Lung cancer is the leading cause of cancer-related

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1 Advanced Non-Small Cell Lung Cancer: Induction Chemotherapy and Chemoradiation Before Operation Arnold Cyjon, MD, Moshe Nili, MD, Gershon Fink, MD, Mordechai R. Kramer, MD, Eyal Fenig, MD, Judith Sandbank, MD, Aaron Sulkes, MD, and Erica Rakowsky, MD Institutes of Oncology and Pathology, Assaf Harofeh Hospital, Zrifin, Departments of Cardiothoracic Surgery, Pulmonology, and Oncology, Rabin Medical Center, Beilinson Campus, Petah Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel Background. Induction chemotherapy before operation is beneficial for patients with advanced locoregional non-small cell lung cancer. However, no optimal regimen has been established. This study assesses feasibility, response, resectability, and survival of chemotherapy followed by chemoradiation before operation in patients with non-small cell lung cancer. Methods. Fifty-seven stage IIIA and selected IIIB patients with non-small cell lung cancer received 2/3 cycles of cisplatin and oral etoposide, followed in 3/4 weeks by chemoradiation with daily cisplatin before each radiation fraction. Patients achieving a resectable status underwent operation. Results. Response to induction treatment was documented in 73%; 69% achieved a resectable status and 53% underwent operation. Median survival was 16 months. The 1-, 2-, and 3-year survival rates were 65%, 35% and 22%, respectively. There was no difference in survival between stage IIIA and IIIB disease. Myelotoxicity was moderate to severe (grade III/IV in 61% of patients). Three patients died of late complications of pneumonectomy. Conclusions. Our presurgery chemotherapy and chemoradiation protocol yields high response and resectability rates, with moderate to severe myelotoxicity. Pneumonectomy is associated with a relatively high rate of late complications. (Ann Thorac Surg 2002;74:342 7) 2002 by The Society of Thoracic Surgeons Lung cancer is the leading cause of cancer-related mortality in the United States, with more than 157,000 deaths in 1995 alone [1]. Nearly one-third of all patients with non-small cell lung cancer (NSCLC) present with advanced locoregional disease (stage IIIA,B) and no evidence of metastatic spread [2]. Stage III disease has traditionally been viewed as nonresectable [3], and until recently, patients were offered treatment with radiotherapy alone, which provides good palliation but marginal survival benefit [4]. No single treatment modality has been able to control both the primary tumor as well as the occult systemic disease to ensure long-term survival. Clinical research efforts in the past decade have focused on the possible application of combined modalities wherein chemotherapy plays the pivotal role. Induction chemotherapy in the preoperative setting offers important theoretical advantages, such as a reduction in local tumor burden and a potential increase in resectability rate. There may also be a lower systemic failure rate owing to the increased chemosensitivity of smaller tumors, which may have a faster growth rate and a higher proportion of cells in S phase. In addition, chemotherapy may be better tolerated when given before local treatment [5]. According to several phase II studies, induction therapy with or without radiotherapy was beneficial in Accepted for publication April 24, Address reprint requests to Dr Cyjon, Institute of Oncology, Assaf Harofeh Hospital, Zrifin 70300, Israel; acyjon@netscape.net. patients with stage IIIA and selected patients with stage IIIB NSCLC, with response rates of 51% to 77% and resectability rates of 63% to 90% [6 13]. Complete surgical resection was done in 40% to 70% of the patients, and complete pathologic remission was achieved in 10% to 25%. In addition, two phase III studies have demonstrated survival benefits for patients given neoadjuvant treatment before surgical resection [14, 15]. In both, however, the number of patients was small and survival in the control arm was shorter than expected. The aim of the present study was to determine the feasibility of a multistep protocol of induction chemotherapy and chemoradiation followed by radical operation, when feasible, in patients with advanced locoregional NSCLC. For chemotherapy, we used cisplatin and protracted oral etoposide on the assumption that the latter drug would be more effective when administered for prolonged periods of time rather than according to the standard intravenous schedule of 3 to 5 days every 21 days [16 18]. The chemoradiation took advantage of the radiosensitizing properties of cisplatin [19]. Resectability rate, local control, incidence of distant spread, and survival were assessed. Patients and Methods The study sample consisted of 57 consecutive patients seen at a single institution from October 1991 to August 1999 for histologically or cytologically confirmed stage 2002 by The Society of Thoracic Surgeons /02/$22.00 Published by Elsevier Science Inc PII S (02)

2 Ann Thorac Surg CYJON ET AL 2002;74:342 7 COMBINED TREATMENT OF ADVANCED NSCLC 343 IIIA or IIIB NSCLC. None had either pleural effusion or supraclavicular lymph node metastases. Other inclusion criteria were performance status of two or less according to the World Health Organization scale, adequate cardiopulmonary and bone marrow function, creatinine clearance of more than 40 ml/min, and no previous treatment. The pretreatment evaluation included complete medical history and physical examination, computerized tomography (CT) of the brain, chest, and upper abdomen, and bone scan in all patients. Although surgical staging was not required, 12% of the 42 patients entering the study before December 1996 and 64% of the 16 patients who entered the study in December 1996 or later underwent mediastinoscopy as part of the initial staging. Patients received a combination of 100 mg/m 2 of cisplatin delivered as an 8-hour infusion with adequate hydration on day 1 and 100 mg/d of oral etoposide on days 1 to 14 at 28-day intervals, with proper antiemetic therapy. From October 1991 to December 1994, two cycles of induction chemotherapy were delivered. From January 1995 to August 1999, a third cycle was added, in an attempt to decrease the incidence of distant spread. Three to 4 weeks after completion of induction chemotherapy, chemoradiation was instituted. Cisplatin (3 mg/ m 2 ) was delivered 1 hour before each radiation fraction. The total dose of radiation was 45 Gy, given in 25 fractions of 180 cgy five times a week. The radiation field comprised the primary tumor, the ipsilateral hilum, and the mediastinum. Response was assessed after completion of induction chemotherapy, with chest and upper abdominal CT scan. Brain, chest, and abdominal CT scans were repeated at completion of preoperative therapy. Cardiopulmonary evaluation was done in all candidates for operation. Patients considered to have a resectable tumor underwent thoracotomy within 30 days of chemoradiation. The primary tumor and ipsilateral mediastinal hilar nodes were resected when feasible. Nineteen patients underwent lobectomy, 8 pneumonectomy, and 4 bilobectomy. Follow-up consisted of physical examination and laboratory tests every 2 months. Chest and upper abdominal CT scans were performed 2 months after operation, and then every 6 months for 2 years, and yearly thereafter. Complete clinical response was defined as the disappearance of all measurable disease and the absence of new lesions; partial response as a reduction of more than 50% of the sum of the products of the cross-sectional diameters of all measurable lesions and the absence of new lesions; and minimal response as a reduction of more than 25% but less than 50% in the cross-sectional diameters of all measurable lesions and the absence of new lesions. Stable disease was defined as a reduction of less than 25% of the sum of the products of the crosssectional diameters of all measurable lesions and the absence of new lesions; and progressive disease as an increase of more than 25% in the sum of the products of the cross-sectional diameters of all measurable lesions or the appearance of new lesions. Survival was defined as the interval between treatment Table 1. Patient Characteristics Characteristics No. of Patients % Gender Male Female Age 70 years years Histology Squamous cell carcinoma Adenocarcinoma Large cell carcinoma Tumor size 4 cm cm TN categories T3 N0/1 3 5 T4 N AnyTN Any T N Stage IIIA IIIB Performance status Weight loss 5% body weight % body weight onset and death or date of last follow-up. Survival was assessed by univariate and multivariate analysis in relation to age, gender, histologic type, performance status, stage, weight loss, number of cycles, and response to treatment and operation. The Kaplan-Meier product limit method was applied using SPSS software (SPSS Inc, Chicago, IL) [20]. The log-rank test [21] was used to compare survival between groups divided according to the variables mentioned. Cox proportional hazards regression models [22] were applied for multivariate analysis. The relationship between response rate and all the variables was evaluated with 2 test. Results Patient Characteristics The patient characteristics are described in Table 1. As expected, the majority (79%) were men. Median age was 66 years, with a range of 40 to 79 years; 35% were older than 70 years. The vast majority of patients (88%) were symptomatic at the time of diagnosis. Median tumor size was 6 cm. Three patients (5.3%) had T3 N0 or T3 N1 disease, 7 (12.3%) had T4 N0 disease, and 8 (14%) had N3 disease. There was a slight preponderance of patients with stage IIIB disease. Only 23% of patients had lost more than 5% of their body weight in the 3 months before diagnosis.

3 344 CYJON ET AL Ann Thorac Surg COMBINED TREATMENT OF ADVANCED NSCLC 2002;74:342 7 Table 2. Correlation Between Clinical Characteristics and Response Variable Response Rate p Value Gender Male (n 44) 70% Female (n 11) 82% Age 70 (n 36) 72% 70 (n 19) 74% Histology Squamous cell (n 26) 81% Adeno (n 12) 76% Large cell (n 12) 50% Stage IIIA (n 25) 72% IIIB (n 30) 73% Performance status 0(n 7) 86% 1(n 44) 70% 2(n 4) 75% Weight loss 5% (n 43) 70% 5% (n 12) 83% Number of cycles a 2(n 23) 78% 3(n 30) 73% a Two patients received only one cycle of chemotherapy due to disease progression. Response Two patients died of sepsis after the first cycle of induction chemotherapy. Therefore, 55 patients were assessable for response, but all 57 were assessable for toxicity and survival. A major objective response (complete or partial) was noted in 65% of the 55 evaluable patients after two or three cycles of induction chemotherapy and in 73% after chemoradiation; 5.5% of patients had a minimal response and 7% had stable disease. In 14.5%, the disease progressed during treatment. No significant correlation was found between the response before operation and the clinical characteristics (gender, age, histologic type, stage, performance status, weight loss, and number of chemotherapy cycles), as shown in Table 2. Thirty-eight of the 55 patients alive at completion of the preoperative treatment (69%) were considered to have resectable disease. Of the remainder 17 patients, resection was precluded by the extent of local disease, as determined by CT scan, in 7 (13%), presence of metastases in 9 (16%), and both local and systemic progression in 1 (2%). Two of these 17 patients had no evidence of disease progression after evaluation at completion of preoperative therapy but brain metastases were detected immediately before planned operation. In addition, 4 patients with resectable disease refused operation, and 1 was considered medically inoperable. Thus, a total of 33 patients underwent operation. At thoracotomy, 2 patients were found to have metastatic pleural spread and 1 had unresectable local disease that was not detected by preoperative CT scan. The latter patient underwent partial resection (R2), and he died of stump leakage 13 days later. The other 30 patients underwent complete resection of all macroscopic disease: 18 lobectomy, 4 bilobectomy, and 8 pneumonectomy. Nevertheless, microscopic disease was found at the surgical margins in 3 of them (R1). The pathologic specimen showed no evidence of residual tumor in 5 patients (17%) and only microscopic residual disease in 14 (47%). Site of First Failure Seven of the 30 operated patients (23%) had local recurrence and 9 (30%) had distant metastases. Of the 19 patients who had either a complete pathologic response or only microscopic residual tumor in the surgical specimen, 7 (37%) relapsed, and 6 of them in distant sites. Of the 8 patients with macroscopic residual tumor in the surgical specimen, 6 relapsed, 4 of them locally. Of the 3 patients with positive surgical margins, 2 had local recurrence. Five of the 9 distant relapses occurred in the brain, 3 of them as a single metastasis. Survival The median survival of all 57 patients was 16 months (95% confidence interval 13 to 20 months) (Fig 1). The 1-, 2-, and 3-year survival rates were 65%, 35%, and 22%, respectively. At the time of analysis, 16 patients were alive, 9 of them with no evidence of disease. One patient with severe chronic obstructive pulmonary disease died of massive pneumonia with no evidence of disease and was considered lost to follow-up at the time of analysis. Of the 40 patients considered dead of disease, 6 died of complications related to chemotherapy or operation: neutropenic fever after the first cycle of induction therapy in 2 patients; bronchopleural fistula after a partial resection of an unresectable tumor 13 days after thoracotomy in 1, and late complications of operation in 3 Fig 1. Survival: all patients. Number of patients at risk at 0 (n 57), 12 (n 31), 24 (n 14), 36 (n 8), and 48 (n 4) months.

4 Ann Thorac Surg CYJON ET AL 2002;74:342 7 COMBINED TREATMENT OF ADVANCED NSCLC 345 patients. All 3 latter patients had a pneumonectomy (right lung in 2 patients and left lung in 1 patient); two developed stump insufficiency. Repair by muscle and omental flaps was performed, but the patients died 6 and 19 months after initial surgery. The third patient developed recurrent empyema requiring repeated drainage and antibiotic treatment and died 16 months after operation. At the time of analysis, the median follow-up among the surviving patients was 17 months. Variables evaluated on univariate analysis were gender, age, histologic type, tumor size, disease stage, performance status, weight loss, number of cycles, response before operation, complete pathologic response, and radical operation. Age (p 0.045), tumor size (p 0.029), response to preoperative therapy (p 0.007), complete pathologic response (p 0.045), and radical operation (p 0.001) had a significant impact on survival (Table 3). However, on multivariate analysis including all these variables, only radical operation (relative risk 3.4, 95% confidence interval 1.7 to 7.0, p 0.000) and tumor size (relative risk 2.3, 95% confidence interval 1.0 to 5.2, p 0.039) proved to be independent predictors of survival (Figs. 2 and 3). Analysis of survival by T and N categories yielded no significant differences (Table 1). Toxicity Grades III and IV neutropenia occurred in 61% of the 57 patients; 33% of them required hospitalization for neutropenic fever. Two patients died of neutropenic sepsis after the first cycle of chemotherapy. Grades III and IV thrombocytopenia was seen in 9% of the patients, with no episodes of bleeding. Ten patients (18%) had grades III and IV anemia, and 8 required blood transfusions. No prophylactic hematologic support with growth factors was administered. Nausea and vomiting, when they occurred, were mild to moderate, easily manageable with antiemetics. In 13 patients (23%), a decrease in creatinine clearance of at least 20% was observed after induction chemotherapy. There was no sensory peripheral neuropathy in the patients who received only two or three courses of cisplatin therapy. There were no cases of severe radiation esophagitis or pneumonitis. Comment The prognosis of patients with stage III NSCLC given local treatment only, whether radiotherapy, operation, or a combination of both, is poor. Since the late 1980s, numerous phase II and some phase III studies have shown that the addition of chemotherapy to operation or to radiation therapy may improve survival of these patients [6 13]. However, the optimal drug combination and schedule, as well as the exact role of radiotherapy and operation, are still being investigated [23, 24]. In our series, 57 patients with stage IIIA or IIIB disease received sequential chemotherapy and chemoradiotherapy. The chemotherapy consisted of cisplatin and etoposide. Radiation therapy was given to a total of 45 Gy with daily cisplatin. The response rate was 73%, which is close Table 3. Survival Univariate Analysis Variable Median Survival (mo) p Value Gender Male (n 45) 17 Female (n 12) Age 70 (n 37) (n 20) Histology Squamous cell (n 27) 16 Adeno (n 17) 19 Large cell (n 13) Tumor size 4 cm(n 17) 17 4 cm(n 38) Stage IIIA (n 26) 16 IIIB (n 31) Performance status 0(n 7) 27 1(n 46) 16 2(n 4) Weight loss 5% (n 44) 16 5% (n 13) Number of cycles 2(n 23) 16 3(n 30) Response Yes (n 40) 22 No (n 15) Path complete response Yes (n 5) 36 No (n 52) Radical surgery Yes (n 30) 22 No (n 27) to data published by the Southwest Oncology Group [25], the Lung Cancer Study Group [11], and the Rush- Presbyterian study [7]. In all these studies, however, the induction chemotherapy was given concurrently with radiotherapy. In the Southwest Oncology Group trial [25], 126 patients received cisplatin and etoposide and radiotherapy, 45 Gy, with a response rate of 59%. In the Lung Cancer Study Group trial [11], 85 patients received cisplatin and 5-fluorouracil with 30 Gy radiation therapy, with a 50% response rate. The Rush-Presbyterian study [7] included 85 patients given a combination of cisplatin and 5-fluorouracil with or without etoposide and a split course of radiotherapy, to a total dose of 40 Gy. The response rate was rather high 92% but this included also patients with stable disease. Thirty patients (53%) in our series underwent complete gross resection of the residual tumor. Similar resectability rates were reported by the other investigators [7, 11, 25]. The complete pathologic response rate in our series was 17%; in another 47% of patients, the surgical specimen

5 346 CYJON ET AL Ann Thorac Surg COMBINED TREATMENT OF ADVANCED NSCLC 2002;74:342 7 Fig 2. Survival by radical operation. Fig 3. Survival by tumor size. showed only microscopic residual disease. The corresponding complete response rates in the Southwest Oncology Group, Lung Cancer Study Group, and Rush-Presbyterian trials were 21%, 16%, and 27%. However, the latter two studies had a smaller number of patients with stage IIIB disease (13% and 16%, respectively) than the Southwest Oncology Group trial (40%) or the present one (54%). The operative mortality, usually defined as death within 30 days of operation, was 3% in our series. One of the operated patients died of a complication related to a bronchopleural fistula 13 days after operation. The operative mortality rates reported in the other trials ranged from 4% to 15% [7, 11, 25]. The delayed mortality related to the surgical procedure, seldom reported, deserves attention. In our series, 3 patients who underwent radical resection died at 6, 16, and 19 months after operation from late complications of the surgical procedure. Two of them had prolonged stump insufficiency requiring repeated surgical and bronchoscopic repair attempts, and the third developed a chronic empyema, which warranted multiple hospitalizations for drainage and antibiotic therapy. In all 3 patients, pneumonectomy was needed to achieve a gross resection. These late complications may be the result of the difficulties encountered by the surgeon after chemotherapy and radiation, which cause fibrosis and friability of the tissues within the surgical bed. Vester and colleagues [26] reported that of 33 patients in whom a bronchopleural fistula developed after resection of a lung tumor, 20 had received radiation or chemoradiation before operation. Furthermore, the risk of developing stump insufficiency was higher in the patients undergoing pneumonectomy. Another reason for complications of pneumonectomy is the greater likelihood of advanced and centrally located tumors in these patients [27]. Hematologic toxicity was moderately severe. Two patients died of sepsis after the first cycle of induction chemotherapy. Thirty-three percent of the patients were hospitalized for treatment of neutropenic fever. The toxicity was related to the type of induction chemotherapy, which included protracted oral etoposide in combination with a relatively high dose of cisplatin in patients with a high prevalence of severe pulmonary and cardiovascular diseases. A similar hematologic toxicity was described by Burkes and associates [10], namely, 4 deaths among 55 patients during induction chemotherapy with the MVP regimen (mitomycin C, vinblastine, cisplatin). Median survival in our group of patients was 16 months, which is comparable with the survival achieved for similar populations in most phase II studies (13 to 22 months). In the Southwest Oncology Group trial the one with the largest number of patients and a proportion of IIIB disease similar to ours the 2- and 3-year survival rates were 38% and 25%, respectively. Our rates were close, 35% and 22%, respectively. On multivariate analysis, the favorable prognostic factors for survival were radical resection and tumor size not exceeding 4 cm. Other investigators also found complete resection to be a predictor of favorable outcome [10, 13, 28]. Tumor size was not usually included in the analysis in other studies. Unexpectedly, we failed to find a significant difference in survival between patients with stage IIIA and IIIB disease. The same result was reported in the Southwest Oncology Group study [25]. In conclusion, induction chemotherapy followed by chemoradiation, such as that administered in our study, can achieve high response and resectability rates. However, the gain in survival may be hampered by the significant hematologic and surgical toxicities associated with aggressive chemotherapy and operation after chemoradiation, especially in patients with tumors requiring pneumonectomy. The use of myelopoietic growth factors and surgical techniques with muscle or omental flaps in patients undergoing a pneumonectomy after induction treatments may contribute to decreased hematologic and surgical toxicities. The decision to perform a pneumonectomy must be individualized and carefully balanced against the severity of prognosis associated with a less aggressive therapy. Selected patients with stage IIIB tumors may benefit from this approach, similar to patients with IIIA disease. In view of the high rate of brain

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