|Year : 2013 | Volume
| Issue : 3 | Page : 227-232
Stereotactic body radiotherapy in early stage non-small cell lung cancer: First experience from an Indian Centre
S Kundu1, A Mathew1, A Munshi1, K Prabhash2, CS Pramesh3, JP Agarwal1
1 Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Surgical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||23-Sep-2013|
J P Agarwal
Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Surgery is the standard of care for early stage (T1-2, N0, M0) non-small cell lung cancer. A considerable number of these patients are ineligible for surgery due to age and comorbidities. Hypo fractionated high-dose stereotactic body radiotherapy (SBRT) is being performed for these group of patients. There is paucity of literature regarding this novel technique from the Indian subcontinent. Aims and Objectives: We hereby report the dosimetry, response and outcome of our small cohort of early stage non-small cell lung cancer patients treated with SBRT. Materials and Methods: Between December 2007 and December 2010, 8 patients of early stage (T1-2N0M0) underwent SBRT at our centre. All the patients had undergone whole body PET-CT scan, MRI brain and pulmonary function test (PFT with DLCO). The SBRT schedules included 48 Gy in 6 fractions for peripherally located and 48 Gy in 8 fractions for centrally located tumors. Response and toxicity were assessed in 3 monthly follow up visits. Results: The median duration of follow up was 18 months (range 8-44 months). The median age of the patients was 70 years (range 63-82 years) and the median tumor diameter was 4 cm (range 2.8-5.0 cm). The mean PTV volume was 165 cc(range 127.3- 193.9 cc). The mean dose to the PTV was 99.5% (range 97.7- 102.1%). After 3 months, 7 patients had complete metabolic response and 1 patient had partial metabolic response. Overall survival at 1.5 years was 87.5%. One patient had grade 2 pneumonitis. No toxicities of grade 3 or higher were identified. Conclusion: SBRT for early stage NSCLC resulted in excellent local control with minimal toxicity and can be considered as a treatment option in properly selected patients.
Keywords: Early lung cancer, hypo fractionated radiotherapy, non-small cell lung cancer, Stereotactic body radiotherapy
|How to cite this article:|
Kundu S, Mathew A, Munshi A, Prabhash K, Pramesh C S, Agarwal J P. Stereotactic body radiotherapy in early stage non-small cell lung cancer: First experience from an Indian Centre. Indian J Cancer 2013;50:227-32
|How to cite this URL:|
Kundu S, Mathew A, Munshi A, Prabhash K, Pramesh C S, Agarwal J P. Stereotactic body radiotherapy in early stage non-small cell lung cancer: First experience from an Indian Centre. Indian J Cancer [serial online] 2013 [cited 2019 Aug 18];50:227-32. Available from: http://www.indianjcancer.com/text.asp?2013/50/3/227/118739
| » Introduction|| |
Carcinoma lung is the leading cause of cancer with 1.4 million new cases every year and causes 1.2 million deaths every year in both men and women worldwide. Lung cancer is the most common cancer among Indian males.  Surgery is accepted as standard of care for Stage I (T1 or T2, N0, M0) non-small cell lung cancer (NSCLC). Overall survival rates of all patients with T1 N0 disease have been reported to be 82% at 5 years and 74% at 10 years while those for patients with T2 N0 disease are 68% and 60% at 5 and 10 years respectively.  However, a significant number of Stage I non-small cell lung cancer patients become medically inoperable (poor lung and cardiac function, bleeding tendency or other comorbid conditions) or refuse surgery due to various reasons. Radical radiotherapy is the therapeutic alternative in such cases. The results of conventional fractionated radiotherapy (60 to 66 Gy in 1.8- or 2-Gy fractions) in patients with Stage I non-small cell lung cancer is unsatisfactory with reported 5 year local control and overall survival rates ranging from 30% to 50% and 10% to 30% respectively.  As early stage NSCLC is not inherently a systemic disease, significant emphasis should be given to local tumor obliteration in order to improve overall survival.
Hypo fractionated high-dose stereotactic body radiotherapy (SBRT) is a relatively novel technique that involves the use of a few sessions of precise, high dose radiotherapy. This technique is being performed in inoperable early stage lung cancer over the last decade. Various published literatures have documented 3 year local control of 80% to 92% and overall survival of 50% to 60% with the application of SBRT in early stage NSCLC. ,,
In India, lung cancer patients usually present at a late stage. Hence, high dose and high precision radical radiotherapy is not a treatment option in majority of the patients. Till date, there is no published data from the Indian subcontinent regarding the use and efficacy of SBRT in early stage NSCLC. In our centre, we started treating with SBRT (high dose conformal precision treatment) in early stage lung cancer since 2007. We report the preliminary dosimetry, response and outcome of our cohort of early stage NSCLC patients treated with SBRT.
| » Materials and Methods|| |
All patients being reported in the study were reviewed at multi-disciplinary thoracic cancer meetings that comprised of thoracic surgeons, radiologists, pathologists, radiation and medical oncologists. The patients who were deemed to be medically inoperable due to deranged pulmonary function or other comorbidities e.g. poor cardiac status and who had early stage NSCLC (T1-2N0M0) were then reviewed to be treated with stereotactic body radiotherapy (SBRT). The following selection criteria were observed while taking patients for SBRT 1) Patients had histologically proven squamous or adenocarcinoma of the lung 2) Patients with stage T1-2N0M0 non-small cell lung cancer (NSCLC) 3) KPS > 60% 4) Tumors away from "Proximal bronchial tree" (2 cm volume in all directions around carina, right and left main bronchi, upper lobe bronchi, lower lobe bronchi and right middle lobe bronchus). 5) Patients not operated due to their comorbidities or poor lung function.
Staging investigations included computed tomography (CT) scan of the thorax, magnetic resonance imaging (MRI) scan of the brain, whole body FDG PET-CT scan and hematological tests. All patients underwent pulmonary function test (PFT with DLCO) to ascertain the pulmonary status.
Between December 2007 and December 2010, 8 patients underwent SBRT for stage T1-2N0M0 medically inoperable NSCLC. All the tumors were located in upper lobes. 3 patients had tumors close to proximal bronchial zone (>2 cm but ≤3 cm). The patients' characteristics are detailed in [Table 1].
Patients were immobilized in an evacuated cushion (VacLoc, Civco Medical Solutions, Kalona, IA) and underwent treatment simulation in a CT-simulator. CT cuts were taken in the free breathing phase with 3 mm slice thickness from neck to mid-abdomen. The gross tumor volume (GTV) was contoured as it was visible in the CT images using the lung parenchymal window with width of = 1600 and level of = -600. The clinical target volume (CTV) was generated using a uniform margin of 0.7 cm across the GTV, both for squamous and adenocarcinoma. As we were treating all the patients in free breathing phase, the planning target volume was designed by growing 0.7 cm margin across the CTV to account for physiological organ motion and set-up errors. 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 non-opposing, coplanar/non-coplanar beams with the dosimetric mandate that at least 95% of the planning target volume (PTV) would be covered by 95% isodose surface. Plans were done by 3-dimensional conformal radiotherapy (3D-CRT). The dose fractionation used for peripheral tumors (away from the midline mediastinal structures) was 48 Gy over six fractions and those for the centrally located tumor was 48 Gy over eight fractions.
Treatment was given thrice weekly on alternate days and the median duration of treatment was 16 days (range 12-18 days). Before each fraction, treatment was verified using either electronic portal imaging device (EPID) or recently acquired on-line cone-beam CT (CBCT) with volumetric image guidance. The CBCT images were registered with the contours from the three-dimensional CT planning datasets and were used for patient localization. Pretreatment CBCT and patient positioning was repeated until the patient was confirmed to be within ±3 mm and 2° of the intended location.
All the patients were assessed by the radiation oncologist before the first fraction of treatment, then twice weekly and at the end of the treatment to assess the acute toxicities. All of them were given Mucaine gel (Oxetecaine, Aluminium hydroxide and Magnesium hydroxide) prophylactically for esophagitis during and 2 weeks after completion of radiation. The patients were then followed up at 6 weeks and every 3 months thereafter. At each visit, the patients underwent history, physical examination and toxicity and symptom assessment. Acute toxicities were graded according to RTOG Acute Radiation Morbidity Scoring Criteria and late toxicities were evaluated using RTOG/EORTC Late Radiation Morbidity Scoring Schema. A whole body FDG-PET scan was repeated after 3 months to evaluate the response to SBRT. Patient were followed up with chest CT scans every 6 monthly after treatment. Apart from these, patients who had any symptoms of local or regional failure at follow up were evaluated with whole body FDG-PET scan.
| » Results|| |
All the patients completed treatment without any interruption. The median duration of follow up is 18 months (range 8-44 months).
In all the patients, the dose prescription point was at the isocenter located at the centre of the planning target volume (PTV). The mean PTV volume was 165 cc (range 127.3- 193.9 cc). In all patients, 95% of PTV was at least covered by 95% isodose line. The mean dose to the PTV was 99.5% (range 97.7- 102.1%). In only 1 patient, the maximum dose to the PTV exceeded 107%. All the patients completed treatment with no modification required.
In our study, lung contours were limited to air-inflated lung parenchyma. PTV overlapping the normal lungs was subtracted using the Boolean intersection. The mean lung-PTV volume was 4271 cc (range 2740-6514 cc). The mean lung-PTV volume receiving 20 Gy (V20) was 8.35% (range 5.45-13.29%). The mean lung-PTV volume receiving 12 Gy (V12) was 15% (range 8.16-25.03%).
Only 2 patients had maximum point dose to the spinal cord in excess of 25 Gy. These patients had their tumors located in the paravetebral region, though the maximum dose to the spinal cord was well within the accepted normal range.
The mean dose to the esophagus was 5.5 Gy (range 0.6-14.5 Gy). The mean volume of heart was 474 cc (range 393.5-780.6 cc). 1 patient received maximum point dose to the heart in excess of 45 Gy (≈7.5 Gy/#). The dosimetries of 8 patients treated with SBRT are detailed in [Table 2].
|Table 2: Dosimetric data of 8 patients of primary NSCLC treated with SBRT in our study|
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At first follow up after 3 months of completion of treatment, whole body PET-CT scan was done in all patients. Complete metabolic response was noted in 7 out of 8 patients and 1 patient had partial metabolic response (residual disease). At a median 18 months 7 out of 8 patients were surviving. The patient, who had residual disease died due to cancer unrelated cause (myocardial infarction). No patient had local recurrence or distant metastases during the median follow up period.
During the course of radiation, 2 patients presented with grade 2 esophagitis manifested as difficulty in swallowing which was managed conservatively.
During the follow up period, only 1 patient presented with symptoms of cough and dyspnea after 8 months of completion of radiation. HRCT thorax and pulmonary function test was done in that patient and features were suggestive of restrictive lung disease. A diagnosis of radiation induced pneumonitis was made and was treated with steroids and it eventually resolved after 2 months.
No other toxicities occurred during radiation or in the median follow up period.
| » Discussion|| |
Our study has reiterated the safety and efficacy of using SBRT in NSCLC. The control rates and survival outcomes of our patients have been quite satisfactory and at par with the published literature [Table 3]. One of the reasons for this would have been the careful selection criteria we observed for patients being treated with this technique. We used a relatively soft hypo fractionation regimen of 48 Gray in 6-8 fractions as this was the start of the SBRT program in the hospital. Encouraged by the response in our patients, we now plan to escalate the dose further in suitable patients, besides also considering patients with tumors more close to the mediastinum.
|Table 3: Selected series of stereotactic body radiotherapy (SBRT) in primary non-small cell lung cancer (NSCLC)|
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While there have been reports of stereotactic radiosurgery (SRS) for small intracranial tumors from India, there are paucity of literature regarding extra cranial stereotaxy. The reasons could be issues related to fixation and internal motion and general apprehension of using such high doses of radiation. However, as shown in our report, meticulous attention to immobilization, planning and image guidance can lead to smooth delivery of SBRT.
The main modality of treatment for early stage non-small cell lung cancer (NSCLC) in our institute as well as in our country is surgery in suitable patients. But a small number of patients of early stage NSCLC present in our institute who are not suitable candidates for surgery due to comorbidities and are medically not fit for anesthesia or surgery. Radical radiotherapy is the attractive alternative in such cases. However, conventional radiotherapy has relatively dismal outcomes. A possible explanation for low local control rates with conventional radiotherapy is the low total dose which is insufficient for tumor control. In the case of NSCLC, there does seem to be a dose-response relationship.  A detailed theoretical analysis of radiotherapy response of NSCLC and rationale for dose escalation was provided by Mehta et al. According to them, higher biological effective dose (BED) delivered during a short period of time is necessary for better local control in lung cancer.  Various published studies have shown that stereotactic body radiotherapy (SBRT) is effective in such cases. ,,,,,, Larger doses per fraction are used and a moderate internal dose gradient achieved with the idea to ablate all tissues within the PTV and minimal destruction of adjacent normal tissues.
Another notable feature, in radiobiological terms is the relative failure of the linear-quadratic (LQ) model of radiation dose response. This model is widely accepted for the purpose of comparing the biological potency of different schedules of conventionally fractionated radiation therapy. The LQ model describes the probabilities of double-stand DNA breaks (DSB's) which is governed by a linear component that represents single-track damage, and a quadratic component which represents double-track damage causing DSB's. Although the LQ model has been widely validated for quantitative prediction of cell-kill in fractionated treatments with low dose per fraction (i.e. 1.8-2 Gy per fraction), its applicability in high dose per fraction treatments like SBRT is widely debated.  The nonlinear relationship between radiation dose and cytotoxic effect, whereby one or a few large individual doses of radiation therapy have substantially more cell-killing effect than the same dose of radiation given in smaller individual doses is the radiobiological basis of SBRT. In the absence of other suitable models, the LQ model remains widely used to make quantitative estimates of radio-biologic effectiveness for SBRT.  SBRT reduces the organ volume, and thus the absolute number of parallel functioning subunits destroyed by radiation. Because of an organ reserve, with redundancy of function, the undamaged functional subunits can maintain the organ function (as occurs in lung, liver and kidney) and/or regenerate new functional subunits (as occurs in liver). In our study, we have treated with 6 × 8 Gy for peripherally placed and 8 × 6 Gy for centrally located tumors. Assuming a a/β = 10 for early responding tissues, including tumors, the biological effective dose (BED) was 86.5 Gy for peripherally located and 76.4 Gy for centrally placed tumors [Figure 1] and [Figure 2].
|Figure 1: The beam arrangement and dosimetry of a centrally placed tumor treated with SBRT (Dose: 48 Gy in 8 fractions)|
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|Figure 2: The beam arrangement and dosimetry of a peripherally placed tumor treated with SBRT (Dose: 48 Gy in 6 fractions)|
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There is a large variation in dose and fractionation across the SBRT series published till date [Table 3]. Several studies have reported significantly improved local control and survival using SBRT in patients with stage I lung cancer. Onishi et al. reported the delivery of 60 Gy to the planning target volume (PTV) in 10 fractions (6 Gy/fraction) in patients with stage I NSCLC. The 2-year overall survival rate was 58% in all patients and 83% in those with operable disease.  Nagata et al. reported the delivery of 48 Gy to the isocenter in 4 fractions (12 Gy/fraction) in patients with early stage NSCLC. The local control rate was 98% and 5-year overall survival rate was 83% in patients with stage Ia disease and 72% in those with stage Ib disease. None of the patients had grade 3 or higher toxic effects.  In our cohort, complete response was seen in 7 patients after 3 months of completion of radiation and partial response was noted in 1 patient. This patient was treated with salvage chemotherapy. After the median follow up period, the overall survival was 87.5%. The single death was due to causes unrelated to cancer. This probably reflects the significant comorbidities associated with this elderly cohort. Our patients had also an acceptable rate of toxicity. Only 2 patients suffered from acute esophagitis during radiation. These patients had their lesions close to the body of the vertebra. Hence, esophagus received considerable amount of dose. Radiation pneumonitis was seen in only 1 patient. We made vigorous attempt to restrict V20 (lung-PTV) to ≤10%. When we did a retrospective audit of the patient's dosimetry, we saw his V20 (lung-PTV) to be 13.3% which can be further reduced by intensity modulated radiotherapy (IMRT).
There are also some limitations in our study. First and foremost is the small number of patients. Till date, there are no published reports from Indian subcontinent regarding the use of high dose per fraction in extra cranial sites including lung. That's why we are reporting our early experience in cohort of patients of early stage NSCLC who have been treated with SBRT. The total dose and dose per fraction given in our patients is also less. It is our preliminary experience and we are over cautious in execution of the plans to our patients. We are definitely planning for dose and dose per fraction escalation in our subsequent cohort of patients.
To summarize, Stereotactic body radiotherapy (SBRT) is the combination of multiple beam angles to achieve sharp dose gradients, high-precision localization, and high-dose per fraction in an extra cranial location. Fractionated SBRT is a bridge between the extremes of conventional fractionated radiotherapy and radiosurgery. Unlike radiosurgery, the main problem in extra cranial sites is inter- and - intra-fraction motion of the tumor and normal tissues. This is associated with higher chances of radiation to normal tissues. We have reported out initial experience with SBRT of lung tumors. Based on our encouraging response, we plan to escalate the dose further and take wider inclusion criteria for future treatments.
| » Conclusion|| |
SBRT is definitely an attractive treatment option for early stage non-small cell lung cancer patients who cannot undergo surgery with an excellent local control rate and minimal toxicity. Future researches should be directed towards dose and dose per fraction escalation in these set of patients. IMRT and 4D-CT planning should be incorporated to account for respiratory motion during treatment.
| » References|| |
|1.||Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 10. |
|2.||Martini N, Bains MS, Burt ME, Zakowski MF, McCormack P, Rusch VW, et al. Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 1995;109:120-9. |
|3.||Kaskowitz L, Graham MV, Emami B, Halverson KJ, Rush C. Radiation therapy alone for stage I non-small cell lung cancer. Int J Radiat Oncol Biol Phys 1993;27:517-23. |
|4.||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 (7 Suppl 3):S94-100. |
|5.||Baumann P, Nyman J, Lax I, Friesland S, Hoyer M, Rehn Ericsson S, et al. Factors important for efficacy of stereotactic body radiotherapy of medically inoperable stage I lung cancer. A retrospective analysis of patients treated in the Nordic countries. Acta Oncol 2006;45:787-95. |
|6.||Zimmermann FB, Geinitz H, Schill S, Thamm R, Nieder C, Schratzenstaller U, et al. Stereotactic hypo fractionated radiotherapy in stage I (T1-2 N0 M0) non-small-cell lung cancer (NSCLC). Acta Oncol 2006;45:796-801. |
|7.||Timmerman R, Papiez L, McGarry R, Likes L, DesRosiers C, Frost S, et al. Extra cranial stereotactic radioablation: Results of a phase I study in medically inoperable stage I non-small cell lung cancer. Chest 2003;124:1946-55. |
|8.||Timmerman R, McGarry R, Yiannoutsos C, Papiez L, Tudor K, DeLuca J, et al. 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;24:4833-9. |
|9.||Fakiris AJ, McGarry RC, Yiannoutsos CT, Papiez L, Williams M, Henderson MA, et al. Stereotactic body radiation therapy for early-stage non-small-cell lung carcinoma: Four-year results of a prospective phase II study. Int J Radiat Oncol Biol Phys 2009;75:677- 82. |
|10.||Olsen JR, Robinson CG, El Naqa I, Creach KM, Drzymala RE, Bloch C, et al. Dose-response for stereotactic body radiotherapy in early-stage non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2011;81:e299-303. [Epub ahead of print]. |
|11.||Taremi M, Hope A, Dahele M, Pearson S, Fung S, Purdie T, et al. Stereotactic body radiotherapy for medically inoperable lung cancer: Prospective, single-center study of 108 consecutive patients. Int J Radiat Oncol Biol Phys 2012;82:967-73. |
|12.||Qiao X, Tullgren O, Lax I, Sirzén F, Lewensohn R. The role of radiotherapy in treatment of stage I non-small cell lung cancer. Lung Cancer 2003;41:1-11. |
|13.||Mehta M, Scrimger R, Mackie R, Paliwal B, Chappell R, Fowler J. A new approach to dose escalation in non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2001;49:23-33. |
|14.||Kirkpatrick JP, Meyer JJ, Marks LB. The linear quadratic model is inappropriate to model high dose per fraction effects in radiosurgery. Semin Radiat Oncol 2008;18:240-43. |
|15.||Kavanagh BD, McGarry RC, Timmerman RD. Extra cranial radiosurgery stereotactic body radiation therapy) for oligometastases. Semin Radiat Oncol 2006;16:77-84. |
|16.||Onishi H, Kuriyama K, Komiyama T, Tanaka S, Sano N, Marino K, 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. |
|17.||Nagata Y, Takayama K, Matsuo Y, Norihisa Y, Mizowaki T, Sakamoto T, 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;63:1427-31. |
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]
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