Adjuvant Treatment of Early Stage Non–Small-Cell Lung Cancer

Cure rates for non–small-cell lung cancer (NSCLC) remain low and the prognosis for patients with even stage IA disease is poor. Complete surgical resection is still the first-line treatment for NSCLC, but many investigators are studying the benefit of postoperative adjuvant chemotherapy as a means of destroying residual tumor and micrometastasis. However, given the high recurrence rate and the trauma of surgery, consideration of drug toxicity and the patient’s quality of life is important. Uracil and tegafur (UFT) is a tolerable and active drug in NSCLC that, as a prodrug and biochemical modulator, provides extended tumor exposure to 5-fluorouracil (5-FU). Early evidence from studies with UFT described here indicate that it may be a safe and effective alternative to cisplatin (Platinol)-based therapy for the postoperative adjuvant chemotherapy of early stage NSCLC. Further results are awaited.

Introduction

Standard first-line treatment for non–small-cell lung cancer is surgical therapy. It offers the best possibility for prolonged survival in stage I and II non–small-cell lung cancer with no mediastinal metastasis. Many patients, however, develop recurrent disease or remote metastasis relatively soon after resection. Early recurrence and remote metastasis following surgery have been assumed to be attributable to the existence of micrometastasis not detectable before or during surgery. For this reason and to improve therapeutic results, systemic chemotherapy following surgical resection is being studied.

Since the 1960s, various postoperative adjuvant chemotherapies have been investigated. Oral administration of alkylating agents tended to shorten survival, and postoperative adjuvant chemotherapy seldom proved effective. In fact, no standard adjuvant chemotherapy has been established as efficacious to date.

This comparison of intensive chemotherapy (cisplatin [Platinol]-based therapy), with good antitumor activity, and mild chemotherapy (UFT) with consideration of patient quality of life will attempt to set a standard of chemotherapy for postresection patients with early stage non–small-cell lung cancer.

Effects of Intensive Cisplatin-Based Chemotherapy

Relatively powerful chemotherapy regimens with high antitumor activity have been studied as postoperative adjuvant treatment of non–small-cell lung cancer (Table 1).[1-5] Holmes et al[1] and members of the Lung Cancer Study Group in the United States reported the first efficacy trial of postoperative chemotherapy. The investigators divided patients who had undergone complete resection of stage II and III adenocarcinoma and large-cell cancer into two groups: one group received cyclophosphamide (Cytoxan, Neosar), Adriamycin (doxorubicin), plus cisplatin (CAP) therapy once a month for 6 months, and the other received intraperitoneal administration of bacillus Calmette-Guérin vaccine (BCG) and consecutive 3-day oral administration of levamisole (Ergamisol) once every 2 weeks for 18 months. The median recurrence-free survival period was significantly longer for the chemotherapy group (7 months) than for the immunotherapy group. It is difficult to assess the impact of these results, however, because overall survival was similar between groups (P = .078) and the control group received immunotherapy.

As reported by Feld et al, the Lung Cancer Study Group conducted a later comparative study using CAP in stage I and II (T2, N0 and T1, N1) patients who had undergone resection.[3] In this study, the dose of cisplatin was increased from 40 mg/m2 to 60 mg/m², and only four courses rather than six courses of medication were administered. No significant differences were observed between groups in terms of recurrence-free or overall survival.

Niiranen et al[2] treated patients ranging from T1, N0 to T3, N0 who had undergone resection of lung cancer with CAP or no chemotherapy. The 5-year survival rates were 56% for the control (surgery-alone) group and 67% for the CAP group, demonstrating a significant benefit for chemotherapy. The limitations of this trial, however, included the small number of patients, the enrollment of T3, N0 patients who should have been excluded from postoperative adjuvant chemotherapy due to advanced stage, and a bias observed in the patients’ background toward certain surgical techniques.

In a Japanese study, vindesine (Eldesine) plus Platinol (VP) was reported to be more effective than CAP in the treatment of stage IIIA patients who had undergone a complete resection.[4] There was no difference, however, in the recurrence-free or overall survival rate between the untreated and VP groups.

Effects of Mild UFT Chemotherapy

Uracil/tegafur-a more tolerable chemotherapy option-has been studied in Japan as postoperative adjuvant chemotherapy for gastrointestinal and breast cancers. The drug was developed as a biochemical modulator,[6] yielding a 5-fluorouracil (5-FU) area under the concentration-time curve (AUC) equivalent to that obtained following continuous infusion.[7] This characteristic makes it possible to expose residual or micrometastatic cancer to 5-FU (a time-dependent drug delivered orally) for many hours. In view of the burden of surgical invasion, this approach is based on the theory that chemotherapy that reduces quality of life and immunologic capacity should be avoided. To achieve this end, it is necessary to select mild chemotherapy regimens. The West Japan Study Group (WJSG) for Lung Cancer Surgery (The Japan Lung Cancer Research Group on Postsurgical Adjuvant Chemotherapy) was organized to examine this need and to identify effective and safe postoperative adjuvant chemotherapy regimens.

UFT has been evaluated by the WJSG as a mild chemotherapy option. In the first study,[8] a stratified analysis showed that the prognosis for pN2 non–small-cell lung cancer patients treated with UFT was better than for those receiving tegafur. Adverse reactions were minor in both groups, suggesting that long-term administration of UFT raised no safety problem.

In the second study,[5] conducted as an exploratory evaluation, patients were assigned to one of three treatment groups: a cisplatin, vindesine, and UFT treatment group, a UFT treatment group, and a surgery-alone group. Both postoperative adjuvant chemotherapy groups experienced better survival than the surgery-alone group. A significant improvement in the survival rate was observed in the UFT-alone group, as compared with the surgery-alone group.

In the Central District of Japan (Chubu), another study compared outcome among patients treated with cisplatin, doxorubicin, and UFT vs surgery alone.[9] More patients in the chemotherapy group had an advanced pN-an important prognostic factor affecting treatment outcome-comprising a significant bias between the two groups. Consequently, a correction was carried out using the Cox proportional hazards model, with the results revealing that survival was significantly prolonged in the chemotherapy groups, including the UFT group, as compared to the surgery-alone group.

Discussion

TNM Classification

Lung cancer is a malignancy with a consistently poor prognosis. In the fifth edition of the Union International Contre le Cancer (UICC) TNM classification, revised in 1997, stages I and II lung cancer are classified into stages IA, IB, IIA, and IIB, with T3, N0, M0 assigned to stage IIB. If tumors besides the primary tumor are in the same lobe of the lung, the lung cancer is classified as T4; if they are in other lobes, it is classified as M1.

Based on these new TNM classifications, 5-year survival was recently reported to be 77.4%[10] and 67%[11] for all stage I/II patients, even those with stage IA disease. This limited survival, at even the earliest stage of disease, substantiates the poor prognosis for this cancer relative to the prognosis of cancer in other organs. These poor results are assumed to be due to the existence of micrometastasis and remote metastasis, even in patients who had undergone complete resection of early stage lung cancer. To improve therapeutic results, investigators are evaluating the effect of the combination of chemotherapy, ie, systemic therapy, and surgical therapy.

Postoperative Adjuvant Chemotherapy

With respect to the postoperative adjuvant chemotherapies that have been studied to date, a 1997 consensus report[12] from the International Association for the Study of Lung Cancer (IASLC) noted the following (Table 2): There is no convincing evidence that any postoperative treatment prolongs survival of non-small-cell lung cancer patients who have undergone complete surgical resection of their neoplasm. In fact, no clear benefit has been observed in studies by Holmes et al,[1] Niiranen et al,[2] Feld et al,[3] or Ohta et al[4] employing highly effective postoperative adjuvant chemotherapy drugs, including cisplatin. Early studies with chemotherapy, including UFT, have not shown clear benefit, although preliminary results are promising.

With respect to the selection of postoperative adjuvant chemotherapy, the consensus report states: “The chemotherapy regimens used should be those thought to be most active in advanced non–small-cell lung cancer at the time the trial is designed.” This thinking has been consistently reiterated since the first consensus report in 1991.[13] Indeed, the view that active drugs with proven antitumor efficacy should be used in postoperative adjuvant chemotherapy is logical. The question remains, however, whether it is appropriate to apply the same dose as that administered for advanced cancer to postoperative adjuvant chemotherapy in order to achieve the anticipated effect.

In reality, it is often difficult to administer full-dose chemotherapy to patients experiencing the aftereffects of surgical invasion. Nonetheless, a meta-analysis[14] showed that chemotherapy including cisplatin improved the 5-year survival rate by 5%. In this meta-analysis, the cisplatin, vindesine, plus UFT group in the above-mentioned WJSG second study and the cisplatin, doxorubicin, plus UFT group in the Chubu study were included in the cis-platin category. Postoperative cisplatin was administered once at a dose of 50 mg/m² (the second study by the WJSG) or 66 mg/m² (Chubu). Thus, doses used were insufficient to treat advanced cancer and studies that included UFT were analyzed, making it difficult to reach any conclusions regarding cisplatin-based chemotherapy.

The activity of UFT has been presented in several reports, including one from our institution. We retrospectively compared the 5-year survival rates with and without UFT treatment of patients who had undergone surgery from 1976 to 1992. The 5-year survival rates were 76.5% and 58.6% for the UFT-treated and UFT-untreated groups, respectively, demonstrating a significant difference between groups (P = .005) (Figure 1).[15] Multivariate analysis of these results also indicated that UFT treatment is an important factor in treatment prognosis.

Furthermore, the inhibition of micrometastasis was recently observed in a basic science experiment. Antimetastasis, or a metastasis-inhibiting effect, was seen in a natural pulmonary metastasis model; it was suggested that vascularization inhibition was the likely mode of action.[16,17]

In light of these findings, it is necessary to consider postoperative adjuvant chemotherapy for non–small-cell lung cancer not only for its antitumor effect but also from various other perspectives, such as duration of tumor exposure to time-dependent 5-FU and patients’ quality of life and immunologic capacity. In fact, the 1997 consensus report also observed, “there is a possibility of the usefulness of chemotherapy not based on cisplatin being ascertained in the future.”

Conclusions

It is important to consider mild agents (UFT) for postoperative adjuvant chemotherapy for non–small-cell lung cancer. The outcomes of the fourth study on the usefulness of administering UFT alone currently being conducted by the WJSG (stage I; surgery-alone vs UFT) and that of the Japanese Society for Study on Postoperative Adjuvant Chemotherapy for Lung Cancer (T1, N0, M0 and T2, N0, M0 adenocarcinoma; surgery alone vs UFT) are anticipated.

References:

1. Holmes EC, Gail M: Surgical adjuvant therapy for stage II and stage III adenocarcinoma and large-cell undifferentiated carcinoma. J Clin Oncol 4:710-715, 1986.

2. Niiranen A, Niitamo-Korhonen S, Kouri M, et al: Adjuvant chemotherapy after radical surgery for non–small-cell lung cancer: Randomized study. J Clin Oncol 10:1927-1932, 1992.

3. Feld R, Rubinstein L, Thomas PA, and the Lung Cancer Study Group: Adjuvant chemotherapy with cyclophosphamide, doxorubicin, and cisplatin in patients with completely resected stage I non–small-cell lung cancer. J Natl Cancer Inst 85:299-306, 1993.

4. Ohta M, Tsuchiya R, Shimoyama M, et al: Adjuvant chemotherapy for completely resected stage III non–small-cell lung cancer. J Thorac Cardiovasc Surg 106:703-708, 1993.

5. Wada H, Hitomi S, Teramatsu T, et al: Adjuvant chemotherapy after complete resection in non–small-cell lung cancer. J Clin Oncol 14:1048-1054, 1996.

6. Fujii S, Ikenaka K, Fukushima M: Effects of coadministration of uracil or cytosine in the antitumor activity of clinical doses of 1-(2-tetrahydrofuryl)-5-fluororacil and level of 5-fluorouracil in rodents. Gann 70:209-214, 1979.

7. Ho DH, Pazdur R, Covington W, et al: Comparison of 5-fluorouracil pharmacokinetics in patients receiving continuous 5-fluorouracil infusion and oral uracil plus N1-(2¢-tetrahydrofuryl)-5-fluorouracil. Clin Cancer Res 4:2085-2088, 1998.

8. Wada H, Tanaka F, Hitomi S: Postoperative adjuvant chemotherapy for non–small-cell lung cancer: West Japan Study Group for Lung Cancer Surgery: The Japan Lung Cancer Research Group on Postsurgical Adjuvant Chemotherapy. Oncology 11(suppl 10):98-102, 1997.

9. The Study Group of Adjuvant Chemotherapy for Lung Cancer (Chubu, Japan): A randomized trial of postoperative adjuvant chemotherapy in non–small-cell lung cancer (the second cooperative study). Eur J Surg Oncol 21:69-77, 1995.

10. Naruke T: Result of resected lung cancer based on the new UICC TNM classification, 5th edition. Gan To Kagaku Ryoho 24:2289-2295, 1997.

11. Mountain CF: Revisions in the international system for staging lung cancer. Chest 111:1710-1717, 1997.

12. Johnson D, Arriagada R, Barthelemy N, et al: Post-operative adjuvant therapy for non–small-cell lung cancer. Lung Cancer 17(suppl 1)23-25, 1997.

13. Holmes EC, Bleehen NM, Le Chevalier T, et al: Postoperative adjuvant treatments for non–small-cell lung cancers: A consensus report. Lung Cancer 7:11-13, 1991.

14. Non-Small-Cell Lung Cancer Collaborative Group: Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomized clinical trials. Br Med J 311:899-909, 1995.

15. Tanaka F, Miyahara R, Ohtake Y, et al: Advantage of post-operative oral administration of UFT (uracil and tegafur) for completely resected p-stage I-IIIa non–small-cell lung cancer (NSCLC). Eur Cardiothorac Surg 14:256-262, 1998.

16. Kurabayashi J, Nukatsuka M, Fujioka A, et al: Postsurgical oral administration of uracil and tegafur inhibits progression of micrometastasis of human breast cancer cells in nude mice. Clin Cancer Res 3:653-659, 1997.

17. Shibata J, Murakami K, Abe M, et al: Life prolonging effects of antitumor agents on postoperative adjuvant therapy in the lung spontaneous metastasis model in mice. Anticancer Res 18:1203-1209, 1998.