Journal of Thoracic Oncology:
Stereotactic Radiation Therapy Workshop
Hypofractionated Stereotactic Radiotherapy (HypoFXSRT) for Stage I Non-small Cell Lung Cancer: Updated Results of 257 Patients in a Japanese Multi-institutional Study
Onishi, Hiroshi MD*; Shirato, Hiroki MD†; Nagata, Yasushi MD†; Hiraoka, Masahiro MD‡; Fujino, Masaharu MD†; Gomi, Kotaro MD§; Niibe, Yuzuru MD∥; Karasawa, Katsuyuki MD∥; Hayakawa, Kazushige MD¶; Takai, Yoshihiro MD#; Kimura, Tomoki MD**; Takeda, Atsuya MD††; Ouchi, Atsushi MD‡‡; Hareyama, Masato MD‡‡; Kokubo, Masaki MD§§; Hara, Ryusuke MD∥∥; Itami, Jun MD∥∥; Yamada, Kazunari MD¶¶; Araki, Tsutomu MD*
*Department of Radiology, School of Medicine, Yamanashi University, Yamanashi, Japan; †Department of Radiology, School of Medicine, Hokkaido University, Sapporo, Japan; ‡Department of Therapeutic Radiology and Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan; §Department of Radiation Oncology, Cancer Institute Hospital, Tokyo, Japan; ∥Department of Radiation Oncology, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan; ¶Department of Radiology, Kitasato University, Kanagawa, Japan; #Department of Radiology, School of Medicine, Tohoku University, Sendai, Japan; **Department of Radiology, School of Medicine, Hiroshima University, Hiroshima, Japan; ††Department of Radiology, Tokyo Metropolitan Hiroo Hospital, Tokyo, Japan; ‡‡Department of Radiology, Sapporo Medical University, Sapporo, Japan; §§Department of Image-Based Medicine, Institute of Biomedical Research and Innovation, Kobe, Japan; ∥∥Department of Radiation Oncology, International Medical Center of Japan, Tokyo, Japan; ¶¶Department of Radiation Oncology, Tenri Hospital, Tenri, Japan.
Disclosure: The authors report no conflict of interest.
This study was presented in part at the 42nd Annual Meeting of the American Society of Oncology (ASCO), June 2–6, 2006, Atlanta, GA.
Address for correspondence: Hiroshi Onishi, Department of Radiology, School of Medicine, Yamanashi Medical University, 1110 Shimokato, Chuo-city, Yamanashi, Japan 409-3898. E-mail: email@example.com
Introduction: Hypofractionated stereotactic radiotherapy (HypoFXSRT) has recently been used for the treatment of small lung tumors. We retrospectively analyzed the treatment outcome of HypoFXSRT for stage I non-small cell lung cancer (NSCLC) treated in a Japanese multi-institutional study.
Methods: This is a retrospective study to review 257 patients with stage I NSCLC (median age, 74 years: 164 T1N0M0, 93 T2N0M0) were treated with HypoFXSRT alone at 14 institutions. Stereotactic three-dimensional treatment was performed using noncoplanar dynamic arcs or multiple static ports. A total dose of 18 to 75 Gy at the isocenter was administered in one to 22 fractions. The median calculated biological effective dose (BED) was 111 Gy (range, 57–180 Gy) based on α/β = 10.
Results: During follow-up (median, 38 months), pulmonary complications of above grade 2 arose in 14 patients (5.4%). Local progression occurred in 36 patients (14.0%), and the local recurrence rate was 8.4% for a BED of 100 Gy or more compared with 42.9% for less than 100 Gy (p < 0.001). The 5-year overall survival rate of medically operable patients was 70.8% among those treated with a BED of 100 Gy or more compared with 30.2% among those treated with less than 100 Gy (p < 0.05).
Conclusions: Although this is a retrospective study, HypoFXSRT with a BED of less than 180 Gy was almost safe for stage I NSCLC, and the local control and overall survival rates in 5 years with a BED of 100 Gy or more were superior to the reported results for conventional radiotherapy. For all treatment methods and schedules, the local control and survival rates were better with a BED of 100 Gy or more compared with less than 100 Gy. HypoFXSRT is feasible for curative treatment of patients with stage I NSCLC.
In Japan, due to the routine use of computed tomography (CT), detection of early-stage lung cancer is increasing. For patients with stage I (T1 or 2, N0, M0) non-small cell lung cancer (NSCLC), full lobar or greater surgical resection and regional lymphadenectomy is the standard treatment choice; the local control rates exceed 80% and the overall 5-year survival rates surpass 50%.1 However, surgical resection is often not feasible or involves a high risk for lung cancer patients with tobacco-related pulmonary illnesses, severe cardiovascular disease, or other medical conditions. Moreover, a small proportion of the patients who are fit for surgery may refuse it for personal reasons.
Radiotherapy (RT) can offer a therapeutic alternative in these cases, but the outcome with conventional RT is unsatisfactory.2 The reason for the poor survival with conventional RT is thought to be that the dose of conventional RT is too low to control the local tumor. To give a higher dose to the tumor without increasing the adverse effects, hypofractionated high-dose stereotactic RT (HypoFXSRT) has recently been used to treat small cell lung tumors, particularly in Japan.3–6 Although the optimal treatment technique and schedule of HypoFXSRT for stage I NSCLC are unknown, the nationwide number of Japanese patients with stage I NSCLC who are treated with small-volume stereotactic RT (SRT) has increased rapidly.
Therefore, it is meaningful to investigate the results of SRT for stage I NSCLC from many institutions, even in a retrospective manner, despite the large differences in treatment protocols. Previously, we reported the result of a Japanese multi-institutional review of 300 patients with stage I NSCLC treated with SRT.7 We concluded that SRT with a biological effective dose (BED) of less than 150 Gy is effective for the curative treatment of patients with stage I NSCLC and that the local control and survival rates are better with a BED of 100 Gy or more compared with less than 100 Gy.
The survival rates in selected medically operable patients with a BED of 100 Gy or more were promising and potentially comparable with those of surgery. These results for SRT were encouraging for stage I NSCLC patients; however, the 300 subjects in that report included 17 patients irradiated with comparatively small fractions (<4 Gy) and 26 patients irradiated in combination with conventional RT. This article presents the results for patients irradiated with HypoFXSRT alone in a multi-institutional study. In this study, we compared the reported results for surgery and conventional RT with those for HypoFXSRT.
PATIENTS AND METHODS
This was a retrospective study to review patients who were treated by HypoFXSRT for their stage I NSCLC in 14 different hospitals in Japan.
All the patients enrolled in this study satisfied the following eligibility criteria: identification of T1N0M0 or T2N0M0 primary lung cancer on chest and abdominal CT, bronchoscopy, bone scintigraphy, or brain magnetic resonance imaging; histological confirmation of NSCLC; performance status of 2 or less according to the World Health Organization (WHO) guidelines; and an inoperable tumor due to a poor medical condition or refusal to undergo surgery.
No restrictions were imposed concerning the locations of eligible tumors, irrespective of whether they were located adjacent to a major bronchus, blood vessel, chest wall, or the esophagus. Patients were informed of the concept, methodology, and rationale of this treatment, which was performed in accordance with the 1983 revision of the Declaration of Helsinki.
The patient pretreatment characteristics are summarized in Table 1. From April 1995 to March 2004, a total of 257 patients with primary NSCLC was treated using high-dose HypoFXSRT in the following 14 institutions: Hokkaido University, Kyoto University, Cancer Institute Hospital, Tokyo Metropolitan Komagome Hospital, Kitasato University, Tohoku University, Hiroshima University, Tokyo Metropolitan Hiroo Hospital, Sapporo Medical University, Institute of Biomedical Research and Innovation, International Medical Center of Japan, Tenri Hospital, Kitami Red Cross Hospital, and University of Yamanashi. Of the 257 patients, 158 were considered medically inoperable mainly because of chronic pulmonary disease, advanced age, or other chronic illness. The remaining 99 patients were considered medically operable, but had refused surgery or had been advised to select HypoFXSRT by medical oncologists.
All the patients were irradiated using stereotactic techniques. For the purposes of this study, all the hypofractionated stereotactic techniques met five requirements: reproducibility of the isocenter of 5 mm or less, as confirmed for every fraction; slice thickness on CT of 3 mm or less for three-dimensional (3-D) treatment planning; irradiation with multiple noncoplanar static ports or dynamic arcs; dose per fraction size more than 4 Gy; and a total treatment period of fewer than 25 days. Details of the techniques and instruments used to achieve SRT in the 14 institutions were summarized in a previous report.7 The clinical target volume (CTV) marginally exceeded the gross target volume (GTV) by 0 to 5 mm. The planning target volume (PTV) comprised the CTV, a 2- to 5-mm internal margin and a 0–5-mm safety margin. A high dose was concentrated on the tumor-bearing area, while sparing the surrounding normal lung tissues using SRT. The irradiation schedules also differed among the institutions. The number of fractions ranged between 1 and 14, with single doses of 4.4 to 35 Gy. A total dose of 30 to 84 Gy at the isocenter was administered with 6- or 4-MV x-rays within 20% heterogeneity in the PTV dose. No chemotherapy was administered before or during RT.
To compare the effects of various treatment protocols with different fraction sizes and total doses, the BED was used in a linear-quadratic model.8 Here, the BED was defined as nd(1 + d/α/β), with gray units, where n is the fractionation number, d is the daily dose, and α/β is assumed to be 10 for tumors. The BED was not corrected with values for the tumor doubling time or treatment term. In this study, the BED was calculated at the isocenter. The median BED was 111.0 Gy (range, 57.6–180.0). The BED was 100 Gy or more in 215 patients and less than 100 Gy in 42 patients. The median BED for the less than 100 Gy and 100 Gy or more subgroups was 79.6 Gy (range, 57.6–98.6) and 117.0 Gy (range, 100.0–180.0), respectively.
Dose constraints were set for the spinal cord only. The BED limit for the spinal cord was 80 Gy (α/β was assumed to be 2 Gy for chronic spinal cord toxicity).
The objectives of this study were to retrospectively evaluate the toxicity, local control rate, and survival rate according to the BED. All patients underwent follow-up examinations by radiation oncologists. The first examination took place 4 weeks after treatment, and patients were subsequently seen every 1 to 3 months. Tumor response was evaluated using the Response Evaluation Criteria in Solid Tumors by CT.9 Chest CT (slice thickness, 2–5 mm) was usually obtained every 3 months for the first year and repeated every 4 to 6 months thereafter. A complete response (CR) indicated that the tumor had disappeared completely or was replaced by fibrotic tissue. A partial response (PR) was defined as a 30% or more reduction in the maximum cross-sectional diameter. It was difficult to distinguish between residual tumor tissue and radiation fibrosis. Any suspicious confusing residual density after RT was considered evidence of a PR, so the actual CR rate might have been higher than that given here. Local recurrence was considered to have taken place only when enlargement of the local tumor continued for more than 6 months on follow-up CT. Two radiation oncologists interpreted the CT findings. The absence of local recurrence was defined as locally controlled disease. Lung, esophagus, bone marrow, and skin were evaluated using version 2 of the National Cancer Institute–Common Toxicity Criteria (NCI-CTC).
The local recurrence rates in the two groups were compared with the χ2 test. The BED among patient groups at each pulmonary toxicity grade was compared using the Kruskal-Wallis test. The cumulative local control and survival curves were calculated and drawn applying the Kaplan-Meier algorithms with day of treatment as the starting point. Subgroups were compared using log-rank statistics. Values of p < 0.05 were considered statistically significant. Statistical calculations were conducted using version 5.0 StatView software (SAS Institute, Cary, NC).
All the patients completed the treatment with no particular complaints. The median duration of follow-up for all patients was 38 months (range, 2–128).
Local Tumor Response
Of the 257 patients evaluated using CT, CR was achieved in 66 (25.7%) and PR in 157 (61.1%). The overall response rate (CR + PR) was 86.8%. The overall response rates for tumors with a BED of 100 Gy or more (n = 215) or less than 100 Gy (n = 42) were 87.5% and 86.7% in 3 years (?), respectively. A typical case of a T1 tumor after HypoFXSRT is shown in Figure 1.
Symptomatic radiation-induced pulmonary complications (NCI-CTC criteria grade >1) were noted in 28 patients (10.9%). Pulmonary fibrosis or emphysema before treatment was observed in 25 (89%) of the 28 patients with pulmonary complications above grade 1. Pulmonary complications of NCI-CTC criteria above grade 2 were noted in only 14 patients (5.4%). The pulmonary symptoms resolved in most patients without steroid therapy, but six patients who had very poor respiratory function or severe pulmonary fibrosis before irradiation needed continuous oxygen. Chronic segmental bronchitis and wall thickening causing atelectasis in the peripheral lung was observed in one patient (0.4%). Transient grade 3 esophagitis was observed in two patients (0.8%) with tumors adjacent to the esophagus. Grade 3 or 4 dermatitis was observed in three patients (1.2%) with tumors adjacent to the chest wall. Rib fracture adjacent to the tumor was found in four patients (1.6%). No vascular, cardiac, or bone marrow complications had been encountered as of the last follow-up.
The recurrence rates of local, regional nodal, and distant lesions according to the BED and stage are listed in Table 2. The local recurrence rate was significantly lower for a BED of 100 Gy or more compared with a BED of less than 100 Gy (8.4 versus 42.9%, p < 0.01). For greater BED subgroups, the local recurrence rate was 11.8% for a BED of 120 Gy or more (n = 93) and 8.1% for a BED of 140 Gy or more (n = 37). The local recurrence rates for adenocarcinoma and squamous cell carcinoma were 13.3% (16/120) and 17.1% (19/111), respectively in 3 years. The cumulative local control rate curves according to BED subgroup are shown in Figure 2. The 5 (3? according to Table 2)-year local control rates of the BED of 100 Gy or more and less than 100 Gy subgroups were 84.2% (95% confidence interval [CI]: 77.7%–90.8%) and 36.5% (95% CI: 10.4%–62.6%), respectively. According to subgroup analysis, stage IB patients had a significantly higher rate of local recurrence than stage IA patients. The nodal and distant recurrence rates were almost identical in the stage IA and IB subgroups.
In the patients with regional nodal recurrence, nodal failures overlapped local failure in 3.1%, distant metastases in 3.9%, or both in 0.8% of the patients. Isolated local, nodal, and distant recurrences were observed in 8.6%, 5.1%, and 13.6% of the patients, respectively.
The overall 3- and 5-year survival rates for all patients were 56.8% (95% CI: 50.2%–63.5%) and 47.2% (95% CI: 38.7%–53.5%), respectively. The cause-specific 3- and 5-year survival rates were 76.9% (95% CI: 70.6%–83.2%) and 73.2% (95% CI: 66.1%–80.2%), respectively. The overall survival rates differed significantly according to medical operability, with intercurrent death in 36.8% of inoperable patients and 10.3% of operable patients. The overall 5-year survival rates of medically operable and inoperable patients (Figure 3) were 64.8% (95% CI: 53.6%–75.9%) and 35.0% (95% CI: 25.9%–44.1%), respectively. The overall survival rates according to the BED in all patients differed significantly between the BED of less than 100 Gy and 100 Gy or more subgroups. The overall 5-year survival rates of the BED 100 Gy or more and less than 100 Gy subgroups were 53.9% (95% CI: 46.0%–61.8%) and 19.7% (95% CI: 5.9%–33.4%), respectively. For the subgroup of medically operable patients with a BED of 100 Gy or more, the 3- and 5-year overall survival rates were 80.4% (95% CI: 71.0%–89.7%) and 70.8% (95% CI: 59.3%–82.2%), respectively (Figure 2). The overall 5-year survival rate according to stage in the operable patients irradiated with a BED of 100 Gy or more was 72.3% (95% CI: 59.1%–85.6%) for stage IA and 65.9% (95% CI: 43.0%–88.9%) for stage IB patients (Figure 4).
Reproducibility of the Data Among Institutions
Table 3 compares the irradiation method and results for three major institutions enrolled in this study. These institutions used a BED of 100 Gy or more. The local control and 3-year survival rates were almost identical.
At present, surgery is the standard treatment for stage I NSCLC. RT is offered to patients who are unsuitable for surgery because of medical problems and to patients who refuse surgery. Most information on the results of RT for stage I NSCLC is based on retrospective studies of RT-treated inoperable NSCLC cases. Therefore, the role of RT for stage I NSCLC, as a curative modality, has not yet been established.
Qiao et al. summarized 18 papers on stage I NSCLC treated with conventional RT alone published between 1988 and 2000.10 Local recurrence was the most common reason for treatment failure of stage I NSCLC with conventional RT, but the frequency of recurrence varied considerably according the report (between 6.4% and 70%). The 3-year recurrence rate was approximately 60%,11–13 with a median time to relapse that ranged from 21 to 30 months.12,14,15 Generally, smaller tumor size, low T stage, and increased dose had a favorable impact on local control, and increased local control was followed by increased survival.14,16 However, the overall treatment results were disappointing. The median survival in these studies ranged from 18 to 33 months. The 3- and 5-year overall survival rates were 34 ± 9% and 21 ± 8% (mean ± 1 SE), respectively. The cause-specific survival rates at 3 and 5 years were 39 ± 10% and 25 ± 9% (mean ± 1 SE), respectively. Regarding treatment toxicity, severe (grade 3 or above) radiation esophagitis14 and pneumonitis11 occurred in 4.1% and 6.1% of the cases, respectively. Better local control may be achieved when the total dose is increased,15,16 and a trend has been growing toward seeking better local control by increasing the BED13–15 for a relatively limited span of doses (BED 59–76 Gy). Dose escalation has been the focus of developmental therapeutic strategies for inoperable stage I NSCLC to improve local control and survival.
Mehta et al.17 provided a detailed theoretical analysis regarding the responses of NSCLC to RT and a rationale for dose escalation. They concluded that a greater BED irradiated during a short period must be given to gain local control of lung cancers. Giving a higher dose to the tumor without increasing the adverse effects was shown to be possible using the SRT technique; this is now feasible due to the technological progress that allows increasing the accuracy of localization to the tumor-bearing area using various imaging tools. SRT can also reduce the overall treatment time substantially, from several weeks for conventional RT to a few days, offering an important advantage to the patient.
After Uematsu et al.18 reported a landmark study on SRT for stage I NSCLC using a CT-linac system, SRT has been actively investigated for stage I NSCLC in Japan and the United States. In the reports listed in Table 4,3–6,19–21 the local control rates of primary lung cancer with SRT ranged from 87% to 97% when the BED exceeded 100 Gy. Uematsu et al.3 showed excellent survival rates for medically operable patients, approximating those for full lobar surgical resection; however, they studied only a few patients, and it is not known whether the result is reproducible. Table 5 compares the results of Uematsu et al.3 with the HypoFXSRT results presented here. These results suggest that the local control and survival rates of HypoFXSRT for stage I NSCLC are promising and reproducible when the BED exceeds 100 Gy.
In Japan, we consider a BED greater than 100 Gy to be a satisfactory dose for HypoFXSRT of stage I NSCLC, with a local control rate better than 85%, and a further dose escalation study is not necessary for tumors smaller than 4 cm in diameter. Conversely, in the United States, Timmerman et al.22 concluded that 60 Gy in three fractions (BED = 180 Gy) is the proper dose, and they adopted this dose and fraction protocol for their prospective study. We need to observe the results of ongoing phase II studies on SRT for stage I NSCLC conducted in Japan (12 Gy × 4 = 48 Gy prescribed to the isocenter) and the United States (20 Gy × 3 = 60 Gy prescribed to cover 95% of the PTV).
The 5-year overall survival rate for medically operable patients with HypoFXSRT is encouraging (Table 6). Representative 5-year overall survival rates for clinical stage IA and IB with surgery range from 61% to 72% and 40% to 50%, respectively.23–25 According to our data, the survival rate for SRT was not worse than that for large surgical series. Furthermore, concerning toxicity, approximately 3% of patients died as a result of surgery, and chronic morbidity occurs in 10% to 15% of patients after surgery.26 HypoFXSRT is much less invasive than surgery, and it is postulated that SRT will become a major treatment choice for stage I NSCLC, at least for medically inoperable patients.
Multi-institutional phase II studies of SRT for stage I NSCLC have been started in Japan (JCOG0403)27 and the United States (RTOG0236).28 However, it will take several years to obtain conclusive results, and an inevitable selection bias exists in comparing SRT with surgical series for patients in retrospective or phase II studies.
Although the differences in techniques and schedules of the institutions enrolled in this study may be large, it is meaningful that a safe, effective BED was suggested because the optimal dose-fraction schedule of SRT for stage I NSCLC is not known. Furthermore, this is the only report that gives the results of SRT for a large number of medically operable stage I NSCLC patients. Based on our excellent SRT results, it is arguable that a phase III study comparing surgery and SRT for medically operable patients is warranted. However, it is very difficult to perform a phase III study because most patients will opt for less invasive therapy such as SRT. We need much more experience and must study more patients with a longer follow-up duration to establish a safe, effective irradiation method that will instill both medical and social confidence in SRT for treatment of stage I NSCLC.
When we compare the results of conventional RT and surgery with those of HypoFXSRT, we conclude that HypoFXSRT has the following benefits for stage I NSCLC. First, HypoFXSRT is a safe and promising treatment modality. Second, the local control and survival rates are superior to those of conventional RT. Third, HypoFXSRT should be a standard of care for medically inoperable patients. Fourth, HypoFXSRT should be randomly compared with surgery for medically operable patients. Finally, we need additional experience with a longer follow-up duration to conclusively validate these points.
1. Smythe WR. American College of Chest Physicians: treatment of stage I non-small cell lung carcinoma. Chest 2003;123:S181–S187.
2. Qiao X, Tullgren O, Lax I, et al. The role of radiotherapy in treatment of stage I non-small cell lung cancer. Lung Cancer 2003;41:1–11.
3. Uematsu M, Shioda A, Suda A, et al. Computed tomography-guided frameless stereotactic radiography for stage I non-small-cell lung cancer: 5-year experience. Int J Radiat Oncol Biol Phys 2001;51:666–670.
4. Nagata Y, Takayama K, Matsuo Y, et al. 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.
5. Fukumoto S, Shirato H, Shimizu S, et al. Small-volume image-guided radiotherapy using hypofractionated, coplanar, and noncoplanar multiple fields for patients with inoperable stage I nonsmall cell lung carcinomas. Cancer 2002;95:1546–1553.
6. Onishi H, Kuriyama K, Komiyama T, et al. Clinical outcomes of stereotactic radiotherapy for stage I non-small cell lung cancer using a novel irradiation technique: patient self-controlled breath-hold and beam switching using a combination of linear accelerator and CT scanner. Lung Cancer 2004;45:45–55.
7. Onishi H, Araki T, Shirato H, et al. Stereotactic hypofractionated high-dose irradiation for stage I nonsmall cell lung carcinoma. Cancer 2004;101:1623–1631.
8. Yaes RJ, Patel P, Maruyama Y. On using the linear-quadratic model in daily clinical practice. Int J Radiat Oncol Biol Phys 1991;20:1353–1362.
9. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000;92:205–216.
10. Qiao X, Tullgren O, Lax I, et al. The role of radiotherapy in treatment of stage I non-small cell lung cancer. Lung Cancer 2003;41:1–11.
11. Sibley GS. Radiotherapy for patients with medically inoperable stage I nonsmall cell lung carcinoma. Cancer 1998;82:433–438.
12. Cheung PC, Mackillop WJ, Dixon P, et al. Involved-field radiotherapy alone for early-stage non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2000;48:703–710.
13. Hayakawa K, Mitsuhashi N, Saito Y, et al. Limited field irradiation for medically inoperable patients with peripheral stage I non-small cell lung cancer. Lung Cancer 1999;26:137–142.
14. Jeremic B, Shibamoto Y, Acimovic YL, et al. Hyperfractionated radiotherapy alone for clinical stage I non-small cell lung cancer. Int. J. Radiat Oncol Biol Phys 1997;38:521–525.
15. Kaskowitz L, Graham MV, Emami B et al. Radiation therapy alone for stage I non-small cell lung cancer. Int J Radiat Oncol Biol Phys 1993;27:517–523.
16. Kupelian PA, Komaki R, Allen P. Prognostic factors in the treatment of node-negative non-small cell lung carcinoma with radiotherapy alone. Int J Radiat Oncol Biol Phys 1996;36:607–613.
17. Mehta M, Scringer R, Mackie R, et al. A new approach to dose escalation in non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2001;49:23–33.
18. Uematsu M, Shioda A, Tahara K, et al. Focal, high dose, and fractionated modified stereotactic radiation therapy for lung carcinoma patients: a preliminary experience. Cancer 1998;82:1062–1070.
19. Hof H, Herfarth KK, Munter M, et al. Stereotactic single-dose radiotherapy of stage I non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2001;49:23–33.
20. McGarry RC, Papiez L, Williams M, et al. Stereotactic body radiotherapy of early-stage non-small cell lung carcinoma: phase I study. Int J Radiat Oncol Biol Phys 2005;63:1010–1015.
21. Wulf J, Hadinger U, Oppitz U, et al. Stereotactic radiotherapy for primary lung cancer and pulmonary metastases: a noninvasive treatment approach in medically inoperable patients. Int J Radiat Oncol Biol Phys 2004;60:186–96.
22. Timmerman R, Papiez L, McGarry R, et al. External stereotactic radioablation: results of a phase I study in medically inoperable stage I non-small cell lung cancer patients. Chest 2003;124:1946–1955.
23. Mountain CF. The international system for staging lung cancer. Semin Surg Oncol 2000;18:106–115.
24. Naruke T, Tsuchiua R, Kondo H, et al. Prognosis and survival after resection for bronchogenic carcinoma based on the 1997 TNM-staging classification: the Japanese experience. Ann Thorac Surg 2001;71:1759–1764.
25. Shirakusa T, Kobayashi K. Lung cancer in Japan: analysis of lung cancer registry for resected cases in 1994. Jpn J Lung Cancer 2002;42:555–562.
26. Deslauriers J, Ginsberg RJ, Dubois P, et al. Current operative morbidity associated with elective surgical resection for lung cancer. Can J Surg 1989;32:335–339.
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Radiotherapy and OncologySystemic review of the patterns of failure following stereotactic body radiation therapy in early-stage non-small-cell lung cancer: Clinical implicationsRadiotherapy and Oncology
Medical PhysicsAnniversary Paper: Role of medical physicists and the AAPM in improving geometric aspects of treatment accuracy and precisionMedical Physics
Cancer Treatment ReviewsParticle therapy in lung cancer: Where do we stand?Cancer Treatment Reviews
Annals of Thoracic SurgerySurvival of Patients With True Pathologic Stage I Non-Small Cell Lung CancerAnnals of Thoracic Surgery
Anales Del Sistema Sanitario De Navarra
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Controversies in Treatment of Lung Cancer
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Seminars in Radiation OncologyThe Treatment of Early-Stage DiseaseSeminars in Radiation Oncology
CancerOutcomes of Stereotactic Radiotherapy for a New Clinical Stage I Lung Cancer Arising PostpneumonectomyCancer
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Expert Review of Anticancer TherapyState-of-the-art lung cancer radiation therapyExpert Review of Anticancer Therapy
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Radiotherapy and OncologyStereotactic body radiotherapy for medically inoperable patients with stage I non-small cell lung cancer - A first report of toxicity related to COPD/CVD in a non-randomized prospective phase II studyRadiotherapy and Oncology
Radiation OncologyDeveloping and evaluating stereotactic lung RT trials: what we should know about the influence of inhomogeneity corrections on doseRadiation Oncology
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ChestAmerican College of Chest Physicians and Society of Thoracic Surgeons Consensus Statement for Evaluation and Management for High-Risk Patients With Stage I Non-small Cell Lung CancerChest
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Plos OneCritical Structure Sparing in Stereotactic Ablative Radiotherapy for Central Lung Lesions: Helical Tomotherapy vs. Volumetric Modulated Arc TherapyPlos One
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Thoracic Surgery ClinicsCan Stereotactic Ablative Radiotherapy in Early Stage Lung Cancers Produce Comparable Success as Surgery?Thoracic Surgery Clinics
RespirationSimultaneous Computed Tomography-Guided Biopsy and Radiofrequency Ablation of Solitary Pulmonary Malignancy in High-Risk PatientsRespiration
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Lung CancerMetabolic imaging metrics correlate with survival in early stage lung cancer treated with stereotactic ablative radiotherapyLung Cancer
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Strahlentherapie Und OnkologieStereotactic ablative radiotherapy for small lung tumors with a moderate dose Favorable results and low toxicityStrahlentherapie Und Onkologie
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Radiation OncologyHigh-dose accelerated hypofractionated three-dimensional conformal radiotherapy (at 3 Gy/fraction) with concurrent vinorelbine and carboplatin chemotherapy in locally advanced non-small-cell lung cancer: a feasibility studyRadiation Oncology
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Cancer ImagingStereotactic ablative body radiotherapy (SABR) for primary and secondary lung tumoursCancer Imaging
Current Opinion in Pulmonary MedicineStereotactic radiotherapy for nonsmall cell lung cancerCurrent Opinion in Pulmonary Medicine
Stereotactic radiotherapy; Non-small cell lung cancer; Stage I; Hypofractionated
© 2007International Association for the Study of Lung Cancer
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