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ORIGINAL ARTICLE
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Stereotactic body radiation therapy for medically inoperable early-stage lung cancer: Tata Memorial Hospital perspective and practice recommendations


1 Department of Radiation Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
2 Department of Medical Physics, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
3 Department of General Medicine, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
4 Department of Nuclear Medicine, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
5 Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India

Correspondence Address:
Jai Prakash Agarwal,
Department of Radiation Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_216_18

  Abstract 


BACKGROUND: Stereotactic body radiotherapy (SBRT) is now considered the standard treatment for medically inoperable early-stage non-small lung cell cancer (ES-NSCLC).
PURPOSE: There is a paucity of data related to outcomes with SBRT in ES-NSCLC from the developing countries. We report the early outcomes of ES-NSCLC patients treated with SBRT at our institute.
MATERIALS AND METHODS: Between 2007 and 2015, 40 consecutive patients with histologically proven ES-NSCLC were treated with SBRT. Median age was 71 years (range: 46–88 years) and median Charlson comorbidity index (CCI) was 3. The majority had stage I (70%) and 45% of the tumors were centrally located. The median tumor diameter was 3.8 cm (range: 2–7.6 cm). The mean gross tumor volume was 41 cc (range: 4–139 cc) and the mean planning target volume (PTV) was 141 cc (range: 27–251 cc). Varying dose and fraction (fr) sizes were used depending on tumor location, tumor size, and treatment period. The median biologically effective dose (BED) was 77 Gy10 (range: 77–105 Gy10) for the initial cohort (2007–2012) and 105 Gy10 (range: 77–132 Gy10) for the subsequent cohort (2013–2015).
RESULTS: After a median follow-up of 16 months (range: 3–99 months), the 2-year local control (LC), overall survival, and cancer-specific survival (CSS) rates were 94%, 41%, and 62%, respectively. The univariate and multivariate analysis determined CCI >3 and PTV >80.6 cc as significant predictors of worse OS and CSS (P < 0.01). The clinical stage, tumor location, BED, and treatment period (2007–2012 vs. 2013–2015) did not significantly predict any of the outcomes. The most common acute toxicities were skin erythema (10%), grade 1 esophagitis (8%), and exacerbation of previous chronic obstructive pulmonary disease (10%). Grade ≥2 late radiation pneumonitis was seen in 17.5%. One patient developed a rib fracture. No neurological or vascular complications were seen.
CONCLUSIONS: SBRT results in excellent local control (LC) and acceptable survival in medically inoperable ES-NSCLC with minimal adverse effects. Charlson comorbidity index and target volume are important prognostic factors and may aid in patient selection.


Keywords: Early stage, lung cancer, outcomes, stereotactic body radiotherapy



How to cite this URL:
Agarwal JP, Pilar A, Mummudi N, Gupta M, Laskar SG, Pathak RS, Tibdewal AR, Kinhikar R, Ghadi Y, Tandon S, Purandare N, Prabhash K, Patil V. Stereotactic body radiation therapy for medically inoperable early-stage lung cancer: Tata Memorial Hospital perspective and practice recommendations. Indian J Cancer [Epub ahead of print] [cited 2020 Jan 17]. Available from: http://www.indianjcancer.com/preprintarticle.asp?id=275194





  Background Top


Lung cancer is a leading cause of cancer-related deaths worldwide,[1] a finding partly attributed to the advanced stage at presentation in the majority of patients. Early-stage non-small cell lung cancers (ES-NSCLC) constitute only a small proportion of patients in current practice.[2],[3] However, with increasing awareness in the community, regarding the benefit of low-dose computed tomography (CT) screening, an increase in the incidence of ES-NSCLC is expected in the coming years.[4],[5] Surgical resection is currently the standard treatment for the operable ES-NSCLC, with 10-year survival rates ranging from 45% to 75%.[6] However, about 20% of the patients with stage I lung cancer do not undergo surgery [7] owing to poor lung, cardiac function, and perceived higher risk of mortality with surgery and frailty especially in elderly patients.[8],[9] With increasing life expectancy and cancer awareness, this number is expected to increase.

With encouraging results from long-term retrospective series, phase II and III studies stereotactic body radiotherapy (SBRT) is now considered as the standard treatment for the medically inoperable ES-NSCLC with 5-year local control (LC) rates ranging between 92% and 73%, and the overall survival (OS) from 50% to 70%.[10],[11],[12],[13],[14] Even in technically operable patients, OS with SBRT seems to be comparable to that of surgical resection.[14],[15],[16]

Despite consistent clinical outcomes, it is well known that dose fractionation heterogeneity and technical expertise may influence the outcome with SBRT.[17],[18],[19] There is a paucity of literature highlighting the experience and outcomes with SBRT in ES-NSCLC from the developing countries. In this report, we improve upon our previously published small cohort of patients [20] and report the long-term outcomes with SBRT in ES-NSCLC from the Indian subcontinent.


  Materials and Methods Top


Patient and tumor characteristics

Between December 2007 and December 2015, 40 patients with lung cancer were treated with SBRT at our institute. The decision for SBRT was taken in the multidisciplinary tumor board after a patient was deemed to be medically inoperable, either due to deranged lung and/or cardiac function or due to other comorbidities, and frailty of age that precluded surgical resection. The patients were eligible if they satisfied all the following criteria: (a) the tumor was histologically proven squamous or adenocarcinoma of the lung; (b) nonmetastatic on CT scan of thorax and abdomen or whole body FDG PET-CT scan; (c) Karnofsky performance status (KPS) >60%; (d) no prior radiation therapy to the site of SBRT; and (e) medically inoperable.

The patient and tumor-related characteristics are summarized in [Table 1]. The median age was 71 years (range: 46–88 years) and median KPS was 80 (range 60–90). Median, Charlson comorbidity index (CCI) was 3 (range: 0–6). Chronic obstructive pulmonary disease (COPD) was the most common cause of inoperability. In two patients, SBRT was performed on a second primary lung tumor, and in two patients, it was performed for recurrent disease after prior surgery.
Table 1: Patient, tumor, and treatment characteristics

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The median tumor diameter was 3.8 cm (range: 2.0–7.6 cm). Adenocarcinoma (47.5%) was the most common histology. Central and ultracentral tumors constituted 45% of the cohort (defined as, within 2 cm of the proximal bronchial tree, as per the RTOG 0813 study [21] and abutting the proximal bronchial tree or major blood vessels as per Chaudhuri et al.,[22] respectively). While majority of the tumors were stages I–II (90%), a small proportion of tumors (10%) was staged as IIIA due to their ultracentral location.

Treatment characteristics

[Table 1] also summarizes the treatment-related characteristics of the entire group. Target delineation, treatment planning, and treatment delivery have been described in detail previously.[20] The majority of the cases (68%) were planned using three-dimensional conformal radiotherapy (3DCRT) technique and rest (32%) with intensity modulated radiotherapy (IMRT) technique. Varying dose and fraction sizes were used depending on tumor location, tumor size, and the treatment year. For the first 20 patients (treatment year group: 2007–2012), commonly used dose fractionation for peripheral tumors was 48 Gy/6 fr (8 Gy/fr) and for central tumors was 48 Gy/8fr (6Gy/fr). The dose was escalated for small peripheral tumors; they received 48 Gy/4 fr (12 Gy/fr). The dose fractionation was revised after successful initial experience with SBRT treatment planning and delivery. There was also a growing body of evidence in support of dose escalation to ≥100 Gy10 biologically effective dose (BED), for better LC. Therefore, subsequently (treatment year group: 2013–2015), peripheral tumors received 60 Gy/5 fr (12 Gy/fr), and central tumors received 60 Gy/8 fr (7.5 Gy/fr). The median (BED Gy10) was 77 Gy (range: 77–105 Gy) for the first 20 patients, whereas it increased to 105 Gy (range: 77–132 Gy) for subsequent patients. Treatment was delivered thrice a week on alternate days and the median duration of treatment was 14 days (range: 9–22 days).

Follow-up and statistical analysis

After completion of SBRT, all patients underwent a whole-body FDG PET-CT scan at 8–10 weeks, for response assessment. Subsequently, they were followed up at every 3 months with clinical examination and a cross-sectional imaging every 6–9 months. The treatment response [Figure 1] was measured using response evaluation criteria in solid tumors (RECIST, version 1.1[23]), considering the best response at any time from SBRT.
Figure 1: Shows axial images of pre-SBRT and post-SBRT FDG PET-CT scan, showing complete metabolic as well as a morphological response in one of the patients who underwent SBRT

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The primary endpoint of this study was 2-year LC and the secondary endpoints were treatment-related acute and late toxicities, progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). Local failure was defined as tumor progression at the irradiated site (within 2 cm of the gross tumor volume [GTV]). PFS was defined by disease progression at any site (local, regional, or distant). CSS was defined as death due to lung cancer. Patients who died due to other causes were censored. All the survival endpoints were calculated from the date of treatment completion and were censored at death or the last follow-up in case they did not experience the event. Lung toxicity was graded according to the radiation therapy oncology group (RTOG) acute radiation toxicity score (for events occurring within 90 days from the treatment completion) and Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) late radiation toxicity score (for events occurring beyond 90 days).

LC, PFS, CSS, and OS were estimated using the Kaplan–Meier method and the log-rank test was used to test the differences between the groups. Receiver operating characteristic curves were used to identify cut-off to test the prognostic significance of gross tumor volume (GTV) and planning target volume (PTV). The multiple-covariate analysis was performed using the Cox's proportional hazards model. All hazard ratios (HR) for Cox proportional hazards regression models were reported at the 95% confidence level. All statistical analysis was performed using SPSS, version 21.0.0 (SPSS Inc., Chicago, IL).


  Results Top


After a median follow-up of 16 months (range: 3–99 months), 15 patients had progressed. Various sites of relapse were local failure (n = 1), regional nodal failure (n = 2), distant failure (n = 9), and combination of distant failure with local (n = 1) or nodal (n = 2). Distant failure constituted the main site of relapse, seen in 12/15 (80%) patients. Two patients with isolated nodal failures had mediastinal nodes on pretreatment PET-CT also; however, these were considered to be infective etiology and may not represent true failures or early stage disease.

Twenty-nine patients had died, 12 due to disease progression and 17 from other causes (cardiac or pulmonary causes), at the time of last follow-up.

Survival

The 2-year LC, PFS, OS, and CSS rates were 94%, 55%, 41%, and 62%, respectively. The median survival was 19 months (CI: 13.6–24.3 months). The 3-year OS and CSS were 29% and 55%, respectively. [Figure 2] shows Kaplan–Meier curves for LC and OS, respectively.
Figure 2: Kaplan–Meier curves for local control and overall survival

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Prognostic factors affecting OS and CSS are summarized in [Table 2]. None of the factors significantly predicted for LC. On univariate analysis, CCI >3, PTV >80.6 cc, and histology (non-adeno and squamous) were predictors of poor OS [Table 2] and [Figure 3], while only CCI >3 and histology predicted a worse CSS (P = 0.011). Other factors, such as clinical stage, tumor location, BED (Gy10), and treatment year group (2007–2012 vs. 2013–2015) were not statistically significant. On multivariate analysis, CCI >3 and PTV >80.6 remained as independent predictors of overall survival and CSS [Table 3].
Table 2: Univariate analysis of prognostic factors influencing outcomes

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Figure 3: The impact of Charlson comorbidity index (CCI) and planning target volume (PTV) on overall survival, CCI >3, and PTV >80.6 cc were significantly associated with worse overall survival

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Table 3: Multivariate analysis of prognostic factors (*) for overall survival

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Toxicity

SBRT was very well tolerated in most patients. Most common acute toxicities were skin erythema (10%), Grade I esophagitis (8%), and exacerbation of previous COPD (10%). All of these acute toxicities were transient and reversed with conservative treatment. Grade 2 or more radiation pneumonitis, seen in 7 (17.5%) patients was the most common late toxicity. Only one patient developed a grade 3 radiation pneumonitis requiring more aggressive measures. One patient developed rib fracture after SBRT. Radiation pneumonitis did not correlate with the dose–volume parameters. Mean V20 (percentage of the lung volume receiving >20 Gy) was 10.4% in patients with Grade 0–1 pneumonitis and 14.2% in patients with Grade 2 or more pneumonitis (P = 0.319). Mean V5 (percentage of the lung volume receiving >20 Gy) was 29.2% in patients with Grade 0–1 pneumonitis and 37.6% in patients with Grade 2 or more pneumonitis (P = 0.254). Location of the primary (peripheral vs. central) did not significantly affect the incidence of radiation pneumonitis as well (P = 0.567). Brachial plexopathy or vascular complications were not seen in our patient population.


  Discussion Top


For medically inoperable ES-NSCLC, SBRT has consistently demonstrated excellent LC [10],[11],[12],[13] with minimal adverse effects on quality of life [24] or pulmonary function [25] and is considered as the treatment of choice for these patients. Currently, it is under investigation for operable early-stage lung cancer.[15] This study demonstrates excellent LC (2-year LC: 94%) and acceptable OS (2-year OS: 41%) with SBRT, in a cohort of elderly and frail (median-71 years), patients with higher CCI (median CCI: 3), and advanced stage (30% stages II–IIIA). One-third of our patients (35%) had a CCI >3, which is a known predictor of poor survival, evident from the fact that 2-year OS was 42%, whereas the 2-year CSS was 62%. An advanced stage and higher CCI (>3) in more than one-third of our patients explains the lower OS in the current series, compared with various other SBRT series [Table 4].
Table 4: Selected series of stereotactic body radiotherapy (SBRT) in non-small cell lung cancer (NSCLC)

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Sixty percent of the deaths in our cohort was not due to cancer but due to worsening of pre-existing cardiac or respiratory diseases. The relatively high noncancer mortality may be due to higher CCI of patients as seen in other prospective SBRT series.[12] The CCI ≤3 demonstrated a 2-year OS of 60% (median survival: 34 months), whereas CCI >3 had a dismal survival rate of just about 9% (median survival: 11 months). Kopek et al.[28] in a series of 88 patients of ES-NSCLC treated with SBRT had demonstrated that CCI was a significant predictor of OS, patients with an age-adjusted CCI score of ≤3 had a median survival of 41 months versus only 11 months for those scoring ≥6. Klement et al.[29] attempted to determine, whether death within a short interval (<6 months) can be predicted reliably to select a subgroup of patients, which may not have a benefit from SBRT; however, overall accuracy of their model was low and they concluded that SBRT should be offered to all patients irrespective of their comorbidities. Larger PTV (>80.6 cc) also predicted a worse OS and CSS in our study. Our data confirm some of the previous reports, which have shown better outcomes for smaller tumors. In a prospective trial by Ricardi et al., the target volume was the only independent predictor of OS, where smaller volumes were associated with better outcomes. In another study by Nyman et al.,[30] a smaller PTV (<71 cc) showed a trend for improved survival (P = 0.04). The CCI and target volumes may aid in excluding patients that may not benefit from SBRT especially in resource-limited settings in the developing countries.

Distant metastases were the most common pattern of failure and were seen in 12 out of 15 (80%) relapsed patients. Isolated nodal relapses occurred in only 2 out of 60 patients. These failure patterns are in agreement with various published series of SBRT.[12],[31],[32] The high rate of systemic metastases warrants further research regarding the institution of systemic treatment. In a retrospective review of 245 patients by Onishi et al.,[33] the 5-year LC was significantly improved with BED >100 Gy10 (92% vs. 73.6%; P < 0.001). Contrary to their experience, in our study, there was no significant detriment in LC in patients treated with BED <100 Gy10, which could be attributed to a small number of patients in our series. Similarly, there was no difference in LC or OS based on tumor location in spite of the lower doses prescribed to the central tumors. A recent systematic review [34] of 563 patients reported a LC rate of >85% with prescription dose (BED10) ≥100 Gy and Grade 3–4 toxicities in <9% for patients with central lung tumors. “Risk-adapted” fractionation strategy to deliver ≥100 Gy BED in a higher number of fractions, appears to be a safe and effective treatment strategy for central and ultracentral tumors.[35],[36]

SBRT was well tolerated in most patients with acceptable toxicity. Grade 3 radiation pneumonitis was seen in 1/40 (2.5%) patients and is consistent with published rates of 4%–8% across the literature.[36] Lung toxicity could not be correlated with dose–volume parameters or location of the primary. Complications of fatal bleeding and brachial plexopathy are rare in the current era of risk-adaptive SBRT and our series also did not demonstrate any such complications.

Though our study was simple, it had a few limitations, such as the retrospective nature of the data, smaller sample size, and heterogeneity in dose fractionation. Benefit from dose escalation in the patients treated from 2013 to 2015 was not apparent in our cohort of patients and could be due to limited sample size and the limited follow-up of these patients. The strengths of our study were that all the patients had biopsy-proven lung cancer unlike a few series in literature where many patients were treated based on imaging suspicion alone.[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37] Our study is among the largest reported Indian series with a reasonable follow-up.


  Conclusions Top


SBRT results in excellent LC and acceptable survival in medically inoperable ES-NSCLC with minimal complications. The Charlson comorbidity index and planning target volume are important prognostic determinants and may aid in patient selection. Differences related to dose fractionation did not seem to affect the outcome in this small cohort.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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[PUBMED]  [Full text]  
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

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



 

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