You are here

Best practices in the management of toxicities related to anti-EGFR agents for metastatic colorectal cancer

European Journal of Oncology Nursing, 4, 14, pages 337 - 349

Abstract

Purpose

To provide oncology nurses with an overview of the toxicity management associated with the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab in patients with metastatic colorectal cancer.

Methods

Monoclonal antibodies such as cetuximab and panitumumab that target EGFR have provided patients with metastatic colorectal cancer with effective treatment options. Both antibodies can be used as monotherapy; cetuximab is also approved for use in combination with chemotherapy. We reviewed the literature regarding the signs and symptoms, assessment of severity, and strategies available to prevent and manage adverse events associated with these agents.

Key results

This class of therapeutics is associated with an overall acceptable adverse event profile that is distinctly different from conventional chemotherapeutics. In contrast to cytotoxic chemotherapy, which causes myelosuppression, mucositis, and nausea and vomiting, common toxicities reported for anti-EGFR therapy include the more frequent cutaneous toxicities, electrolyte imbalances, and diarrhoea, as well as the less frequent ocular toxicities. Infusion reactions are also observed with the chimerical monoclonal antibody cetuximab.

Conclusions

Oncology nurses play a key role in the administration of multi-agent treatment regimens, especially with respect to the identification and management of toxicities, patient education, and patient support. By reducing the incidence and severity of the adverse events associated with anti-EGFR therapy, oncology nurses have the potential to sustain patient adherence to completion of treatment, identify signs and symptoms early, proactively manage adverse events, and provide appropriate treatment interventions, thereby improving patient quality of life.

Keywords: Toxicities, Anti-EGFR agents, Colorectal cancer, Panitumumab, Cetuximab, Infusion reactions, Dermatologic, Ocular, Hypomagnesaemia, Diarrhoea.

Introduction

Colorectal cancer is a leading cause of cancer death worldwide, with an estimated 20% of patients presenting with advanced disease at diagnosis ( Pohl et al., 2008 ). Historically, metastatic colorectal cancer (mCRC) has been treated with a combination regimen that includes a fluoropyrimidine plus leucovorin. More recently, either oxaliplatin or irinotecan has also been included (Douillard et al, 2000, Grothey et al, 2004, Saltz et al, 2000, and Tournigand et al, 2004). Recent advances in therapeutic interventions for mCRC include the addition of monoclonal antibodies to the combination chemotherapy regimen. Bevacizumab (Avastin, Genentech) is a monoclonal antibody that is directed against the vascular endothelial growth factor ligand. Cetuximab (Erbitux, ImClone Systems) and panitumumab (Vectibix, Amgen) are directed against the epidermal growth factor receptor (EGFR). All of these monoclonal antibodies have shown promising results for the treatment of mCRC when used as monotherapy or when added to standard chemotherapeutic regimens (Amado et al, 2008, Cunningham et al, 2004, Hurwitz et al, 2004, Karapetis et al, 2008, Saltz et al, 2004, and Van Cutsem et al, 2007).

This article focuses on the two monoclonal antibodies directed against EGFR, cetuximab and panitumumab, which have been approved for the treatment of refractory mCRC in Europe and the United States (Erbitux PI; Erbitux SmPC; Vectibix PI; Vectibix SmPC). Although both antibodies are directed against EGFR, cetuximab is a recombinant, chimeric antibody whereas panitumumab has a fully human structure. The European Medicines Agency and the United States Food and Drug Administration have approved both antibodies as monotherapy for the treatment of patients with EGFR-positive mCRC who have progressed after conventional oxaliplatin- and irinotecan-based chemotherapy. Cetuximab is also indicated for use in combination with chemotherapy. The approval of both products is limited to patients with an unmutated or wild-type copy of the Kirsten rat sarcoma-2 virus oncogene (KRAS).

Cetuximab and panitumumab exert their effects by binding specifically to EGFR on cancer cells (Wu et al, 2008, Zhang et al, 2006, and Zuckerman and Clark, 2008). Several normal cells of epithelial origin, such as the epidermis, hair follicles, sebaceous glands, mucosal tissues, and ocular tissues (cornea and conjunctiva) also produce high levels of EGFR (Melosky et al, 2009 and Segaert et al, 2009). When the antibodies block EGFR on the normal tissues, they cause unique and class-specific adverse events that are distinct from those commonly observed with conventional chemotherapeutics (Basti, 2007, Jean and Shah, 2008, and Segaert et al, 2009). Whereas cytotoxic chemotherapy regimens are associated with alopecia and haematological toxicities, such as myelosuppression, the common toxicities associated with cetuximab and panitumumab include the more frequently observed dermatologic reactions, diarrhoea, and hypomagnesaemia, as well as the less frequently observed ocular toxicities (Basti, 2007, Grothey, 2006, Lacouture et al, 2006, Melosky et al, 2009, and Segaert et al, 2009).

This article briefly describes the mechanisms of action and efficacy of anti-EGFR agents and provides a more detailed review of the most common toxicities associated with EGFR-based treatment regimens for mCRC, as well as the range of clinical and lifestyle modification options that are available to prevent or reduce the severity of these reactions.

Mechanisms of action and efficacy of anti-EGFR agents

The EGFR pathway is essential for normal organ development, contributing to cell proliferation, differentiation, apoptosis, and angiogenesis ( Jean and Shah, 2008 ). EGFR signalling activates a strong proliferative pathway that is strictly controlled in normal physiology. In tumour cells, however, EGFR signalling is uncontrolled, which results in tumour cell proliferation, invasion of surrounding normal tissues, and angiogenesis (Ciardiello and Tortora, 2008, Jean and Shah, 2008, and Wu et al, 2008). It is estimated that between 60% and 80% of colorectal cancers overexpress EGFR, which increases the risk of metastasis, reduces sensitivity to chemotherapy, and is associated with decreased survival rates (Cunningham et al, 2004 and Jean and Shah, 2008). Anti-EGFR agents inhibit tumour cell survival, growth, proliferation, and transformation, and may also increase the vulnerability of cancer cells to the cytotoxic effects of chemotherapy and radiotherapy (Ciardiello and Tortora, 2008, Jean and Shah, 2008, Lee and Chu, 2007, and Wu et al, 2008). EGFR inhibition combined with chemotherapy is hypothesised to cause irreparable damage to cancer cells and increase apoptosis.

Both cetuximab and panitumumab exert their antitumour effects by binding with high affinity to EGFR, thereby preventing endogenous ligands from activating the receptor. Both antibodies also cause the EGFR on the tumour cells to be internalised, thus reducing the number of receptors on the cell surface. These combined mechanisms lead to a reduction in EGFR-mediated signalling and tumour cell growth and proliferation (Ciardiello and Tortora, 2008, Jean and Shah, 2008, and Wu et al, 2008).

The efficacy of both agents for the treatment of mCRC has been evaluated in several trials ( Table 1 ). Panitumumab has proven activity as monotherapy (Amado et al, 2008 and Van Cutsem et al, 2007) with studies ongoing in combination with chemotherapy (Greil et al, 2009, Peeters et al, 2008, and Siena et al, 2008). Cetuximab has been studied as monotherapy (Jonker et al, 2007, Karapetis et al, 2008, and Saltz et al, 2004), as well as in combination with chemotherapy (Bokemeyer et al, 2009, Cunningham et al, 2004, Saltz et al, 2007, Sobrero et al, 2008, and Van Cutsem et al, 2009). The presence of wild-type or nonmutated KRAS is associated with response to both panitumumab and cetuximab, but patients with KRAS mutations do not respond to anti-EGFR agents (Amado et al, 2008, Karapetis et al, 2008, and Bokemeyer et al, 2009). The effect of the KRAS mutation on response was observed when cetuximab and panitumumab were used as monotherapy (Amado et al, 2008 and Karapetis et al, 2008), as well as when cetuximab was used in combination with chemotherapy ( Bokemeyer et al., 2009 ). It is now accepted that the mutational status of KRAS can be used as a biomarker for lack of response to EGFR inhibition therapy (Amado et al, 2008, Benvenuti et al, 2007, Di Fiore et al, 2007, Karapetis et al, 2008, Lemmens, 2008, Lievre et al, 2008, and Siena et al, 2009). These findings present practitioners with the option to personalise treatment plans for patients with mCRC on the basis of the genetic features of the cancer (Lemmens, 2008 and Siena et al, 2009).

Table 1 Summary of key trials evaluating the efficacy of cetuximab and panitumumab for the treatment of metastatic colorectal cancer.

Study/citation Study design Intervention Outcomes
Cetuximab trials
Saltz et al. (2004) Open-label, phase II

Irinotecan-refractory patients

N = 57
Cetuximab 400 mg/m2 first dose; 250 mg/m2 subsequent doses PR: 9%; 95% CI, 3–19%

SD: 35%

Median survival: 6.4 months

Median TTP overall: 1.4 months

Median TTP for patients with PR: 4.2 months
BOND

Cunningham et al. (2004)
RCT

Irinotecan-refractory patients

N = 329
Irinotecan + cetuximab 400 mg/m2 first dose 250 mg/m2 subsequent doses (n = 218) vs. Cetuximab 400 mg/m2 first dose; 250 mg/m2 subsequent doses (n = 111) TTP: HR, 0.54; 95% CI, 0.42–0.71 in favour of irinotecan + cetuximab (P < 0.0001)
NCI CTG CO 17

Jonker et al. (2007)

Karapetis et al. (2008)
RCT, phase III

Second-line setting

N = 572
Cetuximab 400 mg/m2 first dose; 250 mg/m2 subsequent doses + BSC (n = 287) vs BSC (n = 285) OS: HR, 0.77; 95% CI, 0.64–0.92 (P = 0.005); OS for patients with wild-type KRAS: HR, 0.55; 95% CI, 0.41–0.74 (P < 0.001) OS for patients with mutant KRAS: 0.98; 95% CI, 0.70–1.37 (P = 0.89)

PFS: HR, 0.68; 95% CI, 0.57–0.80 (P < 0.001)

PFS for patients with wild-type KRAS: HR, 0.40; 95% CI, 0.30–0.54; P < 0.001

PFS for patients with mutant KRAS: 0.99; 95% CI, 0.73–1.35 (P = 0.96)
BOND-2

Saltz et al. (2007)
RCT, phase II

Irinotecan-refractory patients

N = 83
Cetuximab 400 mg/m2 first dose; 250 mg/m2 subsequent doses + bevacizumab 5 mg/kg + irinotecan at same as last dose (n = 40) vs Cetuximab 400 mg/m2 first dose; 250 mg/m2 subsequent doses + bevacizumab 5 mg/kg (n = 43) TTP: 7.3 months vs 4.9 months

RR: 37% vs 20%

OS: 14.5 months vs 11.4 months
EPIC

Sobrero et al. (2008)
Open-label phase III

Fluoropyrimidine- and oxaliplatin-failed patients

N = 1298
Cetuximab weekly (400 mg/m2 first dose; 250 mg/m2 subsequent doses) + irinotecan 350 mg/m2 q3w (n = 648) vs Irinotecan 350 mg/m2 q3w (n = 650) PFS: HR, 0.692 in favour of cetuximab + irinotecan (P < 0.0001)

RR: 16.4% vs 4.2% in favour of cetuximab + irinotecan (P < 0.0001)
OPUS

Bokemeyer et al. (2009)
RCT, phase II

Newly diagnosed patients

N = 337
Cetuximab weekly (400 mg/m2 first dose; 250 mg/m2 subsequent doses) + FOLFOX4 (n = 169)

vs FOLFOX4 alone (n = 168)
ORR for all patients: 46% vs 36%, OR = 1.52 in favour of cetuximab + FOLFOX4 (P = 0.064)

ORR for patients with KRAS wild-type: 61% vs 37%; OR, 2.54 in favour of cetuximab + FOLFOX4 (P = 0.011)
CRYSTAL

Van Cutsem et al. (2009)
RCT, phase III

Newly diagnosed patients

N = 1217
Cetuximab 400 mg/m2 first dose; 250 mg/m2 subsequent doses + FOLFIRI (n = 608) vs FOLFIRI (n = 609) RR: 46.9% vs 38.7% in favour of cetuximab (P = 0.005)

PFS: 8.9 months vs 8 months in favour of cetuximab (P = 0.036)

PFS for patients with wild-type KRAS: 9.9 vs 8.7 months, HR = 0.68 in favour of cetuximab + FOLFIRI (P = 0.017)

PFS for patients with mutant KRAS: 8.1 vs 7.6 months (HR = 1.07; P = 0.75)
 
Panitumumab trials
Van Cutsem et al. (2007) Open-label, phase III

Chemotherapy-refractory patients

N = 463
Panitumumab 6 mg/m2 q2w and BSC (n = 231) vs BSC (n = 232) PFS: HR, 0.54 in favour of panitumumab + BSC (P < 0.0001)
Amado et al. (2008) RCT, phase III Panitumumab 6 mg/m2 q2w and BSC (n = 208) vs BSC (n = 219) PFS for patients with wild-type KRAS: 12.3 vs 7.3 weeks; HR, 0.45 in favour of panitumumab + BSC (P < 0.001)

PFS for patients with mutant KRAS: 7.4 vs 7.3 weeks

BSC, best supportive care; CI, confidence interval; FOLFIRI, irinotecan 180 mg/m2 + leucovorin 400 mg/m2 + fluorouracil 400 mg/m2 bolus followed by 2,400 mg/m2 infusion over 46 h; FOLFOX4, oxaliplatin 85 mg/m2 on day 1 + leucovorin 200 mg/m2 + fluorouracil 400 mg/m2 bolus followed by a 600 mg/m2 infusion on days 1 and 2; HR, hazard ratio; KRAS, Kirsten rat sarcoma-2 virus oncogene; OR, overall response; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; q2w, every 2 weeks; q3w; every 3 weeks; RCT, randomised controlled trial; RR, response rate; TTP, time to progression.

Administration guidelines for anti-EGFR monoclonal antibodies

The product labels for both cetuximab and panitumumab require that these agents be administered only to patients with EGFR-expressing tumours (Erbitux SmPC; Vectibix SmPC). Results from several trials now suggest that clinical benefit is observed regardless of EGFR expression status and that the intensity of EGFR staining by immunohistochemistry does not correlate with efficacy (Chung et al, 2005, Lenz et al, 2006, and Hecht et al, 2008).

Both cetuximab and panitumumab are administered intravenously. Cetuximab is given weekly with a recommended loading dose of 400 mg/m2 infused over 2 hours, followed by maintenance doses of 250 mg/m2 as 1-hour infusions. Premedication with an antihistamine, such as diphenhydramine 50 mg or clemastine 2 mg, is recommended with cetuximab to prevent infusion reactions before the first infusion, as well as in all subsequent cycles of treatment (Erbitux SmPC; Jean and Shah, 2008, Chung et al, 2005, and Lenz et al, 2006). The recommended dose of panitumumab is 6 mg/kg infused over 1 h every 2 weeks, with doses greater than 1000 mg administered over 90 min (Vectibix SmPC; Jean and Shah, 2008 ). No premedications are required with panitumumab, which is a fully human monoclonal antibody and, therefore, less likely to cause an infusion reaction. Dose adjustments are not suggested for renal or hepatic impairment, however, they are recommended for patients who experience infusion reactions or dermatologic adverse events ( Jean and Shah, 2008 ).

Management of adverse events associated with anti-EGFR antibodies

In general, anti-EGFR agents are well tolerated when administered as monotherapy with dermatologic reactions, ocular toxicities, hypomagnesaemia, and diarrhoea being frequently reported for both cetuximab and panitumumab ( Jean and Shah, 2008 ). In addition, infusion and hypersensitivity reactions are early adverse events observed primarily with cetuximab. Clinical trials of cetuximab given with chemotherapy show that the combination has a manageable safety profile that is consistent with the toxicities expected from individual agents. The combination produced a substantial increase in the incidence of acneiform rash, diarrhoea, and electrolyte imbalances (Bokemeyer et al, 2009, Cunningham et al, 2004, Saltz et al, 2007, Sobrero et al, 2008, and Van Cutsem et al, 2009). In two trials, the incidence of neutropenia was much greater with the combination than with cetuximab alone, however, the frequency was still considered within the expected range for chemotherapy alone (Cunningham et al, 2004 and Saltz et al, 2007).

The severity of the adverse effects associated with cetuximab and panitumumab is defined by the Common Terminology Criteria for Adverse Events (CTCAE), which is summarised in Table 2 ( National Cancer Institute, 2009 CTCAE v4.0). These recently released grading scales were developed to provide more objective criteria that better reflect the current management of toxicities associated with the use of targeted therapies. The incidence, signs and symptoms, and common strategies for the prevention and treatment of each of these adverse effects are described herein.

Table 2 Common terminology criteria for adverse events v 4.0: Adverse events associated with epidermal growth factor receptor agents (National Cancer Institute CTCAE v4.0).

Adverse event Definition Grade
1 2 3 4 5
Dermatologic toxicities
Papulopustular rash A disorder characterised by an eruption consisting of papules (small, raised pimples) and pustules (small pus-filled blisters), typically appearing in face, scalp, and upper chest and back. Unlike acne, this rash does not present with whiteheads or blackheads, and can be symptomatic, with itchy or tender lesions. Papules and/or pustules covering <10% BSA, which may or may not be associated with symptoms of pruritus or tenderness Papules and/or pustules covering 10–30% BSA, which may or may not be associated with symptoms of pruritus or tenderness; associated with psychosocial impact; limiting instrumental ADL Papules and/or pustules covering >30% BSA, which may or may not be associated with symptoms of pruritus or tenderness; limiting self-care ADL; associated with local superinfection with oral antibiotics indicated Papules and/or pustules covering any % BSA, which may or may not be associated with symptoms of pruritus or tenderness and are associated with extensive superinfection with IV antibiotics indicated; life-threatening consequences Death
Bullous dermatitis A disorder characterised by inflammation of the skin characterised by the presence of bullae, which are filled with fluid. Asymptomatic; blisters covering <10% BSA Blisters covering 10–30% BSA; painful blisters; limiting instrumental ADL Blisters covering >30% BSA; limiting self-care ADL Blisters covering >30% BSA; associated with fluid or electrolyte abnormalities; ICU care or burn unit indicated Death
Erythroderma A disorder characterised by generalised inflammatory erythema and exfoliation; the inflammatory process involves > 90% of the BSA Erythema covering >90% BSA without associated symptoms; limiting instrumental ADL Erythema covering >90% BSA with associated symptoms (eg, pruritus or tenderness); limiting self-care ADL Erythema covering >90% BSA with associated fluid or electrolyte abnormalities; ICU care or burn unit indicated Death
Rash acneiform A disorder characterised by an eruption of papules and pustules, typically appearing in face, scalp, upper chest and back Papules and/or pustules covering <10% BSA, which may or may not be associated with symptoms of pruritus or tenderness Papules and/or pustules covering 10–30% BSA, which may or may not be associated with symptoms of pruritus or tenderness; associated with psychosocial impact; limiting instrumental ADL Papules and/or pustules covering >30% BSA, which may or may not be associated with symptoms of pruritus or tenderness; limiting self-care ADL; associated with local superinfection with oral antibiotics indicated Papules and/or pustules covering any % BSA, which may or may not be associated with symptoms of pruritus or tenderness and are associated with extensive superinfection with IV antibiotics indicated; life-threatening consequences Death
Rash maculopapular A disorder characterised by the presence of macules (flat) and papules (elevated). Also known as morbilliform rash, it is one of the most common cutaneous adverse events, frequently affecting the upper trunk, spreading centripetally and associated with pruritus. Macules or papules covering <10% BSA with or without symptoms (e.g., pruritus, burning, tightness) Macules or papules covering 10–30% BSA with or without symptoms (e.g., pruritus, burning, tightness); limiting instrumental ADL Macules/papules covering >30% BSA with or without associated symptoms; limiting self-care ADL
Paronychia A disorder characterised by an infectious process involving the soft tissues around the nail. Nail fold oedema or erythema; disruption of the cuticle Localised intervention indicated; oral intervention indicated (e.g., antibiotic, antifungal, antiviral); nail fold oedema or erythema with pain; associated with discharge or nail plate separation; limiting instrumental ADL Surgical intervention or IV antibiotics indicated; limiting self-care ADL
Pruritis/itching A disorder characterised by an intense itching sensation. Mild or localised; topical intervention indicated Intense or widespread; intermittent; skin changes from scratching (e.g., oedema, papulation, excoriations, lichenification, oozing/crusts); oral intervention indicated; limiting instrumental ADL Intense or widespread; constant; limiting self-care ADL or sleep; oral corticosteroid or immunosuppressive therapy indicated
Dry skin (xerosis) A disorder characterised by flaky and dull skin; the pores are generally fine; the texture is a papery thin texture. Covering <10% BSA and no associated erythema or pruritus Covering 10–30% BSA and associated with erythema or pruritus; limiting instrumental ADL Covering >30% BSA and associated with pruritus; limiting self-care ADL
Other skin and subcutaneous tissue disorders   Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated Moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate instrumental ADL Severe or medically significant but not immediately life-threatening; hospitalisation or prolongation of existing hospitalisation indicated; disabling; limiting self-care ADL Life-threatening consequences; urgent intervention indicated Death
 
Ocular toxicities
Dry eye A disorder characterised by dryness of the cornea and conjunctiva. Asymptomatic; clinical or diagnostic observations only; mild symptoms relieved by lubricants Symptomatic; multiple agents indicated; limiting instrumental ADL Decrease in visual acuity (<20/40); limiting self-care ADL
Watering eyes A disorder of excessive tearing in the eyes; it can be caused by overproduction of tears or impaired drainage of the tear duct. Intervention not indicated Intervention indicated Operative intervention indicated
Eyelid function disorder A disorder characterised by impaired eyelid function. Asymptomatic; clinical or diagnostic observations only; intervention not indicated Symptomatic; nonoperative intervention indicated; limiting instrumental ADL Limiting self-care ADL; operative intervention indicated
Keratitis A disorder characterised by inflammation to the cornea of the eye. Symptomatic; medical intervention indicated (eg, topical agents); limiting instrumental ADL Decline in vision (worse than 20/40 but better than 20/200); limiting self-care ADL Perforation or blindness (20/200 or worse) in the affected eye
Eye disorders—other   Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated Moderate; minimal, local or non-invasive intervention indicated; limiting age appropriate instrumental ADL Severe or medically significant but not immediately sight-threatening; hospitalisation or prolongation of existing hospitalisation indicated; disabling; limiting self-care ADL Sight-threatening consequences; urgent intervention indicated; blindness (20/200 or worse) in the affected eye
 
Other toxicities
Infusion related reaction A disorder characterised by adverse reaction to the infusion of pharmacological or biological substances. Mild transient reaction; infusion interruption not indicated; intervention not indicated Therapy or infusion interruption indicated but responds promptly to symptomatic treatment (e.g., antihistamines, NSAIDS, narcotics, IV fluids); prophylactic medications indicated for ≤24 h Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalisation indicated for clinical sequelae Life-threatening consequences; urgent intervention indicated Death
Hypomagnesaemia A disorder characterised by laboratory test results that indicate an elevation in the concentration of magnesium in the blood. <LLN-1.2 mg/dL; < LLN-0.5 mmol/L <1.2–0.9 mg/dL; <0.5–0.4 mmol/L <0.9–0.7 mg/dL; <0.4–0.3 mmol/L <0.7 mg/dL; <0.3 mmol/L Death
Diarrhoea A disorder characterised by frequent and watery bowel movements. Increase of <4 stools per day over baseline; mild increase in ostomy output compared to baseline Increase of 4–6 stools per day over baseline; moderate increase in ostomy output compared to baseline Increase of ≥7 stools per day over baseline; incontinence; hospitalisation indicated; severe increase in ostomy output compared to baseline; limiting self-care ADL Life-threatening consequences; urgent intervention indicated Death

ADL, activities of daily living; BSA, body surface area; ICU, intensive care unit; IV, intravenous; LLN, lower limit of normal; NSAIDS, nonsteroidal anti-inflammatory drugs.

Dermatologic reactions

Dermatologic toxicities associated with the use of cetuximab and panitumumab fall into three categories ( Burtness et al., 2009 ):

  • Skin rash
  • Xerosis (dry skin) and pruritus (itching)
  • Paronychia (inflammation around the nail)

Each of these adverse dermatologic reactions is summarised in Table 3 and is discussed in greater detail below.

Table 3 Patient education and management strategies for cutaneous reactions to EGFR agents.

Reaction Description Timing Management strategies Precautions Helpful tips
Rash Usually affects upper body, such as the face, neck, shoulders, behind ears, chest, and head because these areas have the most follicular glands

May also cause itching
Almost 80% of patients develop this rash with onset within 1–2 days after starting treatment but improving by 4 weeks

Some patients will have rash for the entire course of treatment

Usually disappears without leaving scars
Shower in warm water for short intervals (∼5 min) and apply a nonperfumed moisturiser after shower

Moisturise your skin regularly with nonperfumed products

Ask your nurse or physician to recommend a good skin moisturiser

Use nonperfumed, water-based sunscreen (SPF ≥ 15) or water-based skin camouflage makeup
Avoid use of antiacne gels or lotions that will dry your skin

Avoid exposure to direct sunlight by wearing hats
Talk with physician or nurse if you notice skin problems

Antihistamines may relieve itching caused by the rash and can be prescribed by your physician

More severe rashes can be helped by using medical creams or antibiotics that can be prescribed by your physician or a dermatologist
Xerosis and pruritus Occurs due to lack of fats and moisture in the skin

Also caused by cold weather and low humidity, which causes the skin to become dry more quickly

Usually affects the neck, shoulders, trunk, and sometimes the arms and legs

Skin may turn red and scale off

Often feels very itchy

Small cracks or fissures may develop in the skin
Usually occurs within a few weeks after start of treatment but improvement often occurs after about 4 weeks Shower in warm water for short intervals (∼5 min) and remember that showers are preferred over baths

Use nonperfumed, water-based sunscreen (SPF > 15)

Use moist evaporators in your home to keep the air moist

Use nonperfumed, fat creams

When using makeup, apply water-based skin camouflage makeup
Avoid heating your house too warmly because this can dry the air, which can cause your skin to become dry more quickly

Avoid wearing tight clothing

Avoid exposure to sunlight and windy, dry, or cold weather

Avoid use of alcohol-based skin cleansers and perfumes as well as strong perfumes and oils on your skin
Antihistamines may relieve itching caused by the dry skin and can be prescribed by your physician

If you have eczema, moist skin, or blister, you may be referred to a dermatologist
Paronychia Inflammation of the ridge of the fingernail or the nail on the big toe, which can be very painful Usually occurs within 7–8 weeks after initiation of treatment Cut fingernails and toenails as straight and short as possible

Tell the nurse or physician about cuts or wounds on hands or feet in case treatment is needed to prevent infections
Avoid tight-fitting shoes and wear house slippers or house shoes instead

Avoid work or tasks that may damage skin on hands and feet
Bathe hands and feet in a diluted chloramine bath

Disinfect small cuts and wounds with an iodine ointment

Do not use products that contain alcohol as these may cause severe pain

The physician or nurse may refer you to a dermatologist

Skin rash

Signs and symptoms

Both cetuximab and panitumumab have been associated with the development of a papulopustular skin rash that usually appears on the face, scalp, chest, or trunk. Clinical presentation can be similar to acne, including macular or papular lesions; however, comedones are generally not evident ( Fig. 1 ) (Agero et al, 2006, Burtness et al, 2009, Galimont-Collen et al, 2007, and Lynch et al, 2007). The Common Terminology Criteria for Adverse Events (CTCAE) now recognises the following five conditions as components of skin rash or desquamation: papulopustular rash, bullous dermatitis, erythroderma, acneiform rash, maculopapular rash ( National Cancer Institute, 2009 CTCAE v4.0). The definitions of these disorders, as well as grading criteria, are shown in Table 2 .

gr1

Fig. 1 Clinical manifestation of acneiform eruption: (A) pustular eruption on face; (B) pustular eruption on trunk; and (C) follicular pustules.

Incidence and timing

Cutaneous rash affects between 80% and 90% of patients treated with anti-EGFR therapy, with onset usually occurring within the first three weeks following initiation of treatment (Jean and Shah, 2008, Lenz et al, 2006, Melosky et al, 2009, and Saltz et al, 2004). Most cases are considered mild or moderate (grade 1 or 2) with grade 3 or 4 acneiform-type rash being reported in 5% to 20% of patients (Agero et al, 2006, Cunningham et al, 2004, and Lacouture, 2007).

The rash typically progresses through a series of stages, each characterised by different symptoms (Burtness et al, 2009, Lynch et al, 2007, and Melosky et al, 2009):

  • Phase 1 reaction is erythema, swelling, and sensory disruptions (within the first week of treatment)
  • Phase 2 reaction is a papulopustular eruption (from weeks 1 to 3)
  • Phase 3 reaction is the crusting of lesions (at week 4)
Treatment and management

Oncology nurses, who play a key role in the education and training of patients, should first help them to recognise and manage the rash. Oncology nurses should encourage patients to notify their nurse and healthcare team at the first signs of cutaneous reactions, since early management can improve quality of life by limiting pain, discomfort, and psychosocial impact ( Lacouture, 2007 ). A brief summary of patient education strategies for the management of cutaneous reactions is presented in Table 3 .

Dermatologic reactions can be managed by modifying treatment with anti-EGFR agents, either by reducing the dose of the antibodies, delaying treatment, or discontinuing therapy. In fact, package inserts for both cetuximab and panitumumab recommend that severe dermatologic reactions (grade 3 or 4) should be managed with dose delays until the severity of the condition reduces to at least grade 2. Subsequent doses of panitumumab should be reduced by 50% and then 75%, and cetuximab doses may be reduced to as low as 150 mg/m2 as appropriate for the severity of the dermatologic toxicity (Erbitux SmPC; Oishi, 2008 ; Vectibix SmPC).

In a retrospective survey of physicians who used anti-EGFR agents in their practice, 32% reported discontinuing treatment and 76% reported interrupting or delaying treatment because of skin toxicity ( Boone et al., 2007 ). Because dose reductions or treatment discontinuations have the potential to negatively influence treatment outcomes, oncology nurses should be proactive in the management of skin rash and other dermatologic toxicities associated with the use of anti-EGFR therapy (Burtness et al, 2009 and Melosky et al, 2009).

Pre-emptive management of skin rash

To reduce the risk of rash in response to anti-EGFR treatment, patients should be counselled to take appropriate protective measures against the sun because exposure can exacerbate the severity of rash in uncovered areas of the body ( Melosky et al., 2009 ). They should be instructed to apply sun protection with SPF ≥15 several times a day and to avoid tanning salons. Physical sun protection should be recommended over chemical sun protection, which can further irritate the skin. Patients should also limit their exposure to rain, wind, and frosty or cold weather ( Boers-Doets and Ouwerkerk, 2008 ).

In addition, patients should also be advised to avoid activities and products that dry the skin ( Melosky et al., 2009 ). Patients should be instructed to protect their hands by using rubber gloves when washing dishes or cleaning. They should also be advised that showers are recommended over baths; showers should be short in duration (5 min), using only warm water; and a moisturising, nonperfumed lotion or cream should be applied following the shower. Agents that dry the skin, such as alcohol-based products, including antiacne gels or lotions, perfumes, and household cleaning agents should be avoided. Mild soaps may be used for skin cleansing. The use of cosmetics to conceal signs of the rash is acceptable, but not in the acute phase. The use of gentle, non-alcohol-based cleansers should be recommended to remove these products (Boers-Doets and Ouwerkerk, 2008, Lynch et al, 2007, Oishi, 2008, Perez-Soler et al, 2005, and Sipples, 2006).

Clinical trials have also evaluated the benefits of prophylactic treatment with oral antibiotics in managing skin rash resulting from anti-EGFR agents. Two small placebo-controlled trials that evaluated prophylaxis with oral minocycline or tetracycline showed a decrease in the severity of skin rash induced by anti-EGFR agents (Jatoi et al, 2008 and Scope et al, 2007). Another phase II trial, the Skin Toxicity Evaluation Protocol with Panitumumab (STEPP) study, showed that patients who used topical steroids and oral doxycycline prophylactically had lower rates of grade 2 rash than those who used reactive treatment ( Lacouture et al., 2009 ). Taken together, these studies highlight the need for the further development of new prophylactic and proactive management strategies for dermatologic toxicities, as well as additional studies in larger populations of patients.

Treatment of skin rash

Treatment options for skin rash vary based on the severity of the condition. Most of these reactions are mild to moderate in severity (Burtness et al, 2009 and Lacouture, 2007 Melosky et al., 2009 ).

  • Mild reactions (grade 1) may require topical agents, which include the antibiotic 2% clindamycin and the steroid 1% hydrocortisone.
  • Moderate reactions (grade 2) may require systemic treatment with an oral tetracycline antibiotic, such as doxycycline or minocycline, in addition to the topical treatments used for mild reactions.
  • Severe or life-threatening reactions (grade 3 or 4), which are very rare, require immediate discontinuation of anti-EGFR therapy.

Oncology nurses should also monitor affected areas of skin for the development of infection. If an infection is suspected, discharges from the rash should be cultured to determine whether the infection is bacterial or viral in origin and treatment with sensitivity-directed antibiotics should be promptly initiated in cases of bacterial superinfection (Burtness et al, 2009 and Lacouture, 2007).

Patients should be referred to a dermatologist experienced in treating rash associated with anti-EGFR agents if:

Skin reaction and response

The analysis of therapeutic response in some of the key phase III trials for cetuximab and panitumumab suggest that the occurrence of skin rash may be associated with a better response rate and longer overall survival. For example, post hoc analysis of BOND indicated an improved response rate of 13% in patients who experienced skin reactions compared with 0% in patients with no skin reactions. Similarly, median overall survival was 8–9 months for patients who had a skin reaction compared with 2.5–3 months for those who did not have a rash ( Cunningham et al., 2004 ). In the same study, grade 3 or 4 rash was also associated with a better response rate (59% and 25% for cetuximab plus irinotecan and cetuximab monotherapy, respectively) compared with grade 1 or 2 rash (20% and 11% for cetuximab plus irinotecan and cetuximab monotherapy, respectively) ( Cunningham et al., 2004 ). Similarly, the presence of grade 2, 3, or 4 rash in response to treatment with panitumumab was associated with a 41% reduction in mortality compared with patients who had grade 1 rash ( Van Cutsem et al., 2007 ). A pooled analysis of five panitumumab trials revealed longer median overall survival for patients with grade 2, 3, or 4 rash when compared with those patients with grade 1 rash (8.5 vs 4.5 months, P < 0.0001) ( Berlin et al., 2007 ).

Not all patients who experience a rash, however, respond to treatment with EGFR inhibitors, and some patients with documented responses show no evidence of rash (Jean and Shah, 2008 and Peréz-Soler and Saltz, 2005). This topic remains under evaluation; it is anticipated that findings from the EVEREST trial will clarify this correlation ( Jean and Shah, 2008 ).

Xerosis and pruritus

Signs and symptoms

Patients treated with cetuximab and panitumumab have reported xerosis (dry skin with fine scales) on their arms and legs, which can develop into eczema ( Galimont-Collen et al., 2007 ). Painful tips of fingers and toes (pulpitis sicca), as well as fissures on the hands and heels, have also been reported ( Agero et al., 2006; Galimont-Collen et al., 2007 ). Pruritus or itching, which can be a response to the xerosis or papulopustular rash, can cause pain and burning and can prevent patients from sleeping well (Burtness et al, 2009 and Lacouture, 2007). The grading criteria for xerosis and pruritus are shown in Table 2 ( National Cancer Institute, 2009 CTCAE v4.0).

Incidence and timing

Approximately 35% of patients experience dry itchy skin several weeks after the initiation of treatment with anti-EGFR agents ( Galimont-Collen et al., 2007 ). Pruritus is more common in patients treated with panitumumab (57% [2%, grade 3–4]) than with cetuximab (11% [<1%, grade 3–4]) (Erbitux, 2008, Erbitux, 2009, Lacouture, 2007, Vectibix, 2008, and Vectibix, 2009).

Treatment and management

As described in the previous section on skin rash, all patients should be counselled to take precautions that are aimed at maintaining the hydration of the skin ( Galimont-Collen et al., 2007 ). They should be told to take short showers, avoid soaps, and frequently use emollients.

If xerosis occurs, it should be treated with standard emollients; ointments should be avoided because they can occlude the fissures and cause folliculitis ( Galimont-Collen et al., 2007 ). Fissures on the palms and soles can be sealed with liquid bandages or adhesive tape ( Lacouture, 2007 ). Eczema can be treated with a potent steroid. Wet eczema should be cultured to ensure that there is no bacterial or viral infection. In the case of a bacterial superinfection, systemic therapy should be considered ( Galimont-Collen et al., 2007 ).

Antihistamines, such as diphenhydramine or hydroxyzine, or topical gels containing collagen, aloe, vitamin E, and lidocaine may be used to provide relief from the itching and the burning sensation associated with pruritus ( Lacouture, 2007 ).

Severely xerotic skin may be at risk for infections, with this risk being made greater by itching and scratching (Burtness et al, 2009 and Lacouture, 2007). Potential infections should be cultured to identify the colonizing pathogen, and appropriate treatment should be initiated promptly.

Paronychia (nail changes)

Signs and symptoms

Paronychia is a soft tissue infection that occurs around finger and toenails. It is characterised by redness and inflammation of the sides of the nails, with increasing soreness and tenderness that may result in the formation of infectious granulomas and abscesses ( Fig. 2 ) (Galimont-Collen et al, 2007 and Viale and Sommers, 2007). Both fingernails and toenails can be affected, with the thumb and big toe being the two most likely to be impacted. The pain associated with paronychia can be a significant burden for patients and can interfere with walking and the performance of activities of daily living ( Burtness et al., 2009 ).

gr2

Fig. 2 Clinical manifestations of paronychia: ulcerated area on (A) lateral wall of nail and (B) ulcerative erythematous area with exudative granulation tissue in the oedematous nail wall of digits 1–4.

Incidence and timing

Paronychia may affect up to 15% of patients (Burtness et al, 2009, Galimont-Collen et al, 2007, and Viale and Sommers, 2007). It typically develops later than skin rash, usually from 4 weeks to 6 months after the initiation of anti-EGFR therapy.

Treatment and management

Oncology nurses should advise patients with paronychia to cut the nails as straight and short as possible; to cushion the inflamed, sore areas; and to wear loose-fitting shoes to prevent unnecessary pressure on the toenails (Galimont-Collen et al, 2007 and Sipples, 2006). Patients should also avoid damage to the nails that can be caused by biting fingernails or the application of artificial nails. Soaking the nails in a solution of diluted chloramine, aluminum acetate, or Epsom salts may be helpful, and fissures in the nails can be covered with liquid bandages (Lacouture, 2007 and Sipples, 2006). Topical colloidal silver products, such as silver nitrate applicators, will treat bleeding (Dick and Crawford, 2005 and Galimont-Collen et al, 2007). The presence of a purulent discharge may be a sign of infection; the discharge should be cultured to confirm if the paronychia is infected with Staphylococcus aureus, methicillin-resistant S. aureus, enterococcus, or pseudomonas, and appropriate antibiotic treatment should be initiated ( Burtness et al., 2009 ).

Ocular toxicities

Signs and symptoms

Ocular toxicities that can occur with the use of EGFR inhibitors are a consequence of the presence of EGFR in basal epithelial cells of the cornea and conjunctiva, eyelid skin, lash follicles, tear glands, and sebaceous/sweat glands (Basti, 2007, Burtness et al, 2009, and Zhang et al, 2007). Eye disorders that have been observed with cetuximab and panitumumab can be broadly categorised as:

Incidence and timing

Ocular adverse events in response to anti-EGFR therapy affect approximately 15% of patients treated with cetuximab or panitumumab although severe toxicities are observed in <1% of patients treated with the antibodies as monotherapy (Basti, 2007 and Dranko et al, 2006; Erbitux SmPC; Jean and Shah, 2008 ; Vectibix SmPC). According the Erbitux prescribing information, conjunctivitis was commonly observed with cetuximab, whereas blepharitis and keratitis were uncommon (Erbitux SmPC). In addition, trichomegaly (Bouche et al, 2005, Dueland et al, 2003, Vaccaro et al, 2009, and Vano-Galvan et al, 2009), and corneal erosion ( Foerster et al., 2008 ) have also been reported in the literature as case reports of patients treated with cetuximab. Similarly, according to the Vectibix prescribing information, ocular toxicities that were reported in registrational trials included conjunctivitis (4%), ocular hyperaemia (3%), increased lacrimation (2%), and eye/eyelid irritation (Vectibix SmPC).

Ocular toxicities are generally considered a rare adverse event of anti-EGFR treatment; however, some investigators believe that their true incidence may be underreported. The research conducted at the Skin and Eye Reactions to Inhibitors of EGFR and Kinases (SERIES) Clinic suggests that as many as one-third of patients treated with anti-EGFR agents experience some kind of ocular toxicity ( Basti, 2007 ). Although most events were found to be less severe (grade 1 or 2), patients frequently expressed the desire to discontinue therapy because of the discomfort, underscoring the importance of appropriate assessment and treatment.

Treatment and management

Most ocular toxicities observed with cetuximab and panitumumab do not cause a loss of vision; however, early recognition and management of these adverse reactions are necessary to improve patient comfort, to facilitate compliance, and to avoid interruption of therapy (Basti, 2007 and Burtness et al, 2009). Table 4 summarises the most frequent ocular toxicities reported for patients undergoing anti-EGFR therapy, as well as suggested management strategies for mild, severe, and nonresponsive reactions.

Table 4 Presentation and management of ocular toxicities associated with EGFR agents (Basti, 2007 and Burtness et al, 2009).

Condition Description Signs and symptoms Treatment
Squamous blepharitis Inflammation of the eyelid follicles that typically presents with hyperaemia of the eyelid margin

Often accompanies the acneiform/papulopustular rash

Usually responds to treatment within a week
Affects the skin of the eyelid, lid margin, lashes, and meibomian glands

Soreness of the lid margin

Crusting and matting of the eyelashes after sleep

Pruritus, irritation, and redness
Acute reactions

Warm compresses with a moist washcloth

Regular cleaning of the eyelid

Artificial tears

Short course of topical fluorometholone (0.1%) to skin and lid margin of eye for 1 week and no longer than 2 weeks with an evaluation of ocular pressure within 4 weeks of initiation of therapy by an ophthalmologist

Chronic reactions

Tacrolimus ointment 0.03% or pimecrolimus cream twice daily; if minimal response to low dose of tacrolimus, can increase to 0.1% tacrolimus

Advise patient that these agents are only intended for the skin of the eyelid and should not get in the eye

Do not treat with tacrolimus or pimecrolimus for longer than 6 months
Meibomitis Inflammation of the back of the eyelid margin

Swollen openings of the Meibomian glands, which causes the oily substance secreted by these glands to become thicker

Causes dysfunctional tear syndrome and makes tear film less effective for eye lubrication
Swollen/red eyelid margins

Dryness and burning of the eye

Blurry vision

Gritty feeling

Frequent sties

Variable fluctuation in visual acuity

Often observed only upon awakening
Eyelid scrubs by patient

Application of warm moist compresses with a washcloth to the eyelid for at least 5 min twice daily

Topical or oral antibiotics such as tetracycline, doxycycline, or erythromycin (e.g., oral doxycycline 50 mg twice a day for 2 weeks then once per day for 4 weeks)
Trichomegaly Patchy loss of eyelashes, misdirected lashes (trichiasis) Lashes or eyebrows appear elongated, patchy, thickened, or hyper-pigmented

Rare instances of lashes turning inward and rubbing on the eyeball, which can cause corneal abrasions or epithelial erosion

Loss of eyebrows

Patchy loss of eyelashes

Misdirected eyelashes
No specific treatment at this time

Condition will resolve after treatment with EGFR is complete

Refer to ophthalmologist if misdirected lashes irritate the eye and need to be epilated
Dysfunctional tear syndrome Suboptimal production of tear film

Can co-occur with squamous blepharitis, trichomegaly, or meibomitis
Fluctuations in visual acuity upon blinking

Mild decrease or impairment in vision

Feeling of a foreign body in the eye (sandy sensation)

Tired sensation in the eye (eye fatigue)

Transient sharp pain or burning in the eye

Dry or teary eyes

Itching eyes

Mucous secretion
Mild symptoms

Application of artificial or supplemental tears 4–6 times daily

Severe symptoms or no improvement

Refer to ophthalmologist

Use of anti-inflammatory medications
Corneal erosion/epithelial defects   Redness

Pain

Sensitivity to light
Refer to ophthalmologist for evaluation, treatment (epilation), and monitoring

EGFR, epidermal growth factor receptor.

Oncology nurses should counsel patients about the possible symptoms of ocular toxicities, which include eyelid and eye irritation, oily secretions, burning sensation and dryness, crusty skin, eyelash growth, and vision fluctuation. Patients should be instructed to promptly report any eye discomfort, pain, or vision problems to their healthcare provider. In addition, during regular appointments, oncology nurses should ask patients whether they have any problems with their eyes or any fluctuations or decreases in vision, and should examine patients for symptoms of ocular toxicity ( Basti, 2007 ).

All reports of ocular reactions require careful evaluation of the eye and eyelid with a penlight to ensure early identification of any changes. Eyelid dermatitis may benefit from treatment with topical steroids, which require monitoring for changes in intraocular pressure. Warm compresses, topical antibiotics, and gentle cleansing of the eyelids may relieve symptoms of blepharitis and meibomitis, whereas dysfunctional tear syndrome responds well to treatment with over-the-counter tear products administered four to six times daily ( Basti, 2007 ). Patients with severe cases of ocular toxicities may require referral to an ophthalmologist. Symptoms that necessitate a referral to the ophalmologist include (Basti, 2007 and Burtness et al, 2009):

  • Persistent ocular pain, significant loss of vision or decreased acuity of vision.
  • Severe redness of the eye or light sensitivity.
  • Trichomegaly (for lash epilation to prevent irritation of the conjunctiva or cornea).
  • Failure to respond within 1 week of initiation of treatment for squamous blepharitis, meibomitis, or dysfunctional tear syndrome.

Hypersensitivity and infusion reactions

Signs and symptoms

Hypersensitivity and infusion reactions are signs or symptoms experienced by patients during the infusion of a pharmacologic or biologic agent or within 24 h of administration of the drug ( Kang and Saif, 2007 ). Common symptoms include chills, rigors, dyspnoea, tachycardia, bronchospasms, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioeodema, pain, pruritus, sweating, tremors, shaking, cough, and visual disturbances. These reactions can range in severity from mild flushing and itching to anaphylaxis and even death (see Table 2 ).

Incidence and timing

In pivotal clinical trials, 20% of patients with mCRC treated with cetuximab and best supportive care experienced infusion reactions, with 5% of these being severe (grade 3 or 4) (Erbitux PI). The overall frequency of infusion reactions was 4% for panitumumab, with 1% of these being grade 3 or 4 (Vectibix SmPC). The vast majority (90%) of infusion reactions occur during the first infusion, with onset usually occurring in the first few minutes following initiation of the infusion ( Viale and Sommers, 2007 ).

Treatment and management

The incidence of infusion reactions is reduced by the prophylactic use of antihistamines and corticosteroids before the infusion (see Administration Guidelines). As described earlier, panitumumab does not require premedication ( Jean and Shah, 2008 ). Despite premedication, infusion reactions can occur, and oncology nurses should, therefore, carefully monitor patients during every infusion. They should also educate the patients and their caregivers to inform staff if they notice any symptoms of a reaction.

The management of infusion reactions must be rapid, and the infusion should be discontinued at the first sign of a suspected reaction. Treatment options include the use of antihistamines, corticosteroids, epinephrine, oxygen, and bronchodilators. Intensive care treatment may be required depending on the severity of the reaction. Immediate and permanent discontinuation of treatment is recommended for grade 3 or 4 infusion reactions for both panitumumab and cetuximab (Chung et al, 2005 and Lenz et al, 2006).

Hypomagnesaemia

Signs and symptoms

Hypomagnesaemia is an electrolyte disturbance in which there is an abnormally low level of magnesium in the blood. Common symptoms include neuromuscular irritability, muscle cramps, and atrial fibrillation, as well as central nervous system hyperexcitability, irritable affect, and cognitive confusion. Severe cases can result in seizures and cardiac events (Fakih et al, 2006 and Schrag et al, 2005).

Incidence and timing

Both cetuximab and panitumumab can cause hypomagnesaemia, with estimated rates of all grades being between 50% and 65% for cetuximab and 36% for panitumumab (Jean and Shah, 2008, Carson et al, 2005, Fakih et al, 2006, and Van Cutsem et al, 2007). Rates of grade 3 and 4 hypomagnesaemia are between 10%–27% among patients treated with cetuximab and 3% among those given panitumumab (Jean and Shah, 2008, Fakih et al, 2006, Schrag et al, 2005, and Van Cutsem et al, 2007). Concomitant hypokalaemia and hypocalcaemia may also occur, with onset usually noted 6–8 weeks following initiation of treatment (Carson et al, 2005, Fakih et al, 2006, and Schrag et al, 2005).

Treatment and management

Treatment of hypomagnesaemia involves the temporary discontinuation of anti-EGFR therapy and replacement with either oral or intravenous magnesium (Carson et al, 2005, Fakih et al, 2006, Jean and Shah, 2008, and Schrag et al, 2005).

Diarrhoea

Incidence and timing

Diarrhoea is a common adverse event observed in patients treated with anti-EGFR agents. When cetuximab was given as monotherapy, approximately 28% of patients with advanced CRC experienced diarrhoea of any grade, with 2% of these events classified as severe (grade 3 or 4) ( Jean and Shah, 2008 ). Comparable rates have been reported for panitumumab, with diarrhoea of all grades being reported in 21% of patients, and 2% of those classified as grade 3 or 4 ( Jean and Shah, 2008 ).

Diarrhoea is more common with cetuximab given in combination with chemotherapy than monotherapy. The overall incidence of diarrhoea was 72% (with 22% grade 3 or 4) in patients treated with cetuximab and irinotecan ( Jean and Shah, 2008 ).

Treatment and management

Oncology nurses should educate patients about adequate hydration and fluid intake (including fluids with appropriate electrolyte balance). The use of high-dose loperamide offers effective relief for mild to moderate diarrhoea; other products may be available in other countries ( Jean and Shah, 2008 ). Patients with more severe diarrhoea, however, may require hospitalisation and intravenous fluid and electrolyte replacement ( Saltz, 2003 ).

Conclusions

Agents that target EGFR offer patients with wild-type KRAS mCRC a promising treatment alternative with an acceptable overall adverse event profile when administered as single-agent therapy or in combination with chemotherapeutic agents, such as irinotecan and oxaliplatin. Only a small number of patients are at risk of infusion reactions that can result in mortality. Fewer infusion reactions are reported with panitumumab therapy than cetuximab therapy. Awareness of the clinical symptoms of such reactions and the rapid response by oncology nurses to discontinue treatment and implement appropriate clinical interventions can reduce the need for intensive care support and potentially prevent death. Diarrhoea, cutaneous reactions, and ocular reactions can all quickly progress and cause serious clinical consequences, including pain, discomfort, disfigurement, and impaired vision, if left untreated. Patients receiving anti-EGFR agents are also at risk for metabolic and gastrointestinal adverse events. The onset and progression of toxicities related to anti-EGFR therapy are variable, and some adverse events, such as cutaneous reactions, can persist for several weeks after completion of the treatment regimen.

Oncology nurses are in an ideal position to minimise the severity of common adverse events caused by EGFR agents. Early identification, patient education, and proactive clinical interventions can reduce the severity of these adverse events and prevent their progression. Effective strategies are available to manage and treat adverse events when they do occur, including nonpharmacologic and lifestyle modifications that can minimise the severity and progression of symptoms. By empowering patients to be more involved in their treatment and in the management of treatment-related toxicities, oncology nurses can help patients maintain their quality of life and promote treatment adherence.

Conflict of interest

J. Ouwerkerk has served as a paid consultant for or has been on the Advisory Board of Amgen, GlaxoSmithKline, and Roche.

C. Boers-Doets has received research support from GlaxoSmithKline, Roche, Amgen, and Novartis. She has also served as a paid consultant for or been on the Advisory Board of Amgen, Bayer, GlaxoSmithKline, Novartis, and MerckSerono.

Funding source

Amgen (Europe) GmbH sponsored an external agency for writing support.

Acknowledgements

The authors acknowledge the medical writing assistance provided by Supriya Srinivasan, PhD, and Carole Chrvala, PhD.

References

  • Agero et al., 2006 A. Agero, S.W. Dusza, C. Benvenuto-Andrade, K.J. Busam, P. Myskowski, A.C. Halpern. Dermatologic side effects associated with the epidermal growth factor receptor inhibitors. Journal of the American Academy of Dermatology. 2006;55:657-670 Crossref
  • Amado et al., 2008 R.G. Amado, M. Wolf, M. Peeters, E. Van Cutsem, S. Siena, D.J. Freeman, T. Juan, R. Sikorski, S. Suggs, R. Radinsky, S.D. Patterson, D.D. Chang. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. Journal of Clinical Oncology. 2008;26:1626-1634 Crossref
  • Basti, 2007 S. Basti. Ocular toxicities of epidermal growth factor receptor inhibitors and their management. Cancer Nursing. 2007;30:S10-S16 Crossref
  • Benvenuti et al., 2007 S. Benvenuti, A. Sartore-Bianchi, F. Di Nicolantonio, C. Zanon, M. Moroni, S. Veronese, S. Siena, A. Bardelli. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Research. 2007;67:2643-2648 Crossref
  • Berlin et al., 2007 J. Berlin, E. Van Cutsem, M. Peeters, J.R. Hecht, R. Ruiz, M. Wolf, R.G. Amado, N.J. Meropol. Predictive value of skin toxicity severity for response to panitumumab in patients with metastatic colorectal cancer (mCRC): a pooled analysis of five clinical trials. Journal of Clinical Oncology. 2007;25:18s (abstr 4134)
  • Boers-Doets and Ouwerkerk, 2008 Boers-Doets, C., Ouwerkerk, J., August 17–21, 2008. EGFR-Inhibitors induced skin reactions. Presented at the International Society of Nurses in Cancer Care Conference, Singapore, China.
  • Bokemeyer et al., 2009 C. Bokemeyer, I. Bondarenko, A. Makhson, J.T. Hartmann, J. Aparicio, F. de Braud, S. Donea, H. Ludwig, G. Schuch, C. Stroh, A.H. Loos, A. Zubel, P. Koralewski. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. Journal of Clinical Oncology. 2009;27:663-671 Crossref
  • Boone et al., 2007 S.L. Boone, A. Rademaker, D. Liu, C. Pfeiffer, D.J. Mauro, M.E. Lacouture. Impact and management of skin toxicity associated with anti-epidermal growth factor receptor therapy: survey results. Oncology. 2007;72:152-159 Crossref
  • Bouche et al., 2005 O. Bouche, H. Brixi-Benmansour, A. Bertin, G. Perceau, S. Lagarde. Trichomegaly of the eyelashes following treatment with cetuximab. Annals of Oncology. 2005;16:1711-1712 Crossref
  • Burtness et al., 2009 B. Burtness, M. Anadkat, S. Basti, M. Hughes, M.E. Lacouture, J.S. McClure, P.L. Myskowski, J. Paul, C.S. Perlis, L. Saltz, S. Spencer. NCCN Task Force Report: management of dermatologic and other toxicities associated with EGFR inhibition in patients with cancer. Journal of the National Comprehensive Cancer Network. 2009;7(Suppl. 1):S5-S21 quiz S22–S24
  • Carson et al., 2005 E.J. Carson, A.M. Novak, P.J. Stella. Hypomagnesemia in patients with stage IV colorectal cancer treated with cetuximab as a single agent. Journal of Clinical Oncology. 2005;23(Suppl. 16s) (abstr 3655)
  • Chung et al., 2005 K.Y. Chung, J. Shia, N.E. Kemeny, M. Shah, G.K. Schwartz, A. Tse, A. Hamilton, D. Pan, D. Schrag, L. Schwartz, D.S. Klimstra, D. Fridman, D.P. Kelsen, L.B. Saltz. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. Journal of Clinical Oncology. 2005;23:1803-1810 Crossref
  • Ciardiello and Tortora, 2008 F. Ciardiello, G. Tortora. EGFR antagonists in cancer treatment. New England Journal of Medicine. 2008;358:1160-1174 Crossref
  • Cunningham et al., 2004 D. Cunningham, Y. Humblet, S. Siena, D. Khayat, H. Bleiberg, A. Santoro, D. Bets, M. Mueser, A. Harstrick, C. Verslype, I. Chau, E. Van Cutsem. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. New England Journal of Medicine. 2004;351:337-345 Crossref
  • Dick and Crawford, 2005 S.E. Dick, G.H. Crawford. Managing cutaneous side effects of epidermal growth factor receptor (HER2/EGFR) inhibitors. Community Oncology. 2005;2:492-496 Crossref
  • Di Fiore et al., 2007 F. Di Fiore, F. Blanchard, F. Charbonnier, F. Le Pessot, A. Lamy, M.P. Galais, L. Bastit, A. Killian, R. Sesboüé, J.J. Tuech, A.M. Queuniet, B. Paillot, J.C. Sabourin, F. Michot, P. Michel, T. Frebourg. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. British Journal of Cancer. 2007;96:1166-1169 Crossref
  • Douillard et al., 2000 J.Y. Douillard, D. Cunningham, A.D. Roth, M. Navarro, R.D. James, P. Karasek, P. Jandik, T. Iveson, J. Carmichael, M. Alakl, G. Gruia, L. Awad, P. Rougier. Irinotecan combined with fluorouracil compared with fluorouracil alone as the first-line treatment for metastatic colorectal cancer. A multicentre randomised trial. Lancet. 2000;355:1041-1047 Crossref
  • Dranko et al., 2006 S. Dranko, C. Kinney, R.K. Ramanathan. Ocular toxicity related to cetuximab monotherapy in patients with colorectal cancer. Clinical Colorectal Cancer. 2006;6:224-225 Crossref
  • Dueland et al., 2003 S. Dueland, T. Sauer, F. Lund-Johansen, B. Ostenstad, K.M. Tveit. Epidermal growth factor receptor inhibitor induces trichomegaly. Acta Oncology. 2003;42:345-346 Crossref
  • Erbitux, 2008 Erbitux (Cetuximab) Prescribing Information. (Bristol-Meyers Squbb, Branchburg, NJ, 2008) http://packageinserts.bms.com/pi/pi_erbitux.pdf Available from:(accessed 9 July 2009)
  • Erbitux, 2009 Erbitux (Cetuximab) Summary of Product Characteristics. (Merck KGaA, Darmstadt, Germany, 2009) http://www.emea.europa.eu/humandocs/PDFs/EPAR/erbitux/H-558-PI-en.pdf Available from:(accessed 11 November 2008)
  • Fakih et al., 2006 M.G. Fakih, G. Wilding, J. Lombardo. Cetuximab-induced hypomagnesaemia in patients with colorectal cancer. Clinical Colorectal Cancer. 2006;6:152-156 Crossref
  • Foerster et al., 2008 C.G. Foerster, C. Cursiefen, F.E. Kruse. Persisting corneal erosion under cetuximab (Erbitux) treatment (epidermal growth factor receptor antibody). Cornea. 2008;27:612-614 Crossref
  • Galimont-Collen et al., 2007 A.F.S. Galimont-Collen, L.E. Vos, A.P.M. Lavrijsen, J. Ouwerkerk, H. Gelderblom. Classification and management of skin, hair, nail, and mucosal side-effects of epidermal growth factor receptor (EGFR) inhibitors. European Journal of Cancer. 2007;43:845-851 Crossref
  • Greil et al., 2009 R. Greil, H. Letocha, E. Gamelin, J. Thaler, R. Hofheinz, L. Mineur, J. Thaler, R. Hofheinz, L. Mineur, E. Fernebro, M. Karthaus, L. Wright, C. Köhne. Updated analysis of a phase II study (20060314) of panitumumab (pmab) with FOLFIRI as first-line treatment of patients (pts) with metastatic colorectal cancer (mCRC). Journal of Clinical Oncology. 2009;27(Suppl. 15s) (abstr 4085)
  • Grothey, 2006 A. Grothey. Recognizing and managing toxicities of molecular targeted therapies for colorectal cancer. Oncology (Williston Park). 2006;20:21-28
  • Grothey et al., 2004 A. Grothey, D. Sargent, R.M. Goldberg, H.J. Schmoll. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. Journal of Clinical Oncology. 2004;22:1209-1214 Crossref
  • Hecht et al., 2008 Hecht, J., Mitchell, E.P., Baranda, J., Richards, D., Reiner, M., Stout, S., Amado, R.G., 2008. Panitumumab (pmab) efficacy in patients (pts) with metastatic colorectal cancer (mCRC) with low or undetectable levels of epidermal growth factor receptor (EGFr): final efficacy and KRAS analyses. In: Presented at the 2008 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, January 25–27, 2008; Orlando, FL (abstract 343).
  • Hurwitz et al., 2004 H. Hurwitz, L. Fehrenbacher, W. Novotny, T. Cartwright, J. Hainsworth, W. Heim, J. Berlin, A. Baron, S. Griffing, E. Holmgren, N. Ferrara, G. Fyfe, B. Rogers, R. Ross, F. Kabbinavar. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. New England Journal of Medicine. 2004;350:2335-2342 Crossref
  • Jatoi et al., 2008 A. Jatoi, K. Rowland, J.A. Sloan, H.M. Gross, P.A. Fishkin, S.P. Kahanic, P.J. Novotny, P.L. Schaefer, D.B. Johnson, L.K. Tschetter, C.L. Loprinzi. Tetracycline to prevent epidermal growth factor receptor inhibitor-induced skin rashes: results of a placebo-controlled trial from the North Central Cancer Treatment Group (N03CB). Cancer. 2008;113:847-853 Crossref
  • Jean and Shah, 2008 G.W. Jean, S.R. Shah. Epidermal growth factor receptor monoclonal antibodies for the treatment of metastatic colorectal cancer. Pharmacotherapy. 2008;28:742-754 Crossref
  • Jonker et al., 2007 D.J. Jonker, C.J. O’Callaghan, C.S. Karapetis, J.R. Zalcberg, D. Tu, H.J. Au, S.R. Berry, M. Krahn, T. Price, R.J. Simes, N.C. Tebbutt, G. van Hazel, R. Wierzbicki, C. Langer, M.J. Moore. Cetuximab for the treatment of colorectal cancer. New England Journal of Medicine. 2007;357:2040-2048 Crossref
  • Kang and Saif, 2007 S.P. Kang, M.W. Saif. Infusion-related and hypersensitivity reactions of monoclonal antibodies use to treat colorectal cancer—identification, prevention, and treatment. The Journal of Supportive Oncology. 2007;5:451-457
  • Karapetis et al., 2008 C.S. Karapetis, S. Khambata-Ford, D.J. Jonker, C.J. O’Callaghan, D. Tu, N.C. Tebbutt, R.J. Simes, H. Chalchal, J.D. Shapiro, S. Robitaille, T.J. Price, L. Shepherd, H.J. Au, C. Langer, M.J. Moore, J.R. Zalcberg. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. New England Journal of Medicine. 2008;359:1757-1765 Crossref
  • Lacouture et al., 2009 Lacouture, M.E. Mitchell, E.P., Shearer, H., Iannotti, N., Piperdi, B., Pillai, M.V., Xu, F., Yassine, M., 2009. Impact of pre-emptive skin toxicity (ST) treatment (tx) on panitumumab (pmab)-related skin toxicities and quality of life (QOL) in patients (pts) with metastatic colorectal cancer (mCRC): results from STEPP. Presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, January 15–17, 2009; San Francisco, CA (abstract 291).
  • Lacouture, 2007 M.E. Lacouture. Insights into the pathophysiology and management of dermatologic toxicities to EGFR-targeted therapies in colorectal cancer. Cancer Nursing. 2007;30:S17-S25
  • Lacouture et al., 2006 M.E. Lacouture, S. Basti, J. Patel, A. Benson 3rd. The SERIES clinic: an interdisciplinary approach to the management of toxicities of EGFR inhibitors. The Journal of Supportive Oncology. 2006;4:236-238
  • Lee and Chu, 2007 J.J. Lee, E. Chu. First-line use of anti-epidermal growth factor receptor monoclonal antibodies in metastatic colorectal cancer. Clinical Colorectal Cancer. 2007;6:S42-S46 Crossref
  • Lemmens, 2008 Lemmens, L., 2008. Personalised cancer therapy: what is KRAS and what does it mean for patients with metastatic colorectal cancer? EONS Newsletter. Fall, 28–31.
  • Lenz et al., 2006 H.J. Lenz, E. Van Cutsem, S. Khambata-Ford, R.J. Mayer, P. Gold, P. Stella, B. Mirtsching, A.L. Cohn, A.W. Pippas, N. Azarnia, Z. Tsuchihashi, D.J. Mauro, E.K. Rowinsky. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. Journal of Clinical Oncology. 2006;24:4914-4921 Crossref
  • Lievre et al., 2008 A. Lievre, J.B. Bachet, V. Boige, A. Cayre, D. Le Corre, E. Buc, M. Ychou, O. Bouché, B. Landi, C. Louvet, T. André, F. Bibeau, M.D. Diebold, P. Rougier, M. Ducreux, G. Tomasic, J.F. Emile, F. Penault-Llorca, P. Laurent-Puig. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. Journal of Clinical Oncology. 2008;26:374-379 Crossref
  • Lynch et al., 2007 T.J. Lynch, E.S. Kim, B. Eaby, J. Garey, D.P. West, M.E. Lacouture. Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007;12:610-621 Crossref
  • Melosky et al., 2009 B. Melosky, R. Burkes, D. Rayson, T. Alcindor, N. Shear, M. Lacouture. Management of skin rash during EGFR-targeted monoclonal antibody treatment for gastrointestinal malignancies: Canadian recommendations. Current Oncology. 2009;16:16-26
  • National Cancer Institute, 2009 Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.0. (National Cancer Institute, 2009) http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev4.pdf Available from:(accessed November 15, 2009)
  • Oishi, 2008 K. Oishi. Clinical approaches to minimize rash associated with EGFR inhibitors. Oncology Nursing Forum. 2008;35:103-111 Crossref
  • Peeters et al., 2008 M. Peeters, G. Wilson, M. Ducreux, A. Cervantes, T. André, Y. Hotko, F. Lordick, S. Collins, M. Shing, T.J. Price. Phase III study (20050181) of panitumumab (pmab) with FOLFIRI versus FOLFIRI alone as second-line treatment (tx) in patients (pts) with metastatic colorectal cancer (mCRC): pooled safety results. Journal of Clinical Oncology. 2008;26(Suppl. 15s) (abstr 4064)
  • Perez-Soler et al., 2005 R. Perez-Soler, J.P. Delord, A. Halpern, K. Kelly, J. Krueger, B.M. Sureda, J. von Pawel, J. Temel, S. Siena, D. Soulières, L. Saltz, J. Leyden. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR inhibitor rash management forum. Oncologist. 2005;10:345-356 Crossref
  • Peréz-Soler and Saltz, 2005 R. Peréz-Soler, L. Saltz. Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining?. Journal of Clinical Oncology. 2005;23:5235-5246
  • Pohl et al., 2008 A. Pohl, W. Zhang, Y. Ning, P.C. Manegold, G. Lurje, H.-J. Lenz. Targeting metastatic colorectal cancer in 2008: a long way from 5-FU. Oncology. 2008;22:456-462
  • Saltz, 2003 L.B. Saltz. Understanding and managing chemotherapy-induced diarrhea. The Journal of Supportive Oncology. 2003;1:35-46
  • Saltz et al., 2000 L.B. Saltz, J.V. Cox, C. Blanke, L.S. Rosen, L. Fehrenbacher, M.J. Moore, J.A. Maroun, S.P. Ackland, P.K. Locker, N. Pirotta, G.L. Elfring, L.L. Miller. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. New England Journal of Medicine. 2000;343:905-914 Crossref
  • Saltz et al., 2007 L.B. Saltz, H.J. Lenz, H.L. Kindler, H.S. Hochster, S. Wadler, P.M. Hoff, N.E. Kemeny, E.M. Hollywood, M. Gonen, M. Quinones, M. Morse, H.X. Chen. Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in the irinotecan-refractory colorectal cancer. Journal of Clinical Oncology. 2007;25:4557-4561 Crossref
  • Saltz et al., 2004 L.B. Saltz, N.J. Meropol, P.J. Loehrer Sr., M.N. Needle, J. Kopit, R.J. Mayer. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J. Clin. Oncol. 2004;22:1201-1208 Crossref
  • Schrag et al., 2005 D. Schrag, K.Y. Chung, C. Flombaum, L. Saltz. Cetuximab therapy and symptomatic hypomagnesemia. Journal of National Cancer Institute. 2005;97:1221-1224 Crossref
  • Scope et al., 2007 A. Scope, A.L. Agero, S.W. Dusza, P.L. Myskowski, J.A. Lieb, L. Saltz, N.E. Kemeny, A.C. Halpern. Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption. Journal of Clinical Oncology. 2007;25:5390-5396 Crossref
  • Segaert et al., 2009 S. Segaert, G. Chiritescu, L. Lemmens, K. Dumon, E. Van Cutsem, S. Tejpar. Skin toxicities of targeted therapies. European Journal of Cancer. 2009;45(Suppl. 1):295-308 Crossref
  • Siena et al., 2009 S. Siena, A. Sartore-Bianchi, F. Di Nicolantonio, J. Balfour, A. Bardelli. Biomarkers predicting clinical outcome of epidermal growth factor receptor-targeted therapy in metastatic colorectal cancer. Journal of National Cancer Institute. 2009;101:1308-1324 Crossref
  • Siena et al., 2008 S. Siena, J. Tabernero, R.L. Burkes, J. Cassidy, D. Cunningham, M.E. Barugel, Y. Humblet, C. McPhie, M. Shing, J. Douillard. Phase III study (PRIME/20050203) of panitumumab (pmab) with FOLFOX compared with FOLFOX alone in patients (pts) with previously untreated metastatic colorectal cancer (mCRC): pooled safety data. Journal of Clinical Oncology. 2008;26(Suppl. 15s) (abstr 4034)
  • Sipples, 2006 R. Sipples. Common side effects of anti-EGFR therapy: acneform rash. Seminars in Oncology Nursing. 2006;22:28-34 Crossref
  • Sobrero et al., 2008 A.F. Sobrero, J. Maurel, L. Fehrenbacher, W. Scheithauer, Y.A. Abubakr, M.P. Lutz, M.E. Vega-Villegas, C. Eng, E.U. Steinhauer, J. Prausova, H.J. Lenz, C. Borg, G. Middleton, H. Kröning, G. Luppi, O. Kisker, A. Zubel, C. Langer, J. Kopit, H.A. Burris III. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. Journal of Clinical Oncology. 2008;26:2311-2319 Crossref
  • Tournigand et al., 2004 C. Tournigand, T. Andre, E. Achille, G. Lledo, M. Flesh, D. Mery-Mignard, E. Quinaux, C. Couteau, M. Buyse, G. Ganem, B. Landi, P. Colin, C. Louvet, A. de Gramont. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer. A randomized GERCOR study. Journal of Clinical Oncology. 2004;22:229-237
  • Vaccaro et al., 2009 M. Vaccaro, A. Pollicino, O. Barbuzza, B. Guarneri. Trichomegaly of the eyelashes following treatment with cetuximab. Clinical and Experimental Dermatology. 2009;34:402-403 Crossref
  • Van Cutsem et al., 2009 E. Van Cutsem, C.H. Köhne, E. Hitre, J. Zaluski, C.R. Chang Chien, A. Makhson, G. D’Haens, T. Pintér, R. Lim, G. Bodoky, J.K. Roh, G. Folprecht, P. Ruff, C. Stroh, S. Tejpar, M. Schlichting, J. Nippgen, P. Rougier. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. New England Journal of Medicine. 2009;360:1408-1417 Crossref
  • Van Cutsem et al., 2007 E. Van Cutsem, M. Peeters, S. Siena, Y. Humblet, A. Hendlisz, B. Neyns, J.L. Canon, J.L. Van Laethem, J. Maurel, G. Richardson, M. Wolf, R.G. Amado. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. Journal of Clinical Oncology. 2007;25:1658-1664 Crossref
  • Vano-Galvan et al., 2009 S. Vano-Galvan, P. Moreno-Martin, P. Jaén. Progressive trichomegaly. The Netherlands Journal of Medicine. 2009;67:35-36
  • Vectibix, 2008 Vectibix (Panitumumab) Prescribing Information. (Amgen, Inc., Thousand Oaks, CA, 2008) http://www.vectibix.com/pdfs/misc/vectibix_pi.pdf Available from:(accessed 9 July 2009)
  • Vectibix, 2009 Vectibix (Panitumumab) Summary of Product Characteristics. (Amgen Europe BV, Breda, The Netherlands, 2009) http://www.emea.europa.eu/humandocs/PDFs/EPAR/vectibix/H-741-PI-en.pdf Available from:(accessed 11 November 2008)
  • Viale and Sommers, 2007 P.H. Viale, R. Sommers. Nursing care of patients receiving chemotherapy for metastatic colorectal cancer: implications of the treatment continuum concept. Seminars in Oncology Nursing. 2007;23:22-35 Crossref
  • Wu et al., 2008 M. Wu, A. Rivkin, T. Pham. Panitumumab: human monoclonal antibody against epidermal growth factor receptors for the treatment of metastatic colorectal cancer. Clinical Therapeutics. 2008;30:14-30 Crossref
  • Zhang et al., 2007 G. Zhang, S. Basti, L.M. Jampol. Acquired trichomegaly and symptomatic external ocular changes in patients receiving epidermal growth factor receptor inhibitors: case reports and a review of the literature. Cornea. 2007;26:858-860
  • Zhang et al., 2006 W. Zhang, M. Gordon, H.J. Lenz. Novel approaches to treatment of advanced colorectal cancer with anti-EGFR monoclonal antibodies. Annals of Medicine. 2006;38:545-551 Crossref
  • Zuckerman and Clark, 2008 D.S. Zuckerman, J.W. Clark. Systemic therapy for metastatic colorectal cancer: current questions. Cancer. 2008;112:1879-1891 Crossref

Footnotes

a Department of Clinical Oncology, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, The Netherlands

b Waterland Hospital, Purmerend, The Netherlands

Corresponding author. Tel.: +31 71 5261965; fax: +31 71 5266725.


Search this site

E-Alert

Subscribe to our E-Alert to keep up to date with the new items in the Resource Centre

NEW! Free access to the digital version of a new publication in Cancer Supportive Care


Cancer cachexia: mechanisms and progress in treatment

Authors: Egidio Del Fabbro, Kenneth Fearon, Florian Strasser

This book was supported by an educational grant from Helsinn Healthcare SA.

Featured videos

Quality of Life promotional video

Made possible by an educational grant from Helsinn

Helsinn does not have any influence on the content and all items are subject to independent peer and editorial review

Society Partners

European Cancer Organisation Logo

Share