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Preoperative chemotherapy for lung cancer does not increase surgical morbidity
Preoperative Chemotherapy for Lung Cancer Does Not Increase Surgical Morbidity Michael P. Siegenthaler, MD, Katherine M. Pisters, MD, Kelly W. Merriman, MS, Jack A. Roth, MD, Stephen G. Swisher, MD, Garrett L. Walsh, MD, Ara A. Vaporciyan, MD, W. Roy Smythe, MD, and Joe B. Putnam, Jr, MD Departments of Thoracic and Cardiovascular Surgery and Thoracic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
Background. Preoperative chemotherapy (CⴙS) for non–small cell lung cancer (NSCLC) has increased in an attempt to improve survival. Patients receiving CⴙS potentially may have an increase in postoperative morbidity and mortality compared with surgery alone (S). We reviewed our experience with CⴙS and S in a tertiary referral center. Methods. Three hundred eighty consecutive patients underwent lobectomy or greater resection for NSCLC between August 1, 1996, and April 30, 1999: 335 patients (259 S; 76 CⴙS) were analyzed; 45 additional patients were excluded for prior NSCLC, other chemotherapy for other malignancy, or radiation. We compared morbidity and mortality overall, and by subset analysis (clinical
stage, pathological stage, procedure, and by protocol use) for both CⴙS and S patients. Results. Demographics, comorbidities, and spirometry were similar. We noted no significant difference in overall or subset mortality or morbidity including pneumonia, acute respiratory distress syndrome, reintubation, tracheostomy, wound complications, or length of hospitalization. Conclusions. CⴙS did not significantly affect morbidity or mortality overall, based on clinical stage, postoperative stage, or extent of resection. The potential for enhanced survival in resectable NSCLC justifies continued study of CⴙS. (Ann Thorac Surg 2001;71:1105–12) © 2001 by The Society of Thoracic Surgeons
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therapy on surgical outcomes by comparing patients receiving preoperative chemotherapy (C⫹S) with patients undergoing surgery alone (S).
ung cancer remains a significant public health problem in the United States with an estimated 171,600 new cases in 1999; 158,900 of those will eventually die from this disease [1]. However, even in its earliest stages, which are amenable to surgical resection, survival after complete resection is compromised by local and systemic recurrences [2, 3]. Survival is poor (0% to 10% at 5 years) for patients with advanced stage non–small cell lung cancer (NSCLC) (stages III and IV) [3]. To improve survival, multiple studies have explored the role of adjuvant therapies including pre- and postoperative chemotherapy and radiation for NSCLC. After disappointing results of postoperative chemotherapy with no improvement in survival [4, 5], most clinical trials in the past decade have explored preoperative chemotherapy or chemoradiation therapy to enhance local and systemic therapy in advanced stage (IIIA) lung cancer. Two small (single institution) prospective randomized trials showed benefit of this approach in stage IIIA NSCLC [6, 7]. However, several reports [8 –11] have reported significant surgical morbidity and mortality associated with preoperative treatment. We examined the influence of preoperative chemo-
Presented at the Thirty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 31–Feb 2, 2000. Address reprint requests to Dr Putnam, Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 109, Houston, TX 77030; e-mail: [email protected].
© 2001 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
Patients and Methods We reviewed 380 consecutive patients undergoing anatomic pulmonary resection (lobectomy or greater) for NSCLC between August 1, 1996, and April 30, 1999. Forty-five anatomic resections were excluded from the analysis for a history of a prior lung cancer (n ⫽ 21), prior chest radiation or chemoradiation therapy for positive N2 nodes (n ⫽ 17), or history of any malignancy other than nonmelanoma skin cancer within the past year (n ⫽ 7). During this same time, an additional 140 segmentectomies and other nonanatomic resections for NSCLC were performed (generally in high-risk patients) and not included in the analysis. Our study population included 335 patients: 259 patients had surgery alone (S) and 76 patients had preoperative chemotherapy (C⫹S).
Data Acquisition Beginning in August 1996, we concurrently collected postoperative events (eg, any event that had an impact on the patient’s convalescence or treatment) and stored them electronically. At the time of discharge, the physician caring for the patient completed a scannable data sheet to record postoperative events. These events included pulmonary, cardiac, gastrointestinal, blood usage, 0003-4975/01/$20.00 PII S0003-4975(01)02406-7
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wound infections, other wound problems, and other events. All database elements were prospectively defined within a database dictionary for consistency of data collection. These definitions allowed for a more precise use of clinical terms such as “adult respiratory distress syndrome” (ARDS) or “pneumonia,” which are used differently by many authors [12–16]. The collected data were reviewed monthly at our quality assurance (morbidity and mortality) conference. Data validity and quality was controlled at this conference by review of the physicians responsible for each patient’s care and by periodic selective randomized retrospective chart audits. All of the end points in this study were derived from this database. None of the end points was collected retrospectively. Patients’ preoperative comorbidities were collected retrospectively by one of us (M.P.S.). Pulmonary function values were collected from our database. The extent of surgical resection was obtained by review of the operative reports. Surgical mortality was defined as any death occurring within 30 days, or after 30 days if the patient was continuously hospitalized after surgery.
Preoperative Treatment Multiple chemotherapy agents were used. These chemotherapy agents and the administration of chemotherapy on a clinical protocol or in an “ad hoc” manner were recorded. Time intervals between the last dose of chemotherapy and surgery as well as the number of chemotherapy cycles were recorded.
Clinical and Pathologic Staging Preoperative clinical staging (cStage) was based on all information before definitive resection. These information sources included the patients’ preoperative clinic notes, radiology reports, review of selected computed tomography scans of the chest and all invasive staging methods such as bronchoscopy, mediastinoscopy, needle biopsy, or other techniques. Patients who responded to preoperative treatment (disappearance of N2 nodes or regression of the primary tumor on computed tomography scan) were clinically “down-staged” based on imaging information alone. The postoperative (pathologic) stage (pStage) was obtained from our departmental database. After review by a trained research nurse, final pathology stage was based on the final written pathology report and operative findings. Pathological stage was further reviewed and validated by the senior surgeon responsible for that patient. Patients with two histologically different, concurrent tumors (4 patients) were staged by the more advanced TNM status of the two tumors.
Data Analysis Differences between the C and C⫹S treatment groups were tested for significance by the 2 test for categorical variables and the Student’s t test for continuous variables. The
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Table 1. Patient Demographics
Characteristic Age (years) Gender Male Female Comorbidities Hypertension Diabetes mellitus Coronary artery disease Pathology Squamous cell carcinoma Adenocarcinoma Other Spirometry FEV1 (average % predicted) FVC (average % predicted) DLCO (average % predicted) Postoperative stagea 1A, 1B 2A, 2B 3A 3B, 4 Surgical procedure Lobectomy Bilobectomy/sleeve resection Pneumonectomy a
Chemotherapy and Surgery (n ⫽ 76)
Surgery Alone (n ⫽ 259)
n (%)
n (%)
p
62.42 (⫾10.10)
64.95 (⫾11.19)
0.08
44 (57.9) 32 (42.1)
149 (57.5) 110 (42.5)
0.96
22 (28.9) 7 (9.2) 9 (11.8)
85 (32.8) 18 (6.9) 31 (12)
0.52 0.51 0.97
19 (25)
72 (27.8)
0.43
47 (61.8) 10 (13.2)
140 (54.1) 47 (18.1)
84.11
83.32
0.791
91.44
93.44
0.336
74.00
80.54
0.066
34 (44.7) 19 (25) 20 (26.3) 3 (3.9)
151 (58.3) 43 (16.6) 40 (15.4) 25 (9.7)
0.02
60 (78.9) 8 (10.5)
212 (81.9) 19 (7.3)
0.67
8 (10.5)
28 (10.8)
Postoperative stage, combines pathological stage and surgical findings.
DLCO ⫽ diffusing capacity of carbon monoxide; FEV1 ⫽ forced expiratory volume in 1 second; FVC ⫽ forced vital capacity.
patients were analyzed by surgical procedure, cStage, pStage, and by chemotherapy given on a study protocol or in an “off protocol” setting. Statistical significance was defined as p less than 0.05. All statistical analyses were performed using SPSS software (SPSS Inc, Chicago, IL). A logistic regression model was constructed with occurrence of a major complication as the dependent variable. Any hospital mortality, pneumonia, reintubation, tracheostomy, ARDS, empyema, bronchopleural fistula, wound complication, blood transfusion, readmit to hospital, or readmit to intensive care unit was defined as a major event. The other covariates included in the model were age, history of coronary artery disease, hypertension, or diabetes, preoperative treatment (chemotherapy versus no chemotherapy), pathologic stage (1,2 versus 3,4), and procedure (lobectomy, sleeve-resection, bilobectomy versus pneumonectomy).
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Table 2. Clinical Staging Accuracy
Clinical Staging Accuracy Surgery alone (n ⫽ 259) Chemotherapy and surgery (n ⫽ 76)
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Table 4. Chemotherapy Regimens
Same pStage and cStage
pStage Lower Than cStage
pStage Higher Than cStage
n (%)
n (%)
n (%)
26 (10)
70 (27)
22 (29.0)
14 (18.4)
163 (63.0) 40 (52.6)
All Patients “On (%) Protocol” “Ad Hoc” (n ⫽ 76) (n ⫽ 40) (n ⫽ 36)
Regimen Carboplatin and paclitaxel Cisplatin and etoposide Cisplatin and vinorelbine Vinorelbine and gemcitabine Cisplatin only
71 (93.4) 1 (1.3) 2 (2.6) 1 (1.3) 1 (1.3)
40 0 0 0 0
31 1 2 1 1
p ⫽ 0.0005. pStage ⫽ postoperative stage, combines pathological stage and surgical findings; cStage ⫽ clinical stage, combines all preoperative imaging and invasive staging methods.
Results Data Quality Departmental review at the quality assurance conference as well as selective randomized chart reviews validated and confirmed accuracy of recorded data.
Patient Characteristics The C⫹S and S alone groups had similar demographics (Table 1). The S group tended to be slightly older (median 65 versus 62.4 years, p ⫽ NS). Comorbidities, histology, and lung functions were also similar in both groups (Table 1). The stage distribution between the two groups was significantly different, with more early stage NSCLC (stages 1A, 1B) in the S group ( p ⫽ 0.02). The correlation of the clinical staging with the postoperative (pathologic) staging is shown in Table 2. The final postoperative stage tended to be significantly lower ( p ⱕ 0.005) in the C⫹S group (Table 2). The extent of surgical resections performed in both groups was similar overall and in stage-specific analysis (Table 3).
Preoperative Treatment Seventy-six patients received preoperative chemotherapy (Table 4). Forty patients were treated on an “early stage protocol” [17], and the remainder (n ⫽ 36) were treated in an “off protocol” setting. The most commonly used combination chemotherapy was paclitaxel and carboplatin (n ⫽ 71, 93%). On the early stage protocol, paclitaxel 225 mg/m2 was given as a 3-hour infusion and carboplatin (area under the curve ⫽ 6) was given every 21
days. No routine growth factor support was used. Two preoperative cycles were given until August 31, 1998. After an interim analysis, which showed a pathologic complete response rate of only 6% and a low completion rate of the scheduled postoperative chemotherapy cycles (46%), this protocol-regimen was changed to three preoperative chemotherapy cycles. No patient was converted from the protocol into an “off protocol” regimen. Patients treated in an “ad hoc” manner received this combination or several other chemotherapy agents (Table 4). The influence of specific chemotherapeutic agents or combination regimens on surgical outcomes could not be evaluated because of small sample size.
Surgical Outcomes Overall, patients receiving C⫹S had no increase in the measured postoperative events than patients receiving S (Table 5). Subsequent subset analysis was performed. The patients were grouped according to clinical (cStage) and pathologic stage (pStage). To have sufficient statistical power, the patients were grouped by stage into four groups; patients with stages Ia and Ib, stages IIa and IIb, stage IIIa, and patients with all higher stages. This stage-specific analysis revealed no difference in postoperative complications and events (Tables 6 and 7). We noted a nonsignificant trend towards increased pulmonary morbidity ( p ⫽ 0.08) and prolonged hospital stay ( p ⫽ 0.09) in the early pStage C⫹S group (stages Ia and Ib). No difference was noted in operation-specific outcomes in the two groups (Table 8). Patients receiving chemotherapy “on protocol” and in an “off protocol” setting were compared. No differences in postoperative
Table 3. Resection by Postoperative Stage (pStage) Bilobectomy/Sleeve Resections
Lobectomy
Pneumonectomy
Resection by pStage
C⫹S (%)
S (%)
C⫹S (%)
S (%)
C⫹S (%)
S (%)
All stages (n ⫽ 335) Stage 1A, 1B Stage 2A, 2B Stage 3A Stage 3B, 4
60 (78.9) 32 (94.1) 14 (73.7) 13 (65) 1 (33.3)
212 (81.9) 137 (90.7) 30 (69.8) 25 (62.5) 20 (80)
8 (10.5) 2 (5.9) 2 (10.5) 4 (20.0) 0
19 (7.3) 9 (6.0) 5 (11.6) 4 (10.0) 1 (4.0)
8 (10.5) 0 3 (15.8) 3 (15) 2 (66.7)
28 (10.8) 5 (3.3) 8 (18.6) 11 (27.5) 4 (16.0)
pStage ⫽ postoperative stage, combines pathological stage and surgical findings; p ⫽ not significant, all groups.
C ⫽ chemotherapy;
S ⫽ surgery.
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event. Preoperative chemotherapy was not a significant variable.
Table 5. Postoperative Events Chemotherapy and Surgery (n ⫽ 76)
Surgery Alone (n ⫽ 259)
n (%)
n (%)
p
34 (44.7) 1 (1.3) 10 (13.2) 8 (10.5) 6 (7.9) 4 (5.3) 2 (2.6) 0 0 4 (5.3) 7 (9.2) 8.38 (⫾8.76) 5 (6.6) 3 (3.9)
132 (51) 13 (5.0) 30 (11.6) 25 (9.7) 14 (5.4) 9 (3.5) 8 (3.1) 3 (1.2) 3 (1.2) 13 (5.0) 25 (9.7) 8.55 (⫾6.75) 14 (5.4) 12 (4.6)
0.205 0.134 0.421 0.485 0.287 0.337 0.596 0.461 0.461 0.564 0.555 0.860 0.439 0.546
Event All events Mortality Major pulmonarya Pneumonia Reintubation Tracheostomy ARDS Empyema Bronchopleural fistula Wound complication Blood transfusion LOS (⫾SD) Readmit to hospital ICU readmit
Comment Preoperative treatment for advanced stage NSCLC has been evaluated in several phase 2 and 3 clinical trials [18 –21]. These studies had acceptable treatment related complication rates. However, patient selection was restrictive and patients with significant comorbidities were likely to be excluded from these studies. Other studies reported a relatively high surgical morbidity and mortality after preoperative treatment [8 –10]. These series reviewed a small number of patients who received preoperative combined modality chemoradiation treatment. An increased incidence of culture negative infiltrates (ARDS) and bronchopleural fistulas was found, mainly after pneumonectomy. Another recently published report found no increased incidence in these complications in 19 consecutive patients who all received combined modality therapy and definitive radiation of more than 59 Gy [22]. In this series all but 1 patient had carefully harvested intercostal flap coverage of the bronchial stump. The 1 patient without this flap developed a bronchopleural fistula. A recent abstract [11] retrospectively reviewed a small number of patients receiving only preoperative chemotherapy with carboplatin and paclitaxel and no concurrent radiation. A mortality rate of 8% and a 32% incidence of life-threatening complications were found. Our study did not confirm these findings. We analyzed all consecutive patients with NSCLC who had an anatomic lung resection and were operated on with curative intent. We excluded patients with recurrent NSCLC or history of another recent malignancy. No
a
Major pulmonary includes pneumonia, reintubation, tracheostomy, or ARDS. Patients may have had one or more of these events. ARDS ⫽ acute respiratory distress syndrome; ICU ⫽ intensive care unit; LOS ⫽ length of stay in hospital; SD ⫽ standard deviation.
events were noted for patients having chemotherapy on protocol or in an ad hoc manner (Table 9).
Multivariate Analysis On multivariate analysis only the presence of coronary artery disease (odds ratio [OR] ⫽ 2.05, confidence interval [CI] ⫽ 1.02 to 4.12, p ⫽ 0.0451) and pneumonectomy (OR ⫽ 2.17, CI ⫽ 1.05 to 4.49, p ⫽ 0.037) were found to be independent risk factors for a major postoperative Table 6. Postoperative Events by Postoperative Stage (p Stage)a Event by Pathological Stage
Stage 1A, 1B (n ⫽ 185) C⫹S (%) (n ⫽ 34)
All events 19 (55.9) Mortality 1 (2.9) Major 6 (17.6) pulmonaryb Pneumonia 5 (14.7) Reintubation 4 (11.8) Tracheostomy 3 (8.8) ARDS 2 (5.9) Wound 2 (5.9) complication Blood transfusion 3 (8.8) Mean LOS (⫾SD) 10.2 (⫾12.13) Readmit to 2 (5.9) hospital ICU readmit 2 (5.9)
Stage 2A, 2B (n ⫽ 62)
S (%) (n ⫽ 151)
C⫹S (%) S (%) (n ⫽ 19) (n ⫽ 43)
p
71 (47.0) 4 (2.6) 12 (7.9)
0.228 0.642 0.086
8 (42.1) 0 4 (21.1)
10 (6.6) 6 (4.0) 4 (2.6) 2 (1.3) 8 (5.3)
0.116 0.088 0.117 0.155 0.579
3 (15.8) 2 (10.5) 1 (5.3) 0 1 (5.3)
p
24 (55.8) 0.236 3 (7.0) 0.326 7 (16.3) 0.451 6 (14.0) 3 (7.0) 1 (2.3) 2 (4.7) 1 (2.3)
0.565 0.489 0.522 0.478 0.522
Stage 3A (n ⫽ 60) C⫹S (%) (n ⫽ 20) 6 (30.0) 0 0
S (%) (n ⫽ 40)
Stage 3B, 4 (n ⫽ 28) p
24 (60.0) 0.027 3 (7.5) 0.289 5 (12.5) 0.12
0 0 0 0 1 (5.0)
4 (10.0) 2 (5.0) 2 (5.0) 2 (5.0) 2 (5.0)
0.187 0.441 0.441 0.441 0.745
C⫹S (%) (n ⫽ 3) 1 (33.3) 0 0 0 0 0 0 0
S (%) (n ⫽ 25)
p
13 (52.0) 0.500 3 (12) 0.702 6 (24) 0.470 5 (20.0) 3 (12.0) 2 (8.0) 2 (8.0) 2 (8.0)
0.541 0.702 0.794 0.794 0.794
9 (6.0) 0.384 1 (5.3) 6 (14.0) 0.301 3 (15.0) 4 (10.0) 0.429 0 6 (24.0) 0.470 7.9 (⫾5.52) 0.091 7.1 (⫾5.3) 8.8 (⫾4.8) 0.225 6.5 (⫾3.0) 9.63 (⫾8.8) 0.132 8.3 (⫾2.5) 10.4 (⫾11) 0.757 8 (5.3) 0.579 2 (10.5) 1 (2.3) 0.223 1 (5.0) 3 (7.5) 0.593 0 2 (8.0) 0.794 8 (5.3)
0.579
1 (5.3)
1 (2.3)
a Postoperative stage, combines pathological stage and surgical findings. ARDS. Patients may have had one or more of these events.
ARDS ⫽ acute respiratory distress syndrome; surgery; SD ⫽ standard deviation.
c ⫽ chemotherapy;
b
0.522
1 (5.0)
1 (2.5)
0.667
0
2 (8.0)
0.794
Major pulmonary includes pneumonia, reintubation, tracheostomy, or
ICU ⫽ intensive care unit;
LOS ⫽ length of stay in hospital;
S ⫽
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Table 7. Postoperative Events by Clinical Stage (c Stage)a Stage 1A, 1B (n ⫽ 210) Event by Clinical Stage
C⫹S (%) (n ⫽ 25)
S (%) (n ⫽ 185)
All events 12 (48.0) 89 (48.1) Mortality 1 (4) 10 (5.4) Major pulmonaryb 5 (20) 17 (9.2) Pneumonia 4 (16) 15 (8.1) Reintubation 3 (12.0) 9 (4.9) Tracheostomy 2 (8.0) 9 (4.9) ARDS 1 (4.0) 6 (3.2) Wound 2 (8.0) 5 (2.7) complication Blood transfusion 1 (4.0) 15 (8.1) Mean LOS (⫾SD) 9.6 (⫾11.1) 8.4 (⫾6.8) Readmit to 2 (8.0) 7 (3.8) hospital Readmit ICU 2 (8.0) 10 (5.4)
Stage 2A, 2B (n ⫽ 71)
p
C⫹S (%) (n ⫽ 22)
S (%) (n ⫽ 49)
0.581 0.615 0.101 0.174 0.159 0.385 0.594 0.197
9 (40.9) 0 2 (9.1) 2 (9.1) 1 (4.5) 1 (4.5) 0 0
27 (55.1) 2 (4.1) 11 (22.4) 9 (18.4) 4 (8.2) 0 2 (4.1) 6 (12.2)
p
S (%) (n ⫽ 8)
0.052 0.386 0.496 0.671 0.371 0.614 0.614 0.67
2 (100) 0 0 0 0 0 0 0
4 (50) 0 1 (12.5) 0 1 (12.5) 0 0 1 (12.5)
0.407 1 (4.5) 8 (16.3) 0.161 5 (18.5) 2 (11.8) 0.441 0.407 6.8 (⫾4.5) 9.3 (⫾6.7) 0.109 8.6 (⫾9.3) 8.3 (⫾6.6) 0.909 0.291 1 (4.5) 4 (8.2) 0.504 1 (3.7) 3 (17.6) 0.153
0 7 (⫾0) 1 (50)
0
1 (2.0)
0.198 11 (40.7) 0.473 0 0.15 3 (11) 0.267 2 (7.4) 0.504 2 (7.4) 0.310 1 (3.7) 0.473 1 (3.7) 0.098 2 (7.4)
12 (70.6) 1 (5.9) 1 (5.9) 1 (5.9) 0 0 0 1 (5.9)
Stage 3B, 4 (n ⫽ 10) C⫹S (%) (n ⫽ 2)
0.431
S (%) (n ⫽ 17)
p
0.690
a Clinical stage, combines all preoperative imaging and invasive staging methods. tomy, or ARDS. Patients may have had one or more of these events.
ARDS ⫽ acute respiratory distress syndrome; surgery; SD ⫽ standard deviation.
Stage 3A (n ⫽ 44) C⫹S (%) (n ⫽ 27)
C ⫽ chemotherapy;
retrospectively collected end points were included in our analysis. We compared those factors that are known to influence surgical morbidity, including age, spirometry results, type of surgical resection, diabetes, coronary artery disease, and hypertension. We found no differences in our two study populations (C⫹S and S alone). The study groups appear to be similar on retrospective review; however, only a prospective randomized trial allows for stratification of these variables. We did not measure other risk factors that may influence surgical outcomes, including current smoking status, nutritional status, surgical incision, type of postoperative pain control, or results of the surgeons. Sophisticated risk scoring sys-
1 (3.7)
b
1 (5.9)
0.629
p 0.333 0.800 0.800
0.800
0 8.6 (⫾6.2) 0.732 0 0.200
0
0
Major pulmonary includes pneumonia, reintubation, tracheos-
ICU ⫽ intensive care unit;
LOS ⫽ length of stay in hospital;
S ⫽
tems have been developed in several surgical specialties such as in trauma, critical care, and cardiac surgery [23–26], and only recently such a risk scoring system has been tested for noncardiac thoracic surgery patients [27]. The preoperative side effects and complications of chemotherapy have been well documented in the two prospectively randomized controlled trials [6, 7]. Chemotherapy-related complications were also carefully reported in a recent phase 2 study for early stage NSCLC [17]. In this multicenter study of 94 patients, significant toxicity after preoperative paclitaxel and carboplatin included grade 3 to 4 neutropenia in 35% with no hospital admissions for febrile neutropenia. Also common were moderate (grade 2) myalgias and arthralgias in 26%. Most
Table 8. Postoperative Events by Procedure Lobectomy
Bilobectomy/Sleeve Resection
Event by Procedure
C⫹S (%) (n ⫽ 60)
S (%) (n ⫽ 212)
p
C⫹S (%) (n ⫽ 8)
S (%) (n ⫽ 19)
All events Mortality Major pulmonarya Pneumonia Reintubation Tracheostomy ARDS Wound complication Blood transfusion Mean LOS (⫾SD) Readmit to hospital ICU readmit
28 (46.7) 1 (1.7) 10 (16.7) 8 (13.3) 6 (10.0) 4 (6.7) 2 (3.3) 3 (5.0) 5 (8.3) 8.8 (⫾9.7) 4 (6.7) 3 (5.0)
102 (48.1) 10 (4.7) 22 (10.4) 19 (9.0) 9 (4.2) 8 (3.8) 5 (2.4) 7 (3.3) 19 (9.0) 8.3 (⫾6.5) 4 (1.9) 12 (5.7)
0.480 0.259 0.135 0.220 0.08 0.260 0.481 0.385 0.558 0.654 0.074 0.570
4 (50) 0 0 0 0 0 0 0 2 (25) 7.6 (⫾4.5) 0 0
10 (52.6) 0 2 (10.5) 1 (5.3) 1 (5.3) 0 0 3 (15.8) 1 (5.3) 9.4 (⫾5.6) 2 (10.5) 0
a
Pneumonectomy
p 0.615 0.487 0.704 0.704 0 0 0.331 0.201 .441 0.487 0
C⫹S (%) (n ⫽ 8)
S (%) (n ⫽ 28)
p
2 (25) 0 0 0 0
20 (71.4) 3 (10.7) 6 (21.4) 5 (17.9) 4 (14.3) 1 (3.6) 3 (10.7) 3 (10.7) 5 (17.9) 9.6 (⫾9.4) 8 (28.6)
0.026 0.459 0.193 0.261 0.348 0.778 0.459 0.652 0.261 0.281 0.337
1 (12.5) 0 5.8 (⫾2.5) 1 (12.5) 0
Major pulmonary includes pneumonia, reintubation, tracheostomy, or ARDS. Patients may have had one or more of these events.
ARDS ⫽ acute respiratory distress syndrome; surgery; SD ⫽ standard deviation.
C ⫽ chemotherapy;
ICU ⫽ intensive care unit;
LOS ⫽ length of stay in hospital;
S ⫽
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Table 9. Comparison of Patients Receiving Three Different Treatments
Patient Characteristics Mean age (years) Comorbidities Hypertension Diabetes mellitus Coronary artery disease All events Mortality Mean LOS (⫾SD) Pulmonary morbiditya Wound complications
Chemotherapy “On Protocol”
Chemotherapy “Ad Hoc”
Surgery Alone (n ⫽ 259)
n ⫽ 40 (12%)
n ⫽ 36 (11%)
n ⫽ 259 (77%)
p
64.9
59.6
64.9
0.023
11 (27.5) 5 (12.5) 8 (20.0) 18 (45.0) 1 (2.5) 8.6 (⫾9.1) 6 (15.0) 2 (5.0)
11 (30.6) 2 (5.6) 1 (2.8) 16 (44.4) 0 8.1 (⫾8.5) 4 (11.1) 2 (5.6)
85 (32.8) 18 (6.9) 31 (12) 132 (51) 13 (5) 8.6 (⫾6.8) 30 (11.6) 13 (5.0)
0.784 0.415 0.070 0.633 0.315 0.939 0.814 0.990
a
Pulmonary morbidity includes pneumonia, reintubation, tracheostomy, or acute respiratory distress syndrome. Patients may have had one or more of these events. LOS ⫽ length of stay in the hospital;
SD ⫽ standard deviation.
of these complications resolved within a week. More severe hematologic and neuromuscular complications were found in less than 5%. During induction chemotherapy in this study 1 patient (1%) died of a cerebrovascular accident while recovering from chemotherapy-induced toxicity, 96% of patients completed the preoperative chemotherapy, and 94% were operated on with intent to cure. Reasons for not undergoing an operation included disease progression (n ⫽ 3), loss to follow-up, unresectable status, or death in 1 patient each. Thirty-four of the 94 patients from that multicenter study were treated at our institution and included in our analysis. Morbidity induced by preoperative chemotherapy for early NSCLC appears to be acceptable. However, to further study this modality, a multi-institutional (phase III Intergroup) prospective randomized trial (SWOG S9900) is currently underway. Patients in our study were not analyzed on an intentto-treat basis. Only patients who underwent surgical resection were entered into our thoracic surgery database and analyzed. In contrast to advanced stage NSCLC [6, 7] there is currently no prospective evidence for a survival advantage after preoperative chemotherapy for stage 1 or 2 NSCLC; this treatment should be given only after informed consent in a protocol setting. Given the intensity of chemotherapy combinations used, it appears surprising that no significant impact on surgical morbidity could be measured. Surgical outcomes were similar for patients if they were given chemotherapy on protocol or in an uncontrolled ad hoc setting, or if no chemotherapy was given. The number of patients in this series was large enough to measure surgical morbidity stratified by several risk groups, including clinical and pathological stage, extent of surgical resection, and protocol enrollment. Our study population and the number of events observed were not large enough to detect small differences in these surgical morbidities. A trend toward increased pulmonary morbidity in early stage lung cancers was noted in this study. In summary, preoperative chemotherapy did not sig-
nificantly affect morbidity or mortality overall, based on clinical or pathological stage, nor by the extent of the pulmonary resection performed. These data, coupled with the well-known preoperative side effects and complications of chemotherapy, justify continued study of preoperative chemotherapy for NSCLC. This work was supported in part by the Texas Tobacco Settlement Fund and the Charles and Beverly Adams Fund for Thoracic Surgery Research.
References 1. Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1999. CA Cancer J Clin 1999;49:8–31. 2. Nesbitt JC, Putnam JBJ, Walsh GL, Roth JA, Mountain CF. Survival in early-stage non–small cell lung cancer. Ann Thorac Surg 1995;60:466–72. 3. Mountain CF. Revisions in the international system for staging lung cancer. Chest 1997;111:1710–7. 4. Pisters KM, Kris MG, Gralla RJ, et al. Randomized trial comparing postoperative chemotherapy with vindesine and cisplatin plus thoracic irradiation with irradiation alone in stage III (N2) non–small cell lung cancer. J Surg Oncol 1994; 56:236– 41. 5. Figlin RA, Piantodosi S. A phase 3 randomized trial of immediate combination chemotherapy vs delayed combination chemotherapy in patients with completely resected stage II and III non–small cell carcinoma of the lung. Chest 1994;106:310S–2. 6. Roth JA, Fossella F, Komaki R, et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non–small-cell lung cancer. J Natl Cancer Inst 1994;86:673– 80. 7. Rosell R, Gomez-Codina J, Camps C, et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non–small-cell lung cancer. N Engl J Med 1994;330:153– 8. 8. Bonomi P, Faber LP, Warren W, et al. Postoperative bronchopulmonary complications in stage III lung cancer patients treated with preoperative paclitaxel-containing chemotherapy and concurrent radiation. Semin Oncol 1997;24:S12. 9. Fowler WC, Langer CJ, Curran WJJ, Keller SM. Postoperative complications after combined neoadjuvant treatment of lung cancer. Ann Thorac Surg 1993;55:986–9.
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10. Deutsch M, Crawford J, Leopold K, et al. Phase II study of neoadjuvant chemotherapy and radiation therapy with thoracotomy in the treatment of clinically staged IIIA non–small cell lung cancer. Cancer 1994;74:1243–52. 11. Roberts JR, DeVore RF, Carbone DP, et al. Neoadjuvant chemotherapy increases perioperative complications in patients undergoing resection for NSCLC [Abstract]. Proc ASCO 2000;18:465A. 12. Bernard GR, Artigas A, Brigham KL, et al. Report of the American-European Consensus conference on acute respiratory distress syndrome: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Consensus Committee. J Crit Care 1994;9:72– 81. 13. Schuster DP. Identifying patients with ARDS: time for a different approach. Intensive Care Med 1997;23:1203. 14. Sachdeva RC, Guntupalli K. Acute respiratory distress syndrome. Crit Care Clin 1997;13:503–21. 15. Meduri GU, Johnanson WG. International Consensus Conference: clinical investigation of ventilator-associated pneumonia. Chest 1992;102:551S–2. 16. Pingleton SK, Fagon JY, Leeper KV. Patient selection for clinical investigation of ventilator-associated pneumonia. Chest 1992;105:553S– 6. 17. Pisters KM, Ginsberg RJ, Giroux DJ, et al, on behalf of the Bimodality Lung Oncology Team (BLOT). Induction chemotherapy before surgery for early-stage lung cancer: a novel approach. J Thorac Cardiovasc Surg 2000;119:429–39. 18. Roth JA, Atkinson EN, Fossella F, et al. Long-term follow-up of patients enrolled in a randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non–small-cell lung cancer. Lung Cancer 1998;21:1– 6. 19. Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cispla-
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tin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non–small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 1995;13:1880–92. Sugarbaker DJ, Herndon J, Kohman LJ, Krasna MJ, Green MR. Results of cancer and leukemia group B protocol 8935. A multiinstitutional phase II trimodality trial for stage IIIA (N2) non–small-cell lung cancer. Cancer and Leukemia Group B Thoracic Surgery Group. J Thorac Cardiovasc Surg 1995;109:473– 85. Yashar J, Weitberg AB, Glicksman AS, Posner MR, Feng W, Wanebo HJ. Preoperative chemotherapy and radiation therapy for stage IIIa carcinoma of the lung. Ann Thorac Surg 1992;53:445– 8. Sonnett JR, Krasna MJ, Suntharalingam M, et al. Safe pulmonary resection after chemotherapy and high-dose thoracic radiation. Ann Thorac Surg 1999;68:316–20. Marik PE, Varon J. Severity scoring and outcome assessment. Crit Care Clin 1999;15:633– 46. Sauaia A, Moore FA, Moore EE, Lezotte DC. Early risk factors for postinjury multiple organ failure. World J Surg 1996;20:392– 400. Daley J. Criteria by which to evaluate risk-adjusted outcomes programs in cardiac surgery. Ann Thorac Surg 1994; 58:1827–35. Parsonnet V, Dean D, Bernstein AD. A method of uniform stratification of risk for evaluating the results of surgery in acquired adult heart disease. Circulation 1989;79:1–3. Brunelli A, Fianchini A, Gesuita R, Carle F. POSSUM scoring system as an instrument of audit in lung resection surgery. Physiological and operative severity score for the enumeration of mortality and morbidity. Ann Thorac Surg 1999;67: 329–31.
DISCUSSION DR JOHN C. WAIN (Boston, MA): I would like to thank Dr Siegenthaler and his colleagues for the opportunity to review this paper before its presentation. I think they are to be commended on two points. They certainly have a lucid and well-documented presentation that demonstrates the immense utility of a real-time data collection system for outcome assessment in patients. A methodology as straightforward and simple as what they described here, which involves recording data about patients at the time of discharge, followed by validation at the weekly or monthly quality assurance conferences, or mortality and morbidity conferences, I think is really invaluable. Not only does the real-time data recording result in ready data for answering clinical questions such as the one posed by the article here, but it is also useful for systematic evaluations and improvements in patient care. Most importantly, perhaps, this is a study in which the methodology and the data were designed, implemented, and managed by the surgeons who were involved in the patient’s care. So that in fact if anyone has any questions about the data they can provide answers quickly and easily. The second major point I would like to emphasize is that I think the surgical outcomes here are excellent, particularly as demonstrated by the low mortality rate of only 1.7% in patients undergoing lobectomy after preoperative chemotherapy, certainly answering the question posed by the tile of the paper. I have only three questions for the authors: 1. What would be the indications for chemotherapy in the patients, particularly the early stage patients? I appreciate that some of the patients were on protocol and some were not, but I wondered how much subjectivity there might be
in selecting those patients who did not receive chemotherapy, particularly the ones off protocol. 2. The low incidence of pneumonectomy in the preoperative chemotherapy group, particularly in the stage III-A group, is striking, and I was wondering if the authors have any indication that their preoperative chemotherapy in fact resulted in a downstaging to the extent that a resection less extensive than a pneumonectomy was possible? 3. And lastly, as the authors noted, there was a trend toward longer hospital stay and increased pulmonary morbidity, somewhat surprisingly, in the early stage group receiving chemotherapy, and I was wondering if they have any hypothesis as to why this might have happened whether it relates to factors not controlled for here, such as smoking or nutritional status, or other factors unique to chemotherapy such as the use of granulocyte colony-stimulating factor, which may induce inflammation in the lung in the postoperative period? And in view of this finding, would they recommend the concept of using chemotherapy in earlier stage lung cancers, which certainly seems to be a developing trend in the management of lung cancer, but perhaps should be rethought. Again, my congratulations to the authors and my thanks to them and the Society for the privilege to discuss this article. Thank you. DR JOHN ROBERTS (Nashville, TN): I enjoyed your paper very much as well, and I had three quick questions. First, I did not understand slide very well, but it appeared that you had a 4.5% mortality for the surgery-alone group. Is that true?
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Second, fewer than 25% of your patients received preoperative chemotherapy. That surprises me for your institution. Do all of your III-A patients receive preoperative chemotherapy or do more of them go into chemoradiotherapy? Finally, your data are at odds with the data that we presented at ASCO, and with the increased mortality that Elias found in the CALGB group study that was conducted a few years ago. I wondered if you had any comment about that? DR MUHAMMAD MUMTAZ (Overland Park, KS): What was the protocol for chemotherapy and how much time did you wait before surgery? Did you have any patients that are not listed here that were initially going to have to go to a surgery arm but did not because of morbidity related to chemotherapy? DR SIEGENTHALER: Thank you Dr Wain, for your kind comments and questions. I would like to start with your questions first. What were the indications for chemotherapy? We tried to include every patient on our early stage protocol, which includes patients with stages 1b, 2a and b as well as the T3N1 group, which is a subgroup of stage 3a. This protocol is now available as the BLOT Intergroup trial. Every patient who is eligible and willing to participate in this trial gets enrolled. In all other patients, we would perform surgery alone. Only through a formal protocol can we determine a survival advantage. Your second question addresses a possible down-staging effect, given the low incidence of pneumonectomy in the chemotherapy and surgery group. I think we have to be careful here. Our study group was fairly small. We also noted, when we correlated the clinical preoperative stage with the final postoperative stage, that there was a significant difference after preoperative chemotherapy. The chemotherapy group had a much higher number of patients that were down-staged, which again could be a sign of a treatment effect. The study population was
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too small and the patient selection was uncontrolled to make such a conclusion. The third question was about the trend for an increased length of stay and pulmonary morbidity. I think there are uncontrolled factors, as you mentioned, which were not analyzed. An answer would be purely speculative. It might be a chemotherapyassociated effect. Ninety percent of our patients received Carboplatin and Taxol. The usual dose limiting toxicity for those agents is neuropathies and neurotoxicities, not bone marrow suppression. No routine growth factor support was used. I think this also explains Dr Mumtaz’s first question. His second question was about the time interval between the surgery and chemotherapy. On the protocol, the surgery was usually performed 1 month after the last administration of chemotherapy. However, this was flexible if longer recovery from the chemotherapy was necessary. We collected the data about the timing between chemotherapy and surgery, but since we found no difference in the univariate analysis, we did not analyze the time interval further. To Dr Robert’s questions, mortality was higher in the surgery alone group, most likely due to the higher number of patients receiving pneumonectomy. The mortality rate was 5%. We did not find the same morbidity associated with preoperative chemotherapy that you found in your previous investigation. I cannot explain this difference between our institutions although our study population was larger. Your last question was why only 25% of patients received chemotherapy. I think the overall proportion was higher. Patients receiving preoperative chemoradiation for stage 3a were excluded from the analysis. A high proportion of our clinical stage 3a patients received preoperative treatment. For earlier stages, however, we do not believe that chemotherapy should be given in an “off protocol” setting , since there is no hard data proving a survival benefit for this patient group.
Background. Preoperative chemotherapy (CⴙS) for non–small cell lung cancer (NSCLC) has increased in an attempt to improve survival. Patients receiving CⴙS potentially may have an increase in postoperative morbidity and mortality compared with surgery alone (S). We reviewed our experience with CⴙS and S in a tertiary referral center. Methods. Three hundred eighty consecutive patients underwent lobectomy or greater resection for NSCLC between August 1, 1996, and April 30, 1999: 335 patients (259 S; 76 CⴙS) were analyzed; 45 additional patients were excluded for prior NSCLC, other chemotherapy for other malignancy, or radiation. We compared morbidity and mortality overall, and by subset analysis (clinical
stage, pathological stage, procedure, and by protocol use) for both CⴙS and S patients. Results. Demographics, comorbidities, and spirometry were similar. We noted no significant difference in overall or subset mortality or morbidity including pneumonia, acute respiratory distress syndrome, reintubation, tracheostomy, wound complications, or length of hospitalization. Conclusions. CⴙS did not significantly affect morbidity or mortality overall, based on clinical stage, postoperative stage, or extent of resection. The potential for enhanced survival in resectable NSCLC justifies continued study of CⴙS. (Ann Thorac Surg 2001;71:1105–12) © 2001 by The Society of Thoracic Surgeons
L
therapy on surgical outcomes by comparing patients receiving preoperative chemotherapy (C⫹S) with patients undergoing surgery alone (S).
ung cancer remains a significant public health problem in the United States with an estimated 171,600 new cases in 1999; 158,900 of those will eventually die from this disease [1]. However, even in its earliest stages, which are amenable to surgical resection, survival after complete resection is compromised by local and systemic recurrences [2, 3]. Survival is poor (0% to 10% at 5 years) for patients with advanced stage non–small cell lung cancer (NSCLC) (stages III and IV) [3]. To improve survival, multiple studies have explored the role of adjuvant therapies including pre- and postoperative chemotherapy and radiation for NSCLC. After disappointing results of postoperative chemotherapy with no improvement in survival [4, 5], most clinical trials in the past decade have explored preoperative chemotherapy or chemoradiation therapy to enhance local and systemic therapy in advanced stage (IIIA) lung cancer. Two small (single institution) prospective randomized trials showed benefit of this approach in stage IIIA NSCLC [6, 7]. However, several reports [8 –11] have reported significant surgical morbidity and mortality associated with preoperative treatment. We examined the influence of preoperative chemo-
Presented at the Thirty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 31–Feb 2, 2000. Address reprint requests to Dr Putnam, Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 109, Houston, TX 77030; e-mail: [email protected].
© 2001 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
Patients and Methods We reviewed 380 consecutive patients undergoing anatomic pulmonary resection (lobectomy or greater) for NSCLC between August 1, 1996, and April 30, 1999. Forty-five anatomic resections were excluded from the analysis for a history of a prior lung cancer (n ⫽ 21), prior chest radiation or chemoradiation therapy for positive N2 nodes (n ⫽ 17), or history of any malignancy other than nonmelanoma skin cancer within the past year (n ⫽ 7). During this same time, an additional 140 segmentectomies and other nonanatomic resections for NSCLC were performed (generally in high-risk patients) and not included in the analysis. Our study population included 335 patients: 259 patients had surgery alone (S) and 76 patients had preoperative chemotherapy (C⫹S).
Data Acquisition Beginning in August 1996, we concurrently collected postoperative events (eg, any event that had an impact on the patient’s convalescence or treatment) and stored them electronically. At the time of discharge, the physician caring for the patient completed a scannable data sheet to record postoperative events. These events included pulmonary, cardiac, gastrointestinal, blood usage, 0003-4975/01/$20.00 PII S0003-4975(01)02406-7
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wound infections, other wound problems, and other events. All database elements were prospectively defined within a database dictionary for consistency of data collection. These definitions allowed for a more precise use of clinical terms such as “adult respiratory distress syndrome” (ARDS) or “pneumonia,” which are used differently by many authors [12–16]. The collected data were reviewed monthly at our quality assurance (morbidity and mortality) conference. Data validity and quality was controlled at this conference by review of the physicians responsible for each patient’s care and by periodic selective randomized retrospective chart audits. All of the end points in this study were derived from this database. None of the end points was collected retrospectively. Patients’ preoperative comorbidities were collected retrospectively by one of us (M.P.S.). Pulmonary function values were collected from our database. The extent of surgical resection was obtained by review of the operative reports. Surgical mortality was defined as any death occurring within 30 days, or after 30 days if the patient was continuously hospitalized after surgery.
Preoperative Treatment Multiple chemotherapy agents were used. These chemotherapy agents and the administration of chemotherapy on a clinical protocol or in an “ad hoc” manner were recorded. Time intervals between the last dose of chemotherapy and surgery as well as the number of chemotherapy cycles were recorded.
Clinical and Pathologic Staging Preoperative clinical staging (cStage) was based on all information before definitive resection. These information sources included the patients’ preoperative clinic notes, radiology reports, review of selected computed tomography scans of the chest and all invasive staging methods such as bronchoscopy, mediastinoscopy, needle biopsy, or other techniques. Patients who responded to preoperative treatment (disappearance of N2 nodes or regression of the primary tumor on computed tomography scan) were clinically “down-staged” based on imaging information alone. The postoperative (pathologic) stage (pStage) was obtained from our departmental database. After review by a trained research nurse, final pathology stage was based on the final written pathology report and operative findings. Pathological stage was further reviewed and validated by the senior surgeon responsible for that patient. Patients with two histologically different, concurrent tumors (4 patients) were staged by the more advanced TNM status of the two tumors.
Data Analysis Differences between the C and C⫹S treatment groups were tested for significance by the 2 test for categorical variables and the Student’s t test for continuous variables. The
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Table 1. Patient Demographics
Characteristic Age (years) Gender Male Female Comorbidities Hypertension Diabetes mellitus Coronary artery disease Pathology Squamous cell carcinoma Adenocarcinoma Other Spirometry FEV1 (average % predicted) FVC (average % predicted) DLCO (average % predicted) Postoperative stagea 1A, 1B 2A, 2B 3A 3B, 4 Surgical procedure Lobectomy Bilobectomy/sleeve resection Pneumonectomy a
Chemotherapy and Surgery (n ⫽ 76)
Surgery Alone (n ⫽ 259)
n (%)
n (%)
p
62.42 (⫾10.10)
64.95 (⫾11.19)
0.08
44 (57.9) 32 (42.1)
149 (57.5) 110 (42.5)
0.96
22 (28.9) 7 (9.2) 9 (11.8)
85 (32.8) 18 (6.9) 31 (12)
0.52 0.51 0.97
19 (25)
72 (27.8)
0.43
47 (61.8) 10 (13.2)
140 (54.1) 47 (18.1)
84.11
83.32
0.791
91.44
93.44
0.336
74.00
80.54
0.066
34 (44.7) 19 (25) 20 (26.3) 3 (3.9)
151 (58.3) 43 (16.6) 40 (15.4) 25 (9.7)
0.02
60 (78.9) 8 (10.5)
212 (81.9) 19 (7.3)
0.67
8 (10.5)
28 (10.8)
Postoperative stage, combines pathological stage and surgical findings.
DLCO ⫽ diffusing capacity of carbon monoxide; FEV1 ⫽ forced expiratory volume in 1 second; FVC ⫽ forced vital capacity.
patients were analyzed by surgical procedure, cStage, pStage, and by chemotherapy given on a study protocol or in an “off protocol” setting. Statistical significance was defined as p less than 0.05. All statistical analyses were performed using SPSS software (SPSS Inc, Chicago, IL). A logistic regression model was constructed with occurrence of a major complication as the dependent variable. Any hospital mortality, pneumonia, reintubation, tracheostomy, ARDS, empyema, bronchopleural fistula, wound complication, blood transfusion, readmit to hospital, or readmit to intensive care unit was defined as a major event. The other covariates included in the model were age, history of coronary artery disease, hypertension, or diabetes, preoperative treatment (chemotherapy versus no chemotherapy), pathologic stage (1,2 versus 3,4), and procedure (lobectomy, sleeve-resection, bilobectomy versus pneumonectomy).
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Table 2. Clinical Staging Accuracy
Clinical Staging Accuracy Surgery alone (n ⫽ 259) Chemotherapy and surgery (n ⫽ 76)
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Table 4. Chemotherapy Regimens
Same pStage and cStage
pStage Lower Than cStage
pStage Higher Than cStage
n (%)
n (%)
n (%)
26 (10)
70 (27)
22 (29.0)
14 (18.4)
163 (63.0) 40 (52.6)
All Patients “On (%) Protocol” “Ad Hoc” (n ⫽ 76) (n ⫽ 40) (n ⫽ 36)
Regimen Carboplatin and paclitaxel Cisplatin and etoposide Cisplatin and vinorelbine Vinorelbine and gemcitabine Cisplatin only
71 (93.4) 1 (1.3) 2 (2.6) 1 (1.3) 1 (1.3)
40 0 0 0 0
31 1 2 1 1
p ⫽ 0.0005. pStage ⫽ postoperative stage, combines pathological stage and surgical findings; cStage ⫽ clinical stage, combines all preoperative imaging and invasive staging methods.
Results Data Quality Departmental review at the quality assurance conference as well as selective randomized chart reviews validated and confirmed accuracy of recorded data.
Patient Characteristics The C⫹S and S alone groups had similar demographics (Table 1). The S group tended to be slightly older (median 65 versus 62.4 years, p ⫽ NS). Comorbidities, histology, and lung functions were also similar in both groups (Table 1). The stage distribution between the two groups was significantly different, with more early stage NSCLC (stages 1A, 1B) in the S group ( p ⫽ 0.02). The correlation of the clinical staging with the postoperative (pathologic) staging is shown in Table 2. The final postoperative stage tended to be significantly lower ( p ⱕ 0.005) in the C⫹S group (Table 2). The extent of surgical resections performed in both groups was similar overall and in stage-specific analysis (Table 3).
Preoperative Treatment Seventy-six patients received preoperative chemotherapy (Table 4). Forty patients were treated on an “early stage protocol” [17], and the remainder (n ⫽ 36) were treated in an “off protocol” setting. The most commonly used combination chemotherapy was paclitaxel and carboplatin (n ⫽ 71, 93%). On the early stage protocol, paclitaxel 225 mg/m2 was given as a 3-hour infusion and carboplatin (area under the curve ⫽ 6) was given every 21
days. No routine growth factor support was used. Two preoperative cycles were given until August 31, 1998. After an interim analysis, which showed a pathologic complete response rate of only 6% and a low completion rate of the scheduled postoperative chemotherapy cycles (46%), this protocol-regimen was changed to three preoperative chemotherapy cycles. No patient was converted from the protocol into an “off protocol” regimen. Patients treated in an “ad hoc” manner received this combination or several other chemotherapy agents (Table 4). The influence of specific chemotherapeutic agents or combination regimens on surgical outcomes could not be evaluated because of small sample size.
Surgical Outcomes Overall, patients receiving C⫹S had no increase in the measured postoperative events than patients receiving S (Table 5). Subsequent subset analysis was performed. The patients were grouped according to clinical (cStage) and pathologic stage (pStage). To have sufficient statistical power, the patients were grouped by stage into four groups; patients with stages Ia and Ib, stages IIa and IIb, stage IIIa, and patients with all higher stages. This stage-specific analysis revealed no difference in postoperative complications and events (Tables 6 and 7). We noted a nonsignificant trend towards increased pulmonary morbidity ( p ⫽ 0.08) and prolonged hospital stay ( p ⫽ 0.09) in the early pStage C⫹S group (stages Ia and Ib). No difference was noted in operation-specific outcomes in the two groups (Table 8). Patients receiving chemotherapy “on protocol” and in an “off protocol” setting were compared. No differences in postoperative
Table 3. Resection by Postoperative Stage (pStage) Bilobectomy/Sleeve Resections
Lobectomy
Pneumonectomy
Resection by pStage
C⫹S (%)
S (%)
C⫹S (%)
S (%)
C⫹S (%)
S (%)
All stages (n ⫽ 335) Stage 1A, 1B Stage 2A, 2B Stage 3A Stage 3B, 4
60 (78.9) 32 (94.1) 14 (73.7) 13 (65) 1 (33.3)
212 (81.9) 137 (90.7) 30 (69.8) 25 (62.5) 20 (80)
8 (10.5) 2 (5.9) 2 (10.5) 4 (20.0) 0
19 (7.3) 9 (6.0) 5 (11.6) 4 (10.0) 1 (4.0)
8 (10.5) 0 3 (15.8) 3 (15) 2 (66.7)
28 (10.8) 5 (3.3) 8 (18.6) 11 (27.5) 4 (16.0)
pStage ⫽ postoperative stage, combines pathological stage and surgical findings; p ⫽ not significant, all groups.
C ⫽ chemotherapy;
S ⫽ surgery.
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event. Preoperative chemotherapy was not a significant variable.
Table 5. Postoperative Events Chemotherapy and Surgery (n ⫽ 76)
Surgery Alone (n ⫽ 259)
n (%)
n (%)
p
34 (44.7) 1 (1.3) 10 (13.2) 8 (10.5) 6 (7.9) 4 (5.3) 2 (2.6) 0 0 4 (5.3) 7 (9.2) 8.38 (⫾8.76) 5 (6.6) 3 (3.9)
132 (51) 13 (5.0) 30 (11.6) 25 (9.7) 14 (5.4) 9 (3.5) 8 (3.1) 3 (1.2) 3 (1.2) 13 (5.0) 25 (9.7) 8.55 (⫾6.75) 14 (5.4) 12 (4.6)
0.205 0.134 0.421 0.485 0.287 0.337 0.596 0.461 0.461 0.564 0.555 0.860 0.439 0.546
Event All events Mortality Major pulmonarya Pneumonia Reintubation Tracheostomy ARDS Empyema Bronchopleural fistula Wound complication Blood transfusion LOS (⫾SD) Readmit to hospital ICU readmit
Comment Preoperative treatment for advanced stage NSCLC has been evaluated in several phase 2 and 3 clinical trials [18 –21]. These studies had acceptable treatment related complication rates. However, patient selection was restrictive and patients with significant comorbidities were likely to be excluded from these studies. Other studies reported a relatively high surgical morbidity and mortality after preoperative treatment [8 –10]. These series reviewed a small number of patients who received preoperative combined modality chemoradiation treatment. An increased incidence of culture negative infiltrates (ARDS) and bronchopleural fistulas was found, mainly after pneumonectomy. Another recently published report found no increased incidence in these complications in 19 consecutive patients who all received combined modality therapy and definitive radiation of more than 59 Gy [22]. In this series all but 1 patient had carefully harvested intercostal flap coverage of the bronchial stump. The 1 patient without this flap developed a bronchopleural fistula. A recent abstract [11] retrospectively reviewed a small number of patients receiving only preoperative chemotherapy with carboplatin and paclitaxel and no concurrent radiation. A mortality rate of 8% and a 32% incidence of life-threatening complications were found. Our study did not confirm these findings. We analyzed all consecutive patients with NSCLC who had an anatomic lung resection and were operated on with curative intent. We excluded patients with recurrent NSCLC or history of another recent malignancy. No
a
Major pulmonary includes pneumonia, reintubation, tracheostomy, or ARDS. Patients may have had one or more of these events. ARDS ⫽ acute respiratory distress syndrome; ICU ⫽ intensive care unit; LOS ⫽ length of stay in hospital; SD ⫽ standard deviation.
events were noted for patients having chemotherapy on protocol or in an ad hoc manner (Table 9).
Multivariate Analysis On multivariate analysis only the presence of coronary artery disease (odds ratio [OR] ⫽ 2.05, confidence interval [CI] ⫽ 1.02 to 4.12, p ⫽ 0.0451) and pneumonectomy (OR ⫽ 2.17, CI ⫽ 1.05 to 4.49, p ⫽ 0.037) were found to be independent risk factors for a major postoperative Table 6. Postoperative Events by Postoperative Stage (p Stage)a Event by Pathological Stage
Stage 1A, 1B (n ⫽ 185) C⫹S (%) (n ⫽ 34)
All events 19 (55.9) Mortality 1 (2.9) Major 6 (17.6) pulmonaryb Pneumonia 5 (14.7) Reintubation 4 (11.8) Tracheostomy 3 (8.8) ARDS 2 (5.9) Wound 2 (5.9) complication Blood transfusion 3 (8.8) Mean LOS (⫾SD) 10.2 (⫾12.13) Readmit to 2 (5.9) hospital ICU readmit 2 (5.9)
Stage 2A, 2B (n ⫽ 62)
S (%) (n ⫽ 151)
C⫹S (%) S (%) (n ⫽ 19) (n ⫽ 43)
p
71 (47.0) 4 (2.6) 12 (7.9)
0.228 0.642 0.086
8 (42.1) 0 4 (21.1)
10 (6.6) 6 (4.0) 4 (2.6) 2 (1.3) 8 (5.3)
0.116 0.088 0.117 0.155 0.579
3 (15.8) 2 (10.5) 1 (5.3) 0 1 (5.3)
p
24 (55.8) 0.236 3 (7.0) 0.326 7 (16.3) 0.451 6 (14.0) 3 (7.0) 1 (2.3) 2 (4.7) 1 (2.3)
0.565 0.489 0.522 0.478 0.522
Stage 3A (n ⫽ 60) C⫹S (%) (n ⫽ 20) 6 (30.0) 0 0
S (%) (n ⫽ 40)
Stage 3B, 4 (n ⫽ 28) p
24 (60.0) 0.027 3 (7.5) 0.289 5 (12.5) 0.12
0 0 0 0 1 (5.0)
4 (10.0) 2 (5.0) 2 (5.0) 2 (5.0) 2 (5.0)
0.187 0.441 0.441 0.441 0.745
C⫹S (%) (n ⫽ 3) 1 (33.3) 0 0 0 0 0 0 0
S (%) (n ⫽ 25)
p
13 (52.0) 0.500 3 (12) 0.702 6 (24) 0.470 5 (20.0) 3 (12.0) 2 (8.0) 2 (8.0) 2 (8.0)
0.541 0.702 0.794 0.794 0.794
9 (6.0) 0.384 1 (5.3) 6 (14.0) 0.301 3 (15.0) 4 (10.0) 0.429 0 6 (24.0) 0.470 7.9 (⫾5.52) 0.091 7.1 (⫾5.3) 8.8 (⫾4.8) 0.225 6.5 (⫾3.0) 9.63 (⫾8.8) 0.132 8.3 (⫾2.5) 10.4 (⫾11) 0.757 8 (5.3) 0.579 2 (10.5) 1 (2.3) 0.223 1 (5.0) 3 (7.5) 0.593 0 2 (8.0) 0.794 8 (5.3)
0.579
1 (5.3)
1 (2.3)
a Postoperative stage, combines pathological stage and surgical findings. ARDS. Patients may have had one or more of these events.
ARDS ⫽ acute respiratory distress syndrome; surgery; SD ⫽ standard deviation.
c ⫽ chemotherapy;
b
0.522
1 (5.0)
1 (2.5)
0.667
0
2 (8.0)
0.794
Major pulmonary includes pneumonia, reintubation, tracheostomy, or
ICU ⫽ intensive care unit;
LOS ⫽ length of stay in hospital;
S ⫽
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Table 7. Postoperative Events by Clinical Stage (c Stage)a Stage 1A, 1B (n ⫽ 210) Event by Clinical Stage
C⫹S (%) (n ⫽ 25)
S (%) (n ⫽ 185)
All events 12 (48.0) 89 (48.1) Mortality 1 (4) 10 (5.4) Major pulmonaryb 5 (20) 17 (9.2) Pneumonia 4 (16) 15 (8.1) Reintubation 3 (12.0) 9 (4.9) Tracheostomy 2 (8.0) 9 (4.9) ARDS 1 (4.0) 6 (3.2) Wound 2 (8.0) 5 (2.7) complication Blood transfusion 1 (4.0) 15 (8.1) Mean LOS (⫾SD) 9.6 (⫾11.1) 8.4 (⫾6.8) Readmit to 2 (8.0) 7 (3.8) hospital Readmit ICU 2 (8.0) 10 (5.4)
Stage 2A, 2B (n ⫽ 71)
p
C⫹S (%) (n ⫽ 22)
S (%) (n ⫽ 49)
0.581 0.615 0.101 0.174 0.159 0.385 0.594 0.197
9 (40.9) 0 2 (9.1) 2 (9.1) 1 (4.5) 1 (4.5) 0 0
27 (55.1) 2 (4.1) 11 (22.4) 9 (18.4) 4 (8.2) 0 2 (4.1) 6 (12.2)
p
S (%) (n ⫽ 8)
0.052 0.386 0.496 0.671 0.371 0.614 0.614 0.67
2 (100) 0 0 0 0 0 0 0
4 (50) 0 1 (12.5) 0 1 (12.5) 0 0 1 (12.5)
0.407 1 (4.5) 8 (16.3) 0.161 5 (18.5) 2 (11.8) 0.441 0.407 6.8 (⫾4.5) 9.3 (⫾6.7) 0.109 8.6 (⫾9.3) 8.3 (⫾6.6) 0.909 0.291 1 (4.5) 4 (8.2) 0.504 1 (3.7) 3 (17.6) 0.153
0 7 (⫾0) 1 (50)
0
1 (2.0)
0.198 11 (40.7) 0.473 0 0.15 3 (11) 0.267 2 (7.4) 0.504 2 (7.4) 0.310 1 (3.7) 0.473 1 (3.7) 0.098 2 (7.4)
12 (70.6) 1 (5.9) 1 (5.9) 1 (5.9) 0 0 0 1 (5.9)
Stage 3B, 4 (n ⫽ 10) C⫹S (%) (n ⫽ 2)
0.431
S (%) (n ⫽ 17)
p
0.690
a Clinical stage, combines all preoperative imaging and invasive staging methods. tomy, or ARDS. Patients may have had one or more of these events.
ARDS ⫽ acute respiratory distress syndrome; surgery; SD ⫽ standard deviation.
Stage 3A (n ⫽ 44) C⫹S (%) (n ⫽ 27)
C ⫽ chemotherapy;
retrospectively collected end points were included in our analysis. We compared those factors that are known to influence surgical morbidity, including age, spirometry results, type of surgical resection, diabetes, coronary artery disease, and hypertension. We found no differences in our two study populations (C⫹S and S alone). The study groups appear to be similar on retrospective review; however, only a prospective randomized trial allows for stratification of these variables. We did not measure other risk factors that may influence surgical outcomes, including current smoking status, nutritional status, surgical incision, type of postoperative pain control, or results of the surgeons. Sophisticated risk scoring sys-
1 (3.7)
b
1 (5.9)
0.629
p 0.333 0.800 0.800
0.800
0 8.6 (⫾6.2) 0.732 0 0.200
0
0
Major pulmonary includes pneumonia, reintubation, tracheos-
ICU ⫽ intensive care unit;
LOS ⫽ length of stay in hospital;
S ⫽
tems have been developed in several surgical specialties such as in trauma, critical care, and cardiac surgery [23–26], and only recently such a risk scoring system has been tested for noncardiac thoracic surgery patients [27]. The preoperative side effects and complications of chemotherapy have been well documented in the two prospectively randomized controlled trials [6, 7]. Chemotherapy-related complications were also carefully reported in a recent phase 2 study for early stage NSCLC [17]. In this multicenter study of 94 patients, significant toxicity after preoperative paclitaxel and carboplatin included grade 3 to 4 neutropenia in 35% with no hospital admissions for febrile neutropenia. Also common were moderate (grade 2) myalgias and arthralgias in 26%. Most
Table 8. Postoperative Events by Procedure Lobectomy
Bilobectomy/Sleeve Resection
Event by Procedure
C⫹S (%) (n ⫽ 60)
S (%) (n ⫽ 212)
p
C⫹S (%) (n ⫽ 8)
S (%) (n ⫽ 19)
All events Mortality Major pulmonarya Pneumonia Reintubation Tracheostomy ARDS Wound complication Blood transfusion Mean LOS (⫾SD) Readmit to hospital ICU readmit
28 (46.7) 1 (1.7) 10 (16.7) 8 (13.3) 6 (10.0) 4 (6.7) 2 (3.3) 3 (5.0) 5 (8.3) 8.8 (⫾9.7) 4 (6.7) 3 (5.0)
102 (48.1) 10 (4.7) 22 (10.4) 19 (9.0) 9 (4.2) 8 (3.8) 5 (2.4) 7 (3.3) 19 (9.0) 8.3 (⫾6.5) 4 (1.9) 12 (5.7)
0.480 0.259 0.135 0.220 0.08 0.260 0.481 0.385 0.558 0.654 0.074 0.570
4 (50) 0 0 0 0 0 0 0 2 (25) 7.6 (⫾4.5) 0 0
10 (52.6) 0 2 (10.5) 1 (5.3) 1 (5.3) 0 0 3 (15.8) 1 (5.3) 9.4 (⫾5.6) 2 (10.5) 0
a
Pneumonectomy
p 0.615 0.487 0.704 0.704 0 0 0.331 0.201 .441 0.487 0
C⫹S (%) (n ⫽ 8)
S (%) (n ⫽ 28)
p
2 (25) 0 0 0 0
20 (71.4) 3 (10.7) 6 (21.4) 5 (17.9) 4 (14.3) 1 (3.6) 3 (10.7) 3 (10.7) 5 (17.9) 9.6 (⫾9.4) 8 (28.6)
0.026 0.459 0.193 0.261 0.348 0.778 0.459 0.652 0.261 0.281 0.337
1 (12.5) 0 5.8 (⫾2.5) 1 (12.5) 0
Major pulmonary includes pneumonia, reintubation, tracheostomy, or ARDS. Patients may have had one or more of these events.
ARDS ⫽ acute respiratory distress syndrome; surgery; SD ⫽ standard deviation.
C ⫽ chemotherapy;
ICU ⫽ intensive care unit;
LOS ⫽ length of stay in hospital;
S ⫽
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Table 9. Comparison of Patients Receiving Three Different Treatments
Patient Characteristics Mean age (years) Comorbidities Hypertension Diabetes mellitus Coronary artery disease All events Mortality Mean LOS (⫾SD) Pulmonary morbiditya Wound complications
Chemotherapy “On Protocol”
Chemotherapy “Ad Hoc”
Surgery Alone (n ⫽ 259)
n ⫽ 40 (12%)
n ⫽ 36 (11%)
n ⫽ 259 (77%)
p
64.9
59.6
64.9
0.023
11 (27.5) 5 (12.5) 8 (20.0) 18 (45.0) 1 (2.5) 8.6 (⫾9.1) 6 (15.0) 2 (5.0)
11 (30.6) 2 (5.6) 1 (2.8) 16 (44.4) 0 8.1 (⫾8.5) 4 (11.1) 2 (5.6)
85 (32.8) 18 (6.9) 31 (12) 132 (51) 13 (5) 8.6 (⫾6.8) 30 (11.6) 13 (5.0)
0.784 0.415 0.070 0.633 0.315 0.939 0.814 0.990
a
Pulmonary morbidity includes pneumonia, reintubation, tracheostomy, or acute respiratory distress syndrome. Patients may have had one or more of these events. LOS ⫽ length of stay in the hospital;
SD ⫽ standard deviation.
of these complications resolved within a week. More severe hematologic and neuromuscular complications were found in less than 5%. During induction chemotherapy in this study 1 patient (1%) died of a cerebrovascular accident while recovering from chemotherapy-induced toxicity, 96% of patients completed the preoperative chemotherapy, and 94% were operated on with intent to cure. Reasons for not undergoing an operation included disease progression (n ⫽ 3), loss to follow-up, unresectable status, or death in 1 patient each. Thirty-four of the 94 patients from that multicenter study were treated at our institution and included in our analysis. Morbidity induced by preoperative chemotherapy for early NSCLC appears to be acceptable. However, to further study this modality, a multi-institutional (phase III Intergroup) prospective randomized trial (SWOG S9900) is currently underway. Patients in our study were not analyzed on an intentto-treat basis. Only patients who underwent surgical resection were entered into our thoracic surgery database and analyzed. In contrast to advanced stage NSCLC [6, 7] there is currently no prospective evidence for a survival advantage after preoperative chemotherapy for stage 1 or 2 NSCLC; this treatment should be given only after informed consent in a protocol setting. Given the intensity of chemotherapy combinations used, it appears surprising that no significant impact on surgical morbidity could be measured. Surgical outcomes were similar for patients if they were given chemotherapy on protocol or in an uncontrolled ad hoc setting, or if no chemotherapy was given. The number of patients in this series was large enough to measure surgical morbidity stratified by several risk groups, including clinical and pathological stage, extent of surgical resection, and protocol enrollment. Our study population and the number of events observed were not large enough to detect small differences in these surgical morbidities. A trend toward increased pulmonary morbidity in early stage lung cancers was noted in this study. In summary, preoperative chemotherapy did not sig-
nificantly affect morbidity or mortality overall, based on clinical or pathological stage, nor by the extent of the pulmonary resection performed. These data, coupled with the well-known preoperative side effects and complications of chemotherapy, justify continued study of preoperative chemotherapy for NSCLC. This work was supported in part by the Texas Tobacco Settlement Fund and the Charles and Beverly Adams Fund for Thoracic Surgery Research.
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10. Deutsch M, Crawford J, Leopold K, et al. Phase II study of neoadjuvant chemotherapy and radiation therapy with thoracotomy in the treatment of clinically staged IIIA non–small cell lung cancer. Cancer 1994;74:1243–52. 11. Roberts JR, DeVore RF, Carbone DP, et al. Neoadjuvant chemotherapy increases perioperative complications in patients undergoing resection for NSCLC [Abstract]. Proc ASCO 2000;18:465A. 12. Bernard GR, Artigas A, Brigham KL, et al. Report of the American-European Consensus conference on acute respiratory distress syndrome: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Consensus Committee. J Crit Care 1994;9:72– 81. 13. Schuster DP. Identifying patients with ARDS: time for a different approach. Intensive Care Med 1997;23:1203. 14. Sachdeva RC, Guntupalli K. Acute respiratory distress syndrome. Crit Care Clin 1997;13:503–21. 15. Meduri GU, Johnanson WG. International Consensus Conference: clinical investigation of ventilator-associated pneumonia. Chest 1992;102:551S–2. 16. Pingleton SK, Fagon JY, Leeper KV. Patient selection for clinical investigation of ventilator-associated pneumonia. Chest 1992;105:553S– 6. 17. Pisters KM, Ginsberg RJ, Giroux DJ, et al, on behalf of the Bimodality Lung Oncology Team (BLOT). Induction chemotherapy before surgery for early-stage lung cancer: a novel approach. J Thorac Cardiovasc Surg 2000;119:429–39. 18. Roth JA, Atkinson EN, Fossella F, et al. Long-term follow-up of patients enrolled in a randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non–small-cell lung cancer. Lung Cancer 1998;21:1– 6. 19. Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cispla-
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DISCUSSION DR JOHN C. WAIN (Boston, MA): I would like to thank Dr Siegenthaler and his colleagues for the opportunity to review this paper before its presentation. I think they are to be commended on two points. They certainly have a lucid and well-documented presentation that demonstrates the immense utility of a real-time data collection system for outcome assessment in patients. A methodology as straightforward and simple as what they described here, which involves recording data about patients at the time of discharge, followed by validation at the weekly or monthly quality assurance conferences, or mortality and morbidity conferences, I think is really invaluable. Not only does the real-time data recording result in ready data for answering clinical questions such as the one posed by the article here, but it is also useful for systematic evaluations and improvements in patient care. Most importantly, perhaps, this is a study in which the methodology and the data were designed, implemented, and managed by the surgeons who were involved in the patient’s care. So that in fact if anyone has any questions about the data they can provide answers quickly and easily. The second major point I would like to emphasize is that I think the surgical outcomes here are excellent, particularly as demonstrated by the low mortality rate of only 1.7% in patients undergoing lobectomy after preoperative chemotherapy, certainly answering the question posed by the tile of the paper. I have only three questions for the authors: 1. What would be the indications for chemotherapy in the patients, particularly the early stage patients? I appreciate that some of the patients were on protocol and some were not, but I wondered how much subjectivity there might be
in selecting those patients who did not receive chemotherapy, particularly the ones off protocol. 2. The low incidence of pneumonectomy in the preoperative chemotherapy group, particularly in the stage III-A group, is striking, and I was wondering if the authors have any indication that their preoperative chemotherapy in fact resulted in a downstaging to the extent that a resection less extensive than a pneumonectomy was possible? 3. And lastly, as the authors noted, there was a trend toward longer hospital stay and increased pulmonary morbidity, somewhat surprisingly, in the early stage group receiving chemotherapy, and I was wondering if they have any hypothesis as to why this might have happened whether it relates to factors not controlled for here, such as smoking or nutritional status, or other factors unique to chemotherapy such as the use of granulocyte colony-stimulating factor, which may induce inflammation in the lung in the postoperative period? And in view of this finding, would they recommend the concept of using chemotherapy in earlier stage lung cancers, which certainly seems to be a developing trend in the management of lung cancer, but perhaps should be rethought. Again, my congratulations to the authors and my thanks to them and the Society for the privilege to discuss this article. Thank you. DR JOHN ROBERTS (Nashville, TN): I enjoyed your paper very much as well, and I had three quick questions. First, I did not understand slide very well, but it appeared that you had a 4.5% mortality for the surgery-alone group. Is that true?
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Second, fewer than 25% of your patients received preoperative chemotherapy. That surprises me for your institution. Do all of your III-A patients receive preoperative chemotherapy or do more of them go into chemoradiotherapy? Finally, your data are at odds with the data that we presented at ASCO, and with the increased mortality that Elias found in the CALGB group study that was conducted a few years ago. I wondered if you had any comment about that? DR MUHAMMAD MUMTAZ (Overland Park, KS): What was the protocol for chemotherapy and how much time did you wait before surgery? Did you have any patients that are not listed here that were initially going to have to go to a surgery arm but did not because of morbidity related to chemotherapy? DR SIEGENTHALER: Thank you Dr Wain, for your kind comments and questions. I would like to start with your questions first. What were the indications for chemotherapy? We tried to include every patient on our early stage protocol, which includes patients with stages 1b, 2a and b as well as the T3N1 group, which is a subgroup of stage 3a. This protocol is now available as the BLOT Intergroup trial. Every patient who is eligible and willing to participate in this trial gets enrolled. In all other patients, we would perform surgery alone. Only through a formal protocol can we determine a survival advantage. Your second question addresses a possible down-staging effect, given the low incidence of pneumonectomy in the chemotherapy and surgery group. I think we have to be careful here. Our study group was fairly small. We also noted, when we correlated the clinical preoperative stage with the final postoperative stage, that there was a significant difference after preoperative chemotherapy. The chemotherapy group had a much higher number of patients that were down-staged, which again could be a sign of a treatment effect. The study population was
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too small and the patient selection was uncontrolled to make such a conclusion. The third question was about the trend for an increased length of stay and pulmonary morbidity. I think there are uncontrolled factors, as you mentioned, which were not analyzed. An answer would be purely speculative. It might be a chemotherapyassociated effect. Ninety percent of our patients received Carboplatin and Taxol. The usual dose limiting toxicity for those agents is neuropathies and neurotoxicities, not bone marrow suppression. No routine growth factor support was used. I think this also explains Dr Mumtaz’s first question. His second question was about the time interval between the surgery and chemotherapy. On the protocol, the surgery was usually performed 1 month after the last administration of chemotherapy. However, this was flexible if longer recovery from the chemotherapy was necessary. We collected the data about the timing between chemotherapy and surgery, but since we found no difference in the univariate analysis, we did not analyze the time interval further. To Dr Robert’s questions, mortality was higher in the surgery alone group, most likely due to the higher number of patients receiving pneumonectomy. The mortality rate was 5%. We did not find the same morbidity associated with preoperative chemotherapy that you found in your previous investigation. I cannot explain this difference between our institutions although our study population was larger. Your last question was why only 25% of patients received chemotherapy. I think the overall proportion was higher. Patients receiving preoperative chemoradiation for stage 3a were excluded from the analysis. A high proportion of our clinical stage 3a patients received preoperative treatment. For earlier stages, however, we do not believe that chemotherapy should be given in an “off protocol” setting , since there is no hard data proving a survival benefit for this patient group.