Treatment-Related Adverse Effects in Lung Cancer Patients after Stereotactic Ablative Radiation Therapy
Table 2
SABR-related toxicities in clinical trials.
Author
Sample size
Treatment Details
Toxicities
Comments
PHASE 3 CLINICAL TRIALS
Chang et al. [10] Pooled analysis of 2 independent randomised phase 3 trials 2015
58 patients with cT1-2aN0M0 operable NSCLC
STARS trial - 54Gy/3# [peripheral] 50Gy/4# [central] ROSEL trial - 54Gy/3# or 60Gy/5# STARS - CyberKnife ROSEL - linear accelerator.
3 patients had grade 2 SABR-related events - 3 had CW pain, 2 had dyspnoea and 1 had fatigue and a rib fracture. No patients experienced grade 4 or 5 events.
Toxicity scored with NCI CTCAE v.3.0. This study compared lobectomy and SABR - found that surgery results in increase procedure-related mortality and morbidity compared with SABR.
PHASE 2 CLINICAL TRIALS
Lindberg et al. [11] Analysis of phase 2 multi-centre trial results 2015
57 patients with T1-2N0M0 inoperable NSCLC Male n=26; Female n=31
45Gy/3# prescribed to 67% isodose line encompassing PTV. Centre of PTV receiving 66Gy/3# Elekta linear accelerator. 6MV.
No grade 5 toxicities. 17 grade 3-4 toxicities, 3 presenting > 36 months - rib fracture, dyspnoea, ventricular tachycardia. Within first 36 mths - 1 patient with grade 4 dyspnoea died of respiratory failure not attributed to SABR. Late toxicities - 3 grade 3 1 patient grade 3 rib fracture. 1 patient with grade 3 dyspnoea. 1 patient with ventricular tachycardia. Atelectasis: Early - grade 2 COPD exacerbation: Late - grade2 . Cough - Early - grade 2 , grade 3-4 - Late - grade 2 Dyspnoea - Early - grade 2 , grade3-4 - Late - grade 2 , grade 3-4 Exudate - Early - grade 2 , grade 3-4 - Late grade 2 . Fatigue - Early - grade 2 , grade 3-4 . Fibrosis - Early - grade 2 , grade 3-4 Heart - Early - grade 2 , grade 3-4 . Lung infection - Early - grade 2 , grade 3-4 - Late grade 2 . Pain - Early - grade 2 , grade 3-4 Pericardial effusion - Early - grade 2 Pneumonitis - Early - grade 2 . Rib fracture - Early - grade 2 - Late grade 2 . grade 3-4 Skin and subcutaneous - Early - grade 2
Toxicity scored with NCI CTCAE v.4.0 and the RTOG late toxicity scale. Patients with ≥grade 2 fibrosis had larger PTVs compared to patients without fibrosis but no association between dose to lung and fibrosis was observed. For patients with ≥grade 2 fibrosis, no association between lung dose and fibrosis was observed.
127 patients with Stage 1 NSCLC Male n=53; Female n=74
48Gy/4# or 60Gy/5# Elekta Synergy or Axesse [some IMRT and VMAT]
At 12 months, there was a 4.1% decline in FEV1 and at 24 months a 7.6% decline. At 9 months, there was a 6.1% decline in DLCO and a 5.2% decline at 12 months. At 12 months, there was a 5.7% decrease in FVC and at 24 months a 5.2%. 3.1% grade 2 RP and 0.8% grade 3 RP. No grade 3 FEV1 or FVC toxicities were experienced. 95% experienced grade 0-1 FEV1 decline at 6 months and 92% at 12 months. 97% experienced a grade 0-1 FVC decline at 6 months and 95% experienced a decline at 12 months. 85% experienced grade 0-1 DLCO toxicity at 6 months and 88% experienced at 12 months.
RTOG pulmonary function text toxicity scale and NCI CTCAE v.3.0. used to grade toxicity. The 12 month decline in FEV1 only observed in patients with a baseline FEV1 ≥50% compared to patients with a baseline FEV1 ≤50%. Decline in DLCO at 12 months in both the baseline-corrected DLCO ≥50% and baseline corrected DLCO ≤50%. A correlation between GTV volume and TLC reduction at 12 months - but no significant correlations between pulmonary tests and other volumetric parameters.
26 patients with oligometastatic NSCLC Male n=20; Female n=6
50Gy/10# TomoTherapy Hi-Art II system or VERO SBRT system
4 patients acute grade 2 toxicity - 1 with dyspnoea, 2 with dysphagia and 1 with RP. No major late toxicities were observed. Toxicity rate of 8%.
NCI CTCAE v.3.0. used to score the patient toxicities.
Chang et al. [15] Prospective analysis of phase 2 clinical trial 2012
130 patients with Stage 1 NSCLC Male n=67; Female n=63
50Gy/4# Machine not specified. 6MV used.
15 patients with RP - 9.2% had grade 2 RP and 2.3% had grade 3 RP. 12 patients with RP - 8.5% experienced grade 2 CW pain and 0.8% experienced grade 3 CW pain. 8 patients with dermatitis - 6.2% with grade 2 or 3 dermatitis. 1 patients [1.5%] developed grade 1 oesophagitis.
No difference in occurrence of RP between central and peripheral lesions. Ipsilateral mean lung dose ≥9.14Gy was significantly associated with RP on multivariate analysis, p=0.005. In patients with an ipsilateral mean lung dose <9.14Gy, only 1 patient had grade 2-3 RP [p<0.001]. On univariate analysis, lung volumes from 5-40Gy and mean lung dose were associated with the incidence of grade 2-3 RP, p<0.05.
40 patients with T1-3N0M0 NSCLC Male n=33; Female n=7
60Gy/3# for peripherally located lesions - 60Gy/4# for central lesions Novalis system. Energy not specified.
≥grade 3 late toxicity was seen in 8 patients [20%]. The average decline in FEV1 and DLCO was 3% for both. Grade 1 FEV1 changes occurred in 18% and grade 2 changes occurred in 15%. Grade 1 DLCO changes occurred in 13% and grade 2 changes occurred in 20%. 1 patient with a dermal fibrotic reaction developed an ulcer. 6 patients persistent grade 1 or 2 weight loss and 1 fatigue. 2 patients acute grade 3 RP; 8 chronic grade 1 RP, 5 grade 2 RP, 6 grade 3 RP. 21 acute grade 1 cough, 5 grade 2 cough, 2 grade 3 cough; 3 chronic grade 1 cough, 1 chronic grade 2 cough. 2 acute grade 1 dyspnoea, 2 grade 2 dyspnoea; 3 chronic grade 1 dyspnoea, 3 grade 2 dyspnoea, 1 grade 3 dyspnoea. 1 chronic grade 3 stenosis. Dysphagia, nausea, anorexia, pyrosis, fatigue, skin reactions, fever, pain in several patients.
NCI CTCAE v.3.0. used to score the patient toxicities along with the RTOG acute and late morbidity scoring system. Lung toxicity-free survival estimate at 2 years was 74%. Group analysis showed a correlation between 2 year lung toxicity-free survival and location: peripheral 84% vs. central 60% [p=0.06] and PTV size [<65cc vs. ≥65cc, p=0.02]. No correlation between the degree of lung toxicity and the absolute or relative lung volume receiving 20Gy or 10Gy, mean lung dose, the gradient, CI, or the total lung volume. Baseline FEV1 or DLCO did not predict for lung toxicity. Pulmonary function test changes at 3 months were not related to the lung doses, mean lung dose, the gradient, CI or the total lung volume.
Timmerman et al. [17] RTOG trial 0236 Phase 2 North American multicentre trial 2010
55 patients with T1-2N0M0 NSCLC Male n=21; Female n=34
124 patients with Stage 1 NSCLC 60% of patients were female.
T1 tumours - 48Gy/4#; T2 tumours - 60Gy/5#
No grade 4 or 5 toxicities were experienced. SABR related toxicities- 21% grade 1-3 RP. 9% grade 1, 9% grade 2 and 2% grade 3. 12% grade 1-2 rib fractures with 7% being symptomatic requiring treatment. 27% grade 1 fatigue. 38% grade 1 radiation dermatitis. 21% grade 1-3 acute dyspnoea. 8% developed grade 1-3 chronic dyspnoea. 4% developed acute myositis; 10% developed chronic myositis.
NCI CTCAE v.3.0. used to score toxicities. Study comparing SABR and wedge resection for the stage 1 NSCLC. The occurrence of myositis was related to tumour-chest wall proximity.
Baumann et al. [20] Prospective phase 2 trial 2009
57 patients with T1-2N0M0 inoperable NSCLC Male n=26; Female n=31
Fakiris et al. [21] Prospective phase 2 trial 2009
70 patients with stage 1 NSCLC
60Gy/3# - T1 tumours; 66Gy/3# - T2 tumours
10.4% of patients with peripheral tumours had grade 3-4 toxicity; 27.3% of patients with central tumours developed grade 3-4 toxicity. 27.7% of the patients not oxygen dependent pre-SABR became oxygen dependent at a median of 55.6 months post-SABR. 6 grade 3, 1 grade 4 and 5 grade 5 toxicities possibly SABR-related. 1 grade 4 apnoea, 1 pneumonia, 2 pleural effusion, 2 with pulmonary function decline, 1 with anxiety. The grade 5 toxicities were - 3 pneumonia, 1 haemoptysis and 1 respiratory failure. 2 grade 3 toxicities - pneumonia and erythema - were attributed to SABR.
Toxicity scored with NCI CTCAE v.2.0. Study states that there was no significant difference between patients with peripheral and central tumours [p=0.697]. While estimate toxicity rates in central tumour patients [27.3%] were near 3 times higher than the rates of peripheral tumour patients [10.4%], this did not reach statistical significance.
31 patients with medically inoperably stage 1 NSCLC Male n=25; Female n=6
45Gy/3#; if close to OAR - 60Gy/8# Varian linear accelerator - Clinac23EX. 6MV
24 patients grade 1 acute RP, 3 patients grade 2 acute RP, and 1 patient experienced grade 3 acute RP. 2 patients did not developed RP. No ≥grade 2 toxicity was observed outside the lungs. 1 patient developed grade 3 pulmonary toxicity due to an upper bronchus obstruction.
70 patients with stage 1 NSCLC Male n=34; Female n=36
T1 tumours - 60Gy/3#; T2 tumours - 66Gy/3#
58 of the 70 patients had grade 1-2 toxicity - fatigue, musculoskeletal discomfort and RP. 8 patients were identified as having grade 3-4 toxicity post-SABR: decreased pulmonary function, pneumonia, pleural effusion, apnoea and skin reactions. SABR may have contributed to the death of 6 patients - grade 5 toxicity. 4 deaths were via bacterial pneumonia - 1 patient died of a pericardial effusion and 1 patient experienced fatal massive haemoptysis.
Toxicity graded according to NCI CTCAE v.2.0. In both univariate and multivariate analyses of those patients experiencing grade 3-5 toxicities, the location of the tumour [hilar/pericentral vs. peripheral] was a strong predictor of toxicity, p=0.004. On multivariate analysis, the GTV size was a significant predictor of toxicity.
28 patients with medically inoperable stage 1 NSCLC Male 14; Female 14
45Gy/3# Siemens Primus or a Varian Clinac 2100/2300. Energy not specified.
Aggravated dyspnoea was registered in 11 patients [40%] of the cohort. 1 of these patients experienced an increase of 1 grade - the remaining 7 experienced an increase of 2 grades.
WHO toxicity scoring of SABR side-effects. No significant association between DVH parameters and changes in dyspnoea. No association between age, gender, tumour volume and localisation performance status, and aggravated dyspnoea. COPD showed the closest association with the occurrence of aggravated dyspnoea post-SABR. No association between dose, irradiated lung volume and dyspnoea.
49 patients with lung metastases Males n=22; Females n=27
Preferred - 50Gy/5# Novalis Shaped Beam Surgery.
17 patients [35%] grade 1 pulmonary toxicity. 3 patients [6.1%] grade 2 complaints and 1 patient had grade 3 toxicity. One patient grade 3 malignant pleural effusion - this was managed with pleurocentesis and sclerosis. Most grade 2 toxicity was a cough. 4.1% grade 1 oesophagitis, 2% grade 3 pleural effusion, 2% grade 3 pericardial effusion. 35% grade 1 RP/pulmonary infiltrates. 6.1% grade 2 RP/pulmonary infiltrates.
Toxicity graded against the NCI CTCAE v.3.0. Metastases from breast, lung, renal, endocervical and colon primaries. Toxicity was not clearly associated with V20.
PHASE 1 CLINICAL TRIALS
Onimaru et al. [26] Multi-institutional phase 1 trial 2015
15 patients with peripheral stage 1 NSCLC Male n=8; Female n=7
40Gy; 45Gy; 50Gy; 55Gy; 60Gy Machine not specified. 4-6MV.
1 patient grade 2 RP - this patient was treated with 60Gy/4# at D95 of PTV. The remaining patients had grade 1 or lower RP. All patients had RP within 180 days post-SABR. 2 patients developed a cough after 180 days. 4 patients dyspnoea after 180 days. 1 patient hypoxia 180 days post-SABR. 3 patients fractures 180 days post-SABR. 1 patient brachial plexopathy.
Toxicity graded with NCI CTCAE v.3.0. Probability of the percentage of grade 2 RP at 55Gy is above 25%. Recommended dose for SABR T2N0M0 NSCLC with PTV <100cc is 55Gy/4#.
15 patients with peripheral lung tumours Male n=10; Female n=5
60Gy/5# to 60% isodose line - this equals 100Gy/5#. Varian linear accelerator - Dynamic conformal multiple arc therapy. 6MV.
6 months post-SABR, 5 patients were grade 0 RP, 9 patients were grade 1 RP, 1 patient was grade 2 RP. The usual RP occurred in and around the PTV.
NCI CTCAE v.4.0. used to score toxicities.
Rusthoven et al. [28] Multi-institutional phase 1/2 trial 2009
38 patients with lung metastases
48Gy/3#, 54Gy/3#, 60Gy/3#. Linear accelerator. 6-15MV
No cases of grade 4-5 toxicity. 3 patients grade 3 toxicity. 10.5% grade 2 radiation dermatitis. 2.6% symptomatic grade 2 RP. 2 of 3 cases of grade 3 toxicity involved the chest wall or skin in patients with peripheral lesions.
