Evolution of a milkshed and role of alternative milk collection centres in Egypt

Annabelle Daburon
UMR SELMET
CIRAD
Campus international de BaillarguetC-112, 34398, Cedex 5MontpellierTAFrance

Mohamed Radwan
Department of Animal Production
Faculty of Agriculture
Cairo University
GizaEgypt

Véronique Alary
UMR SELMET
CIRAD
Campus international de BaillarguetC-112, 34398, Cedex 5MontpellierTAFrance

ICARDA
Station ExpBP 6299

INRA-Quich
rue Hafiane Cherkaoui

Agdal Rabat-Institutes
RabatMorocco

Ahmed Ali
Animal Production System Research Department
Animal Production Research Institute
Dokki, GizaEgypt

Sherif Abdelghany
Department of Animal Production
Faculty of Agriculture
Cairo University
GizaEgypt

Karim Fouad
ICARDA
15 G. Radwan Ibn El-Tabib StreetGizaEgypt

Evolution of a milkshed and role of alternative milk collection centres in Egypt
10.1051/cagri/2016049RESEARCH ARTICLE / ARTICLE DE RECHERCHE
In Egypt, an agro-industrial company, in association with a non-governmental organization, began setting up milk collection centres within producers' organizations in 2011. The project was very active in the Beni Suef Governorate. This article analyses the milkshed evolution over the past 50 years and the project impact.

Introduction

Demographic and dietary changes, including greater consumption of animal products, have led to an increase in demand for dairy products in all continents. A few major private agro-industries are competing for shares in the new markets, which are often in developing countries and involve the use of dried milk, from the global market and locally produced fresh milk. Dairy mega-farms are being developed, but companies are increasingly in contact with family farms as a sourcing strategy (Nestlé Milk District Model, Danone Ecosystem initiatives, etc.), promoting inclusive businesses (Kelly et al., 2016). Milk-sourcing projects are often associated with non-governmental organizations (NGO) (Gold et al., 2013). By providing agricultural services to producers' community, companies and NGOs seek to improve the quality and quantity of the raw material collected to meet agroindustrial standards. These projects carry development opportunities and risks. Understanding the general context where they operate appears essential to ensure their sustainability (Vatin, 2008). Egypt faces tough challenges. Its population has more than quadrupled in 60 years (92 million in 2015). Urban encroachment threatens arable land availability and water resource is scarce. Most milk is produced by family farms, with a peak production in winter. Large and mega dairy farms breeding thousands of cows complete the national production. Yet, Egypt has to import 2 million tons of milk equivalent, increasing the national trade deficit (Fig. 1). In this context, an agro-industrial enterprise has been promoting milk collection centres (MCC) since 2011; an NGO is responsible for developing MCCs within pre-existing farmers organizations supervised by public employees. The project's aim was to collect cow milk from family farms to supply a yogurt processing plant in Greater Cairo and to encourage local development in the regions hosting the MCCs. It has been very active in the Beni Suef (BS) Governorate since 2011 and claimed its key role in milk market development.

This paper explores the role of the agro-industry milksourcing project in the evolution of the dairy sector of the BS milkshed. Did the project initiate the creation of a local milk market? Our hypothesis is that MCCs: (i) arrived in an already highly competitive market; (ii) modified milk prices in favour of small suppliers (farmers and milk collectors) and achieved lasting improvements to dairy hygiene.

Material and Methods

Project promoters intensively invested in the Nile Valley of BS Governorate justifying our choice of investigating the milkshed of this area. The BS milkshed surrounds the city of Beni Suef (120 km south of Cairo) (Fig. 2) and follows the Nile Valley borders (excluding desert land and Fayoum Oasis in the west). A literature review helped us to identify relevant data on the BS region: history, demographic trends and changing demands.

An in-itinere socio-economic impact study of the project has been conducted during three years (2014-2016) at farms, community and supply chain level. In BS, three villages were selected according to their involvement with the project in 2014 (had an MCC, will receive an MCC and no link with the project). A total of 76 farmers were interviewed, selected according to their milk marketing practices (dealing with MCC or not). 11 dairy collectors and 4 MCC of these villages were also interviewed. They all received a visit every year. Semi-structured interviews were performed to collect data on socio-economic and technical characteristics of these diverse systems. Historical qualitative data were also collected on their dairy activity and the milkshed recent evolution. It will be the main material for this analysis. Participatory meetings were also held in the village with the longest involvement of the project to assess the dairy sector evolution after the MCC opening, including milk hygienic quality evolution. It gathered diverse dairy stakeholders of the village: a milk collector, 2 farmers, a feed trader, 2 MCC employees, a veterinary, an animal trader, and 2 cooperative employees. Additional data were collected via open discussions with key figures involved in the local dairy sector and in the project. Our analysis is consistent with a realistic narrative approach (Vaara et al., 2016). By combining these diverse sources, we tried to rebuild the recent evolution of BS milkshed.

Results

The evolution of BS milkshed is depicted in Figure 3 and will be detailed in the following paragraphs.

3.1 Before 1980: dairy products marketed on the local market In 1947, the governorate's population was 600,000 (Shousha, 1947) (Fig. 4). Its economy was based on  agriculture. BS city was linked to Cairo, but the infrastructure was poor. The majority of the city population were rural migrants, who maintained a rural lifestyle (Ibrahim and Ibrahim, 2003). The demographic evolution led to an increase in local demand for homemade processed dairy products, as well as for cow and buffalo milk (Galal, 2002). The largest rural population was and remains "Fellahin", peasant working in small family farms. They combined integrated crop and livestock production (Ayrout and Williams, 2005) on less than 1 ha. Agriculture was subject to State planning and farmers had to plant important areas with cotton. Cereals (maize and wheat), vegetables (tomatoes, onions, etc.) and green fodder (berseem,   maize fodder) were also grown (Ibrahim and Ibrahim, 2003). Small herds were kept (one or two cows, one buffalo and a few sheep or goats). Calves were fed on milk. Women used the surplus to make butter or cheese (Karish or Mesh) for home consumption or sale (neighbours or local markets). Buffalo butter or cheese was particularly appreciated. Although several larger farms existed, dairy speculation was absent in the 70 s. Product quality was tested using organoleptic analysis. At that time, the fluid milk market was limited as selling milk was considered a sign of poverty.

1980-2000: a "milkshed centred" development in the dairy sector

During the 1980s, the population increased throughout the BS Governorate and in BS city. Major developments, including the construction of a bridge across the Nile, a highway to Cairo, an extension to BS University and the creation of a new city on the east bank of the Nile (New BS) stimulated local economy. Urban encroachment on arable land and population growth increased farm fragmentation. Between 1980 and 1990, the total number of farmers increased by 12.9 % (Ayeb, 2010), mainly among small farms (< 1 ha) (Robson et al., 2012) in Egypt. Urban growth and dietary changes increased local demand for dairy products. Several farmers from Zarabi, a village 3 km from BS city, began collecting small volumes of cow milk (< 50 kg/day) in a perimeter of less than 2 to 3 km. The daily round was made on a donkey or bicycle. Milk was sold to cafés in downtown BS. Initially, milk collection provided a supplementary income for farmers. By the end of the 80 s, they became milk collectors, gathering 100-200 kg/day of cow milk, with a farm activity on the side. The arrival of cheap equipment from Asia (motorbikes, tricycles) meant they could extend the collection perimeter (up to 5 km). Subsequently, several milk collectors began renting premises in downtown BS to sell directly to consumers. In the mid-nineties, Zarabi became a dairy cluster in the governorate: 20 families collected 0.5 to 1 t/day of milk from farmers and employed two or three family members. Milk was sold to creameries and a few families started processing milk, using traditional techniques. At the same time, agro-industrial products appeared on the local market in direct competition with artisanal products. Gradually, the taboo regarding liquid milk marketing disappeared, so women could supplement family incomes by selling fresh milk sparing processing time. With the liberalization of the agricultural sector, farmers had more freedom to choose their cropping pattern and increased fodder and dairy production. Taking advantage of the city's proximity, they relied on intermediaries to sell their milk on the urban market. Until then, dairy quality was subject to organoleptic controls. The number of both cows and buffalos increased during this period at the national level. Holstein genetic spread through artificial insemination and resulted in important local genetic losses. Private industrial dairies multiplied in the country encouraged by authorities while informal sector remained neglected.

2000 to 2011: structuration and emergence of major local operators

In the 90 s, demographic trajectories continued their upward trend: in 2003, the population in Greater Cairo reached 15 million. Dairy products consumption and liquid milk demand increased as well (EMHP, 2012). The number of dairies using industrial processes increased in the megalopolis.

They produced Roumi (hard cheese similar to Parmesan), White cheeses (fetatype cheeses), Mozzarella, yogurt, etc., collecting several tons of whole and/or skimmed milk, completed with dried milk, on a daily basis. Simultaneously, giant agribusinesses were developing their activity in and around Cairo. In addition to milk powder, their milk supply was guaranteed by their own mega-farms (thousands of dairy cattle) in the New Reclaimed Land (desert land developed for farming through national policies initiated in the 50's and continuing nowadays) and by collecting from  private industrial farms or milk collectors. Although the demand trends provided new opportunities for regional collectors, industrial processes imposed new milk quality standards. In BS, most milk collectors continued to collect from fellahin and sold their products to consumers in milk shops on an increasingly competitive urban market. Few milk collectors' families invested in equipment (coolers, large tanks, pick-ups) to reach Cairo's market. Five larger operators emerged in the BS milkshed, centralizing 1-5 t/day of cow milk (raw and skimmed), collected from farmers and small local milk collectors. It allowed for few speculative dairy farms to appear (20-50 cows, with up to 20 ha) in the governorate. In 2010, milk intermediaries paid 1.5 EGP (Egyptian Pound)/kg (in January 2015, 1 euro equalled 8.57 EGP) for cow milk at the farm gate and sold to urban consumers at 2.2 EGP/kg. With the new industrial quality requirements, large milk traders had to start to use electronic devices to test milk quality.

After 2011: agro-industry competing on the local milk market

The agro-industry entered the milk collection market in the BS milkshed in 2011, while demographic and urbanization trends continued (Fig. 4). Since then, several marketing channels in the region have been co-existing to add value to milk off-farm ( Fig. 5 shows average milk prices and volume for winter 2015): -The traditional local market: women sell their dairy products to neighbours or on the local market. Butter (buffalo milk) was sold to consumers for 35-40 EGP/kg. -The skimmed milk channel: some women own a milk separator (centrifugal device that separates milk into cream and skimmed milk), which they can rent to other woman in the village (average of 3 EGP/animal/week). These milkprocessing houses also give women the opportunity to socialize. After skimming, customers bring back cream and skimmed milk for home processing. Skimmed milk was collected for 1.10-1.20 EGP/kg by dedicated milk collectors. -The whole milk channel (mainly cow milk in BS): small intermediaries collect two times a day, 100-200 kg/day from farms in all the villages in the governorate, using a tricycle and no cooling system (2.48 EGP/kg at farm gate). They can sell some milk to rural consumers (3.5 EGP/kg) during their round or to bigger milk collectors (2.95 EGP/ kg) as well as MCC. Most of the larger milk collectors are from Zarabi, a village that has become a dairy cluster with a regional influence. Its members channel most of the milk  from the milkshed to the city of BS city and the Cairo area. Almost 40 families collect 0.5-2.0 t/day of milk (mainly cow milk) from BS farms (2.48 EGP/kg at farm gate) and other milk collectors. Processing remains a marginal activity for these families. Buffalo milk collection is uncommon in the BS milkshed. It is primarily supplied by milk collectors from the Fayoum milkshed (4.15 EGP/kg). It was sold at 6 EGP/kg to consumers in BS city. In priority, BS milk collectors market their products in their milk shop in BS city (an estimated total of 50 shops). Cow milk was sold at 4.5 EGP/kg and yogurt at 0.65 P/100 g. Surplus is sold to one of the five major collectors in the area connected with agro-industries and cheese laboratories in Cairo (2.95 GP/kg) or to MCC (2.70 GP/kg). The five large collectors test their supply of milk for fat and protein content introducing quality bonuses and penalties. However, the rest of the chain lacks the equipment to test for quality. Almost all milk collectors provide financial services (credit and loans) to their suppliers. Thus they play a key role in agricultural activity and maintain longterm relationship with their suppliers and outlets without formal contracts.

-MCC channel: since 2011, MCCs have opened. The main terms of the contract between the agro-industry and agricultural association receiving a new MCC include: the delivery of all the milk collected for a period of 5 years in exchange for the MCC's equipment, agricultural services for suppliers during the initial phase of development (training courses, veterinary services, feed, etc.) focused on woman empowerment, management support and advantageous milk prices when the MCC first opened. The business model is designed to maintain agricultural services by using some of the proceeds from milk sales. The MCC accepts any quantity of milk from its suppliers. Alcohol tests are performed occasionally. Milk composition (and rarely presence of antibiotic residue) is analysed when large quantities of milk are supplied and before each delivery to the plant in the outskirts of Cairo (150-200 km away depending on the MCCs' location). Sales are concluded when the milk delivered meets the company's requirements (quality and quantity). Milk failing to meet requirements is rejected. MCC then have to find alternative marketing channels without bargaining power. When it opened, the MCC was very attractive to farmers and local milk collectors. Its direct link with a major multinational company suggested increased security and new perspectives. In 2012, this company offered an average of 2.70 GP/ kg to MCC. The recommended margin was set at 0.25-0.30 EGP. Thus, the estimated MCC price was 2.40 GP/kg for suppliers (farmers and milk collectors) compared to milk collectors who paid 1.5 EGP/kg the previous year. In 2012, MCC received an average of 4 t/day. Local milk intermediaries resisted by increasing their prices. Thus, milk prices for farmers increased and the volume collected by MCC decreased. In 2014, the average volume collected decreased from 4 t/day to 2.5 t/day as five MCCs collected milk regularly in the BS area. MCC offered an average price of 2.70 EGP/kg in the winter of 2015. The conventional milk collectors offered lower prices (2.48 EGP/kg), but had lower quality requirements and collected at home.

Milk hygienic quality evolution in the village was assessed during participatory meetings. According to this group, by introducing new milk quality requirements and offering courses, the MCC helped farmers improving their production practices. Based on their perception, the milk hygienic quality improvement was scored to 30% in the village. Families adjusted their practices to benefit from the MCC's high initial prices. Regardless their marketing channels, they kept the new practices to protect their families' health. The standards enforced by independent traders also contributed to this evolution. However, the company regularly rejected MCC milk for quality reasons. Subsequently, milk was sold to other businesses below cost price, which undermined the MCC's economic balance. Consequently, when the company stopped providing financial support, the MCC found it difficult to maintain agricultural services for farmers. Over the years, the MCC collected smaller quantities (Fig. 5).

Discussion-Conclusion

Demographic growth and diets evolution led to an increase in the demand for dairy products. It also generated the bottomup structuration of the Beni Suef (BS) dairy sector, which was made possible by more liberal policies and improved infrastructure. The evolution of the BS milkshed until the 90 s is comparable to the Brasil Novo milkshed, in Brazil (Poccard-Chapuis and Carvalho, 2015) where local urban demand and know-how facilitated the organization of the dairy sector within the milkshed. This evolution has not been observed in Ethiopia, where the increasing urban demand did not lead to the local dairy sector structuration (Geleti et al., 2014). After the 90's, the opening up of the BS milkshed strengthened the dairy sector structuration. Few operators were able to reach the demands of cheese-processing units and agroindustrial in Greater Cairo. Meanwhile industrial dairy products entered BS market. This validates the first hypothesis: a dynamic dairy activity had developed in the BS milkshed before the agro-industry began to collect milk locally.

In 2011, when milk collection centers (MCC) arrived, a new sequence started. Similar to the cases in Turkey, MCCs could be conceived as proximity operators that stimulated the dairy network locally and created a new "bridge" between producers and agribusiness (Sayin et al., 2011). The MCCs generated positive competition in BS. They stimulated a rise in milk prices and improved local milk quality. Farmers and small local collectors could diversify their marketing channels, increasing their resilience. Interesting research perspectives would be to consider the impact of this evolution on the access to dairy products for the poorest segment of the population which might have been hindered. Large traditional collectors were quick to respond to the new competition and the MCCs faced difficulties. Meeting the agro-industrial quality and quantity requirements regularly remains difficult for MCCs. It undermines their economic stability. As in the case of Morocco (Faysse and Simon, 2015), the MCCs' strategy to improve milk quality was limited to farmers delivering directly their milk (without intermediary). Encompassing all the actors of the local value chain in a management that would focus on both improving milk quality of MCC suppliers (farmers and milk intermediaries) and dealing with milk quality heterogeneity, by relying on the local value chain, might be a more efficient strategy.

This last sequence can be considered in the light of two cases from Senegal. In 1992, Nestlé tried to develop a local milk collection system. It faced problems similar to those seen in the model currently promoted in Egypt: high transport costs, milk quality issues and fairly unattractive prices offered by agro-industries compared to the local market. The company withdrew its activity after 10 years (Vatin, 2008). On the contrary, La Laiterie du Berger is a successful dairy in Senegal. Local milk collection and milk powder are processed into high quality value-added dairy products for urban consumers. An agro-industrial group has recently invested in the enterprise (Corniaux, 2015). La Laiterie du Berger raises the question of the possibility for a MCC to diversify sources of income by taking advantage of nearby urban markets while continuing to supply raw milk to the agro-industry. Diversifying MCCs activities by processing and diversifying marketing channels would help overcome the problem of milk heterogeneity and might improve financial stability. Gender dimension was a corner stone of the MCC project. It provided to woman employment, trainings and opportunity to market raw milk (reducing processing time). As in the Bengali case study, the role of women may have been strengthened by the MCCs projects (Quisumbing et al., 2013). Paradoxically, it also competed with traditional businesswomen (those with a separator or who sell cheeses in the market).

Several development pathways can be considered for the future development of the BS milkshed. Population growth and changing diets will continue to drive demand. It will create new market opportunities for businesses and agro-industries will continue to invest in their search for new milk sources. Fellahin are likely to remain the main milk producers in Egypt for years to come. They will continue to raise agro-industrial interest. The sustainability of the top-down models currently promoted is uncertain in the short term, given their precarious economic situation. As long as agro-industry enterprises do not offer incentives competing with the informal chain, attempts to secure their milk supply will remain precarious. In order to develop adapted business strategies, a deeper acknowledgement of the local contexts is essential. Adjusting these initiatives in a process of co-construction with local milk collectors seems to be a pathway to explore. MCC could benefit their social anchorage, as well as their knowledge of the region (Kelly et al., 2016). Diversifying marketing channels by relying partially on them is a key for MCC to deal with milk quality heterogeneity and thus become more profitable. Furthermore, in a context where consumer's expectations regarding quality are increasing and a new food law is under preparation, MCCs involvement towards diverse dairy actor's hygienic practices could constitute an added synergy between public decision makers, project managers and micro-enterprises from the informal market. More generally, competition for land use and water scarcity calls into question the future of agriculture and dairy sector in BS. The escalating cost of feed (fodder and concentrates) is already problematic for dairy production. If agro-industry plans to maintain its family farm supply, optimizing efficiency of local resources use and limiting tensions by promoting inclusive coordination mechanisms is a pathway. Interbranch organizations dedicated to build inclusive value chains, rather than integrated, could help to progress towards values creation benefiting both the investing company as well as the local stakeholders. Ultimately they could contribute to the advent of a more sustainable territory.

Fig. 1 .
1National dairy production and imports in relation to demographic growth in Egypt from 1961 to 2012.Fig. 1. Production, importations laitières et croissance démographique en Égypte de 1961 à 2012.

Fig. 2 .
2Beni Suef Governorate and the limit of the milkshed in 2015.

Fig. 2 .Fig. 3 .
23Gouvernorat de Beni Suef et périmètre du bassin laitier considéré en 2015. Beni Suef milkshed chronicle.

Fig. 3 .
3Chronique du bassin laitier de Beni Suef.

Fig. 4 .
4Beni Suef population evolution and average milk volumes collected by MCCs and milk traders.

Fig. 4 .
4Évolution de la population de Beni Suef et moyennes des volumes de lait collecté par les MCC et les collecteurs de lait indépendants.

Fig. 5 .
5Beni Suef contemporary supply chain. Average prices are in Egyptian pounds and for cow milk in winter 2015 when no other product is specified.Fig. 5. Filière laitière contemporaine de Beni Suef. S'il n'y a pas de précision, les prix moyens indiqués sont ceux du lait de vache pendant l'hiver 2015.
A.Daburon et al. : Cah. Agric. 2016, 25, 65008
Acknowledgements. This study was conducted within the framework of project SIADEEP financed by Danone Ecosystem. We wish to thank the researchers from APRI and Cairo University who participated in the study, as well as the producers and intermediaries in the sector who kindly gave us their time.
La crise de la société rurale en Egypte. H Ayeb, La fin du Fellah ? Hommes et sociétés. ParisKarthalaAyeb H. 2010. La crise de la société rurale en Egypte. La fin du Fellah ? Hommes et sociétés. Paris: Karthala.

The Egyptian peasant. Cairo. H H Ayrout, J A Williams, American University in Cairo PressNew YorkAyrout HH, Williams JA. 2005. The Egyptian peasant. Cairo; New York: American University in Cairo Press.

Bassin laitier de la basse vallée du fleuve Sénégal (Sénégal). C Corniaux, Voies Lactées. Dynamique des bassins laitiers entre globalisation et territorialisation. Napoléone M, Corniaux C, Leclerc BAvignon (FranceCardèreCorniaux C. 2015. Bassin laitier de la basse vallée du fleuve Sénégal (Sénégal). In: Napoléone M, Corniaux C, Leclerc B, eds. Voies Lactées. Dynamique des bassins laitiers entre globalisation et territorialisation. Avignon (France): Cardère.

Egypt Nutrition Landscape analysis report 2012. Cairo: Egyptian Ministry of health and population; Unicef. EMHP. Egyptian Ministry Of Health And Population)EMHP (Egyptian Ministry Of Health And Population). 2012. Egypt Nutrition Landscape analysis report 2012. Cairo: Egyptian Ministry of health and population; Unicef. Available from https://www. unicef.org/mena/Landscape_Anaylsis_Report_January_2013(1).pdf

Holding all the cards? Quality management by cooperatives in a moroccan dairy value chain. N Faysse, C Simon, European Journal of Development Research. 271Faysse N, Simon C. 2015. Holding all the cards? Quality management by cooperatives in a moroccan dairy value chain. European Journal of Development Research 27(1): 140-155.

The nutrition transition in Egypt: obesity, undernutrition and the food consumption context. O M Galal, 10.1079/PHN2001286Public Health Nutrition. 51Galal OM. 2002. The nutrition transition in Egypt: obesity, undernutrition and the food consumption context. Public Health Nutrition 5(1): 141-148. doi: 10.1079/PHN2001286

Analysis of fluid milk value chains at two peri-urban sites in western oromia, Ethiopia: Current status and suggestions on how they might evolve. D Geleti, M Hailemariam, A Mengistu, A Tolera, 10.5829/idosi.gv.2014.12.01.81164Global Veterinaria. 121Geleti D, Hailemariam M, Mengistu A, Tolera A. 2014. Analysis of fluid milk value chains at two peri-urban sites in western oromia, Ethiopia: Current status and suggestions on how they might evolve. Global Veterinaria 12(1): 104-120. doi: 10.5829/idosi.gv.2014.12.01.81164

Sustainable supply chain management in "base of the pyramid" food projects-a path to triple bottom line approaches for multinationals?. S Gold, R Hahn, S Seuring, 10.1016/j.ibusrev.2012.12.006International Business Review. 225Gold S, Hahn R, Seuring S. 2013. Sustainable supply chain management in "base of the pyramid" food projects-a path to triple bottom line approaches for multinationals? International Business Review 22(5): 784-799. doi: 10.1016/j.ibusrev.2012.12.006

Egypt: An economic geography. F N Ibrahim, B Ibrahim, London: I.B. TaurisIbrahim FN, Ibrahim B. 2003. Egypt: An economic geography. London: I.B. Tauris.

Inclusive business models -Guidelines for improving linkages between producer groups and buyer of agricultural produce. S Kelly, N Vergara, H Bammann, Kelly S, Vergara N, Bammann H. 2016. Inclusive business models - Guidelines for improving linkages between producer groups and buyer of agricultural produce. Rome: FAO, Available from http:// www.fao.org/3/a-i5068e.pdf

Bassin laitier de Brasil Novo (Brésil). L'émergence d'un bassin laitier localisé sur un front pionnier. R Poccard-Chapuis, S Carvalho, Voies Lactées. Dynamique des bassins laitiers entre globalisation et territorialisation. Napoléone M, Corniaux C, Leclerc BAvignon (FranceCardèrePoccard-Chapuis R, Carvalho S. 2015. Bassin laitier de Brasil Novo (Brésil). L'émergence d'un bassin laitier localisé sur un front pionnier. In: Napoléone M, Corniaux C, Leclerc B, eds. Voies Lactées. Dynamique des bassins laitiers entre globalisation et territorialisation. Avignon (France): Cardère.

Can dairy value-chain projects change gender norms in rural Bangladesh? Impacts on assets, gender norms. A R Quisumbing, S Roy, J Njuki, K Tanvin, E Waithanji, Quisumbing AR, Roy S, Njuki J, Tanvin K, Waithanji E. 2013. Can dairy value-chain projects change gender norms in rural Bangladesh? Impacts on assets, gender norms. Washington: IFPRI Available from http://ebrary.ifpri.org/utils/getfile/collection/ p15738coll2/id/127982/filename/128193.pdf

Spatial disintegration and arable land security in Egypt: A study of smalland moderate-sized urban areas. J S Robson, H M Ayad, R A Wasfi, A M El-Geneidy, 10.1016/j.habitatint.2011.10.001Habitat International. 362Robson JS, Ayad HM, Wasfi RA, El-Geneidy AM. 2012. Spatial disintegration and arable land security in Egypt: A study of small- and moderate-sized urban areas. Habitat International 36(2): 253-260. doi: 10.1016/j.habitatint.2011.10.001

The roles of milk collection centers in milk distribution channels in turkey: A case study of. C Sayin, M N Mencet, S Karaman, Sayin C, Mencet MN, Karaman S. 2011. The roles of milk collection centers in milk distribution channels in turkey: A case study of

. 10.5897/AJAR09.789Antalya. African Journal of Agricultural Research. 61Antalya. African Journal of Agricultural Research 6(1): 174-180. doi: 10.5897/AJ AR09. 789

Cholera epidemic in egypt (1947): A preliminary report. A T Shousha, Bulletin World Health Organization. 12Shousha AT. 1949. Cholera epidemic in egypt (1947): A preliminary report. Bulletin World Health Organization 1(2): 353-381.

Narratives as Sources of Stability and Change in Organizations: Approaches and Directions for Future Research. E Vaara, S Sonenshein, D Boje, 10.1080/19416520.2016.1120963The Academy of Management Annals. 101Vaara E, Sonenshein S, Boje D. 2016. Narratives as Sources of Stability and Change in Organizations: Approaches and Directions for Future Research. The Academy of Management Annals 10(1): 495-560. doi: 10.1080/19416520.2016.1120963

Comparaison dans l'espace et dans le temps. F Vatin, Travaux et documents de l'ATP Icare 1. Montpellier: CIRAD. Available from. Le lait et le marchéVatin F. 2008. Le lait et le marché. Comparaison dans l'espace et dans le temps. In : Travaux et documents de l'ATP Icare 1. Montpellier: CIRAD. Available from http://epe.cirad.fr/fr2/icare/docs/Icare_ WP_comm_1_Vatin_VF.pdf

Evolution of a milkshed and role of alternative milk collection centres in Egypt. A Daburon, M Radwan, V Alary, A Ali, S Abdelghany, K Fouad, Cah. Agric. 2565008Cite this article asCite this article as: Daburon A, Radwan M, Alary V, Ali A, Abdelghany S, Fouad K. 2016. Evolution of a milkshed and role of alternative milk collection centres in Egypt. Cah. Agric. 25: 65008.


Systematic evaluation of the methodology of randomized controlled trials of anticoagulation in patients with cancer

Gabriel Rada
Holger J Schünemann
Nawman Labedi
Pierre El-Hachem
Victor F Kairouz
Elie A Akl
Systematic evaluation of the methodology of randomized controlled trials of anticoagulation in patients with cancer
R E S E A R C H A R T I C L E Open Access
Background: Randomized controlled trials (RCTs) that are inappropriately designed or executed may provide biased findings and mislead clinical practice. In view of recent interest in the treatment and prevention of thrombotic complications in cancer patients we evaluated the characteristics, risk of bias and their time trends in RCTs of anticoagulation in patients with cancer.Methods: We conducted a comprehensive search, including a search of four electronic databases (MEDLINE, EMBASE, ISI the Web of Science, and CENTRAL) up to February 2010. We included RCTs in which the intervention and/or comparison consisted of: vitamin K antagonists, unfractionated heparin (UFH), low molecular weight heparin (LMWH), direct thrombin inhibitors or fondaparinux. We performed descriptive analyses and assessed the association between the variables of interest and the year of publication.

Results:

We included 67 RCTs with 24,071 participants. In twenty one trials (31%) DVT diagnosis was triggered by clinical suspicion; the remaining trials either screened for DVT or were unclear about their approach. 41 (61%), 22 (33%), and 11 (16%) trials respectively reported on major bleeding, minor bleeding, and thrombocytopenia. The percentages of trials satisfying risk of bias criteria were: adequate sequence generation (85%), adequate allocation concealment (61%), participants' blinding (39%), data collectors' blinding (44%), providers' blinding (41%), outcome assessors' blinding (75%), data analysts' blinding (15%), intention to treat analysis (57%), no selective outcome reporting (12%), no stopping early for benefit (97%). The mean follow-up rate was 96%. Adequate allocation concealment and the reporting of intention to treat analysis were the only two quality criteria that improved over time.

Conclusions: Many RCTs of anticoagulation in patients with cancer appear to use insufficiently rigorous outcome assessment methods and to have deficiencies in key methodological features. It is not clear whether this reflects a problem in the design, conduct or the reporting of these trials, or both. Future trials should avoid the shortcomings described in this article.

Background

Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common disorder in patients with cancer [1]. It is an important cause of morbidity and one of the leading causes of death in that population [2].

Anticoagulants are used for treatment of VTE and for thromboprophylaxis in high risk conditions such as surgery or the presence of an indwelling central venous catheter [3][4][5][6]. A survival benefit from anticoagulants as a result of VTE prevention and a possible direct antitumor effect has also been explored [7,8].

High-quality randomized controlled trials (RCTs) are the preferred method to establish the effects on efficacy and safety outcomes, since they minimize systematic error (bias). However, the reliability of their results depends on the extent to which potential sources of bias have been avoided [9]. Both the Cochrane Collaboration and the GRADE working group have advanced the methods to define which criteria should be evaluated in order to judge the risk of bias of a trial or a body of trials [9,10]. Poorly designed and/or conducted RCTs may lead to biased results, mislead clinical practice and adversely affect patients' outcomes. Unfortunately, overwhelming evidence shows the quality of RCTs is not optimal [11].

A few studies assessing the quality or the reporting of RCTs in patients with cancer have concluded that the quality of reporting is low, and some suggest that it is lower than in other areas [12][13][14][15][16]. However, we have identified no study focusing on trials of anticoagulation in patients with cancer.

The objective of this study is to systematically describe the characteristics, the risk of bias and their time trends in RCTs of anticoagulation in patients with cancer [3][4][5][6][7][8].

Methods

The study sample consists of all trials included in a series of six Cochrane systematic reviews of anticoagulation in patients with cancer [3][4][5][6][7][8]. The series covered the majority of topics for which RCTs were conducted in this field: parenteral anticoagulation for survival benefit (VTE thromboprophylaxis trials in ambulatory patients with cancer), oral anticoagulation for survival benefit, central venous catheters thromboprophylaxis, perioperative thromboprophylaxis, initial anticoagulation treatment of VTE, and long term anticoagulation treatment of VTE. A common search was conducted for all the reviews.

Eligibility criteria

Inclusion criteria for this study were the following: studies describing random allocation; participants with cancer of any type or stage; intervention and/or comparison consisting of vitamin K antagonists, unfractionated heparin (UFH), low molecular weight heparin (LMWH), ximelagatran, dabigatran, rivaroxaban, apixaban, or fondaparinux. We have included the details of the eligibility criteria for each of the six Cochrane systematic reviews in Additional file 1.

Search strategy

We electronically searched the following databases: the Cochrane Central Register of Controlled Trials (CEN-TRAL) (The Cochrane Library 2010, Issue 1), MEDLINE (1966 to February 2010; accessed via Ovid), EMBASE (1980 to February 2010; accessed via Ovid) and ISI Web of Science (February 2010). The search strategies combined free text and controlled vocabulary terms for cancer and anticoagulants, and a sensitive search strategy to retrieve randomized clinical trials (available from the authors). We have included the details of these electronic search strategies in Additional file 2.

In addition, we hand searched the conference proceedings of the American Society of Clinical Oncology (ASCO, starting with its first volume, 1982) and of the American Society of Hematology (ASH, starting with its 2003 issue); we screened the reference lists of included studies and of other relevant systematic reviews; and we used the related article feature in PubMed. We did not use language restrictions. Detailed eligibility criteria for each systematic review are reported in Additional file 1 [3][4][5][6][7][8].

Selection of studies

Two reviewers independently screened the titles and abstracts of identified citations for potential eligibility. Then, two reviewers independently screened the full text of articles potentially eligible using a standardized form. They resolved disagreements by discussion or by consulting a third reviewer.

Data extraction

Two reviewers independently extracted the data in duplicate from each study. They used a standardized form and resolved their disagreements by discussion or by consulting a third author. We considered all available reports for any particular trial to assess methodological quality. We attempted to contact authors for missing or unclearly reported data.

We extracted information about: publication year, language, funding (governmental, for profit, not for profit), population studied, number of participants, interventions, outcomes and assessment methods of DVT and PE (screening and diagnosis). Additionally, we evaluated the following risk of bias criteria: adequacy of sequence generation; adequacy of allocation concealment; blinding of participants, providers, data collectors, outcome assessors and data analysts; intention to treat analysis; absence of selective outcome reporting; no early stopping for benefit; and percentage of follow-up. For questions about blinding we further categorized unclearly reported data into 'probably yes' and 'probably no' using validated specific instructions (see Figure 1 in Akl et al., Journal of Clinical Epidemiology) [17].

Statistical analyses

We used frequency percentage, median and interquartile range to describe the trials' general characteristics and risk of bias criteria. We also assessed temporal trends for funding, number of participants, assessment methods, and outcome reporting.

Given that number of trials was not equally distributed in time, with a small sample in the 80s, we assessed the association between methodological quality criteria and the year of publication using chi-square test for linear trend.

We used 9-year intervals in order to cover the 27 year interval since the publication of the oldest trial identified. We assessed the association between industry funding and risk of bias criteria using chi-square test. Also, we performed regression analyses considering each of the risk of bias criteria as the dependent variable and year, sample size, review topic and funding as independent variables.

We performed all analyses using SPSS (version 17.0).

Results

Search results Figure 1 shows the study flow with reasons for exclusions. The search identified 8187references, of which we included sixty-seven unique RCTs, including a total of 24071 participants.

General characteristics

The publication year was in the 1980s, 1990s, and 2000s for 7%, 36% and 57% of trials respectively. Figure 2 shows the distribution by the year of publication from 1984 to 2010. Tables 1 and 2 provide the general characteristics and the methods of assessment of VTE in the studies.

English was the language of publication in 100% of studies. The more common source of funding was private for profit (n=41; 61%). Fourteen studies (21%) did not report the funding source. No specific type of funding has increased or decreased significantly over time.   Forty seven studies (70%) assessed participants with different types of cancer, while 15 (22%) included only one type (lung, colorectal, gynecologic, prostate, breast, pancreatic, hematological, hematological and solid tumors).

The most frequently studied medication class was low molecular weight heparin in 53 studies (79%). Nine studies evaluated intervention against a placebo (13%). The comparison with placebo was associated with later years of publication (p=0.009).

Studies reported data for death, venous thromboembolism, pulmonary embolism, and DVT in 53 (79%), 25 (37%), 31 (46%), and 38 (57%) of cases respectively. Only 21 studies (31%) reported data on diagnosis  triggered by clinical suspicion; the rest reported data on DVT screening or did not report data. Assessments of venous thromboembolism and of major bleeding were associated with more recent years of publication (p=0.002 and 0.001 respectively). The number of trials reporting some method for the screening of DVT decreased from 69 % in the first period to 26% in the later period (p=0.005).

The use of the 125I-fibrinogen-uptake test, a test with inferior diagnostic properties, was associated with earlier publication (p<0.001). Use of Ventilation/Perfusion scan as a screening tool was associated with earlier publication (p=0.01), and use of Doppler with diagnostic purpose was associated with recent publication (p<0.001). Table 3 describes the risk of bias of the included RCTs.

Reported risk of bias of RCTs

The reporting of only two risk of bias criteria has significantly improved over time. Adequate allocation concealment increased from 39% before 1993 to 71% after 2001 (p=0.046), and the reporting of an intention to treat analysis increased from 31% to 77% (p=0.033). The remaining risk of bias criteria did not significantly change with the year of publication.

In the bivariable analysis, industry funding was significantly associated with absence of caregiver blinding (p=0.043) and use of intention to treat analysis (p=0.01). Regression analysis showed that intention to treat was significantly associated with type of funding (OR 0.172; 95% CI 0.046-0.648). None of the other risk of bias criteria was significantly associated with type of funding, review topic, year, or sample size.

Discussion

Our study describes the characteristics, the risk of bias and the related time trends in randomized trials of anticoagulation in cancer. We used a comprehensive search strategy and a systematic methodology for selecting studies and abstracting data.

We found that the majority of RCTs of anticoagulation in patients with cancer appear to use insufficiently rigorous outcome assessment methods and to have deficiencies in key methodological features. Specifically, included studies had low rates of blinding of participants and caregivers, and intention to treat analysis. Our findings likely reflect a problem in the design, conduct and the reporting of these trials.

It has to be acknowledged it might be particularly challenging for trials of anticoagulation in the cancer setting, relative to other types of interventions in other populations, to adhere to some of the methods employed to reduce the risk of bias. For example, clinicians caring for patients with active cancer might be reluctant to accept to be blinded given their patients are already at increased risk of bleeding, frequently undergo invasive procedures, and might have chemotherapy-induce thrombocytopenia.

Our findings are consistent with those of several methodological studies in cancer [12][13][14][15][16][18][19][20][21][22][23]. When improvement over time has been explored, they have also found advances in some criteria, but at a rate slower than expected [16,18]. One study suggested that reporting is the main problem in trials of radiation therapy in oncology [13].

Given standard treatments have been established by previous studies as effective and safe, 70% of included trials had an active comparator (as opposed to placebo or no intervention). In our assessment of risk of bias, we did not consider the use of an active comparator as inappropriate. Rather, we focused on whether those involved in the trial were blinded to allocation. While blinding of providers and participants is feasible in these cases, it is challenging in the situations where different routes of administration are used, and dosage adjustments are required. However, given the risk of bias associated with a lack of blinding, this could be overcome with double dummy designs, sham-adapted dosages and several other techniques [24]. Considering that lack of blinding can overestimate treatment effect estimates, it is important to make every effort to ensure blinding in studies [25]. Failure to report intention to treat analysis can incorporate systematic and unpredictable bias in a trial [26]. Other types of analysis (i.e. per protocol analysis) should not be presented in isolation. It is surprising that only the reporting of adequate allocation concealment and of intention to treat analysis significantly changed over time. However, and especially for the latter, there is ample room for improvement.

Only 31% of studies reported data on diagnosis of deep vein thrombosis triggered by clinical suspicion and the rest reported data on DVT screening. However, estimating absolute symptomatic events from studies that included screening may be misleading [27]. If screening is positive, patients will typically receive anticoagulation. If they had not received anticoagulation, some of them would likely have developed symptomatic VTE. This would underestimate the number of symptomatic VTE and the benefit of any intervention that reduces VTE. Bias in the opposite direction is also possible. A positive screening test may lead to interpreting any minor symptom, that otherwise might not have warranted investigation, as a symptomatic VTE. This would overestimate the number of symptomatic VTE, and the benefit of any intervention that reduces VTE. Others might argue that screening-identified asymptomatic may be more informative than misleading. Indeed, there is evidence that incidentally diagnosed PEs have similar prognostic value on survival as symptomatic PEs [28,29]. Moreover, false positive results should be minimized in the hands of experienced imaging centers thus avoiding some of the above concerns. More research is needed to shed more light on this controversial area.

Interestingly, 20% of trials do not report the source of funding. Of those who report, 3 of every 4 trials are completely or partially funded by private for profit sources. Industry funded trials were more likely to report intention to treat analysis, and less likely to report caregiver blinding. It is well known that industry sponsored trials favor products made by the company funding the research, but one of the more likely explanations is not because a higher risk of bias but through the selection of an inappropriate comparator to the product being investigated [30,31].

We have found that the topic of the systematic review not to be associated with risk of bias. While this might reflect the absence of such association, it might be simply due to lack of statistical power given the relatively small number of studies included in the analysis.

Implications for future trial conduct and reporting

Existing guidelines of reporting are widely available. Trialists of anticoagulation in patients with cancer should design more rigorous trials and transparently report their methods and findings.

Implications for future methodological research

A recent systematic review found 177 studies evaluating the methodological quality of RCTs. While this type of studies is increasing, they suffer from a heterogeneity of criteria used and lack of clear definitions. Our study fulfills most of the criteria of quality of reporting proposed by these authors [32]. In the absence of other specific guidelines for the reporting of this type of methodological reviews, these criteria could inform future work.

Conclusions

Many RCTs of anticoagulation in patients with cancer appear to use insufficiently rigorous outcome assessment methods and to have deficiencies in key methodological features. It is not clear whether this reflects a problem in the design, conduct or the reporting of these trials, or both. Future trials should avoid the shortcomings described in this article.

Participants blinded

Caregiver blinded

Data collector blinded

Outcome assessor blinded

Follow up

The median sample size was 156 participants (Q1-Q3: 74-355), having increased over time from 100 participants per trial (Q1-Q3: 52-352) before 1993 to 186 after 2001 (Q1-Q3: 88-385) (p<0.001).

Figure 1
1Study flow.

Figure 2
2Time trend of the number of randomized controlled trials evaluating anticoagulation in cancer.

Table 1
1General characteristics of randomized controlled trialsOverall, n (%) N=67

Funding source

governmental
12 (18)

private not for profit
3 (4)

private for profit
41 (61)

Private for profit plus other source
4 (6)

Not funded
3 (4)

Not reported
14 (21)

Publication language

English
67 (100)

Sample size

Median (Q1-Q3)
156 (74-355)

n <200
39 (58)

n ≥200
28 (42)

Type of cancer

Participants with different cancer types
47 (70)

Cancer type not reported
5 (7)

All participants with same cancer type
15 (22)

Lung
5 (33)

Colorectal
2 (13)

Gynecologic
2 (13)

Prostate
1 (7)

Breast
1 (7)

Pancreatic
1 (7)

Hematological
2 (13)

Hematological and solid tumors
1 (6)

Cancer as subgroup of the study
27 (40)

Intervention

LMWH
53 (79)

UFH
33 (49)

Vitamin K antagonist
20 (30)

Direct thrombin inhibitors
5 (7)

Fondaparinux
3 (4)

Comparator

Active treatment
47 (70)

Placebo
9 (13)

No treatment
11 (17)

LMWH=Low molecular weight heparin, UFH=Unfractioned Heparin,
VTE=Venous thromboembolism, PE=Pulmonary embolism, DVT=Deep
vein thrombosis.

Table 2
2Assessment of VTEOverall, n (%) N=67

Table 3
3Risk of bias in randomized controlled trialsOverall, n (%) N=67Sequence generation

Adequate
57 (85)

Not clear
10 (15)

Inadequate
0 (0)

Allocation concealment

Adequate
41 (61)

Inadequate
3 (5)

Not clear
23 (34)

Table 3
3Risk of bias in randomized controlled trials (Continued)For benefit
2 (3)

For harm
1 (2)

For insufficient accrual
4 (6)

http://www.biomedcentral.com/1471-2407/13/76
AcknowledgementsAdditional filesAdditional file 1: Eligibility criteria for individual reviews.Additional file 2: Search strategies for electronic databases.Competing interestsThe authors declare that they have no competing interests.Authors' contributions GR performed the statistical analysis and drafted the manuscript. HS participated in the design of the study and provided methodological expertise. NL, PE and VK extracted the data from individual studies. EA conceived the study, participated in its design and coordination, extracted the data from studies and helped to draft the manuscript. All authors read and approved the final manuscript.
Risk of recurrent venous thromboembolism according to malignancy characteristics in patients with cancer-associated thrombosis: a systematic review of observational and intervention studies. M L Louzada, H Majeed, V Dao, P S Wells, Blood Coagul Fibrinolysis. 222Louzada ML, Majeed H, Dao V, Wells PS: Risk of recurrent venous thromboembolism according to malignancy characteristics in patients with cancer-associated thrombosis: a systematic review of observational and intervention studies. Blood Coagul Fibrinolysis 2011, 22(2):86-91.

Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. A A Khorana, C W Francis, E Culakova, N M Kuderer, G H Lyman, J Thromb Haemost. 53Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH: Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 2007, 5(3):632-634.

Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer. E A Akl, N Labedi, M Barba, I Terrenato, F Sperati, P Muti, H Schunemann, Cochrane Database Syst Rev. 66650Akl EA, Labedi N, Barba M, Terrenato I, Sperati F, Muti P, Schunemann H: Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev 2011, (6):CD006650.

Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer. E A Akl, S R Vasireddi, S Gunukula, M Barba, F Sperati, I Terrenato, P Muti, H Schunemann, Cochrane Database Syst Rev. 46649Akl EA, Vasireddi SR, Gunukula S, Barba M, Sperati F, Terrenato I, Muti P, Schunemann H: Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev 2011, 4:CD006649.

Anticoagulation for patients with cancer and central venous catheters. E A Akl, S R Vasireddi, S Gunukula, V E Yosuico, M Barba, F Sperati, D Cook, H Schunemann, Cochrane Database Syst Rev. 46468Akl EA, Vasireddi SR, Gunukula S, Yosuico VE, Barba M, Sperati F, Cook D, Schunemann H: Anticoagulation for patients with cancer and central venous catheters. Cochrane Database Syst Rev 2011, 4:CD006468.

Low molecular weight heparin versus unfractionated heparin for perioperative thromboprophylaxis in patients with cancer. E A Akl, N Labedi, I Terrenato, M Barba, F Sperati, E V Sempos, P Muti, D Cook, H Schunemann, Cochrane Database Syst Rev. 119447Akl EA, Labedi N, Terrenato I, Barba M, Sperati F, Sempos EV, Muti P, Cook D, Schunemann H: Low molecular weight heparin versus unfractionated heparin for perioperative thromboprophylaxis in patients with cancer. Cochrane Database Syst Rev 2011, 11:CD009447.

Parenteral anticoagulation in patients with cancer who have no therapeutic or prophylactic indication for anticoagulation. E A Akl, S Gunukula, M Barba, V E Yosuico, F F Van Doormaal, S Kuipers, S Middeldorp, H O Dickinson, A Bryant, H Schunemann, Cochrane Database Syst Rev. 46652Akl EA, Gunukula S, Barba M, Yosuico VE, van Doormaal FF, Kuipers S, Middeldorp S, Dickinson HO, Bryant A, Schunemann H: Parenteral anticoagulation in patients with cancer who have no therapeutic or prophylactic indication for anticoagulation. Cochrane Database Syst Rev 2011, 4:CD006652.

Oral anticoagulation in patients with cancer who have no therapeutic or prophylactic indication for anticoagulation. E A Akl, S R Vasireddi, S Gunukula, V E Yosuico, M Barba, I Terrenato, F Sperati, H Schunemann, Cochrane Database Syst Rev. 126466Akl EA, Vasireddi SR, Gunukula S, Yosuico VE, Barba M, Terrenato I, Sperati F, Schunemann H: Oral anticoagulation in patients with cancer who have no therapeutic or prophylactic indication for anticoagulation. Cochrane Database Syst Rev 2011, (12):CD006466.

The Cochrane Collaboration's tool for assessing risk of bias. In Cochrane Handbook for Systematic Reviews of Interventions Version 510 Available from wwwcochrane-handbookorg edn. J P Higgins, D G Altman, J A Sterne, Higgins JPT. GS: The Cochrane Collaboration5Higgins JP, Altman DG, Sterne JA: Chapter 8.5: The Cochrane Collaboration's tool for assessing risk of bias. In Cochrane Handbook for Systematic Reviews of Interventions Version 510 Available from wwwcochrane-handbookorg edn. Edited by Higgins JPT. GS: The Cochrane Collaboration; 2011.

GRADE guidelines: 4. Rating the quality of evidence--study limitations (risk of bias). G H Guyatt, A D Oxman, G Vist, R Kunz, J Brozek, P Alonso-Coello, V Montori, E A Akl, B Djulbegovic, Y Falck-Ytter, J Clin Epidemiol. 644Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso-Coello P, Montori V, Akl EA, Djulbegovic B, Falck-Ytter Y, et al: GRADE guidelines: 4. Rating the quality of evidence--study limitations (risk of bias). J Clin Epidemiol 2011, 64(4):407-415.

Explanation and Elaboration: Updated guidelines for reporting parallel group randomised trials. D Moher, S Hopewell, K F Schulz, V Montori, P C Gotzsche, P J Devereaux, D Elbourne, M Egger, D G Altman, Consort, J Clin Epidemiol. 638Moher D, Hopewell S, Schulz KF, Montori V, Gotzsche PC, Devereaux PJ, Elbourne D, Egger M, Altman DG: CONSORT 2010 Explanation and Elaboration: Updated guidelines for reporting parallel group randomised trials. J Clin Epidemiol 2010, 63(8):e1-e37.

Citation indexes do not reflect methodological quality in lung cancer randomised trials. T Berghmans, A P Meert, C Mascaux, M Paesmans, J J Lafitte, J P Sculier, Ann Oncol. 145Berghmans T, Meert AP, Mascaux C, Paesmans M, Lafitte JJ, Sculier JP: Citation indexes do not reflect methodological quality in lung cancer randomised trials. Ann Oncol 2003, 14(5):715-721.

Bad reporting does not mean bad methods for randomised trials: observational study of randomised controlled trials performed by the Radiation Therapy Oncology Group. H P Soares, S Daniels, A Kumar, M Clarke, C Scott, S Swann, B Djulbegovic, BMJ. 3287430Soares HP, Daniels S, Kumar A, Clarke M, Scott C, Swann S, Djulbegovic B: Bad reporting does not mean bad methods for randomised trials: observational study of randomised controlled trials performed by the Radiation Therapy Oncology Group. BMJ 2004, 328(7430):22-24.

Evaluation of the quality of radiotherapy randomized trials for painful bone metastases. T P Shakespeare, A Thiagarajan, V Gebski, Cancer. 1039Shakespeare TP, Thiagarajan A, Gebski V: Evaluation of the quality of radiotherapy randomized trials for painful bone metastases. Cancer 2005, 103(9):1976-1981.

Methodological quality and reporting of ethical requirements in phase III cancer trials. J J Tuech, P Pessaux, G Moutel, V Thoma, S Schraub, C Herve, J Med Ethics. 315Tuech JJ, Pessaux P, Moutel G, Thoma V, Schraub S, Herve C: Methodological quality and reporting of ethical requirements in phase III cancer trials. J Med Ethics 2005, 31(5):251-255.

Quality of randomized controlled trials reporting in the primary treatment of brain tumors. R Lai, R Chu, M Fraumeni, L Thabane, J Clin Oncol. 247Lai R, Chu R, Fraumeni M, Thabane L: Quality of randomized controlled trials reporting in the primary treatment of brain tumors. J Clin Oncol 2006, 24(7):1136-1144.

E A Akl, X Sun, J W Busse, B C Johnston, M Briel, S Mulla, J J You, D Bassler, F Lamontagne, C Vera, Specific instructions for estimating unclearly reported blinding status in randomized trials were reliable and valid. 2012Akl EA, Sun X, Busse JW, Johnston BC, Briel M, Mulla S, You JJ, Bassler D, Lamontagne F, Vera C, et al: Specific instructions for estimating unclearly reported blinding status in randomized trials were reliable and valid. J Clin Epidemiol 2012, 65(3):262-267.

Quality, evolution, and clinical implications of randomized, controlled trials on the treatment of lung cancer. A lost opportunity for meta-analysis. A Nicolucci, R Grilli, A A Alexanian, G Apolone, V Torri, A Liberati, JAMA. 198915Nicolucci A, Grilli R, Alexanian AA, Apolone G, Torri V, Liberati A: Quality, evolution, and clinical implications of randomized, controlled trials on the treatment of lung cancer. A lost opportunity for meta-analysis. JAMA 1989, 262(15):2101-2107.

Critical review of the quality and development of randomized clinical trials (RCTs) and their influence on the treatment of advanced epithelial ovarian cancer. S Marsoni, W Torri, A Taiana, A Gambino, R Grilli, P Liati, M G Franzosi, V Pistotti, F Parazzini, F Focarile, Ann Oncol. 15Marsoni S, Torri W, Taiana A, Gambino A, Grilli R, Liati P, Franzosi MG, Pistotti V, Parazzini F, Focarile F, et al: Critical review of the quality and development of randomized clinical trials (RCTs) and their influence on the treatment of advanced epithelial ovarian cancer. Ann Oncol 1990, 1(5):343-350.

Methodologic issues in effectiveness research on palliative cancer care: a systematic review. G C Rinck, G A Van Den Bos, J Kleijnen, H J De Haes, E Schade, C H Veenhof, J Clin Oncol. 154Rinck GC, van den Bos GA, Kleijnen J, de Haes HJ, Schade E, Veenhof CH: Methodologic issues in effectiveness research on palliative cancer care: a systematic review. J Clin Oncol 1997, 15(4):1697-1707.

Critical review of the randomized trials assessing the role of adjuvant thoracic irradiation and chemotherapy in the treatment of limited-stage small cell lung cancer. S Luce, M Paesmans, T Berghmans, C Castaigne, C Sotiriou, P Vermylen, J P Sculier, Luce S, Paesmans M, Berghmans T, Castaigne C, Sotiriou C, Vermylen P, Sculier JP: [Critical review of the randomized trials assessing the role of adjuvant thoracic irradiation and chemotherapy in the treatment of limited-stage small cell lung cancer].

. Rev Mal Respir. 155Rev Mal Respir 1998, 15(5):633-641.

Maintenance chemotherapy for small cell lung cancer: a critical review of the literature. J P Sculier, T Berghmans, C Castaigne, S Luce, C Sotiriou, P Vermylen, M Paesmans, Lung Cancer. 192Sculier JP, Berghmans T, Castaigne C, Luce S, Sotiriou C, Vermylen P, Paesmans M: Maintenance chemotherapy for small cell lung cancer: a critical review of the literature. Lung Cancer 1998, 19(2):141-151.

Adjuvant Chemotherapy for Resected Non-Small Cell Carcinoma of the Lung: Why We Still Don't Know. S George, M J Schell, F C Detterbeck, M A Socinski, Oncologist. 31George S, Schell MJ, Detterbeck FC, Socinski MA: Adjuvant Chemotherapy for Resected Non-Small Cell Carcinoma of the Lung: Why We Still Don't Know. Oncologist 1998, 3(1):35-44.

Methods of blinding in reports of randomized controlled trials assessing pharmacologic treatments: a systematic review. I Boutron, C Estellat, L Guittet, A Dechartres, D L Sackett, A Hrobjartsson, P Ravaud, PLoS Med. 310425Boutron I, Estellat C, Guittet L, Dechartres A, Sackett DL, Hrobjartsson A, Ravaud P: Methods of blinding in reports of randomized controlled trials assessing pharmacologic treatments: a systematic review. PLoS Med 2006, 3(10):e425.

Bias in clinical intervention research. L L Gluud, Am J Epidemiol. 1636Gluud LL: Bias in clinical intervention research. Am J Epidemiol 2006, 163(6):493-501.

Discordance between reported intention-to-treat and per protocol analyses. N Porta, C Bonet, E Cobo, J Clin Epidemiol. 607Porta N, Bonet C, Cobo E: Discordance between reported intention-to-treat and per protocol analyses. J Clin Epidemiol 2007, 60(7):663-669.

Approach to Outcome Measurement in the Prevention of Thrombosis in Surgical and Medical Patients: ACCP Evidence-Based Clinical Practice Guidelines. G Guyatt, J Eikelboom, M Gould, D Garcia, M Crowther, M Murad, S Kahn, Y Falck-Ytter, C Francis, M Lansberg, Chest. 20122Ninth Edition. supplGuyatt G, Eikelboom J, Gould M, Garcia D, Crowther M, Murad M, Kahn S, Falck-Ytter Y, Francis C, Lansberg M, et al: Approach to Outcome Measurement in the Prevention of Thrombosis in Surgical and Medical Patients: ACCP Evidence-Based Clinical Practice Guidelines (Ninth Edition). Chest 2012, 141(2 suppl):e185S-e194S.

Incidental pulmonary embolism in cancer patients: clinical characteristics and outcome-a comprehensive cancer center experience. Vasc Health Risk Manag. Abdel-Razeq Hn, A H Mansour, Y M Ismael, 7Abdel-Razeq HN, Mansour AH, Ismael YM: Incidental pulmonary embolism in cancer patients: clinical characteristics and outcome-a comprehensive cancer center experience. Vasc Health Risk Manag 2011, 7:153-158.

The clinical and radiological characteristics and evolution of incidentally diagnosed pulmonary thromboembolism. Tallon Guerola, P , Arenas Jimenez, J De La Hoz, R J , Massuti Sureda, B , Garcia Marco, J M , Radiologia. 503Tallon Guerola P, Arenas Jimenez J, de la Hoz RJ, Massuti Sureda B, Garcia Marco JM: [The clinical and radiological characteristics and evolution of incidentally diagnosed pulmonary thromboembolism]. Radiologia 2008, 50(3):239-243.

Pharmaceutical industry sponsorship and research outcome and quality: systematic review. J Lexchin, L A Bero, B Djulbegovic, O Clark, BMJ. 3267400Lexchin J, Bero LA, Djulbegovic B, Clark O: Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 2003, 326(7400):1167-1170.

Factors associated with findings of published trials of drug-drug comparisons: why some statins appear more efficacious than others. L Bero, F Oostvogel, P Bacchetti, K Lee, PLoS Med. 46184Bero L, Oostvogel F, Bacchetti P, Lee K: Factors associated with findings of published trials of drug-drug comparisons: why some statins appear more efficacious than others. PLoS Med 2007, 4(6):e184.

Reviews assessing the quality or the reporting of randomized controlled trials are increasing over time but raised questions about how quality is assessed. A Dechartres, P Charles, S Hopewell, P Ravaud, D G Altman, 10.1186/1471-2407-13-76J Clin Epidemiol. 642Dechartres A, Charles P, Hopewell S, Ravaud P, Altman DG: Reviews assessing the quality or the reporting of randomized controlled trials are increasing over time but raised questions about how quality is assessed. J Clin Epidemiol 2011, 64(2):136-144. doi:10.1186/1471-2407-13-76

Systematic evaluation of the methodology of randomized controlled trials of anticoagulation in patients with cancer. Rada, BMC Cancer. 1376Cite this article asCite this article as: Rada et al.: Systematic evaluation of the methodology of randomized controlled trials of anticoagulation in patients with cancer. BMC Cancer 2013 13:76.