoxyglucose on PET Scan Correlates With Survival and Two Endogenous Markers of Hypoxia (Hypoxia Inducible Factor-1␣ and Carbonic Anhydrase IX) in Non-Small Cell Lung Cancer (NSCLC)
A. van Baardwijk1, C. Dooms2, R. van Suylen3, E. Verbeken4, M. Hochstenbach5, S. Stroobants6, U. Buell7, P. Lambin1, J. Vansteenkiste2, D. De Ruysscher1 1
Dept. of Radiation Oncology (MAASTRO), GROW, University Hospital Maastricht, Maastricht, The Netherlands, 2Dept. of Pulmonology, University Hospital Leuven, Leuven, Belgium, 3Dept. of Pathology, University Hospital Maastricht, Maastricht, The Netherlands, 4Dept. of Pathology, University Hospital Leuven, Leuven, Belgium, 5Dept. of Pulmonology, University Hospital Maastricht, Maastricht, The Netherlands, 6Dept. of Nuclear Medicine, University Hospital Leuven, Leuven, Belgium, 7Dept. of Nuclear Medicine, Aachen University of Technology, Aachen, Germany Purpose/Objective(s): The degree of uptake of 18F-fluoro-2-deoxy-glucose (FDG) in NSCLC was consistently shown to be a significant, independent, prognostic factor. Preclinical studies suggest that hypoxic conditions correspond to a higher FDG uptake. Since hypoxia leads to an increased rate of glycolysis, which in turn, increases the uptake of FDG, we hypothesized that the worse prognosis of NSCLC patients with a high FDG uptake would be related to hypoxia. Therefore we investigated the relation between the FDG uptake on PET scan and endogenous immunohistochemical markers of tumor hypoxia (assessed by the expression of Hypoxia Inducible Factor-1␣, HIF-1 ␣, and Carbonic Anhydrase IX, CAIX), tumor proliferation (Ki67) and glucose metabolism (glucose transporters Glut-1 and Glut-3) in NSCLC.
Materials/Methods: Of 102 patients, operated for NSCLC with curative intent, PET scan data (maximal SUV, SUVmax) and follow-up data were analyzed. For all patients immunohistochemical staining for HIF-1␣, CAIX, Ki67, Glut-1 and Glut-3 on the surgical specimen was performed. Survival data were analyzed using the Kaplan-Meier method and the log-rank test. The Chi-square test and the Mann Whitney U-test were used to analyze the different categorical variables. Results: Actuarial survival was worse for patients showing a higher SUVmax, with a cut-off value of 11 showing the best discriminative value (p⫽0.0029). A higher proportion of tumors with a SUVmax ⱖ 11 showed expression of HIF-1␣ (66.1% versus 39.5%, p⫽0.011), CAIX (51.8% versus 23.7%, p⫽0.006), Glut-1 (83.1% versus 67.4%, p⫽0.066) than tumors with a SUVmax ⬍ 11. No significant difference was found in the expression of Glut-3. Tumors with a high uptake also had a higher average percentage tumor cells positive for Ki67 (46.7% versus 37.2%, p⫽0.021). Conclusion: NSCLC showing a high uptake of FDG on PET is significantly more likely to express the endogenous hypoxia markers, HIF-1␣ and CAIX and a higher fraction of proliferating cells. These patients also showed a worse survival. This study confirms that not only in vitro, but also in vivo, hypoxia increases the uptake of FDG. This might have implications for the treatment in clinical practice. Author Disclosure: A. van Baardwijk, EC FP6 funding (LSHC-CT-2004-505785), B. Research Grant; C. Dooms, None; R. van Suylen, None; E. Verbeken, None; M. Hochstenbach, None; S. Stroobants, None; U. Buell, None; P. Lambin, None; J. Vansteenkiste, None; D. De Ruysscher, None.
49
Comparison of 5-Year Survival Between RTOG-94-10 and a Phase 2 Study of Induction Chemotherapy Followed by Efaproxiral ⴙ Radiotherapy in Patients With Locally Advanced NSCLC
H. Choy1, S. Swann2, A. Nabid3, B. Stea4, W. Roa5, L. Souhami6, W. Curran7 1
UT Southwestern Medical Center at Dallas, Dallas, TX, 2RTOG, Philladelphia, PA, 3Centre Hoˆspitalier Universitaire de Sherbrooke, Sherbrooke, PQ, Canada, 4University of Arizona Health Sciences Center, Tucson, AZ, 5Cross Cancer Institute, Edmonton, AB, Canada, 6Hoˆpital Notre Dame, Montreal, PQ, Canada, 7Thomas Jefferson University, Philadelphia, PA
Purpose/Objective(s): To compare 5-year survival results between RTOG 94-10 and study RT-010 in patients with locally advanced (Stage IIIA/B) non-small cell lung cancer (NSCLC). Materials/Methods: Efaproxiral, a synthetic allosteric modifier of hemoglobin, was studied in a Phase 2 trial (RT-010) as a radiosensitizer in patients receiving chemotherapy (CT) with paclitaxel (225 mg/m2) and carboplatin (AUC ⫽ 6) for 2 cycles, days (D) 1 and 22, followed by thoracic radiotherapy (TRT) (64 Gray [Gy], D 43-50) with concurrent efaproxiral (50 - 100 mg/kg). RTOG 94-10 was a 3-arm Phase 3 trial to determine if concurrent delivery of CT with TRT improves survival compared with sequential delivery of CT followed by RT in patients with newly diagnosed, unresected Stage II-III NSCLC. In this analysis, 2 of the 3 arms on RTOG 94-10 are used: the sequential arm (STD50), which gave cisplatin (P) 100 mg/m2 D 1 and 29 & vinblastine 5 mg/m2/weekly x 5 with 60 Gy RT beginning D 50; and Arm 2, which used the same CT with 60 Gy TRT beginning D 1 (STD1). A total of 402 patients, 201 on each arm, from the STD50 and STD1 Arms of RTOG 94-10 are included in this analysis, along with 49 patients from RT-010. Overall survival is estimated by the Kaplan-Meier method and tested using the log-rank test between the patients on RT-010 and each arm of RTOG 94-10. Survival time is measured from treatment D 1. P values are 2-tailed. Results: Demographic characteristics were comparable among all groups. Median follow-up is 65.4 months for RT-010, 75.8 months for the STD50 Arm, 69.6 months for the STD1 Arm. RT-010 had a median survival time (MST) of 20.6 months compared with an MST of 14.5 months for the STD50 Arm (P ⫽ 0.088) and 16.8 months for the STD1 Arm (P ⫽ 0.65). A case-matched analysis and multivariate Cox model analysis were also performed with similar results. The Kaplan-Meier estimates (Table 1) of 5-year survival rates were 19% in RT-010, 10% in the STD50 Arm, and 16% in the STD1 Arm. The estimates of 5-year survival of the matched cases were 19% in RT-010, and 10% in each of the STD1 and STD50 Arms. Conclusions: RT-010 demonstrated the feasibility of incorporating efaproxiral into a sequential CT-TRT regimen and exhibited comparable 5-year survival rates and MST to the sequential (STD50) and concurrent (STD50) arms of RTOG 94-10.
I. J. Radiation Oncology
48
● Biology ● Physics
Volume 66, Number 3, Supplement, 2006
The Maximum Uptake of 18F-deoxyglucose on PET Scan Correlates With Survival and Two Endogenous Markers of Hypoxia (Hypoxia Inducible Factor-1␣ and Carbonic Anhydrase IX) in Non-Small Cell Lung Cancer (NSCLC)
A. van Baardwijk1, C. Dooms2, R. van Suylen3, E. Verbeken4, M. Hochstenbach5, S. Stroobants6, U. Buell7, P. Lambin1, J. Vansteenkiste2, D. De Ruysscher1 1
Dept. of Radiation Oncology (MAASTRO), GROW, University Hospital Maastricht, Maastricht, The Netherlands, 2Dept. of Pulmonology, University Hospital Leuven, Leuven, Belgium, 3Dept. of Pathology, University Hospital Maastricht, Maastricht, The Netherlands, 4Dept. of Pathology, University Hospital Leuven, Leuven, Belgium, 5Dept. of Pulmonology, University Hospital Maastricht, Maastricht, The Netherlands, 6Dept. of Nuclear Medicine, University Hospital Leuven, Leuven, Belgium, 7Dept. of Nuclear Medicine, Aachen University of Technology, Aachen, Germany Purpose/Objective(s): The degree of uptake of 18F-fluoro-2-deoxy-glucose (FDG) in NSCLC was consistently shown to be a significant, independent, prognostic factor. Preclinical studies suggest that hypoxic conditions correspond to a higher FDG uptake. Since hypoxia leads to an increased rate of glycolysis, which in turn, increases the uptake of FDG, we hypothesized that the worse prognosis of NSCLC patients with a high FDG uptake would be related to hypoxia. Therefore we investigated the relation between the FDG uptake on PET scan and endogenous immunohistochemical markers of tumor hypoxia (assessed by the expression of Hypoxia Inducible Factor-1␣, HIF-1 ␣, and Carbonic Anhydrase IX, CAIX), tumor proliferation (Ki67) and glucose metabolism (glucose transporters Glut-1 and Glut-3) in NSCLC.
Materials/Methods: Of 102 patients, operated for NSCLC with curative intent, PET scan data (maximal SUV, SUVmax) and follow-up data were analyzed. For all patients immunohistochemical staining for HIF-1␣, CAIX, Ki67, Glut-1 and Glut-3 on the surgical specimen was performed. Survival data were analyzed using the Kaplan-Meier method and the log-rank test. The Chi-square test and the Mann Whitney U-test were used to analyze the different categorical variables. Results: Actuarial survival was worse for patients showing a higher SUVmax, with a cut-off value of 11 showing the best discriminative value (p⫽0.0029). A higher proportion of tumors with a SUVmax ⱖ 11 showed expression of HIF-1␣ (66.1% versus 39.5%, p⫽0.011), CAIX (51.8% versus 23.7%, p⫽0.006), Glut-1 (83.1% versus 67.4%, p⫽0.066) than tumors with a SUVmax ⬍ 11. No significant difference was found in the expression of Glut-3. Tumors with a high uptake also had a higher average percentage tumor cells positive for Ki67 (46.7% versus 37.2%, p⫽0.021). Conclusion: NSCLC showing a high uptake of FDG on PET is significantly more likely to express the endogenous hypoxia markers, HIF-1␣ and CAIX and a higher fraction of proliferating cells. These patients also showed a worse survival. This study confirms that not only in vitro, but also in vivo, hypoxia increases the uptake of FDG. This might have implications for the treatment in clinical practice. Author Disclosure: A. van Baardwijk, EC FP6 funding (LSHC-CT-2004-505785), B. Research Grant; C. Dooms, None; R. van Suylen, None; E. Verbeken, None; M. Hochstenbach, None; S. Stroobants, None; U. Buell, None; P. Lambin, None; J. Vansteenkiste, None; D. De Ruysscher, None.
49
Comparison of 5-Year Survival Between RTOG-94-10 and a Phase 2 Study of Induction Chemotherapy Followed by Efaproxiral ⴙ Radiotherapy in Patients With Locally Advanced NSCLC
H. Choy1, S. Swann2, A. Nabid3, B. Stea4, W. Roa5, L. Souhami6, W. Curran7 1
UT Southwestern Medical Center at Dallas, Dallas, TX, 2RTOG, Philladelphia, PA, 3Centre Hoˆspitalier Universitaire de Sherbrooke, Sherbrooke, PQ, Canada, 4University of Arizona Health Sciences Center, Tucson, AZ, 5Cross Cancer Institute, Edmonton, AB, Canada, 6Hoˆpital Notre Dame, Montreal, PQ, Canada, 7Thomas Jefferson University, Philadelphia, PA
Purpose/Objective(s): To compare 5-year survival results between RTOG 94-10 and study RT-010 in patients with locally advanced (Stage IIIA/B) non-small cell lung cancer (NSCLC). Materials/Methods: Efaproxiral, a synthetic allosteric modifier of hemoglobin, was studied in a Phase 2 trial (RT-010) as a radiosensitizer in patients receiving chemotherapy (CT) with paclitaxel (225 mg/m2) and carboplatin (AUC ⫽ 6) for 2 cycles, days (D) 1 and 22, followed by thoracic radiotherapy (TRT) (64 Gray [Gy], D 43-50) with concurrent efaproxiral (50 - 100 mg/kg). RTOG 94-10 was a 3-arm Phase 3 trial to determine if concurrent delivery of CT with TRT improves survival compared with sequential delivery of CT followed by RT in patients with newly diagnosed, unresected Stage II-III NSCLC. In this analysis, 2 of the 3 arms on RTOG 94-10 are used: the sequential arm (STD50), which gave cisplatin (P) 100 mg/m2 D 1 and 29 & vinblastine 5 mg/m2/weekly x 5 with 60 Gy RT beginning D 50; and Arm 2, which used the same CT with 60 Gy TRT beginning D 1 (STD1). A total of 402 patients, 201 on each arm, from the STD50 and STD1 Arms of RTOG 94-10 are included in this analysis, along with 49 patients from RT-010. Overall survival is estimated by the Kaplan-Meier method and tested using the log-rank test between the patients on RT-010 and each arm of RTOG 94-10. Survival time is measured from treatment D 1. P values are 2-tailed. Results: Demographic characteristics were comparable among all groups. Median follow-up is 65.4 months for RT-010, 75.8 months for the STD50 Arm, 69.6 months for the STD1 Arm. RT-010 had a median survival time (MST) of 20.6 months compared with an MST of 14.5 months for the STD50 Arm (P ⫽ 0.088) and 16.8 months for the STD1 Arm (P ⫽ 0.65). A case-matched analysis and multivariate Cox model analysis were also performed with similar results. The Kaplan-Meier estimates (Table 1) of 5-year survival rates were 19% in RT-010, 10% in the STD50 Arm, and 16% in the STD1 Arm. The estimates of 5-year survival of the matched cases were 19% in RT-010, and 10% in each of the STD1 and STD50 Arms. Conclusions: RT-010 demonstrated the feasibility of incorporating efaproxiral into a sequential CT-TRT regimen and exhibited comparable 5-year survival rates and MST to the sequential (STD50) and concurrent (STD50) arms of RTOG 94-10.