The EUROpean Bone Over 40 Sarcoma Study (EURO-B.O.S.S.) was the first prospective international study for patients 41-65 years old with high-grade bone sarcoma treated with an intensive chemotherapy regimen derived from protocols for younger patients with high-grade skeletal osteosarcoma.
Chemotherapy based on doxorubicin, cisplatin, ifosfamide, and methotrexate was suggested, but patients treated with other regimens at the investigators’ choice were also eligible for the study.
The present report focuses on the subgroup of 218 patients with primary high-grade osteosarcoma. With a median follow-up of 47 months, the 5-year probability of overall survival (OS) was 66% in patients with localized disease and 22% in case of synchronous metastases. The 5-year OS in patients with localized disease was 29% in pelvic tumors, and 70% and 73% for extremity or craniofacial locations, respectively.
In primary chemotherapy, tumor necrosis ≥90% was reported in 21% of the patients. There were no toxic deaths; however, hematological toxicity was considerable with 32% of patients experiencing 1 or more episodes of neutropenic fever. The incidence of nephrotoxicity and neurotoxicity (mainly peripheral) was 28% and 24%, respectively. After methotrexate, 23% of patients experienced delayed excretion, in 4 cases with nephrotoxicity.
In patients over 40 years of age with primary high-grade osteosarcoma, an aggressive approach with chemotherapy and surgery can offer the probability of survival similar to that achieved in younger patients. Chemotherapy-related toxicity is significant and generally higher than that reported in younger cohorts of osteosarcoma patients treated with more intensive regimens.
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Article Type: ORIGINAL RESEARCH ARTICLE
AuthorsStefano Ferrari, Stefan S. Bielack, Sigbjørn Smeland, Alessandra Longhi, Gerlinde Egerer, Kirsten Sundby Hall, Davide Donati, Matthias Kevric, Otte Brosjö, Alessandro Comandone, Mathias Werner, Odd Monge, Emanuela Palmerini, Wolfgang E. Berdel, Bodil Bjerkehagen, Anna Paioli, Sylvie Lorenzen, Mikael Eriksson, Marco Gambarotti, Per-Ulf Tunn, Nina L. Jebsen, Marilena Cesari, Thekla von Kalle, Virginia Ferraresi, Rudolf Schwarz, Rossella Bertulli, Anne-Katrin Kasparek, Giovanni Grignani, Fatime Krasniqi, Benjamin Sorg, Stefanie Hecker-Nolting, Piero Picci, Peter Reichardt
- • Accepted on 08/11/2017
- • Available online on 05/12/2017
This article is available as full text PDF.
Surgery combined with adjuvant or neoadjuvant chemotherapy is considered standard management of patients with osteosarcoma (1). Methotrexate (MTX), doxorubicin (Adriamycin [ADM]), cisplatin (CDP), and ifosfamide (IFO) are considered the drugs with proven efficacy against osteosarcoma (1) and have been used according to different schedules in chemotherapy protocols adopted in large studies (2-3-4-5-6-7). The peak incidence of osteosarcoma is in the second decade of life (1) and most of the studies with dose intensive chemotherapy include only patients up to the age of 40 years (2, 3, 5, 6).
Only a few study reports contain data on the use of chemotherapy in patients older than 40 years with high-grade osteosarcoma (8-9-10-11-12). The use of intensive chemotherapy regimens in this age group may be complicated by concomitant diseases and/or physiological changes occurring with aging, including decreased hematopoietic tissue activity as well as decreased renal function with its implications for delayed drug excretion and toxicity (13-14-15).
The rarity of primary high-grade osteosarcoma in adult and elderly patients requires collaborative efforts in order to collect prospective data. With this background, the Italian Sarcoma Group (ISG), the Cooperative Osteosarcoma Study Group (COSS), and the Scandinavian Sarcoma Group (SSG) started an intergroup cooperative study (European over 40 Bone Sarcoma Study, EURO-B.O.S.S., ClinicalTrials.gov ID: NCT02986503) with the aim of evaluating the activity and toxicity of chemotherapy on bone sarcoma patients in this age group. Data on survival and chemotherapy toxicity in the subgroup of patients with high-grade osteosarcoma are presented here.
EURO-B.O.S.S. was a prospective multicenter international study for 41- to 65-year old patients with high-grade bone sarcoma. The study enrolled patients with high-grade osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, leiomyosarcoma, dedifferentiated chondrosarcoma, and angiosarcoma treated with antineoplastic agents used in chemotherapy protocols for younger patients with high-grade skeletal osteosarcoma.
Written informed consent was signed by the patients before study entry. The study was approved by the Institutional Review Board of each participating group and/or center according to national and local rules.
Wide surgical removal of the primary tumor with the addition of systemic treatment based on ADM, CDP, IFO, MTX was the mainstay of the proposed treatment strategy. Patients treated with other regimens at the investigator’s choice were also eligible for the study.
Depending on the clinical features and the feasibility of adequate surgical removal of the tumor, patients were candidates for primary chemotherapy followed by postoperative chemotherapy, or purely adjuvant chemotherapy.
Pathological response to primary chemotherapy was determined according to the grading systems adopted by the participating groups: Huvos system for SSG (16), Salzer-Kuntschik system for COSS (17), and percentage of necrosis for ISG (18). For patients with a histologic response graded Huvos I, Salzer-Kuntschik 5-6 or less than 50% necrosis, MTX was to be added to the postoperative chemotherapy regimen, provided that glomerular function was adequate.
An outline of the scheme of the suggested chemotherapy regimen is reported in
Treatment schedule. ADM = Adriamycin 60 mg/m2, 24 hours IV; CDP = cisplatin 100 mg/m2, 48- to 72-hour continuous infusion IV; IFO = ifosfamide 3 g/m2/day 1- to 2-hour infusions, 2 days, dose per cycle 6 g/m²; IV = intravenous; MTX = methotrexate 8 g/m2, 4-hour infusion IV.
Considering the observational character of the study, patients who met the inclusion criteria and who were to receive other chemotherapy treatments according to institutional choice also could be enrolled in the study.
Surgical complete remission (SCR) was defined as complete surgical removal of all clinically detectable sites of disease (primary tumor and all metastases if metastatic disease was present). Patients who did not obtain complete surgical remission of all sites were recorded to have an event on Day 1. Event-free survival (EFS) was calculated from the date of the diagnostic biopsy to the date of the first of the following adverse events: death, distant or local recurrence, secondary malignancy or treatment-related death; or last follow-up. In SCR patients, disease-free survival (DFS) was calculated from the date of surgery to the date of distant or local recurrence or last follow-up. Overall survival (OS) was calculated from the date of the diagnostic biopsy to the date of death from any cause or last follow-up. Survival curves were calculated by the Kaplan-Meier method and compared using the log-rank test with their respective 95% confidence intervals (CI).
Chemotherapy toxicity was recorded according to National Cancer Institute expanded common toxicity criteria (version 2.0-March 1998) (19). Toxicity and clinical-related event assessment included evaluation of the incidence of hematologic and nonhematologic toxicity (renal, hepatic, and neurotoxicity), the use of granulocyte colony-stimulating factors (G-CSFs), episodes of neutropenic fever, red blood cell (RBC), and platelet (PLT) transfusions. Chi-square evaluated by Fisher’s exact test was used for the comparison of categories when appropriate. Student’s t-test or variance analyses were used to compare continuous variables.
When enrolment was closed in December 2014, 451 patients had been registered into EURO-B.O.S.S. Of these, 259 had osteosarcomas, and 222 primary high-grade osteosarcomas of bone, of which 218, (99 [45%] from COSS, 82 [38%] from ISG, 37 [17%] from SSG) were eligible for the present analysis. Due to missing data on the SCR status, 6 of the 63 patients with synchronous metastases and 4 of the 155 patients with localized disease had to be excluded from the DFS analysis (
Consort diagram. AWD = alive with disease; DFS = disease-free survival; DOC = died of other cause; DOD = died of disease; NED = no evidence of disease; NED II = no evidence of disease after recurrence; OS = overall survival; SCR = surgical complete remission.
They were included in the OS analysis.
Clinical characteristics are reported in
Clinical characteristics of study population
|No. of patients||Localized||Metastatic||p value|
|218||155 (71%)||63 (29%)|
|LDH = lactate dehydrogenase; NOS = high-grade osteosarcoma not otherwise specified; SAP = serum alkaline phosphatase.|
|* Available in 181 patients; normal/high according to the single center reference range.|
|** Available in 186 patients; normal/high according to the single center reference range.|
|Age Median (years)||51 (41-65)||51 (41-65)||50.5 (41-65)||0.8|
|Sex||Male||136 (62%)||95 (70%)||41 (30%)||0.6|
|Female||82 (38%)||60 (73%)||22 (27%)|
|Site||Axial||21 (10%)||14 (67%)||7 (33%)||0.01|
|Extremity||149 (68%)||110 (74%)||39 (26%)|
|Craniofacial||19 (9%)||17 (89%)||2 (11%)|
|Pelvis/Sacrum||29 (13%)||14 (48%)||15 (52%)|
|SAP*||Normal||118 (65%)||90 (76%)||28 (24%)||0.03|
|High||63 (35%)||38 (60%)||25 (40%)|
|LDH**||Normal||141 (76%)||112 (79%)||29 (21%)||0.002|
|High||45 (24%)||23 (51%)||22 (49%)|
|Histology||Osteoblastic||118 (54%)||81 (69%)||37 (31%)||0.3|
|Chondroblastic||28 (13%)||22 (79%)||6 (21%)|
|Fibroblastic||26 (12%)||21 (81%)||5 (19%)|
|Teleangiectatic||12 (6%)||10 (83%)||2 (17%)|
|NOS||34 (15%)||21 (62%)||13 (38%)|
Among 208 evaluable patients, 157 (76%) underwent tumor resection, 32 (15%) had an amputation, 1 had a rotationplasty, 1 a laminectomy, 17 (8%) did not undergo surgery of the primary tumor. SCR was more frequently obtained in localized disease and extremity tumors (
Surgical complete remission (SCR) by site and stage
|No. of patients||SCR||No SCR||p value|
|208||154 (74%)||54 (26%)|
|Stage||Localized||151||142 (94%)||9 (6%)||0.0001|
|Metastatic||57||12 (21%)||45 (79%)|
|Site||Axial||20||13 (65%)||7 (35%)||0.005|
|Extremity||141||114 (81%)||27 (19%)|
|Craniofacial||19||13 (68%)||6 (32%)|
|Pelvis/Sacrum||28||14 (50%)||14 (50%)|
Focusing on patients with localized disease, 110 of 151 (73%) received primary chemotherapy. Information on histologic response of the primary tumor was available for 106 (96%) patients. Overall 50 (47%) patients had less than 50% tumor necrosis and were therefore candidates for the postoperative addition of MTX. Chemotherapy-induced tumor necrosis ranging from 50% to 89% was reported in 34 (32%) patients, and 22 (21%) patients had ≥90% tumor necrosis.
The vast majority of patients (183, 84%) were treated according to the suggested chemotherapy regimen (135 patients with nonmetastatic and 48 with metastatic disease). The remaining 35 (16%) patients (20 patients with nonmetastatic and 15 with metastatic disease) received different schemes that included the same drugs – cisplatin, doxorubicin, and ifosfamide – but administered as single agent and not in combination.
With a median follow-up of 35 months (range: 1-153 months) for all patients and 56 months (1-153 months) for 108 survivors, the 151 patients with localized disease had a 5-year OS of 66% (95% CI, 57-75) and those 57 with synchronous metastases of 23% (95% CI, 6-39) (
Overall survival in localized and metastatic osteosarcoma. Upper line: patients with localized osteosarcoma. Lower line: patients with synchronous metastases.
In patients with localized disease, a worse probability of survival was observed for those with high baseline values of lactate dehydrogenase (LDH) and in pelvic locations (
Probability of survival by clinical characteristics in 151 patients with localized disease at diagnosis
|% 5-year OS (95% CI)||p value|
|CI = confidence interval; LDH = lactate dehydrogenase; NOS = high-grade osteosarcoma not otherwise specified; SAP = serum alkaline phosphatase.|
|* Available for 123 patients.|
|** Available for 130 patients.|
|Age||41-50 years||68 (56-81)||0.4|
|51-65 years||64 (52-76)|
Toxicity by cycle
|CDP/ADM n = 429||IFO/ADM n = 361||IFO/CDP n = 348|
|ADM = Adriamycin; CDP = cisplatin; IFO = ifosfamide; PLT = platelets; RBC = red blood cells; WBC = white blood cells.|
|WBC G4||101/346 (29%)||107/273 (39%)||60/295 (20%)|
|PLT G3-4||123/349 (35%)||80/275 (29%)||113/298 (38%)|
|PLT Transf||40/392 (10%)||18/309 (6%)||46/312 (15%)|
|RBC Transf||83/394 (21%)||100/312 (32%)||87/311 (28%)|
|Febrile Neutropenia||55/391 (14%)||19/309 (6%)||22/312 (7%)|
|Nephrotox||32/388 (8%)||27/312 (9%)||16/312 (5%)|
|Neurotox||18/384 (5%)||39/309 (13%)||26/307 (8%)|
In patients with localized disease, 5-year DFS was 52% (95% CI 43 to 61) and 5-year EFS was 50% (95% CI 42 to 59). No significant differences were found according to sex, age, site, histotype, baseline levels of serum alkaline phosphatase (SAP) and LDH. For patients who received primary chemotherapy, the 5-year DFS was 48% (95% CI, 37-58) and 64% (95% CI, 48-81) in case of adjuvant chemotherapy (p = 0.2).
For those patients who received chemotherapy according to the suggested scheme, the 5-year DFS was 50% (95% CI, 40-59); whereas it was 63% (95% CI, 40-87) in the other chemotherapy regimen (p = 0.9). The corresponding 5-year OS were 64.5% (95% CI, 55-74) and 85% (95% CI, 66-100), respectively (p = 0.3).
Focusing on patients who received primary chemotherapy, the 5-year DFS was 40% (95% CI, 26-55) for less than 50% tumor necrosis, 45% (95% CI, 27-63) with chemo-induced tumor necrosis ranging from 50% to 89%, and 70% (95% CI, 49-90) with 90% or more necrosis (p = 0.1). The corresponding 5-year OS were 54% (95% CI, 38-59), 70% (95% CI, 54-87) and 78% (95% CI, 59-97), respectively (p = 0.2). For patients with localized disease (data available for 93 patients) 5-year OS was 39% (95% CI, 10-68) in 15 patients who received 6 or less cycles and 78% (95% CI, 64-85) in the 78 patients who received 7 or more cycles (p = 0.007).
An overall number of 1,351 cycles reported from 178 patients were evaluable for toxicity. Overall, 1 or more episodes of G4 white blood cells or G3-4 PLT toxicity were reported for 63% and 53% of patients, respectively. Blood or PLT transfusions were reported for 52% and 31% of patients, respectively. One or more cycles required the use of G-CSFs in 82% of patients and 1 or more episodes of febrile neutropenia were experienced by 32%.
The database was not structured to collect data of cardiac function as evaluated with echocardiograms. No cases of clinically relevant cardiotoxicity were reported.
In 20% of patients, 1 or more episodes of neurotoxicity were reported. The majority had CDP-related peripheral neurotoxicity including G3 in 7. In 1 patient, a G4 depressed level of consciousness was documented following IFO.
Regarding nephrotoxicity, 48 (26%) patients were reported to have experienced at least 1 episode, mostly G1 or G2. One patient had G3 urinary electrolyte wasting and G1 creatinine elevation grade. Two patients had G3 creatinine elevation grade. Soon after chemotherapy completion based on ADM, CDP, and IFO, without MTX, 1 patient required dialysis for G4 renal toxicity. Prior to administration of the final chemotherapeutic treatment (IFO), her renal function had been normal.
MTX-toxicity data were available for 48 patients for a total of 154 MTX infusions. At least 1 episode of delayed MTX excretion was reported for 11 (23%) of the 48 patients. In 4 patients, delayed excretion was associated with nephrotoxicity, which was recorded as G3 for 1 and as G1 for the other 3. In 1 patient, G1 creatinine elevation grade was reported in spite of normal clearance of the drug.
The multi-institutional, international EURO-B.O.S.S. series described in this paper represents the largest prospectively collected source of information on high-grade osteosarcoma patients above the age of 40 treated following a uniform multimodal strategy of surgery and multi-drug chemotherapy. Three European groups participated in the study. Despite the efforts made by the groups’ secretariat, difficulties in data collection were encountered and this is a limit in the interpretation of the results, which is partially explained by the rarity of the disease, by the number of the involved centers, and by the observational characteristics of the study.
The EURO-B.O.S.S. treatment concept led to results that seem comparable to those also achieved in younger patients with primary high-grade osteosarcoma, albeit at the cost of relevant side effects.
Mainly based on the documented efficacy observed in younger patients, there is a general agreement that chemotherapy also should be used in patients older than 40 years with high-grade osteosarcoma (1). Some retrospective studies including osteosarcoma patients over 40 treated with chemotherapy have reported survival probabilities similar to those achieved in younger patients (8, 11). A retrospective EMSOS study (10) observed an advantage in terms of prognosis for those patients who received chemotherapy above those who did not; however, it did not provide details of the chemotherapy protocols used. In contrast, a recent paper poses doubts on the need to administer chemotherapy to these patients (12). Some retrospective studies including osteosarcoma patients over 40 treated with chemotherapy have reported data showing a probability of survival similar to those achieved in younger patients (8, 11).
In our study, patients with nonmetastatic high-grade osteosarcoma achieved a 5-year OS of 66%, those with extremity tumors a 5-year OS of 70%, which is similar to reports from studies in younger patients (2-3-4-5-6-7). Our study confirmed the poor prognosis of patients with pelvic osteosarcoma, as reported in other studies (20, 21); whereas those patients with craniofacial osteosarcoma had a probability of survival similar to that of patients with extremity tumors.
The prognosis of patients with primary metastatic disease was poor, again as reported for younger osteosarcoma patients (22). The comparatively high percentage of synchronous metastases in patients with pelvic and central primaries (mainly spine), where tumor surgery is particularly challenging, might lead to a bias when comparing series of older and younger patients, as the relative frequency of axial tumors increases with age. Of note, compared to cohorts of younger patients, our series showed a lower percentage of SCR for primary metastatic extremity tumors. Thus, we cannot exclude some reluctance of surgeons to adopt an aggressive policy in the studied age group.
In the present study, the choice of initial treatment was based upon the clinical judgment of the involved teams. Our data confirm the results of a previous randomized study, which demonstrated that both immediate surgery and postoperative chemotherapy, as well as combined pre- and postoperative chemotherapy, are acceptable management options (23).
In the present study, the percentage of patients with a good (≥90%) histological response was lower compared to that reported in young patients (3, 5), ranging from 23% for extremity tumors to only 12% in pelvic locations. This may be related to the suggested primary chemotherapy regimen. In our protocol, MTX was not used preoperatively and the doses per cycle of CDP and ADM were lower than those adopted in younger patients (3, 5). At the same time we cannot exclude that age-related pharmacokinetics changes (13-14-15) may be responsible for the reduced activity of the drugs in this subset of patients.
No direct conclusions regarding the role of chemotherapy in this age group of patients can be drawn, but it is interesting to notice the lower probability of survival observed in those patients who received a reduced number of cycles of chemotherapy due to refusal or toxicity.
Chemotherapy-related toxicity was considerable, but no toxic deaths were recorded. Hematological toxicity was similar to that reported from younger cohorts of osteosarcoma patients treated with more intensive chemotherapy regimens (3, 5, 6). G-CSFs were commonly used and about one-third of patients experienced at least 1 episode of febrile neutropenia.
The incidence of chemotherapy-induced peripheral neuropathy exceeded the frequency reported for younger patients treated with higher cumulative doses of CDP and ADM (3, 5, 6). However, it is similar to reported levels in adult patients with other CDP-treated cancers, who are more prone to this side effect (24, 25). Approximately one-third of patients experienced 1 or more episodes of nephrotoxicity, mostly G1, but in 1 case dialysis was required. The incidence of nephrotoxicity was higher than that reported for younger patients (3, 5, 6), probably reflecting an age-related decreased renal function not detected by the laboratory tests recommended in the protocol.
Although the methotrexate dose of 8 g/m² was lower than the more standard 12 g/m² used in younger patients, its toxicity data confirm that the drug must be used with caution in this age group. However, when clinically indicated, it seems feasible to administer MTX in a population of patients older than 40 years.
In patients over 40 years of age suffering from primary high-grade osteosarcoma, we conclude that an aggressive approach with age-adapted chemotherapy and surgery can offer a probability of survival similar to that observed in younger patients. Either a combination of pre- and postoperative chemotherapy based upon the same drugs used for the more typical younger osteosarcoma patients, or postoperative chemotherapy only (with the same total treatment duration) should be considered standard options. Chemotherapy-related toxicities are significant and generally higher than those reported from younger patient cohorts treated with more intensive regimens.
The authors thank Alba Balladelli and Cristina Ghinelli for editing and graphic support. Thanks to Eva-Marie Olofsson at the SSG Study Center, to Annalisa Nobile at the ISG Study Center, and to Matthias Kevric at the COSS Study Center for coordinating the administrative work.
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- Bielack, Stefan S. [PubMed] [Google Scholar] 2
- Smeland, Sigbjørn [PubMed] [Google Scholar] 3
- Longhi, Alessandra [PubMed] [Google Scholar] 1
- Egerer, Gerlinde [PubMed] [Google Scholar] 4
- Sundby Hall, Kirsten [PubMed] [Google Scholar] 3
- Donati, Davide [PubMed] [Google Scholar] 1
- Kevric, Matthias [PubMed] [Google Scholar] 2
- Brosjö, Otte [PubMed] [Google Scholar] 5
- Comandone, Alessandro [PubMed] [Google Scholar] 6
- Werner, Mathias [PubMed] [Google Scholar] 7
- Monge, Odd [PubMed] [Google Scholar] 8
- Palmerini, Emanuela [PubMed] [Google Scholar] 1
- Berdel, Wolfgang E. [PubMed] [Google Scholar] 9
- Bjerkehagen, Bodil [PubMed] [Google Scholar] 3
- Paioli, Anna [PubMed] [Google Scholar] 1
- Lorenzen, Sylvie [PubMed] [Google Scholar] 10
- Eriksson, Mikael [PubMed] [Google Scholar] 11
- Gambarotti, Marco [PubMed] [Google Scholar] 1
- Tunn, Per-Ulf [PubMed] [Google Scholar] 12
- Jebsen, Nina L. [PubMed] [Google Scholar] 13
- Cesari, Marilena [PubMed] [Google Scholar] 1
- von Kalle, Thekla [PubMed] [Google Scholar] 2
- Ferraresi, Virginia [PubMed] [Google Scholar] 14
- Schwarz, Rudolf [PubMed] [Google Scholar] 15
- Bertulli, Rossella [PubMed] [Google Scholar] 16
- Kasparek, Anne-Katrin [PubMed] [Google Scholar] 17
- Grignani, Giovanni [PubMed] [Google Scholar] 18
- Krasniqi, Fatime [PubMed] [Google Scholar] 19
- Sorg, Benjamin [PubMed] [Google Scholar] 2
- Hecker-Nolting, Stefanie [PubMed] [Google Scholar] 2
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Oncology Department, Istituto Ortopedico Rizzoli, Bologna - Italy
Stuttgart Cancer Center, Pediatrics 5 (Oncology, Hematology, Immunology), Klinikum Stuttgart Olgahospital, Stuttgart - Germany
Division of Cancer Medicine, Oslo University Hospital and Institute of Clinical Medicine, Oslo - Norway
Department of Hematology, Oncology, and Rheumatology, Heidelberg University Hospital, Heidelberg - Germany
Department of Orthopedics, Karolinska University Hospital, Stockholm - Sweden
Oncology Department, Ospedale Humanitas-Gradenigo, Turin - Italy
Department of Orthopedic Pathology, HELIOS Klinikum Emil von Behring GmbH, Berlin - Germany
Department of Oncology and Radiotherapy, Haukeland University Hospital, Bergen - Norway
Department of Pathology, University Hospital of Muenster, Muenster - Germany
Department of Hematology and Oncology, Klinikum rechts der Isar der TU Muenchen, Muenchen - Germany
Department of Oncology, Skane University Hospital and Lund University, Lund - Sweden
Department of Tumor Orthopedics, HELIOS Klinikum Berlin-Buch, Berlin - Germany
Department of Clinical Science, Haukeland University Hospital and Center for Cancer Biomarkers CCBIO, University of Bergen, Bergen - Norway
Oncology Department, Istituto Regina Elena, Rome - Italy
Department of Radiation Oncology, Medical Center Hamburg-Eppendorf, Hamburg - Germany
Oncology Department, Istituto Nazionale Tumori, Milan - Italy
Department of Internal Medicine, Division of Oncology, Medical University of Graz, Graz - Austria
Oncology Department, Istituto di Candiolo IRCCS, Turin - Italy
Oncology Deparment, University Hospital of Basel, Basel - Switzerland