Ramaswamy Govindan, MD

This video highlights some of the latest developments guiding precision medicine for lung cancer in clinical practice.

We summarize here key findings from the comprehensive analysis of squamous cell lung cancer by The Cancer Genome Atlas group and discuss the clinical implications of these findings.

Dr. Ramaswamy Govindan, Washington U at St. Louis, discusses patient screening, new research in targeted therapies, as well as the continued role of traditional chemotherapy in lung cancer.

Influenza infection is a potential cause of additional morbidity and mortality in patients who are immunocompromised because of cancer or its treatment. Of particular note, influenza infection may delay or interrupt chemotherapy and necessitate hospitalization. Successful immunization depends on an intact immune system that can produce antibodies in response to antigen exposure. Patients with cancer often have a suppressed immune system, resulting from their disease and/or immunosuppressive therapies, and as a consequence they may have a suboptimal serologic response to influenza vaccination. Since vaccination is the only proven method for preventing influenza infection, the Advisory Committee on Immunization Practices recommends seasonal influenza vaccination for adults without contraindications who have disease- or medication-related immunosuppression. Patients with cancer should be given the trivalent inactivated vaccine. Preliminary data suggest that administering the vaccine between cycles of chemotherapy may yield the best results.

Bronchioloalveolar carcinoma (BAC) is a unique subtype of lung adenocarcinoma that has received increasing attention in recent years. Levy and colleagues have provided a comprehensive review of the clinical and pathologic characteristics of this disease, as well as the clinical evidence available to guide treatment of patients with BAC.

Lung cancer in “never-smokers” constitutes only a small proportion of patients with lung cancer. Nevertheless, the topic has recently attracted a good deal of attention. Initially this was due to the fact that never-smokers with lung cancer had better outcomes with epidermal growth factor receptor–tyrosine kinase (EGFR-TK) inhibitors, compared to tobacco smokers with lung cancer. More recently the identification of molecular changes unique to lung cancer in never-smokers has generated further interest in this disease. These findings have the potential to enhance our knowledge of lung cancer biology and lead to the development of new, more effective treatments for lung cancer. In this review, we summarize the existing body of knowledge on lung cancer in never-smokers.

Lung Cancer is the leading cause of cancer-related death in the United States. Non-small cell lung cancer (NSCLC) accounts for more than 85% of all patients with lung cancer.[1] A third of patients with newly diagnosed NSCLC have locally advanced disease.

In this edition of Clinical Quandaries, Ramalingam et al present a 67-year-old man who seeks care for a new, asymptomatic left upper lobe lung mass, which was found incidentally on a routine chest x-ray as part of a preoperative work-up for an elective surgery. Further staging studies included a computed tomography (CT) scan of the chest and a positron-emission tomography (PET) scan followed by a magnetic resonance imaging (MRI) scan of the liver. Pathology from a fine-needle aspiration biopsy of the left lingular lesion was consistent with poorly differentiated adenocarcinoma and immunohistochemical stains consistent with a lung primary. The left lingular lesion and the prevascular lymph node were felt to be the only sites of involvement, making this stage IIIA (T1, N2, M0) lung cancer.

Despite the high prevalence of brain metastases in patients with metastatic lung cancer, these patients have been excluded from enrollment in clinical trials of new therapeutic drugs. The reasons for exclusion have centered on concerns that the blood-brain barrier may impede drug delivery into brain metastases, that brain metastases confer a dismal survival for metastatic lung cancer patients, and that brain metastases carry risk for cerebrovascular hemorrhage. A focused, updated review of these issues, however, clearly shows that these particular concerns are unwarranted. An extensive review of clinical trials on the efficacy of chemotheraputic agents against lung cancer brain metastases is also provided. This collective information describes an area in need of therapeutic development and supports an initiative to evaluate novel targeted therapies for lung cancer brain metastases.

A significant proportion of patients with non-small cell lung cancer (NSCLC) present with locally advanced, unresectable disease. For the most part, fit patients with this diagnosis are treated with combined-modality therapy. Relatively few are rendered resectable. Over the past two decades, combination chemotherapy and radiation, preferably concurrent chemoradiation, has emerged as the standard of care. However, survival gains have been offset, to some extent, by local, normal-tissue, in-field toxicity, particularly esophagitis and pneumonitis.

Although significant advances have been made in the systemic therapy of non–small-cell lung cancer (NSCLC) in patients with a good performance status (PS), the subgroup of patients with a poor PS has not been studied as well.

Lung cancer is one of the most common and deadly malignancies in the United States, with an estimated 213,380 new cases in 2007 and an estimated 160,390 deaths in 2007. Approximately 85% of these patients will be diagnosed with non-small cell lung cancer (NSCLC), and only 10%-20% will have potentially curable disease.

Small-cell lung cancer (SCLC) appears to be declining in frequency. This reduced incidence of SCLC seems to have curtailed interest and investigation as well.

These are exciting times in oncology. Over the past 2 decades, we have made remarkable progress in our understanding of the molecular and cellular processes involved in cancer progression.

Approximately one-third of patients with non-small cell lung cancer (NSCLC) present with locally advanced disease, the majority of whom are treated with concurrent chemotherapy and thoracic radiation therapy. Concurrent chemoradiation therapy is superior to sequential chemotherapy followed by thoracic radiation therapy or thoracic radiation therapy alone.

Lung cancer remains the leading cause of cancer-related mortality in the United States. The predominant histologic type of lung cancer is Non-Small-Cell lung cancer (NSCLC). Approximately 30% of newly diagnosed patients with NSCLC present with stages I-IIIA disease.

The 1-year survival for patients with metastatic non–small-cell lungcancer is only around 35%. We are evaluating the combination ofirinotecan (Camptosar) and carboplatin (Paraplatin) in patients withstage IIIB and IV non–small-cell lung cancer. The first five patientsreceived irinotecan, 250 mg/m2 over 90 minutes followed by carboplatinat an area under the concentration-time curve of 5 over 1 hour. Thedose of irinotecan was subsequently reduced to 200 mg/m2 in view offebrile neutropenia in one of five patients. Chemotherapy cycles arerepeated every 21 days. Patients are reevaluated every two cycles. Of aplanned 42 patients, 37 have been enrolled so far. Of the 37 enrolledpatients, 25 received at least two cycles, 20 received at least four cycles,and 12 received all six planned cycles. Grade 4 neutropenia (absoluteneutrophil count < 500) occurred in 10 patients and 19 treatment cycles.Two of these patients also had grade 4 diarrhea. Thirty-six cycles (30%)were delayed for neutropenia, six of which occurred among the firstfive patients who received irinotecan at 250 mg/m2. Best response totherapy included 7 partial responses (23%), 11 stable disease (37%),with 12 patients having progressive disease (40%). The regimen ofirinotecan and carboplatin administered once every 3 weeks is tolerableand convenient, with early evidence of activity. The main toxicityis hematologic. This study is ongoing and actively accruing patients.

Esophageal cancer frequently expresses cyclooxygenase-2 (COX-2)enzyme. In preclinical studies, COX-2 inhibition results in decreasedcell proliferation and potentiation of chemotherapy and radiation. Wereport preliminary results of a phase II study conducted by the HoosierOncology Group in patients with potentially resectable esophageal cancer.All patients received cisplatin at 75 mg/m2 given on days 1 and 29and fluorouracil (5-FU) at 1,000 mg/m2 on days 1 to 4 and 29 to 32with radiation (50.4 Gy beginning on day 1). Celecoxib (Celebrex) wasadministered at 200 mg orally twice daily beginning on day 1 untilsurgery and then at 400 mg orally twice daily until disease progressionor unexpected toxicities, or for a maximum of 5 years. Esophagectomywas performed 4 to 6 weeks after completion of chemoradiation. Theprimary study end point was pathologic complete response (pCR). Secondaryend points included response rate, toxicity, overall survival, andcorrelation between COX-2 expression and pCR. Thirty-one patientswere enrolled from March 2001 to July 2002. Respective grade 3/4 toxicitieswere experienced by 58%/19% of patients, and consisted of granulocytopenia(16%), nausea/vomiting (16%), esophagitis (10%), dehydration(10%), stomatitis (6%), and diarrhea (3%). Seven patients (24%)required initiation of enteral feedings. There have been seven deathsso far, resulting from postoperative complications (2), pulmonary embolism(1), pneumonia (1), and progressive disease (3). Of the 22 patients(71%) who underwent surgery, 5 had pCR (22%). We concludethat the addition of celecoxib to chemoradiation is well tolerated. ThepCR rate of 22% in this study is similar to that reported with the use ofpreoperative chemoradiation in other trials. Further follow-up is necessaryto assess the impact of maintenance therapy with celecoxib onoverall survival.

The outcomes for patients with metastatic or recurrent esophagealcancer are dismal, with 1-year survival rates of approximately 20%. Inthis phase II study, we studied the combination of docetaxel (Taxotere)and irinotecan (CPT-11, Camptosar) in patients with metastatic orrecurrent esophageal cancer. Eligible patients included those withhistologic or cytologic diagnosis of adenocarcinoma or squamouscancer of the esophagus or gastroesophageal junction who had receivedno previous chemotherapy for metastatic esophageal cancer. Previouschemotherapy in the neoadjuvant or adjuvant setting was allowed.Patients received irinotecan at 160 mg/m2 over 90 minutes followed bydocetaxel at 60 mg/m2 intravenously over 1 hour, with chemotherapycycles repeated every 21 days. Patients were reevaluated every twocycles. Of a planned 40 patients, 15 were enrolled, with 14 patientsevaluable for toxicity and 10 evaluable for response and survival. Thecombination of docetaxel and irinotecan resulted in a response rate of30%. An additional 40% achieved stable disease. The median survivalwas 130 days, with three patients still alive at the time of this analysis.The toxicities included 71% incidence of grade 4 hematologic toxicities,with 43% febrile neutropenia. One patient died of cecal perforationafter one cycle. There was no evidence of pharmacokinetic interaction,as systemic clearance of both drugs was similar to that seen after singleagentadministration. In conclusion, the regimen of docetaxel andirinotecan is active in metastatic or recurrent esophageal cancer.However, this combination chemotherapy regimen has an unacceptablerate of febrile neutropenia. This regimen needs to be modified toreduce the incidence of febrile neutropenia.