Supplementary Information to ‘Cost-effectiveness of an individualized first-line treatment strategy offering erlotinib based on EGFR mutation testing in advanced lung adenocarcinoma patients in Germany’
Katharina Schremser, Wolf H. Rogowski, Sigrid Adler-Reichel, Amanda L.H. Tufman, Rudolf M. Huber, Björn Stollenwerk
1
Webtable 1 Akaike information criterion (AIC) as a measure of the goodness of fit for progression-free survival (PFS) and overall survival (OS). Smaller AIC values indicate better-fitting models.
Model distribution / AIC valuesPFS / OS
Exponential / 1024.2 / 615.8a
Weibull / 1016.7a / 617.6
Log-logistic / 1024.2 / 622.7
Log-normal / 1038.5 / 630.1
Gompertz / 1024.3 / 616.0
Flexible parametric proportional-hazards model using the spline model of Royston and Parmar / 1003.9b / 616.9b
a Base case model
bStructural sensitivity analysis
Adverse events
Based on the clinical experience of our cooperation partners, we estimated the share of outpatient treatment for each adverse event to enable a reliable presentation of clinical practice. If no information on outpatient cost data was available, we used published literature to estimate resource use[1].
Webtable 2Health-care resource use per patient for treatment of adverse events
Grade 3/4 adverse event / Proportion of patients assumed to be treated as outpatients / Outpatient resource use per patient and episode / Inpatient resource use per patient and episodeGrade 3/4 rash / 0.95 / one additional outpatient visit and one tube of Cleocin T gel / one day hospital stay (G-DRG J68B)
Grade 3/4 fatigue / 0.75 / one additional outpatient visit / 2-10 days of hospital stay (G-DRG Z65Z)
Grade 3/4 diarrhea / 0.05 / one additional outpatient visit and intake of loperamide (30 capsules) / 2-7 days of hospital stay (G-DRG G67C)
Grade 3/4 febrile neutropenia / 0 / 2-12 days of hospital stay (G-DRG T64B)
Grade 3/4 neutropenia / 0.98 / one additional outpatient visit and prophylactic G-CSF (filgrastim 480 µg, 10 vials) (19.2% of patients) / one day hospital stay (G-DRG Q60C)
Grade 3/4 anemia / 0.95 / one additional outpatient visit and transfusion of two red blood cell concentrates / one day hospital stay (G-DRG Q61D)
Grade 3/4 thrombocytopenia / 0.95 / one additional outpatient visit and transfusion of one platelet concentrate (20% of patients) / one day hospital stay (G-DRG )
Grade 3/4 aminotransferase rise / 0.98 / one additional outpatient visit / one day hospital stay (G-DRG Z65Z)
Grade 3/4 appetite loss / 0.90 / one additional outpatient visit / 2-11 days of hospital stay (G-DRG K62B)
G-CSF, granulocyte colony-stimulating factor; G-DRG, German Diagnosis Related Groups
Webtable 3 Details on parameters varied in one-way sensitivity analysis
Model input parameter / Base case (mean) / Lower / Upper / ReferenceProbabilities / 95% CI
EGFR mutation prevalence in patients with Adeno-NSCLC / 0.128 / 0.115 / 0.143 / [2]
Not enough tissue for EGFR testing / 0.184 / 0.151 / 0.222 / [3]
Clinical expert
Clinical data do not support rebiopsy / 0.1 / 0.08 / 0.12 / Thoracic Hospital of Heidelberg
Non-informative rebiopsy / 0.175 / 0.15 / 0.20 / Thoracic Hospital of Heidelberg
Complications of biopsy procedures / 95% CI
Pneumothorax (percutaneous needle aspiration biopsy) / 0.066 / 0.062 / 0.07 / [4]
Pneumothorax (bronchoscopic biopsy) / 0.002 / 0.001 / 0.003 / [5, 6]
Severe hemorrhage (percutaneous needle aspiration biopsy) / 0.01 / 0.009 / 0.012 / [4]
Severe hemorrhage (bronchoscopic biopsy) / 0.005 / 0.004 / 0.007 / [5, 6]
Clinical expert
Proportion of patients receiving chemotherapy in inpatient settings / 0.4 / 0.10 / 0.50 / University Hospital of Munich
Proportion of patients receiving different chemotherapeutic regimens /
95% CI
Cisplatin plus docetaxel / 0.061a / 0.035 / 0.103 / [7]
Cisplatin plus gemcitabine / 0.281a / 0.207 / 0.33 / [7]
Carboplatin plus docetaxel / 0.492a / 0.423 / 0.562 / [7]
Carboplatin plus gemcitabine / 0.183a / 0.148 / 0.259 / [7]
Grade 3/4 adverse event probabilities (total reported)
Erlotinib (n=84)
Diarrhea / 0.048 / 0.019 / 0.116 / [8]
Fatigue / 0.06 / 0.026 / 0.132 / [8]
Rash / 0.131 / 0.075 / 0.22 / [8]
Anemia / 0.012 / 0.002 / 0.064 / [8]
Aminotransferase rise / 0.024 / 0.007 / 0.083 / [8]
Platinum-based chemotherapy (n=82)
Anemia / 0.037 / 0.013 / 0.102 / [8]
Fatigue / 0.195 / 0.124 / 0.294 / [8]
Neutropenia / 0.22 / 0.144 / 0.321 / [8]
Febrile neutropenia / 0.037 / 0.013 / 0.102 / [8]
Alopecia / 0.024 / 0.007 / 0.085 / [8]
Thrombocytopenia / 0.146 / 0.086 / 0.239 / [8]
Appetite loss / 0.024 / 0.007 / 0.085 / [8]
Clinical expert
Proportion of patients assumed to be treated as outpatients / University Hospital of Munich
Diarrhea / 0.05 / 0 / 0.1
Fatigue / 0.75 / 0.7 / 0.8
Rash / 0.95 / 0.9 / 1
Anemia / 0.95 / 0.9 / 1
Aminotransferase rise / 0.98 / 0.95 / 1
Neutropenia / 0.98 / 0.95 / 1
Febrile neutropenia / 0 / fixed / fixed
Thrombocytopenia / 0.95 / 0.9 / 1
Appetite loss / 0.9 / 0.8 / 1
Model input parameter / Base case (mean) / Lower / Upper / Reference
Probabilities / 95% CI
Proportion of patients receiving second-line chemotherapy within first-line chemotherapy group / 0.195 / 0.124 / 0.294 / [8]
Proportion of patients receiving second-line chemotherapy within first-line erlotinib group / 0.627 / 0.490 / 0.747 / [8]
Health state utilities
Stable disease while receiving oral therapy / 0.672 / 0.627 / 0.718 / [1, 9]
Stable disease while receiving IV chemotherapy / 0.653 / 0.609 / 0.696 / [9]
Progressive disease / 0.473 / 0.412 / 0.533 / [9]
Disutilities related to adverse events
Diarrhoea / -0.047 / -0.082 / -0.021 / [9]
Fatigue / -0.073 / -0.114 / -0.041 / [9]
Rash / -0.032 / -0.059 / -0.014 / [9]
Neutropenia / -0.09 / -0.122 / -0.062 / [9]
Febrile neutropenia / -0.09 / -0.124 / -0.061 / [9]
Thrombocytopenia / -0.053 / -0.064 / -0.043 / [6]
Pneumothorax / -0.023 / -0.028 / -0.019 / [6]
Haemorrhage / -0.023 / -0.028 / -0.019 / [6]
Hair loss / -0.045 / -0.078 / -0.021 / [9]
Anemia / -0.07 / -0.084 / -0.057 / [10]
Costs / Unit costs 2014 / Upper / Lower / Reference
Drug acquisition / ± 20%
Erlotinib / €1,839 / €1,471 / €2,206 / [11]
Cisplatin plus docetaxel / €1,529 / €1,223 / €1,835 / [11]
Cisplatin plus gemcitabine / €978 / €782 / €1,173 / [11]
Carboplatin plus docetaxel / €1,710 / €1,368 / €2,052 / [11]
Carboplatin plus gemcitabine / €984 / €787 / €1,180 / [11]
1 tube of Cleocin T gel (60 g 1% cream) / €43 / €34 / €51 / [12]
Neupogen (480 µg), 10 vials / €1,616 / €1,293 / €1,939 / [1, 11]
Loperamide (2 mg), 30 tablets / €6 / €5 / €7 / [11]
Medical services (outpatient)
Bronchoscopic biopsy of pulmonary nodules, performed outpatient (EBM codes 13662, 13642) / €121 / €97 / €146 / [13]
EGFR mutation testing using DNA sequencing of exons 19 to 21 (EBM 11212, EBM 11322) / €323 / €258 / €387 / [13]
Outpatient management of oral therapy (EBM codes 13492, 13500, 13502, 86512) / €100 / €80 / €119 / [13]
Outpatient management of IV chemotherapy (EBM codes 13492, 13500, 13502, GOP 86512, 86516) / €268 / €215 / €322 / [13]
Chemotherapy infusion, 4 hours (EBM code 01511) / €97 / €77 / €116 / [13]
Chemotherapy infusion, 30 minutes (EBM code 02100) / €6 / €5 / €7 / [13]
Outpatient visit (dermatology) / €19 / €15 / €23 / [13]
Outpatient visit (internal medicine) / €65 / €53 / €79 / [13]
Red blood cell transfusion (incl. EBM codes 02110, 02111, 32540, 32545, 32556) / €155 / €77 / €232 / [13]
Platelet transfusion (incl. EBM codes 02110, 32540) / €506 / €405 / €607 / [13]
Medical services (inpatient)
Bronchscopic biopsy of pulmonary nodules, with one day hospital stay (or mean length of stay) (G-DRG E71B) / €796
(€1,992) / €636
(€1,594) / €955
(€2,390) / [14]
Costs / Unit costs 2014 / Upper / Lower / Reference
± 20%
Percutaneous needle aspiration biopsy of pulmonary nodules, with 1 day hospital stay (or mean length of stay) (G-DRG E71A) / €1,645 (€4,328) / €1,316
(€3,462) / €1,974
(€5,194) / [14]
Biopsy of metastatic sites, with one day hospital stay (or mean length of stay) (G-DRG E02C) / €2,064.56 (€4,338) / €1,653
(€3,470) / €2,478
(€5,205) / [14]
Hospitalization for pneumothorax (G-DRG E76C) / €3,005 / €2,404 / €3,606 / [14]
Hospitalization for hemorrhage, with one day hospital stay (G-DRG X62Z) / €695 / €556 / €833 / [14]
IV chemotherapy admission with one day hospital stay (G-DRG E71B) / €796 / €636 / €955 / [14]
Oncology day fee / €150 / €120 / €180 / University hospital of Munich
1 day hospital stay for rash (G-DRG J68B) / €612 / €490 / €735 / [14]
Hospitalization for diarrhea (G-DRG G67C) / €1,402 / €1,121 / €1,682 / [14]
Hospitalization for fatigue (G-DRG Z65Z) / €1,610 / €1,288 / €1,932 / [14]
1 day hospital stay for anemia (Q61D) / €944 / €755 / €1,133 / [14]
1 day hospital stay for aminotransferase rise (G-DRG Z65Z) / €701 / €561 / €841 / [14]
1 day hospital stay for non-febrile neutropenia (G-DRG Q60C) / €811 / €649 / €974 / [14]
Hospitalization for febrile neutropenia (G-DRG T64B) / €3,289 / €2,632 / €3,947 / [14]
1 day hospital stay for thrombocytopenia (G-DRG Q60C) / €811 / €649 / €974 / [14]
Hospitalization for anorexia (G-DRG K62B) / €1,957 / €1,566 / €2,349 / [14]
Base case (mean) / Lower / Upper / Reference
Discount rate (per annum) / 0.03 / 0.00 / 0.05
a Each probability was varied while the remaining proportions were adjusted by the same percentage to ensure that the sum of probabilities adds up to one.
Adeno, adenocarcinoma; EBM, ambulatory physicians’ fee schedule (“Einheitlicher Bewertungsmaßstab”); G-DRG, German Diagnosis Related Groups; GOP, fee schedule position ("Gebührenordnungsposition"); incl, including; IV, intravenous; OS, overall survival; NSCLC, non-small cell lung cancer; PFS, progression-free survival
Webfig. 1 Survival curves in patients with first-line erlotinib or chemotherapy in locally advanced/metastatic non-small-cell lung cancer. The original curves from the clinical trial are shown, together with the Weibull and Exponential model estimated for progression-free survival (lower curves) and overall survival (upper curves) separately.
OS, overall survival; PFS, progression-free survival
Webfig. 2 Survival curves in patients with first-line erlotinib or chemotherapy in locally advanced/metastatic non-small-cell lung cancer. The original curves from the clinical trial are shown, together with the flexible spline model estimated for progression-free survival (lower curves) and overall survival (upper curves).
OS, overall survival; PFS, progression-free survival
Webfig. 3 Two-way sensitivity analysis of EGFR mutation prevalence and costs of mutation analysis. Base case values are indicated by horizontal and vertical lines, respectively. Shaded areas represent specified ICER or dominance of individualized strategy vs. non-individualized strategy.
EGFR, epidermal growth factor receptor; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life years
Webfig. 4 Probabilistic sensitivity analysis of individualized strategy versus non-individualized strategy, assuming no uncertainty in the PFS and OS curves. Scatter plot based on 10,000 replications.
Base case ICER was €15,577/QALY compared to non-individualized strategy. The 95% confidence interval ranges from €131to €309 (mean €200) for incremental costs and from 0,009 to 0,017 (mean 0,013) for incremental effects.
OS, overall survival; PFS, progression-free survival; QALYs, quality-adjusted life years
Webfig. 5 Cost-effectiveness acceptability curve (CEAC) of individualized strategy, assuming no uncertainty in survival curves
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