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        <title>CancerWorld</title>
        <description>Education and knowledge through people and facts</description>
        <link>www.cancerworld.com</link>
        <lastBuildDate>Sat, 31 Jul 2010 07:01:41 +0100</lastBuildDate>
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        <item>
            <title>Turning the World Cancer Declaration into action</title>
            <link>http://www.cancerworld.com/Articles/Isseus_37/Editorial/Turning_the_World_Cancer_Declaration_into_action.html</link>
            <description><![CDATA[
Cancer kills more people than AIDS, tuberculosis and malaria combined. Going by recent global health trends, this year will see cancer emerge as the world&rsquo;s single leading cause of death. In an effort to focus the minds of international bodies and national governments on the gravity of the situation, four years ago the World Cancer Congress issued a World Cancer Declaration which called for urgent action to deal with the worldwide crisis. It set 11 targets that need to be reached by 2020 in order to avoid a disastrous escalation in new cancers and to significantly improve cancer survival in all countries. These ambitious goals were based on growing evidence that concerted action can make a big difference even over a short period of time. 

The 2010 World Cancer Congress, gathering this August in Shenzhen, China, will offer the first opportunity to review progress towards meeting the 11 targets. The picture is likely to offer cause for both hope and disappointment. The Declaration has certainly elicited great interest: so far, more than 177,000 people have signed up, promising to help achieve its goals. Many influential associations, from LiveStrong to the World Economic Forum, have taken measures that contribute to achieving many of the targets. Universal access to effective pain control &ndash; target 8 &ndash; for instance, is now a step closer with the launch of the UICC Global Access to Pain Relief Initiative (GAPRI). The intention is to engage with international bodies &ndash; including the relevant UN agencies &ndash; and to stimulate action on pain at a national level in key countries. 

More disappointing is the impression that, over the last two years, efforts to use the Declaration as a template for developing regional or national targets have tailed off, without which it is very difficult to measure progress &ndash; or lack of it &ndash; on the ground. Whether the Declaration has stimulated a significant increase in the number of national cancer control plans, which still represent the most powerful method for realising the 11 targets, is also far from clear. 

The World Cancer Congress in Shenzhen will look at ways to strengthen and further coordinate efforts towards achieving the World Cancer Declaration goals by the target date of 2020. Central to this will be rolling out UICC pilot projects on childhood cancers, cervical cancer and more, which have so far been limited to only a few countries. 

With the United Nations General Assembly having belatedly recognised the urgent need for tackling non-communicable diseases like cancer, in a resolution passed a few weeks ago, we now have a window of opportunity to regalvanise efforts where they are flagging, and prompt action where nothing has yet been done. The World Cancer Declaration will remain a vital roadmap to direct these efforts.

Franco Cavalli is the immediate past president of the UICC ]]></description>
            <author>Franco Cavalli (Guest Editor)</author>
            <category>Editorial</category>
        </item>
        <item>
            <title>Serigne Magueye Gueye: an agent for change</title>
            <link>http://www.cancerworld.com/Articles/Isseus_37/Cover_Story/Serigne_Magueye_Gueye%3A_an_agent_for_change.html</link>
            <description><![CDATA[
When people think of Africa&rsquo;s illness burden, the major communicable diseases such as malaria, tuberculosis, HIV/AIDS and others come to mind as the big killers and causes of chronic conditions. This perception has been outdated for years, if not decades, and it has hampered efforts to prepare the developing world for the explosion in non-communicable diseases such as cancer that we know is coming. 

Cancer already kills more people than AIDS, malaria and tuberculosis combined, in all but the very poorest countries, and it is rising rapidly as progress is made in controlling infectious diseases, and people live longer and start adopting western lifestyles. But the world missed an opportunity to galvanise efforts to meet this challenge when it left cancer off the targets for the Millenium Development Goals &ndash; an omission that has only just begun to be redressed this May, with the United National General Assembly resolution on non-communicable diseases. 

According to Serigne Gueye, president of the African Organisation for Research and Training in Cancer (AORTIC), and a urologist based in Dakar, Senegal, the most damaging omissions, however, have been not so much in the agendas of international organisations, but in Africa itself. 

&ldquo;The problem has been a lack of awareness of cancer among Africans and lack of action by governments, but it is also the case that international agencies have mostly lacked practical strategies for tackling cancer as the focus has been on communicable diseases. 

&ldquo;Cancer in Africa will become a huge problem in the next ten years or so as people live longer, while other diseases common in developed countries will also be major issues, such as diabetes and cardiovascular disease. But we can do much now to prevent many cancers, as in Africa up to 40% are caused by infections. We need to start now with training and research networks across Africa that will address the different needs of the regions &mdash; and we must have Africans setting the agenda, not outside agencies. 

&ldquo;We have not lost the battle against cancer yet &ndash; there is time to get it on government agendas although of course we still have major communicable disease problems.&rdquo;

The reason he stresses prevention is simple &ndash; there is a massive lack of resources to detect and treat cancer in Africa, as revealed in stark data from the International Agency for Research on Cancer (IARC). It has found, for example, that breast cancer survival five years after diagnosis has ranged from just 12% in the Gambia to nearly 80% in countries such as South Korea, while bowel cancer survival is even lower, at 10% in the Gambia and Uganda. The vast majority of patients present with late stage disease.  


The reason he stresses prevention is simple &ndash; there is a massive lack of resources to detect and treat cancer


As Gueye says, the lack of infrastructure will not change dramatically without concerted action by governments. For example, a country as large as Nigeria has only 40 urologists to serve the entire population of 140 million, and many of the continent&rsquo;s 53 countries have no or maybe a single radiotherapy machine, while cancer drugs are simply unaffordable and not yet part of widespread international aid. The epidemic of cancer that is on its way will surely overwhelm already badly stretched healthcare systems. 

&ldquo;We can though prevent cervical cancer, hepatocellular cancer and HIV-related malignancies, which are all caused by infections, and we can also introduce more effective tobacco and environmental pollution control,&rdquo; says Gueye. &ldquo;And one of our key goals at AORTIC is to urge governments to establish national cancer control programmes that will start to address resourcing issues, such as reversing the brain drain of doctors and scientists away from Africa and putting in place more training and treatment facilities.&rdquo;

Gueye and colleagues also aim to build on research into the characteristics of cancer among Africans, such as why prostate and breast tumours tend to be more common and aggressive among black people not just in Sub-Saharan Africa but also in the Caribbean and North America. 



    
        
            
            THE STATISTICS
            
                 One fifth of all cancers worldwide are caused by a chronic infection, and up to one third of cancers in the developing world are curable if caught early
                100,000 children die unnecessarily each year from cancer 
                Only 5% of global resources for cancer are spent in the developing world 
                African states will account for a million new cases a year out of 16 million worldwide by 2020&nbsp;
                 Low- and middle-income countries account for only 6% of world morphine consumption&nbsp;
                 In Ethiopia, 85% of the population have never seen a healthcare worker&nbsp;
                 Uganda has one cancer unit for 32 million people
            
            
        
    



A particular priority, however, is filling in major knowledge gaps in the incidence of cancer in Africa &ndash; there are few registries that are gathering sufficient data. The IARC notes that there is a &ldquo;dire need for population-based cancer survival information from developing countries&rdquo;, and Gueye says that of all the actions in AORTIC&rsquo;s strategic plan for 2010&ndash;2015 (subtitled &lsquo;Working together to prevent and control cancer in Africa&rsquo;) improving data collection is the first and most important measure. 

Gueye&rsquo;s own position as AORTIC president is also a sign that cancer has more chance of being a serious proposition for national governments on the continent. Until fairly recently, he says, the organisation was not an effective force, as it had been set up and run mainly by expatriate Africans in the US (it was founded as far back as 1983). Now Gueye and colleagues in Africa who have become involved recently have managed to revitalise the organisation, such that last November in Tanzania its biennial conference attracted some 700 delegates, and a call was made by Tanzanian president Jakaya Kikwete for African leaders to include cancer control in national health plans. 

&ldquo;What is also helping is that people are becoming better informed about cancer thanks to the Internet and programmes on the BBC and CNN, and stories in local media, while prominent people who have cancer have been speaking out, such as Desmond Tutu in South Africa,&rdquo; says Gueye. Events such as World Cancer Day (4 February, led by the UICC, the International Union Against Cancer) also contribute &ndash; this year the focus was on prevention, including tackling the infections that can cause cancer. 

Uniting a continent as large and diverse as Africa around cancer is a daunting task, but Gueye feels that getting the messages across about what is most appropriate for African countries offers considerable hope in the years ahead. &ldquo;The critical force is the African Union &ndash; the highest level meeting of nations &ndash; to which we aim to take our strategic plan. If we can engage all political leaders we can make similar progress to that in HIV/AIDS, such as opening up channels for cheap or free generic drugs.&rdquo; 

Gueye&rsquo;s reason for pursuing a medical a career is rooted in personal tragedy. &ldquo;I lost my father when I was just 11 &ndash; he went into the medical centre in Thies and didn&rsquo;t come back. I don&rsquo;t know why he died, but it was probably related to malaria. I thought then I wanted to go into medicine to do what I could.&rdquo; 

He was the first in his family to go to college, let alone medical school, and was attracted to urology while on rotation by one of his key mentors, Aristide Mensah, the professor of urology. He was fortunate, he adds, that Senegal has a long tradition of investing in training. &ldquo;The first medical school in Francophone Africa was in Senegal and the country has had a stable democratic culture since its independence 50 years ago.&rdquo;

He trained as a urological surgeon and with the country&rsquo;s links with France did more than three years of fellowships in Bordeaux and Paris, learning the then latest techniques such as radical prostatectomy and bladder replacement surgery. He is also a master trainer in reconstructive urology, such as repairing uro-genital fistula, and continues to play an important role in healing the scars left by the widespread rape that has been a feature of many wars in the region. Today he is not only head of urology at Grand Yoff general hospital in Dakar, but also the chief medical officer at the hospital, and professor of surgery and urology at Dakar&rsquo;s Cheikh Anta Diop University. What&rsquo;s more, he is also still the president of the Pan-African Urological Surgeon&rsquo;s Association &ndash; but as he says, in Africa it is not unusual to find doctors performing multiple jobs. 

&ldquo;But we are fortunate in my hospital that we have multidisciplinary teams in urology and other specialties, which is not the case of course for many African surgeons. At present I do mainly surgery and hormone therapy for prostate cancer, which is my main specialty, and I have colleagues who specialise in other operations and who administer chemotherapy. We are also able to carry out procedures such as radical prostatectomy that are not available in many places in Africa owing to a lack of trained surgeons and resources. Before we introduced the latest surgical techniques, people just came to the hospital and received palliation and died. Now we are able to track cases earlier and people are more confident about undergoing surgery and we carry out radical procedures on a daily basis.&rdquo; 

That said, Senegal has just one radiotherapy machine for the whole country &ndash; it is based in another hospital in Dakar &ndash; and it is only recently that planning for cancer has become more organised. &ldquo;It was when we held the AORTIC conference in Dakar in 2005 that our minister of health and prevention made cancer a focal point for the first time, and we now have a national cancer plan that includes activities such as outreach and education work, early detection for cervical cancer and mammography in some places, and it is now much easier for people to see doctors about cancer.&rdquo; 


&ldquo;We now have a cancer plan that includes education, early detection for cervical cancer and mammography&rdquo;

The country is one of the few in Sub-Saharan Africa with a cancer plan, he adds &ndash; others that do, at least in draft form, are Ghana, Nigeria and Tanzania; the Nigerian plan was launched this year to coincide with World Cancer Day.

But Senegal, he adds, does not yet have a population cancer registry, and with most data about cancer in Africa coming only from hospitals, there is gross underreporting of cancer incidence and countries tend to focus on what doctors see in practice, and the true scale of the problem is hidden. 

&ldquo;That is why I see developing population-based cancer registries as so important, and I think the best route to achieve this more consistently is through the World Health Organization, as it has an office in each country and already collects data on malaria and TB and other diseases from health ministries, and has influence with governments. In fact the WHO regional office for Sub-Saharan Africa in Brazzaville, Republic of the Congo, has started to train people in cancer registration, but rolling this out will take five years or more.&rdquo; 

There are differences in the types of cancer most common in different parts of Africa, adds Gueye. North Africa has obvious differences with Sub-Saharan Africa, as the people in the north are mainly from Arabic inheritance. A striking difference is, for example, the high incidence of bladder cancer in Egypt, which is linked to schistosomiasis, a parasitic disease, although Gueye notes that there is now a shift to tobacco-related bladder tumours in the country (and inevitably, smoking is becoming an increasing problem throughout Africa). 

Regions in Sub-Saharan Africa show some patterns, such as prostate cancer being more common in West Africa, and Kaposi&rsquo;s sarcoma, the cancer related to HIV infection, reported more in Central and East Africa. &ldquo;Breast and cervical cancers are common everywhere, with cervical being the most common female cancer, while hepatocellular cancer is the most commonly diagnosed cancer overall, when you combine data from both men and women, and it is the most common cancer in men and by far the major male cancer killer.&rdquo; 

Hepatocellular carcinoma &ndash; liver cancer &ndash; is a deadly disease that can be caused by chronic infections with hepatitis B and C viruses (especially B), and also by concurrent exposure to alfatoxins, produced by funguses that infect crops and which are extremely carcinogenic. Clearly, halting transmission of hepatitis B can greatly help cut the incidence of the disease, and a vaccine for the virus has been available for 20 years. But Gueye says that, given the high prevalence of infection, especially in East and West Africa, much research remains to be done on how the disease develops and on appropriate antiviral treatments for carriers, in a similar way to the development of HIV drug treatments. 

While liver cancer is very much a disease of the developing world, so too are HIV/AIDS-related malignancies, which include not only Kaposi&rsquo;s sarcoma, but also increased susceptibility to cervical cancer and non-Hodgkin&rsquo;s lymphoma. &ldquo;Kaposi&rsquo;s sarcoma is a particular problem in Central and East Africa where the HIV infection rate is high and people do not get early anti-retroviral treatment, which increases the prevalence of Kaposi&rsquo;s, although we do not know the full natural history of this disease. Some countries are reporting that 25% of new cancer cases are HIV/AIDS-related so we urgently need to develop better treatment programmes for these patients,&rdquo; says Gueye. 

Senegal, he adds, has a relatively low HIV incidence &ndash; about 1% of the population &ndash; and has taken a hard line with HIV carriers, passing a law that allows doctors to inform patients&rsquo; partners of their infection status. &ldquo;I did a study with a colleague where we found that 25% of men didn&rsquo;t change their behaviour when they knew they were HIV positive &ndash; they didn&rsquo;t tell their wife and didn&rsquo;t use a condom,&rdquo; says Gueye. 

While Senegal does not see much HIV/AIDS-related cancer, Gueye says he saw many Kaposi&rsquo;s sarcomas when he worked as a United Nations surgeon in Rwanda towards the end of the genocidal conflict there. His humanitarian work there won him several honours, including a UN Peace Medal.

At least generic drugs for the major communicable diseases such as HIV/AIDS are now available to many Africans free of charge, he notes, although not without a considerable struggle with patent holders. But that is not the case for most cancer drugs. With increasing numbers of standard chemotherapy drugs coming out of patent, more low-cost anti-cancer agents could be available, but the latest targeted therapies will be way out of reach for most &ndash; not to mention the lack of medical oncologists, who are much rarer than surgeons. 

Vaccines are another class of drug where price is an issue, he adds, with vaccines against human papillomavirus (HPV &ndash; the cause of cervical cancer) currently unaffordable for most countries. Attempts to introduce HPV vaccines are now being made by organisations such as the GAVI Alliance &ndash; it aims to bring the costs down greatly with its large purchasing power. The vaccines do not, however, protect against all strains of HPV, and are not a substitute for screening (see also cover story on Vesna Kesic, Cancer World Nov&ndash;Dec 2009) and Gueye adds that some Africans can reject vaccines, fearing that HPV shots, for example, could render girls infertile.

In turn, screening has major drawbacks in Africa, says Gueye, apart from the huge logistical issues that entails. &ldquo;It is simply that it is unethical to screen everyone and then not be able to offer treatment to all for diseases we detect,&rdquo; he says. &ldquo;The day we have mass treatment for everyone is the day we start talking about mass screening.&rdquo; Instead, as in Senegal presently, the approach should be one of raising awareness and carrying out examinations when, for example, women attend a family planning clinic. &ldquo;We need to target certain groups instead,&rdquo; he says, adding that it is especially important to head off the growth of controversial screening tests such as PSA for prostate cancer.


&ldquo;It is simply unethical to screen everyone and then not be able to offer treatment to all for diseases we detect&rdquo;
  
Gueye became involved in international prostate cancer research in the late 1990s, notably on a programme that is looking at the reasons why black people, particularly of West African origin, have the world&rsquo;s highest incidence and mortality from the disease. He has been working with colleagues at the University of Pennsylvania on some of the first studies to examine the risk factors for prostate cancer outcomes for African-American and West African men, and also European Americans, who have lower incidence. Now under the umbrella programme title of MADCaP (Men of African Descent and Carcinoma of the Prostate), there were initial parallel studies in Dakar and Philadelphia that have gathered data on incidence, genetic differences (and possible candidate genes) and environmental factors such as diet, revealing, says Gueye, that African men seem to be at higher risk than their African-American counterparts, which may be partly explained by Caucasian genes mixed in as the diaspora expanded to North America. 

What especially interests Gueye as a clinician is that this research could lead to better targeting of men most at risk, and also the opportunities it is bringing for capacity building for researchers and infrastructure for carrying out such studies, not only in Dakar but in the other African sites that are interested in participating alongside a growing number of American centres in MADCaP, such as in Nigeria, Ghana, Zambia and Uganda.

However, this type of research &ndash; which is also being conducted with women to find out why African American women are more likely to suffer from aggressive &lsquo;triple negative&rsquo; breast cancer &ndash; is not without possible controversy. Gueye says there is a danger of black Africans being used as guinea pigs for trials, with rich countries leaving research sites behind with little support once trials are complete (and he goes as far as mentioning the infamous Tuskegee syphilis experiment in the US, where poor African-Americans were left untreated after the discovery of penicillin). &ldquo;We have to be very careful about collaboration &ndash; it must be an equal partnership,&rdquo; he says. 

For his own part, Gueye has organised several successful collaborations, not just in research but also in training, which he sees as particularly vital to building capacity and keeping young African doctors in their countries. &ldquo;For example we have had paediatric urologists from Pittsburgh, Pennsylvania, here in Dakar at a workshop on paediatric urology, attended by more than 50 people. And every year, for more than five years, residents and staff from surrounding countries have received training in radical prostatectomy with the help of Albert Ruenes, a urologist from Doylestown, Pennsylvania. I see onsite training as the key &ndash; we can&rsquo;t go on sending doctors to train abroad, otherwise we will continue to lose some. Also, if you send someone away for training there is no guarantee they will teach others when they return. 

&ldquo;I could easily have stayed in France &ndash; indeed, I was advised to &ndash; and I chose to come back. But we must also put in infrastructure for people to work and train with.&rdquo; As he says, it is pointless sending a state of the art scanner to a site where it will fall into disuse if no one can use and maintain it, while a surgeon will not be able to work on prostate cancer if they can&rsquo;t request scan to determine if a tumour is localised or not.

&ldquo;And maintaining skills is vital to carrying out radical procedures such as prostatectomy and nephrectomy, otherwise urologists and other surgeons will fall back to late management of cases and palliation only. Then when a patient comes in presenting early they can&rsquo;t provide a service.&rdquo; 

Other important topics in the AORTIC strategic plan, says Gueye, include paediatric cancers such as Wilm&rsquo;s tumour and Burkitt&rsquo;s lymphoma. While relatively rare, although undoubtedly under-reported in Africa, the cure rates for African children are shockingly low &ndash; about 5% compared with some 80% in the developed world. The UICC with pharmaceutical company Sanofi-Aventis, is having some success with raising the profile of childhood cancers in poor countries with the My Child Matters programme, notes Gueye, and it is now running in 26 countries including several in Africa.  

Given the late presentation of far too many cancer patients, pain and palliative care are other big issues, not least for children, says Gueye. Morphine availability and use is particularly poor in Francophone countries, he says, and he would like to see more local facilities to manufacture drugs. &ldquo;And palliative care must be a priority in any national cancer plan.&rdquo; 

There is, he adds, the African Palliative Care Association, and other bodies on the continent working in various aspects of cancer control, so it is not the case that there is little support for AORTIC&rsquo;s agenda (there is also a pan-African radiotherapy group &ndash; even though the vast majority of machines are in South Africa and the North African countries).

&ldquo;One of AORTIC&rsquo;s tasks at present is building a database of organisations in Africa &ndash; that&rsquo;s almost done now,&rdquo; says Gueye. &ldquo;And of course we also need international collaboration with agencies such as the International Cancer Registry Association and IARC, US bodies like ASCO, AACR, NCI/NIH, ACS and so on, and also the UN agencies.&rdquo; 

There are certainly many organisations outside Africa with interests in supporting cancer work on the continent, and no shortage of declarations of intent, such as the London Declaration on Cancer Control in Africa, adopted at a conference in London in 2007 and put forward by AfrOx (Africa Oxford Cancer Foundation &ndash; now working in Ghana, and established by David Kerr, who has helped with cancer plans for Ghana and other African countries). This built on a flurry of developing world conferences and declarations, including the Cape Town Declaration on Cancer Control in Africa.

For Gueye, the test is whether such initiatives are progressing beyond talk to action, and action determined by Africans, and not by agendas set from afar. &ldquo;We call it NATO &ndash; no action, talk only &ndash; but as we refine the AORTIC strategic plan to make it more practical we hope organisations will be able to integrate more with what Africa needs.&rdquo; 


The test is whether such initiatives are progressing beyond talk to action, and action determined by Africans


Of all the many programmes that are making some headway on the ground, he picks out the IAEA (International Atomic Energy Agency) Programme of Action for Cancer Therapy (PACT), which was set up in 2004 and which partners with the WHO and a range of other organisations to build public&ndash; private partnerships and mobilise resources for cancer control in the developing world. One of its six demonstration pilot projects is in Tanzania, and the IAEA is challenging companies to produce equipment suitable for use in poorer countries. 

Certainly, Gueye has extensive contacts with many organisations now, which he can bring to bear to further AORTIC&rsquo;s mission, though moving the organisation forward has required overcoming opposition from long-standing interests, he says, while bridging the language barrier that divides French-speaking from English-speaking countries is always a challenge. 

Gueye certainly seems to have what it takes to meet the challenge. Tim Rebbeck, professor of epidemiology, at the University of Pennsylvania&rsquo;s School of Medicine, who co-leads the US/Africa prostate risk factors study with Gueye and others, comments particularly on his leadership skills, and the great respect he commands among those he works with. &ldquo;He has an exceptional way of dealing with people. He seems to have no ego to get in the way of his work, but nurtures and motivates those around him to get things done.&rdquo; 

Gueye is a family man &ndash; his wife Ramatulaye is a language specialist and teacher, and he has three children, two now grown up, so the extensive travel he undertakes now may not be so disruptive. 

&ldquo;My aim now, along with the AORTIC executive council, is to finish the strategic planning for AORTIC and then build capacity for research and training by establishing regional centres of excellence that will cover all aspects of the cancers we see in Africa, and we have plans for this. We must have research infrastructure that promotes capacity building, such as helping young researchers to apply for grants and write protocols.

&ldquo;We can&rsquo;t tell countries what to do &ndash; just help shape policies at national and pan-African level. But if we don&rsquo;t lobby for our strategic plan we will deserve to disappear as an agent of change.&rdquo; 

Gueye himself seems determined to continue as an agent for change at this critical period, helping Africa meet the challenge of its rising tide of cancer. 



    
        
            
            GLOBAL AND AFRICAN EFFORTS
             The World Cancer Congress &ndash; held every two years &ndash; will be highlighting system changes at the 2010 event in Shenzhen, China, in August. Topics such as cancer registries as a basis for cancer prevention and control, the untapped potential of public health law and policy in cancer control, and &lsquo;ending the pain&rsquo; &ndash; what has to be done for 5 million sufferers &ndash; are central to the World Cancer Declaration road map and of crucial importance to AORTIC&rsquo;s agenda in Africa. The UN General Assembly recently adopted a resolution calling for the curbing of premature deaths from non-communicable diseases, and for a high-level meeting on the issue, with the participation of heads of state, to take place in New York in September 2011. 
            Apart from AORTIC, and major organisations such as the WHO and the IAEA (International Atomic Energy Agency), agencies and projects seeking to improve cancer control within Africa include the Pan-African Clinical Trials Registry (www.pactr.org), the African Radiation Oncology Group, the African Tobacco Control Alliance, the African Palliative Care Association, the African Cancer Network, Cancer-Africa, AfrOx and EDUCARE (EDUcation for Cancer in African Regions). 
        
    


]]></description>
            <author>Marc Beishon</author>
            <category>Cover Story</category>
        </item>
        <item>
            <title>Pitfalls and uncommon problems in thyroid cancer management</title>
            <link>http://www.cancerworld.com/Articles/Isseus_37/e-Grand_Round/Pitfalls_and_uncommon_problems_in_thyroid_cancer_management.html</link>
            <description><![CDATA[
The European School of Oncology presents weekly e-grandrounds which offer participants the opportunity to discuss a range of cutting-edge issues, from controversial areas and the latest scientific developments to challenging clinical cases, with leading European experts in the field. One of these is selected for publication in each issue of Cancer World. 

In this issue, Jean-Pierre Droz, Professor Emeritus of Medical Oncology at the Centre L&eacute;on-B&eacute;rard, Lyon, France, reviews the medical treatment of advanced disease in patients with thyroid cancers that pose particular challenges, drawing on the centre&rsquo;s experience in the management of approximately 250 patients. 

Christelle de la Fouchardi&egrave;re, also of the Centre L&eacute;on-B&eacute;rard, poses questions that explore the issue further. The presentation is summarised by Susan Mayor. 

The recorded version of this and other e-grandrounds is available at www.e-eso.net/ho&nbsp; 


Thyroid cancers are quite common cancers and they can generally be cured. They are managed primarily by endocrinologists, surgeons specialised in endocrine surgery and specialists in nuclear medicine. A small proportion of patients, no more than 1 in 20, experience a poor outcome. Drawing on our experience of managing more than 250 cases of this kind at the Centre L&eacute;on-B&eacute;rard at Lyon, this e-grandround explores the different types of thyroid cancer and their diagnosis, behaviour and management, as well as key challenges such as loss of radio iodine uptake and the management of bulky metastases and metastases that have mutated from the primary cancer. It also looks at the potential of new drugs developed in this setting, several of which are also being studied in more common cancers.  

DIFFERENTIATED THYROID CANCER
There are two histological subtypes of differentiated thyroid cancer: papillary thyroid carcinoma (PTC) and PTC with follicular differentiation (FTC).A good review by Martin Jean Schlumberger published ten years ago in the New England Journal of Medicine (NEJM 1998, 338:297&ndash;306) showed that patients with PTC had a better prognosis than those with FTC, particularly those with poorly differentiated FTC. Age is also an adverse prognostic factor. 

In general, the guidelines for the treatment of differentiated thyroid cancer recommend initial management with a total thyroidectomy and radioactive iodine (I131) therapy. Patients then have a good inhibition of thyroid stimulating hormone (TSH) production and their thyroglobulin is followed. In cases of recurrence, the standard treatment is radioactive iodine therapy (Eur J Endocrinol 2006, 154:787&ndash;803) 

The first challenging issue in differentiated thyroid cancer is that there are patients with metastatic disease with radio iodine uptake who can lose their uptake. For example, the CT scans for a patient with differentiated thyroid cancer lung metastases, shown in the figure below, show an initially strong uptake of radio iodine. However, five years later, after four applications of radio iodine, there was no more uptake of radio iodine in the lungs. 



There are two explanations for this observation. The first is that the disease is still differentiated &ndash; papillary or follicular thyroid carcinoma &ndash; but it becomes functionally different with the loss of radio iodine uptake. The other possibility is that the disease becomes poorly differentiated. This is the problem of pathological switch. Poorly differentiated carcinoma is often called &lsquo;insular carcinoma&rsquo;. 

A case study that illustrates this was that of a 40-year-old woman who had initially multiple bulky bone metastases without lung metastases. In 1999, she had a thyroidectomy for papillary + follicular thyroid carcinoma without any undifferentiated components within the thyroid. She received several radio iodine applications and then had surgery to treat spinal cord compression and hip fracture with hip replacement. In 2002, she had a bulky iliac metastasis, which grew. A biopsy showed poorly differentiated carcinoma. 

One year later, this woman had multiple lung micronodules without I131 uptake. Histology showed both solid and insular patterns. Iodine scintigraphy showed absolutely no uptake of iodine. We can assume that in this patient the development of lung metastases may have been linked to the switch from differentiated carcinoma to poorly differentiated carcinoma. 

Another possible scenario is the coexistence of both histological patterns. For example, a 48-year-old woman had a thyroidectomy in 2000 for the combination of papillary thyroid carcinoma and poorly differentiated thyroid cancer. At the same time, she had lung and right shoulder/arm bone metastases. She received several applications of radio iodine, but despite a good iodine uptake she had growing shoulder metastases with fracture. The decision was made to perform surgery, with the upper part of the humerus being replaced. The figure below shows the humeral metastasis, the presence of lung metastasis and very good iodine uptake on the scintigraphy both in the lung and in the arm. Histology showed a classic vesicular pattern and a solid pattern of poorly differentiated carcinoma. 



There is growing interest in functional imaging with PET scans in patients with differentiated thyroid cancer. A case study illustrating its value is that of a 41-year-old woman who underwent a thyroidectomy for papillary thyroid carcinoma in 1995. Her thyroglobulin increased despite several administrations of radio iodine. She had absolutely no uptake. Eleven years later, a PET scan showed the presence of bone metastases in the pelvis (see figure below). This patient was managed with a RANK-ligand inhibitor.


A scan several months later showed extension of bone metastases. The thyroglobulin level increased despite the presence of good inhibition of thyroid-stimulating factor. There was no more iodine uptake, and the FDG radiotracer uptake showed metastases in the adrenal gland and extended metastases within the bone. As at the start, the use of functional imaging was interesting, but the metastases could also be seen on anatomical imaging in a CT scan.  

THE PROBLEM OF BULKY METASTASES
Bulky metastases pose a very difficult problem and there is no consensus on management. The challenge is illustrated by the case of a 50-year-old man with no known history of thyroid problems. In 2005, he felt pain in his spine, and was found to have a large-volume iliac metastasis and thyroid cancer. A biopsy of the metastasis showed the presence of follicular thyroid carcinoma. Shortly after, he had a thyroidectomy for a combination of papillary thyroid carcinoma and poorly differentiated thyroid cancer. He had major iodine uptake of I131, and a decision was made to proceed with debulking surgery of the unique iliac bone metastasis. 

The huge uptake of I131 on the right part of the pelvis can be seen in the figure below. There is residual uptake after thyroidectomy, although this is common. The original CT scan shows a huge metastasis within the bone, and also within the muscle. It is very unlikely that this patient could be managed only with I131, because the activity would be small in this large tumour. 


After debulking surgery, the PET scan shows there is still uptake of the FDG radiotracer, and this area is clearly tumoural, so there is a need to perform additional treatment with radio iodine.

MEDULLARY CARCINOMA
Medullary carcinoma is not really cancer of the thyroid because it is derived from normal C cells. 

There are three main points in the recommendations for management: 


     It is important to determine information on the genetics of the disease, and particularly the possibility of a hereditarymedullary cancer or even a mutation in the RET gene. 
    It is important to look for adrenal gland abnormality, and particularly a phaeochromocytoma, as well as hyperparathyroidy.
     Surgery is clearly the standard treatment. Patients must have thyroidectomy plus level VI compartmental lymph node resection. This is the only curative treatment.

A patient&rsquo;s calcitonin level, as well as carcinoembryonic antigen (CEA), must be followed carefully. If calcitonin is raised, imaging should be used for further investigation. A solitary metastasis should be managed with surgery, while a patient found to have extensive metastases should be considered for a clinical trial. 

Differential diagnosis of medullary carcinoma can be challenging. We have observed two patients where this has been a problem. The first was a 55-year-old man, who had backbone metastases with muscle invasion. He underwent a thyroidectomy and the initial diagnosis was differentiated carcinoma (papillary thyroid carcinoma). There was absolutely no radio iodine uptake and his thyroglobulin levels were low (0.3 ng/ml) without antibodies. Scintigraphy showed no radio iodine uptake on the bone metastases and MRI showed cervical and lumbar metastases, muscle invasion and spinal cord compression (see figure below). 


What were the hypotheses? The first was dedifferentiation, with the possibility that it was a papillary thyroid carcinoma that may have switched to an insular or poorly differentiated carcinoma. Another possibility was metastatic disease of other origin. But the most likely possibility was medullary carcinoma. The serum tumour marker profile was strongly in favour of this diagnosis, with a slight elevation of carcinoembryonic antigen (20 ug/L), elevation of theNSE (neuro-specific enolase) biomarker (68 ng/ml) and elevation of calcitonin (800 ng/ml), which was very significant. Review of the pathology slides showed an immunohistochemistry profile that strongly supported a diagnosis of medullary carcinoma, with no uptake of thyroglobulin, staining with calcitonin and carcinoembryonic antigen. 

IMAGING MEDULLARY THYROID CANCER
When a patient undergoes surgery and has increased serum calcitonin levels, a range of different imaging techniques are indicated. These included ultrasound to explore the neck, CT scan for the liver (but this can be difficult to interpret, MRI is also useful for the liver imaging), functional imaging with FDG-PET scan, octreoscan, MIBG-I131 scanning, an Indium scan and laparoscopy. 

What about liver metastases? In medullary thyroid carcinoma, liver metastases are sometimes difficult to see; for example, some metastases are more visible on the portal phase of a CT scan than on the arterial phase. In these cases MRI may be more accurate, particularly with the use of gadolinium enhancement. Injection of gadolinium is the best method to visualise liver metastases in such a patient.  

THE POTENTIAL OF TARGETED DRUGS
There are several different targets in thyroid cancers. These include the angiogenesis receptors, such as VEGFR; PDGF-R, C-KIT and, more importantly RET, particularly in medullary carcinoma, and fusion genes RET/PTC in PTC, and BRAF in papillary thyroid carcinoma. A study with sorafenib suggested there is a relationship between the drug&rsquo;s activity and particular mutations of BRAF (MS Brose et al., abstract A6002, ASCO 2009). Other receptors are EGF-R and c-MET. RET is a transmembrane receptor, which is a tyrosine kinase. It needs dimerisation for activity.

Trials in differentiated thyroid cancer
Published phase II trials
There are three important trials in differentiated thyroid cancer. The first is a trial with motesanib, with the targets of VEGFR, PDGF-R and C-KIT. The trial included 93 patients and showed a partial response rate of 14%, with 33% of patients having stable disease at more than six months (NEJM 359:31&ndash;42).More than 50% of patients had clinical benefit &ndash; a combination of partial response plus stable disease for more than six months.

The second trial is with sorafenib. Clinical benefit in a fairly large series was found to be around 70%.

The third trial is with axitinib, which acts on VEGF-R. This resulted in a 30% partial response rate and a 70% clinical benefit in total.

Published abstracts of phase II trials
Abstracts of early trials in differentiated thyroid cancer treated with sunitinib published in 2008 showed clinical benefit of around 80%. There is now an ongoing phase II randomised trial of vandetanib versus placebo.

The results from trials with sorafenib in differentiated thyroid cancer show a good proportion of patients achieving partial response and stable disease, but anaplastic or poorly differentiated carcinoma does not respond.

However, there are adverse events with sorafenib, such as hand foot syndrome, which affects 90% of patients, as well as diarrhoea and hypertension. Dose reduction is required in 50% of patients treated with the drug, and 20% of patients came off the drug due to its toxicity.

Future trials
A randomised trial is planned of sorafenib versus placebo with crossover in patients with differentiated thyroid cancer. A phase II trial is also planned of the new drug E7080, which acts on PDGFR, VEGF-R and EGF-R, in 104 patients with differentiated thyroid cancer who are refractory to I131, either upfront or further down the line.

Trials in medullary carcinoma
Published phase II trials 
There is a very good study with motesanib where the rate of clinical benefit &ndash; mainly stable disease at more than six months &ndash; is around 80% (JCO 27:3794&ndash;3801). 

Vandetanib, which acts on RET, EGF-R and VEGF-R, has been studied specifically in hereditary medullary carcinoma, showing a partial response rate of 20%and an overall clinical benefit of 70% (JCO 28:767&ndash;772). 

Very small trials have also been conducted with gefitinib and axitinib. 

Published abstract phase II trials  
There is a very interesting study of XL184, which acts on VEGF-R2 and RET and c-MET, with a response rate of 40%and clinical benefit of 80% (Kurzrock 2008, Proc 20th EORTC&ndash;NCI symposium on Molecular Targets and Cancer Therapeutics, abstract 379). 

Future trials
The most important trial planned for medullary carcinoma is a study randomising to XL-184 versus placebo without crossover. There is also a phase II trial of E7080 planned in patients with progressive medullary carcinoma.

DRUGS AVAILABLE IN CLINICAL PRACTICE
At the moment, no drug has been registered for the treatment of differentiated thyroid carcinoma or medullary carcinoma. In differentiated thyroid cancer, we consider that sorafenib is likely to be used in the future. There is interest in sunitinib, although efficacy has yet to be demonstrated. There is clearly uncertainty around the development of motesanib, and it is too early for vandetanib. In medullary carcinoma, the early results of new drugs are promising but it is too early to draw any conclusions for vandetanib and XL-184.  

METASTATIC SITES
There are some surprising observations regarding the sites where metastasis occurs. The most common metastatic site is the cervical lymph nodes, followed by the mediastinal lymph nodes and lungs.

Bone metastases are also observed commonly. The main problem for bone metastasis is fracture, but spinal cord compression can also occur. 

Uncommon metastatic sites
Metastases sometimes occur at very uncommon sites, which can complicate differential diagnoses. This is illustrated by the case history of a 35-year-old woman with no familial history who underwent a thyroidectomy for her thyroid tumour. The tumour was a locally involved, poorly differentiated medullary carcinoma, which was absolutely typical. She had elevated calcitonin after surgery, but no metastases at that time. Five months later, her calcitonin had increased, but, more importantly, CT scans showed uncommon metastatic disease. She had two metastases in the breast, which were confirmed by microbiopsy, and a pancreatic metastasis with dilatation of the biliary tract. The patient was treated with etoposide and cisplatin, but this failed. She then developed epidural and CNS involvement (see figure below). 


Another patient had involvement of the bronchus, which could be differentiated from a primary lung cancer. This proved to be a thyroid tumour. A further patient had a kidney metastasis, with a solid tumour on the left kidney. It is important to remember that there are patients with kidney metastases whose primary tumour is thyroid, underlining the need to perform a biopsy to be certain of the diagnosis. We have also seen metastasis in the adrenal gland in a patient with differentiated thyroid cancer. In the case of medullary carcinoma, the problem is a differential diagnosis with phaeochromocytoma. 

Another case showed a leukaemic reaction &ndash; a frail woman, aged 83 years, who had a huge thyroid cancer, which on biopsy proved to be an anaplastic thyroid carcinoma. She had hyperleukocytosis with leukaemoid reaction in both the blood and marrow smear. The possible mechanism for this may be hypersecretion of G-CSF and GM-CSF. 

Another uncommon presentation we have observed is paraneoplastic syndrome. This was found in a 40-year-old man who in 2000 had a thyroidectomy for locally advanced disease, which was found to be medullary carcinoma. His calcitonin level was greatly increased, but he had no metastases on CT scan at that time. One year later, he developed a neuropathy, and five years later he developed metastatic disease in the mediastinal lymph node and in the liver.

Paraneoplastic neuropathy developed as increasing sensitive neuropathy in the foot, leg, thigh and elbows, with pain and no paresthesia. There was slight hypoesthesia, but no other clinical abnormality. The diagnosis was neuronal sensitive neuropathy on EMG. We found no antineuronal antibodies. We know that subacute sensitive neuropathy is paraneoplastic in half (47%) of patients, and the majority have antibodies, although this was not the case in this patient.

Question: In the results from clinical trials, the majority of differentiated thyroid cancer patients show a very slow progression and maintain a good quality of life for months or years, even without any specific treatment. Is six months follow-up really appropriate to evaluate the response in new drug trials? And is a stable disease response really due to therapy, or the natural history of the disease? 
Answer: I am also involved in renal cancer, which is treated with the same drugs, and there we have the same problem. In medullary cancer, the randomised trial that is comparing XL-184 against placebo without any crossover should be able to answer the question of whether there is an impact on survival. In trials, six months is generally considered to be a good surrogate for activity. I should mention that some trials have required evidence that a patient had progressive disease during the six months before starting the treatment as a condition for them joining the trial. This could be a good way to approach this problem. To conclude, the question is well put, but I think the effect of these treatments is completely different from what we saw in the past with chemotherapy. It may be the beginning of a great story of the use of these treatments in patients who are not likely to receive standard treatment &ndash; surgery, radio iodine and even radiotherapy.

UNCOMMON PATHOLOGIES
There are several variants or uncommon pathologies, including: poorly differentiated carcinoma (insular), H&uuml;rthle cell carcinoma, tall-cell carcinoma and diffuse sclerosing papillary thyroid carcinoma. In general, they have a worse prognosis than standard papillary, or even follicular, thyroid carcinoma.   

Anaplastic thyroid carcinoma
Anaplastic thyroid carcinoma (ATC) is a rare tumour, accounting for less than 2% of thyroid cancers. It occurs in patients aged over 65 years. The origin is differentiated thyroid cancer or goitre. There are specific mutations, including RAS, BRAF and p53, and the diagnosis is generally made under a huge cervical mass (see figure below). Approximately 40% of patients have metastases at diagnosis.  

The pathology shows aspects of both papillary and anaplastic thyroid carcinoma. On immunochemistry, anaplastic thyroid carcinoma shows no staining for TTF-1 (thyroid transcription factor-1) or for thyroglobulin, as is shown with papillary thyroid carcinoma. 

An example of anaplastic thyroid cancer is shown in the case of a 50-year-old woman, who presented with a huge ATC. In 1996, she had total thyroidectomy plus cutaneous cervical reconstruction. She received chemotherapy with doxorubicin 50 mg/m&sup2; + cisplatin 50 mg/m&sup2;, with supportive care (G-CSF + erythropoietin + nutritional supplementation) and radiotherapy (total dose around 60 Gy). The treatment schedule was two cycles of chemotherapy and then radiotherapy, followed by four cycles of chemotherapy. She completed the therapy and recovered very well and was followed by CT scan until 2006.

The patient&rsquo;s post-radiotherapy fibrosis was very limited, but there were several, very limited lung metastases. We administered radio iodine, and there was absolutely no uptake, but then this patient had a positive PET scan. We decided to perform a surgical excision of all metastases and we observed that the recurrence was due to a papillary differentiated tumour. She was treated four years ago and is currently in complete remission and very well.

Question: Why did you decide to administer radio iodine in the patient who had an anaplastic thyroid carcinoma? Answer: The initial diagnosis was anaplastic thyroid carcinoma plus a small proportion of papillary thyroid carcinoma. We took the chance. Ten years later, she had lung metastases we wanted to know whether radio iodine could be active. There was no uptake, so we then decided to operate. Fortunately, it was papillary thyroid carcinoma.

TAKE HOME MESSAGES


     Careful pathological diagnosis is the cornerstone of decision making in thyroid cancer management.
    Total thyroidectomy remains the only curative treatment for thyroid cancer in general. It is added to radio iodine in differentiated cancer, but is the only curative treatment in medullary carcinoma. 
    The majority of patients are cured by surgery and radio iodine.
    In progressive disease, it is important to control serum tumour markers, and to combine morphological and functional imaging.
    	Targeted drugs become important in the clinical management of these rare cases, at least in the setting of clinical trials.  

Question: We have a 38-year-old man with papillary and follicular thyroid carcinoma, maybe in a mixed pattern, who has lung metastases but who is asymptomatic. He has received seven doses of radio iodine and has shown no radiological response but remains asymptomatic. How long should you continue with radio iodine treatment?  
Answer: What is important is the patient&rsquo;s benefit. This patient is not curable, but while he is asymptomatic you can wait, you can observe and make decisions depending on progression. Sometimes, you can observe progression with imaging, such as a CT scan. It is important also to check for uptake.  At some time, you must decide to include the patient in a trial, when he requests to do so or when there is progression or a symptom. It is a palliative treatment, and what you have to do is achieve the best quality of life for the patient. These new treatments are very interesting, but they are toxic.  

Question: Are there any validated immunochemistry markers for premalignant thyroid lesions? 
Answer: This is not my field of expertise. What I would say is that there is an evolution from an atypical adenoma, but there is no immunochemistry staining that is useful here. There are, however, interesting studies that look at the differences in gene expression between true differentiated carcinoma and suspected adenoma. 

The presenter, Jean-Pierre Droz, would like to thank Martin Schlumberger (Institut Gustave-Roussy, Villejuif) for his mentorship and Christelle de la Fouchardi&egrave;re, Claire Bournaud, Fran&ccedil;oise Borson-Chazot and Jean-Louis Peix, at the Thyroid Cancer Consortium Hospices Civils-Centre L&eacute;on-B&eacute;rard and Department of Endocrinology and Nuclear Medicine, Hospices Civils, Lyon, France.   

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            <author>Sue Mayor</author>
            <category>e-Grand Round</category>
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