Soft tissue sarcomas are a heterogeneous group of rare malignant tumours originating from connective tissue [
Patients with advanced soft tissue sarcoma (ASTS) present with either locally advanced “inoperable” or metastatic disease [
Palliative chemotherapy is the mainstay of treatment for ASTS where the aim is to establish disease control and improve both quantity and quality of life. Sarcomas have proved resistant to many conventional cytotoxic therapies with only doxorubicin and ifosfamide showing significant response rates when used alone or in combination as first-line treatments [
Trabectedin is a newly licensed chemotherapeutic agent for the treatment of ASTS, with demonstrable clinical response and an acceptable toxicity profile [
A systematic literature search was performed using the search term of ASTS plus one of the following: incidence, prevalence, epidemiology, doxorubicin or Adriamycin and/or ifosfamide, liposomal doxorubicin or Caelyx, ifosfamide and epirubicin, trabectedin or ecteinascidin-743, gemcitabine and/or docetaxel, gemcitabine and dacarbazine, gemcitabine and vinorelbine, gemcitabine and paclitaxel, trofosfamide and/or etoposide, CYVADIC or cyclophosphamide and vincristine and Adriamycin and dacarbazine, utilities, quality of life, cost effectiveness, cost utility, resource utilisation, and economics and cost. The search strategy was not limited by year of publication; English, Italian, Spanish, and Swedish language papers were included. A manual literature search was also undertaken, based on citations in the published papers.
The search included studies published between 1988 and 2010 and included prospective and retrospective studies, randomised and nonrandomised studies, multicentre trials, single centre reports, and clinical reviews. Publications that only reported outcomes for specific subtypes of ASTS were excluded. The review yielded 53 different studies providing data on 2,977 patients. Analysis of the publications provided an estimate of the probability of patients achieving complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD), the median duration of each type of response, survival rates, the incidence of grades 3-4 haematological complications including the incidence of anaemia, febrile neutropenia, neutropenia, and thrombocytopenia.
The literature search was unable to find any health economic studies on ASTS in Italy, Spain, or Sweden. Hence, estimates of healthcare resource use were obtained by interviewing six oncologists in each country who treated patients with sarcoma. The interviews used a structured questionnaire and focused on patient management and resource utilisation.
A Markov model was constructed depicting the management of a 65-year-old patient with ASTS (Figure
Markov model depicting the management of ASTS in Italy, Spain, and Sweden.
All patients enter the model with PD and receive treatment with either doxorubicin/ifosfamide or trabectedin. Within the model, following first-line chemotherapy, patients can remain in the PD health state, move into one of the other three health states (i.e., CR, PR, or SD), or die. Patients remain in the CR, PR, and SD health states for the median duration of response, before moving to the PD health state. The model assumed that patients who remain in the PD health state would be switched to a second-line chemotherapy after three cycles of their first-line treatment.
After second-line chemotherapy, patients can again remain in the PD health state, move into one of the other three health states, or they can die. The model only considered first- and second-line chemotherapies. Therefore, following failure of second-line chemotherapy, patients with disease progression were assumed to only receive palliative care alone.
Within the model, patients in any health state can die from age-related factors in accordance with the background death rate. Additionally, patients in the PD health state can die from ASTS-related factors.
No publications were identified that quantified healthcare resource use for the management of ASTS in Italy, Spain, or Sweden. Therefore, this was estimated using information obtained from interviews with six oncologists in each country who managed ASTS and who collectively saw
According to the interviewees, patients would be seen on an outpatient basis and would have a mean of 3 visits before a diagnosis of ASTS is confirmed. The tests and procedures performed during the diagnostic phase depend on the site of the disease and the histological sub-type of sarcoma. Nevertheless, all patients would have a full clinical examination and undergo the following diagnostic procedures: blood tests (100% of patients), other nonspecified pathological tests (100% of patients), biopsy (50–100% of patients), computerized tomography (CT scan; 75–100% of patients), magnetic resonance imaging (MRI; 40–80% of patients), positron emission tomography (PET scan; 5–35% of patients), chest X-ray (10–20% of patients), and ultrasound scan (5–50% of patients). Also, patients would be assessed for their performance status using the Eastern Cooperative Oncology Group (ECOG) scales and criteria, with regard to disease progression and its influence on patients’ daily living abilities [
Probabilities of receiving second-line treatments.
Regimen | Probability of receiving second-line treatment in | ||
---|---|---|---|
Italy | Spain | Sweden | |
Following first-line treatment with doxorubicin/ifosfamide | |||
CYVADIC∧ | <0.01 | <0.01 | 0.10 |
Gemcitabine/dacarbazine | <0.01 | 0.12 | <0.01 |
Gemcitabine/docetaxel | 0.18 | 0.20 | 0.48 |
Gemcitabine/paclitaxel | <0.01 | 0.10 | <0.01 |
Gemcitabine/vinorelbine | <0.01 | 0.08 | <0.01 |
Gemcitabine monotherapy | <0.01 | 0.12 | <0.01 |
Ifosfamide monotherapy | 0.20 | 0.12 | <0.01 |
Liposomal doxorubicin | 0.12 | <0.01 | <0.01 |
Trofosfamide | <0.01 | <0.01 | 0.12 |
Trabectedin monotherapy | 0.50 | 0.26 | 0.30 |
Following first-line treatment with trabectedin monotherapy | |||
Docetaxel monotherapy | 0.26 | <0.01 | <0.01 |
Doxorubicin/ifosfamide | <0.01 | <0.01 | 0.67 |
Doxorubicin monotherapy | <0.01 | <0.01 | <0.01 |
Gemcitabine/docetaxel | 0.05 | 0.44 | 0.25 |
Ifosfamide/epirubicin | 0.16 | <0.01 | <0.01 |
Ifosfamide monotherapy | 0.53 | 0.56 | <0.01 |
Trofosfamide/etoposide | <0.01 | <0.01 | 0.08 |
∧CYVADIC: cyclophosphamide, vincristine, adriamycin, and dacarbazine.
It has to be noted that treatment patterns identified during the clinician interviews are only indicative, since a significant proportion of patients would be enrolled in clinical trials or only managed with palliative care following treatment failure.
There are no established third-line treatments for ASTS, and any chemotherapy drug that has not been used along the treatment pathway could be used as a third-line treatment and subsequently. Third-line treatments depend on many factors, including previous treatments, the patients’ ECOG performance status, their preferences, the histological sub-type of sarcoma, and the level of tolerable toxicity. Consequently, only second-line treatments have been modelled in the present study. Patients who remain alive following failure of a second-line treatment were assumed to only receive palliative care.
The characteristics of all the chemotherapy regimens utilised by the interviewees that have been incorporated in the model are summarised in Table
Characteristics of chemotherapy regimens incorporated into the model.
Regimen | Mean dose per cycle | Admissions/outpatient clinic attendances per cycle |
---|---|---|
CYVADIC∧ | 600 mg/m2 cyclophosphamide | 4 outpatient clinic attendances |
1 mg/m2 vincristine | ||
30 mg/m2 doxorubicin | ||
250 mg/m2 dacarbazine | ||
Docetaxel | 100 mg/m2 docetaxel | 1 outpatient clinic attendance |
Doxorubicin | 75 mg/m2 doxorubicin | 1 outpatient clinic attendance |
Doxorubicin/ifosfamide | 66 mg/m2 doxorubicin | 3-4-day admission |
8.5 g/m2 ifosfamide | ||
Ifosfamide | 12.5 g/m2 ifosfamide | 4-day admission or 2 outpatient clinic attendances |
Ifosfamide/epirubicin | 100 mg/m2 epirubicin | 3-day admission |
5 g/m2 ifosfamide | ||
Gemcitabine | 1,000 mg/m2 gemcitabine | 2 outpatient clinic attendances |
Gemcitabine/dacarbazine | 1,766 mg/m2 gemcitabine | 2 outpatient clinic attendances |
700 mg/m2 dacarbazine | ||
Gemcitabine/docetaxel | 1,000 mg/m2 gemcitabine | 2 outpatient clinic attendances |
75 mg/m2 docetaxel | ||
Gemcitabine/paclitaxel | 1,000 mg/m2 gemcitabine | 2 outpatient clinic attendances |
125 mg/m2 paclitaxel | ||
Gemcitabine/vinorelbine | 1,250 mg/m2 gemcitabine | 2 outpatient clinic attendances |
25 mg/m2 vinorelbine | ||
Liposomal doxorubicin | 50 mg/m2 doxorubicin | 1 outpatient clinic attendance |
Trabectedin | 1.3 mg/m2 trabectedin | 2-day admission |
Trofosfamide | 200 mg/m2 trofosfamide | Oral administration over ~10 days, no hospital attendance |
Trofosfamide/etoposide | 150 mg/m2 trofosfamide | Oral administration over ~10 days, no hospital attendance |
25 mg/m2 etoposide |
∧CYVADIC: cyclophosphamide, vincristine, adriamycin, and dacarbazine.
Approximately 6–30% of patients experiencing haematological toxicity require dose adjustments, which are very individual and depend on a patient’s weight, their tolerance levels, and general performance status. Normally, the chemotherapy dose for the next cycle would be reduced by
Following completion of the chemotherapy phase, patients with complete or partial response would be seen every 3–6 months by oncologists and radiotherapists only. In some cases patients may require closer monitoring. Those with stable disease would be seen anywhere between every 3 weeks and every 3 months by oncologists and radiotherapists.
In all three countries a granulocyte-colony-stimulating factor (G-CSF, filgrastim 6 mg) would be administered to prevent neutropenia in
All patients receiving an ifosfamide-containing chemotherapy would also receive mesna. Typically, the dose of mesna administered would be the same as the ifosfamide dose.
Clinical outcomes associated with the management of ASTS were estimated from the literature review. Published clinical outcomes analysed included the probability of achieving CR, PR, SD, and PD (Table
Efficacy rates and duration of response associated with different chemotherapy regimens for ASTS.
Probability of achieving: | Median duration of response (months) in: | ||||||
---|---|---|---|---|---|---|---|
Complete remission | Partial remission | Stable disease | Progressive disease | Complete remission | Partial remission | Stable disease | |
First-line treatments | |||||||
Doxorubicin/ifosfamide | 0.06 | 0.21 | 0.38 | 0.35 | 15.44 | 7.69 | 6.41 |
[ |
[ |
[ |
[ |
[ |
[ |
[ | |
Trabectedin | 0.03 | 0.11 | 0.14 | 0.72 | 17.74 | 8.75 | 7.48 |
[ |
[ |
[ |
[ |
[ |
[ |
[ | |
Second-line treatments | |||||||
CYVADIC*∧ | 0.03 | 0.19 | 0.39 | 0.39 | 12.13 | 6.57 | 5.75 |
Docetaxel | 0.00 | 0.11 | 0.25 | 0.64 | 0.00 | 6.60 | 7.17 |
[ |
[ |
[ |
[ |
[ |
[ |
[ | |
Doxorubicin | 0.02 | 0.07 | 0.31 | 0.61 | 12.13* | 6.57* | 5.75* |
[ |
[ |
[ |
[ |
||||
Doxorubicin/ifosfamide | 0.05 | 0.27 | 0.37 | 0.31 | 12.13* | 6.57* | 5.75* |
[ |
[ |
[ |
[ |
||||
Gemcitabine | 0.00 | 0.08 | 0.33 | 0.59 | 0.00 | 4.46 | 3.86 |
[ |
[ |
[ |
[ |
[ |
[ |
[ | |
Gemcitabine/dacarbazine | 0.01 | 0.10 | 0.39 | 0.51 | 10.48 | 6.50 | 5.79 |
[ |
[ |
[ |
[ |
[ |
[ |
[ | |
Gemcitabine/docetaxel | 0.05 | 0.19 | 0.41 | 0.35 | 12.13* | 6.57* | 5.75* |
[ |
[ |
[ |
[ |
||||
Gemcitabine/paclitaxel* | 0.03 | 0.19 | 0.39 | 0.39 | 12.13 | 6.57 | 5.75 |
Gemcitabine/vinorelbine | 0.02 | 0.10 | 0.10 | 0.78 | 16.10 | 16.10 | 9.60 |
[ |
[ |
[ |
[ |
[ |
[ |
[ | |
Ifosfamide | 0.02 | 0.13 | 0.24 | 0.61 | 13.77 | 8.75 | 7.61 |
[ |
[ |
[ |
[ |
[ |
[ |
[ | |
Ifosfamide/epirubicin* | 0.05 | 0.27 | 0.37 | 0.31 | 12.13 | 6.57 | 5.75 |
Liposomal doxorubicin* | 0.02 | 0.07 | 0.31 | 0.61 | 12.13 | 6.57 | 5.75 |
Trabectedin | <0.01 | 0.07 | 0.44 | 0.49 | 16.14 | 10.25 | 8.91 |
[ |
[ |
[ |
[ |
[ |
[ |
[ | |
Trofosfamide | 0.00 | 0.03 | 0.19 | 0.79 | 12.13* | 6.57* | 5.75* |
[ |
[ |
[ |
[ |
||||
Trofosfamide/etoposide* | 0.03 | 0.19 | 0.39 | 0.39 | 12.13 | 6.57 | 5.75 |
*Values were estimated. ∧CYVADIC: cyclophosphamide, vincristine, adriamycin and dacarbazine.
Probabilities of patients developing haematological toxicities stratified by chemotherapy regimen.
Probability of developing | ||||
---|---|---|---|---|
neutropenia | febrile neutropenia | thrombocytopenia | anaemia | |
First-line treatments | ||||
Doxorubicin/ifosfamide | 0.82 | 0.12 | 0.23 | 0.35 |
[ |
[ |
[ |
[ | |
Trabectedin | 0.33 | 0.00 | 0.00 | 0.03 |
[ |
[ |
[ |
[ | |
Second-line treatments | ||||
CYVADIC*∧ | 0.52 | 0.19 | 0.17 | 0.16 |
Docetaxel | 0.90 | 0.12 | 0.03 | 0.08 |
[ |
[ |
[ |
[ | |
Doxorubicin | 0.84 | 0.19 | 0.09 | 0.18* |
[ |
[ |
[ |
||
Doxorubicin/ifosfamide* | 0.52 | 0.19 | 0.17 | 0.18 |
Gemcitabine | 0.18 | 0.07 | 0.18 | 0.11 |
[ |
[ |
[ |
[ | |
Gemcitabine/dacarbazine | 0.46 [ |
0.19* | 0.12 [ |
0.23 [ |
Gemcitabine/docetaxel | 0.31 | 0.09 | 0.33 | 0.18 |
[ |
[ |
[ |
[ | |
Gemcitabine/paclitaxel* | 0.52 | 0.19 | 0.17 | 0.16 |
Gemcitabine/vinorelbine | 0.38 [ |
0.08 [ |
0.10 [ |
0.05 [ |
Ifosfamide | 0.82 | 0.39 | 0.13 | 0.12 |
[ |
[ |
[ |
[ | |
Ifosfamide/epirubicin* | 0.52 | 0.19 | 0.17 | 0.18 |
Liposomal doxorubicin* | 0.07 | 0.02 | 0.00 | 0.35 |
Trabectedin | 0.50 | 0.06 | 0.16 | 0.18 |
[ |
[ |
[ |
[ | |
Trofosfamide | 0.52* | 0.19* | 0.17* | 0.25 [ |
Trofosfamide/etoposide* | 0.52 | 0.19 | 0.17 | 0.16 |
∧CYVADIC: cyclophosphamide, vincristine, adriamycin, and dacarbazine.
*Values were estimated.
Survival rates associated with first-line treatment with doxorubicin/ifosfamide and trabectedin.
Survival rates associated with second-line treatments.
The outcomes from studies in which doxorubicin/ifosfamide and trabectedin were used as first-line chemotherapies are shown separately from those studies in which these agents were used as second-line treatments. The literature review could not identify any publications reporting efficacy rates for second-line chemotherapy with CYVADIC (cyclophosphamide, vincristine, adriamycin, and dacarbazine), trofosfamide/etoposide, and gemcitabine/paclitaxel. Therefore, the efficacy rates for these cytotoxic agents were assumed to be the average of all the efficacy rates that were available for second-line chemotherapy (i.e., doxorubicin/ifosfamide, gemcitabine/docetaxel, and gemcitabine/dacarbazine). Also, efficacy rates for second-line chemotherapy with ifosfamide/epirubicin were assumed to be the same as those for doxorubicin/ifosfamide, as they were both ifosfamide-containing regimens, and the rates for liposomal doxorubicin were assumed to be the same as those for doxorubicin monotherapy since both are anthracyclines.
The literature review could not identify any publications reporting median duration of response following second-line chemotherapy with doxorubicin/ifosfamide, doxorubicin monotherapy, ifosfamide/epirubicin, gemcitabine/docetaxel, gemcitabine/paclitaxel, trofosfamide, trofosfamide/etoposide, CYVADIC, and liposomal doxorubicin monotherapy. Hence, the reported average median duration of response associated with second-line ifosfamide monotherapy, gemcitabine/dacarbazine, and gemcitabine monotherapy was used to estimate the median duration of response associated with these regimens, since the median duration of response was only available for these second-line regimens. It was decided to exclude trabectedin’s duration of response from this extrapolation since it was the only new generation chemotherapeutic agent.
Table
The estimated survival rates following first-line treatment with doxorubicin/ifosfamide and trabectedin monotherapy that have been incorporated in the model are shown in Figure
Also not reported was the incidence of grades 3-4 haematological complications following second-line treatment with liposomal doxorubicin monotherapy. The relationship between the incidence rates associated with first-line doxorubicin monotherapy and liposomal doxorubicin monotherapy was used to estimate the missing incidence rates. This assumption was made on the basis that liposomal doxorubicin monotherapy has equivalent activity to doxorubicin monotherapy treatment [
Table
Health state utilities for ASTS elicited from the general public using time trade-off methodology were assigned to the health states in our model [
By assigning unit costs in Euros at 2010/2011 prices (Table
Unit resource costs (in Euros at 2010/2011 prices) used in the model.
Resource | Unit costs (in Euros at 2010/2011 prices) | |||||
---|---|---|---|---|---|---|
Italy | Spain | Sweden | ||||
Aprepitant (125 mg) | €90.9 | [ |
€63.8 | [ | ||
Betapred (4 mg) | €6.4 | [ | ||||
Betamethasone (8 mg) | €3.2 | [ | ||||
Biopsy | €129.1 | [ |
€603.7 | [ |
€314.1 | [ |
Bone scintigraphy | €296.8 | [ |
||||
Chest X-ray | €16.2 | [ |
€6.5 | [ |
€48.7 | [ |
CT scan | €86.3 | [ |
€87.5 | [ |
€313.6 | [ |
Cyclophosphamide (200 mg) | €4.1 | [ | ||||
Dacarbazine (1000 mg) | €21.7 | [ |
||||
Dacarbazine (200 mg) | €8.9 | [ | ||||
Dexamethasone (0.75 mg, 10 tablets) | €1.1 | [ |
||||
Dexamethasone (1 mg, 30 tablets) | €3.0 | [ |
||||
Diphenhydramine (25 mg, 25 capsules) | €1.4 | [ |
||||
Docetaxel (10 mg) | €84.4 | [ |
||||
Docetaxel (100 mg) | €182.8 | [ |
||||
Docetaxel (80 mg) | €403.1 | [ | ||||
Doxorubicin (50 mg) | €119.5 | [ |
€4.1 | [ |
€59.8 | [ |
Echocardiography | €51.7 | [ |
€18.2 | [ |
€214.9 | [ |
Electrocardiogram | €13.0 | [ |
€13.5 | [ |
€334.2 | [ |
Epirubicin (50 mg) | €81.2 | [ |
||||
Etoposide (100 mg) | €20.8 | [ | ||||
Filgrastim (300 mcg) | €94.8 | [ |
||||
Filgrastim (6 mg) | €149.8 | [ |
||||
Gemcitabine (1000 mg) | €113.2 | [ |
€75.7 | [ |
€104.6 | [ |
General surgeon consultation | €230.3 | [ | ||||
Granisetron (1 mg, 10 tablets) | €133.9 | [ |
€48.1 | [ |
||
Haematology tests | €3.7 | [ |
€20.5 | [ |
€5.2 | [ |
Hospitalisation for chemotherapy infusion/day | €238.3 | [ |
€212.9 | [ |
€288.6 | [ |
Ifosfamide (1 g) | €30.7 | [ |
€19.7 | [ |
||
Ifosfamide (2 g) | €65.7 | [ | ||||
Lenograstim (1 vial) | €153.4 | [ |
||||
Levocetirizine (5 mg, 20 tablets) | €10.5 | [ |
||||
Liver function test | €9.2 | [ |
€11.7 | [ |
||
Liposomal doxorubicin (2 mg) | €548.2 | [ |
||||
Managing anaemia | €1,354.8 | [ |
€900.0 | [ |
€548.6 | [ |
Managing febrile neutropenia | €3,305.0 | [ |
€3829.5 | [ |
€2,892.0 | [ |
Managing neutropenia | €523.3 | [ |
€2086.1 | [ |
||
Managing thrombocytopenia | €1,354.8 | [ |
€900.0 | [ |
€548.6 | [ |
Mesna (3 g) | €13.2 | [ |
||||
Mesna (6 g) | €25.7 | [ |
||||
Mesna (5 g) | €192.2 | [ | ||||
Metoclopramide (250 mL) | €2.7 | [ |
||||
MRI scan | €285.8 | [ |
€168.0 | [ |
€386.4 | [ |
Multidisciplinary team assessment | €48.7 | [ |
€61.3 | [ |
€1,816.5 | [ |
Nuclear medicine specialist consultation | €61.5 | [ |
||||
Nurse home visit | €51.2 | [ |
€56.5 | [ |
||
Oncologist consultation | €21.6 | [ |
€61.5 | [ |
€283.7 | [ |
Ondansetron (4 mg, 6 tablets) | €57.8 | [ |
||||
Ondansetron (4 mg, 15 tablets) | €36.3 | [ |
||||
Orthopaedic surgeon consultation | €21.6 | [ |
€61.5 | [ |
€102.4 | [ |
Outpatient attendance for chemotherapy | €122.8 | [ |
€98.9 | [ |
€288.6 | [ |
Paclitaxel (30 mg) | €83.8 | [ |
||||
Palliative care per patient | €3,265.0 | [ |
€2167.7 | [ |
€1,343.9 | [ |
Palonosetron (250 mcg) | €104.6 | [ |
||||
Pathologist consultation | €21.6 | [ |
€61.5 | [ |
||
Pegfilgrastim (1 syringe) | €1,062.6 | [ |
€1,322.5 | [ | ||
PET scan | €1,071.7 | [ |
€500.0 | [ |
€314.1 | [ |
Radiologist consultation | €21.6 | [ |
€61.5 | [ |
||
Radiotherapist consultation | €21.6 | [ |
€61.5 | [ |
||
Renal function test | €5.0 | [ |
€8.9 | [ |
||
Secondary care hospital specialist visit | €61.5 | [ |
||||
Trabectedin (1 mg, 1 vial) | €2,970.1 | [ |
€2,049.9 | [ |
€1,913.3 | [ |
Trofosfamide 50 mg/m2 | €1.4 | [ | ||||
Tropisetron (5 mg) | €20.5 | [ | ||||
Ultrasound scan | €17.6 | [ |
€18.2 | [ |
||
Urine analysis | €6.1 | [ |
€1.8 | [ |
€20.9 | [ |
Vincristine (1 mg) | €16.2 | [ | ||||
Vinorelbine (1 mL) | €24.1 | [ |
In Sweden unit costs were converted from Swedish Krona (SEK) to Euros at the rate of €1 = 9.55 SEK.
The primary measure of clinical effectiveness in the model was the number of quality-adjusted life years (QALYs) two years after starting first-line treatment with doxorubicin/ifosfamide or trabectedin monotherapy. The model also estimated successful treatment at two years in terms of the proportion of patients achieving CR, PR, and SD.
In accordance with the guidelines for economic evaluations in Italy [
The incremental cost effectiveness of doxorubicin/ifosfamide compared to trabectedin monotherapy was calculated as the difference between the expected discounted costs of the two treatment strategies over 2 years divided by the difference between the expected discounted number of QALYs of the two strategies over 2 years. Hence, the incremental cost effectiveness of doxorubicin/ifosfamide compared to trabectedin monotherapy was defined as the cost per QALY gained. If a treatment resulted in more QALYs for less cost, it was defined as a dominant treatment.
Probabilistic sensitivity analyses (PSA) using Monte Carlo iterations (10,000 iterations of the model) were undertaken by simultaneously varying all the probabilities, utilities, unit costs, and resource use values within the model. The probabilities and utilities were varied randomly according to a beta distribution and the resource use estimates and unit costs were varied randomly according to a gamma distribution. Results from these analyses were used to construct cost effectiveness acceptability curves showing the probability of first-line treatment with doxorubicin/ifosfamide compared to trabectedin monotherapy to be cost effective at varying cost per QALY thresholds.
Deterministic sensitivity analyses were also performed to assess the impact of independently varying individual parameter values within the model. The parameter estimates were varied over plausible ranges by altering them to 20% below and 20% above the base case values.
The outcomes at two years following initial treatment with doxorubicin/ifosfamide or trabectedin are summarised in Table
Clinical outcomes at two years.
Italy | Spain | Sweden | ||||
---|---|---|---|---|---|---|
Doxorubicin/ifosfamide | Trabectedin | Doxorubicin/ifosfamide | Trabectedin | Doxorubicin/ifosfamide | Trabectedin | |
Probability of | ||||||
complete response | 0.01 | <0.01 | <0.01 | <0.01 | <0.01 | 0.01 |
partial response | 0.01 | <0.01 | 0.01 | <0.01 | 0.01 | 0.01 |
stable disease | 0.02 | 0.01 | 0.02 | 0.01 | 0.02 | 0.01 |
progressive disease | 0.54 | 0.51 | 0.54 | 0.53 | 0.54 | 0.59 |
dying | 0.43 | 0.47 | 0.42 | 0.45 | 0.42 | 0.39 |
Number of QALYs per patient | 0.595 (0.593, 0.597) | 0.530 (0.528, 0.533) | 0.590 (0.587, 0.593) | 0.550 (0.547, 0.553) | 0.608 (0.606, 0.611) | 0.584 (0.582, 0.587) |
95% confidence intervals in parentheses.
The expected costs at two years following initial treatment with doxorubicin/ifosfamide or trabectedin are summarised in Table
Expected healthcare costs (at 2010/2011 prices) over 2 years following first-line treatment with doxorubicin/ifosfamide combination and trabectedin monotherapy.
Resource | Expected healthcare costs per patient (Euros at 2010/2011 prices) over 2 years following first-line treatment | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Italy | Spain | Sweden | ||||||||||
Doxorubicin/ifosfamide | Trabectedin | Doxorubicin/ifosfamide | Trabectedin | Doxorubicin/ifosfamide | Trabectedin | |||||||
Diagnosis | €634.4 | (2%) | €634.4 | (2%) | €1886.5 | (6%) | €1886.5 | (6%) | €2416.8 | (7%) | €2416.8 | (6%) |
First-line cytotoxics | €2302.9 | (6%) | €26885.4 | (66%) | €1491.8 | (5%) | €18432.1 | (54%) | €3172.2 | (9%) | €17934.5 | (45%) |
Second-line cytotoxics | €17007.3 | (44%) | €2556.9 | (6%) | €6524.1 | (21%) | €1761.6 | (5%) | €8469.5 | (23%) | €3224.8 | (8%) |
Evaluations of response | €2025.7 | (5%) | €1641.7 | (4%) | €1280.4 | (4%) | €1098.7 | (3%) | €2758.0 | (8%) | €2453.2 | (6%) |
Hospitalisations for chemotherapy infusion | €5093.0 | (13%) | €3765.6 | (9%) | €4704.7 | (15%) | €3564.3 | (10%) | €4326.8 | (12%) | €3685.2 | (9%) |
Outpatient attendances for chemotherapy | €291.3 | (<1%) | €338.0 | (1%) | €560.9 | (2%) | €423.4 | (1%) | €998.6 | (3%) | €439.0 | (1%) |
Tests before each cycle of chemotherapy | €212.5 | (<1%) | €118.0 | (<1%) | €266.2 | (1%) | €197.9 | (1%) | €244.3 | (1%) | €217.0 | (1%) |
Pre- and postchemotherapy medication | €5706.9 | (15%) | €1107.3 | (3%) | €7621.1 | (25%) | €1665.8 | (5%) | €11732.4 | (32%) | €7458.6 | (19%) |
Palliative care | €2918.9 | (8%) | €1773.3 | (4%) | €1942.7 | (6%) | €1932.3 | (6%) | €1200.9 | (3%) | €1265.9 | (3%) |
Management of haematological toxicity | €2728.6 | (7%) | €1811.1 | (4%) | €4421.0 | (14%) | €3233.7 | (9%) | €1187.2 | (3%) | €685.2 | (2%) |
| ||||||||||||
Total | €38921.7 | (100%) | €40631.7 | (100%) | €30699.4 | (100%) | €34196.3 | (100%) | €36506.7 | (100%) | €39780.2 | (100%) |
(Percentage of total expected cost is in parenthesis).
In Spain and Sweden the primary cost driver in patients starting chemotherapy with doxorubicin/ifosfamide was the cost of pre- and postchemotherapy medications. However, in Italy, the primary cost driver was the cost of second-line chemotherapy regimens. In all three countries, the primary cost driver in patients starting chemotherapy with trabectedin was the acquisition cost of this cytotoxic agent (Table
Starting treatment with doxorubicin/ifosfamide instead of trabectedin monotherapy is expected to lead to a cost reduction of €1,710 in Italy, €3,497 in Spain, and €3,274 in Sweden. Additionally, starting treatment with doxorubicin/ifosfamide instead of trabectedin monotherapy is expected to lead to an improvement in health status at two years of 0.07 QALYs in Italy, 0.04 QALYs in Spain, and 0.02 QALYs in Sweden. Hence, doxorubicin/ifosfamide was found to be a dominant treatment relative to trabectedin in all three countries with a cost per QALY of −€26,308, −€87,423, and −€136,396 in Italy, Spain, and Sweden, respectively.
Probabilistic sensitivity analyses highlighted the distribution in the incremental costs and QALYs at two years (Figure
Scatterplot of the incremental cost effectiveness of doxorubicin/ifosfamide compared to trabectedin monotherapy (10,000 iterations of each model).
Cost effectiveness acceptability curves generated from the probabilistic sensitivity analyses showed the probability of doxorubicin/ifosfamide to be cost effective compared to trabectedin monotherapy across a wide range of cost per QALY thresholds (Figure
Acceptability curves.
Extensive deterministic sensitivity analyses (Table
Sensitivity analyses.
Scenario | Base case value in Italy | Base case value in Spain | Base case value in Sweden | Effect |
---|---|---|---|---|
Duration of partial remission following first-line treatment with doxorubicin/ifosfamide ranges from 6.1 to 9.2 months | 7.7 months | 7.7 months | 7.7 months | Doxorubicin/ifosfamide remains a dominant treatment |
Duration of stable disease following first-line treatment with doxorubicin/ifosfamide ranges from 5.1 to 7.7 months | 6.4 months | 6.4 months | 6.4 months | Doxorubicin/ifosfamide remains a dominant treatment |
Duration of partial remission following first-line treatment with trabectedin ranges from 7.0 to 10.6 months | 8.8 months | 8.8 months | 8.8 months | Doxorubicin/ifosfamide remains a dominant treatment |
Duration of stable disease following first-line treatment with trabectedin ranges from 6.0 to 9.0 months | 7.5 months | 7.5 months | 7.5 months | Doxorubicin/ifosfamide remains a dominant treatment |
Probability of being in stable disease after first-line doxorubicin/ifosfamide ranges from 0.3 to 0.5 | 0.38 | 0.38 | 0.38 | Doxorubicin/ifosfamide remains a dominant treatment |
Probability of being in stable disease after first-line trabectedin ranges from 0.1 to 0.2 | 0.14 | 0.14 | 0.14 | Doxorubicin/ifosfamide remains a dominant treatment |
Probability of being in stable disease after second-line trabectedin ranges from 0.35 to 0.50 | 0.44 | 0.44 | 0.44 | Doxorubicin/ifosfamide remains a dominant treatment |
Probability of switching to trabectedin after first-line doxorubicin/ifosfamide ranges from 80% below to 20% above the base case value | 0.50 | 0.26 | 0.30 | Doxorubicin/ifosfamide remains a dominant treatment except in Italy where its costeffectiveness ranges from being dominant to €21,500 per QALY, breaking even at a probability of 0.55 |
Length of hospital stay for doxorubicin/ifosfamide infusion ranges from 1 to 5 days | 3 days | 4 days | 3 days | Doxorubicin/ifosfamide remains a dominant treatment except in Italy where its costeffectiveness ranges from being dominant to €16,400 per QALY, breaking even at 4 days |
Unit cost of doxorubicin ranges from 80% below to 20% above the base case value | €119.50 | €4.11 | €59.79 | Doxorubicin/ifosfamide remains a dominant treatment |
Unit cost of ifosfamide ranges from 80% below to 20% above the base case value | €30.71 | €19.71 | €65.65 | Doxorubicin/ifosfamide remains a dominant treatment |
Unit cost of trabectedin ranges from 80% below to 20% above the base case value | €2,970.10 | €2,049.91 | €1,913.29 | Doxorubicin/ifosfamide remains a dominant treatment except in Italy where its costeffectiveness ranges from €11,200 per QALY to being dominant, breaking even at €2,570 |
Cost of managing adverse events ranges from 80% below to 20% above the base case values | Doxorubicin/ifosfamide remains a dominant treatment | |||
Cost of pre- and postchemotherapy medications ranges from 80% below to 20% above the base case values | Doxorubicin/ifosfamide remains a dominant treatment | |||
Cost of palliative care ranges from 80% below to 20% above the base case values | Doxorubicin/ifosfamide remains a dominant treatment | |||
Utility for progressive disease ranges from 0.24 to 0.36 | 0.30 | 0.30 | 0.30 | Doxorubicin/ifosfamide remains a dominant treatment |
Utility for stable disease ranges from 0.34 to 0.52 | 0.43 | 0.43 | 0.43 | Doxorubicin/ifosfamide remains a dominant treatment |
Difference in QALYs gained following the start of treatment with doxorubicin/ifosfamide and trabectedin ranges from 80% below and 20% above the base case value | 0.07 | 0.04 | 0.02 | Doxorubicin/ifosfamide remains a dominant treatment |
Additionally, doxorubicin/ifosfamide remained a dominant treatment when the use of second-line treatments was excluded from the patients’ pathways, by assuming that those who do not respond to first-line chemotherapy, or those with disease progression, only receive palliative care. In these circumstances, starting chemotherapy with doxorubicin/ifosfamide or trabectedin is expected to lead to a two-year cost of €14,567 and €32,858 per patient, respectively, in Italy, €18,085 and €26,198 per patient, respectively, in Spain, €21,385 and €23,410 per patient, respectively, in Sweden.
Additionally, starting chemotherapy with doxorubicin/ifosfamide or trabectedin is expected to lead to 0.274 QALYs and 0.178 QALYs per patient, respectively, at two years, irrespective of country.
There have been several studies assessing the efficacy of first-line treatment of ASTS with trabectedin [
There are potential limitations with the model, mainly due to the combination of numerous sources and data assumptions. The clinical basis of the model was diverse studies that included patients with different types of ASTS, different severity of disease, different age of sufferers, different administration schedules, and prior treatments. Therefore, the patient populations may not be identical in all the studies. Consequently, the clinical outcomes observed in this study may not necessarily reflect those observed in clinical practice. Also, the Markov model was based on many assumptions pertaining to cancer-related mortality, chemotherapy efficacy rates, and duration of response. These assumptions were necessary due to the limited availability of data pertaining to some of the regimens employed by the interviewed oncologists. Nevertheless, these assumptions were tested using extensive deterministic and probabilistic sensitivity analyses and found to be robust to changes in the model inputs. Notwithstanding this, there is potential for confounding in this study due to the lack of any direct comparative evidence between the two first-line treatment regimens and some of the second-line treatment efficacy estimates are based on assumptions.
The literature search was unable to identify any published studies assessing healthcare resource utilisation and chemotherapy patterns for ASTS. Because of the low incidence of the disease, healthcare resource utilisation was not collected prospectively but was estimated from interviews with six oncologists in each country. Consequently, resource use for the “average clinician” throughout each country may not be the same as that for those clinicians who participated in this study.
The interviewees indicated that there are no treatment guidelines for the management of ASTS, and in Sweden, only ~20–30% of patients are covered by the Scandinavian Sarcoma Group protocol (SSG XX) [
The model incorporated resource use and utility values for an “average patient” and did not take into account stage of disease and patients’ characteristics such as age, gender, suitability of patients for different chemotherapy regimens, and other comorbidities. The model considered only direct healthcare costs borne by the secondary healthcare sector in each country and did not consider costs borne by the community. Moreover, the costs and consequences of managing patients who survive beyond two years are also excluded. Also, the study excluded costs incurred by patients, families, and/or their caregivers and indirect costs incurred by society as a result of patients taking time off work and/or not being able to lead productive lives, although the majority of patients are expected to have a mean age of 65 years. Consequently, inclusion of these costs may affect the study’s results and need to be studied further in larger populations.
First-line treatment with doxorubicin/ifosfamide was found to be cost effective when compared to first-line trabectedin monotherapy in Italy, Spain, and Sweden. In this study, patients’ health status, in terms of the number of QALYs at two years, is a reflection of the probability of being in different health states over the study period and the duration of being in each health state. According to the Markov model, first-line treatment with doxorubicin/ifosfamide yields more QALYs than with trabectedin monotherapy, irrespective of whether second-line chemotherapy is included in the analysis. Additionally, in all three countries use of doxorubicin/ifosfamide leads to lower two-year healthcare costs. Moreover, at a threshold of €35,000 per QALY, >90% of a cohort is expected to be cost effectively treated with doxorubicin/ifosfamide compared to trabectedin monotherapy in all three countries. The primary cost driver of managing patients in the trabectedin monotherapy group is the unit cost of this cytotoxic agent. Subsequent to completion of this study the results of the landmark EORTC62012 study comparing doxorubicin with doxorubicin/ifosfamide as first-line treatment for ASTS have been reported as an abstract [
In the absence of any published health economic studies assessing the cost effectiveness of treatments for the management of ASTS in any country, it is not known how the results of the present analysis would generalise to other settings and patient groups and whether all important factors for the decision under consideration have been taken into account. Nevertheless, within the limitations of the present study, doxorubicin/ifosfamide (or single agent doxorubicin [
In conclusion, within the model’s limitations, first-line treatment of patients with ASTS with doxorubicin/ifosfamide instead of trabectedin monotherapy affords a cost-effective use of publicly funded healthcare resources in Italy, Spain, and Sweden. These findings support the recommendation that trabectedin should remain a second/third-line treatment.
The authors wish to thank the following oncologists for their contributions to this study: Dr. R. Berardi, Azienda Ospedaliero, Universitaria Ospedali Riuniti Umberto I, Ancona, Italy; Dr. M. Berretta, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy; Dr. A. Comandone, Gradenigo Hospital and Gruppo Piemontese Sarcomi, Torino, Italy; Dr. M. C. Deidda, Policlinico Universitario di Monserrato, Cagliari, Italy; Dr. L. Tomasello, National Cancer Research Institute, Genoa, Italy; Dr. B. Vincenzi, University Campus Bio-Medico, Rome, Italy; Dr. C. Balaña, Hospital Germans Trias i Pujol, Badalona, Spain; Dr. J. M. Broto, Hospital Universitario Son Dureta, Palma De Mallorca, Spain; Dr. J. F. Gonzalez, Grupo Hospitalario Quirón, Pozuelo de Alarcón, Spain; Dr. V. M. Marín, Hospital Universitario La Paz, Madrid, Spain; Dr. A. L. Pousa, Hospital De Sant Pau, Barcelona, Spain; Dr. J. I. Verdum, Clínica Corachan, Barcelona, Spain; Dr. E. Lidbrink, Karolinska Institute, Stockholm, Sweden; Professor H. Hagberg, University Hospital, Uppsala, Sweden; Dr. K. Engström, Sahlgrenska University Hospital, Gothenburg, Sweden; Dr. M. Erlanson, University Hospital, Umeå, Sweden; Dr. M. Jerkeman, University Hospital, Lund, Sweden; and Dr. N. Wall, University Hospital, Linköping, Sweden. This study was supported by Baxter Healthcare, Zurich, Switzerland. However, Baxter Healthcare did not have any control of the methodology, conduct, results, or conclusion of this study or editorial involvement in this paper. The authors have no other conflict of interests that is directly relevant to the content of this paper, which remains their sole responsibility.