2002 Highlights From: 27th Congress of the European Society for Medical Oncology; Nice, France October 18–22, 2002

m eeting highlights

2002

Highlights From: 27th Congress of the European Society for Medical Oncology Nice, France October 18-22, 2002 The Addition of Cisplatin to Gemcitabine/Vinorelbine Improves Response Rate But Does Not Prolong Survival in Advanced Non–Small-Cell Lung Cancer Platinum-containing chemotherapy doublets are the standard of care for advanced non–small-cell lung cancer (NSCLC).1 Various doublets combining cisplatin or carboplatin with new chemotherapeutic agents such as the taxanes, gemcitabine, or vinorelbine have about the same efficacy, with overall response rates (ORRs) of 17%-32% and a median survival of 7.4-9.9 months.2,3 As it appears that the efficacy of chemotherapy doublet regimens has reached a plateau, various means to surpass that plateau are under investigation. Laack and colleagues hypothesized that the addition of a third cytotoxic agent to an efficacious doublet could improve efficacy, and thus, they conducted a phase II trial of gemcitabine/vinorelbine/cisplatin in patients with NSCLC.4 This triplet was associated with an ORR of 45% and a median survival time of 12.8 months. World Health Organization grade 4 leukopenia occurred in only 3 of 31 pa-

tients (10%), suggesting that this triplet was feasible. These data prompted a phase III study to determine if the gemcitabine/ vinorelbine/cisplatin triplet results in survival superior to that found with the gemcitabine/vinorelbine doublet; the results of this phase III study were presented at the 27th Congress of the European Society for Medical Oncology (ESMO) held October 2002 in Nice, France.5 The study enrolled patients 18-75 years of age with stage IIIB or IV NSCLC and a Karnofsky performance status (PS) > 70%. Patients on arm A received gemcitabine 1000 mg/m2 plus vinorelbine 25 mg/m2 on days 1 and 8 every 3 weeks. Patients on arm B received gemcitabine/ vinorelbine as in arm A plus cisplatin 75 mg/m2 on day 2 every 3 weeks. Three hundred patients were enrolled,

Table 1: Efficacy of Gemcitabine/Vinorelbine Versus Gemcitabine/Vinorelbine/Cisplatin in Metastatic Non–Small-Cell Lung Cancer Gemcitabine/ Vinorelbine

Gemcitabine/ Vinorelbine/ Cisplatin

(n = 108)

(n = 106)

Response Overall Response Rate Complete response Partial response Survival Median Survival (Weeks)

Prepared by: David Lee, PhD, Lori Johnson, PhD, Heather DeGrendele, PhD Reviewed by: Chandra P. Belani, MD, Michael Perry, MD, Harvey Pass, MD

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of whom 287 were eligible. There were 143 patients on the gemcitabine/vinorelbine arm and 144 patients on the gemcitabine/vinorelbine/cisplatin arm. Patient characteristics were similar in both arms. The median age on each arms was 61 years. The addition of cisplatin to gemcitabine/vinorelbine showed improved ORRs but not improved survival (Table 1). There were only 14 partial responses (PRs, 13%) and no complete responses (CRs) with the combination of gemcitabine/ vinorelbine, for an ORR of 13%. On arm B, there were 4 CRs and 26 PRs, for an ORR of 28% (P = 0.004). Median survival times were 36 weeks and 32 weeks for arms A and B, respectively (P = 0.73). There was also no significant difference between arms A and B for median time to

1-Year survival Time to progression (weeks) Only 214 patients were evaluable for best response Abbreviations: NR = not reported

P Value

13%

28%

0.004

0

4 (3.8%)

NR

14 (13%)

26 (24.5%)

NR

(n = 143)

(n = 144) 0.73

36

32

34%

28%

NR

19

22

0.35

Table 2: Selected Toxicities of Gemcitabine/Vinorelbine Versus Gemcitabine/ Vinorelbine/Cisplatin Gemcitabine/ Vinorelbine

Gemcitabine/ Vinorelbine/ Cisplatin

P Value

Neutropenia (3/4)

27%

67%

< 0.001

Anemia (3/4)

3%

27%

< 0.001

Thrombocytopenia (3/4)

4%

48%

< 0.001

Alopecia (2/3)

5%

36%

< 0.001

Nausea/vomiting (2-4)

11%

46%

< 0.001

Increased creatinine (2-4)

0%

9%

< 0.001

Toxicities Hematologic (Grade)

Nonhematologic (Grade)

progression (19 weeks vs. 22 weeks, respectively; P = 0.35) or 1-year survival (34% vs. 28%, respectively). Forty patients (28%) on arm A and 35 patients (24%) on arm B received second-line chemotherapy for recurrent disease. Toxicities were markedly increased by the addition of cisplatin (Table 2). Twentyseven percent of patients on the gemcitabine/ vinorelbine arm experienced grade 3/4 neutropenia compared to 67% on the gemcitabine/vinorelbine/cisplatin arm (P < 0.001). There was also increased grade 3/4 anemia (3% vs. 27%; P < 0.001) and grade 3/4 thrombocytopenia (4% vs. 48%; P < 0.001) with the addition of cisplatin. While there was no significant increase in incidence of neurotoxicity, stomatitis, or phlebitis with the addition of cisplatin, there was increased grade 2-4 nausea/vomiting (11% vs. 46%; P < 0.001) and elevation in serum creatinine (0% vs. 9%; P < 0.001).

Clinical Relevance: The purpose of this study was to determine if gemcitabine/vinorelbine/ cisplatin had improved efficacy and survival over the gemcitabine/vinorelbine doublet for patients with advanced NSCLC. Although the ORR was improved with the addition of cisplatin (13% vs. 28%; P = 0.004), there was no significant difference in median survival for gemcitabine/vinorelbine as compared with gemcitabine/vinorelbine/cisplatin (36 weeks vs. 32 weeks; P = 0.73). Furthermore, toxicities were greatly increased with cisplatin. This study again demonstrated that triplet

chemotherapy combinations provide no significant benefit over standard 2-drug regimens commonly used for patients with advanced NSCLC.

Weekly Administration of Docetaxel in Advanced Non–Small-Cell Lung Cancer

of ESMO held October 2002 in Nice, France.8,9 Both trials were open to advanced or metastatic NSCLC patients who had received previous platinum-based chemotherapy. A PS of ≤ 2 was required. Patients were randomized to receive docetaxel 75 mg/m2 intravenously (I.V.) every 3 weeks or weekly docetaxel (35 mg/m2/week I.V. for 3 out of 4 weeks in the study led by Monika Serke, MD8; 40 mg/m2/week I.V. for 6 out of 8 weeks in the study led by Jean-luc Breton, MD).9 In the study by Breton and colleagues, dexamethasone 8 mg was administered 3 times over 2 days (reduced schedule of prophylactic corticosteroid premedication).9 One hundred sixty-one patients were enrolled in the study by Serke et al, of which 92 patients were evaluable for toxicity (Table 3).8 The median age was 63 years. Eleven patients (12%) had a PS of 2, and 75% of patients had stage IV disease. Significantly fewer patients experienced grade 3/4 toxicities with weekly docetaxel than with the every-3-week docetaxel schedule (3% vs. 5%; P = 0.009). Out of 82 evaluable patients, 1 CR (1%) and 5 PRs (6%) were observed for an ORR of 7% and a clinical benefit rate (CRs plus PRs plus stable disease) of 40% (Tables 4). The second study, led by Dr. Breton, enrolled 125 patients with a median age of 59 years (range, 27-74 years).9 Twenty-six patients (21%) had a PS of 2. Hematological toxicities were greatly reduced by the weekly regimen. Grade 3/4 neutropenia occurred in 30 of the 62 evaluable patients

Weekly administration of docetaxel has been demonstrated to result in less myelotoxicity than every-3-week dosing.6 In a phase I study of weekly docetaxel, Hainsworth and colleagues found that 2052 mg/m2/week of docetaxel for 6 of 8 weeks was associated with grade 3 leukopenia in only 14% of patients, and there was no grade 4 leukopenia.7 In a subsequent study, Hainsworth et al administered 36 mg/m2/week docetaxel to elderly chemotherapy-naive NSCLC patients and found that this treatment resulted in Table 3: Grade 3/4 Toxicities of Docetaxel in Non–Small-Cell Lung Cancer an ORR of 18% (7 of 38 patients), without occurrence of 75 mg/m2 35 mg/m2/Week Serke et al8 Every 3 Weeks grade 4 neutropenia.6 (n = 48) (n = 44) Weekly docetaxel is there0 1 (2%) Neutropenia fore a promising alternative to 1 (2%) 2 (5%) Fever the every-3-week regimen for 1 (2%) 3 (7%) Infection advanced NSCLC and has raised much interest. Two sepa2 75 mg/m 40 mg/m2/Week rate studies were undertaken to Breton et al9 Every 3 Weeks (n = 63) (n = 62) compare the safety and efficacy 10 (16%) 30 (48%) Neutropenia of weekly docetaxel to that of 0 4 (7%) Febrile Neutropenia* standard every-3-week doc7 (11%) 3 (5%) Asthenia etaxel for patients with recur0 0 Hypersensitivity rent NSCLC. The results were *There was 1 toxic death related to febrile neutropenia. presented at the 27th Congress

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Pemetrexed Plus Radiation Therapy in Locally Advanced Lung and Esophageal Cancers

Table 4: Efficacy of Docetaxel in Previously Treated Non–Small-Cell Lung Cancer Serke et al8 Disease Control* Complete response

All Doses (n = 82) 33 (40%) 1 (1%)

Pemetrexed disodium (Alimta®, pemetrexed) is a recently developed multitargeted an75 mg/m2 40 mg/m2/Week Breton et al9 Every 3 Weeks tifolate that suppresses tumor (n = 63) (n = 62) cell proliferation by disruption Disease Control* 32% 25% of DNA synthesis as well as the Median Time to folate metabolic pathway.10 2.1 1.8 Progression (Months) The primary mechanism of acMedian Survival Time 6.3 5.5 tion of pemetrexed is inhibition (Months) of thymidylate synthase. It is *Response rates and stable disease. also a potent inhibitor of dihydrofolate reductase and glycinamide ribonucleotide formyl Table 5: Pemetrexed Dose-Escalation Plan transferase.11 Pemetrexed has Pemetrexed (mg/m2) Number of Patients Dose Level shown encouraging single3-6 1 200 agent activity in mesothelioma 3-6 2 300 and NSCLC, as well as breast, 3-6 3 400 colorectal, and head and neck 3-6 4 500 cancers.12-16 3-6 5 TBD Preclinical studies have also Abbreviation: TBD = to be determined shown that pemetrexed enhances radiation-induced cell toxicity in (48%) in the every-3-week–docetaxel vitro, with an enhancement ratio of 3.3.10 group, but in only 10 patients (16%) in the These results have generated interest in weekly group (Table 3). Febrile neutropepemetrexed-based multimodality regimens nia occurred in 4 patients (7%) in the for patients with NSCLC. Vokes and colevery-3-week group and in none on the leagues have been conducting a phase I weekly group. Hypersensitivity reactions dose-escalation study of the combination of were not seen in either arm despite the repemetrexed and chest radiotherapy to deduced schedule of dexamethasone admintermine the maximum tolerated dose istration. Efficacy was similar in both arms (MTD) and dose-limiting toxicities (Table 4). The disease control rates (PR (DLTs). Preliminary results of this trial plus stable disease) were 32% for the everywere presented in October at the 27th Con3-week docetaxel arm and 25% for the 17 weekly docetaxel regimen. At a median fol- gress of ESMO in Nice, France. Eligible patients had histologically or low-up time of 5.8 months, median time cytologically diagnosed advanced or to progression and survival were similar in metastatic NSCLC or esophageal cancer, a both arms. Partial response Stable disease

5 (6%)

27 (33%)

Clinical Relevance: These randomized studies show that weekly docetaxel results in markedly reduced hematological toxicity, providing an alternative to the standard every-3-week dosing for patients with previously treated advanced NSCLC. The weekly schedule may be especially useful in patients at high risk of developing neutropenic complications and for elderly patients.

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life expectancy of ≥ 12 weeks, and were at least 18 years of age. Prior radiotherapy was allowed only for bone or brain metastases. Patients with clinically significant cardiovascular disease, effusions, or brain metastases were excluded. At least 3 patients were assigned to each dose level, with an initial dose of pemetrexed 200 mg/m2 I.V. every 3 weeks (Table 5). Escalation occurred in 100 mg/m2 increments to ≥ 500 mg/m2. Pemetrexed was administered as a 10-minute infusion on day 1 every 3 weeks for 2 cycles. Upon completion of pemetrexed infusion, radiation therapy was given daily in 200 cGy fractions, with a cumulative dose of 40-66 Gy. Patients were given supplemental folic acid and vitamin B12. Sixteen patients have been enrolled in the study, with a median age of 64 years (range, 32-80 years). Three patients (18.8%) had received prior radiation therapy, and 7 patients (43.8%) had received prior chemotherapy. Most patients (81%) had NSCLC, while 19% of patients had esophageal cancer. The pemetrexed dose has been escalated in cohorts to 200, 300, 400, and 500 mg/m2 every 3 weeks. At the time of this report, 1 patient had completed 2 cycles at the dose level of 600 mg/m2. All 16 patients have received cumulative radiation therapy to a median total dose of ≥ 60 Gy. Administration of pemetrexed at doses up to 600 mg/m2 has not resulted in any grade 4 hematologic DLTs (Table 6). The most severe hematologic toxicity has been grade 3 neutropenia at the 300 mg/m2 and 500 mg/m2 dose levels. Nonhematologic toxicities included grade 3 hypokalemia at 400 mg/m2, and grade 3 infection at 500 mg/m2. Grade 4 dysphagia, esophagitis, and anorexia also were seen at 500 mg/m2.

Table 6: Grade 3/4 Toxicities at Increasing Dose Levels of Pemetrexed 200 mg/m2 (n = 3)

300 mg/m2 (n = 3)

400 mg/m2 (n = 3

500 mg/m2 (n = 6)

600 mg/m2 (n = 1)

–

X

–

X

–

Hypokalemia

–

–

X

–

–

Infection

–

–

–

X

–

Dysphagia

–

–

–

X

–

Esophagitis

–

–

–

X

–

Anorexia

–

–

–

X

–

Toxicities Hematologic Neutropenia Nonhematologic

–

Clinical Relevance: Pemetrexed is a promising new chemotherapeutic agent, having demonstrated single-agent activity in various cancers, including lung cancer and mesothelioma. Preclinical studies have indicated that pemetrexed enhances the activity of radiation therapy. The initial results of this study indicate that the combination of pemetrexed and radiation therapy can be safely administered with manageable toxicities. The MTD of pemetrexed has not been reached but appears to be in excess of 500 mg/m2. Supplementation with folic acid and vitamin B12 is required to minimize grade 3/4 toxicities with pemetrexed.

Safety and Efficacy of Irinotecan and Carboplatin with Concurrent Radiation in Stage III Non–SmallCell Lung Cancer In stage III NSCLC, treatment failure is due not only to local recurrence but also to distant micrometastases, and treatment is typically through a combined modality approach.18,19 Preclinical studies have shown that the topoisomerase I inhibitor, irinotecan, can sensitize tumor cells to radiation.20 The mechanism for this sensitization involves the induction of double-stranded DNA breaks and the inhibition of DNA repair by trapping topoisomerase I and DNA complexes, preventing their dissociation and ultimately leading to a collision with the replication fork.21 When combined with other radiosensitizing agents (like cisplatin or carboplatin), irinotecan has an even higher efficacy than when used alone. Irinotecan has been investigated in combination with radiation therapy in patients with stage III NSCLC, resulting in ORRs ranging from 77%-79%.22,23 Irinotecan has also been combined with cisplatin or carboplatin for the treatment of stage III NSCLC and has ORRs of 60%-65%, with up to 10% being CRs.24-26 The combination of irinotecan and platinum agents with radiation therapy has also been investigated, but the optimal dosing and scheduling remains to be determined. Nakagawa and

Figure 1: Weekly Irinotecan/Carboplatin/Radiation Therapy: Treatment Schema Irinotecan 20-30 mg/m2 Carboplatin AUC=2 2 Gy/day, 5 days per week for 6 weeks

TRT 60 Gy/30 Fractions 1

8

15

22 Days

29

36

Abbreviations: AUC = area under the curve; TRT = thoracic radiation therapy

colleagues reported an ORR of 70% with no DLTs when irinotecan was given up to 50 mg/m2/week in combination with carboplatin 20 mg/m2/week and concurrent radiation for stage III NSCLC.27 Kaneda and colleagues from Japan recently presented the results of a dose-finding study of weekly irinotecan and carboplatin given with concurrent radiation for the treatment of unresectable stage III NSCLC at the 27th Congress of ESMO in October 2002.28 Eligibility requirements included unresectable stage III NSCLC and an Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1. Prior chemotherapy or prior radiation therapy to the chest was not allowed. Patients received radiation therapy to a total dose of 60 Gy over 6 weeks and chemotherapy consisting of weekly carboplatin at an area under the curve (AUC) of 2 along with irinotecan 30 mg/m2 (Figure 1).

A total of 29 patients were enrolled in this study. Patients had a median age of 58 years (range, 41-73 years). All patients had an ECOG PS of 0 or 1. Fourteen patients (48%) each had squamous cell carcinoma or adenocarcinoma. One patient (3%) had adenosquamous cell carcinoma. The incidence of grade 3/4 nonhematological toxicities was low at all irinotecan dose levels. No reports of grade 3/4 diarrhea were given, and 3 patients (10%) had grade 3/4 esophagitis (Table 7). Among all patients, the incidence of grade 3/4 neutropenia was 66% (19 patients), with 2 patients (7%) having grade 3/4 febrile neutropenia. Grade 3 thrombocytopenia was reported in 3 patients (10%). The ORR was 72%. Patients who received irinotecan 30 mg/m2/week had a 50% ORR (0 CR). Patients who received irinotecan 25 mg/m2/week had an ORR of 83% (17% CR), and those who received

Table 7: Irinotecan/Carboplatin/Radiation Therapy: Grade 3/4 Toxicities Weekly Carboplatin AUC=2 plus: Toxicity

Irinotecan 30 mg/m2 Irinotecan 25 mg/m2 Irinotecan 20 mg/m2 All (n = 6) (n = 12) (n = 11) (n = 29)

Neutropenia

5 (83%)

7 (58%)

7 (64%)

0

0

2 (18%)

2 (7%)

Anemia

2 (33%)

1 (8%)

1 (9%)

4 (14%)

Thrombocytopenia

1 (17%)

0

2 (18%)

3 (10%)

0

1 (8%)

2 (18%)

3 (10%)

Febrile Neutropenia

Esophagitis

19 (66%)

Abbreviation: AUC = area under the curve

Table 8: Irinotecan/Carboplatin/Radiation Therapy: Treatment Efficacy Weekly Carboplatin AUC=2 plus: Irinotecan 30 mg/m2 (n = 6) Overall Response Rate Partial response

Irinotecan 20 mg/m2 (n = 11)

3 (50%)

83%

73%

0

2 (17%)

1 (9%)

3 (50%)

8 (67%)

7 (64%)

2 (33%)

2 (17%)

0

0

0

1 (9%)

Complete response Stable Disease

Irinotecan 25 mg/m2 (n = 12)

Progressive Disease Abbreviation: AUC = area under the curve

Clinical Lung Cancer November 2002

143

irinotecan 20 mg/m2/week had an ORR of 73% (9% CR; Table 8).

Clinical Relevance: The authors recommended irinotecan 20 mg/m2/week in combination with carboplatin at an AUC of 2 and concurrent radiation therapy for further trials in patients with stage III NSCLC. The West Japan Thoracic Oncology Group is conducting a randomized trial comparing irinotecan/carboplatin and paclitaxel/carboplatin to a standard regimen of mitomycin/vinblastine/cisplatin given with concurrent radiation in patients with stage III NSCLC, the results of which may provide more information on the efficacy of this combination regimen.

The Use of Oligonucleotide and Tissue Microarrays as Screening Tools in Lung Cancer Lung cancer is frequently detected at a late stage. This fact, coupled with the high mortality rate associated with lung cancer suggests that a means for early detection and better prognostic indicators are needed. Morphological assessment as well as other variables such as tumor size, vascular invasion, and differentiation are currently used to predict patient prognosis.29 Microarray technology, which can simultaneously analyze the expression of large numbers of genes and proteins, can be further utilized to correlate gene expression patterns with numerous clinical parameters. This technology represents a novel tool for predicting patient outcome and perhaps even a screening mechanism for detecting cancer. Most current screening efforts involve radiographic methods but use microarrays, efforts are underway to identify molecules that are uniquely or highly overexpressed by tumor cells compared to normal tissue, which could be more easily detected in bodily fluids such as blood, urine, or sputum.30 Despite numerous recent attempts to identify such markers, there has been little success due to low specificity or low frequency of positive results in early-stage lung cancer patients.31-37 In a recent study by Beer and col-

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Table 9: Correlation of Hierarchical Gene Cluster to Survival in Patients with Stage I or III Non–Small-Cell Lung Cancer

leagues,29 a tissue microarray composed of 86 primary lung adenocarcinomas was analyzed, including 67 stage I tumors, 19 stage III tumors, and 10 normal lung samples. Hierarchical clustering yielded 3 distinct clusters of tumors, with all normal lung samples as well as the highest percentage (42.8%) of the well-differentiated tumors in cluster 1, and the lowest percentage of these tumors falling into cluster 3 (4.7%). Cluster 3 also contained the highest percentage of both poorly differentiated (47.6%) and stage III tumors (42.8%) and the shortest average survival (Table 9). Of interest, a subset of stage I tumors (11) were also present in cluster 3, perhaps identifying a subgroup of patients with a poor prognosis. This suggests that gene expression patterns can be used to identify high-risk groups of patients. At the 27th Congress of ESMO in October 2002 in Nice, France, Sugita and colleagues reported on a novel method for identifying biomarkers in lung carcinomas.30 This group utilized a 3-step schema consisting of a high-density oligonucleotide array to identify overexpressed genes from 2 NSCLC and 2 small-cell lung cancer (SCLC) cell lines but not in normal cultured epithelial cells or lung tissue homogenates. This was followed by confirmation of overexpression by reverse-transcriptase polymerase chain reaction on an expanded set of cell lines, including 13 SCLC, 9 NSCLC, and 3 mesothelioma cell lines. Finally, the cell line data was further validated by immunohistochemical testing of a tissue microarray containing 187 NSCLC clinical samples. The resulting 20 overexpressed genes included 14 that were overexpressed only in SCLC, 4 in NSCLC, and 2 in both. A

Gene Cluster

Average Survival (Months)

Cluster 1

34.5

Cluster 2

48.3

Cluster 3

26.2

wide diversity of gene functions and cellular locations were represented among the gene products. Notably, 30% of the total list consisted of members of the cancer/testis antigen (CTAG) gene group, including 5 melanoma antigen A (MAGE-A) subfamily members and the NY-ESO-1 gene. The CTAG genes are normally expressed only in normal testicular germ cells and have been previously identified in a number of tumor cell types, including NSCLC.38,39 Sugita and colleagues additionally found that expression levels were related to the tumor type, with the MAGE genes being more highly expressed in SCLC than in NSCLC.30 Immunohistochemical analysis of a tissue microarray with an antibody directed against MAGE-A indicated that out of the 187 NSCLC samples, 44% were positive for MAGE-A expression (Table 10), with squamous carcinomas being more frequently positive than adenocarcinomas, large-cell carcinomas, or bronchioloalveolar carcinomas. However, no correlation was found between MAGE-A expression and survival.

Clinical Relevance: While the expression of CTAG gene products does not appear to be of prognostic value, they could prove useful for early detection and surveillance. Further studies to determine whether these gene products can be

Table 10: Correlation of Tumor Histology to MAGE-A Status MAGE-A Expression Histology

Positive

Negative

Total

Squamous cell carcinoma

57

34

91

Adenocarcinoma

19

52

71

Large-cell carcinoma

3

12

15

Bronchioloalveolar carcinoma

1

9

10

Total

80

107

187

Abbreviation: MAGE-A = melanoma antigen A Reproduced with permission from: Sugita M, et al. Combined use of oligonucleotide and tissue microarrays identifies cancer/testis antigens as biomarkers in lung carcinoma. Cancer Res 2002; 62:3971-3979.

easily detected in blood or sputum are necessary. The use of oligonucleotide microarrays to test small numbers of specimens or cell lines combined with validation by tissue microarray could prove to be a lucra-

tive, yet practical, source of new biomarkers. These biomarkers should prove useful as tools to aid in the early detection, diagnosis, and monitoring of lung cancer. Furthermore, the use of microarrays to identify pa-

tients at high risk, specifically patients with stage I disease, would allow the use of adjuvant treatment, which is currently not standard.

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