UK Third National Colorectal Cancer Consensus Meeting 2008

Abstract

Building on the success of two previous years [1Symonds P. National Colorectal Consensus Group UK National Colorectal Cancer Consensus Meeting 2006.Clin Oncol (R Coll Radiol). 2007; 19: 234-236Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 2Glynne-Jones R. UK second National Colorectal Cancer Consensus Meeting 2007.Clin Oncol (R Coll Radiol). 2008; 20: 365-368Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar], the third National Colorectal Cancer Consensus Meeting was held at the Royal College of Physicians in London on 18 November 2008. More than 200 people attended the meeting, including medical and surgical oncologists (42%), nurses (23%), other healthcare professionals (8%) and patients (11%). The meeting included presentations and debates on new national strategies for the delivery of care and on cutting-edge technologies, by a range of experts in oncology, scientific research, law and politics, with interaction from the audience through questions and keypad voting. After the Department of Health's announcement on 4 November 2008 of plans to increase patient access to care, including the option for patients to pay for some of their treatment while still receiving National Health Service (NHS) care (termed ‘co-payment’ or ‘topping up’), much of the meeting focused on these strategies, including the first session introduced by Ivan Trotman, Network Director at the Mount Vernon Cancer Centre in London. The issue of co-payment and ‘exceptional circumstances’ requests have led to a polarised debate, both in the media and the medical press [3Clarke R. Waddell T. Gallagher J. et al.A postcode lottery still exists for cancer patients with exceptional circumstances (Letter).Clin Oncol (R Coll Radiol). 2008; 20: 771-772Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar, 4Sikora K. James N. Top-up payments in cancer care.Clin Oncol (R Coll Radiol). 2009; 21: 1-5Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 5Glynne-Jones R. Beaumont I. Why co-payment is a cop-out for us all.Clin Oncol (R Coll Radiol). 2009; 21: 6-7Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar]. Some argue that patients will suffer, either because they cannot afford to pay for treatments not available on the NHS or because they are being stopped from contributing financially towards part of their own healthcare. When the audience was asked ‘Should patients be denied the right to use their money to prolong their life’, a resounding 86% said ‘no’. Overall, concerns were raised about the lack of widespread discussion before the introduction of the new co-payment plans, and 84% of participants called for a national debate on NHS funding of medicines. Chris Newdick, barrister and professor of health law at the University of Reading, focused on the legal considerations of co-payments. In the Code of Conduct for Private Practice published in 2004 [6Department of Health A code of conduct for private practice: recommended standards of practice for NHS consultants. Department of Health, London2004Google Scholar] the Department of Health specified that ‘A patient cannot be both a private and a NHS patient for the treatment of one condition during a single visit to a NHS organization’. However, the National Health Service Act 2006 [7National Health Service Act 2006 http://www.opsi.gov.uk/Acts/acts2006/ukpga_20060041_en_1Google Scholar] states: ‘The services so provided shall be free of charge except in so far as the making and recovery of charges is expressly provided for’. Thus the Act leaves room for co-payment if it is expressly provided for, and indicates that the Code of Conduct for Private Practice could itself be unlawful in stopping a patient from receiving NHS treatment if one component is only available privately. Professor Newdick also highlighted the difficulties in helping patients make informed decisions, calling for a national standard template that would help doctors explain decision-making issues, such as numbers needed to treat, absolute benefits and relative benefits compared with the next-best available treatment. Ian Gibson, MP for Norwich North and chair of the All-Party Parliamentary Group on Cancer, expressed his belief that co-payment is not the best solution and that it is more important to reform the National Institute for Health and Clinical Excellence (NICE), repair the inefficiencies in the health service and find other ways to increase access to treatment for all. The audience highlighted the need for accurate assessment of patients to identify those in whom treatment is most likely to succeed, so that nobody wastes money on ineffective treatment. Fergus MacBeth, Director of the Centre for Clinical Practice, NICE, gave an update on the development of new clinical guidelines for colorectal cancer. NICE is currently recruiting a chair and lead clinician for the guideline development group. The scope consultation and stakeholder meeting will be in February 2009 and submission of the first draft of the guideline is planned for December 2009, with publication of the guideline planned for July 2010. The guideline will focus on areas of colorectal cancer management where there is uncertainty or variation, or areas where new options are available. It will offer realistic recommendations, looking at what is most appropriate and achievable with the available resources. He welcomed widespread contribution from all healthcare professionals, and provided forms and a website to allow review and comment on an initial outline of what might be included in the clinical guideline. Since the 1970s, mortality from rectal cancer has been decreasing steadily [8Ohlsen A.H. Parkin D.M. Sasieni P. Cancer mortality in the United Kingdom: projections to the year 2025.Br J Cancer. 2008; 99: 1549-1554Crossref PubMed Scopus (63) Google Scholar] as a result of continuing improvement in care rather than one big change. Optimal results depend on accurate preoperative staging, high-quality surgery by a specialist team and appropriate additional therapy. Preoperative radiotherapy can be delivered in a short course of five fractions over 1 week, with surgery within 10 days after the first fraction. Long-course radiotherapy typically involves 25–28 fractions over 5–6 weeks, with a 4–8-week delay before surgery to allow the morbidity to settle. Both strategies can result in significantly lower local recurrence rates, but tumour shrinkage is only achieved with long-course radiotherapy. Ian Geh, Consultant Clinical Oncologist at the Queen Elizabeth Hospital in Birmingham, explained that the rationale for short-course preoperative radiotherapy (SCPRT) comes from the Swedish Rectal Cancer Trial [9Swedish Rectal Cancer Trial Improved survival with preoperative radiotherapy in resectable rectal cancer.N Engl J Med. 1997; 336: 980-987Crossref PubMed Scopus (2266) Google Scholar], in which the rate of local recurrence was reduced from 27% after surgery alone to 11% after SCPRT followed by surgery (P<0.001). Overall 5-year survival also improved from 48% with surgery alone to 58% with SCPRT and surgery (P=0.004). The quality of surgery in that trial was not the current standard of Total Mesorectal Excision (TME), which has local recurrence rates of around 11% [10Peeters K.C. Marijnen C.A. Nagtegaal I.D. et al.The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma.Ann Surg. 2007; 246: 693-701Crossref PubMed Scopus (901) Google Scholar, 11Sebag-Montefiore D. Steele R. Quirke P. et al.Routine short course pre-op radiotherapy or selective post-op chemoradiotherapy for resectable rectal cancer? Preliminary results of the MRC CR07 randomised trial.J Clin Oncol. 2006; 24: 3511PubMed Google Scholar]. Later trials, including the Dutch Colorectal Cancer Group TME trial [10Peeters K.C. Marijnen C.A. Nagtegaal I.D. et al.The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma.Ann Surg. 2007; 246: 693-701Crossref PubMed Scopus (901) Google Scholar] and the Medical Research Council CR07 trial [11Sebag-Montefiore D. Steele R. Quirke P. et al.Routine short course pre-op radiotherapy or selective post-op chemoradiotherapy for resectable rectal cancer? Preliminary results of the MRC CR07 randomised trial.J Clin Oncol. 2006; 24: 3511PubMed Google Scholar] have shown that the use of SCPRT before TME can produce further reductions in local recurrence beyond that achieved with TME alone, from 10.9 to 5.6% (P<0.001) in the Dutch trial [10Peeters K.C. Marijnen C.A. Nagtegaal I.D. et al.The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma.Ann Surg. 2007; 246: 693-701Crossref PubMed Scopus (901) Google Scholar] and from 11.1 to 4.7% (P<0.001) in the CR07 trial [11Sebag-Montefiore D. Steele R. Quirke P. et al.Routine short course pre-op radiotherapy or selective post-op chemoradiotherapy for resectable rectal cancer? Preliminary results of the MRC CR07 randomised trial.J Clin Oncol. 2006; 24: 3511PubMed Google Scholar]. Dr Geh concluded that, as SCPRT reduces local recurrence beyond that achieved by high-quality TME, it should be used in most patients with resectable rectal cancer. Mark Harrison, Consultant Clinical Oncologist at the Mount Vernon Cancer Centre in London, presented the opposing side of the debate, stating that the ‘one size fits all’ hypothesis does not work in rectal cancer therapy. He showed that, in both the Swedish and the Dutch studies, clear benefit was achieved only in patients with later stages of disease (Table 1).Table 1Effect of radiotherapy on 5-year local recurrence rates, by tumour stage in the Dutch TME study 10Peeters K.C. Marijnen C.A. Nagtegaal I.D. et al.The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma.Ann Surg. 2007; 246: 693-701Crossref PubMed Scopus (901) Google ScholarLocal recurrence rates at 5 yearsTNM ITNM IITNM IIISCPRT+TME0.4%5.6%11.2%TME alone1.7%7.7%21.5%Number needed to treat77489SCPRT, short-course preoperative radiotherapy.TME, total mesorectal excision. Open table in a new tab SCPRT, short-course preoperative radiotherapy. TME, total mesorectal excision. Also of concern are the late effects of SCPRT, which was associated with a 35% rate of cardiovascular disease (vs 19% with surgery alone, P=0.032) and a 46% rate of urinary incontinence (vs 27% with surgery alone, P=0.023) in the Swedish trial [12Pollack J. Holm T. Cedermark B. et al.Late adverse effects of short-course preoperative radiotherapy in rectal cancer.Br J Surg. 2006; 93: 1519-1525Crossref PubMed Scopus (161) Google Scholar, 13Birgisson H. Påhlman L. Gunnarsson U. Glimelius B. Adverse effects of preoperative radiotherapy for rectal cancer: long-term follow-up of the Swedish Rectal Cancer Trial.J Clin Oncol. 2005; 34: 8697-8705Crossref Scopus (313) Google Scholar]. Other late problems include fistulae, paralytic bowel, bowel obstruction, abdominal pain and second malignancies [14Birgisson H. Påhlman L. Gunnarsson U. et al.Occurrence of second cancers in patients treated with radiotherapy for rectal cancer.J Clin Oncol. 2005; 23: 6126-6131Crossref PubMed Scopus (190) Google Scholar, 15Braun M.S. Richman S.D. Adlard J.W. et al.for the FOCUS Trial Investigators. Association of topoisomerase-1 (Topo1) with the efficacy of chemotherapy in a randomized trial for advanced colorectal cancer patients (FOCUS).J Clin Oncol. 2006; 24: 10009Google Scholar]. Dr Harrison proposed that, rather than using SCPRT routinely in all patients, it should be used in a subset depending on their disease stage, for example in patients with node-positive T3 tumours with no involved margins (as predicted by magnetic resonance imaging). Earlier stages should have surgery alone, and those with more advanced disease should be given preoperative chemoradiation before surgery. However, identifying the subgroup of patients who would benefit most from preoperative radiotherapy would not be a clear-cut process based on existing evidence. The audience was asked whether the benefits of preoperative radiotherapy for rectal carcinoma were currently being clearly explained to patients; nearly half (47%) said they thought not and a further quarter (23%) were undecided. In addition, 66% of the audience thought that clinicians were not sufficiently transparent when explaining late side-effects and 21% were unsure. When the responses were analysed further, it became clear that the clinician's confidence in their ability to communicate the issues was not always reflected in the patient's experience. One patient related his experience of finding out that he had cancer, being told that he would need radical surgery and being advised against radiotherapy all within 5 min, giving him no time to absorb and process the information. The split between patients and healthcare professionals became even clearer when delegates were asked to balance a 5% increase in cure against a 10% risk of faecal incontinence. Overall, more than half of the respondents said that they would accept the risk under these circumstances, but the acceptance rate was substantially lower among the patients. If the risk of incontinence is raised to 20%, only 40% of respondents overall and no patients would accept the risk. Jim Cassidy, Professor of Medical Oncology at the Beatson Oncology Centre in Glasgow, introduced three presentations on the current status and future direction of molecular profiling of patients. In the first of these presentations, Tim Maughan, Professor of Cancer Studies at Cardiff University, pointed out that, despite growing support for monoclonal antibody therapy, the benefit seems to be limited to only a subset of patients [15Braun M.S. Richman S.D. Adlard J.W. et al.for the FOCUS Trial Investigators. Association of topoisomerase-1 (Topo1) with the efficacy of chemotherapy in a randomized trial for advanced colorectal cancer patients (FOCUS).J Clin Oncol. 2006; 24: 10009Google Scholar, 16Karapetis C.S. Khambata-Ford S. Jonker D.J. et al.K-ras mutations and benefit from cetuximab in advanced colorectal cancer.N Engl J Med. 2008; 359: 1757-1765Crossref PubMed Scopus (3051) Google Scholar]. For example, the monoclonal antibody cetuximab, which targets the epidermal growth factor receptor (EGFR), does not seem to achieve the same benefit in patients with K-ras mutations in their tumours (median survival 4.5 months with cetuximab vs 4.6 months without cetuximab, P=0.89) as it does in patients with wild-type K-ras (median survival 9.5 months with cetuximab vs 4.8 months without cetuximab, P<0.001) [16Karapetis C.S. Khambata-Ford S. Jonker D.J. et al.K-ras mutations and benefit from cetuximab in advanced colorectal cancer.N Engl J Med. 2008; 359: 1757-1765Crossref PubMed Scopus (3051) Google Scholar]. Thus, tests able to identify patients with K-ras mutations may be useful in sparing the individuals from unnecessary antibody treatment. Other tests that could be clinically valuable include those that help to predict toxicity. The UGT1A1 genotype has been licensed by the US Food and Drug Administration to predict toxicity to irinotecan, although it seems to be applicable only at irinotecan doses of 150 mg/m2 or greater [17Hoskins J.M. Goldberg R.M. Qu P. Ibrahim J.G. McLeod H.L. UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters.J Natl Cancer Inst. 2007; 99: 1290-1295Crossref PubMed Scopus (402) Google Scholar]. Similarly, dihydropyrimidine dehydrogenase deficiency is associated with 5-fluorouracil-induced toxicity [18Thomas H.R. Ezzeldin H.H. Guarcello V. Mattison L.K. Fridley B.L. Diasio R.B. Genetic regulation of dihydropyrimidinase and its possible implication in altered uracil catabolism.Pharmacogenet Genom. 2007; 17: 973-987Crossref PubMed Scopus (38) Google Scholar]. In fact, 78% of the audience believed that we should already be using molecular profiling for patients with colorectal cancer, with 38% believing that it should be used whenever EGFR-targeted therapy was being considered and 40% suggesting that a patient should receive K-ras testing at diagnosis of their primary tumour. Ruth Board, Clinical Fellow, Paterson Institute of Cancer Research, University of Manchester, explained that several molecular pathways seem to result in colorectal cancer, with each pathway being associated with particular clinical features (Table 2).Table 2Characteristics of colorectal cancer arising from chromosomal or microsatellite instabilityChromosomal instability (85% of cases)Microsatellite instability (15% of cases)Left/distal colonRight/proximal colonAneuploid/polyploidDiploidHighly differentiatedOften largeRarely mucinousOften mucinousNo lymphocytic infiltrateInflammatory infiltrateMore often node positive and metastaticMore often node negative and non-metastaticAssociated with high CpG island methylator phenotype (CIMP)Greater overall survival than microsatellite stabilityNo benefit from 5-fluorouracil Open table in a new tab Dr Board emphasised the value of biomarkers in providing information on drug target hitting in humans, stratification of patients, toxicity and mechanism-based end points. Ultimately, she hopes that biomarkers will drive clinical trial designs. Current challenges include the development of robust, validated assays for these biomarkers, while new technological approaches offer the potential to develop blood-based tests. In the final presentation in this session, Ricky Sharma, from the Gray Institute for Radiation Oncology and Biology at the University of Oxford, discussed the possibility of personalised therapy with the identification of patients whose tumours are most likely to respond to targeted therapy. Also using the example of irinotecan and UGT1A1 [19Camptosar (irinotecan hydrochloride injection) prescribing information.https://www.pfizerpro.com/product_info/camptosar_pi_adverse_reactions.jspGoogle Scholar, 20Ando Y. Saka H. Ando M. et al.Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis.Cancer Res. 2000; 60: 6921-6926PubMed Google Scholar] it may be possible to predict those who will probably experience severe or intolerable adverse effects of chemotherapy. Prospective studies of the therapeutic efficacy of strategies based on test results are still needed. Nonetheless, 94% of the audience believed that UGT1A1 genotype testing should be available, either within clinical trials (43%) or as part of NHS standard care (51%). The meeting concluded by returning to the topic of co-payment, with a talk by Mike Richards CBE, National Clinical Director for Cancer and author of the consultation report that led to the Department of Health's decision to allow co-payments [21Richards M. Improving access to medicines for NHS patients: a report for the Secretary of State for Health by Professor Mike Richards.http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_089927Google Scholar]. The basis for the report was the number of exceptional case applications made each year in the UK, and the problems that arise when primary care trusts (PCTs) do not approve these applications. Currently, PCTs in England receive around 26 000 exceptional case applications every year, and up to three-quarters of these applications are approved (with wide-ranging variation between PCTs, from 1 to >1000 applications and 0 to 100% approval rates) [3Clarke R. Waddell T. Gallagher J. et al.A postcode lottery still exists for cancer patients with exceptional circumstances (Letter).Clin Oncol (R Coll Radiol). 2008; 20: 771-772Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar, 21Richards M. Improving access to medicines for NHS patients: a report for the Secretary of State for Health by Professor Mike Richards.http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_089927Google Scholar]. To help to improve access to medicines for more patients, Professor Richards has made several recommendations. His first goal is to find ways to minimise the need for patients to purchase additional private drugs, including: (a) improving the timelines for NICE technology appraisals, (b) improving PCT decision making by encouraging greater collaboration between PCTs to set funding policies, (c) looking at ways to make drugs available for end-of-life treatments even if they would not meet NICE's current cost-effectiveness criteria (threshold approximately £30 000/quality-adjusted life-year gained) and (d) working with the pharmaceutical industry to promote more flexible approaches to the pricing and availability of new drugs [21Richards M. Improving access to medicines for NHS patients: a report for the Secretary of State for Health by Professor Mike Richards.http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_089927Google Scholar]. His second aim is to clarify national guidance on how the NHS should handle situations where a patient wishes to purchase additional treatment (Fig. 1) [21Richards M. Improving access to medicines for NHS patients: a report for the Secretary of State for Health by Professor Mike Richards.http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_089927Google Scholar]. He specifically recommends that no patient should lose their entitlement to NHS care that they would have otherwise received, simply because they opt to purchase additional treatment for their condition. However, the NHS and private treatment must be separated [16Karapetis C.S. Khambata-Ford S. Jonker D.J. et al.K-ras mutations and benefit from cetuximab in advanced colorectal cancer.N Engl J Med. 2008; 359: 1757-1765Crossref PubMed Scopus (3051) Google Scholar] to safeguard against perverse incentives, for example if the same clinician is providing both aspects of care. The separation of care delivery can be achieved in a number of ways: some hospitals (<50%) have private wards; many have a private hospital nearby; private healthcare can be provided in the patient's home; or an area of the NHS hospital could be designated as private for a fixed period (in the same way as NHS scanning equipment is treated as private when used for a private patient). It will be up to each strategic health authority, in association with local cancer networks, to decide how to implement the scheme, while ensuring continuity of care for their patients. Prof Richards stressed that the package of recommendations, including improved access to medicine on the NHS and simplified rules for patients who choose to pay for an element of their care, is aimed at improving healthcare for all patients and reducing the number of patients paying for treatment [21Richards M. Improving access to medicines for NHS patients: a report for the Secretary of State for Health by Professor Mike Richards.http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_089927Google Scholar]. The keypad voting responses to questions asked during the day gave a good indication of the audience's concerns and hopes for the future:▪84% wanted an urgent national debate about NHS funding▪87% wanted an urgent review of how NICE works▪81% wanted more consistency across PCTs in decisions about exceptional cases▪95% wanted a standard template to help patients decide about co-payments — the patients, in particular, were critical about the current ability of healthcare professionals to discuss the implications of a cancer diagnosis and its optimal management. The perception is that healthcare professionals are insufficiently transparent about the likelihood and severity of side-effects.▪A recurring theme was that healthcare professionals need an easier, more user-friendly tool to explain to patients both the benefits and the risks of costly treatments when they are considering top-up payments.