Lung Cancer

It's been an interesting time for those of us who treat patients with lung cancer. Over the past few years, non-small-cell lung cancer (NSCLC) has been a target for the numerous companies developing agents that inhibit receptors, growth factors, signaling molecules, and genes involved in tumor growth and development. The "biologic-targeted" approach to treatment is still in its infancy, but it has already given us great expectations, some surprises, some disappointments, and, ultimately, satisfaction that we now have a nonchemotherapeutic option.

Although improved survival is the "gold standard" for proving clinical benefit of oncologic therapy, the US Food and Drug Administration (FDA) has accepted significant results in clinical trials using surrogate endpoints as the basis for drug approval. One surrogate is the amount of tumor reduction, or tumor response. Although tumor shrinkage would seem to be a necessary precondition for improved survival, clinical studies of a variety of oncologic agents have not consistently demonstrated a correlation between the two in patients with renal cell carcinoma. Moreover, tumor response may not be an appropriate endpoint for evaluating the effects of the new targeted therapies, whose putative mechanisms are generally cytostatic rather than cytotoxic. Clinical trials suggest that some patients with other solid tumors, such as lung cancer, may derive clinical benefit from treatment that helps stabilize their disease. There is also controversy as to whether the Response Evaluation Criteria in Solid Tumors (RECIST) provides the most appropriate instrument for assessing tumor burden. Ultimately, use of a variety of endpoints as well as different trial designs may provide an adequate basis for investigating the benefits/risks of newer therapies.

I was saddened to learn this morning of the death of Dana Reeve from lung cancer. Today was a reminder of what it was like to be a doctor, unable to provide a cure for a young person afflicted with cancer Each loss was a personal one, and served as a reminder of how much we needed to accomplish to prevent those tragic deaths.

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.