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Original Research: LUNG CANCER |

Impact of Preoperative Chemotherapy on Pulmonary Function Tests in Resectable Early-Stage Non-small Cell Lung Cancer FREE TO VIEW

M. Patricia Rivera, MD, FCCP; Frank C. Detterbeck, MD, FCCP; Mark A. Socinski, MD, FCCP; Dominic T. Moore, PhD; Martin J. Edelman, MD; Thierry M. Jahan, MD; Rafat H. Ansari, MD; James D. Luketich, MD, FCCP; Guangbin Peng, MS; Matthew Monberg, MS; Coleman K. Obasaju, MD, PhD; Richard J. Gralla, MD
Author and Funding Information

*From the Multidisciplinary Thoracic Oncology Group (Drs. Rivera, Socinski, and Moore), Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC; Yale Comprehensive Cancer Center (Dr. Detterbeck), Yale University, New Haven, CT; University of Maryland Greenebaum Cancer Center (Dr. Edelman), Baltimore, MD; University of California San Francisco (Dr. Jahan), San Francisco, CA; Michiana Hematology/Oncology (Dr. Ansari), South Bend, IN; University of Pittsburgh Physicians (Dr. Luketich), Pittsburgh, PA; Eli Lilly and Company (Mr. Peng, Mr. Monberg, and Dr. Obasaju) Indianapolis, IN; and North Shore-Long Island Jewish Health System (Dr. Gralla), Lake Success, NY.

Correspondence to: M. Patricia Rivera, MD, University of North Carolina Pulmonary and Critical Care Medicine, 4133 Bioinformatics, Chapel Hill, NC 27599-7248; e-mail: mprivera@med.unc.edu


This study was sponsored by Eli Lilly and Company. Preliminary results were previously presented at the 2005 American Society for Clinical Oncology meeting.

Drs. Rivera, Detterbeck, Socinski, Moore, and Ansari have no conflicts of interest to disclose. Dr. Edelman has received consulting fees, research funds, and honoraria from Eli Lilly and Bristol-Myers Squibb. Dr. Jahan discloses consulting with Poniard and stock ownership with Biogen and Hana. Dr. Luketich has received research grants, stock, consulting fees, and honoraria from various companies. Mr. Peng discloses employment and stock ownership with Eli Lilly. Drs. Monberg and Obasaju disclose employment and stock ownership with Eli Lilly. Dr. Gralla discloses prior consulting with Eli Lilly.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).


© 2009 American College of Chest Physicians


Chest. 2009;135(6):1588-1595. doi:10.1378/chest.08-1430
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Background:  Several chemotherapy agents, including gemcitabine and paclitaxel, have been reported to cause interstitial pneumonitis. The incidence of pulmonary toxicity from the combination of gemcitabine and paclitaxel is reported to be approximately 5%. In this report, pulmonary function test (PFT) results were analyzed from two similar randomized phase 2 trials that tested platinum and nonplatinum regimens preoperatively in patients with stage I or II non-small cell lung cancer (NSCLC).

Methods:  The regimens included gemcitabine plus carboplatin, paclitaxel, or cisplatin. PFT and dyspnea scores were obtained at baseline and postchemotherapy, and were compared to one of several secondary end points, including ability to undergo surgical resection.

Results:  Baseline PFT scores varied with smoking status. Mean levels of diffusing capacity of the lung for carbon monoxide (Dlco) adjusted for hemoglobin declined 8% from pre- to postinduction (Wilcoxon signed rank test, p < 0.0001). Changes in FVC, FEV1, and total lung capacity were not statistically significant after chemotherapy. Although 27% of patients in the study had some reduction in PFT results, only 2 of the 85 eligible patients did not undergo surgery due to PFT reduction following chemotherapy. One patient in the study experienced a clinically significant respiratory toxicity (grade 3 dyspnea). Pulmonary toxicity was only statistically associated with male gender.

Conclusion:  In the preoperative setting, gemcitabine-based chemotherapy was well tolerated. The most commonly affected PFT parameter postchemotherapy was the Dlco. Although 15% of patients had a significant reduction in the Dlco postchemotherapy, it did not correlate with clinical symptoms or affect the ability to undergo surgical resection.

Survival outcomes following surgical resection are not optimal in patients with early stage (stage I or II) non-small cell lung cancer (NSCLC).1 Neoadjuvant chemotherapy (prior to surgery) may be beneficial, but this approach has been studied26 predominately in patients with stage III disease. Several issues7 related to neoadjuvant treatment still need to be addressed, including whether regimens used for advanced disease are safe preoperatively, whether more effective chemotherapy regimens can be identified, and whether this aggressive combined-modality approach affects patients' quality of life after the completion of treatment.

The risks and benefits of neoadjuvant chemotherapy are especially important in patients with earlier stage disease.8,9 The lung is a common target of chemotherapy toxicity, and a variety of treatments have been recognized10,11 as causative agents in lung injury. Although the incidence of clinically significant pulmonary toxicity with most agents is low (< 5%),12 pulmonary function tests (PFTs) provide the opportunity for detection of drug-associated pulmonary toxicity prior to its clinical manifestation.10

Gemcitabine (Gemzar; Eli Lilly and Company; Indianapolis, IN), a pyrimidine antimetabolite,13 is used13,14 widely to treat a number of diseases, including advanced NSCLC.1517 Gemcitabine-related pulmonary toxicity has been reported previously.1820 Among 41 patients with diverse cancer types,21 treatment with gemcitabine plus carboplatin was associated with a modest, mostly asymptomatic decrease in diffusion capacity, which was reversible. Paclitaxel and carboplatin also are capable of similar pulmonary changes.22 Further, hypersensitivity pneumonitis has been reported23 in patients with advanced NSCLC treated with gemcitabine plus paclitaxel.

The Gemcitabine in Neoadjuvant Early-Stage Trials project is a series of phase 2 trials24 that evaluates three chemotherapy regimens administered as three cycles prior to surgery. The project's design allows patients to be assigned to treatment without investigator bias and permits a relatively small number of patients to be enlisted to determine the likelihood of either inferior or superior results with a regimen.24 Prior reports from this study have focused on clinical response24 and quality of life25 associated with neoadjuvant treatment. The present study assesses the impact of chemotherapy before and after treatment on lung function in a surgical population and the impact of pulmonary function abnormalities on surgical risk after induction chemotherapy.

Patient Selection

Another study24 associated with this project describes patient selection criteria in detail. Of interest, the present trial enrolled patients with stage I or II NSCLC, a negative mediastinal evaluation, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, adequate organ function, and age ≥ 18 years. Adequate lung function was required to be eligible for surgical resection. Patients were excluded if they had previously received chemotherapy or radiation for NSCLC, bronchioloalveolar carcinoma, or stage IIB tumor involving the superior sulcus (Pancoast tumors). The study was approved by the institutional review board of each participating institution, and all patients provided informed consent.

Chemotherapy Treatment and Surgery

Patients were randomized to receive neoadjuvant therapy in one of two similar, multicenter, phase 2 clinical trials. Patients in the first trial were randomized to receive gemcitabine, 1,000 mg/m2, on days 1 and 8, followed by cisplatin, 80 mg/m2, or carboplatin at an area under the curve of 5.5 on day 1. Patients in the second trial were randomized to receive gemcitabine, 1,000 mg/m2, on days 1 and 8 followed by paclitaxel, 200 mg/m2, or carboplatin at an area under the curve of 5.5 on day 1. Treatment cycles were repeated every 21 days for three cycles. Carboplatin dosing was based on data from the study by Calvert et al.26

Between 2 and 6 weeks after the last dose of chemotherapy, patients underwent surgical resection. Patients with clear evidence of progressive disease before the third cycle of therapy could proceed to surgery sooner, if resectable. Every effort was made to carry out a complete resection if the tumor was resectable. Extent of surgical resection (lobectomy, bilobectomy, or pneumonectomy) was performed based on the prechemotherapy CT scan. Before each course of chemotherapy, a physical examination was performed and respiratory symptoms recorded. Toxicity was evaluated according to National Cancer Institute Common Toxicity Criteria (CTC) version 2.0.27 Radiologic response and quality of life assessment using the Lung Cancer Symptom Scale (LCSS) were performed as specified in earlier reports24,25 of this project.

Pulmonary Assessment

Baseline assessments of lung function with PFTs and arterial blood gas (ABG) measurements were performed within 28 days of randomization to chemotherapy. PFTs consisted of spirometry to measure FVC, FEV1, and forced expiratory flow, midexpiratory phase (FEF25–75%); lung volumes performed using body-box plethysmography to measure total lung capacity (TLC), functional residual capacity, and residual volume (RV); and diffusing capacity for carbon monoxide (Dlco) using the single-breath breath-holding technique. Dlco was adjusted for actual hemoglobin concentration and for alveolar volume (VA) according to American Thoracic Society guidelines.28 ABG measurements assessed Po2, Pao2 and Paco2, and pH. At the end of three cycles of induction chemotherapy, a CT scan was performed and tests repeated. If there was a drop of > 20% in FVC, FEV1, or Dlco, patients underwent additional investigation, which included cardiopulmonary exercise testing. To be eligible for surgery, patients required an FEV1 and a Dlco > 40% predicted or an exercise test result with a maximum oxygen capacity of > 15 mL/kg/min.

Results for FVC, FEV1, TLC, functional residual capacity, RV, and Dlco were reported as the percentage of the predicted value for each patient based on age, gender, and height, whereas the FEV1/FVC ratio was reported as an absolute percentage. According to standards of the American Thoracic Society29 and the European Respiratory Society,30 baseline values of the FEV1/FVC ratio < 75% indicate obstructive airway disease, TLC < 80% predicted indicates restrictive lung disease, and adjusted Dlco < 80% predicted indicates diffusion impairment. In this protocol, pulmonary toxicity was defined as a ≥ 20% decrease in FVC or ≥ 20% decrease in Dlco at the postinduction chemotherapy visit compared with the baseline visit.31,32 PFT changes were reported as the difference between baseline and postinduction values.

Statistical Analysis

Changes in PFT values were analyzed using the Wilcoxon signed rank test, with p ≤ 0.05 considered to be statistically significant and p > 0.05 as nonsignificant. To determine which features might be predictive of PFT scores and whether PFT scores affected patient outcomes, baseline characteristics, assignment to treatment, surgical procedure, response outcomes, and LCSS dyspnea subscale scores were reported for patients with and without pulmonary toxicity. To determine the effect of smoking on PFT scores, smoking status was determined by retrospective chart review. Patients with a smoking history were classified as minimal smokers (< 10 pack-years), medium smokers (10 to 30 pack-years), or heavy smokers (> 30 pack-years), and former smokers were classified by quitting ± 5 years prior to enrollment. All statistical analyses were performed using statistical software (SAS version 9.1.3; SAS Institute Inc; Cary, NC). Ninety-five percent confidence intervals were calculated where appropriate, using exact binomial proportions.

Patients

Between June 2001 and December 2004, 87 patients with stage I or II NSCLC were accrued at 16 investigational centers in the United States. Twelve patients were assigned to receive gemcitabine plus cisplatin, 35 to receive gemcitabine plus paclitaxel, and 40 to receive gemcitabine plus carboplatin. All 87 patients received at least one dose of the study drug. Baseline characteristics and patient disposition for all three treatment groups are summarized in Table 1. The median age of all patients was 62 years, and 75% had an ECOG performance status of 0. Almost half of patients (49%) had stage IB disease. Among all patients, 39% had squamous cell carcinoma, 36% had adenocarcinoma, 17% had disease not otherwise specified, and 2% had large cell carcinoma. Twenty-nine percent of patients had abnormal ECG findings at baseline. Smoking status was determined for 74% of patients, with 9% classified as never-smokers, 7% as minimal smokers, 30% as medium smokers, and 28% as heavy smokers.

Table Graphic Jump Location
Table 1 Patient Characteristics*

*Values are given as mean ± SD or No. (%), unless otherwise indicated. NOS = not otherwise specified.

Lung Function Before and After Chemotherapy

Of 87 patients enrolled in the intent-to-treat population, 1 experienced grade 3 or 4 respiratory CTC toxicity as a result of chemotherapy (grade 3 dyspnea). Two of 85 patients (2%) eligible for surgery did not undergo surgery due to a reduction in PFT results following chemotherapy.

PFT and ABG values at baseline and their change after induction chemotherapy are summarized in Table 2. Mean PFT values indicated mild pulmonary impairment at baseline. Mean adjusted Dlco and FEV1/FVC ratio were slightly below normal ranges. No impairment in lung volume parameters (RV or TLC) was noted prior to induction chemotherapy. A subset of patients (n = 7) had unusually high ABG values as a result of measurements recorded while these patients were receiving oxygen.

Table Graphic Jump Location
Table 2 PFT and ABG Values at Baseline and After Chemotherapy*

*Values are given as mean ± SD, unless otherwise indicated.

Baseline and postinduction chemotherapy FVC and Dlco values were recorded for 73 patients (84%). Of these, 20 patients (27%; 95% confidence interval, 17.6 to 39.1) met the protocol definition of pulmonary toxicity based on reduction of FVC (3 patients) or Dlco (19 patients). Ten patients (14%) had a postinduction chemotherapy Dlco ≤ 40% predicted (within this subgroup, average decrease in Dlco was 17.4%). Following the completion of chemotherapy, lung volume and ABG values were not significantly changed from baseline. Specific measures of pulmonary function (including Dlco, Dlco adjusted for VA [Dlva], FEV1/FVC ratio, and FEF25–75%), however, were statistically lower (p ≤ 0.05). Of all parameters, mean levels of Dlco adjusted for hemoglobin were the most reduced, declining 8% from baseline to postinduction chemotherapy (p < 0.0001). Changes in FVC, FEV1, and TLC were not statistically significant after chemotherapy.

Table 3 summarizes baseline and change from baseline scores according to patient smoking history. Pulmonary impairment at baseline was generally greater for the patients who were heavy smokers. Baseline Dlco scores were 85.2% predicted for never-smokers or minimal smokers, 75.8% predicted for medium smokers, and 68.8% predicted for heavy smokers. Reduction in percent predicted Dlco was significant for medium smokers (p = 0.002) and heavy smokers (p = 0.03) but not for never-smokers or minimal smokers. Dlva and percent predicted FEV1 were lowest at baseline for heavy smokers, and change in FEV1/FVC ratio following chemotherapy was only significant for heavy smokers.

Table Graphic Jump Location
Table 3 Summary of Pulmonary Function Changes by Smoking History*

*Values are given as mean ± SD, unless otherwise indicated.

†Smoking history < 10 pack-years.

‡Smoking history 10 to 30 pack-years.

§Smoking history > 30 pack-years.

Table 4 summarizes baseline and change from baseline scores according to the time since the patient quit smoking. Baseline Dlco, Dlva, and FEV1/FVC ratio were reduced for never-quitters compared with those who had quit > 5 years ago or ≤ 5 years ago. Reduction in percent predicted Dlco following chemotherapy was significant for those who had quit > 5 years ago (p = 0.004) and ≤ 5 years ago (p = 0.002), but not for those who had never quit. Reduction in FEV1/FVC ratio was significant for those who never quit but not for those who had quit.

Table Graphic Jump Location
Table 4 Summary of Pulmonary Function Changes Among Ever-Smokers by Time Since Quit Smoking*

*Values are given as mean ± SD, unless otherwise indicated.

Pulmonary Toxicity

Table 5 summarizes similarities and differences between patients with (n = 20) and without (n = 53) pulmonary toxicity for patient characteristics and outcomes. The only statistically significant difference between patients with and without pulmonary toxicity was male gender, which was associated with a greater likelihood of pulmonary toxicity (p < 0.05). A similar percentage of patients in both groups were never-smokers. At baseline, patients who experienced pulmonary toxicity had a mean LCSS dyspnea subscore of nearly 10 points less than patients who did not experience pulmonary toxicity (difference was not statistically significant). Following induction therapy, LCSS dyspnea scores were similar between patients with and patients without pulmonary toxicity.

Table Graphic Jump Location
Table 5 Summary of Patients With and Without Pulmonary Toxicity Prior to Surgery*

*Values are given as No. (%) or mean ± SD, unless otherwise indicated. Pulmonary toxicity was defined as a ≥ 20% decrease in FVC or ≥ 20% Dlco at the postinduction visit compared with the baseline visit.

†Values given as median/mean ± SD. Indicates that the comparison between groups is statistically significant (p < 0.05).

‡Dyspnea symptoms were measured on a 100 mm visual analog scale, with scores reported from 0 (no impairment) to 100 (maximum impairment).

Table 6 summarizes surgical results by pulmonary toxicity status. A greater percentage of patients with pulmonary toxicity did not undergo surgery (20% vs 8%); however, differences in surgical types and response outcomes were not statistically different. The most common complication related to surgery was generalized pain, which occurred in 34% of patients without pulmonary toxicity and 25% of patients with pulmonary toxicity, and chest pain, which occurred in 13% of patients without pulmonary toxicity.

Table Graphic Jump Location
Table 6 Surgical Results by Pulmonary Toxicity Status*

*Values are given at No. (%). Pulmonary toxicity was defined as a ≥ 20% decrease in FVC or ≥ 20% Dlco at the postinduction visit compared with the baseline visit.

In the preoperative setting, administration of gemcitabine-based chemotherapy was safe with respect to lung toxicity. The most commonly affected PFT parameter following chemotherapy was Dlco. Although there was an 8% reduction in adjusted Dlco, this reduction did not correlate with clinical symptoms, have an impact on the ability to undergo surgical resection, or increase the risk for surgical complications. Patients with and without FVC or Dlco impairment were similarly distributed among types of surgical procedures. Although gemcitabine plus paclitaxel is a combination therapy that has been previously associated with pulmonary toxicity,23 in the current study there was no difference in type of chemotherapy between patients with and patients without pulmonary toxicity.

Only one patient in this study experienced grade 3 or 4 respiratory CTC toxicity as a result of chemotherapy (grade 3 dyspnea), suggesting that respiratory impairment was largely subclinical. Although 27% of patients in the study had some reduction in PFT scores, only 2 of 85 patients (2%) eligible for surgery did not undergo surgery due to PFT measurement reduction following chemotherapy. Most changes in spirometry, lung volumes, or ABG values were not statistically significant.

These results are consistent with those of other studies21,33 that have shown reductions in Dlco but not other pulmonary variables following gemcitabine-based chemotherapy. In those studies, PFT reductions were subclinical and reversible. A multiple regression analysis from Dimopoulou et al21 showed that the change in Dlco after therapy was associated with older age, female gender, and lower baseline Dlco. In the current study, none of these variables was associated with PFT score reduction. Instead, male gender was the only statistically significant variable associated with pulmonary toxicity. Although previous studies23 have suggested that interstitial pneumonitis may be a particular concern associated with gemcitabine-plus-paclitaxel therapy, toxicity in the current study was not associated with any specific regimen.

Changes in FVC and FEV1 may be important predictors of the response to chemotherapy.34 In our study, chemotherapy did not significantly affect FVC or FEV1. Further, pulmonary toxicity was not significantly related to surgical outcome, response, or LCSS score. All patients enrolled had PFT evaluation prior to enrollment and were deemed surgical candidates based on predicted postoperative lung function (ie, predicted postoperative FEV1 and predicted postoperative Dlco). Patients with preoperative lung function that may have altered treatment or surgery were selected out. As such, it may not be surprising that PFT score changes were not correlated with short-term patient outcome.

Mean adjusted Dlco and FEV1/FVC ratio at baseline levels were slightly below normal accepted ranges.28 Baseline impairments in FVC or Dlco were greatest in current smokers and heavy smokers, suggesting that some lung impairment was present prior to intervention with induction chemotherapy. Patients with pulmonary toxicity had greater worsening of LCSS score following induction. The consistency of PFT and LCSS dyspnea values suggests that quality-of-life scales may be another option for assessment of subclinical impairment and that the use of both PFT and LCSS measurements is feasible. The current data indicate that PFT assessment is an effective method to detect pulmonary changes that may not be clinically evident in patients with early- stage NSCLC undergoing preoperative treatment with gemcitabine-containing regimens.

Neoadjuvant chemotherapy in patients with early- stage NSCLC remains controversial due to the lack of available data from definitive trials.35 The current study suggests that pulmonary toxicity does not hinder surgical resectability, does not change the risk of postoperative complications, and should not preclude further evaluation of this strategy in patients with early-stage disease.

ABG

arterial blood gas

CTC

Common Toxicity Criteria

Dlco

diffusing capacity of the lung for carbon monoxide

Dlva

diffusing capacity of the lung for carbon monoxide adjusted for alveolar volume

ECOG

Eastern Cooperative Oncology Group

FEF25–75%

forced expiratory flow, midexpiratory phase

LCSS

Lung Cancer Symptom Scale

NSCLC

non-small cell lung cancer

PFT

pulmonary function test

RV

residual volume

TLC

total lung capacity

VA

alveolar volume

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National Cancer Institute Gefitinib in treating patients who are undergoing surgery for stage I, stage II, or stage III non-small cell lung cancer.Accessed May 7, 2009 Available at:http://www.cancer.gov/clinicaltrials/MCC-13922.
 
Depierre A, Milleron B, Moro-Sibilot D, et al. Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non-small-cell lung cancer. J Clin Oncol. 2002;20:247-253. [PubMed]
 
Martini N, Kris MG, Flehinger BJ, et al. Preoperative chemotherapy for stage IIIa (N2) lung cancer: the Sloan-Kettering experience with 136 patients. Ann Thorac Surg. 1993;55:1365-1373. [PubMed]
 
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Figures

Tables

Table Graphic Jump Location
Table 1 Patient Characteristics*

*Values are given as mean ± SD or No. (%), unless otherwise indicated. NOS = not otherwise specified.

Table Graphic Jump Location
Table 2 PFT and ABG Values at Baseline and After Chemotherapy*

*Values are given as mean ± SD, unless otherwise indicated.

Table Graphic Jump Location
Table 3 Summary of Pulmonary Function Changes by Smoking History*

*Values are given as mean ± SD, unless otherwise indicated.

†Smoking history < 10 pack-years.

‡Smoking history 10 to 30 pack-years.

§Smoking history > 30 pack-years.

Table Graphic Jump Location
Table 4 Summary of Pulmonary Function Changes Among Ever-Smokers by Time Since Quit Smoking*

*Values are given as mean ± SD, unless otherwise indicated.

Table Graphic Jump Location
Table 5 Summary of Patients With and Without Pulmonary Toxicity Prior to Surgery*

*Values are given as No. (%) or mean ± SD, unless otherwise indicated. Pulmonary toxicity was defined as a ≥ 20% decrease in FVC or ≥ 20% Dlco at the postinduction visit compared with the baseline visit.

†Values given as median/mean ± SD. Indicates that the comparison between groups is statistically significant (p < 0.05).

‡Dyspnea symptoms were measured on a 100 mm visual analog scale, with scores reported from 0 (no impairment) to 100 (maximum impairment).

Table Graphic Jump Location
Table 6 Surgical Results by Pulmonary Toxicity Status*

*Values are given at No. (%). Pulmonary toxicity was defined as a ≥ 20% decrease in FVC or ≥ 20% Dlco at the postinduction visit compared with the baseline visit.

References

van Rens MT, de la Riviere AB, Elbers HR, et al. Prognostic assessment of 2,361 patients who underwent pulmonary resection for non-small cell lung cancer, stage I, II, and IIIA. Chest. 2000;117:374-379. [PubMed] [CrossRef]
 
National Cancer Institute Gefitinib in treating patients who are undergoing surgery for stage I, stage II, or stage III non-small cell lung cancer.Accessed May 7, 2009 Available at:http://www.cancer.gov/clinicaltrials/MCC-13922.
 
Depierre A, Milleron B, Moro-Sibilot D, et al. Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non-small-cell lung cancer. J Clin Oncol. 2002;20:247-253. [PubMed]
 
Martini N, Kris MG, Flehinger BJ, et al. Preoperative chemotherapy for stage IIIa (N2) lung cancer: the Sloan-Kettering experience with 136 patients. Ann Thorac Surg. 1993;55:1365-1373. [PubMed]
 
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