Postoperative Adjuvant Therapy for Stage II Non Small-Cell Lung Cancer

Postoperative Adjuvant Therapy for Stage II Non Small-Cell Lung Cancer Jong Ho Park, MD, Young Mog Shim, MD, Hee Jong Baek, MD, Mi-Sook Kim, MD, Du Hwan Choe, MD, Kyung-Ja Cho, MD, Choon-Taek Lee, MD, and Jae Ill Zo, MD Departments of Thoracic Surgery, Radiation Oncology, Diagnostic Radiology, Pathology, and Internal Medicine, Korea Cancer Center Hospital, Seoul, Korea Background. Stage II non small-cell lung cancer is regarded as one of the early lung cancers. Although resection, including the mediastinal lymph nodes, is currently regarded as the standard treatment, the survival rate of this disease is not encouraging. It is well known that the most common causes of death are locoregional recurrences or distant metastases, or both. However, the best adjuvant treatment to improve survival is as controversial an issue as ever. Methods. This study was designed as a randomized, blinded, two-armed study with operation and adjuvant radiotherapy in one arm, versus operation and adjuvant mitomycin C (10 mg/m 2 ), vinblastin (6 mg/m 2 ), and cisplatin (100 mg/m 2 ) (MVP) chemotherapy in the other arm. We assigned 57 resected patients with pathologic proven stage II non-small cell lung cancer to the groups according to our eligibility criteria. Results. The most common pattern of recurrence was distant metastases, and nearly all the recurrences (17 of 18 patients) in both groups were found within 2 years after operation. The rates of the locoregional and distant metastases were 3.6% and 46.4% in the adjuvant radiotherapy group and 6.9% and 10.3% in the adjuvant chemotherapy group (p 0.018). The 5-year disease-free survival rates were 52.0% in the adjuvant radiotherapy group and 74.0% in the adjuvant chemotherapy group (p 0.16, log-rank test). The 2-year, 5-year, and 6-year survival portions were 60.3%, 56.5%, and 28.3% in the adjuvant radiotherapy group, and 82.8%, 70.1%, and 60.1% in the adjuvant chemotherapy group (p 0.01, p 0.17, and p 0.03, Z-test). The difference of the actuarial survival between these two groups was somewhat significant (p 0.09, log-rank test). Conclusions. Our results suggest that the addition of adjuvant MVP chemotherapy may reduce the distant metastasis rates and prolong the survival of the surgically resected stage II non small-cell lung cancer patients. (Ann Thorac Surg 1999;68:1821 6) 1999 by The Society of Thoracic Surgeons Stage II non small-cell lung cancer (NSCLC) was defined as a T1 or T2 tumor of the lung with metastasis to the intrapulmonary or hilar lymph nodes [1]. Survival data from several surgical series show that the 5-year survival for stage II NSCLC patients is significantly inferior to that of stage I patients and that more than 75% of the causes of death are related to locoregional or distant recurrences [2]. It was reported that the 5-year survival rate of patients with stage II disease varied from 29% to 51%, and the mean 5-year survival rate was only 41.2% [3]. Although radical surgery remains the treatment of choice for stage II disease, these poor survival rates speak of the need for additional therapy. However, the best adjuvant treatment has not yet been determined. As a result of these findings, numerous trials for the adjuvant therapy have been undertaken in the past decade to reduce the recurrence rate and to prolong the survival rate of the NSCLC patients. However, there has been no prospective randomized phase III trial confined just to stage II disease up to now. Therefore, we Accepted for publication Apr 27, 1999. Address reprint requests to Dr Zo, Department of Thoracic Surgery, Korea Cancer Center Hospital, 215-4, Gongneung-Dong, Nowon-Ku, Seoul, 139-706, Korea; e-mail: jaylzo@kcchsun.kcch.re.kr. present the results of our prospective trial from Korea Cancer Center Hospital. The aims of this study were to assess the effect of adjuvant treatments on overall survival, disease-free survival, and relapse pattern, as well as its toxicity in the patients who underwent radical operation for stage II NSCLC. We considered the adjuvant radiotherapy group as a control arm based on the end results of the vast and randomized study of the Lung Cancer Study Group [4]. Patients and Methods Experimental Design This study was designed as a randomized, prospective two-armed study with operation and adjuvant radiotherapy in one arm, versus operation and adjuvant chemotherapy in the other arm. A simple randomization was used. After the thoracic surgeons checked the patient s eligibility, a coordinator assigned postoperative adjuvant therapy. In the radiotherapy group, radiotherapy was delivered by megavoltage equipment (with cobalt-60 or a higher energy source) and was directed to the mediastinum. A range of 5,040 to 5,580 cgy was given in a combination of parallel opposed, and anterior and pos- 1999 by The Society of Thoracic Surgeons 0003-4975/99/$20.00 Published by Elsevier Science Inc PII S0003-4975(99)00715-8

1822 PARK ET AL Ann Thorac Surg ADJUVANT THERAPY FOR STAGE II NSCLC 1999;68:1821 6 terior oblique fields, or in any combination chosen at the discretion of the chest radiation oncologist. A daily dose of 1.8 to 2.0 Gy, measured in the central axis at the midplane, was given 5 days per week. The fields were defined inferiorly by a point 5 cm below the carina and superiorly by the suprasternal notch. The radiation field included the tumor bed, bronchial stump, ipsilateral hilum, and vascular shadows of the bilateral mediastinum. Radiotherapy began approximately within 30 days after operation. Patients assigned to the adjuvant chemotherapy group received mitomycin C (10 mg/m 2 ), vinblastin (6 mg/m 2 ), and cisplatin (100 mg/m 2 ) (MVP). The treatment began within 30 days after operation and was repeated every 3 weeks for a total of three cycles. When necessary, dose reduction was done at the discretion of the medical oncologist. Eligibility Patients were required to undergo complete resection of the tumor. Also, completely resected lymph nodes from the subcarinal, paratracheal, hilar, and bronchopulmonary areas were required for pathologic staging. Only the patients with definite diagnosis of NSCLC by histologic examination and at pathologic stage T1 2N1M0 were accepted for the study. The surgeons, after complete total resection of the tumor, had to confirm that the resection margins were microscopically free of tumor and that there was no known microscopic intrathoracic disease remaining. No known metastases in or beyond the mediastinum could exist. Patients who had received previous chemotherapy, immunotherapy, or thoracic irradiation were excluded. Patients in the following groups were considered ineligible: more than 70 years of age; inadequate performance status, pulmonary function test, liver function test, cardiac functions, and renal functions for adjuvant therapy. Patients who recovered without any serious complication within 2 weeks after operation were considered eligible for this study. Two to 3 weeks after the radical operation, patients who fulfilled the entry criteria were randomly assigned to the adjuvant radiotherapy arm or the adjuvant chemotherapy arm. Written consent was obtained in accordance with the human subject guidelines at Korea Cancer Center Hospital. Patient Characteristics Between April 1989 and June 1996, 57 patients with stage II NSCLC entered into this study. Each patient s clinical staging included history and physical examinations, complete blood counts, chemistries, electrocardiograms, and pulmonary function tests. Radiologic testing included chest radiograph and computed tomography of the chest and upper abdomen. Patients also received bronchoscopy, abdominal sonography, and radionuclide bone scanning. Magnetic resonance imaging of the brain was not obtained routinely in all patients before operation; however, it was performed if clinically indicated. When indicated by these tests, mediastinoscopy with lymph node biopsy was performed to exclude contralateral mediastinal lymph node involvement. The disease was staged postoperatively by the international ptnm criteria for cancer staging adopted by the American Joint Committee for Cancer Staging (4th edition) [1]. The pathology reports of all patients were reviewed carefully to ensure that the resection was complete, that no residual tumor, gross or microscopic, was left behind, and that no involved mediastinal lymph nodes were present before enrolling the patients into this study. Evaluation All patients were followed up after being discharged from the hospital. Follow-up examinations were scheduled monthly or bimonthly for the first 6 months, quarterly for the following 18 months, and semiannually thereafter. The parameters recorded during the follow-up were history and physical examination, blood chemistry, chest roentgenogram, chest computed tomography, radionuclide bone scanning, and abdominal sonography. Bronchoscopy was also done when necessary. Chest computed tomography, including the upper abdomen, was scheduled every 6 months for 5 years. The number of days from operation to the detection of the site of first confirmed recurrence constituted the length of the disease-free interval. Also, survival was calculated as the time from the date of operation until death or last contact with the patient. Toxicity of adjuvant therapy was scored according to the Radiation Morbidity Scoring Criteria (Radiation Therapy Oncology Group) and the World Health Organization criteria [5, 6]. The results were based on an analysis performed on February 28, 1998, about 9 years after the initiation of this study. The mean time from randomization to analysis was 42.4 months. Statistical Methods The actuarial survival and the disease-free survival were plotted as curves using the Kaplan-Meier method. Comparison of the survival curves was made with the logrank method. Z-test was used to compare the 2-year, 5-year, and 6-year survival proportions [7]. For comparison of the intergroup differences, the 2 test was used. p values of less than 0.05 were considered statistically significant. Results Randomization and Compliance Of 57 patients, 28 were randomized to the adjuvant radiotherapy group and 29 to the MVP adjuvant chemotherapy group. There were 28 men in the chemotherapy group, 27 men in the radiotherapy group, and only 1 woman in each group. For detailed patient characteristics, see Table 1. The two groups were well balanced with regard to the tumor stage. Twenty-seven patients in the radiotherapy group and 28 in the chemotherapy group had pt2n1m0, that is stage IIB disease according to the new American Joint Committee on Cancer classification [8]. Only 1 patient in each group had pt1n1m0 (stage IIA) disease. Squamous cell carcinoma was the most frequent histologic diagnosis (77.2%). This study was also

Ann Thorac Surg PARK ET AL 1999;68:1821 6 ADJUVANT THERAPY FOR STAGE II NSCLC 1823 Table 1. Characteristics of Patients in Study Characteristics Radiotherapy (n 28) Chemotherapy (n 29) Sex (male : female) 27:1 26:3 Age (mean) 58 6.1 55.2 7.2 Pathologic stage T1N1M0 1 1 T2N1M0 27 28 Histology Squamous cell carcinoma 20 24 Nonsquamous cell carcinoma 8 5 Type of resection Lobectomy or bilobectomy 14 14 Pneumonectomy 14 15 equally distributed with regard to the operation method. Sleeve or segmental resections were not performed in this study. Planned radiotherapy was discontinued at 20 and 30 Gy in 2 of the 28 radiotherapy patients because of pulmonary toxicity in 1 and gastrointestinal symptoms in the other. Four patients (14%) in the chemotherapy group failed to finish the scheduled chemotherapy because of side effects or patient s refusal to receive further therapy. There were 10 dose reductions in the adjuvant chemotherapy group. All randomized patients were included in the analyses regardless of whether their planned treatment was completed or discontinued. There was no patient loss in the follow-up. Disease-Free Survival and Relapse Pattern We have defined local recurrence as evidence of tumor within the same lung or at the bronchial stump and regional recurrence as the clinically manifested disease in the mediastinal nodes despite the mediastinal lymph node dissection during the original operation, lymph node metastasis in contralateral lymph nodes, or lymph node metastasis in the supraclavicular regions. Distant recurrence was defined as the disease in the contralateral lung, distant lymph nodes, or distant organs. Eighteen patients (31.6%) have documented recurrence after treatment (13 patients in the radiotherapy group and 5 in the chemotherapy group, p 0.018). The median time of recurrence was 12.6 months (13.4 months in the radiotherapy group, 10.4 months in the chemotherapy group; range, 1.7 to 54.3 months). Only 2 patients with documented recurrences were alive at the time of this analysis. The pattern of recurrence was different according to the adjuvant therapy. Although there was only one local recurrence, we detected 13 sites of distant metastases in 12 patients in the radiotherapy group. In the chemotherapy group, there were 2 cases of local recurrences and only 3 cases of distant metastases. The brain was the most common site of metastasis. There were six brain metastases in the radiotherapy group, but none in the chemotherapy group. The differences in the incidence of overall recurrence or distant metastasis were significant (p Table 2. Type of Recurrence (18 Documented Patients) Recurrence Radiotherapy (n 13) Chemotherapy (n 5) Locoregional recurrence 1 2 Distant recurrence 13 3 Brain 6 0 Bone 1 1 Contralateral lung 3 0 Systemic lymph node 0 1 Others 3 1 Total 14 5 0.05; Table 2). The recurrence rate/year was particularly high in the first 2 years. All the recurrences except one developed within 2 years after operation. The probability of recurrence in the first year after operation was 32.1% in the radiotherapy group and 10.3% in the chemotherapy group. The probabilities of recurrence in the first 2 years were 42.9% and 17.2%, respectively. The 5-year diseasefree survival rates were 52.0% in the radiotherapy group and 74.0% in the chemotherapy group (p 0.16, log-rank test; Fig 1). The type of operation and histology did not play a statistically significant role in the total incidence of recurrence. Survival The impact of adjuvant therapy on survival of stage II lung cancer patients is shown in Figure 2. At the time of this analysis, 23 patients (40.4 %) were dead, and 34 patients were alive. Fourteen patients in the radiotherapy group and 20 patients in the chemotherapy group were alive with a median follow-up of 42.4 months. Table 3 shows the causes of death. Under the 5% level, the difference in the actuarial survival between these two groups was not statistically significant. However, our Fig 1. Disease-free survival according to adjuvant therapy. The 5-year disease-free survival rate in the operation plus adjuvant chemotherapy group was 74.0% and the 5-year disease-free survival rate in the operation plus adjuvant radiotherapy group was 52.0%; p 0.16, log-rank test. (ChemoTx. postoperative adjuvant MVP chemotherapy; RadioTx. postoperative adjuvant radiotherapy.)

1824 PARK ET AL Ann Thorac Surg ADJUVANT THERAPY FOR STAGE II NSCLC 1999;68:1821 6 emesis was the most disturbing side effect. Two of the 18 patients with nonhematologic side effects experienced grade 3 (World Health Organization classification) nausea and vomiting, and 15 patients had grade 1 or 2 nausea and vomiting. However, they were somewhat controlled with the antiemetics in use at the time of the study. Two patients suffered grade 2 hepatotoxicity, and 1 patient suffered lung abscess, which developed after chemotherapy. Only 1 patient suffered grade 1 peripheral neuropathy. There was no death related to the adjuvant chemotherapy. Fig 2. Survival curves according to adjuvant therapy. The 5-year survival rate in the operation plus chemotherapy group was 70.1%, and the 5-year survival rate in the operation plus radiotherapy group was 56.5%; p 0.09, log-rank test. (ChemoTx. postoperative adjuvant MVP chemotherapy; RadioTx. postoperative adjuvant radiotherapy.) probability value (p 0.09, log-rank test) showed that there was evidence of somewhat of a difference. The 2-, 5-, and 6-year survival rates, calculated from operation, were 60.3%, 56.5%, and 28.3% in the radiotherapy group, and 82.8%, 70.1%, and 60.1% in the chemotherapy group, respectively (p 0.01, p 0.17, and p 0.03, Z-test). The median survival time of the patients with radiotherapy was 61.9 months, whereas that of the 29 patients with chemotherapy had not been reached as of yet. When survival was analyzed separately in the two main surgical groups (lobectomy/bilobectomy versus pneumonectomy), there was no difference in survival. Toxicity of Adjuvant Therapy Pulmonary toxicity (grade 3 to 4) was found in 5 patients in the radiotherapy group; one died of respiratory failure. Gastrointestinal symptoms (grade 1 to 2) developed in 6 patients in the radiotherapy group, but the symptoms were all transient [5]. Hematologic toxicity was not a serious problem; nevertheless, it was observed in 19 patients in the adjuvant chemotherapy group. Ten patients had grade 1 leukopenia (World Health Organization classification) [6]. Three patients had grade 2 anemia and 13 had grade 1 anemia. Thrombocytopenia was observed in 5 patients (grade 1). Nonhematologic side effects occurred in 18 of the patients who received chemotherapy. Cisplatin-induced Table 3. Causes of Death According to Adjuvant Therapy Cause Radiotherapy Chemotherapy Cancer related death 12 6 Noncancer-related death 1 2 Pneumonia 1 1 Cerebrovascular accident 0 1 Unknown 1 1 Total 14 9 Comment The optimal management of stage II NSCLC is a controversial issue. Although surgical resection remains to be the mainstay of therapy, survival data from several surgical series show that the 5-year survival for stage II patients is significantly inferior to that of stage I patients [9, 10]. These results showed the possibility of persistent local disease or distant metastases that were undetectable at operation [11, 12]. In fact, more than 75% of the causes of death are related to relapse, especially, distant metastases [2]. Thus, there is a rationale that an effective adjuvant therapy should include a systemic therapy in addition to the efforts at local control. In the past decade, many investigators have insisted that adjuvant therapy is needed once a nodal involvement is present, even in the favorable subgroup of patients with NSCLC. Although Martini and colleagues [9] reported that there was no improvement in survival with the use of adjuvant therapy, Ferguson [13] and Newman [14] and their colleagues have insisted that resection in combination with adjuvant radiotherapy and chemotherapy offered improved median survival over resection alone in patients with stage II NSCLC. However, they were all studied in a retrospective manner with limitations of small numbers of patients. Recently, a prospective study from Finland [15] has shown a statistically significant prolongation of survival in T1 3N1M0 NSCLC with using adjuvant chemotherapy. However, there are no prospective studies confined just to stage II disease. Therefore, we decided to start this study in 1989. In such a prospective study, a number of issues can be raised with regard to the efficiency of adjuvant chemotherapy in completely resected NSCLC. One of those is the choice of chemotherapy. The use of multidrug regimens including cisplatin has produced prolongation of disease-free survival, but until recently, no overall survival benefit has been shown. However, the Eastern Cooperative Oncology Group reported that the overall response rate of advanced NSCLC to MVP was superior to three other regimens [16]. Also, a randomized study in stage IV patients by the National Cancer Institute of Canada has shown that the commonly used combination of cisplatin and vindesine is superior to the CAP chemotherapy (cyclophosphamide, adriamycin, and cisplatin) [17]. These studies, as well as a number of neoadjuvant chemotherapy studies, reporting response rates of 40% to 70% for MVP regimen have encouraged the use of the

Ann Thorac Surg PARK ET AL 1999;68:1821 6 ADJUVANT THERAPY FOR STAGE II NSCLC 1825 MVP regimen in this study [18]. Another problem in this study was the selection of the control group. We considered the adjuvant radiotherapy group as the control group, although it was not a standard treatment. We based this decision on the end results of the vast and randomized study of the Lung Cancer Study Group [4]. The other reason for using the control group was that a three-group study including the operation-only group was too time consuming for a single institute study, because patients with pathologically proved stage II disease represented only less than 5% to 6% of the total lung cancer population [19, 20]. Also, we wanted to compare the pattern and rate of recurrence in relation to the choice of adjuvant therapy. In this study, patient selection and randomization were stringent. The radiotherapy group and the adjuvant chemotherapy group were well balanced with regard to the well-known prognostic factors such as the pathologic stage, histologic subtype, and the operative method. The recurrence rate in the first 2 years after operation was particularly high. It was observed that almost all recurrences (17 of 18 recurred cases) developed within the first 2 years. We also found that the locoregional recurrences were rare (Table 2), and that they were not important factors in selecting adjuvant therapy for completely resected stage II NSCLC. On the other hand, majority of the first observed recurrences (84.2%) were located at a distant site. There was a significant difference in the overall recurrence rate dependent on the adjuvant therapy, especially in distant metastases. The adjuvant chemotherapy group had significantly fewer distant metastases than the radiotherapy group (p 0.018). Therefore, it seems very likely that adjuvant chemotherapy may prevent the development of micrometastasis, and decrease the incidence of distant metastasis, which is the most important prognostic factor in stage II NSCLC after operation. In addition to this, our findings agree with the results of other researchers in that the most frequent site of metastasis was the brain in early NSCLC after operation [2, 9, 10]. Although there were 6 patients with brain metastases in the 13 recurred patients in the radiotherapy group, there was none in the chemotherapy group. The median time of detection after operation in the 6 patients with brain metastases was 12.4 months (range, 8.4 to 21.5 months). Although it remains an open question as to the exact mechanism for prevention of brain metastases in the chemotherapy group, our results can be explained by the fact that blood vessels formed by metastatic neoplasms are often defective, and that tumor-induced blood vessels have imperfect blood brain barrier in the brain [21, 22]. The median survival period was 61.9 months in the radiotherapy group, but was not reached in the chemotherapy group. Continuous follow-up has shown that the mean survival time has remained stable, and the estimated 2-, 5-, and 6-year survival rates were 60.3%, 56.5%, and 28.3% in the radiotherapy group, and 82.8%, 70.1%, and 60.1% in the chemotherapy group, respectively (p 0.01, p 0.17, p 0.03, Z-test). As mentioned above, the difference in the actuarial survival between our two groups was somewhat significant (p 0.09, log-rank test). In this study, there were more cancer-related deaths in the radiotherapy group than in the chemotherapy group (43% to 21%, p 0.07; Table 3). Therefore, it seems likely that the cancer-related deaths may influence the difference in the actuarial survival in both groups, as the number of noncancer-related deaths was small. Although adjuvant radiotherapy was reported to protect against local recurrence in several other studies, our data demonstrate that this effect does not translate into a demonstrable overall survival benefit in stage II NSCLC [2]. This is largely because 87% of recurrences were outside the radiation field and possibly because radiation may slightly increase the risks of disease other than cancer. This means that the benefit provided by slightly improved local control of postoperative radiotherapy may often be masked by a severe toxic side effect, and in some patients, having a deleterious effect on survival. In fact, there were 5 patients with radiation pneumonitis (grade 3 to 4) and one radiation-related death in our study. The CAP generation of studies encountered significant problems with patient compliance, in large part, attributable to the high incidence of cisplatin-induced emesis. Also in this study, the main problem throughout the adjuvant chemotherapy was not the hematologic toxicity but the cisplatin-induced nausea. However, it was somewhat controlled by the antiemetics in use at the time of the study. It was very important to increase the number of patients able to undergo the fully-planned chemotherapy. Although our results cannot provide sufficient justification to recommend postoperative chemotherapy to stage II NSCLC patients because of the limitations of a small number of patients and the control group, it may provide a possibility for postoperative adjuvant chemotherapy as a newly accepted method. 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