Ann Thorac Surg 2008;85:S785-S791. doi:10.1016/j.athoracsur.2007.10.101
© 2008 The Society of Thoracic Surgeons
Supplement: The Minimally Invasive Thoracic Surgery Summit
Stereotactic Radiosurgery for Thoracic Malignancies
Jamie A. Cesaretti, MDa,*,
Arjun Pennathur, MDf,
Barry S. Rosenstein, PhDa,c,d,e,
Scott J. Swanson, MDb,
Hiran C. Fernando, MDg
a Department of Radiation Oncology, Mount Sinai School of Medicine, New York, New York
b Department of Cardiothoracic Surgery, Mount Sinai School of Medicine, New York, New York
c Department of Dermatology, Mount Sinai School of Medicine, New York, New York
d Department of Community & Preventive Medicine, Mount Sinai School of Medicine, New York, New York
e Department of Radiation Oncology, New York University School of Medicine, New York, New York
f Heart Lung and Esophageal Surgery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
g Department of Cardiothoracic Surgery, Boston Medical Center, Boston, Massachusetts
* Address correspondence to Dr Cesaretti, Mount Sinai School of Medicine, 1184 5th Ave, Box 1236, New York, NY 10029 (Email: jamie.cesaretti{at}msnyuhealth.org).
Presented at the Minimally Invasive Thoracic Surgery Summit, New York, NY, June 8–9, 2007.
| Dr Fernando discloses that he has a financial relationship with Accuray.
|
 |
Abstract
|
|---|
Radiosurgery for lung cancer is a novel and promising concept that warrants thorough review. Stereotactic body radiotherapy enables the selective delivery of an intense dose of high-energy radiation to destroy a tumor with precise targeting. The radiobiology and physics behind the use of radiosurgery are presented, followed by a discussion of promising retrospective and prospective clinical data that has been reported from Japan, Europe, and the United States. The article closes with a discussion of multidisciplinary approaches that include radiosurgery which are on the therapeutic horizon.
Radiosurgery is the application of very high doses of ionizing radiation in larger than traditional fractionation to much smaller than traditional radiotherapy fields, often with the integration of advanced modalities for tumor imaging and devices for tumor immobilization. The concept of radiosurgery was conceived in the early 1950s by a Swedish neurosurgeon, Lars Leskell, and its application in the brain and spine have been consistently applied for both malignant and benign conditions ever since [1, 2]. Body radiosurgery for lung cancer is an offshoot of radiosurgery for the brain and spine. Much is known about the doses used for effective control of brain tumors and cerebral metastatic deposits, and the lung radiosurgery literature is informed by these experiences [3, 4].
In this article, we will discuss such issues as the definition of lung radiosurgery, the radiobiology of large radiation doses, considerations of tumor targeting, and reported efficacy and toxicity of the approach. It is important to remind the reader that the rapidly evolving literature for lung radiosurgery has occurred within the context of the long-standing successful clinical outcomes of this approach in the neurosurgical realm, and considering the many decades it has taken to fully adopt this brain technology, it is safe to conclude that the clinical application of radiosurgery to the lung remains in its early investigational stages.
|
Definition
|
|---|
The definition of radiosurgery for brain lesions had been much pondered, although to our knowledge, no such effort has been made for lung radiosurgery. A review of the available published reports of authors claiming to have performed lung radiosurgery allows for a deduction of an inclusive definition. Radiosurgery for thoracic lesions appears at its simplest to require higher than 3-Gy fractions, which combined add up in biologic effectiveness to a total dose in 2-Gy equivalents that exceeds the 66 to 74 Gy that can be given safely with modern three-dimensional treatment planning. This technique uses fewer than traditional treatment fractions (approximately 10 or less) with the integration of either respiratory gating or attempted tumor immobilization, resulted in a marked reduction in the amount of normal tissue exposed to the therapeutic dose.
Lung radiosurgical efforts at this point are represented by a spectrum of technology. Many of the largest reported series have used standard linear accelerators with usually a pioneer’s eye on immobilization, tumor identification, and respiratory motion [5–7]. There are now several advanced body radiosurgical treatment devices that appear to offer the possibility for institutions to replicate the pioneering efforts of others with a potentially more favorable therapeutic ratio [8–12] (Figure 1).
View larger version (51K):
[in this window]
[in a new window]
|
Fig 1. These computed tomography scans (CT) are of an 80-year-old female ex-smoker with a history of chronic obstructive pulmonary disease and a prior T2 N1 non-small cell lung cancer of the left lower lobe for which she received a left lower lobe sleeve resection and mediastinal chemoradiotherapy to 50.4 Gy in 1999. She presented in 2007 with another T2 N1 tumor now of the right lower lobe with compromised respiratory function. She underwent a wedge resection of the primary tumor and a course of reirradiation to the N1 lymph node agglomeration. (A) Represents the radiotherapy plan using the Novalis radiosurgical system (BrainLAB AG, Feldkirchen, Germany). (B) This CT scan 1 month after delivery of 50 Gy in 10 fractions reveals a complete radiologic response to the therapy.
|
|
|
Radiobiology
|
|---|
Radiobiology is considered one of the three central pillars of radiation oncology. Much is known about the response of cancer and normal tissue to fractionated therapeutic radiation. The use of large fraction sizes in radiosurgery may not take advantage of one of the most valuable attributes associated with the use of small fraction sizes, which is its ability to spare normal tissue while curing the cancer. It is, however, important to note in this context that Fuks and Kolesnick [13, 14] have proposed that the use of large fraction sizes greater than 8 to 10 Gy may be advantageous for tumor control due to the ability of large doses to induce endothelial cell damage, thereby causing microvascular dysfunction that enhances the killing of tumor cells. Evidence has been obtained that large radiation doses induce the translocation of endothelial cell acid sphingomyelinase into the plasma membrane of these cells where it is hydrolyzed to sphingomyelin. This results in the generation of ceramide, which is a second messenger that stimulates apoptosis of the endothelial cells [13–15].
In the thorax, the use of standard fraction sizes has allowed for a significant therapeutic gain in some settings and shortcomings in others. The effect of large fraction sizes can be quantified in its efficacy relative to the use of standard 1.8- to 2.0-Gy fractions through calculation of the biologically effective dose (BED) [16]. The equation commonly used is: BED = nd[1 + (d/
/β)] where n is the number of fractions; d is the dose per fraction; and /β is a specific measured parameter unique to the tissue or cancer in question. Of interest, when referring to /β for lung tumors is that a value of 10 Gy is often used, whereas the /β for lung fibrosis is approximately 3 Gy. It should be noted that the BED to the tumor with radiosurgery is much higher than values with conventional radiation techniques, hence the better local control rates demonstrated in radiosurgery series.
The BED allows one to compare different radiation dose schedules across series and allows for a rational basis for dose escalation and alterations from standard protracted radiation protocols (Table 1). The high doses afforded by radiosurgery allow for the delivery of high BED with the convenience of a much shorter treatment time. In addition, there is no interval between radiation fractions, which means that the tumor is not allowed to grow between fractions.
There are theoretical downsides of radiosurgery that are worth noting. A reason tumor control may be diminished through the use of a small number of large fractions is that the ability for tumor cells to reassort into more sensitive phases of the cell cycle during the interval between fractions may be limited. Also, reoxygenation, a potentially radiosensitizing effect of fractionated radiation, is reduced as a result of the use of a small number of fractions [17].
Of interest is that the dose-rate of radiation therapy may also be a significant issue associated with the use of stereotactic radiosurgery because the rate at which the radiation is delivered can be lower than for a standard radiation treatment. This may allow one to differentiate between the various radiosurgical devices [18]. Repair during the course of the irradiation would generally be considered negligible for dose-rates greater than about 2 Gy/min. If irradiations are delivered at lower dose rates, however, and the repair that occurs during the irradiation may be significant, thereby diminishing the effectiveness of the dose delivered. To our knowledge, this effect has not been well quantified among the various lung radiosurgery techniques or quantified in terms of a time-corrected BED for each available radiosurgical device.
The dose range used for radiosurgery of the lung ranges from single fractions as large as 30 Gy to multiple fractions of 4 to 5 Gy [9, 19]. It has been found that a BED of greater than 100 Gy10 given radiosurgically offers improved outcomes compared with treatment at a lower BED [20, 21]. This serves as a basis for comparison of more traditionally fractionated radiotherapy protocols that have a BED ranging from 60 to 90 Gy10 using an /β of 10 Gy for lung cancer. Theoretically, based on dose-equivalency studies using the BED, one should be able to give either a few large fractions or multiple fractions and compare and roughly predict the outcome for the different regimens based on the applicable BED benchmark. This may offer a flexible approach toward dosing in prospective trials, because in lesions that are close to radiosensitive structures, a high BED can presumably be achieved with a more protracted radiosurgical approach. This would lessen the incidence of severe toxicity, whereas a lesion in the periphery of the lung could be treated with one fraction. This would allow accrual of both patients with central or peripheral types of tumor to the same radiosurgical study and allow the clinician the freedom to make modifications determined by the assessment of potential late effect risk unique to the patient.
|
Physics
|
|---|
There are currently at least seven devices capable of body radiosurgery (Table 2), several of which have been used for lung radiosurgery and are reported in the literature [9–12, 22]. They differ in important ways regarding their shielding requirements, vault size requirements, and physics staff support requirements. They are similar in that they initially require a large outlay of capital funds and a devoted oncology team to assure use of the device is appropriate to the medical needs of the institution and community. To date, no studies have directly compared the efficacy of these stereotactic radiosurgical devices in the treatment of lung cancer.
|
Tumor Immobilization
|
|---|
At present, and as will be discussed below, a major indication for lung radiosurgery in the United States and Europe is for the patient who is medically inoperable with a potentially curable cancer. It is reasonable to generalize that these patients as a group are extremely compromised in terms of cardiopulmonary status. The technology for respiratory "gating" has been reported, although its practical use in patients who are candidates for lung radiosurgery is extremely problematic. It is therefore difficult to make a recommendation that radiosurgery in the lung is predicated on the use of respiratory gating. Many have attempted successfully to limit diaphragmatic movement by abdominal pressure devices or to train the patient to limit the volume of their respiration for short periods [6, 7, 9, 23]. These approaches have been found to be both practical and workable; accuracy in targeting to less than a centimeter is an admirable theoretic possibility and practical in a comparatively few patients. Therefore, we recommend a practical approach at this point, which would include the addition of a patient-specific planning target volume quantified under direct observation using fluoroscopy [6, 24]. Interventions such as trained breathing or abdominal compression should be encouraged as only an improvement in the therapeutic ratio would result. At the University of Pittsburgh, the initial experience with stereotactic radiosurgery utilized a breath hold technique [19]. Currently, a dynamic tracking system (Cyberknife; Accuray, Sunnyvale, CA) for tracking the tumor during breathing is used.
|
Clinical Results
|
|---|
The preliminary results of stereotactic radiosurgery (SRS) for the lung have been encouraging, and it appears that local control is far superior to more traditional methods of radiation (Table 3) [20, 22, 23, 25–27]. One of the most influential studies of SRS for lung cancer is a multicenter trial from Japan of 245 patients with stage I non-small cell lung cancer (NSCLC) who were treated with SRS [20]. In contrast to other trials that have primarily included medically inoperable patients with potentially resectable cancers, this study included 87 patients who were considered good-operative-risk candidates. Overall survival was estimated to be 56% at a median follow-up of 24 months, and 47% at 3 years and 5 years. In the 87 patients who were operative candidates, the estimated 5-year survival was 88% in patients who received more than 100 Gy (BED). In the good-operable-risk patients who received less than 100 Gy (BED), survival was 69%. The higher dose of 100 Gy (BED) appears to be important to achieve better local control. In the whole cohort of 245 patients, local progression was 26.4% in the patients who received less than 100 Gy and was 8.1% in patients who received more than 100 Gy.
Given the decades-long experience of thoracic surgeons who have performed innumerable lobar and sublobar resections for lung cancer, these results appear to be almost too good to be true. This has lead to the premature suggestion that it may now be appropriate to perform a large randomized trial of SRS and lobectomy in good-risk patients with NSCLC [28]. It is true that these results appear to be encouraging, but we have several reservations about the initiation of such a trial.- • In the Japanese trial by Onishi and colleagues, local recurrence was only scored if a recurrence occurred at the tumor. In most surgical studies, local recurrence has included, at a minimum, a recurrence anywhere within the same lobe or the associated hilar lymph nodes, or both [29].
- • Computed tomography scanning has the significant shortcoming of frequently underestimating the presence of nodal disease in situ and can therefore underestimate the frequency of disease recurrence within the associated lymph nodes after extremely conformal radiosurgical treatment [30].
- • Also unlike a lobectomy, the lymph nodes are evaluated by either a formal lymph node dissection or extensive sampling procedure, allowing for radiologically occult disease to be identified and for the patient to be properly risk-stratified regarding the possible efficacy of adjuvant chemotherapy or mediastinal radiotherapy, or both.
- • In addition, if regional nodal disease had been included in the definition of local failure in the Onishi study, local recurrence would have been 36.5% for tumors treated with less than 100 Gy and 15% for those tumors treated at more than 100 Gy, numbers much more in line with what one would expect from such a conformal approach to only the tumor and immediately adjacent tissues [20].
- • The locoregional recurrence rate of 15% is more similar to the recurrence rates seen after wedge resection, although the reported follow-up duration after wedge resection is longer.
Therefore, this very optimistic series should not serve as basis for proceeding with a randomized trial of lobectomy vs radiosurgery. Far too little is yet known about optimal patient selection, optimal radiation dose, necessary preprocedural diagnostic maneuvers, optimal radiation treatment volume, and follow-up imaging interpretation to invest the resources necessary for such a trial with so many serious unknowns remaining to be defined.
Another issue that should also be considered is that there appears to be differences in outcome for both radiosurgery and resection between Japanese and North American reports [31, 32]. This may be related in part to differences in tumor biology between tumors seen in the United States and Europe vs those seen in Japan. Among the 245 patients reported in the Japanese trial, 109 had adenocarcinomas and 26 had other histologies that were not defined. The specific number of bronchiolar cancers, which would have had a more indolent biology, was not reported.
Stereotactic radiosurgery really has not been studied in a population of good-surgical-risk patients outside of Japan; therefore, results outside of Japan have not been as potentially encouraging. Timmerman and colleagues [7] reported their initial experience with SRS in 37 high-risk patients with NSCLC. Tumor response was seen in 87% of these patients, with 27% demonstrating a complete response. At a median follow-up of 15 months, 6 patients experienced local failure. The median time to local progression was 13 months. The disease-free survival was 50%, and overall survival at a median follow-up of 15 months was 64%. This study did meet its goal of demonstrating that it is feasible to deliver high doses of radiation to medically inoperable patients with NSCLC.
The same group of investigators later published a phase I dose-escalation trial in 47 patients [33]. Patients were initially treated with 8 Gy/fraction for 3 fractions (total, 24 Gy). The planned target dose for the study was 24 Gy/fraction over 3 fractions for a total of 72 Gy. The maximum tolerated dose (MTD) was achieved for T2 tumors in this series but not for the T1 tumors. Owing to excessive toxicity for the T2 tumors at the 72 Gy dose level, 66 Gy in three 22-Gy fractions was defined as the MTD for T2 tumors. For the entire group, local failure was seen in 10 of 47 patients (21.3%) at a mean of 15.7 months. Most (90%) of the local failures occurred at doses of less than 16 Gy/fraction (total dose of < 48 Gy). Regional failure occurred in 10 patients (21.3%), but in only 4 patients (40%) treated at low radiation doses of less than 16 Gy. It is not surprising that local control was better with the higher radiation doses. This is a common phenomenon in the radiotherapy of unresected tumors [26, 27]. Regional recurrence, on the other hand, appears not to be affected by higher radiation doses and may be related to occult disease within the lung/thoracic cavity that is not treated at the time of SRS.
The same group then published their phase II trial results, using the MTD of 60 Gy in 3 fractions for T1 NSCLC and 66 Gy for T2 NSCLC that were defined in the above study [23]. The study cohort included 70 patients with stage I NSCLC who were followed up for a median of 17.5 months. At 3 months, 60% of patients demonstrated both a complete or partial response and 40% had stable disease, indicating that local control was initially excellent. At follow-up, 3 patients (4.2%) demonstrated local recurrence and disseminated disease was seen in 7 (10%). The estimated overall 2-year survival was 54%.
Of note, significant toxicity was appreciated in this trial using the 3-fraction approach. There were six deaths (8.5%) related to grade 5 toxicity directly attributable to the radiosurgical intervention. The 2-year freedom from toxicity in central tumors was 54%, significantly (p = 0.004) worse compared with 83% in peripheral tumors. This important finding suggests that in the future, a more protracted fractionation scheme should be pursued for central tumors. By prolonging fractionation to 5 or 10 sessions, the normal tissues of the hilum and mediastinum can be given time to recover and repair the DNA damage caused by each radiosurgical session, thereby allowing the normal tissue to recover.
Investigators from Stanford reported another dose-escalation study [22]. In this study, 32 patients with pulmonary tumors were treated with a single fraction ranging from 20 to 30 Gy using the Cyberknife radiosurgical device. Radiation-related complications occurred in 8 patients who had been at doses exceeding 20 Gy. Most of these toxicities (5 of 8) occurred in patients with central tumors at 5 to 6 months after therapy. The treatment-related mortality rate was significant, with three deaths (9.3%) attributed to radiation complications. As in the previous studies, higher radiation doses were associated with better local control. In patients treated with more than 20 Gy, 91% of patients demonstrated freedom from local progression at 18 months. In patients treated with less than 20 Gy, 54% demonstrated freedom from local progression. These authors reported a 1-year survival of 85% for stage I NSCLC patients.
These studies show that although local control with SRS can be excellent with higher doses, caution must be exercised in selecting the dose schema, particularly in patients with central lesions. It is important to balance the efficacy of the intervention with toxicity when SRS is used to treat patients with lung cancer.
The thoracic oncology group from Pittsburgh reported their initial experience in 32 patients with lung neoplasm treated with a median dose of 20 Gy in a single fraction [19]. More recently, they reported their experiences in 21 patients with no more than stage I NSCLC treated with SRS; 20 Gy in a single fraction was used most patients using the Cyberknife system [34]. There were no procedure-related deaths. At a median follow-up of 21 months, local progression occurred in 9 patients (42%), the median time to local progression was 12.3 months, and the median survival was 26.4 months (confidence interval 95%, 13.6-NR).
|
A Future Direction
|
|---|
Another alternative therapy to SRS that is increasingly being used for medically inoperable patients with NSCLC is radiofrequency ablation (RFA) [35, 36]. Radiofrequency ablation is discussed in more detail elsewhere in this supplement. Currently, RFA has been demonstrated to be feasible and short-term results are encouraging. As with SRS, long-term outcomes are still needed. Although RFA and SRS can be regarded as competing therapies, there may be a role for the combination of these modalities [37]. Hypoxic cells, such as those in the center of a tumor, tend to be more resistant to radiation. Radiofrequency ablation tends to be more effective in these dense central areas of lung tumors and less effective in the more aerated lung surrounding a tumor. Radiofrequency ablation also results in reactive neovascularization of tissue at the periphery of the tumor, making the periphery more susceptible to radiation. This potential synergy of radiation and RFA has been investigated in a rat tumor model [38]. Animals treated with RFA or radiation demonstrated similar survival, and those that received both therapies demonstrated superior survival to either therapy alone.
The combination of RFA and radiation has been reported in humans. In one study, 24 medically inoperable patients with stage I NSCLC received RFA and external beam radiation to a dose of 66 Gy [37]. At a mean follow-up of 26.7 months, there were 14 deaths (58.3%), of which 10 (41.7%) died of cancer, and three (12.5%) of respiratory failure. Although not specified in the article, it is possible that the protracted course of external beam radiation used in these high-risk patients may have added potentially avoidable toxicity to the lungs. We suggest that the alternative radiation approach of radiosurgery rather than a less conformal technology be used in combination with RFA. This combination is likely to be better in terms of tumor control and the minimization of potential morbidity risk.
|
Conclusion
|
|---|
In conclusion, SRS is feasible for NSCLC and appears to be superior to heavily fractionated external beam radiation when used as primary therapy for early-stage NSCLC. A number of issues remain to be resolved, including determining which version of the current conceptions of SRS is optimal for NSCLC in terms of safety and tumor control. Although higher radiation doses allow better local control, morbidity and mortality are increased if the dose is given as a single fraction or as a few fractions, particularly for central tumors. In some SRS series, procedure-associated mortality was much higher with high SRS doses than would be acceptable even after resection, RFA, or a sublobar resection for NSCLC.
Therefore, until further data is available, SRS for NSCLC should be done in the setting of a multidisciplinary thoracic oncology team and reserved for the high-risk patient. In addition, considering the promising results of SRS and RFA as monotherapy, we believe that a multimodality approach rationally combining both procedures offers the potential to further improve the therapeutic ratio in favor of oncologic intervention for the subset of medically inoperable patients with potentially curable tumors.
|
References
|
|---|
- Leksell L. The stereotaxic method and radiosurgery of the brain Acta Chir Scand 1951;102:316.[Medline]
- Andrews DW, Bednarz G, Evans JJ, Downes B. A review of 3 current radiosurgery systems Surg Neurol 2006;66:559-564.[Medline]
- Shaw E, Scott C, Souhami L, et al. Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90–05 Int J Radiat Oncol Biol Phys 2000;47:291-298.[Medline]
- Blomgren H, Lax I, Naslund I, Svanstrom R. Stereotactic high dose fraction radiation therapy of extracranial tumors using an acceleratorClinical experience of the first thirty-one patients. Acta Oncol 1995;34:861-870.[Medline]
- 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.[Medline]
- Lee SW, Choi EK, Park HJ, et al. Stereotactic body frame based fractionated radiosurgery on consecutive days for primary or metastatic tumors in the lung Lung Cancer 2003;40:309-315.[Medline]
- Timmerman R, Papiez L, McGarry R, et al. Extracranial stereotactic radioablation: results of a phase I study in medically inoperable stage I non-small cell lung cancer Chest 2003;124:1946-1955.[Medline]
- Brown WT, Wu X, Amendola B, et al. Treatment of early non-small cell lung cancer, stage IA, by image-guided robotic stereotactic radioablation--CyberKnife Cancer J 2007;13:87-94.[Medline]
- Ernst-Stecken A, Lambrecht U, Mueller R, Sauer R, Grabenbauer G. Hypofractionated stereotactic radiotherapy for primary and secondary intrapulmonary tumors: first results of a phase I/II study Strahlenther Onkol 2006;182:696-702.[Medline]
- Huntzinger C, Friedman W, Bova F, Fox T, Bouchet L, Boeh L. Trilogy image-guided stereotactic radiosurgery Med Dosim 2007;32:121-133.[Medline]
- Fung AY, Grimm SY, Wong JR, Uematsu M. Computed tomography localization of radiation treatment delivery versus conventional localization with bony landmarks J Appl Clin Med Phys 2003;4:112-119.[Medline]
- Hodge W, Tome WA, Jaradat HA, et al. Feasibility report of image guided stereotactic body radiotherapy (IG-SBRT) with tomotherapy for early stage medically inoperable lung cancer using extreme hypofractionation Acta Oncol 2006;45:890-896.[Medline]
- Fuks Z, Kolesnick R. Engaging the vascular component of the tumor response Cancer Cell 2005;8:89-91.[Medline]
- Kolesnick R, Fuks Z. Radiation and ceramide-induced apoptosis Oncogene 2003;22:5897-5906.[Medline]
- Garcia-Barros M, Paris F, Cordon-Cardo C, et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis Science 2003;300:1155-1159.[Abstract/Free Full Text]
- Fowler JF. The linear-quadratic formula and progress in fractionated radiotherapy Br J Radiol 1989;62:679-694.[Abstract/Free Full Text]
- Denekamp J, Fowler JF, Dische S. The proportion of hypoxic cells in a human tumor Int J Radiat Oncol Biol Phys 1977;2:1227-1228.[Medline]
- Murphy MJ, Lin PS. Intra-fraction dose delivery timing during stereotactic radiotherapy can influence the radiobiological effect Medical Physics 2007;2:481-484.
- Pennathur A, Luketich JD, Burton S, et al. Stereotactic radiosurgery for the treatment of lung neoplasm: initial experience Ann Thorac Surg 2007;83:1820-1824discussion 1824–5.[Abstract/Free Full Text]
- Onishi H, Araki T, Shirato H, et al. Stereotactic hypofractionated high-dose irradiation for stage I non-small cell lung carcinoma: clinical outcomes in 245 subjects in a Japanese multi-institutional study Cancer 2004;101:1623-1631.[Medline]
- Hiraoka M, Matsuo Y, Nagata Y. Stereotactic body radiation therapy (SBRT) for early-stage lung cancer Cancer Radiother 2007;11:32-35.[Medline]
- Le QT, Loo BW, Ho A, et al. Result of a phase I dose-escalation study using single fraction stereotactic radiotherapy for lung tumors J Thorac Oncol 2006;1:802-809.[Medline]
- Timmerman R, Kavanagh BD, Cho LC, Papiez L, Xing L. 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.[Abstract/Free Full Text]
- Keall PJ, Mageras GS, Balter JM, et al. The management of respiratory motion in radiation oncology report of AAPM Task Group 76 Med Phys 2006;33:3874-3900.[Medline]
- Saunders M, Dische S, Barrett A, Harvey A, Griffiths G, Palmar M. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: mature data from the randomised multicentre trial Radiother Oncol 1999;52:137-148.[Medline]
- Rosenzweig KE, Fox JL, Yorke E, et al. Results of a phase I dose-escalation study using three-dimensional conformal radiotherapy in the treatment of inoperable nonsmall cell lung carcinoma Cancer 2005;103:2118-2127.[Medline]
- Bradley JD, Wahab S, Lockett MA, Perez CA, Purdy JA. Elective nodal failures are uncommon in medically inoperable patients with stage I non-small-cell lung carcinoma treated with limited radiotherapy fields Int J Radiat Oncol Biol Phys 2003;56:342-347.[Medline]
- Komaki R, Roth J. Introduction J Thorac Oncol 2007;2:S93.
- Fernando HC, Santos R, Benfield JR, et al. Lobar and sublobar resection with and without brachytherapy for small stage Ia non-small cell lung cancer J Thorac Cardiovasc Surg 2005;129:261-267.[Abstract/Free Full Text]
- Ketchedjian A, Daly BD, Fernando HC, et al. Location as an important predictor of lymph node involvement for pulmonary adenocarcinoma J Thorac Cardiovasc Surg 2006;132:544-548.[Abstract/Free Full Text]
- Revisions in the International System for Staging Lung Cancer Chest 1997;111:1710-1717.[Medline]
- Intentional limited pulmonary resection for peripheral T1N0 small-sized cancers J Thorac Cardiovas Surg 2003;125:924-928.[Abstract/Free Full Text]
- McGarry RC, Papiez L, Williams M, Whitford T, Timmerman RD. 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.[Medline]
- Pennathur A, Luketich JD, Burton SA, et al. Stereotactic radio surgery for the treatment of stage I non-small cell lung cancer in high-risk patients Presented at American Association for Thoracic Surgery (AATS) Annual Meeting. Washington, DC, May 5–9, 2007. Proceedings of the American Association of Thoracic Surgery. 2007.
- Radiofrequency ablation for the treatment of non-small cell lung cancer in marginal surgical candidates J Thorac Cardiovasc Surg 2005;129:639-644.[Abstract/Free Full Text]
- Pennathur A, Luketich JD, Abbas G, Chen M, Fernando HC, et al. Radiofrequency ablation for the treatment of stage I non-small cell lung cancer in high-risk patients J Thorac Cardiovasc Surg 2007;134:857-864.[Abstract/Free Full Text]
- Dupuy DE, DiPetrillo T, Gandhi S, et al. Radiofrequency ablation followed by conventional radiotherapy for medically inoperable stage I non-small cell lung cancer Chest 2006;129:738-745.[Medline]
- Reduced tumor growth with combined radiofrequency ablation and radiation therapy in a rat breast tumor model Radiology 2005;235:81-88.[Abstract/Free Full Text]
Top
Abstract
Introduction
