London Cancer New Drugs Group APC/DTC Briefing

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1 London Cancer New Drugs Group Capecitabine and oxaliplatin for advanced gastric and oesophageal (oesophago-gastric) cancer APC/DTC Briefing Capecitabine and oxaliplatin for advanced gastric and oesophageal (oesophago-gastric) cancer Contents Summary 1 Background/Epidemiology 2 Clinical evidence 3 Adverse events/safety issues 5 Economic/Cost implications 7 for consideration References 8 Produced for the London New Drugs Group Contact: Sheetal Ladva Medicines Information Pharmacist London & South East Medicines Information Service Guy s Hospital London SE1 9RT Tel: Fax: sheetal.ladva@gstt.nhs.uk Further copies of this document are available from URL NeLM-Area/Evidence/Drug- Specific-Reviews/ Produced for use within the NHS. Not to be reproduced for commercial purposes Summary Gastric and oesophageal cancer are the fifth and ninth most common cancers in the UK audit data from English Cancer Registries show that in 2005 there were 4680 patients diagnosed with gastric cancer and 6375 diagnosed with oesophageal cancer. Most patients present with advanced, inoperable or metastatic disease in 2005 only 20% of patients that presented with this disease underwent surgical resection. This review considers the management of the advanced form of both cancers (i.e. locally advanced or inoperable). The term oesophago-gastric cancer will be used throughout the review as an umbrella term for both cancers since both are treated similarly. The most established first line treatment regimen for the treatment of advanced oesophago-gastric cancer in the UK contains epirubicin, cisplatin and infused fluorouracil (ECF). ECF is reported to be better tolerated and to have a more favourable risk reduction and median survival than other regimens. Fluorouracil in the ECF regimen can be substituted with capecitabine (ECX). The proposed benefits of this substitution include patient convenience and elimination of central line related complications. Likewise when cisplatin in the ECF regimen is substituted with oxaliplatin (EOF), the potential requirement for lengthy hydration is reduced thereby potentially reducing administration time by up to six hours. When both fluorouracil and cisplatin are substituted the regimen is known as EOX. The REAL- 2 study, the pivotal Phase III study in oesophago-gastric cancer, found capecitabine (as in ECX or EOX) and oxaliplatin (as in EOX or EOF) to be as equally effective as fluorouracil (as in ECF or EOF) and cisplatin (as in ECX or ECF), respectively. An overall response rate of between 40-48% was achieved, progression free survival was between months and overall survival was between months for the four treatment groups. Toxicity of capecitabine and fluorouracil were similar and oxaliplatin was associated with less grade 3 or 4 neutropenia, alopecia, renal toxicity and thromboembolism but with more grade 3 or 4 diarrhoea and neuropathy than cisplatin. One Phase III study (conference abstract) in gastric cancer demonstrated that when capecitabine was substituted for fluorouracil in combination with cisplatin, the substitution was considered to be non-inferior in terms of overall survival (5.6 months for capecitabine and cisplatin versus 5.0 months for fluorouracil and cisplatin). Another Phase III study showed a trend towards improved progression free survival and overall survival when substituting oxaliplatin for cisplatin in combination with fluorouracil. In one Phase II study, four patients who were exposed to a higher dose of capecitabine (1000mg/m 2 ) had grade 5 treatment related toxicities resulting in death. Based on the average patient (1.7m 2 ), the BNF-listed drug costs of one cycle of each regimen is: ECF, 352; ECX, 424; EOF, 923; EOX, 995. However with the discounts available to NHS Trusts it is likely that the ECX may actually cost about 320 per cycle and EOX may cost approximately 400 per cycle. The use of capecitabine instead of fluorouracil (i.e. use of ECX or EOX instead of ECF) removes the need to insert a central line, incur pump costs and also reduces the need for hospital/ day-care attendance from 3 to 1 per cycle. According to data from Roche, over 6 cycles this reduces the associated administration cost from 4551 to The use of oxaliplatin instead of cisplatin reduces the need for pre-hydration this may have logistical benefits for patients that have to travel long distances to treatment centres, have a beneficial impact on quality of life and may reduce pressure on day-care treatment centres. However we were unable to identify any material which enabled us to quantify these benefits and it is only likely have a marginal effect on overall administration costs. Assuming 15 patients per 100,000 patient population in England are eligible for treatment with one of these regimens and receive an average 4 cycles of treatment then at typical NHS prices if EOX was chosen as the regimen of choice (over the current standard ECF), it would cost an additional 6,000 per 100,000 patient population with no significant change in associated administration costs.

2 Background/Epidemiology The recently published National Oesophago-Gastric Cancer Audit showed that in England in 2005, 4680 patients were diagnosed with gastric cancer and 6375 were diagnosed with oesophageal cancer and that 20% of these underwent surgical resection (1). The audit data shows that the incidence of gastric cancer has declined since 1998 but the incidence of oesophageal cancer has increased and the proportion of patients undergoing resection has decreased from 28% over that timeframe (1). There are two main histological types of oesophageal cancer: squamous cell carcinoma (SCC) which usually affects the upper two-thirds of the oesophagus, and adenocarcinoma (AC) which affects the lower third of the oesophagus and the gastro-oesophageal junction (GOJ). Since the 1970 s, the incidence of AC has increased, particularly in men (2). The proportion of patients surviving for one year after diagnosis has increased from 30% to 37% between 1998 and Within the audit report it is estimated that the overall 5-year survival rates for oesophageal and gastric cancers are 7% and 13% respectively (1). This review considers the palliative management of the advanced form of gastric and oesophageal cancers (oesophago-gastric cancer) since both are treated similarly. Existing treatment options Treatment strategies for advanced oesophago-gastric cancer vary depending on the location of the primary tumour, histology, extent of local invasion, presence of metastases and patient co morbidities. The most established first-line treatment regimen used for the treatment of advanced oesophago-gastric cancer contains epirubicin, cisplatin and infused fluorouracil (ECF). The evidence for this is based on a head to head study in untreated patients which demonstrated that ECF had a more favourable risk reduction (overall response rate [ORR], 45 [95% CI 36-54%] vs 21%[13-29%]) and one-year median survival (8.9 vs 5.7 months) compared to fluorouracil, doxorubicin and methotrexate, the gold standard regimen at the time (p=0.002). ECF was associated with more alopecia and severe nausea and vomiting but less neutropenia and infection (3). In another randomised study in untreated patients with advanced oesophago-gastric cancer, ECF demonstrated similar efficacy (ORR, 42 [95% CI 37-48%] vs 44% [38-50%]; median survival 9.4 vs 8.7 months) to mitomycin, cisplatin and fluorouracil (MCF, p=0.692). ECF also maintained quality of life (QOL) at three and six months whereas it was shown to be reduced with MCF. ECF was associated with more neutropenia and alopecia and MCF more erythema and thrombocytopenia (4). three as monotherapy. Since the various trial data included in this review were too heterogeneous to carry out a meta-analysis, the author s conclusions were based on their interpretation of individual trial data (5). Another Cochrane meta-analysis of combination chemotherapy regimens for advanced gastric cancer, found survival data to be superior with regimens containing fluorouracil, anthracyclines and cisplatin (approximately an additional two months). Within this category, ECF was the best tolerated anthracycline/platinum containing regimen (6). Capecitabine is an oral fluoropyrimidine prodrug that gets converted to fluorouracil by enzymatic processes in tumour tissues. It has been accepted as an alternative to intravenously infused fluorouracil but with a differing toxicity profile. Capecitabine offers patient convenience because it is taken by mouth and therefore does not require the need for central venous access and portable infusion pumps. Oxaliplatin, a third generation platinum, can be infused over two hours. As a substitution for cisplatin in the ECF regimen, it reduces the requirement for lengthy hydration (up to eight hours) and the resultant increase in out-patient duration/overnight admission. Further benefits include reduced emesis, renal toxicity and ototoxicity (7). Capecitabine is licensed for first-line treatment of advanced gastric cancer in combination with a platinum-based regimen (8). Oxaliplatin is not licensed specifically for the treatment of gastrooesophageal cancer (9). This review discusses the treatment of advanced oesophago-gastric cancer with capecitabine and oxaliplatin as substitutes for infused fluorouracil and cisplatin, respectively. Clinical evidence The combination of capecitabine and oxaliplatin has been evaluated in the treatment of advanced colorectal cancer and has been found to be safe. In the pivotal Randomised ECF for Advanced and Locally Advanced Esophagogastric Cancer 2 (REAL-2) Phase III study, the investigators evaluated capecitabine and oxaliplatin as alternatives to infused fluorouracil and cisplatin respectively in the ECF regimen. The study was powered to determine noninferiority in overall survival (randomisation to death from any cause), the primary endpoint. To demonstrate non-inferiority, the one-year survival rate was required to be greater than 27% and the upper limit of the 95% confidence interval for the unadjusted hazard ratio for death for the experimental regimen as compared with the ECF regimen was required to be less than 1.23 (10). A Cochrane review of different chemotherapy regimens in patients with metastatic oesophago-gastric (5 RCT s; 1242 participants) found no consistent benefit of any specific chemotherapy regimen. The above two trials were included in the analysis, as were trials comparing fluorouracil monotherapy with fluorouracil and mitomycin C, cisplatin and fluorouracil with cisplatin monotherapy and adriamycin, methotrexate and 5-fluorouracil, all 1002 adults with untreated inoperable or metastatic oesophago-gastric cancer (AC, SCC or undifferentiated cancer of the oesophagus, GOJ or stomach) were randomised to one of four triple therapies: epirubicin and cisplatin plus either fluorouracil (ECF, n=263) or capecitabine (ECX, n=250) or epirubicin and oxaliplatin plus either fluorouracil (EOF, n=245) or capecitabine (EOX, n=244). Since 38 patients were ineligible or withdrew

3 before treatment, the per-protocol population included 964 patients. On day one of each three week cycle, all patients received a bolus of epirubicin. Cisplatin was infused with hydration in the ECF and ECX groups and oxaliplatin was infused over a two hour period in the EOF and EOX groups. Fluorouracil was infused continuously via a central venous access device (CVAD) and oral capecitabine was given daily in two divided doses to the appropriate groups. All patients were started on the above drugs on day one of each three week cycle that were repeated every three weeks for a maximum of eight cycles (table 1 for further dosing information). 1.04; p=0.16). EOX was associated with better overall survival than the ECF group (11.2 vs 9.9 months, HR 0.8; 95% CI, ; P= 0.02). However this was a secondary endpoint and the trial was not adequately powered to assess survival differences between regimens. Further efficacy data are highlighted in table 2. Histological analysis did not significantly affect survival. Epirubicin 50mg/m 2 Day 1 of each cycle Cisplatin 60mg/m 2 Day 1 of each cycle Oxaliplatin 130mg/ m 2 Day 1 of each cycle Fluorouracil 200mg/ m 2 Day 1-21 of each cycle Twice daily capecitabine 625mg/m 2 Day 1-21 of each cycle ECF ECX EOF EOX yes yes yes yes yes yes no no no no yes yes yes no yes no no yes no yes Table 1: Dosing schedule for REAL-2 study Inclusion criteria were measurable disease according to the Response Evaluation Criteria in Solid Tumours (RECIST, Appendix 2) and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or better. Secondary outcomes included survival in the individual regimens (intent to treat), progression free survival (PFS) and response according to RECIST and QOL. The study appeared to be well conducted; the four groups were well balanced and there was no loss to follow-up. The non-inferiority analysis was done using the per-protocol population, i.e. those who had received at least one cycle of chemotherapy (as recommended in such studies to reduce bias). The median number of cycles administered was six in each group. After a median of 17.1 months follow-up, capecitabine and oxaliplatin were shown to be non-inferior to fluorouracil and cisplatin (HR 0.86, 95% CI for the capecitabine fluorouracil comparison; HR 0.92, 95% CI for the oxaliplatincisplatin comparison). A multivariate analysis (performance status, extent of disease, age) confirmed noninferiority for both comparisons after adjustment for covariates. In the intention to treat analysis, overall survival in the capecitabine groups did not differ significantly from that in the fluorouracil groups (HR for death, 0.88; 95% CI, ; p=0.06), nor did overall survival in the oxaliplatin groups differ significantly from that in the cisplatin groups (HR, 0.91; 0.79-

4 Table 2: Efficacy data for REAL 2 study (intention to treat population) Variable ECF (n=263) ECX (n=250) EOF (n=245) EOX (n=244) Death No of patients HR (95% CI) 0.92 ( ) 0.96 ( ) 0.80 ( ) P value Overall survival Median (months) One year survival (%) (%; 95% CI) PFS 37.7 ( ) 40.8 ( ) 40.4 ( ) 46.8 ( ) Median (months) Patients progressed or died HR (95% CI) 0.98 ( ) 0.97( ) 0.85 ( ) P value Response Overall 40.7 ( ) 46.4 ( ) 42.4 ( ) 47.9 ( ) (%; 95% CI) Complete (%) Partial (%) P value The authors concluded that capecitabine and oxaliplatin are as effective as fluorouracil and cisplatin in patients with untreated oesophago-gastric cancer. Findings from the REAL-2 study were supported by a German Phase III trial that compared fluorouracil, leucovorin and oxaliplatin (FLO) versus fluorouracil, leucovorin and cisplatin (FLP) in patients with untreated locally advanced or metastatic oesophago-gastric cancer. The primary endpoint was to demonstrate superiority of FLO over FLP in PFS (3.5 to 5 months) and generally to see whether the risk/benefit ratio could be improved by using oxaliplatin instead of cisplatin. A total of 218 patients (FLO, n=112; FLP, n= 106) were eligible for the intention to treat efficacy analysis. The majority of patients had metastatic disease (94%) with half of these having liver metastasis (11). The response rate (complete and partial remission) was seen in 39 (34.8%) patients receiving FLO and 26 (24.5%) patients receiving FLP. The median duration of treatment was 5.0 months with FLO and 3.1 months with FLP (p=0.003). The median duration of follow up was 14 months. The primary endpoint, was not met but demonstrated a trend towards improved survival; 5.8 months (95% CI, 4.5 to 6.6 months with FLO and 3.9 months (3.1 to 4.8 months) with FLP (p=0.77). There was no statistically significant difference in overall survival; 10.7 months (8.5 to 13.9 months) with FLO and 8.8 months (7.7 to 12 months). In a subgroup analysis, patients older than 65 years (n=94) were found to have significantly superior response rates (41.3 vs 16.7%; p=0.12), time to treatment failure (5.4vs 2.3 months; p=<0.001), PFS (6.0 VS 3.1 months; p=0.029) and improved overall survival (13.9 vs 7.2 months), compared with FLP, respectively (11). Another Phase III study presented at the American Society of Clinical Oncology (ASCO) investigated the safety and efficacy of capecitabine and cisplatin (XP) versus fluorouracil and cisplatin (FP) as first line therapy in 316 patients with advanced gastric cancer (12, conference abstract only). The study was designed to show noninferiority in PFS. The median number of cycles administered was five for both arms and the median follow up was 22.1 months. The primary endpoint was met and demonstrated non-inferiority; 5.6 months (95% CI ) versus 5.0 months ( ; p=0.003) for XP and FP, respectively. XP demonstrated significant superiority for objective response rate; 41% with XP versus 29% with FP. The authors of this study concluded that based on the reported efficacy, reduced hospitalisation time and simplified regimen, capecitabine should become the fluoropyrimidine of choice for advanced gastric cancer. A Phase II study evaluated the safety and efficacy of oxaliplatin and capecitabine as first line therapy in patients with metastatic or localised inoperable oesophagogastric cancer (13). 51 patients received oxaliplatin on

5 day 1 and capecitabine on days 1-14 of a 21 day cycle. Treatment was continued for six cycles, with a maximum of eight courses in cases of ongoing response. Tumour response was assessed according to RECIST criteria. The mean number of cycles administered was four (range 1-8 cycles). Of the 49 patients evaluable for response, 19 achieved a partial response, 21 achieved stable disease and nine patients had disease progression yielding an objective response rate of 39%. The mean duration of response was 5.3 months (range 2-18 months). 51 patients were evaluable for survival data. The median overall survival was 8 months (95% CI 6-9 months, range 2-27 months). Overall survival at years one and two were 26% and 7% respectively. In the QOL analysis, the emotional well-being improved during treatment but the physical functioning scores declined. The global QOL score did not change during the course of treatment. Another Phase II study assessed the combination of oxaliplatin and capecitabine as first line therapy in 43 patients with metastatic cancer of the oesophagus and GOJ. Eligibility criteria included the ability to swallow pills. Following four patient related deaths in the first 24 patients, the dose of capecitabine was reduced from 1000mg/m 2 to 850mg/ m 2 twice daily for the first 14 days. The dose of oxaliplatin was maintained at 130mg/ m 2 on day 1 of a three week cycle. Tumour response was assessed according to RECIST criteria and this was the primary outcome (14). The median number of cycles completed was four (range 1-12 cycles). Although dose reductions were necessary all of the patients received the entire dose of oxaliplatin and patients received % of their capecitabine dose for the first six cycles of chemotherapy. Of the 43 patients evaluated for tumour response, 15 patients had a partial response, consequently the tumour response rate was 35% (95% CI 23-50%). The median duration of response was 3.9 months (range months) for 13 of these 15 patients. Seven of the 24 patients achieved a partial response before the dose reduction of capecitabine and eight of 19 achieved a partial response after the dose reduction was approved. Median time to tumour progression was 4 months (95% CI ) and median survival, 6.4 months (95%CI ) Adverse events/safety issues In the REAL-2 study (10), the EOX group experienced significantly less grade 3 or 4 neutropenia (27.6% vs 41.7%) and alopecia (28.8% vs 44.2%) than the ECF group but significantly more diarrhoea (11.9% vs 2.6%) and peripheral neuropathy (4.4% vs 0.4%). In addition the EOX group experienced significantly lower levels of thromboembolism (all grades) than the ECF group (7.5% vs 16.9%). Compared to the ECF group, the ECX group was associated with significantly more grade 3 or 4 neutropenia (41.7% vs 51.1%) and hand and foot syndrome (4.3% vs 10.3%). Table 3 highlights the most common Grade 3 or 4 toxicities for each of the study groups. In addition, the CVAD used to administer fluorouracil was removed in 10% of patients because of complications related to the device. Table 3:Grade 3-4 toxicities reported for the REAL 2 study Grade 3 or 4 toxicities (%) ECF (n=234) ECX (n=234) EOF (n=225) EOX (n=227) Anaemia* Thrombocytopenia* Neutropenia* Febrile neutropenia* Diarrhoea Stomatitis Hand-foot syndrome Nausea and vomiting Peripheral neuropathy lethargy Alopecia (grade 2 only)

6 * haematological safety population 236 patients in ECF, 229 patients in ECX, 231 patients in EOF and 232 patients in EOX. statistically significant comparisons In the Al-Batran et al study (11), FLO was associated with significantly less anaemia (54 vs 72%), nausea (53 vs 70%), vomiting (31 vs 52%), alopecia (22 vs 39%), fatigue (19 vs 34%), renal toxicity (11 vs 34%), thromboembolic events (0.9 vs 7.8%), serious treatment related adverse events (9 vs 19%) but more peripheral neuropathy (63 vs 22%) than FLP. In the Meerten et al study (13), the most common grade 3 toxicities for the combination of capecitabine and oxaliplatin were vomiting and nausea with one case of grade 4 lethargy. In terms of haematological toxicities, there was one grade 3 neutropenia in one patient and one grade 3 anaemia in another patient. In 22% of patients, toxicity was the reason for stopping treatment. In the Jatoie et al study (14), the most frequent grade 4 toxicity was vomiting and the most frequent grade 3 toxicities were nausea, fatigue and diarrhoea. Neurological and haematological toxicities were not mentioned in this study. Four patients who were exposed to the higher dose of capecitabine had grade 5 treatment related toxicities. The deaths consisted of severe infection, two myocardial infarctions and respiratory failure. Economic/Cost implications Below are the calculations for the cost per cycle (21 days) for the average person (1.7m 2 ) Dose used in REAL-2 study Epirubicin 50mg/m2 Dose for average Price excl VAT ( ) person (1.7m 2) from MIMS, Sept 2008 and BNF, March mg 10mg = mg= mg= Cisplatin 60mg/m2 102mg 50mg= mg=55.64 Fluorouracil 200mg/m 2 / day for 21 days Capecitabine 625mg/m 2 bd for 21 days Oxaliplatin 130mg/m 2 (generic) 340mg 250mg= mg= mg= mg= mg= mg bd 150mg = 60 tabs mg=120 tabs for mg 50mg= mg= Dose rounded to nearest vial/tab 80mg (4x20mg) mg mg x 500mg tabs bd mg Cost excl VAT ( ) per cycle per patient

7 Based on the weight of an average person and the calculations above, one cycle of each regimen would cost the following: ECF: 352 ECX: 424 EOF: 92 EOX: 995 Please note that the above costs do not reflect locally negotiated discounts for oxaliplatin or include VAT. Taking the discounts available to NHS Trusts into account it is likely that the ECX may cost about 320 per cycle and EOX may cost approximately 400 per cycle. A cost minimisation analysis submitted by Roche evaluated the cost effectiveness of replacing infused fluorouracil with capecitabine within the ECF regimen for advanced gastric cancer. The analysis compared the drug costs of ECX versus ECF regimens plus the drug administration costs associated with providing infused fluorouracil from an NHS perspective. Administration costs included hospital visits, transport, staff time and disposables. Other costs included insertion and management of central venous access lines, drug preparation, and use of infusional drug pumps. The researchers found that the additional cost of capecitabine, 634 per patient course, was offset by drug administration savings of 1773, resulting in a net cost saving of 1139 per patient. The researchers concluded that capecitabine is cost-effective for the NHS and oral administration is convenient for patients and cancer services in the treatment of advanced gastric cancer (15). EOX/ ECX administration cost (based on 2005/6 reference costs) Activity Visit/ cycle Cost Total Chemotherapy day-case delivery One each cycle 6 cycles Assuming 15 patients per 100,000 patient population in England are eligible for treatment with one of these regimens and receive an average 4 cycles of treatment then at typical NHS prices if EOX was chosen as the regimen of choice (over the current standard ECF), it would cost an additional 6,000 per 100,000 patient population with no significant change in associated administration costs (personal communication). The Scottish Medicines Consortium (SMC) has approved capecitabine for the first-line treatment of advanced gastric cancer in combination with a platinum based chemotherapy regimen. They state that although capecitabine is more expensive than fluorouracil, the convenience of oral administration may allow changes to service delivery that have individual patient or organisational benefits. In the cost analysis submitted to the SMC, the manufacturer estimated that the direct drug cost of oral capecitabine would be 32k in year 1 for 100 patients, rising to 169k in year 5 for 367 patients. The manufacturer estimated savings due to reduced administration costs which resulted in a net saving of 58k in year 1 and 303k in year 5 (16). They have not addressed the substitution of cisplatin with oxaliplatin. There are no relevant cost analyses for oxaliplatin versus cisplatin, either in published or unpublished literature. Typical administration costs that are relevant to this review are outlined below ECF/ EOF administration cost (based on 2005/6 reference costs) Activity Visit/ cycle Cost Total Line insertion One-off Chemotherapy day-case delivery Pump change/ line flush Pump cost One each cycle 6 cycles Two each cycle 6 cycles Three each cycle 6 cycles TOTAL 4551

8 Discussion points/issues for consideration Capecitabine is licensed for first-line treatment of advanced gastric cancer in combination with a platinumbased regimen but oxaliplatin is not licensed specifically for the treatment of gastro-oesophageal cancer The published data to support the substitution of cisplatin to oxaliplatin and fluorouracil to capecitabine is limited to one large randomised controlled trial (REAL -2) which suggests that oxaliplatin is non inferior to cisplatin and capecitabine is non-inferior to fluorouracil. The REAL-2 study demonstrated that the EOX regimen was associated with better overall survival than the ECF regimen (median 11.2 vs 9.9 months), although this was a secondary endpoint. The actual difference in median overall survival is modest (an additional 5-6 weeks). In terms of clinically important adverse effects, the REAL-2 study showed that the EOX regimen was associated with significantly lower levels of neutropenia and thromboembolism than the ECF regimen. Both of these toxicities confer significant patient morbidity resulting in a large burden on hospital resources. The results of the REAL-2 study provided the evidence base for the licensing of capecitabine for first-line treatment of advanced gastric cancer in combination with a platinum based regimen. Capecitabine is more expensive than 5-FU, however this cost differential may be nullified by the reduced administration costs associated with this oral drug. CVAD-related complications requiring removal of the device occurred in 10% of patients treated with fluorouracil complications like these would be avoided with the oral formulation of capecitabine which does not require administration in this manner. Compared to cisplatin, oxaliplatin does not require pre or post-infusion hydration, thus reducing administration of chemotherapy by six hours. Since the expiry of the patent for oxaliplatin, the cost of has decreased significantly possibly by as much as 75% - this can reduce the costs of EOX from just under 1000 per cycle to around 400 per cycle. The EOX regimen will form the standard arm of the open-label REAL-3 trial which will compare this regimen with or without panitumumab in untreated patients with advanced oesophago-gastric cancer. The trial is a non-sponsored UK- multicentre trial. References 1. Palser T, Cromwell D, van der Mullen J on behalf of the Clinical Effectiveness Unit, The Royal College of Surgeons of England. National Oesophago-gastric cancer audit an audit of the care received by people with oesophago-gastric cancer in England and Wales, first annual report NHS The Information Centre ncer/new%20web%20documents%20(og)/ NHSIC-OGAuditReport-FV-HR.pdf (last accessed 20/4/09) 2. Jackson C, Starling N, Chua YJ et al. Pharmacotherapy for oesophagogastric cancer. Drugs 2007; 67 (17): Webb A, Cunningham D, Scarffe JH et al. Randomised trial comparing epirubicin, cisplatin and fluorouracil versus fluorouracil, doxorubicin and methotrexate in advanced esophagogastric cancer. Journal of Clinical Oncology 1997; 15: Ross p, Nicholson M, Cunningham D et al. Prospective randomised trial comparing mitomycin, cisplatin and protracted venous-infused fluorouracil (PVI 5-FU) with epirubicin, cisplatin and PVI 5-FU in advanced esophagogastric cancer. Journal of Clinical Oncology 2002; 20: Homs MYV, v.d. Gaast A, Siersema PD, Steyerberg EW, Kuipers EJ. Chemotherapy for metastatic carcinoma of the esophagus and gastroesophageal junction. Cochrane Database of Syst ematic Reviews 2006, Issue 4. Art. No.: CD DOI: / CD pub2 6. Wagner AD, Grothe W, Behl S, et al. Chemotherapy for advanced gastric cancer. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD DOI: / CD pub2 7. Chong G, Cunningham D. Editorial: Can cisplatin and infused 5-fluoruracil be replaced by oxaliplatin and capecitabine in the treatment of advanced oesophagogatric cancer? The REAL 2 trial. Clinical Oncology 2005; 17: Roche. Summary of Product Characteristics for Xeloda. Accessed on electronic medicines compendium (last updated 27/03/08, last accessed on 14/05/08) 9. Sanofi Synthelabo. Summary of Product Characteristics for Eloxatin. Accessed on electronic medicines compendium (last updated 06/09/06, last accessed on 18/06/09) 10. Cunningham D, Starling N, Rao S. Capecitabine and oxaliplatin for advanced esophagogastric cancer. NEJM 2008; 358 (1): Al Batran SE, Hartmann JT, Probst S et al. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: A study of the Arbeitsgemeinschaft Internistische Onkologie. Journal Clinical Oncology 2008; 26: Kang Y, Kang WK, Shin DB et al. Randomised phase III trial of capecitabine/cisplatin (XP) vs continuous infusion of 5-FU/cisplatin (FP) as firstline therapy in patients with advanced gastric cancer: efficacy and safety results. Journal of Clinical Oncology 2006 ASCO annual meeting proceedings. Part 1

9 13. van Meerten E, Eskens FALM, van Gameren EC et al. First-line treatment with oxaliplatin and capecitabine in patients with advanced or metastatic oesophageal cancer: a phase II study. British Journal of Cancer 2007; 96: Jatoi A, Murphy BR, Foster NR et al. Oxaliplatin and capecitabine in patients with metastatic adenocarcinoma of the esophagus, gastroesophageal junction and gastric cardia: a phase II study from the North Central Cancer Treatment Group. Annals of Oncology 2006; 17: Cowell W, Summerhayes M. Pharmacoeconomic evaluation of capecitabine (Xeloda) for gastric cancer in the United Kingdom. Unpublished abstract, Tenth Annual European Congress; October Scottish Medicines Consortium. Capecitabine 150mg and 500mg tablets (401 07). September Therasse P, Arbuck SG, Eisenhauer EA. New Guidelines to Evaluate the Response to Treatment in Solid Tumors. Journal of the National Cancer Institute 2000; 92 (3): Appendix 1 - RECIST criteria for evaluating solid tumour response RECIST criteria are a voluntary, international standard, and are not a National Cancer Institute (NCI) standard. They are based on a simplification of former internationally recognised methods (WHO, ECOG) and based on measurable disease, i.e., the presence of at least one measurable lesion. The differences in definitions of each of the response criteria are tabulated below (17). Response according to RECIST criteria Best response Complete response (CR) Partial response (PR) Stable disease (SD) Progressive disease (SD) RECIST criteria disappearance of all target lesions; confirmed at 4 weeks 30% decrease in the sum of the longest diameter of target lesions; confirmed at 4 weeks Neither PR or PD criteria are met 20% increase; no CR, PR, or SD documented before increased disease The document reflects the views of LCNDG and may not reflect those of the reviewers Please direct any comments to Sheetal Ladva, London & South East Medicines Information Service, Guy s Hospital, Great Maze Pond, London SE1 9RT Tel: , Fax: , sheetal.ladva@gstt.nhs.uk