Practical Management of Patients With Non–Small-Cell Lung Cancer Treated With Gefitinib
http://www.100md.com
《临床肿瘤学》
the Thoracic Oncology Service, Division of Solid Tumor Oncology, and Dermatology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center
Departments of Biostatistics, Surgery, and Radiology, Weill Medical College of Cornell University, New York, NY
ABSTRACT
METHODS: This article reviews gefitinib’s indications, dosing, response phenomena, and patterns of relapse in individuals with radiographic response.
RESULTS: We present our recommendations for the management of rash and diarrhea caused by this agent.
CONCLUSION: This information can guide practitioners and help them inform their patients about what to expect when they receive gefitinib.
INTRODUCTION
Gefitinib is an anilinoquinazoline compound that inhibits the EGFR tyrosine kinase in vitro with a 50% inhibitory concentration of 0.27 to 33 μmol/L, more than 100 times less than the concentration required to block the kinases of HER-2, KDR, MEK-1, and MEK-2.5 In its initial clinical study, gefitinib caused radiographic regressions and symptom improvement in patients with non–small-cell lung cancers refractory or resistant to chemotherapy.6-9 Based on this experience, gefitinib has become the most extensively studied and most widely used small molecule inhibitor of the EGFR tyrosine kinase. It has been approved for use by the regulatory authorities in the United States, Japan, and many other countries.
The unique mode of action of gefitinib and its potential for use in patients with a common tumor who frequently need second-, third-, or even fourth-line therapy require a thorough understanding of how to care for individuals receiving this agent. Many of the principles of management relevant to gefitinib are distinct from those with conventional cytotoxic drugs. To meet this need, we present practical guidelines on the use of gefitinib in patients with NSCLC. These recommendations are based on published data as well as our clinical experience.
METHODS
Radiographic Regression Rates in Unselected Patients
Three of the four phase I trials of gefitinib reported radiographic regressions in patients with NSCLC refractory to multiple chemotherapy regimens.6,8,9 In phase I testing, 10% of patients with NSCLC experienced partial radiographic responses often accompanied by rapid symptomatic improvement. This experience prompted two phase II trials in which radiographic regression was seen in 14% and symptomatic improvement in 39% of patients.10,11 Radiographic responses occurred in as little as 1 week. These response rates compared favorably with those of conventional cytotoxic agents used after disease progression with cisplatin or carboplatin. In this setting, docetaxel had a response rate of 8% and vinorelbine 0%.12,13 For our series of 21 patients with partial radiographic regressions, the median duration of response was 12 months. The shortest response lasted 4 months and the longest continues 60+ months after the start of gefitinib.
Pretreatment Clinical Factors Predicting Sensitivity to Gefitinib
Since radiographic responses are seen in only a fraction of patients, investigators have attempted to identify pretreatment characteristics associated with sensitivity to gefitinib (Table 1). In the international study (IDEAL I) where half of the patients were enrolled in Japan, Fukuoka et al10 described a higher response rate in Japanese patients compared to non-Japanese patients (28% compared to 10%; P = .0023). In addition, a multivariable analysis showed that performance status (PS) 0 to 1, female sex, adenocarcinoma histology, and prior immuno-/hormonal therapy (including picibanil, investigational drugs, minomycin, marimastat, and tamoxifen citrate) were prognostic factors associated with objective response to the agent. In the United States study (IDEAL2), higher rates of radiographic response were observed in women (19% compared to 3%) and patients with adenocarcinoma (13% compared to 4%).11 Symptom benefit was also more likely in the same two groups.11 A separate analysis performed by the US Food and Drug Administration on the US trial data detected higher rates of radiographic response in never smokers (29%) compared to previous or current smokers (5%).14
We have recently reported a retrospective review of 139 patients treated with single-agent gefitinib. A history of never smoking cigarettes (P = .0006) and bronchioloalveolar histology (P = .004) were determined to be independent predictors of radiographic response.15 In our series, rates of radiographic response were numerically higher in women as well (19% compared to 8%; P = .14). Based on this data, we calculated the response rates and median survival for groups of patients with none, one, two, or all three pretreatment clinical characteristics associated with higher gefitinib sensitivity (Table 2). The presence of all three characteristics yielded the highest response rates and median survival (56%; 14 months). Response rates and median survival progressively decreased if patients had two, one, or none of the characteristics. Removing sex from the analysis reveals that patients who never smoked cigarettes and who had adenocarcinoma with any bronchioloalveolar carcinoma features16 (and not simply "pure" bronchioloalveolar carcinoma as defined by the WHO) had high response rates and median survival (55%; 14 months; Table 3). We have noted that tumor specimens correctly read initially as NSCLC or NSCLC-NOS (not otherwise specified) may, in fact, contain some areas with bronchioloalveolar features. In an ongoing trial, tumors classified or reclassified as adenocarcinomas with bronchioloalveolar features were three times as likely to respond to an EGFR tyrosine kinase inhibitor as specimens with pure/WHO bronchioloalveolar carcinoma.17
Immunohistochemical or Molecular Characteristics Predicting Sensitivity to Gefitinib
Immunohistochemical studies of tumor specimens have not revealed any protein expression patterns that correlate with response to gefitinib. In an analysis of tumor EGFR expression determined by immunohistochemistry in 157 analyzable specimens submitted from patients enrolled on the two phase II trials of gefitinib, there were no consistent associations between EGFR expression and radiographic or symptomatic improvements.18 This observation parallels the results of clinical trials of the EGFR inhibitors cetuximab and erlotinib, where response also did not correlate with the degree of EGFR expression measured by immunohistochemistry.19,20 The expression of p53 and p-Akt measured by immunohistochemistry also has not been shown to correlate with gefitinib sensitivity.21 Intriguingly, 12 of 15 patients with radiographic regressions had 2+ or 3+ HER-2 expression in our series as opposed to 15 of 28 responders with 0 or 1+ expression (80% v 53%; P = .11).21 However, this was not observed in other series (14% v 13%).22
While immunohistochemical studies have not revealed any protein levels that correlate with gefitinib response, three groups have recently shown that mutations in the tyrosine kinase domain of EGFR are associated with sensitivity of NSCLC to gefitinib.1-3 In total, deletions or amino acid substitutions in exons 18, 19, and 21 of EGFR were found in 20 of 24 tumors sensitive to the drug, but in none of 19 tumors with no response. In primary untreated NSCLCs, such mutations have been found in 29 (12%) of 240 specimens examined, with high frequencies observed in Japanese patients (15 of 58 patients; 28%)1 and in never smokers with adenocarcinoma (seven of 15 patients; 47%).3 Mutations in the EGFR tyrosine kinase domain also appear to associate with sensitivity to erlotinib.3
EGFR mutations were not detected in four of 24 tumors examined from patients who experienced partial responses or marked clinical improvement while on therapy with gefitinib. Possible explanations for these results include: (1) tumor specimens analyzed did not represent the tumors assessed while patients were on drug studies; (2) mutations were present but were below the detection rate of sequencing assays; (3) other kinases crucial for lung tumor survival are affected by gefitinib; or (4) other mechanisms involving wild-type EGFR confer drug sensitivity. In regard to the last point, Hirsch et al23 recently reported that EGFR copy number per cell, as assessed by fluorescent in situ hybridization, may also be used to predict sensitivity to gefitinib, even in EGFR wild-type tumors.
Pharmacology
Gefitinib peak plasma levels occur 3 to 7 hours after oral dosing. The mean oral bioavailability is 60%. The plasma half-life is 48 hours. Steady-state concentrations are achieved within 10 days. The elimination of gefitinib occurs through hepatic metabolism primarily through CYP3A4 and excretion in feces. Renal excretion accounts for less than 4% of the given dose. When tested in patients with moderately and severely elevated liver function tests, pharmacokinetics were found to be the same as in individuals with normal liver function.14
Potential Drug Interactions
Drugs which induce CYP3A4 activity increase the metabolism of gefitinib. Therefore, in patients taking drugs such as rifampin or phenytoin, a gefitinib dose increase to 500 mg daily can be considered in the absence of severe adverse effects. Patients should be closely monitored if the 500-mg dose is used, since the phase II trials showed this dose to cause significantly more rash and diarrhea. Patients taking warfarin should have their International Normalized Ratio (INR) monitored, since INR elevations, as well as bleeding events, have been reported in patients taking both gefitinib and warfarin. The specific reason for this interaction is unknown. Drugs that inhibit CYP3A4 activity (ketoconazole, itraconazole, and others) can lead to higher gefitinib plasma concentrations. Drugs that cause sustained elevations in gastric pH (such as the H2-receptor antagonists ranitidine or cimetidine) may reduce plasma concentrations of gefitinib.24
Dosing
Four phase I trials assessed tolerability by dose and schedule and pharmacokinetics in pretreated patients with solid tumors testing daily oral doses up to 1,000 mg.6-9 These trials identified diarrhea as dose-limiting at daily oral doses of gefitinib at 700 and 1,000 mg. Skin toxicities including a pustular rash, erythema, dryness, or pruritus were also commonly seen. Ten partial radiographic responses were observed in 100 patients with NSCLC treated on these four trials. Responses were seen at doses from 150 mg to 800 mg per day. The majority of adverse events causing dose adjustments were seen in patients receiving more than 600 mg per day. Based on these data, the two doses selected for phase II study were 250 mg and 500 mg, as 250 mg was higher than the lowest dose at which objective tumor regressions were seen, and 500 mg was the highest dose that was well tolerated when administered chronically.
In both phase II trials, improvement in disease-related symptoms and radiographic regression were nearly identical comparing the 250-mg and 500-mg dosages. However, the incidence of adverse events was significantly lower for the 250-mg/d dose.10,11 Based on this data and additional information from the randomized trials comparing the 250-mg and 500-mg doses combined with chemotherapy, the 250-mg daily dosage was recommended. The gefitinib 250-mg daily oral tablet is also the dose and schedule approved by health authorities worldwide. Based on our clinical experience, the incidences of nausea and vomiting appeared to be even lower when patients were instructed to ingest gefitinib at bedtime. Therefore, we recommend gefitinib be routinely taken in this way.
RESULTS
That being said, how can we explain the higher likelihood of benefit among individuals with rash and diarrhea The presence of rash identifies individuals with tumors containing signaling pathways more susceptible to inhibition by gefitinib. Whether this difference lies in the EGFR itself or in downstream effectors is not known. We, and others, are using clinical leads like this to guide preclinical investigations to uncover the molecular mechanisms that underlie sensitivity and toxicity to gefitinib. For example, EGFR contains a pleomorphic region in intron 1 that consists of a variable number of cytosine-adenine (CA) repeats that regulate gene transcription. Perea et al27 have argued that variations of this region of EGFR influence both response and toxicity following gefitinib. They demonstrated greater sensitivity to gefitinib in cell lines with a shorter number of CA repeats as well as a higher frequency of rash in patients whose skin biopsies demonstrate short CA segments in EGFR exon 1. Their theory is further supported by that fact that Asian individuals who have shorter CA repeat segments28,29 also have higher sensitivity to EGFR inhibitors10,30 and a greater likelihood of toxicity with gefitinib.10
Ghosting, a Distinct Type of Radiographic Response With Gefitinib
In our recently reported analysis, 21 patients had partial radiographic regressions.15 In addition to demonstrating the usual decreases in the size and/or number of pulmonary lesions, we have observed a unique pattern of regression on computed tomography (CT) of the chest. Three (14%) of the 21 patients exhibited a decrease in density and virtual complete disappearance of tumor without the decrease in tumor diameter normally seen following conventional cytotoxic chemotherapy. An example of this phenomenon is presented in Figure 1. We have termed this diminution in tumor density seen on helical chest CT, "ghosting." Ghosting appears to be a form of durable objective regression associated with clinical benefit in persons treated with gefitinib. Based on our experience, it appears to be the equivalent of a partial response and should be counted a major objective response in practice and when reporting the results of clinical studies.
In addition to radiographic responses and the associated clinical benefit, other patients with stable disease also derive clinical benefit. The US phase II trial demonstrated that of 44 patients with stable disease, 80% had symptom improvement.11
Effect on CNS Metastases
The degree to which gefitinib crosses the blood-brain barrier remains unclear. Among five sensitive patients in our series with evidence of cerebral metastases when they started gefitinib, two demonstrated objective regressions in their brain lesions. Other investigators have also documented responses in cerebral metastases.22,31-33 However, several of our patients with radiographic regressions developed new or worsening cerebral metastases and leptomeningeal spread, while regressions in their primary tumors and metastatic sites were maintained. This observation is discussed further in the section on relapse below.
Symptom Improvement
In addition to assessing radiographic responses, the phase II trials of gefitinib also measured symptom improvement. Both utilized the Lung Cancer Subscale of the Functional Assessment of Cancer Therapy—Lung.34 At baseline and throughout the studies, patients rated the severity of seven symptoms including shortness of breath, weight loss, clarity of thinking, cough, appetite, chest tightness, and difficulty breathing using a 0 to 4 point scale. A score of zero denotes worst symptoms and 28, no symptoms. Symptom improvement was defined as a ≥ two-point increase in Lung Cancer Subscale score sustained for 4 or more weeks. This two-point change in the summed Lung Cancer Subscale score correlates with both survival and performance status.34,35
In the international phase II trial, documented symptom improvement occurred in 40% of individuals receiving gefitinib 250 mg.10 More than 50% of patients who had stable disease also demonstrated symptom improvement. The US trial reported similar results.11 Confirming phase I observations, over half of the symptom improvements were apparent after only 1 week of treatment. For patients with symptom benefit, improvement was evident in 85% of patients 4 weeks after starting gefitinib. The greatest improvement in Lung Cancer Subscale symptom scores occurred in those patients demonstrating radiographic response, and the least improvement was seen in those with disease progression.36
Side Effects and Their Management
In the phase I trials, diarrhea was dose-limiting and skin toxicity of some type was seen in the majority of patients.6-9 Unlike conventional cytotoxic agents, gefitinib did not cause myelosuppression, neuropathy, significant nausea, vomiting, or alopecia.
Adverse effects reported in the phase II trials using the 250-mg recommended daily dosage were generally mild, manageable, noncumulative, and reversible with discontinuation of drug or sometimes even continued use. The most common adverse events were diarrhea, skin toxicity (variably recorded as rash, acne, dry skin, or pruritus), nausea, and vomiting. As a measure of overall tolerability in the international double-blind trial, only 16% of patients had an adverse event requiring a short treatment interruption, and none required a dose reduction.10 The main events resulting in dose interruptions were skin toxicity, gastrointestinal disturbances, and elevated serum hepatic transaminases. These events necessitated drug withdrawal in 1.9% of patients. Overall, grade 3 or 4 toxicities were seen in 1.5% of patients receiving 250 mg of gefitinib.
The US trial reported similar low frequency and severity of adverse events with gefitinib 250 mg daily. Only one person experienced an adverse event leading to study withdrawal, and one patient required dose reduction for toxicity. Grade 3 or 4 toxicities were reported in seven patients. Our institutional experience with gefitinib has been comparable to the phase II studies.
Skin Toxicity
A characteristic rash has been documented to be a "class adverse effect" of agents that target the EGFR and includes erlotinib20 and cetuximab37 as well as gefitinib. The eruption is characterized by inflammatory papules and pustules most often seen on the face, chest, and back and may resemble folliculitis or an acneiform drug eruption (Fig 2). The distribution of the eruption has been termed acneiform, as lesions are predominantly present at sites where there are large numbers of pilosebaceous units such as the scalp, face, neck, and upper trunk. This eruption is distinguished from classic acne vulgaris in its lack of comedones. Busam et al37 studied histologic sections from patients who developed rashes while receiving cetuximab, and described suppurative folliculitis and superficial perifolliculitis as the most common histologic changes. Microcomedones were notably absent.
The US phase II investigators reported skin toxicity in 62% of patients receiving the 250-mg dose.11 Other cutaneous manifestations reported with gefitinib were pruritus, dry skin, hand, finger, and heel fissures (Fig 3); desquamation; nail and cuticle cracking (Fig 4); nasal ulcers with subsequent epistaxis; and vaginal dryness. All these conditions were graded as mild in the international phase II trial. Pruritus associated with the pustular/papular eruption is a frequent complaint. In most patients, these eruptions resolved either during treatment, following a temporary interruption in treatment, or after treatment cessation. The US phase II investigators reported skin toxicity in 62% of patients receiving the 250-mg dose. In 82% of patients, it developed during the first treatment cycle.
Experience has shown that most dermatologic events can be successfully managed, but seldom resolve completely with continued administration of gefitinib. Clindamycin phosphate 1% gel has been used with good effect for the inflammatory pustular lesions. A combination clindamycin 1% and benzoyl peroxide 5% gel has also been used to elicit a drying effect on the pustules. Gel formulations may, however, cause irritation, and in many cases, systemic oral antibiotics like tetracycline 250 mg four times daily or minocycline 100 mg two times a day are preferable. Oral antibiotics can be quickly discontinued in some patients, while others require continued treatment with continued gefitinib use. Topical retinoids, like the antiacne medication tretinoin, are not recommended, as the eruption seen with gefitinib has a different pathophysiology than acne vulgaris. Topical and systemic corticosteroids have produced variable responses and need further investigation. Some investigators have reported success with the topical immunomodulatory agent pimecrolimus cream 1% currently approved for use in atopic dermatitis.
Dry skin responds well to bland emollients such as Eucerin cream (Beiersdorf, Jobst, Germany), Cetaphil cream (Galderma, Lausanne, Switzerland), and Aquaphor (Beiersdorf) healing ointment. Many patients have told us that Bag Balm (Dairy Association Co, Rock Island, Quebec, Canada) has been helpful in soothing fissures on the palms and soles. Liquid cyanoacrylate (BAND AID Brand Liquid Bandage; Johnson & Johnson, Skilman, NJ) applied into the cracks and fissures may also relieve pain and promote healing. Water-based make-ups and gentle cleansers such as Cetaphil cleanser are well tolerated with the above-mentioned topical and systemic therapies. We recommend that patients with extensive or persistent skin involvement be referred to a dermatologist.
Diarrhea
Diarrhea, as described in the National Cancer Institute Common Toxicity Criteria (version 2.0), occurred in 40% of patients on the 250-mg dose in the international trial.10 Twenty-four percent of patients took antidiarrheals. Diarrhea resolved in 84% of patients. The US study reported diarrhea in 57% of patients on the 250-mg dose (grade 1 to 48 (83%); grade 2 to 9 (15%); grade 3, one patient; grade 4, no patients).11 Approximately one-third of patients took antidiarrheal medications. Diarrhea was observed in the first treatment cycle in 76%.
In most cases, loperamide controls diarrhea caused by gefitinib. We advise our patients to purchase loperamide before starting treatment and to keep it with them at all times. If any diarrhea is experienced, we recommend taking two 2-mg loperamide tablets immediately, followed by one 2-mg tablet after every loose bowel movement, up to a maximum daily dose of 10 tablets (20 mg). If the diarrhea does not resolve with this regimen, we advise the patient to stop taking gefitinib and to call a physician promptly. Other causes of diarrhea should also be entertained in this setting.
Ophthalmologic Toxicity
An unusual consequence of treatment with gefitinib, seen in some individuals taking the drug for many months, is excessive eyelash growth. Rarely, misdirectional growth of eyelashes toward the globe, termed trichiasis, can cause corneal irritation. This can be prevented by regular eyelash trimming and treated by removal of the aberrant eyelash. We suggest checking for excessive eyelash growth at routine physical examinations. Patients with symptoms of corneal irritation should be referred to an ophthalmologist.
Although eye symptoms were noted in all gefitinib trials, none have been dose-limiting or led to treatment withdrawal. Because the study participants have many comorbid conditions and are taking concomitant medications that could also affect the eye, with the exceptions of excessive eyelash growth and trichiasis discussed above, the relationship of the eye symptoms to gefitinib is unclear. The US phase II trial is especially difficult to evaluate because all participants had received docetaxel, a drug that causes conjunctivitis and hyperlacrimation, which can persist after the drug is discontinued.38 Future trials involving gefitinib will provide more information about the possible ophthalmologic effects of gefitinib.
The International phase II trial reported eye toxicity in 21% of patients described as conjunctivitis, blepharitis, keratitis, eye pain, dry eyes, and corneal erosion.10 Grade 1 or 2 eye irritation was reported in 19% of patients in the United States including redness, itchiness, dry eyes, and trichiasis.36 Nonprescription eye drops such as Refresh (Allergen Inc, Irvine, CA) or saline relieve symptoms of dryness and hyperlacrimation.
Interstitial Lung Disease
Interstitial lung disease is a recognized but uncommon adverse effect of cytotoxic drugs39 and has also been described following treatment with the tyrosine kinase inhibitor imatinib as well.40 The overall incidence of interstitial lung disease in patients receiving gefitinib has been reported at approximately 1%. Approximately one third of the affected individuals died. The postmarketing experience in Japan reported an incidence of 2%. The rate was 0.3% in approximately 23,000 patients treated on the US-expanded access program.14 In the trials of NSCLC patients receiving chemotherapy who were randomly assigned to receive concomitant gefitinib or placebo, the observed incidence of interstitial lung disease was less than 1% and slightly higher in the placebo arm. Overall, this incidence of pulmonary toxicity is lower than that reported with the cytotoxic chemotherapy agents now in use for the treatment of NSCLC.
Interstitial lung disease associated with gefitinib has been described as interstitial pneumonia, pneumonitis, and alveolitis. Patients present with the acute onset of dyspnea, sometimes associated with cough or low-grade fever. It occurred in patients receiving prior radiation therapy (31% of reported cases), prior chemotherapy (57% of reported patients), and no prior therapy (12% of reported cases). Most cases occurred in the first month of therapy. Typical chest CT findings include bilateral diffuse ground glass opacities. Patients with concurrent idiopathic pulmonary fibrosis who experience worsening conditions while receiving gefitinib were observed to have a higher mortality compared to those without pulmonary fibrosis.
Inoue et al41 reported four patients in Japan with NSCLC who developed severe acute interstitial pneumonia in association with gefitinib. Two patients recovered after treatment with steroids and two patients with advanced lung cancer died from progressive respiratory failure. Diffuse alveolar damage was noted on specimens taken at autopsy. More patients with interstitial pneumonia also had received prior thoracic irradiation and had poor performance status. These investigators recommended that physicians should be vigilant for lung damage induced by gefitinib, especially in patients with prior chest radiotherapy, a history of idiopathic pulmonary fibrosis, or poor performance status.
If a patient receiving gefitinib experiences the acute onset or worsening of pulmonary symptoms, particularly in the first 4 weeks of therapy, we recommend that gefitinib be interrupted and an investigation of these symptoms be performed promptly. If interstitial lung disease is suspected, the patient should receive appropriate treatment, including corticosteroids, antibiotics, bronchodilators, and supplemental oxygen. There is no information on the safety of restarting gefitinib after its discontinuation in suspected cases of interstitial lung disease. Based on current information, we would not recommend gefitinib in persons who have experienced interstitial lung disease following its use.
Elevation of Serum Hepatic Transaminases
Rarely, asymptomatic increases in ALT and AST have been reported during treatment with gefitinib. Grade 3 transaminase elevation was noted in two of 103 patients on the 250-mg dose in the international phase II trial, necessitating study withdrawal of one of these patients.10 None of the 102 patients on the US trial had grade 3 or 4 transaminase elevations.11 Given the rarity and reversibility of this toxicity and the finding that pharmacokinetics in patients with liver metastasis and elevated blood tests of liver function are similar to those in patients with normal livers, we do not recommend any routine measurement of blood tests of liver function.
Patterns and Sites of Relapse
In the analysis reported by Miller et al,15 among the 21 patients with radiographic regressions, 14 experienced disease progression. Eight patients showed progression of disease in the lung, with one patient suffering both lung and liver progression. Unlike disease progression after conventional chemotherapy, where obvious new metastatic deposits and enlargements of existing lesions are clear cut, patients with initial response following gefitinib in pulmonary lesions who then develop disease progression based on objective criteria can have subtle, millimeter-sized enlargements. Often, reviewing any two consecutive scans does not confirm progression, which can be documented only by a direct comparison to the study that demonstrated the best response. Many patients report a worsening of symptoms and a decreased sense of well-being when gefitinib is discontinued because of objective evidence of disease progression, suggesting that some degree of tumor control persists even after the objective criteria for progression have been met. This situation may be analogous to that of patients with gastrointestinal stromal tumors sensitive to imatinib (another tyrosine kinase inhibitor) whose tumor masses subsequently grow to the point that objective criteria for disease progression are met. When imatinib is stopped, patients report feeling worse and their positron emission tomography scans show increased tumoral fluorodeoxyglucose avidity that can be reversed by the reinstitution of imatinib.42,43 Other investigators studying imatinib-sensitive, then refractory, gastrointestinal stromal tumors have described a nodule within a mass that on biopsy contains a new activating kinase mutation.44 Surrounding tumor tissue, that presumably does not harbor a new mutation, does not grow while imatinib is maintained. Physicians treating clinically well patients who have previously responded to gefitinib should be aware that unusual patterns of progression are possible (and even likely) when using a kinase inhibitor in individuals with tumors harboring activating mutations that underlie their sensitivity to these agents.
Of the 21 patients with partial responses following gefitinib reported by Miller et al,15 seven developed new or worsening metastases in the CNS, in either the brain or leptomeninges.45 In several of these individuals, CNS metastases were the first and only site of relapse. Our experience suggests that the CNS may be a "sanctuary site" for resistant lung cancer cells in persons where the disease is otherwise well controlled. Metastases to the brain or leptomeninges should be high in the differential for patients with tumors sensitive to gefitinib who develop new complaints.
DISCUSSION
Phase II trials selected a single 250-mg daily oral dosage as equally effective and safer than a 500-mg dose. These studies confirmed observations from phase I studies documenting a 14% radiographic regression rate, a 40% symptom improvement rate, and manageable diarrhea and rash as the only common adverse effects. Based on these phase II data, regulatory authorities have approved gefitinib given as a single 250-mg daily oral dose as a treatment for patients with advanced NSCLC with tumors that have failed to respond to cisplatin or carboplatin, docetaxel, and other agents. In contrast, studies combining gefitinib with chemotherapy for the initial treatment of advanced NSCLC failed to improve response or survival over chemotherapy alone.46,47 Until more data emerge, gefitinib should be used only after conventional chemotherapy (which has been proved to improve survival) has failed. Compared to other treatments for advanced NSCLC, gefitinib is generally better tolerated. The adverse effects it causes are nearly always manageable, reversible, and lessen even with continued use in most patients.
Gefitinib should always be administered at a dose of 250 mg orally daily, with follow-up initially after a month, then every 2 to 3 months. Dose escalation is not routinely recommended, as the randomized trials that led to its approval revealed similar efficacy but increased adverse events by doubling the dose. We suggest 1- to 2-week discontinuations for the rare individual who experiences severe skin toxicity or diarrhea despite the supportive measures we have outlined. Treatment-limiting toxicities such as interstitial lung disease are extremely rare. Even that adverse effect can usually be managed effectively by stopping gefitinib and administering corticosteroids, supplemental oxygen, and other supportive care measures.
Unfortunately, the majority of unselected patients with NSCLC derive no benefit from gefitinib. How this situation can best be addressed is now the focus of intense research. Already, several clinical characteristics and the presence of EGFR mutations or amplification can identify patients more likely to benefit, especially persons who have never smoked cigarettes and individuals whose tumors have any features of bronchioloalveolar carcinoma.10,11,14,15 The presence of one or more of these characteristics can help the clinician choose between the conventional chemotherapy choices and gefitinib. By contrast, neither the presence nor the degree of EGFR expression, as measured by immunohistochemistry, predicts outcomes, and therefore they should not be used to select patients for treatment with this agent.18
In the near future, two molecular tests may possibly be used to predict tumor sensitivity to gefitinib: EGFR mutation status, as assessed by DNA sequencing, and EGFR gene copy number, as assessed by fluorescent in situ hybridization or chromogenic in situ hybridization. Although technically validated, widely available testing for the most common mutations will be available in the near future, prospective studies will need to be performed before these kinds of tests are used in routine practice. In the meantime, the clinical characteristics previously discussed can still be useful predictors of gefitinib response.
Gefitinib provides both benefit and hope for patients with NSCLC who have exhausted other options. For the researchers who postulated decades ago that blocking growth factor receptors like EGFR could lead to tumor regressions, gefitinib represents a promise fulfilled. This success has stimulated the search for new kinase inhibitors and other strategies to block signaling in lung cancer cells.
Authors’ Disclosures of Potential Conflicts of Interest
NOTES
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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18. Bailey L, Kris M, Wolf M, et al: Tumor EGFR membrane staining is not clinically relevant for predicting response in patients receiving gefitinib (IRESSA, ZD1839) monotherapy for pretreated advanced non-small cell lung cancer: IDEAL1 and 2. Proc AACR 44:1362, (LB-170) 2003
19. Saltz L, Rubin M, Hochster H, et al: Acne-like rash predicts response in patients treated with cetuximab (IMC-C225) plus irinotecan (CPT-11) in CPT-11-refractory colorectal cancer (CRC) that expresses epidermal growth factor receptor (EGFR). Clin Cancer Res 7:3766S, 2001 (abstr 559)
20. Perez-Soler R, Chachoua A, Huberman M, et al: A Phase II trial of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor OSI-774, following platinum-based chemotherapy, in patients with advanced, EGFR-expressing, non-small cell lung cancer (NSCLC), Proc Am Soc Clin Oncol 22:310a, 2001 (abstr 1235)
21. Miller VA, Shah N, Kris M, et al: Clinical, pathologic, and molecular characteristics of NSCLC patients sensitive to gefitinib. Lung Cancer 41:S71, 2003 (abstr O-241)
22. Cappuzzo F, Ardizzoni A, Soto-Parra H, et al: Epidermal growth factor receptor targeted therapy by ZD 1839 (Iressa) in patients with brain metastases from non-small cell lung cancer (NSCLC). Lung Cancer 41:227-231, 2003
23. Hirsch FR: EGF Receptor Inhibition in Lung Cancer: Where Do We Go Presented at 40th American Society of Clinical Oncology Annual Meeting, New Orleans, LA, June 5-8, 2004
24. DRUGDEX System. MICROMEDEX, In Hutchison TA SD (ed): Greenwood Village, CO, Thompson Pubs, 2003
25. Perez-Soler R: Can rash associated with HER1/EGFR inhibition be used as a marker of treatment outcome Oncology 17:23-28, 2003
26. Saltz L, Kies M, Abbruzzese JL, et al: The presence and intensity of the cetuximab-induced acne-like rash predicts increased survival in studies across multiple malignancies. Proc Am Soc Clin Oncol 22:204, 2003 (abstr 817)
27. Perea S, Oppenheimer D, Amador M, et al: Genotypic bases of EGFR inhibitors pharmacological actions. Proc Am Soc Clin Oncol 23:196, 2004 (abstr 3005)
28. Liu WW, Innocenti F, Chen P, et al: Interethnic difference in the allelic distribution of human epidermal growth factor receptor intron 1 polymorphism. Clin Cancer Res 9:1009-1012, 2003
29. Zhou Q, Kibat C, Cheung YB, et al: Pharmacogenetics of the epidermal growth factor receptor (EGFR) gene in Chinese, Malay and Indian populations. Proc Am Soc Clin Oncol 23:199, 2004 (abstr 3019)
30. Park J, Park B, Kim JY, et al: Gefitinib (ZD1839) monotherapy as a salvage regimen for previously treated advanced non-small cell lung cancer. Clin Cancer Res 10:4383-4388, 2004
31. Fujiwara K, Kiura K, Ueoka H, et al: Dramatic effect of ZD1839 (’Iressa’) in a patient with advanced non-small-cell lung cancer and poor performance status. Lung Cancer 40:73-76, 2003
32. Ceresoli GL, Gregorc V, Cappuzzo F, et al: ZD1839 in non-small cell lung cancer (NSCLC) patients with brain metastases (BM). Proc Am Soc Clin Oncol 22:674, 2003 (abstr 2709)
33. Takahashi H, Ohrui T, Ebihara S, et al: Effect of gefitinib (ZD1839) on metastatic brain tumour. Lung Cancer 43:371-372, 2004
34. Cella DF, Bonomi AE, Lloyd SR, et al: Reliability and validity of the Functional Assessment of Cancer Therapy-Lung (FACT-L) quality of life instrument. Lung Cancer 12:199-220, 1995
35. Cella D, Eton DT, Fairclough DL, et al: What is a clinically meaningful change on the functional assessment of cancer therapy–lung (FACT-L) questionnaire Results from Eastern Cooperative Oncology Group (ECOG) Study 5592. J Clin Epidemiol 55:285-295, 2002
36. Kris M, Natale R, Herbst R, et al: A Phase II trial of ZD1839 (’Iressa’) in advanced non-small cell lung cancer (NSCLC) patients who had failed platinum- and docetaxel-based regimens (IDEAL 2). Proc Am Soc Clin Oncol 21:292a, 2002 (abstr 1166)
37. Busam KJ, Capodieci P, Motzer R, et al: Cutaneous side-effects in cancer patients treated with the antiepidermal growth factor receptor antibody C225. Br J Dermatol 144:1169-1176, 2001
38. Esmaeli B, Hortobagyi GN: Canalicular stenosis as the underlying mechanism for epiphora in patients receiving weekly docetaxel. Oncologist 6:551-552, 2001
39. Cooper JAD Jr, White DR, Matthay R: State of Art. Drug-induced pulmonary disease. Part 1: Cytotoxic drugs. Am Rev Respir Dis 133:321-340, 1986
40. Bergeron A, Bergot E, Vilela G, et al: Hypersensitivity pneumonitis related to imatinib mesylate. J Clin Oncol 20:4271-4272, 2002
41. Inoue A, Saijo Y, Maemondo M, et al: Severe acute interstitial pneumonia and gefitinib. Lancet 361:137-139, 2003
42. Van den Abbeele AD, Badawi R, Manola J, et al: Effects of cessation of imatinib mesylate (IM) therapy in patients (pts) with IM-refractory gastrointestinal stromal tumors (GIST) as visualized by FDG-PET scanning. Proc Am Soc Clin Oncol 23:198, 2004 (abstr 3012)
43. van Oosterom AT, Dumez H, Desai J, et al: Combination signal transduction inibition: A phase I/II trial of the oral mTOR-inhibitor everolimus (E, RADOO1) and imatinib mesylate (IM) in patients (pts) with gastrointestinal stromal tumor (GIST) refractory to IM. Proc Am Soc Clin Oncol 23:195, 2004 (abstr 3002)
44. Desai J, Shankar S, Heinrich MC, et al: Clonal evolution of resistance to imatinib (IM) in patients (pts) with gastrointestinal stromal tumor (GIST: Molecular and radiologic evaluation of new lesions. Proc Am Soc Clin Oncol 23:197, 2004 (abstr 3010)
45. Omuro AMP, Franceschi E, Kris MG, et al: Brain and leptomeningeal metastases in non-small cell lung cancer (NSCLC) responsive to gefitinib: Is the CNS being left behind Annual Meeting of the Neuro-Oncology Society 6:379, 2004
46. Giaccone G, Herbst RS, Manegold C, et al: Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: A phase III trial—INTACT 1. J Clin Oncol 22:777-784, 2004
47. Herbst RS, Giaccone G, Schiller JH, et al: Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: A phase III trial–INTACT 2. J Clin Oncol 22:785-794, 2004(Neelam T. Shah, Mark G. K)
Departments of Biostatistics, Surgery, and Radiology, Weill Medical College of Cornell University, New York, NY
ABSTRACT
METHODS: This article reviews gefitinib’s indications, dosing, response phenomena, and patterns of relapse in individuals with radiographic response.
RESULTS: We present our recommendations for the management of rash and diarrhea caused by this agent.
CONCLUSION: This information can guide practitioners and help them inform their patients about what to expect when they receive gefitinib.
INTRODUCTION
Gefitinib is an anilinoquinazoline compound that inhibits the EGFR tyrosine kinase in vitro with a 50% inhibitory concentration of 0.27 to 33 μmol/L, more than 100 times less than the concentration required to block the kinases of HER-2, KDR, MEK-1, and MEK-2.5 In its initial clinical study, gefitinib caused radiographic regressions and symptom improvement in patients with non–small-cell lung cancers refractory or resistant to chemotherapy.6-9 Based on this experience, gefitinib has become the most extensively studied and most widely used small molecule inhibitor of the EGFR tyrosine kinase. It has been approved for use by the regulatory authorities in the United States, Japan, and many other countries.
The unique mode of action of gefitinib and its potential for use in patients with a common tumor who frequently need second-, third-, or even fourth-line therapy require a thorough understanding of how to care for individuals receiving this agent. Many of the principles of management relevant to gefitinib are distinct from those with conventional cytotoxic drugs. To meet this need, we present practical guidelines on the use of gefitinib in patients with NSCLC. These recommendations are based on published data as well as our clinical experience.
METHODS
Radiographic Regression Rates in Unselected Patients
Three of the four phase I trials of gefitinib reported radiographic regressions in patients with NSCLC refractory to multiple chemotherapy regimens.6,8,9 In phase I testing, 10% of patients with NSCLC experienced partial radiographic responses often accompanied by rapid symptomatic improvement. This experience prompted two phase II trials in which radiographic regression was seen in 14% and symptomatic improvement in 39% of patients.10,11 Radiographic responses occurred in as little as 1 week. These response rates compared favorably with those of conventional cytotoxic agents used after disease progression with cisplatin or carboplatin. In this setting, docetaxel had a response rate of 8% and vinorelbine 0%.12,13 For our series of 21 patients with partial radiographic regressions, the median duration of response was 12 months. The shortest response lasted 4 months and the longest continues 60+ months after the start of gefitinib.
Pretreatment Clinical Factors Predicting Sensitivity to Gefitinib
Since radiographic responses are seen in only a fraction of patients, investigators have attempted to identify pretreatment characteristics associated with sensitivity to gefitinib (Table 1). In the international study (IDEAL I) where half of the patients were enrolled in Japan, Fukuoka et al10 described a higher response rate in Japanese patients compared to non-Japanese patients (28% compared to 10%; P = .0023). In addition, a multivariable analysis showed that performance status (PS) 0 to 1, female sex, adenocarcinoma histology, and prior immuno-/hormonal therapy (including picibanil, investigational drugs, minomycin, marimastat, and tamoxifen citrate) were prognostic factors associated with objective response to the agent. In the United States study (IDEAL2), higher rates of radiographic response were observed in women (19% compared to 3%) and patients with adenocarcinoma (13% compared to 4%).11 Symptom benefit was also more likely in the same two groups.11 A separate analysis performed by the US Food and Drug Administration on the US trial data detected higher rates of radiographic response in never smokers (29%) compared to previous or current smokers (5%).14
We have recently reported a retrospective review of 139 patients treated with single-agent gefitinib. A history of never smoking cigarettes (P = .0006) and bronchioloalveolar histology (P = .004) were determined to be independent predictors of radiographic response.15 In our series, rates of radiographic response were numerically higher in women as well (19% compared to 8%; P = .14). Based on this data, we calculated the response rates and median survival for groups of patients with none, one, two, or all three pretreatment clinical characteristics associated with higher gefitinib sensitivity (Table 2). The presence of all three characteristics yielded the highest response rates and median survival (56%; 14 months). Response rates and median survival progressively decreased if patients had two, one, or none of the characteristics. Removing sex from the analysis reveals that patients who never smoked cigarettes and who had adenocarcinoma with any bronchioloalveolar carcinoma features16 (and not simply "pure" bronchioloalveolar carcinoma as defined by the WHO) had high response rates and median survival (55%; 14 months; Table 3). We have noted that tumor specimens correctly read initially as NSCLC or NSCLC-NOS (not otherwise specified) may, in fact, contain some areas with bronchioloalveolar features. In an ongoing trial, tumors classified or reclassified as adenocarcinomas with bronchioloalveolar features were three times as likely to respond to an EGFR tyrosine kinase inhibitor as specimens with pure/WHO bronchioloalveolar carcinoma.17
Immunohistochemical or Molecular Characteristics Predicting Sensitivity to Gefitinib
Immunohistochemical studies of tumor specimens have not revealed any protein expression patterns that correlate with response to gefitinib. In an analysis of tumor EGFR expression determined by immunohistochemistry in 157 analyzable specimens submitted from patients enrolled on the two phase II trials of gefitinib, there were no consistent associations between EGFR expression and radiographic or symptomatic improvements.18 This observation parallels the results of clinical trials of the EGFR inhibitors cetuximab and erlotinib, where response also did not correlate with the degree of EGFR expression measured by immunohistochemistry.19,20 The expression of p53 and p-Akt measured by immunohistochemistry also has not been shown to correlate with gefitinib sensitivity.21 Intriguingly, 12 of 15 patients with radiographic regressions had 2+ or 3+ HER-2 expression in our series as opposed to 15 of 28 responders with 0 or 1+ expression (80% v 53%; P = .11).21 However, this was not observed in other series (14% v 13%).22
While immunohistochemical studies have not revealed any protein levels that correlate with gefitinib response, three groups have recently shown that mutations in the tyrosine kinase domain of EGFR are associated with sensitivity of NSCLC to gefitinib.1-3 In total, deletions or amino acid substitutions in exons 18, 19, and 21 of EGFR were found in 20 of 24 tumors sensitive to the drug, but in none of 19 tumors with no response. In primary untreated NSCLCs, such mutations have been found in 29 (12%) of 240 specimens examined, with high frequencies observed in Japanese patients (15 of 58 patients; 28%)1 and in never smokers with adenocarcinoma (seven of 15 patients; 47%).3 Mutations in the EGFR tyrosine kinase domain also appear to associate with sensitivity to erlotinib.3
EGFR mutations were not detected in four of 24 tumors examined from patients who experienced partial responses or marked clinical improvement while on therapy with gefitinib. Possible explanations for these results include: (1) tumor specimens analyzed did not represent the tumors assessed while patients were on drug studies; (2) mutations were present but were below the detection rate of sequencing assays; (3) other kinases crucial for lung tumor survival are affected by gefitinib; or (4) other mechanisms involving wild-type EGFR confer drug sensitivity. In regard to the last point, Hirsch et al23 recently reported that EGFR copy number per cell, as assessed by fluorescent in situ hybridization, may also be used to predict sensitivity to gefitinib, even in EGFR wild-type tumors.
Pharmacology
Gefitinib peak plasma levels occur 3 to 7 hours after oral dosing. The mean oral bioavailability is 60%. The plasma half-life is 48 hours. Steady-state concentrations are achieved within 10 days. The elimination of gefitinib occurs through hepatic metabolism primarily through CYP3A4 and excretion in feces. Renal excretion accounts for less than 4% of the given dose. When tested in patients with moderately and severely elevated liver function tests, pharmacokinetics were found to be the same as in individuals with normal liver function.14
Potential Drug Interactions
Drugs which induce CYP3A4 activity increase the metabolism of gefitinib. Therefore, in patients taking drugs such as rifampin or phenytoin, a gefitinib dose increase to 500 mg daily can be considered in the absence of severe adverse effects. Patients should be closely monitored if the 500-mg dose is used, since the phase II trials showed this dose to cause significantly more rash and diarrhea. Patients taking warfarin should have their International Normalized Ratio (INR) monitored, since INR elevations, as well as bleeding events, have been reported in patients taking both gefitinib and warfarin. The specific reason for this interaction is unknown. Drugs that inhibit CYP3A4 activity (ketoconazole, itraconazole, and others) can lead to higher gefitinib plasma concentrations. Drugs that cause sustained elevations in gastric pH (such as the H2-receptor antagonists ranitidine or cimetidine) may reduce plasma concentrations of gefitinib.24
Dosing
Four phase I trials assessed tolerability by dose and schedule and pharmacokinetics in pretreated patients with solid tumors testing daily oral doses up to 1,000 mg.6-9 These trials identified diarrhea as dose-limiting at daily oral doses of gefitinib at 700 and 1,000 mg. Skin toxicities including a pustular rash, erythema, dryness, or pruritus were also commonly seen. Ten partial radiographic responses were observed in 100 patients with NSCLC treated on these four trials. Responses were seen at doses from 150 mg to 800 mg per day. The majority of adverse events causing dose adjustments were seen in patients receiving more than 600 mg per day. Based on these data, the two doses selected for phase II study were 250 mg and 500 mg, as 250 mg was higher than the lowest dose at which objective tumor regressions were seen, and 500 mg was the highest dose that was well tolerated when administered chronically.
In both phase II trials, improvement in disease-related symptoms and radiographic regression were nearly identical comparing the 250-mg and 500-mg dosages. However, the incidence of adverse events was significantly lower for the 250-mg/d dose.10,11 Based on this data and additional information from the randomized trials comparing the 250-mg and 500-mg doses combined with chemotherapy, the 250-mg daily dosage was recommended. The gefitinib 250-mg daily oral tablet is also the dose and schedule approved by health authorities worldwide. Based on our clinical experience, the incidences of nausea and vomiting appeared to be even lower when patients were instructed to ingest gefitinib at bedtime. Therefore, we recommend gefitinib be routinely taken in this way.
RESULTS
That being said, how can we explain the higher likelihood of benefit among individuals with rash and diarrhea The presence of rash identifies individuals with tumors containing signaling pathways more susceptible to inhibition by gefitinib. Whether this difference lies in the EGFR itself or in downstream effectors is not known. We, and others, are using clinical leads like this to guide preclinical investigations to uncover the molecular mechanisms that underlie sensitivity and toxicity to gefitinib. For example, EGFR contains a pleomorphic region in intron 1 that consists of a variable number of cytosine-adenine (CA) repeats that regulate gene transcription. Perea et al27 have argued that variations of this region of EGFR influence both response and toxicity following gefitinib. They demonstrated greater sensitivity to gefitinib in cell lines with a shorter number of CA repeats as well as a higher frequency of rash in patients whose skin biopsies demonstrate short CA segments in EGFR exon 1. Their theory is further supported by that fact that Asian individuals who have shorter CA repeat segments28,29 also have higher sensitivity to EGFR inhibitors10,30 and a greater likelihood of toxicity with gefitinib.10
Ghosting, a Distinct Type of Radiographic Response With Gefitinib
In our recently reported analysis, 21 patients had partial radiographic regressions.15 In addition to demonstrating the usual decreases in the size and/or number of pulmonary lesions, we have observed a unique pattern of regression on computed tomography (CT) of the chest. Three (14%) of the 21 patients exhibited a decrease in density and virtual complete disappearance of tumor without the decrease in tumor diameter normally seen following conventional cytotoxic chemotherapy. An example of this phenomenon is presented in Figure 1. We have termed this diminution in tumor density seen on helical chest CT, "ghosting." Ghosting appears to be a form of durable objective regression associated with clinical benefit in persons treated with gefitinib. Based on our experience, it appears to be the equivalent of a partial response and should be counted a major objective response in practice and when reporting the results of clinical studies.
In addition to radiographic responses and the associated clinical benefit, other patients with stable disease also derive clinical benefit. The US phase II trial demonstrated that of 44 patients with stable disease, 80% had symptom improvement.11
Effect on CNS Metastases
The degree to which gefitinib crosses the blood-brain barrier remains unclear. Among five sensitive patients in our series with evidence of cerebral metastases when they started gefitinib, two demonstrated objective regressions in their brain lesions. Other investigators have also documented responses in cerebral metastases.22,31-33 However, several of our patients with radiographic regressions developed new or worsening cerebral metastases and leptomeningeal spread, while regressions in their primary tumors and metastatic sites were maintained. This observation is discussed further in the section on relapse below.
Symptom Improvement
In addition to assessing radiographic responses, the phase II trials of gefitinib also measured symptom improvement. Both utilized the Lung Cancer Subscale of the Functional Assessment of Cancer Therapy—Lung.34 At baseline and throughout the studies, patients rated the severity of seven symptoms including shortness of breath, weight loss, clarity of thinking, cough, appetite, chest tightness, and difficulty breathing using a 0 to 4 point scale. A score of zero denotes worst symptoms and 28, no symptoms. Symptom improvement was defined as a ≥ two-point increase in Lung Cancer Subscale score sustained for 4 or more weeks. This two-point change in the summed Lung Cancer Subscale score correlates with both survival and performance status.34,35
In the international phase II trial, documented symptom improvement occurred in 40% of individuals receiving gefitinib 250 mg.10 More than 50% of patients who had stable disease also demonstrated symptom improvement. The US trial reported similar results.11 Confirming phase I observations, over half of the symptom improvements were apparent after only 1 week of treatment. For patients with symptom benefit, improvement was evident in 85% of patients 4 weeks after starting gefitinib. The greatest improvement in Lung Cancer Subscale symptom scores occurred in those patients demonstrating radiographic response, and the least improvement was seen in those with disease progression.36
Side Effects and Their Management
In the phase I trials, diarrhea was dose-limiting and skin toxicity of some type was seen in the majority of patients.6-9 Unlike conventional cytotoxic agents, gefitinib did not cause myelosuppression, neuropathy, significant nausea, vomiting, or alopecia.
Adverse effects reported in the phase II trials using the 250-mg recommended daily dosage were generally mild, manageable, noncumulative, and reversible with discontinuation of drug or sometimes even continued use. The most common adverse events were diarrhea, skin toxicity (variably recorded as rash, acne, dry skin, or pruritus), nausea, and vomiting. As a measure of overall tolerability in the international double-blind trial, only 16% of patients had an adverse event requiring a short treatment interruption, and none required a dose reduction.10 The main events resulting in dose interruptions were skin toxicity, gastrointestinal disturbances, and elevated serum hepatic transaminases. These events necessitated drug withdrawal in 1.9% of patients. Overall, grade 3 or 4 toxicities were seen in 1.5% of patients receiving 250 mg of gefitinib.
The US trial reported similar low frequency and severity of adverse events with gefitinib 250 mg daily. Only one person experienced an adverse event leading to study withdrawal, and one patient required dose reduction for toxicity. Grade 3 or 4 toxicities were reported in seven patients. Our institutional experience with gefitinib has been comparable to the phase II studies.
Skin Toxicity
A characteristic rash has been documented to be a "class adverse effect" of agents that target the EGFR and includes erlotinib20 and cetuximab37 as well as gefitinib. The eruption is characterized by inflammatory papules and pustules most often seen on the face, chest, and back and may resemble folliculitis or an acneiform drug eruption (Fig 2). The distribution of the eruption has been termed acneiform, as lesions are predominantly present at sites where there are large numbers of pilosebaceous units such as the scalp, face, neck, and upper trunk. This eruption is distinguished from classic acne vulgaris in its lack of comedones. Busam et al37 studied histologic sections from patients who developed rashes while receiving cetuximab, and described suppurative folliculitis and superficial perifolliculitis as the most common histologic changes. Microcomedones were notably absent.
The US phase II investigators reported skin toxicity in 62% of patients receiving the 250-mg dose.11 Other cutaneous manifestations reported with gefitinib were pruritus, dry skin, hand, finger, and heel fissures (Fig 3); desquamation; nail and cuticle cracking (Fig 4); nasal ulcers with subsequent epistaxis; and vaginal dryness. All these conditions were graded as mild in the international phase II trial. Pruritus associated with the pustular/papular eruption is a frequent complaint. In most patients, these eruptions resolved either during treatment, following a temporary interruption in treatment, or after treatment cessation. The US phase II investigators reported skin toxicity in 62% of patients receiving the 250-mg dose. In 82% of patients, it developed during the first treatment cycle.
Experience has shown that most dermatologic events can be successfully managed, but seldom resolve completely with continued administration of gefitinib. Clindamycin phosphate 1% gel has been used with good effect for the inflammatory pustular lesions. A combination clindamycin 1% and benzoyl peroxide 5% gel has also been used to elicit a drying effect on the pustules. Gel formulations may, however, cause irritation, and in many cases, systemic oral antibiotics like tetracycline 250 mg four times daily or minocycline 100 mg two times a day are preferable. Oral antibiotics can be quickly discontinued in some patients, while others require continued treatment with continued gefitinib use. Topical retinoids, like the antiacne medication tretinoin, are not recommended, as the eruption seen with gefitinib has a different pathophysiology than acne vulgaris. Topical and systemic corticosteroids have produced variable responses and need further investigation. Some investigators have reported success with the topical immunomodulatory agent pimecrolimus cream 1% currently approved for use in atopic dermatitis.
Dry skin responds well to bland emollients such as Eucerin cream (Beiersdorf, Jobst, Germany), Cetaphil cream (Galderma, Lausanne, Switzerland), and Aquaphor (Beiersdorf) healing ointment. Many patients have told us that Bag Balm (Dairy Association Co, Rock Island, Quebec, Canada) has been helpful in soothing fissures on the palms and soles. Liquid cyanoacrylate (BAND AID Brand Liquid Bandage; Johnson & Johnson, Skilman, NJ) applied into the cracks and fissures may also relieve pain and promote healing. Water-based make-ups and gentle cleansers such as Cetaphil cleanser are well tolerated with the above-mentioned topical and systemic therapies. We recommend that patients with extensive or persistent skin involvement be referred to a dermatologist.
Diarrhea
Diarrhea, as described in the National Cancer Institute Common Toxicity Criteria (version 2.0), occurred in 40% of patients on the 250-mg dose in the international trial.10 Twenty-four percent of patients took antidiarrheals. Diarrhea resolved in 84% of patients. The US study reported diarrhea in 57% of patients on the 250-mg dose (grade 1 to 48 (83%); grade 2 to 9 (15%); grade 3, one patient; grade 4, no patients).11 Approximately one-third of patients took antidiarrheal medications. Diarrhea was observed in the first treatment cycle in 76%.
In most cases, loperamide controls diarrhea caused by gefitinib. We advise our patients to purchase loperamide before starting treatment and to keep it with them at all times. If any diarrhea is experienced, we recommend taking two 2-mg loperamide tablets immediately, followed by one 2-mg tablet after every loose bowel movement, up to a maximum daily dose of 10 tablets (20 mg). If the diarrhea does not resolve with this regimen, we advise the patient to stop taking gefitinib and to call a physician promptly. Other causes of diarrhea should also be entertained in this setting.
Ophthalmologic Toxicity
An unusual consequence of treatment with gefitinib, seen in some individuals taking the drug for many months, is excessive eyelash growth. Rarely, misdirectional growth of eyelashes toward the globe, termed trichiasis, can cause corneal irritation. This can be prevented by regular eyelash trimming and treated by removal of the aberrant eyelash. We suggest checking for excessive eyelash growth at routine physical examinations. Patients with symptoms of corneal irritation should be referred to an ophthalmologist.
Although eye symptoms were noted in all gefitinib trials, none have been dose-limiting or led to treatment withdrawal. Because the study participants have many comorbid conditions and are taking concomitant medications that could also affect the eye, with the exceptions of excessive eyelash growth and trichiasis discussed above, the relationship of the eye symptoms to gefitinib is unclear. The US phase II trial is especially difficult to evaluate because all participants had received docetaxel, a drug that causes conjunctivitis and hyperlacrimation, which can persist after the drug is discontinued.38 Future trials involving gefitinib will provide more information about the possible ophthalmologic effects of gefitinib.
The International phase II trial reported eye toxicity in 21% of patients described as conjunctivitis, blepharitis, keratitis, eye pain, dry eyes, and corneal erosion.10 Grade 1 or 2 eye irritation was reported in 19% of patients in the United States including redness, itchiness, dry eyes, and trichiasis.36 Nonprescription eye drops such as Refresh (Allergen Inc, Irvine, CA) or saline relieve symptoms of dryness and hyperlacrimation.
Interstitial Lung Disease
Interstitial lung disease is a recognized but uncommon adverse effect of cytotoxic drugs39 and has also been described following treatment with the tyrosine kinase inhibitor imatinib as well.40 The overall incidence of interstitial lung disease in patients receiving gefitinib has been reported at approximately 1%. Approximately one third of the affected individuals died. The postmarketing experience in Japan reported an incidence of 2%. The rate was 0.3% in approximately 23,000 patients treated on the US-expanded access program.14 In the trials of NSCLC patients receiving chemotherapy who were randomly assigned to receive concomitant gefitinib or placebo, the observed incidence of interstitial lung disease was less than 1% and slightly higher in the placebo arm. Overall, this incidence of pulmonary toxicity is lower than that reported with the cytotoxic chemotherapy agents now in use for the treatment of NSCLC.
Interstitial lung disease associated with gefitinib has been described as interstitial pneumonia, pneumonitis, and alveolitis. Patients present with the acute onset of dyspnea, sometimes associated with cough or low-grade fever. It occurred in patients receiving prior radiation therapy (31% of reported cases), prior chemotherapy (57% of reported patients), and no prior therapy (12% of reported cases). Most cases occurred in the first month of therapy. Typical chest CT findings include bilateral diffuse ground glass opacities. Patients with concurrent idiopathic pulmonary fibrosis who experience worsening conditions while receiving gefitinib were observed to have a higher mortality compared to those without pulmonary fibrosis.
Inoue et al41 reported four patients in Japan with NSCLC who developed severe acute interstitial pneumonia in association with gefitinib. Two patients recovered after treatment with steroids and two patients with advanced lung cancer died from progressive respiratory failure. Diffuse alveolar damage was noted on specimens taken at autopsy. More patients with interstitial pneumonia also had received prior thoracic irradiation and had poor performance status. These investigators recommended that physicians should be vigilant for lung damage induced by gefitinib, especially in patients with prior chest radiotherapy, a history of idiopathic pulmonary fibrosis, or poor performance status.
If a patient receiving gefitinib experiences the acute onset or worsening of pulmonary symptoms, particularly in the first 4 weeks of therapy, we recommend that gefitinib be interrupted and an investigation of these symptoms be performed promptly. If interstitial lung disease is suspected, the patient should receive appropriate treatment, including corticosteroids, antibiotics, bronchodilators, and supplemental oxygen. There is no information on the safety of restarting gefitinib after its discontinuation in suspected cases of interstitial lung disease. Based on current information, we would not recommend gefitinib in persons who have experienced interstitial lung disease following its use.
Elevation of Serum Hepatic Transaminases
Rarely, asymptomatic increases in ALT and AST have been reported during treatment with gefitinib. Grade 3 transaminase elevation was noted in two of 103 patients on the 250-mg dose in the international phase II trial, necessitating study withdrawal of one of these patients.10 None of the 102 patients on the US trial had grade 3 or 4 transaminase elevations.11 Given the rarity and reversibility of this toxicity and the finding that pharmacokinetics in patients with liver metastasis and elevated blood tests of liver function are similar to those in patients with normal livers, we do not recommend any routine measurement of blood tests of liver function.
Patterns and Sites of Relapse
In the analysis reported by Miller et al,15 among the 21 patients with radiographic regressions, 14 experienced disease progression. Eight patients showed progression of disease in the lung, with one patient suffering both lung and liver progression. Unlike disease progression after conventional chemotherapy, where obvious new metastatic deposits and enlargements of existing lesions are clear cut, patients with initial response following gefitinib in pulmonary lesions who then develop disease progression based on objective criteria can have subtle, millimeter-sized enlargements. Often, reviewing any two consecutive scans does not confirm progression, which can be documented only by a direct comparison to the study that demonstrated the best response. Many patients report a worsening of symptoms and a decreased sense of well-being when gefitinib is discontinued because of objective evidence of disease progression, suggesting that some degree of tumor control persists even after the objective criteria for progression have been met. This situation may be analogous to that of patients with gastrointestinal stromal tumors sensitive to imatinib (another tyrosine kinase inhibitor) whose tumor masses subsequently grow to the point that objective criteria for disease progression are met. When imatinib is stopped, patients report feeling worse and their positron emission tomography scans show increased tumoral fluorodeoxyglucose avidity that can be reversed by the reinstitution of imatinib.42,43 Other investigators studying imatinib-sensitive, then refractory, gastrointestinal stromal tumors have described a nodule within a mass that on biopsy contains a new activating kinase mutation.44 Surrounding tumor tissue, that presumably does not harbor a new mutation, does not grow while imatinib is maintained. Physicians treating clinically well patients who have previously responded to gefitinib should be aware that unusual patterns of progression are possible (and even likely) when using a kinase inhibitor in individuals with tumors harboring activating mutations that underlie their sensitivity to these agents.
Of the 21 patients with partial responses following gefitinib reported by Miller et al,15 seven developed new or worsening metastases in the CNS, in either the brain or leptomeninges.45 In several of these individuals, CNS metastases were the first and only site of relapse. Our experience suggests that the CNS may be a "sanctuary site" for resistant lung cancer cells in persons where the disease is otherwise well controlled. Metastases to the brain or leptomeninges should be high in the differential for patients with tumors sensitive to gefitinib who develop new complaints.
DISCUSSION
Phase II trials selected a single 250-mg daily oral dosage as equally effective and safer than a 500-mg dose. These studies confirmed observations from phase I studies documenting a 14% radiographic regression rate, a 40% symptom improvement rate, and manageable diarrhea and rash as the only common adverse effects. Based on these phase II data, regulatory authorities have approved gefitinib given as a single 250-mg daily oral dose as a treatment for patients with advanced NSCLC with tumors that have failed to respond to cisplatin or carboplatin, docetaxel, and other agents. In contrast, studies combining gefitinib with chemotherapy for the initial treatment of advanced NSCLC failed to improve response or survival over chemotherapy alone.46,47 Until more data emerge, gefitinib should be used only after conventional chemotherapy (which has been proved to improve survival) has failed. Compared to other treatments for advanced NSCLC, gefitinib is generally better tolerated. The adverse effects it causes are nearly always manageable, reversible, and lessen even with continued use in most patients.
Gefitinib should always be administered at a dose of 250 mg orally daily, with follow-up initially after a month, then every 2 to 3 months. Dose escalation is not routinely recommended, as the randomized trials that led to its approval revealed similar efficacy but increased adverse events by doubling the dose. We suggest 1- to 2-week discontinuations for the rare individual who experiences severe skin toxicity or diarrhea despite the supportive measures we have outlined. Treatment-limiting toxicities such as interstitial lung disease are extremely rare. Even that adverse effect can usually be managed effectively by stopping gefitinib and administering corticosteroids, supplemental oxygen, and other supportive care measures.
Unfortunately, the majority of unselected patients with NSCLC derive no benefit from gefitinib. How this situation can best be addressed is now the focus of intense research. Already, several clinical characteristics and the presence of EGFR mutations or amplification can identify patients more likely to benefit, especially persons who have never smoked cigarettes and individuals whose tumors have any features of bronchioloalveolar carcinoma.10,11,14,15 The presence of one or more of these characteristics can help the clinician choose between the conventional chemotherapy choices and gefitinib. By contrast, neither the presence nor the degree of EGFR expression, as measured by immunohistochemistry, predicts outcomes, and therefore they should not be used to select patients for treatment with this agent.18
In the near future, two molecular tests may possibly be used to predict tumor sensitivity to gefitinib: EGFR mutation status, as assessed by DNA sequencing, and EGFR gene copy number, as assessed by fluorescent in situ hybridization or chromogenic in situ hybridization. Although technically validated, widely available testing for the most common mutations will be available in the near future, prospective studies will need to be performed before these kinds of tests are used in routine practice. In the meantime, the clinical characteristics previously discussed can still be useful predictors of gefitinib response.
Gefitinib provides both benefit and hope for patients with NSCLC who have exhausted other options. For the researchers who postulated decades ago that blocking growth factor receptors like EGFR could lead to tumor regressions, gefitinib represents a promise fulfilled. This success has stimulated the search for new kinase inhibitors and other strategies to block signaling in lung cancer cells.
Authors’ Disclosures of Potential Conflicts of Interest
NOTES
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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