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Fight against cancer around the Mediterranean area: “Many hands make light work!”
Critical Reviews in Oncology/Hematology 84 (2012) e1–e5
Editorial
Fight against cancer around the Mediterranean area: “Many hands make light work!” Yazid Belkacémi a,∗,1 , Hamouda Boussen b,1 , Sedat Turkan c,1 , Pelagia G. Tsoutsou d,1 , Fady Geara e,1 , Joseph Gligorov f,1 a
APHP, CHU Henri Mondor – University of Paris XII, Créteil, France Abderrahman Mami Hospital, Ariana, University of Tunis, Tunisia c Cerrahpasa Medical School and University of Istanbul, Turkey Univesity of Alexandropoulis, Greece and CHUV, Lausanne, Switzerland e American University of Beirut (AUB), Lebanon f APHP Tenon, CancerEst – University of Paris VI, France b
d
Contents 1.
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The Mediterranean specificity in a new evolving international era . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Mediterranean area: geopolitical specificity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Mediterranean area: specificity in terms of cancer care inequalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Mediterranean cancer specificity in a new era of biology tools and cancer care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Breast cancer in young women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. Inflammatory breast cancer (IBC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Nasopharyngeal cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract The geopolitical and strategic importance of the Mediterranean area is evident since a long time. In terms of health programs and means for cancer care, significant disparities have been reported between countries that borders the Mediterranean basin. AROME project began modestly in 2006 with a group of leaders who recognized the need to promote practical training of young people and, thus, contribute to reduce these inacceptable inequalities in terms of early diagnosis and management. Moreover, our project has been built from our belief that the socio-cultural specificity of this region, its epidemiology, availability of means for diagnosis and treatment, should impose a sustained regional research and better knowledge of tumor biology and identify the specificities that may require particular strategies of care that should not be based only on Western and Asian research data. We must thus take advantage of advances in the identification of intimate biological tumors to provide answers to our ignorance of the specific Mediterranean biology. In this paper, we illustrate this issue describing some particular cancers in this region such as breast and nasopharyngeal cancers. © 2012 Elsevier Ireland Ltd. All rights reserved. Keywords: Mediterranean area; Cancer care; Resources in oncology; Breast cancer; Nasopharyngeal cancer
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Corresponding author at: CHU Henri Mondor, 51 avenue Mal De Lattre de Tassigny, Créteil 94000, France. Tel.: +33 1 49 81 45 22; mobile: +33 6 77 43 98 10. E-mail address: [email protected] (Y. Belkacémi). 1 On behalf of the Association of Radiotherapy and Oncology of the Mediterranean area (AROME; www.aromecancer.org). 1040-8428/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.critrevonc.2012.10.004
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1. The Mediterranean specificity in a new evolving international era 1.1. Mediterranean area: geopolitical specificity The geopolitical and strategic importance of the Mediterranean is obvious as evidenced by the numerous conquests and conflicts that have rocked the region throughout its history. It is difficult to imagine a future in the XXI century that does not take into account globalization and regional groupings, or even more, the pooling of resources available to a single cause, in our case, the fight against cancer. This idea of unity around common projects between the two sides is growing every day, despite the blaze of some of countries from the south shore kept away freedoms too long. In many countries of the south border, the intellectual and political repressions have had a direct impact on the creation and evolution in all fields, including science. The “brain drain”, the abandonment of modern languages, the dismantling of the school system and university has only widen the gap and create a virtual dependence on the south bank of the north shore (then other civilizations more distant) in terms of training, education and development. A vicious circle was thus created, with a demand for expertise increasingly important motivating departure of trainees contrasting over the years with rarer returns. South Mediterranean area is however living a major political metamorphosis that will probably allow a new era of creativity, national spirits and inter-countries collaborations. 1.2. Mediterranean area: specificity in terms of cancer care inequalities Regarding to the current situation in terms of disparities between the two borders, we should not remain passive and watch the situation of professionals deteriorate and therefore the patients. Our association AROME (association of radiotherapy and Oncology of the Mediterranean area; www.aromecancer.org), is committed since 2006 to an innovative project which is to provide practical training in oncology through the exchanges between the two Mediterranean borders with the main objective of reducing inequalities. Very modestly, this project began with a group of leaders who recognized the need to promote practical training of young people in addition to the extensive data provided by new technologies. Training is probably one of the best ways to contribute to the reduction of inequalities in cancer care. To go further in our approach, it is important to plan the next steps. It is certain that our specific Mediterranean cultural plans, customs, religions and lifestyles, we must raise awareness of the need to consider in the near future treatment issues based on specific research related to our own epidemiology. Thus, it is crucial to identify areas of
biological research on specific locations of which the management practice cannot be based on data from distant countries with socio-cultural and lifestyle completely different from ours. In terms of carcinogenesis, for example, many studies have reported the close relationship between environmental factors, lifestyle, eating habits and reducing the risk of cancer in the Mediterranean area. Conversely, for some cancers, genetics, the frequency of presentations locally advanced and biologically aggressive is a virtual specificity in some countries of the south shore of the Mediterranean [1]. In these countries, the demographic transition may explain (at least in part), the fact that the average age of cancer patients is lower than 5–10 years compared to patients in Western countries and that cancer is the fourth cause mortality of the adult population [3]. In terms of results of support, a recently study by CONCORD, comparing in thirty-one countries the percentage of patients survival after 5 years for most common cancers (breast, prostate, colon, rectum), demonstrated that survival rates were better in North America, Australia, Japan or Western Europe. In contrast, survival rates were the lowest recorded in Algeria, Brazil and Eastern Europe [2]. With the prospect of improved survival of patients in these regions, early detection, prevention and access to innovative therapies are clearly identified as key parameters for the successful implementation of plans on cancer south border of the Mediterranean area. However, it is clear that the heterogeneity of resources (including human resources) can be an impediment to the development of innovative treatments and application of international recommendations in the south countries. At the AROME national boards meeting, which took place in 2008 in Istanbul, we addressed the issue of recommendations for clinical practice in the most common cancers in the Mediterranean countries. We have concluded, that the best approach was to define “minimal requirements” thus defining for the most common cancers (breast, cervix, head and neck, lung and urologic), the minimum average diagnostic and treatment be made available to professionals to support patients. It appeared to us to fix this fundamental limit can then apply international recommendations within available means and quality assurance requirements [4]. We further believe that the socio-cultural in this region, its epidemiology, available means for diagnosis and treatment, should impose a sustained regional research and better knowledge of tumor biology to identify these differences (if any) to adapt the strategies of care that should be based only on data from Western and Asian research. We must thus take advantage of advances in the identification of intimate biological tumors to provide answers to our ignorance of the specific Mediterranean biology. To illustrate this issue, we would like to take some specific examples of particular cancers in this region such as breast and nasopharynx.
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2. The Mediterranean cancer specificity in a new era of biology tools and cancer care 2.1. Breast cancer 2.1.1. Breast cancer in young women In the south border of the Mediterranean area, the high incidence of breast cancers among young women has been considered as an epidemiological reality and consequently gives rise to legitimate questioning. However, this has been to be discussed regarding the following points: - From the epidemiological point of view, the data are not exhaustive. - From the perspective of genetic, the studies are not very numerous and of questionable methodology. - In terms of risk factors, “westernization of the lifestyle” (occurring namely though a decrease in fertility and breastfeeding, an increase in age at the first pregnancy, obesity. . .) hampers the interpretation of such differences between the north and the south border, - Finally, from the biological point of view, although there is no evidence available, it seems like some hypothesis deserves demonstration though a deepened and targeted research. In terms of epidemiology, compared to Europe and North America, the median age of breast cancer incidence in North Africa, for example, is lower by 12 years on average (i.e. between 48 and 51 versus between 61 and 63 years). In addition, it is reported that rate of breast cancer among women aged less than 35 years is ranged between 8% and 12% [5]. Besides the population pyramid, the hormonal exposure, the nutritional context, physical activity and other factors are regularly quoted to explain these differences. For tumor presentation and biology, as compared to Europe and North America, the stage and the tumor size at diagnosis of breast cancers in the south border are largely higher. Moreover, the pathological profile of breast cancers seems linked to the patients’ age. In the Chalabi et al. study based on data collected between 2002 and 2007, the Tunisian, Lebanese and Moroccan patients were 10 years younger than the Western patients and suffered more frequently from tumors of luminal B type with more aggressive characteristics: a higher grade and a more important nodal invasion rate. In addition, in this population of the south shore, the common expression of 16 different genes of interest such as MMP9, VEGF, PHB1, BRCA1, TFAP2C, GJA1 and TFF1 [6] was observed. Genetic expression is also important in this particular population. In the Western populations the BRAC1 mutation confers a risk of 80% to develop a breast cancer in the course of life, with an average of 40% of the carriers who will develop a breast cancer by the age of 50 [7]. Recently, a quantitative and sequential analysis study of the
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BRCA1 gene among familial and sporadic cases in Algiers revealed a remarkable frequency of 10% of BRCA1 mutation, observed in the young sporadic cases against 36% in the Algerian family cancer cases as compared to 10% in the French family cases of breast and ovarian cancer. This study also showed that the Algerian non-BRCA1 tumors were of significantly higher grade and appeared at a younger age than the French non-BRCA1 tumors [8]. Altogether this work concluded that a higher frequency of BRCA1 mutation among the cases of breast cancers of the young Algerian woman compared to the European woman could be explained (at least partly) by the strong contribution of genetics revealed by the context of the weak incidence of breast cancer. 2.1.2. Inflammatory breast cancer (IBC) Compared to other types of Breast Cancer, IBC is rare disease (1-2%). The standardized incidence reported from the US SEER series is 2.1/100,000 [9]. In North Africa, particularly in Tunisia, IBC have been extensively studied in the eighties. Since the nineties, IBC diagnosis was made via TNM (T4d) or PEV3 criteria. The systematic clinical classification review according to the TNM classification has lowered the previous high rate of IBC in Tunisia. The rates decreased by more than a half to only 13% in the old cohort (1975-81) and around 5% in the most recent cases [10–12]. The decrease of IBC incidence is partly linked to the slight improvement of socio-economic level in Tunisia as well as the “occidentalisation” of lifestyle like more advanced age at marriage, diet modification or an actual of non-married women among those aged between 25 and 29 years [11]. In the USA, IBC represents 2% of breast cancers compared 5–7% in North Africa or Turkey [9–14]. Moreover, there is a slight difference in terms of age at diagnosis between Tunisian IBC series (mean: 43 y) [11] and those patients recorded in the SEER 1988-2000 registry (mean: 56–61 y) [15]. Furthermore, mean tumor size was >2 cm in 84% of cases within the SEER study, while it was higher than 5 cm in >80% in the Turkish and Tunisian retrospective studies. In terms of outcome, prognosis of IBC is continuously improved by the use of “modern” anthracyclines-taxanes based chemotherapy and more recently trastuzumab for HER2 positive tumors. The 5 years overall survival is now about 50%, but remains lower than that obtained in “neglected” T4b breast cancer [10]. 2.2. Nasopharyngeal cancer Nasopharyngeal carcinoma (NPC) represents a distinct entity among head and neck cancers with well-defined geographic distribution and a strong relation with Epstein-Barr Virus (EBV) primarily in endemic region. NPC is common in the Mediterranean basin with significant variation between different countries. In North African countries, it ranks 2nd among all head and neck cancers, and 9th (2.1%) among all cancers [16,17]. In general, the annual incidence of NPC can
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be divided into 3 categories: high (>10/100,000), intermediate (1-10/100,000), and low (<1/100,000). From published local cancer registries, it is apparent that countries around the Mediterranean area have a wide variation in NPC incidence. Countries like Algeria, Tunisia, and Greece have an intermediate incidence while the rest have a low incidence, similar to that of Western countries [18]. It is worthwhile noting that some countries in the Middle East that are not on the Mediterranean basin like Kuwait and Saudi Arabia have also an intermediate incidence of NPC in the same range of North African countries [17]. There are 2 epidemiologic features that have real relevance to NPC in the Mediterranean area. First, there is a bimodal distribution of the age incidence with an early peak between 15 and 20 years and a late peak around 45-50 years [19]. Although data from Asian countries show an earlier peak than in Western countries [20], this bimodal age-incidence distribution is quite unique to patients from the Mediterranean region. The second feature is the rapid decline of NPC incidence over the past 2 decades. This phenomenon has been clearly described in Tunisia [17,21]. Several hypotheses have been proposed to explain the higher incidence and peculiarity of NPC in the Mediterranean area particularly in North African countries. These include genetic predisposition, EBV infections, and environmental and nutritional factors. These factors differentially affect the incidence of NPC around the world and within the Mediterranean region. For instance, studies have shown specific polymorphisms of the latent membrane protein 1 (LMP1) of EBV infected NPC cells in patients from North African countries [22]. This protein is generally considered to be the main oncogenic product of the virus and plays, in conjunction with environmental and genetic factors, a key role in the development of NPC [23]. Nutritional factors have also been evaluated in these countries. The most incriminated nutrients are rancid butter and preserved meat with a suggestion that a high content of butyric acid which is a viral coactivator, could be a common causal nutritional agent [24].
3. Conclusion Around the Mediterranean Area, countries share common cultural backgrounds but also great disparities with respect to availability of means. AROME is a scientific organization created for the promotion of scientific exchanges between the two borders and overcoming inequalities in clinical practice of oncology around the Mediterranean Area. In an effort to accomplish this goal, our group have developed significant educational programs and established clinical recommendations for most common cancer sites in countries [4]. The structure of these recommendations lies in the concept of minimal requirements in order to help colleagues to change local politics of health. On the other hand, we believe that the socio-cultural in the region, its epidemiology, available means for diagnosis and treatment, should
impose a sustained regional research and better knowledge of tumor biology to adapt the strategies of care that should be based only on data from Western and Asian research.
Conflicts of interest The authors state no current conflicts of interest.
Reviewers Abraham Kuten, M.D., Head, Department of Oncology, Rambam Medical Center, IL-31096 Haifa, Israel.
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Biographies Yazid Belkacémi (M.D., Ph.D.) is a Radiation Oncologist at the University Hospital, Henri Mondor (AP-HP), Créteil, France. He is Professor in Radiation Oncology at the University of Paris XII. He has been elected as Honorary President of AROME this year after being President since AROME foundation in 2006. His research interests include breast, gynaecologic cancers, hematologic malignancies, rare tumors. He is also involved in new technologies development in radiation oncology. His biologic research topics include radiosensitivity and resistance markers of tumors and healthy
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tissues, combinations of targeted therapies and new drugs with ionizing radiation. Hamouda Boussen (M.D.) is Medical Oncologist, he trained at the Institut Salah Azaiz of Tunis and Institut Gustave Roussy, in France. He has been nominated Professor in Oncology at the University of Tunis, Tunisia. He is currently the head of the Medical Oncology Department at the Abderrahman Mami Hospital, Ariana in Tunis. His research is focused on nasopharyngeal carcinoma, adjuvant and palliative care and inflammatory breast cancer. He is elected as AROME vice-president since 2006. Sedat Turkan (M.D.) is a Professor of Radiation Oncology at the Department of Radiation Oncology, Cerrahpasa Medical School and University of Istanbul. He is a member of AROME since 2006. He is Vice-Secretary of AROME’s Executive Board. His main interests are, head and neck and brain tumors, prostate cancer and brachytherapy. He is also involved in all new technologies development for radiation oncology. Pelagia G Tsoutsou (M.D., Ph.D.) is a Radiation Oncologist in the Service de Radio-Oncologie of Center Hospitalier Universitaire Vaudois in Lausanne, Switzerland. Her research interests and topics include breast cancer and radiation sequelae, with a special interest in radiation pneumonitis and fibrosis. Her clinical interests are focused in breast, head and neck and hematologic malignancies. She is currently the Secretary of AROME, and as such, she is focusing on education in Oncology in countries around the Mediterranean Area. Fady Geara (MD, PhD) is a Professor and Chairman of Radiation Oncology Radiation at the American University of Beirut (AUB), Lebanon. He is also the Director of the Naef K Basile Cancer Institute at the AUB Medical Center, and the founder and current president of the Lebanese Society of Radiation Oncology. His research interests include normal tissue tolerance to radiation therapy, radiosensitizers, breast, prostate, and head and neck cancers. He is an active member of AROME since 2007. Joseph Gligorov (M.D.) is Medical Oncologist. He trained in Paris and Rouen, in France. He is currently in charge of Breast Cancer Medicine Department and Head of the Coordination Center for Cancer Care at Tenon Hospital, Assistance Publique Hôpitaux de Paris, University Pierre et Marie Curie. His research is focused in all areas of care related to breast cancer but also optimization of cancer care and cancer education. He is co-founder and elected as Francilian Breast Intergroup President since 2007and co-founder and elected President of AROME since 2011.
Editorial
Fight against cancer around the Mediterranean area: “Many hands make light work!” Yazid Belkacémi a,∗,1 , Hamouda Boussen b,1 , Sedat Turkan c,1 , Pelagia G. Tsoutsou d,1 , Fady Geara e,1 , Joseph Gligorov f,1 a
APHP, CHU Henri Mondor – University of Paris XII, Créteil, France Abderrahman Mami Hospital, Ariana, University of Tunis, Tunisia c Cerrahpasa Medical School and University of Istanbul, Turkey Univesity of Alexandropoulis, Greece and CHUV, Lausanne, Switzerland e American University of Beirut (AUB), Lebanon f APHP Tenon, CancerEst – University of Paris VI, France b
d
Contents 1.
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The Mediterranean specificity in a new evolving international era . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Mediterranean area: geopolitical specificity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Mediterranean area: specificity in terms of cancer care inequalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Mediterranean cancer specificity in a new era of biology tools and cancer care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Breast cancer in young women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. Inflammatory breast cancer (IBC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Nasopharyngeal cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract The geopolitical and strategic importance of the Mediterranean area is evident since a long time. In terms of health programs and means for cancer care, significant disparities have been reported between countries that borders the Mediterranean basin. AROME project began modestly in 2006 with a group of leaders who recognized the need to promote practical training of young people and, thus, contribute to reduce these inacceptable inequalities in terms of early diagnosis and management. Moreover, our project has been built from our belief that the socio-cultural specificity of this region, its epidemiology, availability of means for diagnosis and treatment, should impose a sustained regional research and better knowledge of tumor biology and identify the specificities that may require particular strategies of care that should not be based only on Western and Asian research data. We must thus take advantage of advances in the identification of intimate biological tumors to provide answers to our ignorance of the specific Mediterranean biology. In this paper, we illustrate this issue describing some particular cancers in this region such as breast and nasopharyngeal cancers. © 2012 Elsevier Ireland Ltd. All rights reserved. Keywords: Mediterranean area; Cancer care; Resources in oncology; Breast cancer; Nasopharyngeal cancer
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Corresponding author at: CHU Henri Mondor, 51 avenue Mal De Lattre de Tassigny, Créteil 94000, France. Tel.: +33 1 49 81 45 22; mobile: +33 6 77 43 98 10. E-mail address: [email protected] (Y. Belkacémi). 1 On behalf of the Association of Radiotherapy and Oncology of the Mediterranean area (AROME; www.aromecancer.org). 1040-8428/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.critrevonc.2012.10.004
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1. The Mediterranean specificity in a new evolving international era 1.1. Mediterranean area: geopolitical specificity The geopolitical and strategic importance of the Mediterranean is obvious as evidenced by the numerous conquests and conflicts that have rocked the region throughout its history. It is difficult to imagine a future in the XXI century that does not take into account globalization and regional groupings, or even more, the pooling of resources available to a single cause, in our case, the fight against cancer. This idea of unity around common projects between the two sides is growing every day, despite the blaze of some of countries from the south shore kept away freedoms too long. In many countries of the south border, the intellectual and political repressions have had a direct impact on the creation and evolution in all fields, including science. The “brain drain”, the abandonment of modern languages, the dismantling of the school system and university has only widen the gap and create a virtual dependence on the south bank of the north shore (then other civilizations more distant) in terms of training, education and development. A vicious circle was thus created, with a demand for expertise increasingly important motivating departure of trainees contrasting over the years with rarer returns. South Mediterranean area is however living a major political metamorphosis that will probably allow a new era of creativity, national spirits and inter-countries collaborations. 1.2. Mediterranean area: specificity in terms of cancer care inequalities Regarding to the current situation in terms of disparities between the two borders, we should not remain passive and watch the situation of professionals deteriorate and therefore the patients. Our association AROME (association of radiotherapy and Oncology of the Mediterranean area; www.aromecancer.org), is committed since 2006 to an innovative project which is to provide practical training in oncology through the exchanges between the two Mediterranean borders with the main objective of reducing inequalities. Very modestly, this project began with a group of leaders who recognized the need to promote practical training of young people in addition to the extensive data provided by new technologies. Training is probably one of the best ways to contribute to the reduction of inequalities in cancer care. To go further in our approach, it is important to plan the next steps. It is certain that our specific Mediterranean cultural plans, customs, religions and lifestyles, we must raise awareness of the need to consider in the near future treatment issues based on specific research related to our own epidemiology. Thus, it is crucial to identify areas of
biological research on specific locations of which the management practice cannot be based on data from distant countries with socio-cultural and lifestyle completely different from ours. In terms of carcinogenesis, for example, many studies have reported the close relationship between environmental factors, lifestyle, eating habits and reducing the risk of cancer in the Mediterranean area. Conversely, for some cancers, genetics, the frequency of presentations locally advanced and biologically aggressive is a virtual specificity in some countries of the south shore of the Mediterranean [1]. In these countries, the demographic transition may explain (at least in part), the fact that the average age of cancer patients is lower than 5–10 years compared to patients in Western countries and that cancer is the fourth cause mortality of the adult population [3]. In terms of results of support, a recently study by CONCORD, comparing in thirty-one countries the percentage of patients survival after 5 years for most common cancers (breast, prostate, colon, rectum), demonstrated that survival rates were better in North America, Australia, Japan or Western Europe. In contrast, survival rates were the lowest recorded in Algeria, Brazil and Eastern Europe [2]. With the prospect of improved survival of patients in these regions, early detection, prevention and access to innovative therapies are clearly identified as key parameters for the successful implementation of plans on cancer south border of the Mediterranean area. However, it is clear that the heterogeneity of resources (including human resources) can be an impediment to the development of innovative treatments and application of international recommendations in the south countries. At the AROME national boards meeting, which took place in 2008 in Istanbul, we addressed the issue of recommendations for clinical practice in the most common cancers in the Mediterranean countries. We have concluded, that the best approach was to define “minimal requirements” thus defining for the most common cancers (breast, cervix, head and neck, lung and urologic), the minimum average diagnostic and treatment be made available to professionals to support patients. It appeared to us to fix this fundamental limit can then apply international recommendations within available means and quality assurance requirements [4]. We further believe that the socio-cultural in this region, its epidemiology, available means for diagnosis and treatment, should impose a sustained regional research and better knowledge of tumor biology to identify these differences (if any) to adapt the strategies of care that should be based only on data from Western and Asian research. We must thus take advantage of advances in the identification of intimate biological tumors to provide answers to our ignorance of the specific Mediterranean biology. To illustrate this issue, we would like to take some specific examples of particular cancers in this region such as breast and nasopharynx.
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2. The Mediterranean cancer specificity in a new era of biology tools and cancer care 2.1. Breast cancer 2.1.1. Breast cancer in young women In the south border of the Mediterranean area, the high incidence of breast cancers among young women has been considered as an epidemiological reality and consequently gives rise to legitimate questioning. However, this has been to be discussed regarding the following points: - From the epidemiological point of view, the data are not exhaustive. - From the perspective of genetic, the studies are not very numerous and of questionable methodology. - In terms of risk factors, “westernization of the lifestyle” (occurring namely though a decrease in fertility and breastfeeding, an increase in age at the first pregnancy, obesity. . .) hampers the interpretation of such differences between the north and the south border, - Finally, from the biological point of view, although there is no evidence available, it seems like some hypothesis deserves demonstration though a deepened and targeted research. In terms of epidemiology, compared to Europe and North America, the median age of breast cancer incidence in North Africa, for example, is lower by 12 years on average (i.e. between 48 and 51 versus between 61 and 63 years). In addition, it is reported that rate of breast cancer among women aged less than 35 years is ranged between 8% and 12% [5]. Besides the population pyramid, the hormonal exposure, the nutritional context, physical activity and other factors are regularly quoted to explain these differences. For tumor presentation and biology, as compared to Europe and North America, the stage and the tumor size at diagnosis of breast cancers in the south border are largely higher. Moreover, the pathological profile of breast cancers seems linked to the patients’ age. In the Chalabi et al. study based on data collected between 2002 and 2007, the Tunisian, Lebanese and Moroccan patients were 10 years younger than the Western patients and suffered more frequently from tumors of luminal B type with more aggressive characteristics: a higher grade and a more important nodal invasion rate. In addition, in this population of the south shore, the common expression of 16 different genes of interest such as MMP9, VEGF, PHB1, BRCA1, TFAP2C, GJA1 and TFF1 [6] was observed. Genetic expression is also important in this particular population. In the Western populations the BRAC1 mutation confers a risk of 80% to develop a breast cancer in the course of life, with an average of 40% of the carriers who will develop a breast cancer by the age of 50 [7]. Recently, a quantitative and sequential analysis study of the
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BRCA1 gene among familial and sporadic cases in Algiers revealed a remarkable frequency of 10% of BRCA1 mutation, observed in the young sporadic cases against 36% in the Algerian family cancer cases as compared to 10% in the French family cases of breast and ovarian cancer. This study also showed that the Algerian non-BRCA1 tumors were of significantly higher grade and appeared at a younger age than the French non-BRCA1 tumors [8]. Altogether this work concluded that a higher frequency of BRCA1 mutation among the cases of breast cancers of the young Algerian woman compared to the European woman could be explained (at least partly) by the strong contribution of genetics revealed by the context of the weak incidence of breast cancer. 2.1.2. Inflammatory breast cancer (IBC) Compared to other types of Breast Cancer, IBC is rare disease (1-2%). The standardized incidence reported from the US SEER series is 2.1/100,000 [9]. In North Africa, particularly in Tunisia, IBC have been extensively studied in the eighties. Since the nineties, IBC diagnosis was made via TNM (T4d) or PEV3 criteria. The systematic clinical classification review according to the TNM classification has lowered the previous high rate of IBC in Tunisia. The rates decreased by more than a half to only 13% in the old cohort (1975-81) and around 5% in the most recent cases [10–12]. The decrease of IBC incidence is partly linked to the slight improvement of socio-economic level in Tunisia as well as the “occidentalisation” of lifestyle like more advanced age at marriage, diet modification or an actual of non-married women among those aged between 25 and 29 years [11]. In the USA, IBC represents 2% of breast cancers compared 5–7% in North Africa or Turkey [9–14]. Moreover, there is a slight difference in terms of age at diagnosis between Tunisian IBC series (mean: 43 y) [11] and those patients recorded in the SEER 1988-2000 registry (mean: 56–61 y) [15]. Furthermore, mean tumor size was >2 cm in 84% of cases within the SEER study, while it was higher than 5 cm in >80% in the Turkish and Tunisian retrospective studies. In terms of outcome, prognosis of IBC is continuously improved by the use of “modern” anthracyclines-taxanes based chemotherapy and more recently trastuzumab for HER2 positive tumors. The 5 years overall survival is now about 50%, but remains lower than that obtained in “neglected” T4b breast cancer [10]. 2.2. Nasopharyngeal cancer Nasopharyngeal carcinoma (NPC) represents a distinct entity among head and neck cancers with well-defined geographic distribution and a strong relation with Epstein-Barr Virus (EBV) primarily in endemic region. NPC is common in the Mediterranean basin with significant variation between different countries. In North African countries, it ranks 2nd among all head and neck cancers, and 9th (2.1%) among all cancers [16,17]. In general, the annual incidence of NPC can
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be divided into 3 categories: high (>10/100,000), intermediate (1-10/100,000), and low (<1/100,000). From published local cancer registries, it is apparent that countries around the Mediterranean area have a wide variation in NPC incidence. Countries like Algeria, Tunisia, and Greece have an intermediate incidence while the rest have a low incidence, similar to that of Western countries [18]. It is worthwhile noting that some countries in the Middle East that are not on the Mediterranean basin like Kuwait and Saudi Arabia have also an intermediate incidence of NPC in the same range of North African countries [17]. There are 2 epidemiologic features that have real relevance to NPC in the Mediterranean area. First, there is a bimodal distribution of the age incidence with an early peak between 15 and 20 years and a late peak around 45-50 years [19]. Although data from Asian countries show an earlier peak than in Western countries [20], this bimodal age-incidence distribution is quite unique to patients from the Mediterranean region. The second feature is the rapid decline of NPC incidence over the past 2 decades. This phenomenon has been clearly described in Tunisia [17,21]. Several hypotheses have been proposed to explain the higher incidence and peculiarity of NPC in the Mediterranean area particularly in North African countries. These include genetic predisposition, EBV infections, and environmental and nutritional factors. These factors differentially affect the incidence of NPC around the world and within the Mediterranean region. For instance, studies have shown specific polymorphisms of the latent membrane protein 1 (LMP1) of EBV infected NPC cells in patients from North African countries [22]. This protein is generally considered to be the main oncogenic product of the virus and plays, in conjunction with environmental and genetic factors, a key role in the development of NPC [23]. Nutritional factors have also been evaluated in these countries. The most incriminated nutrients are rancid butter and preserved meat with a suggestion that a high content of butyric acid which is a viral coactivator, could be a common causal nutritional agent [24].
3. Conclusion Around the Mediterranean Area, countries share common cultural backgrounds but also great disparities with respect to availability of means. AROME is a scientific organization created for the promotion of scientific exchanges between the two borders and overcoming inequalities in clinical practice of oncology around the Mediterranean Area. In an effort to accomplish this goal, our group have developed significant educational programs and established clinical recommendations for most common cancer sites in countries [4]. The structure of these recommendations lies in the concept of minimal requirements in order to help colleagues to change local politics of health. On the other hand, we believe that the socio-cultural in the region, its epidemiology, available means for diagnosis and treatment, should
impose a sustained regional research and better knowledge of tumor biology to adapt the strategies of care that should be based only on data from Western and Asian research.
Conflicts of interest The authors state no current conflicts of interest.
Reviewers Abraham Kuten, M.D., Head, Department of Oncology, Rambam Medical Center, IL-31096 Haifa, Israel.
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Biographies Yazid Belkacémi (M.D., Ph.D.) is a Radiation Oncologist at the University Hospital, Henri Mondor (AP-HP), Créteil, France. He is Professor in Radiation Oncology at the University of Paris XII. He has been elected as Honorary President of AROME this year after being President since AROME foundation in 2006. His research interests include breast, gynaecologic cancers, hematologic malignancies, rare tumors. He is also involved in new technologies development in radiation oncology. His biologic research topics include radiosensitivity and resistance markers of tumors and healthy
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tissues, combinations of targeted therapies and new drugs with ionizing radiation. Hamouda Boussen (M.D.) is Medical Oncologist, he trained at the Institut Salah Azaiz of Tunis and Institut Gustave Roussy, in France. He has been nominated Professor in Oncology at the University of Tunis, Tunisia. He is currently the head of the Medical Oncology Department at the Abderrahman Mami Hospital, Ariana in Tunis. His research is focused on nasopharyngeal carcinoma, adjuvant and palliative care and inflammatory breast cancer. He is elected as AROME vice-president since 2006. Sedat Turkan (M.D.) is a Professor of Radiation Oncology at the Department of Radiation Oncology, Cerrahpasa Medical School and University of Istanbul. He is a member of AROME since 2006. He is Vice-Secretary of AROME’s Executive Board. His main interests are, head and neck and brain tumors, prostate cancer and brachytherapy. He is also involved in all new technologies development for radiation oncology. Pelagia G Tsoutsou (M.D., Ph.D.) is a Radiation Oncologist in the Service de Radio-Oncologie of Center Hospitalier Universitaire Vaudois in Lausanne, Switzerland. Her research interests and topics include breast cancer and radiation sequelae, with a special interest in radiation pneumonitis and fibrosis. Her clinical interests are focused in breast, head and neck and hematologic malignancies. She is currently the Secretary of AROME, and as such, she is focusing on education in Oncology in countries around the Mediterranean Area. Fady Geara (MD, PhD) is a Professor and Chairman of Radiation Oncology Radiation at the American University of Beirut (AUB), Lebanon. He is also the Director of the Naef K Basile Cancer Institute at the AUB Medical Center, and the founder and current president of the Lebanese Society of Radiation Oncology. His research interests include normal tissue tolerance to radiation therapy, radiosensitizers, breast, prostate, and head and neck cancers. He is an active member of AROME since 2007. Joseph Gligorov (M.D.) is Medical Oncologist. He trained in Paris and Rouen, in France. He is currently in charge of Breast Cancer Medicine Department and Head of the Coordination Center for Cancer Care at Tenon Hospital, Assistance Publique Hôpitaux de Paris, University Pierre et Marie Curie. His research is focused in all areas of care related to breast cancer but also optimization of cancer care and cancer education. He is co-founder and elected as Francilian Breast Intergroup President since 2007and co-founder and elected President of AROME since 2011.