John P. Griffin

Preoperative assessment of the high-risk patient for lung resection

BACKGROUND We wanted to determine if cardiopulmonary exercise testing could better identify the threshold where physiologic function is irreparably impaired for patients with borderline pulmonary function who are being considered for lung cancer resection. METHODS We performed an open, prospective preoperative trial and a postoperative outcome evaluation with a combined medical, surgical, and exercise physiology evaluation at three university hospitals. All eligible patients had spirometry, lung volume determination, and quantitative perfusion scanning and performed a cardiopulmonary stress test, stair climbing, and a 12-minute walk for distance. Functional status was determined with an Eastern Cooperative Oncology Group score, a dyspnea score, and a cardiopulmonary risk index. RESULTS We identified 12 patients who met strict criteria for borderline pulmonary function during a 1-year study period. The mean forced expiratory volume in 1 second (FEV1) was 1.38 L (48% of predicted). The mean predicted postoperative FEV1 based on pneumonectomy was 700 mL. Eleven of the patients did the stair climb and 10 passed. All 12 patients achieved a maximum oxygen consumption greater than or equal to 10 mL x kg(-1) x min(-1) (mean value, 13.8 mL x kg(-1) x min(-1)). Thirteen operations were performed on the 12 patients. Nine complications occurred in 7 patients. CONCLUSIONS Patients with borderline pulmonary function can undergo resection safely if they have an FEV1 equal to or greater than 1.6 L or 40% of its predicted value, a predicted postoperative FEV1 of 700 mL or more, a maximum oxygen consumption of 10 mL x kg(-1) x min(-1) or greater, or stair climbing of three flights or more. Cardiopulmonary stress testing and stair climbing add valuable clinical information for patients with an FEV1 of less than 1.6 L.

Pharmacodynamics of prolonged oral etoposide in patients with advanced non-small-cell lung cancer.

PURPOSE This study was undertaken to investigate the pharmacodynamic relationship between etoposide drug levels on 21-day oral treatment courses and hematologic toxicities in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Thirty-two patients with stage IIIB or IV NSCLC were treated with oral etoposide 50 mg/m2/d for 21 consecutive days in combination with cisplatin 100 mg/m2 on day 1. Treatment was repeated every 28 days for up to six courses. Patients had not received previous chemotherapy and had a performance status of 0 to 2. Patients were monitored weekly while on treatment for compliance with oral etoposide and toxicity, including complete blood cell counts, and a blood sample before the daily etoposide dose (drug trough levels). Etoposide concentrations were measured in the plasma by high-performance liquid chromatography (HPLC). RESULTS Three patients achieved a complete response (CR) and 10 patients a partial response for an objective response rate of 41% (95% confidence interval, 24% to 58%). The median survival was 4 months (range, 1 to 23). Neutropenia was dose-limiting, and two patients died of neutropenic sepsis. Pharmacodynamic correlations for drug concentrations and hematologic toxicities were available for 27 patients and a total of 76 treatment courses, and correlations were significant for graded hematologic toxicity and nadir counts of leukocytes, neutrophils, hemoglobin, and platelets. The grade of infection (77 courses) was also related to drug levels. Using data from 27 initial courses, a pharmacodynamic model was developed to estimate the nadir leukocyte or neutrophil count (WBCn, ANCn) based on the pretreatment count (WBCp, ANCp) and the etoposide concentration (Ec) as follows: WBCn = 0.35 (1 + WBCp x e-1.12 x Ec) and ANCn = 0.32 (1 + ANCp x e-2.47 x Ec). CONCLUSION Etoposide concentrations are related to the resulting hematologic toxicities. It is possible to predict nadir counts in the first course by a pharmacodynamic model. The above equations need to be validated prospectively and may be useful in future studies of prolonged oral etoposide.

Pharmacodynamics of three daily infusions of etoposide in patients with extensive-stage small-cell lung cancer.

SummaryThe objectives of this study were to define the pharmacodynamics of etoposide and to develop potentially useful models (1) to estimate the plasma clearance using a limited number of samples and (2) to describe the relationship between clearance and the dose-limiting toxicity. A total of 17 patients with extensive-stage small-cell lung cancer were treated with 150 mg/m2 etoposide daily for 3 consecutive days and with 100 mg/m2 cisplatin on day 3 only. Both drugs were given intravenously over 1 h. Treatment was repeated every 21 days for up to six courses. All patients were newly diagnosed (no previous chemotherapy or irradiation) and had a performance status of 0–2. Six patients achieved a complete response as confirmed by repeat bronchoscopy and five patients showed a partial response, for an overall objective response rate of 65% (95% confidence interval, 38%–87%). The median survival was 8 months (range, 1–24+ months). The dose-limiting toxicity was neutropenia. Etoposide pharmacokinetics were measured during the first course and determinations were repeated during courses 3 or 4 and 6. Complete blood counts were obtained weekly. Correlations for etoposide clearance and hematologic toxicities were evaluated for 17 initial courses and for an overall number of 33 courses. Pharmacodynamic correlations were significant for graded hematologic toxicities, as well as nadirs of leukocytes, neutrophils, and platelets for the initial courses and for all courses. To reduce the requirement for numerous blood samples, a limited sampling model was developed to estimate the area under the concentration versus time curve (AUC) with the following equation:

Diagnosis of lung cancer: a bronchoscopist's perspective.

AUC = 15.45 + 3.86 \times C_2 + 7.10 \times C_4 ,

The Standardization of Criteria for Processing and Interpreting Laboratory Specimens in Patients With Suspected Ventilator-Associated Pneumonia

where C2 and C4 represent the etoposide concentrations at 2 and 4 h, respectively. The total plasma clearance was calculated as the dose divided by the AUC; correlations with toxicity were better for clearance expressed in milliliters per minute than for that expressed in milliliters per minute per square meter of body surface area. The absolute neutrophil count at the nadir (ANCn) can be estimated by the following pharmacodynamic model, which is based on 33 courses:

Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: ACCP evidenced-based clinical practice guidelines (2nd edition)

ANC_n = 0.399 + 0.024 \times E_{cl} ,