Thoracoscopic Lobectomy Is Associated With Superior Compliance With Adjuvant Chemotherapy in Lung Cancer

Thoracoscopic Lobectomy Is Associated With Superior Compliance With Adjuvant Chemotherapy in Lung Cancer Jin Gu Lee, MD, Byoung Chul Cho, MD, Mi Kyung Bae, MD, Chang Young Lee, MD, In Kyu Park, MD, Dae Joon Kim, MD, and Kyung Young Chung, MD Departments of Thoracic and Cardiovascular Surgery and Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea Background. Although the survival benefit of adjuvant chemotherapy for nonsmall-cell lung cancer has been proved, 50% to 86% of patients received all planned cycles of chemotherapy. A thoracoscopic procedure may enable more effective administration of adjuvant chemotherapy than a thoracotomy. However, a well-balanced comparison is lacking. Methods. Patients who underwent pulmonary resection and received platinum-based double adjuvant chemotherapy for nonsmall-cell lung cancer were identified from a prospective database. A propensity score-matched analysis was performed to obtain a well-balanced comparison between thoracoscopy and thoracotomy to determine compliance of adjuvant chemotherapy. Results. Seventy-four patients (group A) with thoracoscopy and 278 patients with thoracotomy received adjuvant chemotherapy. Through 1:1 matching, 74 patients (group B) were selected from the thoracotomy group. A higher percentage of group A received four cycles of the planned adjuvant chemotherapy (95.9% versus 82.4%, p 0.015). There was a trend toward better compliance in group A with four cycles of adjuvant chemotherapy without reduced dose (83.8% versus 73.0%, p 0.162), and four cycles of adjuvant chemotherapy without delayed or reduced dose (70.3% versus 62.2%, p 0.385). Conclusions. Thoracoscopy showed better compliance with adjuvant chemotherapy after pulmonary resection for nonsmall-cell lung cancer. (Ann Thorac Surg 2011;91:344 9) 2011 by The Society of Thoracic Surgeons Although survival benefit of adjuvant chemotherapy after complete resection for stage IB and IIIA nonsmall-lung cancer (NSCLC) has been proved [1-5], only 50% to 87% of patients receive all planned cycles of chemotherapy [4-6]. This poor compliance with adjuvant chemotherapy is one of obstacles to improve the survival of patients with NSCLC who need adjuvant chemotherapy. Thus, efforts that facilitate the delivery of chemotherapy may improve survival of patients with lung cancer. Thoracoscopic pulmonary resection is a currently accepted approach for patients with NSCLC and is suggested to be associated with several advantages compared with conventional thoracotomy, including shorter length of hospitalization and chest tube duration, decreased postoperative pain, improved preservation of pulmonary function, and fewer overall complications [7-9]. One of the suggested advantages is to enable more effective administration of adjuvant chemotherapy to patients who need adjuvant chemotherapy [9, 10]. However, a well-balanced comparison of the two procedures related to compliance of chemotherapy is lacking in the literature. We designed this study according to the following hypothesis: thoracoscopic lobectomy is associated with Accepted for publication Sept 15, 2010. Address correspondence to Dr Chung, 250 Seongsanno, Seodaemun-Gu, CPO Box 8044, Seoul 120-752, South Korea; e-mail: kychu@yumc.yonsei.ac.kr. superior compliance with adjuvant chemotherapy compared with conventional thoracotomy in a well balanced comparison. Patients and Methods Patients We retrospectively assessed our prospective data cohort of 1416 patients with NSCLC who underwent pulmonary resection at our institution between January 2000 and December 2009. Patients who underwent lobectomy or bi-lobectomy and received platinum based doublet adjuvant chemotherapy were included in this study. Patients who received preoperative therapy were excluded. Ultimately, a total of 352 patients were evaluated. Of these, 74 patients (group A) underwent thoracoscopic lobectomy and 278 patients underwent thoracotomy. Through propensity score matching, 74 patients (group B) were selected in the thoracotomy group to compare with group A. Pathology staging was based on the 1997 TNM classification system [11]. Blood samples for hematologic cell count had been obtained on admission to the unit before adjuvant chemotherapy. A pain score was measured at the first visit after operation according to the numerical pain intensity scale (scale 0 to 10). The prescription rate for pain medications was analyzed at 2011 by The Society of Thoracic Surgeons 0003-4975/$36.00 Published by Elsevier Inc doi:10.1016/j.athoracsur.2010.09.031

Ann Thorac Surg LEE ET AL 2011;91:344 9 CHEMOTHERAPY COMPLIANCE AFTER THORACOSCOPY the first visit after operation. Delayed administration of adjuvant chemotherapy was defined as more than 1 week delay or readmission for chemotherapy. The Institutional Review Board of Yonsei University College of Medicine approved this retrospective study. The need for individual consent of patients whose records were evaluated was waived because individuals were not identified within the study. Operative Technique During the study period, thoracoscopic lobectomy was performed from 2005. In the beginning period, early stage lung cancer was indicated for thoracoscopic resection, and the indication was extended to patients who need adjuvant treatment after pulmonary resection. In 2009, more than half of the resections for lung cancer were performed by thoracoscopy. Thoracoscopic lobectomy was performed with a 3-cm to 5-cm utility incision at the anterior axillary line at the fourth or fifth intercostal space, using endoscopic instruments without rib spreading and two or three ports for camera, stapler insertion, and assistant. The operation was performed entirely with thoracoscopic visualization. The hilar structures were individually ligated by endovascular staplers, and the mediastinal nodal dissection was performed. Thoracotomy lobectomy was performed through a posterolateral thoracotomy incision. Staplers were routinely used for the transection of vessels and the completion of the fissures. In all patients, an ipsilateral mediastinal lymph node dissection was performed. Adjuvant Chemotherapy Postoperative adjuvant chemotherapy was recommended for all stage II to IIIB lung cancer. For IB patients, the choice of postoperative therapy was determined by the availability of adjuvant therapy protocols and physician preference. Most patients received cisplatin (80 mg/m 2 ) based chemotherapy; the regimens of chemotherapy were not different between the groups. Decisions about dose reduction or dose delay were made by the treating medical oncologist at the time of the scheduled dose using objective criteria (white cell count, absolute neutrophil count, serum creatinine, gastrointestinal symptoms, and neurologic symptoms) and subjective criteria (performance status). Radiation therapy was given sequentially after chemotherapy to selected patients. Statistical Analysis The association between variables was analyzed by either 2 test or t test. A propensity score-matched analysis was performed to get a well-balanced comparison. Propensity scores were generated for all patients eligible to undergo either thoracoscopy or thoracotomy. Thoracoscopy versus thoracotomy was the treatment indicator (dependent variable), and the covariates were age, sex, forced expiratory volume in 1 second (FEV 1 [%]), T stage, N stage, procedure (lobectomy or bilobectomy), histology, and smoking history. 345 The nearest neighbor matching method was used without replacement. A p value of less than 0.05 was considered significant. Data were analyzed using SPSS for Windows (Statistical Package for Social Science; SPSS, Chicago, IL) and matching macro. Results Patient Characteristics Patients who underwent thoracotomy showed a significantly higher incidence of male sex, smoking history, squamous histology, aggressive procedure (bilobectomy versus lobectomy), and advanced stage (T, N, stage) compared with patients who underwent thoracoscopy (group A; Table 1). Through propensity score matching, 74 patients (group B) were selected in the thoracotomy group, and they showed similar characteristics (age, sex, smoking history, pulmonary function, procedure, T, N, stage, histology) as group A (Table 2). Compliance With Adjuvant Chemotherapy A higher percentage of group A received four cycles of the planned adjuvant chemotherapy (95.9% versus 82.4%, p 0.015). There was a trend toward better compliance in group A with four cycles of adjuvant chemotherapy without reduced dose (83.8% versus 73.0%, p 0.162), and four cycles of adjuvant chemotherapy without delayed or reduced dose (70.3% versus 62.2%, p 0.385). There was no significant difference in time to the initiation of chemotherapy after operation (26.9 7.5 versus 28.1 10.7, p 0.447; Table 3). Postoperative Pain, Performance Status, and Hematologic Cell Count Patients in group A showed a lower pain score at the first visit after operation (2.23 1.49 versus 2.88 1.41, p 0.008). The prescription rate for analgesics was also lower in group A (52.7% versus 80.8%, p 0.001). There was a trend toward better performance status in group A before the start of adjuvant chemotherapy. In terms of hematologic cells, patients in group A showed a significantly higher white cell count (7.57 1.78 versus 6.77 1.96, p 0.012) and absolute neutrophil count (476.4 155.7 versus 408.1 154.9, p 0.010) before adjuvant treatment. There was no difference in platelet count between the groups (Table 4). Thoracoscopy and Thoracotomy showed a shorter length of stay in the intensive care unit (0.74 0.57 versus 0.97 0.37, p 0.004) and chest tube duration (5.48 2.59 versus 6.36 2.72, p 0.045), and decreased blood loss during the operation (142.2 229.7 cc versus 239.7 269.6 cc, p 0.020) compared with group B. also showed a trend toward shorter lengths of hospitalization (7.05 2.59 versus 8.04 3.39, p 0.054). Operation time and the incidence of complication were not different between the groups (Table 5). There was no operative mortality in either group. GENERAL THORACIC

346 LEE ET AL Ann Thorac Surg CHEMOTHERAPY COMPLIANCE AFTER THORACOSCOPY 2011;91:344 9 Table 1. Clinical and Surgical Characteristics Before Matching Variables Thoracoscopy (n 74) Thoracotomy (n 278) Age, mean (range) 60.0 (35 76) 60.9 (32 80) 0.467 Sex Male 41 (55.4) 215 (77.3) Female 33 (44.6) 63 (22.7) Smoking history Yes 35 (47.3) 170 (61.2) 0.022 No 39 (52.7) 108 (38.8) ECOG functional class 0 69 (93.2) 190 (68.3) 1 5 (6.8) 83 (29.9) 2 5 (1.8) FEV 1 2.43 0.85 2.37 0.86 0.598 FEV 1 % 95.89 31.06 89.45 29.44 0.099 Procedure 0.002 Lobectomy 71 (95.9) 227 (81.7) Bilobectomy 3 (4.1) 51 (18.3) T stage 0.003 1 15 (20.3) 39 (14.0) 2 55 (74.3) 173 (62.2) 3 1 (1.4) 44 (15.8) 4 3 (4.1) 22 (7.9) N stage 0 42 (56.8) 81 (29.1) 1 12 (16.2) 102 (36.7) 2 20 (27.0) 87 (31.3) 3 0 (0.0) 8 (2.9) Pathology stage IB 39 (52.7) 51 (18.3) IIA 5 (6.8) 21 (7.6) IIB 8 (10.8) 85 (30.6) IIIA 20 (27.0) 92 (33.1) IIIB 2 (2.7) 29 (10.4) Histology Adenocarcinoma 56 (75.7) 127 (45.7) Squamous 11 (14.9) 116 (41.7) Other 7 (9.5) 35 (12.6%) FEV 1 forced expi- ECOG Eastern Cooperative Oncology Group; ratory volume in 1 second. Patients Who Were Intolerant of Adjuvant Chemotherapy Patients who were intolerant of adjuvant chemotherapy were analyzed. Three patients could not complete four cycles of adjuvant chemotherapy in group A. The reason was poor tolerance in 1 patient, grade 3 dyspnea in 1 patient, and recurrence in 1 patient. Thirteen patients could not complete four cycles of adjuvant chemotherapy in group B. The reason was death after pneumonia in 2 patients, pneumonia in 2 patients, poor tolerance in 3 patients, hematologic suppression in 3 patients, recurrence in 2 patients, and refusal in 1 patient. Comment Patients who underwent thoracoscopy showed better compliance rates with adjuvant chemotherapy compared with patients who underwent conventional thoracotomy. Table 2. Clinical and Surgical Characteristics After Propensity Score Matching Variables (n 74) (n 74) Age, mean (range) 60.0 (35 76) 58.3 (35 74) 0.256 Sex 0.740 Male 41 (55.4) 44 (59.5) Female 33 (44.6) 30 (40.5) Smoking history 1.000 Yes 35 (47.3) 36 (48.6) No 39 (52.7) 38 (51.4) ECOG functional class 0.574 0 69 (93.2) 69 (93.2) 1 5 (6.8) 4 (5.4) 2 1 (1.4) FEV 1 2.43 0.85 2.48 0.92 0.699 FEV 1 % 95.89 31.06 96.90 30.07 0.841 Procedure 1.000 Lobectomy 71 (95.9) 72 (97.3) Bilobectomy 3 (4.1) 2 (2.7) T stage 0.408 1 15 (20.3) 11 (14.9) 2 55 (74.3) 54 (73.0) 3 1 (1.4) 1 (1.4) 4 3 (4.1) 8 (10.8) N stage 0.608 0 42 (56.8) 47 (63.5) 1 12 (16.2) 12 (16.2) 2 20 (27.0) 15 (20.3) 3 0 (0.0) 0 (0.0) Pathology stage 0.301 IB 39 (52.7) 39 (52.7) IIA 5 (6.8) 3 (4.1) IIB 8 (10.8) 9 (12.2) IIIA 20 (27.0) 15 (20.3) IIIB 2 (2.7) 8 (10.8) Histology 0.611 Adenocarcinoma 56 (75.7) 54 (73.0) Squamous 11 (14.9) 15 (20.3) Other 7 (9.5) 5 (6.8) Radiotherapy 0.651 Yes 10 (13.5) 13 (17.6) No 64 (86.5) 61 (82.4) White blood cell count, 7.13 1.79 7.36 2.36 0.509 1,000 a Absolute neutrophil 421.4 131.3 461.1 217.8 0.186 count a Platelet count, 1,000 a 273.0 90.4 287.9 78.9 0.295 a Before operation. FEV 1 forced expi- ECOG Eastern Cooperative Oncology Group; ratory volume in 1 second.

Ann Thorac Surg LEE ET AL 2011;91:344 9 CHEMOTHERAPY COMPLIANCE AFTER THORACOSCOPY Table 3. Adjuvant Chemotherapy Compliance After Lobectomy by Surgical Approach Compliance Time to start of 26.9 7.5 28.1 10.7 0.447 chemotherapy, Patients with 0.068 chemotherapy 1 cycle 1 (1.4) 3 (4.1) 2 cycles 1 (1.4) 4 (5.4) 3 cycles 1 (1.4) 6 (8.1) 4 cycles 71 (95.9) 61 (82.4) Patients with 4 cycles 71 (95.9) 61 (82.4) 0.015 Patients with 4 cycles, 62 (83.8) 54 (73.0) 0.162 full dose Patients with 4 cycles, full dose, no delay 52 (70.3) 46 (62.2) 0.385 Postoperative pain score, analgesics prescription rate, and performance status were better for thoracoscopy patients. White cell count and absolute neutrophil count were higher in thoracoscopy patients before adjuvant chemotherapy. Based on these results, we can predict better compliance with adjuvant chemotherapy for the thoracoscopy group, and it seems to be associated with lower postoperative pain, better performance status, and better preserved hematologic function before adjuvant chemotherapy. Thoracoscopic major lung resection for early stage lung cancer has now gained wide acceptance, although some surgeons remain skeptical about its oncologic safety, long-term benefit, and cost effectiveness. The Table 4. Postoperative pain, Functional Status, and Hematologic Cell Count by Surgical Approach Variable Pain score at first visit 2.23 1.49 2.88 1.41 0.008 Prescription for pain at 0.001 first visit None 35 (47.3) 14 (19.2) Nonopioid 9 (12.2) 12 (16.4) Opioid 30 (40.5) 47 (64.4) ECOG score before 0.087 chemotherapy 0 18 (24.3) 10 (13.5) 1 52 (70.3) 54 (73.0) 2 4 (5.4) 10 (13.5) White blood cell count, 7.57 1.78 6.77 1.96 0.012 1,000 a Absolute neutrophil 476.4 155.7 408.1 154.9 0.010 count a Platelet count, 1,000 a 313.5 116.3 319.7 89.4 0.722 a Before adjuvant chemotherapy. ECOG Eastern Cooperative Oncology Group. Table 5. Postoperative Course After Lobectomy Complication 347 Operation time, 175.4 57.1 165.9 53.0 0.298 minutes Intensive care unit stay, 0.74 0.57 0.97 0.37 0.004 Hospitalization, 7.05 2.69 8.04 3.39 0.054 Chest tube duration, 5.48 2.59 6.36 2.72 0.045 Blood loss during 142.2 229.7 239.7 269.6 0.020 operation, cc Complications Total 18 (24.3) 16 (21.6) 0.845 Respiratory failure 0 1 Middle lobe torsion 0 1 Prolonged air leak 5 11 5 Atrial fibrillation 3 4 Pneumonia 3 5 Vocal cord palsy 1 0 Chylothorax 1 0 Pneumothorax 1 1 Abdominal ileus 1 1 Hematoma 1 0 suggested advantages of thoracoscopic resection compared with conventional thoracotomy were shorter length of hospitalization and chest tube duration, decreased postoperative pain, improved preservation of pulmonary function, and fewer overall complications [7-9]. Our results also indicated that thoracoscopic resection was associated with shorter intensive care unit stay and chest tube duration, and decreased blood loss during the operation, and these patients tended to have a shorter hospitalization. Recently, studies have suggested that thoracoscopic lung resection facilitates the delivery of adjuvant chemotherapy, resulting in a higher compliance rate, fewer delays, and reduced dose of chemotherapy [9, 10]. Although the survival benefit of adjuvant chemotherapy has been proven for patients with NSCLC after pulmonary resection, only 50% to 87% of patients received all of the planned cycles of chemotherapy [4-6]. This study focuses on this compliance with adjuvant chemotherapy because the effort to increase the compliance could prolong the survival of patients who need adjuvant chemotherapy after pulmonary resection for NSCLC. The compliance with chemotherapy can be influenced by several factors such as age, sex, and extent of resection [6]. Through propensity score matching, we obtained a well-balanced comparison of the groups, and this comparison showed that thoracoscopic pulmonary resection is associated with better compliance with adjuvant chemotherapy compared with conventional thoracotomy. A possible explanation of this better compliance is associated with a preserved hematologic system after a less traumatic procedure. Major surgery can affect nu- GENERAL THORACIC

348 LEE ET AL Ann Thorac Surg CHEMOTHERAPY COMPLIANCE AFTER THORACOSCOPY 2011;91:344 9 merous immune factors, which may have an impact on postoperative infection and compliance with immunosuppressive chemotherapy. Patients who have to receive adjuvant chemotherapy have suffered from hematologic suppression, and they need adequate immune function to complete planned adjuvant chemotherapy. Most studies thus far on postoperative immunosuppression have been based on open and laparoscopic abdominal surgery [12]. There is growing evidence to suggest that the body s immune function is better preserved after thoracoscopy compared with thoracotomy, as documented by the release of proinflammatory and antiinflammatory cytokines, immune-modulatory cytokines, circulating T cells, natural killer cells, lymphocyte function, and quicker cell recovery [12-14]. Our data showed that the white cell count and absolute neutrophil cell count before adjuvant chemotherapy (26.9 and 28.1 after operation, respectively) were higher in the thoracoscopy group, suggesting that hematologic function is more quickly recovered or better preserved after thoracoscopy compared with thoracotomy. Most patients who were intolerant of adjuvant chemotherapy in our study had had pneumonia and hematologic suppression. The findings from these patients also support this explanation. A second possible explanation seems to be associated with less postoperative pain and better performance status. Less postoperative pain, better performance status, and preserved pulmonary function are already wellknown advantages after thoracoscopic resection [7-9]. Our data also showed less postoperative pain, a lower prescription rate for pain medications, and better performance status after thoracoscopic resection. These advantages could also be associated with better compliance with adjuvant chemotherapy. Compared with previously reported studies about adjuvant chemotherapy compliance after thoracoscopy and thoracotomy, the present study has analyzed adjuvant chemotherapy compliance through a well-balanced comparison with propensity score matching. The present study also suggests that better compliance after thoracoscopic pulmonary resection could be related to preserved hematologic function resulting from less traumatic procedures, aside from less postoperative pain and better performance status. In summary, our results indicate that thoracoscopic pulmonary resection for NSCLC showed better compliance with adjuvant chemotherapy, and this better compliance was correlated with less postoperative pain, a better performance status, and better hematologic function. Based on these results, we can apply the thoracoscopic procedure not only to patients with early stage NSCLC but also to patients who need adjuvant chemotherapy, if it does not disturb oncologic principles. References 1. Arriagada R, Dunant A, Pignon JP, et al. Long-term results of the International Adjuvant Lung Cancer Trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol 2010;28:35 42. 2. Winton TL, Livingstan R, Johnson D, et al. A prospective randomized trial of adjuvant vinorelbine (VNR) and cisplatin (CIS) in completely resected stage Ib and II non small cell lung cancer (NSCLC). Intergroup JBR10. N Engl J Med 2005;352:2589 97. 3. Strauss GM, Hernden J, Maddaus MA, et al. Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in stage Ib non-small cell lung cancer (NSCLC): report of Cancer and Leukemia Group B (CALGB) protocol 9633 [abstract]. J Clin Oncol 2004;22: 621s. 4. Strauss GM, Hernden JE, Maddaus MA, et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group study groups. J Clin Oncol 2008;26:5043 51. 5. Douillard J, Rosell R, Delena M, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 2006;7:719 27. 6. Alam N, Shepherd FA, Winton T, et al. Compliance with post-operative adjuvant chemotherapy in non-small cell lung cancer. An analysis of National Cancer Institute of Canada and Intergroup Trial JBR.10 and a review of the literature. Lung Cancer 2005;47:385 94. 7. Villamizar NR, Darrabie MD, Burfeind WR, et al. Thoracoscopic lobectomy is associated with lower morbidity compared with thoracotomy. J Thorac Cardiovasc Surg 2009;138: 419 25. 8. Paul S, Altorki NK, Sheng S, et al. Thoracoscopic lobectomy is associated with lower morbidity than open lobectomy: a propensity-matched analysis from the STS database. J Thorac Cardiovasc Surg 2010;139:366 78. 9. Nicastri DG, Wisnivesky JP, Litle VR, et al. Thoracoscopic lobectomy: report on safety, discharge independence, pain, and chemotherapy tolerance. J Thorac Cardiovasc Surg 2008;135:642 7. 10. Petersen RP, Pham D, Burfeind WR, et al. Thoracoscopic lobectomy facilitates the delivery of chemotherapy after resection for lung cancer. Ann Thorac Surg 2007;83:1245 50. 11. Mountain CF. Revision of the international system for staging lung cancer. Chest 1997;111:1710 7. 12. Ng CS, Whelan RL, Lacy AM, et al. Is minimal access surgery for cancer associated with immunologic benefits? World J Surg 2005;29:975 81. 13. Ng CS, Lee TW, Wan S, et al. Thoracotomy is associated with significantly more profound suppression in lymphocytes and natural killer cells than video assisted thoracic surgery following major lung resections for cancer. J Invest Surg 2005;18:81 8. 14. Leaver HA, Craig SR, Yap PL, et al. Lymphocyte responses following open and minimally invasive thoracic surgery. Eur J Clin Invest 2000;30:230 8. INVITED COMMENTARY This study by Lee and colleagues [1] analyzes the ability to deliver adjuvant chemotherapy in patients after lobectomy, comparing the thoracoscopic with the open approach. Patients who underwent thoracoscopic lobectomy were better able to tolerate adjuvant chemotherapy, as measured by the percentage of patients who received 2011 by The Society of Thoracic Surgeons 0003-4975/$36.00 Published by Elsevier Inc doi:10.1016/j.athoracsur.2010.09.051