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Use of cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has the potential to increase survival in patients with advanced non-small-cell lung cancer. We therefore compared chemotherapy plus cetuximab with chemotherapy alone in patients with advanced EGFR-positive non-small-cell lung cancer.

Gefitinib is an orally active epidermal growth factor receptor tyrosine kinase inhibitor with activity in previously treated patients with advanced-stage non-small-cell lung cancer (NSCLC). However, little is known of its activity as monotherapy in chemotherapy-naive patients. This phase II study (1839IL/0456) evaluated first-line gefitinib in patients with advanced-stage NSCLC.

Hintergrund:: Das nichtkleinzellige Lungenkarzinom (NSCLC) stellt in den westlichen Industrieländern die häufigste Tumorerkrankung dar. Patienten mit fortgeschrittenem NSCLC haben eine schlechte Prognose und leiden unter vielen tumorassoziierten Symptomen. Die meisten Patienten (ca. 70%) werden im Stadium III/IV diagnostiziert. Die Therapie ist in diesen Stadien palliativ und symptomorientiert. Ein Angriffspunkt der neuen Substanzen ist der epidermale Wachstumsfaktor-Rezeptor (EGFR/HER1). Wirkstoffe, die an diesem Rezeptor angreifen, sind u. a. Erlotinib, Gefitinib und Cetuximab. Klinische Studien:: Erlotinib, Gefitinib und Cetuximab wurden in verschiedenen klinischen Studien auf Wirksamkeit und Verträglichkeit untersucht und zeigten objektive Ansprechraten sowie eine Verbesserung der tumorassoziierten Symptome. Ein Überlebensvorteil konnte bisher nur in der Zweit- und Drittlinientherapie mit Erlotinib beobachtet werden. Alle Substanzen waren gut verträglich. Erlotinib wurde kürzlich für die Zweit- und Drittlinientherapie bei Patienten mit lokal fortgeschrittenem und metastasiertem NSCLC in den USA und Europa als Monotherapie zugelassen. Schlussfolgerung:: Substanzen, die am EGF-Rezeptor angreifen, zeigten in klinischen Studien beim NSCLC eine vielversprechende Antitumoraktivität und ein günstiges Nebenwirkungsprofil. Jedoch sollten einige klinische Fragen im Hinblick auf die Auswahl von Patienten, die potentiell von den Substanzen profitieren, und die optimale Kombination mit anderen Wirkstoffen das Ziel weiterer klinischer Studien sein.

A randomized phase II study was performed to determine whether single-agent gemcitabine or docetaxel with the introduction of the opposite agent in case of disease progression (ie, in the second-line setting) is feasible and effective in chemotherapy-naive patients with advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: The doses were 1000 mg/m2for gemcitabine and 35 mg/m2for docetaxel, each given on days 1, 8, and 15 every 4 weeks. After a planned interim analysis, the docetaxel/gemcitabine arm (ie, docetaxel followed by gemcitabine) was closed after enrollment of 49 patients because of poor predefined feasibility. A total of 98 patients were recruited to the gemcitabine/docetaxel arm (ie, gemcitabine followed by docetaxel). RESULTS: Quality of life remained near baseline levels during the administration of 6 cycles of gemcitabine/docetaxel chemotherapy, whereas it deteriorated after 2 cycles of docetaxel/gemcitabine. Toxicity was comparable between arms. Median times to progression were 4.3 months and 2.2 months with gemcitabine/docetaxel and docetaxel/gemcitabine, respectively, and median overall survival times were 9 months (gemcitabine/docetaxel) and 5 months (docetaxel/gemcitabine; P= 0.029, Wilcoxon rank-sum test). CONCLUSION: These results indicate that first-line gemcitabine followed by second-line weekly docetaxel is feasible, with promising survival in patients with advanced NSCLC.

Despite improvements in conventional treatment, patients with advanced non–small-cell lung cancer (NSCLC) have a poor prognosis, leaving a significant unmet need for novel treatments. One such novel, biologically targeted agent is the orally active epidermal growth factor receptor tyrosine kinase inhibitor gefitinib. This openlabel pilot trial investigated the safety, pharmacokinetics, and efficacy of 2 doses of gefitinib (250 and 500 mg per day) combined with docetaxel (75 mg/m2) in patients with locally advanced or metastatic NSCLC as firstand second-line chemotherapy. Eighteen patients were recruited: 6 received gefitinib 250 mg per day plus docetaxel; 12 received gefitinib 500 mg per day plus docetaxel. Combination therapy was feasible with no overlapping toxicities. No patients experienced dose-limiting toxicities (DLTs) at 250 mg per day; 1 patient had 2 DLT events at 500 mg per day (grade 3 rash and diarrhea for > 4 days). Adverse events were mild to moderate, including fatigue, mucositis, nausea, anorexia, rash, diarrhea, and fever. Docetaxel did not appear to alter steady-state exposure to gefitinib. The effect of gefitinib on exposure to docetaxel was equivocal; with the exception of 2 patients in the gefitinib 250 mg per day dose group, there appeared to be no trend toward a higher or lower exposure to docetaxel when given in the presence of gefitinib compared with that when given alone. Combination therapy was associated with antitumor activity and responses were seen with gefitinib in 2 of 6 patients at 250 mg per day and 4 of 12 patients at 500 mg per day. This combination is feasible and has an acceptable and predictable safety profile, as well as associated antitumor activity.

Despite the desperate struggle for improvement in the therapy of malignant pleural mesothelioma in previous decades, no standard therapy could be established. Pemetrexed (Alimta®), a new multitargeted antifolate, showed significant antitumor activity in combination with cisplatin compared with cisplatin alone in patients with unresectable pleural mesothelioma. Furthermore, this improved efficacy was transformed into a significant symptomatic benefit. These data led to the approval of the drug by the US Food and Drug Administration and recently by the European Medicines Evaluation Agency for this combination in malignant pleural mesothelioma, and consequently founded the first standard of treatment in this disease. This review reflects the development of chemotherapy in malignant pleural mesothelioma, discusses the results of the EMPHACIS trial, and outlines further developments for pemetrexed-containing regimens in malignant pleural mesothelioma.

Patients with advanced non-small-cell lung cancer (NSCLC) have a poor prognosis and suffer many disease-related symptoms. Treatments should therefore aim to palliate these symptoms as well as improve overall quality of life. Gefitinib (‘Iressa’) is a novel epidermal growth factor receptor tyrosine kinase inhibitor that targets cell signaling involved in tumor growth and differentiation. In Phase II trials in recurrent NSCLC, gefitinib provided objective responses and symptom relief, and was generally well tolerated. Now approved for the treatment of advanced NSCLC in over 25 countries, including Japan and the USA, gefitinib has demonstrated significant clinical benefit in a disease area with limited treatment options.

The maximum tolerated dose of the multitargeted antifolate drug pemetrexed is 600 mg/m2every 3 weeks in heavily pretreated patients without folic acid supplementation. However, with folic acid supplementation, higher doses have been given without limiting side effects. The dose-limiting toxicities of pemetrexed are neutropenia, asthenia, and thrombocytopenia. Other adverse effects include anemia, anorexia, rash, nausea, vomiting, peripheral edema, diarrhea, mucositis, and reversible elevations of transaminase and creatinine levels. Multiple pemetrexed combination phase I trials have been completed or are underway. Without folic acidsupplementation, pemetrexed doses of 400 to 600 mg/m2could be safely administered with full therapeutic doses of irinotecan, gemcitabine, cisplatin, carboplatin, oxaliplatin, and 5-fluorouracil. Preliminary data from other ongoing trials (with folic acid and vitamin B12supplementation) have similarly shown that pemetrexed doses of at least 400 to 500 mg/m2can be safely administered with therapeutic doses of vinorelbine, docetaxel, and paclitaxel. Combination studies of pemetrexed with agents active in breast cancer (doxorubicin, epirubicin, and cyclophosphamide) and chest radiotherapy are also now underway. Adverse effects of these combinations have included neutropenia, anemia, thrombocytopenia, asthenia, vomiting, diarrhea, rash, nausea, anorexia, mucositis, and reversible transaminase elevation. The phase I trials of pemetrexed have consistently shown activity against a broad range of tumor types, including colorectal cancer, pancreatic cancer, breast cancer, non–small cell lung cancer, and mesothelioma. This activity has been noted not only in the combination trials, but when pemetrexed is given as a single agent as well. Pemetrexed is a promising drug. It is active against a broad range of cancers, and it has manageable side effects that seem to be lessened with folic acid and vitamin B12supplementation. Semin Oncol 29 (suppl 5):8-16. Copyright 2002, Elsevier Science (USA). All rights reserved.

Paclitaxel is a plant product isolated from the bark of the Western yew (Taxus brevifolia) that promotes the formation and stabilization of microtubules. This leads to growth arrest in the G2/M phase of the cell cycle. Paclitaxel has demonstrated significant antineoplastic activity in different tumor types, most notably in ovarian and breast carcinoma. In two Phase II trials (Eastern Cooperative Oncology Group [ECOG]/M.D. Anderson) in patients with previously untreated Stage IIIB-IV non-small cell lung cancer (NSCLC), response rates of 21% and 24% were reported. We are performing a Phase II trial investigating the efficacy of paclitaxel in patients with inoperable Stage IIIB-IV NSCLC. Forty-three patients were treated, 31 males and 12 females, with a median age of 59 years (range, 29–75), ECOG performance status 0-2, Stage HIB 30%, Stage IV 70%. Patients were treated every 3 weeks with 225 mg/m2s a 3-h infusion with standard premedication. Preliminary efficacy results from 37 patients include partial remissions in eight (21.6%) patients, no change in 22 (59.5%) and disease progression in seven (19%) patients. Eight patients are still receiving therapy. The hematologic toxicities (n = 43) were mild, and no World Health Organization (WHO) Grade 4 neutropenia was observed. Nonhematologic toxicities were Grade 1/2 polyneuropathy in 97.6%, Grade 1-3 myalgia/arthralgia in 76%, and Grade 1-3 nausea/vomiting in 18.6% of the patients. In conclusion, paclitaxel is an active single agent in this patient population. Mild hematologic toxicities were observed in the 3-h infusion setting (compared with 24-h infusion) and therapy was well tolerated. Further Phase II studies with paclitaxel in combination with other drugs having shown activity in NSCLC are indicated, and the results from Phase III studies comparing paclitaxel with standard chemotherapy regimens remain to be seen.

A total of 51 previously untreated patients with non-small-cell lung cancer (NSCLC) were treated with 130 mg/m2carboplatin given every 4 weeks as an i. v. infusion on days 1, 3, and 5. Ten patients achieved a partial response and five, a minor response. The overall response rate was 20% (95% confidence limits, 8%–32%). The median duration of response was 3 months and the median overall survival was 4.5 months. Leucopenia, thrombocytopenia and anemia of WHO grade 3 occurred in 4%–6% of patients and grade 3 nausea and vomiting was observed in 8% of our subjects. Grade 4 thrombocytopenia occurred in 3 (6%) patients. Apart from nausea and vomiting, nonhematologic toxicities above grade 2 were not observed. Further trials using carboplatin in NSCLC as a single agent or in combination with other chemotherapeutic agents or radiation are warranted.

Summary The in vitro formation of benzo[a]pyrene-DNA adducts was determined in peripheral blood monocytes of 22 lung cancer patients with at least one first-degree relative with lung cancer and compared to results obtained in 30 healthy controls. In patients, the mean (SEM) adduct formation was 2.8 (0.3) fmol/µg DNA as compared to 2.1 (0.1) fmol/µg in controls (p<0.05), and it was independent of age and smoking habits. These findings support the hypothesis that carcinogen-DNA adduct formation may be one factor of a constitutionally enhanced lung cancer risk.

Disappointing phase III results for thalidomide combined with gemcitabine and carboplatin in patients with advanced non-small-cell lung cancer might be related to poor efficacy of targeted therapies in unselected patients. We argue that current trial designs are flawed because they expose large numbers of such patients to potentially harmful treatment, and suggest that future research strategies should prioritize identification of predictive markers.