original articles
Annals of Oncology Annals of Oncology 26: 1766–1771, 2015 doi:10.1093/annonc/mdv237 Published online 23 June 2015
Results from a multicenter, open-label, pivotal phase II study of chidamide in relapsed or refractory peripheral T-cell lymphoma Y. Shi1*, M. Dong1, X. Hong2, W. Zhang3, J. Feng4, J. Zhu5, L. Yu6, X. Ke7, H. Huang8, Z. Shen9, Y. Fan10, W. Li11, X. Zhao12, J. Qi13, H. Huang14, D. Zhou15, Z. Ning16 & X. Lu16 1 Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing; 2Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai; 3Department of Lymphoma, 307 Hospital of PLA, Beijing; 4Department of Medical Oncology, Jiangsu Cancer Hospital, Nanjing; 5Department of Medical Oncology, Beijing Caner Hospital, Beijing; 6 Department of Hematology, Chinese PLA General Hospital, Beijing; 7Department of Hematology, Peking University Third Hospital, Beijing; 8Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou; 9Department of Hematology, Ruijin Hospital/Medical College, Shanghai Jiao Tong University, Shanghai; 10 Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou; 11Department of Hematology, the First Hospital, Jilin University, Changchun; 12Department of Hematology, Xiangya Hospital Central South University, Changsha; 13Department of Lymphoma, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin; 14Department of Hematology, the First Affiliated Hospital, Zhejiang University, Hangzhou; 15Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing; 16Chipscreen Biosciences Ltd, Shenzhen, China
Received 29 March 2015; revised 4 May 2015; accepted 11 May 2015
Background: Chidamide is a novel benzamide type of subtype-selective histone deacetylase (HDAC) inhibitor with unique mechanisms of action compared with marketed HDAC inhibitors. This phase II study was to evaluate the efficacy and safety of chidamide in relapsed or refractory peripheral T-cell lymphoma (PTCL) in Chinese population. Patients and methods: Patients with relapsed or refractory PTCL of different subtypes received chidamide of 30 mg orally twice per week. The primary end point was overall response rate (ORR). Responding patients should be confirmed at least 4 weeks after the criteria of the response were first met, and were reviewed by an independent review committee. Results: Eighty-three patients were enrolled and 79 patients with eligible PTCL histology were for efficacy assessments. Patients enrolled over 10% were with subtypes of PTCL not otherwise specified (34%), anaplastic large-cell lymphoma (22%), extranodal natural killer (NK)/T-cell lymphoma, nasal type (20%), or angioimmunoblastic T-cell lymphoma (AITL, 13%). The ORR was 28% (22 of 79) including 14% (11 of 79) with complete response/unconfirmed complete response (CR/CRu). Median progression-free survival and overall survival were 2.1 and 21.4 months, respectively. AITL patients tended to have higher ORR (50%) and CR/CRu rate (40%), as well as more durable responses, to chidamide treatment. Most adverse events (AEs) were grade 1 or 2, and AEs ≥grade 3 that occurred in ≥10% patients were thrombocytopenia (22%), leucopenia (13%) and neutropenia (11%), respectively. Conclusion: Chidamide represents a novel oral benzamide class of HDAC inhibitor with significant single-agent activity and manageable toxicity in relapsed or refractory PTCL, and provides a much needed treatment option in this indication in China. Results led to China Food and Drug Administration approval of chidamide in this indication. Key words: chidamide, HDAC inhibitor, epigenetic, T-cell lymphoma, pivotal trial
introduction Peripheral T-cell lymphoma (PTCL) is a set of rare and heterogeneous group of mature T- and natural killer (NK)-cell neoplasms associated with poor outcome. PTCL makes up *Correspondence to: Prof. Yuan-Kai Shi, Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China. Tel: +86-10-8778-8293; E-mail:
[email protected]
25%–30% of all Non-Hodgkin’s lymphoma (NHL) cases in China [1], much higher than that seen in Western countries of 10%–15% [2]. Subtype distribution of PTCL is also significantly different between China and Western countries, and the most common subtype of PTCL in China is extranodal NK/T-cell lymphoma, nasal type (ENKL), followed by PTCL not otherwise specified (PTCL NOS), anaplastic large-cell lymphoma (ALCL) and angioimmunoblastic T-cell lymphoma (AITL) [1, 2]. Although there currently is no consensus on first-line therapy for patients with PTCL, new agents, such as pralatrexate,
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email:
[email protected].
original articles
Annals of Oncology
romidepsin and belinostat, were approved for patients with relapsed or refractory PTCL in recent years [3–5]. The overall response rates (ORRs) by independent central review for those three drugs are 26%, 25% and 26% for pralatrexate, romidepsin and belinostat, respectively, but all of the pivotal trials led to approvals barely included ENKL. Chidamide (CS055) is a novel benzamide class of histone deacetylase (HDAC) inhibitor rationally designed to block the catalytic pocket of class I HDACs [6] to selectively inhibit activity of HDAC1, 2, 3 and 10 [7]. Previous studies have shown that chidamide induces growth arrest and apoptosis in blood and lymphoid-derived tumor cells [8], activates NK-cell and antigen-specific CD8+ cytotoxic T-lymphocyte-mediated cellular antitumor immunity [7, 9] and reverses epithelial–mesenchymal transitions and drug resistance of tumor cells [10, 11]. Phase I study showed that orally dosed chidamide was generally well tolerated in patients with advanced solid tumors or lymphomas with favorable pharmacokinetics and long-lasting enhanced histone acetylation (up to >72 h after a single dose) [12]. The primary objective of this phase II study was to confirm the activity of chidamide in patients with relapsed or refractory PTCL and to support the China Food and Drug Administration (CFDA) approval of chidamide in this indication.
significant QTc prolongation (>450 ms), myocardial infarction onset within 1 year, congestive heart failure and clinically significant coronary artery disease were excluded from this study. Four weeks were required between prior chemotherapy and protocol enrollment.
efficacy assessments
patients and methods
Efficacy was assessed every 6 weeks by using the IWC for NHLs [14]. For patients with the disease involvement in both lymph node/organ and skin, the final response results were determined according to the following criteria: complete response (CR) required CRs from both assessing systems; unconfirmed complete response (CRu) required CRu from one system, and CR or CRu from the other; partial response (PR) required PR from one system, and any of the efficacy grade [CR/CRu/PR/stable disease (SD)] from the other; SD required SDs from both systems and PD was defined as progression of disease in any of the two systems. Responding patients (PR, CRu and CR) should be confirmed at least 4 weeks after the criteria of the response were first met. Patients with response confirmation were reported as the responding patients in this study. Data for responding patients assessed by site investigators were reviewed with a rigorous two-step process by the independent review committee (IRC): a central blinded radiology assessment of medical imaging data by three radiologists with experience in lymphoma, followed by a meeting of the whole members of IRC (one leading radiologist and four independent hematologic oncologists) to review the broader clinical components of patient data, including radiological imaging data, photographs of skin lesions and other physical examination findings and laboratory data.
study design and treatment
safety assessments
This was an open-label, single-arm, multicenter pivotal phase II study of chidamide monotherapy. Chidamide tablets in 5 mg were provided by Chipscreen Biosciences Ltd. The study (ChiCTR-TNC-10000811) was conducted in accordance with the Declaration of Helsinki and approved by individual ethic committees of all the participated hospitals. All patients have signed informed consent before joined in the study. In an exploratory phase II trial preceded this study, 19 patients with relapsed or refractory PTCL NOS were randomized to receive 30 or 50 mg twice per week for 2 weeks, followed by 1 week of rest. The total drug exposure for the two arms in a 3-week period was 120 and 200 mg, respectively. The ORR was 11.1% for the 30 mg and 40.0% for the 50 mg. One patient in the 50 mg arm experienced drug-related grade 4 thrombocytopenia [13]. Based on the overall results from the phase I and exploratory phase II trials [12, 13], patients in the present study were orally administered with chidamide of 30 mg, twice weekly without 1-week-drug-free breaks, which accounted for a total dosage of 180 mg in a 3-week period. Patients continued to receive chidamide treatment until progression of the disease (PD), unacceptable toxicity, or patient/investigator discretion. The primary end point of the study was ORR. Secondary end points included time to response, duration of response (DOR), progression-free survival (PFS), rate of patients with a DOR ≥12 weeks, overall survival (OS) and safety parameters.
Safety was assessed by evaluating vital signs, changes in clinical laboratory variables for hematologic and biochemical parameters, ECG and pericardial ultrasound to monitor the incidence, severity and relationship of AE to chidamide. AEs were classified according to the Medical Dictionary for Regulatory Activities version 15.0 and were graded using the National Cancer Institute Common Toxicity Criteria for Adverse Events scale, version 3.0. Complete blood count was evaluated once a week, and serum biochemistry was evaluated once every 3 weeks. Other safety parameters were evaluated once every 6 weeks.
patients Patients with PTCL of any subtype were histologically confirmed by local pathologists for study enrollment, but underwent central pathology review to evaluate the final eligibility. Patients for enrollment were required to have relapsed or had disease refractory to one or more systemic therapies. Other inclusion criteria required that all patients had measurable disease according to International Workshop Criteria (IWC) [14], age of 18–75 years. Required laboratory values included absolute white blood cell counts ≥4 × 109/l, platelet counts ≥90 × 109/l and hemoglobin ≥90 g/l. Patients with history of clinically
Volume 26 | No. 8 | August 2015
statistical analysis Per protocol, which was reviewed by the Center for Drug Evaluation of CFDA, if the lower limit of the 95% confidence interval of ORR was more than 15% with the sample size not 3 Histopathology per central review PTCL, not otherwise specified Anaplastic large-cell lymphomaa NK/T-cell lymphoma, nasal type Angioimmunoblastic T-cell lymphoma Primary cutaneous γδ T-cell lymphoma Enteropathy-type T-cell lymphoma Lymphoepithelioid lymphoma CD4+ PTCL Transformed mycosis fungoides
Patients (N = 79) n % 53 26
67 33 53 20–77
28 50 1
36 63 1
3 11 30 35
4 14 38 44 1.1 0.1–9.1 3 1–9
16 15 23 25
20 19 29 32
27 17 16 10 3 2 2 1 1
34 22 20 13 4 3 3 1 1
ALK status: ALK− = 11, ALK+ = 3, unknown = 3. ECOG, Eastern Cooperative Oncology Group; ALK: anaplastic lymphoma kinase.
a
| Shi et al.
after chidamide treatment, with a few cases of best responses observed as late as 18 weeks. The median DOR was 9.9 months with a range of 1.1–40.8 months, and most responders (19 patients) had DOR ≥3 months, which counted for 24% (19/79) of eligible patients for efficacy analysis (Table 2). As shown in Table 3, for the four major subtypes of patients enrolled over 10%, AITL and ALCL (ALK−) tended to have higher response rates (both ORR and the CR/CRu rate). There were no meaningful differences in response rates based on gender, age, disease stage and number of prior systemic therapy. The median PFS was 2.1 months with a range of 1 day to 44.9 months, and the median OS was 21.4 months with a range of 0.3–50.1 months (Figure 1). Four (5%) patients were still progression-free survived and 37 patients (47%) were still alive at the data cutoff date in June 2014. Median follow-up time for all patients still alive at the time of analysis was 29 months. Of the 22 responding patients assessed by IRC, 8 (36%) patients had DOR >12 months. Four (18%) patients remained in chidamide treatment at the time of this analysis, and two of them had DOR >40+ months. Most durable response was seen in three patients with AITL (Table 4).
safety Eighty-two percent patients (n = 68) experienced at least one AE during the study. AEs that occurred in ≥10% patients were thrombocytopenia (51%), leucopenia (40%), neutropenia (22%) and fatigue (10%), respectively. Most AEs were grade 1 or 2, and AEs ≥grade 3 that occurred in ≥10% patients were thrombocytopenia (22%), leucopenia (13%) and neutropenia (11%), Table 2. ORR and time-to-event data
Objective response CR/CRu CR CRu PR ORR (CR+CRu+PR) SD PD NE Time to response, months Median Range DOR, months Median Range DOR >3 months, n (%)
Investigators (N = 79) No. %
IRC (N = 79) No.
%
11 8 3 12 23 10 31 15
11 7 4 11 22
14 9 5 14 28
14 10 4 15 29 13 39 19 1.4 1.2–4.2
9.9 1.1+ ∼ 40.8+ 19 24
+ denotes a censored value. ORR, overall response rates; IRC, independent review committee; CR, complete response; CRu, uncomfirmed complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, not assessable (patients did not have post baseline efficacy evaluation due to early termination); DOR, duration of response.
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original articles
Annals of Oncology
Table 3. ORR based on IRC assessments in patient subgroups Subgroup
Total no. of patients
Gender Male 53 Female 26 Age, years 2 48 PTCL subtypes PTCL NOS 27 ENKL 16 ALCL ALK− 11 ALK+ or unknown 6 AITL 10 Others 9
Table 4. Long-term DOR (>12 months) of individual cases
ORR N
%
CR/CRu rate N %
14 8
26 31
10 1
19 4
16 6
27 30
6 5
10 25
5 17
36 26
4 7
29 11
8 14
26 29
6 5
19 10
6 3
22 19
2 1
7 6
5 2 5 1
45 33 50 11
4 0 4 0
36 0 40 0
1.0 N = 79 Censored
Survival proportion
0.8 OS
0.6
0.4
0.2
PFS
0.0 0
5
10
15
20 25 30 35 Time (months)
40
45
50
55
Figure 1. Kaplan–Meier estimate of progression-free survival and overall survival based on all patients.
respectively (Table 5). The onset of hematological abnormalities tended to be in the first 6 weeks of treatment. For patients who experienced thrombocytopenia, 81.0% (34/42) was in the first 6 weeks and 61.9% (26/42) in the first 3 weeks. The majority of patients tolerated to chidamide. Fourteen (17%) patients discontinued the treatment due to AEs. AEs leading to drug discontinuation for ≥2 patients included thrombocytopenia (n = 3, 3.6%), leucopenia (n = 2, 2.4%) and abnormity of hepatic function (n = 2, 2.4%). Six patients (7.2%) had dose reductions due to AEs, including two patients (2.4%) with grade 3 thrombocytopenia, one patient (1.2%) with grade 4 thrombocytopenia and neutropenia, one (1.2%) with grade 4
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CRF no.
Subtype
03104 ENKL 10035 PTCL NOS 01090 ALCL, ALK unknown 12102 ALCL, ALK− 15097 PTCL NOS 10075 AITL 12053 AITL 12048 AITL
No. of prior Disease systemic staging at therapy enrollment
Best DOR response (months)
2 1 4
IIIB IIIB IIIA
PR CR PR
12.7 13.8 16.5
1 4 1 3 4
IVB IIIA IIA IVB IIIA
CRu PR CR PR CRu
19.1 27.2+ 34.7+ 40.1+ 40.8+
Table 5. Adverse events in ≥5% patients (N = 83) Event
Total n %
Grade 3 n %
Grade 4 n %
Thrombocytopenia Leucopenia Neutropenia Prolongation of QTc interval Fatigue Anemia Decreased appetite Fever Nausea Diarrhea Pericardial effusion Increase of alanine aminotransferase Increase of γ-glutamyltransferase Increase of creatine phosphokinase Lung infection Urine protein Increase of aspartate aminotransferase Decrease of creatine phosphokinase MB Vomiting Rash
42 33 18 11 8 7 7 7 7 7 6 6
51 40 22 13 10 8 8 8 8 8 7 7
13 10 7 1 0 3 2 0 0 0 0 1
16 12 8 13 0 4 2 0 0 0 0 1
5 1 2 0 0 1 0 0 0 0 0 0
6 1 2 0 0 1 0 0 0 0 0 0
5 5
6 6
1 0
1 0
0 0
0 0
5 4 4
6 5 5
1 0 1
1 0 1
0 0 0
0 0 0
4
5
0
0
0
0
4 4
5 5
1 0
1 0
0 0
0 0
leucopenia, one (1.2%) with grade 3 thrombocytopenia and neutropenia and one (1.2%) with grade 2 fatigue and anorexia. Prolongation of QTc interval was observed in 11 (13%) patients, 7 were grade 1, 3 were grade 2 and 1 was grade 3. Pericardial effusion was observed in six (7%) patients, all were grade 1 with no concurrent cardiac symptoms. Eight serious adverse events were reported in seven patients (8%), three of which, cardiac sudden death, lactic acidosis and enterobrosis, caused death due to PD. The patient with ‘cardiac sudden death’ was a 54-year-old male diagnosed with ENKL 4 years ago and experienced multiple radiotherapies and chemotherapies before entering this study. One month preceded the study entry, the patient had progressive swollen face, neck and arms and left-eye blindness due to progressive disease
doi:10.1093/annonc/mdv237 |
original articles accompanied by a constant fever, occasionally as high as 40°C. A total of three doses of chidamide were taken and aggressive fever and swollen arms persisted during the drug administration. Two days after the third dose, the patient died and the cause of death was recorded as ‘cardiac sudden death’. By reviewing full set of data, this death was considered likely as PD.
discussion Eighty-nine percent of patients in this study were PTCL NOS (34%), ALCL (22%), ENKL (20%) and AITL (13%), representing the four major PTCL subtypes in China. Of note, patients with chemorefractory AITL tended to have higher ORR (50%) and CR/CRu rate (40%) in response to chidamide treatment. Furthermore, three patients having the most durable responses (close to or longer than 3 years) were with the subtype of AITL. In contrast, pralatrexate, an antifolate agent, showed in its pivotal study that only 1 of 13 AITL patients (8%) responded to the pralatrexate treatment [3]. Relatively higher response rates in AITL were also reported for romidepsin and belinostat, two other HDAC inhibitors [4, 5]. Recent publications have demonstrated that AITL is characterized by high frequencies of overlapping mutations in epigenetic modifiers in neoplastic T cells [15], suggesting that epigenetic regulation is an important motif in AITL pathogenesis, and thus, may be highly relevant to more clinical benefits by HDAC inhibitors to this PTCL subtype. ENKL is much more common in East Asia than in Western countries [1, 2]. Patients enrolled with ENKL in this study were ∼20% in total, which reflected a significant difference in geographic or racial population of this PTCL subtype in China compared with the studies carried out in Western countries for romidepsin, pralatrexate or belinostat, where appropriately only 1%–2% of patients with ENKL were enrolled in those pivotal trials [3–5]. Three of 16 ENKL patients (19%) in this study obtained responses, including 1 patient with CR (DOR for 13 months) and 2 patients with PR (DOR for 3 and 8 months, respectively). The apparently lower rate of response seen in ENKL may reflect the unique biology of the disease, or simply the small number of patients entered on study. Nevertheless, the results provided the rationale for further clinical observations in chidamide treatment of patients with this most common PTCL subtype in China, both as a single agent and in combination with other therapies. Survival expectations in patients with relapsed or refractory PTCL are generally low. Mak et al. reported in a retrospective survey that patients with the first-time relapsed PTCL treated with chemotherapy only had median OS of 6.5 months [16]. The results of pivotal trials in patients with relapsed or refractory PTCL from recently approved three drugs showed median OS as 14.5, 11.3 and 7.9 months for pralatrexate, romidepsin and belinostat, respectively [3–5]. In the current study, heavily pretreated PTCL patients including 20% of patients with ENKL showed median OS of 21.4 months from the start of chidamide treatment, suggesting a potentially long-term survival benefit of chidamide to this PTCL population. Chidamide was generally well tolerated and the associated AEs were manageable. Most AEs were grade 1–2, and a relatively higher frequency of grade 3/4 AEs were hematological abnormalities, including thrombocytopenia, leucopenia, neutropenia
| Shi et al.
Annals of Oncology
and anemia. Gastrointestinal disturbances and infections were observed in a lower incidence and less severity with chidamide than reported with marketed HDAC inhibitors [4, 5, 17], as well as pralatrexate [3]. Transient prolongations of QTc interval were observed but were not associated with concurrent cardiac symptoms. Currently there are three major classes of HDAC inhibitors by chemical structure under clinical development, including hydroxamates, cyclic peptides and benzamides. These structurally different classes of agents have varying target specificity, mechanisms of action, and properties in pharmacokinetics and pharmacodynamics, thus have significantly different outcomes in laboratory and clinical settings [10, 18]. While hydroxamates, vorinostat and belinostat, and cyclic peptide romidepsin have been approved by FDA for T-cell lymphoma treatment [4, 5, 17], chidamide represents a novel oral benzamide class HDAC inhibitor with significant single-agent activity and manageable toxicity in relapsed or refractory PTCL. Based on the results of this pivotal trial, CFDA approved chidamide in this indication in December 2014 [19].
acknowledgements The authors thank the patients, medical staff and physicians who participated in this study. This study was coordinated by Tigermed Consulting. The authors acknowledge J. Xu for the study design and Z. Wei for the data analysis and interpretation from Tigermed Consulting. The Independent Review Committee (IRC) that commissioned this study was an independent body of scientists including F. Feng, N. Wu, W. Yong, M. Zhou, W. Wei Song and Q. Chen.
funding This study was sponsored by Chipscreen Biosciences, Ltd, Shenzhen, China. The study was also partly supported by grants from the Chinese National ‘863’ Project (2006AA020603, 2008AA02Z303), National ‘New Drug Innovation’ (2009ZX09401003, 2008ZX09312, 2012ZX09303012) and Significant Project in Biotech Field from Guangdong Province (2011A080501009, 2003A10903) and Shenzhen Municipal Government (2010-1600).
disclosure ZN and XL: Chipscreen employment; all other authors and members of IRC have declared no conflicts of interest in the development of chidamide.
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Annals of Oncology 26: 1771–1776, 2015 doi:10.1093/annonc/mdv227 Published online 11 May 2015
Long-term ovarian function in women treated with CHOP or CHOP plus etoposide for aggressive lymphoma J. Meissner1*, D. Tichy2, V. Katzke3, T. Kühn3, S. Dietrich1, T. Schmitt1, M. Ziepert4, E. Kuhnt5, T. Rixecker6, M. Zorn7, M. Witzens-Harig1, M. Pfreundschuh6 & A. D. Ho1 1
Department of Medicine V, University of Heidelberg, Heidelberg; Divisions of 2Biostatistics; 3Cancer Epidemiology, German Cancer Research Center, Heidelberg; 4Institute for Medical Informatics, Statistics and Epidemiology (IMISE); 5Clinical Trial Centre Leipzig, University of Leipzig, Leipzig; 6Department of Medicine I, Saarland University, Homburg; 7Central Laboratory, University of Heidelberg, Heidelberg, Germany
Received 16 February 2015; revised 27 April 2015; accepted 4 May 2015
Background: Chemotherapy-associated ovarian damage comprises not only infertility, but also premature menopause. The latter has been reported as a consequence of alkylating chemotherapy for breast cancer or Hodgkin’s lymphoma. In this study, we assessed the long-term impact of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)like regimens on ovarian function in patients with aggressive non-Hodgkin lymphoma (NHL). Patients and methods: Long-term survivors after CHOP or CHOP plus etoposide (CHOEP) treatment within the Mabthera International Trial or the NHL-B1 trial of the German NHL Study Group were requested to respond to a questionnaire and to consent to blood sampling for hormone assessment. Results: A total of 46 of 81 contacted patients with a median age of 32.5 years at the time of enrolment into the aforementioned clinical trials responded to the questionnaire. The median follow-up after completion of treatment was 14 years. Last menstrual bleeding occurred significantly earlier in patients compared with the general population (47 versus 51 years, P < 0.0001). In comparison to the distribution of menopausal symptoms in the general population, the *Correspondence to: Dr Julia Meissner, Department of Medicine V, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Tel: +49-62218001; Fax: +49-6221-5813; E-mail:
[email protected]
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email:
[email protected].
