Activity endpoints reported in soft tissue sarcoma phase II trials: Quality of reported endpoints and correlation with overall survival

Critical Reviews in Oncology/Hematology 88 (2013) 309–317

Activity endpoints reported in soft tissue sarcoma phase II trials: Quality of reported endpoints and correlation with overall survival夽 Nicolas Penel a,b,∗ , Sophie Cousin a , Alain Duhamel b , Andrew Kramar b,c b

a General Oncology Department, Centre Oscar Lambret, Lille, France Unit Research (EA 2694), Medical School, Lille-Nord-de-France University, Lille, France c Methodology and Biostatistics Unit, Centre Oscar Lambret, Lille France

Accepted 2 May 2013

Contents 1. 2.

3.

4. 5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Data extraction and definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Statistical analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Reported primary activity endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Correlation between the reported activity endpoint and overall survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Reported endpoints in cases of promising and inactive drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Author contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

310 310 310 310 311 311 311 311 311 313 313 314 314 314 314 314 315 316 317

Abstract Background: Despite extensive research over the past 3 decades, few investigational drugs are considered as promising and these drugs failed to improve overall survival. Therefore we performed a systematic review of the literature to improve our understanding of the reasons that explain these failures. Methods: We reviewed 53 phase II trial reports that investigated new treatments in patients with advanced soft tissue sarcoma from 1999 to 2011. We critically reviewed the selected primary endpoint used in these trials.

Abbreviations: BORR, best objective response rate; BTCR, best tumor control rate; EORTC, European Organization on Research and Treatment of Cancer; mPFS, median progression free survival; mOS, median overall survival; PFR3, 3-month progression free rate; PFR6, 6-month progression free rate. 夽 Presented in part at: “The 2012 Annual Meeting of the Connective Tissue Oncology Society (Prague, Czech Republic, 14–17 November 2012)”. ∗ Corresponding author at: Department of General Oncology, Centre Oscar Lambret, 3, rue F Combemale, 59020 Lille Cedex, France. Tel.: +33 3 20 29 59 20; fax: +33 3 20 29 59 63. E-mail addresses: [email protected], [email protected] (N. Penel). 1040-8428/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.critrevonc.2013.05.004

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Results: Forty percent of trials were not interpretable because of major inherent methodological flaws. Only 3 primary endpoints were correlated with median overall survival (mOS): 3- and 6-month progression free rates and median progression-free survival. Nevertheless, the mOS was not significantly higher in the cases of active drugs. Discussion: We need to improve the definition of primary active endpoints and develop better designs for future trials. The current definition of promising drugs must be refined. © 2013 Elsevier Ireland Ltd. All rights reserved. Keywords: Phase II trials; Activity endpoint; Correlation; Advanced soft tissue sarcoma

1. Introduction The traditional aim of phase II trials has been to screen out inactive agents or regimens based on a pre-specified level of activity and to identify the most promising ones for further randomized confirmatory phase III trials. The screening phase II trials constitute a critical go/no-go step for drug development. Additionally, phase II trials include relatively homogeneous patient populations and usually include patients who are less heavily pretreated than those enrolled in phase I trials. Phase II trials may therefore be an ideal setting to test a number of additional hypotheses including: confirming dose and schedule, testing and validating putative predictive factors or demonstrating a proof of concept for selected drugs or regimens [1,2]. For selecting potentially active drugs, phase II trials require the use of standardized and available short time frame primary endpoints. The response according to standardized definitions, such as RECIST guidelines, remains the most frequent metric [3]. However, with the development of targeted molecular agents that act as tumor growth inhibitors, the percentage of tumor shrinkage appears less relevant. Thus, other endpoints which take into account the tumor growth dynamics such as the rate of progression at fixed time points or the ratio of time to progression between two consecutive lines of therapy (growth modulation index) could be considered [4–6]. This latter metric appears appealing, but there is no evidence that traditional primary endpoints (e.g., best objective response rate) and progression-free survival describe the same drug effect and could be considered as interchangeable. The choice of the primary activity endpoint is critical when designing a phase II trial. The use of inappropriate endpoints may lead to erroneous results and thus jeopardize the drug development process. Soft tissue sarcomas (STS) are rare malignant tumors of mesenchymal origin. Treatment of patients with advanced disease is challenging because of the limited number of therapeutic options and their limited efficacy. Although some patients may be salvaged with metastasis surgery, chemotherapy using doxorubicin-based regimens (single agent or combination) is usually suggested for patients with recurrent STS. The median progression-free survival (PFS) with doxorubicin-based regimens is usually less than or equal to 6 months [7]. Most patients die of their disease within 12–15 months following the diagnosis of advanced disease,

and the overall survival rate is approximately 8% after 5 years [8]. These figures have only modestly improved in recent years [9]. Therefore, novel agents with different mechanisms of action are needed to improve the outcome of patients with advanced soft tissue sarcomas [10]. Over the last three decades, experts in the community had launched extensive clinical research programs because of the lack of effective and then consensual treatment. However, the number of drugs considered as promising remains limited [10], and most of them failed to improve the overall patient survival [11]. In light of these disappointing results, we systematically analyzed (i) the quality of the reported primary endpoint, (ii) the correlation between activity endpoints reported in screening phase II trials and the median overall survival and (iii) the distribution of the different activity endpoints reported for “promising” and “inactive” drugs, in all consecutive trials investigating new systemic treatments for STS patients.

2. Materials and methods 2.1. Studies Full English-language reports of phase II clinical trials investigating systemic treatments (chemotherapy or molecularly targeted agents) from January 1999 to August 2011 have been considered for this study. We used Medline and the following key-words (soft tissue sarcoma, phase II trials) and filters (clinical trials, human, adults). Bone sarcoma, rhabdomyosarcoma, GIST and primitive neuroectodermal tumors are not addressed here as their treatment is completely different. Fifty-three publications (and 77 strata) have been selected (Appendix A). 2.2. Data extraction and definitions We collected the following data regarding the primary endpoint: nature of the primary endpoint, available definition of the primary endpoint and the central radiological review performed. We looked for the presence of a statistical hypothesis based on the selected primary endpoint justifying the sample size and guiding the interpretation of the results. We then

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checked whether the reported data were interpretable according to the pre-specified statistical hypothesis and the selected endpoint. For all the published trials, we extracted the following data when available: best objective response rate (BORR; BORR = complete response rate + partial response rate), best tumor control rate (BTCR; BTCR = stable disease rate + complete response rate + partial response rate), median progression-free survival (mPFS) and 3- and 6-month progression free rates (PFR3 and PFR6) and median overall survival (mOS). 2.3. Statistical analyses We calculated the Pearson correlation coefficient using weighted linear regression to measure, in available strata, the degree of association between the different available activity endpoints (BORR, BTCR, PFR3 and PFR6) and overall survival. The weighted linear regression took into account the number of enrolled patients. We categorized the drugs according to the EORTC Soft Tissue and Bone Sarcoma Group criteria. Van Glabbeke et al. defined promising drugs as those providing a PFR3 >39% and a PFR6 >14% [12]. Other drugs have been classified as inactive [10].

3. Results 3.1. Studies We analyzed 53 studies and 77 strata (treatment arms; see Table 1 and Appendix A). Only three studies were randomized (3/53, 5%), and only six studies were stratified (11%), according to histological subtypes in five cases and according to the treatment schedule in 1 case. The median sample size per strata was 27 (range, 2–136).

Fig. 1. Correlation between the 6-month progression free rate and median overall survival. Each circle corresponds to one clinical trial. The size of the circle depends on the sample size of the trial. The figure illustrates the linear correlation between two endpoints: median overall survival (horizontal axis) and 6-month progression-free survival (vertical axis).

According to the selected primary activity endpoint and the inherent statistical hypothesis, the results reported for 77 strata could be interpreted as follows: promising drug (7/77 strata, 9%), ineffective drug (38/77 strata, 49%), results not interpretable because of the absence of a statistical hypothesis (12/77 strata, 15%) and results not interpretable because of the absence of data reporting a primary endpoint (20/77 strata, 25%). We can stipulate that 1083 patients have been enrolled in trials that did not provide informative results (1083/2252, 48%). 3.3. Correlation between the reported activity endpoint and overall survival Only three primary endpoints were correlated with mOS: mPFS, PFR3 and PFR6 (Figs. 1 and 2 and Table 2).

3.2. Reported primary activity endpoints The primary activity endpoints were as follows: BORR (21/53, 39%), mPFS (1/53, 2%), PFR3 (4/53, 4%), PFR4 (2/53, 3%), PFR6 (7/53, 13%), rate of “remission” (1/53, 2%) and the time to progression (2/53, 4%). In 12 studies, the primary activity endpoint was not described (12/53, 22%). The definition of a primary activity endpoint was clearly given in 36 out of the 41 studies with an identified primary endpoint (88%). All identified primary endpoints were based on tumor size measurements; nevertheless, independent and central radiological reviews were performed in only two studies (2/41 of studies with an identified primary endpoint, 5%). A clearly stated statistical hypothesis based on the selected primary activity endpoint was given in 41 studies (41/53, 77%). In 12 studies, the statistical hypothesis was missing, and in these same 12 studies, the primary endpoint was not clearly defined.

Fig. 2. Correlation between the best objective response rate and median overall survival. The figure illustrates the linear correlation between two endpoints: median overall survival (horizontal axis) and best objective response (vertical axis).

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Table 1 Drugs and studies. Mechanism of actiona

Drug

Number of studiesb

Referencesc

Classical cytotoxic agents Alkylation

Trabectedin

4

Brostallicin Temozolomide

1 4

Bendamustine Ifosfamide Trofosfamide 9-Nitrocamptothecin Camptothecin Exetecan Liposomal doxorubicin Gemcitabine

1 1 1 1 1 1 1 7

TZT-1027 Dolastatin Docetaxel

1 1 2

Paclitaxel Gemcitabine plus vinorelbine Gemcitabine plus docetaxel

1 1 3

Gemcitabine plus dacarbazine Paclitaxel plus epirubicin O6-benzylguanine plus carmustine

1 1 1

Demetri et al. (2009) Garcia-Carbonero et al. (2004) Le Cesne et al. (2005) Yovine et al. (2004) Leahy et al. (2007) Garcia-Del Muro et al. (2005) Talbot et al. (2003) Trent et al. (2003) Woll et al. (1999) Hartmann et al. (2007) Van Oosterom et al. (2002) Kollmannsberger et al. (1999) Patel et al. (2003) Reichardt et al. (2003) Reichardt et al. (2007) Toma et al. (2000) Ferraresi et al. (2008) Hartmann et al. (2006) Look et al. (2004) Maki et al. (2007) Merimsky et al. (2000) Okuno et al. (2003) Spaeth-Schwalbe et al. (2000) Svancarova et al. (2002) Patel et al. (2006) Von Mehren et al. (2004) Köstler et al. (2001) Verweij et al. (2000) Penel et al. (2008) Dileo et al. (2007) Hensley et al. (2002) Hensley et al. (2008) Maki et al. (2007) Losa et al. (2007) Pivot et al. (2006) Ryan et al. (2006)

SU5416

2

Thalidomide thrombospondin-1 mimetic angiogenesis inhibitor ABT-510 Perifosine Bryostatin-1 Flavopiridol Biricodar (VX-710) Rosiglitazone Imatinib

1 1 1 1 1 1 1 2

Sorafenib Sunitinib Pazopanib Bortezomib Gefitinib

1 1 1 1 1

Topo-isomerase I inhibitor

Topo-isomerase II inhibitor Antimetabolite

Anti-mitotic agent

Combinations

”Molecularly targeted agents” Anti-angiogenetic agents

AKT inhibitord PKC inhibitore MDR inhibitord PPAR inhibitorf Tyrosine kinase inhibitor

Proteasome inhibitor EGFR inhibitorg a b c d e f g

Heymach et al. (2004) Kuenen et al. (2003) McMeekin et al. (2007) Baker et al. (2008) Bailey et al. (2006) Brockstein et al. (2001) Morris et al. (2006) Bramwell et al. (2002) Debrock et al. (2003) Chugh et al. (2009) Verweij et al. (2003) Maki et al. (2009) Georges et al. (2009) Sleijfer et al. (2009) Maki et al. (2005) Ray-Coquard et al. (2008)

The mechanism of actions is complex, we have used a pragmatic classification that could be discussed. The sum of the studies here is 54 because one randomized study investigated gemcitabine alone and gemcitabine plus docetaxel. See Appendix A. AKT inhibitor: inhibitor of protein kinase B. PKC inhibitor: inhibitor of protein kinase C. PPAR inhibitor: inhibitor of peroxisome proliferator-activated receptors. HER-1 inhibitor: inhibitor of epidermal growth factor receptor.

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Table 2 Studies with soft tissue sarcoma patients receiving a second-line treatment. Correlation between

Strata

R

p

Best objective response rate

Best tumor control rate Progression free rate at 3 months Progression free rate at 6 months Median progression free survival Median overall survival

67 43 45 64 48

0.477 0.634 0.601 0.451 0.276

0.0001 0.0001 0.0001 0.0001 0.058

Best tumor control rate

Progression free rate at 3 months Progression free rate at 6 months Median progression free survival Median overall survival

41 43 62 48

0.733 0.592 0.486 0.276

0.0001 0.0001 0.0001 0.257

Progression free rate at 3 month

Progression free rate at 6 months Median progression free survival Median overall survival

45 41 39

0.862 0.707 0.466

0.0001 0.0001 0.0028

Progression free rate at 6 month

Median progression free survival Median overall survival

43 41

0.782 0.430

0.0001 0.0050

Median progression free survival

Median overall survival

45

0.402

0.0062

3.4. Reported endpoints in cases of promising and inactive drugs All activity endpoints were higher in cases of promising drugs. Conversely, the mOS was not significantly higher in cases of promising drugs (Table 3).

4. Discussion The key-findings of this systematic review were (i) at least one third of phase II trials were poorly designed and consequently approximately 40% of strata generated noninterpretable results, (ii) mOS was only correlated with mPFS, PFR3 and PFR6, (iii) all classical activity endpoints were higher in the cases of promising drugs, and (iv) the current definition of active drugs does not identify drugs able to improve the mOS. The challenges for designing phase II trials currently include the need to identify drugs with a sufficient activity for phase III testing. This screening is based on (i) a pre-specified level of activity (P1), (ii) a pre-specified level of inactivity (P0), and (iii) both using a standardized activity endpoint such as an early response. The success or failure of a clinical trial critically depends on the choice of an appropriate endpoint. This endpoint must be sensitive to the effect of the drug, be able to be unambiguously and reliably measure this effect, and optimally to be clinically relevant. At the time of classical cytotoxic drug development, the consensual endpoint was the BORR because the most rapidly assessable effect of a new drug was its ability to shrink the tumor by killing the tumor cells. With the development of targeted molecular therapies, the trialists tend to measure the delayed tumor growth rather than the tumor shrinkage. Various endpoints could be used including: BORR, progression-free survival, progression free rate at fixed time points, ratio of progression free survival,

time to treatment failure and overall survival. The OS is the most clinically relevant and meaningful endpoint used in confirmatory trials. Furthermore, this endpoint is easy to record, reliable and bias free. However, there are many disadvantages in using OS as a measure of activity because the length of time to complete the study is usually prolonged due to the long-term nature of this endpoint. Additionally, there may be confounding variables such as those related to crossover designs and patients receiving other treatments at the time of progression. Moreover, OS is highly dependent on the distribution of prognostic factors in the enrolled cohort, and may be considered with caution outside the setting of randomized trials [13]. The OS is not a feasible endpoint for screening phase II trials, which are generally small, single-arm preliminary studies. The present analysis underlines the major methodological mistakes associated with the recently issued phase II trials. The most frequently observed errors were the absence of an identified primary endpoint, the absence of a clearly defined primary endpoint, the absence of a statistical hypothesis and the absence of reported data about the primary endpoint. Furthermore, in most studies, there were no central and independent radiological reviews. Studies launched without compliance to these fundamental perquisites are useless, can jeopardize the development of a truly promising drug, are unnecessary time and resource consuming and are unethical because they expose patients to a potentially toxic drug without the ability to provide useful evidence. BORR and BTCR were not correlated with the mOS, undoubtedly because a large number of drugs provide a BORR close to zero (Fig. 2). Conversely, we found that mPFS, PFR3 and PFR6 were correlated with mOS. Nevertheless, the consensual definition of promising drugs (according to EORTC-STBSG criteria) failed to identify drugs with an increased mOS (Table 2). We think that the thresholds

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Table 3 Endpoint repartition in “negative and positive” trials. Drugs

Ineffective

Promising

p

Definition Strata

3-month PFR <39% or 6-month PFR <14% 33

3-month PFR ≥39% and 6-month PFR ≥14% 26

–

BORR (%) Median (range)

0.0 (0.0–19.0)

10.0 (0.0–53.0)

0.0001

BTCR (%) Median (range)

29.0 (6.0–50.0

43.0 (14.0–77.0)

0.00001

3-month PFR (%) Median (range)

26.0 (0.0–42.0)

48.0 (40.0–75.0)

*

6-month PFR (%) Median (range)

9.0 (0.0–39.0)

30.0 (15.0–55.0)

*

Median PFS (months) Median (range)

1.9 (0.2–3.03)

3.35 (1.8–12.0)

0.0001

Median OS (months) Median (range)

10.3 (4.9–22.8)

11.8 (4.9–22.4)

0.463

*

The p-value was <0.0001 in both cases, but PFR3 and PFR6 are part of the definition of promising drugs (Van Glabbeke, 2012).

defining active drugs have to be refined. For example, the observed median of PFR6 in case of promising drugs was 30% and not 14% as set up in the EORTC criteria [12]. This could explain, for example, the disappointing results of confirmatory phase III trials comparing pazopanib and placebo [11]. Pazopanib was considered as a promising drug based on one screening phase II trial designed with 3-PFR as primary endpoint [14]. This drug later failed to demonstrate an overall advantage in a phase III trial, despite the improvement of mPFS [11]. The present retrospective study has methodological limitations because it is based on published data. The definitions of endpoints (e.g., mPFS) could differ across the studies. Biases inherent in patient accrual and publication of phase II trials need to be highlighted. More phase II studies and patient resources are often invested in promising drugs, and these studies are also more likely to be published. Thus, it is a selffulfilling prophecy that better outcomes will be observed with the promising drugs. Moreover, the definition of a “promising drug” is another issue. The classical definition given by the EORTC remains questionable. Moreover, comparing the distribution of activity endpoints observed with “promising” and “inactive” drugs is debatable because the definition of promising/inactive drugs is based on at least one of these endpoints (usually PFR3 and PFR6). Finally, the sample is too limited to explore the difference between studies investigating classical cytotoxic agents and those investigated using molecular targeted therapies.

and PFR6 seem to be correlated with mOS and could be the preferred activity endpoints. Nevertheless, the thresholds defining a promising drug (PFR3 > 39% and a PFR6 > 14%) have to be refined.

Author contributions NP selected the study and extracted the data. NP and AK conceived the study and conducted the statistical analysis. NP, AK, AD and SC interpreted the results, wrote and approved the manuscript. AK and AD provided financial and technical support.

Conflict of interest There are no conflicts of interest to declare.

Reviewers Dr. Nicolas Isambert, Centre Georges-Francois-Leclerc, Department of Medical Oncology, 1, rue du Professeur Marion, F-21079 Dijon, France. Dr. Peter Hohenberger, Head of Division, Surgical Oncology & Thoracic Surgery, Theodor Kutzer Ufer 1, D-68167 Mannheim, Germany.

5. Conclusion Acknowledgement Efforts are necessary to better define the primary endpoint and improve the design of our future trials. The PFR3

We thank Séverine Marchant for editing the manuscript.

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N. Penel et al. / Critical Reviews in Oncology/Hematology 88 (2013) 309–317 soft tissue sarcoma: a phase II study from the European Organisation for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC Study 62043). Journal of Clinical Oncology 2009;27:3126–32.

Biography Nicolas Penel is head of General Oncology Department of Northern France Comprehensive Cancer Centers. He is

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medical oncologist. He had obtained his Science Thesis in 2008 (Epidemiology and Clinical Research Methodology) and his Accreditation to supervise Research (HDR). He is member of the local Ethics Committee as expert in clinical research and methodology. His main fields of clinical expertise are treatments of soft tissue sarcoma, carcinoma of unknown primary and metastatic prostate cancer.