I.S. Grills

Outcomes After Stereotactic Lung Radiotherapy or Wedge Resection for Stage I Non–Small-Cell Lung Cancer

PURPOSE To compare outcomes between lung stereotactic radiotherapy (SBRT) and wedge resection for stage I non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS One hundred twenty-four patients with T1-2N0 NSCLC underwent wedge resection (n = 69) or image-guided lung SBRT (n = 58) from February 2003 through August 2008. All were ineligible for anatomic lobectomy; of those receiving SBRT, 95% were medically inoperable, with 5% refusing surgery. Mean forced expiratory volume in 1 second and diffusing capacity of lung for carbon monoxide were 1.39 L and 12.0 mL/min/mmHg for wedge versus 1.31 L and 10.14 mL/min/mmHg for SBRT (P = not significant). Mean Charlson comorbidity index and median age were 3 and 74 years for wedge versus 4 and 78 years for SBRT (P < .01, P = .04). SBRT was volumetrically prescribed as 48 (T1) or 60 (T2) Gy in four to five fractions. Results Median potential follow-up is 2.5 years. At 30 months, no significant differences were identified in regional recurrence (RR), locoregional recurrence (LRR), distant metastasis (DM), or freedom from any failure (FFF) between the two groups (P > .16). SBRT reduced the risk of local recurrence (LR), 4% versus 20% for wedge (P = .07). Overall survival (OS) was higher with wedge but cause-specific survival (CSS) was identical. Results excluding synchronous primaries, nonbiopsied tumors, or pathologic T4 disease (wedge satellite lesion) showed reduced LR (5% v 24%, P = .05), RR (0% v 18%, P = .07), and LRR (5% v 29%, P = .03) with SBRT. There were no differences in DM, FFF, or CSS, but OS was higher with wedge. CONCLUSION Both lung SBRT and wedge resection are reasonable treatment options for stage I NSCLC patients ineligible for anatomic lobectomy. SBRT reduced LR, RR, and LRR. In this nonrandomized population of patients selected for surgery versus SBRT (medically inoperable) at physician discretion, OS was higher in surgical patients. SBRT and surgery, however, had identical CSS.

Potential for reduced toxicity and dose escalation in the treatment of inoperable non–small-cell lung cancer: A comparison of intensity-modulated radiation therapy (IMRT), 3D conformal radiation, and elective nodal irradiation

PURPOSE To systematically evaluate four different techniques of radiation therapy (RT) used to treat non-small-cell lung cancer and to determine their efficacy in meeting multiple normal-tissue constraints while maximizing tumor coverage and achieving dose escalation. METHODS AND MATERIALS Treatment planning was performed for 18 patients with Stage I to IIIB inoperable non-small-cell lung cancer using four different RT techniques to treat the primary lung tumor +/- the hilar/mediastinal lymph nodes: (1) Intensity-modulated radiation therapy (IMRT), (2) Optimized three-dimensional conformal RT (3D-CRT) using multiple beam angles, (3) Limited 3D-CRT using only 2 to 3 beams, and (4) Traditional RT using elective nodal irradiation (ENI) to treat the mediastinum. All patients underwent virtual simulation, including a CT scan and (18)fluorodeoxyglucose positron emission tomography scan, fused to the CT to create a composite tumor volume. For IMRT and 3D-CRT, the target included the primary tumor and regional nodes either > or =1.0 cm in short-axis dimension on CT or with increased uptake on PET. For ENI, the target included the primary tumor plus the ipsilateral hilum and mediastinum from the inferior head of the clavicle to at least 5.0 cm below the carina. The goal was to deliver 70 Gy to > or =99% of the planning target volume (PTV) in 35 daily fractions (46 Gy to electively treated mediastinum) while meeting multiple normal-tissue dose constraints. Heterogeneity correction was applied to all dose calculations (maximum allowable heterogeneity within PTV 30%). Pulmonary and esophageal constraints were as follows: lung V(20) < or =25%, mean lung dose < or =15 Gy, esophagus V(50) < or =25%, mean esophageal dose < or =25 Gy. At the completion of all planning, the four techniques were contrasted for their ability to achieve the set dose constraints and deliver tumoricidal RT doses. RESULTS Requiring a minimum dose of 70 Gy within the PTV, we found that IMRT was associated with a greater degree of heterogeneity within the target and, correspondingly, higher mean doses and tumor control probabilities (TCPs), 7%-8% greater than 3D-CRT and 14%-16% greater than ENI. Comparing the treatment techniques in this manner, we found only minor differences between 3D-CRT and IMRT, but clearly greater risks of pulmonary and esophageal toxicity with ENI. The mean lung V(20) was 36% with ENI vs. 23%-25% with the three other techniques, whereas the average mean lung dose was approximately 21.5 Gy (ENI) vs. 15.5 Gy (others). Similarly, the mean esophagus V(50) was doubled with ENI, to 34% rather than 15%-18%. To account for differences in heterogeneity, we also compared the techniques giving each plan a tumor control probability equivalent to that of the optimized 3D-CRT plan delivering 70 Gy. Using this method, IMRT and 3D-CRT offered similar results in node-negative cases (mean lung and esophageal normal-tissue complication probability [NTCP] of approximately 10% and 2%-7%, respectively), but ENI was distinctly worse (mean NTCPs of 29% and 20%). In node-positive cases, however, IMRT reduced the lung V(20) and mean dose by approximately 15% and lung NTCP by 30%, compared to 3D-CRT. Compared to ENI, the reductions were 50% and >100%. Again, for node-positive cases, especially where the gross tumor volume was close to the esophagus, IMRT reduced the mean esophagus V(50) by 40% (vs. 3D-CRT) to 145% (vs. ENI). The esophageal NTCP was at least doubled converting from IMRT to 3D-CRT and tripled converting from IMRT to ENI. Finally, the total number of fractions for each plan was increased or decreased until all outlined normal-tissue constraints were reached/satisfied. While meeting all constraints, IMRT or 3D-CRT increased the deliverable dose in node-negative patients by >200% over ENI. In node-positive patients, IMRT increased the deliverable dose 25%-30% over 3D-CRT and 130%-140% over ENI. The use of 3D-CRT without IMRT increased the deliverable RT dose >80% over ENI. Using a limited number of 3D-CRT beams decreased the lung V(20), mean dose, and NTCP in node-positive patients. CONCLUSION The use of 3D-CRT, particul mean dose, and NTCP in node-positive patients. The use of 3D-CRT, particularly with only 3 to 4 beam angles, has the ability to reduce normal-tissue toxicity, but has limited potential for dose escalation beyond the current standard in node-positive patients. IMRT is of limited additional value (compared to 3D-CRT) in node-negative cases, but is beneficial in node-positive cases and in cases with target volumes close to the esophagus. When meeting all normal-tissue constraints in node-positive patients, IMRT can deliver RT doses 25%-30% greater than 3D-CRT and 130%-140% greater than ENI. Whereas the possibility of dose escalation is severely limited with ENI, the potential for pulmonary and esophageal toxicity is clearly increased.

A Collaborative Analysis of Stereotactic Lung Radiotherapy Outcomes for Early-Stage Non–Small-Cell Lung Cancer Using Daily Online Cone-Beam Computed Tomography Image-Guided Radiotherapy

Introduction: We report lung stereotactic-body radiotherapy (SBRT) outcomes for a large pooled cohort treated using daily online cone-beam computed tomography. Methods: Five hundred and five stage I–IIB (T1-3N0M0) non–small-cell lung cancer (NSCLC) cases underwent SBRT using cone-beam computed tomography image guidance at five international institutions from 1998 to 2010. Median age was 74 years (range, 42–92) whereas median forced expiratory volume in 1 second/diffusing lung capacity for carbon monoxide were 1.4 liter (65%) and 10.8 ml/min/mmHg (53%). Of the 505 cases, 64% were biopsy proven and 87% medically inoperable. Staging was: IA 63%, IB 33%, IIA 2%, and recurrent 1%. Median max tumor dimension was 2.6 cm (range, 0.9–8.5). Median heterogeneously calculated volumetric prescription dose (PD) was 54 Gy (range, 20–64 Gy) in three fractions (range, 1–15) over 8 days (range, 1–27). Median biologically equivalent PD biological equivalent doses (BED10) was 132 Gy (range, 60–180). Results: With a median follow-up of 1.6 years (range, 0.1–7.3), the 2-year Kaplan–Meier local control (LC), regional control, and distant metastasis (DM) rates were 94%, 89%, and 20%, respectively, whereas cause-specific and overall survival were 87% and 60% (78% operable, 58% inoperable, p = 0.01), respectively. Stage, gross-tumor volume size (≥ 2.7 cm) and PD(BED10) predicted local relapse (LR) and DM. LR was 15% for BED10 less than 105 Gy versus 4% for BED10 of 105 Gy or more (p < 0.001); DM was 31% versus 18% for BED10 less than 105 versus 105 Gy or more (p = 0.01). On multivariate analysis, PD(BED10) and elapsed days during radiotherapy predicted LR; gross-tumor volume size predicted DM. Grade 2 or higher pneumonitis, rib fracture, myositis, and dermatitis were 7%, 3%, 1%, and 2%, respectively. Conclusions: In the largest early-stage NSCLC SBRT data set to date, a high rate of local control was achieved, which was correlated with a PD(BED10) of 105 Gy or more. Failures were primarily distant, severe toxicities were rare, and overall survival was encouraging in operable patients.

Four-Year Efficacy, Cosmesis, and Toxicity Using Three-Dimensional Conformal External Beam Radiation Therapy to Deliver Accelerated Partial Breast Irradiation

PURPOSE This prospective study examines the use of three-dimensional conformal external beam radiation therapy (3D-CRT) to deliver accelerated partial breast irradiation (APBI). Four-year data on efficacy, cosmesis, and toxicity are presented. METHODS Patients with Stage O, I, or II breast cancer with lesions </=3 cm, negative margins, and negative nodes were eligible. The 3D-CRT delivered was 38.5 Gy in 3.85 Gy/fraction. Ipsilateral breast, ipsilateral nodal, contralateral breast, and distant failure (IBF, INF, CBF, DF) were estimated using the cumulative incidence method. Disease-free, overall, and cancer-specific survival (DFS, OS, CSS) were recorded. The National Cancer Institute Common Terminology Criteria for Adverse Events (version 3) toxicity scale was used to grade acute and late toxicities. RESULTS Ninety-four patients are evaluable for efficacy. Median patient age was 62 years with the following characteristics: 68% tumor size <1 cm, 72% invasive ductal histology, 77% estrogen receptor (ER) (+), 88% postmenopausal; 88% no chemotherapy and 44% with no hormone therapy. Median follow-up was 4.2 years (range, 1.3-8.3). Four-year estimates of efficacy were IBF: 1.1% (one local recurrence); INF: 0%; CBF: 1.1%; DF: 3.9%; DFS: 95%; OS: 97%; and CSS: 99%. Four (4%) Grade 3 toxicities (one transient breast pain and three fibrosis) were observed. Cosmesis was rated good/excellent in 89% of patients at 4 years. CONCLUSIONS Four-year efficacy, cosmesis, and toxicity using 3D-CRT to deliver APBI appear comparable to other experiences with similar follow-up. However, additional patients, further follow-up, and mature Phase III data are needed to evaluate thoroughly the extent of application, limitations, and complete value of this particular form of APBI.

Clinical Applications of Volumetric Modulated Arc Therapy

PURPOSE To present treatment planning case studies for several treatment sites for which volumetric modulated arc therapy (VMAT) could have a positive impact; and to share an initial clinical experience with VMAT for stereotactic body radiotherapy (SBRT). METHODS AND MATERIALS Four case studies are presented to show the potential benefit of VMAT compared with conformal and intensity-modulated radiotherapy (IMRT) techniques in pediatric cancer, bone marrow-sparing whole-abdominopelvic irradiation (WAPI), and SBRT of the lung and spine. Details of clinical implementation of VMAT for SBRT are presented. The VMAT plans are compared with conventional techniques in terms of dosimetric quality and delivery efficiency. RESULTS Volumetric modulated arc therapy reduced the treatment time of spine SBRT by 37% and improved isodose conformality. Conformal and VMAT techniques for lung SBRT had similar dosimetric quality, but VMAT had improved target coverage and took 59% less time to deliver, although monitor units were increased by 5%. In a complex pediatric pelvic example, VMAT reduced treatment time by 78% and monitor units by 25% compared with IMRT. A double-isocenter VMAT technique for WAPI can spare bone marrow while maintaining good delivery efficiency. CONCLUSIONS Volumetric modulated arc therapy is a new technology that may benefit different patient populations, including pediatric cancer patients and those undergoing concurrent chemotherapy and WAPI. Volumetric modulated arc therapy has been used and shown to be beneficial for significantly improving delivery efficiency of lung and spine SBRT.

Volumetric modulated arc therapy for delivery of hypofractionated stereotactic lung radiotherapy: A dosimetric and treatment efficiency analysis

PURPOSE/OBJECTIVE(S) Volumetric modulated arc therapy (VMAT) allows for intensity-modulated radiation delivery during gantry rotation with dynamic MLC motion, variable dose rates and gantry speed modulation. We compared VMAT plans with 3D-CRT for hypofractionated lung radiotherapy. MATERIALS/METHODS Twenty-one 3D-CRT plans for Stage IA lung cancer previously treated stereotactically were selected. VMAT plans were generated by optimizing machine aperture shape and radiation intensity at 10 degrees intervals. A partial arc range of 180 degrees was manually selected to coincide with tumor location. The arc was resampled down to 5 degrees intervals to ensure dose calculation accuracy. Identical planning objectives were used for VMAT/3D-CRT. Parameters assessed included dose to PTV and organs-at-risk (OAR), monitor units, and multiple conformity and homogeneity indices. Plans were delivered to a phantom for time comparison. RESULTS Lung V(20/12.5/10/5) were less with VMAT (relative reduction 4.5%, p = .02; 3.2%, p = .01; 2.6%, p = .01; 4.2%, p = .03, respectively). Mean/maximum-doses to PTV, dose to additional OARs, 95% isodose line conformity, and target volume homogeneity were equivalent. VMAT improved conformity at both the 80% (1.87 vs. 1.93, p = .08) and 50% isodose lines (5.19 vs. 5.65, p = .01). Treatment times were reduced significantly with VMAT (mean 6.1 vs. 11.9 min, p < .01). CONCLUSIONS Single arc VMAT planning achieves highly conformal dose distributions while controlling dose to critical structures, including significant reduction in lung dose volume parameters. Employing a VMAT technique decreases treatment times by 37-63%, reducing the chance of error introduced by intrafraction variation. The quality and efficiency of VMAT is ideally suited for stereotactic lung radiotherapy delivery.

Risk factors for regional nodal failure after breast-conserving therapy: regional nodal irradiation reduces rate of axillary failure in patients with four or more positive lymph nodes

PURPOSE To determine the incidence of, and risk factors for, regional nodal failure (RNF) and to evaluate the effectiveness of, and indications for, regional nodal irradiation (RNI) in patients with Stage I-II breast cancer treated with breast-conserving therapy. METHOD AND MATERIALS A total of 1500 cases of Stage I-II breast cancer were treated with breast-conserving therapy between February 1980 and December 2000. All patients underwent excisional biopsy, and 925 (62%) underwent re-excision. Level I-II axillary lymph node dissection was done in 94% of patients. The lymph nodes were pathologically involved in 335 patients (22%); 255 with 1-3 nodes and 80 with >/=4 nodes involved. All patients received whole breast irradiation to a median dose of 45 Gy, and 97% received a tumor bed boost to a median dose of 61 Gy. Treatment included the breast only in 1309 patients (87%), and the breast and regional lymphatics in 191 (13%). RESULTS With a median follow-up of 8.1 years, 35 patients had failure within the regional nodes: 12 patients (6%) who received RNI and 23 patients (2%) who did not. The 5- and 10-year rate for any RNF was 1.9% and 2.8%, respectively. The 5 and 10-year rates of axillary failure and supraclavicular failure were 0.6% and 1.0% and 0.9% and 1.6%, respectively. In patients with >/=4 positive lymph nodes, RNI reduced the 10-year rate of any RNF from 11% to 2% (p = 0.024), the rate of axillary failure from 5% to 0% (p = 0.019), and the rate of supraclavicular failure from 11% to 2% (p = 0.114). RNI did not affect the rate of axillary failure or supraclavicular failure in patients with 1-3 positive nodes. In node-negative patients, the rate of RNF was significantly greater if <6 nodes were removed at the time of axillary dissection. Multiple clinical, pathologic, and treatment-related factors were analyzed for association with RNF. On univariate analysis, RNF was associated with the number of nodes excised, number of positive nodes, percentage of positive nodes, size of nodal metastasis, presence of angiolymphatic invasion, estrogen receptor status, age, systemic chemotherapy, and RNI. Three subsets of patients had unusually high rates of RNF, those with >/=67% nodes positive (16%), nodal metastasis >/=2.0 cm (44%), or age </=35 years (14%). On multivariate analysis, the only significant predictor of RNF was the maximal size of the nodal metastasis. RNI did not improve the overall survival for any subset of patients. The number of lymph nodes excised had an impact on overall survival, with a 10-year survival rate of 33%, 65%, and 69% in patients with <6, 6-10, and >10 nodes excised, respectively (p = 0.05). CONCLUSION Failure within the regional lymph nodes as an isolated site of first relapse is uncommon in patients with Stage I-II breast cancer treated with breast-conserving therapy. RNI can significantly reduce the rate of RNF (axillary failure) in patients with >/=4 positive lymph nodes. The maximal size of the lymph node metastasis was found to be the only significant independent predictor of RNF, with nodal metastases >/=2.0 cm associated with extremely high regional failure rates. Despite this, young age and the extent of axillary dissection (particularly as related to the number of positive nodes) also appear to be important and should be considered when evaluating patients for RNI. Inadequate axillary dissection was not only associated with increased regional failure, but also reduced survival.

Six-year experience routinely using moderate deep inspiration breath-hold for the reduction of cardiac dose in left-sided breast irradiation for patients with early-stage or locally advanced breast cancer.

Purpose:Moderate deep inspiration breath-hold (mDIBH), using an Active Breathing Control device, has been used in our clinic since 2002 to reduce cardiac dose for patients receiving left-sided breast irradiation. We report our routine use of the mDIBH technique in clinically localized breast cancer, treated to the intact breast, reconstructed breast, or chest wall. Materials and Methods:Ninety-nine patients with left-sided breast cancer were evaluated for Active Breathing Control treatment, of which, 87 patients were treated with mDIBH. Plans for both the free-breathing (FB) and mDIBH computed tomography scans were evaluated. Dose-volume histograms (DVHs) were analyzed for the heart and ipsilateral lung, comparing results for mDIBH versus FB plans. Results:Eighty-seven patients were included for analysis. Of those, 66% received adjuvant chemotherapy with cardiotoxic agents. The mean dose for the whole breast was 47.6 Gy. There was a statistically significant decrease in all DVH parameters evaluated, favoring the delivery of mDIBH over FB plans. mDIBH plans significantly reduced cardiac mean dose (4.23 vs. 2.54 Gy; P<0.001), a relative reduction of 40%. In addition, there were significant reductions in all other heart parameters evaluated (ie, volume of heart treated, V30, V25, V20, V15, V10, and V5). mDIBH also significantly reduced lung dose, including a reduction of the left lung mean dose (9.08 vs. 7.86 Gy; P<0.001), a relative reduction of 13%, as well as significant reduction of all lung DVH parameters evaluated. Conclusions:To date, this series represents the largest experience utilizing mDIBH to reduce cardiac irradiation during left-sided breast cancer treatment. Statistically significant reductions in all heart and lung DVH parameters were achieved with mDIBH over FB plans. mDIBH, for the treatment of left-sided breast cancer, is a proven technique for reducing cardiac dose that may lead to reduced cardiotoxicity and can be routinely integrated into the clinic.

Dose–response relationship with clinical outcome for lung stereotactic body radiotherapy (SBRT) delivered via online image guidance☆

PURPOSE To examine potential dose-response relationships with various non-small-cell lung cancer (NSCLC) SBRT fractionation regimens delivered with online CT-based image guidance. METHODS 505 tumors in 483 patients with clinical stage T1-T2N0 NSCLC were treated with SBRT using on-line cone-beam-CT-based image guidance at 5 institutions (1998-2010). Median maximum tumor dimension was 2.6 cm (range 0.9-8.5 cm). Dose fractionation prescription was according to each institutions protocol with the most common schedules of 18-20 GyX3, 12 GyX4, 12 GyX5, 12.5 GyX3, 7.5 GyX8 (median = 54 Gy, 3 fractions). Median prescription (Rx) BED10 = 132 Gy (50.4-180). Median values (Gy) of 3D planned doses for BED10 were GTV(min) = 164.1, GTV(mean) = 188.4, GTV(max) = 205.9, PTV(min) = 113.9, PTV D99 = 123.9, PTV(mean) = 164.7, PTV D1 = 197.3, PTV(max) = 210.7. Mean follow-up = 1.6 years. RESULTS 26 cases (5%) had local recurrence (LR) for a 2-year rate of 6% and 3-year rate of 9%. All BED10 GTV&PTV endpoints were associated with LR as continuous variables on univariate analysis (p<0.05). Rx and PTV(mean) dose appeared to have the highest correlation with LR with area under ROC curve of 0.69 and 0.65 respectively and optimal cut points of 105 and 125 Gy, respectively. 2-year LR was 4% for PTV(mean)>125 vs 17% for <125 Gy (p<0.01) with sensitivity = 84% and specificity = 57% for predicting LR. 2-year LR for Rx BED10>105 was 4% vs 15% for <105 Gy (p<0.01). Longer treatment duration (⩾ 11 elapsed days) demonstrated a 2-year LR of 14% vs 4% for ⩽ 10 days (p<0.01). GTV size was associated with LR on univariate analysis as a continuous variable (p = 0.02) with 2-year LR = 3% for <2.7 cm vs 9% for ⩾ 2.7 cm (p = 0.03). BED10 (p = 0.01) and elapsed days during RT (p = 0.05) were independent predictors on multivariate analysis as continuous variables. CONCLUSIONS There is a substantial dose-response relationship for local control of NSCLC following image-guided SBRT with optimal PTV(mean) BED10>125 Gy. Shorter treatment duration was also associated with better local control in this dataset.

Is there a lower limit of pretreatment pulmonary function for safe and effective stereotactic body radiotherapy for early-stage non-small cell lung cancer?

Introduction: To evaluate the influence of pretreatment pulmonary function (PF) on survival, early and late pulmonary toxicity after stereotactic body radiotherapy (SBRT) for early-stage non-small cell lung cancer. Methods: Four hundred eighty-three patients with 505 tumors of early-stage non-small cell lung cancer cT1–3 cN0 were treated with image-guided SBRT at five international institutions (1998–2010). Sixty-four percent of the tumors were biopsy-proven and 18F-fluorodeoxyglucose-positron emission tomography was performed for staging in 84%. Image-guided SBRT was performed with a median of three fractions to a median total dose of 54 Gy. Pretreatment PF was available for 423 patients, and 617 posttreatment PF tests from 270 patients were available. Results: A large variability of pretreatment PF was observed: the 90% range of forced expiratory volume in 1 second and diffusing capacity for carbon monoxide was 29 to 109% and 5.5 to 19.1 ml/min/mmHg, respectively. PF was significantly correlated with overall survival but not cause-specific survival: diffusing capacity for carbon monoxide of 11.2 ml/min/mmHg differentiated between 3-year overall survival of 66% and 42%. Radiation-induced pneumonitis grade ≥II occurred in 7% of patients and was not increased in patients with lower PF. A significant and progressive change of PF was observed after SBRT: PF decreased by 3.6% and 6.8% on average within 6 and 6 to 24 months after SBRT, respectively. Changes of PF after SBRT were significantly correlated with pretreatment PF: PF improved for worst pretreatment PF and the largest loss was observed for best pretreatment PF. Conclusions: Image-guided SBRT is safe in terms of acute and chronic pulmonary toxicity even for patients with severe pulmonary comorbidities. SBRT should be considered as a curative treatment option for inoperable patients with pretreatment PF as reported in this study.