The epidermal growth factor receptor as a novel target for cancer therapy: Case studies and clinical implications

S e m i n a r s i n Oneo/ogy N u r s i n g , Vol 1S, No 4, Suppl 4 (November), 2002: pp 11-19

c ~ : using therapies targeted to

ZD1839, and OSt-774.:::: . . . . . . . . . . DATA SOURCES: Research articles, textbooks, clinical protocols, case studies. CONCLUSIONS" Ongoing studies show promise usiT~ monoclonal antibodies and small-molecule tyrosine kinase inhibitors in the treatment (¢' nonsn~tll cell hmg cancer and other rmdignancies. Such therapies can be delivered with limited toxicity to the host, and initial studies have slmwn single-agevtt effieaqv and qfficacw in combination with chemotherapy a n ( ~ r radiation therapy. IMPLICATIONS FOR NURSING PRACTICE: Nurses are directly involved in due delive~ of these novel therapies and the matutgement (g"associated toxieities. ThQv serve to coordinate treatment protocols am1 help to ensure patient understanding and compliance.

11

THE EPIDERMAL GROWTH FACTOR RECEPTOR AS A NOVEL TARGET FOR CANCER

THERAPY: CASE STUDIES AND CLINICAL IMPLICATIONS J E A N N E RIDDLE, P A M E L A L E E , AND M I C H E L L E P U R D O M

From Tke Umversity of Texas M.D. Anderson Cancer Center, Houston, TX. Jeanne Riddle, 1UNC,BSN: Supervisor ~" Research Nurses; Pamela Lee, RN, BSN: Research Coordinator; Michelle Purdom, RN, BSN:Research Coordinator. Thoracic Head and Neck Medical Oncolo~v Department, Tke Universi(v qf Texas M.D. Anderson Cancer Center, Houston, TX. Address reprint requests to Michelle Purdom, RN, BSN, The University of Texas M.D. Anderson Cancer Center, 1400 IIolcombe Blvd, Box 432, Houston, TX 77030.

Copyright 2002, Elsevier Science (USA), All rights reserved. 0 74 9- 2081/0 2/1804-04 03S3 5. 00/0 doi: l O,1053/so nu. 2002.3 7407

L

UNG CANCER, like o t h e r epithelial c a n c e r s , is b e l i e v e d to arise as a result of a m u l t i s t e p carcin o g e n i c p r o c e s s . 1 In 2002 t h e r e will be an estim a t e d 169,400 new eases of lung c a n c e r diagn o s e d and an e s t i m a t e d 154,900 d e a t h s f r o m this disease. 2 The relative S-year survival rate for all stages c o m b i n e d is only 15%. e Thus, i m p r o v e m e n t s in t r e a t m e n t are d e a r l y needed. All histologie types of lung cancers have a b e r r a n t p r o d u c t i o n of multiple growth factors and a b e r r a n t expression of multiple growth factor r e c e p t o r s ) N o n - s m a l l cell lung cancers (NSCLCs) frequently overexpress the epidermal growth factor r e c e p t o r (EGFR), encoded by ErbB1 (IIER1); ErbB2 (tiER2/neu); ErbB3 (HER3);

12

RIDDLE, LEE, AND PURDOM

and ErbB4 (HER4). 4 One new therapeutic app r o a c h that has been receiving a great deal of scientific interest over the past several years is the blockade of growth factor receptors as a target for therapy. This is often referred to as "targeted therapy."

and at targeting c y t o t o x i c s to specific tumors. F u r t h e r m o r e , c o m b i n a t i o n s of these new biologic agents and cytoxic agents have shown synergism and are u n d e r g o i n g intensive clinical evaluation.

RATIONALE FOR TARGETED THERAPY

INHIBITORS OF THE EPIDERMAL GROWTH

AGAINST THE EPIDERMAL GROWTH

FACTOR RECEPTOR

FACTOR RECEPTOR he rationale for a t t e m p t i n g to block growth factor f u n c t i o n as an a p p r o a c h to c a n c e r t h e r a p y is compelling_ s T h e r e is strong e v i d e n c e t h a t neoplastic cells gain a growth advantage b y o v e r e x p r e s s i o n of a v a r i e t y of growth factor receptors and active s e c r e t i o n of growth factors in what c o n s t i t u t e s a u t o c r i n e or p a r a c r i n e stimulation of t u m o r growth. T h e o v e r e x p r e s s i o n and activation of these cell-signaling p a t h w a y s is a p o o r prognostic factor in m a n y malignancies. 6-s Finally, some of these pathways are involved in c a n c e r cell sensitivity to c y t o t o x i e agents, and t h e i r b l o c k a d e or activation can be p o t e n t i a l l y exploited for the targeted c h e m o s e n s i t i z a t i o n of several h u m a n malignancies. 5 N o n - s m a l l cell lung c a n c e r s typically overexpress the EGFR, 9 a t r a n s m e m b r a n e glycoprotein also e x p r e s s e d in m a n y n o r m a l h u m a n tissues and n e o p l a s m s including h e a d and n e c k cancer, 10 gastric cancer, ~ b r e a s t cancer, 12 and p a n c r e a t i c cancer, la Epidermal growth f a c t o r r e c e p t o r is a m e m b e r of a superfamily of structurally and functionally related membrane growth f a c t o r r e c e p t o r s that have an associated t y r o s i n e kinase activity. 5 Advances in u n d e r standing t h e s e pathways during the last few years have r e s u l t e d in the d e v e l o p m e n t of diff e r e n t t h e r a p e u t i c strategies for lung c a n c e r a i m e d at e i t h e r specifically inhibiting lung cancer cell proliferation by growth factor r e c e p t o r blocking agents or targeting selectively cytotoxic agents to lung cancers. The EGFR p a t h w a y is t h o u g h t to play an i m p o r t a n t role in the physiologic t u r n o v e r of the b r o n c h i a l epithelium and in p r o m o t i n g r e g e n e r a t i o n after damage. 14 N u m e r o u s studies have led to the conc e p t i o n a n d d e v e l o p m e n t of t h e r a p e u t i c strategies aimed at controlling cell proliferation t h r o u g h r e c e p t o r blockade by m o n o c l o n a l antibodies or specific r e c e p t o r kinase inhibitors,

T

here are two classes of inhibitors that have received the most study: the small-molecule EGFR tyrosine kinase inhibitors (SMTKIs) and monoclonal antibodies to the receptors. ~5 There is one monoelonal antibody, IMC-C228, discussed in the following three ease presentations and two SMTKIs, ZD1839 (Iressa; AstraZeneca Pharmaceuticals, LP, Wilmington, DE) and OSI-774. These agents are in phase II and III trials in humans. IMC-C225 is a chimeric murinc-human monoclonal antibody that binds selectively and with high affinity to the EGFR_ 16 It blocks ligand-induced activation of the EGFR tyrosine kinase, thereby preventing intracellular signaling and subsequent tumor growth. 17 IMC-C225 may be given in the outpatient setting as a loading dose of 400 mg/m 2 administered intravenously over 2 hours followed by a weekly maintenance dose of 250 mg/m 2 given over 1 hour. is It has been shown to have antitumor activity in animal models against many human cancer cell lines, including NSCLC, ~5 and has shown promise in clinical t r i a l s . 19 T h e EGFR tyrosine kinase inhibitors are a group of orally active c o m p o u n d s that have b e e n u n d e r investigation for several years. Refinem e n t s in s t r u c t u r e have resulted in c o m p o u n d s with high p o t e n c y , oral bioavailability, and selectivity for the ErbB r e c e p t o r s 2 °,21 ZD1839 and OSI-774 are quinazolines that act by interfering with ATP binding in the t y r o s i n e kinase d o m a i n of the ErbB r e c e p t o r . T h e SMTKIs are well abs o r b e d orally and have b e e n a d m i n i s t e r e d on daily and i n t e r m i t t e n t schedules. A phase I Japanese trial gave i n t e r m i t t e n t ZD1839 t h e r a p y (for 14 of e v e r y 28 days) to 31 patients, 23 of w h o m had b e e n previously t r e a t e d for advanced NSCLC. 22 T h e m a x i m u m t o l e r a t e d dose was 700 mg/day. The objective r e s p o n s e rate among the 23 NSCLC patients was 22%. In a n o t h e r study, 23 OSI-774 150 mg was given daily to 56 patients with stage IIIB/IV or r e c u r r e n t meta-

T

EGFR AS A NOVEL

FIGURE 1. Typical grade II acneiform rash on the trunk of a patient receiving IMC-C225. static NSCI,C. O b j e c t i v e r e s p o n s e s w e r e s e e n in s e v e n p a t i e n t s (11%).

TOXICITIES WITH EPIDERMAl, GROWTH FACTOR RECEPTOR |NHIBITORS n c o n t r a s t to the severe toxicities resulting from standard c h e m o t h e r a p y drugs, the toxicity profiles of the I~GFR inhibitors are quite similar, and

I

TARGET FOR CANCER

THERAPY

13

tend to be less debilitating and m o r e manageable. The m o s t c o m m o n toxicity is a skin rash t h a t can vary from mild skin dryness to a m a c u l o p a p u l a r , acneiform eruption that tends to be m o s t severe over the face, neck, and u p p e r t r u n k (Fig 1). T h e rash appears to be a sterile, suppurative form of folliculitis, although s e c o n d a r y infection can occur. e4,25 This toxieity is thought to be caused by direct inhibition of EGFR in the skin. It has b e e n postulated that skin toxicity can serve as a surrogate m a r k e r for the biological efficacy of I~GFR targeting, The rash usually occurs within the first 3 weeks of t r e a t m e n t and then stabilizes or resolves with c o n t i n u e d therapy, e" T r e a t m e n t of the rash with topical or oral antibiotics, topical hydrocortisone, and/or retinoids does not provide consistent clinical benefit, but m a y be considered in selected e a s e s _ e-~,e'' At the University of Texas M_D. Anderson Cancer Center (Ilouston, TX), t r e a t m e n t is n o r m a l l y withheld when the rash progresses to grade 3 or greater (Table 1). The m o s t c o m m o n t r e a t m e n t for rash that progresses to the pustule stage is topical antibiotics. Clindamycin 1% gel is our firstline t r e a t m e n t for pustules. If the rash does not resolve with topical therapy, systemic antibiotics are used. Isolated patients have required hospitalization for grade 4 rash that required s y s t e m i c steroid t h e r a p y to resolve. Patients who experience persistent rash are referred to the Dermatology Clinic for evaluation and treatment. In rare eases, patients who have pre-existing skin disorders such as acne or rosacea can be treated suecessfully with isotretinoin. To date, we have infrequently reduced dosage or delayed t h e r a p y because of rash. No patient has needed to stop t r e a t m e n t b e c a u s e of rash. Once t h e r a p y is dis-

TABLE 1. Skin Rash: National Cancer Institute C o m m o n Toxicity Criteria Version 2.0

0

1

2

3

4

None

Macular or papular eruption or erythema without associated symptoms

Macular or papular eruption or erythema with pruritus or other associated symptoms covering <50% of body surface of local desquamation or other lesions covering <50% of body surface area

Symptomatic generalized erythroderma or macular, papular, or vesicular eruption or desquamation covering >50% of body surface area

Generalized exfoliative dermatitis or ulcerative dermatitis

14

RIDDLE,

LEE, AND PURDOM

continued, the rash generally resolves completely without scarring. Gastrointestinal toxicity is c o m m o n with the SMTKIs_ 27 Diarrhea has been the dose-limiting toxicity related to t r e a t m e n t with ZD1839 and O81-774. IMC-C225 is not known to cause diarrhea. Loperamide is our first-line t r e a t m e n t for diarrhea. If additional t h e r a p y is required, lomotil can be used. In our experienee at the M.D. Anderson Cancer Center, only one patient who had a history of irritable bowel s y n d r o m e and prolapsed r e c t u m has been taken off t h e r a p y for persistent diarrhea. Another patient had t r e a t m e n t delayed for hospitalization because of diarrhea from Clostridium difficile infection, but this toxicity was d e t e r m i n e d not to be related to t r e a t m e n t with the study drug_ Allergic reactions m a y be seen with IMC-C225. In a safety assessment, 31 of 419 patients (7.4%) treated with IMC-C225 either alone or in eombination with c h e m o t h e r a p y and/or radiation had allergic reactions. 26 In rare instances, IMC-C225 has been reported to cause grade 4 anaphylactic reactions. This type of reaction occurs in less than 2% of treated patients, typically with the first infusion. Adequate preparation for anaphylaxis is required in the infusion area for all patients treated with this monoclonal antibody. All patients are pretreated with d i p h e n h y d r a m i n e and d e x a m e t h a s o n e per protocol guidelines before infusions to prevent or ameliorate allergic reactions. The case studies that will be reviewed in this article are of patients who were enrolled in one of three clinical research protocols for the t r e a t m e n t of advanced (stage IIIb or IV) NSCLC. Two of the trials were managed at M.D. Anderson Cancer Center, and the third was managed at Deaconess Beth Israel Hospital in Boston, Massachusetts. All of the patients had either progressed or had recurrence of disease after traditional c h e m o t h e r a p y or c h e m o t h e r a p y and radiation t r e a t m e n t combined. All were treated with a novel EGFR inhibitor as a single agent or in combination with c h e m o t h e r apy. Each patient's experience in the clinical trial, response to treatment, associated toxicities, and their m a n a g e m e n t will be discussed. CASE PRESENTATIONS

Case Study 1 M.H. is a 72-year-old woman who was first diagnosed with NSCLC in June 2001 by a family

physician initially suspecting pneumonia. At that time she had a right upper lobe mass with mediastinal adenopathy_ Thoracentesis of a pleural effusion revealed adenocareinoma. Lung cancer staging was d e t e r m i n e d to be stage IIIb. Her initial t r e a t m e n t was two courses of carboplatin at area u n d e r the coneentration-time curve of 6 and paclitaxel 200 mg/m 2, given 3 weeks apart. Her disease progressed and she sought a second opinion at M.D. Anderson Cancer Center on September 14, 2001. Her past medical history is unremarkable except for a history of cigarette smoking for 34 years, stopping 16 years ago, and degenerative joint disease of the spine. She is a married homemaker with seven children and 26 grandchildren. On presentation to our institution she had no evidence of brain or bone metastases. Lung cancer was present at the above-stated stage, and she had the following signs and symptoms: 6-1b weight loss over 3 months, dry cough with mild chest pain, dyspnea on exertion, dry mouth, dry skin, anxiety, constipation, minimal peripheral neuropathy, and fatigue that resulted in two naps per day. Her performance status was 1. M.H. gave written informed consent and enrolled in a clinical trial that c o m b i n e d docetaxel intravenously every 3 weeks and IMC-C225 intravenously weekly_ The first cycle of therapy started on September 21, 2001. She received six cycles of doeetaxel at 75 mg/m 2 given every 3 weeks, and IMC-C225 given as a loading dose of 400 mg/m 2 on week 1 followed by 250 mg/m 2 weekly thereafter_ After completing the six cycles of doeetaxel, she continued to receive IMC-C225 on a weekly maintenance basis for six more 3-week cycles (a total of 17 weekly treatments; one t r e a t m e n t was missed because of a scheduling conflict). After two cycles, M.H_ exhibited a partial response by Response Evaluation Criteria in Solid Tumors criteria. This m e t h o d of determining response uses a unidimensional m e a s u r e m e n t from c o m p u t e d tomography scans; a 20% reduction in disease is required to be considered a partial response. M.H. maintained a durable response to the therapy. She ultimately reeeived 12 cycles of IMC-C225 before a new lesion was found in her brain_ During her course of treatment, M.H_ experie n c e d minimal toxicity with this regimen. Her most significant adverse effects were grade 2 sMn rash on the face, grade 2 dry skin on the lips and eyelids, and grade 2 fatigue. She had occasional diarrhea. All of these symptoms were attributed to the IMC-C225. M.H. had one hospitalization be-

EGFR AS A NOVEL

cause of urosepsis, which a p p e a r e d unrelated to h e r protocol therapy. She also was able to undergo v e r t e b r o p l a s t y of her l u m b a r and thoracic spine while on m a i n t e n a n c e t h e r a p y with IMC-C225. This would not have b e e n possible during a course of traditional c h e m o t h e r a p y because of the risks associated with myelosuppression. Over the course of her t r e a t m e n t she reported i m p r o v e d quality of life_ She was able to m a i n t a i n an active schedule of travel and social activity, and was able to spend time with her children and grandchildren. Iler IMC-C225-related toxicities of rash, dry skin, and diarrhea were successfully controlled during her therapy. The rash was treated with topical e l i n d a m y e i n gel, and dry skin around the m o u t h was relieved by lip ointment. Dry skin was treated with o v e r - t h e - c o u n t e r lotions. L o p c r a m i d e was used to relieve diarrhea. After failing first-line t r e a t m e n t for NSCLC with standard c h e m o t h e r a p y , M.II. was able to r e m a i n on an e x p e r i m e n t a l protocol combining doeetaxel and IMC-C225 for six cycles followed by 1MCC225 alone, without disease progression, for a period of 10 months.

Cttse Study 2 The second patient, C.F., was a 54-year-old female a d m i m s t r a t i v e assistant initmlly diagnosed with stage IV a d c n o e a r c i n o n m of the lung with metastases to the bone in 2000. She was a nonsmoker. Iler first-line therapy was with carboplatin and paclitaxcl, trot her p u l m o n a r y disease progressed after four cycles. She continued t r e a t m e n t with one cycle of vinorelbine and gcmcitabine along with palliative radiation therapy for painful osseous metastases, but her p u l m o n a r y disease progressed rapidly. This t r e a t m e n t was followed by four cycles of doectaxel. Unfortunately, during t r e a t m e n t with the docetaxel, she developed a liver metastasis. After failing three different regimens, the patient was referred to M_D. Anderson Cancer Center for evaluation and further treatment recommendations. On p r e s e n t a t i o n to our clinic, she had a perform a n c e status of 2 and required the use of a wheelchair. She was using continuous oxygen for dyspnea, and had grade 2 pain in the left c h e s t wall because of rib metastases, tter lung c a n c e r was stage IV b e c a u s e she had multiple osseous metastases, liver metastases, and a pleural effusion_ She also had grade 2 nausea, grade 2 fatigue, and was signifieantly depressed. At that time, she was no longer able to work in her profession b e c a u s e of

TARGET FOR CANCER

THERAPY

15

LCS Scores by W e e k 282420-

y/ R

Lung

,0-

..................

*

~

/_:-:~_ ......................................

Cancer Score 8-

4-

O

0

i

p

i

i

2

4

6

8

,

,

i

,

J

J

10

12

14

16

18

20

Weeks From Randomization LCS = L u n g Cancer Subscale (Score range 028: 0-severe, 28-asymptomatic)

F I G U R E 2. Improvement in lung cancer subscale scores for a patient receiving ZD1839 250 mg daily by mouth as a single agent,

the effects of her disease and the side effects of her c h e m o t h e r a p y and radiation t r e a t m e n t s . After consideration of her t r e a t m e n t options, she gave written informed c o n s e n t and enrolled in the IDEAl, (Iressa Dose Evaluation in Lkdvaneed Lung Cancer) 2 clinical trial_ This trial was a phase I1 ra~ldomized trial c o m p a r i n g response rates and the safety profile of ZD1839 at a dose of 250 mg or 500 mg in patients with r e c u r r e n t NSCLC. S e c o n d a r y o b j e e t i v e s i n c l u d e d qualityof-life m e a s u r e m e n t s . Patients could r e m a i n on t r e a t l n e n t mltil d o c u m e n t a t i o n of disease progression. This trial has b e e n u n b l i n d e d , indicating that this p a t i e n t r e c e i v e d the 2S0-mg dose. Two of the evaluations used in this trial were the lung c a n c e r subscale (LCS) and the Functional A s s e s s m e n t of C a n e e r T h e r a p y - L u n g (FACT-L) questionnaires. These m e a s u r e m e n t s are very helpful in evaluating the effectiveness of new therapies. The scale for LCS is () to 28, with 0 indicating severe s y m p t o m s and 28 being asymptomatie. The seale for the FACT-L questionnaire is 0 to 136, with 0 indicating a p o o r quality of life and higher n u m b e r s indicating i m p r o v e m e n t . In treating patients nearing the end of life, it is imp o r t a n t to balance the effectiveness of a specific therapy with its i m p a c t on quality of life. On e n t r y into the trial, this patient's LCS score was 12 and her FACT-L score was 56, indicating that her quality of life was low (Figs 2 and 3). In patients whose disease is responsive to these novel drugs, clinical, radiographic, and quality-oflife i m p r o v e m e n t s can be seen in a short period of time. Within 6 weeks of starting therapy, this patient's LCS seore had inereased from 12 to 16, and by week 10 it h a d increased to 2(i) (Fig 2). At

16

RIDDLE, LEE, AND PURDOM

136-

.= 98 90 ....... + . . . . ~.~ ...................

o IJ

(n .J

82

86

~.

(J < u.

i

Baseline

i

4

i

8

i

12

16

Weeks from Randomization

FIGURE 3. Improvement in Functional Assessment of Cancer Therapy-Lung (FACT-L) scores in a patient receiving ZD1839 250 mg daily by mouth as a single agent,

week 12 her FACT-L score was 98 (Fig 3) and she showed a partial t u m o r response (Fig 4). She no longer required the use of continuous oxygen or a wheelchair_ She remained on the study for a total

of 10 months. At the end of the t r e a t m e n t period, she continued to have improved quality-of-life scores and was able to work. This i m p r o v e m e n t was realized on single-agent therapy with ZD1839 after failure of traditional therapy. Her primary toxicity was the acneiform rash on the face and back, which was treated effectively with clindamycin topical formulation. She experienced grade 2 nausea throughout the study period, which was satisfactorily controlled with ondansetron. She did not experience diarrhea_ Unfortunately, the patient s u c c u m b e d to her disease in February 2002, but before her death she stated that she was thankful for her therapy with ZD1839 because of her s y m p t o m improvement.

Case Study 3 The third patient, J.M., was a 51-year-old w o m a n diagnosed with stage IIIa adenocarcinoma of the lung in July 1998. Her original t r e a t m e n t was on a research protocol at Beth Israel Deaconess Hospital in Boston, which consisted of treatm e n t with platinum and etoposide combined with

FIGURE 4. (A) Computed tomography of the chest of patient C.F, before receiving ZD1839 and after multiple cancer treatments (February 2001). (B) Follow-up computed tomography of the chest showing a response to treatment after only 3 months of ZD1839 given as a single agent at 250 mg daily (May 2001).

EGFR AS A NOVEL

radiation to the chest, a 6-week break, surgical excision of the involved lung, a 6-week break, and t h e n four cycles of earboplatin and paelitaxel. Following this therapy, the p a t i e n t was determ i n e d to be free of disease and was able to return to work at a large retail establishment, in J a n u a r y 2000 her disease recurred, with lesions in the remaining lung, liver, and bone. At this time, she enrolled in a p h a s e II clinical trial with O81-774. 23 As per protocol, the patient took 150 mg of O81-774 as a single agent, by m o u t h per day. The patient e x p e r i e n c e d d r a m a t i c reduetion of b o t h lung and liver nodules within 4 weeks of starting this t r e a t m e n t . She r e m a i n e d on t r e a t m e n t for 10 m o n t h s with a greatly i m p r o v e d quality of life. However, she ultimately progressed and suee u m b e d to her disease in J a n u a r y 2002. THE NURSING ROLE IN CLINICAL TRLLkLS WITH NOVEL AGENTS n the Thoracic/Head and Neck Medical Oneol.ogy D e p a r t m e n t at M.D. Anderson C a n e e r Center, r e s e a r c h nurses play an integral role in the eare and m a n a g e m e n t of all patients considered for and enrolled in clinical trials. Each of our 26 nurses is assigned to between one and five clinical trials to i m p l e m e n t and manage. Assignments are d e t e r m i n e d by trial complexity, phase, and anticipated aeerual. The r e s e a r e h nurse's involvement begins when a patient is identified by one physieian as a potential candidate for a elinieal trial_ At that point, the nurse begins evaluating the patient for eligibility eriteria either by interview or by review of the medical record. Because this d e p a r t m e n t m a n a g e s between 40 and 60 clinical trials at any given time, the r e s e a r c h nurse b e c o m e s the liaison and prim a r y resource for physicians and patients on his/ her assigned protocols. During the informed consent process, the nurse reviews the entire c o n s e n t d o c u m e n t and plan of eare with the patient and family after the trial has b e e n introduced by the physician. Ideally, the patient is t h e n given a period of time to "digest" the information, and a follow-up a p p o i n t m e n t is given to e o m p l e t e the c o n s e n t process and begin any required testing and t r e a t m e n t . During t r e a t m e n t on protocol, the research nurse is the patient's p r i m a r y c o n t a c t at the treat-

I

TARGET FOR CANCER

THERAPY

17

m e n t facility. She/he schedules all t r e a t m e n t and diagnostic testing in a c c o r d a n c e with the protocol, attends all elinie visits, assesses all toxieities and confers with the physician for t r e a t m e n t or dose modifieations, counsels the patients and families on all aspects of the clinical trial, encourages and evaluates protocol compliance, and c o m p l e t e s all institutional and regulatory m a n d a t e d d o e u m e n tation. A diagnosis of advanced lung or head and n e c k c a n c e r is devastating to m o s t individuals. Not only are they dealing with a potentially terminal disease, but t h e y m u s t also deal with debilitating s y m p t o m s , toxic t r e a t m e n t s , and end-of-life issues. The r e s e a r c h nurse can be i n s t r u m e n t a l in assisting patients and families in coping with m a n y of these issues. Speeifieally, in our department, nurses work closely with individual patients to help manage, control, and mediate the side effects caused by their c a n c e r therapy. In eollaboration with the physician, the nurses assess and grade toxieities according to the National C a n c e r Institute C o m m o n Toxicity Criteria scale. T h e y work with the physicians to suggest remedies as p e r m i t t e d by the specific research protocol. T h e y counsel patients on diet and aetivity r e c o m m e n d a t i o n s and assess w h e t h e r prescribed m e d i c a t i o n s are effeetively controlling toxieities. Because nurses are often m o r e aeeessible to the patients than physicians, they tend to provide m o r e e m o t i o n a l support. T h e y are also better able to work with the t r e a t m e n t centers, diagnostic eenters, and patients to arrange schedules that both c o m p l y with the protocol requirem e n t s and the patient's needs. Because m a n y patients travel from great distances for t r e a t m e n t in clinical trials at our facility, coordination and understanding of the patient's needs is p a r a m o u n t to ensuring c o m p l i a n c e with the protocol. In working with trials that i n c o r p o r a t e EGFR inhibitors into the t r e a t m e n t plan, our nurses have b e c o m e aware of the potential complications with these agents and, through extensive education, are able to help patients recognize and m a n age toxieities. For example, early t r e a t m e n t of the assoeiated rashes and diarrhea is critical to sueeessful m a n a g e m e n t . Before any patient begins t r e a t m e n t on a protocol he or she m u s t receive b o t h general e d u c a t i o n related to t r e a t m e n t with c h e m o t h e r a p y or radiation and very specific information regarding the research protocol. Pa-

18

RIDDLE, LEE, AND PURDOM

tients are counseled to notify the research nurse at the earliest sign of an emerging toxicity. CONCLUSIONS

n s u m m a r y , t r e a t m e n t of advanced NSCLC with •novel EGFR inhibitors has the potential to improve survival and increase quality of life with m a n a g e a b l e toxieities. The p r i m a r y toxicity is aeneiform rash_ In the majority of protocols, the preferred t r e a t m e n t for the rash is a topical agent. Systemic antibiotics and steroids are reserved for refractory rashes. Diarrhea is also frequently seen with SMTKIs and can n o r m a l l y be

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controlled with o v e r - t h e - c o u n t e r medications. Patients m a y tolerate these drugs for e x t e n d e d time periods. Some patients have b e e n able to r e m a i n on these agents for up to 2 years without disease progression. While this is an unusual occurrence, it is not u n c o m m o n for patients to be treated for m a n y m o n t h s for very a d v a n c e d disease that has not r e s p o n d e d to traditional c h e m o t h e r a p y . T h e s e novel agents p r o v i d e n e w h o p e in the fight against a d v a n c e d NSCLC a n d o t h e r life-threate n i n g m a l i g n a n c i e s . T h e y are e n t h u s i a s t i c a l l y r e c e i v e d b y p a t i e n t s h o p i n g for relief of s y m p t o m s and c o n t r o l of disease w i t h o u t debilitating toxicity.

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