Managing Diseases of the Airway

Educational Objectives

The goal of this program is to improve management of common upper respiratory infections and lung cancer. After hearing and assimilating this program, the clinician will be better able to:

1.   Distinguish viral from bacterial causes of acute bronchitis and acute sinusitis, based on clinical findings.

2.   Recognize patients with acute sinusitis who may benefit from antibiotic therapy.

3.   List advantages of using low-dose spiral computed tomography for lung cancer screening.

4.   Select an adjuvant chemotherapy regimen for eligible patients with lung cancer.

5.   Describe the role of monoclonal antibodies such as bevacizumab in the treatment of lung cancer.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of in­terest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Kalemkerian is on the Speakers’ Bureau for Genentech and Lilly. Dr. Kalemkerian has received research grants from Abbott, Merck, and Pfizer, and is a consultant for ImClone and Merck. Drs. Fitch and Walsh and the planning committee reported nothing to disclose.

Acknowledgements

Dr. Fitch was recorded in Myrtle Beach, SC, at the 37th Annual Emery C. Miller Medical Symposium, presented August 4-8, 2008, by the Wake Forest University School of Medicine in partnership with the Northwest Area Health Education Cen­ter. Dr. Walsh spoke in San Francisco, CA, at Primary Care Medicine: Principles and Practice, presented October 29-31, 2008, by the University of California, San Francisco, School of Medicine. Dr. Kalemkerian was recorded in Ann Arbor, MI, on October 3, 2008, at the University of Michigan Medical School’s 21st Annual Update in Pulmonary and Critical Care Medicine. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Antibiotics and Upper Respiratory Infections

Michael T. Fitch, MD, PhD, Assistant Professor, Department of Emergency Medicine, Wake Forest University School of Medicine, Winston-Salem, NC

Acute bronchitis: acute productive cough without pneumonia; median duration of cough, 18 days; 90% of cases caused by viral infection (eg, influenza); presence of purulent sputum not predictive whether etiology viral or bac­terial; nonviral causes include Bordetella, Mycoplasma, and Chlamydia pneumoniae; no evidence Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella cause acute bronchitis; no compelling evidence that antibiotics change course of bacterial bronchitis, but they may reduce duration of cough by 0.6 days; adverse effects associated with antibiotic use in acute bronchitis; antibiotics not indicated for acute bronchitis, even if bacterial etiology sus­pected; use of antibiotics by tobacco smokers with acute bronchitis does not appear to affect duration of illness; studies show 70% of patients in emergency department with acute bronchitis given antibiotics; patients perceive vi­ral illness can be treated with antibiotics; antibiotics more likely to be prescribed if physician perceives patient wants antibiotics (50% of time, physician’s perceptions incorrect); patient satisfaction correlated with better under­standing of illness and adequate time spent by physician with patient; patient education important (inform patient of long duration of cough); reassure patients they do not have pneumonia or other condition requiring antibiotics; symptomatic treatment (eg, decongestants, mucolytics) recommended; role of over-the-counter cough medications unclear; albuterol inhalers possibly helpful in patients with wheezing

Acute sinusitis: typical features include congestion, mucopurulent discharge, sinus pressure, fever, and facial pain; commonly caused by rhinovirus; symptoms can last 1 to 30 days (most improve in 1-2 wk); patients can have pu­rulent nasal drainage; two-thirds of patients with bacterial disease improve without antibiotics

Predictors of bacterial disease: maxillary toothache; abnormal transillumination; poor response to decongestants; colored nasal discharge; mucopurulence on examination; poor predictors of bacterial disease include isolated fe­ver, change in characteristics of nasal discharge, facial pain on percussion, purulent discharge; radiologic studies  —  not recommended for initial evaluation; 40% of patients who undergo computed tomography (CT) for other reasons have incidental findings of sinusitis; 90% of patients with common cold due to adenovirus would have CT findings suggestive of acute sinusitis; patients with symptoms lasting >10 days, initial improvement in symptoms followed by worsening, purulent nasal discharge, maxillary tooth or face pain, and unilateral maxil­lary tenderness likely to have bacterial disease

Treatment of bacterial disease: first-line agents include amoxicillin (£1 g q8h), amoxicillin and clavulanate, cefpo­doxime or cefuroxime, or trimethoprim-sulfamethoxazole or doxycycline in patients allergic to penicillin; sec­ond-line agents (eg, fluoroquinolones) should be reserved for patients refractory to initial treatment or patients with other risk factors suggestive of resistant organism

Group A b-hemolytic streptococci: present in 10% of adults with acute pharyngitis (slightly higher in pediatric pop­ulation; acute pharyngitis most commonly caused by virus); only indication for treating pharyngitis with antibi­otics; antibiotics prescribed to 70% of adults with acute pharyngitis; symptoms  —  fever >101ºF; tonsillar exudate; palatal petechiae; uvular edema; anterior cervical adenopathy; absence of cough, rhinorrhea, or congestion; sand­paper rash

Reasons to treat with antibiotics: symptom relief  —  symptoms of untreated streptococcal pharyngitis last 5 to 10 days; antibiotic therapy may improve symptoms 1 day earlier; treatment must be started within first 48 hr of on­set of symptoms; reduce risk for suppurative complications  —  peritonsillar abscess and retropharyngeal abscess rare; recent studies found most patients with peritonsillar abscesses present with them; poststreptococcal glomer­ulonephritis not affected by antibiotics; reduce transmission  —  risk for transmission decreases after 24 hr of anti­biotic treatment; effect on adult population unclear; may be more important for children in close-contact situations; rheumatic fever incidence  —  in 1994, 60 times lower than in early 1960s; currently, need to treat 3000 to 4000 to prevent 1 case

Centor criteria: clinical risk scoring for group A b-hemolytic streptococci; 1 point each for exudative tonsillitis, swollen or tender anterior cervical lymph nodes, history of fever, or absence of cough; score of 0 to 1 indicates low risk (no testing or treatment recommended); score of 3 to 4 indicates high risk; treatment options  —  1) rapid streptococcal testing for patients with score of 2, 3, or 4 (treat only patients with positive results); 2) rapid strep­tococcal testing for patients with score of 2 or 3 (treat only patients with positive results); treat patients with score of 4, without testing; 3) treat patients with score of 3 or 4, without testing; no role for throat culture in adult pa­tients; arguments for using clinical criteria  —  allows rapid diagnosis in office; allows treatment to be initiated in time for sympto-matic benefit; avoids cost of rapid testing and obtaining cultures; allows for treatment of most patients with group A streptococci while avoiding overtreatment of other patients; Infectious Diseases Society of America agrees low-risk patients should not be tested or treated, but patients should be tested before receiving treatment; rapid streptococcal testing without throat culture reasonable; treatment can be delayed for £9 days and still prevent rheumatic fever; retrospective chart review of »2000 patients found guidelines not followed in 66% of outpatient clinic visits; 78% of treated patients were low-risk, and 30% of patients with negative rapid strepto­coccal test results and negative throat cultures received antibiotics

Questions and answers: chronic obstructive pulmonary disease (COPD) and bronchitis  —  some evidence that some patients with severe COPD may improve faster with antibiotics (evidence not as clear in outpatient settings); pa­tient with Centor score of 4 and negative rapid streptococcal testing  —consider other causes of exudative pharyngi­tis (eg, mononucleosis); no guidelines for selective use of throat culture

Screening for Lung Cancer

Judith M.E. Walsh, MD, MPH, Professor of Medicine, University of California, San Francisco, School of Med­icine

Introduction: prevalence of lung cancer high (in 2007, > 200  000 cases); determine whether treatment of preclinical disease more effective than waiting for development of symptoms; survival better when detected early (ie, stage I); screening improves health outcomes; systematic review found frequent lung cancer screening with chest x-ray as­sociated with increase in mortality rather than decrease; no difference between chest x-ray and sputum cytology, compared to chest x-ray alone

Low-dose spiral computed tomography (CT): helical volumetric studies; can screen entire lung in <20 sec; no in­travenous (IV) contrast required; greater radiation exposure than conventional chest x-ray, but less than conven­tional CT; can detect smaller lesions than conventional chest x-ray

Studies: of 8 published studies on lung cancer screening, 4 in high-risk individuals (eg, tobacco smokers) and 4 in mixed-risk populations; low-dose CT can detect lung cancer, even early-stage lung cancer; baseline screening with low-dose CT in high-risk population found >1% prevalence of lung cancer and 0.5% to 2.0% incidence on subse­quent examinations; International Early Lung Cancer Action Project study  —  screened and followed >31  000 indi­viduals (83% tobacco smokers); of >4000 positive results, 400 found to have lung cancer; on annual screening, another 1400 found positive (»25% lung cancer); most cancers detected were stage I

Conclusions: spiral CT can detect early disease; value of ability of spiral CT to detect early-stage lung cancer uncer­tain (ie, possibility of overdiagnosis); consider whether benefits outweigh risks (many individuals underwent eval­uation of benign nodules); United States Preventive Services Task Force  —  evidence insufficient to recommend for or against screening asymptomatic individuals for lung cancer with any modality; screening may detect lung cancer early; no evidence any screening strategy reduces lung cancer mortality; recommend tobacco smoking cessation

Caring for Lung Cancer Patients

Gregory P. Kalemkerian, MD, Professor of Medicine, University of Michigan Medical School, Ann Arbor

Introduction: in United States, new diagnosis of lung cancer made every 2.5 min (every hour, 18 die); this year, more Americans expected to die from lung cancer than colon, breast, pancreatic, and prostate cancers combined; 25% have easily surgically resectable disease; 5-yr survival rate of stage I disease, 70% to 80%; most patients present in stage III or IV (cure unlikely)

Recent trials of modern adjuvant chemotherapy: most studied platinum-based agents, but one trial studied carbo­platin and paclitaxel (eg, Taxol) regimen; median age in studies, »60 yr (median age of patients with lung cancer, »70 yr); patients should be placed on chemotherapy within 6 to 8 wk of surgery; younger patients recover better and are also better candidates for chemotherapy; European trials exclude patients >75 yr of age; results  —International Adjuvant Lung Cancer Trial (IALT) saw 4% to 5% absolute survival benefit at 5 yr (statistically sig­nificant) in large heterogeneous population (stages I, II, and III); National Cancer Institute of Canada (NCIC) JBR.10 trial of stages IB and II saw 15% improvement in survival and progression-free survival benefit with che­motherapy; Adjuvant Navelbine International Trialist’s Association (ANITA) trial saw »8% improvement in long-term survival rate in broad range of stages; meta-analysis  —  »4500 patients (<10% >70 yr of age) in 5 trials; overall survival benefit, 5% (not statistically significant in stage I); greatest benefit seen in stages II and III

Management with adjuvant chemotherapy: in completely resected patients with stage II or III non-small cell lung cancer (NSCLC), adjuvant chemotherapy recommended; consider chemotherapy for high-risk patients in stage IB; chemotherapy may be beneficial in patients with large (> 4 cm) tumors; patients should be able to tolerate treatment and recover quickly from surgery; treatment duration, 3 to 4 mo

Benefits of treatment: consider interval survival and best supportive care, compared to newer chemotherapeutic agents; double or triple 1-yr survival; significantly improved 2-yr survival; standard chemotherapy regimens result in 20% response rate with median survival benefit of 8 mo

Vascular endothelial growth factor (VEGF) pathway: VEGF molecule produced by tumor cells; receptor on endo­thelial cell stimulates proliferation, chemotaxis, and capillary formation for angiogenesis

Mechanisms for pathway inhibition: monoclonal antibody ties up ligand to prevent binding to receptor; monoclo­nal antibody binds to receptor (external ligand-binding domain) to prevent activation of receptor; small-molecule tyrosine kinase inhibitors (TKIs) block enzymatic activity of receptor

Bevacizumab (Avastin): monoclonal antibody; binds to VEGF ligand to prevent activation of receptor; large ran­domized study  —  exclusion criteria based on risk for bleeding (main side effect of bevacizumab); saw improved re­sponse rate and survival (median survival improvement 2 mo; 1- and 2-yr survival improvement, 7%-8%) in patients who received standard chemotherapy (carboplatin and paclitaxel) and bevacizumab; risk for massive bleed­ing 4% to 5%; significant increase in treatment-related death rate; conclusions  —  for advanced NSCLC, consider bevacizumab in combination with chemotherapy; exclude patients at highest risk for bleeding and clotting; in pa­tients not candidates for bevacizumab, 2-drug platinum-based chemotherapy regimen standard of care

Epidermal growth factor receptor (EGFR) pathway: membrane-bound receptor activates proliferative pathways within cancer cell; cetuximab (C225; Erbitux; monoclonal antibody) inhibits binding of ligand to EGFR; study  —  advanced-stage patients evaluated for EGFR expression (ie, 1 cell immunohistochemically positive); 85% of pa­tients eligible; some improvement in response rate and survival with chemotherapy and cetuximab; improvement in median survival, 5 wk; improvement in overall survival, 5%; no improvement in progression-free survival; suggests small fraction of patients benefit from cetuximab; somewhat statistically significant improvement in median sur­vival and 1-yr survival only in patients with EGFR-positive tumors; cost-effectiveness analysis found cost per year of life gained, $500  000 to $600  000 ($50  000-$100   000 considered reasonable)

Erlotinib (OSI-774; Tarceva): small molecule inhibitor; blocks tyrosine kinase within cell; study found in relapse of advanced NSCLC, response rate low (9%); stable disease rate, 30% to 40%; improvement in 1-yr survival, 9%; characteristics for higher response included no history of tobacco smoking, adenocarcinoma, east Asian ethnicity, and female sex

Gene mutations and amplification: patients with mutations of EGFR gene that occur within tyrosine kinase domain had higher response rates to TKIs; incidence of mutations higher in patients with no history of tobacco smoking, patients with adenocarcinomas, patients of east Asian eth-nicity, and women; patients with gene amplification had increased response rates; expression not sufficient predictor of response; RAS mutation good negative predictor of response; EGFR mutations do not predict stable disease or which patients likely to survive longer; amplification correlates with TKIs and monoclonal antibodies and may be associated with improved survival; earlier use of TKIs in patients with mutations may be rational strategy

Suggested Reading

No authors listed: Is a short course of antibiotics effective for acute exacerbation of chronic bronchitis? J Fam Pract 57:711, 2008; Cabebe E et al: Role of anti-angiogenesis agents in treating NSCLC: focus on bevacizumab and VEGFR tyrosine kinase inhibitors. Curr Treat Options Oncol 8:15, 2007; Clegg A et al: A rapid and systematic review of the clinical effectiveness and cost-effectiveness of paclitaxel, docetaxel, gemcitabine and vinorelbine in non-small-cell lung cancer. Health Technol Assess 5:1, 2001; Cooper RJ et al: Centers for Disease Control and Prevention. Principles of appropriate antibiotic use for acute pharyngitis in adults: background. Ann Emerg Med 37:711, 2001; Gerber MA: Diagnosis of group A beta-hemolytic streptococcal pharyngi­tis. Use of antigen detection tests. Diagn Microbiol Infect Dis 4:5S, 1986; Kumar A et al: Second- and third-line treatments in non-small cell lung cancer. Curr Treat Options Oncol 7:37, 2006; Lindell RM et al: Five-year lung cancer screening experience: CT appearance, growth rate, location, and histologic features of 61 lung cancers. Radiology 242:555, 2007; Lustberg MB et al: Optimal duration of chemotherapy in advanced non-small cell lung cancer. Curr Treat Options Oncol 8:38, 2007; McIsaac WJ et al: Empirical validation of guidelines for the management of pharyngitis in children and adults. JAMA 291:1587, 2004; Robert­son KA et al: Antibiotics for the primary prevention of acute rheumatic fever: a meta-analysis. BMC Cardiovasc Disord 5:11, 2005; Socinski MA et al: Treatment of non-small cell lung cancer, stage IV: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 132:277S, 2007; Sone S et al: CT findings of early-stage small cell lung cancer in a low-dose CT screening programme. Lung Cancer 56:207, 2007; Stinchcombe TE et al: Current treatments for advanced stage non-small cell lung can­cer. Proc Am Thorac Soc 6:233, 2009.