- Email: [email protected]
Clinicopathologic Analysis of Microscopic Extension in Lung Adenocarcinoma: Implications for Defining the Clinical Target Volume (CTV) for Radiotherapy
Proceedings of the 47th Annual ASTRO Meeting
The corresponding 5-year DFS rates were 97%, 91%, and 49% (p ⫽ 0.001) respectively. Similarly the corresponding 5-year rates of disease specific survival (DSS) were 99%, 95%, and 65% (p ⫽ 0.001) respectively. The influence of the extent of surgical staging on DFS within each group was not significant as shown in the table below. Conclusions: By using age ⱖ 60 and grade 3 histology we were able to categorize this cohort of patients with stage IB-II endometrial cancer into three risk-based groups. Such grouping was highly predictive for vaginal/pelvic control, DFS, and DSS which may suggest a potential use to determine which patients should be considered for intensification of adjuvant therapy. The extent of surgical staging, however, did not affect DFS within each group, highlighting the need for a prospective trial to determine the true influence of complete surgical staging on outcome in this group of patients. 5-year DFS and Surgical Staging
Only 23 patients in group III
164
Initial Report of a Prospective Phase II Trial of Stereotactic Body Radiation Therapy for Patients with Medically Inoperable Stage I Non-small Cell Lung Cancer
R. Timmerman,1 R. McGarry,2 L. Papiez,2 C. Yiannoutsos,2 T. Whitford,2 J. DeLuca,2 K. Tudor,2 M. Williams2 Radiation Oncology, Univ. of Texas Southwestern Medical Center, Dallas, TX, 2Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN
1
Purpose/Objective: Stereotactic Body Radiation Therapy (SBRT) uses multiple highly focused beams of radiation directed toward demarcated targets in the body in order to deliver a few very large dose treatments to a target with the goal of tumor ablation. Patients with medically inoperable stage I lung cancer constitute an ideal population for SBRT since standard treatment options (surgery and conventional radiation) are quite toxic and local tumor ablation by itself may lead to cure. This protocol builds on a previous dose escalation study we conducted using SBRT in the same patient population. Materials/Methods: A total of 70 patients with AJCC stage T1 (35 patients) and T2 up to 7 cm (35 patients), N0, M0 (Stage IA and IB) biopsy proven non-small cell lung cancer were enrolled into this prospective study between January 2002 and July 2004. All patients were deemed medically inoperable according to predefined criteria. Patients were positioned in a stereotactic immobilizing frame with abdominal compression to decrease respiratory motion. SBRT was administered in three separate fractions of 20 Gy for T1 tumors (60 Gy total) and 22 Gy for T2 tumors (66 Gy total) over two weeks using a linear accelerator with 10 non-opposing and non-coplanar beams. Patients were followed at three month intervals for control and toxicity assessment. Toxicity grading was confirmed by an independent data safety monitoring committee. Results: All 70 patients completed all three fractions of SBRT. The three month major response rate (complete and partial) was 60%. Fibrotic changes and atalectasis occurred commonly after 6 months making local assessment difficult. Seventeen patients had local enlargement of radiographic changes in the vicinity of the treated tumor prompting a PET scan or biopsy. After a median follow-up of 12 months (range 0.6 –33.4 months), a total of two patients have experienced a local recurrence of cancer. Nineteen patients have died of cancer, treatment or co-morbid illnesses. Actuarial local control at one year is 97.8% and is not appreciably different between T1 and T2 tumors. Kaplan Meier estimates indicate a median overall survival of 32.6 months and actuarial one-year overall and disease free survival of 81.1% and 79.0%, respectively. Grade 3–5 toxicity occurred in a total of 13 patients. Eight patients experienced Grade 3– 4 toxicities (in decreasing order pleural effusion, pneumonia/pneumonitis, decline in pulmonary function tests, apnea, vocal cord palsy, and skin burn) occurring after a range 1–25 months. Grade 5 toxicity occurred in 5 patients (two with pneumonia, two with multifactor respiratory cause, and one with hemoptysis) occurring after range 1–20 months from end of therapy. No differences were noted between T1 and T2 tumor patients with respect to local control, survival, or toxicity. Conclusions: While the follow-up in this trial is limited, SBRT as delivered in this trial has a high rate of initial response and local tumor control. Significant treatment related toxicities have occurred, including some treatment related deaths. However, overall and disease free survival is encouraging given the general frailty of the patient population. Grade 3–5 toxicities related to this therapy generally occur “late” as compared to what has been observed with conventionally fractionated radiotherapy which has implications toward the design of future trials using SBRT in lung or other sites.
165
Clinicopathologic Analysis of Microscopic Extension in Lung Adenocarcinoma: Implications for Defining the Clinical Target Volume (CTV) for Radiotherapy
D.L. Fitch,1 N.S. Goldstein,2 D. Yan,1 I.S. Grills,1 G.W. Chmielewski,1 R.J. Welsh,1 L.L. Kestin1 Radiation Oncology, William Beaumont Hospital, Royal Oak, MI, 2Department of Pathology, William Beaumont Hospital, Royal Oak, MI
1
Purpose/Objective: Minimal data are available for lung cancer to determine the appropriate CTV expansion beyond the gross tumor volume (GTV) as defined on computed tomography (CT) images. We performed a detailed pathologic review of lobectomy specimens and correlated the clinical features of lung adenocarcinoma with the linear distance of microscopic extension (MicExt) in an attempt to determine the appropriate margin to include for the CTV.
S99
S100
I. J. Radiation Oncology
● Biology ● Physics
Volume 63, Number 2, Supplement, 2005
Materials/Methods: From 2001 to 2003, 35 patients with clinical stage I (T1–T2 N0) lung adenocarcinoma underwent wedge resection followed by immediate lobectomy. All slides from each case were reviewed by a single pathologist (NSG). The adenocarcinoma was transected and the grossly visualized perimeter was outlined with ink. The MicExt distance of adenocarcinoma beyond ink was measured. Pathologic analysis included the maximum gross tumor dimensions, maximum MicExt in any direction, and nuclear grade. The gross pathologic tumor(GPT) dimensions and MicExt were summed for a composite(CMP) maximum dimension. Radiologic tumor dimensions were measured using preoperative chest CT scans, on both lung(CTL) and mediastinal(CTM) windows. Results: The mean maximum tumor size on CTL was 25.2 mm (standard deviation (SD)⫽8.8) versus 18.6 mm (SD⫽8.8) on CTM (p⬍0.01). The mean GPT size was 19.4 mm (SD⫽5.0). For all patients, the mean MicExt distance was 7.2 mm (SD⫽3.1), accounting for a mean CMP size (GPT ⫹ MicExt) of 26.5 mm (SD⫽6.4). When examining by nuclear grade, the mean MicExt for grade 1 was 10.1 mm (SD⫽2.1), 7.0 mm (SD⫽2.2) for grade 2, and 3.5 mm (SD⫽0.8) for grade 3 (p⬍0.01). The 90th percentile for MicExt in all cases was 12.0 mm (13.0 mm for grade 1 vs 9.7 mm for grade 2 vs 4.4 mm for grade 3, see figure). CTL overestimated GPT by a mean of 5.8 mm (SD⫽8.4 mm), but underestimated CMP by a mean of 1.2 mm (SD⫽9 mm). Based on these data, if the GTV is contoured on CTL, the margin required to cover MicExt for 90% of cases would be 11.4 mm. When stratified by grade, CTL underestimated the CMP of grade 1 tumors by a mean of 3.0 mm, grade 2 by 2.1 mm, and overestimated grade 3 by 2.4 mm. CTM underestimated GPT by a mean of 1.5 mm and underestimated CMP by a mean of 8.6 mm. Conclusions: When treating lung adenocarcinoma with radiotherapy, the GTV should be contoured using CT lung windows. Although GTV based on CT lung windows would underestimate gross tumor size ⫹ MicExt(CMP) by only 1.2 mm for the average case, the CTV expansion required to cover MicExt in 90% of cases may be as large as 11 mm due to substantial variation in MicExt and accuracy of lung window contours from case to case. The margin required for MicExt may be considerably smaller for grade 3 tumors than for grade 1 tumors.
166
Dose Escalation in Radiotherapy of Lung Tumors by Stereotactic Irradiation: Is There a Dose-Response Relationship for Local Tumor Control?
J. Wulf,1,2 K. Baier,2 M.P. Flentje2 Radiooncology, Lindenhofspital, Bern, Switzerland, 2Radiotherapy, University of Wuerzburg, Wuerzburg, Germany
1
Purpose/Objective: Local tumor control of pulmonary tumors by radiotherapy is dependent on local tumor dose. Therefore dose escalation is an important issue in modern radiotherapy. One approach to achieve this purpose is extracranial stereotactic radiotherapy. Mostly the stereotactic treatment is given as single dose or hypofractionated irradiation with fraction doses of 10Gy to 30Gy. For these high doses no biological data is available to predict its impact on local tumor control. Therefore a total of 91 stereotactically treated lung tumors were evaluated for local control. A dose response curve was calculated using 2Gy equivalent doses and a multivariate analysis of factors influencing local control was performed. Materials/Methods: From 11/97 to 11/2004 a total of 91 lung tumors (36 NSCLC and 55 metastases) were treated in the stereotactic body frame (SBF; ELEKTA Instr.). The tumors were treated by different dose-fractionation schedules: the first patients by 3⫻10Gy (n⫽24), tumors close to the mediastinum by 4 –5⫻7Gy (n⫽3). After 7 local failures the dose was increased to 3⫻12 and 3⫻12.5Gy (n⫽30), all prescribed to the PTV-enclosing 65%-isodose. Additionally a 8⫻6Gy-schedule to the PTV-enclosing 80%-isodose was used for central tumors (n⫽3) and single dose irradiation by 1⫻26Gy/PTV-encl. 80%-isodose was introduced (n⫽31) according to promising results in the literature. Median follow-up was 13 months (2–72 months). The dose prescriptions were recalculated into 2Gy-equivalent doses (for ?/?⫽10) according the Withers-formula. The doses were calculated separately for the isocenter dose and the dose at the PTV-margin. The isocenter 2Gy-equiv. doses were 72Gy (4⫻7Gy/65% PTV), 90Gy (5⫻7/65% PTV), 88Gy (8⫻6Gy/80% PTV), 94Gy (3⫻10Gy/65% PTV), 135Gy (3⫻12.5Gy/65% PTV) and 115Gy (1⫻26Gy/80% PTV). A dose-response curve for local tumors control was calculated by a logistic regression procedure. To address multiple other factors on local control besides dose a multivariate analysis using a stepwise multiple regression was performed. In this procedure the CTV, PTV, PTV/CTV-ratio, the 2Gy-equiv-dose at the PTV-margin and at the isocenter, the target (NSCLC vs. metastasis), stage of NSCLC, histology of primary tumor in metastases and the target location in the lung (close to the thoracic wall, central, close to the mediastinum) were included. Results: Ten local failures occurred out of 91 targets leading to a crude local control rate of 89%. Seven local failures occurred in the 24 tumors irradiated with 3⫻10Gy, one failure each occurred after 4⫻7Gy and 8⫻6Gy and only one local failure was observed in the large group of patients (n⫽29) treated by 3⫻12–12.5Gy (metastasis of kidney cancer treated by 3⫻12.5Gy).
The corresponding 5-year DFS rates were 97%, 91%, and 49% (p ⫽ 0.001) respectively. Similarly the corresponding 5-year rates of disease specific survival (DSS) were 99%, 95%, and 65% (p ⫽ 0.001) respectively. The influence of the extent of surgical staging on DFS within each group was not significant as shown in the table below. Conclusions: By using age ⱖ 60 and grade 3 histology we were able to categorize this cohort of patients with stage IB-II endometrial cancer into three risk-based groups. Such grouping was highly predictive for vaginal/pelvic control, DFS, and DSS which may suggest a potential use to determine which patients should be considered for intensification of adjuvant therapy. The extent of surgical staging, however, did not affect DFS within each group, highlighting the need for a prospective trial to determine the true influence of complete surgical staging on outcome in this group of patients. 5-year DFS and Surgical Staging
Only 23 patients in group III
164
Initial Report of a Prospective Phase II Trial of Stereotactic Body Radiation Therapy for Patients with Medically Inoperable Stage I Non-small Cell Lung Cancer
R. Timmerman,1 R. McGarry,2 L. Papiez,2 C. Yiannoutsos,2 T. Whitford,2 J. DeLuca,2 K. Tudor,2 M. Williams2 Radiation Oncology, Univ. of Texas Southwestern Medical Center, Dallas, TX, 2Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN
1
Purpose/Objective: Stereotactic Body Radiation Therapy (SBRT) uses multiple highly focused beams of radiation directed toward demarcated targets in the body in order to deliver a few very large dose treatments to a target with the goal of tumor ablation. Patients with medically inoperable stage I lung cancer constitute an ideal population for SBRT since standard treatment options (surgery and conventional radiation) are quite toxic and local tumor ablation by itself may lead to cure. This protocol builds on a previous dose escalation study we conducted using SBRT in the same patient population. Materials/Methods: A total of 70 patients with AJCC stage T1 (35 patients) and T2 up to 7 cm (35 patients), N0, M0 (Stage IA and IB) biopsy proven non-small cell lung cancer were enrolled into this prospective study between January 2002 and July 2004. All patients were deemed medically inoperable according to predefined criteria. Patients were positioned in a stereotactic immobilizing frame with abdominal compression to decrease respiratory motion. SBRT was administered in three separate fractions of 20 Gy for T1 tumors (60 Gy total) and 22 Gy for T2 tumors (66 Gy total) over two weeks using a linear accelerator with 10 non-opposing and non-coplanar beams. Patients were followed at three month intervals for control and toxicity assessment. Toxicity grading was confirmed by an independent data safety monitoring committee. Results: All 70 patients completed all three fractions of SBRT. The three month major response rate (complete and partial) was 60%. Fibrotic changes and atalectasis occurred commonly after 6 months making local assessment difficult. Seventeen patients had local enlargement of radiographic changes in the vicinity of the treated tumor prompting a PET scan or biopsy. After a median follow-up of 12 months (range 0.6 –33.4 months), a total of two patients have experienced a local recurrence of cancer. Nineteen patients have died of cancer, treatment or co-morbid illnesses. Actuarial local control at one year is 97.8% and is not appreciably different between T1 and T2 tumors. Kaplan Meier estimates indicate a median overall survival of 32.6 months and actuarial one-year overall and disease free survival of 81.1% and 79.0%, respectively. Grade 3–5 toxicity occurred in a total of 13 patients. Eight patients experienced Grade 3– 4 toxicities (in decreasing order pleural effusion, pneumonia/pneumonitis, decline in pulmonary function tests, apnea, vocal cord palsy, and skin burn) occurring after a range 1–25 months. Grade 5 toxicity occurred in 5 patients (two with pneumonia, two with multifactor respiratory cause, and one with hemoptysis) occurring after range 1–20 months from end of therapy. No differences were noted between T1 and T2 tumor patients with respect to local control, survival, or toxicity. Conclusions: While the follow-up in this trial is limited, SBRT as delivered in this trial has a high rate of initial response and local tumor control. Significant treatment related toxicities have occurred, including some treatment related deaths. However, overall and disease free survival is encouraging given the general frailty of the patient population. Grade 3–5 toxicities related to this therapy generally occur “late” as compared to what has been observed with conventionally fractionated radiotherapy which has implications toward the design of future trials using SBRT in lung or other sites.
165
Clinicopathologic Analysis of Microscopic Extension in Lung Adenocarcinoma: Implications for Defining the Clinical Target Volume (CTV) for Radiotherapy
D.L. Fitch,1 N.S. Goldstein,2 D. Yan,1 I.S. Grills,1 G.W. Chmielewski,1 R.J. Welsh,1 L.L. Kestin1 Radiation Oncology, William Beaumont Hospital, Royal Oak, MI, 2Department of Pathology, William Beaumont Hospital, Royal Oak, MI
1
Purpose/Objective: Minimal data are available for lung cancer to determine the appropriate CTV expansion beyond the gross tumor volume (GTV) as defined on computed tomography (CT) images. We performed a detailed pathologic review of lobectomy specimens and correlated the clinical features of lung adenocarcinoma with the linear distance of microscopic extension (MicExt) in an attempt to determine the appropriate margin to include for the CTV.
S99
S100
I. J. Radiation Oncology
● Biology ● Physics
Volume 63, Number 2, Supplement, 2005
Materials/Methods: From 2001 to 2003, 35 patients with clinical stage I (T1–T2 N0) lung adenocarcinoma underwent wedge resection followed by immediate lobectomy. All slides from each case were reviewed by a single pathologist (NSG). The adenocarcinoma was transected and the grossly visualized perimeter was outlined with ink. The MicExt distance of adenocarcinoma beyond ink was measured. Pathologic analysis included the maximum gross tumor dimensions, maximum MicExt in any direction, and nuclear grade. The gross pathologic tumor(GPT) dimensions and MicExt were summed for a composite(CMP) maximum dimension. Radiologic tumor dimensions were measured using preoperative chest CT scans, on both lung(CTL) and mediastinal(CTM) windows. Results: The mean maximum tumor size on CTL was 25.2 mm (standard deviation (SD)⫽8.8) versus 18.6 mm (SD⫽8.8) on CTM (p⬍0.01). The mean GPT size was 19.4 mm (SD⫽5.0). For all patients, the mean MicExt distance was 7.2 mm (SD⫽3.1), accounting for a mean CMP size (GPT ⫹ MicExt) of 26.5 mm (SD⫽6.4). When examining by nuclear grade, the mean MicExt for grade 1 was 10.1 mm (SD⫽2.1), 7.0 mm (SD⫽2.2) for grade 2, and 3.5 mm (SD⫽0.8) for grade 3 (p⬍0.01). The 90th percentile for MicExt in all cases was 12.0 mm (13.0 mm for grade 1 vs 9.7 mm for grade 2 vs 4.4 mm for grade 3, see figure). CTL overestimated GPT by a mean of 5.8 mm (SD⫽8.4 mm), but underestimated CMP by a mean of 1.2 mm (SD⫽9 mm). Based on these data, if the GTV is contoured on CTL, the margin required to cover MicExt for 90% of cases would be 11.4 mm. When stratified by grade, CTL underestimated the CMP of grade 1 tumors by a mean of 3.0 mm, grade 2 by 2.1 mm, and overestimated grade 3 by 2.4 mm. CTM underestimated GPT by a mean of 1.5 mm and underestimated CMP by a mean of 8.6 mm. Conclusions: When treating lung adenocarcinoma with radiotherapy, the GTV should be contoured using CT lung windows. Although GTV based on CT lung windows would underestimate gross tumor size ⫹ MicExt(CMP) by only 1.2 mm for the average case, the CTV expansion required to cover MicExt in 90% of cases may be as large as 11 mm due to substantial variation in MicExt and accuracy of lung window contours from case to case. The margin required for MicExt may be considerably smaller for grade 3 tumors than for grade 1 tumors.
166
Dose Escalation in Radiotherapy of Lung Tumors by Stereotactic Irradiation: Is There a Dose-Response Relationship for Local Tumor Control?
J. Wulf,1,2 K. Baier,2 M.P. Flentje2 Radiooncology, Lindenhofspital, Bern, Switzerland, 2Radiotherapy, University of Wuerzburg, Wuerzburg, Germany
1
Purpose/Objective: Local tumor control of pulmonary tumors by radiotherapy is dependent on local tumor dose. Therefore dose escalation is an important issue in modern radiotherapy. One approach to achieve this purpose is extracranial stereotactic radiotherapy. Mostly the stereotactic treatment is given as single dose or hypofractionated irradiation with fraction doses of 10Gy to 30Gy. For these high doses no biological data is available to predict its impact on local tumor control. Therefore a total of 91 stereotactically treated lung tumors were evaluated for local control. A dose response curve was calculated using 2Gy equivalent doses and a multivariate analysis of factors influencing local control was performed. Materials/Methods: From 11/97 to 11/2004 a total of 91 lung tumors (36 NSCLC and 55 metastases) were treated in the stereotactic body frame (SBF; ELEKTA Instr.). The tumors were treated by different dose-fractionation schedules: the first patients by 3⫻10Gy (n⫽24), tumors close to the mediastinum by 4 –5⫻7Gy (n⫽3). After 7 local failures the dose was increased to 3⫻12 and 3⫻12.5Gy (n⫽30), all prescribed to the PTV-enclosing 65%-isodose. Additionally a 8⫻6Gy-schedule to the PTV-enclosing 80%-isodose was used for central tumors (n⫽3) and single dose irradiation by 1⫻26Gy/PTV-encl. 80%-isodose was introduced (n⫽31) according to promising results in the literature. Median follow-up was 13 months (2–72 months). The dose prescriptions were recalculated into 2Gy-equivalent doses (for ?/?⫽10) according the Withers-formula. The doses were calculated separately for the isocenter dose and the dose at the PTV-margin. The isocenter 2Gy-equiv. doses were 72Gy (4⫻7Gy/65% PTV), 90Gy (5⫻7/65% PTV), 88Gy (8⫻6Gy/80% PTV), 94Gy (3⫻10Gy/65% PTV), 135Gy (3⫻12.5Gy/65% PTV) and 115Gy (1⫻26Gy/80% PTV). A dose-response curve for local tumors control was calculated by a logistic regression procedure. To address multiple other factors on local control besides dose a multivariate analysis using a stepwise multiple regression was performed. In this procedure the CTV, PTV, PTV/CTV-ratio, the 2Gy-equiv-dose at the PTV-margin and at the isocenter, the target (NSCLC vs. metastasis), stage of NSCLC, histology of primary tumor in metastases and the target location in the lung (close to the thoracic wall, central, close to the mediastinum) were included. Results: Ten local failures occurred out of 91 targets leading to a crude local control rate of 89%. Seven local failures occurred in the 24 tumors irradiated with 3⫻10Gy, one failure each occurred after 4⫻7Gy and 8⫻6Gy and only one local failure was observed in the large group of patients (n⫽29) treated by 3⫻12–12.5Gy (metastasis of kidney cancer treated by 3⫻12.5Gy).