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Cancer Therapy: Clinical |
Authors' Affiliations: 1 Section of Hematology/Oncology, Department of Medicine; 2 University of Chicago Cancer Research Center; Departments of 3 Health Studies and 4 Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois; 5 Division of Medical Oncology, University of Colorado Health Sciences Center and the Denver Veterans Affairs Medical Center, Denver, Colorado; 6 Northwestern University, Feinberg School of Medicine, Evanston Northwestern Healthcare, Evanston, Illinois; and 7 Division of Hematology and Oncology, Long Island Jewish Medical Center, New Hyde Park, New York
Requests for reprints: Ezra Cohen, Section of Hematology/Oncology, Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC2115, Chicago, IL 60637. Phone: 773-702-4137; Fax: 773-834-0188; E-mail: ecohen{at}medicine.bsd.uchicago.edu.
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Abstract |
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Experimental Design: Phase II trial with objective response rate as the primary end point. Measurements of quality of life and levels of serum vascular endothelial growth factor and transforming growth factor-
were assessed before and during therapy.
Results: In 70 patients, 1 (1.4%) partial response was observed. Median progression-free survival and overall survival were 1.8 and 5.5 months, respectively. Quality of life scores improved transiently during the first weeks of therapy before returning to baseline. Median vascular endothelial growth factor and transforming growth factor- levels were above the normal range but were not predictive of outcome. Four patients experienced grade 3 drug-related adverse events. Rash of any grade was observed in 64% of subjects. Correlation between disease control (partial response + stable disease), progression-free survival, and overall survival and grade of cutaneous toxicity was observed (P = 0.001, 0.001, and 0.008 respectively).
Conclusions: Gefitinib monotherapy at 250 mg in recurrent and/or metastatic SCCHN seems to have less activity than was previously observed for 500 mg daily. A dose-response relationship may exist for this agent in SCCHN and grade of cutaneous toxicity attributable to gefitinib is a clinical predictor of better outcome.
40,000 people in the United States annually with up to 50% of patients succumbing to the disease due to recurrence or development of metastases (1). Preclinical studies using a variety of EGFR inhibitors suggested that these agents would be clinically efficacious and EGFR targeted agents have shown reproducible activity in SCCHN (2). For patients with few therapeutic options, the response and survival rates reported were encouraging especially in light of the favorable tolerability of these agents. In a phase II trial involving 52 patients, the objective response rate using the small molecule EGFR tyrosine kinase inhibitor (TKI) gefitinib at a dose of 500 mg daily was 10.6% with a median time to progression and overall survival of 3.4 and 8.1 months, respectively (3). A significant positive correlation between development of skin toxicity and these outcome measures was also observed. Just before that report, results of two randomized phase II trials in non–small cell lung cancer (NSCLC) comparing gefitinib 250 to 500 mg daily showed similar efficacy for both doses, whereas the lower dose was better tolerated (4, 5). Symptom intensity measured with validated indices has been incorporated into previous EGFR TKI trials to explore whether there were potential benefits beyond observed objective responses.
Preclinical data have also suggested that EGFR modulates the level of vascular endothelial growth factor (VEGF) and can be influenced by levels of its ligand, transforming growth factor- (TGF-). A number of in vivo experiments have suggested that EGFR TKIs have antiangiogenic effects by inhibiting VEGF production (6, 7). We hypothesized that serum levels of VEGF would be decreased in patients treated with gefitinib and that the extent of reduction would correlate positively with outcome (i.e., patients with the greatest decrease in circulating VEGF levels would experience the greatest benefit).
Conversely, TGF- has been implicated as the principal ligand for EGFR in the human system, has been shown to promote tumor growth through autocrine mechanisms, and has been negatively correlated with outcome in SCCHN (8, 9). TGF- activation of EGFR signaling can be inhibited by EGFR-targeted therapy and TGF- production per se is reduced upon exposure to gefitinib in preclinical models (7, 10, 11). We hypothesized, therefore, that TGF- serum levels would reflect the tumor microenvironment, that these levels would indicate a tumor that is dependent on TGF-/EGFR signaling, and that patients with higher pretreatment TGF- levels would be more likely to benefit from EGFR TKI therapy. In addition, because TGF- in SCCHN is produced by tumor cells themselves, a reduction in tumor burden should be reflected as lower levels of circulating TGF-.
The current study evaluated the objective response rate, progression-free survival, and overall survival in patients with recurrent or metastatic SCCHN treated with 250 mg gefitinib daily. In addition, the effects of gefitinib on quality of life (QoL), serum TGF-, and serum VEGF were measured.
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Materials and Methods |
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2, leukocyte count 
3,000/µL, absolute neutrophil count 1,500/µL, platelet count 100,000/µL, total bilirubin within institutional normal limits, aspartate amino transferase and amino alanine transferase 2.5 times the institutional normal limit, and creatinine 1.5 mg/dL. Patients were not allowed to have undergone any radiotherapy or chemotherapy within 28 days of entering study and were not allowed any prior EGFR-directed therapy. All patients were required to understand and sign the informed consent document before treatment. Treatment plan and dose modifications. All patients received gefitinib 250 mg daily orally starting from day 1 of therapy without planned interruptions. Feeding tube administration was allowed as there is documented bioequivalence when compared with oral administration (13). Each cycle was defined as 28 days in length. Dose interruption was allowed for a maximum of 14 days in the event of grade 3 or 4 toxicity or unacceptable grade 2 toxicity. In the event of grade 3 or 4 cutaneous or gastrointestinal toxicity, gefitinib was interrupted until resolution to grade 1 or less. Control of diarrhea using over-the-counter antidiarrheal medication was allowed. Antiemetic and other supportive care agents, including remedies for skin toxicity, were allowed. Patients were continued on study until objective progression of disease, an adverse event necessitating discontinuation, voluntary patient withdrawal, or the physician investigator felt it necessary to discontinue therapy.
Response, toxicity, and quality of life assessment. Response Evaluation Criteria in Solid Tumors (12) were used for objective tumor response assessment. Computed tomography scanning was the preferred baseline and reevaluation technique. Patients were seen by a physician every 4 weeks and reevaluated radiographically every 8 weeks. In addition to a baseline scan, confirmatory scans were obtained 4 weeks following initial documentation of an objective response. For metastatic skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, was recommended. The National Cancer Institute Common Toxicity Criteria version 2.0 was used to grade toxicity.
QoL was measured using a recently developed abbreviated instrument, the Functional Assessment of Cancer Therapy–Head and Neck Symptom Index-10 (FHNSI-10). This brief symptom index, designed by David Cella et al. (14) is a more symptom-focused index specifically for use with patients with advanced and/or recurrent/refractory SCCHN. Disease-related symptoms and concerns from the functional assessment of cancer therapy for head and neck cancer were presented to 65 experts in treating advanced head and neck cancer. These experts then selected the five most important symptoms/concerns to assess in treating advanced SCCHN. The 10 items included in the FHNSI-10 represent those items endorsed by 20% or more of the medical experts (15). They are scored on a five-point scale from 0 (not at all) to 4 (very much). This index was selected for use in the current study based on its brevity and feasibility in an ill patient population as well as the fact that it captures the most likely range of symptoms and limitations experienced by this group of patients. In consultation with Dr. Cella, an additional item from the Functional Assessment of Cancer Therapy–General Scale asking patients how bothersome their side effects were was added to more globally describe their experience of treatment. The QoL index was completed by patients before receiving gefitinib at days 7, 14, 21, and 28 of cycle 1, and then on day 28 of every cycle beginning with cycle 2. A higher score reflects fewer symptoms and better QoL with a maximum possible score of 44.
Vascular endothelial growth factor and transforming growth factor- levels. After obtaining separate informed consent, blood samples were collected from patients in 7 mL heparinized tubes before and after 8 weeks of therapy with gefitinib. Triplicate samples were analyzed for serum VEGF and TGF- using commercially available ELISA kits (R&D Systems, Minneapolis, MN). Briefly, plates were coated overnight with anti-VEGF (1 µg/mL) or anti-TGF- (0.4 µg/mL) antibodies and then blocked with 1% bovine serum albumin. Samples were added followed by anti-VEGF (50 ng/mL) and anti-TGF- (300 ng/mL) biotinylated antibodies. Streptadivin peroxidase, substrate solution, and stop solution were added in sequence and plates were read immediately using the Synergy HT Multi-Detection Microplate Reader (Bio-Tek, Winooski, VT) at dual wavelengths of 450 to 540 nm.
Statistical analysis. The primary end point of the study was objective response rate (complete response plus partial response) based on Response Evaluation Criteria in Solid Tumors. A single-stage phase II study design was used to test the null hypothesis that the true response rate was <5% against the alternative that it was at least 15%. A sample size of 63 evaluable patients was planned. If seven or more objective responses were observed, the null hypothesis would be rejected and the study would conclude that 250 mg gefitinib is an effective treatment for SCCHN. With this scenario, the probability of one-sided type I error was 0.037 and the study power was 0.853.
To consider the effect of gefitinib on disease control rate (a secondary end point defined a priori as the addition of complete response, partial response, and stable disease), an interim analysis was conducted. Based on a previous study with 500 mg gefitinib, the rate of disease progression at first evaluation at 8 weeks was expected to be 50% and an 85% rate of disease progression was felt to be the maximum acceptable. If 23 or more of the first 30 evaluated patients had disease progression as their best objective response, the trial would be stopped. The probability of stopping thus was 0.0026 if the true rate of progression was 50% and 0.93 if the true rate of disease progression was 85%.
The secondary end points of progression-free and overall survival were measured from date of registration and summarized by computing Kaplan-Meier curves. Median survival and/or the percentage surviving at specific time points are reported together with corresponding 95% confidence intervals (95% CI). Factors associated with progression-free survival and overall survival were examined using log-rank tests.
All efficacy and toxicity end points were assessed and reported for all registered patients (eligible or not). The primary efficacy analysis included all registered patients who met the eligibility criteria. All registered patients who met the eligibility criteria and received any study drug were included in the analysis of toxicity. A Wilcoxon rank-sum test was used to examine the relationship between disease control rate and cutaneous toxicity and a Fisher's exact test was used to examine the relationship between disease control rate and prior palliative chemotherapy.
The feasibility of using the FHNSI-10 in a group of severely ill recurrent disease patients was explored by calculating the percentage of evaluable patients who completed the questionnaire at each time point. FHNSI-10 items were summed to create an overall QoL summary score. First, change over time for the entire cohort of patients was examined using a random effects linear regression model (16). Second, change in subjects who benefited (partial response and stable disease) and subjects who did not benefit (progressive disease) was examined separately by adding a time-by-response interaction term to the model.
The distribution of VEGF and TGF- were found to be skewed to the right and thus a median and interquartile range was used to describe central tendency and variation. Wilcoxon signed-rank test was used to compare changes in serum markers between baseline and week 8.
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The primary difference in eligibility between the current study and the 500 mg single-agent trial was the number of allowable prior therapies. The current study did not restrict patients with respect to the number of prior therapies, whereas the 500 mg trial allowed a maximum of one prior therapy for recurrent and/or metastatic disease. A subset analysis was done on the current study examining only those patients who had received one or no prior regimens for recurrent and/or metastatic disease. Excluding patients who were nonevaluable, the disease control rate in this group was numerically higher at 44% compared with patients who had received two or more prior regimens (15%, P = 0.11). The subject with responding disease received prior chemotherapy (cisplatin and tirapazamine) with concomitant reirradiation for locally recurrent disease.
A correlation between the development of a rash during EGFR-targeted therapy and therapeutic outcome was reported in previous studies in SCCHN. In the present study, the correlation between disease control rate and cutaneous toxicity showed that partial response or stable disease was significantly associated with grade of skin toxicity: The higher the grade, the more likely were patients to have partial response or stable disease (P = 0.001).
Progression-free and overall survival. At the time of this analysis, with a median follow-up of 18 months, all patients have either experienced progressive disease or died. The median progression-free survival and overall survival for the entire cohort were 1.8 months (95% CI, 1.7-3.1) and 5.5 months (95% CI, 4.0-7.0), respectively (Fig. 1). The 6-month and 1-year survival rates were 47% (95% CI, 35-58%) and 19% (95% CI, 11-29%), respectively. Grade of skin toxicity positively correlated with both progression-free survival (P = 0.001) and overall survival (P = 0.008). The 13 subjects who developed grade 2 or greater skin toxicity experienced median progression-free survival and overall survival of 4.4 and 7.6 months, respectively. These outcome measures were not associated with number of prior therapies (P = 0.67 for progression-free survival and 0.61 for overall survival) or prior chemoradiotherapy (P = 0.17 for progression-free survival and 0.77 for overall survival).
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75% of patients were captured at every time point. Patients were no longer followed for QoL after stopping gefitinib treatment.
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Vascular endothelial growth factor and transforming growth factor-. Serum VEGF and TGF- levels were available at baseline on 61 and 59 patients, respectively. The median VEGF at baseline was 78 pg/mL (interquartile range, 41-167; Fig. 3A). Thirty-nine patients had VEGF measured 8 weeks after baseline with a median level of 68 pg/mL (interquartile range, 17-116). Of 37 patients who had both baseline and follow-up VEGF values, VEGF increased in 15 patients, decreased in 19 patients, and had no change in 3 patients. Overall, there was no significant change from baseline to week 8 (P = 0.86).
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level at baseline was 20 pg/mL (interquartile range, 6-194; Fig. 3B). Thirty-eight patients had TGF- measured at 8 weeks after treatment with a median value of 78 pg/mL (interquartile range, 6-1,101). Of 35 patients who had both baseline and follow-up TGF- values, TGF- increased in 21 patients, decreased in 10 patients, and had no change in 4 patients. Overall, there was a significant increase from baseline to week 8 (P = 0.03). Interestingly, patients with stable disease or partial response trended toward a greater increase in TGF- levels with a median increase of 74 (interquartile range, 0-995) compared with a median increase of 4 (interquartile range, –2-57) in patients with progressive disease (Wilcoxon rank-sum test, P = 0.13). Disease status (P = 0.51) and gender (P = 0.70) were not associated with changes in serum TGF- levels. Neither the baseline levels nor the change from baseline to week 8 were associated with progression-free survival or overall survival for either marker.
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Discussion |
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The results reported here suggest that in the setting of recurrent or metastatic SCCHN, 250 mg of daily gefitinib is less active than 500 mg. This observation has significant implications for both this class of agents and this disease, suggesting that a dose-response relationship for these agents exists in the dose range that should achieve target inhibition. In fact, doses higher than 500 mg may be optimal with respect to efficacy and should be further explored in diseases where single-agent activity has been observed. A phase II trial administering the EGFR TKI erlotinib at 150 mg daily to 115 refractory SCCHN patients observed a 4.3% objective response rate and 9.6-week median progression-free survival and could be viewed as an example of dosing an EGFR TKI at the maximum tolerated dose (18). Those results suggest that efficacy will inevitably plateau with these agents but can be greater than that realized using 250 mg gefitinib daily.
The current results also likely reflect a difference in the mechanism of response to EGFR TKI between SCCHN and NSCLC. In NSCLC, the presence of somatic EGFR tyrosine kinase mutations has been described in 10% of non-Asian and 30% of Asian unselected patients (19). These mutations seem to be a predictor of objective response to EGFR TKI and correlate with demographic factors associated with higher response rates. Thus, a molecular and clinical subset of NSCLC patients most likely to derive a benefit from these agents is identifiable. To date, such mutations have been reported in 7% of 41 unselected SCCHN Asian patients (20). In an analysis of samples from eight SCCHN patients in the United States treated with EGFR TKI, no mutations were discovered in the EGFR tyrosine kinase domain (21). If the mutation frequencies in NSCLC between ethnic groups were mirrored in SCCHN, one would expect substantially lower frequencies in the non-Asian population treated in this study. Moreover, because the majority of EGFR mutations occur in the adenocarcinoma subtype of NSCLC, SCCHN tumors would be expected to contain a significantly lower mutation frequency.
It is possible, therefore, that in tumors with predominantly wild-type EGFR, such as SCCHN, a higher level of EGFR TKI is required to achieve tumor response or clinical benefit, thus substantiating a dose-response observation. Another possibility is that, at higher doses, these agents are more promiscuous in their inhibitory profiles and effect kinases besides EGFR. In fact, a patient responding to 500 mg gefitinib has been described with an ERBB2 kinase domain mutation (21).
Interestingly, despite the lack of objective responses in this study, a positive correlation between all outcome measures and skin toxicity was observed. This association has been noted in every trial administering an EGFR inhibitor in SCCHN and in several other disease-specific studies (2). In the present study, the sample size allowed examination of the correlation in relation to grade of cutaneous toxicity and, similar to the single-agent erlotinib trial in SCCHN, patients who developed higher grades of rash had a higher likelihood of achieving disease control, longer progression-free survival, and improved overall survival. The skin toxicity associated with these agents likely represents a mechanistic effect related directly to EGFR inhibition. The lesions seem to be secondary to recruitment of inflammatory cells, eventually producing the characteristic rosacea-like rash (22, 23).
The explanation of the association between outcome and skin toxicity has not been fully elucidated. The simplest argument suggests that this is a pharmacokinetic phenomenon and draws support from data in patients with advanced NSCLC and breast cancer, demonstrating a correlation between trough concentrations of EGFR TKI and the incidence of rash (24, 25). As a result of this observation, a strategy of escalating the dose of EGFR TKI to produce grade 2 or greater cutaneous toxicity is currently undergoing testing in clinical trials.
However, there is a weak relationship between EGFR TKI concentration and activity and, clearly, there are patients who develop the characteristic rash at low drug plasma concentrations. Polymorphisms of the EGFR gene have been described that seem to influence expression of the protein (26, 27). Amador et al. (27) observed that one such polymorphism involving the number of CA single sequence repeats in intron 1 was associated with sensitivity to erlotinib in a panel of SCCHN cell lines. Furthermore, in SCCHN patients, the number of CA repeats was equivalent in tumor and genomic DNA and, in colorectal cancer patients, the number of repeats correlated with development of skin toxicity. These findings support a pharmacogenetic hypothesis that certain patients are genetically prone to develop the rash, that the rash is directly related to EGFR inhibition, that epithelial tumors retain identical genetic determinants of toxicity, and that these polymorphisms also render the cancer cells sensitive to EGFR blockade. The exploration of EGFR gene polymorphisms and their relationship to toxicity and outcome is currently being evaluated in prospective clinical trials.
The QoL instrument used in this study was very acceptable to patients as evidenced by the high rate of compliance. In addition, whereas there was some suggestion that patients with stable disease showed short-term improvement in QoL, overall there was little change in patients' scores over the course of the study. These results parallel clinical observations that whereas gefitinib 250 mg daily had little effect on SCCHN, it also did not produce significant toxicity nor lead to decline in QoL.
At the start of the trial, we hypothesized that gefitinib would be most effective in tumors that were dependent on EGFR-regulated growth. As a surrogate of this phenotype, we studied serum levels of VEGF and TGF-. Serum levels of both these growth factors were increased above the normal range in the patients enrolled. However, gefitinib treatment did not reduce serum levels of these proteins, and, in fact, TGF- levels rose significantly. Moreover, even in patients whose levels decreased over the interval, there was no evidence of increased efficacy. The lack of effect on VEGF and the increase in TGF- could result from the overall lack of efficacy of the agent at this dose. However, even in patients without progressive disease at 8 weeks whose tumor burden presumably did not increase substantially, an increase in TGF- was observed. Interestingly, an increase in circulating TGF- has been noted in a preclinical model using the monoclonal EGFR antibody, cetuximab (28). This was hypothesized to be secondary to disruption of ligand-receptor interaction caused by cetuximab resulting in greater amounts of free TGF-. The current study suggests that disruption of EGFR signaling per se could produce a paradoxical rise in TGF- through a mechanism that might involve a biochemical feedback loop between the ligand and receptor. Hypothetically, inhibition of EGFR signaling could result in increased production and/or secretion of TGF-.
One must also consider that these proteins are excreted as autocrine and paracrine growth factors that act in the local microenvironment, and circulating levels between baseline and week 8 of therapy do not reflect this. Thus, serum levels of VEGF and TGF- measured in this study may not be appropriate pharmacodynamic surrogates of gefitinib effect and tumor levels may best serve this purpose.
The present study, therefore, strongly suggests that 250 mg gefitinib daily is not as active as 500 mg daily in recurrent and/or metastatic SCCHN. Reasons for the difference between this observation and NSCLC trials are speculative but are consistent with what is being learned regarding mechanisms of response to EGFR TKI. The need to identify SCCHN patients who are most likely to respond to EGFR TKI continues to be of paramount importance although it seems that higher doses of gefitinib are required for maximal benefit in this disease.
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Acknowledgments |
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Footnotes |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 6/ 9/05; revised 8/25/05; accepted 9/ 2/05.
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expression in head and neck squamous carcinoma and inhibition by anti-epidermal growth factor receptor treatments. Cancer Res 2001;61:6500–10.This article has been cited by other articles:
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