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Home , Acne, Desquamation, Paronychia, Rash, Rosacea

GrandRound When treatment gets under your … Caring for patients with drug-induced acneiform eruptions

Ü Anna Wagstaff

EGFR inhibitors represent a bright hope for modern cancer therapies. But treatment comes at a price – an -like and other skin problems that can blight people’s lives. As these drugs become used more widely and at earlier stages of treatment, it becomes increasingly urgent to learn how to treat the side-effects and help patients.

was an odd tled down. Today, Andersen’s regular cal prognosis and decreased survival. feeling in dose of cetuximab leaves him with The skin problems that Andersen the skin. You some red spots around the base of continues to experience appear to be “ have seen the nose and on the chin. His col- common to all drugs that inhibit EGFR those horror leagues have got used to the sight of function. This is true of monoclonal an- movies. My his face, and he is not too bothered tibodies such as cetuximab, panitumu- skinIt was popping up, and about the problem. “I still have some mab (approved in the US but not yet in were breaking out. They were quite on my body, but those pimples are Europe) or matuzumab (still in phase big and a little bit itchy. It’s like acne drying up and falling off and it is not II trials), all of which block the EGF for young people. It was blistering up bad any more. I can handle it.” More receptor on the outside of cell. It is also

in my face and my hair.” of an issue is the around true of small molecules such as erlotinib And rews / ge tt yimages chris This is how one patient describes his fingernails and toenails, which (Tarceva) and (Iressa), which the feeling when, six days into his first developed around a month into the block the kinase pathways that course of cetuximab (Erbitux), he start- treatment, and is another characteris- send the erroneous signal from the re- ed to developed the acne-like skin rash tic side-effect of the drug, along with ceptor, to the inside of the cell, and of that is one of the known side-effects of dry skin, skin fissures, and problems drugs using other mechanisms of action drugs of that class. For the next month, around the eyes, nose and, in women, such as recombinant EGF or Jan Andersen opted to stay out of the the . anti-sense technologies. public eye as far a possible, and went Cetuximab is one of a growing class Current knowledge strongly indi- to work in the evenings when the office of drugs aimed at inhibiting the recep- cates that the mechanism causing the was empty. “I could have shown myself, tors for epidermal growth factor (EGF), skin problems is the same as the mecha- but I didn’t want to, because I would which plays a major role in the develop- nism that suppresses the tumour, which have scared people and I’d have been ment of many solid tumours and is asso- means that you cannot inhibit EGFR asked so many questions.” ciated with aggressive disease, increased without affecting the normal function- With the passage of time and resistance to chemotherapy and radio- ing of the skin. As EGFR inhibitors some helpful advice, the rash has set- therapy, increased metastasis, poor clini- look set to play an expanding role, with

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women. They don’t like to have pimples because they are afraid of the re- action of other people, who may say ‘you are not taking care of yourself,’ and so on. Some of these patients do not want to go out any more.” Segaert emphasises that skin can be effectively controlled with the right treat- ment and time. This treatment is not just cosmetic. Segaert has seen patients come off the drug because they couldn’t live with what it did to their face. “There are some who say: I would rather die than walk around with pimples. This is some- thing oncologists found very hard to understand at first. Of course we [dermatologists] are used to people with skin disease so we do not underestimate the problem, but I think on- cologists were surprised by the strong reaction

And rews / ge tt yimages chris of patients.” a variety of drugs used in a variety of Segaert says it took some oncologists a How bad can it get? solid tumours, including early disease, while to understand the extent to which The (acne-like rash) skin problems will become increasingly these skin problems affect patients’ is one of a series of skin problems as- prevalent. Clinicians, nursing staff, pa- quality of life. “Almost 80% of patients sociated with EGFR inhibitors, though tients and carers need to be equipped have these side effects to some degree. it is probably the one most patients find to deal with them. In the beginning people thought, this hardest to cope with. It tends to appear Dermatologist Siegfried Segaert has is not dangerous for health, not life- relatively quickly, three days to three worked with patients like Jan Andersen threatening, it is not like the severe weeks after starting on the drug, peak in since 2003, when Eric Van Cutsem nausea, vomiting, , diarrhoea severity early on, then settle down in a of the Digestive Oncology Unit of the you get with classic anti-cancer drugs. matter of weeks. However, it is likely to Gasthuisberg University Hospital in It’s just a few pimples. remain present at some level. Leuven, Belgium, started entering “The problem with this eruption is This eruption tends to be concen- patients with metastatic colorectal that you cannot hide it. It has a large trated on the face, neck, scalp and up- cancer into clinical trials. impact on self-esteem, especially with per torso. The pimples are often itchy

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GRADING OF ACNEIFORM ERUPTION the whole picture, combining so many Grade 1 Grade 2 Grade 3 Grade 4 Rash/ different skin problems in one patient, Macular or papular eruption Macular or papular Severe, generalized Generalized exfoliative, is unique. “I had never seen anything or without eruption or erythema with erythroderma or macular, ulcerative, or bullous like this before. It was like a new skin dis- associated symptoms pruritus [itchiness] or other papular or vesicular ease caused by this targeted therapy.” associated symptoms; eruption; desquamation It is clearly important for health localized desquamation covering ≥50% of body professionals and patients to learn how or other covering <50% of body best to manage these distressing skin Rash: acne/acneiform problems. There are also two additional Intervention not indicated Intervention indicated Associated with pain, reasons that make this an urgent issue. or The first is that almost all the evi- desquamation dence now indicates that people who National Cancer Institute Common Toxicity Criteria v3.0 experience a more severe skin reaction benefit most from the drug treatment. A and fill with , usually drying out to versa. Dry skin may be particularly bad consistent picture is emerging of a close form a yellow crust. The face may also at the tips of the fingers and toes, and correlation between skin rash and re- be covered in irritated red patches with can crack, resulting in painful fissures sponse for a number of EGFR inhibitors inflamed capillaries, though these usu- at the knuckles and around the nails. As in a variety of tumours (see p 18). (This ally disappear after a while. the skin becomes more fragile, the con- is not universal: some patients with lit- This acneiform eruption ranges dition can become complicated with tle or no skin rash may respond, while from asymptomatic skin lesions, to by S. aureus or even herpes some patients may have the rash with- a rash with severe itching or pain simplex virus. out a strong response.) Furthermore, through to acute extensive skin tox- Later still, around 14 weeks af- both skin rash and response appear to icity requiring the sort of specialist ter the start of therapy, about 10% of vary according to the dose. This means treatment given at a unit. The patients develop swelling and inflam- that far from hoping to avoid these skin rash has been classified into four mation around the nails () problems, in the future, patients with a grades of severity according to the resembling in-growing toenails. This mild or no rash may be encouraged to National Cancer Institute Common does not usually fade over time, and can increase the drug dose to the point that Toxicity Criteria (NCI CTC v3.0, see make it very painful to walk, or even to a grade 2 or greater rash develops. above). hold a book or a newspaper. It is very This is a possibility being inves- Around 70%–90% of patients on difficult to cure, but the symptoms can tigated in the EVEREST trial, led by EGFR-inhibiting monoclonal antibodies be alleviated. Patients may also develop Van Custem. Patients being treated for are likely to develop some level of rash, ulcers in the nose or mouth, vaginal dry- metastatic colorectal cancer who show while 5%–18% develop a severe rash. ness and problems around the eyes. little skin rash (grade 1 or less) are ran- Grade 3/4 rash appears much less com- None of these symptoms were pre- domised to stay on the standard weekly mon with the tyrosine kinase inhibitors viously unknown, but Segaert says that dose of 250 g/m2/w cetuximab + irinote- gefitinib and erlotinib (see box, below, right), but this may be due to the fact incidence OF ACNEIFORM ERUPTION that doses are limited by other side-ef- EGFR inhibitor Patients with some rash Patients with severe rash Cetuximab 80%–86% 5.2%–18% patients ≥ grade 3. Rash fects such as diarrhoea. tends to be more severe when given Around eight weeks after start- in combination with irinotecan ing on one of these drugs, up to 35% Panitumumab (1–2.5 mg/kg/week) 70%–100% ±10% severe of patients develop very dry, scaly and Panitumumab (6 mg/kg/week) 90% 16% ≥ grade 3 itchy skin on the arms and legs as well Erlotinib (150 mg/day) 67%–79% 2.6% –10.4% ≥ grade 3 Gefitinib (50–700 mg/day) 53% (0%–78%) 1.6% ≥ grade 3 as the areas previously affected by the Gefitinib (150–1000 mg/day) 65% 2.2% grade 3 acneiform eruption. This complicates Lapatinib (+capecitabine) 26% 2% grade 3 the management of the problem, as Sources include: S Segaert, E Van Cutsem. Clinical signs, pathophysiology and management of skin toxicity the treatments that are good for dry during therapy with epidermal growth factor receptor inhibitors. Ann Oncol, vol 16, p 1426 © European Society skin can exacerbate the rash, and vice- for Medical Oncology

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toxicity timeline

Acne-like rash Post inflammatory effects Dry skin Fissures Paronychia

weeks 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Description of severe cases

EGFR inhibitors are associated with a unique combination of skin side-effects, which complicates treatment options. The acne-like rash tends to flare up quickly, and usually settles down after a few weeks; dry skin, fissures and problems may kick in after two or three months Source: TARGET, European Oncology Nursing Society; pictures courtesy of Siegfried Segaert can or to have their dose progressively set to be used for an increasing variety and to putting up with the side-effects increased in steps of 50 g/m2/w up to of cancers, and are coming into use at of cancer drugs. a maximum of 500 g/m2/w until a rash an increasingly early stage. Liesbeth Lemmens is a specialist of at least grade 2 severity appears or a Clinical trials are investigating the nurse at the Gasthuisberg University tumour response occurs. use of EGFR inhibitors as a second- or Hospital in Leuven with several years’ Early results (24 weeks), which even first-line treatment for metastatic experience caring for colorectal pa- were reported at the gastrointesti- colorectal cancer. Other trials, such as tients receiving EGFR inhibitors, in nal meeting of the American Soci- PETACC 8 (Pan-European Trials in Al- settings ranging from third- or fourth- ety of Clinical Oncology (ASCO imentary Tract Cancer), are looking at line therapies to adjuvant treatment. GI) in Orlando in January, show a the effectiveness of cetuximab given in She sees a big difference in attitude partial response rate of 30% in the combination with an oxaliplatin-based between groups of patients. Patients dose-escalation arm compared to chemotherapy as an adjuvant therapy treated in a third- or fourth-line setting 13% in the control arm, although in patients with fully resected grade III may be more likely to say: “As long as the control arm shows a higher pro- colon cancers. There are already signs we can live, we will accept this skin portion of patients with stable dis- that patients receiving the drug in these toxicity, or any toxicity at all.” Patients ease (56% vs 43%) and a slightly earlier settings are finding it harder to treated in an adjuvant setting can find lower proportion with disease pro- accept the skin side-effects. the side-effects harder to accept. gression (22% vs 27%). Van Cutsem This is perhaps not surprising. For “They have just had their cancer believes these results are very en- the first generation of patients like Jan diagnosis, and they need time to get couraging, but stresses it is early Andersen, EGFR inhibitors represent used to that. They are active. They days yet, and clinicians should not a chance of extra months (or more) have their life and their hobbies; many increase the dose beyond the cur- of life. Patients receiving EGFR in- of them go to work.” rent recommended levels outside hibitors in an adjuvant setting, by Jan Andersen, in contrast, had al- of a . contrast, have no clinical evidence ready been through four years of treat- The second reason why it is becom- of disease and may never develop a ment, with at least as many different ing more urgent to spread knowledge recurrence or metastasis. regimens before he was introduced and experience about managing skin On top of this, adjuvant patients to cetuximab, and he remembers the problems is that EGFR inhibitors are are simply less used to having cancer side-effects of all of them. “The worst

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Correlation between rash and response experiences. A conference involving 20 oncologists and dermatologists from centres in Belgium, France, Germany, 18 Italy, Spain and the UK has generated 16 probably the most authoritative, expe- rience-based, consensus guidelines to 14 date (JDDG 2005, vol 3 pp 599–606). 12 Cancer nurses such as Lemmens have also been able to share their ex- 10 periences and pass their knowledge on 8

Survival (months) Survival to others through the TARGET training course on molecular targeted therapies 6 organised by the European Oncology

4 Nursing Society. One of the keys to managing the 2 level of skin problems for most patients

0 lies in good general advice – the ‘Dos Cetuximab erlotinib and Don’ts’ designed to alleviate the CRC CRC CRC CRC Pancreatic scchn NSCLC SCCHN Ovarian 9923 0141 bond Van Cutsem Xiong Kies Perez-Soler Kris 2006 Presentation at problems on the one hand and to avoid Saltz 2001 Saltz 2004 Cunningam 2004 2004 2002 2003 MASCC 18th International exacerbating them on the other (see 2004 Symposium No reaction Grade 1 Grade 2 Grade 3 Grade 2/3 opposite). Patients need this advice in writing and a chance to discuss it both CRC, colorectal cancer; SCCHN, squamous cell head and neck cancer; NSCLC, non-small-cell lung cancer before treatment begins, to ensure Studies looking at different EFGR inhibitors in different cancers and settings indicate a strong and they understand the principles, and consistent correlation between skin rash and clinical benefit during treatment, so they can adapt it according to what works best for their one was Xeloda [capecitabine]. The image and alters the way one is per- lifestyle. skin was peeling off my sole; I couldn’t ceived by others. This can cause prac- For medical treatment of a less walk for three to four days in some cas- tical as well as personal problems. severe rash, the consensus recommen- es. Then I was on oxaliplatin. I lost my Lemmens cites the example of a pa- dations published in the JDDG rec- hair, but that didn’t matter. I could also tient who worked as a waiter. “He feels ommend gel or cream, feel a tingling in my fingers and throat very well, he has a good quality of life, or gel or when I went out into the cold. I felt a but he cannot go to work because no- , gel or cream little bit tired too. Then came CPT11 body wants their spaghetti served by a on the face or in alco- [irinotecan], which had few side-ef- waiter with severe skin toxicity.” holic lotion on the chest/back. To get fects, just a little tiredness.” So when, the best balance between treating the after switching to cetuximab, his face “We can treat it” rash and treating the dry skin, which rash confined him to his home for a While it is important to understand that kicks in a little later, they recommend month, he was philosophical about it. EGFR-related skin toxicity can damage cream in preference to or gels Partly, it is also a matter of person- a patient’s quality of life, those with ex- as the eruption recedes or progresses ality. “ We had one patient who was perience caring for these patients be- to a scaly form. very severely affected, who quipped: lieve there is another equally important For more symptomatic rash (grade ‘Well at least I can have free access to message: “We can treat it.” 2), oral and/or menthol the Hallowe’en party,’” says Lemmens. Though there are not yet any evi- cream can be used against itchiness. “We also have patients who have only dence-based guidelines, and the litera- Oral tetracylines help control the one and are very upset.” She ture on managing EGFR skin problems inflammation. In the case of grade points out that this is not a question of is still in its infancy, a number of treat- 3 rashes (symptomatic lesions over vanity. The face is fundamental to a ment centres have developed their own more than 50% of the body), the rec- person’s sense of identity and self- protocols and are beginning to share ommendation is to delay further drug

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“There is a need for more research and clinical studies to develop evidence-based guidelines” treatment. Applying saline compress- inflamed, highly vascular granulation Dos AND DON’Ts es to the most inflamed areas has been tissue on the skin). found to be very effective, but also The JDDG document has to be n Be prepared for skin side-effects; the dries the skin; oral are viewed as a first stab at offering wel- acneiform eruption will probably peak at good for alleviating itchiness. High- come guidance to professionals and around two weeks, but can also flare up later. dose systemic are rec- patients who are grappling with these It can be alleviated but not cured by careful ommended; however, they can some- problems every day, but the authors management. This is also true of longer-term times be hard on the stomach, and stress that there is a need for more re- side-effects such as dry skin, fissures on the may compound problems caused by search into the mechanism behind skin fingers, toes and heels, inflammation around the anti-cancer drugs. In very severe toxicity, and for more clinical studies to the nails, ulcers in the nose and mouth and cases, where the skin is ulcerating, develop evidence-based guidelines. vaginal dryness treatment similar to that provided in Like all such documents, the n Keep out of the sun. Heat and humidity a burns unit is recommended and the consensus guidelines represent a exacerbates the inflammation and too much patient should come off the drug. compromise. While metronidazole, sun can lead to in the The JDDG document also address- erythromycin, clindamycin and ben- affected areas. es management of non-rash symp- zoyl peroxide are all recommended n Wash skin and hair in lukewarm water, and toms. For dry, scaly skin, moisturising to treat the acneiform eruption, not too frequently. Too much washing dries the emollients are recommended. Should Segaert, who is lead author, says his skin, and the rash is not caused by dirt or infec- this develop into eczema, topical low- preference is to stick with metroni- tion (though these can cause complications) dose can be used for dazole because, unlike the others, it n Use bath or shower oil or special skin- up to two weeks. or sys- is specially formulated for sensitive friendly soaps and shampoos rather than temic are suggested for skin. His view is supported by the normal soaps, shampoos or gels, which can secondary bacterial infection or sys- HER1/EGFR-inhibitor Rash Man- exacerbate dry skin problems – a good rule temic antiviral drugs for viral (herpes agement Forum, which convened is to avoid anything that foams simplex) infection. For skin fissures, in New York in January 2004, and n Wear shoes that don’t press on your toes; early use of salicylic acid is recom- included dermatologists and on- take them off or wear slippers or open-toed mended, with hydrocolloid tape or cologists from Canada, Germany, sandals where possible glue to help alleviate the pain. Italy, Spain and the US. They argue n Use moisturising cream to counter dry skin For the inflammation around the against the use of benzoyl peroxide, on the limbs, but avoid using it on areas af- nails – which can be painful and de- because it would aggravate the dry fected by the acneiform eruption, as this can bilitating – there are few treatment skin, and suggest a clinical trial to suffocate the skin and make the rash worse options. Partial surgery to the nail evaluate the use of topical antibiotics n It’s fine to use make-up, but stick to hypo- does not appear to be an answer. The such as clindamycin. allergenic brands use of / soaks or The use of is another n Don’t worry about diet; it is not a factor creams may ease the pain; some der- area of controversy. These are used as n For treatment of the rash, look for advice matologists recommend a paste con- standard for normal acne and are re- from your oncology team or a specialist der- taining an antiseptic and anti-yeast, portedly used in France for treating matologist. General practitioners, pharma- and in severe cases a , EGFR inhibitor-related skin rash. The cists or dermatologists unfamiliar with the to reduce inflammation and pain. JDDG document keeps on open mind problem may recommend standard anti-acne Silver nitrate can be used to treat as- on these options, stating that “the use treatments, many of which are unsuitable sociated (a small of oral retinoids in this setting remains rounded and often ulcerated mass of experimental.”

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CONsENsUs RECOMMENDATIONs quent communication with the patient. Treatment of skin reactions teams working with EGFR inhibi- Symptomatic patient complaint Signs tors need to build a close collaboration with dermatologists who have expertise Itching Dry skin Dry skin Mild/moderate rash Fissures Paronychia in this area, says Segaert. However, der- EMOllIENT TOPICAl APPROACh TOPICAl APPROACh matologists do not normally need to be ADVICE Antibiotic preparations, Emollients plus salicylic acid Soap substitutes e.g. clindamycin or erythromycin Hydrocolloid dressing directly involved in caring for patients bath oils Acne creams, e.g. benzoyl peroxide (e.g. Comfeel) unless their rash is grade 3 or 4. Shower gels creams, e.g. metronidazole Flurandrenolone tape Regular moisturisers Preparing patients in advance for novel topical retinoids e.g. sparing application Topical antibiotic of 0.1 gel/cream may be tried if infection occurs what is likely to happen to them is es- sential. Gasthuisberg nurse Liesbeth Sedating anti- Moderate/severe rash TOPICAl APPROACh Treat dry skin if present Antiseptic preparations e.g. Lemmens suggests that oncologists Topical approach soaks or creams should start by telling their patients: * Note adverse effects As for mild to moderate with tetracyclines: Plus “We have a lot of experience with this General: GI upset. Specifi c: Systemic approach (>12 weeks) skin toxicity. It can sometimes be se- photosensitivity most Second generation tetracyclines* e.g. 300 mg common with I-II daily, doxycycline 50-100 mg daily, 100 mg vere, but we can treat it.” Illustrations and dose related showing where on the body the differ- This treatment algorithm for EGFR inhibitor-related skin reactions represents a consensus reached by ent problems are likely to appear are oncologists and dermatologists from all over Europe. Some of the recommendations, such as the use helpful, but she advises strongly against of retinoids or benzoyl peroxide, remain controversial. Lead author Siegfried Segaert and the New York showing patients the close-ups of se- HER1/EGFR-inhibitor Rash Management Forum do not recommend their use vere rash used in academic literature, Source: S Segaert, J Tabernero, O Chosidow et al. The management of skin reactions in cancer patients receiving which can be unnecessarily alarming. epidermal growth factor receptor targeted therapies. JDDG vol 8, p603, © Blackwells 2005 Patients at Herlev University Hos- pital in Copenhagen, denmark, are Segaert’s personal view is that all retin- are likely to remain – with doctors now given a ‘green card’ before starting oids are inappropriate, being too irritat- balancing the anti-rash effect against their treatment. this details the sorts ing and without rationale. “they work exacerbating the dry skin problem, of symptoms that may develop, offers on blackheads and whiteheads, which according to their own preferences general advice on dos and don’ts, what you have in acne, but not in EGFRi and the practice in their department. sort of soaps, lotions and creams to use, induced acneiform eruption.” this view Other areas will hopefully be clarifi ed and what additional treatments can be also receives support from the HER1/ through prospective clinical trials, such prescribed by the doctor. It encourages EGFR-inhibitor Rash Management Fo- as the BABEL trial being carried out in patients to report any side-effects that rum, which states that there are no data Belgium, which is seeking to establish bother them. to support the use of retinoids, and use whether oral in addition to At both Herlev and Gasthuisberg in is not advised as their skin-drying topical therapy is more effective than Leuven, patients starting treatment with effects may exacerbate the rash. topical treatment alone for cetuximab- an EGFR inhibitor are routinely given a Segaert also advises strongly against induced acneiform eruption. bag containing recommended lotions, using the oral isotretinoins creams, soaps, shampoos and so on. this Accutane or Roaccutane, at least for FroM gUidance to practice means that patients can apply the treat- now. though it appears to be effec- One of the big challenges for effective ments as soon as symptoms start to ap- tive against EGFRi-associated rash, management of skin problems is the pear – or even before. Inge nielsen, head the drug is known to downregulate different treatment approaches needed nurse at the Herlev unit for experimental EGF receptor, and could thus dimin- to cope with the variety of side-effects, cancer treatment, says it is also very ish the target for the anti-cancer drug. at different stages, with varying severity important psychologically: “the It also causes side-effects that would and impact on the patient’s quality of life. patient feels we care about them.” compound other symptoms – dry skin, Meeting this challenge requires a multi- Under the current experimental nail-fold infl ammation, and a tendency disciplinary approach in which oncolo- protocol for cetuximab, patients being to superinfection with S. aureus. gist, dermatologist and specialist nurse all treated in an adjuvant setting have Some of these areas of controversy play a role, and also requires good and fre- to tolerate the drug for six months.

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“We are absorbed in new treatments, without considering what it is doing to quality of life”

Patients with metastatic disease will “We have to ask the patients to take A similar point is made at Gasthuisberg be on EGFR-inhibitors until they stop off their shoes and look at their feet, by Van Cutsem. “It took me far longer responding. Knowing their oncology because they do not tell us if we don’t in the past. It is important to be well or- team understands the distress these ask them. You need to ask very clearly: ganised. I was able to learn a lot from the side-effects can cause and is commit- ‘Can I see your feet? What about your dermatologist and he was able to learn a ted to helping alleviate the problem is fingers? Do you take the pills we rec- lot from us. Having strong nursing back- likely to be important in helping pa- ommend? Are you using sun protec- up is very important. They can help in- tients stick with the treatment. tion? How are your eyes? Can I look struct for some of the easy aspects, and Lemmens remembers helping one in your nose?’ Another thing that can give a lot of practical tips.” young patient improve the appearance be very irritating is vaginal problems Lemmens has worked alongside of her face sufficiently to attend a par- for women. You have to ask them, be- Van Cutsem for three years with patients ticularly important party. “We treated cause it is very difficult for the women who are on cetuximab and panitumu- her with oral corticosteroids for a cou- to ask us about it. Those problems are mab as third-, second- or first-line treat- ple of days (though this is not standard more common than we even know, and ments or taken as adjuvant treatment. care), and advised her on what cosmet- we are not good at questioning women She says that nurses play a key role with ics she could use, and she went to the about it.” the patients. “You need the oncologist to party and she was happy.” This approach takes time, always prescribe the drugs, unguents and anti- Giving patients a treatment break a scarce resource in oncology depart- biotics and so on. And then there is the is difficult because little is known ments. Developing a standard protocol dermatologist who can advise patients about how quickly the disease is likely for discussing side-effects and select- if the oncologists are not sure what to to progress. When patients start to get ing treatment options is key to saving do… with , with paronychia, really fed up, Lemmens sometimes tells time while ensuring that all patients for more specialised care. The nurses them that skin rash tends to indicate that are cared for appropriately. The treat- can be very helpful as far as the general the cancer is responding well to the treat- ment algorithm published from the recommendations are concerned – the ment. “That makes them feel better.” She consensus conference (p20) is a good dos and the don’ts. They can advise the says, however, that it is important to be starting point. At Herlev, in addition to patients weekly on what to do and what careful about using that information, the ‘green card’ for patients, they have to take. They are a go-between between “You can’t say that from the start, because published an orange booklet that medi- the and the patient.” we do have patients who don’t have skin cal and nursing staff can use to identify Weekly advice is, of course, easier toxicity who also have a good response. grades of rash and other problems, and if the patient has to visit the treat- And you need to check who might over- to select treatments. ment centre that often, as is common hear. Is there is a patient sitting nearby Experience also helps speed up the with cetuximab. Panitumumab, how- who has no toxicity at all?” process. Nielsen says, “In the beginning ever, tends to be administered fort- Under-reporting symptoms can it took a lot of time for us, but now it is nightly, so the oncology team has to also be a problem. Nielsen stresses just part of the treatment to discuss the think ahead and encourage patients that it is important to ask patients side-effects with the patient, and we to phone for advice. The tyrosine ki- about each symptom every time you don’t have to think so much about it.” nase inhibitors gifitinib and erlotinib see them. Sometimes patients keep She sees her patients every two weeks, are both administered orally, resulting quiet because they are worried they and estimates that she needs an average in fewer visits to the treatment centre. may be taken off the treatment. Oth- of 30 minutes, with the greatest time Factoring in the need to control the ers suffer in silence or can’t face tak- usually needed before treatment and in side-effects is therefore particularly ing any more medicines or ointments. the early weeks. important here.

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Filling the knowledge gap that dephosphorylate the gap about how the skin-effects of As increasing numbers of patients are EGFR is currently in the early stages of EGFR inhibitors impact on patients’ treated by EGFR inhibitors at more development. lives. Including quality of life meas- and more treatment centres, it is es- While waiting for a wonder drug, ures as a parameter in clinical trials sential that existing knowledge and however, there is a lot that can be is one of the main recommendations experience about managing the skin learned about how best to use existing of the JDDG document on managing side-effects is rapidly disseminated. treatments. Controversies over the skin toxicities. It is also something Segaert encourages oncologists to use of retinoids, , or the best Nielsen feels particularly strongly communicate with dermatologists, time to start administering systemic about. to learn about the side-effects, read anti-rash treatments such as tetra- “We are still too absorbed in just the papers and go to presentations. cycline, need clarification through looking at what new treatment we can He also says that many dermatologists prospective clinical trials. Lemmens offer, without any consideration of need to get up to speed on how to believes a great deal could also be what it is doing to patients’ quality of manage this unique combination of learned by systematically sharing life. We have to take into account how problems. experiences between treatment cen- the patient is feeling. We shouldn’t Specialist nurses are in the front- tres, and floats the idea of setting up just look at a patient, make up our line of advising patients and admin- a website for this purpose. minds and treat them. We have to ask istering more general treatments, There remains a big knowledge patients what they want from us.” and they also need training – some- thing the TARGET course run by the EGFR inhibitors European Oncology Nursing Soci- ety is designed to do (http://tinyurl. Two EGFR inhibitors are currently approved for use in Europe com/36dvbo). Nielsen admits to feel- n Cetuximab (Erbitux): a monoclonal antibody approved for use in combination with iri- ing isolated when trying to develop notecan in patients with metastatic EGFR-expressing colorectal cancer when previous a protocol at her own department at treatment including irinotecan has failed. This drug is also approved for use in patients Herlev, and says that it is important with locally advanced squamous cell cancers of the head and neck, when it is given in for nurses to have the chance to get combination with radiotherapy. together, compare notes, and pass on n Erlotinib (Tarceva): a tyrosine kinase inhibitor (small molecule) approved for use in patients their experience to others. Both she with locally advanced or metastatic non-small-cell lung cancer after failure of at least one and Lemmens are painfully aware of prior chemotherapy regimen. the lack of evidence-based guidelines Three additional EGFR inhibitors are currently approved in the US that they have to work with. The likeli- n Gefitinib (Iressa): also a tyrosine kinase inhibitor approved for NSCLC. Approval was refused hood is that in six months or a year the by EMEA on the grounds that survival benefit was insufficient across the trial population. advice they will be giving patients may n Panitumumab (Vectibix): a fully human monoclonal antibody approved for use in metastatic be quite different from what they are colorectal cancer following standard chemotherapy. An application for marketing approval saying today. was submitted to EMEA in April 2006. And generating this new knowledge n Lapatinib (Tykerb): a dual ErbB2/EGFR inhibitor, approved by the FDA in March this year for is the second priority. Clinical trials in- patients with HER2-positive locally advanced or metastatic breast cancer who have received volving EGFR inhibitors often include a prior therapy with other cancer drugs, including an anthracycline, a taxane, and trastuzumab translational element looking at the (Herceptin). An application for approval by EMEA was submitted last October. mechanism behind the skin changes. Future directions Early research into possible treatments All the above EGFR inhibitors are being intensively investigated to gauge effectiveness in a targeted at this specific problem may be variety of other indications, including pancreatic, renal cell and ovarian cancers, and at earlier beginning to bear fruit; one promising stages and in different combinations. This includes combining with cytotoxics, with radiotherapy, strategy is to cancel the effect of the and with other targeted drugs, such as bevacizumab (Avastin, which inhibits angiogenesis by EGFR inhibitor specifically in the skin, targeting vascular endothelial growth factor – VEGF) or multi-kinase inhibitors such as sunitinib while still allowing it to function against (Sutent) or (Nexavar). the cancer. A topical phosphatase inhibitor – vitamin K3 – which inhibits

22 n Cancer world n may/june 2007