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a Heart, Lung, and Esophageal Surgery Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
b Department of Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
c University of Pittsburgh Cancer Institute Biostatistics Facility, Pittsburgh, Pennsylvania
Accepted for publication May 7, 2009.
* Address correspondence to Dr Luketich, Heart, Lung, and Esophageal Surgery Institute, University of Pittsburgh, 200 Lothrop St, Pittsburgh, PA 15213 (Email: luketichjd{at}upmc.edu).
Presented at the Forty-fourth Annual Meeting of The Society of Thoracic Surgeons, Ft Lauderdale, FL, Jan 28–30, 2008.
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Abstract |
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Methods: Patients who were medically inoperable were offered stereotactic radiosurgery. Thoracic surgeons evaluated all patients, placed fiducials, and performed treatment planning in collaboration with radiation oncologists. Initially, a median dose of 20 Gy prescribed to the 80% isodose line was administered in a single fraction, and this was subsequently increased to a total of 60 Gy in three fractions. The primary end point evaluated was overall survival.
Results: We treated 100 patients (median age, 70 years; 51 men, 49 women) with stereotactic radiosurgery: 46 (46%) with primary lung neoplasm, 35 (35%) with recurrent cancer, and 19 (19%) with pulmonary metastases. The median follow-up was 20 months. The median overall survival was 24 months. Local recurrence occurred in 25 patients. The probability of 2-year overall survival was 50% for the entire group, 44% for primary lung cancer, 41% for recurrent cancer, and 84% for metastatic cancer.
Conclusions: Our initial experience indicates that stereotactic radiosurgery has reasonable results in these high-risk patients. Resection continues to remain the standard treatment; however, stereotactic radiosurgery may offer an alternative in high-risk patients. Further prospective studies with different dose schema are needed to evaluate the efficacy of stereotactic radiosurgery.
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Introduction |
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Sibley [4] reviewed the results of conventional radiotherapy for stage I NSCLC and reported a 2-year survival of 39%. Of the 122 evaluable patients in the study, recurrences were noted in 55, with local recurrence accounting for 49% of these failures. Higher doses of radiation may improve the local control of these tumors. Stereotactic radiosurgery (SRS), a term coined by Leksell, is an approach using multiple convergent beams, precise localization with a stereotactic coordinate system, rigid immobilization, and single fraction treatment. SRS may allow dose escalation because it delivers beams from multiple collimated paths, which maximizes the delivery to the tumor and minimizes the exposure of healthy tissue [6].
Lung neoplasms recur in more than 25% of patients despite complete resection, and these patients comprise a difficult group to treat [7]. When treatment includes surgical resection for recurrences limited to the lung, the survival appears to be improved compared with other nonoperative therapies [7]. Similarly, surgical resection is also beneficial in selected patients with pulmonary metastases [8]. In patients who are candidates for resection but are otherwise medically inoperable, few effective options are available. Newer technologies such as SRS may offer an alternative in the management of medically inoperable or high-risk patients with lung neoplasm. This article presents our results on the use of SRS for the treatment of lung neoplasm in 100 consecutive patients.
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Material and Methods |
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Selection of Patients
Patients with primary lung neoplasm were routinely staged with chest computed tomography (CT) scan, and most patients (83%) also underwent a positron emission tomography (PET) scan. Patients with primary lung neoplasm and mediastinal lymph nodes greater than 1 cm in short axis or a positive PET scan, or both, underwent mediastinoscopy. Mediastinoscopy was performed in 9 patients with primary lung neoplasm. The inclusion criteria for SRS treatment in this study were:
All patients were evaluated by a thoracic surgeon and a radiation oncologist before SRS treatment. Treatment was delivered using the CyberKnife (Accuray, Sunnyvale, CA) system, which is a frameless system consisting of a 6-MV linear accelerator mounted on a computer-controlled robotic arm. The technology and the protocol used with this system have been described in detail elsewhere [11, 12].
Treatment Protocol
Briefly, in first step of the treatment protocol, thoracic surgeons used CT guidance to place 1 to 4 fiducials, which are small tumor markers, in and around the tumor for tumor tracking. An immobilization device (Alpha cradle, Smithers Medical Products, North Canton, OH), which partially immobilizes the patient to decrease motion and provide a reproducible setup, was custom made for each patient.
A week to 10 days after placement of fiducials, a contrast-enhanced CT scan of the patient's chest and upper abdomen was evaluated by the thoracic surgeon and radiation oncologist and a treatment plan was formulated jointly. The tumor was contoured with 5- to 10-mm margins around the tumor. We made treatment volume considerations to avoid radiation injury in the surrounding critical structures. To further decrease the effects of tumor movement, we used the breath hold technique initially, and more recently have used dynamic respiratory tracking with the patient spontaneously breathing.
On the day of the treatment, the patient was repositioned accurately to simulate the original planning setup. The tumor and the planned isocenter of the treatment field were identified. Patients were treated with 20 Gy prescribed to the 80% isodose line (1 to 3 fractions, total dose 20 to 60 Gy). Initially, a median dose of 20 Gy in a single fraction, prescribed to the 80% isodose line, was used; later, 60 Gy in three fractions was used to treat peripheral lesions.
Patients Follow-Up and Response Assessment
Patients were evaluated at 4-month intervals with clinical examinations, CT scans, and selectively with PET scans. A modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria incorporating both CT scan and PET scan findings was used to assess response to treatment [12]. Patients were evaluated for initial response rate, time to progression (TTP), and overall survival.
Data Collection and Statistical Analysis
The study objective was to evaluate the outcomes of SRS in the treatment of lung neoplasm. Information collected included patient demographics, tumor characteristics, and treatment. Comorbidities were scored by the Charlson comorbidity index (CCI) [13]. Specific end points were complications, clinical response rates, TTP, and overall survival. The pretreatment CT scan was used as a baseline for evaluation of response and disease progression. Local disease progression was defined as progression of the treated nodule and was assessed in accordance with the modified RECIST criteria in comparison with baseline diameter. Progression-free survival was defined as time from the treatment date to the first date of progression at any site. Patients whose first site of progression was regional or distant were censored on their date of progression when local progression-free survival was evaluated. Kaplan-Meier plots were constructed using Greenwood confidence limits. Associations between categoric variables were tested with the Fisher exact test or the 
2 test.
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Results |
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Response to Treatment
Initial response was determined by the modified RECIST criteria. Response was not evaluated in 10 patients. In the remaining patients, an initial complete response was observed in 20% (18 of 90), a partial response was observed in 29%, stable disease was noted in 22%, and progressive disease occurred in 29%.
Time to Progression
Three patients had undetermined disease status at last follow-up, leaving 97 patients available for analysis of progression-free survival. During follow-up, local progression at the treated nodule occurred in 25 patients and the median time to local progression was 22 months (95% confidence interval [CI], 10 months to not reached). Local progression-free survival stratified by group is shown in Figure 1. Overall progression (all sites) occurred in 62 patients, and the median time to progression was 8 months (95% CI, 5 to 10 months). The median time to overall progression was 9 months (95% CI, 6 to 16 months) for primary lung neoplasm, 6 months (95% CI, 4 to 11 months) for recurrent neoplasm (all stages), and 6 months (95% CI, 3 to 10 months) for metastatic lung neoplasm. We compared 28 patients receiving a 60-Gy dose with patients who received a 20-Gy dose. Of those patients with pulmonary metastasis, 56% received 60 Gy compared with 37% of patients with primary and recurrent disease; this difference was statistically significant (p = .045). The higher dose of 60 Gy lengthened the time to local nodule progression.
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The estimated 2-year overall survival for the entire group was 50% (95% CI, 39% to 61%). The estimated 2-year overall survivals by cancer type were 44% (95% CI, 29% to 59%) for patients with primary lung neoplasm (all stages), 41% (95% CI, 23% to 59%) for recurrent lung neoplasm, and 84% (95% CI, 47% to 96%) for metastatic disease (Fig 2).
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Comment |
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Dose escalation may allow better local control of the tumor, and the potential advantage of dose escalation has been reported. Timmerman and colleagues [14] reported the results in 37 patients with stage I NSCLC treated with SRS, where the dose was escalated from 24 to 60 Gy in three fractions. At a median follow-up of 15 months, 13 patients had recurrences, with 6 experiencing local failure. All of these patients who had local failure received less than 18 Gy per fraction. The median time to local progression was 13 months. The disease-free and overall survivals at a median follow-up of 15 months were 50% and 64%, respectively [8]. Onishi and colleagues [18] evaluated clinical outcomes in 245 patients with stage I NSCLC from 13 Japanese centers and reported a lower local recurrence rate when the biologically effective dose of more than 100 Gy was used. We also noticed a trend of an increased time to local progression with a higher dose of 60 Gy compared with a lower dose. Tumor tracking during respiration and delivery of stereotactic radiation is also an important consideration, and in the future, a higher dose, wider margin, and dynamic respiratory tracking may improve the local recurrence rates [12].
An increase in radiation dose may improve local control; however, this may also be associated with increased toxicity, particularly when treating central lesions [11, 19, 20]. In a phase II study of 70 medically inoperable patients with stage I NSCLC treated with SRS using 60 to 66 Gy in three fractions, local control of 95% and an estimated 2-year overall survival of 54% were reported [19]. However, increased toxicity was noted in central tumors, with a 2-year freedom from severe toxicity of 54% in central lesions compared with 83% in peripheral lesions. During a median follow-up of 17.5 months, 6 of the 70 patients (8.6%) died of treatment-related causes. These results led the authors to conclude that this regimen should not be used for patients with tumors near central airways.
Another interesting study that evaluated the balance between toxicity and local progression was reported recently. In this study of 32 patients with lung neoplasm, late toxicity was observed in 8 patients, all of whom had received more than 20 Gy [20]. The treatment-related mortality was 9.7% and occurred entirely in patients who received more than 25 Gy in a single fraction. 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 with toxicity when SRS is used to treat patients [11].
Recurrent Lung Neoplasm
Patients with recurrent lung cancer after surgical resection are difficult to treat. Okamato and colleagues [21] reported the results of 34 patients who were originally treated with radiation and then retreated with external beam radiation for local recurrence of lung cancer. The median dose administered during repeat irradiation was 50 Gy, and the median survival was 8 months. In a more recent report of 19 patients treated with repeat radiation for locally recurrent lung cancer, Tada and colleagues [22] reported an overall 1-year survival of 26%, a 2-year survival of 11%, and a median survival of 7.1 months. Sugimura and associates [6] reported the results of 390 patients from Mayo Clinic with recurrent cancer after complete surgical resection. The median survival after recurrence was 8.1 months, and overall survival was 37% at 1 year and 17% at 2 years. Treatment included surgical resection in a select group among patients with local recurrence, and when the treatment included an operation, median survival was 32.8 months. Median survival was only 13.4 months for nonsurgical treatment and 8.4 months for no treatment. The median survival for recurrent lung cancer after SRS in this study was 20 months. Although this was not a randomized study, these results compare favorably with the reported results of nonsurgical treatments or no treatment.
The International Registry for Lung Metastases (IRLM) reported the outcomes of 5206 patients. The estimated 5-year survival after complete resection was 36%, and the median survival was 35 months. Le and colleagues [20] reported the results of single-fraction radiosurgical treatment in 12 patients with metastatic or recurrent lung neoplasm. The 1-year overall survival was 56% in patients with pulmonary metastases.
In another study, Wulf and colleagues [23] reported the results of SRS (dose range, 26 to 37.5 Gy) in 41 patients with nonoperable pulmonary metastases. The median follow-up was 9 months. The overall survival rates were 85% at 1 year and 33% at 2 years.
In the current study, the patients with pulmonary metastases were a heterogenous group. Our results compare favorably with the results of the above studies using SRS in this group of patients. Despite seemingly good survival, the confidence limits are wide, and the lower confidence limit was only 47%. In addition, patients with metastatic lesions were more likely to receive a higher dose of radiation (60 Gy), and this may have potentially had an effect on the outcome. However, with limited number of patients with metastatic lesions and wide CI, we need more patients and longer follow-up for more mature data. The heterogeneity of the group was another limitation.
We recently presented our results with the use of image-guided RFA for the treatment of lung neoplasm in 100 consecutive patients [24]. The proportion of patients with metastatic disease was higher and proportion with recurrent disease was lower in the group treated with RFA. The median overall survival for the entire group treated with RFA was 23 months, similar to the current study. However, because this was not a randomized study of SRS and RFA, we cannot make any definitive conclusions on the relative efficacy of each modality.
Similar to RFA, pneumothorax was the most common complication after placement of fiducials. This is also one of the most common complications after transthoracic needle biopsy of lung lesions. The reported incidence of pneumothorax after transthoracic needle biopsy varies widely, with an incidence up to 61% [25]. A review of transthoracic needle biopsies reported that most large series had an incidence of 5% to 30% [26]. In the future, other techniques such as navigational bronchoscopy and placement of fiducials may decrease the risk of pneumothorax.
An interesting aspect of this study is that thoracic surgeons were actively involved in patient selection, placement of fiducials, and treatment, in close collaboration with radiation oncologists [11]. It is particularly important that the thoracic surgeon makes the determination of medical inoperability. One factor alone, such as poor pulmonary function tests, may not make a patient inoperable; for example, patients with upper lobe predominant emphysema with coexisting cancer may be still candidates for resection despite marginal results on pulmonary function tests [27]. Therefore, the thoracic surgeon should make the determination of medical inoperability after the patient is evaluated and risks are assessed.
The current study has the limitations that are present in retrospective studies, such as selection bias [11]. These patients form a very heterogeneous group, including not only primary lung neoplasm, but also patients with recurrent lung neoplasm and metastatic disease. Many patients with primary lung neoplasm also had advanced-stage disease. Further, the use of other therapies in the patients treated with SRS confounds the analysis of efficacy of treatment with SRS. Finally, although the current study had a long follow-up compared with some published studies [14, 19], this follow-up is still relatively short. We need longer follow-up with greater maturity of the data for a more complete evaluation of survival end points.
In summary, the results of SRS in 100 consecutive patients for lung neoplasm indicate that SRS in the doses used appears to be safe and may provide an alternative in medically inoperable patients. Further studies are required to optimize patient selection, to determine appropriate dose fractionation, and to balance the efficacy of treatment with toxicity. Surgical resection remains the standard treatment for resectable primary lung cancer; however, SRS may be useful in patients who are medically inoperable or who refuse an operation. In addition, SRS may be a useful modality for local control in selected nonoperable patients with recurrent lung cancer and patients with metastatic disease in the lung. Prospective studies are necessary and are ongoing in our institution and others to address these issues and to define the role of SRS in the treatment of lung neoplasms.
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Discussion |
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DR PENNATHUR: That is an excellent question. We did not see a difference when we broke it down into T1 and T2 in our preliminary analysis, but I think that is a factor of our follow-up. If you follow-up for a longer and equivalent time, in both these groups, I think we might see a difference in terms of the local progression and this is something we will evaluate.
DR FRANK C. DETTERBECK (New Haven, CT): I think the survival data is very confusing when you lump together the patients with metastases and primary lung cancer and so forth, so I have difficulty interpreting that. I want to just sort of focus on the primary lung cancer patients. How did you stage these patients? I am surprised that your survivals were as bad as they were, and it suggests to me that perhaps they weren't staged that well. Certainly in surgery we have learned that you can't just accept the CT [computed tomography] scan, you have to stage the mediastinum more carefully, et cetera, et cetera. We need to use those same lessons that we have learned when we apply these other techniques.
DR PENNATHUR: Thank you for your question. Everybody obviously received a CT scan, and 83% of the patients also got a PET [positron emission tomography] scan for the staging. When the lymph nodes in the mediastinum were greater than 1 cm in short axis or the PET was positive, they underwent a mediastinoscopy in this particular series. About 10 patients in this series underwent a mediastinoscopy for staging. These were the criteria we used for mediastinoscopy. The patient population is quite heterogeneous and one has to interpret the survival results taking into account each group separately, that is between recurrent cancer, metastatic cancer, and primary cancer is difficult, but in the interest of time, I didn't really break it down and show detailed results in each category. With regard to primary lung cancer, this series includes not only early stage lung cancer but also more advanced lung cancer, and survival results are of the entire group. But these patients were staged, and I think in the future we will probably have more PET scans in order to stage these patients adequately, and some of them are such high risk that they are not even candidates for a mediastinoscopy.
DR WAEL Z. TAMIM (Ft. Lauderdale, FL): Any comparison with cryotherapy for such lesions?
DR PENNATHUR: I do not know about the results of cryotherapy for these patients. I have heard that it has been used in some institutions, but I am not aware of the results.
DR AKIF TURNA (Istanbul, Turkey): Are you aware of any data about the applicability of stereotactic radiosurgery in a neoadjuvant setting? Did any of your patients become medically operable after stereotactic radiosurgery, or did any of your patients decide to have surgery after your applications?
DR PENNATHUR: I think that is an excellent point. No, we did not use stereotactic radiosurgery as a strategy for neoadjuvant therapy and possibly following for surgery. These were patients who primarily were either medically inoperable due to multiple comorbidities, and 5 patients refused an operation. So this series we have not used a planned neoadjuvant strategy with the stereotactic radiosurgery.
DR HARVEY I. PASS (New York, NY): Can you tell us a little bit of a comparison between your data and the fairly mature data from Timmerman using the 20, 20, 20 regimen? How do you think they compare? My other question is, did you limit your studies to patients with peripheral zone lesions to try to avoid any sort of bronchostenosis? And where do you think this will go? Do you think that this ought to be considered in the future in patients who are potentially resectable?
DR PENNATHUR: Dr Pass, thank you for your questions. The first question, How is this study compared with the mature data of Dr Timmerman. Well, the median follow-up in Timmerman's first study was 15 months. The second study, when he presented the results of the toxicity, was 17.5 months. The median follow-up of patients in the current study we presented was 20 months. So I do not think the Timmerman data is really mature. At least in this cohort of patients, we do have a longer median follow-up. The data from Japan is very interesting. However, clearly the longer-term data from studies in the United States is required. I think we should continue to investigate this modality, and at this time we are actively investigating its efficacy in non-operable patients. We are very interested in evaluating its long-term efficacy.
The second question is an important one, whether this is used for peripheral or central lesions. In this protocol, we utilized 20-Gy and 60-Gy dosages. It includes both central and peripheral lesions. We do not administer a 60-Gy dosage for central lesions, mainly based on the data of Timmerman who showed close to a 9% procedure-related mortality when such a dose was used, and the mortality was primarily when he was using it on central lesions. So this includes both central and peripheral. For peripheral we administer a 60 Gy dose, 20 Gy times 3, and for the central lesions, in this series it was predominantly 20 Gy. Of late we have been using the Japanese regimen, which is 48 Gy, 12 times 4, equal to a total of 48 Gy for the central lesions, but this particular series does not include those patients.
Thank you for your comments. I would like to thank my colleagues at the University of Pittsburgh and the society for the privilege to present this paper.
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This article has been cited by other articles:
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  C. Schroeder, R. Hejal, and P. A. Linden Coil spring fiducial markers placed safely using navigation bronchoscopy in inoperable patients allows accurate delivery of CyberKnife stereotactic radiosurgery J. Thorac. Cardiovasc. Surg., November 1, 2010; 140(5): 1137 - 1142. [Abstract] [Full Text] [PDF]
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 H. C. Fernando, M. Schuchert, R. Landreneau, and B. T. Daly Approaching the High-Risk Patient: Sublobar Resection, Stereotactic Body Radiation Therapy, or Radiofrequency Ablation Ann. Thorac. Surg., June 1, 2010; 89(6): S2123 - S2127. [Abstract] [Full Text] [PDF]
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