Systematic review
Outcomes of stereotactic ablative radiotherapy for central lung tumours:
A systematic review
Sashendra Senthi
⇑, Cornelis J.A. Haasbeek, Ben J. Slotman, Suresh Senan
Department of Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlandsa r t i c l e
i n f o
Article history:
Received 2 November 2012
Received in revised form 9 January 2013 Accepted 14 January 2013
Available online 22 February 2013 Keywords: Lung cancer Stereotactic Inoperable Central Toxicity Mortality
a b s t r a c t
Background and purpose:Stereotactic ablative radiotherapy (SABR) has improved the survival for medi-cally inoperable patients with peripheral early-stage non-small cell lung cancer (NSCLC). We performed a systematic review of outcomes for central lung tumours.
Material and methods: The systematic review was performed following PRISMA guidelines. Survival out-comes were evaluated for central early-stage NSCLC. Local control and toxicity outout-comes were evaluated for any centrally-located lung tumour.
Results: Twenty publications met the inclusion criteria, reporting outcomes for 563 central lung tumours, including 315 patients with early-stage NSCLC. There was heterogeneity in the planning, prescribing and delivery of SABR and the common toxicity criteria used to define toxicities (versions 2.0–4.0). Tumour location (central versus peripheral) did not impact overall survival. Local control rates wereP85% when the prescribed biologically equivalent tumour dose wasP100 Gy. Treatment-related mortality was 2.7% overall, and 1.0% when the biologically equivalent normal tissue dose was6210 Gy. Grade 3 or 4 toxic-ities may be more common following SABR for central tumours, but occurred in less than 9% of patients.
Conclusions: Post-SABR survival for early-stage NSCLC is not affected by tumour location. SABR achieves high local control with limited toxicity when appropriate fractionation schedules are used for central tumours.
Ó2013 Elsevier Ireland Ltd.
Radiotherapy and Oncology 106 (2013) 276–282
Anatomic surgical resection is the treatment of choice for pa-tients diagnosed with early-stage non-small cell lung cancer (NSCLC)[1,2]. For tumours that are centrally located, more exten-sive surgical procedures are required due to tumour invasion into the major bronchi and/or vessels[3,4], which is associated with a higher mortality and morbidity[5]. Thus, the treatment of central tumours represents a high-risk clinical scenario in which the risks associated with surgery have been deemed acceptable.
As the global population ages, the proportion of elderly lung cancer patients and those with comorbidities will also increase
[6–9]. For the unfit elderly with peripheral early-stage NSCLC, ste-reotactic ablative radiotherapy (SABR) is considered the preferred treatment[2], offering improved survival and quality of life over conventional radiotherapy[10,11]. In an early SABR trial, fractions of 20–22 Gy, delivering total doses of 60–66 Gy to central tumours were associated with a greater than 10-fold increased risk of high-grade toxicity or death[12]. This led to an ongoing Radiation Ther-apy Oncology Group (RTOG) phase I/II trial (0813) specifically for central tumours, to determine the maximum tolerated dose which
can be delivered in five fractions[13]. Similarly, it has lead others to suggest that the risks associated with SABR for central tumours may be prohibitive and high-dose accelerated radiotherapy be the subject of further research[14].
As reports from Japanese and Dutch investigators have reported favourable outcomes in early-stage tumours using daily fractions of 6.0–7.5 Gy to total doses of 48–60 Gy[15,16], many centres have continued to use SABR for central tumours. We performed a sys-tematic review of published literature on the clinical outcomes of SABR for central lung tumours.
Methods
A systematic review was performed according to the PRISMA guidelines [17]. We searched for English-language papers pub-lished from January 2000 to August 2012. The inclusion criteria were:
1. Studies reporting clinical outcomes following SABR for primary NSCLC or metastatic lung tumours and,
2. Studies specifically reporting clinical outcomes for centrally located tumours.
0167-8140Ó2013 Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.radonc.2013.01.004
⇑Corresponding author. Address: Department of Radiation Oncology, VU Uni-versity Medical Center, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands.
E-mail address:[email protected](S. Senthi).
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Studies were excluded if:
1. They were review articles or case reports,
2. They were not the most recently published outcomes, in instances of multiple publications from the same study cohort. Using PubMed, the search was completed in August 2012. The search strategy was (sabr[tw] OR sbrt[tw] OR srt[tw] OR stereotac-tic[tw]) AND lung[tw] AND (central[tw] or centrally[tw]), which identified 86 studies. Two clinicians reviewed these and the refer-ence lists of selected articles to determine which were suitable for inclusion. Survival outcomes were restricted to patients with cen-tral early-stage NSCLC[18]. Local control and toxicity outcomes in-cluded those reported for any central tumour receiving SABR. Toxicity outcomes were included when graded using the Common Toxicity Criteria (CTC) protocol version in place at the time. The prescribed tumour doses were converted into a biologically equiv-alent dose (BED) to enable comparison between studies, acknowl-edging the limitations of this approach [19,20]. The BED was calculated using the assumption that tumour and normal tissue al-pha/beta ratios were 10 Gy (BED10) and 3 Gy (BED3), respectively
[21]. BED10 calculations were made using the dose delivered to
at least 95% of the planning target volume (PTV). BED3calculations
were made using the prescribed dose schedules and the maximum organ at risk doses received when studies provided this detail. BED calculations did not take into account tumour doubling time or the length of treatment.
Results
A total of 20 studies were found suitable for inclusion. Four of these were prospective [22–25], including two Phase II studies
[23,24]. Seven studies reported clinical outcomes for NSCLC to-gether with metastatic tumours [26–32]and one reported out-comes restricted to central early-stage NSCLC alone [32]. From these 20 studies, a total of 563 central tumours (including 315 early-stage NSCLC patients) received SABR. The radiotherapy de-tails of these studies are summarized inTable 1. In these studies toxicities were described using CTC versions 2.0, 3.0 and 4.0. Survival
The only prospective survival outcomes (n= 22) specific to cen-tral early-stage NSCLC were reported by Fakiris et al.[24], updating the initial report from Timmerman et al.[12]. The median overall survival was 24 months (95% CI 18–42), which was not statistically different (p= 0.697) from that of peripheral tumours. Haasbeek et al. reporting outcomes from the largest retrospective cohort, found the 3-year overall survival for central (n= 63) and peripheral (n= 445) early-stage NSCLC was statistically no different, 64% vs. 51% (p= 0.09) respectively[32]. Bradley et al. reported a 2-year overall survival of 75% for all early stage NSCLC and found central (vs. peripheral) location did not impact survival on both univariate (p= 0.429) and multivariate analyses[33]. Similarly, Janssen et al. found fractionation schedule, which depended on tumour location alone, did not impact survival on both univariate and multivariate analyses[31], while Andratschke et al. found tumour location did not impact survival on univariate analysis for histologically proven early-stage NSCLC (p= 0.653)[34]. Cause-specific survivals for cen-tral early-stage NSCLC have been reported to be greater than 80% at 2–3 years[30,33,35].Table 2details all reported survival outcomes. Local control
After a median follow-up of 16 months, a prospective trial by Bral et al. found that tumour location did not impact recurrence,
with the crude local control for central tumours being 94% (1/17)
[23]. Retrospective studies have reported similar local control out-comes, with 2 and 3-year rates typically exceeding 85%[23,26,31– 33,36–38], as shown inTable 2. However, six studies have reported poorer local control, of between 60–76%[27,29,30,34,35]. In two of these, SABR was prescribed to the isocentre, leading to a signifi-cantly lower peripheral tumour doses being delivered[29,35]. In the third study, 23% (12/53) of patients had stage II, III or recurrent stage III disease and 10% (6/63) of lesions had SABR delivered as a radiotherapy boost following conventional radiotherapy [27]. Although stage-specific local control outcomes were not reported, in the latter study the 2-year survival for non-stage I patients was 12%. In the fourth study reporting poorer local control, only 64% (37/58) of tumours had planning target volume coverage above 95% as under-dosage was permitted to meet normal organ con-straints [30]. Additionally, in this study multiple fractionation schedules were utilized, and local control was 85% when the BED10 was P100 Gy and 60% when the BED10 was <100 Gy. In
the last two studies, the modal prescribed doses were 35 Gy[34]
and 40 Gy[27]in five fractions, resulting in a respective BED10of
60 and 72 Gy.
The importance of maintaining a BED10of at least 100 Gy to the
tumour periphery was evident from a number of studies. Using a schedule of five fractions, Olsen et al. reported a 100% 2-year local control using a total dose of 50 Gy (BED10100 Gy) and 50% using
45 Gy (BED10 86 Gy) [38]. Here, fractionation schedule was the
only factor found to impact local control on multivariate analysis (p= 0.019). Similarly, Rowe et al. reported a 2-year local control of 94% with a BED10P100 Gy and 80% when <100 Gy, (p= 0.02)
[37]. Using a SABR schedule of four fractions, Chang et al. reported a crude local control of 100% with a total dose of 50 Gy (BED10113)
vs. 57% using 40 Gy (BED1080 Gy)[26]. Two additional studies in
which central and peripheral tumours were analysed together, also found that a BED10above 100 Gy improved local control[15,25].
The post-SABR regional and distant control rates specifically for central early-stage NSCLC have been infrequently reported. Haasbeek et al. reported 2-year regional and distant control rates of 91% and 73%, respectively, which were no different from peripheral tumours treated by the authors using SABR over the same period, 86% (p= 0.47) and 75% (p= 0.72), respectively
[32]. Two additional studies reported a crude distant recurrence rate of approximately 15%, which was the predominant pattern of recurrence [26,36].
Treatment-related mortality
In a prospective study utilizing a SABR fractionation with a BED3
of 460 Gy, Fakiris et al. reported 18% (4/22) of patients with central tumours had potential treatment-related deaths[24]. Although an independent committee defined these, they included infective pneumonia and haemoptysis in the setting of local recurrence. Bral et al. reported the only other prospectively defined treatment-re-lated death, a case of fatal haemoptysis after stent insertion for bronchial stricture[23]. Milano et al. reported 8.7% (4/46) mortal-ity rate using SABR for central non-stage I NSCLC and no mortali-ties treating central stage I tumours [27]. It must be noted that in three (75%) of these cases, the authors could not exclude respi-ratory infection as the cause of death. Onimura et al. and Unger et al. each reported one treatment-related death, which were caused by an oesophageal ulcer (BED3154 Gy) and bronchial
fis-tula (BED3209 Gy) respectively [15,28]. The latter two cases are
the only cases of treatment-related death observed when the pre-scribed BED3was6210 Gy.
Table 3details all treatment-related mortality reported for cen-trally located tumours. The overall treatment-related mortality rate from central tumours receiving SABR was 2.8% (16/563). For S. Senthi et al. / Radiotherapy and Oncology 106 (2013) 276–282 277
Table 1
Baseline radiotherapy details.
Author (year) Simulation Target volumes Image guidance Prescription Heterogeneity
correction
Total dose gray/ fractions Onimura[15](2003) Inspiration, expiration, standard
CT
ITV + PBM = PTV Orthogonal x-rays Isocentre, PTV got 80% No 48/8
Xia[22](2006) Slow CT and fluoroscopy GTV + 10 mm = PTV Not reported 50% Isodose covering 95% PTV No 50/10
Chang[26](2008) 4-Dimentional CT ITV + 8 mm = CTV + 3 mm = PTV CT-on-rails and orthogonal X-ray 75–90% Isodose covering PTV Yes 50/4
Song[36](2009) Standard CT with fluoroscopy GTV + PBM = PTV Conebeam CT 85% Isodose covering 95% PTV No 48/4a
Milano[27](2009) Expiratory breath hold CT GTV + PBM = PTV Stereoscopic X-ray Isocentre,PTV got 80% No 50/5a
Fakiris[24](2009) Standard CT GTV = CTV + PBM = PTV No reported 80% Isodose covering 95% PTV No 60/3
Guckenberger[40] (2009)
4-Dimentional CT ITV + 5 mm = PTV Conebeam CT 65% Isodose covering PTV Yes 48/8
Unger[28](2010) Inhalation breath hold. fiducials GTV = PTV Respiratory tracking fiducial
markers
70–80% Isodose covering 95% PTV
Yes 40/5
Oshiro[29](2010) Expiratory breath hold CT GTV + PBM = PTV Gated X-ray Not reported, likely to isocentre No 50/5a
Baba[35](2010) Inspiration, expiration, standard CT
ITV + PBM = PTV Not reported Isocentre, 95% of PTV got 80% Yes 50/4
Bradley[33](2010) 4-Dimentional CT ITV + PBM = PTV Not reported 75–85% Isodose covering 95%
PTV
Yesb 45/5
Andratschke[34](2011) Multiple standard and slow CT ITV + PBM = PTV Orthogonal x-rays 60% Isodose covering 100% PTV Yes 35/5a
Haasbeek[32](2011) 4-Dimentional CT ITV + 3 mm = PTV Orthogonal X-ray 80% Isodose covering 99% PTV No 60/8
Bral[23](2011) Planning PET CT and fluoroscopy ITV + 5 mm = PTV Stereoscopic X-ray 95% Isodose covering 95% PTV No 60/4
Olsen[38](2011) 4-Dimentional CT ITV + PBM = PTV Conebeam CT 60–90% Isodose covering 95%
PTV
Yes 50/5a
Stauder[39](2011) 4-Dimentional CT ITV + PBM = PTV Conebeam CT 100% Isodose covering 95% PTV Yesb 48/4
Rowe[37](2012) 4-Dimentional CT ITV + 7 mm = PTV Conebeam CT 100% Isodose covering 95% PTV Yes 50/4a
Nuyttens[30](2012) Standard CT GTV + 5 mm = PTV Respiratory tracking fiducial
markers
75–90% Isodose covering 95% PTV
Yes 60/5a
Taremi[25](2012) 4-Dimentional CT ITV + 5 mm = PTV Conebeam CT 100% Covered 95% of PTV Yesb
60/8
Janssen[31](2012) 4-Dimentional CT ITV + 3 mm = CTV + PBM = PTV Conebeam CT 80% Isodose covering PTV No 48/8
Population based margins (PBM) utilized to account for tumour motion were typically 5 mm radially and 8–10 mm longitudinally. aModal dose fractionation schedule shown when multiple schedules were utilized.
b
Heterogeneity correction not utilized in all treatments.
SABR
for
central
lung
tumours receiving a BED3P210 Gy the rate of treatment-related
death was 3.6% (13/359), while it was 1.0% (2/204) when the SABR schedule had a BED3<210 Gy.
The median duration of follow-up in all 20 studies was 19 months (range 10–50). Of the studies reporting treatment-re-lated death, the median time to death following SABR was 7.5 months (range 5–12.5)[15,24,27,37,39].
Grade 3 or 4 toxicity
Bral et al. reported a 2-year grade 3 or higher lung toxicity free survival of 60% for central tumours in a prospective trial, with a trend towards statistical significance compared to peripheral le-sions (80%,p= 0.06)[23]. Baba et al. observed a similar trend of higher pulmonary toxicity treating central tumours, with the rate of grade 2–3 pneumonitis being 25% vs. 11% for peripheral tumours (p= 0.11)[35]. A detailed description of all grade 3 or 4 toxicities, and the CTC protocol version used to define them are shown in Ta-ble 3. Amongst the toxicities observed, respiratory toxicity includ-ing pneumonitis, pneumonia, dyspnoea (typically increased oxygen requirement in patients already using oxygen) and bron-chial stricture were the most prevalent. There was one reported case of grade 3 esophagitis, rib fracture and pericarditis each
[27,32,40].
Using a wide range of fractionation schemes, Song et al. re-ported that 33% (3/9) of patients with central tumours developed high-grade bronchial stricture post-SABR and that 89% (8/9) devel-oped any stricture[36]. Patients who developed high-grade stric-tures in their report were prescribed 40–48 Gy delivered in four fractions (BED3173–240 Gy). Bral et al. and Nuyttens et al.
ob-served high-grade toxicity in 23.5% (4/17) and 17.2% (10/58), respectively [23,30]. These studies utilized SABR fractionation schemes with a BED3of 360 Gy and 300 Gy (modal). However, all
ten high-grade toxicities seen by Nuyttens et al. were grade 3 pneumonitis, with the authors reporting that seven of these had probable co-existing infections. Three studies, treating 47 central tumours, reported no grade 3 or 4 toxicity when using a BED3
rang-ing between 133–144 Gy[15,22,31].
After excluding studies in which toxicity outcomes for both cen-tral and peripheral tumours or grade 2 and 3 toxicity were not re-ported separately, grade 3 or 4 toxicity occurred in 8.6% (36/418) of central tumours treated with SABR.
Discussion
Although surgery offers the best chance of survival for early-stage NSCLC, patients with a clinical diagnosis of early-stage I NSCLC have a 5-year survival of only 43–50%[1,2]. Surgery is less likely to be recommended for the elderly and those with comorbidities
[9,41]. For these patients, increasing access to SABR has improved population-based survival [41–44]. Due to concerns about the safety of SABR for central tumours, we performed a systematic re-view, which identified 20 studies reporting clinical outcomes for 563 central tumours receiving SABR. Our main findings were that the overall survival reported following SABR for both central and peripheral early-stage NSCLC was similar, and the risk of high-grade toxicity post-SABR for central lung tumours was less than 9%. Moreover, when utilizing appropriate fractionation schedules in which the BED10P100 Gy and BED36210 Gy, local control
ex-ceeded 85% and the risk of treatment-related mortality was less than 1%.
Although pneumonectomy was traditionally performed for cen-tral lung tumours, the use of broncho-angioplastic procedures has reduced pneumonectomy rates for stage I NSCLC to between 5% and 11%[45–47]. However, irrespective of the type of surgery per-formed for central stage I NSCLC, perioperative mortality and sur-gical complication rates are approximately 4.5% and 25%, respectively, as shown inTable 4 [5]. In addition, patients undergo-ing broncho-angioplasty have an 8% risk of stump/anastamotic complication, which includes bronchial necrosis, dehiscence, stric-ture and fistula formation[5]. These findings indicate that the risk of mortality and morbidity in treating central tumours can be con-siderable, even when patients are fit enough to undergo surgery. Despite this, surgery is still recommended whenever possible for early stage NSCLC [1,2]. A randomized trial comparing sublobar resection, with or without brachytherapy, for high-risk operable patients reported 33% of patients in either trial arm had grade 3 or worse toxicity[48]. This suggests that our findings of a 9% risk of high-grade toxicity, and less than 1% risk of treatment-related mortality following SABR for central tumours in elderly patients with comorbidities, should not preclude the continued evaluation of SABR in this patient group.
Despite the potential inaccuracies inherent to the linear-quadratic model to estimate the biologic tumour and normal tissue effects with SABR fractionation schedules[19,20], multiple studies have found a correlation between clinical outcomes and the BED
Table 2
Survival and local control.
Author (year) BED10 Overall survival Cause-specific survival Local control
Chang[26](2008) 113 – Crude rate 89%
Song[36](2009) 106 50% at 2 years – 89% at 2 years
Milano[27](2009) 100 72% at 2 years – 73% at 2 years
Fakiris[24](2009) 180 Median 24 months – –
Unger[28](2010) 72 – – 63% at 1 year
Oshiro[29](2010) 80 – – 60% at 2 years
Baba[35](2010) 90 72% at 3 years 82% at 3 years 66% at 3 years
Bradley[32](2010) 86 75% at 2 yearsa,b
90% at 2 yearsa,b
86% at 2 years
Andratschke[34](2011) 60 29% at 3 years – 64% at 3 years
Haasbeek[32](2011) 105 64% at 3 years – 93% at 3 years
Bral[23](2011) 150 – – Crude rate 94%
Olsen[38](2011) 100 – – 100% at 2 yearsc
Rowe[37](2012) 114 – – 94% at 2 years
Nuyttens[30](2012) 132 53% at 3 yearsb
3 years 80% 76% at 2 years
Janssen[31](2012) 77 – – 87% at 1 yeara
Biologically equivalent tumour dose (BED10). Survival outcomes for central early-stage NSCLC. Local control for all central lung tumours receiving SABR. a Includes central and peripheral tumours with multivariate analysis showing location had no impact on outcome.
b
Outcome not reported specifically but estimated from Kaplan–Meier curve. c
Local control at 2-years using 45 and 50 Gy in five fractions was 50% and 100%, respectively (p= 0.006).
Table 3
Treatment-related mortality and severe toxicity. Author (year published) Follow-up (months) Central tumours (n) Central early-stage NSCLC (n) Central tumours eligible for RTOG 0813
BED3
(Gy)
GTV size (range)e
Grade 5 toxicity (clinical details if provided) Grade 3–4 toxicity (clinical details if provided) Grading system Onimura[15]
(2003)
18 9a,b Not specified Nof 144 Max < 60 mm 1Oesophageal ulcer (5 months. Max dose BED
3154 Gy) None –
Xia[22] (2006)
27 9 9 Unclear 133 Max < 100 mm None None –
Chang[26] (2008) 17 27 13c Nof 258 Max < 40 mm None * – Song[34] (2009) 27 9 9 Yes 240d Median 23 mm (12– 45)
1Bronchial stricture (max dose 48 BED3240 Gy) 2Bronchial stricture (Max dose 40/4 both, BED3
173 Gy) CTC (v2) Milano[27] (2009) 10 63a 7 Yes 217d Median 10 cc (0.5–277)
1Haemoptysis, 3dyspnoea (at median 6.3 months. All patients with stage II-III NSCLC and received multiple courses of SABR)
1Pneumonia, 1pericarditis CTC (v3)
Fakiris[24] (2009)
50 22 22 Yes 460 Max < 70 mm 3Pneumonia, 1haemoptysis, 1dyspnoea (median 12.5 months, 4 in central tumours)
1Apnoea, 1pneumonia, 2pleural effusion, 1anxiety (At median 7.6 months, 2 in central tumours)
CTC (v2) Guckenberger
[40](2009)
14 22 6 Unclear 144 Max < 256 cc None * –
Unger[28] (2010)
10 20 3 Yes 147 Median 73 cc
(23–324)
1Bronchial fistula (max dose 49 Gy BED3209 Gy) 1pneumonitis CTC (v3)
Oshiro[29] (2010)
20 21 1 Yes 217d Median
28 mm (10– 40)
1Haemoptysis (second course BED3230 Gy) 1Bronchial stricture (BED3180 Gy), 1dyspnoea
(BED3217 Gy)
CTC (v3)
Baba[35] (2010)
26 29 29 Unclear 258 Max < 55 mm None * –
Bradley[33] (2010)
18 8 8 Nof 180 Max < 51 mm None * –
Andratschke [34](2011)
21 24 24 Yes 117 Max < 203 cc None * –
Haasbeek[32] (2011)
35 63 63c Nof 210 Median
36 mm (15– 74)
None Acute 1chest wall pain. Late 2dyspnoea, 1rib
fracture, 1chest wall pain (occurred in 5 patients)
CTC (v3)
Bral[23] (2011)
16 17 17 Yes 360 Max < 60 mm 1Bronchial stenosis/haemoptysis Acute 2pneumonitis, 2cough, 1pneumonia. Late 3pneumonitis, 1pneumonia (occurred in 4 patients)
CTC (v3) Olsen[38]
(2011)
11 15 15c Nof 217 Not specified None * –
Stauder[39] (2011)
16 47a,b Not specified Yes 240 Max < 60 mm 1Bronchial stricture (7.5 months) 1dyspnoea CTC (v3)
Rowe[37] (2012)
11 51a,c 30 Nof 258d Median
31 mm (11– 57)
1Haemoptysis (10.5 months. Max dose 54 Gy BED3
297 Gy) 3Dyspnoea, 1pneumonitis CTC (v4) Nuyttens[30] (2012) 23 58a 39 Nof 300d Median 41 mm (12– 105)
None Acute 4pneumonitis. Late 6pneumonitis. (3 were
clearly SABR-related, 7 were more likely felt to be COPD exacerbation).
CTC (v3)
Taremi[25] (2012)
19 20 20 Unclear 210 Max < 57 mm None *
-Janssen[31] (2012)
14 29b Not specified Unclear 144 Max < 142 cc None None
-Biologically equivalent normal tissue dose (BED3). a
Study outcomes reported with respect to number of central tumours not patients. b
Study did not specify number of early-stage non-small cell lung cancer patients although these were included in the study cohort. c Includes early-stage cases with tumours in the lung apex or adjacent to other non-hilar central structures.
d Modal BED3shown if multiple fractionation schedules were utilized.
*Grade 3–4 toxicity specific to central tumours was not reported separately (includes reports in which central and peripheral or grade 2 and 3 outcomes were reported together). These studies were therefore excluded when calculating the overall rate of grade 3 or 4 toxicity.
e
Max gross tumour volume (GTV) of all tumours treated is shown when central tumour sizes are unavailable. f
Include tumours within 2 cm of the mediastinum or brachial plexus, rather than only those in direct contact with the mediastinal or pericardial pleura as specified in radiation therapy oncology group (RTOG) 0813.
SABR
for
central
lung
[40,49–52]. Onishi et al. describing a cohort of 245 patients from multiple Japanese institutions, found using a BED10P100 Gy
sig-nificantly improved both local control (92% vs. 74%,p< 0.05), and 3-year overall survival (88% vs. 69%,p< 0.05)[50]. In addition, local control was not improved further when patients received a BED10
P120 orP140 Gy. More recently, an analysis of a cohort of 505 pa-tients treated across five counties found that a BED10P105 Gy was
associated with higher local control, 96% vs. 85% (p< 0.001)[52]. Our analysis found that central tumours had the same dose–re-sponse relationship for local control, with four studies reporting improved outcomes with a BED10 P100 Gy compared to lower
doses[26,30,37,38]. Interestingly, we observed a similar dose–re-sponse relationship for treatment-related mortality, with a BED3
6210 Gy reducing the risk of death by approximately 75%.
Multiple fractionation schedules may or may closely achieve a BED10 P100 Gy and BED3 6210 Gy. These include schedules of:
50 Gy in 5 fractions, 54 Gy in 6 fractions, 56 Gy in 7 fractions and 60 Gy in 8 fractions. 50 Gy in 5 fractions was the modal fraction-ation schedule used in three studies[27,29,38]. Of these, Milano et al. reported the only treatment-related deaths (n= 2) when uti-lizing 50 Gy in 5 fractions, both of which occurred in patients receiving SABR for node-positive NSCLC[27]. In two studies, 83 central early-stage NSCLC patients were treated using 60 Gy in 8 fractions and none died as a result of their treatment[25,32]. As the aforementioned studies ensured the PTV received at least 95% of the prescribed dose without deliberate under-dosing to re-duce organ at risk toxicity, it is likely that these schedules enable the safe treatment of central lung tumours. Of the 20 studies in-cluded in this review, deliberate under-dosing of the PTV was de-scribed in only one study which may, in part, have accounted for a lower local control rate of 76% at 2 years[30].
A number of limitations in this analysis must be recognized. Follow-up amongst the included publications was generally lim-ited, with the median being 19 months (range 10–50). However, this may be sufficiently long as a study of post-SABR patterns of recurrence in 676 patients with early-stage NSCLC found the med-ian times to local, regional and distant recurrences were 14.9, 13.1 and 9.6 months, respectively[53]. There was significant heteroge-neity within the included studies with respect to the planning, pre-scribing and delivery of SABR (Table 1). We found variations in the way SABR doses were prescribed[29,35]and how normal organs were contoured[15]which may have impacted local control and toxicity, respectively. In addition, there was heterogeneity in the definition of ‘central’, with little additional details on location to enable assessment of the toxicity risk for given clinical scenarios. The majority of the publications in this review did not use 4-dimentional CT based planning, instead used techniques which could have led to larger target volumes and an increased risk of toxicity [54,55]. When considering the treatment of central tu-mours, careful contouring of organs at risk[56]and strict quality assurance of all aspects of treatment planning and delivery are re-quired[57,58]. Additionally, current treatments must account for the fact that dose calculation algorithms in use today are more accurate than those used historically, even if the impact of this may be less with central lung tumours[59,60].
In summary, this systemic review suggests SABR offers a safe and effective curative treatment for patients with central tumours who unfit for surgery. Data from the ongoing RTOG 0813 trial will provide prospective data to determine more reliable normal organ constraints with respect to the SABR fractionation schedules being assessed.
Conflict of interest
The VU University Medical Center has a research collaboration with Varian Medical Systems. SUS and BJS have received honoraria and travel support from Varian Medical Systems. BJS has received honoraria and travel support from BrainLAB AG. SAS and CJH de-clare no conflicts of interest.
Role of funding source
No external funding supported this research.
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Table 4
Clinical outcomes of stage I lung cancer by surgical technique.
Surgical technique Patients
(n) 5-year Survival (%) Loco-regional recurrence (%) Any recurrence (%) 30-day mortalitya (%) Operative complicationsa (%) Bronchoplasty[5] 355 61.0 10.0 17.5–22.5 4.4 23.6
Bronchoplasty and angioplasty [4]
39 48.0 5.1 33.0 3.3 32.4
Pneumonectomy[5] 224 49.0 19.7 40.9 4.8 26.2
a
Outcomes not restricted to stage I tumours.
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