Volume 70, Issue 3 , Pages 685-692, 1 March 2008
Outcomes of Risk-Adapted Fractionated Stereotactic Radiotherapy for Stage I Non–Small-Cell Lung Cancer
Article Outline
Purpose
High local control rates can be achieved using stereotactic radiotherapy in Stage I non–small-cell lung cancer (NSCLC), but reports have suggested that toxicity may be of concern. We evaluated early clinical outcomes of “risk-adapted” fractionation schemes in patients treated in a single institution.
Methods and Materials
Of 206 patients with Stage I NSCLC, 81% were unfit to undergo surgery and the rest refused surgery. Pathologic confirmation of malignancy was obtained in 31% of patients. All other patients had new or growing 18F-fluorodeoxyglucose positron emission tomography positive lesions with radiologic characteristics of malignancy. Planning four-dimensional computed tomography scans were performed and fractionation schemes used (3 × 20 Gy, 5 × 12 Gy, and 8 × 7.5 Gy) were determined by T stage and risk of normal tissue toxicity.
Results
Median overall survival was 34 months, with 1- and 2-year survivals of 81% and 64%, respectively. Disease-free survival (DFS) at 1 and 2 years was 83% and 68%, respectively, and DFS correlated with T stage (p = 0.002). Local failure was observed in 7 patients (3%). The crude regional failure rate was 9%; isolated regional recurrence was observed in 4%. The distant progression-free survival at 1 and 2 years was 85% and 77%, respectively. SRT was well tolerated and severe late toxicity was observed in less than 3% of patients.
Conclusions
SRT is well tolerated in patients with extensive comorbidity with high local control rates and minimal toxicity. Early outcomes are not inferior to those reported for conventional radiotherapy. In view of patient convenience, such risk-adapted SRT schedules should be considered treatment of choice in patients presenting with medically inoperable Stage I NSCLC.
Lung cancer, Stereotactic radiotherapy, Four-dimensional, Medically inoperable, Toxicity
Introduction
Surgery is the preferred treatment option for patients with Stage I non–small-cell lung cancer (NSCLC), despite the observation that nearly 35% of patients will relapse after the initial surgery and consequently have a poor prognosis 1, 2. Furthermore, population-based analyses in Europe show 30-day postlobectomy mortality rates of between 2.4 and 4.9%, with comparable US data reporting mortality rates of 4.5% 3, 4. In addition, between 5 and 10% of patients with Stage I NSCLC undergo a pneumonectomy 5, 6, a procedure associated with an even higher mortality and morbidity (7).
Almost 25% of patients with Stage I NSCLC will not undergo a thoracotomy because of patient refusal or because of coexisting illnesses that preclude surgery (8). The survival in untreated Stage I NSCLC is very poor as shown by a population-based analysis of 1,432 patients who did not undergo surgical resection or treatment with chemotherapy or radiation, with a median overall survival of 9 months (95% CI, 8–10 months) and the estimated 5-year survival of 7% (9). Patients who are unfit for surgery typically undergo conventional radiotherapy delivered over a 5-week to 6-week period. However, the poor outcomes with radiotherapy are reflected in Surveillance, Epidemiology, and End Results data since 1988 or later showing lung cancer-specific survival rates of 69% (95% CI, 67–71%) at 1 year, 29% (95% CI, 27–32%) at 3 years, and 15% (95% CI, 13–17%) at 5 years (8).
Local control rates in excess of 85–95% have recently been reported using stereotactic radiotherapy (SRT), a technique characterized by the use of accurate repositioning during treatment simulation and delivery and ablative doses that are typically delivered in three to five fractions 10, 11, 12, 13, 14. A retrospective analysis of multi-institutional SRT data suggests that the toxicity of this treatment is low (15).
Even when three-dimensional conformal radiotherapy techniques were applied, we observed local failures in up to 75% of T2 tumors at 3 years' follow-up (16). Consequently, we implemented SRT as our standard treatment in 2003 for all patients who had medically inoperable disease or who refused surgery. A multislice respiration-correlated computed tomography (4DCT) was performed for planning SRT this allowed for an evaluation and incorporation of patient-specific mobility margins (17). Because dose-dependent late bronchial, cardiac, and esophageal toxicity has been reported after conventionally fractionated high-dose radiotherapy or chemoradiotherapy for lung tumors (18), we tailored the SRT schemes to the potential risk of toxicity to normal organs. We now report on local control and toxicity in 206 patients treated in this fashion.
Methods and Materials
Review of a prospective database containing details of all patients treated with SRT identified a total of 219 patients with primary lung tumors with a minimum follow-up of 3 months. After the exclusion of patients who presented with synchronous brain metastases (n = 7), a new Stage I NSCLC after prior high-dose conventional radiotherapy (n = 2), SRT combined with chemoradiotherapy for a synchronous Stage III lung cancer (n = 2), and locally recurrent SCLC (n = 2), a total of 206 patients with Stage I NSCLC remained for analysis. The median follow-up of patients was 12 months (range, 3–44 months).
Patient characteristics
Relevant patient and tumor characteristics are summarized in Table 1. All patients were discussed in a multidisciplinary team before treatment and patients with Stage I lung cancer were only accepted for SRT if they were considered medically inoperable (n = 167; 81%) or had refused surgery (n = 39; 19%). Eligible patients had to have a tumor of 6 cm or less in diameter, cytologic or histologic evidence of malignancy, and the absence of metastases on an 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) scan. In the absence of the cytohistologic evidence of malignancy, patients with a new or growing lesion with an appearance on a multislice CT scan that was consistent with malignancy (19), in conjunction with a local uptake of 18FDG-PET were also accepted for treatment.
Table 1. Characteristics of patient and tumors
| Gender | |
 Male | n = 115 (56%) |
| Female | n = 91 (44%) |
| Median age | 73 years |
| Tumors (n = 219) | |
| T1 | n = 129 (59%) |
| T2 | n = 90 (41%) |
| Reason for referral | |
| Medically inoperable | n = 167 (81%) |
| Refusing surgery | n = 39 (19%) |
| Pathological confirmation | |
| Yes | n = 64 (31%) |
| No | n = 142 (69%) |
| Histology (n = 64) | |
| Adenocarcinoma | n = 23 (36%) |
| Squamous cell carcinoma | n = 19 (30%) |
| Undifferentiated NSCLC | n = 22 (34%) |
| Fractionation scheme (n = 219) | |
| 20 Gy × 3 | n = 93 (43%) |
| 12 Gy × 5 | n = 99 (45%) |
| 7.5 Gy × 8 | n = 27 (12%) |
| GOLD class | |
| No COPD | n = 36 (18%) |
| Class I | n = 16 (8%) |
| Class II | n = 60 (29%) |
| Class III | n = 75 (36%) |
| Unknown | n = 19 (9%) |
The cohort included 115 males (56%) and 91 (44%) females, with a median age of 73 years. Common reasons for inoperability were poor pulmonary function, cardiovascular comorbidity, advanced age in combination with poor general condition, or synchronous second malignancy. Spirometry findings before SRT were available in 187 patients (91%) and the median forced expiratory volume in 1 s (FEV1) was 54% of predicted. The majority of patients had a history of chronic obstructive pulmonary disease (COPD), with 36% categorized as having GOLD Class III disease (http://www.goldcopd.org). A history of prior malignancy was present in 39%, including 37 patients (18%) who had a prior lung cancer diagnosed at a median of 2 years before SRT. Treatment for a prior lung cancer consisted of pneumonectomy (n = 7), bilobectomy (n = 2), lobectomy (n = 17), wedge resection (n = 2), chemoradiotherapy (n = 3), radiotherapy (n = 5), or endobronchial therapy (n = 1).
Tumor characteristics
Pretreatment staging of patients included a whole-body 18FDG-PET scan in all but 3 patients. None of the patients had evidence of regional or distant metastases on either 18FDG-PET or chest CT scans. T classification was based on measurement of maximum tumor diameter on a pretreatment planning CT scan; 129 tumors were classified as T1 (59%), and 90 as T2 tumors (41%). Most tumors were located in the upper lobes (63%), followed by the lower lobes (31%) and middle lobe (6%).
A cytologic or histologic confirmation of malignancy was available in 31% of patients (Table 1). When no pathologic confirmation could be obtained, patients were required to have a new or growing lesion, which showed CT characteristics of malignancy and 18FDG-PET uptake, before being accepted for SRT. We retrospectively calculated the probability of malignancy in patients using published criteria (20), which was recently updated in a Dutch population with information on 18FDG-PET-uptake (21).
Treatment planning and delivery
Computed tomography-based individualized treatment margins were derived for SRT, and all but the first 8 underwent 4DCT (17). Briefly, 4DCT scans are generated during uncoached free breathing on a 16-slice CT scanner (GE Healthcare, Waukesha, WI), while recording the respiratory signal using the Varian Real-time Position Management system (Varian Medical Systems, Palo Alto, CA). The acquired axial images are sorted out into spatiotemporal bins representing 10 phases of respiration on an Advantage Workstation 4.1 (GE Healthcare, Waukesha, WI). The summation of tumor position during all phases of respiration is used to generate an individualized internal target volume for each tumor, to which a margin of 3 mm is added in order to derive the planning target volume (PTV). The mean PTV was 34 mL (range, 4–208 mL). Treatment planning was performed with the BrainLab software (Brainscan v. 5.2, BrainLab Inc., Feldkirchen, Germany) using 8–12 noncoplanar static beams aimed at the target volume using micromultileaf collimation. All SRT plans were optimized to limit high dose regions to the chest wall, mediastinum, or lung hilus.
Fractionation schemes
Three fractionation schemes that were derived from the published literature were consistently applied; three fractions of 20 Gy (for T1 tumors), five fractions of 12 Gy (for T1 tumors with broad contact with the thoracic wall, or T2 tumors), or eight fractions of 7.5 Gy (for tumors adjacent to the heart, hilus, or mediastinum). All doses were prescribed at the PTV encompassing 80% isodose and calculated biologically effective doses (BED10Gy) for the three-, five-, and eight-fraction schemes are 180 Gy, 132 Gy, and 105 Gy, respectively. The proportion of patients treated with each of the three fractionation schemes were 43%, 45%, and 12%, respectively. Repeat 4DCT scans and treatment planning midway through a course of treatment was performed until 2006, but subsequent delivery was based on a single 4DCT as analysis revealed a high reproducibility of target volumes defined using 4D imaging 22, 23.
Follow-up
Patients were routinely followed up at 3 months, 6 months, 1 year, and annually thereafter. Follow-up CT scans were performed at each visit. For the present report, such scans were available for 200 patients at 3 months, 143 patients at 6 months, and 88 patients at 1 year follow-up. 18FDG-PET scans were repeated only when there was suspicion of disease relapse in patients who were fit to undergo salvage treatment. For patients who were unable or unwilling to attend follow-up at our center, the general practitioner or referring lung physician was contacted for follow-up.
Treatment outcomes were evaluated using Kaplan-Meier analysis of overall and disease-free survival (DFS), local progression-free survival, regional progression-free survival, and distant progression-free survival in SPSS, version 14.0. Factors investigated for prognostic value with respect to these outcome parameters were: age, gender, World Health Organization score (WHO), GOLD classification, FEV1 values (≥1,000 mL vs. <1,000 mL), tumor stage, lesion characteristics (new vs. growing lesions), history of prior malignancy, history of prior lung cancer, medical inoperability, PTV size, pathologic verification of diagnosis, and BED10Gy.
Results
The median overall survival (OS) of all patients was 34 months, with actuarial survival rates at 1 year and 2 years of 81% and 64%, respectively (Fig. 1a). Univariate analysis showed that the stage (T1 vs. T2; p = 0.06) and absolute pretreatment FEV1 value (≥1,000 mL vs. <1,000 mL; p = 0.06) failed to correlate significantly with OS. Other factors including age (p = 0.43), histologic verification of malignancy (p = 0.55), history of prior malignancy (p = 0.55), medical inoperability (p = 0.64), and GOLD classification (p = 0.28) also did not significantly influence OS.
Fig. 1
Overall (a), disease-free (b), local progression free (c), regional progression-free (d), and distant progression-free survival in 206 patients.
The mean likelihood of malignancy calculated using the Swensen method (20) in all 206 patients was 0.86 ± 0.19 (1 SD), and no significant difference was seen between patients with and without a pathologic verification of malignancy (0.80 ± 0.20 vs. 0.83 ± 0.19, respectively). The mean probability of malignancy in 203 patients who had a pretreatment 18FDG-PET as calculated using the method described by Herder et al. (21) was 0.94 ± 0.06, and this was also not different between patients with and without pathologic verification of malignancy (0.94 ± 0.09 vs. 0.94 ± 0.07, respectively).
At a median follow-up of 12 months, the crude incidence of recurrence at any location was 21% (43 patients), and the patterns of failure are illustrated in Table 2. The DFS rates at 1 and 2 years were 83% and 68%, respectively. DFS correlated significantly only with the tumor stage (p = 0.002). DFS rates for T1 tumors were 88% and 81% at 1 and 2 years, respectively, compared with 76% and 54% for T2 tumors (Fig. 2). A local disease failure was suspected in 7 patients (3%), and this was an isolated local failure in two patients. Histologic confirmation of local recurrence was obtained in only a single patient, with local recurrence established on the basis of CT scans and 18FDG-PET findings in the rest. The actuarial local progression-free survival rates at 1 and 2 years were 98% and 93%, respectively (Fig. 1b). Local recurrences were seen in 2 (of 129) T1 tumors and 5 (of 90) T2 tumors, a difference that did not reach statistical significance (p = 0.13).
Table 2. Patterns of failure
| Patterns of failure (n = 43) | ||
|---|---|---|
| Distant only | 21 patients | 10% |
| Regional only | 8 patients | 4% |
| Regional + distant | 7 patients | 3% |
| Local only | 2 patients | 1% |
| Local + distant | 2 patients | 1% |
| Local + regional | 2 patients | 1% |
| Local + regional + distant | 1 patient | 0.5% |
Fig. 2
Disease-free survival for T1 and T2 tumors.
The actuarial regional failure-free survival rates at 1 and 2 years were 94% and 83%, respectively. The crude rate of regional failure was 9% (18 patients); isolated regional recurrences were observed in 8 patients (4%). All regional failures manifested within 2 years after SRT, and these were located in the mediastinum and the hilus (8 patients), mediastinum only (5 patients), or in the hilus only (5 patients). Of note is the finding that 2 of 3 patients who did not have a pretreatment 18FDG-PET scan subsequently developed regional metastases. The incidence of regional relapse correlated significantly with tumor stage (p = 0.04). Actuarial regional progression-free survival rates at 1 and 2 years were 94% and 92% for T1 tumors, and 94% and 71% for T2 tumors, respectively.
The crude rate of distant failure was 15% (31 patients) with distant metastases most commonly reported in bone (6%), brain (5%), liver (4%), and lungs (4%). The actuarial distant failure-free survival rates at 1 and 2 years were 85% and 77%, respectively. Tumor stage was the only factor significantly correlated with distant progression-free survival (p = 0.04). A summary of all prognostic factors investigated with respect to OS, local-, regional-, and distant- progression-free survival, and DFS are shown in Table 3.
Table 3. Univariate analysis of potential prognostic factors for overall survival, local progression-free survival, regional progression-free survival, distant progression-free survival, and disease-free survival
| Factor | Overall survival | Local progression-free survival | Regional progression-free survival | Distant progression-free survival | Disease-free survival |
|---|---|---|---|---|---|
| p value | |||||
| Gender | 0.51 | 0.13 | 0.36 | 0.88 | 0.55 |
| Age | 0.43 | 0.43 | 0.88 | 0.90 | 0.99 |
| WHO score | 0.45 | 0.16 | 0.24 | 0.23 | 0.26 |
| Pathologic diagnosis | 0.85 | 0.42 | 0.51 | 0.62 | 0.86 |
| Stage IA vs. IB | 0.06 | 0.13 | 0.04 | 0.04 | 0.002 |
| Histology | 0.17 | 0.48 | 0.54 | 0.43 | 0.21 |
| Prior malignancy | 0.45 | 0.89 | 0.48 | 0.64 | 0.82 |
| Inoperability | 0.43 | 0.85 | 0.56 | 0.58 | 0.16 |
| COPD | 0.58 | 0.13 | 0.49 | 0.53 | 0.18 |
| New vs. growing | 0.67 | 0.45 | 0.52 | 0.57 | 0.24 |
| FEV1 s, absolute | 0.06 | 0.84 | 0.99 | 0.96 | 0.88 |
| FEV1 s, relative | 0.15 | 0.56 | 0.40 | 0.54 | 0.86 |
| BED10Gy | 0.76 | 0.55 | 0.31 | 0.21 | 0.09 |
| GOLD class | 0.28 | 0.69 | 0.59 | 0.80 | 0.71 |
| Prior lung cancer | 0.07 | 0.75 | 0.54 | 0.71 | 0.32 |
| Planning target volume | 0.42 | 0.40 | 0.48 | 0.90 | 0.87 |
Toxicity
SRT was well tolerated, with all but 1 patient who developed a fatal cerebrovascular accident during treatment, completing the planned treatment. One hundred and five patients (51%) reported no side effects at all. Commonly encountered early side effects were fatigue (31%), local chest wall pain (12%), nausea (9%), dyspnea (6%), and cough (6%). Severe late toxicity was uncommon, with Grade ≥3 radiation pneumonitis observed in 6 patients (3%), which required treatment with steroids. In 4 patients, rib fractures developed at the site of the high dose area on the thoracic wall (Fig. 3) 1–2 years after SRT, in the absence of local tumor progression. Finally, chronic thoracic pain syndromes were observed in 3 patients.
Fig. 3
Stereotactic radiotherapy (SRT) planning for a peripheral T2 tumor, with the high-dose area adjacent to the thoracic wall (left). The right panel shows rib fractures 2 years after SRT, in the absence of local tumor progression.
Discussion
This analysis of 206 patients treated with SRT in a uniform fashion using 4DCT planning scans represents the largest single-center experience in Stage I NSCLC to date. The use of 4DCT planning enabled individualized, and generally smaller, treatment fields to be used compared to standard planning margins (17). All patients were treated with risk-adapted SRT schemes with a BED in excess of 100 Gy. Local recurrences were observed in only 3.5% of patients, which is much less than previously reported by us using conventional radiotherapy in Stage I NSCLC (16).
A major problem is that only a minority of our patients had pathologic confirmation of malignancy. This was mainly because of the peripheral location of the tumor, which made it inaccessible to bronchoscopic biopsy, and the poor pulmonary function in many patients was regarded as a relative contraindication for transthoracic biopsy because of the risk of developing a pneumothorax. Even when a transthoracic biopsy was performed, it failed to establish a definitive diagnosis in 13 patients who were subsequently treated with SRT because they fulfilled the other criteria. An inconclusive biopsy presents a clinical dilemma as was highlighted by a report of 397 patients who underwent a transthoracic biopsy, of which 132 showed no signs of malignancy on initial cytologic study (24). However, 33% of these patients were subsequently found to have malignancy.
An inability to establish a diagnosis before thoracotomy is not uncommon in trials evaluating management of small peripheral nodules (25). Similar findings were observed in 1,039 patients who underwent surgical resection for a diagnosis of lung cancer or suspected lung cancer, and in whom routine preoperative workup resulted in a histologic diagnosis of lung cancer in only 523 patients (26). Performing a thoracotomy to establish a diagnosis of malignancy in such a situation is not without risks, as evidenced by a complication rate of 27% and an operative mortality of 1.7% of patients in a fitter patient group who participated in a CT screening study (27). Our selection of patients with a new or growing lesion, with CT characteristics of malignancy and 18FDG-PET uptake, ensured that the likelihood of malignancy in these older patients with a smoking history and COPD (96% and 83% of patients in this series, respectively) is extremely high (21). When a diagnosis of clinical Stage I NSCLC was made using both CT and 18FDG-PET scans in a recent US study, only 8% of operated patients were subsequently found to have benign nodules (28). Although some benign PET-positive lesions may have been included in this series, the finding of a similar DFS between patients with and without a pathologic diagnosis is reassuring. Despite the calculated mean probability of 0.94 for malignancy in our patients using the Swenson and Herder criteria, we continue to recommend a cytologic or histologic diagnosis when possible, particularly because a preoperative transthoracic biopsy has not been shown to be associated with an increased risk of death (29). The ability to predict the likelihood of malignancy may be further increased using gene expression in cytologically normal lower airway cells obtained at bronchoscopy as a lung cancer biomarker, with a reported 95% sensitivity and a 95% negative predictive value (30).
The median follow-up of 12 months implies that our analysis may underestimate the incidence of local and regional failures. Most in-field recurrences for early-stage NSCLC are observed in the 2 years after treatment 31, 32, 33, 34. Despite the use of pretreatment 18FDG-PET scans, regional or distant failures were the predominant patterns of relapse. The crude rate of 15% distant relapses and 9% regional relapses is consistent with data from previous studies of radiotherapy for medically inoperable patients with Stage I NSCLC 16, 31. Similarly, follow-up of 598 patients who underwent resection for Stage I NSCLC, as well as a mediastinal nodal dissection in 94% of cases, revealed an overall incidence of recurrence of 27% (35). Of the latter, only 7% were local or regional, whereas 20% were systemic metastases.
However, our series provides an independent verification of the low normal tissue toxicity rates reported in an earlier multicenter analysis from Japan (15).This is particularly important as an interim analysis of a Phase II trial in the United States found Grades 3–5 toxicity to be significantly more likely in patients treated for tumors in the regions around the proximal bronchial tree or central chest region (36). However, the SRT treatment scheme used in the US trial was 60–66 Gy delivered in three fractions, and conventional CT scans, and not 4DCT, planning scans were used. A total of 12% of our patients had centrally located tumors which were treated to eight fractions of 7.5 Gy, the early toxicity results of this risk-adapted SRT scheme is encouraging. Serial data on quality of life and pulmonary function tests in our patient cohort have been collected and will be the subject of future reports.
The low morbidity observed in our patients, 18% of whom had a previous treatment for lung cancer, contrasts with the outcome of repeated surgery after a previous lung tumor resection, carrying a 30-day mortality rate of 11% and morbidity of 19% (37). Similarly, the low incidence of late thoracic wall toxicity including rib fractures and chronic thoracic wall pain syndromes has to be weighed against postthoracotomy pain syndromes observed in 3–5% of postsurgical cases, which can persist for years after surgery 38, 39. The excellent results of SRT in patients with Stage IA NSCLC, with disease-free survival rates of 88% and 81% at 1 and 2 years, raises the question whether SRT could serve as a treatment alternative in patients who are fit to undergo an anatomical resection. The improved staging of regional nodal metastases using CT-PET scans is likely to reduce the unsuspected incidence of Stage II disease (in 11% of cases) and Stage III (in 5% of cases) in patients presenting with clinical Stage I NSCLC (5). We are currently initiating a nationwide prospective randomized trial of surgery and SRT that could answer this question. Similar studies are also in preparation in North America and Japan.
In conclusion, early evaluation of outcomes after SRT in patients with extensive comorbidity shows high local control rates and minimal toxicity. Longer follow-up will be needed to fully establish regional and distant failures, but results of SRT appear superior to those reported using conventional radiotherapy, and the schemes are more patient-friendly in a population with considerable comorbidity. Our data indicate that SRT should be considered the treatment of choice in patients with stage I NSCLC who are at high risk for surgical toxicity.
References
- . Regional lymph node classification for lung cancer staging. Chest. 1997;111:1718–1723
- Survival in early-stage non-small cell lung cancer. Ann Thorac Surg. 1995;60:466–472
- A case-mix model for monitoring of postoperative mortality after surgery for lung cancer. Lung Cancer. 2006;51:123–129
- Patterns of surgical care of lung cancer patients. Ann Thorac Surg. 2005;80:2051–2056
- Morbidity and mortality of major pulmonary resections in patients with early-stage lung cancer: initial results of the randomized, prospective ACOSOG Z0030 trial. Ann Thorac Surg. 2006;81:1013–1019
- Mitotic index does not predict prognosis in stage IA non-small cell lung cancer. Lung Cancer. 2002;38:163–167
- Pneumonectomy for stage I (T1N0 and T2N0) nonsmall cell lung cancer has potent, adverse impact on survival. Ann Thorac Surg. 2003;76:1023–1028
- Radiation therapy for the treatment of unresected stage I-II non-small cell lung cancer. Chest. 2005;128:1461–1467
- Natural history of stage I non-small cell lung cancer: Implications for early detection. Chest. 2007;132:193–199
- Focal, high dose, and fractionated modified stereotactic radiation therapy for lung carcinoma patients: A preliminary experience. Cancer. 1998;82:1062–1070
- Stereotactic radiotherapy of targets in the lung and liver. Strahlenther Onkol. 2001;177:645–655
- Stereotactic single-dose radiotherapy of stage I non-small-cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys. 2003;56:335–341
- Extracranial stereotactic radioablation: Results of a phase I study in medically inoperable stage I non-small cell lung cancer. Chest. 2003;124:1946–1955
- . Stereotactic hypofractionated radiotherapy for stage I non-small cell lung cancer-mature results for medically inoperable patients. Lung Cancer. 2006;51:97–103
- Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: updated results of 257 patients in a Japanese multi-institutional study. J Thorac Oncol. 2007;2(Suppl 3):S94–S100
- Has 3-D conformal radiotherapy (3D CRT) improved the local tumour control for stage I non-small cell lung cancer?. Radiother Oncol. 2002;63:151–157
- Four-dimensional CT scans for treatment planning in stereotactic radiotherapy for stage I lung cancer. Int J Radiat Oncol Biol Phys. 2004;60:1283–1290
- Bronchial stenosis: An underreported complication of high-dose external beam radiotherapy for lung cancer?. Int J Radiat Oncol Biol Phys. 2005;61:64–69
- Malignant versus benign nodules at CT screening for lung cancer: Comparison of thin-section CT findings. Radiology. 2004;233:793–798
- Solitary pulmonary nodules: Clinical prediction model versus physicians. Mayo Clin Proc. 1999;74:319–329
- Clinical prediction model to characterize pulmonary nodules: Validation and added value of 18F-fluorodeoxyglucose positron emission tomography. Chest. 2005;128:2490–2496
- Reproducibility of target volumes generated using uncoached 4-dimensional CT scans for peripheral lung cancer. Radiat Oncol. 2006;1:43
- Is adaptive treatment planning required for stereotactic radiotherapy of stage I non-small-cell lung cancer?. Int J Radiat Oncol Biol Phys. 2007;67:1370–1374
- The clinical outcome of needle aspirations of the lung when cancer is not diagnosed. Ann Thorac Surg. 1986;41:592–596
- Optimal distance of malignant negative margin in excision of nonsmall cell lung cancer: a multicenter prospective study. Ann Thorac Surg. 2004;77:415–420
- Evaluation of resected tumors that were not diagnosed histologically but were suspected of lung cancer preoperatively. J Thorac Oncol. 2007;2(Suppl 4):S422
- Thoracic surgical operations in patients enrolled in a computed tomographic screening trial. J Thorac Cardiovasc Surg. 2004;128:254–259
- Cost-effectiveness of routine mediastinoscopy in computed tomography- and positron emission tomography-screened patients with stage I lung cancer. J Thorac Cardiovasc Surg. 2006;131:822–829
- . Diagnostic percutaneous transthoracic needle biopsy does not affect survival in stage I lung cancer. Am J Respir Crit Care Med. 2006;174:684–688
- Airway epithelial gene expression in the diagnostic evaluation of smokers with suspect lung cancer. Nat Med. 2007;13:361–366
- The role of radiotherapy in treatment of stage I non-small cell lung cancer. Lung Cancer. 2003;41:1–11
- Stereotactic body radiation therapy of early-stage non-small-cell lung carcinoma: phase I study. Int J Radiat Oncol Biol Phys. 2005;63:1010–1015
- Clinical outcomes of a phase I/II study of 48 Gy of stereotactic body radiotherapy in 4 fractions for primary lung cancer using a stereotactic body frame. Int J Radiat Oncol Biol Phys. 2005;63:1427–1431
- Curative treatment of stage I non-small-cell lung cancer with carbon ion beams using a hypofractionated regimen. Int J Radiat Oncol Biol Phys. 2007;67:750–758
- Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg. 1995;109:120–129
- Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol. 2006;24:4833–4839
- Morbidity of lung resection after prior lobectomy: results from the Veterans Affairs National Surgical Quality Improvement Program. Ann Thorac Surg. 2007;83:425–431
- . Chronic pain after thoracic surgery: A follow-up study. Acta Anaesthesiol Scand. 1999;43:563–567
- The morbidity, time course and predictive factors for persistent post-thoracotomy pain. Eur J Pain. 2001;5:89–96
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Conflict of interest: none.
PII: S0360-3016(07)04468-9
doi:10.1016/j.ijrobp.2007.10.053
© 2008 Elsevier Inc. All rights reserved.
Volume 70, Issue 3 , Pages 685-692, 1 March 2008