Skin rash and good performance status predict improved survival with gefitinib in patients with advanced non-small cell lung cancer

M. K. Mohamed1, S. Ramalingam1, Y. Lin2, W. Gooding2 and C. P. Belani1,*

1 Division of Hematology–Oncology, University of Pittsburgh School of Medicine; 2 Biostatistics Facility, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

* Correspondence to: Professor C. P. Belani, University of Pittsburgh School of Medicine, 5150 Centre Avenue, UPMC Cancer Pavilion, Ste #552, Pittsburgh, PA 15232, USA. Tel: +1 412 648 6619; Fax: +1 412 664 6579. Email: belanicp{at}upmc.edu


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:: Gefitinib (Iressa®) is active as a single agent in the treatment of select patients with recurrent non-small cell lung cancer (NSCLC). The clinical characteristics of patients treated with gefitinib on an Expanded Access Program (EAP) at our institution identified predictive variables associated with better outcome.

Patients and methods:: Patients (n=199) with advanced NSCLC were treated with gefitinib (250 mg) upon progression with chemotherapy. Baseline patient characteristics were: median age, 69 years; males, 57%; adenocarcinoma, 56%.

Results:: Partial responses were noted in two patients (1%) and disease stabilization in 66 (35%) patients. The median survival (MS) was 5.9 months [95% confidence interval (CI) 4.1–7.1] and median time to progression was 3 months (95% CI 2.0–3.0). The predictive factors analyzed were gender, skin rash, diarrhea, tumor histology and performance status (PS). Patients who developed skin rash (any grade) had MS of 10.8 months versus 4.0 months for those without rash (P <0.0001, log rank test). Patients with PS 0, 1 and 2 had MS of 8.4, 6.2 and 2.8 months, respectively (P <0.0002). The other factors did not impact survival.

Conclusions:: Occurence of skin rash and baseline PS of 0/1 were associated with improved survival with gefitinib for recurrent NSCLC patients at our institution.

Key words: gefitinib, non-small cell lung cancer, performance status, skin rash


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality in the USA [1Go]. It is characterized by detection at an advanced stage, aggressive course and a fatal outcome in a majority of patients. Though improvements in survival and quality of life have been demonstrated for patients with advanced NSCLC, the benefit has been modest at best [2Go]. Further, it appears that an efficacy plateau has been reached with chemotherapy in both first-line and second-line treatment of advanced NSCLC [3Go, 4Go]. Therefore, identification of novel molecular targets that are critical for the sustenance of the cancer cell and effective methods to interrupt such cell-signaling pathways are essential steps in our efforts to improve the outcome for patients with this disease.

Epidermal growth factor receptor (EGFR) is a transmembrane receptor protein found primarily on cells of epithelial origin [5Go]. It is a member of the erbB family. Upon binding to its natural ligand, homodimerization of EGFR or heterodimerization with other members of the erbB family occurs. This results in phosphorylation of the intracellular tyrosine kinase domain of the protein and activation of a signal transduction cascade, which leads to proliferation, angiogenesis, invasion and metastases of the tumor cells [6Go, 7Go]. Therefore, blocking the EGFR pathway does constitute a relevant target for cancer therapy. EGFR is overexpressed in 40–80% of NSCLC [8Go], and has been linked to poor prognosis [9Go–11Go]. Gefitinib is a novel small molecule inhibitor of the EGFR tyrosine kinase (TK). It has been approved as monotherapy for the treatment of patients with advanced NSCLC who have progressed following first- and second-line chemotherapy containing platinum and docetaxel [12Go]. The efficacy of gefitinib in NSCLC has been established by two large, randomized clinical trials, IDEAL I (Europe and Japan) and II (USA) (Iressa Dose Evaluation in Advanced Lung cancer) [13Go, 14Go]. These trials demonstrated response rates of 9–19% along with symptom improvement and benefit in quality of life. Gefitinib is fairly well tolerated as monotherapy and the salient adverse effects are mild to moderate skin rash and diarrhea [15Go]. Interstitial pneumonitis, which has been reported in 3–6% of Japanese patients, is noted in <1% of the patients in the USA [16Go, 17Go].

Though gefitinib was developed as an inhibitor of the EGFR, there appears to be no consistent correlation between EGFR overexpression and response to therapy with gefitinib [14Go, 18Go]. Early experience with this agent has suggested higher likelihood of response in females, adenocarcinoma histology, never-smokers and patients of Japanese origin [18Go–20Go]. The clinical benefit rate (partial response rate + disease stabilization rate) is approximately 45% with gefitinib monotherapy in patients with recurrent NSCLC. Identification of baseline patient and tumor-specific characteristics and treatment-related factors that predict improved outcome, will maximize the utility of gefitinib. Therefore, we conducted an analysis of patients treated with gefitinib as part of the Expanded Access Program (EAP) at our institution.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Eligibility criteria for the EAP included: patients with stage IIIB (pleural or pericardial effusion)/IV; progression of NSCLC following first- and second-line chemotherapy or patients who were not candidates for chemotherapy due to co-morbid illnesses; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2; life expectancy >3 months; adequate renal (serum creatinine ≤1.5 mg/dl), hepatic (total bilirubin ≤1.5 times the upper limit of normal and AST/SGOT ≤2.5 times upper limit of normal) and bone marrow function (ANC ≥1500/mm3, platelet ≥100 000/mm3) and willingness to sign informed consent. Patients were not allowed to receive concurrent radiotherapy, chemotherapy or other experimental agents.

Baseline laboratory work-up included complete blood count, chemistry panel and liver function tests. A computed tomography (CT) scan demonstrating measurable disease was required within 60 days of the registration. Patients were treated with a 250 mg daily oral dose of gefitinib. Physical examination, assessment of PS and evaluation of laboratory parameters were conducted once every 30 days. Imaging studies with CT scan or Chest radiograph (CXR) were performed every 2 months during treatment. Responses were defined according to the RECIST criteria and required confirmation with at least two scans obtained 30 days apart. Treatment with gefitinib continued until disease progression, unacceptable toxicity, patient refusal or death. Patients were followed for toxicity, radiographic response and overall survival.

Statistical analysis
The response rate was computed as the proportion of patients with a complete or partial response among evaluable patients. The Clopper–Pearson 95% confidence interval (CI) for the response rate was also calculated. Probabilities of survival and time to progression were estimated by the Kaplan–Meier method. Greenwood's formula was used to calculate the standard error of the estimates. Group comparisons were conducted with the log rank test. Analysis of the predictive factors was retrospective in nature. The effects of demographic data, tumor stage, histology, PS and the common adverse effects i.e. skin rash and diarrhea, on survival were analyzed.


    Results
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 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
Two hundred and thirty-six patients with advanced/recurrent NSCLC were enrolled on the EAP at the University of Pittsburgh Cancer Institute from August 2001 to April 2003. Thirty-seven patients were excluded from the analysis because they did not receive any gefitinib or were missing pertinent data. The remaining 199 patients were included in this analysis. The baseline patient characteristics are shown in Table 1. A majority of the patients were male and >90% were Caucasian. Approximately 80% of the patients had a good PS (0–1). The most common histologic subtype was adenocarcinoma (56%). Eighty-one percent of the patients had received prior platinum-based chemotherapy.


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Table 1. Baseline patients characteristics

 
Toxicity
Gefitinib therapy was tolerated well overall. Skin rash and gastrointestinal toxicity (diarrhea) were the most common adverse events noted with gefitinib. Skin rash was observed in 62 out of 179 (34.6%) patients. This was observed within the first 2 months after initiation of therapy in all patients. The severity of the skin rash was grade 1 or 2 in a majority of the patients. Grade 1 or 2 diarrhea was observed in 38 out of 175 (21.7%) patients. Diarrhea was easily managed with anti-diarrheal therapy. Nausea and vomiting, mild in severity, was noted in 9.5% of the patients. No other significant adverse events were seen in this study. None of the patients discontinued therapy due to toxicity.

Efficacy
There were no complete responses (CR) noted. Two (both females) out of 189 (1.1%) evaluable patients had a partial response (PR). Both the responders had adenocarcinoma. One of the two responders had skin rash with gefitinib therapy. A total of 66 patients (66/189; 35%) had stable disease, 37 (56%) of whom were females. Thirty-nine of 66 (59%) patients with stable disease had adenocarcinoma and three had bronchioloalveolar carcinoma (BAC) histology. Twenty-nine patients with stable disease experienced skin rash (29/66; 44%). Progressive disease (PD) occurred in 121 (121/189; 64%) patients.

Survival data were available for 177 patients at the time of this analysis. The median survival for the entire cohort was 5.9 months (95% CI 4.1–7.1 months). Follow up ranged from 2.7 months to 19.4 months (median = 10.3 months). The 6-month survival rate for the entire cohort was 50% (95% CI 42–57%). As shown in Figure 1, there was a significant difference in survival between patients who developed skin rash of any grade (10.7 months, 95% CI 8.0–19.0 months) and those without rash (4.0 months, 95% CI 2.8–5.9 months) (P <0.0001). Overall PS had a significant impact on survival. The median survival for patients with PS 0 and 1 was 8.4 (95% CI 6.7–11.0 months) and 6.2 (95% CI 3.9–7.4) months, respectively, compared with 2.8 months (95% CI 1.6–3.8) (P=0.0002) for those with a PS of 2 (Figure 2). A multivariate Cox regression model was fitted to the data to test the effects of skin rash on overall survival controlling for the PS effect. The results suggested a strong correlation between skin rash and overall survival (hazard ratio = 0.41, P value <0.0001).



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Figure 1. Kaplan–Meier plot of overall survival for patients with and without skin rash (any grade). Patients with skin rash had a median survival of 10.8 months compared to 4 months for patients without a rash (log rank P <0.0001).

 


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Figure 2. Kaplan–Meier plot of overall survival based on performance status (PS). Survival was highly correlated with PS. Better PS was associated with improved survival rate (log rank P=0.0002).

 
There was a trend towards longer survival for females, though the differences did not reach statistical significance (Table 2). The median survival for females was 6.4 months compared to 4.5 months for males (P=0.33). A univariate survival analysis did not demonstrate any correlation between stage, histology and gastrointestinal adverse events with survival. The median time-to-progression (TTP) for the entire cohort (135 evaluable patients) was 3 months (95% CI 2–3). Skin rash was the only significant predictive factor for improved TTP. Patients who developed skin rash had a median TTP of 3 months (95% CI 3–5) compared to 2 months (95% CI 2–3) for those without rash (P=0.03). A marginal significant difference of TTP in men and women was observed (P value = 0.06). There were no significant differences between TTP and diarrhea (P=0.60), PS (P=0.62) or histological type (P=0.90).


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Table 2. Univariate analysis of predictive factors

 

    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Inhibition of the EGFR pathway has become an established strategy to treat patients with advanced NSCLC. The results of our study further substantiate the benefit from gefitinib in patients with advanced NSCLC who progressed following prior chemotherapy. In our study, the subjects were heavily pre-treated and the inclusion criteria were less stringent, representing the ‘real world’ situation. These may in fact be the reasons for the low response rate (only 2%) noted in our study. However, the percentage of patients who experienced benefit, including disease stabilization and the median survival of 5.9 months are comparable to that seen in the IDEAL trials [13Go, 14Go]. The magnitude of benefit with gefitinib was higher in Japanese women treated on IDEAL I and in Korean patients with NSCLC (response rate, 21–26%; disease control rate 40–60%) [13Go, 21Go]. This might be related to ethnic differences and perhaps due to a higher prevalence of EGFR mutations in this population.

In this analysis, we found two predictive factors, skin rash and good PS, to be associated with improved survival. Patients who developed skin rash had a statistically significant increase in median survival compared to patients who did not have skin rash. Janne et al. [22Go] have also reported better survival for patients with gefitinib-induced skin rash (10.0 months). However, in their analysis, the correlation between skin rash and survival did not reach statistical significance (P=0.088). In the Southwest Oncology Group (SWOG) trial of gefitinib for advanced BAC (S0126) the median survival was 13 months compared to 5 months for those with and without skin rash, respectively [23Go]. It is to be noted that the SWOG trial utilized a higher dose of gefitinib (500 mg daily). Similar observations have been reported in patients who developed skin rash with erlotinib in a small phase II study of 57 patients [24Go]. The median survival was 46.5 days in patients with no rash, compared with 257 days in those with grade I rash (P <0.0001) and 597 days in those with grade 2/3 rash (P <0.0001). In contrast, the randomized study of erlotinib versus placebo for patients with advanced NSCLC failed to detect a significant correlation in survival between those with and without skin rash [25Go].

Skin rash is more consistently seen with EGFR monoclonal antibody treatment [26Go]. Saltz et al. [27Go] have reported a consistent association between the severity of the skin rash and improved survival for patients with renal cell, pancreatic and head and neck cancers treated with cetuximab. In a study for patients with metastatic colorectal cancer treated with the combination of cetuximab and irinotecan, Cunningham et al. [28Go] noted a higher response rate in patients with skin reactions compared to those without any skin rash (25.8% versus 6.3%, P=0.005). Thus, occurrence of rash with EGFR inhibition may be a useful predictor of efficacy not only in NSCLC but also in other tumor types.

In the IDEAL I and II trials, though skin rash was more common with the 500 mg dose (68% and 75%) of gefitinib, the efficacy was not superior to that seen with the 250 mg dose (47% and 62%) [13Go, 14Go]. These randomized phase II studies were not adequately powered to show significant differences in outcome between the two doses. In a prospectively designed trial with appropriate sample size it may be possible to see the effect of skin rash on survival as has been observed in our analysis. The other possibility is to escalate gefitinib dose to the occurrence of rash in individual patients in order to look for a greater benefit.

Recent studies have explored the mechanisms that may be responsible for the observed correlation between skin rash and improved efficacy with EGFR inhibitors. Perea et al. [29Go] evaluated the number of CA repeats in the highly polymorphic intron 1 of the EGFR gene. Shorter CA segments were associated with higher EGFR gene and protein expression. Skin rash was more common in patients with short CA segments compared to those with long CA repeats (61% versus 17%). The downstream molecular effects of EGFR inhibition were also more pronounced in the post-treatment skin biopsy of patients with short CA repeats. Immunological mechanisms have also been hypothesized to contribute to the development of skin rash with EGFR inhibition. This is supported by the presence of focal mononuclear infiltrates with vacuolar degeneration of the basal cell layer and apoptotic keratinocytes in hair follicles and interfollicular epidermis in the post-treatment skin biopsy of patients treated with gefitinib [30Go]. In fact, the enhanced anti-tumor effect seen in patients with skin rash may reflect a more functional anti-tumor immune response in such individuals. These are not definitive but thought provoking and it is clear that additional work is necessary to understand the mechanistic aspects of the correlation between skin rash and tumor response with EGFR inhibition. Evaluation of effects on downstream signals following EGFR inhibition in paired tumor and skin tissue will be an important step to understand this observation. Clinical studies are underway to determine whether escalation of the dose of EGFR inhibitor until the development of skin rash will lead to improved outcome.

Our study also demonstrated improved survival with gefitinib in patients with a good PS. The median survival of patients with a poor PS was only 2.8 months. Poor PS has been clearly linked with an inferior outcome for patients with advanced NSCLC [31Go]. In fact, patients with a poor PS are more likely to receive single agent chemotherapy or EGFR tyrosine kinase inhibitor (TKI) due to intolerance to standard chemotherapy doublets. The findings of our study illustrate the limitations of currently available treatment modalities in this sub-group of patients and the need for evaluation of innovative approaches. It is also important to distinguish patients with poor PS related directly to the disease, i.e. lung cancer from those who have debilitating co-morbid illness, since the utility of EGFR inhibition may be different between these two subsets.

Somatic mutations were recently identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response. Similar mutations were detected in tumors from two of 25 patients with primary NSCLC who had not been exposed to gefitinib (8%) [32Go]. The mutations were small in-frame deletions or amino acid substitutions clustered around the ATP binding pocket of the tyrosine kinase domain. EGFR mutations appear to be more common in females, adenocarcinoma histology, Japanese ethnicity and never-smokers [33Go]. Treatment with an EGFR inhibitor in patients with such mutations has resulted in impressive responses. We plan to evaluate the tumor tissue from patients treated in our study for the presence of EGFR mutations and to correlate with disease stabilization rate and other clinical characteristics.

It is clear that these recent developments have led to a new era in the treatment of advanced NSCLC. Since lung cancer exhibits wide molecular heterogeneity, it is likely that an individualized therapy approach with proper patient selection will be critical to the success of targeted therapies.


    Acknowledgements
 
Presented at the 39th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, USA.

Received for publication October 20, 2004. Revision received December 27, 2004. Accepted for publication January 4, 2005.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Jemal A, Tiwari RC, Murray T et al. Cancer statistics, 2004. CA Cancer J Clin 2004; 54: 8–29.[Abstract/Free Full Text]

2. Ramalingam S, Belani CP. State-of-the-art chemotherapy for advanced non-small cell lung cancer. Semin Oncol 2004; 31: 68–74.

3. Fossella FV, DeVore R, Kerr RN et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 2000; 18: 2354–2362.[Abstract/Free Full Text]

4. Hanna N, Shepherd FA, Fossella FV et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004; 22: 1589–1597.[Abstract/Free Full Text]

5. Baselga J. Targeting the epidermal growth factor receptor with tyrosine kinase inhibitors: small molecules, big hopes. J Clin Oncol 2002; 20: 2217–2219.[Free Full Text]

6. Baselga J, Albanell J. Targeting epidermal growth factor receptor in lung cancer. Curr Oncol Rep 2002; 4: 317–324.[Medline]

7. Ranson M, Hammond LA, Ferry D et al. ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial. J Clin Oncol 2002; 20: 2240–2250.[Abstract/Free Full Text]

8. Hirsch FR, Varella-Garcia M, Bunn PA Jr et al. Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 2003; 21: 3798–3807.[Abstract/Free Full Text]

9. Selvaggi G, Novello S, Torri V et al. Epidermal growth factor receptor overexpression correlates with a poor prognosis in completely resected non-small-cell lung cancer. Ann Oncol 2004; 15: 28–32.[Abstract/Free Full Text]

10. Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Eur J Cancer 2001; 37 (Suppl 4): S9–S15.[ISI][Medline]

11. Brabender J, Danenberg KD, Metzger R et al. Epidermal growth factor receptor and HER2-neu mRNA expression in non-small cell lung cancer is correlated with survival. Clin Cancer Res 2001; 7: 1850–1855.[Abstract/Free Full Text]

12. Cohen MH, Williams GA, Sridhara R, Chen G, Pazdur R. FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets. Oncologist 2003; 8: 303–306.[Abstract/Free Full Text]

13. Fukuoka M, Yano S, Giaccone G et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 2003; 21: 2237–2246.[Abstract/Free Full Text]

14. Kris MG, Natale RB, Herbst RS et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. J Am Med Assoc 2003; 290: 2149–2158.[Abstract/Free Full Text]

15. Shah NT, Kris MG, Pao W et al. Practical Management of Patients With Non-Small-Cell Lung Cancer Treated With Gefitinib. J Clin Oncol 2005; 23(1): 165–174.[Abstract/Free Full Text]

16. Seto T, Yamamoto N. Interstitial lung diseases (ILD) induced by gefitinib in patients with advanced non-small cell lung cancer (NSCLC): Results of a West Japan Thoracic Oncology Group (WJTOG) epidemiological survey. Proc Am Soc Clin Oncol 2004; 23: 629 (Abstr 7064).

17. Hotta K, Harita S, Bessho A, Yonei T, Gemba K, Aoe K. Interstitial lung disease (ILD) during gefitinib treatment in Japanese patients with non-small cell lung cancer (NSCLC): Okayama Lung Cancer Study Group. Proc Am Soc Clin Oncol 2004; 23: 629 (Abstr 7063).

18. Takano T, Ohe Y, Kusumoto M et al. Risk factors for interstitial lung disease and predictive factors for tumor response in patients with advanced non-small cell lung cancer treated with gefitinib. Lung Cancer 2004; 45: 93–104.[CrossRef][ISI][Medline]

19. Miller VA, Kris MG, Shah N et al. Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol 2004; 22: 1103–1109.[Abstract/Free Full Text]

20. Haringhuizen A, van Tinteren H, Vaessen HF et al. Gefitinib as a last treatment option for non-small-cell lung cancer: durable disease control in a subset of patients. Ann Oncol 2004; 15: 786–792.[Abstract/Free Full Text]

21. Park J, Park BB, Kim JY et al. Gefitinib (ZD1839) monotherapy as a salvage regimen for previously treated advanced non-small cell lung cancer. Clin Cancer Res 2004; 10: 4383–4388.[Abstract/Free Full Text]

22. Janne PA, Gurubhagavatula S, Yeap BY et al. Outcomes of patients with advanced non-small cell lung cancer treated with gefitinib (ZD1839, ‘Iressa’) on an expanded access study. Lung Cancer 2004; 44: 221–230.[CrossRef][ISI][Medline]

23. West H, Franklin WA, Gumerlock PH et al. Gefitinib (ZD1839) therapy for advanced bronchioloalveolar lung cancer (BAC): Southwest Oncology Group (SWOG) Study S0126. Proc Am Soc Clin Oncol 2004; 23: 618.

24. Perez-Soler R, Chachoua A, Hammond LA et al. Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol 2004; 22: 3238–3247.[Abstract/Free Full Text]

25. Shepherd FA, Pereira J, Ciuleanu TE et al. A randomized placebo-controlled trial of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) following failure of 1st line or 2nd line chemotherapy. A National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial. Proc Am Soc Clin Oncol 2004; 23: 622.

26. Baselga J. The EGFR as a target for anticancer therapy–focus on cetuximab. Eur J Cancer 2001; 37 (Suppl 4): S16–S22.[ISI][Medline]

27. Saltz L, Kies M, Abbruzzese JL, Needle M. The presence and intensity of the cetuximab-induced acne-like rash predicts increased survival in studies across multiple malignancies. Proc Am Soc Clin Oncol 2003; 22: 204.

28. Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004; 351: 337–345.[Abstract/Free Full Text]

29. Perea S, Oppenheimer D, Amador M et al. Genotypic bases of EGFR inhibitors pharmacological actions. J Clin Oncol 2004; 22: 196.[Free Full Text]

30. Albanell J, Rojo F, Averbuch S et al. Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition. J Clin Oncol 2002; 20: 110–124.[Abstract/Free Full Text]

31. Albain KS, Crowley JJ, LeBlanc M, Livingston RB. Survival determinants in extensive-stage non-small-cell lung cancer: the Southwest Oncology Group experience. J Clin Oncol 1991; 9: 1618–1626.[Abstract]

32. Lynch TJ, Bell DW, Sordella R et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350: 2129–2139.[Abstract/Free Full Text]

33. Paez JG, Janne PA, Lee JC et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304: 1497–1500.[Abstract/Free Full Text]