Clinical, laboratory and molecular factors predicting chemotherapy efficacy and toxicity in colorectal cancer

https://doi.org/10.1016/j.critrevonc.2010.07.012Get rights and content

Abstract

Colorectal cancer (CRC) treatment has evolved significantly over the last ten years with the use of active chemotherapeutic agents including fluoropyrimidines, oxaliplatin and irinotecan plus targeted monoclonal antibodies bevacizumab, cetuximab and panitumumab. The addition of newer chemotherapeutic agents and targeted therapies has improved patient outcomes at the cost of increased toxicity with not all patients benefiting from these treatments. It is necessary for clinicians to more accurately predict clinical outcomes particularly in the predominantly elderly CRC patient population. This review aims to summarise existing data regarding the use of clinical and laboratory variables plus molecular markers in predicting response, survival and toxicity to chemotherapy agents and targeted monoclonal antibodies currently used in the treatment of CRC.

Introduction

Treatment for patients with colorectal cancer (CRC) has evolved significantly over the last ten years with the use of active chemotherapeutic agents including fluoropyrimidines, oxaliplatin and irinotecan plus targeted monoclonal antibodies bevacizumab, cetuximab and panitumumab. Significant advances in the treatment of patients with locally advanced cancer with the addition of oxaliplatin to fluoropyrimidines has also improved patient outcomes and there is ongoing investigation of newer agents such as targeted monoclonal antibodies for treatment of stages II and III CRC.

The addition of newer chemotherapeutic agents has resulted in increased toxicity, and not all patients will benefit from these treatments creating the need for improved ability to accurately predict clinical outcomes, particularly in the predominantly elderly CRC patient population. Ultimately, advances in the knowledge of molecular medicine, in addition to risk algorithms based on clinical and laboratory indices may guide clinicians towards selecting the best treatment for individual patients. Examples of these include emerging evidence regarding resistance of patients with KRAS mutations to anti-EGFR therapy such as cetuximab and panitumumab. ‘Personalised’ treatment for individual patients will require knowledge of such molecular markers using new techniques in combination with baseline clinical and laboratory variables which predict response, survival and toxicity to treatment for CRC. This applies to the approach to cancer treatment in both the adjuvant and metastatic settings.

This review aims to summarise existing data regarding the use of clinical and laboratory variables in predicting response, survival and toxicity to chemotherapy agents used in treatment of CRC including the fluoropyrimidines, oxaliplatin and irinotecan in addition to the targeted antibodies bevacizumab, cetuximab and panitumumab. The available evidence will be categorised according to baseline clinical and laboratory variables predictive of response, survival and toxicity followed by recent developments in our understanding of molecular influences on chemotherapy predictive factors.

Section snippets

Age

A pooled analysis from seven phase III randomised trials involving 3351 patients investigated the effects of postoperative 5-fluorouracil (5-FU) plus leucovorin or 5-FU plus levamisole compared with the effects of surgery alone in patients with stage II or III colon cancer [1]. Patients were analysed according to four 10-year age range categories of equal size (≤50, 51–60, 61–70, and >70 years) with similar benefits derived from adjuvant chemotherapy irrespective of age, suggesting that age

Baseline laboratory predictive variables

Various baseline laboratory parameters have been identified as potential prognostic and/or predictive factors in CRC. The most commonly examined variables can be categorised into (1) white cell and differential counts; (2) haemaglobin; (3) lactate dehydrogenase; (4) liver function tests (alkaline phophatase, albumin, bilirubin, transaminases); (5) tumour markers [carcinoembryonic antigen (CEA)] and (6) coagulation tests. More recently, scores or markers reflecting systemic inflammation such as

5-fluorouracil

Over the last few decades, 5-FU has remained a key component in the treatment of both early and mCRC. It is an anti-metabolite used either as a single agent or in combination with oxaliplatin and irinotecan. The main mechanism of action of 5-FU is via inhibition of thymidylate synthase (TS). TS is the main enzyme involved in de novo synthesis of nucleotides for DNA and FdUMP, the active metabolite of 5-FU inhibits TS by forming a covalent ternary complex with TS and methylenetetra-hydrofolate

Epidermal growth factor receptor (EGFR) inhibitors

The EGFR inhibitors cetuximab and panitumumab have been shown to improve PFS and OS in mCRC when used either alone or in combination with chemotherapy. Cetuximab (a chimeric anti-EGFR monoclonal antibody) has been shown to be effective in both first-line [164], [165] and chemotherapy refractory settings [166], [167] while panitumumab (a fully humanised monoclonal antibody) has demonstrated efficacy in the chemotherapy-refractory setting [168] with preliminary results reported in the first-line

Conclusion

Significant advances in CRC drug development over the last few decades has not been paralleled with similar advances in clinically useful biomarkers for treatment selection. KRAS mutational analysis and use of EGFR monoclonal antibodies is the exception to this and has thus far, been the only useful biomarker proven from retrospective tumour tissue analysis from prospective RCTs. Divergent and inconsistent results for the use of various molecular markers from multiple retrospective studies have

Reviewers

Dr. Michael Michael, Peter MacCallum Cancer Centre, Division of Hematology & Medical Oncology, St Andrews Place, East Melbourne, Victoria 3002, Australia.

Dr. Daniela E. Aust, University Hospital Carl Gustav Carus, University of Technology Dresden, Institute of Pathology, Fetscherstr. 74, D-01307 Dresden, Germany.

Conflicts of interest

None.

Acknowledgements

Wei Chua was supported by NSW Cancer Institute (Australia) Clinical Fellowship and Maple-Brown Scholarship and recipient of a Pfizer Cancer Research Study Grant. Melissa M Moore is a National Health and Medical Research Council (NHMRC) Medical Postgraduate Scholar and recipient of a GlaxoSmithKline (GSK) Postgraduate Support Grant.

Stephen J Clarke is a medical oncologist and clinical pharmacologist and is currently professor and Head of the Discipline of Medicine at the Concord Hospital Clinical School of Sydney Medical School. He obtained his medical degree from Sydney University in 1983 and then undertook specialty training in medical oncology. He completed a PhD at the Royal Marsden Cancer Hospital and the Institute of Cancer Research in Sutton, Surrey, UK, and returned to Australia in 1994. He has clinical

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    Stephen J Clarke is a medical oncologist and clinical pharmacologist and is currently professor and Head of the Discipline of Medicine at the Concord Hospital Clinical School of Sydney Medical School. He obtained his medical degree from Sydney University in 1983 and then undertook specialty training in medical oncology. He completed a PhD at the Royal Marsden Cancer Hospital and the Institute of Cancer Research in Sutton, Surrey, UK, and returned to Australia in 1994. He has clinical appointments as a Senior Staff Specialist in Medical Oncology at the Sydney Cancer Centre. He has clinical and translational research interests in mesothelioma, and colorectal and lung cancer and has over 150 publications.

    Wei Chua is a medical oncologist and currently a PhD candidate at the University of Sydney investigating predictive markers in colorectal cancer with a particular interest in inflammation. Her main clinical interests are translational research, gastrointestinal and gynaecological malignancies.

    Patricia S Kho is a medical oncologist who is currently pursuing a Masters of Philosophy (Medicine) at the University of Sydney. Her thesis is focusing on optimising adjuvant treatment for colorectal cancer. Her main interests are in translational research and breast, thoracic and gastrointestinal oncology.

    Melissa M Moore is a medical oncologist who is currently undertaking studies towards a Doctor of Philosophy at the University of Sydney. Her main clinical interests include the treatment of gastrointestinal and genitourinary cancers.

    Kellie A Charles graduated with a Bachelor of Science (First class honours) and a PhD in cancer pharmacology from the University of Sydney. Dr Charles’ research interests are to understand the role of inflammation in tumour progression and chemotherapeutic drug response. Her aim is to translate further investigations of novel, pharmacological anti-inflammatory strategies as potential cancer treatments. She is the author of 23 peer-reviewed publications (H index 14, >600 citations), holds three competitive grants and has received numerous prizes.

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