Breaking Boundaries in Lung Cancer

25/04/2014 10:12 Number 60

May-June 2014 May-June

breaking boundaries in lung cancer breaking Enriqueta Felip WHAT HAPPENED NEXT? WHAT EORTC turns its attention to the survivors of past trials BETTER, LONGER, CHEAPER The compelling case for integrated care palliative NEUROTOXIC DRUGS NEUROTOXIC Are more doing we damage than realise? we

CancerWorld 60 May-June 2014 pagina_I_cover_v4.indd 1 Cancerworld Shaping the future of cancer care Contents

Editor 3 Editorial Kathy Redmond [email protected] Cancer control is (still) a vote winner

Managing Editor Anna Wagstaff 4 Cover Story

Editorial Coordinator Enriqueta Felip: breaking boundaries in lung cancer Corinne Hall

Editorial Advisors 12 Cutting Edge Matti Aapro Protecting patients’ nervous systems: are we getting Felipe A. Calvo Fatima Cardoso the care–cure balance right? Franco Cavalli Alberto Costa Fedro Peccatori 20 Best Cancer Reporter David Zaridze The patient touts Contributing Writers Marc Beishon, Simon Crompton Alexander Eggermont, Christiane Hawranek 28 Systems & Services Janet Fricker, Marco Maurer Living with or dying of cancer? The case for earlier palliative care Susan Mayor, Peter McIntyre Caroline Robert, Anna Wagstaff 36 Spotlight Publishing Advisor Gillian Grifﬁth What did we learn from the European Partnership for Action Against Cancer? Art Editor Jason Harris 42 Patient Voice Production Top trials group turns its attention to survivors HarrisDPI www.harrisdpi.com 49 e-Grand Round Printed by Graﬁche Porpora How Europe can develop better, cheaper cancer drugs

Cover photograph Jorge Nogueira 56 Impact Factor

Published by Smart therapeutic strategies in immuno-oncology European School of Oncology

Direttore responsabile 60 Newsround Alberto Costa Selected news reports Registrazione Tribunale di Roma Decreto n. 436 del 8.11.2004

All enquiries about Cancer World should be made to: ESO Editorial Ofﬁce Via Turati 29 20121 Milano, Italy e-mail: [email protected] Tel: +39 02 8546 4522 Fax: +39 02 8546 4545 All correspondence should be sent to the Editor at [email protected]

Cancer World is published six times per year by the European School of Oncology. Copyright ©2014 European School of Oncology. It is distributed at major conferences, mailed to subscribers and to European All rights reserved opinion leaders, and is available online at www.cancerworld.org

May-June 2014 I CancerWorld I 1 EDITORIAL Cancer control is (still) a vote winner

KATHY REDMOND EDITOR

member states have just kicked tered to the citizens of Europe – and Mitterand, off the second ‘joint action’ on as we now know, had by chance just been diag- cancer, which is set to run until nosed with prostate cancer. That early invest- 2017. The Comprehensive Can- ment was crucial in raising awareness about the EU cer Control Joint Action (CAN- social and economic burden of cancer, which CON) will pick up where the recently ended then opened the way to several further Euro- European Partnership for Action Against Can- pean initiatives. cer (EPAAC) left off. It will cover many of the EU laws have a significant yet often unac- same areas, but with a greater focus on inte- knowledged impact on cancer control and, while grating cancer services at a regional level and member states continue to resist European inter- on the role of primary and community care – ference in decisions on healthcare spending, areas traditionally considered to be beyond the there is a growing recognition of the potential scope of European collaboration. for learning from each other and adopting com- The benefits of working at an EU level to mon strategies that can be adapted as needed, as improve cancer control were first convincingly most recently demonstrated by EPAAC. What’s demonstrated by Europe Against Cancer, which really positive about its successor, CANCON, ran from 1987 to 2000, with a primary focus on is the increasing focus on quality improvement. raising awareness as well as screening, data col- This spans the entire spectrum of cancer control, lection and tobacco control. Whether this added from prevention through to palliative care, with value can also be realised in the organisation cancer services – including community care, sur- and delivery of cancer services is a question we vivorship and rehabilitation – on the agenda for address in an article (page 36) that looks at what the first time. we have learned from the experience of EPAAC. This programme has the potential to address The unparalleled level of public health invest- the ongoing and unacceptable disparities in ment in cancer made by the EU over the past 30 cancer outcomes that still exist between dif- years was recently showcased at the EU Sum- ferent European countries, and the European mit on Chronic Diseases. Initially this invest- cancer community needs to get behind it. Euro- ment arose from a combination of opportunism pean Parliamentary elections will take place and serendipity. Europe Against Cancer was the in late May, and this gives us all the chance to brainchild of Presidents Craxi and Mitterand, argue for candidates to continue to give cancer of Italy and France, who were looking for ways the attention it deserves at an EU level, and to show that Europe was more than just a free to show their electorates that Europe can still market, and could deliver on things that mat- deliver on things that matter.

May-June 2014 I CancerWorld I 3 COVERSTORY

Enriqueta Felip: breaking boundaries in lung cancer

SIMON CROMPTON

Building a lung cancer team that works seamlessly to do the best for each patient was the biggest challenge in Enriqueta Felip’s career. Her focus today is on increasing collaboration across Europe, which she sees as key if patients are to beneﬁt quickly from the new opportunities offered by personalised therapies.

t’s a clear and crisp morning, but the anything but the clearest evidence. And when it air outside Vall d’Hebron Hospital comes to smoking, she is unequivocal. overlooking Barcelona is far from fresh. “Around 85% of lung cancer would not exist There’s the pervasive smell of tobacco if it were not for smoking,” says Felip, who is I smoke outside the red-marbled hospi- Associate Professor of Medicine at Barcelona’s tal reception as patients stand around getting Universidad Autónoma. “So yes, it deeply wor- their nicotine ﬁx. Around the corner, in less con- ries me when I see people smoking, especially spicuous places, there are people in white coats outside the hospital. As professionals, we have doing the same thing. to give out messages to stop tobacco use every It’s a sight that deeply disturbs Enriqueta day... but it is not easy. It is an addiction.” Felip, head of the hospital’s lung cancer unit. Those working in lung cancer must, perhaps, Felip, who has established her unit as one of have special qualities. Their conviction that Europe’s most important centres for research- things could – should – be different is coun- ing innovative lung cancer therapies, is not a tered by a deep pragmatism about making the woman given to making statements based on best of things as they are, and a non-judgemental

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compassion for their patients. Felip, who is in charge of both management of lung cancer and trials at the hospital, is full of both qualities: there’s a job to be done to help people. “I always tell my patients it’s not their fault. Give up smoking now, yes, but don’t feel guilty.” The last thing her patients need is a guilt- trip. Although advances in the management of non-small-cell lung cancer, which makes up more than eight out of every ten lung cancers, have led to small increases in ﬁve-year survival rates across Europe over the past 30 years, the prognosis for most people diagnosed with lung cancer is still poor. Averaged across Europe, only 13% of people survive for ﬁve years after diagnosis, according to the EUROCARE-5 study published this year. In most cases the disease is already advanced by the time it is diagnosed. Fully 50% of Felip’s patients are diagnosed with stage 4 disease, 30% at stage 3 and only 20% at stages 1 and 2 – so palliative therapy has long been the mainstay of treatment. But things are beginning to change. Specialist care in Barcelona has taken a major upturn since Felip established the thoracic unit from scratch 20 years ago – a time when there was still debate over whether patients with stage 4 disease should be treated at all. And thanks to increasing understanding of the molecular biology of the disease, the landscape of lung cancer treatments is changing radi- cally, giving future patients – and those currently included in clinical trials – the prospect of new life-extending options. One of the main reasons that Enriqueta Felip has remained at Vall d’Hebron is that phase I facilities are available that have allowed her to work on the development of the next generation of drugs for lung cancer. New approaches are desperately needed to improve not only patients’ prospects but also

the perception of lung cancer within oncology JORGE NOGUEIRA

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“They are having mammographies for breast cancer and that is good, but they are still smoking”

as a specialism where the success rate is pitifully In 2007, we started a national collaboration to poor and progress depressingly slow. Lung cancer capture the clinical characteristics of women is the commonest form of cancer globally (13% of with lung cancer, and we thought it would take all cases, according to the International Agency eight to nine years to collect enough women, for Research on Cancer), and the main cause of but we did it within five.” death from cancer (accounting for 1.59 million Felip has noted another alarming trend: peo- deaths a year). Even though lung cancer causes ple with lung cancer are getting younger. The more cancer deaths than prostate, breast and average age people receive a lung cancer diag- colon cancer put together, it struggles in most nosis is 65, but Felip is today treating her young- countries for the attention of politicians, funders est patient ever, a 25 year old. “I don’t have clear and the public, compared to gender-specific can- data on this, but it is certainly true that nowa- cers. As Felip points out, the economic crisis in days I see younger patients with stage 4 disease countries such as Spain has recently made the – 33, 35, 37 years old is not unusual.” fight for funding for translational research even Despite this, and despite her perplexity that more difficult. “We currently have support, but smoking is still blithely pursued by so many, we need to be sure that this will be maintained, Felip refuses to be gloomy. or increased, in the future.” “I think the scenario is changing,” she says. “We The struggle for profile isn’t helped by persist- have some patients who are living a long time, ing attitudes that those with lung cancer have and clinical trials with very impressive results.” only brought the disease on themselves – con- The big game changer in the past decade was veniently overlooking the role of industry in the discovery, in 2004, that up to 20% of non- turning them into addicts in the first place. small-cell lung cancers cases harbour mutations The alarming fact is that lung cancer is on the in the epidermal growth factor receptor (EGFR) rise among women. In the early 1900s, Felip proto-oncogene. Studies have indicated that points out, lung cancer was virtually unheard of treating this subgroup of patients with oral in women. “But since the 1960s it has progres- tyrosine kinase inhibitors (TKIs) that inhibit sively reached epidemic proportions, becoming EGFR extends their progression-free survival the leading cause of cancer deaths among women and improves their quality of life – and is more in the United States, and the third most common effective than chemotherapy as a first-line treat- cause of cancer death in women in Europe.” ment. Testing for the mutation makes it possible The increase may well be solely because to identify which patients will particularly ben- women are smoking more, or it may also be efit from this treatment. because they are more susceptible to the carcin- “This has significantly changed treatment,” ogens in tobacco smoke – several case control says Felip. But things have moved on further. studies have indicated this, though the associa- Research by Felip has revealed the molecular tion is still far from established. mechanisms by which many people acquire “Women tend to be much more aware of other resistance to this treatment, after an initially cancers, such as breast cancer,” she says. “They dramatic response. The presence of an EGFR are having mammographies for breast cancer mutation, designated T790M, is linked with and that is good, but they are still smoking, even resistance, and Felip is now involved in ongoing though lung cancer is the main reason for can- clinical trials evaluating T790M-specific inhibi- cer-related death in some countries. Around a tors. “We are seeing very good responses to this.” quarter of the patients I see in my office are The other big story in lung cancer was the dis- women, and this was not the case ten years ago. covery in 2007 that around 5% of patients with

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non-small-cell lung cancer – often never smokers – have a gene inversion on chromo- some 2 which results in an oncogene called EML4-ALK or the ALK translocation oncogene. Recent preclinical and ﬁrst-in-human studies have demonstrated that an oral ALK-inhibiting TKI achieves a response in almost six out of ten patients. A randomised trial in patients with advanced ALK-positive tumours has shown that treatment with an ALK inhibitor signiﬁcantly extends progression-free survival and improves quality of life when compared to chemother-

apy. New ALK inhibitors are GETTY/ULRICH BAUMGARTEN now in the pipeline, and new molecular markers are continually being identi- “Importantly, these drugs are well tolerated and A disturbing trend. fied, providing potential for more targeted thera- we have seen long-lasting responses,” says Felip. Felip has seen a pies. “It’s a very exciting area,” says Felip. With treatment horizons moving towards indi- steady rise in the That is the present. The future will pre- vidualised molecular approaches, the availabil- proportion of women sent more treatment options. Immunotherapy ity of biomarker testing is now becoming an treated at her clinic, is about to change treatment algorithms for important priority for people with lung cancer. and patients are patients with non-small-cell lung cancer, says “Lung cancer is becoming a paradigm for per- getting younger Felip. Until now, the big idea of using the body’s sonalised therapy, and we need to ensure that own immune system to attack cancer cells has all lung cancer patients in Europe are tested for yielded little of practical value for people with EGFR and ALK alterations, and treated accord- lung cancer. But advances in the understand- ingly. There are also other biomarkers that we ing of the immune response to tumours – par- are beginning to understand are important, such ticularly the programmed death (PD) pathways as BRAF, HER2, and ROS1.” – have led to the development of several new It’s with a view to making the most of these antibody-based treatments. developments in a coordinated way across Recent phase I trials in lung cancer have Europe that Felip has this year accepted the role shown a response in more than two in ten of programme co-ordinator for lung cancer with patients who had already undergone previous the European School of Oncology. She organ- treatment. What is especially exciting is that ised the first ever ESO ‘Lung Cancer Observa- the patients who benefit most from immuno- tory’ at the European Lung Cancer Conference therapy are those for whom ALK- or EGFR- in Geneva this March. Drawing together medi- inhibiting drugs are unlikely to bring benefits. cal oncologists, surgeons, pathologists, biologists, “Nowadays I see younger patients with stage 4 disease – 33, 35, 37 years old is not unusual”

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“Oncology offered the opportunity not just for research, but to have a relationship with people living with disease”

other health professionals and patients, it effec- scans. It’s true that there are a number of aspects tively set an agenda for the ESO lung cancer pro- that should be resolved before this becomes a gramme for the next 12 months. standard of care. We need to know it is cost effi- “We need to push forward with a European cient, we need specialised centres, and we need programme for lung cancer, so I’m very excited skilled radiologists, because interpreting these that in forums like this we have the opportunity images is not easy. But there is currently a lack to share, discuss and work together on the pri- of awareness of the issue among clinical oncolo- orities at a European level.” gists, and no clear guidance on screening strate- European collaboration is, Felip believes, one gies. So for me this is a clear area to discuss at of the biggest challenges facing lung cancer. It is the European level.” already happening to some extent through ESO Felip, a subject editor of minimum clinical and the European Thoracic Oncology Platform, recommendations for diagnosis, treatment and but if surgeons, oncologists, pathologists and all follow-up in lung cancer for ESMO, is today one those specialising in lung cancer could do more of Europe’s most respected names in lung can- to break their national boundaries, collaborate cer. She has achieved her reputation by quiet on trials and share information, important ques- diligence, not by blowing her own trumpet. tions would be answered more quickly. She was born in Barcelona, and has always For Felip, there are clear priorities for action. lived there. She says she went into medicine One is finding ways to involve increasing num- simply because she liked people and liked sci- bers of patients in clinical trials of “these excit- ence – and the subject combined both. After ing new molecules” in early-phase development. completing her medical degree at the Univer- Another is to find ways of integrating the molec- sidad Autónoma in 1987, she decided to take ular profiling of patients into clinical practice a residency in medical oncology at the associ- throughout Europe. “In the next decade, lung ated Vall d’Hebron Hospital: “I knew surgery cancer treatment should change to be the para- wasn’t for me; with oncology there was the digm of personalised therapy; to my mind it is opportunity not just for research, but to have now essential to know whether the patient has a relationship with people living with disease. EGFR or ALK mutations.” This is important: it’s our objective, it’s the Implementing screening programmes to most important thing.” And she was immedi- increase detection of non-small-cell lung cancer ately drawn into lung cancer. During her resi- at a much earlier stage, when it can still poten- dency, she spent three months working at the tially be cured by surgery, is also a priority, Felip thoracic unit of the Memorial Sloan Ketter- believes. Although ESMO advised, in 2010, ing Cancer Center in New York, and on her that trials of low-dose CT scanning of high-risk return and completion of her PhD her then people had not yet produced enough evidence boss, José Baselga (now at Memorial himself), of overall benefit, the ESMO Guidelines Work- encouraged her to set up a thoracic unit with ing Group is currently looking at newer data specialised staff. with a view to updating the guidelines. “Up until then, nobody was doing lung can- “To me it is clear,” says Felip, who serves on cer in my institution,” she says. “There were the Guidelines Working Group editorial board. people treating breast cancer and colon can- “The study from the National Cancer Institute cer, but not lung cancer. So when I finished my in America showed a 20% reduction in lung residency in 1992 there was this opportunity to cancer deaths among current or former heavy build something. smokers who were screened with low-dose CT “For years I was the only medical oncologist

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in my hospital seeing people with lung cancer. early-phase clinical trials: “I have the opportu- But today I have a department with four spe- nity here to work on immunotherapy, T790M cialist medical oncologists seeing more than inhibitors and ALK second-generation inhibi- 400–500 new patients a year. The situation has tors, because we have the facilities.” changed hugely, and I have had great support For the past ten years, tumour boards and from my bosses, but it has not been easy. You multidisciplinary collaboration have been fun- have to ﬁght for excellence in lung cancer, and damental to the Vall d’Hebron approach – and I think specialised professionals are essential if Felip continually emphasises their fundamental you want to achieve the best results.” importance in lung cancer. This is growing as There have been opportunities for Felip to treatments become more advanced, and there is move on, but what has kept her in Barcelona the need for input from the patient and pallia- has been the prospect of building the thoracic tive care teams from the earliest stages. unit even further, the opportunities available for “The biggest challenge I have had in my career trial collaborations, and the good facilities for has been building a good team. It is important “Working closely with pathologists and biologists has become so important in lung cancer”

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“I believe it’s very important to interact with people and share information – it’s part of my job”

for so many reasons. It means we can give the range of their experience with men, and that is best possible attention to the patient. It means important if we are working together. But per- we have support and can share with colleagues sonally, I don’t see any problems with being a in sad situations. woman in oncology.” “Today, we have tumour committee meetings She is reluctant to be drawn on the sub- twice a week. We discuss a tailored approach ject because (being a stickler for evidence) “I for each patient, how to get a good picture of don’t have a clear picture of the situation,” and the extent of disease. We know that for a group acknowledges that her view is dictated by her of patients, combined chemotherapy and radio- own experience. She has a seven-year-old son, therapy achieves good results. We have also and has been lucky to have the constant help learned how to select patients for individualised of her retired parents, who looked after him therapy, so we discuss the best ways to get tis- when he was a baby, and get him to school and sue samples for molecular marker testing. Work- back today. ing closely with pathologists and biologists has “Our lives are very busy. I do a lot of travel- become so important in lung cancer – tumour ling to conferences because I believe it’s very sampling is vital, and the number of markers important to interact with people and share you are looking for is growing all the time. It information – it’s part of my job. It’s not a means we are working with thoracic surgeons problem – I can do it. And it shouldn’t be a in a different way. Even with stage 4 disease, problem for men either.” where surgery wouldn’t otherwise be indicated, So what advice would she offer to a young we sometimes need their involvement to pro- woman wanting a career in oncology? “I think vide samples.” they should work hard, apply for grants, talk to I raise the subject of women in oncology. Felip oncologists in key positions, go to congresses, is, after all, a high-flyer in a male-dominated be involved. They should compromise.” I’m world. She was also a panellist at the ESMO intrigued she feels that compromise should Women for Oncology (W4O) Forum at the be important to the work of oncologists, and 2013 European Cancer Congress. W4O aims then become puzzled when she uses the word to help female oncologists access leadership again, as I ask her about the greatest influ- positions, in the light of a recent ESMO survey ence on her career. which indicated that less than 15% of women “Compromise,” she says. “Getting involved. oncologists have a leadership position. Improving our patients’ profile. Learning every So does she think that women face problems day.” I ask her to explain what she means by in reaching the top in oncology? Her answer is compromise, and then we work out that we are guarded. Both men and women face the challenge experiencing one those linguistic misunder- of having enough time, especially time for a fam- standings that can cause complications at inter- ily, says Felip. She agrees that some women defi- national level. The Spanish word “compromiso” nitely have problems with childcare and taking a means commitment in English. break in their career, but argues that it is families Far from saying that it is important to adjust that need support, not necessarily women. your own views according to those of oth- “We have a lot of women oncologists in Spain ers, she is asserting the opposite – the need and in Europe, and many in very senior positions, to pledge oneself to a cause. And if there is and I don’t think we are under-represented,” she a cause that needs the commitment of people says. “I think W4O is a good initiative, because like Felip – bringing profile, knowledge and it is good that women physicians can share the hope – it is lung cancer. n

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Protecting patients’ nervous systems Are we getting the care-cure balance right?

MARC BEISHON

The debilitating impact neurotoxic drugs can have on patients’ long-term quality of life has been systematically underestimated. Can oncologists do more to pick up potential symptoms before they become irreversible?

ancer patients about to start treatment, but it can manifest itself ment that can prevent it or do chemotherapy are often faced strongly just after treatment, and can much to alleviate it. It affects C with a long list of possible impact very heavily on a patient’s life 30–40% of patients across side-effects, depending on the type of for a long time, if not indeﬁnitely. all neurotoxic drugs, but with cancer and the drug or drug combina- CIPN is a condition that mainly some agents up to 70–90% of tion involved. They may also be facing damages the long nerves that extend patients may be affected. side-effects from surgery and radi- to the feet and hands – a ‘stocking and This presents a serious obsta- otherapy, so there is a lot to take in. gloves’ distribution – and can affect cle to successful treatment and, Some side-effects, such as neutrope- sensory or motor function, most often like all long-term effects, the prob- nia, pose a serious risk, but only dur- the former, with symptoms such as lem is becoming more widespread ing treatment. Others, such as heart numbness and shooting pains. Some as the population of cancer patients damage, may be irreversible, and have people are so severely affected that expands. While it only occurs in cer- a lifelong impact on the quality of a they may regret having the curative tain classes of chemotherapies used patient’s life. Chemotherapy-induced cancer treatment that caused it. Its in some cancers, the treatments are peripheral neuropathy (CIPN) is one mechanisms are not well understood, among the more common, such as of these. Not only can it cause a range with little indication of who will suf- taxanes for breast cancer, and plati- of mild to severe problems during fer most, and there is no current treat- num agents for colorectal tumours

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Common symptoms Cavaletti explains that the incidence of CIPN is much more frequent with the older chemotherapy drugs, although some of the newer biological therapies can also be neurotoxic. Numbness is the typical sensory symptom – being unable to feel heat or cold, or a pin prick. Motor symptoms include unsteadiness on one’s feet, or even being unable to walk far at all, in more severe cases. There are also pain symptoms: neuropathic pain is one of the most complicated pain types managed by neurologists or pain specialists, says Cavaletti. What is a puzzle with CIPN is that, while it is known that nerve endings start to be damaged and can get pro- gressively worse with chemotherapy, currently there is no way to tell what an individual’s risk is for developing neuropathy. “If I have ten patients, maybe two will develop severe neuropathy, four will have nothing and the rest some degree of symptoms – but we haven’t been able to identify the risk factors for who will get severe problems,” says Cavaletti. Also unexplained is when CIPN will take hold, or what the symptoms will be. Dawn Storey, a CIPN has moved up the side- consultant medical oncologist at the effects agenda in recent years, says Beatson West of Scotland Cancer Cen- (see table, page 14). Guido Cavaletti, a neurologist at tre in Glasgow, who has researched Oncologists are often Milan-Bicocca University, Italy, who CIPN as part of her strong interest in faced with a difﬁcult has been treating and research- supportive oncology, says: “The onset decision about whether ing this condition for more than 20 of acute neuropathy varies from patient to stop or alter potentially years. “That’s because patients have to patient. Some get symptoms early life-saving treatment, and prob- been asking for a better quality of on and have to stop treatment pre- lems with neuropathy are a com- life as oncologists have been able to maturely, whereas some get through mon reason for patients themselves improve survival, and there has been treatment without many symptoms, deciding to stop therapy. Where a particular push for more attention but then may develop severe pain and severe problems arising from to CIPN in the US, where patients disability after treatment stops – that’s nerve damage do develop, health tend to be more demanding, and as what we call ‘coasting’, and it is often professionals also face the challenge other side-effects can now be better seen with platinum drugs.” of how to help patients to manage managed,” he says. “But we still have Although things do get better for

SHUTTERSTOCK the symptoms. virtually nothing for CIPN.” the majority of people over several

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“If someone cannot feel the pedals in a car, they can’t drive, or they may be too unbalanced to walk far”

months, she adds, there are those quite warm outside.” bedclothes over them, Sto- who are left with long-term life-limit- If someone cannot feel rey adds. “I got interested ing symptoms, and little is understood the pedals in a car, they in CIPN because I was about why patients develop different can’t drive, or they may disheartened that people symptoms at different times, and why be too unbalanced to were being cured of their some and not others are left with long- walk far. colorectal cancer, but I term problems. Storey says that oxali- was seeing them in their What is clear is the harm that can platin is a drug that tends to 50s or early 60s being unable be done to patients, who can suffer a have different symptoms during to dress themselves, walk, write range of debilitating conditions. They the acute, treatment phase and post- or drive safely, and losing their jobs may be relatively minor – Cavaletti treatment. In the acute stage, people because of their disability – that’s not mentions women who have had taxa- can become hypersensitive to cold success to me.” nes, who report they can no longer wear and experience difﬁculty swallowing – As Cavaletti also says: “What we have elegant shoes to the theatre as they feel these usually go away in a few days, now are cancer survivors living with too tight. “But imagine you are wear- she notes. “Long term chronic symp- severe damage. It’s a small group but we ing boots and gloves permanently, or if toms tend to be the typical neuropa- need to eliminate it. For example, there you feel you have to wear gloves but it’s thy, like numbness, shooting pains, is a young psychologist colleague here pins and needles and problems with who had testicular cancer two years ago NEUROTOXIC DRUGS actions such as fastening buttons, and was cured with cisplatin – but now writing and even toileting, as patients he cannot work as he can’t hold a pen. A variety of anti-cancer drugs oper- can’t feel the toilet paper.” Other drugs And he’s only 32 years old.” ating via different mechanisms have such as taxanes tend to have similar the capacity to damage patients’ symptoms in both phases, although An underestimated problem nerves, including: paclitaxel can cause a speciﬁc acute Knowledge about CIPN’s incidence Platinum analogues pain syndrome during treatment that also appears to be lacking, although Cisplatin affects the hips and trunk. it is almost certain that long-term Carboplatin One group of cancer patients who effects are underreported both in Oxaliplatin have a particularly high incidence of clinics and in trials. “Estimates of Antitubulins CIPN are those with multiple mye- the proportion of patients affected Paclitaxel loma. In this group, the nerve con- by functional impairment due to Docetaxel dition is not just a side-effect of the neuropathy two years after the com- Ixabepilone biological therapies, bortezomib (Vel- pletion of treatment for colorectal Vincristine cade) and thalidomide, but can also cancer are about 4%, but it’s probably Proteasome inhibitor develop as a complication to the mye- much higher than that,” says Storey. Bortezomib loma itself. About 30% of patients are “In audit work I have done it seems Other affected and it is a common topic of that about 20–30% have some sort of Thalidomide discussion at support groups. People impairment – and the disparity arises report some awful symptoms of being because published studies focused Source: Adapted from Guido Cavaletti and unable to walk, pain and sleeplessness more on the anti-cancer effect of the Paola Marmiroli (2010) Nature Rev Neurol at night, and feelings of hopelessness. chemotherapy rather than reporting 6:657–666 Pain can be extreme to the extent long-term side-effects, which some that some patients can’t bear to have oncologists rate as less important.”

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GRADING OF NEUROPATHY: NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE) v4.03

ADVERSE EVENT DESCRIPTION GRADE 1 GRADE 2 GRADE 3 GRADE 4 GRADE 5

Peripheral motor Inﬂammation or Asymptomatic; Moderate symp- Severe symptoms; Life-threatening Death neuropathy degeneration of the clinical or diagnos- toms; limiting limiting self-care consequences; peripheral motor nerves tic observations instrumental ADL ADL; assistive urgent interven- only; intervention device indicated tion indicated not indicated

Peripheral sensory Inﬂammation or degen- Asymptomatic; Moderate symp- Severe symptoms; Life-threatening Death neuropathy eration of the peripheral loss of deep toms; limiting limiting self-care consequences; sensory nerves tendon reﬂexes or instrumental ADL ADL urgent interven- paresthesias tion indicated

Dysesthesia Distortion of sensory Mild sensory Moderate sensory Severe sensory –– perception, resulting alteration alteration; limiting alteration; limiting in an abnormal and instrumental ADL self-care ADL unpleasant sensation

Neuralgia Intense painful sensa- Mild pain Moderate pain; Severe pain; limit- –– tion along a nerve or a limiting instrumen- ing self-care ADL group of nerves tal ADL

Paresthesia Functional disturbances Mild symptoms Moderate symp- Severe symptoms; –– of sensory neurons toms; limiting limiting self-care resulting in abnormal instrumental ADL ADL cutaneous sensations of tingling, numbness, pressure, cold and warmth that are experienced in the absence of a stimulus

The earlier version of this grading scale (CTCAE v3) was the one used in most clinical trials and was strongly criticised as not reﬂecting patients’ experiences. This version (v4.03) contains many amendments, but the continued reliance on how patients interpret the terms “mild”, “moderate” and “severe” remains controversial Instrumental ADL – preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc Self-care ADL – bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden Source: Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf

Another contributing factor is partly a 3, which is ‘severe interference with 3 because functional impairment of result of the way that CIPN is assessed, daily living’. But distinguishing this any degree matters hugely to patients.” she adds. Long-term studies used in from grade 2 – ‘moderate’ limits on In practice, this has probably guidelines have adopted the US NCI’s daily living – can be an artificial judge- resulted in considerable harm. “From Common Terminology Criteria for ment, says Storey, so “CTCAEv3 is the point of view of most oncologists, Adverse Events (CTCAEv3) – one of now recognised as unfit for purpose in if it’s grade 3 the drug is stopped, but if several tools that can be used for CIPN assessing CIPN. CTCAE v4 is a slight grade 2 it tends to continue to be given – and most often significant neurotox- improvement, but I would still encour- – so oncologists have probably been icities have been reported only at grade age investigators to report grade 2 and giving far too much oxaliplatin and

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caused more nerve damage than was example did her work on CIPN at the oncologists the confidence that, for realised. There is no official guidance Edinburgh Cancer Research Centre, example, mild symptoms are not pro- on applying the criteria and oncologists where there are palliative and sup- gressing so there is no need to move tend to be biased in favour of giving a portive care specialisms – Caval- to a lower or less frequent dose, or drug rather than stopping it, because etti says that up until the last another agent, or discontinue of course they want to prolong life or few years it was common chemotherapy. prevent a cancer from coming back.” in some countries for “It’s about managing the A recent indication of the extent neurologists to carry out patient and not the side- of long-term CIPN in people given much of the research on effect that emerges,” he oxaliplatin for colorectal cancer was CIPN, and indeed to see says, noting that when reported at the EORTC survivorship patients, when oncolo- thalidomide first became summit (see also page 42), by Lon- gists should really have available for trials in mul- neke van de Poll-Franse, from Til- been doing more. tiple myeloma, there were burg University in the Netherlands. “Oncologists should be pre- concerns that it would need A quality of life questionnaire was pared to properly recognise and score specialist neurologic monitoring. “Now, sent to more than 1600 patients, on the severity of CIPN and not just in work on producing an improved average six years after diagnosis, 500 send patients to us once they are assessment tool, it is clear that in 99% of whom had received chemotherapy. sure there is neuropathy – that’s not of cases a clinical evaluation is suffi- About one in three of those who had very useful for the patient.” Cavaletti cient – you don’t need instrumental been treated with oxaliplatin reported makes a comparison with neuropathy evaluation.” tingling, painful hands or feet up to caused by diabetes. “I don’t see these But that clinical evaluation must ten years after diagnosis, and indi- patients unless they are very different comprise two elements, he adds – cated that this CIPN “tremendously from usual – they are well managed both the doctor’s assessment of nerve impacted on quality of life” across by diabetes specialists, and we need changes and the patient’s own report, scores for social and physical func- to achieve the same with oncologists, although initially it can seem that the tioning, and overall health. some of whom are wary of a neurologi- different viewpoints can be hard to Oncologists who specialise in can- cal exam – they think it is complicated reconcile. “But it is the same problem cers such as colorectal and multiple and difficult but that’s not true.” from two perspectives, and is particu- myeloma will tend to be more The critical point in manag- larly important as we have no objective experienced with CIPN, as ing CIPN during treatment tools to say measure pain in a patient. they see it most often, and is not to wait until it’s too We don’t have an operational patient- they may therefore stop late: the treatment should reported outcome measure in CIPN or reduce doses and be changed before symp- yet, but we are working on it and com- switch to alternatives toms become so severe bining it with clinical evaluation is a earlier. But there needs that they are irreversible. goal for our research.” to be both a refinement In the absence of effec- Asking patients about symptoms, of the assessment tools tive treatment for CIPN and ensuring they understand the and greater interest in neu- itself, this is about the only potential long-term implications, is ropathy among oncologists, primary strategy of value, says particularly important, as studies have according to Cavaletti. Cavaletti. He agrees that the NCI’s shown that patients often don’t like to While there are the usual centres CTC scale is inadequate and a more mention side-effects for fear that their of excellence in cancer – Storey for robust method is needed to give treatment might be stopped. “These patients are well managed by diabetes specialists – we need to achieve the same with oncologists”

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“Part of the answer lies in improved communication with patients, including at the start of treatment”

As Storey adds: “We also know from point is echoed by van de Poll-Franse, oxaliplatin by infusing calcium and research that patients are more likely who was involved in the study of magnesium, but a recent trial he led to disclose their symptoms to a nurse patients treated for colorectal cancer. has proved negative (JCO doi:10.1200/ than to a doctor, who patients often She agrees that quality of life should be JCO.2013.52.0536). assume is more focused on cancer part of the discussion when consider- The NCI guidelines are unable to management than on issues such ing oxaliplatin as an adjuvant therapy. offer any recommendation on preven- as fatigue, anxiety, depression and There are various treatments that tion, due to the lack of high-quality CIPN. And, patients who are cured can alleviate symptoms in some peo- consistent evidence. often don’t want to sound ungrateful, ple, and an increasing number of As Cavaletti laments, there is saying they can put up with CIPN – trials are investigating which work much more interest in funding work but I know some who have said they best for CIPN. Antioxidants, antide- on CIPN in the US, where he says would not have taken the chemother- pressants, anticonvulsants (such as that the National Institutes of Health apy if they had known it was going to pregabalin), opioids and analgesics, (NIH) has launched a programme to make them feel that bad. But most including topical substances such as discover the mechanisms that cause won’t tell you and they certainly won’t menthol, and acupuncture, are all in it, and there have also been meetings if you don’t ask.” the frame. Storey has trialled menthol on improving outcome measures in cream and found a good response to clinical trials, which have had strong Improving evaluation pain, although she says it may worsen participation from patient associa- Cavaletti is principal investigator for it in some cases. tions. “To my knowledge there is the CI-PeriNomS group, which is test- Newly published guidelines from nothing like this in Europe and it’s a ing existing scales for assessing CIPN ASCO recommend treatment with gap we need to fill,” he says. together with quality of life tools, the antidepressant duloxetine, Storey agrees, saying that including the EORTC’s QLQ (qual- and suggest that gabapentin, research funding in pallia- ity of life questionnaire), with the aim and a compounded topical tive and supportive care of producing a standardised outcome gel containing baclofen, has been curtailed in measure, and a new cohort of patients amitriptyline HCL, and the UK, and that not is being assessed this year. “We had ketamine may also be all cancer centres have our first meeting in 2007 and while used, as their utility has the multidisciplinary we have expanded the study group to been shown in other neu- resources of Edinburgh, 20 centres, most in Europe and some ropathic pain conditions. where there is access to in the US, we have been unable to get Finding biomarkers and neurologists, anaesthetists any support for our work,” he says. genomic information that can and palliative care colleagues Most of the researchers are neurolo- predict who will suffer most is also a for problematic cases. In fact she gists, but more oncologists have come research avenue, and of course more says that some of the most useful on board, he adds. personalised treatment will cut the help that her patients receive is from Storey, who has been involved with number of patients receiving neuro- colleagues in occupational health. In the group, feels part of the answer lies toxic drugs in the first place. a pilot in Glasgow they are helping in better communication with patients, Genetic information may indeed be with adaptations in the home, such including at the start of treatment. “I the best path, as Charles Loprinzi, a as foam handles for kettles, elastic discuss drug options at length with medical oncologist at the Mayo Clinic shoelaces, temperature checks for patients, asking about hobbies, such in Rochester, US, and an expert in bathwater. “We must talk to patients as knitting or playing an instrument, CIPN, has recently noted. There were about CIPN because they are often that CIPN could adversely affect.” The hopes for a prevention approach for battling on their own,” she says. n

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The patient touts

Christiane Hawranek and Marco Maurer, freelance print and radio journalists, won a Best Cancer Reporter Award for their exposé of the agencies that exploit foreign patients seeking treatment for cancer and other serious conditions. They published this piece in Die Zeit, and the story was also broadcast on radio by Bayerischer Rundfunk.

uslana Fadiwa is dancing, watched by her grandpar- R ents. Klavdia Petrowa, 65, and her husband Leonti Fadiw, 62, are in a gymnasium in the city of Yoshkar-Ola, 700 kilometres east of Moscow. While their eight-year-old granddaughter competes in her ﬁrst major gymnastics event, they are talking about a place that they have never been to: Düsseldorf. “Do you remember how I walked round the Kremlin in Kazan three times in the hope that Ruslana would get well again in Düsseldorf?” Klavdia says

to her husband. Ruslana had cancer BR/ ALEXANDER STAHL, and was treated in the University Award winners. Christiane Hawranek and Marco Maurer Hospital in Düsseldorf when she was four years old. from the German town of Lüden- lawsuit because they believe he vast- “Yes, of course,” replies Leonti, and scheid: he certainly helped save their ly overcharged for his services. The the couple go on to describe their granddaughter’s life, but the family amount involved is some €45,000. dealings with a medical travel agent are now embroiled in a long-running Medical travel agents arrange for

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patients from other countries to be treated in German hospitals; they trade on the outstanding reputation of German healthcare. Most agents have roots in their patients’ home Exposed. This well-researched piece of investigative country; their work includes find- journalism is adding to pressures to regulate the agencies ing the patient a suitable hospital in that make money from patients seeking to travel to Germany, agreeing costs and dates, Germany for medical treatment translating medical reports into Ger- man and providing an interpreter during the patient’s stay in Germany. A noble occupation, it might seem. But examples from German hospitals show that agents do not always deal fairly with their cus- tomers. One doctor tells of an agent who allegedly charged the patient twice the actual cost of the hospital treatment. The head of the Coordinating Of- fice for International Patients at Düsseldorf University Hos- pital says she has had “dis- tasteful experiences” with the agencies. Bavaria’s Secretary of State for the Environment and Health says she knows of “only one or two agencies that are perhaps reputable”. A member of the board of a state chamber of physicians re- Sankt Augustin, where fers not to “medical travel agents” he is a researcher in the Department attempts to attract sheikhs and oli- but to “patient touts”. Frank Ulrich of Economics. Juszczak has been garchs. No mention is made of the Montgomery, President of the Ger- studying medical tourism for the last fact that less-well-heeled patients, man Medical Association, asserts ten years. On his desk are the latest such as Ruslana Fadiwa, are also that there are “dubious agents” who research figures, which show that being persuaded to come to Ger- ‘import’ patients into Germany. A some 200,000 international patients many. And virtually no one speaks nurse at a German university hospi- came to Germany in 2012. They of the agents who have interposed tal goes so far as to say that some contribute about a billion dollars a themselves between hospitals and agents “stop at nothing”. year to the tight budgets of German patients. Juszczak says that about Jens Juszczak is sitting in his of- hospitals, which is why talk of medi- two-thirds of all hospitals that treat fice – room E108 on the first floor of cal tourism usually paints a positive international patients make use of the Bonn-Rhein-Sieg University in picture, and points to the clinics’ such agents. “If you pay the money today, you can be in Germany tomorrow”

May-June 2014 I CancerWorld I 21 BESTREPORTER

Medical travel agents, like estate agents, work on a commission basis – they receive payment for each patient that they introduce. The market is not transparent. Juszczak states that up to 1,000 agents work with German hospitals; to do their job they need nothing but a mobile phone, contacts abroad and knowledge of the relevant language. Any- one can call themselves an agent.

Doctors and nurses are usually un- SERGEY KOZMIN/AGENTUR FOCUS FÜR DIE ZEIT aware of what agents have agreed with their clients. This is confirmed by Marlies von Borries, head of the Coordinating Office for Internation- al Patients at Düsseldorf University Hospital: “No, we don’t know that,” she says. The day after Ruslana’s competition, her father, Roman Fadiw, is sitting at the kitchen table in the bright two-bedroom flat on the fourth floor of the five-storey building in Yoshkar- Ola where he lives with his wife Nadezhda and their two children, Ruslana and Serafin. In front of him Ruslana Fadiwa, who was treated in Germany for Burkitt’s lymphoma, with her parents Roman and Nadezhda is a calculation of costs amounting to €100,000, drawn up by the medical – please don’t touch.” Roman Fadiw former USSR people usually use the travel agency in Lüdenscheid. He pauses in front of the plant and says: Russian search engine Yandex. Typ- has sent his daughter to play in her “living in Russia is alright if you are ing “treatment in Germany” into Yan- bedroom – he doesn’t want her to lis- in good health and don’t get ill.” dex brings up virtually nothing but ten to the story of her illness. In Feb- Just four months after the initial names of medical travel agents – the ruary 2008 Ruslana was constantly investigation in Yoshkar-Ola, and hospitals themselves are not men- complaining of stomach ache. The after several misdiagnoses in Mos- tioned. The Fadiws decided on the children’s hospital in Yoshkar-Ola cow hospitals (“oncological disease agency in Lüdenscheid because its attributed the pain to a gastric cyst – ruled out”), the Fadiws discovered website looked professional – there the first misdiagnosis, as the Fadiws what was wrong with their daugh- were pictures of the owner with now know. ter: Burkitt’s lymphoma, a cancer confidence-inspiring men in white Ruslana’s father insists on taking of the lymph glands with good pros- overalls. Towards the end of July the reporters to the hospital at 104 pects of a cure if treated promptly. 2008 they telephoned the agency Volkova – a red and grey building Because the Russian doctors had and were told: “If you send me the erected in the heyday of the Eastern taken four months simply to arrive at money today, you can be in Germany Bloc. Brown-stained mattresses are a diagnosis, the family had by now tomorrow.” “I can get the money to- stacked high, out-of-date drugs lie lost trust in Russian hospitals. They gether,” replied Fadiw. By western about in battered boxes, and in one searched on the internet for one in European standards the Fadiws are corner stands a plant with a note at- Germany. According to Juszczak, an ordinary middle-class family, nei- tached to the pot: “This plant is sick this is what most people do; in the ther oligarchs nor desperately poor –

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The hospitals looked about for extra sources of income and discovered patients from abroad four of them in a two-bedroom flat, The agency responded to questions they seek to attract at medical fairs bunk beds for the children, wash- from Die Zeit through its lawyer, in Dubai or Moscow. These patients ing machine; the father, Roman, who stated that the company had are self-payers; their money goes owns four fashion boutiques in the also paid the family’s accommoda- direct to the hospital and can be city. The bank gave them a loan of tion costs and that this was the rea- used, for example, to buy new medi- €80,000. They also borrowed money son for the large bill. The Fadiws dis- cal equipment, from which German from friends. To meet their debts pute this. They say they stayed with patients funded by health insurers and pay off the first loan, they later acquaintances in Düsseldorf and also benefit. The law acknowledges had to take out a second one, which they produced photos of a student that the prices paid by self-payers they have still not paid off. flat near the hospital which they are freely negotiable. But profiteer- When they arrived in Düsseldorf, say they paid for themselves. Even ing – which is defined as occurring the family say they felt “helpless and when reminded, the lawyer sent no when the payment is twice the mar- speechless”. The interpreter provid- proof of additional costs, but only ket value of the service provided – is ed by the agency was unable to cope the invoices from the hospital and frowned on. Judges assume that the with medical terminology; in meet- the interpreter, amounting to some profiteer is exploiting the weak situ- ings that the Fadiws had with a sen- €45,000. In his letter, the lawyer ation of his customer, which in the ior doctor at the university hospital, proposed that the parties “await the case of Ruslana Fadiwa was probably he frequently said: “I can’t translate judicial verdict”. true – her parents feared for their that – I don’t understand it.” Roman Every German hospital receives a daughter’s life. Fadiw tried to complain to the agen- fixed sum for a particular treatment The Coordinating Office for In- cy, but whenever he phoned he was – €1,500 for a birth without com- ternational Patients at Düsseldorf told that the deposit of €100,000 was plications, around €100,000 for a University Hospital is prepared for not enough and he needed to send liver transplant. Part of the purpose clients from abroad; on the way to more money. Fadiw became suspi- of these flat-rate payments, which the office we pass a large blue sign cious. He asked the agency whether have been in place for ten years, is in Cyrillic and Arabic script. Mar- he could see the hospital’s invoices. to reduce the length of hospital stays lies von Borries, who is in charge On being told that this was not pos- and cut costs. Previously a hospi- of the department, admits that her sible, he made further enquiries at tal could boost its profits by keep- hospital works with agencies, but the hospital’s International Office. ing patients for as long as possible; says that it has become more cir- He discovered that the hospital’s charges were based on the number cumspect – and it no longer does bill had amounted to about €40,000 of days spent in hospital. Under the business with the particular agency – far less than the initial payment flat-rate system, by contrast, hospi- in Lüdenscheid. Moreover, a year Fadiw had made. In addition, the tal staff need to ensure that patients and a half ago the hospital started Fadiws had viewed the €100,000 as a do not exceed the “maximum length sending out its invoices in duplicate: security deposit – if any money were of stay” – if they do, the health in- one copy to the agency, the other to left over, they thought they would get surer reduces the amount it pays. the patient. Von Borries repeatedly it back, less the commission. This This has resulted in empty beds and emphasises that her hospital has was confirmed by the district court forced the closure of some hospi- adopted a “special approach”, since of Hagen in a partial judgment pro- tals, especially in rural areas. it pays no commissions. nounced in 2010. The judge declared, The hospitals looked about for Experts such as the economist Jens “No lump-sum payment was made extra sources of income and discov- Juszczak maintain, however, that (…) but a deposit, a lodgement.” ered patients from abroad, whom many hospitals pay “the commissions

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The doctor wondered what the agent had promised his patient to persuade her to come to Germany that are usual in the sector”. This she uses the same phrase repeatedly: cial Union (CSU), believes it is in- means that agencies receive “bounty she died “totally alone”, says Laube, appropriate for the “grey area” of payments” if they send foreign pa- looking over her shoulder as if to re- the medical travel agencies to be in- tients to these hospitals. Many also assure herself that she is not being cluded in the glossy white and blue charge the patient a fee – usually overheard. If her boss got to hear brochures used all over the world to 15% of the treatment costs. So the that she had been talking about in- publicise Bavaria as a centre of med- agencies cash in twice – they get paid ternal hospital affairs, she could be ical excellence, and attract patients by the patients and by the hospitals. fired. “Totally alone”. such as the Fadiws to Germany. The Towards the end of 2011 the Kiel Nevertheless, Laube wants to talk. Secretary of State, who is herself a district court ruled that the com- She no longer wishes to be part of a doctor, therefore plans to set up a mission agreement between hospi- system in which patients from other special government office that will tal and agent was itself unethical. countries are at the mercy of medi- provide reliable information to inter- A medical travel agent had sued a cal travel agents, hospital adminis- national patients seeking treatment university hospital in north Ger- trators and the pressure to cut costs. in Germany – thereby bypassing the many that had promised the agent “Seeing how my patient died thou- agencies. The office is set to open a 22% commission for each patient, sands of kilometres away from her this year; the Bavarian government which it had not paid. “The court family was devastating,” says Laube. has funded the project to the tune found that the agreement was in- The woman had pancreatic cancer. of €5 million. valid, because it damaged the re- “At least a month before her death Bavaria’s Minister President Horst lationship of mutual trust between it was clear that we were never go- Seehofer (CSU) has himself spoken doctor and patient through inappro- ing to cure her.” But her family had out in favour of the scheme. Roman priate commercialisation,” explains no money to come and visit her. The Fadiw, too, sees it as a good way of Norman Langhoff, a Berlin lawyer doctor wondered what the agent had getting patients to come to Germa- who specialises in medical law. promised his patient to persuade ny. If this option had been available Die Zeit is in possession of letters her to come to Germany in the first when Ruslana was diagnosed, he from a number of German hospitals place. She asked the senior consult- might not be having to go to Hagen that contain promises of such com- ant whether there were any rules for in April for the next court hearing*. missions. For Ulrich Montgomery, medical travel agents and their pa- When asked whether he had not President of the German Medical tients. “No”, was the concise answer. perhaps acted somewhat naively and Association, these represent “clear There are no rules governing what overhastily back in 2008, he replies cases of referral for payment, which medical travel agents do, and no that he would have grasped at any is prohibited under the medical quality control either. The Green straw to save his daughter. “Wouldn’t profession’s rules”. Party’s spokeswoman for preven- you do the same?” n Julia Laube [name has been tion and patient rights, Maria Klein- changed] is no longer prepared to Schmeink, wants to change that, *The court ruled in favour of the family last keep quiet. She is a young assis- and is calling for a certification September, and they received a refund of tant doctor at a university hospital scheme for agencies, on the grounds around €50,000. and understands the importance that foreign patients are “too easily This article was first published in Die Zeit on of international patients to her em- exploitable”. 11 April 2013, and is reprinted by permission, ployer. But when she speaks of the Melanie Huml, Secretary of State © Die Zeit 2013 Russian woman whose treatment in in the Bavarian Ministry of Health Cooperative research by BR-Hörfunk and ARD- her clinic was arranged by an agency, and a member of the Christian So- ‘Report München’

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Living with cancer or dying of cancer? The case for earlier palliative care

PETER MCINTYRE

People do better throughout their cancer journey when their physical, psychological and spiritual care needs are attended to. But how do we overcome entrenched mind sets that still resist integrating palliative and oncologic care?

hilip Larkin, associate profes- The value of palliative care early in earlier involvement of palliative care sor in clinical nursing at Uni- the progression of cancer is becoming in the overall care of certain groups P versity College, Dublin, began increasingly clear. The World Health of patients meant they would have working as a palliative care specialist Organization, and the European and a better outcome in terms of quality 25 years ago in rural West of Ireland. US oncology societies ESMO and of life and the quality of their death. “What was called palliative care then ASCO, all advocate its early introduc- End of life care was still part of the was very much terminal care. We tion alongside treatments designed to spectrum, but we started to see much were called at the end of life, liter- increase survival. earlier referrals, seeing people not ally hours and in some cases minutes In 2002, the WHO changed the def- within hours of their death but prob- before death. It was not unknown to inition of palliative care to “[care that] ably within weeks or months.” arrive at the house and find that the improves the quality of life of patients patient had already died.” and families who face life-threatening Research supports Larkin contrasts his clinical work illness, by providing pain and symp- early intervention today at Our Lady’s Hospice and Care tom relief, spiritual and psychosocial The most cited research comes Services in Dublin with the marginal support, from diagnosis to the end of from Jennifer Temel and colleagues role that palliative care was afforded life”. The definition specifies that pal- at Massachusetts General Hospi- in a general hospital setting when he liative care “is applicable early in the tal in Boston, where 151 patients began. “We used to go into hospital course of illness, in conjunction with with metastatic non-small-cell lung predominantly to visit cancer patients. other therapies that are intended to cancer were randomised to receive If the oncologist was on his ward round prolong life, such as chemotherapy or early palliative or standard oncologi- we were not allowed on the ward. He radiation therapy…” cal care (NEJM 2010, 363:733–742). did not want to see us; he did not want Larkin strongly supported the Those who received early palliative to know. That has all changed.” change. “We started to see that the care reported better quality of life,

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while fewer had depressive symptoms. The most startling finding was that the patients who received early palliative care survived more than two months longer on average than those on standard care (11.6 months vs 8.9 months), despite receiving less aggressive treatment. Quality of life in the palliative care group actually improved over the trial period, comparable to improvements seen in patients who respond to cisplatin-based chemotherapy – “a formidable challenge,” Temel observed, “given the progressive nature of the illness.” Temel speculated that poor quality of life and depression may themselves be factors leading to earlier death. It was also possible that integrating palliative and oncologic care ensured the best possible anticancer therapy, especially during the final months of life. A larger study, conducted at Prin- cess Margaret Cancer Centre, Ontario, was reported by Camilla Zimmermann and colleagues in the Lancet in February 2014. Oncology units were randomised to deliver early specialised palliative care or standard oncological care to 461 patients with advanced cancer. Specialist intervention included a multidisciplinary assessment, telephone contact from a palliative care nurse, a monthly outpatient clinic and a 24-hour on-call service. The trial measured change in quality of life, symptom control and satisfaction with care. After three months, the change in scores from the baseline were significantly different between the two

ALAMY/ DARTMOUTH-HITCHCOCK MEDICAL CENTER ALAMY/ DARTMOUTH-HITCHCOCK MEDICAL groups for Quality of Life at the End

May-June 2014 I CancerWorld I 29 SYSTEMS&SERVICES

“We need to adopt a grey scale of curative therapy, supportive care and end of life care” of Life (QUAL-E), and satisfaction fessor of palliative care at King’s Col- surgery and radiotherapy in 2012. with care (FAMCARE-P16), though lege London, agrees that palliative In 2013 his doctors discovered lung not for symptom control (Edmonton care is about helping people to live. metastases. After two rounds of spe- Symptom Assessment System, ESAS) “I find the term ‘end of life care’ a bit cialised surgery, using a laser knife, or for communication with healthcare misleading for people, and frighten- Wilson has since been tumour free – providers (CARES-MIS). The change ing. A lot of what we do is helping although not cured. in the score for the Functional Assess- people live well despite a chronic or “The black and white line between ment of Chronic Illness Therapy- deteriorating illness or knowing they curative and palliative care has got to Spiritual Well-Being (FACIT-Sp) are dying. If you manage the symp- go. We need to adopt a grey scale of scale – which was the primary end- toms, and help people to live as well curative therapy, supportive care and point – was also better in patients as possible, when it comes to the end end of life care. We need to get the receiving palliative care than the con- of life they have done the things they medical community on board. Being trol group (an improvement of 1.60 wanted to and spoken to the people able to cross these grey boundaries is compared to a deterioration of -2.00), they wanted to speak to.” very important. but the result was not statistically sig- The question of whether someone “Many patients who are not curable nificant. At four months, however, is living with cancer or dying from it are receiving tyrosine kinase inhibi- the improvements in the interven- becomes less clear-cut as treatments tors and antibodies which can extend tion group were significant on all extend life. life and alleviate disease symptoms scales except for communication with Roger Wilson, president of Sar- and side-effects. Their cancer is not healthcare providers. coma UK, was diagnosed with a soft terminal and may never become ter- Both sets of researchers called for tissue sarcoma in 1999 and with minal. In this context, supportive further studies to address these issues. regional metastases in the following care seems a very practical and sen- year. After surgery and chemother- sible term.” Helping people to live apy, his surgeon told him that the Alongside medical care for symp- Larkin points out that helping peo- cancer was not curable. “I suppose toms and side-effects and measures ple live until they die has been a key I have been in palliative care ever to prevent recurrence, Wilson lists principle of palliative care since it was since,” he said. “I am now in year 15 psychological care, spiritual support expounded by Cicely Saunders, the and I still have periods with active and rehabilitation as key parts of founder of the palliative care move- disease, although none is actually supportive care. “Each patient has a ment. “We are there to help people detectable at the moment.” set of needs which have to be con- to live as fully as they can within the Wilson, who was an independ- nected to some form of service deliv- confines of their illness, until natural ent producer and writer for the BBC ery attached to a menu. Patients need death occurs.” before becoming ill, prefers the term to be guided through the menu.” However, changing public and clin- ‘supportive care’ as descriptive of his Higginson agrees that the line ical perceptions is not so easy. ”We own experience of episodes of acute between living with cancer and dying as practitioners can say, ‘This is who treatment, followed by rehabilitation, from cancer is ever more blurred. we are and this is what we do,’ but it physiotherapy, prosthetics care and “For a lot of people who get cancer, is a bigger struggle to get people to psychological support. the decision of whether it is curable understand that it is not just about After seven years of remission, a or not curable is not so much one or the dying.” recurrence led to the amputation of the other. There is a grey area where Irene Higginson, director of the the lower part of his left leg in 2007. you might be having life extension. Cicely Saunders Institute and pro- Further recurrence was treated with Most advances in cancer treatment

30 I CancerWorld I May-June 2014 SYSTEMS&SERVICES

are not new cures, rather they dis- care of patients where there is no ments in the oncology day hospital,” cover life extension or put someone prospect of cure, integrating the best says Cherny. back into remission.” anti-cancer treatments with the best Most specialists agree on the need Sometimes palliative care is given to supportive and palliative care strate- for a close working relationship, but resolve symptoms so patients can con- gies, is much more difficult,” he says. believe that palliative care should tinue with potentially curative therapy. “It requires personal and infrastruc- remain as a distinct specialty. Philip Severe mucositis, for instance, may tural resources, and is much more Larkin says: “Palliative care has need treating in patients with a hae- reliant on interdisciplinary coopera- something unique to offer to the care matological cancer. Even after a cure, tion. There is a need for a higher of patients. In the same way as you palliative care may be appropriate. level of specialisation and expertise have a gerontology team or an oncol- Higginson gives as an example some- to assist in management and optimis- ogy team, you should have a palliative one who was successfully operated on ing the outcomes for these patients.” care team.” for lung cancer but had a pre-existing Higginson says this is especially chronic obstructive pulmonary dis- important as palliative care expands ease. “They suddenly got very breath- its role for patients with stroke or heart less. The problem was that surgery diseases or other conditions. “Increas- removed a big part of their lung, and ingly, people who have cancer are because they had been sitting still also elderly and have arthritis or they became debilitated. We are respiratory conditions or heart able to make them feel a lot bet- disease, because people who get ter by treating their pre-existing cancer are living longer.” This lung disease and strengthening older age group often misses out their muscles.” on palliative care, and extending Nathan Cherny, director of provision is essential to avoid dis- Cancer Pain and Palliative Medi- crimination, she says. cine Services at Shaare Zedek Medi- However, Higginson also sees the cal Center, Jerusalem, chaired the benefits for patients of inviting pal- ESMO palliative care working group Integrated care liative care specialists into the multi- from 2008 until 2013 and has led or separate specialty? disciplinary team. “I bring something efforts to integrate palliative care into In Cherny’s Shaare Zedek Center, that a lot of other people in the room oncology. He wishes change would oncologists have palliative care train- cannot bring: a wider view of the per- happen more quickly. “Oncologists in ing and the two services share a team son’s other medical and health prob- general are very quick on the uptake of social workers, psychologists and lems. Palliative care doctors are very of disease-modifying new innova- spiritual care providers. They also good at looking at the whole person. tions, but palliative care is one of share space in the day hospital, allow- “Oncology is becoming more spe- those innovations where the oncology ing patients to be screened by palliative cialised as oncologists learn more and world in general has been fairly slow. care nurses with members of the multi- more about the specific management There is a mind-set problem.” disciplinary team on site to provide care of groups of tumour cells. You expect Cherny argues that the treatment in real time. “The patients who have got the oncologist to have a certain level of patients with early-stage disease physical and psychological symptoms of core skills in palliative care, but it and a high possibility of cure is the are the same patients who are present- is not enough to say oncologists can easy part of cancer treatment. “The ing for chemotherapy or other treat- do it themselves – that would imply “Palliative care is an innovation where the oncology world has been fairly slow. There is a mind-set problem”

May-June 2014 I CancerWorld I 31 SYSTEMS&SERVICES

“I bring something that a lot of other people in the room cannot – a wider view of the person’s other health problems” that what we do in 10 years’ time avoiding disease or early detection. respectful, and thorough. will be the same as what we do now. The patients who are not going to “When patient needs are well tended Without a specialty, that is what you be cured are in a sense like the ugly and the patient is well cared for, the would get.” step-sister of cancer care. surviving family will never forget the Palliative care is increasingly seen “The term personalised medi- experience. When they are neglected, as cost-effective. Xavier Gomez, who cine has essentially been hijacked it results in harm to the patient and developed the Catalonia Project – a to reflect the bio-science model of long-term harm to the surviving fami- WHO demonstration project that medical care, and I think we need to lies – it is never forgiven.” provides inpatient, outpatient and vigorously reclaim the social model. Irene Higginson uses similar lan- community-based services for more Targeted approaches are potentially guage: “I would really like to recapture than 23,000 patients across a region important, but biological targeted person-centred and individualised of 7.3 million people – says that the therapeutics is only a part of person- care being about what the individual €52 million spent on delivering this alised medicine. needs, with all their diseases, rather type of care results in a net saving Cherny argues that patients want than it just being about their genetic of €16.7 million by reducing use of to be seen and treated as more than make-up,” she says. acute and emergency beds. the biology of their diseases. They Higginson devised the Palliative Despite this growing consen- want a commitment of care that is Care Outcomes Scale (POS) to cap- sus, there are huge gaps in care sensitive to their complex and often ture patient priorities and concerns, across Europe, and a need for fur- changing needs, and they want phy- beyond what can be seen in blood tests ther research. In 2010 the EU pro- sicians who are confident, empa- and scans. “POS tells you what prob- vided a grant worth €4 million to thetic, humane, personal, forthright, lems someone has, their symptoms, create a EURO IMPACT network and what matters to them. It is a bit in palliative care research, aimed at ECONOMIC BENEFITS like having a scan for how the person monitoring and improving palliative is. We are finding for some diseases care. However, in 2011 Irene Hig- €68.7 million that POS is a better marker of deterio- ginson reported that just 0.2% of can- €52 million ration than biological tests. How the cer research funding in the UK was person is feeling goes off first, before being spent on researching palliative their blood tests reveal it.” and end of life care. This suggests that patients should be given a greater role in assess- Personalised care ing their own conditions. However, For the palliative care specialist, ‘per- some clinicians are reluctant to let sonalised care’ means much more go of their high-tech security blanket. than targeted drugs. In his work for “That’s interesting,” observed one col- ESMO, Cherny promotes a human league, looking at her data. “It shows approach to cancer care, where per- we need a better biomarker.” sonalised medicine is about the per- Higginson sighs: “Why don’t we son, not just about the science, and just get better at asking people what where people who cannot be cured The Catalonia palliative care project led their symptoms are? We do all these are just as important as those who to overall savings of €16.7 million due to fancy tests to look inside the body, can. “There is a clear tendency to reduced use of acute and emergency care when simply asking someone how focus on the hope for a cure or of they are tells you a lot.”

32 I CancerWorld I May-June 2014 SYSTEMS&SERVICES

She feels that open-ended questions, resent, so that patients don’t get mis- such as “What is your main problem leading messages.” at the moment?”, give patients per- He cites the case of a man with mission to raise issues they did not prostate cancer having radiotherapy think the clinical team would want to to prevent spinal cord compression know. “The job of the clinician is to and reduce the risk of paralysis. “We read those things and try to respond,” know that the radiotherapy is simply she says. “We medics tend too much to manage the condition. My concern to go on knowing the answer rather is, does the patient understand that than finding out where the person is.” it is not curative? Is there something POS has identified neglected phys- within them that is hoping that it is?” ical issues, including breathlessness, Larkin teaches his students that fatigue and weakness, as well as psy- honesty is the best policy, but says chological issues, ranging from the that does not mean it has to be brutal need for information to depression, honesty. “The first few meetings can anxiety and fear, and family issues. be quite gentle as you feel your way to figure out where people are at,” he Supportive care or palliative care? suggests. “On a first visit a patient The language used to describe care may say: ‘The doctor says you are a and therapy reflects nuances and pain specialist’. I would say, ‘Yes, I differences of approach. ESMO dis- am here to deal with your pain and students to think about what they can tinguishes between ‘supportive care’, I come from the palliative care team do for people who are dying that is to optimise comfort, function and and we look after the symptoms.’ I am different to any other practitioner. social support at all stages of illness; constantly checking in with people. “What is your added value, because ‘palliative care’, when cure is not Do they have a concept of what the all nurses care for dying people?” possible; and ‘end of life care’, when palliative care team means?” They came to the conclusion that death is imminent. It’s not a question of having to talk they have particular expertise in man- Roger Wilson would expand the about death and dying, he adds, but aging the transition between living definition of ‘supportive care’ to cover of being honest with patients about and dying. “If a patient is given bad everything between a cure and end who you are and what your role is. news about their illness, one of their of life care, and drop the term ‘pal- “There may come a time when I need questions they have in their head is liative care’ altogether. But Philip the patient to trust me; that won’t ‘How long have I got?’ That is some- Larkin, while supportive of many of happen if he feels that I misled him thing that palliative care is very good Wilson’s aims, is concerned that lan- at the beginning,” says Larkin. at being able to manage in a sensitive guage should not confuse patients. way. They are able to lead patients “When people speak about the 50% End of life care and families very gently along a path of people they cannot cure as having The fact that palliative care has a role of realisation.” supportive care, it is not entirely clear to play in many stages of treatment Larkin was amazed, when working who delivers it and where palliative should not disguise the fact that it in the West of Ireland, at how rural fits within that. We as professionals still has a critical role when a patient communities could read indicators. have a responsibility to be very clear is indeed dying. “There was myself and four women in about who we are and what we rep- Larkin challenges his palliative care the community team, and they used “The term personalised medicine has been hijacked to reflect the bio-science model of medical care”

May-June 2014 I CancerWorld I 33 SYSTEMS&SERVICES

“We do all these fancy tests to look inside the body, when simply asking someone how they are tells you a lot” to say that if the women came you and what happens to me now? If I am ably has a rougher journey in many were doing fine, but if the man came going to die – what happens?’ respects. I go into hospital and lie on you were on your way.” “I am definitely not talking about a couch and they stick needles in me They would watch who came to religion. For people who have a reli- or chop a bit out. There is a predeter- the door and what they brought with gion, their minister can be a tremen- mined course and you get on with it. them, especially looking out for the dous support and guide, but for those For her, there are all kinds of uncer- syringe driver that allows a combina- who do not have a religion or reject reli- tainties during that 12 or 24 hours.” tion of drugs to be delivered subcuta- gion, there is still something needed – He has had a long time to think neously (and is today used in the active some form of existential counselling. ‘I about his own illness and his own management of symptoms). Larkin am going to die – what happens?’” mortality. “I feel very committed to recalls: “The lay perception was that if At a critical moment, Wilson found talking as openly as I can. I want oth- the syringe driver came to someone’s his own guide. “I went through a very ers to open up and to get their views house, it meant they would be going to bad time psychologically when I had in the whole context of supportive a funeral in two or three days.” the first recurrence – the regional care. As far as I am concerned, I am Roger Wilson believes patients metastasis in 2000. I found a coun- not fighting cancer. I am not going need support to address issues of life sellor who was a Buddhist. I got a lot to be a loser as and when I die. I and death and their spiritual needs of very practical approaches to living am someone who hopefully will be from an early stage. “It comes down, and to dying. remembered for having done his best at the end of the day, to being able to “I have a very, very supportive to come through it, face it, and help answer for yourself some of the diffi- partner. I could not imagine surviv- other people through the challenges cult questions like, ‘Why did I get this ing without her. Your partner prob- it presents.” n

SURVIVAL BENEFITS

8.9 months Integrating palliative care with Month Month Mont anti-cancer treatment not only hMonth Month h improves quality of life, but Mont Month Month Month can even extend life, as was 4 6 8 shown by the Temel study of 1 2 5 7 9 patients with metastatic non- 3 small-cell lung cancer (NEJM 2010, 363:733–742) 11.6 months h Mont MontMonth Month MonthMontMonthh h Month Month Month 4 6 8 Month Month 1 2 3 5 7 9 10 11 12

34 I CancerWorld I May-June 2014 SPOTLIGHTON

What did we learn from the European Partnership for Action Against Cancer?

ANNA WAGSTAFF

The recently concluded Partnership programme marked the ﬁrst time that EU member states have taken a joint approach to improving cancer plans and the organisation of services. Was it a worthwhile exercise? And where do we go from here?

an countries improve the way (Communication from the European through the Commission. they organise and deliver can- Commission COM/2009/0291). n Its budget was around 80% C cer care by working together at The Partnership was set up by smaller, shared equally between a European level? It’s hard to know the European Commission in June the participating member states until it’s been tried. As member states 2009 to run for ﬁve years. The move and the Commission. consider healthcare to be a purely was in response to sustained pres- n Along with health promotion, national policy area, EU involvement sure from some member states, from quality screening, statistics and has not been welcome and the option the European Parliament and from indicators, its remit included has not been on the table. many European advocacy groups, healthcare policy and organisa- Not, that is, until ﬁve years ago who wanted the EU to continue the tion – areas that had been out when a limited opportunity opened efforts started with Europe Against of bounds for previous European up with the establishment of the Cancer, a programme that ran from work on cancer. European Partnership for Action 1987 to 2000. Against Cancer (EPAAC), “to more However, this new initiative dif- Shared solutions effectively coordinate activities and fered from its predecessor in three to a common problem actions that are taken within differ- important ways. European countries are struggling ent policy areas by Member States n Its work was to be carried out to cope with common problems of and other stakeholders, with the aim through a ‘Joint Action’, led by ageing populations, rising rates of of reducing the increasing and une- representatives from participat- cancer, more people living longer qual European burden of cancer.” ing member states, rather than with cancer, and escalating costs

36 I CancerWorld I May-June 2014 SPOTLIGHTON

of treatment, at a time AN PART admits, however, to a certain early of tight constraints PE NE scepticism about whether the on health spending, O RS Joint Action format could be so working together R H made to work. His coun- to ﬁnd solutions U IP try, Slovenia, had played should make per- a major role in get- E fect sense. F ting the project off Yet major differ- O the ground – it was ences in the organisa- at the conclusion R

tion of healthcare across countries of their presidency

A raise questions about how feasi- A in 2008 that the

ble or desirable it is to coordinate European Council

C the search for solutions. National C called on the Com-

histories, cultures, and priorities are T mission to present I I

reﬂected in which healthcare profes- O an EU Action Plan

sionals deliver what services in what N that would expressly

A A

settings, as well as in who is responsi- G include consideration A A

I I N N

S ble for commissioning healthcare and S of “the appropriate frame- T

how it is funded, governed and evalu- T work for effective cancer

C ated. These differences are jealously C control policies and sharing best

guarded under the principle of ‘sub- practices in cancer prevention and ANCE sidiarity’, which deﬁnes healthcare ANCE regional levels – care”. However, the idea that the pro- policy, among other areas, as the sole brought to the table gramme would be patched together prerogative of each member state. their own agendas and from the various agendas of inter- The great advantage of working were invited to a ‘horse ested parties, was not necessarily

together through a Joint Action was trading’ session to agree what they had had in mind.

R that this is a voluntary activity led R the full programme of Of the 10 ‘work packages’ that and organised by member states action. It took a little emerged from the horse trading, that wish to be involved, and it more than a year to get Albreht mentions, in particular, the was therefore free from any sense the whole thing up and one on healthcare. “The care issue of ‘Europe’ telling countries how to running. finally worked out very well. But at run their health services. The The Joint Action came that particular workshop, there were potential downside, however, to an end in March of so many issues put forward that I was the challenge of organising this year, having run for thought it would be pretty amazing if work across the full spectrum of its allocated three years. they really could be managed within a cancer control, entirely through Tit Albreht, who served on the single work package. It almost seemed co-operation and compromise. steering committee and led like a separate project in itself.” Participants – not just member states, work on cancer plans, is posi- The work package in question but also all interested partners, from tive about the interaction between had no fewer than 12 ‘delivera- professional groups, institutes, advo- representatives from member states bles’, including the “identification cacy and industry, working at inter- and the results achieved, given the and assessment of best practices on national, European, national or even limited resources and timescale. He organisational approaches to cancer Differences in how healthcare is organised raise questions about the feasibility of finding common solutions

May-June 2014 I CancerWorld I 37 SPOTLIGHTON

“The networks issue has been very local or regional and there are few forums to discuss experiences” care” – which might be seen as a field istry of health, had given him plenty sible, and probably useful, and raised of study in its own right rather than of experience in consensus building, the interest of all the stakeholders,” merely one of 12 topics in one of 10 and he welcomed the diversity of he says. work packages of a three-year project. both the participants and goals. Other healthcare topics included the Reports of the work done by the Cancer networks feasibility of harmonising clinical healthcare and other work packages Borràs singles out the discussions guidelines at an EU level, developing can be found on the epaac.eu web- about networks as a model for organ- common standards in care for chil- site and in a book, Boosting Innova- ising cancer care as one of the more dren with cancer, assessing palliative tion and Cooperation in European significant in terms of showing the care needs, and implementing clini- Cancer Control, which presents key European added value. cal guidelines. findings, and is downloadable from Conducting the analysis of different The man in charge of delivering on the site. They document the success- models of cancer networks was quite these deliverables, together with 15 ful completion of the overwhelming a challenge, he says, because there collaborative partners and 14 asso- majority of the planned projects. For are very different models. Some are ciated partners, was Josep Borràs, a Borràs, however, while the outcomes strongly supported by health adminis- professor of public health at the Uni- are clearly important and will have an trations, while others are more infor- versity of Barcelona, director of the impact, the big achievement of the mal, “more of an agreement between Catalan cancer strategy, and scien- healthcare work package was that organisations or between profes- tific coordinator of the Spanish can- it demonstrated that, despite differ- sionals that works quite fluidly, with cer strategy. Happily, this latter role, ences between healthcare systems, it nothing very strong from the organi- which involves reaching agreement is possible for European countries to sational point of view.” between Spain’s highly autonomous work together to improve standards There was, however, no lack of regional health systems and the min- of cancer care. “We showed it is fea- enthusiasm, he says. “People were really interested in learning from BEST PRACTICE FOR CANCER NETWORKS other experiences, because the networks issue has been very local or The consensus conclusions on best practice for cancer networks reached by the regional and there are few forums to EPAAC healthcare work package include: discuss experiences. Most of them Organisation: Some level of structure and leadership is essential to give stability don’t even have a proper evaluation and continuity. This may require some adjustment to regulation and funding mecha- to be published and discussed. There nisms, which often do not facilitate inter-organisational coordination. are a couple of assessments of net- Patient input: Many networks were struggling with this, often because of lack of works in France, Spain or Italy, but organisation – patients can’t have a voice when there are no structures they can there is not a body of knowledge. In participate in. that way the interest of the partners Primary care: GPs and other primary healthcare professionals will have an increas- involved was very high and they were ingly important role, particularly in the care of patients living with cancer, so networks very happy with the experience.” need to find effective ways to relate to this sector. Three networks were analysed in Evaluation: This was recognised as a key element of good practice, even though detail: one in the Lombardy region currently it is carried out only by a small minority of networks. Linking outcomes of Italy, another in Belgium and the data to cancer registries was suggested as a way of monitoring quality and driving third in Spain. Participants from four quality improvement. further networks, in England, France, the Netherlands and Denmark, also

38 I CancerWorld I May-June 2014 SPOTLIGHTON

contributed at a workshop on the group’, with other countries, including there were some member states who topic, which developed a consensus Finland, Germany, Spain and France, said: ‘If you are going to present a list over best practice that was felt to be also contributing a great deal. But of new indicators then you can forget valid across all health systems. it was the level of engagement and about us ever discussing this’– though With the EPAAC work now over, interest right across the 27 countries this was in fact never our intention.” Borràs is looking forward to carrying of the EU, plus Norway and Iceland, Their work was made easier, says on Europe-level work on networks that was the most pleasant surprise. Albreht, by the wide diversity of coun- and the organisation of cancer care Albreht had anticipated having to tries involved: small like Malta, large through a new Joint Action, which spend time and effort getting coun- like Germany, highly centralised like will run for a further three years, tries to respond to the survey sent out France, and highly regionalised like under the title CANCON. This will to establish whether they had a cancer Spain. Some had a strong emphasis be the ﬁnal funding for joint actions plan, and if so how it was organised on primary healthcare, community on cancer and Borràs wonders how and what it covered. In the event, few care, and nursing involvement, others the opportunity to work together needed prompting, and the real prob- were more geared to high-end care in on these issues, which has engaged lem became analysing the large a hospital setting. Each had a and enthused so many participants amounts of detailed informa- different funding mecha- EAN PARTN OP ER from so many countries, will be able tion that came back. Most R SH nism and service deliv- U IP E to continue. countries also took great F ery model. Albreht O

interest in the results of R believes that this

A A C

Cancer plans the survey, “which helped C diversity made com-

T T

I I

O O

N N

Albreht, who heads up the Centre for engage national and regional promise easier. “If A A

G G

A A

I I N N

S S

T T

Health Care at Slovenia’s Institute health authorities in the analysis you are seeking solu-

C C ANCE for Public Health, reports a similar of the plans,” says Albreht “and ANCE tions on the basis of

level of engagement and enthusi- prompted them to take a more what will work, for instance, R asm among people from the different critical look at their own.” R in a decentralised system, then the member states working with him on Participating in the work was centralised systems may feel that is mapping and analysing cancer plans harder for smaller member not something they will want to pur- in Europe, with a view to drawing up states, particularly those with- sue. I’m not saying that in the EU you guidelines of best practice. out their own cancer strategy; in have to go for the minimum common He points out that giving govern- some cases a single person in a minis- denominator at any cost, but you have ment representatives the chance to try is responsible for all non-commu- to take note of important differences exchange information and experi- nicable diseases. But there are ways in health systems – and not just in ences directly is much more pro- around this, says Albreht, such as health systems but simply in the way ductive than exchanges confined to appointing an expert to be the point that a country operates.” academic discourse or conducted at of contact on cancer policy issues, A consensus was reached about ministerial level: “you didn’t have this “something I feel actually developed the key elements of a well-structured political style of plenary discussion of during the course of EPAAC in quite national cancer plan, which is shown what are basically professional issues, a few member states.” overleaf. A guide on how to develop but it operated more as a sort of ‘back There were also some warning shots cancer plans, with sections address- office’”. Representatives from Slove- fired by countries worried about being ing each aspect, is currently being nia, the Netherlands, Belgium, Ire- pressured into doing things against finalised and will be published on the land, Malta and Italy formed a ‘core their will, he adds: “For instance, epaac.eu website very shortly. The Interest in the results of the survey of cancer plans prompted countries to take a more critical look at their own

May-June 2014 I CancerWorld I 39 SPOTLIGHTON

“We are always showing something is feasible, and then we stop and have to begin again” guide will also define a set of indica- Institute or any supranational insti- effort of having a 300-strong staff tors by which countries can monitor tute that would take this over, and worrying about a problem that is progress on each aspect of the plan I’m not authorised to say one should clearly a known and important chal- – which will be the bare minimum be established, though we feel that lenge for health systems, but is not needed to do the job, Albreht hastens a European Union body should be comparable from the point of view to add. responsible for the future steps after of the burden of disease, cost, and Like Borràs, who led the work on 2017.” He sees the agreement to re- cost in the burden of life. So there models of cancer care organisation, establish an EU committee of experts are voices that say there should also Albreht believes that the experience nominated by member states as a wel- be a department for non-communica- and outcomes of the EPAAC Joint come start, “but of course an experts’ ble diseases, and such a department Action show that it is feasible and committee is not a structure that can could have an analytical and monitor- highly worthwhile to work together to deal with day to day challenges.” ing role, as opposed, for instance, to find common solutions in healthcare. One possible solution would be to just being a data collection centre.” He is hopeful that a way will be found extend the remit of an existing struc- His sentiments are shared by Josep to continue the work started by the ture, such as the European Centre Borràs. “Now we have shown that Partnership after CANCON finishes for Disease Control, in Stockholm, this is feasible and probably useful in 2017, though quite how this could which currently only deals with com- through many experiences within be done remains an open question. municable diseases. “There are peo- EPAAC, I think something more “We don’t have a European Cancer ple who ask: why do we invest this permanent should be provided by the EU, to promote these kinds of BEST PRACTICE FOR CANCER PLANS changes in a more permanent way. We are always demonstrating some- This EPAAC work package involved representatives from all member states, EUREGHA thing – showing that it is feasible – (which represents regional and local health authorities), WHO Europe, the European and then we stop and have to begin Observatory on Health Systems and Policies, and others. again, but in a slightly different way, A survey revealed that, by the end of 2011, 23 out of 27 member states already had because continuing in the same way some kind of a cancer plan. While some were truly comprehensive, others exclude is not considered appropriate. So one key areas of care, particularly in relation to survivorship issues, while a few focused of the issues here is to guarantee exclusively on rolling out new areas such as screening. some kind of continuity.” A consensus was reached on the elements that should be present in a truly compre- Neither Borràs nor Albreht is a hensive cancer plan, which formed the basis for drawing up a guide countries can ‘eurocrat’, and both have taken high- refer to in developing their own. level responsibility for improving These include: cancer care in their own countries. n Governance Their verdict is that EPAAC did n Cancer data and information indeed demonstrate that countries n Psychosocial care can improve the way they organise n Palliative and end of life care and deliver cancer care by working n Resources, infrastructure, technology, drugs and cancer-specific expenditure together at a European level. The n Survivorship and rehabilitation question now is whether these coun- n Early detection and screening tries can agree a long-term way to n Cancer prevention and health promotion allow this to go forward in a smooth and continuous fashion. n

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Top trials group turns its attention to survivors

MARC BEISHON

EORTC boosts efforts to address the long-term problems faced by people who have been treated for cancer.

he number of people who are do see themselves as having battled living long lives after cancer through and are happy to have sur- T treatment has been rising year vived long after diagnosis and treat- on year, leading to a quadrupling of ment, but others don’t want to be this population between 1975 and ‘labelled’ in a way that ties them to 2005, with an estimated 35 million such a major event once they are of issues – health, psychosocial and survivors now living in the developed told they are cured. Many people economic – that are common to peo- world. Yet interest in their needs has living with metastatic disease also ple who have been treated for cancer. developed only recently. reject the word as not reflecting Most of these issues are still poorly One reason is that the issues their day-to-day lives. recognised and, all too often, survi- faced by survivors vary greatly owing Yet ‘survivorship’ is a term that has vors are being left to try to organise to differences in ages and cultures, become widely adopted for a field the care they need on their own. and also different cancers and treat- of research on care and support for This is an area of research where ments. There is a wide spectrum of the phase of life that follows pri- the US took the lead and remains well needs and priorities. Even the word mary treatment to the end of life, ahead of Europe. But Europe is now ‘survivor’ carries different connota- or recurrence (different definitions beginning to catch up, with a num- tions for different people – some are used), covering a wide spectrum ber of important initiatives launched

42 I CancerWorld I May-June 2014 “There hav “There which organisesandcoordinates cer treatmentcomestoanend. care plandevelopedastheiranti-can patient has theirneedsassessed and a integrated programmetoensureevery and theUKlaunchoffirstnational vors ofchildandadolescentcancers on survivorship,anetworkforsurvi Most recently, theEORTC, ment of a collaborative group ment ofacollaborativegroup leaf), includingtheestablish in recentyears(seeboxover and data can now be collected from those patients” those from cannow becollected and data Qualityuality of Life e been five decades of large-scale clinical trials, clinicaltrials, e beenfive decadesoflarge-scale - - - - the natureofchallengethey outlined tothesummitparticipants palimaud CancerCentreinLisbon, ogy atthebreastunitofCham force, andheadofradiationoncol in BrusselsthisJanuary. ising atwo-daysurvivorshipsummit survivorship taskforce,andorgan arena, launchingitsowncancer across Europe,steppedintothe clinical andtranslationalresearch Elizabeth Moser, chairofthetask - - - ties in cancer treatments,thereis has beendonetoreducetoxici said Moser, andalthoughmuch are needed to inform guidelines, worse outcomes?”Muchmoredata at risk,andwhatwe can dotoavoid vivors thereareandhowmany size oftheproblem–howmanysur do wehavetheinformationon social workers and care givers. But spread informationtoclinicians, are tryingtoaddress.“We haveto May-June 2014 PATIENT 4

I Cancer VOICE World I 43 - -

ILLUSTRATION: FRED VAN DEELEN, WWW.ORGANISART.CO.UK PATIENTVOICE

“Little is known about combination of treatments, modern radiotherapy techniques, targeted agents...” a big knowledge gap in long-term treatments, modern radiotherapy broader range of issues encountered follow-up. techniques, targeted agents, and by cancer survivors, including infer- The good news, she added, is that hormonal treatments. Few studies tility and sexuality, cognitive dys- there have been five decades of large- have obtained data directly from function, and social impact, such scale clinical trials, and data can patients and/or have considered as difficulties in obtaining work or now be collected from patients who preexisting co-morbidity, lifestyle, insurance. underwent them. This, however, and obesity of survivors. There are requires much greater organisation few guidelines for the management Early results and communication across countries, of adult cancer survivors, and little Moser reported on the initial sur- and will be the biggest part of the sur- is known about management and vivorship research, in lymphoma vivorship research effort. barriers in healthcare within differ- trials. Questionnaires were sent The task force is calling for col- ent European countries.” to thousands of patients across lection of patient data from around Initially, the task force intends Europe, which has so far resulted Europe to provide the basis for devel- to look at the main physical late- in published studies on semen pres- oping prediction risk scores for late effects such as heart problems and ervation, premature ovarian failure, physical and mental effects. It also secondary cancers following certain and parenthood. Analysis of fac- wants to collect information on cur- common and rare primary tumours tors such as radiotherapy dosing rent management of late-effects at (in adults, not children) – lym- and impact on overall health, work, national level, and promote broad phoma, breast, colorectal, pros- finance and more is yet to come. It’s networking among not only primary tate, gynaecological and testicular. a lot of work, she said, and needs care professionals and patient advo- However its remit will also cover a to take into account sources of bias cates but also politicians, the insurance industry and economists. CATCHING UP WITH THE US As a research organisation and a pioneer of quality of life measures, Europe has been slower than the US to focus on the problems faced by sur- the EORTC is well-placed to co- vivors, but a number of initiatives have been launched in recent years ordinate research into late treat- 1986 US National Coalition for Cancer Survivors is launched. ment effects from its clinical trials 1996 US National Cancer Institute sets up the Office of Cancer Survivorship. work, and it recognises the urgency 2000 American Society of Clinical Oncology launches the Study of Cancer Survivors. of this work, as current information 2008 The Pan-European Network for Care of Survivors after Child and Adolescent on late-effects is often hopelessly Cancer, PanCare (pancare.eu), is launched (see also Cancer World 2014). out of date. As Moser and colleagues 2008 National Cancer Survivor Initiative starts in England (ncsi.org.uk), and point out in setting out the ration- produces a model for planning care that is ahead of the US in terms of health ale for the survivorship task force, care organisation, particularly with respect to primary care. while there are well-documented 2012 The European Collaborative Group on Cancer Survivorship (ecgcs.eu) is serious late-effects from chemo- established. and radiotherapy, “the literature is 2013 CANWON, a cancer and work network, is launched to address workforce- focused on treatments dating from related issues for cancer survivors. the 1960s to the 1980s” – and many Survivorship now also features as part of the activities and conferences of organisa- of these are obsolete (Eur Oncol tions such as the European Cancer Patient Coalition (ECPC) and Europe’s medical Haematol 2013; 9:74–76). “Lit- and radiation oncology societies ESMO and ESTRO. tle is known about combination of

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such as people who have died. survivorship health problems, con- cer survivors products such as life This work on lymphoma and also vincing someone with fatigue to take and travel insurance, and loans. leukaemia survivorship is now inform- a walk can be hard. Insurers are major number- ing solid tumour research. Moser men- crunchers in their own right, as they tioned a survivorship project on early Long-term data collect information to inform their breast cancer, which aims to update The need for long-term data, espe- risk assessments. John Turner, of the results from six trials that took place cially on toxicity, was addressed by reinsurer Swiss Re, said that can- between 1986 and 2011. Barriers must Connie Vrieling, a radiation oncol- cer is the cause of two-thirds of come down between tumour-specific ogist from Switzerland. Looking private critical illnesses payouts in groups, she said, because late-effects at breast cancer, she noted how the UK, and few claims are denied. such as second malignancies and car- more patients are living with the But what about insuring people diovascular problems are often related consequences of treatment – “and who have had cancer? “The prob- to specific treatments rather than spe- if we stop at ten years in the fol- lem is how we make it insurable – cific cancers. low-up of our trials we simply do it is a serious threat to life. But we A multidisciplinary effort will also not get the data.” As an example, have to reflect the improvements be crucial in addressing issues such she gave data from long-term out- in survival.” He charted how insur- as fertility, cognitive dysfunction, comes from treating DCIS breast ers model insurance applicants with and psychosocial functioning – the cancer with either excision or exci- a history of cancer, and how things latter being the most complicated sion plus radiotherapy – and noted have changed – the current recom- because of the variety of factors. that a higher rate of secondary mendation for stage 1 breast cancer Can we also intervene in the life- cancers in the radiotherapy group is to offer a standard premium after styles of survivors? Moser pointed could call into question applying two to three years – whereas in 1995 out that it is particularly hard to radiotherapy to all women. She that wouldn’t have been offered influence younger people, who often also asked whether it is possible to until after ten years. drink and smoke, increasing their get at data on risk factors such as Krish Shastri, chief executive of risk of developing problems later on. smoking – in some places this is InsureCancer, a travel insurance Other speakers emphasised that tak- possible – and she mentioned the firm that only insures people who ing exercise, changing diet and mak- potential for gene expression and have a diagnosis of cancer, said: “For ing other lifestyle changes can greatly proteomic profiling from studies us, survivorship starts from the min- improve outcomes and/or quality of where tissue is stored. ute of diagnosis to the end of life,” life, but noted that peers rather than Researchers, health policy mak- noting that for his business, it is health professionals are probably the ers and advocates are not the only hospitalisations that carry the most best influencers. The American Can- ones with an interest in long-term risk – and there are very few data on cer Society has drawn up nutrition data on cancer survivors, however. this. Travel for all sorts of reasons is and physical activity guidelines for Delegates at the summit may have crucial to quality of life, he added, cancer survivors, reported Catherine been surprised to hear no fewer than and he appealed for more knowl- Alfano, deputy director of the US three presentations from insurance edge from aggregating European National Cancer Institute’s cancer and banking executives in the open- data that would enable better insur- survivorship research programme. ing session. As the executives made ance underwriting to address the She added, however, that while exer- clear, their companies need the data frustration voiced by many survivors cise and maintaining a healthy body too so they can accurately reflect the about the lack of affordable insur- weight are the best ways to tackle risk they undertake in offering can- ance options. “Use of radiotherapy to treat all DCIS could be called into question if data show it leads to more secondaries”

May-June 2014 CancerWorld I 45 PATIENTVOICE

Cancer registries can be used to send out questionnaires to collect data on quality of life

Patient-reported outcomes where the cancer registry is used to after a range of cancers and for spe- Lonneke van de Poll-Franse, profes- send out questionnaires in an open cific conditions such as chemother- sor of cancer epidemiology and sur- access project called PROFILES – apy-induced peripheral neuropathy vivorship at Tilburg University in the Patient Reported Outcomes Follow- (see also Protecting Patients’ Nerv- Netherlands, described how data can ing Initial treatment and Long-term ous Systems, on page 12). About be collected on quality of life, with Evaluation of Survivorship. Patients 60% of patients aged under 50 in one reference to the Eindhoven region are being asked about quality of life sample reported problems in obtaining life insurance, for example. PREVALENCE OF LONG-TERM EFFECTS As she added, by continuously monitoring the long-term impact of cancer and new therapies, regis- At least 1 in 4 (500,000) people tries become focused on patients, in the UK are facing poor health or not just cancer. “By collecting data disability after treatment for cancer on patient reported outcomes, we can contribute to discussion on the At least 1 in 6 (350,000) people added value of new therapies in daily living with and beyond cancer are clinical practice, and also socio-eco- experiencing chronic fatigue nomic implications.” Other registries are doing the same, she said, citing a systematic review that looked at At least 1 in 6 (350,000) are hav- how this is a work in progress as a ing sexual difficulties resource for survivorship studies (Cancer 2013, 119:2109–23). Kathy Oliver, from the Interna- Around 1 in 8 (240,000) are living with tional Brain Tumour Alliance, spoke mental health problems, which can on the input that advocacy can pro- include moderate to severe anxiety vide for the clinical trial community, affirming the need to build patient- At least 1 in 10 (200,000) are liv- reported outcomes into research, and ing with moderate to severe pain mentioning biobanking as another after curative treatment area for collaboration with patient groups. She also added yet more Around 1 in 13 (150,000) are items to an already long list of sur- affected by urinary problems such vivorship issues, such as the guilt as incontinence often experienced by survivors, and she emphasised how important care plans are once main treatments ends. These estimates relate to the UK's population of around 2 million cancer survivors. The picture is likely to be broadly similar across Europe. An integrated national survivor plan (2013) Source: Throwing Light on the Consequences of Cancer and its Treatment It was fitting that the UK’s approach Macmillan Cancer Support to survivorship care plans was presented at the summit, given the lead

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the country is taking. Jane Maher, A call for global collaboration National Health Service improvement lead for cancer, said that by 2009 International collaboration, not just in Europe but across the world, was called for by it was recognised that one in three several speakers at the summit, notably Catherine Alfano, deputy director of the US patients had unmet needs by the end National Cancer Institute’s cancer survivorship research programme. She presented of their treatment, from a population five themes that she said can best be answered through global collaboration: of two million survivors. She outlined 1. Identifying ideal care models. One way to do this is to test diverse models, the stages between treatment and end such as provision from multiple agencies. Alfano noted that it is hard for countries to of life – recovery, early and late mon- do this alone. In Germany, for example, it is impossible to test rehabilitation because itoring, and progressive illness – and it is mandated and cannot be randomised. pointed out that differences between 2. Learning from each other’s cultural influences on care – for example people cancers means the timeframes for in the UK seem to be receptive to the model of ‘self-management’, which Alfano com- these stages can vary widely. mented is “great”, but is the opposite of what Americans demand from their provid- Central to the strategy, she said, ers (though she suggested it might perhaps be carefully marketed to them). is a recovery package surrounded 3. Technology, such as using registries to drive personalised care, telemedicine for by reviews, care planning, wellbeing remote areas, managing survivorship plans, empowering survivors to engage in care, events, financial support, and manag- and rapid learning for improvement. ing treatment consequences. These 4. Optimal collaboration among health providers – oncology, primary care, have been shown to help the majority cardiology, physiotherapy, psychology and so on. Alfano illustrated this with a of breast cancer survivors, and about slide showing each specialist is talking to the survivor but not to each other. “Who half of survivors of colorectal and should be responsible for survivorship care?” she asked, given challenges such as prostate cancer, into ‘self-manage- a projected shortage of oncologists and primary care professionals, and obtaining ment’ away from hospitals. To enable reimbursement. this, a holistic needs assessment is 5. Prevention. “We have to focus survivorship care on prevention,” said Alfano. The used to ‘shape a conversation’ at the paradigm should be to focus on health behaviours as well as late-effects, as many end of treatment, from which a care people with early-stage cancer will not die of the disease. It is about creating ‘well sur- plan is sent to the person’s GP. The vivors’. Prevention, she noted, is one of four pillars of survivorship care identified by GP then writes a treatment summary, the US Institute of Medicine, along with surveillance, intervention and collaboration. which is a tool to improve communi- As part of the answers, Alfano considered that much could be learnt from how cation between cancer services and large businesses focus on certain projects with measurable goals, and choose primary care. Testing of both paper partners strategically to maximise individual strengths and productivity. “If you and electronic needs assessment want to go fast, go alone. If you want to go far, go together,” she concluded, quot- has been underway for some time in ing an African proverb. about 200 hospitals. Maher said it is a big challenge to change the perception of can- One approach to care planning may vivors. But there are steps that can cer from only being managed in not work elsewhere. and should be taken now, such as acute settings to one where the out- The message from the summit combining current data and making side community shares its perspec- is that cancer survivorship is on a it widely available, starting to plan tive with specialists, and there are steep learning curve and there is a for care, support and prevention, clearly major cultural and organisa- long journey ahead, given the many and collaborating both at European tional differences among countries. issues and the rising numbers of sur- level and worldwide. n “It is a big challenge to change the perception that cancer can only be managed in acute settings”

May-June 2014 CancerWorld I 47 e-GRANDROUND

How Europe can develop better, cheaper cancer drugs

Modern tools of biological investigation give us opportunities to develop drugs much more efﬁciently. The president of Europe’s most important trials organisation explains how these opportunities can – and must – be exploited to start delivering drugs that are more effective and more affordable.

he road to developing a new medicine – translating a new T idea into a drug licensed European School of Oncology to treat patients – is long, often too long. Traditional drug development e-grandround moves through preclinical studies to phase I, II and III trials, with increasing resources needed for each stage, The European School of Oncology pre- from 25–30% of costs for preclinical sents weekly e-grandrounds which offer work to the bulk of 40% for phase III participants the chance to discuss a late-stage development. The attrition range of cutting-edge issues with lead- rate is enormous. For every 10,000 ing European experts. One of these is compounds screened, only one will selected for publication in each issue of make it successfully to the clinic. But Cancer World. are we really sure that the remain- In this issue, Roger Stupp, head of the ing 9,999 others are really not use- Cancer Centre at the Zurich University ful in any way? The current approach Hospital and president of the EORTC, means we don’t know how many explores the challenges and opportu- potentially useful compounds we nities associated with clinical research may have missed. to develop new therapies for cancer in The figure overleaf shows the attri- Europe today, and suggests key meas- tion rates for therapies in recent phase ures to optimise academic participation III trials, with nearly 60% failing due in future research. Denis Lacombe, sci- to lack of efficacy (Nat Rev Drug entific director at the EORTC in Brussels, Discovery 2013; 12:569). Oncology is poses questions raised by participants the leading therapeutic area for late- during the live online presentation. stage failures. We’re doing something Edited by Susan Mayor. wrong when we fail so late, and particularly in oncology if we fail more The recorded version of this and other e-grandrounds is available at www.e-eso.net often than in other areas.

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Academia is currently involved rather ATTRITION RATES IN PHASE III TRIALS 2011/12 late in the traditional drug development model (see below), usually at CAUSES OF FAILURE FAILURE BY THERAPEUTIC AREA phase III for larger trials or at phase IV for investigator-driven optimisa- tion or extension of indication after approval, with perhaps some work in target and drug discovery. Everything in between is largely led and organised by pharmaceutical companies, but I think there are opportunities for academics to contribute more in the earlier stages of clinical development. Research and development costs for a novel oncology compound are more than $1 billion, and the costs are increasing. Despite this high cost, 75% of cancer drugs have no meaningful effect on the patient. The number of clinical trials has declined Better testing at early trial stages could avoid wasting time and resources on phase III trials that over the past decade, but costs and are destined to fail failure rates remain high. Why do so Source: J Arrowsmith and P Miller (2013) Nat Rev Drug Discovery 12:569 Reprinted with permis- many trials fail? Up to 30% of trial sion from Macmillan publishers Ltd sites never recruit a single patient, expending costs and effort for nothing. This could improve with better trials do not meet their enrolment tar- in terms of failure to provide useful selection, knowing which centres gets, so will never give us an answer, information. can really deliver. Over half of the which is worse than a negative trial The current model of drug development is not sustainable. It has a POSITION OF ACADEMIA IN TREATMENT DEVELOPMENT high failure rate, the high cost of new drugs results in some people being denied access and, most importantly, large numbers of patients continue to being treated with ineffective or insufficient regimens as a consequence. Drug development needs to change in a way that recognises the far-reaching changes to the landscape of how we conduct trials: with more modern and efficient tools, we can do more, and we can do it more efficiently. The landscape is also changing in how we prac- tise medicine, moving from working in separate medical specialties to interdisciplinary disease manage- Better drug development requires input from academia at a much earlier stage ment teams using a problem-centred rather than discipline-based

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approach. Non-specific chemother- It is important to recognise that designed to protect patient safety, sti- apy is being replaced by rational and expression profiles of thousands of fle patients’ access to innovation. It targeted treatments; organ- and histol- patients are needed to generate a is important to focus on measurable ogy-based classifications are moving robust gene list that accurately pre- parameters and define what consti- to an approach that is driven by sig- dicts outcomes in cancer, and some tutes a meaningful endpoint, includ- nalling pathways, which can be used current predictors are not as repro- ing quality of survival. How low or to detect patients at risk and develop ducible as we would like to think. how high do we want to set the bar more effective drugs with less toxic- Only by bringing a lot of data together for new treatments? Is a median sur- ity. We are also moving from treating can we analyse molecular subtypes vival prolongation of six weeks worth disease symptoms and loss of normal accurately and understand what is it? Does the median mean anything? function to prevention, intervening happening. Analysing thousands of These are all questions that we have before symptoms appear, with the aim variables in hundreds of samples to ask and for which answers have of preserving normal function. poses a major challenge, requiring to be found individually for each expert support from biostatisticians. tumour type and treatment we inves- Towards personalised medicine The idea that a targeted treatment tigate. We need to ensure that trials The future for more efficient treat- blocking a single signalling path- are representative of the ‘real world’. ment development is to move towards way will be effective is too simplistic personalised medicine, resulting in because there are multiple redundant Collaboration versus competition the right treatment for each individ- signalling pathways, so blocking one Disease fragmentation is a challenge, ual patient so they can receive the means an alternative is then used. but it can be overcome with effec- optimal treatment according to their We also need to recognise that not tive collaboration and sharing of data, personal profile, the host profile, and every target identified is druggable. In including finding a way for competing the tumour profile. The move from order to identify druggable targets we groups and industries to collaborate histology to molecular disease classi- need companion diagnostics and also where there are synergies. National fication results in disease fragmenta- standardisation of testing. healthcare systems need to find ways tion from relatively common cancers We need help from regulators to to work together, and different medi- into many different, rarer subtypes, facilitate new drug development using cal disciplines need to collaborate. as illustrated below for lung and a personalised medicine approach. Two examples of precompeti- breast cancer. Many current regulations that are tive collaboration are the Structural

MOLECULAR DISEASE CLASSIFICATIONS

As the disease becomes increasingly fragmented into smaller molecular subgroups, access to vast quantities of data becomes essential to accurately predict outcomes

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Genomics Consortium (SGC) at the RESHAPING DRUG DEVELOPMENT Universities of Oxford and Toronto, supported by private funders and charities, and the Innovative Medi- cines Initiative (IMI), which brings together the European Commis- sion and the European Federation of Pharmaceutical Industries and Asso- ciations. They work in a precompet- itive way by carrying out the basic science relevant to drug discovery. This is now done largely in the preclinical field – in imaging and in new technology – but I think we can also find ways for more collaboration, rather than competition, on the clinical side. The issue of intellectual property (IP) is often a concern in consortium Greater effort made at an earlier stage will increase the chances of successful pivotal trials agreements, and can lead to undue delays or good ideas may not be pursued at all, even though it may be number of patients to potentially ensuring tumours are subtyped and more rewarding to have a small share ineffective and toxic agents. Then categorised at a molecular level early of a successful operation than 100% we will be able to carry out pivotal on, and then if their cancer recurs of a failure. trials in enriched populations, which after standard treatment upfront they The changing approach to drug will require fewer patients to demon- can enter a trial for second- or third- development requires more focus in strate efficacy, because there will be line treatment that fits their charac- the early phases to ensure we expose a much greater signal. We can then teristics. This requires collaboration fewer patients to pivotal trials that move on to test a new drug again between industry and academia to fail (see figure). We need to ask the on a larger scale in the real world, ensure new treatments can be used right questions upfront in early clini- which requires learning how to col- in appropriate patients. Having an cal trials: is the target present and lect data in a simplified manner. independent molecular screening is the target relevant for the tumour We need to reshape the interaction platform ensures that patients can be being investigated? What is the inter- between the different stakeholders directed to appropriate trials. action between the tumour and the and develop new models of partner- In this approach the patient’s stroma? What redundancy of path- ships. Data collection and data shar- tumour tissue goes to a biobank ways is there? We also need to learn ing is in the interests of each and upfront where it is analysed in a more about the pharmacology and every patient, and it should be man- quality controlled manner, and the assessing whether the drug reaches datory – overemphasising data pro- information is stored in a clinical the target and if there are any off- tection obstructs progress. database. If the patient progresses, target effects. Can we image the drug Everybody talks about translational information is exchanged to assess effect with modern technology? research, however not much is done suitability for trials of novel treat- Greater investment in early clini- in practice. One way the EORTC ments that would be appropriate. cal trials requires that we learn more is addressing this is with a molecu- The trial may sometimes go to the from every single patient we treat, lar screening platform – the Screen- patient or sometimes the patient will mandating translational research ing Patients for Efficient Clinical travel to the trial. rather than seeing it as optional. Trials Access (SPECTA) platform. The EORTC SPECTA programme This will ensure we expose the least This ‘takes the trial to the patient’ by tries to categorise different types

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of cancers. A platform is already ACCESS TO CLINICAL TRIALS up and running in colorectal cancer, with others in advanced development for lung, prostate, brain and melanoma. We are working closely with pathologists, experts in biobanking, biostatisticians, industry, patient representatives and regulators to ensure procedures meet regulatory standards. Standards and quality assurance are essential to ensure that pathol- ogy and molecular testing are done in the same way in different labora- tories. Individual academic labora- tories alone may not have sufficient numbers of samples to fulfil accred- itation and standardisation procedures; however, collaboration with Screening patients for their molecular subtype at the time they are diagnosed can help ensure a certified platform may allow them they are quickly enrolled into relevant trials if their disease progresses to develop the expertise in a specific area. A centralised platform offers a service that can be much cheaper Where do we have opportunities cal cancer, over the last twenty years and more efficient. as academics? has always been made when we com- The EORTC infrastructure sup- I think there are plenty of opportunities bined drugs and radiation. There are ports new-generation clinical trials. for academics to work, for example, on plenty of opportunities to explore new We have quality assurance plat- combination radiotherapy plus drugs approaches of combined treatments forms in radiotherapy, and we have and/or radiosensitisers. Progress in the with radiation, but this can only be a platform for imaging so that we treatment of numerous solid tumours, done when we work in close collabo- can analyse and compare images in including brain tumours, head and ration among academics and together a unified way. neck cancer, lung cancer and cervi- with industry partners. When you consider collaboration – VARIABLE MODELS OF COLLABORATION and EORTC is an example of an academic cooperative group – every one of the stakeholders has something to bring to the table. But there is a lot of overlap and things we can do better together. There are variable models of Getting the model of collaboration depending on the pro- collaboration right ject, and depending on the new treat- between academia, the ment and approach (see figure left). pharmaceutical industry I think we need to bring academia and contract research to the table early on when it comes organisations is key to to the scientific concept, protocol developing better development, site selection, how to cancer treatments carry out trials, and how to do it in more efficiently the most efficient way. What can an academic consortium

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such as EORTC offer? We offer Effective collaborative research share a common control arm. expertise in clinical development and needs a network of people who trust Academic consortia such as the in specific disease areas that is only each other and who are highly moti- EORTC can provide the experience available in a highly sophisticated vated. They need to feel part of some- and expertise to get a trial done effi- and well-run group with appropriate thing, which ensures they are highly ciently, from the initial concept to experience, with members who know motivated and so perform better than protocol development and trial enrol- each other and who have worked just being ‘hired for service’ in trials ment. We are often asked the time to on several previous protocols. This run solely by industry. I think inde- first patient enrolment, but the more expertise spans decades, not just a pendence is important and a plat- important question is the time to enrol few years. Previous experience means form of academics can be helpful the last patient – that’s what matters – academia has expertise in disease for trials that test several competi- and we ensure we get the last patient benchmarking. Only academia has tors’ compounds and strategies. We in efficiently. Time to the first patient a long-term horizon: with EORTC, can achieve synergies including use is confounded by regulatory issues, trials have been followed up for up to of one molecular testing platform, delays in contracts, remarks and 50 years. How else would you deter- testing for a series of aberrations and diverging recommendations by ethics mine long-term toxicity complica- then directing patients to the most committees. Here inclusion of patient tions or secondary malignancies? promising protocol. Trials may even advocates may be helpful. n

Denis Lacombe, headquarters director of the European Organisation for Treatment and Research in Cancer (EORTC), Brussels, hosted a live question and answer session

Q: Do you think the ‘pick the winner’ ensure rational combinations of differ- model proposed by acute myeloid leu- ent anticancer agents are used together kaemia researcher Alan Burnett [head earlier in the development process, of the Experimental Cancer Medicine despite competition between different Centre in Cardiff, Wales] is a good companies? platform to develop and assess new A: We need to hit several targets at drugs for clinical trials? several levels so we need to combine A: It’s one among many models, and treatments. Doing this in a non-com- there is not going to be one single petitive way using a somewhat neutral approach. It depends on how many platform will help. Pharma is used to compounds and approaches you collaborating in joint ventures and A: We need to stand together in have to test in parallel and what dis- co-developments, so this could be Europe otherwise pharmaceutical ease is being studied, but it goes in applied to early development perhaps, industry drug development is going the right direction. It also depends at with two compounds in combination. to move elsewhere. Our healthcare what stage of the development we use Currently 56% of trials fail because of systems are too fragmented, with a it. Using the ‘pick the winner’ model lack of efﬁcacy, so we need to over- national rather than international with some controlled randomised come this. focus. Other regions of the world are designs early on and trying to discard Q: We need more international access bringing resources together, picking the losers very early on would help a to patients because of disease fragmen- up in innovation. I would call on the lot. We currently have too many losers tation. How do you see the future of EU and regulators to partner with us that we take along too far in the drug this in Europe, because we do not nec- in order to develop better treatments development process. essarily operate in an optimal regula- to achieve improved health and qual- Q: How can we better collaborate to tory environment? ity of life for the European population.

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CLINICAL ONCOLOGY

Smart therapeutic strategies that blocks cytotoxic T-lymphocyte- associated antigen-4 (CTLA-4), has in immuno-oncology the potential to survive for at least three years – and up to ten years – from treatment initiation, which ALEXANDER EGGERMONT AND CAROLINE ROBERT more than doubles results with con- ventional drugs.2 Similarly, treating patients with antibodies that block For cancer therapies to succeed, induction of an anticancer immune the programmed death-1 (PD1) response is required. Immuno-oncology approaches are shaping the receptor, or its ligand, PD-L1, has treatment landscape for patients with advanced-stage melanoma and proved highly promising.3,4 Results of other solid tumours. These new approaches may enhance immune extended phase I trials evaluating two system activity to improve outcomes, including the potential to anti-PD1 antibodies (nivolumab and achieve long-term survival benefits in many patients. MK-3475) showed objective response rates (ORRs) of 30–50% in patients This article was first published online in Nature Reviews Clinical Oncology on 4 March 2014, and is published with with advanced-stage melanoma, permission. © 2014 Nature Publishing Group. doi: 10.1038/nrclinonc.2014.36 with most responders having durable benefit.1 Results with nivolumab showed an unprecedented 44% of he knowledge that tumour through treatments for advanced-stage patients surviving for at least two cells can use complex and melanoma; they also show considera- years.1 Additional trials could inform T overlapping mechanisms to ble promise in other tumour types, par- the optimal sequencing of anti-PD1 avoid immune detection laid the ticularly renal cell carcinoma and lung and anti-CTLA-4 therapies: although foundations for immuno-oncology to cancer.1 anti-PD1 therapy is effective fol- become an anticancer treatment. Cur- Unlike other therapies approved for lowing prior treatment with ipili- rent strategies are based on agents advanced-stage melanoma that tar- mumab, does the same hold true for that can break immune tolerance. The get tumour cells directly, checkpoint the reverse sequence? Anti-CTLA-4 most recognised class of immuno- inhibitors modulate T-cell activ- antibodies centrally target the inter- oncology agents – checkpoint inhibi- ity to enhance antitumour immune action between antigen-presenting tors – modulate pathways that either responses. The most striking benefit cells and T-cells in the lymph-node switch off T-cell activity (reducing of this approach is durable tumour compartment, whereas anti-PD1 tumour-induced immune suppres- control and survival.2 Mature data antibodies act mainly peripherally on sion), or stimulate T-cell activity, thus in thousands of patients have shown the interaction between tumour cells potentiating antitumour responses.1 that around one in five patients and T-cells at the tumour site. Thus, These agents are recognised as break- treated with ipilimumab, an antibody various opportunities for synergy or

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optimal sequencing of the drugs are receptors) are all being investigated become the next standard of care, to be explored. Current studies are in clinical trials and serve as poten- based on the efficacy of this combina- addressing these questions. tial components of a combination tion to significantly prolong progres- There is little doubt that impressive strategy.6 It is possible that once the sion-free survival (PFS) compared results have been obtained by inhib- ‘brakes’ elicited by the immune sys- with dabrafenib alone.7 Compared iting a single immune checkpoint, tem have been released with one with a PFS of approximately two but could antitumour immunity be antibody, the inclusion of an agonis- months with dacarbazine, and around enhanced through dual or triple block- tic antibody such as anti-OX40 could six months with a BRAF inhibitor, a ade? Early results seem promising. augment antitumour immune activity PFS of more than nine months was Among 53 patients with a response further. In other words, breaking tol- observed with the combination of a to the ipilimumab–nivolumab com- erance at the central (anti-CTLA-4) BRAF inhibitor and MEK inhibitor.7 bination regimen, blocking CTLA-4 and peripheral (anti-PD1) levels, The distinct activity profiles of the and PD1 resulted in an ORR of 40%, opens the door for efficacy of ago- two classes of agents, together with and clinical activity was observed in nists, whereas the use of T-cell acti- recent evidence that BRAF inhibition 65% of patients; at the maximum vators (monoclonal antibodies or has immune-enhancing properties, doses associated with an acceptable cytokines) alone does not lead to suggest combination therapy might level of adverse events, most patients appreciable success, as T-cells are prove beneficial. A phase I study to had a reduction in tumour volume neutralised at both the central level investigate the combination of ipili- of at least 80%, according to WHO as well as the tumour site. Of course, mumab and vemurafenib, however, criteria of response. Responses were the potential for overlap- was associated with four deep but also rapid, occurring within ping and/or additive toxic “In other words, to five times higher-than- 12 weeks.5 These results, how- effects of the individual expected rates of hepa- ever, might not differ significantly agents, particularly those breaking tolerance totoxicity, suggesting that from those results obtained with resulting from over stim- at the central and concurrent treatment may MK-3475 alone in 135 patients, in ulation of the immune not be possible.8 However, whom response rates of 41% were system, would need to be peripheral levels, the timing of administra- observed using RECIST criteria.4 carefully monitored. opens the door tion of the various agents However, direct cross-study com- Potential combination in this dual approach parisons of these trials are not scien- strategies are not limited for efficacy of (immunotherapy and cyto- tifically valid owing to differences in to the different immune agonists” toxic agents of any nature, patient populations, the number of checkpoint ligands and including tyrosine kinase patients, number and timing of prior receptors. A rationale also exists inhibitors) will be of great interest. In therapies and prognostic factors. In for combining checkpoint inhibi- this approach, the administration of contrast to treatment with anti-PD1 tors with other immunotherapeutic agents that induce a quick transient alone, the rate of grade 3–4 adverse approaches, such as cytokines that response (such as seen with BRAF effects related to the ipilimumab– increase the number of activated and MEK inhibitors) can create the nivolumab combination regimen was T-cells in the circulation, or con- time and space to administer immuno- high (53%).5 Data from phase II and ventional cancer therapies, such as oncologic agents. Being able to deliver III randomised studies including the targeted kinase inhibitors, chemo- immunotherapy by smart sequencing ipilimumab–nivolumab regimen are therapy or radiotherapy. of different treatments will become eagerly anticipated to determine if Patients with BRAF-mutated an increasingly important strategic this regimen is superior to anti-PD1 advanced-stage melanoma have the goal. Treatment with some chemo- monotherapy and, if so, at what price option of receiving treatment with therapies can result in tumour cell in terms of toxicity. ipilimumab or a BRAF inhibitor (such stress and death that stimulate a Monoclonal antibodies against as vemurafenib or dabrafenib). Possi- tumour-specific immune response, other immune checkpoint proteins, bly, in the near future, a combination or increase levels of tumour surface such as TIM3, LAG3, OX40, and of a BRAF inhibitor and a MEK inhib- molecules that facilitate recognition KIRs (killer immunoglobulin-like itor (dabrafenib plus trametinib), will by the immune system. Immuno-

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genic cell-death-inducing agents can term survival depend on harnessing References for this article can be found at thus be successfully combined with the power of the immune system. www.cancerworld.org an immuno-oncologic agent, resulting Data with agents that block CTLA-4, in an enhanced antican- PD1 and other checkpoint Author affiliations: Alexander Eggermont cer immune response.9 “Being able to proteins are not only pro- (Cancer Institute) and Caroline Robert Another interesting con- viding a benchmark against (Department of Dermatology), Gustave Roussy deliver immuno- Cancer Campus, Paris, France cept is the possibility of which future therapies will inducing immune-medi- therapy by smart be compared, but are stim- Acknowledgements: The authors take full ated abscopal effects, as ulating interest in alterna- responsibility for the content of this publication, sequencing … and confirm that it reflects their viewpoint and seen with radiotherapy. tive sequencing or smart medical expertise. StemScientific, funded by Here, significant tumour will become an combination approaches Bristol-Myers Squibb, provided writing and editing regression both at the site that could improve out- support. Bristol-Myers Squibb did not influence increasingly the content of the manuscript, nor did the authors of irradiation and outside comes even further. In receive financial compensation for authoring the areas support the notion important changing the treatment manuscript of an enhanced systemic landscape, immuno-oncol- strategic goal” Competing interests: immune response and ogy advances currently Alexander Eggermont has participated in advisory suggest localised radio- offer renewed hope to boards for Amgen, Bristol-Myers Squibb, therapy in combination with immuno- patients with advanced melanoma GlaxoSmithKline, MedImmune, MSD; Caroline 10 Robert has participated in advisory boards oncology is worth pursuing. and to patients with other solid for Amgen, Cellgene, Bristol-Myers Squibb, Durable tumour control and long- tumours in the near future. n GlaxoSmithKline, MSD, Novartis, Roche

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58 I CancerWorld I May-June 2014 NEWSROUND newsround Selected reports edited by Janet Fricker

Optimal time for initiation chemo therapy after 60 days (P=0.01). exacerbated by trastuzumab, and that the of adjuvant chemotherapy Patients with triple-negative breast cancer results shown… are not entirely related to had a 74% decrease in overall survival if they delayed administration of chemotherapy.” according to subtype started chemotherapy between 31 and 60 Since two-thirds of the patients had hor- n Journal of Clinical Oncology days of surgery compared with starting within mone-receptor-positive disease, they add, 30 days (HR 1.74, 95% CI 1.32–2.29, P<0.001). there is no indication that time to initiation The subgroup of patients with stage III of chemotherapy makes much difference for disease had a 76% decrease in overall sur- the majority of patients. ime delays in initiation of adjuvant vival if they started chemotherapy more Tchemotherapy have an adverse effect than 60 days after surgery versus 30 days n D de Melo Gagliato, A Gonxalex-Angulo, on outcomes for breast cancer patients or less (HR 1.76, 95%CI 1.26–2.46, P<0.001). X Lei et al. Clinical impact of delaying initiation with stage II and III disease, triple-negative Among patients with stage II disease, the dis- of adjuvant chemotherapy in patients with breast tumours and HER2-positive tumours treated tant-relapse-free survival (DRFS) decreased cancer. JCO 10 March 2014, 32:735–744 with trastuzumab, a single-institution retro- by 20% if they started chemotherapy more n M Colleoni, R Gelber. Time to initiation of spective cohort study has found. than 60 days after surgery versus 30 days adjuvant chemotherapy for early breast cancer Randomised clinical trials have shown or less (HR 1.20, 95% CI 1.02–1.43, P=0.03). and outcome: the earlier, the better? [editorial] survival benefits associated with use of The timing of chemotherapy showed no ibid pp 717–719 adjuvant chemotherapy in early-stage effect on outcomes (OS, RFS, or DRFS) in breast cancer. The optimal time to initia- patients with stage I disease, HER2-positive tion of adjuvant chemotherapy and impact tumours not treated with trastuzumab, and Young families a barrier according to breast cancer subtype, how- hormone-receptor-positive tumours. ever, are less clear. “Among patients with stage II and III to radiotherapy for In the current study, Mariana Chavez- BC [breast cancer], TNBC [triple-nega- breast cancer MacGregor and colleagues, from MD Anderson tive BC], and HER2-positive tumors, every n JNCI Cancer Center, retrospectively reviewed the effort should be made to avoid postponing medical records of 6,827 women with stage I the initiation of adjuvant chemotherapy,” to III invasive primary breast cancer who write the authors. Since adverse outcomes ompeting demands of childcare create received adjuvant chemotherapy between occurred when chemotherapy was delayed Cbarriers for women completing radia- 1997 and 2011. Patients were categorised by more than 60 days, they add, medical tion therapy after breast cancer surgery. A according to time from definitive surgery oncologists should have sufficient time to US study has found that having at least one to adjuvant chemotherapy into one of three initiate treatment. child aged less than seven years old resulted groups: <30 days, 31 to 60 days and >60 days. In an accompanying commentary, Marco in statistically significant lower odds of Results show that for patients with Colleoni, from the European Institute of receiving radiotherapy than having no chil- HER2-positive tumours who received tras- Oncology, Milan, and Richard Gelber, from dren or older children. tuzumab, the five-year overall survival the Dana-Farber Cancer Institute, Boston, Evidence-based literature has confirmed (OS) estimate was 88% for those starting write: “A review of the cause of death for the effectiveness of radiotherapy after breast- chemotherapy within 30 days, versus 87% these patients may reveal that co morbidities conserving surgery, especially among young for those starting chemotherapy within (e.g., cardiac) delaying initiation of anthra- patients. While several population-based 31 to 60 days, and 75% for those starting cycline-containing chemotherapy may be studies have investigated factors associated

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with radiotherapy compliance, the major- home is a barrier to completion of appropri- burnout among US oncologists. Altogether ity have focused on elderly populations. Esti- ate breast cancer therapy underscores the 2,998 US oncologists were contacted, of mates suggest that approximately 60% of unique challenges confronted by younger whom 1,117 (37.3% of overall sample) com- breast cancer patients diagnosed between (aged 20–50 years) cancer patients,” write pleted full-length surveys. Of these, 377 2005 and 2009 were aged less than 65 years. the authors. Additional work, they add, is (33.8%) worked in academic practice, and The current study by Ya-Chen Tina Shih needed to understand the impact of family 482 (43.2%) in private practice, with the and colleagues, from the University of Chi- structure on other aspects of cancer care and remainder working in other settings. The cago, explored factors associated with non- to develop robust interventions tailored to full-length survey included 60 questions compliance with radiotherapy among insured the unique needs of younger cancer patients. exploring a variety of personal and profes- young patients (aged 20–64 years). The sional characteristics, with burnout meas- investigators used a nationwide database to n I-W Pan, BD Smith, Y-CT Shih. Fac- ured using the Maslach Burnout Inventory review medical and prescription records of tors contributing to underuse of radiation (MBI) – a 22-item questionnaire. 21,008 patients with insurance coverage who among younger women with breast cancer. Overall results showed that 484 oncolo- received breast cancer surgery between Janu- JNCI, published online 7 December 2013, gists (44.7%) were burned out on the emo- ary 2004 and December 2009. doi:10.1093/jnci/djt340 tional exhaustion and/or depersonalisation Results showed that 892 women (4.25%) domain of the Maslach Burnout Inven- had at least one child under seven years old; tory, with 45.9% of oncologists in academic 1,584 (7.54%) had all children older than Survey finds hours of practice displaying burnout versus 50.5% of six years and at least one aged 7–12 years; those in private practice (P=0.18). In a mul- 2,016 (9.6%) had all children older than 12 care related to burnout tivariable analysis, younger age and greater and at least one child aged 13–17 years; and n Journal of Clinical Oncology number of hours spent seeing patients each 16,516 (78.62%) had no children or all chil- week were independently associated with dren aged older than 18. burnout for oncologists in both practice set- In comparison with women with one child ours per week devoted to patient care is tings. Each additional year of age reduced the under 7, those with at least one child aged Hthe dominant professional factor asso- risk of burnout by approximately 4–5%, and 7– 12 were 32% more likely to receive radio- ciated with oncologist ‘burnout’, a survey by each additional hour spent seeing patients therapy (OR 1.32, 95%CI 1.05–1.66, P=0.02); the American Society of Clinical Oncology increased the risk of burnout by 2–4%. those with one child aged 13–17 were 41% (ASCO) has found. The survey, which is the Differences between oncologists working more likely to receive radiotherapy (OR 1.41, first national study to evaluate burnout and in the different settings included that oncolo- 95%CI 1.13–1.75, P=0.002); and those with career satisfaction among US oncologists gists in academic practice were more likely to no children or children older than 18 were since 2003, reports that 45% of oncologists focus on treating patients with one particular 38 % more likely to receive radiotherapy have at least one symptom of burnout and type of cancer, spent a greater proportion of (OR=1.38, 95%CI 1.13–1.68, P=0.001). that oncologists in academic practice dis- their time supervising physicians in training, Statistically significant lower odds of play greater job satisfaction than those in and saw nearly half as many patients in out- receiving radiotherapy were observed private practice. patients per week as those in private practice among patients enrolled in a Health Main- The very fact that oncologists work long (37. 4 vs 74.2; P<0.001). tenance Organization (HMO) or Preferred hours, and are continually exposed to death Overall a higher percentage of respondents Provider Organization (PPO) with capita- and suffering, places them at risk of burn- working in academic practice than private tion versus other plan types (OR 0.70, 95% out, a syndrome characterised by emotional practice said they would become a physician CI 0.63–0.77), and for patients who trav- exhaustion, treating people as if they are again (87.5% vs 79.2%, P=0.0016) and the elled long distances for radiotherapy treat- objects, and loss of meaning or purpose in same was true about becoming an oncologist ment, determined by evaluating whether work. Studies suggest that physicians experi- again (85.1% vs 77.5%, P=0.0053). the patient’s geographical area differed encing burnout are more likely to reduce their “The strong, incremental relationship from her healthcare provider (OR = 0.72; work hours and/or pursue early retirement. between time devoted to patient care and 95%CI 0.60–0.86). In addition, results show Between October 2012 and March 2013, burnout is concerning, especially given the that patients who are the primary holders Tait Shanafelt and colleagues, supported projected shortage in the supply of oncolo- of insurance policies are more likely to have by ASCO, undertook a survey evaluating gists during the coming decades,” write the radiotherapy (OR = 1.20; 95%CI 1.10–1.31). the personal and professional characteris- authors. Given the prevalence of burnout and “Our finding that a young child in the tics associated with career satisfaction and evidence that it erodes physician personal

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health and quality of care, they add, future and social consequences of their disease and rience in the care of patients with head and studies need to focus on how to address this its treatment with advice, emotional support, neck cancer and good communication skills, problem. education and behavioural training. and are self-reliant and able to work closely Nurses opened sessions with discus- with other professionals. n TD Shanafelt, WJ Gradishar, M Kosty et al. sions of current physical problems and Burnout and career satisfaction among US oncol- explored life domains including home situ- n IC van der Meulen, AM May, JRJ de Leeuw ogists. JCO 1 March 2014, 32:678–686 ations, (resuming) work, household and lei- et al. Long-term effect of a nurse-led psychoso- sure activities, mood and emotional distress, cial intervention on health-related quality of life partner relations and intimacy and family in patients with head and neck cancer: a ran- and social life. Patients could be referred to domised controlled trial. BJC 4 February 2014, Head and neck cancer: psychiatrists or health professionals special- 110:593–601 nurse-led interventions ising in psychosocial problems. improve quality of life Patients received a maximum of six counselling sessions lasting 45 to 60 minutes Complications of prostate n British Journal of Cancer every two months, over a period of one year, starting six weeks after completion of can- cancer treatment defined urse counselling and after therapy cer treatment. Health-related quality of life n Lancet Oncology Nintervention (NUCAI) improved health- was evaluated with the EORTC QLQ-C30 and related quality of life and depressive symp- QLQ H&N35, while depressive symptoms toms among patients with head and neck were evaluated with the CES-D. atients with prostate cancer undergoing cancer, a Dutch longitudinal randomised Results show that at 12 months the inter- Pprimary radiotherapy have higher inci- controlled trial has found. vention group showed a significant improve- dences of hospital admissions, rectal or anal Patients with head and neck cancers are ment in emotional and physical functioning, procedures, open surgical procedures and prone to have poor health-related quality of including pain, swallowing, social contact, secondary malignancies than patients under- life (HRQoL) following treatment, with peo- mouth opening and depressive symptoms going surgery, a population-based retrospec- ple known to experience deterioration of (P<0.05). At 18 months, global quality of tive cohort study has found. Conversely, the HRQoL directly after starting treatment and life, role and emotional functioning, pain, Canadian investigators showed that patients up to 11 years after completion. The mul- swallowing, mouth opening and depressive who had primary surgery were more likely to tidimensional problems observed include symptoms were significantly better among undergo subsequent urological procedures. issues with emotional and physical func- patients in the intervention group than in Studies of complications resulting from tion, general cancer symptoms (e.g. fatigue the control group, and at 24 months emo- surgery or radiotherapy for prostate cancer and pain) and symptoms specific to head tional functioning and fatigue were signifi- have focused largely on symptoms of incon- and neck cancers (e.g. swallowing and dry cantly better in the intervention group. tinence and erectile dysfunction. In the cur- mouth). Nurses, who are already involved The programme, believe the authors, rent study, Robert Nam and colleagues, from with patient care, and have skills and knowl- appears a promising intervention for Sunnybrook Health Sciences Centre, Toronto, edge around medical and practical aspects implementation in daily clinical practice. set out to assess other complications associ- of head and neck cancer, are considered to “Compared with other, more intensive, ated with prostate cancer treatments. be in a key position to deliver interventions. interventions… we consider the NUCAI to The team used administrative hospital data, Between January 2005 and September be a relatively low-cost intervention, given physician billing codes, and cancer registry 2007, Ingeborg van der Meulen and col- its nurse-led approach and the relatively data to analyse a cohort of 32,465 men in leagues, from the University Medical Centre few sessions involved. Moreover, findings Ontario who underwent either radical pros- Utrecht, the Netherlands, randomly allocated suggest that it can be implemented in the tatectomy (n=15,870) or radiotherapy alone 205 patients with head and neck cancer from follow-up care for HNC [head and neck can- (n=16,595) to treat prostate cancer, between outpatient oral maxillofacial and otorhino- cer] patients, although the overall costs and 2002 and 2009. They measured the five-year laryngology clinics to NUCAI (n=103) or feasibility of the intervention remain to be cumulative incidence of key treatment-related usual care (n=102). The NUCAI intervention, investigated,” write the authors. complication endpoints: hospital admissions, provided by trained nurses, aimed to help It is important, they add, that nurses who urological, rectal, or anal procedures, open patients manage the physical, psychological offer the intervention have extensive expe- surgical procedures and secondary malignan-

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cies. To assess the baseline incidence of these Oncol February 2014, 15:223–231 Among subjects with intermediate thickness outcomes in the general population, the team n MT Eble. Complications from treatment of melanomas, ten-year disease-free survival was randomly identified 32,465 age-matched con- localised prostate cancer. ibid pp134–135 71.3% for patients in the biopsy group versus trols with no history of prostate cancer. 64.7% for those in the observation group (HR Results showed that patients given for recurrence or metastasis = 0.76; P=0.01). radiotherapy had a higher incidence of Sentinel node biopsy: For subjects with thick melanomas, ten-year complications for hospital admissions, rec- disease-free survival was 50.7% for patients in tal or anal procedures, open surgical proce- patients with intermediate the biopsy group versus 40.5% for those in the dures, and secondary malignancies at five thickness melanomas observation group (HR 0.70; P=0.03). years than did those who underwent sur- benefit most For patients with intermediate-thickness gery (adjusted hazard ratios ranged from melanomas and nodal metastases, biopsy- 2.08 to 10.8, P<0.0001). The cumulative n New England Journal of Medicine based management improved ten-year incidence in years 5 to 9 of developing a distant-disease-free survival (HR distant second malignancy was 4.5% (95%CI 3.8– metastasis 0.62; P=0.02) and ten-year mel- 5.5) in the radiotherapy group versus 1.8% entinel node biopsy prolongs distant anoma-specific survival (HR for death from (95%CI 1.3–2.4) in the surgery group. Sdisease-free survival and melanoma- melanoma = 0.56; P=0.006). This was not The most common site of second malig- specific survival in patients with lymph seen in patients with thick melanomas. For nancies was the gastrointestinal tract (87 node metastasis from primary tumours of the overall study population (where only one per 100,000 person-years in the radiother- intermediate thickness, the final ten-year in five subjects had nodal metastases) treat- apy group and 28 per 100,000 person-years analysis of the Multicenter Selective Lym- ment-related differences were not found for in the surgery group; P<0·0001). phadenectomy Trial (MSLT-I) has concluded. ten-year melanoma-specific survival. The number of urological procedures, The MSLT-I trial, initiated in 1994, set “Although some patients with nodal however, was lower in the radiotherapy out to investigate whether sentinel-node metastases from thick melanomas may group than in the surgical group (adjusted biopsy with immediate lymphadenectomy benefit from lymphadenectomy, our find- HR 0.66, 95%CI 0·63–0·69; P<0·0001). All of involved nodes yielded better outcomes ings suggest that the timing of that inter- risks were significantly higher for prostate in melanoma than ‘watchful waiting’ with vention is not as critical as it is for patients cancer patients than the 32,465 matched delayed lymphadenectomy, performed only with intermediate-thickness melanomas,” controls with no history of prostate cancer. when nodal recurrence becomes evident write the authors, adding that the number “Clinicians should discuss these complica- during observation. Sentinel-node biopsy of patients in the trial with thin melanomas tions, in addition to the well-known adverse was developed by Donald Morton, the first was too small to draw conclusions. effects of incontinence and erectile dys- author of the current study, who died just In an accompanying commentary, Charles function, with their patients when talking before publication. The five-year results of Balch from the University of Texas South- about treatment options for clinically local- the third interim analysis, published in 2006, western Medical Center, Dallas, and Jef- ised prostate cancer,” write the authors. focused on patients with intermediate frey Gershenwald from MD Anderson In an accompanying commentary, Michael thickness primary tumours, while the cur- Cancer Center, Houston, write: “This practice J Eble from RWTH Aachen University, Ger- rent ten-year follow-up data also includes changing trial shows the important role of many, writes that, while population-based patients with thick primary melanomas. early identification and surgical removal of studies have the advantage of delivering The final report involved 1,560 patients regional metastases, both in obtaining stag- sufficient patient numbers to identify small with localised cutaneous primary melano- ing information and in improving survival in increases in the risk of secondary malignan- mas who were randomly assigned to undergo defined cohorts of patients with melanoma.” cies, the effects can be “negated by the pres- sentinel-node biopsy plus immediate lym- ence of unbalanced confounders”. phadenectomy if metastases were detected n DL Morton, JF Thompson, AJ Cochran. Final in sentinel nodes (n=943) or close observa- trial report of sentinel-node biopsy versus nodal n R Nam, P Cheung, S Herschom et al. Inci- tion with delayed lymphadenectomy if nodal observation in melanoma. NEJM 13 February dence of complications other than urinary metastases developed during observation 2014, 370:599–609 incontinence or erectile dysfunction after radi- (n=617). Altogether 1,270 patients had inter- n CM Balch, JE Gershenwald. Clinical value of cal prostatectomy or radiotherapy for prostate mediate thickness lesions (1.20–3.50 mm) and the sentinel-node biopsy in primary cutaneous cancer: a population-based cohort study. Lancet 290 patients had thick lesions (>3.50 mm). melanoma. ibid pp663–664

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