Radiotherapy and Oncology 121 (2016) 1–8

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Radiotherapy and Oncology

journal homepage: www.thegreenjournal.com

Phase III randomised trial

SPACE – A randomized study of SBRT vs conventional fractionated

radiotherapy in medically inoperable stage I NSCLC
Jan Nyman a,⇑, Andreas Hallqvist a, Jo-Åsmund Lund b, Odd-Terje Brustugun c, Bengt Bergman a,
Per Bergström d, Signe Friesland e, Rolf Lewensohn e, Erik Holmberg a, Ingmar Lax e
a
Sahlgrenska University Hospital, Gothenburg, Sweden; b Trondheim University Hospital; c Oslo University Hospital, Norway; d Norrlands University Hospital, Umeå; and e Karolinska
University Hospital, Stockholm, Sweden

a r t i c l e i n f o a b s t r a c t

Article history: Background: Stereotactic body radiotherapy (SBRT) has been introduced for small lung tumors due to
Received 13 June 2016 excellent local control and few side effects, even though there are no comparative studies. SPACE
Received in revised form 12 August 2016 (Stereotactic Precision And Conventional radiotherapy Evaluation) is the first randomized phase II trial
Accepted 20 August 2016
comparing SBRT and conventional fractionated radiotherapy (3DCRT).
Available online 3 September 2016
Methods: Patients with stage I medically inoperable NSCLC were randomized to receive SBRT to 66 Gy in
3 fractions (one week) or 3DCRT to 70 Gy (7 weeks). Patients were followed to assess efficacy, toxicity
Keywords:
and HRQL.
SBRT
SABR
Findings: Between 2007 and 2011, 102 patients were randomized. Mean age 74 (57–86), 60% women, the
NSCLC vast majority (92%) had COPD or cardiovascular comorbidity. The SBRT arm included more patients with
Stage I T2-tumors (p = 0.02) and male gender (p = 0.35). The median follow-up was 37 months with a 1-, 2- and
Medically inoperable 3-year PFS of: SBRT: 76%, 53%, 42% and 3DCRT: 87%, 54% 42%, HR = 0.85 (95% CI 0.52–1.36) with no dif-
Randomized ference between the groups and no difference in OS (HR = 0.75, 95% CI 0.43–1.30). At the end of the study
70% of SBRT patients had not progressed compared to 59% (3DCRT, p = 0.26). Toxicity was low with no
grade 5 events. Pneumonitis of any grade was observed in 19% (SBRT) and 34% (3DCRT, p = 0.26), and
esophagitis in 8% and 30% respectively (p = 0.006).
Findings: HRQL was evaluated with the EORTC QLQ 30 and LC14 module and patients treated with
3DCRT experienced worse dyspnea (p = 0.01), chest pain (p = 0.02) and cough (>10 points difference).
Interpretation: There was no difference in PFS and OS between SBRT and conventionally treated patients
despite an imbalance of prognostic factors. We observed a tendency of an improved disease control rate
in the SBRT group and they experienced better HRQL and less toxicity. SBRT is convenient for patients and
should be considered standard treatment for patients with inoperable stage I NSCLC.
Ó 2016 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 121 (2016) 1–8

Surgery is the standard treatment for stage I non-small cell lung early nineties which included a body frame for set-up and fixation,
cancer (NSCLC). However, a substantial proportion of patients are soft-tissue imaging and hypofractionation with generally three
medically inoperable, mainly due to poor lung function or comor- fractions [2]. Since then, the interest in this treatment technique
bidity, such as cardiovascular disease. Traditionally, these patients for small lung tumors has grown exponentially. There is an exten-
have received radiotherapy, conventionally fractionated to total sive amount of literature describing excellent results in terms of
doses around 60 Gy. Several retrospective reports have been pub- local control and low toxicity for SBRT in stage I NSCLC [3–19].
lished with diverging results. In a review of the literature, Qiao However, no randomized study has been performed; the data con-
et al. [1] found a mean overall survival of 34% at three years and sist of retrospective series or rather small prospective studies. The
a low rate of local control. Scandinavian SBRT study group aimed to compare SBRT in a ran-
A method for stereotactic body radiotherapy of extracranial tar- domized way with conventional fractionated radiotherapy deliv-
gets (SBRT, synonymous with stereotactic ablative radiotherapy – ered in a modern setting using relevant doses and embarked on
SABR) was developed at the Karolinska University Hospital in the the SPACE-study (Stereotactic Precision And Conventional radio-
therapy Evaluation). The study was designed as a multicenter ran-
domized phase II trial with progression-free survival as the
⇑ Corresponding author. primary endpoint.
E-mail address: jan.nyman@oncology.gu.se (J. Nyman).

http://dx.doi.org/10.1016/j.radonc.2016.08.015
0167-8140/Ó 2016 Elsevier Ireland Ltd. All rights reserved.
2 SPACE – SBRT vs 3DCRT

Methods Follow-up
The same schedule was used for both study groups consisting of
The inclusion criteria were patients in WHO performance status
CT-scans at 7 weeks, 3, 6, 12, 18, 24 and 36 months. WHO-criteria
zero to two with stage I (T1–2N0M0, AJCC 6th edition) non-small
were used for response assessment. Toxicity was scored at the
cell lung cancer who were medically inoperable or refused surgery.
same time-points using CTC version 3.0 by the investigators. A
The tumors should be morphologically verified. If that was impos-
dynamic spirometry was repeated at 12 months and quality of life
sible due to peripheral lesion and poor lung function (intolerance
questionnaires EORTC QLQ 30 and LC 14 were sent out by mail at
for pneumothorax), there had to be an increasing tumor size in
7 weeks, 6, and 12 months after treatment.
repeated CT-scans and a positive PET-scan. The main exclusion cri-
Ethical approval was received from the regional ethics board in
teria were central tumor growth adjacent to trachea, main
Gothenburg, Sweden. Additional approvals were obtained from the
bronchus or esophagus, maximal tumor diameter >6 cm, patients
University of Trondheim and Arhus for Norway and Denmark. The
with prior malignancy in the last five years and if previous radio-
trial was registered at www.clinicaltrial.gov with the number
therapy had been delivered to the thorax. There were no restric-
NTC01920789. The study was conducted in accordance with the
tions with regard to lung function.
Declaration of Helsinki and Good Clinical Practice guidelines as
The diagnostic work-up consisted of a CT-scan of the chest and
defined by the International Conference on Harmonization. Writ-
upper abdomen, a PET-scan (optional), dynamic spirometry and a
ten informed consent was collected from all the patients before
CO-diffusion test, blood tests, WHO performance status and base-
enrollment.
line assessment of quality of life (EORTC QLQ 30 and LC 14 for-
mula). Patients who after oral and written information accepted
participation were randomized 1:1 to the two treatment arms with Statistics
no stratification. Neoadjuvant or adjuvant chemotherapy or tar-
The study was originally planned as a phase III trial with an esti-
geted drugs were not used in this study.
mated survival difference at three years of 50% (SBRT) vs. 30%
(3DCRT). With 80% power, a two-sided alpha significant level of
95% and an inclusion rate of 40 patients per year, the study popu-
Study arm A: Stereotactic radiotherapy lation would be 91 patients per arm. Taking into account a drop-
A stereotactic body frame with vacuum-pillow was used for set- out rate of 10%, the total number would add up to 200 patients.
up and fixation, respectively, with lasers being set to skin marks. If However, the 30% survival rate at three years for conventional
tumor movements were larger than 10 mm during fluoroscopy, radiotherapy was considered very uncertain due to lack of data
abdominal pressure was applied to reduce movements. The tumor on the survival of stage I patients after modern staging and up to
tissue visible on CT constituted the gross tumor volume (GTV) and date radiotherapy techniques. Therefore the study was scaled
clinical target volume (CTV) comprised the GTV including diffuse down to a phase II approach with 50 patients in each arm decreas-
margins at the tumor border. Planning target volume (PTV) was ing the power to 67% while changing the primary endpoint to PFS.
defined as the CTV with a 5 mm margin in the transversal plane PFS was defined as the date of randomization to progression or
and 10 mm in the longitudinal direction. A dose plan was created death, and PFS and OS were analyzed with the Kaplan–Meier
normally with 5–7 static coplanar or non-coplanar fields with 6 method. Possible differences between the SBRT and 3DCRT groups
MV photons. In addition to the CT used for dose planning, a second were analyzed with the log-rank test and potential impact of prog-
CT was performed before the first treatment to verify tumor repro- nostic factors (i.e. gender, stage, performance status, histology)
ducibility with predefined tolerance limits. CBCT (cone beam CT) were analyzed independently.
and 4DCT was allowed but only available at a few sites. A hetero- HRQL was analyzed with EORTC QLQ30 and LC 14, where aggre-
geneous dose distribution within the PTV was used. The prescribed gated scale scores were calculated according to the EORTC guide-
dose was 22 Gy times three at the isocenter during one week
(15 Gy at the periphery of PTV, corresponding to the 68% isodose). Table 1
Patient demographics.

A: SBRT n = 49 B: 3DCRT n = 53 p-Value

Study arm B: Conventional fractionated radiotherapy Age mean (range) 73 (57–86) 75 (62–85) 0.04
Gender
A vacuum-pillow was used for fixation and set-up, with lasers Male 22 (45%) 19 (36%) 0.35
being set to skin marks. GTV and CTV were delineated in the same Female 27 (55%) 34 (64%)
way as in arm A and the PTV was defined as the CTV with a 20 mm Cardiovascular disease 28 (57%) 28 (53%) 0.66
margin in all directions. Three to four coplanar fields with 6 MV COPD 35 (71%) 34 (64%) 0.43
FEV1 mean 1.3L (0.5–3.2) 1.6L (0.6–2.9)
photons were used with a homogeneous dose distribution. The % (of predicted) 53% (25–110%) 61% (22–130%) 0.48
prescribed dose was 70 Gy with 2.0 Gy per fraction, five days a CO diffusion capacity 57% (22–96%) 52% (22–109%) 0.29
week for seven weeks. The 95% isodose was required to cover % (of predicted)
95% of the PTV. Portal imaging with bone and soft tissue matching Histology
Adenocarcinoma 16 (33%) 17 (32%)
was used for set-up verification with 5 mm deviation as the action
SCC 9 (18%) 15 (28%)
level. NSCLC NOS 5 (10%) 2 (4%)
Dose constrains were set for the spinal cord with 21 Gy in arm A Not performed 18 (37%) 19 (36%)
and 48 Gy in arm B, no other constraints were used but doses to Missing 1 (2%) 0.46
organs at risk were registered. ECOG performance status
0 11 (22.5%) 5 (9.5%) 0.19
1 27 (55%) 33 (62%)
2 10 (20.5%) 14 (26.5%)
Endpoints Missing 1 (2%) 1 (2%)
Tumor stage
The primary endpoint was progression free survival at three T1 26 (53%) 40 (75%) 0.02
years. Secondary endpoints were overall survival, local control, T2 23 (47%) 13 (25%)
Diagnostic PET-CT 30 (61%) 36 (68%) 0.48
acute toxicity, late toxicity and quality of life.
 J. Nyman et al. / Radiotherapy and Oncology 121 (2016) 1–8 3

Fig. 1. Progression free survival by treatment arm (A = SBRT, B = 3DCRT), ITT analysis. HR = 0.85, 95% CI: 0.52–1.36.

Fig. 2. Overall survival by treatment arm (A = SBRT, B = 3DCRT), ITT analysis. HR = 0.75, 95% CI: 0.43–1.30.

lines. For analysis of HRQL changes over time, repeated measures 66 Gy in three fractions during one week (n = 49, arm A) or conven-
ANOVA was used with a p-value of < 0.05 being significant. A dif- tionally fractionated 3DCRT to 70 Gy in 35 fractions during seven
ference of more than 10 points was also considered clinically sig- weeks (n = 53, arm B). The mean age was 74 years (range 57–86)
nificant [20]. and the population was 60% women. Significant comorbidity, COPD
and/or cardiovascular disease, was seen in 92% of the patients.
With regard to lung function, the mean FEV1 was 1.4L (range
Role of the funding source
0.5–3.2) and mean diffusion capacity was 55% (range 22–109).
The funders of the study had no role in the study design, data Sixty-four percent had a histopathological diagnosis where the
collection or data analysis. The corresponding author had full majority was adenocarcinomas. T1 tumors were seen in 65% and
access to all of the data in the study and had the final responsibility T2 in 35%. The two treatment arms differed somewhat in terms
for the decision to submit for publication. of tumor size and gender where the SBRT arm included more
patients with T2 tumors (47% and 25% respectively, p = 0.02) and
Results male gender (45% vs 36%, p = 0.35), both negative prognostic fac-
tors. In contrast arm A had more patients with a WHO performance
Between January 2007 and July 2011, 102 patients were ran- status of zero (22.5% vs. 9.5%, p = 0.19). See Table 1 for details.
domized in nine Scandinavian centers to receive either SBRT to Three patients did not receive the planned treatment; they were
4 SPACE – SBRT vs 3DCRT

Fig. 3. Overall survival by tumor stage (p = 0.32), gender (p = 0.13) and performance status (p = 0.0003).
 J. Nyman et al. / Radiotherapy and Oncology 121 (2016) 1–8 5

Table 2 Toxicity was generally mild in both treatment arms. We did not
Response at end of study. CR = complete remission, PR = partial remission, SD = stable see any grade five toxicities and only one grade four occasion
disease, PD = progressive disease.
which was thrombocytopenia in arm B, most likely not related to
A: SBRT n = 49 B: 3DCRT n = 53 radiotherapy. However, there were numerically more toxicities
CR 6 (12%) 7 (13%) reported in arm B in most variables except for rib fractures which
PR 12 (24%) 7 (13%) were more common in arm A. Toxicity is presented in Table 3.
SD 13 (27%) 15 (28%) Esophagitis was significantly worse in the conventional arm
PD 13 (27%) 20 (38%)
Missing 5 (10%) 4 (8%)
(p = 0.006) and pneumonitis and dyspnea borderline significant.
Quality of life: HRQL was evaluated with EORTC QLQ30 and LC
14 at baseline, and at seven weeks, six and 12 months follow-up.
The compliance rates were 98% and 94% for questionnaire No.
all randomized to SBRT but received 3DCRT due to wrong inclusion
one in the SBRT and 3DCRT group respectively, which decreased
with more advanced growth (n = 2) or withdrawal of consent
to 92% and 77% at 12 months (questionnaire No. four). The
(n = 1). Those patients are included in the intention-to-treat
repeated measures ANOVA, to compare the treatment arms over
analysis.
time, was performed on the patients that submitted all four formu-
The gross tumor volumes (GTV) were larger in arm A, 15.5 cm3
las (70%). Patients treated with 3DCRT experienced worse dyspnea
(mean, range 1–67), compared to arm B, 8.9 cm3 (mean, range 1–
(p = 0.01), chest pain (p = 0.02) and cough (p = 0.4 but > 10 points
32, p = 0.02). Due to the treatment technique, the PTV’s were larger
difference) compared to the SBRT patients, a decrease that also
in arm B, 180 cm3 (mean, range 40–430) compared to arm A,
lasted over time (Fig. 4). Other variables did not display clinically
74 cm3 (mean, range 22–210, p < 0.001). The means (range) of
significant differences.
the maximal physical doses to organs at risk in arm A and B were
as follows (not corrected for fractionation differences); for esopha-
gus 13 Gy (0.5–36.5) versus 19 Gy (0.5–45.0), for spinal cord 12 Gy Discussion
(1.1–23.4) versus 18 Gy (0.9–47.8) and the percentages of lung vol-
umes receiving more than 20 Gy (V20) were 6% (1.5–23.6) and 16% SBRT has become the recommended standard of care for medi-
(6.7–33.5), respectively. cally inoperable patients with stage I NSCLC, for example in the
The median follow-up was 37 months and the 1-, 2- and 3-year ESMO guidelines [21], even though there is no randomized evi-
progression free survival (PFS) was 76%, 53% and 42% in arm A and dence for superiority over conventional therapy. However, favor-
87%, 54% and 42% in arm B, respectively. The hazard ratio was 0.85 able results in terms of local control (74–100%), low rate of grade
(95% CI 0.52–1.36) with no statistical difference (Fig. 1).There was three to five toxicities, and a stable quality of life post-treatment,
no difference between the groups when analyzed per protocol. have been reported for peripheral tumors in an extensive body of
The overall survival (OS) at 1-, 2- and 3 years was 81%, 68% and literature [3–19].
54% for arm A and 89%, 72% and 59%, for arm B, respectively, with a SPACE is, to our knowledge, the first randomized study compar-
hazard ratio of 0.75, (95% CI 0.43–1.30) also no significant differ- ing SBRT and external beam radiotherapy (EBRT) in stage I NSCLC
ence (Fig. 2), and no difference when analyzed per protocol. We patients. We did not observe any significant difference between
did not observe any survival difference between patients with the treatments in terms of progression free survival, overall sur-
and without a histopathological diagnosis (data not shown), but vival or local control. The ability to detect such a difference is of
there was a significant survival difference with regard to perfor- course hampered by the phase two design with a relatively low
mance status (p < 0.001) and trends for gender and T-stage (Fig. 3). power. Toxicity was mild (mostly grade 1–2) in both treatment
Response was measured by CT-scan during the follow-up per- arms, but less toxicity was observed with SBRT in terms of
iod. Response at the end of study at 36 months is shown in Table 2. esophagitis and trends for less pneumonitis and dyspnea. Differ-
Seventy percent of the patients in arm A did not have any progres- ences in toxicity are probably explained by the smaller treatment
sion at the end of the study, compared to 59% in arm B. The relapse volumes in SBRT. Quality of life was significantly better in the SBRT
pattern showed local progression in six patients in arm A and arm for dyspnea, cough and chest pain, and it is obviously more
seven patients in arm B, rendering a local control of 86.4% in arm convenient with three treatment visits compared to 35, both for
A and 85.7% in arm B. Regional recurrence was observed in 7% in the patients and the health care providers. The results of the SBRT
arm A and 8% in arm B, and distant metastases were found in arm are consistent with previous studies from our group [4,11,16],
24% and 23%, respectively. In total, seven patients had combined but we were partly surprised by the comparatively good results for
recurrences. EBRT regarding local control and a three-year survival of nearly
Eighteen patients died during follow up in arm A, five of them 60% with low toxicity. Most of the poorer EBRT results in the liter-
from lung cancer (10%). In arm B, 21 patients died, eight from lung ature are 10–20 years old with inferior staging procedures and
cancer (15%). Other causes of death were cardiovascular disease treatment techniques according to today’s standard [1].
(n = 6), COPD (n = 4), infections (n = 3), other malignancy (n = 2), There are two other ongoing studies with similar concepts as
dementia (n = 2) and miscellaneous (n = 11). the SPACE trial. In Australia, the CHISEL study has recruited 101

Table 3
Maximal toxicity CTC-AE v. 3.0, grade 1–3, by treatment arm.

Toxicity A: SBRT n = 48, grade: B: 3DCRT n = 53, grade: p-Value for difference between arms
1 2 3 1 2 3
Esophagitis 4 (8%) 0 0 15 (28%) 1 (2%) 0 0.006
Pneumonitis 7 (15%) 2 (4%) 0 13 (24%) 4 (8%) 1 (2%) 0.085
Dyspnea 19 (40%) 8 (17%) 5 (10%) 22 (42%) 16 (30%) 5 (9%) 0.097
Fibrosis 20 (42%) 4 (8%) 0 24 (45%) 2 (4%) 1 (2%) 0.925
Cough 19 (40%) 5 (10%) 1 (2%) 31 (58%) 3 (6%) 0 0.22
Skin reactions 13 (27%) 2 (4%) 1 (2%) 17 (32%) 5 (10%) 0 0.40
Rib fractures 6 (13%) 2 (4%) 0 5 (9%) 1 (2%) 0 0.44
6 SPACE – SBRT vs 3DCRT

100
90
80
70
60
50 LC14cough SRT
40 LC14cough 3DCRT
30
20
10
0
1 2 3 4

100
90
80
70
60
50 LC14Dys SRT
40 LC14Dys 3DCRT
30
20
10
0
1 2 3 4

100
90
80
70
60 LC14ChPain SRT
50
40 LC14ChPain
30 3DCRT

20
10
0
1 2 3 4

Fig. 4. Health Related Quality of Life by treatment arm. LC14cough = cough according to the EORTC lung cancer specific module LC 14, Dys = Dyspnea, ChPain = chest pain.
1 = at baseline, 2 = at seven weeks, 3 = at six months, 4 = at twelve months.

patients and is closed for inclusion (NCT01014130 at ClinicalTri- to a hypofractionated EBRT, 60 Gy in 15 fractions. Both of these tri-
als.gov). SBRT (18 Gy 3 or 12 Gy 4) is compared to EBRT to als are also investigating quality of life.
66 Gy in 33 fractions or 50 Gy in 20. The first analysis is planned There are at least four retrospective series and one meta-
for 2017. The LUSTRE trial is ongoing in Canada (NCT01968941) analysis comparing SBRT and EBRT that have been published
and has included approximately 10% of its planned 324 patients. [22–26]. They all have shortcomings e.g. EBRT cohorts being trea-
SBRT (12 Gy 4 or 7.5 Gy 8 for central tumors) will be compared ted at earlier time periods and there are differences between
 J. Nyman et al. / Radiotherapy and Oncology 121 (2016) 1–8 7

patients groups. Jeppesen et al. [22] compared 100 medically inop- 70 Gy for the EBRT arm). If BED calculations are applied and an
erable patients treated with two different fractionation schedules a/b of 10, BED = 112.5 Gy for SBRT at the periphery and 84 Gy for
of SBRT in 2005–2012 with a cohort of 32 patients treated with EBRT. The high BED for the SBRT group may be ‘‘overkill” as pro-
EBRT to 80 Gy in 35–40 fractions in 1998–2011. They found a supe- posed by van Baardwijk et al. [28].
rior median overall survival for the SBRT group, 36.1 vs. 24.4, but With improved local therapy distant metastases may be a grow-
no difference in local control. Widder et al. [23] investigated the ing problem, which almost a quarter of the patients in this trial
results of 202 medically inoperable patients treated with SBRT experienced (24%), most of them with local control. The figures
with two different fractionation schedules in 2006–2009 and a are similar to surgically treated groups of patients [29], where
group of 27 patients treated with 70 Gy in 35 fractions in 1994– adjuvant chemotherapy has become a standard for patients with
1996. Overall survival and local control were significantly better stage IB or higher. Adjuvant chemotherapy was not used in this
for the SBRT group and quality of life was stable, whereas it study and most patients were not fit for chemotherapy due to sev-
decreased for the EBRT group. Shirvani et al. [24] compared the ere comorbidity. A theoretically attractive alternative could be
effect of five different treatment strategies for patients 67 years adjuvant immunotherapy with a superior toxicity profile. In addi-
or older with stage I NSCLC from a national database in 2001– tion a so called abscopal effect has been demonstrated with tumor
2007 including 124 patients treated with SBRT and 1613 with regression outside the irradiated area due to an induced immuno-
EBRT. In a matched pair analysis of 124 patients the overall sur- genic response [30,31]. Studies with this concept are in progress.
vival was significantly better for the SBRT group compared to EBRT To summarize, this is the first randomized study on SBRT and
patients, but not for lung-cancer specific survival. Chiang et al. [25] EBRT for stage I NSCLC and it did not show any difference in terms
matched 57 patients treated with SBRT 48–52 Gy in 4–5 fractions of progression free survival, overall survival or local control
with an earlier cohort of 57 patients treated with EBRT 48–60 Gy between arms. However, quality of life was significantly better
in 12–15 fractions. Local control and OS were statistically for the parameters dyspnea, cough and chest pain with SBRT, and
improved for the SBRT group; however staging was different less radiotherapy related CTC-scored toxicities were observed. A
between the groups. Grutters et al. [26] performed a meta- recent editorial highlighted unresolved issues with SBRT [19] and
analysis including 11 observational studies of SBRT in 2001–2008 this trial adds information about survival, toxicity and HRQL in
(895 patients) and another 11 studies of EBRT (1326 patients). an elderly and comorbid population in a randomized and prospec-
Two- and five-year OS and LCSS were significantly better for the tive manner. Reduced treatment costs have been demonstrated for
SBRT studies. SBRT compared with EBRT in a previous study [32], and together
A shortcoming in our study is that approximately one third of with the convenience of three fractions instead of thirty-five, SBRT
the patients (36%) did not have a histological verification of the is in our opinion justified as the standard treatment for peripheral
tumor. This was mainly due to poor lung function and a risk for stage I NSCLC.
serious complications if a pneumothorax occurred when the tumor
was biopsied. To include these patients, there had to be a growing
tumor on repeated CT scans and a positive PET scan. We observed Contributors
identical survival and local control for patients with and without
histological confirmation implying similarity but because the JN, RL and IL were involved in the study design. JN, AH, JÅL, OTB,
majority died of other causes than lung cancer the interpretation PB, and SF ran the trial. BB was responsible for the quality of life
must be cautious. PET-positive lesions without a histopathological analyses and EH for the statistics. All of the authors were responsi-
confirmation have been studied by a Dutch group where they did ble for data interpretation and analysis. JN and AH wrote the initial
not find any difference in results in 591 patients with or without manuscript, with review and revisions made available to all of the
histology. Using FDG PET scans, the probability of malignancy authors.
using a clinical diagnosis (absence of pathology) was 92.5% [27].
There were some imbalances according to known prognostic Conflicts of interest
factors between the two treatment arms. There were 47% T2
tumors in the stereotactic arm compared to 25% in the EBRT arm. None of the authors have any relevant conflicts of interest to
There was also a male predominance (45% vs 36%), both negative disclose.
factors. In contrast, more patients with ECOG performance status
0 were included in the stereotactic arm, 23% vs 10%. The impacts
of these factors on survival for the entire study population are Acknowledgements
shown in Fig. 3.
There has been a substantial technical development of SBRT This study was supported by grants from the Nordic Cancer
since this study was planned which most likely influences the Union, NCU, and King Gustav V Jubilee Clinic Cancer Foundation
results. CBCT (cone beam computer tomography) for patient posi- in Gothenburg. We would like to thank the co-investigators: Stefan
tioning in the treatment room was introduced during the study Bergström Gävle Hospital, Britta Lödén Karlstad Central Hospital,
and for approximately the latter half of the patients this technique Morten Høyer Århus University Hospital, Ninni Drugge Sahlgren-
was used. 4DCT was only used at one center for a few patients at ska University Hospital and Kristina Nilsson Uppsala University
the end of the study. Hospital.
There is no clear consensus on how to prescribe and report
doses with SBRT, especially with a heterogeneous dose- References
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