Clinical Expert Submission Template

Clinical Expert Submission Template Thank you for agreeing to give us a personal statement on your view of the technology and the way it should be used in the NHS. Health care professionals can provide a unique perspective of the technology within the context of current clinical practice which is not typically available from the published literature. To assist you in making your statement we have provided a template. The questions are intended as prompts to guide you. It is not essential that you answer all of them. Your statement can be as brief as you like. We suggest a maximum limit of 8 pages. If there are special circumstances for exceeding this limit please attach an Executive Summary. What is the place of the technology in current practice? We would like to know how the condition is currently treated in the NHS. Is there significant geographical variation in current practice? Are there differences in opinion between professionals as to what current practice should be? What are the current alternatives to the technology and what are their respective advantages and disadvantages? Are there any subgroups of patients with the condition who have a different prognosis from the typical patient? Are there differences in the capacity of different subgroups to benefit from or to be put at risk by the technology? In what setting should/could the technology be used for example, primary or secondary care, specialist clinics? Would there be any requirements for additional professional input (for example, community care, specialist nursing, other healthcare professionals)? If the technology is already available, is there variation in how it is being used in the NHS? Is it always used within its licensed indications? If not, under what circumstances does this occur? Please tell us about any relevant clinical guidelines and comment on the appropriateness of the methodology used in developing the guideline and the specific evidence that underpinned the various recommendations. Adjuvant treatment for breast cancer current practise Invasive primary breast cancer (ie breast cancer which is macroscopically confined to breast and regional lymph nodes) is ordinarily treated by excision of the tumour, followed by a course of adjuvant chemotherapy (if appropriate), breast radiotherapy (following breast-conserving surgery and to chest wall for higher risk patients following mastectomy) and by 5 years of endocrine therapy if the tumour is steroid hormone receptor positive. There is no identifiable subgroup of patients that does not potentially benefit from chemotherapy. Adjuvant chemotherapy confers a fixed relative risk reduction within the constraints of the parameters discussed below. Patients with a higher risk of breast cancer death will therefore experience a greater absolute risk reduction than those with a lower risk. There are 4 main factors that determine the likely chance that chemotherapy will benefit an individual. 1. Risk associated with disease: risk is defined by the conventional pathological parameters of nodal involvement, grade and tumour size, modified by secondary parameters including receptor expression and vascular invasion. Patients at highest risk by virtue of histological characteristics of their tumour will benefit most from chemotherapy. 2. The benefits of chemotherapy decline with increasing age. It is generally accepted that chemotherapy should be offered to all women under 35 to 40 whilst there is insufficient evidence to justify routine treatment of the over 70 s. 3. Chemotherapy is relatively less effective for women with steroid hormone receptor positive disease over the age of 50. The situation in younger women is less clear cut because chemotherapy-induced ovarian failure interacts with the chemotherapy effect unlike tamoxifen (or aromatase inhibitors). The 2000 Oxford Overview (Lancet 2005, 365:1687-717) suggests that steroid hormone receptor status is unimportant but several recent trials using chemotherapy not particularly likely to cause ovarian failure suggest an attenuated effect in hormone receptor positive disease. 4. The choice of chemotherapy regimen will affect benefit. Historically 6 months of the CMF combination (cyclophosphamide, methotrexate & fluorouracil administered twice during a 28-day cycle) or 3 months of AC (doxorubicin & cyclophosphamide given once every 3 weeks for 4 cycles ie ACx4) were used. These two regimens, which have been shown to be equivalent in two large randomised clinical trials have been largely superseded by more effective combinations in the NHS and indeed globally (see below). There are no generally accepted national guidelines for selecting which patients should be offered adjuvant chemotherapy. However there is a broad consensus amongst oncologists, reflected in local guidelines, that for patients without major co-morbidities, the threshold for offering adjuvant chemotherapy should be an estimated reduction in the risk of death at 10 years of 3-5%. This would include all patients with involved axillary lymph nodes under the age of 70 and patients with significant risk factors who do not have nodal disease. Many oncologists use a computerised tool to refine risk and benefit estimates. The best known of these is Adjuvant! (http://www.adjuvantonline.com), which has been validated in a community setting (Olviotto, J Clin Oncol 2005, 23:2716-25). 1

The most widely used adjuvant chemotherapy regimens current in the NHS are the anthracycline-based FEC (fluorouracil, epirubicin & cyclophosphamide given once every 3 weeks for 6 cycles) and E-CMF (epirubicin given once every 3 weeks for 4 cycles, followed by 4 monthly cycles of the CMF combination, a block sequential regimen). E-CMF has been shown to be approximately 40% superior to 6 months of CMF in the NEAT trial. Whilst there are no individual trials that show FEC as used in the UK to be superior to CMF or ACx4, the 2000 Oxford Overview suggests that FEC is some 25% better than CMF. No formal efficacy comparison has been performed between the two regimens but the TACT trial may provide some information when the initial analysis is performed, probably in late 2006. There are uncertainties as to the optimal epirubicin dose to be used in the FEC combination most Networks have recently escalated from the 60mg/m 2 used in TACT to 75mg/m 2 but there is only weak evidence to support this dose, rather than the 90-100mg/m 2 used in much of Europe. Nevertheless FEC is a simpler and shorter regimen than E-CMF (6 vs 12 injections) and as it uses fewer resources, is preferred by patients and is not obviously inferior to E-CMF, it is the regimen of choice in about 60% of NHS units. There is general agreement amongst oncologists that when adjuvant chemotherapy is given, it should be the first treatment following surgery. Radiotherapy treatment is not commenced until chemotherapy is completed because of the unpredictable interaction between some cytotoxics, particularly anthracyclines, and radiation. Similarly endocrine therapy is not given concurrently with chemotherapy because of concerns about a possible increased incidence of venous thromboembolism and because of recent data from a randomised controlled trial that suggests that concomitant tamoxifen decreases the efficacy of chemotherapy. Primary chemotherapy current practise The use of primary chemotherapy ie initial treatment of primary breast cancer with chemotherapy, followed by surgery is variable in the NHS. The generally accepted indications are to make locally advanced inoperable tumours operable and to down-stage larger tumours to permit breast-conserving surgery. The second indication is very much dependent on the attitudes that prevail in individual MDT s. Until recently, the most commonly used chemotherapy regimens used for primary chemotherapy has been 6 cycles of AC or EC (epirubicin & cyclophosphamide). Many Networks have now revised their guidelines to suggest that if there is an incomplete tumour response after 4 cycles of AC/EC then chemotherapy should be switched to docetaxel. This has been informed by the NSABP B27 trial (Bear, J Clin Oncol 2003 21:4165-74), which showed that 4 cycles of AC followed by 4 cycles of docetaxel increased clinical and pathological response rates by 50% in comparison to ACx4 alone, by UK clinician experience with the Anglo-Celtic II trial and by data from the NSABP B17 primary chemotherapy trial that shows that pathological complete response is associated with improved survival. The current NCRN-approved Neo-tAnGo trial incorporates a randomised comparison between paclitaxel and paclitaxel-gemcitabine. Treatment setting All chemotherapy, including chemotherapy for breast cancer should be supervised by a trained oncologist or consultant nurse and be administered by suitably trained staff as specified by the Manual for Cancer Standards. Current use of Docetaxel Adjuvant docetaxel is little used in the NHS (in contrast to North America), because of funding issues. There is however a strong groundswell of opinion amongst NHS oncologists that it should be used for higher risk patients. Some Networks are now incorporating adjuvant docetaxel for high risk younger patients into their guidelines and are applying for funding of adjuvant docetaxel therapy in high-risk patients on a cost-per-case basis. The great majority of adjuvant docetaxel used for NHS patients is administered using block-sequential regimens such as FECx4 followed by docetaxelx4 which are used in preference to combination regimens such as TAC (docetaxel, doxorubicin & cyclophosphamide) although the only licensed indication for adjuvant docetaxel is in the context of the TAC regimen. The reasons for this preference include the greater cost of the TAC regimen (which cannot be administered without haematological growth factor, ie G-CSF support), familiarity with block-sequential regimens from participation in the UK TACT study and in the primary chemotherapy setting, and the general move away from doxorubicin amongst UK breast oncologists because of concern about cardiac toxicity. The use of adjuvant docetaxel in privately funded patients is more widespread but the regimens in use seem to be similar to those used in NHS practise. Docetaxel is widely used for off-study primary chemotherapy for breast cancer (see above). There is a strong desire to incorporate trastuzumab into docetaxel-containing primary chemotherapy regimens following the small but highly positive study conducted at the MD Anderson Cancer Center (Buzdar, J Clin Oncol 2005 23:3676-85). Docetaxel is widely used to treat advanced breast cancer (and is NICE approved for this purpose). The majority of taxane treatment of advanced disease is with docetaxel monotherapy rather than with paclitaxel or with the docetaxel-capecitabine combination. Docetaxel-capecitabine has been recommended by NICE but is widely considered to be associated with unacceptable toxicity. The preference for docetaxel over paclitaxel is informed by the results of a randomised comparison between the two drugs, administered at licensed doses in the metastatic setting (Jones, J Clin Oncol 2005: 23:5542-51), which showed a greater overall survival for patients treated with docetaxel. Guidelines There are no accepted guidelines for adjuvant use of docetaxel apart from local Network guidelines, as discussed above. NICE has issued guidance on docetaxel in the metastatic setting. The Scottish Medicines Consortium has approved the TAC regimen (docetaxel, doxorubicin & cyclophosphamide) for adjuvant use. 2

The advantages and disadvantages of the technology NICE is particularly interested in your views on how the technology, if available, compares with current alternatives used in the UK. Is the technology easier of more difficult to use and are there any practical implications (for example, concomitant treatments, other additional clinical requirements, patient acceptability/ease of use or the need for additional tests) surrounding its use? If appropriate, please give your view on the nature of any rules, informal or formal, for starting and stopping the use of the technology; this might include the requirement for additional testing to identify appropriate subgroups for treatment or to assess response and the potential for discontinuation. If you are familiar with the evidence base for the technology, please comment on whether the use of the technology in clinical practice reflects that observed under clinical trial conditions. Do the circumstances in which the trials were conducted reflect current UK practice, and if not, how could the results be extrapolated to a UK setting? What, in your view, are the most important outcomes and were they measured in the trials? If surrogate measures of outcome were used, do they adequately predict long-term outcomes? What is the relative significance of any side effects or adverse reactions? In what ways do these have an impact on the management of the condition and the patient s quality of life? Are there any adverse effects that were not apparent in the clinical trials but have come to light subsequently during routine clinical practice? Comment on the adjuvant docetaxel trials and current UK adjuvant chemotherapy practise Two trials have clearly demonstrated the superiority of docetaxel-containing adjuvant chemotherapy over regimens similar to those in current use in the NHS. BCIRG 001 (Martin, New Engl J Med 2005 352:2302-13), which was conducted in women with node-positive breast cancer showed an approximately 30% improvement in both relapse-free survival and overall survival in women treated with 6 3-weekly cycles of TAC (docetaxel, doxorubicin & cyclophosphamide) compared to 6 cycles of FAC (fluorouracil, doxorubicin & cyclophosphamide). The result is highly significant and since the FAC regimen used in this study closely resembles current chemotherapy in use in the NHS (FAC and FEC seem to be equivalent according to the 2000 Oxford Overview), this study is clearly relevant. Significant haematological toxicity was associated with this regimen (discussed below) and there is a preference by many UK oncologists for the blocksequential regimens such as those used in PACS 01 and NSABP B27. PACS 01 (presented at the San Antonio Breast Cancer Symposium (SABCS) in December 2004 but not yet formally published) was also conducted in women with node-positive primary breast cancer. The randomisation was between 6 cycles of FEC (with an epirubicin dose of 100mg/m 2 ) given every 3 weeks and 3 cycles of FEC followed by 3 cycles of docetaxel every weeks. In this study, there was a 17% reduction in risk of recurrence and a 23% reduction in risk of death. It is noteworthy that haematological toxicity was greater in the control arm of this study. The trial design is broadly similar to the as yet unanalysed UK TACT study, which used a experimental arm of 4 cycles of FEC (epirubicin dose 60mg/m 2 ) followed by 4 cycles of docetaxel. Nearly 4200 patients were randomised to TACT and the majority of UK oncologists treating breast cancer participated. Although epirubicin doses used in FEC have been increased in many Networks since the completion of TACT in 2002, there is still reluctance by the majority to use the 100mg/m 2 dose used in the PACS study. When adjuvant taxanes are used in the UK in block-sequential regimes, in the majority of cases, the regimen used is FEC x4 (with epirubicin 60mg/m 2 or 75mg/m 2 ) followed by docetaxel x4. The incorporation of taxanes into neoadjuvant chemotherapy (discussed in the previous section) is informed by the block-sequential regimens used in the NSABP B27 trial, which used a very similar regimen. It is always difficult to make between trial and regimen comparisons, but FEC with the higher dose of epirubicin used in the PACS study has previously been shown to superior to FEC with 50mg/m 2 epirubicin) in the FACS 05 study (J Clin Oncol 2001, 19:602-11). Many of the FEC studies that were included in the 2000 Oxford Overview used lower doses of epirubicin, so it seems likely that FEC with 100mg/m 2 epirubicin (FEC100) is superior to FAC (and to FEC60). The apparent difference between docetaxel benefit in the BCIRG and PACS trials may therefore be the consequence of difference in the control arms rather than in the experimental regimens. The positive result from the PACS study confirms that docetaxel really does confer a significant added benefit to an optimal anthracycline regimen. The US Oncology study 9735 (Jones, Proc ASCO 2003 abstr 59, updated at SABCS 2005) has demonstrated a 33% improvement in disease-free survival for patients treated with 4 cycles of doxorubicin-docetaxel in comparison to 4 cycles of AC. The similar ECOG E2197 (Goldstein, Proc ASCO 2005 abstr 512) however has failed to demonstrate a significant advantage for doxorubicin-docetaxel. As the control arm used in both studies is considered inferior to FEC or E-CMF used in current NHS practise, it is difficult to see their relevance. All of these trials have used disease-free survival as their primary endpoint. This is usually a composite endpoint incorporating local recurrence (which is treatable but is associated with increased future mortality), distant recurrence (which is inevitably fatal, although on average not for 2-3 years) and death. The most relevant endpoint to clinical practise is overall survival although it must be emphasised that the experience of local recurrence is deeply distressing to the vast majority of affected women. Experience from the vast majority of historical trials of adjuvant for chemotherapy is that improvements in disease-free survival are in the fullness of time translated into improvements in overall survival. Disease-free survival is therefore an acceptable surrogate endpoint for overall survival, especially as due to the prolonged natural history of breast cancer, there can often be an interval of several years between the emergence of DFS and OS benefits. 3

Docetaxel toxicity Docetaxel, in contrast to current anthracycline chemotherapy regimens is neurotoxic. A significant minority of women develop a sensory peripheral neuropathy during treatment which may take many months to resolve. The long-term outcome of taxane neuropathy has in my view been inadequately studied. This is clearly relevant to a patient population that will hopefully survive for many years and in which the number needed to treat for benefits to accrue may be significant. All oncologists who prescribe taxanes are familiar with this toxicity and with modifying chemotherapy to minimise it. In the BCIRG 001 study, the incidence of severe (grade 3-4) toxicities in patients treated with TAC (docetaxel, doxorubicin & cyclophosphamide) was 36% compared to those treated with 27% FAC (fluorouracil, doxorubicin & cyclophosphamide). Most of the difference is due to the increased incidence of haematological toxicities with TAC, with 25% of patients experiencing febrile neutropenia rate compared to 2.5% with FAC. Although the majority of these episodes were not severe and there were no consequent deaths, febrile neutropenia in the NHS is ordinarily managed by emergency admission for intravenous antibiotics. Such admissions typically last for 3-5 days, sometimes longer. The risk of febrile neutropenia can be minimised by dose reduction, which is undesirable because a potential reduction in treatment efficacy or by the administration of prophylactic G-CSF. G-CSF exists in 2 formulations. The standard form is given by daily subcutaneous injection (typically day 4-11), whilst the more expensive pegylated formulation requires one injection per cycle. The cost of G-CSF prophylaxis should be considered as part of the evaluation of the TAC regimen. Any additional sources of evidence? Are you aware of any relevant evidence which may not be found by a technology-focused systematic review of the available trial evidence? This could be information on recent and informal unpublished evidence or information from registries and other nationally coordinated clinical audits. Any such additional information must be accompanied by sufficient detail to enable a judgement to be made as to the quality of the evidence and to enable potential sources of bias to be determined. Recent trial results The BCIRG 006 study was presented at the at the San Antonio Breast Cancer Symposium in December 2005. This 3-arm study was restricted to women with HER2 +ve breast cancer. The control arm consisted of 4 cycles AC followed by 4 cycles of docetaxel. The 2 experimental arms both incorporated 12 months of adjuvant trastuzumab in combination with either the AC-docetaxel control arm, or a novel combination of carboplatin & docetaxel. Both experimental trastuzumab arms showed a highly significant reduction in the risk of recurrence apparently a smaller effect (but not statically significantly so) with carboplatin-docetaxel. Whilst this is a trial of trastuzumab and not docetaxel, the strongly positive results do emphasise the role of docetaxel & trastuzumab combination therapy in HER2 +ve breast cancer. The synergy between trastuzumab and cytotoxic drugs, particularly both docetaxel and paclitaxel has previously been demonstrated in metastatic breast cancer (Marty, J Clin Oncol 2005 23:4265-73; Slamon, New Engl J Med 2001 344:783-92). Outstanding clinical trials ADEBAR: Study in higher risk patients comparing 4 cycles of epirubicin & cyclophosphamide followed by either 4 cycles of docetaxel or 4 cycles of a 28-day FEC regimen. Approximately 1200 patients were entered when the trial closed in September 2004. TACT: UK trial comparing either 8 cycles of FEC60 or E-CMF (centres were allowed to choose control arm) with 4 cycles of FEC60 followed by 4 cycles of docetaxel. Approximately 4200 patients were randomised. The initial analysis is expected in late 2006. DEVA: A randomised trial of sequential epirubicin and docetaxel (3 cycles each) versus epirubicin alone (6 cycles) in node-positive, postmenopausal breast cancer. Closed to recruitment in 2005. BCIRG 005: An ongoing randomised trial of AC (4 cycles) followed by docetaxel (4 cycles) compared to TAC (6 cycles) in 3,130 patients with node-positive early breast cancer. BIG 02-98: Ongoing trial comparing two regimens of doxorubicin, cyclophosphamide, methotrexate and fluorouracil, either with or without docetaxel, in women with node-positive, early breast cancer. 4

Implementation issues How would possible guidance have an impact on the delivery of care for patients with this condition? Would there be any need for NHS staff to be educated and trained? Would any additional resources be required (for example, facilities or equipment)? Under the Department of Health and Welsh Assembly Government, the NHS is required to provide funding and resources for medicines and treatments that have been recommended by NICE technology appraisals. This provision has to be made within 3 months from the date of publication of the guidance. If the technology is unlikely to be available in sufficient quantity or the staff and facilities to fulfil the general nature of the guidance can not be put in place within 3 months, NICE may advise the Department of Health and Welsh Assembly Government to vary this direction. Please note that NICE can not suggest variation in the direction on the basis of budgetary constraints alone. Implementation All oncologists treating breast cancer and the majority of chemotherapy daycare units are familiar with taxanes. Docetaxel is administered over 1 hour, which will will have no impact on the total chair time required to give adjuvant chemotherapy treatment. Docetaxel is unstable once diluted and the dose has to be within 6 hours of manufacture. This makes docetaxel unsuitable for batch manufacture and will place an additional burden on manufacturing units. The issue of febrile neutropenia and the need for prophylactic G-CSF support with the TAC regimen has been discussed above. Most patients can be trained to self administer G-CSF but its widespread adoption will require some community nursing resource, especially when the cheaper non-pegylated formulation is used. 5