Stereotactic Body Radiation Therapy in Centrally and Superiorly Located Stage I or Isolated Recurrent Non–Small-Cell Lung Cancer

Chang. IJROBP 2008;72:967 The University of Texas M. D. Anderson Cancer Center

Image-guided hypofractionated stereotactic body radiation therapy (SBRT) can deliver a high biologic effective dose to the target while minimizing toxicity to the surrounding normal tissue, which may translate into improved local control and survival rates. However, for lesions close to critical structures, SBRT has been associated with a high incidence (46%) of Grade 3 and Grade 5 toxicities when 60–66 Gy was delivered in three fractions to lesions within 2 cm of the proximal bronchial tree.

To minimize toxicity while delivering an ablative dose of radiotherapy to the cancer site, it is crucial to use image-guided radiotherapy. In this report, we analyzed our early results of SBRT in centrally or superiorly located, defined as within 2 cm of the proximal bronchial tree, critical mediastinal structures, brachial plexus, or vertebral body, but 1 cm away from the spinal canal, Stage I or isolated recurrent non–small-cell lung cancer (NSCLC) using 4-dimensional (4D) computed tomography (CT) and in-room CT-guided SBRT.

We analyzed 27 patients with centrally and superiorly located Stage I (T1: ≤3 cm, T2: >3 cm but <4 cm or with the visceral pleural involvement, N0 M0, n = 13) or isolated lung parenchyma recurrent (i.e., treated by definitive radiotherapy with or without chemotherapy or surgical resection before SBRT, size <4 cm, n = 14) NSCLC who were treated consecutively with minimal 6 months follow-up at The University of Texas M. D. Anderson Cancer Center between 2004 and 2007. Patients were enrolled in an institutional review board–approved protocol. A central or superior location was defined as being within 2 cm of the bronchial tree, major vessels, esophagus, heart, trachea, pericardium, brachial plexus, or vertebral body, but 1 cm away from the spinal canal. Any patients with involvement of main bronchus, lymph node or association with atelectasis, or collapsed lobe were excluded.

 

In all patients, diseases were staged using chest CT, positron emission tomography (PET), and brain magnetic resonance imaging. Four-dimensional CT images were obtained using a GE simulator and a Varian RPM system. Internal gross tumor volume (GTV) was delineated using a maximal intensity projection created by combining data from multiple 4D CT datasets at different breath phases and then modifying these contours by visual verification of the coverage in each phase of the 4D CT dataset. Clinical target volume was defined as internal GTV plus an 8-mm margin, and a 3-mm setup uncertainty margin was added to determine the planning target volume (PTV). Most plans had between six and nine noncoplanar beams using 6 MV X-rays. Daily CT-on-rail simulation was conducted during each fraction of radiotherapy, and coverage of target volume and sparing of critical structure were verified or adjusted. Orthogonal port films were taken to confirm isocenters.

Patients underwent chest CT scans every 3 months for 2 years as a follow-up and then every 6 months for another 3 years. PET scans were recommended 3–5 months after SBRT. Toxicities were scored according to the NCI Common Terminology Criteria for Adverse Effects-3. Clinical responses were evaluated using Response Evaluation Criteria in Solid Tumor based on both PET and CT images. The local tumor recurrence was defined as progressive abnormal CT images corresponding to avid lesion on PET or positive post-SBRT biopsy.

The first 7 patients (≤3 cm: 5 cases, >3 cm but <4 cm: 2 cases) received a prescribed dose of 40 Gy to the PTV in the 75–90% isodose lines with heterogeneity correction and delivered in 4 consecutive days. After observing no Grade III or higher toxicity with a minimal follow up of 3 months, dose was escalated to 50 Gy for subsequent patients (≤3 cm: 17 cases, >3 cm but <4 cm: 3 cases). Dose–volume constraints for nearby critical structures, based on biologic effective dose calculations and previous clinical experience,

If the dose–volume constraints of critical structures conflicted with the required dose coverage for PTV or clinical target volume, critical organ dose–volume constraints were prioritized. However, the GTV plus a 3-mm setup margin was required to receive >95% prescribed dose and GTV was required to receive >100% prescribed dose.

Follow-up was determined from the data of the last SBRT for median follow-up calculation and clinical response analysis. Timing of recurrence was scored at the time of first image (PET or CT) showing abnormalities.
Results

With a median follow-up of 17 months (range, 6–40 months), the crude local control at the treated site was 100% using 50 Gy. However, 3 of 7 patients had local recurrences when treated using 40 Gy. Of the patients with Stage I disease, 1 (7.7%) and 2 (15.4%) developed mediastinal lymph node metastasis and distant metastases, respectively. Of the patients with recurrent disease, 3 (21.4%) and 5 (35.7%) developed mediastinal lymph node metastasis and distant metastasis, respectively. Four patients (28.6%) with recurrent disease but none with Stage I disease developed Grade 2 pneumonitis. Three patients (11.1%) developed Grade 2-3 dermatitis and chest wall pain. One patient developed brachial plexus neuropathy. No esophagitis was noted in any patient.

Conclusions

Image-guided SBRT using 50 Gy delivered in four fractions is feasible and resulted in excellent local control.

Discussion 

Optimal SBRT regimens for centrally or superiorly located lesions remain controversial. Dr. Onishi revealed that biologic effective dose ≥100 Gy was required to achieve optimal tumor control. Dr. Timmerman in their Phase I study showed that all local recurrence happened in patients who received <48 Gy in three fractions except for 1 patient. However, in their Phase II study, toxicity of 60–66 Gy in three fractions without heterogeneity correction (60 Gy without heterogeneity correction is equivalent to 54 Gy with heterogeneity correction) was considered too toxic for lesions located within 2 cm of proximal bronchial tree. Treating peripheral lesions, Dr. Nagata and Dr. Onimaru achieved >90% 2 years local control using 48 Gy in four fractions prescribed to isocenter. A total of 48 Gy prescribed to the isocenter delivered about 40 Gy to PTV. In our current study, when 40 Gy was prescribed to PTV (biologic effective dose in PTV: 80 Gy), with isocenter receiving 45–50 Gy, higher local recurrence (in 3 of 7 patients with follow up of 12, 14, and 27 months, respectively) was noted compared with 50 Gy regimen (0 of 17 patients). However, in addition to lower dose, higher local recurrence could be related higher tumor stage because two of three recurrences had tumors between 3 and 4 cm. Our data indicated that 50 Gy in four fractions prescribed to the PTV (biologic effective dose in PTV: 112.5 Gy), with the GTV receiving approximately 54–60 Gy, was needed to achieve sufficient local control for centrally and superiorly located lesions in T1-T2 N0M0 disease. Although priority was given to keep normal tissue dose volume constraints when it conflicted with target coverage, GTV plus 3-mm setup uncertainty was required to receive >95% prescribed dose in both 50 Gy and 40 Gy cohorts. In 50 Gy cohort, 70–97% PTV volumes were covered by prescription isodose line and 100% PTV volumes received >35 GY except in one worse case shown. In 40 Gy cohort, at least 90% PTV volume was covered by prescription isodose line and 100% PTV volume received >35 Gy. Therefore the higher local recurrence in 40 Gy cohort was not caused by lower percentage PTV coverage compared with 50 Gy cohort. The available clinical data have led to the initiation of an international randomized study to compare surgical resection with SBRT in operable Stage I NSCLC. The SBRT regimens to be tested include 60 Gy delivered in three fractions for peripheral lesions and 50 Gy delivered in four fractions for central/superiorly lesions

The chronic toxicity for SBRT in centrally and superiorly located lesions is a major concern. Dr. Xia and Dr. Lagerward reported 93–95% local control with minimal toxicities in central lesions treated with 70 Gy to GTV in 10 fractions or 60 Gy to PTV in 8 fractions, respectively. Using our 4D CT–based SBRT planning and in-room CT-guided daily setup, we were able to deliver an ablative dose (50 Gy) to the GTV in only four fractions. Our data suggest that 35–40 Gy in four fractions would likely be a threshold for chronic toxicity with regard to the skin and neuropathy. As yet, with 17 months of median follow-up, no toxicity has been noted in major vessels, the spinal cord, or the esophagus, and there was no Grade 3 and higher pneumonitis. Longer follow-up is still needed. It should be noted that our definition of central/superior lesions is different from Dr. Timmerman's definition of central lesions. In addition, esophagus was not included in the treatment field in most of cases in our study and highest dose esophagus received was 35 Gy in 1 mL (median <5 Gy, range <5 Gy to 35 Gy).