Commentary (Arora/Freifeld): Infectious Complications of Lung Cancer

The article by Dr. Seo provides a comprehensive review of the epidemiology, presentation, and treatment of infection in lung cancer patients. Infection is a significant cause of morbidity and mortality in cancer patients, as a consequence of immunologic abnormalities that result from the cancer itself as well as from cytotoxic cancer therapies. Granulocytopenia and lymphocyte dysfunction commonly occur following intensive therapy for many solid tumors such as lung cancer, and these cellular deficiencies particularly predispose patients to certain infections. Respiratory infections are common during the course of lung cancer, often as a result of direct effects on the lung including radiation therapy and tumor burden causing obstruction, especially with bronchogenic carcinomas or carcinoid tumors. Postsurgical infections, following biopsy or thoracotomy for resection, are also common. Infectious complications are problematic for both patient and oncologists because they may delay treatment and impair quality of life.

Microbiologic Flora and Types of Infection

The author cites various studies that have made an attempt to outline the microbiologic flora and sites of infection in patients with lung cancer.[1,2] In all of these studies, bacteria account for the vast majority of infectious agents. The sites of infection differ, depending on the neutrophil counts of the patient. Lung cancer patients with normal neutrophils were found to have a majority of infections in the tracheobronchial tree, whereas patients with neutropenia[3] were frequently found to have a distribution of infections at various sites-predominantly gastrointestinal, respiratory, and bloodstream- reflective of the common sites involved in other neutropenic patients. Thus, it appears that neutropenia is a great equalizer in terms of the types and sites of infection, regardless of underlying cancer type.

It has been observed for decades that bacteria are clearly associated with infections during neutropenia, and lung cancer patients are no exception. However, it is notable that gram-negative bacteria (followed by gram-positive bacteria and fungi) were the most common pathogens identified in lung cancer patients. This is in contrast to data suggesting that gram-positive infections predominate in patients with neutropenia and fever.[4] In a recent retrospective analysis, gram-negative bacilli were also found to be the most common cause of nosocomial pneumonia in patients who underwent thoracotomy for lung cancer.[5] It is possible that lung cancers and their therapy, as well as surgical interventions, may shift the normal flora colonizing the upper respiratory tract, resulting in a more prominent gram-negative component that is likely to cause subsequent lower tract infection.

Fungal infections have also become increasingly recognized in the setting of lung cancer. In a very recent retrospective analysis, investigators attempted to identify risk factors associated with nosocomial fungal infections. Patients with lung cancer, those with a history of receiving chest radiotherapy, and those on chemotherapy were identified to be at a high risk for fungal infections.[6]

Diagnosis of Infection in Lung Cancer

In patients with lung cancer, the diagnosis of pulmonary infection may be difficult. These patients often present with nonspecific pulmonary symptoms that could be related to their underlying chronic obstructive lung disease-a common comorbid condition in this population-or from their lung malignancy. Radiologic abnormalities such as pleural effusion, atelectasis, and changes from radiation therapy may also complicate the diagnosis of infection in these patients. Chemotherapy and radiation therapy used for the treatment of lung cancer can also cause fever and radiographic abnormalities similar to the clinical picture of infectious pneumonitis. Given that the treatment for radiation- or drug-induced pneumonitis is different from that of infectious pneumonitis, Seo appropriately stresses that biopsy is needed for the diagnosis and management of these patients.

Newer chemotherapeutic agents such as the pyrimidine antagonist gemcitabine (Gemzar) and the taxanes can cause hypersensitivity pneumonitis, and patients can present with cough and dyspnea.[7] Interstitial lung disease also is an infrequent side effect of epidermal growth factor receptor (EGFR) inhibitors that are now used in the treatment of adenocarcinoma of the lung. The frequency of interstitial lung disease-type events in Japanese patients (1.9%) appears to be higher than in the rest of the world (0.3%). On the other hand, bronchoalveolar cell carcinoma often appears as an alveolar infiltrate mimicking bacterial pneumonia.

Again, aggressive pursuit of a diagnosis with bronchoalveolar lavage and a biopsy, if necessary, is advocated in order to guide specific therapy.

Surgical and Radiation Therapy- Related Infections

In recent years, the use of lungconserving surgery and the availability of video-assisted thoracoscopic surgery is associated with a reduction in surgical morbidity especially in selected patients, such as those who are elderly and have significant medical comorbidity. Newer techniques, such as three-dimensional conformal radiotherapy and intensity-modulated radiotherapy, are essentially improved techniques to deliver external-beam radiotherapy more accurately and with fewer side effects.

Neutropenia and Infection in NSCLC

A review of clinical trials in non- small-cell lung cancer (NSCLC) is a useful adjunct to Seo's paper. Platinum- based doublets are the current standard of care for adjuvant and advanced- stage lung cancer treatment. The combination of platinum with newer third-generation chemotherapeutic agents (gemcitabine, vinorelbine [Navelbine], and taxanes) is frequently used and is associated with a better response rate and longer median survival time compared to older combination regimens.

Neutropenia is an adverse event often associated with cytotoxic chemotherapy, but neutropenia and other toxicities are less often seen with these newer combinations. In the International Adjuvant Lung Cancer Trial using a cisplatin doublet, at least one episode of grade 4 neutropenia was observed in 17.5 % of patients.[8] Less than 1% of patients died from toxicity of chemotherapy. In a phase III trial comparing different platinum-based regimens in advanced lung cancer, grade 3 and higher febrile neutropenia was seen in less than 10% of patients.[ 9] In the same trial, investigators saw grade 3 and higher infection in less than 5% of patients.

In another randomized controlled trial comparing chemotherapy with best supportive care (N = 725), a majority of patients died from progressive lung cancer, with less than 5% dying from complications of chemotherapy. Only one patient died from respiratory infection.[ 10] A recent study in advanced NSCLC (N = 264), assessing whether a combination of gemcitabine with eieither paclitaxel or vinorelbine was more effective than paclitaxel or vinorelbine alone in elderly patients and those with poor performance status, reported grade 4 and febrile neutropenia in less than 5% of patients.[11]

Novel Treatment Approaches

Novel approaches to the treatment of lung cancer might be expected to result in fewer infectious complications if they are associated with less cytotoxicity than currently used standard regimens. The cytoprotective agent amifostine (Ethyol) has been shown to reduce the severity and incidence of acute esophageal, pulmonary, and hematologic toxicity resulting from concurrent cisplatin-based chemotherapy and radiotherapy for inoperable locally advanced NSCLC.[12]

The novel agents erlotinib (Tarceva) and geftinib (Iressa)[13] are orally available, potent, reversible, and selective inhibitors of EGFR tyrosine kinase, approved as second- and thirdline agents, respectively, for NSCLC after disease progression on standard chemotherapy. In a recent randomized trial,[14] a response rate of 12% was seen in geftinib-treated patients who had received at least two prior therapies. In another placebo-controlled trial (N = 731), patients randomized to erlotinib (n = 488) with advanced stage III or IV NSCLC who had progressive disease after standard chemotherapies showed improved symptoms (slower progression of cough, breathing problems, and pain) and increased survival.[15] These drugs were not associated with any significant neutropenia or infections.

Management of Infection

Newer antimicrobial agents, including antifungals such as voriconazole (Vfend) and antibiotics such as carbapenems and fourth-generation cephalosporins have become available in recent years. In lung cancer patients with obvious pulmonary infection, antimicrobial agents should be started empirically and later modified upon availability of microbiologic data.

Patients who are not neutropenic when diagnosed with pulmonary infection will generally have microorganisms similar to those of community-acquired respiratory infections and are managed similarly. Neutropenic patients may lack both symptoms and physical findings of pneumonia, due to blunted inflammatory response. If they are febrile or show evidence of specific infection, they are managed similarly to other cancer patients with chemotherapy-induced fever and neutropenia, ie, with empiric broad-spectrum antibiotics that have excellent gram-negative activity.

Use of Growth Factors

Hematopoietic growth factors are increasingly used to prevent infections, although their use is limited for most lung cancer regimens. For highly cytotoxic chemotherapy regimens, granulocyte colony-stimulating factor (G-CSF [Neupogen]) has been shown to reduce episodes of febrile neutropenia by as much as 50%, with reductions in antibiotic use and hospitalization rates. A baseline incidence of febrile neutropenia of at least 40% from a particular chemotherapy regimen is necessary in order for prophylactic growth factors to have a significant impact in terms of cost-benefit and cost-effectiveness.[16] For less toxic regimens, it is not worthwhile to provide prophylactic growth factors. The pegylated form of G-CSF (pegfilgrastim [Neulasta]) offers the convenience of weekly administration rather than daily administration and is used increasingly for prophylaxis.

Therapeutic use of G-CSF is less well-substantiated in terms of benefits and should be limited to patients with severe infections. It is probably reasonable to treat those with hypotension, sepsis syndrome, pneumonia, invasive fungal infections, and uncontrolled primary disease who have not responded to standard antimicrobials.

Outcomes and Prevention

Infectious complications may adversely affect outcome in lung cancer. In a retrospective study, a decrease in median survival was seen in patients with pulmonary infection when compared to patients with no infection (4.2 vs 12.9 months, P < .05).[17] Resistant pathogens may emerge that are difficult to treat with standard antimicrobial agents. For this reason, routine antibiotic prophylaxis is not recommended, even in immunocompromised patients. Delays in diagnosis, as outlined above, may allow infections to progress unabated. Therefore, efforts are being made not only to reliably diagnose, but also to prevent and treat various infections seen in cancer patients, including those with lung cancer. Standard adult vaccinations are recommended for prophylaxis against influenza and pneumococcal disease.

In conclusion, infections in patients with lung cancer not only cause significant morbidity but also significantly impair quality of life. Early recognition and treatment of these infections can prevent morbidity and mortality from these infections in lung cancer patients.

Disclosures:

Dr. Freifeld is a consultant for and has received a research grant from Enzon, Inc, and is a member of the speaker’s bureaus for Pfizer and Merck.

References:

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