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Eur J Cardiothorac Surg 2005;27:1086-1091
© 2005 Elsevier Science NL

Postoperative adjuvant chemotherapy for stage I non-small cell lung cancer

Jong Ho Parka,*, Choon-Taek Leeb, Hae Won Leea, Hee Jong Baeka, Jae Ill Zoa, Young Mog Shima

a Department of Thoracic Surgery, Korea Cancer Center Hospital, Nowon-Ku Gongneung-Dong 215–4, Seoul 139–706, South Korea
b Department of Internal Medicine, Korea Cancer Center Hospital, Nowon-Ku Gongneung-Dong 215–4, Seoul 139–706, South Korea

Received 3 September 2004; received in revised form 18 January 2005; accepted 20 January 2005.

* Corresponding author. Tel.: 822-970-1240; fax: 822-970-2401. (E-mail: jhpark{at}kcch.re.kr).


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 Appendix A. Conference...
 References
 
Objective: Surgery constitutes the mainstay of treatment in stage I non-small cell lung cancer (NSCLC). However, a significant fraction of patients after surgical resection die mainly due to systemic relapse. Nonetheless, the best adjuvant treatment to improve survival and decrease relapse rate remains as an ever controversial issue. Therefore, we conducted a randomized trial to determine whether postoperative adjuvant chemotherapy is beneficial in prolonging survival and decreasing recurrence in patients with completely resected stage I NSCLC. Methods: It was designed as a randomized, prospective two-armed study with surgery only (control group, 59 patients) versus surgery plus adjuvant MVP (mitomycin C, vinblastin and cisplatin) chemotherapy (study group, 59 patients). Results: Data for all the patients were complete. Twenty-four patients in the control group and nine patients in the study group experienced tumor recurrence during the follow-up. Neither histological type nor surgical extent correlated with recurrence. However, the addition of adjuvant MVP chemotherapy could decrease the rate of recurrence and the incidence of cancer-related death after surgery in the patients of stage I NSCLC (P<0.05). We followed up at least 5 years, and the duration of mean follow-up was 7.3 years. The rates of the loco-regional and distant metastases were 3.4 and 40.7% in the control group, and 3.4 and 11.9% in the study group, respectively. The 5- and 10-year survival rates were 74.6 and 56.3% in the control group, and 81.4 and 65.0% in the study group, respectively (P=0.19, log-rank test). The 5- and 10-year disease-free survival rates were 64.8 and 54.8% in the control group, and 88.8 and 76.8% in the study group, respectively (P=0.002, log-rank test). Conclusions: Our results suggest that the addition of adjuvant MVP chemotherapy may reduce the incidence of distant metastasis and prolong the disease-free survival of the patients with stage I NSCLC after surgery.

Key Words: Stage I • Non-small cell lung cancer • Adjuvant therapy • MVP chemotherapy


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Discussion
 Appendix A. Conference...
 References
 
Radical surgery is considered as the primary treatment for early stage NSCLC. However, in spite of curative resection, the long-term survival is not satisfactory, and local and distant recurrences may account for the disappointing survival rates after resection [1]. More than 30% of the patients with pathologic stage I disease die of tumor progression after surgical resection. In 70% of cases, recurrence occurs outside the chest [2,3], and this is probably due to micrometastases present at the time of surgery, but not detectable [4,5]. Therefore, one of the foremost goals of the therapeutic strategy for lung cancer has been the development of adjuvant treatments to avert distant dissemination. However, in spite of several prospective studies, the role of adjuvant chemotherapy following surgical resection remains unproven [6,7].

In 1998, Socinski et al. conducted a meta-analysis of 11 cisplatin-based randomized trials, by comparing surgical resection with surgical resection plus systemic chemotherapy, and reported that cisplatin-based adjuvant chemotherapy was associated with a 5.6% marginally significant 5-year survival advantage in the five predominantly node-negative trials (P=0.06). However, that risk reduction was of borderline statistical significance [8]. Nevertheless, some reports have proposed the introduction of adjuvant chemotherapy after radical surgery of early NSCLC [9–12].

When we initiated this study in 1989, there was no prospective randomized phase III trial which was confined just to stage I NSCLC. In the present report, we describe the results of our clinical study conducted at Korea Cancer Center Hospital, Seoul, Korea. The aims of this study were to assess the effect of adjuvant MVP chemotherapy on overall survival, disease-free survival, and pattern of relapse, as well as its toxicity in the patients who had undergone radical surgery for stage I NSCLC.


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Discussion
 Appendix A. Conference...
 References
 
2.1. Study design
This trial was initiated by the Lung Cancer Research Team at Korea Cancer Center Hospital March 1989, and enrollment was stopped September 1998. The study was designed as a randomized, prospective two-armed study with surgery in one arm versus surgery plus adjuvant MVP chemotherapy in the other arm. A simple randomization was used. A coordinator assigned the patients into two groups after thoracic surgeons checked the patient's eligibility. The ethics committee at Korea Cancer Center Hospital approved the proposal. The adjuvant chemotherapy began within 30 days of surgery and was repeated every 3 weeks for total three or four cycles. The chemotherapy regimen consisted of mitomycin C (10mg/m2 on day 1), vinblastin (6mg/m2 on day 1) and cisplatin (100mg/m2 on days 1–5), given every 3 weeks. Chemotherapy was administrated only if adequate hematological recovery had occurred (neutrophil count>1500/mm3 and platelet count>100,000/mm3). However, if recover did not occur, treatment was delayed for a week. When necessary, dose adjustment was done at the discretion of medical oncologist.

2.2. 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 definitive diagnosis of NSCLC by histological examination and in pathologic stage T1-2N0M0 were included in the study. It was staged by the international tumor-node-metastasis (TNM) criteria for cancer staging adopted by the American Joint Committee for Cancer Staging, and the staging system used in this study has been revised in 1986 [13]. Surgeons, following 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 should exist. Patients who had received previous chemotherapy, immunotherapy or thoracic irradiation and patients who underwent sleeve or wedge resection of tumor were not included in this study. Furthermore, patients in the following subgroups were considered ineligible: over 70 years of age or inadequate performance status, pulmonary function test, liver function test, cardiac function test, and renal function test for adjuvant chemotherapy. Patients who recovered without any serious complication within 2 weeks after surgery were considered eligible for this study. Two to three weeks after the radical surgery, patients who fulfilled the entry criteria were randomly assigned into the two arms. Written informed consent was obtained from all patients or their surrogates in accordance with the human subject guidelines at Korea Cancer Center Hospital.

2.3. 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 historical and physical examination, blood chemistry, chest X-ray film, chest computed tomography (CT), radionuclide bone scanning and abdominal sonography. Bronchoscopic examination or magnetic resonance imaging of brain was also done when necessary. Chest CT, including the upper abdomen, was scheduled every 6 months. The primary endpoint was overall survival, which was defined as the duration from randomization to death from any cause. Secondary endpoints were disease-free survival, defined as the duration from randomization to relapse or death from any cause, and toxicity associated with chemotherapy.

The results were based on an analysis performed in December 2003, about 15 years after the initiation of this study. The mean duration of follow-up from randomization to analysis was 7.3 years.

Chemotherapy-related toxicity was assessed and recorded after each cycle of treatment. Toxicity of adjuvant therapy was scored according to the World Health Organization (WHO) criteria [14].

2.4. Statistical analysis
The actuarial survival and the disease-free survival were plotted as curves by using the Kaplan–Meier method, and comparison of the survival curves was made with the log-rank method. We used the Cox's proportional hazards model for multi-variate analysis. For comparison of the inter-group differences, the X2-test was used. P values of less than 0.05 were considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Discussion
 Appendix A. Conference...
 References
 
3.1. Patient characteristics
From March 1989 to September 1998, we enrolled 118 patients with pathologic stage I NSCLC into this study; randomly assigned 59 patients received surgery only and 59 patients received surgery plus adjuvant MVP chemotherapy. Table 1 lists the characteristics of the patients. The two groups were well matched with regard to the tumor stage, histology and extent of resection. There were no significant differences in the base-line characteristics between the two groups. Except for those who died early, we tried to follow-up all the patients for a period of at least 5 years. The mean duration of follow-up was 7.3 years.


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  		Table 1. Clinical characteristics of patients (n=118)
 
3.2. Treatment compliance
Five patients (8.5%) who were assigned to the adjuvant chemotherapy group did not start the chemotherapy: They declined the adjuvant therapy. Seven patients (11.9%) received just one cycle of chemotherapy, 13 patients (22.0%) received two cycles, and 34 patients (57.6%) received three or four cycles of chemotherapy. The average number of chemotherapy performed in the study group was 2.4 cycles per patient. The most common reasons for not completing the planned chemotherapy were patient's refusal and drug toxicity.

3.3. Disease-free survival and relapse pattern
We defined loco-regional recurrence as an evidence of tumor in the ipsilateral hemithorax or mediastinum. Distant recurrence was defined as the disease in the contralateral lung, distant lymph nodes or distant organs. Recurrence was documented in 24 patients in the control group (40.7%) and 9 patients in the study group (15.3%) (P=0.002). There was a significant difference even in the pattern of recurrence between the two groups: even though only two loco-regional recurrences were found in each group, 24 distant recurrences were documented in the control group and 7 in the study group (P=0.0004). The most frequent sites of recurrence were contralateral lung, brain and bone. There was no significant difference in local versus distance recurrences, stratified for tumor stage, histology or extent of resection. We documented the sites of recurrence in Table 2.


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  		Table 2. Type of recurrence
 
Fig. 1 shows the disease-free survival curves of the two groups. The 5- and 10-year disease-free survival rates were 64.8 and 54.8% in the control group and 88.8 and 76.8% in the study group, respectively. The median time of disease-free survival was not yet reached in both the groups (Table 2). There was a significant difference in the disease-free survival between the two groups (P=0.002, log-rank test).



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  		Fig. 1. Disease-free survival curves. The 5-year disease-free survival rate of the control and study groups was 64.8 and 88.8%, respectively (P=0.002, log-rank test).

 
Comparison of the two groups by using Cox's proportional hazards model with respect to some risk factors revealed no significant difference in the disease-free survival, except the tumor stage (P=0.043) and adjuvant chemotherapy (P=0.001).

3.4. Survival
The impact of adjuvant MVP chemotherapy on the survival of stage I NSCLC patients is shown in Fig. 2 At the time of this analysis, 40 patients (33.9%) were dead and 78 patients were alive. Thirty-six patients in the control group and 42 patients in the study group were alive. There was a significant difference in the rate of cancer-related death between the two groups (P=0.02). Table 3 shows the causes of death.



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  		Fig. 2. Overall survival curves. The 5-year survival rate of the control and study groups was 74.6 and 81.4%, respectively. (P=0.19, log-rank test).

 

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  		Table 3. Risk of death
 
The median survival time of the patients in the control group was 11.9 years and that of the study group has not yet been reached (Fig. 2). However, the difference in the overall survival between these two groups was not statistically significant (P=0.19, log-rank test). The 5- and 10-year survival rates were 74.6 and 56.3% in the control group, and 81.4 and 65.0% in the study group, respectively (Table 4).


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  		Table 4. Toxicity of adjuvant MVP chemotherapy (n=143 cycles)
 
When the two groups were compared by using the Cox's proportional hazards model according to subgroups such as sex, age, tumor stage, histology, surgical extent and adjuvant chemotherapy, there was also no significant difference in overall survival (P=0.188).

3.5. Toxicity of adjuvant chemotherapy
Total 143 cycles of chemotherapy were performed in the study group, and the toxicity of adjuvant chemotherapy in each cycle of each patient was checked. The adjuvant systemic therapy was generally well tolerated by the patients. However, there were two deaths in the study group due to chemotherapy-induced pneumonitis.

The most frequent problems were hematological and gastrointestinal toxicities. Even though hematological toxicity was not serious, we confirmed 11.9% of leucopenia (grades 3–4), 3.5% of anemia (grades 3–4) and 1.4% of thrombocytopenia (grades 3–4) among the total cycles. Gastointestinal toxicities, including nausea and vomiting, were particularly somewhat serious. Especially, cisplatin-induced emesis was the most disturbing side effect at first; 71 events in grades 1–2 and 25 events in grades 3–4. However, we were somewhat able to control them with the use of antiemetics in the later stage of this study. Finally, we also experienced 44 neurotoxicites (grades 1–2).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
Appendix A. Conference...
 References
 
This study was undertaken with the patients, who were assigned to surgery alone, as the control group, because it is widely accepted as the standard treatment for stage I NSCLC. There is no doubt that surgery will remain as the cornerstone of treatment in the early stage of disease and even in stage IIIA N2 disease, because complete resection together with down-graded mediastinal involvement is one of the strongest predictors of survival. However, a significant fraction of the patients relapse and die after surgical resection, mainly due to systemic relapse [1–3]: many of these patients, even in early stage NSCLC, have either locally or systemically undetectable remaining viable tumor cells, which were not eradicated by surgery, implying that NSCLC is a chronic systemic disease regardless of the TNM stage. Hence, an effective systemic adjuvant therapy appears to be logical strategy to improve the clinical results of early NSCLC patients. In this regard, adjuvant chemotherapy for early stage of disease could be advantageous for several reasons: it allows early systemic therapy of potential micrometastases after surgery, and low tumor load and high growth rate within micrometastases may result in better response, compared to advanced stage.

However, the efficacy of adjuvant chemotherapy in completely resected NSCLC remains controversial, even though the results of 11 randomized clinical trials of adjuvant cisplatin-based combination chemotherapy have currently been available. Results of 1998 meta-analysis of NSCLC, especially in the five predominantly node-negative trials, indicated that the composite 5-year survival rates of the chemotherapy and the control arms were 61 and 55%, respectively. There was no evidence of heterogeneity of effect between the trials (Qw=1.68, P=0.79). Overall, a 5.6% marginally significant 5-year survival advantage for chemotherapy was obtained with the standard error being 3.0% (P=0.06) [8]. However, in spite of these benefits, it failed to influence clinical practice, not because of too small absolute gain, but because of imprecision of the survival benefit estimate, which ranged from a 1% detriment to a 13% benefit.

When we initiated the present study, there was no clinical study, which was confined only to stage I NSCLC, for adjuvant cisplatin-based chemotherapy. During the intervening years, a Finnish group reported on a postoperative CAP-chemotherapy in patients who were completely resected for stage T1-3N0M0. Although T3 tumors were included, about 90% of the patients had stage I, T1-2N0M0, disease, showing that the disease-free survival was significantly better in the chemotherapy arm with 67% of 5-year disease free survival rate, compared to 56% in the control arm [9]. However, stratification for the type of surgical procedure was not performed in the above study. In a Japanese study, three cycles of vindesine and cisplatin were used, followed by the application of tegafur and uracil over 1-year period. In the control arms, patients received either 1-year of uracil alone or no therapy after surgery [15]. The 5-year survival rates for the chemotherapy plus uracil group and the patients on uracil alone were about 60 and 64%, respectively, compared with 49% for the no adjuvant therapy group: The overall survival of the two chemotherapy treatment arms, therefore, showed a significant advantage for those given adjuvant chemotherapy, compared to the surgery only group. However, another Japanese cooperative prospective study with 2-year oral administration of uracil plus tegafur (UFT) in the patients of stage I–II NSCLC found negative results [16]: the 5-year disease-free survival rates were 78% for the adjuvant group and 71% for the control group (P=0.24), and 5-year overall survival rates were 79 and 75% (P=0.70), respectively.

EORTC (European Organization for Research and Treatment of Cancer) 08952 was a cooperative phase III study by using adjuvant MVP chemotherapy completed recently [17]. The study compared surgery plus adjuvant MVP chemotherapy versus surgery alone. The chemotherapy consisted of cisplatin (100mg/m2 on day 1), mitomycin C (8mg/m2 on day 1), and vindesne (3mg/m2 on days 1 and 8), given every 3 weeks for three cycles and starting 3–6 weeks postoperatively. During 5 years, 1209 patients with stages I, II, IIIA NSCLC were enrolled. Unfortunately, however, it failed to confirm a statistically significant role for adjuvant chemotherapy in completely resected NSCLC. On the other hand, another well designed phase III study in Italy concluded a positive result of postoperative adjuvant chemotherapy in the patients with stage IB NSCLC [12]. The regimen consisted of cisplatin (100mg/m2 on day 1) and etoposide (120mg/m2 on days 1–3) for a total of six cycles. Sixty-six patients were included, and the 5-year disease-free survival rates were 59% in the adjuvant group and 30% in the control group (P=0.02). Also, there was a significant difference in the 5-year overall survival rates (P=0.04).

The above-mentioned studies together with ours came to relatively similar conclusions, nevertheless, they do not provide a definitive answer as to the role of adjuvant chemotherapy in completely resected early stage NSCLC. Several possible explanations deserve discussion. First, some of the studies enrolled heterogeneous patient populations (stages I–IIIA). One should remember that there is no stronger prognostic factor than pathologic staging in NSCLC. Although it may increase the accrual rate, it results in combing different groups of patients in clinical and biological courses for study [1]. Second, all the studies included very small numbers of patients. If clinicians calculate the sample size to detect an increase of 10% in 5-year survival at a significance level {alpha}=5% and a power of 80%, at least 300 patients/arm in a two-arm study for a total of 600 patients are required. Unfortunately, however, the majority of the studies failed to fulfill the patient number, even in the several multi-center cooperative studies. To overcome this problem, a multi-center cooperative prospective study is desired. However, it may not be so easy to standardize the treatment protocols, including surgical techniques between medical centers. As is known, there are so many strong prognostic factors and biases in the course of treatment that can influence the clinical results of NSCLC patients, compared to adjuvant therapy. As mentioned above, the two multi-center large-scale studies in Japan, using oral chemotherapeutic agents, showed absolutely different results, although the design of the studies was similar. These above factors might limit the statistical power of all these studies to detect small but clinically meaningful improvements in survival. Third, most of the studies were not designed with appropriate and realistic end points in mind. However, it is not so easy to remedy this problem, because of the accrual problem of patients and the relatively long survival even in the control group of early disease state. In fact, we could not reach median survival of the study group in the overall and disease-free survival, even though we followed up the patients for a mean duration of 7.3 years. Fourth are the problems of therapeutic agents, its compliance and dosage. The dose of cisplatin was different in every study, ranging from 50 to 100mg/m2. Even in the same dosage, dose intensity could be different. In every study, many patients failed to finish the scheduled cycles of adjuvant therapy after randomization because of drug toxicity or personal choice. In our study, five patients withdrew their consents to participate after randomization. To increase the compliance, more effective delivery of more active drugs should be advanced in the outpatient delivery and supportive care of patients by using new and more effective antiemetic agents, growth factors, appropriate hydration schedules, and less-toxic chemotherapeutic agents.

In the present study, we obtained a positive impact of adjuvant chemotherapy in the stage I NSCLC by using the MVP regimen. However, chemotherapy protocols with new drugs in the future should carefully be evaluated. When the present trial was planned, platinum and etoposide with or without mitomycin became quite fashionable, particularly after the Canadian trial in advanced disease was published [18–20]. However, it is now generally accepted that chemotherapy regimens, based on newer agents such as paclitaxel, vinorebine, or gemcitabine, may be more advantageous than the older cisplatin-based regimens in terms of intrinsic activity, tolerability and improved delivery of adequate dose-time schedule [6]. In addition, it may be helpful to develop new diagnostic methods to select those patients who would benefit from specific chemotherapeutic agents. Potential parameters for this selection include angiogenesis, expression of oncogenes, mutations of tumor suppressor genes, and presence of drug-resistant mechanisms [21]. Finally, issues such as high-dose chemotherapy, adjuvant immunotherapy, prophylactic cranial irradiation or neoadjuvant chemotherapy for early stage of disease should be addressed in the future [22–25].


   Appendix A. Conference discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 Appendix A. Conference...
References
 
Dr M. Dusmet (London, UK): You had 118 patients over 10 years. Were all eligible patients that you saw during this period included in the study?

Dr Park: No. Many people refused to attend the study. The most difficult thing was the enrollment of patient. Actually, we could not reach the final goal. As you know, we spent almost 10 years to enroll the 120 patients.

Dr D. Branscheid (Grosshansdorf, Germany): What was the reason for 26 pulmonectomies in stage I? The second question is, to which group did they belong afterwards, because pulmonectomy has by itself little problems in the long-term survivors.

Dr Park: Can you ask the second question again?

Dr Branscheid: To what group did those 26 pulmonectomies belong to, to the group with chemotherapy or to the control group?

Dr Park: Even with the stage I lung cancers, sometimes we need pneumonectomy. As I showed you before in the slide, the patients with pneumonectomy were evenly distributed to the two arms.

Dr P. van Schil (Edegem, Belgium): I noticed from your abstract that this was a blinded study. Do you really mean that it was a placebo-controlled trial? Secondly, what were the causes of death in your group 1? I noticed that the overall survival was not very different between the two groups.

Dr Park: Can I ask you again the first question?

Dr van Schil: In your abstract you say it is a blinded study.

Dr Park: Yes, that's right.

Dr van Schil: Does it mean that it was placebo-controlled?

Dr Park: Simple randomization. It means if the patients agreed to enroll in this study, the coordinator put them into one of the two arms.

Dr Weder: So blinded is wrong in the abstract?

Dr Park: Yes.

Dr Weder: You cannot blind patients nor physicians in this study.

Dr Park: No, it's a blind study.

Dr Weder: It's not a blinded study. It cannot be, because if you treat with cispaltin based chemotherapy, you know who is treated.

Dr Park: Yes.

Dr van Schil: I think it can only be blinded when you have a placebo-controlled.

Dr Weder: But even with placebo control, chemotherapy with cisplatin cannot be blinded. You cannot blind the patient. You cannot blind the physician. Nobody can be blinded.

Dr Park: You are right. There was a mistake to use the term "blind" in this study. It's my mistake.

Dr T. Daniel (Charlottesville, VA, USA): Did you have enough numbers to stratify stage IA from IB?

Dr Park: The number of IA patients is very few. Maybe a total number of stage I is about 20 patients.

Dr Daniel: So very few. You could have left them out and perhaps made a more meaningful study including IB only.

Dr Park: As you know, the most important problem is the accrual. 10 years ago the number of patients operated for lung cancer, especially in stage I lung cancer, was very few compared to other staging. So we included all the stage I lung cancer to reach the goal.


   Acknowledgments
 
This work was supported in part by Institute-Supported Research Project appointed by Korea Cancer Center Hospital.


   Footnotes
 
{star} Presented at the joint 18th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 12th Annual Meeting of the European Society of Thoracic Surgeons, Leipzig, Germany, September 12–15, 2004.


   References
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 Appendix A. Conference...
 References
 

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