Options for metastatic colorectal cancer beyond the ... - CyberLeninka

Digestive and Liver Disease 46 (2014) 105–112

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Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld

Review article

Options for metastatic colorectal cancer beyond the second line of treatment夽 Fanny Foubert, Tamara Matysiak-Budnik, Yann Touchefeu ∗ Gastroenterology Department, Gastrointestinal Oncology Unit, University Hospital, Nantes, France

a r t i c l e

i n f o

Article history: Received 17 January 2013 Accepted 1 July 2013 Available online 15 August 2013 Keywords: Chemotherapy Intra-arterial therapies Metastatic colorectal cancer Molecular targeted therapies Multiline strategy

a b s t r a c t Colorectal cancer is the third most common cancer, with recent advances in the management of unresectable metastatic lesions. The aim of this review is to discuss the remaining options for heavily pretreated patients with unresectable metastatic colorectal cancer. Beyond second-line treatment, two epidermal growth factor receptor (EGFR) inhibitors, cetuximab and panitumumab, have a demonstrated clinical interest in patients with KRAS wild-type tumours. However, few data exist in patients pretreated with an anti-EFGR and who are being rechallenged with anti-EGFR drugs. Reintroduction of chemotherapy should be considered. In September 2012, regorafenib, a multi-kinase inhibitor was approved by the US Federal Drug Administration for patients refractory to other standard treatments. In the case of metastases limited to the liver, transarterial chemoembolization, hepatic artery infusion and radioembolization could also be discussed in selected patients. With the multiplication of therapeutic options in first-line, second-line treatment, and beyond, the concept of subsequent lines of chemotherapy should be replaced by a multiline strategy, dependent on the patient and on tumour biology. A better understanding of the tumour biology and predictive factors for the response to these therapies is needed, and further strategic trials are urgently warranted. © 2013 The Authors. Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l. All rights reserved.

1. Introduction Colorectal cancer is the third most commonly diagnosed cancer with around 1 million new cases and more than 500,000 deaths every year worldwide [1]. Patients with advanced and unresectable disease can be eligible for multiple lines of treatment. Three major chemotherapeutic agents (5-fluorouracil (5-FU), irinotecan and oxaliplatin), one anti-vascular endothelial growth factor (anti-VEGF, bevacizumab) and two epidermal growth factor receptor inhibitors (cetuximab and panitumumab) have shown well-demonstrated clinical activity for the treatment of metastatic colorectal cancer. Most patients can receive the three chemotherapeutic agents during their first two lines of treatment [2]. Moreover, the simultaneous administration of fluorouracil, oxaliplatin and irinotecan in first-line treatment showed better antitumoural

夽 This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited. ∗ Corresponding author at: Institut des Maladies de l’Appareil Digestif, Gastrointestinal Oncology Unit, University Hospital, 1 Place Alexis Ricordeau, 44093 Nantes Cedex 1, France. Tel.: +33 2 40 08 31 52; fax: +33 2 40 08 31 54. E-mail address: [email protected] (Y. Touchefeu).

activity than a doublet regimen [3]. Phase III trials reported the efficacy of bevacizumab in the first or second line [4–6], but there are no data supporting its prescription beyond the second line. Anti-epidermal growth factor receptor drugs (cetuximab, panitumumab) demonstrated clinical activity in third-line treatment, but can also be recommended in first- and second-line treatment [7,8]. The use of cetuximab in colorectal cancer has recently been reviewed [9,10]. In case of disease progression after two lines of treatment, the survival is about 4–6 months with best supportive care (BSC) alone [11,12]. However, some patients are still able and willing to receive further therapy. While all major therapeutic agents can be recommended in first- and second-line treatment, what are the remaining options for third-line treatment and beyond? The aim of this review is to highlight the current therapeutic options for patients progressing after two lines of therapy for metastatic unresectable colorectal cancer. 2. Chemotherapy can still be an option 2.1. Strategic trials investigating third-line therapy Median overall survival depends on patients’ access to the three major chemotherapy agents (fluorouracil, irinotecan and oxaliplatin) [13]. All three agents are often administered in

1590-8658/$36.00 © 2013 The Authors. Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l. All rights reserved. http://dx.doi.org/10.1016/j.dld.2013.07.002

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F. Foubert et al. / Digestive and Liver Disease 46 (2014) 105–112

Table 1 Strategic trials with a third-line treatment planned in the protocol. FFCD 2000–2005 [34] Groups

Sequential treatment 1st line: LV5FU2 2nd line: FOLFOX 6 3rd line: FOLFIRI

CAIRO [33] Combined treatment 1st line: FOLFOX 6 2nd line: FOLFIRI 3rd line: Capecitabine, LV5FU2 or other

Sequential treatment 1st line: Capecitabine 2nd line: irinotecan 3rd line: CAPOX

Combined treatment 1st line: CAPIRI 2nd line: CAPOX No third-line

Number of patients

205

205

p

401

402

p

Overall survival (months [95% CI]) Progression free survival in third line (months [95% CI]) Overall response rate (% [95% CI])

16.4 [14.5–18.6]

16.2 [14.4–18.4]

0.85

16.3 [14.3–18.1]

17.4 [15.2–19.2]

0.3281

13.2 [11.7–14.3]

12.9 [11.9–14.4]

0.62

10.3 [9–11.1]

8 [3–13]

9 [3–15]

first- and second-line treatment with doublet regimens or even in first-line treatment with triplet regimens. The third-line therapy can be anticipated in a multiline therapeutic strategy (Table 1). A strategic trial on 820 patients evaluated a sequential treatment with capecitabine in first-line, irinotecan in second-line and capecitabine plus oxaliplatin in third-line treatment versus an up-front combined therapy with capecitabine plus irinotecan in first-line and capecitabine plus oxaliplatin in second-line treatments [14]. The median overall survival of the two groups did not differ, but only 36% of patients in the sequential group received a third-line treatment, and the rate of patients who received a thirdline treatment not planned in the protocol in the combination group was not specified. The FFCD 2000–05 trial included 410 patients who were randomized to receive either sequential chemotherapy (LV5FU2 then FOLFOX 6 then FOLFIRI then any fourth-line therapy) or combined chemotherapy (FOLFOX 6 then FOLFIRI then any thirdand fourth-line therapies at the investigator’s discretion). Fiftyfive percent of patients received the planned third-line treatment in the sequential arm and 44% of patients received any third-line treatment in the combined arm. In the third-line treatment, disease control and response rate were 47% and 8% respectively with FOLFIRI in the sequential arm, and 24% and 9% in the combined arm. The overall survival in the two groups did not differ significantly (16.4 months in the sequential arm versus 16.2 in the combination arm, P = 0.85) [15]. In these trials, the median overall survival from first-line treatment is low, probably because these studies were conducted before the use of targeted therapies. If the sequential strategy is chosen, the question on the third-line treatment is easier, as every patient with metastatic colorectal cancer with good performance status should receive both oxaliplatin and irinotecan. Some patients can receive a triple chemotherapy regimen as the first-line treatment. In this setting, to our knowledge, no data have been published concerning a third-line therapy. The strategy must be decided upon according to the patient’s symptoms and the objectives of the treatment. If there is hope of the patient becoming eligible for surgery, a combination therapy with a high expected response rate in front-line therapy should be recommended. However, in patients with advanced disease (multiple metastases at different organ sites (liver, lungs, carcinomatosis), but few symptoms, a monochemotherapy with or without a monoclonal antibody could be appropriate [16].

2.2. Fluorouracil or capecitabine beyond second-line treatment, in combination or as single agents In the FFCD 2000–05 trial, 44% of the patients receiving the up-front combined strategy were treated with third-line therapy, which could be infusional 5-FU, capecitabine, or another drug. There are few data on the effectiveness of 5FU or capecitabine as

0.85

4 [1–9]

–

–

–

–

single agents after the failure of 5FU-based doublet regimens. In a study published in 2003, 463 patients progressing after first-line IFL therapy (irinotecan, bolus fluorouracil and leucovorin) were randomized to receive either LV5-FU2 or Folfox-4 regimens. For patients treated with LV5-FU2, the response rate was 0%, and the median time to progression was 2.7 months (95% confidence interval (CI) 1.8 to 3.0 months) [17]. Capecitabine is activated through a three-step process into 5-FU, resulting in higher concentrations of 5 FU in tumour cells compared with normal tissues. In preclinical trials, responses to capecitabine in 5FU-resistant tumour cell lines had been demonstrated [18]. A retrospective study included 20 patients with metastatic colorectal cancer to be treated with third-line therapy, after progression on 5FU combinations with oxaliplatin and irinotecan. With capecitabine in third-line treatment, the response rate was 0%, and the time to progression was 2.8 months. The most common side effects were hand-foot syndrome and diarrhoea. One patient died due to febrile neutropaenia. Capecitabine as a monotherapy did not provide any clinical benefit [19]. These data do not support the use of capecitabine or 5FU as single agents after the failure of doublet regimens. However, the use of capecitabine was investigated in combination with other chemotherapy agents. Capecitabine requires thymidine phosphorylase to metabolize to 5FU. Mitomycin C is an antitumour antibiotic that induces upregulation of intratumoural thymidine phosphorylase in vivo [20]. In third-line therapy, the combination of capecitabine with mitomycin C has been investigated in phase II studies. In a study including 21 patients, the response rate was 4.8%, there was 19% stable disease, the progression-free survival was 2.6 months and the overall survival was 6.8 months [21]. Another study gave more encouraging results. Thirty-five patients were included, the response rate was 15.2%, 48.5% of patients had stable disease, the progression-free survival was 5.4 months (95% CI 4.6 to 6.2), the overall survival was 9.3 months (95% CI 6.9 to 11.7) [22].

2.3. Oxaliplatin reintroduction The reintroduction of a previously used agent can be considered. For patients treated by FOLFOX and FOLFIRI in first- and secondline therapy, the reintroduction of previously used chemotherapy could be an option. The OPTIMOX trial randomly compared two chemotherapy schedules in 620 patients. One group of patients received a Folfox-4 regimen until progression, another group received Folfox-7 for 6 cycles, followed by LV5FU for 12 cycles and then planned Folfox-7 reintroduction. Progression-free survival and overall survival were similar in both groups. However, oxaliplatin was reintroduced in only 40% of patients included in the stop-and-go strategy [23]. Oxaliplatin reintroduction was an independent factor and had significant impact on survival (Hazard ratio (HR) = 0.51, 95% CI 0.3 to 0.9, P = 0.009) [24]. Three hundred and


thirty patients were included in a study presented at the American society of clinical oncology (ASCO) 2009 meeting. Patients had been included in OPTIMOX 1 and 2 studies, or had relapsed after metastases surgery and neoadjuvant or adjuvant FOLFOX. All patients had been rechallenged with oxaliplatin. Progression-free survival and median overall survival were significantly better when the oxaliplatin-free interval was more than 12 months (7.1 and 22.1 months, respectively) versus 4.8 and 7.6 months for an oxaliplatinfree interval of between 6 and 12 months, and 4.8 and 7.6 months for an interval of less than 6 months [25]. Reintroduction of oxaliplatin in third-line therapy can therefore be an option for patients previously treated with this drug in first- or second-line treatment, in particular if oxaliplatin was stopped because of toxicity and if the oxaliplatin-free interval was long. It is important to note that the OPTIMOX study investigated a stop-and-go strategy. Reintroduction is then not a true different line of treatment. This study does not support the reintroduction of oxaliplatin in patients who have progressed under oxaliplatin. However, it highlights the importance of considering oxaliplatin reintroduction if the drug has been stopped as part of a stop-and-go strategy or because of temporary toxicity. 2.4. Anti-EGFR therapies: clinical activity beyond second-line treatment The EGFR signalling pathway regulates cell differentiation, proliferation, migration, angiogenesis and apoptosis. Cetuximab is a chimeric monoclonal antibody that binds to the extracellular domain of EGFR to modulate tumour cell growth. Cetuximab has been associated with improved overall survival (6.1 months versus 4.6 months, HR = 0.77; 95% CI 0.64 to 0.92; P = 0.005) and progression-free survival (HR = 0.68; 95% CI 0.57 to 0.80; P < 0.001) compared with best supportive care alone in a prospective study based on 572 patients previously treated with 5FU, irinotecan and oxaliplatin [11,26]. The BOND study randomized 329 patients with irinotecan-refractory colorectal cancer into two groups (cetuximab and irinotecan or cetuximab monotherapy) and demonstrated efficacy of cetuximab in combination with irinotecan, as the response rate (22.9% [95% IC 17.5 to 29.1%] versus 10.8% [95% IC 5.7 to 18.1%], P = 0.007), the progression-free survival (4.1 months versus 1.5 months, HR = 0.54; 95% CI 0.42 to 0.71; P < 0.001) and the overall survival (8.6 months versus 6.9 months, HR = 0.91; 95% CI 0.68 to 1.21; P = 0.48) were higher in this group [27]. For these two studies, about eighty percent of patients received two or more previous cancer therapies before inclusion. Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) status was not determined in the BOND study. Health quality of life reports showed that the effect of cetuximab on survival and progression-free survival (PFS) was associated with improved quality of life [28]. Panitumumab is a fully humanized anti-EGFR antibody. Panitumumab was first evaluated as a single agent for chemotherapy in 463 patients with refractory metastatic colorectal cancer randomized into two groups (panitumumab plus BSC versus BSC alone), and was associated with improved progression-free survival (8 weeks versus 7.3 weeks, HR = 0.54; 95% CI 0.44 to 0.66, P < 0.0001) and objective response rate (10% versus 0%, P < 0.0001) [12]. In this phase III study, no significant difference in overall survival was observed (HR = 1.00; 95% CI 0.82 to 1.22), but the high rate of crossover of the BSC patients could have biased the overall survival data. In the selected patients with wild-type KRAS tumours, lower scores of deterioration in quality of life were observed in the panitumumab group than in the BSC alone group. These scores evaluate the most important symptoms associated with colorectal cancer (including fatigue, pain, weight loss, nausea, diarrhoea, ability to enjoy life and contentedness in quality of life) and less specific dimensions such as mobility, self care, anxiety, and depression.

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Patients treated with panitumumab showed significantly better control of the symptoms, and better quality of life, despite skin toxicity associated with panitumumab treatment [29]. The results from clinical trials testing the effect of anti-EGFR antibodies in third-line therapy are summarized in Table 2. Many studies reported that the benefits of anti-EGFR drugs are limited to the patients with KRAS wild-type tumours. The role of KRAS status as a strong predictive factor for cetuximab therapy was first retrospectively identified [30] and then confirmed in further large clinical trials [7,8,26,31–33]. As therapeutic benefits are limited to patients with wild-type KRAS tumours, it is now recommended that monoclonal antibody-mediated EGFR inhibition should be limited to these patients only. Thirty to 45% of patients have KRAS mutant tumours, and are not eligible for anti-EGFR therapies [34]. The discordance of KRAS mutation between the primary tumour and distant metastases occurs in 5–10% of metastatic colorectal cancers [35–37]. It could partly explain the lack of efficiency of anti-EGFR drugs in some patients with wild-type KRAS status identified on their primary tumour. Moreover, other predictive factors need to be validated, such as v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations, phosphatidylinositide 3-kinases (PI3K) mutations, and loss of phosphatase and tensin homologue (PTEN). These factors may enable better selection of patients for anti-EGFR drugs. These findings highlight the potential need for repeated biopsies along the therapeutic course, to obtain the molecular signature of targeted lesions, and refine the predictive factors of anti-EGFR drugs and potentially other treatments. Cetuximab and panitumumab have demonstrated clinical activity in first- and second-line treatment [7,8,31,32]. This raises the question of re-challenge with anti-EGFR drugs beyond the second line, in patients pretreated with anti-EGFR drugs. Recently, a prospective phase II study investigated the rechallenge of cetuximab-plus-irinotecan-based chemotherapy in 39 patients who had previously experienced a clinical benefit with the same regimen, and then a progression. The results are encouraging, as the overall response rate was 53.8%, the partial response rate was 48.7%, complete response rate was 5.1% and the stable disease rate was 35.9%. Median progression-free survival was 6.6 months [38]. Patients could also be rechallenged with another anti-EGFR antibody. In a recently published single-arm phase II study, 20 patients with prior progression on cetuximab were treated with panitumumab. There was no objective response; 45% patients had a stable disease. Median progression-free survival was 1.9 months and median overall survival was 5.2 months [39]. However, the results of a French institutional prospective study (PANERB study) have recently been updated, including 106 patients with KRAS wildtype tumours, progressing on cetuximab associated with irinotecan and then treated with panitumumab. Forty-five percent of patients had an objective response to the initial cetuximab-based therapy, and 18% had an objective response to panitumumab. Among the 48 patients who had an initial response to cetuximab, 31% had a response to panitumumab, and 16% had a stable disease. Among the 28 patients who initially had a resistance to cetuximab, 2 patients had an objective response to panitumumab, and 2 patients had stable disease [40]. This question of anti-EGFR rechallenge is thus controversial and further larger prospective trials are warranted. Cetuximab resistance can be mediated by the activation of alternative pathways [41], but another mechanism of resistance to cetuximab has recently been unveiled. An acquired mutation of the EGFR ectodomain was detected, preventing the binding of cetuximab to the receptor and conferring drug resistance. However, the binding of panitumumab is not impaired. This mutation was identified in 2 out of 10 patients progressing on cetuximab therapy. One patient with the mutation responded to further panitumumab therapy [42]. The knowledge of the mechanisms of drug resistance

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Table 2 Epidermal growth factor receptor inhibitor trials in third-line therapy.

Cetuximab studies: Jonker DJ et al. [9] Karapetis CS et al. [11]

Study protocol

Number of patients in third line or more (%)

KRAS status

Group

Number of patients

Median overall survival

HR (95% CI)

Median PFS

HR (95% CI)

Overall response rate (%)

C + BSC versus BSC alone depending on KRAS status

321 (81.5)

WT KRAS

C + BSC

117

9.5 months*

0.55 (0.41–0.74)

3.7 months*

0.40 (0.30–0.54)

12.8

BSC

113

4.8 months*

C + BSC

81

4.5 months

BSC C+I

83 218

4.6 months 8.6 months

C

111

6.9 months

WT KRAS

P + BSC

124

8.1 months

M KRAS

BSC P + BSC

119 84

7.6 months 4.9 months

BSC

100

4.4 months

M KRAS

Cunningham D et al., [12]

Panitumumab studies: Van Cutsem E et al., [10] Amado RG et al., [18]

C + I versus C alone

P + BSC versus BSC alone depending on KRAS status

261 (79)

270 (63.2)

Not evaluated

0.98 (0.7–1.37) 0.91 (0.68–1.21)

0.99 (0.75–1.29)

1.02 (0.75–1.39)

1.9 months* 1.8 months 1.8 months 4.1 months* 1.5 months* 12.3 weeks*

7.3 weeks* 7.4 weeks 7.3 weeks

0 0.99 (0.73–1.35) 0.54 (0.42–0.71)

1.2 0 22.9 10.8

0.45 (0.34–0.59)

0.99 (0.73–1.36)

17

0 0 0

Abbreviations: Nb: number; C: cetuximab; BSC: best supportive care; I: irinotecan; P: panitumumab; WT: wild-type; M: mutated; OS: overall survival; HR: hazard ratio; PFS: progression-free survival; ORR: overall response rate = complete tumour response and partial tumour response. * Statistically significant results.

could enable better selection of patients who may benefit from two lines of anti-EGFR antibodies. When cetuximab was evaluated in third-line therapy, previous bevacizumab therapy was permitted, but a subgroup analysis on this population has not been published. Fifty-eight consecutive patients were included in a recently published report. Patients with advanced colorectal cancer were treated with cetuximab, with or without prior anti-VEGF therapy. Patients with prior anti-VEGF therapy had a significantly lower disease-specific survival, compared with naïve patients (9.1 months versus 4.9 months; P = 0.026; HR = 2.2; 95% CI 1.1 to 4.5, P = 0.03) [43]. In the randomized trial investigating the combination of panitumumab with FOLFIRI in second-line therapy, a subgroup analysis investigated the effect of a prior treatment with bevacizumab. Panitumumab significantly improved PFS (HR = 0.77, 95% CI 0.61 to 0.96) in the 482 patients who did not receive bevacizumab in first-line treatment, but the difference was not significant in the 115 patients who received bevacizumab (HR = 0.71, 95% CI 0.45 to 1.13). However, this lack of statistically significant effect may be related to a relatively low number of patients and a lack of power [8]. Prospective studies are required, since these results highlight the crucial need for clinical trials evaluating multi-line treatments to identify the best therapeutic sequences.

2.5. Regorafenib, a new option Regorafenib (Stivarga® ) is an oral multi-targeted tyrosine kinase inhibitor. The CORRECT trial randomized 760 patients to receive regorafenib or placebo plus best supportive care, with an improved overall survival as a primary endpoint. Patients had previously failed all approved standard therapies, including 5FU, oxaliplatin, irinotecan, bevacizumab, and anti-EGFR drug in patients with

KRAS wild-type cancers. Hazard ratio for overall survival was 0.77 (95% CI 0.64 to 0.94, P = 0.0052). Median overall survival was 6.4 months for regorafenib and 5.0 months for placebo. Hazard ratio for progression-free survival was 0.49 (95% CI 0.42 to 0.58; P < 0.0001), median progression-free survival was 1.9 months for regorafenib and 1.7 months for placebo. Notably, regorafenib was associated with significant adverse effects, mainly fatigue, hypertension, hand–foot syndrome, diarrhoea and cutaneous rash. However, these adverse effects were mostly manageable, and regorafenib was associated with a maintained quality of life [44]. Regorafenib was approved by the US Federal Drug Administration in September 2012. Regorafenib can be considered a new standard of care in patients with chemotherapy-refractory disease, but should only be discussed in patients in good condition, after information about the potential benefits and adverse effects of the treatment. The recommended dose is 160 mg (four 40 mg tablets) orally, once daily, with a low-fat breakfast, for the first 21 days of each 28-day cycle.

2.6. Other anti-angiogenic therapies Bevacizumab is a recombinant humanized monoclonal antibody that binds to and neutralizes vascular endothelial growth factor (VEGF). In the first- and second-line chemotherapy regimens for metastatic colorectal cancer, this biological therapy improves progression-free survival and overall survival when combined with irinotecan plus LV/FU [4] and when combined with oxaliplatin, fluorouracil and leucovorin [6,45]. Recent studies strongly support the concept of sustained VEGF inhibition in firstand second-line therapy [46,47]. However, there is no published phase III trial investigating anti-VEGF therapies beyond second-line treatment. In a single-arm phase II study, 339 patients progressing after treatment with both oxaliplatin- and irinotecan-based


chemotherapy regimens were treated using a combination of bevacizumab, fluorouracil and leucovorin. The response rate was 1%, the progression-free survival was 3.5 months and median overall survival was 9.1 months [48]. In another phase II study, bevacizumab was evaluated in 48 heavily pretreated patients, after a first-line oxaliplatin-based chemotherapy, a second-line irinotecan-based chemotherapy and a third-line treatment with cetuximab plus irinotecan. The response rate was 6.25%, the median time to progression was 3.5 months and the median overall survival was 7.7 months. Eight patients had grade 3 or 4 haemorrhage and in one patient a fatal outcome occurred after an urgent surgical procedure. Importantly, none of the patients had previously received bevacizumab [49]. Brivanib alaninate is a tyrosine kinase inhibitor targeting vascular endothelial and fibroblast growth factor receptors. A phase III trial randomized 750 patients to receive cetuximab plus either brivanib alaninate or placebo, and the results were presented at the 2012 Gastrointestinal Cancers Symposium. Patients had metastatic chemotherapy refractory K-RAS wild-type colorectal cancer. Ninety-two percent of patients had received more than 3 previous chemotherapy regimens and 41% had received prior anti-VEGF therapy. Progression-free survival (5.0 months versus 3.4 months, HR = 0.72; 95% CI 0.62 to 0.84; P < 0.0001) and response rate (13.6% versus 7.2%, P = 0.004) were increased in the experimental arm. However, median overall survival was not statistically improved in the brevanib alaninate arm, compared with placebo (8.8 months versus 8.1 months, HR = 0.88; 95% CI 0.74 to 1.03; P = 0.12) [50]. 2.7. Toxicity profile of targeted agents To select the most appropriate targeted therapy, it is important to consider some expected toxicities and to discuss them with the patient. Some adverse effects can be observed with different therapies, such as fatigue, gastrointestinal effects (nausea, constipation or diarrhoea) and haematological toxicities. Anti-EGFR drugs are well known to provide dermatological toxicity (papulopustular rash, xerosis, desquamation, pruritus, hair change, paronychia). Skin toxicity can have a severe impact on patients’ physical, psychological and social well-being and can lead to treatment discontinuation, dose reduction and complications. Appropriate prophylaxis and therapeutic interventions should therefore be proposed to all patients treated with cetuximab or panitumumab [51]. In the CORRECT study, 54% of patients had grade 3/4 toxicities related to regorafenib. Most frequent grade 3/4 adverse effects included hand-foot skin reaction (17%), fatigue (10%), diarrhoea (7%), hypertension (7%) [44]. Anti-VEGF agents can lead to cardiovascular events such as hypertension, myocardial infarction, venous and arterial thrombosis, and pulmonary embolism. Proteinuria should also be monitored during anti-VEGF treatment. Comprehensive information should be given to the patients, and the treatment should be adapted to the patient’s comorbidities. 2.8. Intra-arterial therapies for hepatic metastasis without extrahepatic disease The liver is the most common site for colorectal cancer metastases. About 30% of patients with TNM stage III develop hepatic metastases [52]. Normal liver vascularization is supplied 70% by the portal vein and 30% by hepatic arteries, while tumour lesions are mainly supplied by hepatic arteries. Thus, intra-arterial therapies were investigated, aimed at delivering therapeutic agents directly into the liver and concentrating the drugs in the tumours. Different intra-arterial therapies have been developed.

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2.9. Transarterial chemoembolization Transarterial chemoembolization (TACE) is a procedure aimed at delivering a high dose of chemotherapy directly into the liver, through the arteries supplying the lesions. The chemotherapy is associated with a blockage of arterial blood supply with an embolic agent. The most common procedure consists of the injection of a chemotherapy agent emulsified with lipiodol, followed by the injection of the embolic agent. More recently, drug eluting beads (DEB) loaded with chemotherapy agents have been investigated. This technique has been largely developed for the treatment of hepatocellular carcinoma because they are hypervascularized tumours. Few published studies evaluated TACE for metastatic colorectal cancer beyond the second-line treatment. Only one randomized study has been included in a Cochrane review investigating the impact of TACE in liver metastases [53]. This study included 22 patients with colorectal liver metastases treated with TACE and 20 treated with best supportive care. There has been no significant difference in the median survival of the two groups (7.0 months in the TACE arm versus 7.9 months in the control arm). However, few patients have been included, and most patients had tumours involving more than 75% percent of the liver [54]. In a recent large study, 121 patients were treated by chemoembolization with mitomycin C, doxorubicin and cisplatin, emulsified in ethiodized oil. Forty-six percent of patients previously received two or more lines of chemotherapy. Patients received a median of 2 procedures. There was a 2% response rate and a 41% stable disease rate. Median survival from chemoembolization was 9 months. Median survival for patients previously treated by 0–1, 2, or more than 2 was 12, 11 and 6 months respectively [55]. Another recently published study included 55 patients refractory to chemotherapy and targeted therapies, the majority having failed to respond to 5FU, irinotecan, oxaliplatin, bevacizumab and anti-EGFR drugs. Patients were treated with a median of 2 sessions of TACE with irinotecan-preloaded DEB (DEBIRI). The median progression-free survival was 11 months, the overall survival 19 months, and the response rate was 75% at 12 months [56]. In another prospective study, 85 patients were included to receive a DEBIRI therapy after one or two lines of chemotherapy. Fifty patients had received two lines of chemotherapy. Patients received a median of 2.2 (range 1 to 4) procedures. The response rate was 78% at 3 months. The median progression-free survival was 8 months and the median overall survival was 25 months [57]. 2.10. Hepatic artery infusion Hepatic artery infusion (HAI) consists of a direct administration of chemotherapy, through a catheter placed in the hepatic artery. Port-catheters can be surgically implanted, or percutaneously, most commonly through the femoral artery. The catheter tip can be placed in the gastroduodenal artery and the gastroduodenal artery is then embolized. The catheter is perforated with a side hole placed to enable infusion into the hepatic artery (Fig. 1A). To prevent extrahepatic infusion, the right gastric artery and other accessory branches to extrahepatic destinations are embolized. The catheter is connected to a subcutaneous port to allow easy access and repeated administrations (Fig. 1B). By using the transarterial route of administration, a more than 10-fold increase in drug concentration within the liver can be achieved, compared with that achieved through the intravenous route, with limited systemic side effects [58]. Floxuridine, 5-fluorodeoxyuridine, oxaliplatin and mitomycin-C are commonly used. A clinical study evaluating HAI in third-line therapy was recently published. Forty-four patients who had previously received a median of 2 therapies, were included, and 28 patients (63%) had received both oxaliplatin and irinotecan. There were treated by HAI of oxaliplatin (100 mg/m2 over 2 h),

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Fig. 1. Implantation of an intrahepatic catheter for hepatic artery infusions. (A) The catheter tip is placed in the gastro-duodenal artery with coils around it. The side hole is located in the common hepatic artery for the perfusion. (a) Diagram. (b) Routine follow-up angiography performed with contrast medium injected through an arterial port catheter. (B) Femoral implantation of an arterial port catheter. Courtesy of Dr Frédéric Deschamps, Institut Gustave Roussy, Villejuif, France.

combined with intravenous leucovorin and 5 fluorouracil (LV5FU2 regimen), every 2 weeks. Median progression-free survival and overall survival were 7 and 16 months respectively. Twelve of the 28 patients refractory to both oxaliplatin and irinotecan obtained a partial response (43%) [59]. There is no controlled trial in third-line therapy or beyond evaluating HAI. 2.11. Radioembolization The radioembolization procedure is quite similar to that of chemoembolization, but the delivery device is a radioactive particle, and for hepatic metastases of colorectal cancer, this radioactive particle is microspheres of yttrium 90, a radioisotope with a halflife of 64.1 h, pure emitter of ␤ particles with an average energy of 0.94 MeV and a mean path in tissue of 2.5 mm. The microspheres are too big to pass through to the venous circulation, but can preferentially reach the tumours vascularised by the arterial system [60]. A preliminary angiogram must be performed to determine the arterial supply of the liver. The gastroduodenal artery, the right gastric artery and any extra-hepatic branch originating from the hepatic artery must be embolized with coils to prevent yttrium 90 from refluxing to the stomach and duodenum. The main side effect reported is gastrointestinal ulcer, mainly due to unrecognized arteries supplying the gastrointestinal tract. In a study published in 2009 on radioembolization with yttrium 90, 28 of the 72 patients included had received the three major chemotherapy agents (5-fluorouracil, irinotecan and oxaliplatin) before the radioembolization. Most of them had liver-confined disease. There was a 40.3% response rate and a 14.5-month overall survival, with acceptable toxicities [61]. Another trial evaluated retrospectively

41 patients with colorectal liver metastases. Four of them had other metastatic involvement. They had all previously received and failed with standard first-line FOLFOX, second-line FOLFIRI and third-line chemotherapies. Nineteen patients (46.3%) had a response (2 had a complete response and 17 had a partial response), the median progression-free survival was 9.2 months and the median survival time was 11.6 months. One patient had grade 4 hepatic failure, probably due to radiation-induced hepatitis [62]. Some studies compared radioembolization with other treatments in patients previously treated with chemotherapy. As a salvage treatment for liver-dominant colorectal metastatic adenocarcinoma, no difference was observed between chemoembolization with cisplatin, doxorubicin and mitomycin C and radioembolization, as median survival was 7.7 months and 6.9 months respectively (P = 0.27). These results were obtained in a case-controlled study including 36 patients who had progressed after previous lines of systemic chemotherapy that included the FOLFOX regimen, the FOLFIRI regimen, capecitabine, bevacizumab and cetuximab [63]. In a phase III prospective multicenter randomized trial, intravenous fluorouracil alone was compared with the combination of radioembolization plus intravenous fluorouracil, in 46 patients with liver-limited metastatic colorectal cancer, refractory to standard chemotherapy (FU, oxaliplatin and irinotecan). The overall response rate was low (9.5% in the combined therapy group versus 0% in the 5FU group), but the median time to progression was statistically longer in the group that received radioembolization (4.5 months versus 2.1 months in the 5FU alone group, HR = 0.51; 95% CI 0.28 to 0.94; P = 0.03). There was no significant difference in median overall survival between the treatment arms, likely because crossover was permitted and 70% of patients in the FU-only arm received


further therapy, including radioembolization [64]. Radioembolization should be considered a palliative option for the treatment of metastatic colorectal cancer, but for selected patients with liverlimited metastases. However, the technique is limited to only a few centres. Further controlled trials are needed to determine if this therapy should be used earlier in first- or second-line treatment. 3. Conclusion Patients with unresectable metastatic colorectal cancers can be candidates for multiple lines of therapy. Even in previously heavily treated patients, different options should be considered. In patients with KRAS wild-type tumours, anti-EGFR must be considered. The impact of panitumumab in patients pretreated with cetuximab should be further investigated. Chemotherapy can still be an option. If the patient has not already received all major chemotherapy agents, the never-used agent should be considered. Moreover, a drug previously used with a good response could be reintroduced. Regorafenib, a multi-kinase inhibitor, has recently been approved by the US FDA and is now standard in patients who have failed all other standard therapies. In the case of hepatic metastasis, intra-arterial therapies should be discussed. Promising results have been reported with transarterial chemoembolization, hepatic artery infusion and radioembolization, but these techniques, especially HAI and radioembolization, are limited to a few expert centres only, and larger trials should support their interest. Different lines of intra-arterial therapy could be considered, and the best sequences should be identified. Patients able and willing to receive further therapy should first be considered for inclusion in clinical trials. Nevertheless, many options can be discussed. The choice of a treatment depends on previously used therapies, on the patient and on the tumour biology. A multiline strategy based on both the patient and the cancer should be anticipated. Strategic trials are urgently needed to determine the best therapeutic sequences. Acknowledgements We would like to thank Professor Jean-Yves Douillard (Institut de Cancérologie de l’Ouest, Saint-Herblain, France) for his critical review of the manuscript. References [1] Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA: A Cancer Journal for Clinicians 2005;55:74–108. [2] Van Cutsem E, Nordlinger B, Cervantes A. Advanced colorectal cancer: ESMO Clinical Practice Guidelines for treatment. Annals of Oncology 2010;21(Suppl. 5):v93–7. [3] Falcone A, Ricci S, Brunetti I, et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. Journal of Clinical Oncology 2007;25:1670–6. [4] Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. New England Journal of Medicine 2004;350:2335–42. [5] Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. Journal of Clinical Oncology 2007;25:4779–86. [6] Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. Journal of Clinical Oncology 2007;25:1539–44. [7] Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. Journal of Clinical Oncology 2010;28:4697–705.

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