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Winthrop-University Hospital, Mineola, New York
INTRODUCTION
This is the first of four executive summaries from the Clinical Year in Review presented at the 2005 International Meeting of the American Thoracic Society. The salient points of each talk have been abstracted by the session chair. In all, 16 topics presented will be summarized in the next 6 months.
LUNG CANCER
M. Patricia Rivera
Division of Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
Five articles of importance published this past year were highlighted. Two such articles addressed the role of adjuvant therapy in the treatment of early stage non–small cell lung cancer (NSCLC). The first such study (1) was a multicenter randomized phase III study of 1,867 patients with pathologically documented stage I, II, and III NSCLC who had undergone complete surgical resection. Patients were then randomized to chemotherapy (cisplatin + either vindesine, vinblastine, or etoposide at individual clinician's discretion) or to a control group who received no chemotherapy. Dosing and concomitant use of radiotherapy was left to the discretion of the enrolling center. The primary endpoint was 5-year survival, and a statistical (albeit small) difference in favor of chemotherapy was noted (44.5% vs. 40.4%; hazard's ratio, 0.86; p = 0.03). Patients assigned to the chemotherapy arm had a significantly higher disease-free survival rate (39.4% vs. 34%) at 5 years. Seven patients (0.8%) died of chemotherapy-induced toxic effects, and 22.6% in the chemotherapy group had at least one episode of grade 4 toxicity. Although the limitations of this trial have been addressed (2), in properly selected patients adjuvant therapy appears to offer a survival advantage. In the second clinical trial (3), 979 patients with resected stage I adenocarcinoma were studied in a randomized strategy employing oral uracil-tegafur (UFT) (491 patients) administration or observation (488 patients). Follow-up over 73 months revealed a statistically significant survival advantage for those receiving UFT (p = 0.04). Toxicities were infrequent, with grade 3 toxicity seen in only 22 of the treated patients, making this a promising strategy.
The role of pemetrexed as an adjuvant to docetaxel in patients with NSCLC who had been previously treated with chemotherapy and relapsed was the subject of another important study this year (4). This randomized study examined 571 such patients who received either docetaxel or pemetrexed. Overall no significant differences in response rates or median survival were noted, with 1-year survival rate in each group at 29.7%. However, toxicities were lessened in the pemetrexed group, sparing patients more often from neutropenia, febrile neutropenia, hospitalization for neutropenic fever, and all grade alopecia, suggesting a role for this agent in these patients.
Two studies of significance focused on the role of epidermal growth factor receptor (EGFR) mutations in NSCLC treatment strategies. In the first (5), Lynch and coworkers examined somatic mutations in EGFR and assessed functional consequences in patients with geftinib (an inhibitor of the tyrosine kinase domain of EGFR)-responsive lung cancer. Eight of nine such patients had heterozygous mutations in the tyrosine kinase domain of EGFR. All had enhanced in vitro activity of tyrosine kinase in response to EGF, with increased sensitivity to inhibition with geftinib. This work raises the possibility of "customized chemotherapy" in the future based on individual genetic predisposition. In the final study (6), the role of the EGFR inhibitor erlotinib in patients with advanced stage NSCLC was assessed in a phase II trial of 731 patients. All had previously been treated with chemotherapy. Randomization to erlotinib or placebo in a 2:1 fashion was employed. Statistically and clinically relevant differences were seen in survival and progression-free survival over a median duration of 34 weeks. Rash and diarrhea were the most common side effects, with 5% of the patients discontinuing erlotinib due to toxicity versus 2% in the placebo group.
INTERVENTIONAL PULMONOLOGY
Atul Mehta
Department of Pulmonary, Allergy, and Critical Care Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio
The impact that an educational program can have on reducing equipment maintenance and repair costs at an interventional pulmonary training program in an era of fiscal constraints was the subject of a recent study (7). This retrospective study covering the 3 preceding years at the Beth Israel Deaconess Medical Center culled data and compared it to the 5 years after institution of an educational program aimed at reducing repair costs. At baseline, $42/procedure in repair costs was noted, and this was reduced to $8/procedure after the institution of the education program. The majority of the cost savings were encountered in the prevention of fiberoptic bronchoscope damage.
Exciting developments are occurring in the arena of bronchoscopic lung-volume reduction (LVR) using one-way valves, and although still in its infancy, growing interest in offering the benefits of LVR to patients who are not operative candidates has spurred the development of valves designed to be placed by the bronchoscopist. In a recent study by Venuta and colleagues (8) of 13 patients who had such valves placed in the most hyperinflated parts of emphysematous lung (11 unilaterally, and 2 bilaterally) significant improvements in FEV1, residual volume, 6-minute walk distances, and a decrease in the Medical Research Council dyspnea score were observed. Forty-six percent were able to discontinue their supplemental oxygen use. Six complications occurred in three patients; two had bilateral pneumothoraces and one had a contralateral pneumothrorax. It is of concern that these all occurred in a delayed fashion.
Endobronchial ultrasound (EBUS) use has been limited historically by the single-channel design of the fiberoptic bronchoscope. A study published in 2004 (9) employed new technology allowing direct real-time biopsy with a convex ultrasound Doppler probe placed at the bronchoscope's distal end. This scope has a viewing angle of 30 degrees and a 2.2-m working diameter channel. In this pilot study, 70 patients underwent EBUS-guided biopsies (58 mediastinal, 12 hilar nodes). The sensitivity, specificity, and accuracy of the EBUS-guided technique were 95.7%, 100%, and 97.1%, respectively. No complications were noted. Although exciting, this technique requires a dedicated large bronchoscope that is difficult to manipulate and difficult to divert to the aorto-pulmonic window.
Peripheral lung lesions are historically difficult to sample by fiberoptic bronchoscopy, and as such represent a challenge for the practicing bronchoscopist. In an attempt to overcome this, an electromagnetic mapping technique to guide the bronchoscopist to the correct subsegments in three dimensions was presented by Becker and coworkers (10) in a pilot study of this technique. Electromagnetic navigation using an electromagnetic location board beneath the patient, a retractable sensor probe mounted on a flexible cable, and computer software allowed graphic representation on a monitor to let the bronchoscopist know where his biopsy forceps were in real-time. Using this aid, conclusive biopsies of peripheral lesions were obtained in 69% in 29 patients, comparing favorably to the 30 to 50% yields in simple fluoroscopic guided reports. One pneumothorax and three cases of minor self-limited bleeding occurred. This technique adds considerable time and expense and may not be widely applicable to all bronchoscopy centers.
NONINVASIVE MASK VENTILATION
Stefano Nava
Instituto Scientifico di Pavia, Fondazione S. Maugeri, Respiratory and Intensive Care Medicine, Pavia, Italy
The role of noninvasive mask ventilation (NIMV) in the treatment of respiratory failure from severe acute respiratory syndrome (SARS) was examined in a study by Cheung and colleagues (11). This was a retrospective observational study of patients affected in the Hong Kong epidemic. NIMV was applied to 20 out of 87 patients with coronavirus-induced respiratory failure. NIMV was applied 9.6 days on average from onset of illness, with a mean of 85 hours of use noted. Seventy percent avoided intubation with this strategy, and ICU length of stay was shorter than their intubated counterparts. Chest radiography scores also improved in the first 24 hours to a greater extent than in those intubated. Importantly, no infections were observed in the 105 health care workers caring for those on NIMV. Although uncontrolled and nonrandomized, these data lend credence to the safe use of NIMV in SARS.
The use of NIMV in "do-not-intubate" (DNI) patients was examined in an interesting study by Levy and coworkers (12). One hundred fourteen hospitalized patients with DNI status were studied, and a surprising 43% survived to discharge. Survivals were greatest in those with elevated PaCO2 at baseline and congestive heart failure and chronic obstructive pulmonary disease diagnoses. The study suggests that use of NIMV may be appropriate in DNI patients with reversible causes, but the authors cautioned that effects of NIMV on dyspnea and quality-of-life need further study.
Another important contribution to the field asked the question: "When is it appropriate to use NIMV if signs of respiratory failure are encountered after extubation?" (13). One hundred fourteen patients were assigned to NIMV and 107 to standard medical therapy. All patients had been extubated a minimum of 48 hours and then showed signs of respiratory failure within 2 days. The rate of reintubation was similar in the two groups, while the rate of death in the ICU was greater in the NIMV group. The median time from failure to reintubation was greater in the NIMV group, and this delay may indeed have been harmful. The study does not imply that NIVM ventilation is an ineffective tool to prevent the need for reintubation in patients at risk, even if this trial suggested it may not be an appropriate tool to treat respiratory failure once established.
Park and colleagues tackled a controversial area for NIMV use—its role in cardiogenic pulmonary edema (CPE) (14). Eighty patients with CPE were assigned to one of three treatment groups; continuous positive airway pressure (CPAP), bilevel NIMV, or oxygen use alone. Both CPAP and NIMV reduced dyspnea and heart rates and improved oxygenation to a greater degree than oxygen therapy alone. Forty-nine percent in the oxygen-alone group required intubation, whereas only 7% of the CPAP and NIMV groups required this (p = 0.001). Of importance no increase in the rate of acute myocardial infarction occurred in the ventilated groups. Mortality was higher at 15 days in the oxygen-treated patients, and the authors concluded that NIMV should be seen as a treatment and not just a supportive measure in this group of patients.
PULMONARY VASCULAR DISEASE
Terence K. Trow
Director, Pulmonary Hypertension Center, Winthrop-University Hospital, Mineola, New York
The study published by Pengo and coworkers (15) earlier this year gave us new information about the incidence and timing of pulmonary hypertension development after pulmonary embolism (PE). Whereas previous expert estimations of chronic thromboembolic pulmonary hypertension (CTPH) were 0.1% of those surviving PE, Pengo and colleagues report a 4% rate, underscoring that this dreaded complication occurs more often than previously believed. In addition, CTPH was felt in past reports to develop over many years and as a delayed phenomenon. This trial of 273 patients followed for up to 10 years revealed that all cases of CTPH occurred within 2 years of the acute PE event. Risk factors for the development of CTPH were a younger age at presentation, an idiopathic presentation, prior history of PE, and larger perfusion defects at PE onset.
There is growing realization that hemoglobinopathies can result in pulmonary hypertension (PH) at surprisingly high incidence, with potentially deleterious outcomes. Gladwin and colleagues (16) studied 195 patients with sickle cell disease (SCD) and 41 age- and sex-matched control subjects to gain insight into the likelihood and consequences of PH in these unfortunate patients. Patients were followed for 1.5 years. Transthoracic echocardiography criteria were used to establish a PH diagnosis, with tricuspid jet velocity (TJV) greater than 2.5 m/second considered diagnostic. Only 18 patients had right heart catheterization (RHC) confirmation of PH. The authors found that 32% of patients with SCD had PH, and that 17/18 undergoing RHC had confirmed PH. A striking increase in the rate of death for these patients was noted for patients with TJV greater than 2.5 m/second (hazards rate ratio, 10:1; p = 0.004). Elevated lactate dehydrogenase and alkaline phosphatase levels, low transferrin levels, systemic hypertension, and self-reported cardiovascular and renal disease appeared associated with PH development. Importantly, however, the absence of RHC confirmation of PH in the majority raises the possibility of overestimation of PH. In addition, pulmonary vascular resistances (PVR) in the 18 patients who did undergo RHC were surprisingly normal (1.8 Wood units), raising the possibility that high output or left-sided causes of PH may be at play in these patients with SCD, rather than true vasculopathy.
The recognition that sildenafil can have beneficial effects in patients with PH has stirred great interest in this therapeutic strategy. Although anecdotal reports abound in the literature, this year marks the first multicenter, double-blind, placebo-controlled trial of sildenafil in PH (17). Two hundred seventy-eight patients with idiopathic, connective tissue–related, or repaired congenital heart diseases with persistent PH were enrolled and randomized to placebo, sildenafil 20 mg three times a day, sildenafil 40 mg three times a day, or sildenafil 80 mg three times a day. At onset, and again at 12 weeks, pulmonary hemodynamics by RHC and 6-minute walk distances were recorded. Sildenafil demonstrated statistically significant improvements across all three doses in mean pulmonary artery pressure (PAPm), PVR, cardiac output, mean venous oxygen saturation, and 6-minute walk distances. This trial has validated in an important way the role of sildenafil as a treatment option for PH. Longer-term studies are needed to assess duration of benefit, and impact on survival.
The safety and efficacy of bosentan in the treatment of PH associated with human immunodeficiency virus (HIV) was explored by our French colleagues earlier this year (18). Sixteen patients were followed in a prospective uncontrolled trial over 16 weeks. Standard dosing of 125 mg twice daily of bosentan was attempted, though down-titration was allowed based on liver function and symptoms. Fifteen of the 16 were on concomitant highly active antiretroviral therapy (HAART). Sitbon and coworkers found that the treatment was generally well tolerated and that 6-minute walk distances improved by 91 meters (± 60 m). Borg dyspnea scores also improved, as did quality-of-life measures. Cardiac index, PVR, and PAPm all improved significantly. No obvious deletrious effects on viral loads were noted. This study was an important one despite its small size and uncontrolled design because it is our first experience with bosentan in HIV-associated PH indicating that endothelin-1 is mechanistically important in these patients. Larger studies examining drug–drug interactions with HAART medications are warranted.
FOOTNOTES
Conflict of Interest Statement: T.K.T. has spoken for Actelion in the past 3 years giving grand rounds, and dinner programs to educate the community on pulmonary hypertension in general.
* Co-Chair, Clinical Year in Review 
REFERENCES
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