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Eur J Cardiothorac Surg 1999;15:438-443
© 1999 Elsevier Science NL

Postoperative adjuvant chemotherapy with PVM (Cisplatin+Vindesine+Mitomycin C) and UFT (Uracil+Tegaful) in resected stage I–II NSCLC (non-small cell lung cancer): a randomized clinical trial¹

West Japan Study Group For Lung Cancer Surgery, Department of Thoracic Surgery, Kyoto University, 53 Kawahara-cho, Shougoin, Sakyo-ku, Kyoto, Japan

Received 21 September 1998; received in revised form 14 December 1998; accepted 12 January 1999.

Corresponding author. Tel.: +81-75-751-3837; fax: +81-75-751-4647; e-mail: wada@frontier.kyoto-u.ac.jp

	Abstract

Top Abstract Introduction Subjects and methods Results Discussion Appendix A. Institutions... Appendix B. Conference... References

 
Objective: The West Japan Study Group For Lung Cancer Surgery (WJSG) conducted a randomized controlled trial in order to assess the usefulness of adjuvant chemotherapy for NSCLC. Methods: Patients with completely resected NSCLC (stages I and II) were enrolled in the trial. These patients were randomized into two groups: a surgery alone group; and a chemotherapy group which received intravenous administration of two courses of 4-week PVM chemotherapy (80 mg/m² of Cisplatin on day 1, 2–3 mg/m² of Vindesine on day 1 and/or day 8, and 8 mg/m² of Mitomycin C on day 1), after which they took 400 mg/day of UFT (Uracil+Tegaful) orally for 1 year. Results: Among 229 patients registered for the study from August 1988 to July 1990, 225 were available cases (116 patients in the surgery alone group, and 109 patients in the chemotherapy group). No bias in prognostic factors could be found between the two groups. The 5-year survival rate was 71.1% for the surgery-alone group and 76.8% for the chemotherapy group with no significant difference observed. However, subset analysis demonstrated that PVM therapy improved the post operative survival of pT1N0 patients (the 5-year survival rats: 75.3% for the surgery alone group, and 90.7% for the chemotherapy group P<0.05). Conclusions: It is interesting to find that among pT1N0 patients, who were not regarded as a target of chemotherapy, those receiving chemotherapy showed significantly better prognostic results. These findings suggest the necessity of further studies on the adjuvant chemotherapy, even in the early stages.

Key Words: Early stage • Non-small cell lung cancer • Adjuvant chemotherapy • Uracil+Tegaful • Long-term oral administration

	Introduction

Top Abstract Introduction Subjects and methods Results Discussion Appendix A. Institutions... Appendix B. Conference... References

 
It is generally accepted that radical surgery plays an important role in providing survival benefits for locoregional non-small cell lung cancer (NSCLC) patients, especially c-stage I and II patients, without mediastinal involvement. But some reports have suggested, the existence of undetectable micro-metastatic lesions at the time of operation. Matthews et al., reported, for example, that 24% of patients who had died of other diseases, within 30 days after complete resection of lung cancer, were found to have distant metastasis [1]. Also, Feld et al., reported in the results of the lung cancer study group (LCSG) protocol 771, that 65–75% of the first recurrences involve distant sites [2]. We consequently organized a multi-institutional cooperative study group in association with facilities located in Western Japan and conducted a series of randomized studies to investigate the effectiveness of post operative adjuvant chemotherapy. As concerns about stage IIIa, over 50% of the patients suffered a relapse within 1 year, as was the results of LCSG 791 [3]. Recently, many randomized studies have been conducted to investigate the effectiveness of preoperative induction chemotherapy for c-stage IIIa NSCLC patients [4]. We thought there were some ethical questions concerning the creation of a non-treatment patient group of p-stage IIIa patients, and we could not obtain agreement to conduct a randomized trial in the West Japan Study Group for Lung Cancer Surgery (WJSG) (Appendix A). The patients targeted by this study, therefore, belong to p-stage I or II. The selected chemotherapy regimen consists of two parts, the first is Cisplatin+Vindesine+Mitomycin C (PVM) therapy, which has been reported to be one of the most effective regimens, as concerns the response rate for advanced NSCLC patients [5], and the second is long-term oral administration of Uracil+Tegaful (UFT), which we expected to prolong the effects of post operative chemotherapy.

	Subjects and methods

Top Abstract Introduction Subjects and methods Results Discussion Appendix A. Institutions... Appendix B. Conference... References

 
Patient eligibility criteria and methods
The eligibility criteria for the study patients were as follows: (1), completely resected NSCLC patients in pathological stage I or II who had no treatment prior to surgery (2), patients aged 75 years or less (3), a performance status of grade 0–2 (4), no other organ (such as liver, kidney or heart) dysfunction limiting the study protocol. After informed consent was obtained and following confirmation of histological typing and pathological TNM classification by a central telephone registration office, the enrolled patients were divided randomly into two groups. One was a surgery alone group (group A) and the other was a chemotherapy group (group B). Group B patients received two courses of 4-week PVM chemotherapy (80 mg/m² of Cisplatin on day 1, 2–3 mg/m² of Vindesine on day 1 and/or day 8, and 8 mg/m² of Mitomycin C on day 1), and then 400 mg/day of UFT for 1 year ( Fig. 1 ).

View larger version (11K): [in this window] [in a new window]   Fig. 1. WJSG – Third study protocol. WJSG; West Japan Study Group for Lung Cancer Surgery. UFT: Uracil+Tegaful.

Statistical analysis
An ², t-test and U-test were used to examine deviations in the patients' background factors. The survival time was counted from the day of surgery, and the 5-year survival rate was calculated using the Kaplan–Meier method. All causes of death were treated as final events. A log-rank test was used to compare the survival curves.

	Results

Top Abstract Introduction Subjects and methods Results Discussion Appendix A. Institutions... Appendix B. Conference... References

 
Patient population
During the 2 years from August 1988 to July 1989, a total of 229 patients from 36 institutions were registered to the study. Among these, two cases from group A who had received incomplete resection and who were histologically diagnosed for lymphoepithlioma, and two cases from group B, one belonging to p-stage IIIa and another, whose clinical records were lost, were excluded from the study. Thus, 226 patients, 116 patients in group A and 109 patients in group B were evaluated as eligible for investigation (Table 1).

Treatment compliance
Our regimen consisted of two parts, or PVM therapy and daily administration of UFT. Treatment compliance was evaluated for each part for group B patients (n=109). In reference to the first part, PVM therapy, 103 patients (94.5%) actually received this part and the remaining six did not received it (three refused, one suffered renal failure, and no reason was reported for two). Among the 103 patients, 29 patients (26.6%) received one course, and 74 patients (67.9%) received two courses. As concerns part two, or oral administration of UFT for 1 year, 86 patients (78.8%) received administration. Among those who did not receive UFT administration (n=23), two rejected it (the same patients as those rejecting PVM therapy), one suffered renal failure (the same patient who could not receive PVM therapy), nine stopped receiving therapy due to the adverse effects of PVM therapy, and ten gave no reason. The mean total doses of UFT administrated to 86 patients were 127.6±75.3 g, and the ratio of medication to the maximum basic amount was 87.4%. There were three patients who received adjuvant chemotherapy after surgery in group A (1, oral administration of UFT; 1, Cisplatin+Vindesine; 1, Cisplatin+Vindesine+Mitomycin C).

Recurrence and survival
A follow-up survey on 5-year survival rates was successfully completed for 91% of the patients. There were 61 recurrences (27/109, or 24.8%, in the chemotherapy group, and 34/116 or 29.3%, in the surgery alone group).

Twenty-five deaths occurred in the chemotherapy group and 33 in the surgery alone group. As concerns the causes of death, the primary disease and other causes of death, including other diseases, accidents and unknown causes accounted for 26 and seven in group A and 20 and 5 in group B, respectively. The number of cases of death for each subclass are shown in Table 2.

View larger version (13K): [in this window] [in a new window]   Fig. 2. Survival curves for all patients.

View larger version (12K): [in this window] [in a new window]   Fig. 3. Survival curves for patients with pT1N0.

	Discussion

Top Abstract Introduction Subjects and methods Results Discussion Appendix A. Institutions... Appendix B. Conference... References

UFT a designed combination drug which consists of Tegaful (FT), a fluolouracil (5-FU) derivative, and uracil at a molar ratio of 1:4. When administrated orally, FT shows good absorption characteristics, and it is gradually converted into 5-FU, in vivo [16]. The coexistence of uracil prevents degradation of 5-FU antagonistically and maintain the levels of 5-FU in tumor tissue for a long period [17]. In addition, minimal adverse effects of UFT permit long-term oral administration by outpatient clinics. In fact, oral administration of UFT has already been applied clinically for digestive tract cancer, breast cancer, and head and neck cancer [18]. The West Japan Surgery Group (WJSG) planned to investigate the efficacy of post operative adjuvant chemotherapy and reported the superiority of UFT over FT in the first trial [19]. The second trial by the WJSG and the study group of adjuvant chemotherapy for lung cancer (Chubu, Japan) conducted randomized trials of post operative adjuvant chemotherapy, which included oral administration of UFT, and the efficacy of UFT was indicated. In the former trial, the 5-year survival rates for the UFT group, the Vindesine/Cisplatin/UFT group, and control group were 64.1, 60.6 and 49.0%, respectively [20]. In the latter trial the 5-year survival rates for the Doxorubicin/Cisplatin plus daily UFT group and the control group were 61.8 and 58.1%, respectively. After adjustment of patients background by Cox's proportional hazard model, the chemotherapy group had a significantly higher survival rate than the control group [21]. According to these two trials, the efficacy of UFT was suggested.

In the present trial, early-stage patients (completely resected NSCLC patients in pathological stage I or II) were enrolled. The post operative chemotherapy consisted of two courses of Cisplatin/Vindesine/Mitomycin C and daily UFT for 1 year. Eighty-six patients out of 109 patients (78.8%) received oral administration of UFT. Among the 23 patients who did not receive UFT, nine canceled, apparently due to adverse effects of PVM therapy, and ten canceled after PVM therapy with no reported reason. We, therefore, think PVM therapy was responsible for the cancellation in these 19 patients. On the other hand, the ratio of those receiving medication to the maximum basic amount was 87.4%, so oral administration of UFT showed good treatment compliance. Thus, it seems that PVM therapy reduced the compliance with UFT therapy in this study. The 5-year survival rate and disease-free survival rare were 76.8 and 74.1% in the chemotherapy group (B), and 71.1 and 69.8% in the surgery alone group A, respectively. Statistically, the overall or disease-free survival between two groups was found to be similar. But in terms of subgroups which were divided according to the fifth revision of the International System for Staging Lung Cancer (pT1N0, pT2N0, pT1N1, pT2N1), it is very interesting that for pT1N0 group patients, who comprised the majority of the study population, the comparison of 5-year survival rates revealed a significant difference between groups A and B (P=0.03: log-rank; P=0.03). This result indicated that prolongation of survival may be achieved in the earliest stage group of patients by post operative chemotherapy which include long-term oral administration of UFT.

For NSCLC patients were divided into subgroups according to the 5th revision of the International System for Staging Lung Cancer, the 5-year survival rate for stage IA was reported as 77.4% by Naruke [22], and as 67% by Mountain [23], results which cannot be considered satisfactory, in comparison with the results for other organs. Post operative adjuvant chemotherapy must, thus be, attempted targeting undetectable distant micro-metastasis at surgery. Since, inpatients who received complete resection, even though early-stage patients, metastatic lesions (mainly distant) were always manifested after a somewhat long interval following surgical treatment, it is suggested that malignant cells in such lesions have various biological characteristics that might undergo a change after some period following surgery. Tanaka et al., for example, reported the importance of p53 status, not only as a prognostic factor but also as the proceeding factor for efficacy of post operative administration of UFT [24]. With reference to the post operative chemotherapy targeting micro-metastatic lesions, the biological characteristics of cancer cells might be taken into consideration when the anti-cancer drugs are selected. We think that drugs that can maintain contact with cancer cells over a long period in vivo without reduction in performance status can be expected to produce good results.

Including the results of the present study, evidence for the efficacy of the long-term oral administration of UFT for post operative adjuvant chemotherapy in early-stage NSCLC patients has been accumulated. From this point of view, the other 373 patients who belonged to p-stage I were randomly assigned to a daily UFT group and to a control group in the 4th WJSG trial that followed, and we are now waiting for the results to come in.

	Footnotes

 
Presented at the 12th Annual Meeting of the European Association for Cardio-thoracic Surgery, Brussels, Belgium, September 20–23, 1998.

The following principal investigators and institutions participated in these studies: S. Hitomi (Chairman, Kyoto University), H. Ayabe (Nagasaki University), S. Ikeda (Kyoto Katsura Hospital), M. Ito (National Shigaraki Hospital), H. Kato (Siga University of Medical Science), K. Genga (National Okinawa Hospital), N. Shimizu (Okayama University), N. Tsubota (Hyogo Medical Center for adults), S. Namikawa (Mie University), M. Maeda (Kagawa Medical School), Y. Monden (Tokusima University), M. Yamakido (Hirosima University), Y. Watanabe (Kanazawa University), M. Ohta (National Kyushu Cancer Center), R. Soejima (Kawasaki Medical School), Y. Matsubara (Kyoto Katsura Hospital), H. Wada (Kyoto University), T. Sakurai (Tokyo University).

	Appendix A. Institutions cooperating in the prospective randomized trial, West Japan Study Group for lung cancer surgery (WJSG)

Top Abstract Introduction Subjects and methods Results Discussion Appendix A. Institutions... Appendix B. Conference... References

 

Kyoto University Shimane Medical University Kyoto Katsura Hospital Kanazawa University Yamaguchi University Toyama Prefectural Central Hospital Kagawa Prefectural Central Hospital Toyama Medical and Pharmaceutical University Osaka City University Medical School Shiga University of Medical Science Fukui Red Cross Hospital Nara Medical University Kurume University Hyogo Prefectural Amagasaki Hospital Kyoto City Hospital Mie University Nagasaki University Kochi City Hospital Tokusima University Kagosima University National Shikoku Cancer Center Hospital Kansai Medical University Wakayama Medical College National Utano Hospital Osaka Medical College Kagawa Medical School Fukui Medical School Okayama University National Okinawa Hospital Hyogo Medical Center for Adults Kawasaki Medical School Tenri Hospital National Kyoto Hospital Hiroshima University National Hyogo Central Hospital University of Occupational and Environmental Health

	Appendix B. Conference discussion

Top Abstract Introduction Subjects and methods Results Discussion Appendix A. Institutions... Appendix B. Conference... References

 
Dr P. Van Schil (Edegem, Belgium): I was just wondering if you looked at the complications of the chemotherapy itself? Was there a difference in the causes of death between the two groups, those who received chemotherapy and those who did not receive chemotherapy?

Dr Miyahara: Concerning the cause of death, there is no chemotherapy death in the chemotherapy group. Cancer death was the main reason for death in both groups.

Dr A.B. de la Riviere (Nieuwegein, The Netherlands): Could you speculate upon a possible explanation for the difference found between N0 and N1?

Dr Miyahara: In this study, patient population was low in the N1 group, so in the patients with N1 disease the difference in survival rates between groups A and B was not manifested.

Dr P. Macchiarini (Le Plessis–Robinson, France): Do you suggest that in T1N0 patients you should administer post-chemotherapy routinely.

Dr Miyahara: Yes.

Dr Macchiarini: Okay. Then there is a problem with your statistical analysis. Since the endpoint of surgery in T1 or T2, or whatever early stage non-small cell lung cancer, is not the survival, it's disease-free survival. When you plot together all the patients for the survival analysis, then you have the operative deaths, you have patients dying from something else, not from the cancer, etc. Also, you still have 70–80% of survival at 5 years. If you plot the survival against the disease-free survival, you have an extra gain of 15% more disease-free survival at 5 years. So that means that you have a 95% disease-free survival at 5 and 10 years. So why should you expose patients to chemotherapy.

Dr Miyahara: According to our experiences nearly all patients died of cancer recurrence even in early stage diseases. For example, in this study, the rates of cancer death were 79% for group A and 80% in group B. So we think it may be possible to utilize survival for the end-point. In addition, since even early stage patients may have undetected micro-metastasis, we think it may be important to administrate anti-cancer drugs with low toxicity for long duration.

	References

Top Abstract Introduction Subjects and methods Results Discussion Appendix A. Institutions... Appendix B. Conference... References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Hiromi Wada Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wada, H. Articles by Hitomi, S. Search for Related Content PubMed PubMed Citation Articles by Wada, H. Articles by Hitomi, S.