Lung Cancer

Anti-EGFR (epidermal growth factor receptor) therapies, including tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, demonstrate activity in a variety of tumor types. While both inhibit the EGFR pathway, they act via different mechanisms.

Since initial characterization over 40 years ago, strong preclinical and clinical data have clearly established the epidermal growth factor receptor (EGFR) as a worthy molecular target for intervention in cancer therapy. The receptor is expressed, overexpressed, or mutated in many human tumors, including head and neck, colorectal, pancreatic, non-small-cell lung, ovarian, esophageal, gastric, breast, prostate, bladder, and renal cancers. Experiments in several model systems have confirmed that EGFR signaling is involved in regulating several key biologic processes, including cell proliferation, epithelial development, organogenesis, apoptosis, angiogenesis, and differentiation. Furthermore, EGFR function has been shown to be altered and/or dysregulated in a variety of spontaneous tumors.

Overexpression of the epidermal growth factor receptor (EGFR) is correlated with poor prognosis in many human cancers. Two main classes of anticancer agents affect the EGFR: those targeting the extracellular ligand-binding domain and those that block the intracellular tyrosine kinase (TK) domain. Cetuximab (Erbitux) is a mouse/human chimeric monoclonal antibody that targets the ligand-binding domain of the EGFR, whereas erlotinib (Tarceva) and gefitinib (Iressa) are small-molecule TK inhibitors. Common toxicities of agents targeting the EGFR differ from those associated with traditional chemotherapy. Given the common pathway through which these agents work, some adverse events are similar. Many patients treated with these agents develop an acne-like rash on the face and upper body, most likely related to keratinocyte alterations and hair follicle proliferation and maturation. Although clinical manifestation of this reaction closely resembles acne vulgaris, the histology is more similar to infectious folliculitis. Other adverse events appear to be related to a drug class or individual agent. For example, interstitial lung disease is a rare but potentially fatal reaction that has been reported with gefitinib. Hypomagnesemia reported in association with cetuximab may be related to EGFR blockade in the kidney. Anaphylactic or anaphylactoid infusion reactions are also seen with cetuximab, as with other monoclonal antibodies.

Millennium Pharmaceuticals and Johnson & Johnson have initiated a randomized, phase II open-label study of the potential benefit of combining two targeted therapies with different mechanisms of action—bortezomib (Velcade) and pemetrexed (Alimta, Eli Lilly)—in previously treated patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC).

Elderly patients with stage I-III non-small-cell lung cancer (NSCLC) constitute a peculiar patient population and need specific therapeutic approaches. Limited resections are an attractive alternative for elderly patients with resectable NSCLC because of the potential reduction in postoperative complications. Curative radiation therapy is an acceptable alternative for elderly patients who are unfit for or refuse surgery. Hypofractionated stereotactic body radiation therapy is of particular interest for this population because of its favorable tolerance.

Elderly patients with stage I-III non-small-cell lung cancer (NSCLC) constitute a peculiar patient population and need specific therapeutic approaches. Limited resections are an attractive alternative for elderly patients with resectable NSCLC because of the potential reduction in postoperative complications. Curative radiation therapy is an acceptable alternative for elderly patients who are unfit for or refuse surgery. Hypofractionated stereotactic body radiation therapy is of particular interest for this population because of its favorable tolerance.

Elderly patients with stage I-III non-small-cell lung cancer (NSCLC) constitute a peculiar patient population and need specific therapeutic approaches. Limited resections are an attractive alternative for elderly patients with resectable NSCLC because of the potential reduction in postoperative complications. Curative radiation therapy is an acceptable alternative for elderly patients who are unfit for or refuse surgery. Hypofractionated stereotactic body radiation therapy is of particular interest for this population because of its favorable tolerance.

Cell Therapeutics' Xyotax (paclitaxel poliglumex), a biologically enhanced chemotherapeutic that links paclitaxel to a biodegradable polyglutamate polymer, has gained fast track status from the FDA for the first-line treatment of advanced non-small-cell lung cancer (NSCLC) in women with poor performance status.

The epidermal growth factor receptor (EGFR) promotes the growth of different cell types and has been implicated in tumorigenesis. The EGFR comprises a family of four structurally similar tyrosine kinases with a complex link to downstream signaling molecules that ultimately regulate key cell processes. Anti-EGFR agents have been developed as promising therapeutic anticancer targets, and some have been recently approved for the treatment of non-small-cell lung cancer and colon cancer. The two anti-EGFR therapies with the greatest clinical application are monoclonal antibodies that block the binding of ligands to EGFR and small-molecule tyrosine kinase inhibitors that inhibit the binding of adenosine triphosphate to the internal tyrosine kinase receptor of EGFR. We attempt to give an overview of the EGFR function and biology, focusing on the most important clinical findings and applications of EGFR inhibitors in lung and head and neck cancer.

The epidermal growth factor receptor (EGFR) promotes the growth of different cell types and has been implicated in tumorigenesis. The EGFR comprises a family of four structurally similar tyrosine kinases with a complex link to downstream signaling molecules that ultimately regulate key cell processes. Anti-EGFR agents have been developed as promising therapeutic anticancer targets, and some have been recently approved for the treatment of non-small-cell lung cancer and colon cancer. The two anti-EGFR therapies with the greatest clinical application are monoclonal antibodies that block the binding of ligands to EGFR and small-molecule tyrosine kinase inhibitors that inhibit the binding of adenosine triphosphate to the internal tyrosine kinase receptor of EGFR. We attempt to give an overview of the EGFR function and biology, focusing on the most important clinical findings and applications of EGFR inhibitors in lung and head and neck cancer.

The epidermal growth factor receptor (EGFR) promotes the growth of different cell types and has been implicated in tumorigenesis. The EGFR comprises a family of four structurally similar tyrosine kinases with a complex link to downstream signaling molecules that ultimately regulate key cell processes. Anti-EGFR agents have been developed as promising therapeutic anticancer targets, and some have been recently approved for the treatment of non-small-cell lung cancer and colon cancer. The two anti-EGFR therapies with the greatest clinical application are monoclonal antibodies that block the binding of ligands to EGFR and small-molecule tyrosine kinase inhibitors that inhibit the binding of adenosine triphosphate to the internal tyrosine kinase receptor of EGFR. We attempt to give an overview of the EGFR function and biology, focusing on the most important clinical findings and applications of EGFR inhibitors in lung and head and neck cancer.

In both chemonaive and heavily pretreated patients with non-small-cell lung cancer (NSCLC), investigations of canfosfamide (TLK286, Telcyta) are yielding "exciting" findings, Howard A. Burris III, MD, reported at the Chemotherapy Foundation Symposium XXIII (abstract 7).

In February 2005, Mark McClellan, MD, PhD, head of the Centers for Medicare & Medicaid Services (CMS), appointed Peter Bach, MD, MAPP, an associate attending physician at Memorial Sloan-Kettering Cancer Center, to serve as senior advisor on health care quality and cancer policy. A pulmonologist and intensivist by training, Dr. Bach has a strong reputation for research on quality cancer care, helping develop guidelines for lung cancer and chronic obstructive pulmonary disease (COPD).

The epidermal growth factor receptor (EGFR) promotes the growth of different cell types and has been implicated in tumorigenesis. The EGFR comprises a family of four structurally similar tyrosine kinases with a complex link to downstream signaling molecules that ultimately regulate key cell processes. Anti-EGFR agents have been developed as promising therapeutic anticancer targets, and some have been recently approved for the treatment of non-small-cell lung cancer and colon cancer. The two anti-EGFR therapies with the greatest clinical application are monoclonal antibodies that block the binding of ligands to EGFR and small-molecule tyrosine kinase inhibitors that inhibit the binding of adenosine triphosphate to the internal tyrosine kinase receptor of EGFR. We attempt to give an overview of the EGFR function and biology, focusing on the most important clinical findings and applications of EGFR inhibitors in lung and head and neck cancer.

This case study illustrates some of the nonmedical issues your cancer patients often encounter, particularly when they are unable to return to work as a result of their disease or its treatment. Questions about disability benefits are something you may have to face on a regular basis. For patients, pursuing disability benefits is often a rocky road that is difficult to navigate even without the added burden of dealing with a cancer diagnosis. This case study portrays how you can help your patients deal with such issues and what resources are available to them.

WASHINGTON-After many decades with few advances in radiotherapy, important new methods of delivering radiotherapy have emerged in the past 10 years, a number of which show the promise of increasing local control-and thus, survival-in lung cancer, said Robert D. Timmerman, MD, vice-chair, Department of Radiation Oncology, University of Texas Southwestern Medical Center at Dallas. Speaking at the Geriatric Oncology Consortium 2005 meeting, "Advancing Cancer Care in the Elderly," Dr. Timmerman discussed new radiotherapy techniques of potential benefit to elderly patients with early lung cancer.

The role of screening in order todetect lung cancer at an earlierstage has been widely debatedfor the past 4 decades. In this review,Dr. Mulshine focuses on the currentissues in lung cancer screening in lightof the findings of the InternationalEarly Lung Cancer Action Project(I-ELCAP) As the article mentions, thediagnosis of lung cancer is often madeat a stage when the disease is no longer amenable to cure. This is probably themost important cause for the dismaloutcomes of patients with lung canceroverall.

In this issue of ONCOLOGY, Solomon,Mitchell, and Bunn providean excellent review on adjuvanttherapy for resected non–smallcelllung cancer (NSCLC). Theauthors have thoroughly reviewed therecent literature and highlight severalimportant areas for discussion. Theauthors appropriately frame the importanceof the clinical issue at hand.

Because of the high rate of distant disease recurrence, the 5-yearsurvival of patients who have undergone complete surgical resectionof localized non–small-cell lung cancer (NSCLC) is approximately 50%.Initial results from early studies of adjuvant postoperative chemotherapyreported an adverse effect of alkylating agent and older chemotherapyregimens on survival. Cisplatin-based combinations were the first toshow a survival advantage. A 1995 meta-analysis of these studies suggesteda 13% reduction in the hazard ratio for death (HR = 0.87), leadingto a 5% survival benefit at 5 years. Still, these trials involved limitednumbers of patients (N = 1,394), and the results failed to reach statisticalsignificance (P = .08). Of the five largest subsequent randomizedtrials of platinum-based adjuvant therapy, three showed a significantsurvival advantage. Although it is impossible to determine the reasonsfor the differing outcomes of these studies, several key features distinguishthem, and the data suggest that medically fit patients with resectedstage IB or II NSCLC should be offered chemotherapy with a platinum/new drug combination.

The review by Jan Buter andGiuseppe Giaccone in this issueof ONCOLOGY is an excellentoverview of the current statusof the anti–epidermal growth factorreceptor (EGFR) agents gefitinib (Iressa),erlotinib (Tarceva), and cetuximab(Erbitux). The authors addresssome of the most important issuesregarding anti-EGFR agents currently in clinical development. Key amongthese are the importance of patientselection and drug dosage in the successand failure of various clinicaltrials. This article raises several veryinteresting questions in the developmentof this class of agents.

Inhibitors targeting the family ofepidermal growth factor receptors(EGFRs) are novel antitumor compoundsinvestigated in many cancertypes, including non–small-cell lungcancer (NSCLC). In this special lungcancer issue of ONCOLOGY, Drs.Buter and Giaccone provide us withan updated review of clinical researchon two classes of these agents inNSCLC: small-molecule tyrosinekinase inhibitors (TKIs) and monoclonalantibodies. The former classincludes gefitinib (Iressa) and erlotinib(Tarceva), two orally availablequinazoline derivatives targeting thetyrosine kinase domain of EGFR. Thelatter includes cetuximab (Erbitux), achimeric monoclonal antibody directedagainst EGFR. The authors extensivelydiscuss single-agent andcombination activities of these drugsin NSCLC.

Lung cancer causes more deathsin American men and womenthan the total number of deathsfrom breast, prostate, and colon cancercombined. Recently the lung cancerdeath rate has reached a plateau inthe United States, primarily because asignificant number of American menhave stopped smoking. However,smoking incidence in adult Americanwomen, as well as teenagers of bothgenders and of all ethnicities, has notdecreased significantly.

Lung cancer continues to be themost common cause of cancerdeaths in the United States forboth men and women. Unfortunately,the majority of patients presentwith local or distant disease at thetime of diagnosis. Surgical resectioncontinues to offer the best chance forlong-term survival; however, less than25% of patients have surgically resectabledisease. Even after surgicalresection for early-stage disease a significantnumber of patients will developrecurrent disease, with themajority being distant in nature. Developmentof distant disease usuallyproves to be the terminal event inmost patients. Multiple treatmentmodalities have been investigated asadjuvant therapy to decrease the incidenceof distant disease after completesurgical resection. Untilrecently, no modality has shown asurvival advantage in patients afterresection for non–small-cell lung cancer(NSCLC).

In this review we will discuss issues inherent to the lung cancer screening process, including the value of smoking cessation strategies, the challenge with the rapid pace of developments in the field, cost concerns, consideration of biases in trial design (overdiagnosis, for example), overtreatment, and radiation risk. We discuss recommendations from several organizations, such as the US Preventive Services Task Force and the American Cancer Society.

Drs. Laskin and Sandler havedone an excellent job of summarizingthe results of chemotherapyin the treatment of stageIV non–small-cell lung cancer. Theyhave pointed out that a meta-analysispublished in 1995 showed that chemotherapyprovided a modest survivaladvantage compared to supportivecare alone. In addition, they have citedstudies that have shown the treatmentis cost-effective and that it relieveslung cancer–related symptoms.They have thoroughly discussed thefact that multiple phase III trials testingnewer chemotherapy doubletsshow slightly different toxicity profiles with virtually identical efficacy,and that giving more than four coursesof therapy with regimens that consistof three or more drugs does notprovide significant benefit.

Targeted therapies inhibiting the epidermal growth factor receptor(EGFR) have been introduced in the treatment of patients with advancednon–small-cell lung cancer (NSCLC). Many inhibitors of theEGFR have been developed, targeting either the extracellular receptordomain with antibodies or the intracellular tyrosine kinase bindingdomain with small molecules. The tyrosine kinase inhibitor (TKI)gefitinib (Iressa) was the first targeted drug to be registered for thetreatment of NSCLC after failure of chemotherapy. Given concurrentlytogether with platinum combination chemotherapy both TKIs gefitiniband erlotinib (Tarceva) failed to increase activity. Sequential targetedtherapy after chemotherapy is currently being investigated further. Studieswith the monoclonal antibody cetuximab (Erbitux) combined withchemotherapy are ongoing. Side effects of the small molecules aremainly skin rash and diarrhea, whereas the antibodies do not give diarrhea.Selection of patients, based on molecular markers and patientcharacteristics, has become an important issue for the further developmentof these drugs, given there is activity in a relatively small group ofpatients with NSCLC. Newer drugs inhibiting more than one receptorpathway are being investigated in order to find activity in a broadergroup of patients.

In their excellent review of firstlinechemotherapy for patientswith advanced non–small-cell lungcancer (NSCLC), Laskin and Sandlerare clear, direct, and positive. Chemotherapyworks in stage IV disease:

With best supportive care alone, patients with metastatic non–smallcelllung cancer (NSCLC) have a median survival of 4 to 5 months anda 1-year survival rate of approximately 10%. Trials carried out in the1980s and 1990s comparing chemotherapy to best supportive care reportedvariable efficacy results; however, a pivotal meta-analysis of thesedata indicated that cisplatin-based chemotherapy provided a survivalbenefit in advanced NSCLC. In the past decade newer agents such asgemcitabine (Gemzar), vinorelbine, paclitaxel, and docetaxel (Taxotere)have all demonstrated activity in NSCLC as single agents; consequentlythese agents have been combined with cisplatin or carboplatin. Randomizedphase III trials comparing these “newer” platin-based doubletshave failed to identify an optimal platinum-based doublet therapyregimen. Though it is clear that chemotherapy is an appropriate treatmentfor many patients with lung cancer, there a sense in which the useof traditional chemotherapeutic agents has reached a therapeutic plateau.Increased understanding of cancer biology has revealed numerouspotential therapeutic strategies, including targeting the epidermalgrowth factor receptor, protein kinase C, rexinoid receptors, and theangiogenesis pathway. The Eastern Cooperative Oncology Group studyE4599 comparing paclitaxel/carboplatin with/without bevacizumab isthe first phase III randomized trial to show a survival advantage withthe addition of a molecularly targeted agent to chemotherapy in thechemotherapy-naive patient population. Future studies will involve theevaluation of additional targeted agents plus chemotherapy as well aslooking at combinations of these targeted agents alone or with chemotherapy.

LEIDEN, The Netherlands-In a prospective 100-patient study that may have direct applicability to clinical practice, a team of Dutch researchers has demonstrated improved identification of mediastinal tumor invasion (T4) or lymph node metastases (N2/N3) in patients with non-small-cell lung cancer (NSCLC) when preoperative staging employed transesophageal ultrasound–guided fine-needle aspiration (EUS-FNA) in addition to mediastinoscopy. The finding, they said, is attributable to the "complementary reach" of these diagnostic tools in assessing regional lymph node stations and in the ability of EUS-FNA to detect mediastinal tumor invasion.

The patient is a 74-year-old gentleman who presented with a visual disturbance and right shoulder pain. On routine chest x-ray, he was found to have a right apical lung mass.