NE Oncology Issue – November 2006

Colorectal cancer (CRC) continues to be a leading cause of cancer morbidity and mortality worldwide. Over the last 50 years, the treatment of metastatic colorectal cancer (mCRC) has consisted of 5-fluorouracil (5-FU) -based chemotherapy. In the past decade, treatment options for patients with colorectal cancer have increased with the advent of newer combination chemotherapy regimes (Figure 1). New molecular targets have provided novel opportunities in the treatment of mCRC (Table 1). One of the most advanced approaches to date is the use of targeted inhibitors of the epidermal growth factor receptor (EGFR).

At ESMO this year, there were numerous oral and poster sessions that provided the latest data on therapeutic strategies in the treatment of colorectal cancer, with particular interest and excitement surrounding the latest data for the monoclonal antibodies (MAbs) cetuximab, panitumumab, and bevacizumab. The overall conclusion of experts attending the meeting was that despite these clinical advances, new strategies are warranted in order to improve the efficacy as well as the safety of new therapies.

XELOX as Effective as FOLFOX as First-Line Therapy in mCRC

According to phase 3 results presented by Dr. Jim Cassidy during the Presidential Symposium at ESMO 2006, the chemotherapy combination XELOX (oral Xeloda® plus oxaliplatin) is as effective as FOLFOX (oxaliplatin, 5-FU, leucovorin) as first-line therapy for mCRC.1 The primary objective of the original two-arm study was to show non-inferiority of XELOX compared with FOLFOX. By February 2004, 634 patients had been enrolled. At this point in time, the investigators altered the protocol to a 2x2 and added bevacizumab to a random subset versus placebo, and enrolled a further 1,401 patients. At a median follow-up of 18.6 months, progression-free survival (PFS) was 8.0 months for XELOX and 8.5 months for FOLFOX.

Furthermore, the addition of bevacizumab to either treatment regimen provided a small but significant improvement in PFS among these patients compared to chemotherapy alone. When both regimens are considered together, those patients who were given bevacizumab had a PFS of 9.4 months versus 8.0 months with placebo (P=0.0023).

Cetuximab and Panitumumab: Targeted Therapies for Metastatic Colorectal Cancer

The epidermal growth factor receptor was one of the first proto-oncogenes recognized. It is a member of the erbB (or HER) family of genes. In the normal mammalian cell, EGFR is important in the control of cellular growth and differentiation. EGFR knockout in mice is essentially a lethal mutation. In the malignant cell, EGFR and its downstream effects have been shown to control cell cycle control, apoptosis, angiogenesis, invasion, and metastasis.2 EGFR is not just a proliferative signal but one of many components of the apparatus that a normal or malignant cell uses to decide whether to survive (or undergo apoptosis/cell death). Perturbation of EGFR leads to a strong survival signal whereas blockade of EGFR should decrease the impetus to survive in the face of cell damage induced by insults such as chemotherapy and radiation.

It has been demonstrated that EGFR expression is associated with many epithelial tumours, in particular 25–77% of colorectal cancers (all stages).3 In many of these tumours there is evidence from small series that EGFR or ligand over-expression is an adverse prognostic factor for tumour metastasis, recurrence, and overall survival. At least one study suggests there is no correlation between the level of EGFR expression and clinical response to EGFR targeting therapies in patients with CRC, so it is unlikely that it could be used to select patients for treatment with EGFR inhibitors.4

Clinical trials have been conducted on selected tumours to assess the potential benefits of EGFR inhibitors alone or in combination with chemotherapy, radiotherapy, or other hormonal/targeted agents. There have been two strategies for the development of anti-EGFR agents: MAbs to the extra-cellular domain of EGFR (cetuximab [chimeric], matuzumab [humanized], and panitumumab [human]) and small molecule, adenosine triphosphate – competitive inhibitors of the receptor’s tyrosine kinase (gefitinib and erlotinib).

Cetuximab

Cetuximab (Erbitux®) is a human-chimeric monoclonal antibody of the immunoglobulin G1 (IgG1) subtype. It binds the extra-cellular domain of EGFR to inhibit binding of its ligands such as EGF and TGF-alfa. In vitro, cetuximab has been associated with cell-cycle arrest (at G1 to S transition) and enhanced apoptosis. Synergy and additive cytotoxicity have been demonstrated with radiation and cytotoxics including platinum therapy, gemcitabine, taxanes, and camptothecins; therefore, it seemed logical to develop it as a combination therapy. Cetuximab has been evaluated both alone and in combination with radiotherapy and various cytotoxic chemotherapeutic agents in a series of phase 2/3 trials that studied primarily treated patients with either head and neck cancer or CRC.2 Cetuximab has been shown to re-sensitize tumours to chemotherapy in patients with colorectal cancer receiving irinotecan (the BOND trial).4 In EGFR-positive patients with irinotecan-refractory mCRC, cetuximab alone had minimal activity (10.8% response rate [RR]); however, when combined with irinotecan it had a 22% RR (P=0.007) and modestly increased progression-free and overall survival. It was this study that prompted the Food and Drug Administration (FDA) to approve it in February 2004 for use in the treatment of mCRC. Health Canada issued a Notice of Compliance for cetuximab in mCRC on September 9, 2005.

Panitumumab

Panitumumab (Vectibix™) is a recombinant fully human IgG2 MAb which binds specifically to the EGFR and competitively inhibits the binding of ligands to this receptor. Panitumumab differs from cetuximab in that it has a higher affinity for the receptor and it produces fewer hypersensitivity reactions.5 The compound was shown to be active in a phase 2 study in advanced colorectal cancer. In this study, 15 (10%) of 148 patients that had experienced failure with first-line chemotherapy achieved a clinical response to panitumumab.6 The safety and efficacy of the agent was further evaluated in a phase 3 randomized controlled trial of 463 patients who were EGFR-positive and had mCRC or metastatic rectal cancer.7 Patients were randomly assigned to receive panitumumab plus best supportive care or best supportive care alone (BSC) until disease progression. Panitumumab treat-ment resulted in a significant prolongation in PFS (96 days) compared to BSC alone (60 days). Based on the results, panitumumab became the second EGFR inhibitor approved by the FDA for the treatment of mCRC in September, 2006 (Table 1).

Safety of Anti-EGFR MAbs

Toxicity has been a major obstacle in the development of therapeutic antibodies for cancer. Cross-reactivity with normal tissues can cause significant side effects for unconjugated (naked) antibodies. In particular, skin toxicity is a problem facing the EGFR inhibitors in CRC (Table 2). An acneiform rash commonly occurs on the face and trunk in a majority of patients.4–7 In addition, hypersensitivity reactions have been reported for both agents, though they are more common with cetuximab. Severe infusion reactions occur in approximately 2–3% of patients treated with cetuximab, usually with the first infusion and requiring immediate discontinuation of treatment.4 In the pivotal trial of panitumumab, severe infusion reactions occurred in only 1% of patients.7

As presented at ESMO, Hecht et al.8 reviewed the safety and tolerability data of ten clinical studies of panitumumab monotherapy for mCRC in enrolled patients after failure of oxaliplatin and/or irinotecan chemotherapy. They found that panitumumab was generally well tolerated, and while most patients (93%) had at least one adverse event considered related to panitumumab, only 22% reported an adverse event of Grade 3 or higher (Table 3). As expected, the most common adverse events were rash, fatigue, nausea, diarrhea and vomiting. Grade 3 or higher hypomagnesemia was reported in 5% of patients.

Interestingly, in the pivotal trial for cetuximab, there appeared to be a higher response rate among patients who experienced a skin rash.4 This finding has led to the suggestion that there may be a physiologic correlation between the onset of skin toxicity and adequate EGFR response. In a late-breaking abstracts session at ESMO, Dr. Eric van Cutsem presented the interim results of the EVEREST trial, a small (n=166) randomized, multicentre study that is evaluating this hypothesis using a “escalating dose-to-rash” strategy.9 Patients with EGFR-expressing mCRC failing prior irinotecan treatment were initially treated with cetuximab (initial dose 400 mg/m2, then 250 mg/m2/week) plus irinotecan (2-weekly regimen 180 mg/m2). After 22 days of treatment, patients with mild to absent rash were randomized to one of two arms: continuation on standard dose (Arm A) or dose escalation (Arm B; dose increases of 50 mg/kg every week) until development of more severe rash, tumour response or dose =500 mg/m2. Patients who had already demonstrated a severe rash on the standard dose were excluded from the dose-escalation arm (Arm C). The results of skin and tumour biopsies taken before and after treatment suggest that patients who received the dose increases (Arm B) developed more severe rashes and demonstrated an increase in response rate that was similar to the response rate in the severe skin rash group (Arm C) (Table 4). Doses up to 500 mg were well tolerated. Van Cutsem cautioned against over-interpretation of the premature phase 2 data as the results have yet to reach statistical significance.

How do they compare?

In his discussion of the targeted therapy data presented at ESMO, Dr. Alberto Sobrero suggested that at the present time there is little difference in the rationale for using either anti-EGFR MAb therapy. In regimens tested thus far, both cetuximab and panitumumab result in slight increases in the time to progression and the response rate. In terms of monotherapy, response rates of about 10–15%, stable disease rates of about 20–30%, and progression-free survival improvements of two to three months are consistent among studies of either agent (Table 5).

In his discussion of the targeted therapy data presented at ESMO, Dr. Alberto Sobrero suggested that at the present time there is little difference in the rationale for using either anti-EGFR MAb therapy. In regimens tested thus far, both cetuximab and panitumumab result in slight increases in the time to progression and the response rate. In terms of monotherapy, response rates of about 10–15%, stable disease rates of about 20–30%, and progression-free survival improvements of two to three months are consistent among studies of either agent (Table 5).

References: 1. Aapro MS et al.; for the EORTC G-CSF Task Force. European organisation for research and treatment of cancer (EORTC) guidelines and hematopoietic support. Ann Oncol 2006;17(Suppl 9):ix51. Abstract 77IN. 2. Aapro MS et al. EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours. Eur J Cancer 2006;42(15):2433–53. 3. Smith TJ et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006; 24(19):3187-205. 4. von Minckwitz G et al. Primary prophylaxis with 3-weekly pegfilgrastim and ciprofloxacin effectively prevent (febrile) neutropenia and infection during neoadjuvant chemotherapy with docetaxel/doxorubicin/cyclophosphamide in breast cancer patients. J Clin Oncol 2005;23:731S. Abstract 8008. 5. López-Pousa A et al. Risk assessment model for first-cycle chemotherapy-induced neutropenia (CIN) in patients with solid tumours (ST). On behalf of the DELFOS Study group. Ann Oncol 2006;17(Suppl 9):ix286. Abstract 990O. 6. López-Pousa A et al. Risk assessment model for first-cycle chemotherapy-induced neutropenia (CIN) among breast cancer patients. On behalf of the DELFOS Study group. Ann Oncol 2006;17(Suppl 9):ix296. Abstract 1028P. 7. Rizzo JD, Lichtin AE, Woolf SH et al.; American Society of Clinical Oncology. American Society of Hematology. Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol 2002; 20(19):4083–107. 8. Canon JL et al. Randomized, double-blind, active-controlled trial of every-3-week darbepoetin alfa for the treatment of chemotherapy-induced anemia. J Natl Cancer Inst 2006;98(4):273–84. 9. Schwartzberg L et al. A randomized, controlled, noninferiority study to assess the impact of once per cycle correction and maintenance dosing of darbepoetin alfa (DA) in patients (pts) with nonmyeloid malignancies with chemotherapy induced anemia (CIA). Ann Oncol 2006;17(Suppl 9):ix292. Abstract 1012P. 10. Cavill I et al. Iron and the anemia of chronic disease: a review and strategic recommendations. Curr Med Res Opin 2006; 22:731–37. 11. Bastit L et al. Darbepoetin alfa (DA) every 3 weeks (q3w) +/– parenteral iron in patients (pts) with chemotherapy-induced anaemia (CIA). Ann Oncol 2006;17(Suppl 9):ix293. Abstract 1015P.12. Worthington HV et al. Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev 2006;(2):CD000978. 13. Sorensen J et al. Prophylaxis of chemotherapy-induced oral mucositis: double blind placebo-controlled randomized study of chlorhexidine versus placebo and with nonblinded randomized comparison to oral cooling (cryotherapy). Ann Oncol 2006;17(Suppl 9):ix286. Abstract 988O. 14. Fabian CJ et al. Pyridoxine therapy for palmar-plantar erythrodysesthesia associated with continuous 5-fluorouracil infusion. Invest New Drugs 1990;8:57–63.15. Kang Y-K et al. Pyridoxine is not effective for the prevention of capecitabine-induced hand foot syndrome (HFS): results of a randomized double-blind placebo-controlled study. Ann Oncol 2006;17(Suppl 9):ix286. Abstract 991O.

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Contributors

dr.lemonde
Manon Lemonde, MB
Associate Professor, Faculty of Health Sciences, University of Ontario Institute of Technology (UOIT
Dr. Manon Lemonde received her PhD in biomedical sciences from the Université of Montréal. She has many publications related to symptom management and social support. She has presented at oncology conferences and was also instrumental in developing workshops on fatigue in cancer. Dr. Lemonde’s oncology research interests are related to quality of life, human health resources planning in terms of recruitment and retention, and work environment.

dr-ellis
Peter Ellis, MBBS, MMed (Clin Epi), PhD, FRACP
Associate Professor in the Departments of Medicine and Clinical Epidemiology & Biostatistics, McMaster University
Chair of the Juravinski Cancer Centre Lung Disease Site Team
Executive Member of the National Cancer Institute of Canada (NCIC) Clinical Trials Group Lung Disease Site Committee Dr. Peter Ellis is a staff medical oncologist at the Juravinski Cancer Centre (JCC). He is a member of Cancer Care Ontario’s Practice Guideline Initiative, Provincial Lung Disease Site Group. He is also an investigator on several NCIC and pharmaceutical industry-sponsored multi-centre phase III clinical trials in breast and lung cancer. Dr. Ellis has a research interest in the role of the consumer in decision making, and is an investigator in several studies in this area. He is also co-principal investigator in a systematic review examining diffusion and dissemination of cancer control interventions.

dr-clemons
Mark Clemons, MB, BSc, MRCP(UK), MD
Associate Professor of Medicine and Oncology, McGill University Division of Hematology, McGill University Health Centre Head of Breast Medical Oncology, Princess Margaret Hospital
Assistant Professor, Department of Medicine, University of Toronto
Dr. Mark Clemons is a staff oncologist at the Princess Margaret Hospital, Toronto. He has published widely on the management of breast cancer, and has a research program evaluating the mechanisms of resistance and sensitivity to treatment for bone metastases and locally advanced breast cancer.

dr-cole
Dana Cole, BScPharm, ACPR, PharmD
Clinical Pharmacist and Pharmacy Residency Coordinator, Prince George Regional Hospital
Head of Breast Medical Oncology, Princess Margaret Hospital
Assistant Professor, Department of Pharmacology, University of Northern British Columbia
Clinical Assistant Professor, Faculty of Pharmaceutical Sciences, University of British Columbia
Dana Cole’s clinical interests are in supportive care, particularly anemia management, venous thromboembolism and palliative care. She has served as a reviewer for the professional development and assessment program, as a member of the advanced practitioner credentialing committee with the College of Pharmacists of BC, and as a member of the Canadian Association of Pharmacy in Oncology and the Canadian Society of Hospital Pharmacists.

dr-sehdev
Sandeep Sehdev, MD
Oncologist, William Osler Health Centre, Brampton
Dr. Sehdev is a community-focused medical oncologist at one of Canada’s largest community hospitals. He completed his fellowship at the Princess Margaret in Toronto in 1991, and his clinical practice treats most types of cancer. However, he has a keen interest in breast cancer, lung cancer, and patient education. Dr. Sehdev has been involved in breast cancer clinical trials through NCIC and BCIRG groups and has recently chaired several medical advisory board meetings on the role of hormonal therapy in breast cancer. In particular, Dr. Sehdev has been part of one of the largest and longest running breast cancer trials ever, the ATAC trial.