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The Oncologist, Vol. 7, Suppl 4, 9-15, August 15, 2002
© 2002 AlphaMed Press

ZD1839 (IressaTM) in Non-Small Cell Lung Cancer

Roy S. Herbst, Merrill S. Kies

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

Correspondence: Roy S. Herbst, M.D., M.D. Anderson Cancer Center, Thoracic/Head and Neck Medical Oncology, 1515 Holcombe Blvd., Box 432, Houston, Texas 77030, USA. Telephone: 713-792-6363; Fax: 713-796-8655; e-mail: rherbst{at}mail.mdanderson.org


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Conclusions
 References
 
After completing this course, the reader will be able to:

  1. Identify the current status of Phase I, II, and III trials of ZD1839 in non-small cell lung cancer (NSCLC).
  2. Describe the clinical development plan for ZD1839 in second line, adjuvant (maintenance), and prevention in patients with NSCLC.
  3. Identify treatment options for patients with NSCLC.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Conclusions
 References
 
Despite the advent of cisplatin-based combination chemotherapy for advanced non-small cell lung cancer (NSCLC), the prognosis for this patient population remains poor. Novel biologically targeted agents currently in development have the potential for greater efficacy against NSCLC, and possibly less toxicity than is associated with conventional cytotoxic chemotherapy. The epidermal growth factor receptor (EGFR) is recognized as a potentially useful target, and the small molecule, orally active EGFR-tyrosine kinase inhibitor ZD1839 (IressaTM) is currently the furthest along in clinical development of the anti-EGFR agents. This review summarizes the currently available clinical data on the use of ZD1839 in the treatment of NSCLC.

Key Words. ZD1839 (IressaTM) • NSCLC • Phase I • Phase II • Phase III


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Conclusions
 References
 
Current Treatment Practice in Non-Small Cell Lung Cancer
As non-small cell lung cancer (NSCLC) is usually asymptomatic in the early stages, many patients present initially with locally advanced or metastatic disease, which generally has a poor prognosis (Table 1Go) [1]. Standard first-line treatment for patients with unresectable or metastatic NSCLC consists of platinum-based combination chemotherapy (Fig. 1Go). A meta-analysis of eight trials comparing treatment with cisplatin-based chemotherapy plus best supportive care versus best supportive care alone revealed a 10% improvement in 1-year survival and a 27% reduction in the risk of death in favor of cisplatin-based chemotherapy [2]. Combination chemotherapy regimens such as carboplatin plus paclitaxel, cisplatin plus docetaxel, or cisplatin plus gemcitabine or vinorelbine, have predictable activity with response rates ranging from 17%-30% in patients with advanced NSCLC [3-5]. However, these regimens have limited efficacy, with a number of combination therapies showing 2-year survival rates of less than 15% [4], and median survival times ranging from 7.4-8.5 months (Fig. 2Go) [4, 5]. Moreover, these benefits come at the expense of substantial toxicity. Preliminary results of the Big Lung Trial, which focused on the value of cisplatin-based chemotherapy, have recently been reported: in the supportive care setting, patients receiving cisplatin-based chemotherapy had a significant survival advantage compared with patients who did not receive chemotherapy [6]. However, sub-studies did not show evidence of quality of life or economic benefits for patients on chemotherapy. Combination chemotherapy is usually combined with surgery and/or thoracic radiotherapy in patients with locally advanced disease, and with palliative treatments (e.g., brachytherapy, laser bronchoscopy, palliative radiotherapy, or best supportive care) in patients with distant metastases.


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  		Table 1. Stage distribution and associated survival rates of NSCLC [1]
 


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  		Figure 1. Treatment options for NSCLC. {Uparrow}= standard treatment options; {dashuparrow} = potential treatment options; {image} = maintenance treatment. Abbreviations: CT = chemotherapy; RT = radiotherapy; S = surgery; +CT = potential adjuvant therapy.

 


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  		Figure 2. Survival of patients with stage IV NSCLC receiving four different platinum-based combination chemotherapy regimens. Reprinted by permission from the New England Journal of Medicine 2002;346:92-98. ©2002 Massachusetts Medical Society. All rights reserved [5].

 
Increasing patient and physician interest in systemic therapy, and the limitations of first-line chemotherapy, have prompted heightened efforts to identify active alternative regimens. At present, docetaxel is the only drug that is approved for use in advanced NSCLC following relapse after first-line platinum-based chemotherapy [7, 8]. Second-line treatment with docetaxel significantly improved survival and time to progression compared with best supportive care alone; median overall survival was 7.5 compared with 4.6 months, respectively [8]. In a second trial in advanced NSCLC, second-line docetaxel demonstrated significantly greater efficacy than two other chemotherapeutic agents, vinorelbine and ifosfamide [7]. In both of these trials, docetaxel treatment was associated with a high incidence of hematologic toxicity; overall, 65.3% of patients had grade 3/4 neutropenia, 49.4% had grade 3/4 leukopenia, and 9.1% had grade 3/4 anemia.

There is a clear need for additional treatment strategies. A retrospective analysis of patients with advanced NSCLC receiving third- and fourth-line chemotherapy demonstrated that response rates decreased with each successive chemotherapy regimen, questioning the value of such an approach and calling for the development of more effective and less toxic treatments [9].

As described in Baselga’s article in this issue [10], the epidermal growth factor receptor (EGFR), which is expressed or highly expressed in advanced NSCLC [11-15], is a prime target for anticancer therapies. A variety of agents are being developed that selectively inhibit the EGFR. The furthest along in clinical development is the small-molecule EGFR tyrosine kinase inhibitor (EGFR-TKI) ZD1839 (IressaTM) (Table 2Go).


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  		Table 2. Status of clinical trials of EGFR inhibitors in NSCLC
 
Preclinical studies have demonstrated that single-agent ZD1839 has substantial activity against NSCLC xenografts, and that addition of ZD1839 to cytotoxic chemotherapy results in additive or supra-additive antitumor activity [16, 17].

Clinical Experience with ZD1839 in Advanced NSCLC
ZD1839 is currently under investigation as monotherapy in clinical trials in patients with advanced NSCLC who have relapsed following previous treatment with chemotherapy, and in combination therapy with cytotoxic agents in previously untreated patients.

ZD1839 Monotherapy

Phase I Studies
The efficacy and tolerability of ZD1839 (at doses up to 1,000 mg/day) have been investigated in four open-labeled, multicenter, phase I dose-escalation studies involving patients with a variety of solid malignant tumors, including NSCLC [18-20]. These trials included 252 heavily pretreated patients, 100 of whom had advanced NSCLC.

ZD1839 was well tolerated in all four trials: the maximum tolerated dose was >=700 mg/day. The most common adverse events seen in these trials were diarrhea, nausea, rash/acne, vomiting, and asthenia (Fig. 3Go). Most of these adverse events were transient and mild in severity (National Cancer Institute common toxicity criteria [CTC] grade 1 or 2). The incidence and severity of ZD1839-related adverse events generally increased as the dose increased.



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  		Figure 3. Commonly occurring grade 1/2 and grade 3/4 adverse events in a phase I trial [20].

 
ZD1839 exhibited encouraging antitumor activity (partial tumor response or disease stabilization) at a range of dose levels in patients with advanced NSCLC (Table 3Go). There was also anecdotal evidence for symptomatic control or improvement with ZD1839; some patients noted a reduction in pain and dyspnea, which returned within 3 days of cessation of ZD1839 therapy on the intermittent schedule [20]. Furthermore, 28% of patients remained on ZD1839 for at least three 28-day treatment cycles and 20% remained on ZD1839 for at least six cycles.


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  		Table 3. Number of NSCLC patients showing partial response or stable disease in phase I trials of ZD1839
 
Thus, all four of these phase I studies showed evidence for antitumor activity with ZD1839 in advanced NSCLC and an acceptable tolerability profile. Dose selection for subsequent trials of ZD1839 in advanced NSCLC was based on the data from these phase I studies. Responses were seen across the dose range 150-700 mg/day, with no clear dose-response relationship. Despite inter-patient variability in exposure, biologically relevant plasma concentrations (exposure levels well above the inhibitory concentration that causes 90% inhibition [IC90] for KB oral carcinoma cells) were maintained at doses of 150 mg/day and above. Fixed doses of 250 and 500 mg/day were therefore selected for subsequent phase II and III studies; 250 mg/day is higher than the lowest dose level at which objective tumor regression was seen, while 500 mg/day is the highest dose that was well tolerated when taken chronically in phase I trials.

Phase II Studies
Following these encouraging phase I studies, two large-scale, multicenter, randomized, double-blind, parallel-group phase II studies, IressaTM Dose Evaluation in Advanced Lung cancer (IDEAL) 1 and 2, were undertaken to evaluate the efficacy and tolerability of ZD1839 monotherapy in patients with locally advanced or metastatic NSCLC who had previously received platinum-based chemotherapy. Preliminary results from these studies have recently been presented at the American Society for Clinical Oncology [21, 22]. In IDEAL 1, 209 patients (from Europe, Australia, South Africa, and Japan) received treatment with ZD1839, and 216 patients (from the USA only) received ZD1839 in IDEAL 2. Both studies compared two oral doses of ZD1839 (250 and 500 mg/day) administered once daily until disease progression, intolerable toxicity, withdrawal of consent, or trial closure.

Patients in both studies had been pretreated and, while all patients had a poor prognosis, patients in IDEAL 1 had a better prognosis than those in IDEAL 2: the entry criteria for IDEAL 1 included one to two prior chemotherapy regimens, at least one of which included a platinum-based agent, and the entry criteria for IDEAL 2 included >=2 prior chemotherapy regimens including a platinum-based regimen and docetaxel administered concurrently or as separate regimens (Fig. 4Go). All patients in IDEAL 2 had disease-related symptoms at baseline; in IDEAL 1, 65% of patients treated with 250 mg/day ZD1839 and 69% treated with 500 mg/day were symptomatic.



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  		Figure 4. Number of prior chemotherapy regimens received in IDEAL 1 and 2.

 
In neither trial were there significant differences in efficacy variables between the 250 and 500 mg/day dose groups. However, 250 mg/day was better tolerated than 500 mg/day in both trials, and is thus the recommended dose for NSCLC patients who have previously received platinum-based chemotherapy. Only data from patients who received 250 mg/day ZD1839 are discussed here.

Treatment with 250 mg/day ZD1839 resulted in clinically significant antitumor activity in both trials (Table 4Go). Response rates were 18.4% and 11.8% in IDEAL 1 and IDEAL 2, respectively. Objective responses were achieved irrespective of the number of prior chemotherapy regimens. Median progression-free survival was 2.7 and 1.9 months, and median overall survival was 7.6 and 6.5 months in IDEAL 1 and IDEAL 2, respectively. The median number of months on treatment was 2.3 in IDEAL 1 and 1.8 in IDEAL 2.


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  		Table 4. Antitumor activity in IDEAL 1 and 2
 
Many patients in both trials reported a significant improvement in disease-related symptoms and quality of life [23, 24]. Symptom improvement rates were 40.3% and 43.1% in IDEAL 1 and IDEAL 2, respectively. These data are reviewed in this issue [25].

Adverse events with 250 mg/day ZD1839 were generally mild in severity (CTC grade 1 or 2) and reversible, and there was a low incidence of dose reductions or withdrawals due to drug-related adverse events. As in the phase I studies, the main adverse events were diarrhea, mild skin rash, pruritus, and dry skin. Only 8.7% (IDEAL 1) and 6.9% (IDEAL 2) of patients experienced drug-related CTC grade 3 or 4 adverse events. The results from both of these trials were consistent with those obtained in phase I studies and demonstrate that ZD1839 has antitumor activity as a single agent and is well tolerated in patients with advanced NSCLC who have relapsed following prior chemotherapy.

The favorable tolerability profile of ZD1839 also suggests that it might be suitable for long-term administration. ZD1839 could provide a valuable treatment alternative for patients with advanced NSCLC who have received prior chemotherapy.

ZD1839 in Combination Therapy

Phase I Studies
Two phase I studies were undertaken to examine the effect of adding ZD1839 (250 and 500 mg once daily) to two different standard cytotoxic chemotherapy regimens commonly used in the first-line treatment of advanced NSCLC.

In a study that combined ZD1839 with carboplatin and paclitaxel in 24 chemotherapy-naïve patients with advanced NSCLC, it was shown that this combination was well tolerated, with no new, increased, or cumulative toxicity [26]. After having received two courses of cytotoxic chemotherapy plus either 2 or 8 weeks of ZD1839, approximately three out of every five patients received clinical benefit; six (25%) patients showed a partial response and a further eight (33%) showed disease stabilization.

A second study investigated the tolerability, pharmacokinetics and antitumor activity of ZD1839 combined with cisplatin and gemcitabine in 18 chemotherapy-naïve patients with advanced solid tumors, including NSCLC [27]. In this study, ZD1839 did not appear to increase the overall toxicity of the cytotoxic agents; adverse events were predictable and manageable. The pharmacokinetic data showed that the combination had no clinically significant effect on the exposure to ZD1839, cisplatin, or gemcitabine. The activity data were promising; of the 17 evaluable patients, nine (five NSCLC) had a partial response and seven (four NSCLC) had disease stabilization. The results of these preliminary studies suggest that first-line combination therapy with ZD1839 and platinum-based chemotherapy is feasible and support further study of these combinations in NSCLC.

Phase III Studies
Two multinational, randomized, double-blind, placebo-controlled phase III studies of ZD1839 in combination with chemotherapy have been conducted. The IressaTM NSCLC Trial Assessing Combination Treatment (INTACT) 1 and 2 studies are investigating the efficacy and safety of ZD1839 (250 and 500 mg once daily) versus placebo in combination with cisplatin plus gemcitabine, and carboplatin plus paclitaxel, respectively, in chemotherapy-naïve patients (>1,000 in each study) with advanced NSCLC (Fig. 5Go).



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  		Figure 5. Study designs of INTACT 1 and 2.

 
The primary end point for each trial is overall survival. Other end points include progression-free survival, symptom improvement, objective tumor response, disease control rate, quality of life, and safety. Results from INTACT 1 and 2 are expected in 2002.

Future Directions in the Treatment of NSCLC
Despite the unprecedented response rates seen in patients with pretreated, advanced NSCLC in IDEAL 1 and 2, most patients do not exhibit an objective tumor response. In order to build on the initial benefit achieved with ZD1839, it is necessary to understand why it is that not all patients with NSCLC tumors known to express EGFR respond to this EGFR-TKI. Possible lines of investigation to address this issue include assessing expression levels of EGFR or other EGFR family members within the target tissue, measuring levels of EGFR activation, identifying mutations in EGFR or other components of the signaling pathway, and studying biochemical changes in patients who develop resistance to EGFR inhibitors [28].

As NSCLC is a heterogeneous disease, it seems likely that additional clinical benefit will be derived from using ZD1839 in combination with other anticancer agents, either the traditional cytotoxic agents, or newer biologic agents such as angiogenesis inhibitors. Trials are under way/planned to compare the activity of ZD1839 as second-line therapy in combination with docetaxel versus docetaxel/placebo (European Organization for Research and Treatment of Cancer [EORTC] 08011), and as induction chemotherapy for stage IIIA/N2 in combination with gemcitabine/cisplatin versus gemcitabine/cisplatin/placebo (EORTC 08013). A number of further trials are ongoing/planned to determine the benefits of single-agent ZD1839 in different clinical settings: as maintenance therapy following chemoradiotherapy and consolidatory docetaxel in patients with inoperable stage III NSCLC (Southwest Oncology Group S0023), as adjuvant therapy after complete resection of stage IB, II, and IIIA NSCLC (National Cancer Institute of Canada Clinical Trials Group BR19), and as a chemopreventive agent in former or current smokers with a previous specified smoking-related cancer (Specialized Program in Research Excellence).


   CONCLUSIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Conclusions
References
 
Most patients diagnosed with NSCLC present with advanced disease, for which the standard first-line treatment is systemic chemotherapy. Current cytotoxic therapies provide only a modest improvement in outcome compared with best supportive care and are often associated with significant toxicity. Biologically targeted agents, such as those that selectively inhibit the EGFR, have the potential to provide antitumor activity while being better tolerated than conventional cytotoxic drugs. ZD1839, a novel and selective EGFR-TKI, is the first molecular-targeted agent for NSCLC.

Phase I and II clinical studies demonstrated that ZD1839 monotherapy is well tolerated and provides clinically significant antitumor activity and symptom relief in patients with advanced NSCLC who have previously received prior treatment with cytotoxic chemotherapy. Furthermore, preliminary studies have shown that combinations of ZD1839 with platinum-based chemotherapy are feasible, have manageable and predictable tolerability profiles, and possess antitumor activity. Large-scale studies to assess the clinical benefit of ZD1839 versus placebo when combined with cisplatin/gemcitabine and carboplatin/paclitaxel as first-line treatment of NSCLC will soon be reported.

In summary, ZD1839 may provide a valuable addition to the therapeutic options available for the treatment of advanced NSCLC, both as monotherapy and first-line therapy in combination with other agents, and may also have potential for use in early NSCLC.


   ACKNOWLEDGMENT
Top
 Learning Objectives
 Abstract
 Introduction
 Conclusions
 References
 
Dr. R.S. Herbst is a consultant for, receives grant support from, and is a member of the Speaker’s Bureau for AstraZeneca. Merrill S. Kies is a member of the Speaker’s Bureau for AstraZeneca. At the time of publication, this paper discusses the investigational usage of ZD1839.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Conclusions
 References
 

  1. Ries LAG, Eisner MP, Kosary CL. SEER Cancer Statistics Review, 1973-1998. Bethesda, MD: National Cancer Institute, 2001.
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  4. Schiller JH, Harrington D, Belani CP et al. Comparison of four chemotherapy regimens for advanced non-small cell lung cancer. N Engl J Med 2002;346:92–98.[Abstract/Free Full Text]
  5. Lilenbaum RC, Herndon J, List M et al. Single-agent (SA) versus combination chemotherapy (CC) in advanced non-small cell lung cancer (NSCLC): a CALGB randomized trial of efficacy, quality of life (QOL), and cost-effectiveness. Proc Am Soc Clin Oncol 2002;21:1a (A2).
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  15. Volm M, Rittgen W, Drings P. Prognostic value of ERBB-1, VEGF, cyclin A, FOS, JUN and MYC in patients with squamous cell lung carcinomas. Br J Cancer 1998;77:663–669.[Medline]
  16. Ciardiello F, Caputo R, Bianco R et al. Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (‘Iressa’), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res 2000;6:2053–2063.[Abstract/Free Full Text]
  17. Sirotnak FM, Zakowski MF, Miller VA et al. Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res 2000;6:4885–4892.[Abstract/Free Full Text]
  18. Kris M, Herbst R, Rischin D et al. Objective regressions in non-small cell lung cancer patients treated in phase I trials of oral ZD1839 (‘Iressa’), a selective tyrosine kinase inhibitor that blocks the epidermal growth factor receptor (EGFR). Lung Cancer 2000;29(suppl 1):72 (A233).
  19. Negoro S, Nakagawa K, Fukuoka M et al. Final results of a Phase I intermittent dose-escalation trial of ZD1839 (‘Iressa’) in Japanese patients with various solid tumors. Proc Am Soc Clin Oncol 2001;20:324 (A1292).
  20. Ranson M, Hammond L, Ferry D et al. ZD1839 (‘Iressa’), a selective oral EGFR-TKI (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]
  21. Fukuoka M, Yano S, Giaccone G et al. Final results from a Phase II trial of ZD1839 (‘Iressa’) for patients with advanced non-small-cell lung cancer (IDEAL 1). Proc Am Soc Clin Oncol 2002;21:298a (A1188).
  22. Kris MG, Natale RB, Herbst RS 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 2002;21:292a (A1166).
  23. Douillard JY, Giaccone G, Horai T et al. Improvement in disease-related symptoms and quality of life in patients with advanced non-small-cell lung cancer (NSCLC) treated with ZD1839 (‘Iressa’) (IDEAL 1). Proc Am Soc Clin Oncol 2002;21:299a (A1195).
  24. Natale RR, Skarin AT, Maddox AM et al. Improvement in symptoms and quality of life for advanced non-small-cell lung cancer patients receiving ZD1839 (‘Iressa’) in IDEAL 2. Proc Am Soc Clin Oncol 2002;21:292a (A1167).
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Received June 27, 2002; accepted for publication July 25, 2002.




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K. I. Amiri, L. W. Horton, B. J. LaFleur, J. A. Sosman, and A. Richmond
Augmenting Chemosensitivity of Malignant Melanoma Tumors via Proteasome Inhibition: Implication for Bortezomib (VELCADE, PS-341) as a Therapeutic Agent for Malignant Melanoma
Cancer Res., July 15, 2004; 64(14): 4912 - 4918.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
P. F. Bross, R. Kane, A. T. Farrell, S. Abraham, K. Benson, M. E. Brower, S. Bradley, J. V. Gobburu, A. Goheer, S.-L. Lee, et al.
Approval Summary for Bortezomib for Injection in the Treatment of Multiple Myeloma
Clin. Cancer Res., June 15, 2004; 10(12): 3954 - 3964.
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 Molecular Cancer TherapeuticsHome page
E. G. Mimnaugh, W. Xu, M. Vos, X. Yuan, J. S. Isaacs, K. S. Bisht, D. Gius, and L. Neckers
Simultaneous inhibition of hsp 90 and the proteasome promotes protein ubiquitination, causes endoplasmic reticulum-derived cytosolic vacuolization, and enhances antitumor activity
Mol. Cancer Ther., May 1, 2004; 3(5): 551 - 566.
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 BloodHome page
Q. Wang, T. Liu, Y. Fang, S. Xie, X. Huang, R. Mahmood, G. Ramaswamy, K. M. Sakamoto, Z. Darzynkiewicz, M. Xu, et al.
BUBR1 deficiency results in abnormal megakaryopoiesis
Blood, February 15, 2004; 103(4): 1278 - 1285.
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H.-F. Zhang, A. Tomida, R. Koshimizu, Y. Ogiso, S. Lei, and T. Tsuruo
Cullin 3 Promotes Proteasomal Degradation of the Topoisomerase I-DNA Covalent Complex
Cancer Res., February 1, 2004; 64(3): 1114 - 1121.
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 Molecular Cancer TherapeuticsHome page
N. Laurent, S. de Bouard, J.-S. Guillamo, C. Christov, R. Zini, H. Jouault, P. Andre, V. Lotteau, and M. Peschanski
Effects of the proteasome inhibitor ritonavir on glioma growth in vitro and in vivo
Mol. Cancer Ther., February 1, 2004; 3(2): 129 - 136.
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 Arterioscler. Thromb. Vasc. Bio.Home page
X. Wang, N. Adhikari, Q. Li, Z. Guan, and J. L. Hall
The Role of {beta}-Transducin Repeat-Containing Protein ({beta}-TrCP) in the Regulation of NF-{kappa}B in Vascular Smooth Muscle Cells
Arterioscler. Thromb. Vasc. Biol., January 1, 2004; 24(1): 85 - 90.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
A. Onn, A. M. Correa, M. Gilcrease, T. Isobe, E. Massarelli, C. D. Bucana, M. S. O'Reilly, W. K. Hong, I. J. Fidler, J. B. Putnam, et al.
Synchronous Overexpression of Epidermal Growth Factor Receptor and HER2-neu Protein Is a Predictor of Poor Outcome in Patients with Stage I Non-Small Cell Lung Cancer
Clin. Cancer Res., January 1, 2004; 10(1): 136 - 143.
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 The Annals of PharmacotherapyHome page
B. L Stanford and S. D Zondor
Bortezomib Treatment for Multiple Myeloma
Ann. Pharmacother., December 1, 2003; 37(12): 1825 - 1830.
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 The Annals of PharmacotherapyHome page
C. Y Liu and S. Seen
Gefitinib Therapy for Advanced Non-Small-Cell Lung Cancer
Ann. Pharmacother., November 1, 2003; 37(11): 1644 - 1653.
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 Am. J. Pathol.Home page
H. Luo, J. Zhang, C. Cheung, A. Suarez, B. M. McManus, and D. Yang
Proteasome Inhibition Reduces Coxsackievirus B3 Replication in Murine Cardiomyocytes
Am. J. Pathol., August 1, 2003; 163(2): 381 - 385.
[Abstract] [Full Text] [PDF]

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