Cetuximab therapy in the treatment of metastatic colorectal cancer: The future frontier?

REVIEW International Journal of Surgery 11 (2013) 507e513

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Review

Cetuximab therapy in the treatment of metastatic colorectal cancer: The future frontier? D. Gomez a, A. De Rosa a, A. Addison a, A. Brooks a, H.Z. Malik b, I.C. Cameron a, * a Department of Hepatobiliary Surgery and Pancreatic Surgery, Queen’s Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom b Department of Liver Surgery, Aintree University Hospital NHS Foundation Trust, Liverpool, United Kingdom

a r t i c l e i n f o

a b s t r a c t

Article history: Received 7 January 2013 Received in revised form 10 April 2013 Accepted 27 April 2013 Available online 6 May 2013

Background: To review the outcomes following cetuximab therapy in patients with metastatic colorectal cancer. Methods: Relevant articles were reviewed from the published literature using the Medline database. The search was performed using the keywords “colorectal cancer”, “cetuximab”, “liver metastases”, “liver resection” and “hepatectomy”. Results: Cetuximab was first used in the palliative setting and an increase in response rates were seen, however with no improvement in overall survival. Published data have observed that cetuximab may be beneficial as part of a down-staging programme. The addition of cetuximab to chemotherapy regimens in patients with KRAS wild-type colorectal cancer has been shown to increase the response rates and the number of patients being down-staged and offered potentially curative resection. The OPUS and CRYSTAL trials observed good response rates following the addition of cetuximab but low resection rates. The CELIM and POCHER studies reported higher resection rates due to better patient selection and study design. However, the majority of published studies tend to report minimal surgical data and lack shortand long-term outcomes. Conclusion: The use of cetuximab to conventional chemotherapy regimens may improve the efficacy of down-staging programmes, leading to more patients being offered potentially curative resection. Ó 2013 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.

Keywords: Hepatectomy Cetuximab Liver metastases Colorectal cancer

1. Introduction Colorectal cancer is the third most common cancer worldwide,1 and approximately 25% of patients have distant metastatic disease at the time of diagnosis. Overall, approximately 50% of patients will develop metastases during the course of the disease, with the liver being the most common site.2 Hepatic resection has become the treatment modality of choice for resectable colorectal liver metastases (CRLM) and is associated with long-term survival in these patients.3e5 More recently, studies have reported successful downstaging chemotherapy regimens and subsequent hepatic resection of initially unresectable CRLM.6,7 The addition of biological agents, such as Cetuximab to these chemotherapy regimens in the neoadjuvant setting is thought to improve tumour response rates

* Corresponding author. Department of Hepatobiliary and Pancreatic Surgery, E Floor, West Block, Queen’s Medical Centre, Derby Road, Nottingham NG7 2UH, United Kingdom. Tel.: þ44 0115 9249924. E-mail addresses: [email protected] (D. Gomez), iain.cameron@ nuh.nhs.uk (I.C. Cameron).

and consequently the survival of patients with unresectable CRLM, as well as increasing hepatic resection rates. Cetuximab is a monoclonal immunoglobulin G1 antibody that targets the epidermal growth factor receptor (EGFR); this gene is up-regulated in 60e80% of colo-rectal cancer cases.8 The EGFR signalling pathway is involved in processes critical to tumour growth and progression, including angiogenesis, apoptosis inhibition, invasion, and metastatic spread.9,10 Cetuximab has a higher affinity than EGFR’s natural ligands such as EGF and transforming growth factor-a, thereby inhibiting the effects of EGFR activation. However, besides the detection of EGFR expression, mutation of the KRAS gene is an important predictive marker of resistance to cetuximab treatment. Studies have demonstrated that cetuximab efficacy is confined only to tumours without the KRAS gene mutation, i.e. KRAS wild-type tumours.11e15 Since Cunningham et al. showed an improved survival in patients with metastatic colorectal cancer following the addition of cetuximab, various studies have reported the outcomes following cetuximab therapy.16 This present systematic review focuses on studies reporting the outcome of cetuximab in the treatment of

1743-9191/$ e see front matter Ó 2013 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijsu.2013.04.014

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metastatic colorectal cancer, in particular, in the neo-adjuvant setting to down-stage unresectable CRLM sufficiently to allow for potentially curative resection. 2. Methods An electronic search was performed of the Medline database for the period 2000 e present using the MeSH headings: “colorectal cancer”, “cetuximab”, “liver metastases”, “liver resection” and “hepatectomy”. The search was limited to English language publications and human subjects. All titles and abstracts were reviewed, and appropriate papers further assessed. The reference sections of all papers deemed appropriate were further reviewed to identify papers that may have been initially missed. Studies were included if they described the survival outcome following cetuximab in patients with metastatic colorectal cancer. The minimal data set required for inclusion was: patients with metastatic colorectal cancer treated with cetuximab; documentation of survival; description of chemotherapy regimens and response rate; and resection rates if available (Fig. 1). All series fitting the search specifications independent of the study population were included. Publications that included other biological agents were excluded. Case reports, editorials, abstracts and reviews were also excluded. Following the initial search that identified 1236 studies, a total of 1003 studies were excluded: case reports (n ¼ 121); abstracts (n ¼ 346); review articles (n ¼ 256); non-English publications (n ¼ 165); and non-human studies (n ¼ 115). Two hundred and thirty three studies were retrieved and evaluated, of which 30 studies were included in this review. The remaining 204 studies were excluded as they were case reports (n ¼ 61); abstracts (n ¼ 78); review articles (n ¼ 36); and duplicated studies (n ¼ 29).

3. Early experience of cetuximab The initial experience with cetuximab in the treatment of metastatic colorectal cancer patients was as a single agent. Overall, studies (Table 1) have reported an average partial response in 8.0e 11.6% patients, with an overall survival of 6.1e12.3 months.10,17e19 There was also a significantly better survival and quality of life in patients treated with cetuximab compared to best supportivecare.19 Following these promising results, investigators have since reported the results of cetuximab as a combination therapy (Table 2). In the BOND trial,16 the authors showed that metastatic colorectal cancer patients receiving the combination therapy of cetuximab with irinotecan had a significantly higher response rates and reduced tumour progression compared to patients treated with cetuximab alone. In a randomised trial consisting of 1298 patients with metastatic colorectal cancer refractory to fluoropyrimidine

Potential relevant studies identified and screened for retrieval n = 1236 Studies excluded n = 1003 Case reports n = 121 Abstracts n = 346 Review articles n = 256 Non-English n = 165 Non-human n = 115

Studies retrieved for more detailed evaluation n = 233 Studies excluded n = 204 Case reports n = 61 Abstracts n = 78 Duplicate series n = 29 Review articles n = 36

Studies included in review n = 30 Fig. 1. Diagram demonstrating studies included in this review following the search criteria.

and oxaliplatin treatment, Sobrereo et al.20 observed that cetuximab and irinotecan significantly increased both the response rates and progression-free survival compared to irinotecan alone. Nevertheless, the overall survival in both the above studies did not significantly improve with the addition of cetuximab.16,20 The COIN trial reported that although the addition of cetuximab to oxaliplatin-based chemotherapy in first-line treatment of patients with advanced colorectal cancer increased the response rate, there was no significant benefit with respect to progression-free or overall survival compared to patients that received oxaliplatinbased chemotherapy only.21 Other studies have reported similar findings with respect to overall survival.22e25 The above published studies confirm that the response rates in patients with metastatic colorectal cancer that were refractory to irinotecan and/or oxaliplatin-based regimens improved following the addition of cetuximab,16,24,26e29 suggesting that resistance to previous chemotherapy regimens are not a negative predictor for response to cetuximab. Nevertheless, the increase in response rates following combination therapy of cetuximab and chemotherapy regimens is not translated into a significant improvement in overall survival, even in patients with KRAS wild-type metastatic colorectal cancer, and hence its use in the palliative setting cannot be recommended. 4. Cetuximab as part of a down-staging programme Based on the above results, the addition of cetuximab does increase the response rates compared to chemotherapy-only regimens in metastatic colorectal cancer patients, but this does not translate into improvement in survival rates. Hence, the role of cetuximab has been explored in down-staging chemotherapy programmes (Table 3), with the four landmark clinical trials known as the OPUS,30 CRYSTAL,31 CELIM,32 and POCHER trials.33 4.1. Cetuximab with oxaliplatin-based chemotherapy In the OPUS study,30 the authors reported an overall response rate of 72% in 43 patients with metastatic colorectal cancer treated with first-line combination therapy of cetuximab and FOLFOX-4. The median progression free and overall survival was 12.3 and 30.0 months, respectively. Ten patients (23%) that were deemed to have unresectable disease were down-staged and underwent potentially curative surgery, of which nine patients had R0 resection. Curative surgery included hepatic resection (n ¼ 8), lung resection (n ¼ 1) and adrenalectomy (n ¼ 1).30 However, the authors did not specify the type of liver resection performed or provide separate survival data for patients who underwent surgery following down-staging therapy compared to patients that were not operated on. Arnold and colleagues34 observed a resectability rate of 8.2% (n ¼ 4) following down-staging of CRLM with cetuximab and oxaliplatin-based chemotherapy, of which an R0 resection was achieved in 50% of cases. The median progression free and overall survival was 8.1 and 28.2 months, respectively.34 However, this study did not report type of liver resection and extent of disease burden of patients that underwent liver resection. 4.2. Cetuximab with irinotecan- and/or oxaliplatin- based chemotherapy In the CRYSTAL study, Van Cutsem et al. investigated the efficacy of first-line cetuximab with FOLFIRI compared to FOLFIRI alone in patients with unresectable, metastatic colorectal cancer.31 Tumour responses were seen in 281 (46.9%) patients receiving cetuximab and FOLFIRI and in 232 (38.7%) patients receiving FOLFIRI alone. In

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509

Table 1 Published studies on results of cetuximab mono-therapy on patients with metastatic colorectal cancer in the palliative setting. Study (Centre)

Study type

Patient groups

Saltz et al. (2004),17 Multi-center, USA Lenz et al. (2006),10 Multi-centre Jonker et al. (2007),19 Multi-centre

Phase II study Phase II study Randomised trial

Pessino et al. (2008),18 2 centres, Italy

Phase II study

Response, n (%)

Cetuximab ¼ 57 Cetuximab ¼ 346 Cetuximab ¼ 287 Best supportive care ¼ 285 Cetuximab ¼ 39

Complete

Partial

Stable

Progression

0 0 0 0 1

5 40 23 0 3

21 110 90 31 13

21 160 224 178 22

(0) (0) (0) (0) (2.6)

(8.8) (11.6) (8.0) (0) (7.7)

(36.8) (31.8) (31.4) (10.9) (33.3)

(36.8) (46.2) (78.0) (62.5) (56.4)

Median overall survival (months) 6.4 NR 6.1 4.6 12.3

NR ¼ Not reported.

the cetuximab-FOLFIRI group, 7% of patients had surgery with curative intent for metastases compared with 3.7% in the FOLFIRI only group. The rate of R0 resection was also higher in the cetuximab-FOLFIRI group (4.8%) compared to the FOLFIRI only group (1.7%). However, no details with respect to surgery for metastatic disease and pattern of recurrence were reported. The median progression free and overall survival was 8.9 and 8.0 months; and 19.9 months and 18.6 months; respectively in the cetuximabFOLFIRI group and FOLFIRI only group.31 This similarity in survival between treatment groups was likely to be secondary to posttrial therapy (25.4% of patients in the FOLFIRI group and 6.2% in the cetuximab-FOLFIRI group received EGFR antibody therapy poststudy). Raoul and co-investigators showed an overall response rate of 48% and median duration of response of 9.9 months following treatment with cetuximab combined with FOLFIRI.35 This study also showed that the cetuximab combination therapy successfully down-staged 14 (27%) patients that were deemed to have inoperable disease prior to therapy, of which most had liver metastases, 2% for lung and 4% for metastases at other sites. These patients underwent surgery with curative intent and the R0

resection rate was 71% (n ¼ 10) of cases.35 The median overall survival was 22.4 months in the whole cohort.35 No further details with regards to post-operative morbidity and survival were reported. In another randomised study assessing the combination therapy of cetuximab with or without the FOLFOX-4 regimen, Bokemeyer et al. reported a better overall response rate in the cetuximab and FOLFOX-4 group compared to the FOLFOX-4 only group with no difference in median progression-free survival.36 Cetuximab combination therapy doubled the R0 resectability rate (n ¼ 6, 9.8% versus n ¼ 3, 4.1%) compared to chemotherapy only in patients with KRAS wild-type tumours.36 The authors did not report details regarding surgery following down-staging treatment, and survival outcome.36 Borner and co-investigators randomised 74 patients with metastatic colorectal cancer to first-line treatment with oxaliplatin and capecitabine (XELOX) alone or in combination with cetuximab.37 The median overall survival was 16.5 months and 20.5 months in the XELOX only group and in the XELOX and cetuximab group, respectively. Four out of ten patients in the XELOX group and four

Table 2 Published studies on results of cetuximab in combination with chemotherapy on patients with metastatic colorectal cancer in the palliative setting. Study (Centre)a

Study type

Patient groups

Complete Partial 16

Cunningham et al. Randomised trial (2004), 56 centres 25 Vincenzi et al. (2006), Italy Phase II study Retrospective study Meyerhardt et al.43 (2006), USA Souglakos et al.28 Phase II study (2007), Greece Koo et al. (2007),23 Phase II study South Korea 44 Pfeiffer et al. (2007), Case controlled study 3 centres Denmark 22 Pfeiffer et al. (2008), Case controlled study 2 centres Denmark Martín-Martorel et al. Phase II study (2008),45 Spain Wilke et al. (2008),24 Non-randomised study 197 centres

Sobrero et al. (2008),20 221 centres Ocvirk et al. (2010),29 28 centres Lim et al. (2011),26 25 centres Maughan et al. (2011),21 Multi-centres

Randomised trial Randomised trial Phase II study Randomised trial

Overall survivalb

Response, n (%) Stable

Progression

Cetuximab þ Irinotecan ¼ 218 Cetuximab ¼ 111 Cetuximab þ Irinotecan ¼ 55 Cetuximab þ Irinotecan ¼ 20 Cetuximab ¼ 4 Cetuximab, Capecitabine þ Oxaliplatin ¼ 40

0 0 0 0

1 (2.5)

7 (17.5)

11 (27.5)

21 (52.5)

10.7

Cetuximab þ FOLFIRI ¼ 31

0 (0)

8 (25.8)

10 (32.3)

11 (35.5)

10.9 (3.8e18.0)

Cetuximab þ Irinotecan ¼ 65

0 (0)

12 (18.5)

31 (47.7)

15 (23.1)

10.4 (7.2e13.1)

Cetuximab þ Irinotecan ¼ 74

1 (1.4)

18 (24.3)

38 (51.4)

13 (17.6)

8.9 (7.0e10.5)

Cetuximab þ Irinotecan ¼ 39

2 (5.1)

7 (17.9)

15 (37.5)

15 (37.5)

8.0

Cetuximab þ Irinotecan ¼ 93 Cetuximab þ 2 weekly Irinotecan ¼ 670 Cetuximab þ 3 weekly Irinotecan ¼ 356 Cetuximab þ other Irinotecan ¼ 28 All patients ¼ 1147 Cetuximab þ Irinotecan ¼ 648 Irinotecan ¼ 650 Cetuximab þ FOLFOX6 ¼ 74 Cetuximab þ FOLFIRI ¼ 77 Cetuximab þ Irinotecan ¼ 123

1 1 0 1 3 9 1 2 6 1

(0) (0) (0) (0)

(1.1) (0.1) (0) (3.6) (0.3) (1.4) (0.2) (2.7) (7.8) (0.8)

Oxaliplatin þ Capecitabine or FU ¼ 815 Cetuximab þ Oxaliplatin,Capecitabine/FU ¼ 815

NR ¼ Not reported; FOLFOX ¼ Folinic acid, Fluorouracil, Oxaliplatin; FOLFIRI ¼ Folinic acid, Fluorouracil, Irinotecan.

50 12 14 3

16 16 92 5 228 97 26 31 27 16

(22.9) (10.8) (25.4) (12.5)

(17.2) (17.2) (25.8) (17.9) (19.9) (15.0) (4.0) (41.9) (35.1) (13.0)

71 24 21 13

23 159 99 7 288 292 271 31 24 44

209 (57.0)b NR 232 (64.0)b NR

(32.6) (21.6) (38.2) (54.2)

(24.7) (23.7) (27.8) (25.0) (25.1) (45.1) (41.7) (41.9) (31.2) (35.8)

68 59 19 6

45 340 134 9 528 174 243 6 9 52 NR NR

a: Single centre unless otherwise stated. b: Survival data presented as median (95% confidence interval) months where available. b: Results here represent patients with a complete or partial response in KRAS wild-type patients in the control group and cetuximab group.

(31.2) (53.2) (34.4) (25.0)

(48.4) (50.7) (37.6) (32.1) (46.0) (26.9) (37.4) (8.1) (11.7) (42.3)

8.6 6.9 9.8 (3.9e10.1) NR

8.3 (6.9e11.3) 9.2 (8.4e9.8) 10.3 (8.7e11.3) 7 (4.6e10.2) 9.2 (8.6e9.8) 10.7 (9.6e11.3) 10 (9.1e11.3) 17.4 (14.9e22.6) 18.9 (14.7e23.9) 9.5 (7.5e11.7) 17.9 (10.3e29.2) 17.0 (9.4e30.1)

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Table 3 Published studies on results of cetuximab on down-staging disease in patients with metastatic colorectal cancer. Study (Centre)a

Folprecht et al. (2006), 3 centres, Germany

46

Tabernero et al. (2007),30 Multi-centre Adam et al. (2007),47 France

Study type

Patient groups

Phase I/ II trial

Cetuximab þ Irinotecan, FA, low dose 5-FU ¼ 6 Cetuximab þ Irinotecan, FA, high dose 5-FU ¼ 15 All ¼ 21 Cetuximab þ FOLFOX-4 ¼ 43

Phase II trial Case series RCT

Complete Partial

Cetuximab þ Irinotecan or Oxaliplatin ¼ 151 Capecitabine þ Oxaliplatin ¼ 37 Borner et al. (2008), Multi-centre Cetuximab þ Capecitabine þ Oxaliplatin ¼ 37 Phase Ib/ Cetuximab þ Oxaliplatin, FA, Arnold et al. (2008),34 Multi-centre II trial low dose 5-FU ¼ 8 Cetuximab þ Oxaliplatin, FA, high dose 5-FU ¼ 41 All ¼ 49 31 RCT Cetuximab þ FOLFIRI ¼ 599 Van Custem et al. (2009), Multi-centre FOLFIRI ¼ 599 RCT FOLFOX-4 ¼ 168 Bokemeyer et al. (2009),36 79 centres Cetuximab þ FOLFOX-4 ¼ 169 Phase I/ FOLFIRI þ Cetuximab Raoul et al. (2009),35 Multi-centre II study (low dose 5-FU) ¼ 7 FOLFIRI þ Cetuximab (high dose 5-FU) ¼ 45 All ¼ 52 Phase Cetuximab þ Irinotecan ¼ 79 Buzaid et al. (2010),27 Multi-centre II trial Phase Cetuximab þ chrono-chemotherapy Garufi et al. (2010),33 2 centres, Italy II trial (Irinotecan, 5-FU, leucovorin þ Oxaliplatin) ¼ 43 48 5-FU, Irinotecan þ Bevacizumab or Brouquet et al. (2010), USA Retrospective Cetuximab in 42/60 (70%) ¼ 60 RCT Cetuximab þ FOLFOX6 ¼ 53 Folprecht et al. (2010),32 Multi-centre Cetuximab þ FOLFIRI ¼ 53 Case Cetuximab, 5-FU þ Irinotecan Lévi et al. (2011),41 France series (61%), Oxaliplatin (25%) or both (14%) ¼ 53 37

Response, n (%) Stable

Progression

Resection rate: n(%)c [R0 ¼ n]

Overall survivalb

4(19) [4]

33 (20 e not reached)

1 (16.7)

3 (50.0)

2 (33.3)

0 (0)

1 (6.7)

9 (60.0)

4 (26.7)

1 (6.7)

2 (9.5) 4 (9.3)

12 (57.1) 27 (62.8)

6 (28.6) 10 (23.3)

1 (4.8) 1 (2.3)

10 (23.2)d [9]

30 (17.8e33.8)

0 (0)

23 (15.2)

4 (2.6)

0 (0)

25 (16.6) [10]

20 (NR)

e

0 (0) 0 (0)

5 (13.5) 15 (40.5)

23 (62.1) 13 (35.1)

6 (16.2) 7 (18.9)

4/10 4/14e

16.5 (14.3e27.0) 20.5 (15.5e27.2)

0 (0)

5 (62.5)

1 (12.5)

1 (12.5)

4 (8.2) [2]

28.2 (14.7enot reached)

22 (53.7)

9 (22.0)

6 (14.6)

7.0% (R0 ¼ 4.8%) 3.7% (R0 ¼ 1.7%)f [R0 ¼ 3 of 73, R0 ¼ 6 of 61]g

19.9 (18.5e21.3) 18.6 (16.6e19.8) NR NR 18.1 (8.7e24.9)

1 (2.4) 1 3 2 1 2 0

(2.0) (0.5) (0.3) (0.6) (1.2) (0)

0 (0)

27 278 230 59 75 0

(55.1) 10 (20.4) 7 (14.3) (46.4) 224 (37.4) NR (38.4) 280 (46.7) NR (35.1) 76 (45.2) 21 (12.5) (44.4) 67 (39.6) 18 (10.7) (0) 2 (28.7) 1 (14.3)

0 (0)

18 (40.0)

4 (8.9)

20 (38.5) 5 (9.6) 23 (29.1) 30 (38.0)

22.6 (16.5e25.6) h

0 (0) 1 (1.3)

0 (0) 20 (25.3)

0 (0)

34 (79.1)

1 (1.7)

21 (35.0)

22 (36.7) 16 (26.7)

60 (100) [48]

5 year: 22%

0 (0) 0 (0) 3 (5.6)

36 (67.9) 30 (56.6) 14 (26.4)

15 (28.3) 2 (3.8) 16 (30.2) 7 (13.2) 18 (34.0) 18 (34.0)

22 (41.5%) [20] 23 (43.4%) [16] 11 (20.8%)j [9]

NR

5 (11.6) NR

14 (26.9) [71%] 2 (2.5)i [NR]

22.4 (16.5e24.9) 9.2 (7.9e10.8)

26 (60.5) [R0 ¼ 60%] 37.0 (21.0e53.0)

13.7 (8.1e19.2)

RCT ¼ Randomised controlled trial; NR ¼ Not reported; FA ¼ Folinic acid; FU ¼ Fluorouracil; FOLFOX ¼ Folinic acid, Fluorouracil, Oxaliplatin; FOLFIRI ¼ Folinic acid, Fluorouracil, Irinotecan. a Single centre unless otherwise stated. b Survival data presented as median (95% confidence interval) months where available. c Liver resection rate reported unless otherwise stated. d 10 (23%) patients had surgery; liver surgery (n ¼ 8), lung surgery (n ¼ 1) and adrenal surgery (n ¼ 1). e 4 out of 10 and 4 out of 14 patients were suitable for liver resection following down-staging of CRLM. f Surgical results presented as percentages, with no further details of surgery reported. g Cetuximab doubled the R0 resection rate in patients that were KRAS wild-type tumour. h 14 patients had surgery: liver resection (21%), lung resection (2%) and other sites (4%). The R0 resection rate was presented as a percentage. i No surgical details given. j Nine patients had R0 resection: liver resection (n ¼ 4), lung surgery (n ¼ 3), lymph node resection (n ¼ 1) and pelvic recurrence resection (n ¼ 1).

out of 14 patients in the XELOX and cetuximab group had disease confined to the liver that was down-staged and suitable for liver resection. However, no details of hepatic resection were reported. Folprecht and co-workers conducted a multi-centre randomised (CELIM) study to assess the efficacy of cetuximab in different chemotherapy regimens (FOLFOX-6 versus FOLFIRI) in the treatment of 106 patients with technically non-resectable or five or more CRLM.32 A total of 45 (42.4%) patients underwent liver resection, of which 22 (41.5%) patients were from the cetuximabFOLFOX-6 group and 23 (43.4%) patients were from the cetuximab-FOLFIRI group. The overall R0 resection rate was 34% (n ¼ 36) [cetuximab-FOLFOX-6 ¼ 20 (38%) and cetuximabFOLFIRI ¼ 16 (30%)]. Although this study reported significantly better down-staging of CRLM with the addition of cetuximab to conventional chemotherapy, details of type of liver resection, postsurgical outcomes and survival data were not reported.

4.3. Cetuximab with chrono-modulated chemotherapy More recently, two studies have shown promising outcomes following the combination of cetuximab with chrono-modulated chemotherapy regimens. Previous studies have suggested improved efficacy of chrono-modulated chemotherapy compared to constant rate infusion chemotherapy for first-line treatment of patients with metastatic colorectal cancer.38e40 In the POCHER trial, Garufi et al.33 evaluated the rate of CRLM resection in 43 patients with unresectable metastatic colorectal cancer following treatment with cetuximab and chrono-modulated chemotherapy which consisted of irinotecan, 5-fluorouracil, leucovorin and oxaliplatin. This study reported an overall response rate of 79.1%, and 26 (60.5%) patients underwent liver resection with an R0 resection rate of 60%: multiple metastectomies (n ¼ 13); two-stage hepatectomy (n ¼ 9); right hepatectomy (n ¼ 3) and left hepatectomy

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(n ¼ 1). In the four patients that had lung metastasis, only one patient had both liver and lung resection, while one patient had disease progression following liver resection and two patients did not have surgery. The median time from discontinuation of chemotherapy to surgery was 5 weeks (range: 1e11). The 2-year survival was significantly better in patients that had surgery (80.6%) compared to unresected patients (47.1%). Twenty patients had disease recurrence following liver resection [intra-hepatic (n ¼ 10, 38%); extra-hepatic (n ¼ 4, 15%) and both intra- and extra- hepatic (n ¼ 6, 23%)]. Five patients with isolated liver recurrences had repeat hepatectomy. The median time from surgery until relapse was 11 months.33 Lévi and co-workers observed promising results following cetuximab and circadian-based chrono-modulated chemotherapy (irinotecan, oxaliplatin, 5-fluorouracil and leucovorin) in 53 patients with advanced metastatic colorectal cancer who had disease progression on at least one prior chemotherapy regimen.41 The objective response rate was 36% and nine (17.0%) patients underwent R0 resection [liver (n ¼ 4); lung (n ¼ 3); lymph node (n ¼ 1); and pelvic (n ¼ 1) disease] and two patients underwent R1 liver resection. The median progression-free and overall survival was 4.6 and 13.7 months, respectively. The median relapse-free survival for these 11 surgically treated patients was 10.0 months.

5. Discussion Currently, randomised trials have shown that the addition of cetuximab to irinotecan- or oxaliplatin- based chemotherapy regimens increased tumour response and down-staging of initially unresectable disease, leading to an increased resection rate for metastases compared to conventional chemotherapy regimens. The role of cetuximab in down-staging of metastatic disease has led to clinical “controversies” with respect to patient selection, preoperative staging, response rates and resection rates. In addition, the cost of cetuximab and other secondary costs also need to be taken into account. Folprecht et al. analysed published or presented trials and retrospective studies that reported the rate of objective response following neo-adjuvant chemotherapy and the resection rates of initially unresectable metastases to correlate objective response and the rate of resection of colorectal metastases.42 The authors reported a resection rate of 24e54% following chemotherapy in patients with CRLM only, compared to 1e26% of patients in trials that included non-selected patients with metastatic colorectal cancer. A significant correlation was found between response rates and resection rates in studies that included patients with liverlimited disease, and the authors showed that with a response rate of approximately 70%, a resection rate of around 50% can be expected.42 This emphasises that the main end-point of downstaging chemotherapy in CRLM patients is to achieve potentially curative liver resection and long-term survival.

511

To achieve an appropriate resection rate following neo-adjuvant therapy, patient selection and efficacy of therapy are both important predictors for resectability of CRLM. The majority of current published studies with respect to cetuximab have not clearly stated their selection criteria or defined non-resectability. There is currently no standard definition of non-resectable or borderline disease, and hence this has an impact on patient selection for downstaging therapy. Both the CRYSTAL and OPUS trial observed an overall response rate of 46.9% and 72%. In addition, the CRYSTAL trial showed an increase in the resection rate from 3.7% to 7.0% following the addition of cetuximab to FOLFIRI,31 while the OPUS trial reported that the addition of cetuximab to FOLFOX doubled the rate of liver resection from 2.4% to 4.7%.36 Although both trials noted a higher R0 resection rate with the addition of cetuximab therapy, no details with respect to type of surgery and survival outcome were reported.31,36 Although both these trials did report better response rates following the addition of cetuximab to conventional chemotherapy, the resection rates were still less than 10%. As previously reported by Folprecht and co-workers,42 resection rates of 1e26% following chemotherapy was achieved in studies that included nonselected patients with metastatic colorectal cancer. Both the CRYSTAL and OPUS trials observed this finding, as patients with multiple metastatic sites were included, which were mainly designed to identify the efficacy and tolerability of new cetuximab regimens and secondary resection was probably reported as an incidental observation. In addition, disease resectability in these patients was determined by general oncologist, rather than liver surgeons. In contrast, the CELIM study reported resection rates of 38% with the combination of cetuximab and FOLFOX and 30% with cetuximab and FOLFIRI following a response rate of 67.9% and 56.6%, respectively.32 However, patients included in this trial had liverlimited (technically non-resectable or 5 liver metastases) disease. The authors also noted a significantly better response in patients with KRAS wild-type tumours (70%) compared to patients with KRAS-mutated tumours (41%). Of note, in a retrospective review, the authors blinded eight liver surgeons to review the computer tomography scans following down-staging; and although there was some disagreement regarding resectability, there was a general consensus that resectability rates increased significantly from 32% to 60% after neo-adjuvant therapy. In the POCHER trial, Garufi et al. observed a 60.5% liver resection rate following neoadjuvant therapy (cetuximab and chrono-modulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin) that resulted in a 79.1% response rate.33 The authors showed a significantly better 2-year survival of 80.6% following liver resection compared to 47.1% in patients with unresectable disease. The higher resection rates observed in both the CELIM32 and POCHER33 trials were likely to be influenced by patient selection and study design. These trials included patients with liver-limited disease and a high proportion of patients with KRAS wild-type tumours, of which cetuximab is more effective. In addition, chronomodulated chemotherapy with cetuximab produced a higher

Table 4 Differences between the main published studies on results of cetuximab on down-staging disease in patients with metastatic colorectal cancer. Study (Name) 30

Tabernero et al. (OPUS) Van Custem et al. (CRYSTAL)31 Folprecht et al. (CELIM)32 Garufi et al. (POCHER)33

Patient recruitment

Overall response rates with cetuximab (%)

Decision on resectability

Resection rate: n(%)a [R0 ¼ n]

General oncologist General oncologist MDT with Liver surgeon MDT with Liver surgeon

72.0 46.9 62.3 79.1

General oncologist General oncologist MDT with Liver surgeon MDT with Liver surgeon

10 (23.2%)b [R0 ¼ 9] 7.0% [R0 ¼ 4.8%]c 45 (34.0%) [R0 ¼ 36] 26 (60.5) [R0 ¼ 60%]

MDT ¼ Multi-Disciplinary Team Meeting. a Liver resection rate reported as percentage of overall response rate. b 10 (23%) patients had surgery; liver surgery (n ¼ 8), lung surgery (n ¼ 1) and adrenal surgery (n ¼ 1). c Surgical results presented as percentages, with no further details of surgery reported.

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response rate and resection rates33,41 Both these trials specifically selected patients into a down-staging regimen and their primary outcome was to assess the resectability rates. Patients were recruited as part of a multi-disciplinary meeting that included liver surgeons, and resectability was determined by liver surgeons (Table 4). Both the results of CELIM and POCHER trials are in keeping with the analysis by Folprecht et al.42 To enable these results to be replicated in other centres, downstaging trials need to be designed with strict selection criteria for patients that can be potentially down-staged for liver and/or lung resection. In addition, all patients included in such trials need to be managed by specialist inter-disciplinary teams, that includes oncologists, radiologist and liver surgeons with an interest in metastatic colorectal cancer. It cannot be stressed enough the importance of these multi-disciplinary teams meetings are, in particular, in patients with metastatic colorectal cancer. These meetings assist in determining the type and duration of neoadjuvant chemotherapy as well as an objective assessment of down-staging. The duration of neo-adjuvant therapy should be based on tumour shrinkage sufficient to allow R0 liver resection, rather than to achieve complete response. Nevertheless, the majority of published studies with cetuximab therapy tend to report minimal surgical data and lack details regarding unresectability. Following down-staging of disease, most studies did not report the type of liver surgery undertaken or the post-operative outcomes. Although most studies showed an improved response with the addition of cetuximab, the reporting of overall survival in the sub-group of patients that underwent liver resection following neo-adjuvant cetuximab therapy was limited. 6. Conclusion In summary, cetuximab may be beneficial in down-staging programmes for patients with metastatic colorectal cancer. However, these early promising results require further appraisal. In the down-staging setting, resectability following neo-adjuvant cetuximab and chemotherapy is a distinct end-point from the more classical end-points of response rates, progression-free survival or median survival. More trials managed by specialist interdisciplinary teams are required, with the aim to define which patients are likely to benefit from the more aggressive approach of neo-adjuvant cetuximab and subsequent resection. Further longterm outcome following this down-stage programme is clearly the next step to be evaluated. Ethical approval Not relevant. Funding None obtained. Author contribution Study concepts: Gomez, Brooks, Malik, Cameron. Study design: Gomez, Brooks, Malik, Cameron. Data acquisition: De Rosa, Addison. Quality control of data and algorithms: Brooks, Malik, Cameron. Data analysis and interpretation: Gomez, De Rosa, Addison, Malik. Manuscript preparation: Gomez, De Rosa, Addison. Manuscript editing: Gomez, Brooks, Malik, Cameron. Manuscript review: Brooks, Malik, Cameron. Conflict of interest None declared.

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