Patients
Between 2002 and 2009 50 lesions of 43 consecutive patients with NSCLC (n = 27, St. I-II in the primary situation and III-IV including patients with controlled brain metastases or local relapse after primary standard therapy) and lung metastases of various primary tumors (n = 16; 2 melanoma; 3 oropharyngeal, 1 laryngeal, 1 prostate, 4 colorectal, 1 pancreatic and 1 breast cancer; 1 transitional cell and 2 renal cell carcinoma) were consecutively treated with intensity-modulated breath-hold igSABR after informed consent. All lesions were considered to be technically or medically inoperable by an interdisciplinary tumor-conference. Patient and tumor characteristics are summarised in Table
1, while the NSCLC series is further described in detail in Table
2.
Table 1
Patients (n = 43) characteristics
Gender: | |
Male | 32 (74%) |
Female | 11 (26%) |
Age: | |
Ys, Median; (range) | 69 (49–84) |
Tumor entities: | |
NSCLC | 27 (63%) |
Lung metastasis of various primary tumors | 16 (37%) |
Table 2
Further characteristics of patients with NSCLC (n = 27)
Histologic diagnosis Squamous cell carcinoma Adenocarcinoma others | 9 (33%) 13 (48%) 5 (19%) | Stage(AJCC) | |
Ia | 6 (22%) |
Ib | 4 (15%) |
IIa | 3 (11%) |
IIb | 3 (11%) |
IIIa* | 5 (19%) |
IIIb* | 1 (3%) |
IV* | 5 (19%) |
Chemotherapy before or after RT | Tumor: | |
T1a | 2 (7%) |
yes | 12 (45%) | T1b | 10 (37%) |
T2a | 5 (19%) |
no | 15 (55%) | T2b | 1 (3%) |
T3 | 4 (15%) |
T4 | 5 (19%) |
Comorbidity: | | Lymphnodes | |
N0 | 18 (67%) |
N1 | 5 (19%) |
Pulmonary disease (COPD) | 6 (22%) |
Cardiovascular disease | 7 (26%) |
Both | 12 (45%) | N2 | 3 (11%) |
None of the above | 2 (7%) | N3 | 1 (3%) |
| | Metastasis: | |
M0 | 22 (82%) |
M1a | 1 (3%) |
| | M1b | 4 (15%) |
Data were evaluated retrospectively regarding overall survival (OS), progression-free-survival (PFS), progression pattern, local control (LC), acute and late toxicity based on clinical symptoms and CTC/LENT-SOMA scales.
Radiotherapy planning, dose calculation and treatment
Planning CT scans were acquired with a spiral-CT (Somatom Emotion, Siemens, Erlangen, Germany, thereafter Brilliance Big Bore Oncology, Philips, Hamburg, Germany) after an initial patient training session in inspiratory breath-hold at approximately 70% of vital capacity with ABC® [
9]. Radiotherapy planning was initially performed as manually weighted Intensity Modulated RadioTherapy (IMRT) with OTP (Theranostic GmbH, Solingen, Germany) and thereafter with inverse planned step-and-shoot IMRT or VMAT (Volumetric Modulated Radiotherapy) with Monaco® (Elekta AB, Stockholm, Sweden).
PTV was calculated from CTV by adding a 5 mm margin radially and 10 mm in the craniocaudal direction to compensate residual intrafractional error of the ABC®-based positioning [
11].
Dose calculation was performed initially by a pencil beam (PB) algorithm (11 patients), thereafter both with PB and collapsed cone (CC) algorithms (32 patients). After the change to CC algorithm, the PB was still calculated in order to compare the resulting nominal dose distributions.
Dose prescription was initially performed to the isocenter (forward-planned IMRT), typically in the vicinity of the median dose) and later as the median dose in the PTV (inverse IMRT) with the 90% isodose line covering the PTV. Dose constraints for OAR were as shown in Table
3[
5,
12‐
15]. The planning constraints are the constraints for the final dose level of typically 5x12 Gy. While we attempted to fulfill the planning goals whenever possible for this regimen, we had, however, for example for tumors close to the chest wall or the plexus, to deviate from these constraints on occasion depending on individual physician and patient preference if adhering to constraints would have precluded applying sufficient tumor dose. Dose constraints for the other regimens were adjusted for each regimen.
Table 3
Dose constraints for OAR (
OAR,
Organs at risk;
D
max
,
maximal dose in PTV; V15 and V20, percentage of irradiated tissue covering the 15 or 20 Gy isodose [[
5,
11‐
14]
])
Healthy lung V15 | <30% |
Healthy lung V20 | <20% |
Spinal cord Dmax | 18-20 Gy |
Trachea/main bronchus Dmax | 36 Gy |
Esophagus Dmax | 18 Gy |
Brachial plexus Dmax | 18 Gy |
Ribs/Thoracic wall Dmax | 30 Gy |
Heart and major vessels Dmax | 30 Gy |
Skin Dmax | 40 Gy |
PTV-coverage was analysed based on relevant parameters (D99 (dose encompassing 99% of the PTV), minimal, maximal, mean and median PTV-dose.
Implementing results from published literature reports [
5,
13‐
16] regarding dose escalation and fractionation, dose to the patients was adjusted during the reported period and varied between single-fraction doses of 20-26 Gy initially (depending on tumor and healthy lung volume) and various hypofractionated regimens with the current, final protocol prescribing 5x12 Gy every other day to peripheral tumors and 12x5 Gy to central lesions [
15]. For exact fractionation schedules of each lesion, see Additional file
1: Table S1.
To be able to retrospectively compare these various fractionation regimens, we introduced Biologically Effective Dose in 2 Gy fractions (BED2 [
17]). BED2 was calculated [
18] with an assumed α/β ratio of 10 with the following formula: BED2 = Dx(d + α/β)/(2 + α/β).
Patients were treated as described previously [
17]. Shortly, a linac with 6MV photons was used (Synergy®, Elekta AB, Stockholm, Sweden). Daily image-guidance was performed with EPIDs (Electronic Portal Imaging Device) and since 2005 with repeat breath-hold CBCT (XVI®, Elekta AB, Stockholm, Sweden [
17,
19]). Planning-CT images were matched online with the daily CBCT images using manual fusion with respect to soft-tissue anatomy [
20]. Online surveillance of breath-hold was performed based on the continuous acquisition of MV-frames during irradiation allowing position verification of the tumor itself, if possible, or of a surrogate structure such as the diaphragm [
6].
Patient follow-up (FU) was scheduled 6 weeks after radiotherapy and every 3 months thereafter with clinical examination and thoracic CT with i.v. contrast. An assessment of tumor response was performed using the RECIST (Response Evaluation and Criteria in Solid Tumors) criteria. Response was graded as complete response (CR), partial response (PR), stable disease (SD) or progression.
Acute (first 90days) and late toxicity (>90 days) was evaluated based on clinical symptoms (graded based on the CTC-scale in the acute phase and on the LENT-SOMA criteria (late effects in normal tissues subjective, objective, management and analytic scales) in the late phase). Recorded clinical symptoms were general condition, coughing, dyspnoea, pneumonitis, pulmonary oedema, dysphagia, pleural effusion, fever and skin symptoms for assessing acute toxicity; rib fracture, pulmonary fibrosis, thoracic pain, dyspnoea and coughing for late toxicity. Pneumonitis analysis was based on presence of symptoms requiring treatment and thoracic CT imaging.
Statistics
Statistical analysis was performed with the SAS-software, release 9.01 (SAS, Cary, NC, USA). OS (Overall-Survival), PFS (Progression-Free-Survival) and LC (Local Control) were recorded and subject to actuarial analysis. OS was calculated from the day of irradiation until either the day of death (event) or the day of the last FU (censored data). PFS was calculated from the day of irradiation until either the day of relapse or death (events) or the last FU without relapse (censored data when at the last FU the patient lived without any evidence of progression). LC was calculated from the day of irradiation until either the day of local progression (event) or the last FU/death without local progression (censored data). For LC, number of patients at risk was calculated for each time point. Kaplan-Meier-plots for OS, PFS and LC were calculated in order to assess median survival/control times. Correlation of the local control time with PTV size and BED2 was analysed by the Kaplan-Meier log-rank test. P-values < 0.05 were considered as significant, 0.05 < p < 0.15 as a trend to significance.