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Late Pulmonary Toxicity Associated with Chemotherapy and Radiation for Locally Advanced Non-Small Cell Lung Cancer (NSCLC)
S414
I. J. Radiation Oncology
● Biology ● Physics
Volume 63, Number 2, Supplement, 2005
Materials/Methods: The gating mode of the Exactrac™ system (BrainLab) is a localization and treatment system using both IR cameras and KV x-rays. A gating signal pattern is established using the IR tracking system and IR markers to model breathing. Precise target localization is done by triggering stereoscopic KV x-rays to the breathing pattern and implanted fiducials are used to ensure accurate alignment. Fig. 1 shows a breathing pattern, trigger line and x-ray from a patient. Multiple x-rays may be taken in the breathing cycle to assess organ motion. Localization and gating accuracy was tested using a small motion phantom (2.0 cm vertically and longitudinally). A Tungsten target placed on the motion table was localized and verification portal images were taken with the gated beam, with dose measured using an ion chamber. The clinical study sample consisted of 10 patients with non-small cell lung tumors. Gold localization markers (2.0⫻0.7 cm Visicoil™) were transcutaneously implanted in the tumors with 18G needles under fluroscopic or CT guidance. Planning CTs were then obtained with exhalation breath hold. Conformal treatments were delivered to the tumor plus margin with no nodal coverage to 70 Gy in 35 fractions. Results: When using the default 20% window for gating, corresponding to about 6 mm motion with the motion table, the localization accuracy was better than 3 mm. Ion chamber readings showed no change in dose due to gating. Ten patients had marker placement and 7 were treated to date. All patients had upper lobe lesions ranging from 8.5 cc to 50 cc. Of the 10 patients implanted, 3 developed pneumothorax (all resolved). Treatment plans consisted of 6 to 8 conformal beams planned with 8.0 mm lateral/vertical and 10 mm longitudinal margin. Of the 7 patients who did undergo treatment to date, tumor motion (as assessed by x-ray) was ⬍5 mm in all cases. Patients were treated with gating windows set at 20% of the overall breathing motion. Most patients were localized and treated within 20 minutes. All implanted markers were visualized on x-ray as shown in Fig. 1. Verification images indicate that the tumors were within 3 mm of their original location, except in instances when patients had moved or were repositioned. Conclusions: Gating treatment technique from Exactrac™ is an effective tool for treating lung tumors. This initial evaluation of the system verified the accuracy of the localization system under Gated mode. Implanted fiducials are localizable in patients, and gating is possible. No problems were noted with the gating aspect of the linear accelerator. The benefit of this system is the potential to decrease treatment margins and improve targeting. Continued evaluation of this system would help to define patient specific dose margins and beam-on windows for treatment.
Breathing signal based on body markers and one of 2 corresponding x-rays at the trigger line (bottom of breathing cycle). Arrow shows implanted marker.
2309
Late Pulmonary Toxicity Associated with Chemotherapy and Radiation for Locally Advanced Non-Small Cell Lung Cancer (NSCLC)
S. Spencer, H.J. McCarty, K. Harper, M. Hyatt, D. Carey, F. Robert Radiation Oncology, Univ. of Alabama, Birmingham, Birmingham, AL Purpose/Objective: This is a prospective study assessing the tolerance of induction chemotherapy as compared to consolidation chemotherapy, using gemcitabine and cisplatin for locally advanced NSCLC, in patients also treated with concurrent chemoradiation. Materials/Methods: An initial cohort consisted of 35 patients treated with induction cisplatin 80mg/m2 days 1 and 22 and gemcitabine 1250mg/m2 days 1, 8, 22, and 28. This was followed by chemoradiation, using gemcitabine 300mg/m2 and paclitaxel 135mg/m2 every 21 days, concurrent with thoracic radiation to a dose of 60 Gy. Twenty-five of these patients were part of a Phase II study. A second cohort of 8 evaluable patients began treatment with chemoradiation as outlined above, with no induction chemotherapy. Chemoradiation was then followed by consolidation chemotherapy with the same dosing that was used for induction chemotherapy. Data collected include response to treatment, field size, mean lung dose and dose-volume histograms (DVHs) for the radiation, as well as acute and late esophageal and pulmonary toxicity. Results: The first cohort had an objective response rate to induction of 53%, with stable disease in an additional 43%. Median survival was 23 months (95% CI 16 –38), and three-year survival was 38%. Grade 1–2 late pulmonary toxicity was noted in 24 of 35 patients, while grade 3–5 was observed in 2 of 35 patients. The second cohort was terminated early secondary to unacceptable late pulmonary toxicity after 8 evaluable patients. Grade 1–2 late pulmonary toxicity was seen in 5 of 8 patients, while grade 3–5 was noted in 3 of 8 patients. This second cohort included one death from pneumonitis. The mean lung dose in the second cohort (20.1 Gy) was lower than that in the first (29.0 Gy). Data on DVHs and responses for the second cohort are to be analyzed with intent of presentation in the future. Conclusions: Further investigation is warranted regarding the optimal timing for chemotherapy and radiation, particularly in regard to newer chemotherapeutics. In this study, induction chemotherapy followed by chemoradiation seemed to be much better tolerated than chemoradiation followed by consolidation chemotherapy. The size of the radiation ports was not the driving force for increased toxicity. In fact, the mean lung dose for the second cohort was actually higher than that from the first. There is a possibility for a recall effect, in which chemotherapy administered after radiation is more toxic than chemotherapy given before radiation, but this also will need further study.
Proceedings of the 47th Annual ASTRO Meeting
2310
Advantages of Respiration-Gated Radiotherapy for Stage III Lung Cancer
R. Underberg, J. van Sornsen de Koste, B. Slotman, S. Senan Department of Radiation Oncology, VU University Medical Center, Amsterdam, Netherlands Purpose/Objective: Radiotherapy planning for stage III lung cancer is commonly based on a gross tumor volume (GTV) contoured in a single CT scan, to which standard margins are applied for subclinical tumor spread, mobility and set-up errors. Respiration-gated radiotherapy permits the use of smaller treatment fields, but a recent paper suggested that the benefits of respiratory gating were limited to mobile tumors with a GTV of 100 cm3 or less [Starkschall 04]. However, the abovementioned study did not utilize respiration-correlated (or 4D) CT scans, which allow for an individualized determination of intrafractional mobility of the target volume. We analyzed 4DCT datasets of patients with stage III NSCLC in order to determine the geometric and dosimetric benefits of respiration-gated radiotherapy. Materials/Methods: 4DCT scans were performed in 15 consecutive patients with stage III-N2 NSCLC. All scans were performed on a 16-slice CT scanner (GE Medical Systems) equipped with the Real-time Position Management system (RPM; Varian Medical Systems) during quiet, uncoached respiration. Images were automatically sorted into 10 different respiratory phase bins, using 4D software (Advantage 4D, GE Medical Systems). The same software was used to define a gating window, which consisted of 3 or 4 consecutive bins at end-expiration that showed minimal tumor motion. GTVs were contoured in each 4D phase bin, and the following planning target volumes (PTVs) generated: (i) PTVroutine, derived from the bin at the center of the gating window plus an isotropic margin of 1.5 cm (2.0 cm cranio-caudally for lower lobe tumors); (ii) PTVall bins, consisting of the volume encompassing all ten GTVs, plus an isotropic margin of 1.0 cm for microscopic disease and set-up inaccuracy; (iii) PTVgating, consisting of the encompassing volume of the GTVs in the gating window, plus an isotropic margin of 1.0 cm. Treatment planning was performed using the Eclipse planning system (Varian Medical Systems), and the PTV received a minimum of 95% of the prescribed total dose. A 3 or 4 field technique was used to plan a standard dose of 60 Gy (30⫻2 Gy), but a pre-operative dose of 45 Gy (25⫻1.8 Gy) was planned when spinal doses exceeded 50 Gy. The V20 of all plans was derived using a standard lung volume, which we defined as the total lung volume minus PTVgating. The mean lung dose (MLD) was derived for all plans. Results: The mean PTVroutine for all patients was 657.1cc (range 389.7 - 939.7 cc) and the resulting V20 was 28.7% (SD 5.4) and the MLD was 19.1 Gy (SD 4.7). In 3 patients, high spinal doses led to use of a 45 Gy plan using anterior-posterior fields. Use of PTVgating would have reduced the mean V20 and MLD by 4.6% and 2.8 Gy, respectively, relative to the PTVroutine. The mean dosimetric benefit of PTVgating versus an individualized approach incorporating all 4D mobility (PTVall bins) was only 1.9% (range 0.5–3.6%) for the V20, and 0.9 Gy (range 0.0 –1.7Gy) for the MLD. After 9 upper lobe tumors (including 3 superior sulcus tumors) were excluded, PTVgating resulted in mean reductions in V20 and MLD (relative to PTVroutine) of 5.2% and 3.5 Gy, respectively. Similarly, use of PTVgating versus PTVall bins in non-upper lobe lesions would have reduced the V20 by 2.8% (range 1.6 –3.6%), and the MLD by 1.3 Gy (range 0.8 –1.7 Gy). Data on the dosimetric gains for the esophagus and spinal cord will be presented. Conclusions: 4-dimensional respiratory gating can achieve meaningful reductions in lung irradiation for large stage III lung tumors of the middle and lower lobes.
2311
Target Delineation in Radiation Therapy of Non-Small Cell Lung Cancer: A Correlation Study with Local Tumor Failure
F.Y. Feng,1 F.P. Kong,1 L.E. Quint,2 D. Tatro,1 J.A. Hayman,1 R.K. Ten Haken1 1
Radiation Oncology, University of Michigan, Ann Arbor, MI, 2Radiology, University of Michigan, Ann Arbor, MI
Purpose/Objective: The use of dose escalation protocols in the treatment of lung cancer highlights the importance of accurate definition of tumor borders. The purposes of this study are to determine: 1)if gross tumor volumes (GTV) delineated by radiation oncologists differ from those defined by radiologists and 2)if the deviations in target definition correlate with regions of local failure. Materials/Methods: The study sample included 19 non-small cell lung tumors, demonstrated on pre-treatment planning CT, from 17 patients treated with 3D conformal RT in a dose escalation trial. All selected patients had at least one site of local-regional failure demonstrated on a follow-up CT. The primary GTVs were independently defined by radiation oncologists (ROGTV) and radiologists (RADGTV) on pre-treatment CTs. At the time of contouring, all physicians had no knowledge of the recurrence, which was contoured on a follow-up CT by consensus between a different radiologist and radiation oncologist. Volume differences between the initial GTVs defined by the radiation oncologists and the radiologists were recorded, with significance analyzed using paired t-test. Consistency between the two GTVs was further analyzed qualitatively for local contour differences at each tumor border. A contour difference was defined as a ⱖ1cm linear difference in the GTV borders on at least 2 consecutive 5mm CT sections. Locations of recurrences were compared to areas of contour differences. Results: There were significant volumetric differences between ROGTVs and RADGTVs. The mean absolute volume difference was 25.6 cc(95% CI 14.7–36.4,p⫽0.03) or 21.9%(95% CI 18.9 –25.0,p⬍0.01). Local contour differences were also noted between ROGTVs and RADGTVs. In 7 of 19 cases, the radiologists contoured the hilum more extensively. In another 7 of 19 cases, radiation oncologists contoured the lung parenchyma more fully. The relationship between mismatched GTVs and recurrent tumor were further examined. There were four cases of local failure at the hilum. Two of these coincided with a mismatched region, with the recurrence falling within RADGTV (Fig 1). Conclusions: There were significant volumetric differences between ROGTVs and RADGTVs. Of interest, a common trend in deviations was demonstrated, with radiologists including more of the hilum in their contours and radiation oncologists
S415
I. J. Radiation Oncology
● Biology ● Physics
Volume 63, Number 2, Supplement, 2005
Materials/Methods: The gating mode of the Exactrac™ system (BrainLab) is a localization and treatment system using both IR cameras and KV x-rays. A gating signal pattern is established using the IR tracking system and IR markers to model breathing. Precise target localization is done by triggering stereoscopic KV x-rays to the breathing pattern and implanted fiducials are used to ensure accurate alignment. Fig. 1 shows a breathing pattern, trigger line and x-ray from a patient. Multiple x-rays may be taken in the breathing cycle to assess organ motion. Localization and gating accuracy was tested using a small motion phantom (2.0 cm vertically and longitudinally). A Tungsten target placed on the motion table was localized and verification portal images were taken with the gated beam, with dose measured using an ion chamber. The clinical study sample consisted of 10 patients with non-small cell lung tumors. Gold localization markers (2.0⫻0.7 cm Visicoil™) were transcutaneously implanted in the tumors with 18G needles under fluroscopic or CT guidance. Planning CTs were then obtained with exhalation breath hold. Conformal treatments were delivered to the tumor plus margin with no nodal coverage to 70 Gy in 35 fractions. Results: When using the default 20% window for gating, corresponding to about 6 mm motion with the motion table, the localization accuracy was better than 3 mm. Ion chamber readings showed no change in dose due to gating. Ten patients had marker placement and 7 were treated to date. All patients had upper lobe lesions ranging from 8.5 cc to 50 cc. Of the 10 patients implanted, 3 developed pneumothorax (all resolved). Treatment plans consisted of 6 to 8 conformal beams planned with 8.0 mm lateral/vertical and 10 mm longitudinal margin. Of the 7 patients who did undergo treatment to date, tumor motion (as assessed by x-ray) was ⬍5 mm in all cases. Patients were treated with gating windows set at 20% of the overall breathing motion. Most patients were localized and treated within 20 minutes. All implanted markers were visualized on x-ray as shown in Fig. 1. Verification images indicate that the tumors were within 3 mm of their original location, except in instances when patients had moved or were repositioned. Conclusions: Gating treatment technique from Exactrac™ is an effective tool for treating lung tumors. This initial evaluation of the system verified the accuracy of the localization system under Gated mode. Implanted fiducials are localizable in patients, and gating is possible. No problems were noted with the gating aspect of the linear accelerator. The benefit of this system is the potential to decrease treatment margins and improve targeting. Continued evaluation of this system would help to define patient specific dose margins and beam-on windows for treatment.
Breathing signal based on body markers and one of 2 corresponding x-rays at the trigger line (bottom of breathing cycle). Arrow shows implanted marker.
2309
Late Pulmonary Toxicity Associated with Chemotherapy and Radiation for Locally Advanced Non-Small Cell Lung Cancer (NSCLC)
S. Spencer, H.J. McCarty, K. Harper, M. Hyatt, D. Carey, F. Robert Radiation Oncology, Univ. of Alabama, Birmingham, Birmingham, AL Purpose/Objective: This is a prospective study assessing the tolerance of induction chemotherapy as compared to consolidation chemotherapy, using gemcitabine and cisplatin for locally advanced NSCLC, in patients also treated with concurrent chemoradiation. Materials/Methods: An initial cohort consisted of 35 patients treated with induction cisplatin 80mg/m2 days 1 and 22 and gemcitabine 1250mg/m2 days 1, 8, 22, and 28. This was followed by chemoradiation, using gemcitabine 300mg/m2 and paclitaxel 135mg/m2 every 21 days, concurrent with thoracic radiation to a dose of 60 Gy. Twenty-five of these patients were part of a Phase II study. A second cohort of 8 evaluable patients began treatment with chemoradiation as outlined above, with no induction chemotherapy. Chemoradiation was then followed by consolidation chemotherapy with the same dosing that was used for induction chemotherapy. Data collected include response to treatment, field size, mean lung dose and dose-volume histograms (DVHs) for the radiation, as well as acute and late esophageal and pulmonary toxicity. Results: The first cohort had an objective response rate to induction of 53%, with stable disease in an additional 43%. Median survival was 23 months (95% CI 16 –38), and three-year survival was 38%. Grade 1–2 late pulmonary toxicity was noted in 24 of 35 patients, while grade 3–5 was observed in 2 of 35 patients. The second cohort was terminated early secondary to unacceptable late pulmonary toxicity after 8 evaluable patients. Grade 1–2 late pulmonary toxicity was seen in 5 of 8 patients, while grade 3–5 was noted in 3 of 8 patients. This second cohort included one death from pneumonitis. The mean lung dose in the second cohort (20.1 Gy) was lower than that in the first (29.0 Gy). Data on DVHs and responses for the second cohort are to be analyzed with intent of presentation in the future. Conclusions: Further investigation is warranted regarding the optimal timing for chemotherapy and radiation, particularly in regard to newer chemotherapeutics. In this study, induction chemotherapy followed by chemoradiation seemed to be much better tolerated than chemoradiation followed by consolidation chemotherapy. The size of the radiation ports was not the driving force for increased toxicity. In fact, the mean lung dose for the second cohort was actually higher than that from the first. There is a possibility for a recall effect, in which chemotherapy administered after radiation is more toxic than chemotherapy given before radiation, but this also will need further study.
Proceedings of the 47th Annual ASTRO Meeting
2310
Advantages of Respiration-Gated Radiotherapy for Stage III Lung Cancer
R. Underberg, J. van Sornsen de Koste, B. Slotman, S. Senan Department of Radiation Oncology, VU University Medical Center, Amsterdam, Netherlands Purpose/Objective: Radiotherapy planning for stage III lung cancer is commonly based on a gross tumor volume (GTV) contoured in a single CT scan, to which standard margins are applied for subclinical tumor spread, mobility and set-up errors. Respiration-gated radiotherapy permits the use of smaller treatment fields, but a recent paper suggested that the benefits of respiratory gating were limited to mobile tumors with a GTV of 100 cm3 or less [Starkschall 04]. However, the abovementioned study did not utilize respiration-correlated (or 4D) CT scans, which allow for an individualized determination of intrafractional mobility of the target volume. We analyzed 4DCT datasets of patients with stage III NSCLC in order to determine the geometric and dosimetric benefits of respiration-gated radiotherapy. Materials/Methods: 4DCT scans were performed in 15 consecutive patients with stage III-N2 NSCLC. All scans were performed on a 16-slice CT scanner (GE Medical Systems) equipped with the Real-time Position Management system (RPM; Varian Medical Systems) during quiet, uncoached respiration. Images were automatically sorted into 10 different respiratory phase bins, using 4D software (Advantage 4D, GE Medical Systems). The same software was used to define a gating window, which consisted of 3 or 4 consecutive bins at end-expiration that showed minimal tumor motion. GTVs were contoured in each 4D phase bin, and the following planning target volumes (PTVs) generated: (i) PTVroutine, derived from the bin at the center of the gating window plus an isotropic margin of 1.5 cm (2.0 cm cranio-caudally for lower lobe tumors); (ii) PTVall bins, consisting of the volume encompassing all ten GTVs, plus an isotropic margin of 1.0 cm for microscopic disease and set-up inaccuracy; (iii) PTVgating, consisting of the encompassing volume of the GTVs in the gating window, plus an isotropic margin of 1.0 cm. Treatment planning was performed using the Eclipse planning system (Varian Medical Systems), and the PTV received a minimum of 95% of the prescribed total dose. A 3 or 4 field technique was used to plan a standard dose of 60 Gy (30⫻2 Gy), but a pre-operative dose of 45 Gy (25⫻1.8 Gy) was planned when spinal doses exceeded 50 Gy. The V20 of all plans was derived using a standard lung volume, which we defined as the total lung volume minus PTVgating. The mean lung dose (MLD) was derived for all plans. Results: The mean PTVroutine for all patients was 657.1cc (range 389.7 - 939.7 cc) and the resulting V20 was 28.7% (SD 5.4) and the MLD was 19.1 Gy (SD 4.7). In 3 patients, high spinal doses led to use of a 45 Gy plan using anterior-posterior fields. Use of PTVgating would have reduced the mean V20 and MLD by 4.6% and 2.8 Gy, respectively, relative to the PTVroutine. The mean dosimetric benefit of PTVgating versus an individualized approach incorporating all 4D mobility (PTVall bins) was only 1.9% (range 0.5–3.6%) for the V20, and 0.9 Gy (range 0.0 –1.7Gy) for the MLD. After 9 upper lobe tumors (including 3 superior sulcus tumors) were excluded, PTVgating resulted in mean reductions in V20 and MLD (relative to PTVroutine) of 5.2% and 3.5 Gy, respectively. Similarly, use of PTVgating versus PTVall bins in non-upper lobe lesions would have reduced the V20 by 2.8% (range 1.6 –3.6%), and the MLD by 1.3 Gy (range 0.8 –1.7 Gy). Data on the dosimetric gains for the esophagus and spinal cord will be presented. Conclusions: 4-dimensional respiratory gating can achieve meaningful reductions in lung irradiation for large stage III lung tumors of the middle and lower lobes.
2311
Target Delineation in Radiation Therapy of Non-Small Cell Lung Cancer: A Correlation Study with Local Tumor Failure
F.Y. Feng,1 F.P. Kong,1 L.E. Quint,2 D. Tatro,1 J.A. Hayman,1 R.K. Ten Haken1 1
Radiation Oncology, University of Michigan, Ann Arbor, MI, 2Radiology, University of Michigan, Ann Arbor, MI
Purpose/Objective: The use of dose escalation protocols in the treatment of lung cancer highlights the importance of accurate definition of tumor borders. The purposes of this study are to determine: 1)if gross tumor volumes (GTV) delineated by radiation oncologists differ from those defined by radiologists and 2)if the deviations in target definition correlate with regions of local failure. Materials/Methods: The study sample included 19 non-small cell lung tumors, demonstrated on pre-treatment planning CT, from 17 patients treated with 3D conformal RT in a dose escalation trial. All selected patients had at least one site of local-regional failure demonstrated on a follow-up CT. The primary GTVs were independently defined by radiation oncologists (ROGTV) and radiologists (RADGTV) on pre-treatment CTs. At the time of contouring, all physicians had no knowledge of the recurrence, which was contoured on a follow-up CT by consensus between a different radiologist and radiation oncologist. Volume differences between the initial GTVs defined by the radiation oncologists and the radiologists were recorded, with significance analyzed using paired t-test. Consistency between the two GTVs was further analyzed qualitatively for local contour differences at each tumor border. A contour difference was defined as a ⱖ1cm linear difference in the GTV borders on at least 2 consecutive 5mm CT sections. Locations of recurrences were compared to areas of contour differences. Results: There were significant volumetric differences between ROGTVs and RADGTVs. The mean absolute volume difference was 25.6 cc(95% CI 14.7–36.4,p⫽0.03) or 21.9%(95% CI 18.9 –25.0,p⬍0.01). Local contour differences were also noted between ROGTVs and RADGTVs. In 7 of 19 cases, the radiologists contoured the hilum more extensively. In another 7 of 19 cases, radiation oncologists contoured the lung parenchyma more fully. The relationship between mismatched GTVs and recurrent tumor were further examined. There were four cases of local failure at the hilum. Two of these coincided with a mismatched region, with the recurrence falling within RADGTV (Fig 1). Conclusions: There were significant volumetric differences between ROGTVs and RADGTVs. Of interest, a common trend in deviations was demonstrated, with radiologists including more of the hilum in their contours and radiation oncologists
S415