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Toxicity associated with combination oxaliplatin plus fluoropyrimidine with or without cetuximab in the MRC COIN trial experience

Toxicity associated with combination oxaliplatin plus fluoropyrimidine with or without cetuximab... British Journal of Cancer (2009) 100, 251 – 258 & 2009 Cancer Research UK All rights reserved 0007 – 0920/09 $32.00 www.bjcancer.com Toxicity associated with combination oxaliplatin plus fluoropyrimidine with or without cetuximab in the MRC COIN trial experience 1,3 2,3 1 2 2 2 2 ,1 RA Adams , AM Meade , A Madi , D Fisher , E Kay , S Kenny , RS Kaplan and TS Maughan on behalf of the COIN trial TMG and investigators 1 2 Velindre Hospital, Cardiff University, Velindre Road, Whitchurch, Cardiff CF14 2TL, UK; Medical Research Council Clinical Trials Unit, Euston Road, London, UK We present the preliminary toxicity data from the MRC COIN trial, a phase III randomised controlled trial of first-line therapy in advanced colorectal cancer, with particular reference to the addition of cetuximab to an oxaliplatin–fluoropyrimidine combination. A total of 804 patients were randomised between March 2005 and July 2006 from 78 centres throughout the United Kingdom. Patients were allocated to oxaliplatin plus fluoropyrimidine chemotherapy with or without the addition of weekly cetuximab. The choice of fluoropyrimidine (either 5-fluorouracil (5FU) or capecitabine) was decided by the treating physician and patient before randomisation. Toxicity data were collected from all patients. Two hundred and three patients received 5FU plus oxaliplatin (OxMdG, 25%), 333 oxaliplatinþ capecitabine (Xelox, 41%), 102 received OxMdGþ cetuximab (OxMdGþ C, 13%) and 166 Xeloxþ cetuximab (21%). Percent grade 3/4 toxicities included diarrhoea 6, 15, 13 and 25%, nausea/vomiting 3, 7, 7 and 14% for OxMdG, Xelox, OxMdGþ C and Xeloxþ C, respectively. Sixty-day all-cause mortality was 6, 5, 5 and 7%. Statistically significant differences were evident for patients receiving Xeloxþ cetuximab vs Xelox alone: diarrhoea relative risk (RR) 1.69 (1.17, 2.43, P¼ 0.005) and nausea/vomiting RR 2.01 (1.16, 3.47, P¼ 0.012). The excess toxicity observed in the oxaliplatin-, capecitabine-, cetuximab-treated patients led the trial management group to conclude that a capecitabine dose adjustment was required to maintain safety levels when using this regimen. British Journal of Cancer (2009) 100, 251 – 258. doi:10.1038/sj.bjc.6604877 www.bjcancer.com & 2009 Cancer Research UK Keywords: colorectal cancer; cetuximab; oxaliplatin; fluoropyrimidine; metastatic; first line Advanced colorectal cancer (ACRC) causes over half a million higher proportion of patients with skin rash, a known side effect of deaths worldwide each year (http://www-dep.iarc.fr/). The treat- EGFR inhibitor therapy. In the past year, the first randomised data ment of ACRC is improving. Average survival has improved from 6 on the combination of oxaliplatin and capecitabine in the first-line months with best supportive care alone, through 10–12 months ACRC setting have been presented (Cassidy et al, 2008). In with single-agent 5-fluorouracil (5FU) regimens up to 16–21 addition, first-line data are also now available from randomised months in randomised trials using irinotecan, oxaliplatin and trials investigating the addition of cetuximab to combination bevacizumab as well as 5FU. chemotherapy regimens containing both irinotecan (Van Cutsem Cetuximab was licensed for use in epidermal growth factor et al, 2007) and oxaliplatin (Bokemeyer et al, 2007). receptor (EGFR)-expressing ACRC on the basis of the phase II Antibodies targeting the EGFR have now shown efficacy in third-, BOND trial (Cunningham et al, 2004) in which 218 irinotecan- second- and first-line therapies. In the Crystal trial, the addition of refractory patients received cetuximab and irinotecan combination cetuximab to first-line irinotecan, infusional 5FU and folinic acid therapy and 111 received cetuximab monotherapy. Although there resulted in an 8% increase in response rate and a significant was no chemotherapy are comparator arm in this trial, the data improvement in progression-free survival (P¼ 0.036) (Van Cutsem suggested no greater toxicity with the combination therapy than is et al, 2007). The EPIC trial explored the use of irinotecan in expected in patients receiving single-agent irinotecan, other than a combination with cetuximab in the second line, after irinotecan failure. This trial has recently been published and demonstrated a response rate with cetuximab and irinotecan of 16.4% (95% *Correspondence: Professor TS Maughan, Velindre Hospital, Velindre confidence interval (CI), 13.6–19.4), compared with 4.2% (95% CI, Road, Whitchurch, Cardiff CF14 2TL, UK; 2.8–6.0) with irinotecan alone (P¼ 0.0001) (Sobrero et al, 2008). E mail: tim.maughan@velindre-tr.wales.nhs.uk COIN is an open-label multicentre randomised controlled trial Original data presented at ASCO (Chicago) 2007 sponsored by the UK Medical Research Council (MRC) and These authors contributed equally to this work coordinated by the MRC Clinical Trials Unit (MRC CTU), Received 8 August 2008; revised 4 December 2008; accepted 14 comparing two experimental arms with the control arm of December 2008 oxaliplatin and fluoropyrimidine chemotherapy in the first-line Clinical Studies Clinical Studies Combination oxaliplatin plus fluoropyrimidine in the MRC COIN trial RA Adams et al treatment of ACRC. The fluoropyrimidine can be either capecita- 2000) WHO performance status 0–2; no previous chemotherapy bine or bolus and infusional 5FU (in a modified FOLFOX for metastatic disease; neutrophils41.5 10 per l, platelet regimen), and is chosen on a per-patient or per-institution basis count4100 10 per l, serum bilirubinr1.25 upper limit of before randomisation. Two primary questions are being addressed normal (ULN), alkaline phosphatasep5 ULN, calculated GFR or in the trial. The first question asks whether the addition of EDTA clearance X50 ml min ; and age 418 years. Exclusion cetuximab to combination chemotherapy will increase overall criteria include patients receiving combination chemotherapy survival, whereas the second asks whether intermittent chemo- before the resection of operable liver metastases (patients of therapy treatment is comparable with continuous treatment to uncertain operability are eligible), brain metastases, prior adjuvant progression or cumulative toxicity. chemotherapy with oxaliplatin and uncontrolled medical co- The use of intermittent chemotherapy is controversial. A previous morbidity likely to compromise treatment. MRC trial showed no detriment in overall survival, with an improvement in toxicity and quality of life for patients receiving Randomisation and treatment intermittent single-agent 5FU chemotherapy (Maughan et al, 2003). Patients were randomised centrally by the MRC CTU to one of the The Optimox 1 trial showed that discontinuation of oxaliplatin after three trial arms on a 1 : 1 : 1 basis using a stratified, minimisation six cycles of OxMdG, with continuation of infusional 5FU and procedure. Treatment is started as soon as possible after subsequent reintroduction of oxaliplatin, resulted in equivalent randomisation and within 4 weeks of the baseline radiological disease control and survival (Tournigand et al,2006).The Optimox2 disease assessment using CT scan. The trial arms are as follows: study, however, has raised doubts about the overall survival equivalence for patients given a chemotherapy-free interval. The Arm A: original design of Optimox 2 was a phase III trial of 600 patients; Continuous chemotherapy (control arm) The chemotherapy regi- however, accrual was discontinued when bevacizumab became men is a combination of oxaliplatin and a fluoropyrimidine. available. At this stage, only 200 patients had been entered. The The regimens are: trial reported a non-significant overall median survival difference of 25 months with continuous infusional 5FU, compared with 19 OxMdG: a combination of l-folinic acid (175 mg i.v. over 2 h) OR months in the arm with chemotherapy-free intervals (P¼ 0.056) d,l-folinic acid (350 mg i.v. over 2 h), concurrent administration (Maindrault-Goebel et al, 2007). Owing to the failure of this trial to of oxaliplatin (85 mg m i.v. over 2 h) plus bolus 5FU complete accrual as planned, and therefore answer the question (400 mg m ) followed by a 46-h i.v. infusion of 5FU originally posed, it is of utmost importance to obtain reliable phase 2400 mg m repeated every 2 weeks as used in the FOCUS trial III evidence of the relative benefits of continuous chemotherapy vs (Seymour et al, 2007) or intermittent chemotherapy with a chemotherapy-free interval in the Xelox: a combination of oxaliplatin 130 mg m i.v. over 2 h on treatment of ACRC. The COIN trial will be the largest randomised day 1 plus capecitabine 1000 mg m b.d., p.o. on days 1–14 controlled trial of continuous vs intermittent chemotherapy carried repeated thrice weekly. out to date. If successful, the intermittent chemotherapy strategy would not only benefit patients, who value time off chemotherapy Patients continue chemotherapy until RECIST-defined progres- very highly, but also open a new therapeutic window for the sive disease is identified, or the development of cumulative toxicity evaluation and use of novel agents to maintain disease control or because of patient choice to stop chemotherapy. Patients should during intervals off chemotherapy. have no more than a 3-week interval off treatment for any reason. In this paper, we present toxicity reported during the first 12 weeks of treatment for the first 804 patients randomised into the Arm B: COIN trial. During the first 12 weeks, there is no difference in the Continuous chemotherapy plus cetuximab Cetuximab is adminis- treatment received by those patients randomised to the control tered once weekly in combination with the chemotherapy schedules arm of COIN and those randomised to intermittent therapy. as above. On day 1 of the first cycle of chemotherapy, an initial Therefore, the focus of this paper is the toxicity experience in the loading dose of 400 mg m cetuximab is given by 2-h i.v. infusion first 12 weeks associated with the addition of cetuximab to two and then continued weekly at a dose of 250 mg m over 60 min. The different oxaliplatin and fluoropyrimidine combination che- following pre-medication is administered at each administration: i.v. motherapy regimens. The 12-week time point has been chosen as chlorphenamine 10 mg, paracetamol (acetaminophen) 1 g p.o. and this is when patients randomised to intermittent therapy stop ranitidine 150 mg p.o. Dexamethasone 8 mg i.v. is given on days treatment. We propose to publish the longer term toxicity data when oxaliplatin is also given. Patients continue chemotherapy plus (relating to the intermittent vs continuous strategies) at a later cetuximab as in arm A above. Cetuximab may be continued if date, together with quality of life and primary outcome data. In the chemotherapy is stopped because of toxicity or patient choice, but meantime, however, we feel that the initial toxicity experience should be discontinued on evidence of disease progression or contains information of value to clinicians employing combina- unacceptable cetuximab toxicity. tions of these widely available agents. Arm C: PATIENTS AND METHODS Intermittent chemotherapy These patients are treated initially for 12 weeks as in arm A. Patients who have radiologically confirmed Accrual update progressive disease at this point come off study, as in arms A and B. The COIN trial opened to accrual in March 2005 and closed in May Patients with stable or responding disease stop chemotherapy and 2008 after completing accrual ahead of schedule; 2445 patients are monitored clinically, at least six weekly, and with CT scans at 12- have been randomised from 111 centres in the United Kingdom weekly intervals. On evidence of radiological disease progression or and Republic of Ireland. on clinical evidence of deterioration, the same chemotherapy is restarted, for a further 12-week course. At that point, treatment is again interrupted. Patients with chemosensitive disease may have an Eligibility criteria unlimited number of 12-week treatments alternating with treatment Patients have histologically confirmed colorectal adenocarcinoma, breaks. When the patient demonstrates resistance to this treatment with inoperable metastatic or locoregional disease. Eligibility as evidenced by progressive disease during a period on chemo- criteria include disease measurable by RECIST (Therasse et al, therapy, they move on to second-line therapy or supportive care. British Journal of Cancer (2009) 100(2), 251 – 258 & 2009 Cancer Research UK Combination oxaliplatin plus fluoropyrimidine in the MRC COIN trial RA Adams et al Protocol dose modifications Table 1 Base-line patient and tumour characteristics Detailed dose reduction and delay protocols are given in the Treatment arm A B C protocol. In general, unresolved grade X2 toxicity required a 1-week delay, whereas grade X3 toxicity or two delays for grade 2 Total patients 269 (33%) 268 (33%) 267 (33%) toxicity required a 20% dose reduction. Chemotherapy selection Ox+Cap 167 (62%) 166 (62%) 166 (62%) Assessments OxMdG 102 (38%) 102 (38%) 101 (38%) Investigator assessments of toxicity are made at six-weekly Sex intervals while on protocol treatment and scored using NCI CTC Male 173 (64%) 167 (62%) 174 (65%) criteria (version 3.0). Safety is assessed continuously throughout Female 96 (36%) 101 (38%) 93 (35%) the trial by monitoring of adverse events by the treating physician. Reported serious adverse events are reviewed by an experienced Age (years) o45 12 (4%) 18 (7%) 14 (5%) practicing oncologist. All deaths, together with the treating 45 – 54 46 (17%) 34 (13%) 48 (18%) physician’s assessment of causality, are also reported. A further 55 – 64 88 (33%) 100 (37%) 91 (34%) assessment of cause of death is also undertaken centrally by an 65 – 74 99 (37%) 95 (35%) 94 (35%) experienced practicing oncologist (TSM, RA or AyM). 75+ 24 (9%) 21 (8%) 20 (7%) Median age (IQR) 63 (56, 69) 63 (58, 69) 63 (55, 70) Statistical methods WHO PS As arms A and C are identical during the first 12 weeks of protocol 0 120 (45%) 124 (46%) 126 (47%) treatment, they are combined for the purpose of this analysis. All 1 128 (48%) 127 (47%) 126 (47%) 2 21 (8%) 17 (6%) 15 (6%) comparisons were tested for significance using Fisher’s exact tests. All reported P-values are two-sided, and P-values less than 0.05 Current status of primary tumour were considered to indicate statistical significance. Resected 152 (57%) 144 (54%) 140 (52%) Unresected/unresectable 103 (38%) 100 (37%) 108 (40%) Role of the funding source Local recurrence 14 (5%) 24 (9%) 19 (7%) The trial is funded by Cancer Research UK, the MRC and Metastases supported by an educational grant from Merck Serono. Patient No 2 (1%) 2 (1%) 1 (o1%) informed consent and data collection were supported by staff from Yes 267 (99%) 266 (99%) 266 (499%) the National Cancer Research Networks across the United King- Type of metastases dom. Liver only 55 (20%) 69 (26%) 67 (25%) Liver 197 (73%) 195 (73%) 194 (73%) Trial governance Nodes 127 (47%) 109 (41%) 119 (45%) Lung 107 (40%) 103 (38%) 99 (37%) COIN is an investigator-initiated trial sponsored by the MRC in the Peritoneum 40 (15%) 40 (15%) 40 (15%) United Kingdom. Certain sponsor responsibilities are delegated to Other 38 (14%) 45 (17%) 36 (13%) the Irish Clinical Oncology Research Group for investigator sites in Mean no. of metastatic sites 2.32 2.3 2.3 the Republic of Ireland. Multicentre and Institutional Research at baseline Ethics Committee and appropriate regulatory approval have been Site of primary tumour obtained, and all patients provide written informed consent. Trial Colon 147 (55%) 142 (53%) 136 (51%) management is by the MRC Clinical Trials Unit following the Rectum 82 (30%) 88 (33%) 83 (31%) principles of ICH GCP and overseen by an Independent Trial Rectosigmoid junction 34 (13%) 37 (14%) 48 (18%) Steering Committee. An Independent Data Monitoring Committee Other 2 (1%) 1 (o1%) 0 (0%) meets at regular intervals (approximately six monthly) for trial Missing data 4 (1%) 0 (0%) 0 (0%) oversight, including review of safety data and interim outcome analyses at pre-specified intervals. Prior treatment for patient with metastatic disease Radiotherapy 9 (3%) 6 (2%) 2 (1%) Surgery 54 (20%) 49 (18%) 53 (20%) RESULTS PS¼ performance status. Characteristics of patients At least one dose reduction in a COIN trial drug was instituted From March 2005 to July 2006, 804 patients were randomised at 78 for toxicity in 28, 44, 22 and 49% of patients in the regimens, centres in the United Kingdom. Baseline characteristics (Table 1) respectively. This doubling of dose reductions when chemotherapy were well balanced across the three arms. Thirty-eight percent was given with cetuximab was highly statistically significant received OxMdG and 62% of patients received Xelox. Patients on (Po0.001). These broke down as indicated in Table 2 (online). average have a high burden of disease at baseline, with Median dose intensities are as indicated in Table 3 (online). It is of approximately 40% having an unresected or unresectable primary particular note that in patients on Xeloxþ C, the oxaliplatin dose tumour and each patient having on average 2.3 metastatic sites. was reduced in 33% of patients compared with 15% on Xelox alone (Po0.001). Treatment received Toxicity Two hundred and three patients received 5FU plus oxaliplatin (OxMdG, 25%), 102 received OxMdGþ cetuximab (OxMdGþ C, Toxicity data during the first 12 weeks of treatment are available 13%), 333 oxaliplatinþ capecitabine (Xelox, 41%) and 166 for 97% of patients. Table 4 (online) indicates all grades of toxicity Xeloxþ cetuximab (21%). reported, whereas Table 5 shows grade 3 or 4 toxicities observed & 2009 Cancer Research UK British Journal of Cancer (2009) 100(2), 251 – 258 Clinical Studies Clinical Studies Combination oxaliplatin plus fluoropyrimidine in the MRC COIN trial RA Adams et al Table 2 Chemotherapy dose reductions over the first 12 weeks of treatment broken down by regimen and therapeutic agent, on line only Arms A+C (no cetuximab) Arm B (cetuximab) OxMdG XELOX OxMdG XELOX Total Total N 203 333 102 166 804 Trial drug 5FU 48 31 79 % of patients with 5FU dose reduction (24%) (30%) (26% ) Capecitabine 65 60 125 % of patients with capecitabine dose reduction (20%) (36%) (25% ) Oxaliplatin 28 50 16 54 148 % of patients with oxaliplatin dose reduction (14%) (15%) (16%) (33%) (18%) Cetuximab 24 33 57 % of patients with cetuximab dose reduction (24%) (20%) (21% ) Any trial drug 57 73 45 81 256 % of patients with any trial drug dose reduction (28%) (22%) (44%) (49%) (32%) 5FU¼ 5-fluorouracil. On line only. Denominator is valid subjects only. Table 3 Dose intensities (first 12 weeks; medians and IQRs) Arms A+C (no cetuximab) Arm B (cetuximab) OxMdG XELOX OxMdG XELOX Total Total 203 333 102 166 804 Complete data on first round of treatment (0 – 12 weeks) 158 247 76 119 600 Median (IQR) Median (IQR) Median (IQR) Median (IQR) Median (IQR) 5FU infusion 91 (81, 99) 85 (78, 94) 88 (80, 97) 5FU bolus 91 (75, 99) 83 (68, 93) 88 (71, 97) Capecitabine 96 (86, 100) 88 (80, 100) 93 (84, 100) Oxaliplatin 89 (82, 98) 97 (89, 100) 86 (78, 94) 92 (80, 99) 93 (83, 99) Cetuximab, day 1 85 (78, 94) 96 (87, 100) 92 (81, 99) Cetuximab, day 8 83 (75, 92) 93 (78, 100) 89 (77, 99) Cetuximab, day 15 91 (75, 100) 91 (75, 100) 5FU¼ 5-fluorouracil. Table 4 Dose intensities (first 12 weeks; percentage of patients with o80%) on line only Arms A+C (no cetuximab) Arm B (cetuximab) OxMdG XELOX OxMdG XELOX Total Total 203 333 102 166 804 Complete data on first round of treatment (0 – 12 weeks) 158 247 76 119 600 N (%) N (%) N (%) N (%) N (%) 5FU infusion 3 (2) 5 (7) 8 (3) 5FU bolus 24 (15) 16 (21) 40 (17) Capecitabine 11 (4) 17 (14) 28 (8) Oxaliplatin 5 (3) 4 (2) 6 (8) 14 (12) 29 (5) Cetuximab, day 1 1 (1) 12 (10) 13 (7) Cetuximab, day 8 7 (9) 23 (19) 30 (15) Cetuximab, day 15 29 (24) 29 (24) 5FU¼ 5-fluorouracil. within the first 12 weeks of treatment for the first 804 patients increased in patients receiving infusional 5FU (17% without and randomised to COIN. 26% with cetuximab) compared with those taking oral capecita- The addition of cetuximab to oxaliplatin- and fluoropyrimidine- bine (2% without and 1% with cetuximab, Po0.001), and this based chemotherapy results in an absolute increase in any grade 3/ translates into neutropaenic sepsis in 4, 5, 1 and 0%, respectively. 4 toxicity of approximately 25% (35–63% with OxMdG, 35–57% Gastrointestinal toxicities, namely nausea, vomiting and diar- with Xelox, Po0.001). Grade 3/4 neutropaenia is significantly rhoea, are all significantly increased in patients receiving Xelox British Journal of Cancer (2009) 100(2), 251 – 258 & 2009 Cancer Research UK Combination oxaliplatin plus fluoropyrimidine in the MRC COIN trial RA Adams et al Table 5 All grades of toxicity reported in the first 12 weeks of treatment Arms A+C (no cetuximab) Arm B (cetuximab) Significance* ± ± OxMdG XELOX OxMdG XELOX Cap. Cet. N 203 333 102 166 N (%) N (%) N (%) N (%) Any grade 1+ 194 (96) 316 (95) 100 (98) 161 (97) Neutropaenia 91 (45) 42 (13) 46 (45) 9 (5) Po0.001 Nausea or vomiting 113 (56) 215 (65) 56 (55) 95 (57) Diarrhoea 115 (57) 207 (62) 75 (74) 117 (70) Po0.05 Skin rash 23 (11) 44 (13) 87 (85) 139 (84) Po0.001 Hypersensitivity Any 2 (o1) 6 (2) 0 (0) 4 (2) Oxaliplatin 1 (1) 4 (1) 0 (0) 1 (o1) Cetuximab — 0 (0) 2 (1) Not specified 1 (1) 2 (1) 0 (0) 1 (1) Lethargy 157 (77) 266 (80) 91 (89) 144 (87) Po0.05 Hand – foot syndrome 33 (16) 89 (27) 42 (41) 70 (42) Po0.001 Peripheral neuropathy 155 (76) 230 (71) 76 (75) 117 (70) Hypomagnesaemia 6 (3) 7 (2) 9 (9) 7 (4) Po0.05 Po0.05 *Fisher’s exact test. ‘Cap.’¼ presence vs absence of capecitabine; that is, XELOX vs OxMdG. ‘Cet.’¼ presence vs absence of cetuximab; that is, arm B vs arms A and C. Table 6 Grade 3 and 4 toxicities reported over first 12 weeks of treatment Arms A+C (no cetuximab) Arm B (cetuximab) Significance* ± ± OxMdG XELOX OxMdG XELOX Cap. Cet. N 203 333 102 166 N (%) N (%) N (%) N (%) Any grade 3 or 4 72 (35) 118 (36) 64 (63) 95 (58) Po0.001 Neutropaenia 35 (17) 5 (2) 27 (26) 1 (1) Po0.001 Neutropaenic sepsis/febrile neutropaenia 9 (4) 3 (1) 5 (5) 0 (0) Po0.001 Nausea or vomiting 6 (3) 23 (7) 7 (7) 23 (14) Po0.05 Po0.05 Diarrhoea 13 (6) 50 (15) 13 (13) 42 (25) Po0.001 Po0.05 Skin rash 0 (0) 2 (1) 12 (12) 16 (10) Po0.001 Hypersensitivity Any 0 (0) 1 (o1) 0 (0) 2 (1) Oxaliplatin 0 (0) 1 (o1) 0 (0) 0 (0) Cetuximab — 0 (0) 1 (1) Not specified 0 (0) 0 (0) 0 (0) 1 (1) Lethargy 15 (7) 27 (8) 21 (21) 28 (17) Po0.001 Hand—foot syndrome 1 (o1) 7 (2) 4 (4) 7 (4) Peripheral neuropathy 4 (2) 14 (4) 0 (0) 10 (6) Po0.05 Hypomagnesaemia 0 (0) 1 (o1) 0 (0) 0 (0) *Fisher’s exact test. ‘Cap.’¼ presence vs absence of capecitabine; that is, XELOX vs OxMdG. ‘Cet.’¼ presence vs absence of cetuximab; that is, arm B vs arms A and C. compared with those receiving OxMdG chemotherapy. These cetuximab). Hand–foot syndrome was significantly more common toxicities are further increased by the addition of cetuximab, with with capecitabine, with 40% experiencing any grade but only 2– an incidence of grade 3/4 diarrhoea of 25% in patients receiving 4% experiencing grade 3 hand–foot syndrome. There was a trend the Xelox plus cetuximab combination. Statistically significant to an increased incidence of hand–foot syndrome in patients differences were evident for patients receiving Xelox in combina- treated with cetuximab. tion with cetuximab-based therapy vs Xelox alone for grade 3/4: In earlier studies, hypersensitivity reactions have been reported relative risk (RR) of diarrhoea 1.69 (1.17, 2.43, P¼ 0.005), nausea in 1.8% of patients receiving oxaliplatin chemotherapy, increasing or vomiting RR 2.01 (1.16, 3.47, P¼ 0.012) and lethargy RR 2.08 to 4.1% when cetuximab is added to this chemotherapy regimen (1.27, 3.41, P¼ 0.003). (Bokemeyer et al, 2007). In this cohort, there was no such increase As expected, patients receiving cetuximab have a significantly in oxaliplatin hypersensitivity with the addition of cetuximab, increased incidence of the skin rash associated with EGFR although numbers are small. inhibitors such as cetuximab. This increase is similar irrespective Lethargy is reported in 8% of patients receiving Xelox and 7% of of the chemotherapy regimen (84% in patients receiving patients receiving OxMdG chemotherapy. The addition of Xeloxþ cetuximab and 85% in patients receiving OxMdG plus cetuximab results in an increase in lethargy, with 17% of patients & 2009 Cancer Research UK British Journal of Cancer (2009) 100(2), 251 – 258 Clinical Studies Clinical Studies Combination oxaliplatin plus fluoropyrimidine in the MRC COIN trial RA Adams et al Table 7 All-cause 60-day mortality Arms A+C (no cetuximab) Arm B (cetuximab) OxMdG XELOX OxMdG XELOX No. of patients randomised 203 333 102 166 N (%) N (%) N (%) N (%) 60-day all-cause mortality 12 (6%) 18 (5%) 5 (5%) 12 (7%) Treatment-related death within 60 days 2 (1%) 2 (1%) 1 (1%) 3 (2%) Table 8 A comparison of toxicities among a variety of chemotherapy regimens within four clinical trials in which cetuximab was used Cetuximab+ Cetuximab+ Cetuximab+ Cetuximab+ a a b b c d a a c d XELOX OxMdG FOLFOX XELOX FOLFIRI FOLFOX-4 XELOX OxMdG FOLFIRI FOLFOX-4 N 333 203 649 655 602 168 166 102 600 170 Any grade 3 or 4 35 35 78.3 71.5 59.5 NS 57 63 78.0 NS toxicity Neutropaenia 2 17 43.8 7.0 23.3 31.5 1 26 26.7 27.6 Nausea or vomiting 7 3 NS NS 5.0 NS 14 7 4.5 NS Diarrhoea 15 6 11.2 20.2 10.5 6.0 25 13 15.2 7.1 Skin rash 1 0 NS NS 0.2 0 10 12 18.7 14.1 Hypersensitivity NS NS 0 1.8 2.3 4.1 2.0 Lethargy 8 7 NS NS 4.5 3.0 17 21 5.0 3.5 a b c d COIN TRIAL. Roche N966. Crystal trial. OPUS trial. receiving Xelox plus cetuximab and 21% of patients receiving mature and a full report on (early and late) toxicities accompanies OxMdG plus cetuximab experiencing grade 3/4 lethargy within the the analysis, data on k-ras status for almost all of these patients will first 12 weeks of their treatment in the COIN trial. be available. It is possible that there may be differences in toxicity Peripheral neuropathy is rare in this report, as the time for the that relate to tumour k-ras mutational status, but that is not the report is ‘toxicities within the first 12 weeks of therapy’ and expectation. The COIN data thus far reflect a typical usage of oxaliplatin neuropathy emerges slightly later than 12 weeks in cetuximab to date in first-line combinations in patients without most patients in whom it occurs. Longer term data will be available molecular selection. when the overall trial outcomes are reported. Similarly in this A number of interesting toxicity issues are addressed by this cohort, hypomagnesaemia is under-reported here because the study, relating to confirmatory evidence of the differences between protocol was modified in October 2005 to make magnesium oxaliplatin regimens with either capecitabine or 5FU and to the concentration monitoring and reporting mandatory, by which time novel issues of adding cetuximab to either of these regimens. The findings of the COIN trial are consistent with other most of these patients had commenced treatment. international trials including the Roche-sponsored Xelox-1/ NO16966 phase III trial in first-line treatment of colorectal cancer, Deaths within 60 days of randomisation which reported comparative toxicity for oxaliplatin plus 5FU compared with oxaliplatin plus capecitabine. The COIN trial also Tables 6 and 7 shows the numbers and percentages of deaths shows a significantly higher incidence of neutropaenia (with a within 60 days of randomisation, both all-cause and those 4.8% incidence of febrile neutropaenia), and half the incidence of attributed to trial treatment. All-cause 60-day mortality is similar diarrhoea with the infusional 5FU regimen compared with irrespective of the chemotherapy regimen or the addition of capecitabine. Treatment-related mortality in the NO16966 study cetuximab. On review of causation by an experienced practicing was 2.1% with Xelox compared with 1.7% with FOLFOX (Cassidy oncologist on behalf of the MRC as a sponsor of the trial, et al, 2008) (see Table 8 for comparisons). treatment-related deaths were not statistically significantly differ- The addition of cetuximab to oxaliplatin-based regimens has not ent between treatment regimens. been previously reported in a phase III trial, but data from the large OPUS phase II study show no significant uplift in toxicity when combining cetuximab with FOLFOX-4 (a regimen with a DISCUSSION lower infused 5FU dose compared with that used in the COIN trial) The COIN trial was designed and completed recruitment during a (Bokemeyer et al, 2007). period when no strong predictor of response to EGFR-inhibiting The addition of cetuximab to 5FU plus irinotecan (FOLFIRI) therapies was known or available. K-ras mutation on tumour was evaluated in the Crystal trial. A minor increase in grade 3 and samples has since been identified as predictive of minimal 4 diarrhoea (from 10 to 15%) was seen with the addition of likelihood of benefit from the addition of cetuximab in various cetuximab (Van Cutsem et al, 2007). colorectal clinical settings. However, there is as yet no evidence Table 8 shows the comparative toxicities from the COIN, Roche that somatic k-ras status is associated with differences in toxicity N966, Crystal and OPUS trials. The only studies that have of EGFR antibodies or small molecule inhibitors. The initial COIN previously reported the addition of capecitabine-containing trial data reported herein encompass the whole eligible population combinations with cetuximab are the SAKK group, the AIO CRC regardless of k-ras mutation status. When the outcome data are study group phase II trials and the single-institution study from British Journal of Cancer (2009) 100(2), 251 – 258 & 2009 Cancer Research UK Combination oxaliplatin plus fluoropyrimidine in the MRC COIN trial RA Adams et al Heraklion (Borner et al, 2006; Heinemann et al, 2007; Souglakos fluoropyrimidine. In addition, the data from the revised dose et al, 2007). The SAKK group performed a randomised phase II would provide evidence for a more manageable combination trial of 74 patients in whom all received Xelox (as used in COIN) schedule for the future, which would be consistent with other on a three-weekly basis and half of the patients received cetuximab international data of capecitabine plus oxaliplatin when used in weekly; the toxicity data have recently been published and combination with a biological agent. Finally, this would provide demonstrate a non-significant increase in grade 3/4 diarrhoea for a more equitoxic comparison between arm A (full-dose Xelox) from 16 to 22%, with the addition of cetuximab (Borner et al, and arm B (dose-reduced Xeloxþ cetuximab). 2008). The AIO group trial randomised patients to XELIRI or The disadvantages were considered to be that we would be using Xelox both with the addition of cetuximab. In the 41 patients a different regimen for the comparator in arm A (full-dose Xelox) receiving Xelox plus capecitabine (in a similar dose and schedule vs arm B (dose-reduced Xeloxþ C). This reduced dose intensity for to COIN), grade 3/4 toxicity was seen in 19.5%. The single-centre all subsequent patients on Xeloxþ cetuximab might impact on the Heraklion trial recruited 40 patients and used the two-weekly efficacy of this combination. This could in turn cause difficulties in capecitabine plus oxaliplatin (CAPOX) regimen in combination reporting the trial in view of the mid-trial dose reduction for a with cetuximab (weekly) with only 7 days of capecitabine. The rate subset of patients in arm B. The arm B comparisons of toxicity and of grade 3/4 diarrhoea in this trial was 7.5%. effectiveness would need to be reported as the total intention-to- The key finding of this report is the synergistic effect on treat population (1614 patients) and as three subsets: (1) those diarrhoeal toxicity of the oxaliplatin, capecitabine and cetuximab treated on OxMdG: OxMdG vs OxMdGþ cetuximab (c 613 patients combination. This finding had been observed in an earlier IDMC on current 38% usage of OxMdG); (2) those on full-dose Xelox report and the TMG had, on the instruction of the IDMC, until dose reduction imposed (696 patients); (3) those on modified improved the patient information cards and fed back the data to Xelox comparing full-dose Xelox vs mXELOXþ cetuximab (295 investigators so that they include this information in their patients). On this basis, the TMG considered that the dose discussions with patients regarding selection of capecitabine- or reduction at this point in the trial would have a modest effect on 5FU-based treatment. Despite this, the rate of diarrhoea was the efficacy data, but was required for patient safety. gradually increasing: for those patients receiving oxaliplatin, The option appraisal paper and the toxicity and advised dose capecitabine and cetuximab, a grade 3/4 diarrhoea rate of 23% reduction data were reviewed by the IDMC and independent TSC was reported in the ASCO abstract (Maughan, 2007) submitted in and the decision to apply the dose reduction was approved and December 2006 and this had reached 30% (on the data set from the immediately implemented from July 2007. March IDMC, released to the TMG as of July 2007). Thus, there was no sign of an improvement with greater experience of the regime by investigators despite information to investigators and improved CONCLUSION patient information. This increased toxicity is reflected in the increased incidence of This data set is consistent with previous data reporting the toxicity dose reduction in those patients receiving cetuximab. Overall, of the addition of cetuximab to combination chemotherapy. There patients receiving cetuximab had a dose reduction of any agent is an increased incidence of grade 3 and 4 toxicities overall. The twice as often as those without cetuximab. In particular, those specific toxicities affect the skin, gastrointestinal tract and treated with Xeloxþ cetuximab had a 33% incidence of oxaliplatin lethargy. Infusion-related reactions are relatively rare and can be dose reductions compared with 15% on Xelox alone. It is possible largely prevented with combination pre-medication regimens. The that such dose reductions may contribute to the impaired combination of oxaliplatin (130 mg m , i.v., q21d), capecitabine outcomes seen in the OPUS trial in the ras mutant sub-group (2000 mg m for 14 out of 21 days) and cetuximab was associated treated with FOLFOX plus cetuximab, and this will be analysed with an unacceptable rate of grade 3, 4 diarrhoea, and a dose 2 1 further in the outcomes of the COIN trial. reduction of capecitabine from 2000 to 1700 mg m day has The trial management group reviewed the data in greater detail been introduced into the trial protocol and is advised for off and discussed the possible options. The options included first protocol use of this triple combination. making no protocol change, but urging further diligence in information giving and dose reduction in face of toxicity; dose reduction in the face of grade 2 toxicity rather than grade 3; or alternatively, an immediate dose reduction of capecitabine from ACKNOWLEDGEMENTS 1000 to 850 mg m b.d. from cycle 1, which was in line with the TREE 2 doses and the Expert C protocol. The COIN trial is supported by a grant from CRUK, UK Medical The advantages of this second option were that this would be the Research Council funding and an educational grant from Merck safest and swiftest course of action to reduce the toxicity for Sorono. Professor TS Maughan has received honoraria and patients on arm B who choose to use capecitabine as the research funding from Merck Sorono. REFERENCES Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, Borner M, Mingrone W, Koeberle D, Von Moos R, Rauch D, Saletti P, Zampino M, Donea S, Ludwig H, Zubel A, Koralewski P (2007) Herrmann R, Dietrich D, Lanz D, Roth A (2006) The impact of cetuximab Cetuximab plus 5-FU/FA/oxaliplatin (FOLFOX-4) versus FOLFOX-4 in on the capecitabine plus oxaliplatin (XELOX) combination in first-line the first-line treatment of metastatic colorectal cancer (mCRC): OPUS, a treatment of metastatic colorectal cancer (MCC): A randomized phase II randomized phase II study. J Clin Oncol 25(S): 4035 trial of the Swiss Group for Clinical Cancer Research (SAKK). 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Ann Oncol 18: 305– 310 Maindrault-Goebel F, Lledo G, Chibaudel B Mineur L, Andre T, Bennamoun Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein M, Mabro M, Artru P, Louvet C, de Gramont A (2007) Final results of L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther OPTIMOX2, a large randomized phase II study of maintenance therapy or SG (2000) New guidelines to evaluate the response to treatment in solid chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic tumours. J Natl Cancer Inst 92: 205– 216 colorectal cancer (MRC): A GERCOR study. JClin Oncol 25(S): 4013 Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, Mineur L, Maughan T, on behalf of the COIN Trial Management Group Investigators Carola E, Etienne PL, Rivera F, Chirivella I, Perez-Staub N, Louvet C, Cetuximab (C), oxaliplatin (Ox) and fluoropyrimidine (Fp) (2007) Andre T, Tabah-Fisch I, de Gramont A (2006) OPTIMOX1: a randomized Toxicity during the first 12 weeks of treatment for the first 804 patients study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-Go entered into the MRC COIN (CR10) trial. J Clin Oncol 25(S): 4070 fashion in advanced colorectal cancer – a GERCOR study. J Clin Oncol Maughan TS, James RD, Kerr DJ, Ledermann JA, Seymour MT, Topham C, 24: 394– 400 McArdle C, Cain D, Stephens RJ (2003) Comparison of intermittent and Van Cutsem E, Nowacki M, Lang I, Cascinu S, Shchepotin I, Maurel J, continuous palliative chemotherapy for advanced colorectal cancer: a Rougier P, Cunningham D, Nippgen J, Ko¨hne C (2007) Randomized multicentre randomised trial. Lancet 361: 457– 464 phase III study of irinotecan and 5-FU/FA with or without cetuximab in Seymour MT, Maughan TS, Ledermann JA, Topham C, James R, Gwyther the first-line treatment of patients with metastatic colorectal cancer SJ, Smith DB, Shepherd S, Maraveyas A, Ferry DR, Meade AM, (mCRC): The CRYSTAL trial. J Clin Oncol 25(S): 4000 Thompson L, Griffiths GO, Parmar MK, Stephens RJ (2007) Different strategies of sequential and combination chemotherapy for patients with This work is licensed under the Creative Commons poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised Attribution-NonCommercial-NoDerivs 3.0 License. controlled trial. Lancet 370: 143– 152 To view a copy of this license, visit http://creativecommons.org/ Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, Vega-Villegas ME, Eng C, Steinhauer EU, Prausova J, Lenz HJ, Borg licenses/by-nc-nd/3.0/. British Journal of Cancer (2009) 100(2), 251 – 258 & 2009 Cancer Research UK http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Cancer Springer Journals

Toxicity associated with combination oxaliplatin plus fluoropyrimidine with or without cetuximab in the MRC COIN trial experience

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Springer Journals
Copyright
Copyright © 2009 by The Author(s)
Subject
Biomedicine; Biomedicine, general; Cancer Research; Epidemiology; Molecular Medicine; Oncology; Drug Resistance
ISSN
0007-0920
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1532-1827
DOI
10.1038/sj.bjc.6604877
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Abstract

British Journal of Cancer (2009) 100, 251 – 258 & 2009 Cancer Research UK All rights reserved 0007 – 0920/09 $32.00 www.bjcancer.com Toxicity associated with combination oxaliplatin plus fluoropyrimidine with or without cetuximab in the MRC COIN trial experience 1,3 2,3 1 2 2 2 2 ,1 RA Adams , AM Meade , A Madi , D Fisher , E Kay , S Kenny , RS Kaplan and TS Maughan on behalf of the COIN trial TMG and investigators 1 2 Velindre Hospital, Cardiff University, Velindre Road, Whitchurch, Cardiff CF14 2TL, UK; Medical Research Council Clinical Trials Unit, Euston Road, London, UK We present the preliminary toxicity data from the MRC COIN trial, a phase III randomised controlled trial of first-line therapy in advanced colorectal cancer, with particular reference to the addition of cetuximab to an oxaliplatin–fluoropyrimidine combination. A total of 804 patients were randomised between March 2005 and July 2006 from 78 centres throughout the United Kingdom. Patients were allocated to oxaliplatin plus fluoropyrimidine chemotherapy with or without the addition of weekly cetuximab. The choice of fluoropyrimidine (either 5-fluorouracil (5FU) or capecitabine) was decided by the treating physician and patient before randomisation. Toxicity data were collected from all patients. Two hundred and three patients received 5FU plus oxaliplatin (OxMdG, 25%), 333 oxaliplatinþ capecitabine (Xelox, 41%), 102 received OxMdGþ cetuximab (OxMdGþ C, 13%) and 166 Xeloxþ cetuximab (21%). Percent grade 3/4 toxicities included diarrhoea 6, 15, 13 and 25%, nausea/vomiting 3, 7, 7 and 14% for OxMdG, Xelox, OxMdGþ C and Xeloxþ C, respectively. Sixty-day all-cause mortality was 6, 5, 5 and 7%. Statistically significant differences were evident for patients receiving Xeloxþ cetuximab vs Xelox alone: diarrhoea relative risk (RR) 1.69 (1.17, 2.43, P¼ 0.005) and nausea/vomiting RR 2.01 (1.16, 3.47, P¼ 0.012). The excess toxicity observed in the oxaliplatin-, capecitabine-, cetuximab-treated patients led the trial management group to conclude that a capecitabine dose adjustment was required to maintain safety levels when using this regimen. British Journal of Cancer (2009) 100, 251 – 258. doi:10.1038/sj.bjc.6604877 www.bjcancer.com & 2009 Cancer Research UK Keywords: colorectal cancer; cetuximab; oxaliplatin; fluoropyrimidine; metastatic; first line Advanced colorectal cancer (ACRC) causes over half a million higher proportion of patients with skin rash, a known side effect of deaths worldwide each year (http://www-dep.iarc.fr/). The treat- EGFR inhibitor therapy. In the past year, the first randomised data ment of ACRC is improving. Average survival has improved from 6 on the combination of oxaliplatin and capecitabine in the first-line months with best supportive care alone, through 10–12 months ACRC setting have been presented (Cassidy et al, 2008). In with single-agent 5-fluorouracil (5FU) regimens up to 16–21 addition, first-line data are also now available from randomised months in randomised trials using irinotecan, oxaliplatin and trials investigating the addition of cetuximab to combination bevacizumab as well as 5FU. chemotherapy regimens containing both irinotecan (Van Cutsem Cetuximab was licensed for use in epidermal growth factor et al, 2007) and oxaliplatin (Bokemeyer et al, 2007). receptor (EGFR)-expressing ACRC on the basis of the phase II Antibodies targeting the EGFR have now shown efficacy in third-, BOND trial (Cunningham et al, 2004) in which 218 irinotecan- second- and first-line therapies. In the Crystal trial, the addition of refractory patients received cetuximab and irinotecan combination cetuximab to first-line irinotecan, infusional 5FU and folinic acid therapy and 111 received cetuximab monotherapy. Although there resulted in an 8% increase in response rate and a significant was no chemotherapy are comparator arm in this trial, the data improvement in progression-free survival (P¼ 0.036) (Van Cutsem suggested no greater toxicity with the combination therapy than is et al, 2007). The EPIC trial explored the use of irinotecan in expected in patients receiving single-agent irinotecan, other than a combination with cetuximab in the second line, after irinotecan failure. This trial has recently been published and demonstrated a response rate with cetuximab and irinotecan of 16.4% (95% *Correspondence: Professor TS Maughan, Velindre Hospital, Velindre confidence interval (CI), 13.6–19.4), compared with 4.2% (95% CI, Road, Whitchurch, Cardiff CF14 2TL, UK; 2.8–6.0) with irinotecan alone (P¼ 0.0001) (Sobrero et al, 2008). E mail: tim.maughan@velindre-tr.wales.nhs.uk COIN is an open-label multicentre randomised controlled trial Original data presented at ASCO (Chicago) 2007 sponsored by the UK Medical Research Council (MRC) and These authors contributed equally to this work coordinated by the MRC Clinical Trials Unit (MRC CTU), Received 8 August 2008; revised 4 December 2008; accepted 14 comparing two experimental arms with the control arm of December 2008 oxaliplatin and fluoropyrimidine chemotherapy in the first-line Clinical Studies Clinical Studies Combination oxaliplatin plus fluoropyrimidine in the MRC COIN trial RA Adams et al treatment of ACRC. The fluoropyrimidine can be either capecita- 2000) WHO performance status 0–2; no previous chemotherapy bine or bolus and infusional 5FU (in a modified FOLFOX for metastatic disease; neutrophils41.5 10 per l, platelet regimen), and is chosen on a per-patient or per-institution basis count4100 10 per l, serum bilirubinr1.25 upper limit of before randomisation. Two primary questions are being addressed normal (ULN), alkaline phosphatasep5 ULN, calculated GFR or in the trial. The first question asks whether the addition of EDTA clearance X50 ml min ; and age 418 years. Exclusion cetuximab to combination chemotherapy will increase overall criteria include patients receiving combination chemotherapy survival, whereas the second asks whether intermittent chemo- before the resection of operable liver metastases (patients of therapy treatment is comparable with continuous treatment to uncertain operability are eligible), brain metastases, prior adjuvant progression or cumulative toxicity. chemotherapy with oxaliplatin and uncontrolled medical co- The use of intermittent chemotherapy is controversial. A previous morbidity likely to compromise treatment. MRC trial showed no detriment in overall survival, with an improvement in toxicity and quality of life for patients receiving Randomisation and treatment intermittent single-agent 5FU chemotherapy (Maughan et al, 2003). Patients were randomised centrally by the MRC CTU to one of the The Optimox 1 trial showed that discontinuation of oxaliplatin after three trial arms on a 1 : 1 : 1 basis using a stratified, minimisation six cycles of OxMdG, with continuation of infusional 5FU and procedure. Treatment is started as soon as possible after subsequent reintroduction of oxaliplatin, resulted in equivalent randomisation and within 4 weeks of the baseline radiological disease control and survival (Tournigand et al,2006).The Optimox2 disease assessment using CT scan. The trial arms are as follows: study, however, has raised doubts about the overall survival equivalence for patients given a chemotherapy-free interval. The Arm A: original design of Optimox 2 was a phase III trial of 600 patients; Continuous chemotherapy (control arm) The chemotherapy regi- however, accrual was discontinued when bevacizumab became men is a combination of oxaliplatin and a fluoropyrimidine. available. At this stage, only 200 patients had been entered. The The regimens are: trial reported a non-significant overall median survival difference of 25 months with continuous infusional 5FU, compared with 19 OxMdG: a combination of l-folinic acid (175 mg i.v. over 2 h) OR months in the arm with chemotherapy-free intervals (P¼ 0.056) d,l-folinic acid (350 mg i.v. over 2 h), concurrent administration (Maindrault-Goebel et al, 2007). Owing to the failure of this trial to of oxaliplatin (85 mg m i.v. over 2 h) plus bolus 5FU complete accrual as planned, and therefore answer the question (400 mg m ) followed by a 46-h i.v. infusion of 5FU originally posed, it is of utmost importance to obtain reliable phase 2400 mg m repeated every 2 weeks as used in the FOCUS trial III evidence of the relative benefits of continuous chemotherapy vs (Seymour et al, 2007) or intermittent chemotherapy with a chemotherapy-free interval in the Xelox: a combination of oxaliplatin 130 mg m i.v. over 2 h on treatment of ACRC. The COIN trial will be the largest randomised day 1 plus capecitabine 1000 mg m b.d., p.o. on days 1–14 controlled trial of continuous vs intermittent chemotherapy carried repeated thrice weekly. out to date. If successful, the intermittent chemotherapy strategy would not only benefit patients, who value time off chemotherapy Patients continue chemotherapy until RECIST-defined progres- very highly, but also open a new therapeutic window for the sive disease is identified, or the development of cumulative toxicity evaluation and use of novel agents to maintain disease control or because of patient choice to stop chemotherapy. Patients should during intervals off chemotherapy. have no more than a 3-week interval off treatment for any reason. In this paper, we present toxicity reported during the first 12 weeks of treatment for the first 804 patients randomised into the Arm B: COIN trial. During the first 12 weeks, there is no difference in the Continuous chemotherapy plus cetuximab Cetuximab is adminis- treatment received by those patients randomised to the control tered once weekly in combination with the chemotherapy schedules arm of COIN and those randomised to intermittent therapy. as above. On day 1 of the first cycle of chemotherapy, an initial Therefore, the focus of this paper is the toxicity experience in the loading dose of 400 mg m cetuximab is given by 2-h i.v. infusion first 12 weeks associated with the addition of cetuximab to two and then continued weekly at a dose of 250 mg m over 60 min. The different oxaliplatin and fluoropyrimidine combination che- following pre-medication is administered at each administration: i.v. motherapy regimens. The 12-week time point has been chosen as chlorphenamine 10 mg, paracetamol (acetaminophen) 1 g p.o. and this is when patients randomised to intermittent therapy stop ranitidine 150 mg p.o. Dexamethasone 8 mg i.v. is given on days treatment. We propose to publish the longer term toxicity data when oxaliplatin is also given. Patients continue chemotherapy plus (relating to the intermittent vs continuous strategies) at a later cetuximab as in arm A above. Cetuximab may be continued if date, together with quality of life and primary outcome data. In the chemotherapy is stopped because of toxicity or patient choice, but meantime, however, we feel that the initial toxicity experience should be discontinued on evidence of disease progression or contains information of value to clinicians employing combina- unacceptable cetuximab toxicity. tions of these widely available agents. Arm C: PATIENTS AND METHODS Intermittent chemotherapy These patients are treated initially for 12 weeks as in arm A. Patients who have radiologically confirmed Accrual update progressive disease at this point come off study, as in arms A and B. The COIN trial opened to accrual in March 2005 and closed in May Patients with stable or responding disease stop chemotherapy and 2008 after completing accrual ahead of schedule; 2445 patients are monitored clinically, at least six weekly, and with CT scans at 12- have been randomised from 111 centres in the United Kingdom weekly intervals. On evidence of radiological disease progression or and Republic of Ireland. on clinical evidence of deterioration, the same chemotherapy is restarted, for a further 12-week course. At that point, treatment is again interrupted. Patients with chemosensitive disease may have an Eligibility criteria unlimited number of 12-week treatments alternating with treatment Patients have histologically confirmed colorectal adenocarcinoma, breaks. When the patient demonstrates resistance to this treatment with inoperable metastatic or locoregional disease. Eligibility as evidenced by progressive disease during a period on chemo- criteria include disease measurable by RECIST (Therasse et al, therapy, they move on to second-line therapy or supportive care. British Journal of Cancer (2009) 100(2), 251 – 258 & 2009 Cancer Research UK Combination oxaliplatin plus fluoropyrimidine in the MRC COIN trial RA Adams et al Protocol dose modifications Table 1 Base-line patient and tumour characteristics Detailed dose reduction and delay protocols are given in the Treatment arm A B C protocol. In general, unresolved grade X2 toxicity required a 1-week delay, whereas grade X3 toxicity or two delays for grade 2 Total patients 269 (33%) 268 (33%) 267 (33%) toxicity required a 20% dose reduction. Chemotherapy selection Ox+Cap 167 (62%) 166 (62%) 166 (62%) Assessments OxMdG 102 (38%) 102 (38%) 101 (38%) Investigator assessments of toxicity are made at six-weekly Sex intervals while on protocol treatment and scored using NCI CTC Male 173 (64%) 167 (62%) 174 (65%) criteria (version 3.0). Safety is assessed continuously throughout Female 96 (36%) 101 (38%) 93 (35%) the trial by monitoring of adverse events by the treating physician. Reported serious adverse events are reviewed by an experienced Age (years) o45 12 (4%) 18 (7%) 14 (5%) practicing oncologist. All deaths, together with the treating 45 – 54 46 (17%) 34 (13%) 48 (18%) physician’s assessment of causality, are also reported. A further 55 – 64 88 (33%) 100 (37%) 91 (34%) assessment of cause of death is also undertaken centrally by an 65 – 74 99 (37%) 95 (35%) 94 (35%) experienced practicing oncologist (TSM, RA or AyM). 75+ 24 (9%) 21 (8%) 20 (7%) Median age (IQR) 63 (56, 69) 63 (58, 69) 63 (55, 70) Statistical methods WHO PS As arms A and C are identical during the first 12 weeks of protocol 0 120 (45%) 124 (46%) 126 (47%) treatment, they are combined for the purpose of this analysis. All 1 128 (48%) 127 (47%) 126 (47%) 2 21 (8%) 17 (6%) 15 (6%) comparisons were tested for significance using Fisher’s exact tests. All reported P-values are two-sided, and P-values less than 0.05 Current status of primary tumour were considered to indicate statistical significance. Resected 152 (57%) 144 (54%) 140 (52%) Unresected/unresectable 103 (38%) 100 (37%) 108 (40%) Role of the funding source Local recurrence 14 (5%) 24 (9%) 19 (7%) The trial is funded by Cancer Research UK, the MRC and Metastases supported by an educational grant from Merck Serono. Patient No 2 (1%) 2 (1%) 1 (o1%) informed consent and data collection were supported by staff from Yes 267 (99%) 266 (99%) 266 (499%) the National Cancer Research Networks across the United King- Type of metastases dom. Liver only 55 (20%) 69 (26%) 67 (25%) Liver 197 (73%) 195 (73%) 194 (73%) Trial governance Nodes 127 (47%) 109 (41%) 119 (45%) Lung 107 (40%) 103 (38%) 99 (37%) COIN is an investigator-initiated trial sponsored by the MRC in the Peritoneum 40 (15%) 40 (15%) 40 (15%) United Kingdom. Certain sponsor responsibilities are delegated to Other 38 (14%) 45 (17%) 36 (13%) the Irish Clinical Oncology Research Group for investigator sites in Mean no. of metastatic sites 2.32 2.3 2.3 the Republic of Ireland. Multicentre and Institutional Research at baseline Ethics Committee and appropriate regulatory approval have been Site of primary tumour obtained, and all patients provide written informed consent. Trial Colon 147 (55%) 142 (53%) 136 (51%) management is by the MRC Clinical Trials Unit following the Rectum 82 (30%) 88 (33%) 83 (31%) principles of ICH GCP and overseen by an Independent Trial Rectosigmoid junction 34 (13%) 37 (14%) 48 (18%) Steering Committee. An Independent Data Monitoring Committee Other 2 (1%) 1 (o1%) 0 (0%) meets at regular intervals (approximately six monthly) for trial Missing data 4 (1%) 0 (0%) 0 (0%) oversight, including review of safety data and interim outcome analyses at pre-specified intervals. Prior treatment for patient with metastatic disease Radiotherapy 9 (3%) 6 (2%) 2 (1%) Surgery 54 (20%) 49 (18%) 53 (20%) RESULTS PS¼ performance status. Characteristics of patients At least one dose reduction in a COIN trial drug was instituted From March 2005 to July 2006, 804 patients were randomised at 78 for toxicity in 28, 44, 22 and 49% of patients in the regimens, centres in the United Kingdom. Baseline characteristics (Table 1) respectively. This doubling of dose reductions when chemotherapy were well balanced across the three arms. Thirty-eight percent was given with cetuximab was highly statistically significant received OxMdG and 62% of patients received Xelox. Patients on (Po0.001). These broke down as indicated in Table 2 (online). average have a high burden of disease at baseline, with Median dose intensities are as indicated in Table 3 (online). It is of approximately 40% having an unresected or unresectable primary particular note that in patients on Xeloxþ C, the oxaliplatin dose tumour and each patient having on average 2.3 metastatic sites. was reduced in 33% of patients compared with 15% on Xelox alone (Po0.001). Treatment received Toxicity Two hundred and three patients received 5FU plus oxaliplatin (OxMdG, 25%), 102 received OxMdGþ cetuximab (OxMdGþ C, Toxicity data during the first 12 weeks of treatment are available 13%), 333 oxaliplatinþ capecitabine (Xelox, 41%) and 166 for 97% of patients. Table 4 (online) indicates all grades of toxicity Xeloxþ cetuximab (21%). reported, whereas Table 5 shows grade 3 or 4 toxicities observed & 2009 Cancer Research UK British Journal of Cancer (2009) 100(2), 251 – 258 Clinical Studies Clinical Studies Combination oxaliplatin plus fluoropyrimidine in the MRC COIN trial RA Adams et al Table 2 Chemotherapy dose reductions over the first 12 weeks of treatment broken down by regimen and therapeutic agent, on line only Arms A+C (no cetuximab) Arm B (cetuximab) OxMdG XELOX OxMdG XELOX Total Total N 203 333 102 166 804 Trial drug 5FU 48 31 79 % of patients with 5FU dose reduction (24%) (30%) (26% ) Capecitabine 65 60 125 % of patients with capecitabine dose reduction (20%) (36%) (25% ) Oxaliplatin 28 50 16 54 148 % of patients with oxaliplatin dose reduction (14%) (15%) (16%) (33%) (18%) Cetuximab 24 33 57 % of patients with cetuximab dose reduction (24%) (20%) (21% ) Any trial drug 57 73 45 81 256 % of patients with any trial drug dose reduction (28%) (22%) (44%) (49%) (32%) 5FU¼ 5-fluorouracil. On line only. Denominator is valid subjects only. Table 3 Dose intensities (first 12 weeks; medians and IQRs) Arms A+C (no cetuximab) Arm B (cetuximab) OxMdG XELOX OxMdG XELOX Total Total 203 333 102 166 804 Complete data on first round of treatment (0 – 12 weeks) 158 247 76 119 600 Median (IQR) Median (IQR) Median (IQR) Median (IQR) Median (IQR) 5FU infusion 91 (81, 99) 85 (78, 94) 88 (80, 97) 5FU bolus 91 (75, 99) 83 (68, 93) 88 (71, 97) Capecitabine 96 (86, 100) 88 (80, 100) 93 (84, 100) Oxaliplatin 89 (82, 98) 97 (89, 100) 86 (78, 94) 92 (80, 99) 93 (83, 99) Cetuximab, day 1 85 (78, 94) 96 (87, 100) 92 (81, 99) Cetuximab, day 8 83 (75, 92) 93 (78, 100) 89 (77, 99) Cetuximab, day 15 91 (75, 100) 91 (75, 100) 5FU¼ 5-fluorouracil. Table 4 Dose intensities (first 12 weeks; percentage of patients with o80%) on line only Arms A+C (no cetuximab) Arm B (cetuximab) OxMdG XELOX OxMdG XELOX Total Total 203 333 102 166 804 Complete data on first round of treatment (0 – 12 weeks) 158 247 76 119 600 N (%) N (%) N (%) N (%) N (%) 5FU infusion 3 (2) 5 (7) 8 (3) 5FU bolus 24 (15) 16 (21) 40 (17) Capecitabine 11 (4) 17 (14) 28 (8) Oxaliplatin 5 (3) 4 (2) 6 (8) 14 (12) 29 (5) Cetuximab, day 1 1 (1) 12 (10) 13 (7) Cetuximab, day 8 7 (9) 23 (19) 30 (15) Cetuximab, day 15 29 (24) 29 (24) 5FU¼ 5-fluorouracil. within the first 12 weeks of treatment for the first 804 patients increased in patients receiving infusional 5FU (17% without and randomised to COIN. 26% with cetuximab) compared with those taking oral capecita- The addition of cetuximab to oxaliplatin- and fluoropyrimidine- bine (2% without and 1% with cetuximab, Po0.001), and this based chemotherapy results in an absolute increase in any grade 3/ translates into neutropaenic sepsis in 4, 5, 1 and 0%, respectively. 4 toxicity of approximately 25% (35–63% with OxMdG, 35–57% Gastrointestinal toxicities, namely nausea, vomiting and diar- with Xelox, Po0.001). Grade 3/4 neutropaenia is significantly rhoea, are all significantly increased in patients receiving Xelox British Journal of Cancer (2009) 100(2), 251 – 258 & 2009 Cancer Research UK Combination oxaliplatin plus fluoropyrimidine in the MRC COIN trial RA Adams et al Table 5 All grades of toxicity reported in the first 12 weeks of treatment Arms A+C (no cetuximab) Arm B (cetuximab) Significance* ± ± OxMdG XELOX OxMdG XELOX Cap. Cet. N 203 333 102 166 N (%) N (%) N (%) N (%) Any grade 1+ 194 (96) 316 (95) 100 (98) 161 (97) Neutropaenia 91 (45) 42 (13) 46 (45) 9 (5) Po0.001 Nausea or vomiting 113 (56) 215 (65) 56 (55) 95 (57) Diarrhoea 115 (57) 207 (62) 75 (74) 117 (70) Po0.05 Skin rash 23 (11) 44 (13) 87 (85) 139 (84) Po0.001 Hypersensitivity Any 2 (o1) 6 (2) 0 (0) 4 (2) Oxaliplatin 1 (1) 4 (1) 0 (0) 1 (o1) Cetuximab — 0 (0) 2 (1) Not specified 1 (1) 2 (1) 0 (0) 1 (1) Lethargy 157 (77) 266 (80) 91 (89) 144 (87) Po0.05 Hand – foot syndrome 33 (16) 89 (27) 42 (41) 70 (42) Po0.001 Peripheral neuropathy 155 (76) 230 (71) 76 (75) 117 (70) Hypomagnesaemia 6 (3) 7 (2) 9 (9) 7 (4) Po0.05 Po0.05 *Fisher’s exact test. ‘Cap.’¼ presence vs absence of capecitabine; that is, XELOX vs OxMdG. ‘Cet.’¼ presence vs absence of cetuximab; that is, arm B vs arms A and C. Table 6 Grade 3 and 4 toxicities reported over first 12 weeks of treatment Arms A+C (no cetuximab) Arm B (cetuximab) Significance* ± ± OxMdG XELOX OxMdG XELOX Cap. Cet. N 203 333 102 166 N (%) N (%) N (%) N (%) Any grade 3 or 4 72 (35) 118 (36) 64 (63) 95 (58) Po0.001 Neutropaenia 35 (17) 5 (2) 27 (26) 1 (1) Po0.001 Neutropaenic sepsis/febrile neutropaenia 9 (4) 3 (1) 5 (5) 0 (0) Po0.001 Nausea or vomiting 6 (3) 23 (7) 7 (7) 23 (14) Po0.05 Po0.05 Diarrhoea 13 (6) 50 (15) 13 (13) 42 (25) Po0.001 Po0.05 Skin rash 0 (0) 2 (1) 12 (12) 16 (10) Po0.001 Hypersensitivity Any 0 (0) 1 (o1) 0 (0) 2 (1) Oxaliplatin 0 (0) 1 (o1) 0 (0) 0 (0) Cetuximab — 0 (0) 1 (1) Not specified 0 (0) 0 (0) 0 (0) 1 (1) Lethargy 15 (7) 27 (8) 21 (21) 28 (17) Po0.001 Hand—foot syndrome 1 (o1) 7 (2) 4 (4) 7 (4) Peripheral neuropathy 4 (2) 14 (4) 0 (0) 10 (6) Po0.05 Hypomagnesaemia 0 (0) 1 (o1) 0 (0) 0 (0) *Fisher’s exact test. ‘Cap.’¼ presence vs absence of capecitabine; that is, XELOX vs OxMdG. ‘Cet.’¼ presence vs absence of cetuximab; that is, arm B vs arms A and C. compared with those receiving OxMdG chemotherapy. These cetuximab). Hand–foot syndrome was significantly more common toxicities are further increased by the addition of cetuximab, with with capecitabine, with 40% experiencing any grade but only 2– an incidence of grade 3/4 diarrhoea of 25% in patients receiving 4% experiencing grade 3 hand–foot syndrome. There was a trend the Xelox plus cetuximab combination. Statistically significant to an increased incidence of hand–foot syndrome in patients differences were evident for patients receiving Xelox in combina- treated with cetuximab. tion with cetuximab-based therapy vs Xelox alone for grade 3/4: In earlier studies, hypersensitivity reactions have been reported relative risk (RR) of diarrhoea 1.69 (1.17, 2.43, P¼ 0.005), nausea in 1.8% of patients receiving oxaliplatin chemotherapy, increasing or vomiting RR 2.01 (1.16, 3.47, P¼ 0.012) and lethargy RR 2.08 to 4.1% when cetuximab is added to this chemotherapy regimen (1.27, 3.41, P¼ 0.003). (Bokemeyer et al, 2007). In this cohort, there was no such increase As expected, patients receiving cetuximab have a significantly in oxaliplatin hypersensitivity with the addition of cetuximab, increased incidence of the skin rash associated with EGFR although numbers are small. inhibitors such as cetuximab. This increase is similar irrespective Lethargy is reported in 8% of patients receiving Xelox and 7% of of the chemotherapy regimen (84% in patients receiving patients receiving OxMdG chemotherapy. The addition of Xeloxþ cetuximab and 85% in patients receiving OxMdG plus cetuximab results in an increase in lethargy, with 17% of patients & 2009 Cancer Research UK British Journal of Cancer (2009) 100(2), 251 – 258 Clinical Studies Clinical Studies Combination oxaliplatin plus fluoropyrimidine in the MRC COIN trial RA Adams et al Table 7 All-cause 60-day mortality Arms A+C (no cetuximab) Arm B (cetuximab) OxMdG XELOX OxMdG XELOX No. of patients randomised 203 333 102 166 N (%) N (%) N (%) N (%) 60-day all-cause mortality 12 (6%) 18 (5%) 5 (5%) 12 (7%) Treatment-related death within 60 days 2 (1%) 2 (1%) 1 (1%) 3 (2%) Table 8 A comparison of toxicities among a variety of chemotherapy regimens within four clinical trials in which cetuximab was used Cetuximab+ Cetuximab+ Cetuximab+ Cetuximab+ a a b b c d a a c d XELOX OxMdG FOLFOX XELOX FOLFIRI FOLFOX-4 XELOX OxMdG FOLFIRI FOLFOX-4 N 333 203 649 655 602 168 166 102 600 170 Any grade 3 or 4 35 35 78.3 71.5 59.5 NS 57 63 78.0 NS toxicity Neutropaenia 2 17 43.8 7.0 23.3 31.5 1 26 26.7 27.6 Nausea or vomiting 7 3 NS NS 5.0 NS 14 7 4.5 NS Diarrhoea 15 6 11.2 20.2 10.5 6.0 25 13 15.2 7.1 Skin rash 1 0 NS NS 0.2 0 10 12 18.7 14.1 Hypersensitivity NS NS 0 1.8 2.3 4.1 2.0 Lethargy 8 7 NS NS 4.5 3.0 17 21 5.0 3.5 a b c d COIN TRIAL. Roche N966. Crystal trial. OPUS trial. receiving Xelox plus cetuximab and 21% of patients receiving mature and a full report on (early and late) toxicities accompanies OxMdG plus cetuximab experiencing grade 3/4 lethargy within the the analysis, data on k-ras status for almost all of these patients will first 12 weeks of their treatment in the COIN trial. be available. It is possible that there may be differences in toxicity Peripheral neuropathy is rare in this report, as the time for the that relate to tumour k-ras mutational status, but that is not the report is ‘toxicities within the first 12 weeks of therapy’ and expectation. The COIN data thus far reflect a typical usage of oxaliplatin neuropathy emerges slightly later than 12 weeks in cetuximab to date in first-line combinations in patients without most patients in whom it occurs. Longer term data will be available molecular selection. when the overall trial outcomes are reported. Similarly in this A number of interesting toxicity issues are addressed by this cohort, hypomagnesaemia is under-reported here because the study, relating to confirmatory evidence of the differences between protocol was modified in October 2005 to make magnesium oxaliplatin regimens with either capecitabine or 5FU and to the concentration monitoring and reporting mandatory, by which time novel issues of adding cetuximab to either of these regimens. The findings of the COIN trial are consistent with other most of these patients had commenced treatment. international trials including the Roche-sponsored Xelox-1/ NO16966 phase III trial in first-line treatment of colorectal cancer, Deaths within 60 days of randomisation which reported comparative toxicity for oxaliplatin plus 5FU compared with oxaliplatin plus capecitabine. The COIN trial also Tables 6 and 7 shows the numbers and percentages of deaths shows a significantly higher incidence of neutropaenia (with a within 60 days of randomisation, both all-cause and those 4.8% incidence of febrile neutropaenia), and half the incidence of attributed to trial treatment. All-cause 60-day mortality is similar diarrhoea with the infusional 5FU regimen compared with irrespective of the chemotherapy regimen or the addition of capecitabine. Treatment-related mortality in the NO16966 study cetuximab. On review of causation by an experienced practicing was 2.1% with Xelox compared with 1.7% with FOLFOX (Cassidy oncologist on behalf of the MRC as a sponsor of the trial, et al, 2008) (see Table 8 for comparisons). treatment-related deaths were not statistically significantly differ- The addition of cetuximab to oxaliplatin-based regimens has not ent between treatment regimens. been previously reported in a phase III trial, but data from the large OPUS phase II study show no significant uplift in toxicity when combining cetuximab with FOLFOX-4 (a regimen with a DISCUSSION lower infused 5FU dose compared with that used in the COIN trial) The COIN trial was designed and completed recruitment during a (Bokemeyer et al, 2007). period when no strong predictor of response to EGFR-inhibiting The addition of cetuximab to 5FU plus irinotecan (FOLFIRI) therapies was known or available. K-ras mutation on tumour was evaluated in the Crystal trial. A minor increase in grade 3 and samples has since been identified as predictive of minimal 4 diarrhoea (from 10 to 15%) was seen with the addition of likelihood of benefit from the addition of cetuximab in various cetuximab (Van Cutsem et al, 2007). colorectal clinical settings. However, there is as yet no evidence Table 8 shows the comparative toxicities from the COIN, Roche that somatic k-ras status is associated with differences in toxicity N966, Crystal and OPUS trials. The only studies that have of EGFR antibodies or small molecule inhibitors. The initial COIN previously reported the addition of capecitabine-containing trial data reported herein encompass the whole eligible population combinations with cetuximab are the SAKK group, the AIO CRC regardless of k-ras mutation status. When the outcome data are study group phase II trials and the single-institution study from British Journal of Cancer (2009) 100(2), 251 – 258 & 2009 Cancer Research UK Combination oxaliplatin plus fluoropyrimidine in the MRC COIN trial RA Adams et al Heraklion (Borner et al, 2006; Heinemann et al, 2007; Souglakos fluoropyrimidine. In addition, the data from the revised dose et al, 2007). The SAKK group performed a randomised phase II would provide evidence for a more manageable combination trial of 74 patients in whom all received Xelox (as used in COIN) schedule for the future, which would be consistent with other on a three-weekly basis and half of the patients received cetuximab international data of capecitabine plus oxaliplatin when used in weekly; the toxicity data have recently been published and combination with a biological agent. Finally, this would provide demonstrate a non-significant increase in grade 3/4 diarrhoea for a more equitoxic comparison between arm A (full-dose Xelox) from 16 to 22%, with the addition of cetuximab (Borner et al, and arm B (dose-reduced Xeloxþ cetuximab). 2008). The AIO group trial randomised patients to XELIRI or The disadvantages were considered to be that we would be using Xelox both with the addition of cetuximab. In the 41 patients a different regimen for the comparator in arm A (full-dose Xelox) receiving Xelox plus capecitabine (in a similar dose and schedule vs arm B (dose-reduced Xeloxþ C). This reduced dose intensity for to COIN), grade 3/4 toxicity was seen in 19.5%. The single-centre all subsequent patients on Xeloxþ cetuximab might impact on the Heraklion trial recruited 40 patients and used the two-weekly efficacy of this combination. This could in turn cause difficulties in capecitabine plus oxaliplatin (CAPOX) regimen in combination reporting the trial in view of the mid-trial dose reduction for a with cetuximab (weekly) with only 7 days of capecitabine. The rate subset of patients in arm B. The arm B comparisons of toxicity and of grade 3/4 diarrhoea in this trial was 7.5%. effectiveness would need to be reported as the total intention-to- The key finding of this report is the synergistic effect on treat population (1614 patients) and as three subsets: (1) those diarrhoeal toxicity of the oxaliplatin, capecitabine and cetuximab treated on OxMdG: OxMdG vs OxMdGþ cetuximab (c 613 patients combination. This finding had been observed in an earlier IDMC on current 38% usage of OxMdG); (2) those on full-dose Xelox report and the TMG had, on the instruction of the IDMC, until dose reduction imposed (696 patients); (3) those on modified improved the patient information cards and fed back the data to Xelox comparing full-dose Xelox vs mXELOXþ cetuximab (295 investigators so that they include this information in their patients). On this basis, the TMG considered that the dose discussions with patients regarding selection of capecitabine- or reduction at this point in the trial would have a modest effect on 5FU-based treatment. Despite this, the rate of diarrhoea was the efficacy data, but was required for patient safety. gradually increasing: for those patients receiving oxaliplatin, The option appraisal paper and the toxicity and advised dose capecitabine and cetuximab, a grade 3/4 diarrhoea rate of 23% reduction data were reviewed by the IDMC and independent TSC was reported in the ASCO abstract (Maughan, 2007) submitted in and the decision to apply the dose reduction was approved and December 2006 and this had reached 30% (on the data set from the immediately implemented from July 2007. March IDMC, released to the TMG as of July 2007). Thus, there was no sign of an improvement with greater experience of the regime by investigators despite information to investigators and improved CONCLUSION patient information. This increased toxicity is reflected in the increased incidence of This data set is consistent with previous data reporting the toxicity dose reduction in those patients receiving cetuximab. Overall, of the addition of cetuximab to combination chemotherapy. There patients receiving cetuximab had a dose reduction of any agent is an increased incidence of grade 3 and 4 toxicities overall. The twice as often as those without cetuximab. In particular, those specific toxicities affect the skin, gastrointestinal tract and treated with Xeloxþ cetuximab had a 33% incidence of oxaliplatin lethargy. Infusion-related reactions are relatively rare and can be dose reductions compared with 15% on Xelox alone. It is possible largely prevented with combination pre-medication regimens. The that such dose reductions may contribute to the impaired combination of oxaliplatin (130 mg m , i.v., q21d), capecitabine outcomes seen in the OPUS trial in the ras mutant sub-group (2000 mg m for 14 out of 21 days) and cetuximab was associated treated with FOLFOX plus cetuximab, and this will be analysed with an unacceptable rate of grade 3, 4 diarrhoea, and a dose 2 1 further in the outcomes of the COIN trial. reduction of capecitabine from 2000 to 1700 mg m day has The trial management group reviewed the data in greater detail been introduced into the trial protocol and is advised for off and discussed the possible options. The options included first protocol use of this triple combination. making no protocol change, but urging further diligence in information giving and dose reduction in face of toxicity; dose reduction in the face of grade 2 toxicity rather than grade 3; or alternatively, an immediate dose reduction of capecitabine from ACKNOWLEDGEMENTS 1000 to 850 mg m b.d. from cycle 1, which was in line with the TREE 2 doses and the Expert C protocol. The COIN trial is supported by a grant from CRUK, UK Medical The advantages of this second option were that this would be the Research Council funding and an educational grant from Merck safest and swiftest course of action to reduce the toxicity for Sorono. Professor TS Maughan has received honoraria and patients on arm B who choose to use capecitabine as the research funding from Merck Sorono. 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Published: Jan 22, 2009

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