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  Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 55  |  Issue : 2  |  Page : 170-175
 

Stereotactic body radiotherapy for lung tumors: Dosimetric analysis and clinical outcome


1 Department of Radiation Oncology, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Mumbai, Maharashtra, India
2 Department of Medical Oncology, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Mumbai, Maharashtra, India
3 Department of Medical Oncology, Bombay Hospital and Medical Research Centre, Mumbai, Maharashtra, India
4 Department of Surgical Oncology, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Mumbai, Maharashtra, India

Date of Web Publication31-Dec-2018

Correspondence Address:
Dr. Dipanjan Majumder
Department of Radiation Oncology, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_555_17

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 » Abstract 


INTRODUCTION: Stereotactic body radiotherapy (SBRT) has emerged as an important modality in malignant lung tumor treatment both in early localized primary and oligometastatic setting. This study aims to present the results of lung SBRT both in terms of dosimetry and clinical outcome. MATERIALS AND METHODS: Twenty-seven patients were assessed from 2012 to 2016. Both the primary and oligometastatic lung tumors were evaluated. Respiratory motion management was done employing ANZAI (Siemens, Germany) based four-dimensional computed tomography (CT). Commonly used fractionations were 60 Gy/5 fractions for peripheral tumors and 48 Gy/6 fractions for central tumors. Radiation Therapy Oncology Group toxicity criteria were used for toxicity and whole-body positron emission tomography-CT scan was done at follow-up for response evaluation. RESULTS: Twenty-seven patients were evaluated, 18 (66.7%) patients had a primary, and 9 (33.3%) patients had metastatic lung tumors. The male-to-female ratio for the entire cohort was 2:1. The median age at diagnosis was 65.8 years. Mean planning target volume (PTV) D2cc was 54.9 ± 9.04 Gy and mean internal target volume diameter was 3.0 ± 1.07 cm. Mean V20 Gy, V10 Gy, and V5 Gy of (lungs total-PTV) and (Lung ipsilateral - PTV) were 5.4 ± 4% and 10.9 ± 7.9%, 11.7 ± 5.8% and 24.2 ± 14.0%, and 22.05 ± 12.4% and 33.2 ± 15.3%, respectively. In total 21 (84%) patients and 4 patients (16%) showed a complete and partial response, respectively. One (3%) patient developed Gr 3 radiation pneumonitis. One year local control was in 18 (81%) patients whereas 4 (14%) patients progressed and three patients did not report. A higher prescribed dose significantly correlated with 1 year tumor control (P = 0.036). CONCLUSION: This study infers the feasibility and a favorable outcome for lung cancer amenable to SBRT in addition to being one of the largest clinical experiences for lung stereotactic treatment in our country.


Keywords: ANZAI, four-dimensional computed tomography, lung tumor, oligometastatic, respiratory motion management, stereotaxy


How to cite this article:
Talapatra K, Majumder D, Chadha P, Shaju P, Goyle S, Smruti B K, Mistry R. Stereotactic body radiotherapy for lung tumors: Dosimetric analysis and clinical outcome. Indian J Cancer 2018;55:170-5

How to cite this URL:
Talapatra K, Majumder D, Chadha P, Shaju P, Goyle S, Smruti B K, Mistry R. Stereotactic body radiotherapy for lung tumors: Dosimetric analysis and clinical outcome. Indian J Cancer [serial online] 2018 [cited 2019 Mar 25];55:170-5. Available from: http://www.indianjcancer.com/text.asp?2018/55/2/170/249207





 » Introduction Top


Lung cancer is leading cause of mortality worldwide. Estimated lung and bronchus cancer cases in United States of America are 1, 18, 080 (14%) in male, 1, 10, 110 (14%) in female, and estimated death is 87,260 (28%) in male and 72,220 (26%) in female. Five years survival of lung and bronchus carcinoma according to the stage is 16%, 52%, 25%, and 4% for all stages, local disease, regional disease, and distant spread, respectively.[1] Non-small cell lung cancer (NSCLC) comprises >80% of lung cancers, one third of them detected at an early stage.[2] However, there are pertinent aspects and parameters to choose between the radical treatment options. Surgery till date has been the mainstay of treatment in patients diagnosed with early lung cancer. About 20–30% of patients with early lung carcinomas are not candidates for surgery due to medical comorbidities.[3] SBRT has emerged as an excellent option to treat these tumors. Early studies by Timmerman et al. showed encouraging results in lung SBRT.[4] A total of 37 patients were evaluated for SBRT in medically inoperable early lung cancer in that dose escalation study, 87% of patients responded to treatment and patients tolerated dose escalation up to 20 Gy × 3 fractions. Even surgical candidates have equal results that came in a metanalysis, where it was found that age-adjusted disease-free survival, overall survival (OS) in both the surgery and SABR groups not differ significantly.[5] With the curative potential of SBRT in early lung tumor, it has also been tried in oligometastatic lung disease.[6] With the advancement of respiratory motion management system more lung SBRT now practiced but both dosimetric analysis and clinical outcome data from India are limited. Hence, in the present study, we aimed to assess the local control (LC) in treated patients of lung SBRT and also to report the dosimetric analysis and its relation to the outcome.


 » Materials and Methods Top


A total of 27 patients were evaluated from 2012 to 2016. All patients being reported in the study were reviewed at multidisciplinary tumor board that comprised thoracic surgeons, radiation and medical oncologists, radiologists, and pathologists. The patients who were deemed medically inoperable due to deranged pulmonary function or other comorbidities, for example, poor cardiac status and who had early-stage NSCLC (T1-2N0M0) or oligometastatic disease with single pulmonary lesion were reviewed and decided to be treated with stereotactic body radiotherapy (SBRT). There was a subset of patients who refused surgery also included in the study. The following selection criteria were observed while taking patients for SBRT: (1) patients had histologically proven squamous or adenocarcinoma of the lung for primary disease or metastatic lung disease proved on fine-needle aspiration cytology, (2) patients with stage T1-2N0M0 NSCLC or oligometastatic disease with single pulmonary metastasis, (3) Karnofsky performance score >80%, (4) inoperable due to their comorbidities, for example, impaired cardiac function and poor lung function, and 5) patient's refusal for surgery.

Computed tomography (CT) scan of the thorax, magnetic resonance imaging scan of the brain, whole-body18 F-fluorodeoxyglucose (FDG) positron emission tomography CT (PET-CT) scan for staging evaluation, and baseline hematological tests were performed. Pretreatment pulmonary function test was done to assess respiratory reserve.

Treatment simulation and image segmentation

Patients were immobilized in an evacuated cushion (VacLoc, Civco Medical Solutions, Kalona, IA) and CT simulation was done. CT cuts were taken in the free-breathing phase and then 4D CT scan acquisition was done with 2-mm slice thickness from neck to mid-abdomen. Four-dimensional CT (4D CT) scan set consisted of a series of three-dimensional (3D) CT image sets acquired at different respiratory phases. After the acquisition, the images were sorted into different phases of respiratory cycles and maximum intensity projection (MIP) images generated that was transferred to Eclipse planning system with the free-breathing scan. To take 4D CT scan, we used ANZAI belt (Siemens, Germany) based respiratory motion management system, the tumor volume respecting internal motion, internal target volume (ITV) was contoured as it was visible in the MIP CT images using the lung parenchymal window level of 0 to − 1,000 HU. Then, images were fused to free-breathing scan to assess the tumor coverage with a respiratory motion by playing 4D CT image dataset. The planning target volume (PTV) was designed by growing 0.5 cm margin across the ITV to account for physiological organ motion and setup errors.

Treatment planning

The SBRT plan was created by the commercial treatment planning system; Eclipse (Varian Medical Systems, Palo Alto, CA). The dose was prescribed at the isocenter and the plans constituted of 4–7 nonopposing, coplanar or noncoplanar beams with 100% dose to be prescribed at isocenter and 80–90% isodose coverage at the periphery. Plans were done by 3D conformal radiotherapy (3D-CRT). We have kept all the dose constraints strict. The dose fractionation commonly used for peripheral tumors (away from the midline mediastinal structures) was 60 Gy/5 fractions and those for the centrally located tumor was 48 Gy/6 fractions.

Treatment delivery

Treatment was delivered on daily basis. Before each fraction, treatment was verified using on-line cone beam CT (CBCT) with volumetric image guidance. The CBCT images were registered with the contours from the 3D CT planning datasets and were used for patient localization. After CBCT acquisition, shifts were applied to match the present image with pretreatment CBCT then if the image matching is satisfactory by the radiation oncologist, treatment was delivered.

Assessment

All the patients were assessed by the radiation oncologist daily before the stereotactic treatment delivery and at the end of the treatment to assess the acute toxicities. The patients were then followed up at 6 weeks and every 3 months thereafter. At each visit, the patients underwent a history, physical examination, and toxicity and symptom assessment. Acute toxicities were graded according to Radiation Therapy Oncology Group (RTOG) Acute Radiation Morbidity Scoring Criteria and late toxicities were evaluated using RTOG/European Organization for Research and Treatment of Cancer Late Radiation Morbidity Scoring Schema. A whole-body FDG-PET scan was repeated after 3 months to evaluate the response to SBRT. PERCIST (1.0) criteria followed for response assessment. Patients who had any symptoms of local or regional failure at postresponse follow-up were evaluated with whole-body FDG-PET scan.

Statistics

SPSS 21 version was used for statistical calculations. Chi-square test was employed for categorical variables whereas association between dosimetric parameters and response outcomes was determined using Pearson's correlation.


 » Results Top


Twenty-seven patients were evaluated [patients' characteristics are summarized in [Table 1]. Eighteen patients (66.7%) have the primary disease and 17 (63%) were male patients. Totally, 10 patients had the chronic obstructive pulmonary disease and eight patients had known cardiac disease in the form of coronary artery disease, impaired cardiac function, or previous cerebrovascular events. Nine patients opted for SBRT as a treatment option as they were not willing to undergo surgery.
Table 1: Patient characteristics

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Dosimetric analysis

Tumor dose

The prescribed dose (Dp) to isocenter were 60 Gy/5 fractions for peripheral tumors and 48 Gy/6 fractions for central tumors, mean prescription dose being 55.5 Gy ± 7.5 Gy [dosimetric parameters are summarized at [Table 2]. Mean PTV volume was 55.4 ± 49.5 cc and mean ITV volume was 19.6 ± 20.4 cc. A static conformal beam technique for the planning was used [Figure 2]a.
Table 2: Dosimetric analysis

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Figure 2: (a) 40-year-old male patient with primary head neck squamous cell carcinoma post-treatment developed oligometastatic disease with one lung lesion which was treated with static conformal beams. (b) Response after 1 year of the same patient. No other new lesion detected

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The dose received for PTV were as follows:

D2 (mean 54.9 ± 9.04 Gy),

D98 (mean 43.9 ± 6.23 Gy) dose prescribed (mean 55.26 ± 7.6 Gy).

Mean conformity index (CI) for the plans was 1.16 ± 0.2.

(CI, TV/PTV; TV, treated volume, volume enclosed by the Dp at periphery, PTV, planning target volume).

Mean homogeneity index (HI) was 0.2 ± 0.06.

(HI = D2– D98/Dp × 100; where D2 = minimum dose to 2% of the target volume indicating the “maximum dose,” D98 = minimum dose to the 98% of the target volume indicating the “minimum dose,” and Dp = prescribed dose).

Dosimetric analysis of organs at risk

Lung

Lung dosimetry was calculated for both V5 Gy, V10 Gy, and V20 Gy [Table 2] and [Figure 1]. Mean of volume dose to lungs total-PTV and lung ipsilateral-PTV V20 was 5.4 ± 4 Gy and 10.9 ± 7.9 Gy, respectively. Mean lung doses for total lung-PTV and ipsilateral lung-PTV were 4.27 ± 1.9 and 6.4 ± 3.5 Gy. Lung dose-constraints were met without any minor or major deviation.
Figure 1: 20 Gy (V20) received by lung volume in % was plotted in frequency table (a) Ipsilateral lung – planning target volume (b) Bilateral lung – planning target volume (c) Mean lung dose plotted for study population and (d) Comparative lung dose for central versus peripheral tumors

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Spinal cord/esophagus/trachea/great vessels

Mean cord Dmax and mean esophagus, Dmax were 13.9 ± 6.5 Gy, and 18.12 ± 12 Gy, mean heart dose was 1.65 ± 1.2 Gy [Table 2] well within the dose-toxicity limits. Other OAR doses, including mean of Dmax trachea is 19.16 ± 14.6 Gy, mean of Dmax of great vessels is 39.87 ± 20.6 Gy.

Toxicities

Two (7%) patients had grade 2 radiation pneumonitis and 1 (3.5%) patient had grade 3 radiation pneumonitis. Maximum toxicities reported up to 1 year of follow-up from treatment start are summarized at [Table 3]. Two (7%) patients died in the follow-up period. Both the patients initially had the metastatic disease to start with. One of them had a partial response at the local site then developed brain metastasis after 6 months, we have treated with whole brain radiotherapy 30 Gy/10 fractions, responded well to the treatment initially, but again deteriorated and ultimately died after 10 months from starting of treatment. Another patient died at local place 14 months postradiotherapy, which we have confirmed by a telephonic conversation with the relative, but the cause of death cannot be ascertained.
Table 3: Toxicity

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Response

Treatment response assessed after 3 months of completion of treatment. On first follow-up, 21 (77.8%) patients showed complete response whereas two patients did not report other showed a partial response [treatment response summarized at [Table 4]a, [Table 4]b, [Table 4]c]. Of 25 patients reported the complete response was 84%.


Click here to view


Fifteen of 18 (83.3%) patients and 6 (66.7%) of 9 patients with peripheral and central tumors showed a complete response after 3 months, respectively (P = 0.112). In total 13 (48%) and 5 (18.5%) patients with peripheral and central tumors remained controlled at 1 year (P = 0.261). After 1 year, three patients not reported and two patients, follow-up dates are due. A total of 18/22 (82%) patients remained controlled after 1 year. Fifteen (55.5%) male patients showed a complete response at 3 months and 13 (48.1%) remained controlled after 1 year [Figure 2]b. Complete response rate at first follow-up was 88.8% in male patients. Fifteen (55.5%) patients with primary disease showed a complete response after 3 months, whereas 14 (51.85%) patients are controlled after 1 year. About 83% and 77.8% of all patients with primary disease showed a complete response at 3 months and at 12 months. Two patients with the primary disease did not report after 1 year if we exclude them from analysis then LC will be 87.5% after 1 year [Table 4]c. Four patients (15%) showed the distant failure of which three were initially diagnosed with metastatic disease.

Response predicting factors

Both responses at 3 months and 12 months were correlated with different parameters such as ITV diameter, ITV volume, PTV diameter, PTV volume, and Dose prescribed at isocenter (Diso). All the parameters except (Diso) had no significant association with the treatment response at 1 year. With the higher Diso control rate at 1 year increased statistically significantly (P = 0.036).


 » Discussion Top


With the development in volumetric imaging and the tools of motion management, SBRT has emerged as an extremely effective option of treatment of primary early-stage lung cancer medically inoperable patients. One initial study of 70 patients with primary lung carcinoma 60–66 Gy/3 fractions were delivered. At a median follow-up of 50 months, the 3-year LC rate was 88.1% and the 3-year OS rate was 42.7%. The grades 3–5 toxicity rate in peripheral tumors was 10.8%, but for central tumors this rate was 27.3%.[7] In prospective phase II study, the RTOG 0236, 55 evaluable patients with biopsy-proven stage I NSCLC with peripheral tumors were treated with 54 Gy/3 fractions. At a median follow-up of 34.4 months, the 3-year LC was 97.6%, and the 3-year OS was 55.8%. The grade 3 toxicity rate was 12.7%, the grade 4 toxicity rate was 3.6%, and there was no grade 5 toxicity. This trial, therefore, showed an excellent LC (97.6% at 3 years) with acceptable toxicity.[8] In our study, initially, 84% patients and 81% of total patients including central and peripheral tumors maintained the complete response at 3 months and 12 months follow-up. At 1 year follow-up, if we exclude the patients not reported. Overall response rate at first follow-up was 92.6% for combined primary metastasis and central, peripheral tumors. In our study, the grade 3 lung toxicity is 3.7% no other major toxicities reported.

Onishi et al. compared 5-year OS data for their SBRT-treated patients (72% for stage IA disease and 66% for stage IB disease) with the results of published surgical series (61–72% for stage IA disease and 40–50% for stage IB disease). The OS for SBRT in stage I patients, therefore, compares favorably with the rates following surgical resection.[9] In a metaanalysis based on 40 SBRT and 23 surgery studies for stage I NSCLC it was found that age-adjusted disease-free survival, OS in both the groups not differs significantly and also they differs in both the groups in terms of age and operability.[5] Our study also comprised of a good number of patients who willingly opted for SBRT as the mainstay of treatment instead of radical surgery and our results of complete response are quite encouraging.

The Dutch group treated both central and peripheral tumors (n = 206) with a fractionation regime of 60 Gy/3–8 fractions depending on tumor location. The LC was 97% at 1 year and the OS rate was 64% at 2 years.[10] Another German group also treated both peripheral and central tumors to a lower total dose of 24–45 Gy/3–5 fractions. Five-year LC data are reported at 83%, 3-year OS was 38%, and rib fracture was in 3.3%.[11] In our study, the prescription dose varied and with higher prescription dose 1 year control rate is more that is statistically significant (P = 0.036).

The ROSEL and STARS for stage I NSCLC patient's randomized to surgery or SABR.[12] Thirty-one of total 58 patients randomly assigned to receive SABR with a median follow-up of 40.2 months. Estimated OS of SABR group was 95% compare to surgery group where it was 79% (HR) 0·14 (95% CI 0.017–1.190) log-rank P = 0.037. Recurrence-free survival at 3 years was 86% (95% CI 74–100) in the SABR group and 80% (65–97) in the surgery group (HR 0.69 [95% CI 0.21–2.29], log-rank P = 0.54). In SABR group, three patients had (10%) chest wall pain, two (6%) dyspnea or cough, and one (3%) fatigue and rib fracture; whereas in the surgery group, one (4%) patient died of surgical complications and 12 (44%) patients had grades 3–4 treatment-related adverse events. In our study, although we have taken medically inoperable patients, no major toxicities reported. Our patients had a response rate of 92.5% after 3 months and 88% after 1 year with three patients not reported after treatment at 1 year follow-up. This result is quite encouraging as we have also included oligometastatic lung lesions and both central and peripheral tumors were treated with a relatively higher dose of radiation.

With the curative potential of SBRT in early lung tumors, it has also been tried in oligometastatic lung disease. In a study, SBRT done for 10–15 lesions and the median OS time from the time of treatment completion of the curatively treated patients was 23.4 months. The progression-free survival of the same group of patients was 25% and 16% at 12 and 24 months, respectively. Median survival time and progression-free survival both appear better than that achieved with standard care alone.[13] Our study showed 66.7% LC at first follow-up for the oligometastatic patients but one patient did not came for 1 year follow-up three patients developed distant metastasis for that they received palliative chemotherapy and 4 (57%) remained controlled after 1 year. There is limited data in India of lung SBRT. In a study, clinical results of eight patients with early lung carcinoma treated with SBRT were presented. The median duration of follow-up was 18 months (range 8–44 months). After 3 months, seven patients had a complete metabolic response and one patient had a partial metabolic response. Overall survival at 1.5 years was 87.5%. One patient had grade 2 pneumonitis.[14] In our study, we have included a larger number of patients and we have simulated with ANZAI respiratory motion management system. For the primary, 1 year LC is 87.5%, and for combined primary and metastatic patients, the rate is 81.8%. Yamashita et al. reported radiation pneumonitis (RP) grade P2 in seven of 25 patients after SBRT and reported that only the plan conformity index was significantly associated with the risk of RP.[15] Guckenberger et al. analyzed 59 patients treated with SBRT for primary NSCLC and pulmonary metastases and reported that mean dose to ipsilateral lung was the only factor significantly correlating with RP.[16] Borst et al. reported similar findings using mean lung dose calculated over total lung volume excluding gross tumor volume.[17] Our study had significantly lower grade 2 RP only 7.4%, and 1 (3.5%) patient reported grade 3 RP. That is probably due to our strict lung dose constraints. SBRT already considered treatment of choice in early stage medically inoperable lung cancer[18] our study comprising oligometastatic patients and medically operable patients who willingly opted for SBRT still showing reasonable good response with favorable toxicity profile.


 » Conclusion Top


There are a number of studies for both early lung cancer and patients with oligometastatic lung disease, however paucity of data from India on lung stereotaxy makes it an important study with reasonable follow-up period. This study also includes the clinical results of oligometastatic lung disease. This is one of the largest studies to report clinical results of lung stereotaxy done with ANZAI-based respiratory motion management. Encouraging clinical outcome with reasonable toxicity warrants further prospective studies. This is one of the largest published clinical experiences for lung stereotactic treatment in our country till date.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

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Timmerman R, Paulus R, Galvin J, Michalski J, Straube W, Bradley J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 2010;303:1070-6.  Back to cited text no. 8
    
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Onishi H, Shirato H, Nagata Y, Hiraoka M, Fujino M, Gomi K, et al. 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:S94-100.  Back to cited text no. 9
    
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Andratschke N, Zimmermann F, Boehm E, Schill S, Schoenknecht C, Thamm R, et al. Stereotactic radiotherapy of histologically proven inoperable stage I non-small cell lung cancer: Patterns of failure. Radiother Oncol 2011;101:245-9.  Back to cited text no. 11
    
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Chang JY, Senan S, Paul MA, Mehran RJ, Louie AV, Balter P, et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: A pooled analysis of two randomised trials. Lancet Oncol 2015;16:630-7.  Back to cited text no. 12
    
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Okunieff P, Petersen AL, Philip A, Milano MT, Katz AW, Boros L, et al. Stereotactic Body Radiation Therapy (SBRT) for lung metastases. Acta Oncol 2006;45:808-17.  Back to cited text no. 13
    
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Kundu S, Mathew A, Munshi A, Prabhash K, Pramesh CS, Agarwal JP, et al. Stereotactic body radiotherapy in early stage non-small cell lung cancer:First experience from an Indian centre. Indian J Cancer 2013;50:227-32.  Back to cited text no. 14
[PUBMED]  [Full text]  
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Yamashita H, Nakagawa K, Nakamura N, Koyanagi H, Tago M, Igaki H, et al. Exceptionally high incidence of symptomatic grade 2-5 radiation pneumonitis after stereotactic radiation therapy for lung tumors. Radiat Oncol 2007;2:21.  Back to cited text no. 15
    
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Guckenberger M, Baier K, Polat B, Richter A, Krieger T, Wilbert J, et al. Dose-response relationship for radiation-induced pneumonitis after pulmonary stereotactic body radiotherapy. Radiother Oncol 2010;97:65-70.  Back to cited text no. 16
    
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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