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Comparing notes: UK's cancer leaders discuss the latest advances

Published on 28/10/09 at 08:57am
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The field of oncology is one of the most dynamic in medicine today, with developments in technology and practices helping to revolutionise treatment and extend patients' lives as never before. The pace of change is so fast that clinicians need regular updates, and to that end a Cancer Congress Update was organised by medical education agency Succinct Healthcare Communications in London in July.

The meeting, sponsored by a group of pharma companies working in oncology - AstraZeneca, Novartis, Roche, Sanofi-Aventis and Teva - was aimed at helping clinicians glean the key, UK-relevant issues from the past year's international cancer meetings.

Clinicians are increasingly specialising along the lines of tumour type, which makes it difficult for them to keep up to date with developments outside their own field.

Mark Verrill, consultant medical oncologist at the Northern Centre for Cancer Care, was the first to underline the value of comparing notes. Opening the meeting, he said: "We all work in specialist niches in cancer, and when we go to the big international meetings, we attend the talks relating to our own area of work. But today's event is a terrific opportunity to see what is happening in the other cancer specialities."

This observation was reiterated throughout the day, as specialists in colorectal, breast, prostate, lung and haematological cancers shared observations and ideas. Leading oncologists and haematologists who might never meet professionally suddenly found they had a great deal to learn from each other, and several common themes emerged between seemingly disparate tumour groups.

Morning sessions

In keeping with the broad range of cancer specialities represented in the audience, the morning sessions were chaired by a professional whose work crosses the boundaries of the tumour groups - David Thomson, chair of the British Oncology Pharmacy Association (BOPA). He observed that the classification of cancers looks likely to be subdivided even further as molecular studies spot key differences between tumours with seemingly identical histology. "This knowledge will allow us to deliver the right drugs to the right patients," he said. "But to apply this knowledge in clinical care, we will need to have access to predictive tests, and we know from the introduction of HER2 testing that this is not always easy. We will also need to change services. We are told that targeted therapy will cut treatment costs, but I am not sure whether costs will be lower overall."

Keynote address: Cancer - a chronic disease?

Whereas cancer was seen largely as a terminal disease just 10 - 15 years ago, there are now moves to classify it as a chronic disease, with an emphasis on long-term disease control.

David Cameron, director of the National Cancer Research Network, said focusing initially on the four most common solid tumour sites - breast, lung, colorectal and prostate - would help promote this agenda. "Some of the indolent malignancies, such as follicular lymphoma, are already chronic conditions, but they affect only small numbers of patients. Managing the four most common solid tumours as chronic diseases will present far more of a challenge."

Taking breast cancer as an example, he cited the enormous improvements in survival over the past three decades, not only in women receiving adjuvant treatment, but also in those who present with metastatic disease. Advances have been made in all the modalities, including screening, surgery, radiotherapy, chemotherapy and endocrine therapy. "It's been a real team effort," he said. "And as a result, metastatic breast cancer is beginning to look like a chronic condition - 25% of these women are still alive at five years." However, he stressed that his primary aim in managing locally advanced breast cancer would remain cure. "Local disease can be incredibly destructive. It is better to get rid of it than manage it chronically.

He emphasised the key differences between the two approaches. A cure would mean a patient's risk of death was the same as that in the underlying population, an outcome that can take decades to demonstrate. Chronic disease management, on the other hand, meant accepting that patients might not survive as long as their peer group.

If cancer does start to fall into the chronic disease category, it will be important to address the issues facing survivors - for example, recognition of signs of recurrence, recognition and management of long-term toxicities and difficulties with employment and financial security. Cancer specialists will also have to learn to "let go" of patients into shared care, since hospitals will not be able to manage large numbers of survivors, and it is inappropriate to ask patients to attend frequent appointments in secondary care during a management period that might span decades.

Professor Cameron pondered whether headline biological therapies such as imatinib (in gastrointestinal stromal tumours) and trastuzumab (in breast cancer) would need to be given for a longer duration - and thus greater cost - in a chronic disease management context. "Will we be able to afford it?" he asked. Chronic management would also rely on a better understanding of how to target therapy at tumour subgroups. Furthermore chronic care would intensify the importance of balancing treatment benefits and side effects.

From a financial perspective, chronic management would increase the burden to the NHS. "Chronically ill patients are expensive to look after," he reminded everyone.

He closed his presentation by stating: "We need to continue to aspire to cure cancer as well as control it."

The discussion then turned to practical implications of shared care for chronic cancer. Prof Cameron said services would need to be redesigned. "We can't just hand patients back to primary care," he said. Instead, he proposed shared care could be facilitated if just one GP across each local area became trained and recognised as a specialist in chronic cancer management. He warned that service re-design might prove expensive.

Advances in colorectal cancer

The theme around current single disease entities splitting into multiple conditions was revisited by Rob Glynne-Jones, consultant clinical oncologist at Mount Vernon Hospital in Middlesex. He recalled how delegates at the 2009 meeting of the American Society of Clinical Oncology (ASCO) learnt that stage II and stage III colon cancers show significant differences in the frequency of several key markers. This finding, which has emerged from the PETACC 3 adjuvant trial, offers the intriguing suggestion that stage II and stage III are different diseases, rather than sequential steps in one cancer.

Another highlight of ASCO was the presentation of results from NSABP C-08, a phase III trial in which patients with colon cancer were treated with mFOLFOX6 (5-fluorouracil, leucovorin and oxaliplatin) with or without the angiogenesis inhibitor bevacizumab, which was given for 12 months. Although there was no significant difference in disease-free survival (DFS) at three years, patients in the bevacizumab group were more likely to survive to one year than those treated with mFOLFOX6 alone (hazard ratio, 0.6; p=0.0004). "So bevacizumab is obviously doing something - while patients are receiving it," said Dr Glynne-Jones.

He also cited evidence presented at this year's ASCO and the 2009 World Congress on Gastrointestinal Cancer (WCGIC) showing high response rates in patients treated with a biological agent as well as chemotherapy. For example, cetuximab (an epidermal growth factor receptor [EGFR] inhibitor) improves the response rate in patients with the wild-type KRAS marker, while bevacizumab is effective in those with mutant KRAS and improves the quality of the response. Dr Glynne-Jones was particularly impressed to see response rates in colorectal cancer as high as 77% for patients receiving FOLFOXIRI (irinotecan, oxaliplatin, 5-fluorouracil and leucovorin) plus bevacizumab (Masi et al, WCGIC 2009) and 79% for those receiving irinotecan, oxaliplatin and 5-fluorouracil plus cetuximab. He said this sort of therapeutic approach might be used in future to improve long-term survival in a range of different patients with locally confined unresectable disease, for example in the liver or lung. There was also evidence, he said, from the LIFE, FOCUS and CAIRO 1 studies suggesting that monotherapy might be appropriate for selected patients with unresectable disease.

Returning to the issue of disease markers, Dr Glynne-Jones summarised several presentations from ASCO 2009 that focused on features that might predict treatment outcomes. Lambrechts showed that KRAS, BRAF and NRAS markers are mutually exclusive, and occur in 47% of patients with colorectal cancer. Jonker presented data showing that wild-type KRAS and high expression of epiregulin (an EGFR ligand) predicted a good response to cetuximab. Prennan et al showed that low EGFR ligand expression predicts a poor outcome after treatment with cetuximab plus irinotecan. Loupakis reported response rates of 37% in patients with wild-type KRAS and high EGFR ligand levels, compared with 9% in those with low EGFR.

Another topic of interest at ASCO 2009 was the importance of good-quality surgery to outcomes in colorectal cancer. Dr Glynne-Jones cited a report from Germany showing that radical surgery achieves 70¿80% 5-year overall survival without any chemotherapy being given. In light of this evidence, he questioned the common UK NHS practice of delegating right hemicolectomy to registrars.

The ensuing discussion focused initially on the cost of biological agents, the likely optimum duration of their use and the question of whether bevacizumab, for example, works by killing cancer cells or by inhibiting disease progression. Dr Glynne-Jones said: "We really do not understand what is happening in the adjuvant setting, but if bevacizumab was cheap I think we would consider using high doses for perhaps three years. Meanwhile, we could select very high-risk patients, but we have to consider whether we can afford the extremely high cost- even if it works."

Asked if any oral biological alternatives to bevacizumab or cetuximab were available. Dr Glynne-Jones said evidence was emerging on the use of oral tyrokinase inhibitors (TKIs), and that phase III data should be available in the next 12 - 18 months.

Referring to the high rate of five-year survival following radical surgery alone for colorectal cancer, a delegate asked if postsurgical PET scanning was routinely used to check the excision of lymph nodes. Dr Glynne-Jones said PET would produce aberrant results in the first six weeks, but acknowledged that there is not always a "sophisticated" approach to the assessment of surgical outcomes.

Dr Verrill remarked that the approach to surgery was one feature that sharply divided the management of breast cancer and colorectal cancer, smaller resections being increasingly the norm in the former. Dr Glynne-Jones expressed concern about the risk of residual tumour after colorectal surgery.

Emerging data and therapies for patients with lung cancer

Having listened to Dr Glynne-Jones, the next presenter - Nicholas Thatcher from The Christie Hospital in Manchester - commented on the fascinating similarities and differences between colorectal and lung cancer.

Among recent trials of first-line targeted therapy, Professor Thatcher highlighted Scagliotti's work on cisplatin plus pemetrexed (an inhibitor of thymidylate synthase) versus cisplatin plus gemcitabine in non-small-cell lung cancer (NSCLC). Although no difference in overall survival was seen in the study group as a whole, pemetrexed was associated with an increase in overall survival in patients with adenocarcinoma. "This is a break point for NSCLC," said Professor Thatcher.

Looking at the data now accumulating on anti-angiogenic targeted therapies in lung cancer, he noted that patients with squamous tumours tend to do less well than those with non-squamous disease, in terms of both survival and toxicity. The reasons for this difference are not yet known.

The FLEX trial, reported at ASCO 2009, has shown that the addition of cetuximab to chemotherapy for patients with advanced, EGFR-expressing NSCLC improves survival during the maintenance phase, and the effect persists after cetuximab is stopped. Moreover, cetuximab's effects are evident in all NSCLC pathologies, including squamous. Patients in the cetuximab group who develop a rash show improved survival compared with those who do not - thus suggesting a possible predictive marker. More on FLEX

Professor Thatcher observed that there have been few trials of maintenance therapy in NSCLC, largely because the disease progresses rapidly and only about 50% of patients are ever eligible for maintenance. However, delegates at ASCO learnt that patients with non-squamous NSCLC or adenocarcinoma gained extended overall survival in response to pemetrexed maintenance therapy versus placebo, both combined with best supportive care.

Turning to the SATURN trial of sequential erlotinib (an oral TKI) in unresectable NSCLC, Professor Thatcher questioned the value of progression-free survival (PFS) as a study endpoint - erlotinib was associated with a significant improvement in PFS at both 12 and 24 weeks. He cited various pitfalls to the use of PFS. Progression can be silent. Poor data handling and hence missing data tend to maximise PFS values. Large differences in PFS are needed to translate into a survival benefit. Furthermore, repeated assessments increase the burden on patients. In any case, the correlation between PFS and overall survival is extremely poor in lung cancer - in contrast to the good correlation seen in colorectal cancer.

He noted also that ethnicity could have a major effect on the prevalence of disease markers, and hence on the response to biological agents. For example, a trial in Japanese patients found a 100% rate of EGFR mutations, and a 66% overall response to therapy targeted at this marker (gefitinib). However, the INSTEP study of gefitinib versus placebo, based on patients from Europe and Australia, found no significant effects.

Professor Thatcher posed a question: "Is EGFR mutation a favourable prognostic factor rather than a predictive factor?" He cited retrospective evidence showing that patients with EGFR mutation survive longer than those without, regardless of treatment. "So we are talking about two different cancers, even though they look the same at histology," he said.

Because erlotinib is targeted at EGFR, rational use of the drug will require EGFR testing. "We need to get this test up and running in the NHS now," Professor Thatcher insisted.

He added that while surgical quality was a key issue in colorectal cancer, the work of the pathologist was key in NSCLC. The current level of variability in pathology reports could be a problem if a treatment is approved for use in, for example, adenocarcinoma, but not other forms. On the other hand, if clinical predictors such as rash prove to be significant "our eyes and hands may be as useful as fancy lab tests."

Targeting breast cancer: tailoring management

Paul Ellis, consultant medical oncologist at Guy's and St Thomas', London, considered three key areas of targeted management in breast cancer - HER2, angiogenesis inhibition and treatment for triple-negative disease.

He said that pivotal trials, involving more than 13,000 women, all agreed that adjuvant trastuzumab provided an overall survival benefit. This same assurance was delivered to delegates at the 2009 Primary Therapy in Early Breast Cancer (PTEBC) conference in Switzerland. In the HERA trial, an apparent loss of significant benefit after 4 years of follow up is explained by extensive crossover to the trastuzumab arm in 2005. Indeed, a landmark analysis, presented at PTEBC, shows a clear separation in disease-free survival between those who crossed over and those who did not. A similar trend is apparent in overall survival, but it is not possible to rule out bias related to why patients did or did not elect to cross over.

Presentations at both ASCO and the latest San Antonio Breast Cancer Symposium (SABCS) looked at the use of trastuzumab in patients with low-risk HER2-positive disease. For example, Rakkhit et al showed evidence that the treatment benefits even those with tumours no larger than 1 cm in diameter.

Dr Ellis said: "Many women with low-risk breast cancer ask me if they can have trastuzumab. What is the answer? Would they benefit from trastuzumab - alone or with chemotherapy? If we do add chemotherapy, would the gain be worthwhile? Is there an appetite for a trial in low-risk patients?"

SABCS was also the venue for evidence from the NOAH trial, which has previously shown that neoadjuvant trastuzumab improves pathological complete response rates in HER2-positive women. The latest data on event-free and disease-free survival have not reached significance, largely because of cardiac toxicity, but Dr Ellis described the trial so far as providing "food for thought" in the neoadjuvant setting.

Abstracts presented at ASCO and SABCS addressed dual targeting with both pertuzumab and trastuzumab in women with metastatic breast cancer who had already received trastuzumab, and suggested that the combination is effective, with manageable toxicity. Further trial results are awaited.

Dr Ellis went on to look at data presented at ASCO 2009 on the use of bevacizumab in metastatic breast cancer. He said he felt encouraged by the efficacy and safety profile of the treatment in this setting, although it is still not clear how the drug would fit into UK practice. Again there remain unanswered questions. Should bevacizumab be the standard of care for metastatic breast cancer? Should it be used with a taxane? When should the treatment stop? Can the UK afford to use the treatment until disease progression?

Returning to the recurrent theme of disease sub-classification, Dr Ellis pointed out that triple-negative breast cancer is defined by negative test results, and is thus not just one disease. However, promising results are emerging from studies of targets and disease pathways.

A small trial presented at ASCO 2009, based on the effects of platinum agents on the DNA repair pathway, used cisplatin monotherapy in BRCA1 carriers with triple-negative breast cancer and produced complete response rates of 72% and partial response rates also of 72%. A randomised trial will be needed before these findings affect practice.

Results are awaited from TNT, a UK-based randomised phase III trial comparing docetaxel and carboplatin in triple-negative disease.

Poly(ADP-ribose) polymerase (PARP) also plays a role in DNA repair, and studies of PARP inhibitors were the subject of two major presentations at ASCO 2009. The oral PARP inhibitor olaparib, used in BRCA1/2 carriers, has produced encouraging results in a multicentre proof-of-concept study. The survival results in a small study of a PARP inhibitor known as BSI-201, used in combination with gemcitabine and carboplatin, were described as "impressive" by Dr Ellis, and he is looking forward to data from a larger trial, scheduled to start in summer 2009. He said: "It feels as though we are entering a new chapter in the management of triple-negative breast cancer, a disease that often has comparatively poor outcomes with conventional chemotherapy."

The discussion following this presentation kicked off with a reiteration of the need for - and cost of - clinical trials of novel treatments. Mr Thomson pointed out that studies of side effects could be run by pharmacists and/or nurses, at a lower cost than doctor-led research.

Professor Thatcher suggested that nurses could also be key to ensuring effective management of patients who experience side effects in the community. He said some GPs stop erlotinib treatment when patients develop a rash, being unaware that it is a positive indicator. Dr Verrill took up the point of late side effects, which are rarely reported to oncologists. Crucially, cardiac toxicity associated with anthracyclines is generally referred to cardiology rather than cancer services.

The afternoon sessions were chaired by Annie Young, past president of the UK Oncology Nursing Society (UKONS). She said she had been to ASCO many times "and believe me, this is better." Like Dr Verrill, she appreciated an overview of different tumour types as well as a UK perspective, and was intrigued by the similarities and differences evident between cancers.

Developing systemic strategies in prostate cancer

Amit Bahl, consultant clinical oncologist at the Bristol Haematology and Oncology Centre, began his talk by explaining that the term "hormone refractory" is now obsolete in prostate cancer, and that castration-resistant prostate cancer (CRPC) is the preferred term.

He then focused on several presentations from ASCO. One showed that the time to prostate-specific antigen (PSA) relapse, not Gleason score, is the key prognostic determinant in the disease. A PSA doubling time of less than three months suggests metastases will develop within one year, whereas a doubling time of 15 months or longer predicts at least a decade without metastases.

Also highlighted were results from SWOG S9921, a trial of adjuvant combined androgen deprivation with or without mitoxantrone chemotherapy in patients with high-risk prostate cancer. The findings suggest that 2 years of combined androgen deprivation is effective but that longer follow up will be needed to examine any survival benefits from mitoxantrone.

Another ASCO 2009 presentation reported encouraging initial findings with MDV 310, a second-generation anti-androgen engineered for activity in prostate cancer. A phase III trial in docetaxel pre-treated patients begins in 2009.

Clusterin, a protein that confers resistance to radiation and cytotoxic drugs in prostate cancer, is now a novel treatment target. Dr Bahl described a phase II study, presented at ASCO 2009, in which men with metastatic CRPC were given docetaxel with or without OGX-011, an anti-sense nucleotide to clusterin. Median overall survival was 23.8 months in the OGX-011/docetaxel group, compared with 16.9 for docetaxel alone.

Dr Bahl then turned to recent findings in the field of immunotherapy - and admitted: "even a sceptic like me can start to believe that vaccines may have a role in prostate cancer". He said that although the modality has so far failed to show any effect on pain, PSA or measurable disease, some unexpected survival improvements have been seen in phase II trials of the vaccine sipuleucel. PROSTVAC-VF-Tricom has also produced some encouraging results.

A delegate posed a particular interesting question for Dr Bahl during the discussion period. "Could we develop an antagonist for the PSA receptor." Dr Bahl said PSA was "both a blessing and a curse" as a prostate cancer marker, and often produced anomalous results. He hopes that a better marker, a measure of circulating tumour cells, will soon come into clinical practice. Cost is currently a barrier to uptake, although patients are already asking for access to the new test.

Dr Verrill asked why chemotherapy is so little used in prostate cancer, particularly in comparison with breast cancer. Dr Bahl said that low awareness of the potential benefits of chemotherapy among urologists continues to be a barrier to oncology referral for many men. "We need to change perceptions about chemotherapy for prostate cancer," he said.

New developments in myeloma and lymphoma

Steve Schey, consultant haematologist at King's College Hospital, London, said that several new developments in myeloma and lymphoma had been reported at major meetings.

O'Shaughnessy et al reported to ASCO 2009 that an 80-gene signature after treatment with bortezomib (post-BOR) can identify high-risk versus low-risk multiple myeloma. There were also reports of new agents for the condition. Carfilzomib (as yet unlicensed) has produced evidence of durable disease control without serious toxicity problems in a phase II trial, and there are encouraging phase I data on popalidomide. Other novel treatments for multiple myeloma discussed at ASCO 2009 include NPI-0052 (a proteasome inhibitor), vorinostat and tanespimycin.

Dr Schey said that three-drug and four-drug combinations were being explored in myeloma. ASCO 2009 witnessed data on bortezomib, melphalan and prednisone (VMP) versus VMP plus thalidomide (VMPT). Although the complete response rate was higher with the four-drug regimen, no difference was seen in survival outcomes.

Various three-drug and four-drug combinations for myeloma were described at the American Society of Hematology (ASH) conference in 2008. Lenalidomide, cyclophosphamide and dexamethasone produce an overall response rate of 78% in patients with newly diagnosed myeloma. There is a 90% overall response rate to a combination of bortezomib, cyclophosphamide, thalidomide and dexamethasone used as first-line therapy for multiple myeloma. Another four-drug regimen - bortezomib, dexamethasone, cyclophosphamide and lenalidomide - produces a "very good response rate" of 68%.

The past year has also seen interesting developments in the use of novel agents in patients receiving autologous stem cell transplantation, either in place of or in addition to current high-dose therapy. High rates of partial response, complete response and very good response have been reported with various conditioning and maintenance regimens. But Dr Schey pointed out that the costs involved are "huge."

He concluded that the past year has been an "exciting, helter-skelter time" for lymphoma and multiple myeloma, and that survival has improved over the past 10 years. However, most patients with follicular lymphoma or myeloma still die from their disease. "The treatment paradigm is changing, and we need well designed clinical trials to show how best to use novel agents," he said.

Mr Thomson commented that there appears to be "an embarrassment of riches" in myeloma, but it remains difficult to see how some established agents fit in to clinical practice. Dr Schey pointed out that myeloma is a heterogeneous disease, and that new agents, perhaps combined with genetic analysis, may facilitate individualised patient management.

Implications for cancer treatment in UK: discussion

The two congress chairs and some of the previous speakers were joined by Jamie Ferguson, consultant in public health medicine at Lambeth PCT and medical director of the SE London Cancer Network, to form a discussion panel in the final session of the congress.

As a purchaser, Dr Ferguson was asked to comment on how the current financial climate would affect PCTs. He said: "In theory, the current spending review runs until March 2011, but I don't think this means that NHS spending will be left alone until then. There is now an atmosphere of prioritisation. We can expect to see pay freezes, changes to NICE thresholds and decisions at a national level aimed at making savings. We might even hear the R word [rationing].

"At local level, you will hear more about programme budgeting, which means comparing your spending in a given disease area with that of others across the country. You can expect to be challenged. And if you want to introduce a new drug you will need to show evidence of savings that will be made elsewhere."

Dr Schey maintained that money was still in the system, referring to current NHS spending on tattoo removal, the cost of "just one antihypertensive drug" and the government's bail-out of a well known bank.

Dr Verril commented that money appears to be available for people to "beancount and check on targets" yet it was difficult to fund clinical trials.

Ms Young suggested that healthcare professionals could help by improving their clinical data collection systems. Mr Thomson agreed, saying that data on how we use drugs is urgently needed.

Mr Thomson suggested that the quality of adjusted life year (QALY) that underpins health technology decisions is a crude measure. Dr Ferguson agreed, saying there was a long way to go in health economics and said there was little involvement of patients in assessing how life is valued.

Dr Bahl said that healthcare professionals could not simply deny the effects of financial pressure. "We have to take responsibility for spending. The NHS is not an endless pot. We need to look more carefully at clinical trials and make sure, for example, that proper comparators are used."

A debate involving panel members and delegates centred again on the clinical meaningfulness of PFS. Dr Verrill said PFS is useful in breast cancer research, where it correlates well with overall survival. "We're impatient - and PFS helps to get data out quickly. But it's a surrogate endpoint, and doesn't mean very much to patients."

There had been several references during the meeting to molecular markers for cancer, and Dr Verrill said there was a need for robust testing systems with quality assurance. Dr Ferguson agreed that the NHS has been "slow off the blocks" with molecular testing, but he feared that the current financial situation did not bode well for the development of an effective testing infrastructure. "But patients will demand the new tests and the new drugs, and the NHS might not be able to say no."

Congress close

Dr Verrill said: "This has been a great meeting. We all usually talk to people who treat the same cancers as ourselves, and it has been fascinating to see the amount of commonality between different tumours. The congress has brought us into one big cancer family."

He warmly thanked the sponsors, AstraZeneca, Novartis, Roche, sanofi-aventis and Teva - without whom this valuable meeting would not have happened.

Looking back over the main themes of the day, Dr Verrill welcomed the news of so many new tests and new treatments for common cancers, but he quipped: "The showstopper will be the development of grade 5 financial toxicity."

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