Elsevier

European Journal of Cancer

Volume 109, March 2019, Pages 70-83
European Journal of Cancer

Review
Treatment sequencing in metastatic colorectal cancer

https://doi.org/10.1016/j.ejca.2018.12.019Get rights and content

Highlights

  • Optimal sequencing of cytotoxic/targeted agents in metastatic colorectal cancer remains unclear.

  • First-line choice of therapy is critical as it affects treatment decisions in later lines.

  • Molecular profiling has established new targets that may impact sequencing.

  • Recent knowledge of tumour evolution also has clinical implications for sequencing.

Abstract

Metastatic colorectal cancer (mCRC) remains incurable in most cases, but survival has improved with advances in cytotoxic chemotherapy and targeted agents. However, the optimal use and sequencing of these agents across multiple lines of treatment is unclear. Here, we review current treatment approaches and optimal treatment sequencing across the first-, second- and third-line settings in mCRC, including biological aspects affecting sequencing and rechallenge. Effective first-line therapy is a key determinant of treatment outcomes and should be selected after considering both clinical factors and biological markers, notably RAS and BRAF. The second-line regimen choice depends on the systemic therapies given in first-line. Anti-angiogenic agents (e.g. bevacizumab, ramucirumab and aflibercept) are indicated for most patients, whereas epidermal growth factor receptor (EGFR) inhibitors do not improve survival in the second-line setting. Molecular profiling is important in third-line treatment, with options in RAS wild-type patients including EGFR inhibitors (cetuximab or panitumumab), regorafenib and trifluridine/tipiracil. Immunotherapy with pembrolizumab or nivolumab ± ipilimumab may be considered for patients with high microsatellite instability disease. Targeting HER2/neu amplification shows promise for the subset of CRC tumours displaying this abnormality. Sequencing decisions are complicated by the potential for any treatment break or de-escalation to evoke a distinct clinical progression type. Ongoing trials are investigating the optimal sequencing and timing of therapies for mCRC. Molecular profiling has established new targets, and increasing knowledge of tumour evolution under drug pressure will possibly impact on sequencing.

Introduction

Colorectal cancer (CRC) is one of the most commonly diagnosed tumours worldwide and a leading cause of cancer death [1]. Recent advances in therapy and multidisciplinary care have led to significant improvements in survival, but a cure is not possible for most patients with metastatic CRC (mCRC). A major challenge has been the finding that anti-epidermal growth factor receptor (EGFR) antibodies are rendered ineffective by alterations in RAS genes (KRAS/NRAS exons 2–4) [2], [3], [4]. This is particularly important given that ∼50% of colorectal tumours are known to have a mutated RAS gene [5], and this patient population has benefitted significantly less from improvements in treatment. Current options for mCRC include cytotoxic chemotherapy and targeted therapies across multiple lines of treatment [6]. However, the optimal use and sequencing of these agents has yet to be determined [7]. Despite favourable outcomes reported from first-line trials [4], [8], the effect on survival of continuing therapy beyond the specified study treatment remains uncertain and can only be estimated from trials of second-line and subsequent therapy.

In this review, we discuss current treatment approaches in the first-, second- and third-line settings in mCRC, together with recent developments in treatment sequencing across multiple lines of treatment, and their future implications.

Section snippets

Treatment lines and treatment efficacy

First-line therapy is the key determinant of successful systemic treatment in mCRC, because it has the longest treatment duration, is the most effective in terms of response and progression-free survival and is the only line of therapy that all treated patients are sure to receive (Table 1) [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]. For the majority of patients, effective first-line therapy is therefore crucial, whereas subsequent therapy addresses only a subset of

First-line treatment

Multiple factors influence the choice of first-line treatment in mCRC, including both clinical factors and molecular markers.

Second-line treatment

Typical second-line chemotherapy options for mCRC patients include fluorouracil, folinic acid and irinotecan (FOLFIRI) and fluorouracil, folinic acid and oxaliplatin (FOLFOX) [22], [23], depending on the systemic therapies given in the first-line setting [36]. The choice of first-line therapy initiates the treatment sequence, leading to algorithms based on varying levels of clinical evidence, as shown in Box 1.

Whereas the chemotherapy sequence of FOLFOX then FOLFIRI or vice versa does not seem

Role of molecular subgroups in second-line therapy

As discussed above, second-line therapy may be considered the least attractive setting for EGFR-targeted agents based on the available evidence from first-line and later-line trials. Consequently, it is questionable whether the corresponding biomarker (i.e. RAS status) has an impact on the choice of second-line therapies [9], [14], [39], [40], [41], [45], [48], [49], [50], [51].

While it is generally assumed that VEGF-targeted agents, which significantly improve overall survival in second-line

Third-line treatment and beyond

For patients receiving third-line CRC treatment, molecular profiling of the cancer and consideration of clinical trial enrolment are important aspects of management [23]. According to ESMO guidelines, cetuximab or panitumumab should be considered in RAS wild-type and BRAF wild-type patients not previously treated with EGFR antibodies [22]. Either regorafenib or the antimetabolite trifluridine/tipiracil (TAS-102) is recommended in patients previously treated with fluoropyrimidines, oxaliplatin,

Clinical understanding of sequencing and timing of therapies

The optimal sequencing of therapy centres on first-line decisions, as all other lines and combinations depend on the choice of up-front treatment. In patients with untreated mCRC, therapeutic goals may range from cure to palliation. The choice of first-line therapy therefore takes into account both the treatment goal and the molecular subtype of the tumour [22]. In this context, the sequence of systemic treatment is of particular importance both in patients with secondary resection of

Transition from first- to second-line treatment

Preclinical data have provided insight on how VEGF- and EGFR-targeted therapeutics can modulate the cancer environment and thus impact the optimal sequencing of these agents, while clinical trials have established that concomitant administration of VEGF and EGFR inhibitors increases toxicity with no improvement in survival [84]. For the transition from first- to second-line treatment, it is well established that bevacizumab exposure in CRC is associated with an increase in serum levels of

Future perspectives

For the transition from first-line to second-line treatment, most preclinical evidence concerning the interaction between VEGF and EGFR pathways upon pharmacological inhibition indicates a reduced activity of EGFR-targeting antibodies following exposure to bevacizumab [107], whereas the reverse strategy may lead to favourable outcomes [44]. On the other hand, for patients starting with chemotherapy in combination with bevacizumab, using VEGF-targeted agents beyond and after progression is an

Conclusions

Upfront testing of molecular markers (RAS/BRAF) plus consideration of primary tumour locations enables personalised medicine in the first-line therapy of mCRC. In contrast, molecular markers currently do not impact significantly on the choice of second-line therapy, for which the available evidence suggests that VEGF-targeted agents provide a significant survival benefit and are suitable options, irrespective of molecular subtype and pre-treatment. Third-line therapies in mCRC are associated

Conflict of interest statement

D.P.M. has had advisory roles with and/or honoraria from Amgen, Merck, Roche, Bristol-Myers Squibb, Sirtex, Merck Sharp & Dohme, Servier, Pfizer, Boehringer-Ingelheim, Taiho, travel support from Amgen, Roche, Merck, Bristol-Myers Squibb, Servier, Taiho and research grant from Amgen, Merck, Roche. S.P. has nothing to disclose. A.S.-B. is a member of advisory boards for Amgen, Bayer and Sanofi. GI connect is supported by an Independent Educational Grant from Bayer.

Acknowledgements

This review article was written on behalf of GI CONNECT; for more information visit www.giconnect.info. Editorial support was provided by Mark English and Rachael Pepperle of COR2Ed.

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