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        <title>CancerWorld</title>
        <description>Education and knowledge through people and facts</description>
        <link>www.cancerworld.org</link>
        <lastBuildDate>Tue, 07 Feb 2012 08:41:50 +0200</lastBuildDate>
        <generator>FeedCreator 1.7.2</generator>
        <item>
            <title>Aspirin for cancer prevention: why wait?</title>
            <link>http://www.cancerworld.org/Articles/Isseus_46/Editorial/Aspirin_for_cancer_prevention%3A_why_wait%3F.html</link>
            <description><![CDATA[
The prospect is too exciting to dismiss: a single pill &ndash; a cheap one too &ndash; that, taken regularly, can reduce the risk of not only heart attack, but also developing or dying from several types of cancer. 

Evidence that regular use of aspirin can reduce the risk of dying from cancer has been steadily growing. It was boosted last year with publication in the Lancet[1] of a meta-analysis of eight trials by Peter Rothwell and colleagues, which showed a substantial reduction in mortality for a number of different cancers. 

The study showed that a low dose of aspirin (75 mg per day, or a quarter of the nor- mal dose taken for pain relief), taken for longer than five years, reduces death rates from all cancers by 34%, and for gastrointestinal cancers by as much as 54%. 

The risk of death remained 20% lower for all solid cancers over a period of 20 years, with the risk from gastrointestinal cancers dropping by 35% &ndash; even though the participants would probably have stopped taking aspirin after the trials ended. The 20-year risk of death was cut by about 30% for lung, 40% for colorectal and 60% for oesophageal cancer. 

With data like these, why has no medical organisation issued guidelines or recommendations on the use of aspirin as an anticancer therapy? The problem is that we still lack strong evidence from adequately powered randomised trials. None of the trials included in the meta-analysis was designed specifically to assess whether aspirin reduces cancer incidence or mortality. And although many studies, including a few clinical trials, indicated that aspirin does play a preventive role, other studies have reached a different conclusion. It would take a very long time and a very large study to demonstrate an effect in any trial that took cancer mortality as an end- point &ndash; indeed it may not be possible, particularly as many people are already taking aspirin for cardiac prevention and pain relief.  

Potential side-effects have also to be taken into consideration, since aspirin can substantially increase the risk of serious gastrointestinal bleeding, even at low doses. 

One issue that needs urgent investigation is the effective dose. Rothwell argues that a daily low dose (such as 75 mg) may be the right choice, while others suggest up to 325 mg at least twice a week. Contributing to the debate is a recent study[2] using aspirin at 300 mg twice a day for two years, in a high-risk population, which cut the rate of colorectal cancer by 63%. 

It would be great to be able to say that this century-old pill represents the next great clinical advance in cancer. Yet for the moment, at least, the emergence of aspirin into a cancer prevention role seems to be on hold. The experts are recommending neither for nor against, advising only that any decision about daily aspirin use should be &ldquo;made only in consultation with your healthcare professional&rdquo;. Posterity will judge whether they are right.  

Andrea DeCensi is head of the Department of Medical Oncology, Ospedali Galliera, Genoa, Italy.&nbsp;


References

1: Rothwell PM, Wilson M, Elwin CE, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. 2010 Nov 20;376(9754):1741-50.

2: Burn J, Gerdes AM, Macrae F, et al on behalf of the CAPP2 Investigators. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet. 2011 Oct 27. [Epub ahead of print]
]]></description>
            <author>Andrea DeCensi</author>
            <category>Editorial</category>
        </item>
        <item>
            <title>Stein Kaasa: Let me show you what integrated palliative care can do</title>
            <link>http://www.cancerworld.org/Articles/Isseus_46/Cover_Story/Stein_Kaasa%3A_Let_me_show_you_what_integrated_palliative_care_can_do.html</link>
            <description><![CDATA[
 The World Health Organization has a definition of palliative care, but it is by no means a short one. Yes, it is &ldquo;an approach that improves the quality of life of patients and their families facing the problem associated with life threatening illness.&rdquo; But that is just the start. We need to have &ldquo;early identification and impeccable assessment and treatment of pain and other problems&rdquo;, integration of &ldquo;psychological and spiritual aspects of patient care&rdquo;, &ldquo;support systems&rdquo; for patients and their families, and a &ldquo;team-based approach&rdquo;. 

A crucial part of the definition, as Stein Kaasa, a palliative care expert and head of the Cancer Clinic at Trondheim University Hospital (St Olavs)in Norway affirms, is the last point: &ldquo;It is applicable early in the course of illness, in conjunction with other therapies that are intended to prolong life, such as chemotherapy or radiation therapy, and includes those investigations needed to better understand and manage distressing clinical complications.&rdquo; 

For Kaasa, who has advised the WHO on its cancer work, the definition throws down a challenge to what he calls &ldquo;mainstream oncology&rdquo;.&ldquo;Although palliative care, and palliative medicine as it&rsquo;s also termed, has been around for a long time it is still not integrated properly into many cancer departments, which means patients can fall into gaps in their care,&rdquo; he says. The problem, he adds, is that some health professionals &ndash; such as cancer doctors and nurses in hospitals &ndash; still see it as a specialism that is mainly about taking care of the dying and their families, and they worry that bringing it into the mainstream will mean pursuing futile oncological treatments.&ldquo;Nurses, especially, may say that palliative care belongs in a nursing home or hospice, and if we work there we shouldn&rsquo;t be part of acute medicine.&rdquo; 

Kaasa argues the opposite point of view. &ldquo;Palliative care is important much earlier in the disease trajectory, especially as about 60% of cancer patients receive non-curative care. When you are giving chemo- and radiotherapy as part of life-prolonging treatment &ndash; where someone may live two to three years or more &ndash; they will have many symptoms and may often need to be supported at home.&rdquo;There is so much new in oncology and in symptom control, says Kaasa, &ldquo;Patients deserve to have palliative care specialists as part of the oncology team during their cancer journey. I strongly believe that oncology is better if the voice of palliative care is firmly integrated in the healthcare system.&rdquo; 

The WHO, he adds, has recently revised its definition of palliative care to include collaboration throughout the care pathway, and integration with oncology where appropriate. Those looking for a model of where that integration is taking place will find one at Trondheim, where Kaasa has also recently established the European Palliative Care Research Centre to drive the evidence base for his speciality. 

There are a number of other compelling reasons for bringing palliative care into the mainstream, he notes. They include the best use of expensive treatments in metastatic disease &ndash; a huge issue for hard-pressed healthcare systems. Knowledge of metastatic disease itself is an underlying issue, given that it is often the poor relation of efforts put into the curative side of cancer treatment. Palliative care should also be pivotal in bringing together all the parts of healthcare systems and related professions that play a role in caring for cancer patients and their families, whether in the home or in primary care or acute settings. Everything from psycho-oncology to bereavement counselling and complementary therapies comes under the umbrella. 

Among the general range of side-effects of progressive disease and treatments, two core symptoms stand out which can be extreme for many patients &ndash; pain and cachexia (muscle wasting).&ldquo;In epidemiological studies on pain, about half of cancer patients are not sufficiently treated even when using opioids, and we know now that we need to start earlier when treating the many people with cachexia who have lost a lot of weight and muscle mass,&rdquo; says Kaasa. 


&ldquo;We know now that we need to start earlier when treating the many people with cachexia&rdquo;  


As he explains, there is a great deal of research to be carried out on pain and cachexia, as well as on other aspects of palliative care. Such research includes a recent move to investigate biological mechanisms as well as clinical approaches that have been the mainstay. &ldquo;The problem we have is that in pain, for example, the quality of evidence for management of people with cancer is very low&ndash; the studies are poor. There are too many small studies that are inconclusive &ndash; they don&rsquo;t have the power we need.&rdquo; 

Fragmented research and small studies are common in cancer, he concedes, &ldquo;but in palliative care it is even more challenging because patients are hard to reach and often very sick, and you need to design studies that can comply with an intervention or medication.&rdquo; 

Despite the lack of major studies, the last 10 years have seen a step up in focusing on palliative care and oncology in Europe. This is thanks in part to Kaasa&rsquo;s success in putting the subject on the map in Trondheim when he moved there in 1993, as professor of palliative medicine at the Norwegian University of Science and Technology, which was one of the first such job titles in Europe at the time. He went on to establish a pain and palliative care research group that has carried out and coordinated many studies. &ldquo;For example, we won an EU grant in the 6th framework programme in 2005 to co--ordinate the European Palliative Care Research Collaborative, under which we ran work packages on understanding and assessing pain and cachexia, and we also produced European guidelines on managing cachexia and depression.&rdquo; 

As always, the issue is the short-term nature of these programmes, and although there are other EU projects underway, Kaasa says that so far there isn&rsquo;t anywhere near the critical mass of support for the wider collaboration and research networks he feels that palliative care needs. 

While palliative medicine is by no means just about cancer, it is now such a major part of the speciality that the majority of his own researchers and clinicians in Trondheim are exclusively involved in oncology, as are other units with which they collaborate internationally in countries such as the UK and Canada. The European Association for Palliative Care (EAPC), for which Kaasa is a past president, has a strong oncology track and supported the establishment of the European Palliative Care Research Centre in Trondheim in 2009. 

This cancer-only initiative is certainly one of the biggest steps forward recently, but Kaasa says the majority of its funding is from the Norwegian Cancer Society, and from his own hospital as well as the university. Without his vision for palliative care in oncology and the backing of Norway&rsquo;s advocacy groups this centre would not be up and running, although it is attracting various grants from the EU and other sources, and of course enjoys the support of the EAPC and international colleagues. 

Given his achievements so far, Kaasa is now aiming high at Trondheim &ndash; &ldquo;I want to build a structure for integrated oncology and palliative care that will be a window for the world that will show what can be done,&rdquo; he says. It&rsquo;s an ambitious goal for what is a northern outpost in Europe, but as he says, he has already fought and won the battles to prove the need for integration locally, and with longstanding expertise in international networking there is every chance that he will ensure that Trondheim will be seen as the global model he envisions. 


&ldquo;I want to build a structure for integrated oncology and palliative care that will show the world what can be done&rdquo;  


Kaasa was a national cross-country skiing champion when at high school in Norway, and gained a great start for his early career when he landed a sports skiing scholarship at Denver University in the United States, where he was also able to model his own &lsquo;pre-med&rsquo; course in anticipation of a return to Norway. Then in Oslo, he completed his medical training, taking in surgery, internal medicine and family practice. The latter was a career option until, unsure of what direction to take, he contacted Herman H&oslash;st, the &lsquo;father &rsquo;of Norwegian oncology, and gained a short-term post at Oslo&rsquo;s Radiumhospital. 

&ldquo;There I was challenged by a senior lecturer to look at lung cancer patients and the use of cisplatin in people with a short life expectancy, and I worked on a randomised trial between chemo- and radiotherapy, which was the basis of my PhD thesis. We were one of the first to actually ask people how they felt during their treatment &ndash; what we now call patient-reported outcomes &ndash; and our group was one of the movers in the development of the QLQ-C30 questionnaire at the EORTC for assessing the quality of life of cancer patients.&rdquo; 

It was the opportunity to do this kind of research that quickly convinced Kaasa that his career lay in oncology and not as a family doctor. He then gained his oncology board certification working on the spectrum of cancer issues at the Radiumhospital and, like oncologists in certain countries such as the UK and other Nordic countries, Kaasa is certified in both chemo- and radiotherapy, as a clinical oncologist. But his academic focus was on the non-curative side &ndash; and he duly completed a PhD on quality of life and survival. 

&ldquo;Although palliative care had been developed primarily in the UK back in the 1960s, thanks to the hospice movement, it was mainly outside of main stream healthcare. In hospital oncology it hasn&rsquo;t really taken off until recently,&rdquo; says Kaasa. &ldquo;That&rsquo;s because in the late 1980s we had a strong belief that we would see the sort of major improvements in cure rates that we had seen with testicular cancer and lymphoma, for example. When I was working on lung cancers we really thought we would cure them with high-dose chemotherapy and bone marrow transplants.&rdquo; 

Recent years have seen a repeat of this belief, he says, as the new targeted therapies have again pushed back palliative care to some extent, fuelled by the huge promotional activity of the pharmaceutical industry &ndash; although he adds that pharma was the first in offering support for quality of life studies when he was starting out. &ldquo;Companies realised it was important to document subjective factors as well as response rate,&rdquo; he says. 

After establishing himself as a consultant oncologist in Oslo, the opening for the palliative medicine professorship in Trondheim came up. &ldquo;In Norway we had been debating what we should do about palliative care and it was again the Norwegian Cancer Society that was instrumental in putting out a bid to set up a programme at one of our university hospitals. Trondheim won and I was asked to apply.&rdquo; 

Although Kaasa enjoyed the support of the hospital&rsquo;s oncology department and the head of nursing, he still encountered most of the objections about actually integrating palliative care. &ldquo;I won the battle by bringing in the academic side and starting a research programme, and putting a lot of energy into international collaboration and leadership. It&rsquo;s hard for opponents to criticise solid research &ndash;especially as, after seven years or so, we were producing as much as 80%of the publications from the Cancer Clinic.&rdquo; 

Kaasa also argued from a clinical perspective that patients suffering, for instance, from pain with bone metastases needed to be treated with radiotherapy, and that to carry out academic medicine properly on such approaches palliative care had to be applied early in the journey rather than waiting for oncologists to deliver patients to palliative care professionals in another location. 

From humble beginnings &ndash; when he started Kaasa had just one other doctor and two nurses &ndash;the palliative care team in Trondheim is now almost 30 strong, with molecular biologists and social scientists, more than 20 PhD students, a number of international researchers and visiting professorial placements, and various clinical and research input from other specialists in the university hospital, such as pain specialists. 

Kaasa was asked to head the entire Cancer Clinic in 2010, and so is in the ideal position to oversee the integration he promotes. &ldquo;And that&rsquo;s what you would see is different here &ndash; palliative care doctors at our morning case meetings, which we hold every day. I don&rsquo;t see patients myself now but I do become involved in particularly challenging cases.&rdquo; 

An early randomised study comparing specialist palliative care with care as usual, published in the Lancet, played a critical role in setting the agenda, says Kaasa. One major finding was that patients in the intervention group benefited from an integrated pathway by being able to stay longer at home. &ldquo;An interesting spinoff was that the families reported better health even one year after the patient had died,&rdquo; he says. Trondheim has now produced hundreds of studies related to palliative care, many of them in top-rated journals, according to Kaasa. Other studies have focused particularly on treatments, finding benefits for example in reducing the number of radiation fractions that need to be given to treat lung cancers and bone metastases, saving much trouble for patients and also costs.  


&ldquo;An interesting spinoff was that the families reported better health even one year after the patient had died&rdquo;  


Current research priorities for the field are revealed in a pan-European survey under an EU7th framework programme project called PRISMA, which shows that the top topics are pain, assessment tools, quality of death and last days of life, fatigue and cachexia, and family and carers. The main barriers are, inevitably, lack of funding, time, expertise and personnel. 

Pain is still a major problem, says Kaasa. One reason he cites is that many patients are not diagnosed and followed-up appropriately. Another is that they do not receive effective treatments because they fall into gaps &ndash; a hospice physician may have no access to radiotherapy to treat bone metastases, while a radiotherapist may not know enough about opioids. &ldquo;Optimal pain control needs a combined approach, including specialists at pain clinics. We have a close relationship with our pain clinic in Trondheim &ndash; but there can be little such collaboration between pain specialists and palliative care around Europe, as the pain clinics deal mainly with non-malignant conditions. We also have a growing population of cancer survivors who suffer non-malignant pain from side-effects later in life. We have to collaborate more for patients.&rdquo; 

One urgent need is to establish a consensus on pain assessment tools in palliative care and to update guidelines based on much stronger evidence. Kaasa points to some progress here: a recent special issue of Palliative Medicine (July 2011) published updated pain guidelines from the EAPC, the evidence base for a set of review articles, and there is now a much better platform on which to build cancer pain research. 

Kaasa&rsquo;s group is the leader of the European Pain Opioid Study (EPOS), which is a translational research project looking at the biological action of the drug. A major change in recent years, he notes, is a move to joining forces with basic scientists to research the biology of late-stage disease and effects, in addition to the patient-reported clinical studies. 

&ldquo;We have also been researching the genetic basis of pain to see if we could find a biomarker for pain response, but we had a negative result, which is still important to publish. We have been critical of the methodology often used in this type of research &ndash; those who go on &lsquo;fishing trips&rsquo; for single nucleotide polymorphisms to find such biomarkers in clinical medicine, when there are so very few in use in oncology. But we have more encouraging signs for our work in cachexia.&rdquo; (See box, below).


One aspect of his field particularly annoys Kaasa, and that is terminology. As far as he is concerned, it is called &lsquo;palliative care&rsquo; or &lsquo;palliative medicine&rsquo; and should cover the vast majority of the advanced cancer journey. But he says confusion can be spread by the use of &lsquo;end of life care&rsquo; and &lsquo;supportive care&rsquo;. &ldquo;In some cancer centres this is often about competing for resources, with some focusing on what they call earlier symptom control in &lsquo;supportive care&rsquo;, while leaving others to do the &lsquo;end of life&rsquo;. Yes, if you have a large palliative care team you can have people focusing more on early symptoms, but really this is often about a resources battle and not integrated care, and of course again it is the patients who fall into the gaps.&rdquo; 

A powerful way to get the message across about palliative care, he believes, is to have many more doctors gaining a palliative medicine qualification as an addition to their main work. &ldquo;We now have a two-year course in the Nordic countries that we started in 2003, and it was officially endorsed, recently, for any doctor to study palliative medicine during their normal job, although they do have to take about six weeks out to attend the various modules, which are run at various locations in Scandinavia.&rdquo; The Nordic Specialist Course in Palliative Medicine, as it&rsquo;s called, is based on the British curriculum in palliative medicine, which is a standard for many countries. 

There&rsquo;s a big difference though between Britain and Norway when it comes to full-time palliative care practitioners, says Kaasa. &ldquo;In Britain you can train from the start as a palliative medicine specialist, but here you need to have another speciality, such as oncology, first &ndash; all the palliative doctors in my unit are also oncologists.&rdquo; In fact, one other issue he had to deal with on taking up his professorship at Trondheim was that his department was expected to handle conditions other than cancer, such as coronary heart disease and neurological illnesses. 

&ldquo;But to work in specialist palliative care you have to know the disease you are working with, in my view. After 10 years or so we stopped everything except oncology.&rdquo; A cardiologist with a palliative medicine qualification is much better placed to work with heart patients, he says. &ldquo;But outside the hospital a GP with palliative care knowledge can see everyone.&rdquo; 


&ldquo;To work in specialist palliative care you have to know the disease you are working with&rdquo;  


An early success in clinical care in Trondheim was being allowed to involve multidisciplinary teams in seeing patients at home, and not just as in and out patients, which was a start in widening the care pathway. &ldquo;There was no reimbursement system for visiting patients outside the hospital and so we went to the health authority and were granted a special arrangement &ndash; financial incentives can be very powerful in changing practice, I feel.&rdquo; 

Since then he has helped promote a palliative care strategy that works across all levels of health care, and which has been part of Norway&rsquo;s cancer plan. Notable steps have been establishing service development units in each health region, encouraging more hospital directors to set up palliative care units, and making better provision for specialist beds in nursing homes. In 2004, a Norwegian standard for palliative care was published. 

Kaasa has also made his mark in Norway in strategies for the wider healthcare system and the country&rsquo;s cancer plan &ndash; among his many posts he is currently the national cancer director .He stresses how crucial it is to develop evidence-based guidelines in healthcare &ndash; guideline work has been among the more successful parts of Norway&rsquo;s cancer plan. What many other countries lack, in his view, is the kind of palliative care model that Norway now has. 

The EAPC, with partner organisations such as the International Association for Hospice and Palliative Care(IAHPC) and the Worldwide Palliative Care Alliance (WPCA), has set out a framework for development (the so-called Budapest commitments), which is an initiative aimed at national associations and includes defining standards of care. An EU 7th framework project, IMPACT (implementation of quality indicators in palliative care study), is looking at cancer and dementia care with work packages on organisation and implementation of care (see www.impactpalliativecare.eu). 

These are good steps, says Kaasa, but Europe is some way from widespread quality-audited palliative care in a majority of oncology departments. He would like to see the EAPC gain funding to produce an oncology training curriculum, for palliative care to get a seat at the top table in ECCO, and for the subject to be addressed better at general cancer conferences, where it is often a side session that is not well attended. ESMO, the European Society for Medical Oncology, to which he belongs, could do much more on palliative care, he feels; in contrast, EONS, the nursing society &ldquo;is much more supportive.&rdquo; Next June, Trondheim is hosting EAPC&rsquo;s 7th world research congress, which will be an ideal place to hear the issues first hand. 

Again he mentions the value of politicians setting economic incentives to drive change, and Trondheim&rsquo;s Cancer Clinic is an example of what can be achieved with integration &ndash; the number of beds has been cut from 68 to 36 following success in managing more cancer cases as outpatients &ndash; a caseload that is rising of course. &ldquo;Metastatic disease incidence will increase 2% a year up to2020,&rdquo; he says. 

Not least of the issues is the cost of treatments in people with advanced disease, which Kaasa has also been advising the Norwegian authorities about. &ldquo;We are seeing debates now about the cost&ndash;benefits of modern oncology even in the US &ndash; 10 years ago, the drug budget at our department in Trondheim was a tenth or so of what it is now.&rdquo;He mentions a recent US study that randomised palliative care against mainstream oncology early in lung cancer. It found the intervention group lived longer and had fewer depressive symptoms, while the control group received more chemotherapy (NEJM 2010, 363:733&ndash;742).


The palliative care group lived longer, while the control group received more chemotherapy  


Naturally, he may not be the most popular person with pharmaceutical companies, given his insistence for his team to use evidence-based approaches where possible even in advanced disease. &ldquo;I&rsquo;ve been in oncology a long time and I can see no major breakthroughs and just that growing metastatic burden.&rdquo;He adds though that he is of course interested in promising drugs, and also in new uses, such as investigating how chemotherapy can be used to treat pain and other symptoms &ndash; an under-researched field. 

There is still a pioneering air about palliative care in oncology given the major multidisciplinary research agenda still ahead, and indeed in the US a recent spate of articles in the mainstream media have just &lsquo;discovered&rsquo; the speciality as an evidence based way to approach care for terminally ill patients, for whom futile treatment is common &ndash;countering the right-wing&rsquo;s insistence that discussing end-of-life options will lead to rationing and bureaucratic &lsquo;death panels&rsquo;. Kaasa says Europe is ahead in models of palliative care, thanks to pioneers such as the UK&rsquo;s Geoff Hanks, who was one of the founders of the EAPC, an advisor to the European Palliative Care Research Centre and a mentor when Kaasa was venturing into the field. &ldquo;It was controversial when I started to focus on quality of life at the Radiumhospital, and I did push palliative care perhaps too strongly in the early years &ndash; but I think I was right,&rdquo; he says. 

Kaasa has four children and has remarried, to Anne Kari Knudsen, a pain researcher in his department. Skiing and fitness still play a big part in his routine. 

&ldquo;My aim now is to help establish a sustainable network of international centres conducting large scale research on palliative care in cancer, and in particular I want to gain new insights into pain and cachexia. I won&rsquo;t stop pushing too for even better integration in Norway&rsquo;s healthcare system. And I&rsquo;ll stay here in Trondheim&ndash;the skiing&rsquo;s better.&rdquo;     ]]></description>
            <author>Marc Beishon</author>
            <category>Cover Story</category>
        </item>
        <item>
            <title>Optimising dose-dense regimens for early breast cancer</title>
            <link>http://www.cancerworld.org/Articles/Isseus_46/e-Grand_Round/Optimising_dose-dense_regimens_for_early_breast_cancer.html</link>
            <description><![CDATA[
Dose-dense regimens are intended to increase efficacy, not by increasing the patient&rsquo;s total exposure to a drug, but by decreasing the time between doses. Does it work? And what happens to toxicity, especially where targeted agents are added? Clifford Hudis takes a look at the evidence in early breast cancer.  

Why escalate the dose of cancer therapies? The rationale is that escalating the dose should kill more cancer cells. This has been seen many times in preclinical models in laboratory experiments and sometimes in the clinic, but not consistently. For example, two large, randomised trials, including a total of nearly five thousand patients in the NSABP (National Surgical Adjuvant Breast and Bowel Project) in the US showed no effect of escalated doses of cyclophosphamide on outcomes. These trials tested five dose levels, where the dose was doubled in dose size, doubled in dose exposure, doubled in dose size again, and doubled in total exposure again, so that doses ranged from 600 mg/m2 every three weeks to four times greater (see figure below). Results showed no impact on either disease-free or overall survival across these two sequential studies. 


Previous results, such as those from Budman et al. (CALGB 8541) suggest that there could be a dose&ndash;response relationship for cyclophosphamide, but only at lower doses; the NSABP data show that this does not continue at higher doses. We have seen similar results for anthracyclines and taxanes and most other chemotherapy drugs.  

In optimising chemotherapy regimens with regard to dose and schedule, there are essentially two aspects to consider. On the one hand there is the Gompertzian growth kinetics of breast cancer cells, as is true for all other solid tumours, and indeed all cell and tissue types. The tumour, while always growing, appears to have a decreasing rate of growth over time. This is not actually true when you look at raw numbers, but it is true when you look at volumes. That is because of the effect of three dimensions in minimising the perception of volume change. It is also a reflection of the balance (or imbalance) between cell division and cell death as it changes with tumour growth, perhaps due to alterations in the delivery of nutrients and other factors. 

If we administer chemotherapy based on the Skipper&ndash;Schabel model (see figure, below), the green arrows indicate the further reduction with each dose of chemotherapy, which we have always been taught is a log kill effect. The black arrows show the result of shortening the time between treatments on the log kill effect, which is what we call dose density. More frequent (dense) dosing decreases the time for tumour regrowth in between doses. It allows for the treatment each successive time of an ever smaller volume of tumour and that, in turn, results in a greater overall cell-kill.   


Is the log cell-kill model reflected in the clinic?  

A study from Milan (see below) explored sequential or alternating treatment with CMF (cyclophosphamide, methotrexate, 5-fluorouracil) (in yellow) and doxorubicin (in red). The theory was that alternating these non-cross-resistant treatments would yield greater cell-kill. That is the arm represented by the top row of the figure. As a control, they administered the same four doses of the doxorubicin first, followed by the same total eight doses of CMF sequentially. Over the nine months of treatment, every patient on this study received the same four drugs, CMF and doxorubicin, with the same size doses of each drug and the same total dose of each drug. This emerges as an elegant test of dose density. The results speak for themselves, favouring the dose-dense regimen.  


Janice Gabrilove and colleagues, at my institution, first used growth factors  &ndash; specifically granulocyte colony-stimulating factor (G-CSF), also known as filgrastim &ndash; to reduce neutropenia and associated morbidity due to chemotherapy in patients with bladder cancer. Although they gave full chemotherapy at a standard interval, all of the patients (100%) had full recovery of blood counts by day 14, and would have been able to receive planned chemotherapy, compared to only 29% of those not given G-CSF (NEJM 1988; 318:1414&ndash;22). As investigators were beginning to explore significant dose escalation, based on the hypothesis that the dose-response relationship was linear, we instead went in a different direction and began to explore dose density, meaning shortening of the intervals between treatments.  

The figure below summarises three sequential pilot studies at the Memorial Sloan-Kettering Cancer Center (MSKCC). First, we were able to give high-dose cyclophosphamide (a very high dose of 3.0 g/m2) at two-week intervals with growth factor support. The second study added paclitaxel, in one of the first trials to add this, or any, taxane as adjuvant therapy (the ATC regimen &ndash; Adriamycin (doxorubicin), Taxol (paclitaxel), Cyclophosphamide). In this study the dose interval for doxorubicin was shortened &ndash; we gave three doses of each of the three drugs, all at two-week intervals and demonstrated feasibility, albeit with significant toxicities attributable to the use of higher doses of the individual agents than are currently employed. 

Later, in a third study, we randomised patients to concurrent or sequential therapy with paclitaxel and cyclophosphamide, but all drugs were given in a dose-dense regimen. This study demonstrated that with these high doses, the concurrent regimen was no better in terms of toxicity. These studies were all too small (or non-randomised) to allow for efficacy comparisons.   


As one considers the results of trials that employ dose-dense regimens, it is important to be wary of possible confounders that can compromise the interpretation of such studies. For example, while we can achieve a dose-dense regimen with short intervals, testing it requires carefully controlled studies. Comparing four cycles of low-dose versus high-dose chemotherapy tests dose size. Comparing four cycles of a drug versus six cycles of the same size dose tests number of doses, and also tests total drug exposure, but not density. Controlling dose size but changing the frequency of administration &ndash; or density &ndash; while controlling the total dose number, is a pure test of dose density.  

A typical design &ndash; and I have taken part in these studies myself &ndash; is four cycles of low-dose chemotherapy over three-week intervals, compared to three cycles of higher-dose every two weeks. This changes several parameters so it is not always clear what is being tested. 

One example of a positive study was the AGO (Arbeitsgemeinschaft Gynaekologische Onkologie) trial (see below). Here, a dose-dense regimen of epirubicin, paclitaxel and cyclophosphamide (ETC), given with growth factor support, was superior in long-term follow-up to the conventional epirubicin/ cyclophosphamide (EC) paclitaxel regimen (JCO 2004, 22:6s, abstr 513). However, the number of doses of the three drugs varies and the size of the doses varies, as well as the dosing interval. Hence, while this study clearly demonstrated the superiority of a dose-dense regimen, critics could claim that this was due to other factors, such as the larger doses of the individual drugs.    


Weekly paclitaxel has been called &ldquo;dose-dense&rdquo; by us and others. However, here again there can be confusion in terms of what is tested in clinical trials. In the ECOG 1199 (Eastern Cooperative Oncology Group) study, AC was given at three-week intervals, followed by one of two taxanes &ndash; paclitaxel or docetaxel &ndash; using one of two schedules: weekly or three-weekly (q3). 

Weekly paclitaxel appeared to be superior to q3 paclitaxel. However, we note that 80 mg/m2 weekly of paclitaxel for 12 weeks is not the same as 175 mg/m2 q3, and so there are multiple variables at work here: dose number, dose size and frequency of administration. 

The Cancer and Leukemia Group B dose-density trial CALGB 97-41 also employed a factorial design (see below). We asked two questions: the first question was about the frequency of administration, comparing q2 therapy with G-CSF support to q3; the second compared concurrent AC therapy with sequential therapy. What makes this study interpretable for us is that every patient had the same four doses of the same three drugs. All that varies across the four treatment assignments is concurrent or sequential dosing, and dose density.


Results show that q2 therapy was superior to q3 for disease-free survival; this was also true for overall survival. There was no difference between sequential and concurrent therapy. We continue to use concurrent therapy most of the time because it allows us to get the treatment completed faster. But that is not the same as saying it is better, other than in terms of convenience.  

Toxicity 

Once one accepts the superior efficacy of dose-dense treatment, the next concern is toxicity. This has become a particular issue in an era of trastuzumab and HER2-directed therapies for patients with HER2-positive disease. 

The cardiotoxicity results from CALGB 97-41 showed the only acute cardiac event occurred in the patient you would have least expected: one treated with q3 single-agent doxorubicin. Looking at the total number of cardiac events &ndash; although this was purely exploratory and done retrospectively &ndash; showed that numerically there were twice as many events with q3 therapy as with q2 (2.5% vs 1.5%). This gave us some comfort that dose-dense therapy does not raise the risk of cardiac toxicity compared to q3.  

This allowed us to go forward with pilot studies of dose-dense therapy and trastuzumab and also bevacizumab. The tables below show three studies of dose-dense AC with targeted therapy done by our group at MSKCC, and colleagues at the University of California San Francisco (UCSF), and the Dana-Farber Cancer Institute. The right-hand table summarises the cardiac toxicities, showing essentially no signal of acute cardiac toxicity over the four doses of AC across the several hundred patients.   


Longer term follow-up does not show any clear signal that dose density represents a special challenge for the delivery of full doses and durations of these  regimens (JCO 2009, 27:6117&ndash;23). For comparison, in the cooperative group  trials, about 65% of patients finished their full year of trastuzumab, whereas this number was about 80% in our studies. 

Taking dose-dense therapy forward 

We incorporated the results of CALGB 97-41 into CALGB 40101. Initially this was a study of weekly paclitaxel for 12 or 18 weeks, versus AC q3 for four or six cycles with G-CSF. It was a two-by-two factorial design, comparing AC against single-agent paclitaxel for low-risk breast cancer. It was also a comparison of a longer therapy (six months) versus shorter (four months). There were those who argued that the superiority of AC followed by paclitaxel (or docetaxel) was not really attributable to taxanes per se but instead to the eight cycles of treatment which were presumed to be superior to four. Others have argued that six cycles of AC-containing therapy is better than four.  

Based on the results of CALGB 97-41 we were motivated to change the study. With fewer than six hundred patients recruited, we modified it to include dose-dense therapy (q2 administration) and six cycles versus four. We continued the AC versus paclitaxel randomisation. In a still later modification of the study we dropped the six versus four cycle randomisation, making it a simple two-way comparison of paclitaxel versus AC, each then only administered for four cycles. 

Results reported by Larry Shulman at San Antonio (2010) showed recurrence-free survival and overall survival with four cycles of treatment versus six were indistinguishable. We do not yet have the results of the AC versus paclitaxel comparison, but our data and safety monitoring board confirmed that they do not confound our results.   

Is there a better AC or paclitaxel schedule? 

SWOG study S0221 used a two-by-two factorial design of six cycles of dose-dense AC compared to a regimen of low-dose weekly doxorubicin regimen along with oral daily cyclophosphamide. Apart from that randomised comparison, they compared q2 paclitaxel for six cycles versus low-dose weekly paclitaxel for 12 weeks. Recently, they dropped the AC portion of the randomisation and shortened it to four cycles of every other week dosing. This was based on a futility analysis that weekly doxorubicin and oral cyclophosphamide could never be superior to the six cycles of AC. It does not mean it is worse. Hence the simplified design is now four doses of q2 AC, and the taxane comparison of low-dose weekly paclitaxel versus higher-dose q2 continues. 

The NSAPB B-38 trial (see below) compares dose-dense AC paclitaxel (middle row) with TAC (top row &ndash; Taxotere [docetaxel], Adriamycin [doxorubicin], Cyclophosphamide) and experimental therapy of dose-dense AC paclitaxel with gemcitabine (bottom row). The tAnGo study, a UK-based trial that looked at the potential benefits of adding gemcitabine to an anthracycline- and taxane-containing adjuvant treatment regimen in early breast cancer, was negative. This suggests that the notion that gemcitabine as a fourth chemotherapy drug is going to add to this cohort of patients is unlikely to be supported. 


Can we further decrease intervals and increase dose density? 

The ECOG 5103 bevacizumab trial is comparing AC, followed by weekly paclitaxel alone, with AC plus bevacizumab followed by paclitaxel plus bevacizumab, or AC followed by paclitaxel, both with bevacizumab and then followed by bevacizumab (see below). If bevacizumab adds a benefit, this study also allows us to ask about the duration of its use. Because clinicians have different views on the appropriateness of dose-dense therapy, the dose-dense regimen is allowed, as is q3 administration, and the patients were simply stratified on that basis. 


Our group has gone ahead asking whether we can push this further. The first pilot study, conducted by Monica Fornier, looked at 10- to 11-day intervals with sequential EC and paclitaxel using conventional G-CSF, because you cannot use pegylated G-CSF with such a short interval. The study demonstrated that this was feasible, but a randomised trial would be needed to show efficacy. 

We then turned our attention to  intravenous CMF, which was given two weeks on and two weeks off in the Milan studies in the past. Here we gave it every 14 days without breaks, which modelled the dose-dense experience of the CALGB. All we wanted to demonstrate was that it was feasible, because there are clinical reasons, from time to time in individual patients, to try to accelerate CMF, and when we treat patients in the low-risk setting this can be a viable alternative. For this not to be justifiable, we would have to show that shortening the interval makes the therapy less effective, but we have never seen evidence of that. Feasibility was strained at intervals of 10 &ndash;11 days but not at 14 days. 

Dose-dense treatment in the palliative setting 

Typically, we do not do studies of dose density in the palliative setting, because our goal here is not necessarily to achieve the highest response rate, or quickly deliver the lifetime tolerable (cardiac safe) dose of AC when it is used for palliation. Instead, our goal is to use the least toxic therapy that we can.  

Capecitabine has high efficacy but also toxicity; giving the drug continuously for 14 days on a 21-day cycle results in a high rate of diarrhoea and gastrointestinal distress in the second week. We looked at mouse models of a capecitabine-sensitive tumour cell line. The maximal impact of therapy occurred eight days after starting treatment. This means that each day after that time point, if we continued to dose with capecitabine, cell-kill still occurred but it was less than the day before. The downside is that the toxicities accumulate so a week off is still needed to recover. We modelled the impact of a dose-dense schedule, which consists of one week on and one week off and this predicted that stopping therapy earlier, at one week, would allow for the earlier imposition of the needed seven-day break, but then an earlier re-initiation of treatment with resumption of greater cell-kill.  

In the clinical extension of this work, our phase I study showed that this was feasible, and we have now done phase II studies with weekly (one week on, one week off) capecitabine combined with lapatinib or with bevacizumab, all of which have been feasible. This schedule has been widely adopted by clinicians because, as a practical matter, they so often have to stop before 14 days because of toxicity. This is a demonstration of the way in which a dose-dense schedule can be advantageous in the palliative setting as well as more curative in the adjuvant setting.   

Conclusion 

Dose scheduling &ndash; specifically in terms of density &ndash; is important, and it should be maintained in the adjuvant setting for both efficacy and toxicity. For example, using growth factor support with dose-dense AC not only enhances efficacy but also halves the hospitalisation rate (typically due to neutropenic fever). At the same time, it is fair to say that the cost issue is not fully addressed. Growth factor support is not inexpensive and the cost varies widely, making it unlikely that we will ever be able to develop an absolute answer on this issue. Cost-effectiveness in the curative setting depends, in part, on how much value is put on lives saved. 

Finally, supportive care, in the form of growth factor use, is what facilitates the improved chemotherapy effect, so that is a critical part of the story. As we move further into the era of molecularly targeted therapies, it is important to note that dose-dense therapy does not preclude, and in fact supports, the use of these agents.


Q: [Ukraine]: In your opinion, should we use metronomic chemotherapy or dose-dense chemotherapy? Which of the two will be the preferred option for the future? 
CH: A metronome is, of course, the device that we use in piano lessons to keep time. The term is now being used, typically, to refer to low-dose weekly therapy, but essentially every regimen we ever use matches the metronome, with regular cycling of therapy. I reviewed a couple of studies with cyclophosphamide, doxorubicin and paclitaxel that directly answer the question on low-dose weekly therapy. Perhaps the best was a SWOG study with low-dose, weekly doxorubicin with oral daily cyclophosphamide compared to dose-dense AC, showing it was not better but somewhat more toxic. A study with low-dose weekly paclitaxel, which I suppose you could call metronomic, compared to q2 high-dose, or dose-dense, is open, so we do not have an answer.  For other drugs, we would need to make comparisons to provide you with an evidence-based answer. That said, my heart lies with low-dose, less toxic therapy, especially in the palliative setting. I do not disagree with those who advocate metronomic chemotherapy as palliation for incurable disease, although I am a little less convinced that we have meaningful data yet in the adjuvant setting. Clearly, we, and others, are continuing to study this. 
FC: I totally agree and I believe that we should probably test both, but my feeling is that what we call metronomic is probably better for the advanced setting, while dose-dense therapy makes more sense for the early setting. We need to let the trials end.  

Q: Do you have any data about the long-term risk of leukaemia by adding G-CSF to dose-dense regimens for breast cancer? 
CH: That was one of the interesting observations that we made &ndash; when we give AC across all of our CALGB studies, long-term follow-up averaged out at about a 0.5&ndash;0.7% incidence of acute myeloid leukaemia (AML). For our patient population, nearly half of those leukaemias are expected based on the natural history ageing rather than treatment.  We have never demonstrated that growth factor support for a dose-dense regimen was associated with any increase in risk. For example, the incidence of AML in our study was 0.7% with q2 and q3 and was, paradoxically, higher with the sequential regimen in one of the comparisons and the concurrent regimen in the other.  The NSAPB saw a significant increase of AML early on with dose-escalated cyclophosphamide and G-CSF support. When they gave 2400 mg/m2 of cyclophosphamide q3 with growth factor support, they saw an increased incidence, and I recall going to the National Cancer Institute in the 1990s to talk about whether this was worrisome. The problem here is that high-dose cyclophosphamide is clearly leukaemogenic. The dilemma is whether it is the growth factor causing this or the high-dose cyclophosphamide. In that context, CALGB 97-41 shows no difference in leukaemia with or without G-CSF. But where the doses are controlled and steady, I think it is probably not the case that  G-CSF is contributing anything in terms of AML and lymphoma risk.  
FC: If we look at non-dose-dense chemotherapy and the use of G-CSF in these situations, there is no conclusive evidence of an increased risk of leukaemia/ lymphoma in patients who need G-CSF, either as primary or secondary prophylaxis.  

Q: What could be the role of dose-dense chemotherapy in the neoadjuvant setting? 
CH: This question is not coming up quite as much these days, but used to come up quite a lot. Looking at the data, people are convinced of the benefit of giving dose-dense therapy postoperatively, but when I am trying to shrink a cancer preoperatively, I would give q3. This is because we do not yet have the right data to prove that a dose-dense regimen is better preoperatively. 


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, Clifford  Hudis, from Memorial Sloan-Kettering Cancer Center, New York, provides  an update on optimising dose-dense regimens for women with early breast  cancer. This is based on a News and Views article in Nature Reviews  Clinical Oncology (2010, 7:678&ndash;679).&nbsp; Fatima Cardoso, from  Champalimaud Cancer Centre, in Lisbon, Portugal, poses questions arising  during the e-grandround live presentation. It as summarised by Susan  Mayor. The recorded version of this and other e-grandrounds, together  with 15 minutes of discussion, is available at www.e-eso.net ]]></description>
            <author>Susan Mayor</author>
            <category>e-Grand Round</category>
        </item>
        <item>
            <title>Picture this: The new imaging techniques that can help doctors select the right treatment at ...</title>
            <link>http://www.cancerworld.org/Articles/Isseus_46/Cutting_Edge/Picture_this%3A_The_new_imaging_techniques_that_can_help_doctors_select_the_right_treatment_at_the_right_time.html</link>
            <description><![CDATA[
 On the road towards personalised cancer therapies, the tasks of identifying new targets and devising ways to hit them seem to be coming along quite nicely. Right now, the big challenge is all about finding ways to work out which of the rapidly expanding selection of therapies will work best for the patient in front of you. Clinicians are crying out for validated cost-effective and patient-friendly methods for gathering biological information (&lsquo;biomarkers&rsquo;) that help them to select the most appropriate therapy option.    

Some of these biomarkers are already well known &ndash; the FISH test for HER2 amplification predicts response to therapies designed to block HER2 signalling, such as trastuzumab or lapatinib, while KRAS mutation is a marker predicting resistance to EGFR inhibitors such as cetuximab and panitumumab. And long before these, oncologists were using levels of oestrogen receptor and progesterone receptor as markers for response to hormonal therapy, for instance in breast cancer.   

Progress can be seen in the way that pathology labs are introducing an increasing number of tests for biomarkers into the diagnostic routine. Outside the hospital setting, a whole diagnostics industry is mushrooming to provide testing kits to hospital labs and to offer diagnostic services for more high-tech tests. Examples include Genomic Health&rsquo;s Oncotype Dx multi-gene assays and the Agendia and Affymetrix genomic microarrays, which can be used to help select patients for adjuvant chemotherapy&ndash; technologies developed initially for use in breast cancer, but now introduced across a variety of cancers.   

Progress is also taking place in an area not so well known to the oncology community. The next big thing in biomarkers may be all about &lsquo;functional&rsquo; imaging, which tells you not what a tumour looks like, but about what it is up to biologically. Two imaging technologies in particular are exciting interest for the potential they offer to help inform clinical decision making. The most surprising, perhaps, is MRI. Valued for decades for its ability to provide anatomic images of soft tissue lesions, this technique turns out also to have potential for imaging tumour microenvironments and cell metabolism &ndash; necrosis, cell density, metabolism, tissue perfusion and oxygenation. This can provide vital information about the nature of a tumour and how it is responding, or likely to respond, to a given therapy. 

The other technique of interest comes from the field of nuclear medicine, in the form of PET (positron emission tomography) or SPECT (single-photon emission computed tomography). These techniques make it possible to visualise how an injected substance moves around the body by &lsquo;labelling&rsquo; it with a tiny amount of radioactive tracer.   

Oncologists will be familiar with the increasing use of FDG-PET for measuring response to treatment, particularly cytostatic treatments of solid tumours, where response typically does not take the form of tumour shrinkage, with the result that traditional anatomical imaging using CT or MRI can be misleading. This PET procedure uses FDG, a glucose analogue labelled with a fluorine radio isotope (18F-fluorodeoxyglucose), to map levels of glucose uptake around the body. This is in the process of being validated as a RECIST (Response Evaluation Criteria In Solid Tumours) marker of early response. 

Glucose uptake &ndash; a generic marker of tumour activity &ndash; is only one of a number of markers of interest for clinical decision makers. The PET technique, in theory at least, can be adapted to map any biological process or molecular marker that can be delineated by a labelled compound that can safely be used in a patient. This includes specific targets such as oestrogen, HER2 or EGF receptors, as well as more generic biological markers of hypoxia, cell proliferation, and cell death.  

A new generation of PET-MRI scanners has addressed many of the technical and practical challenges of functional imaging. The question now needs to be answered for both PET and MRI: in what way can they contribute to the everyday practice of personalised cancer therapies?    

An alien in the imaging world  

Elisabeth de Vries is a professor of medical oncology at the University Medical Centre Groningen, in the Netherlands. So convinced is she of the potential value of imaging for clinical decision making that she has waded in as &ldquo;an alien in the imaging world&rdquo;. Her recent research efforts have focused on investigating the clinical use of PET/SPECT, and more recently fluorescence imaging.   

de Vries believes these imaging techniques offer a way to address some of the knottiest problems in personalising cancer therapies &ndash; not least, the growing recognition that the biology of a tumour can vary markedly from one area to the next and metastatic lesions do not necessarily resemble the primary tumour. &ldquo;We all want to move to personalised medicine. We want to know who needs what drug either before or early during treatment. But one of the things that I find remarkable is this heterogeneity in tumour lesions. Tumour biopsies provide only static information on the status of a marker in a small part of the tumour and disregard the remaining tumour and possible metastases. Imaging can give us a better wholebody picture and insight into all lesions.&rdquo; What&rsquo;s more, she adds, because it is noninvasive it can be used repeatedly.   

Access to this level of information can be particularly important in cases where standard diagnostic tests are giving conflicting information, says de Vries. &ldquo;You have a patient with two breast cancers, for instance &ndash; one on the right and one on the left. This patient develops metastases, and they are hard to biopsy. You know one primary is oestrogen receptor positive and the other is not. If you can do a PET scan using 18F-oestradiol [FES], which binds to the oestrogen receptor, you can confirm whether or not ER is present on the metastasis&rdquo; &ndash; potentially important information when it comes to choosing a therapy.   

de Vries is setting up a prospective study in three Dutch centres enrolling patients with non-rapidly progressive metastatic breast cancer. The study will assess the added value of FES-PET and 89Zr trastuzumab-PET (using tiny quantities of radiolabelled trastuzumab) to predict non-response to targeted treatment with hormone or anti-HER2 therapy before therapy initiation, and of FDG-PET to predict non-response early during drug treatment. &ldquo;What you want to prove is that it does make sense to get insight into whole-body tumour expression of ER and HER2 to make treatment decisions,&rdquo; she says.   

For de Vries, that study represents only one example of many potential uses for molecular imaging. The technique, she argues, is a perfect tool for understanding how to use targeted therapy. As these therapies, by definition, are designed to hunt down a target, if you want to know the extent to which the target is present in a given patient, all you have to do is circulate a trace amount of the product with a radiolabel attached. Potentially these techniques could also be very helpful to evaluate whether targeted drugs are achieving the desired effect on their target in any given patient. In a number of preclinical studies, de Vries and colleagues have demonstrated the impact of a variety of targeted drugs on the expression of the relevant genes as visualised on PET imaging. They are now conducting clinical trials to visualise the effects of drugs specifically on ER, HER2 and VEGF expression. 


&ldquo;Radiolabelled PET is a perfect tool for understanding how to use targeted therapy&rdquo; 


Molecular imaging can probably even help with identifying the appropriate dose, she says. &ldquo;For instance, we know from clinical trials, and also from our own work, that if you study the pharmacokinetics of trastuzumab in the blood, it varies considerably from patient to patient. This seems to be related to a large extent to the total tumour volume in a patient, which makes sense: if your antibodies specifically go to tumour lesions, there will be a larger sink for the drug &ndash; and therefore more drug required &ndash; if you have more tumour on board.&rdquo; One implication might be that we may be using more trastuzumab than is necessary in adjuvant settings. 

Right now de Vries is actively exploring the potential for using fluorescence as an additional cheaper, easier and safer alternative to radioisotopes. The concept is identical to PET scanning, except that the chosen compound is labelled with a fluorescent marker. de Vries says that the advantages are that you don&rsquo;t need radioactivity, and fluorescence is also better at detecting very small lesions. &ldquo;You need only a few cells to get the signal. Often for PET scanning you need a lesion to be between 0.5 and 1.0 cm to detect it.&rdquo; The main problem at the moment is that it is impossible to get a whole-body reading, given the limited penetration of light. &ldquo;Happily several interesting novel devices are in development that are able to detect fluorescence, for instance during surgery, by endoscopy, with a handheld probe or using diffuse optical tomography to identify fluorescence-labelled lesions in the breast.   

de Vries is now keen to join multicentre imaging trials in collaboration with US and European centres. She may feel herself to be something of an alien in this field but the traffic is not all one way. Plenty of imaging specialists are now crossing the border in the other direction to join forces with the clinical cancer community to see how techniques they have spent years developing can function in the real world.    

An all-around picture

One of these travellers is the current president of the International Cancer Imaging Society, Anwar Padhani, a radiologist at the Paul Strickland Scanner Centre in London. Padhani shares de Vries&rsquo; belief that imaging could offer a vital tool for personalising therapies, but his interest is not so much on imaging molecular targets that may be specific to a cancer phenotype, as building up an all-round picture of how a tumour is sustaining itself and how it is responding to treatment. Learning how to do this effectively could be of enormous benefit to speed up drug development and cut costs as well as making it easier to take informed decisions on the management of individual patients.   

Angiogenesis, for instance, is known to be important in delivering the oxygen and nutrients that growing tumours need, and radiologists have developed a technique &ndash; dynamic contrast-enhanced (DCE) MRI/CT &ndash; that can provide whole-body images of the rate of contrast medium uptake, which is a marker for vascularisation. &lsquo;Before&rsquo; and &lsquo;after&rsquo; imaging can tell you how effective anti-angiogenic therapies such as bevacizumab and sunitinib are in a given patient. However, further research is needed to see how accurate imaging is at predicting response and patient benefit.   

Exciting though this may be, Padhani is looking for something more comprehensive to guide the use of multitargeted therapies. &ldquo;Just because you alter the blood vessels in a particular tissue doesn&rsquo;t mean that patients will benefit. You also need to look at what is happening to other processes in the tumour environment. If you kill some cells but make the tumour hypoxic in the process, you can make things even worse, because we know that hypoxic tumours are more resistant.&rdquo; Getting information on hypoxia requires different types of imaging, such as PET scanning using 18F-misonidazole or 64Cudiacetl- bis (N4-methylthiosemicarbazone). There are also scans that can help show the extent of cell death (such as diffusion-weighted MRI), or levels of proliferation (PET using 18F-fluorothymidine or 11C-choline) or glucose metabolism (FDG-PET).   

As many of these processes are linked, it is not always straightforward to interpret the signals. Tumour cells that are starved of oxygen, for instance, tend to respond by switching on more glucose receptors. The FDG-PET scan will tell you where glucose metabolism is upregulated, &ldquo;but is that because it is more hypoxic or because the tumour phenotype is intrinsically producing more receptors?&rdquo; Either way, he adds, you know you have an aggressive tumour.   

This array of imaging tools offers potential for understanding what a patient needs and how they are responding to selected treatments. But Padhani says there are many challenges to overcome before they can be introduced into clinical practice. These include the issue of how many tests you can do multiple times (cost, logistics and toxicity can be factors here). Then there is the issue of how imaging information is complementary to other biomarkers such as circulating tumour cells, tumour markers, urine biomarkers, immunohistochemistry. &ldquo;Where does imaging fit in, how does it correlate with these other biomarkers? There are exploratory investigations into this area but they have not progressed far,&rdquo; says Padhani. He reviewed some of these issues in a paper he co-authored on Multiparametric Imaging of Tumour Response to Therapy, published in Radiology in 2010 (vol 258, pp 348&ndash;364).  


&ldquo;There are many challenges to overcome beforethey can be introduced into clinical practice&rdquo;  


There is also a question about proof of clinical benefit. &ldquo;A lot of this imaging hasn&rsquo;t yet been correlated with patient outcomes. For FDG-PET we have firm evidence that changes in PET scans actually affect how patients feel and how they survive. This has been shown and in a number of different cancer types, including as a marker of response. But for the vast majority of others it hasn&rsquo;t been done, and the roadmap of how to do it has not been defined.&rdquo;   

He and his fellow researchers are calling on oncologists to get engaged in this work. &ldquo;We can&rsquo;t do it ourselves. We can develop the techniques, but we need active cooperation from the oncologists to be able to take the technique forward, to find its role, what its &lsquo;killer app&rsquo; is going to be. The landscape will change and they will need to become much more familiar with imaging as we need to be familiar with what they do. We need to do this together.&rdquo;    

Speeding progrss to the clinic 

Efforts to progress the use of imaging in personalised therapies have been concentrated in countries where major research bodies are capable of taking on this task, such as Germany and the UK. Harpal Kumar, chief executive of Cancer Research UK, for instance, recognised in 2008 that &ldquo;imaging is fast becoming one of the most effective means of detecting cancer early and of determining which treatment works for which patient.&rdquo; The charity almost quadrupled its funding for this area of work to &pound;50 million (&euro;58 million euros) over five years. A lot of work is also being done in the US, which applies a lighter regulatory hand to the use of new radioactive tracers for investigational procedures. 

EU funding for developing imaging biomarkers was boosted in 2006 with the Innovative Medicines Initiative (IMI), a &euro;2 billion EU&ndash;industry partnership. Some of this is targeted to: 


    create disease-specific European Imaging Networks, 


    develop regional centres of excellence, creating disease-specific European centres for the validation of new biomarkers and 


    enhance collaboration with patients and regulatory authorities. 


The EORTC has already secured funding for a trial investigating the value of diffusion-weighted MRI and PET imaging for proliferation and apoptosis for use as surrogate markers in early clinical trials.   

Leading this work is Sigrid Stroobants, head of the Department of Nuclear Imaging at the University of Antwerp, and chair of the EORTC&rsquo;s Imaging Group, which was established in early 2010. Stroobant&rsquo;s imaging group scans all new trial proposals submitted to the EORTC to identify opportunities for tacking on an imaging study to the protocol. She says that a lot of observational trials with imaging are needed simply to relate the signals they find to what they see in preclinical studies without interfering in the treatment.   

Such imaging add-ons can be very expensive, however &ndash; around &euro;500 for an MRI scan, &euro;800 for FDG-PET, and closer to &euro;1000&ndash;1500 for other PET tracers, which are not so widely available. There is also a question of capacity. The EORTC imaging group is coordinating with the UK imaging network set up by Cancer Research UK, and between them they cover around 100 centres, but not all of them can do what is required. &ldquo;Not all clinical centres have the capacity to do these high fancy imaging techniques and you sometimes see a discordance between what we need for imaging and what we need for the clinical department. Sometimes they lack the special sequences we need for diffusion MR or they don&rsquo;t have access to FLT [18F-fluorothymidine, an alternative PET tracer].&rdquo;   

Stroobants believes that some of the more generic markers that Padhani talks about are good candidates for replacing the traditional RECIST criteria for measuring response in many situations, using FLT- and FDG-PET scanning and probably dynamic contrast-enhanced MRI and diffusion-weighted MRI. She believes that the diffusion-weighted MRI technique may develop to the point where it may start to be used in preference to FDG-PET scans, which are more expensive, involve radioactivity, and are logistically more demanding. 

But there is a lot of work to do before this technique can be used in multicentre trials because there is no standardisation yet, and still a lot to learn. &ldquo;Very simple things that can influence the signals are not known yet. Does the patient need to be fastened in a fixed position or not? What influence does the use of contrast enhancement have? Does it depend on the age of the patient?&rdquo;   

Cross-calibration is required before MRI can be used in multicentre trials, to make sure that differences between images from different centres represent real biological differences and not just different machine settings, and this is one of the work packages from the IMI project. &ldquo;We hope with the extra funding we received from the EU we will be able to solve that problem, let&rsquo;s say within one year&rsquo;s time,&rdquo; says Stroobants. I&rsquo;m hoping that within five years we can validate these as biomarkers of response.&rdquo; 

Key to carrying out such multicentre studies will be the imaging platform that EORTC has developed in coordination with Cancer Research UK, which will be used to collect the images centrally and conduct centralised analysis. An imaging &lsquo;warehouse&rsquo; has also been established which will link to information on clinical data, tissue, blood and plasma samples stored in biobanks.   

The challenge is to find the funding to conduct these trials and to convince clinicians that it is worthwhile taking them on. Stroobants says this can be very hard to do, but that larger multicentre trials are needed. &ldquo;It is important that we try to incorporate imaging in trials and that we move away from doing single-centre studies and trying to analyse data in our own way. This will not move the field forward. We need to think bigger, multicentre, standardised &ndash; the time to play in individual centres is over.&rdquo;    


&ldquo;We need to think bigger, multicentre, standardised &ndash; the time to play in individual centres is over&rdquo;    

]]></description>
            <author>Anna Wagstaff</author>
            <category>Cutting Edge</category>
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