Vepesid

Small cell lung cancer (SCLC) is usually a systemic disease at the time of initial diagnosis. It has a rapid growth rate and is metastatic outside the thorax in most patients at initial presentation.[1,2] However, SCLC is sensitive to chemotherapeutic agents and radiation,[3] so combination chemotherapy is useful in the treatment of SCLC.[4] Responses occur in 80 to 90% of patients with limited-stage (LD) SCLC (LD-SCLC) treated with combination chemotherapy, with a median survival time (MST) of 12 to 16 months and 2-year survival rates of 20 to 30%.[4-6] Although 40 to 80% of patients with LD-SCLC achieve a complete remission (CR), only 15% are continuously disease free for 2 years.[7] Most initial relapses are intrathoracic.[8] Thoracic radiation therapy does not appear to prevent local recurrence.[7,9] Recent reports indicate that pulmonary resection in SCLC may offer extended survival and lessen the incidence of local recurrence.[10,11] Resection may provide protection from local recurrence. According to Davis et al[12] in their study of 1,538 SCLC patients, the only factor that correlated with greater than 2-year survival was whether surgery was performed as part of the initial therapy. Surgical resection in combination with chemotherapy for stage I and probably stage II disease is now commonly accepted in the management of SCLC.[13] More recently, Meyer et al[14] and Shepherd et al[15] have reported the possibility that surgical resection after chemotherapy for SCLC improved local control and also prolonged survival. In the present study for resectable stage I to IIIA SCLC, we evaluated the feasibility and efficacy of induction chemotherapy followed by surgical excision of the primary tumor and any regional lymph node metastases for providing better local control of the tumor and a longer survival time than "state-of-the-art" therapy.[16]

MATERIALS AND METHODS

Patients

Between March 26, 1987 and March 30, 1993, 22 patients with histologic or cytologic proof of SCLC, who were believed to be surgical candidates on the basis of resectable stage I to IIIA disease (N0, N1, or early N2 disease), were eligible for this study. Cytologic diagnoses were confirmed during a central review by the Niigata Cancer Center Hospital Pathology Committee. All preoperative and postoperative pathology samples were reviewed by two or more pathologists. The patients had no prior treatment with chemotherapy or radiation and had an Eastern Cooperative Oncology Group performance status (PS)[17] of 0 or 1. All patients were younger than 70 years old. Pretreatment studies included history, physical examination, CBC counts, standard blood chemistry studies, a chest radiograph, CT scans of the brain, thorax, and abdomen, a bone scan, bone marrow aspiration, and bronchoscopy. Mediastinoscopy was not used to determine the pathologic N2 staging. Contraindications to protocol treatment included a WBC count [is less than] 4,000/[micro] L, a platelet count [is less than] 100,000/[micro] L, a creatinine concentration [is greater than] 1.3 mg/dL, an uncontrolled infection, poor cardiopulmonary function, or other serious illnesses. Patients with a history of cancer, unless they had at least a 3-year disease-free interval without treatment, were excluded. All patients provided informed consent.

Preoperative clinical staging was reported according to the new international staging system for lung cancer.[18] The World Health Organization response criteria were used to assess the response to therapy.

Treatment Program

The first group of patients received combination chemotherapy consisting of cisplatin (80 mg/[m.sup.2]) and doxorubicin hydrochloride (Adriamycin) (30 mg/[m.sup.2]), all given on day 1, and etoposide (VePesid) (60 mg/[m.sup.2]), given daily for 5 days (CAV II regimen). CAV II was repeated IV every 3 weeks, for two cycles. At the completion of chemotherapy, the previous staging procedures were repeated to confirm response and exclude progressive disease. Responding patients underwent surgical resection, which was determined by the site of the primary disease at the initial presentation. All the patients received a radical mediastinal lymph node dissection. About 4 weeks after surgery, the responding patients with good PS received CAV II for three additional cycles.

After March 1990, the postoperative chemotherapy regimen was changed to cisplatin (80 mg/[m.sup.2]) given on day 1, and etoposide (VePesid), 100 mg/[m.sup.2], given daily for 3 days (CV regimen). After November 1991, patients with N1 and N2 disease received preoperative CAV II chemotherapy for four cycles, and no postoperative chemotherapy. The patients with N0 disease received the same preoperative and postoperative (CAV II and CV, respectively) regimens as previously described.

Statistical Methods

All patients have been followed up for at least 41 months, and their survival times have been calculated from the date of first treatment with chemotherapy until the date of death or last follow-up visit. Actuarial survival curves were prepared using the Kaplan-Meier method,[19] and comparisons of survival were done with the log-rank test. Differences with p values [is less than] 0.05 were considered to be statistically significant. The survival curves were generated on the basis of their pretreatment clinical stage, whether or not the patients underwent a surgical resection.

RESULTS

During this study period, approximately 150 patients with SCLC were treated at our institution. Twenty-two patients entered into this study. There were 21 men and one woman with a median age of 60.5 years (range, 39 to 70 years). Pretreatment clinical TNM staging revealed 11 patients with stage I tumors, four with stage II tumors, and seven with stage IIIA tumors. The preoperative histologic examination revealed four cases of oat cell type and 18 of intermediate cell type.

The overall response rate to chemotherapy was 95.5% (CR, five of 22 [22.7%] and partial response, 16 of 22 [72.7%]). One patient achieved a minor response (a decrease from 25 to 50% in the average sum of the diameters of the measurable lesions) while receiving chemotherapy. Following reassessment after induction chemotherapy, all patients were believed to be candidates for surgical resection. The mean duration from the start of chemotherapy until the operation was 69.9 days, while the mean duration for two or four cycles of chemotherapy was 61 and 99 days, respectively. Twenty-one of the patients underwent a thoracotomy. One patient was considered ineligible for the operation because of a cerebrovascular accident after chemotherapy. Of the 21 patients who underwent a thoracotomy, 19 required a lobectomy, one a pneumonectomy, and one a segmentectomy. There was one operative death because of an uncontrolled postoperative infection.

The postoperative pathologic examination showed no residual tumor in five patients, only SCLC in 15, and only adenocarcinoma in one. After the postoperative pathologic examination and TNM staging, five patients had TON0 disease, 10 had stage I disease, four had stage II disease, and two had stage IIIA disease.

The overall survival for all 22 patients is shown in Figure 1. Their median survival was 61.9 months and the actuarial 3-year survival rate was 63.6%. Eleven patients are currently alive. Four patients have survived longer than the MST (61.9 months), another five have survived for more than 48 months, and the remaining two survivors have survived for more than 36 months. The median survival for the 21 patients undergoing a thoracotomy also was 61.9 months, and their actuarial 3-year survival rate was 66.7%. Within this group, patients with clinical stages I and II disease (N0 and N1, 14 patients) had significantly longer survival times than did patients with clinical stage IIIA disease (N2, seven patients) (actuarial 3-year survival rates of 73.3% and 42.9%, respectively; p=0.018) (Fig 2). A similar statistically significant difference in survival was not observed when the 21 surgical patients were analyzed according to their postoperative pathologic stage, because only two patients had pathologic stage IIIA disease.

[Figure 1-2 ILLUSTRATION OMITTED]

As shown in Table 1, 11 of the 21 surgical patients were disease free from 41.1 to 107.6 months. One patient died at 48.0 months because he developed brain metastases after 16 months. Five died after suffering relapses at 10.3, 12.6, 17.1, 19.1, 36.1 months after the start of chemotherapy. One patient died of another malignancy (esophageal cancer) at 61.9 months. Three patients died of recurrences, but whether it was from local or distant relapses could not be determined because they died at other hospitals. One patient with N2 disease died because of an operation-related infection. Five of the six patients with recurrent disease had lymph node metastases.

Table I--Clinical Features of All 2a Patients Treated With Induction Chemotherapy(*)

The mean ([+ or -] SD) interval from the start of chemotherapy for two or four cycles to the operation was 61 [+ or -] 8.8 and 99 [+ or -] 6.5 days, respectively. The only major adverse reaction was an operation-related death of one patient with N2 disease, but other serious side effects were not seen. So, this regimen of induction chemotherapy (CAV II) is feasible.

In conclusion, surgical treatment after induction chemotherapy for those with up to resectable stage IIIA SCLC is feasible, and we have achieved good local control and long-term survival in those with clinical stage I and II disease. However, a remaining problem is distant relapses, suggesting that the chemotherapeutic dose intensity was not sufficient. New drugs or new combinations are needed to battle this disease. We hope to undertake a cooperative randomized trial in stage I and II SCLC patients who undergo surgery after induction chemotherapy vs chemoradiotherapy alone.

REFERENCES

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(*) From the Departments of Internal Medicine and Thoracic Surgery, Niigata Cancer Center Hospital, Niigata, Japan. This work was supported in part by Grants-in-Aid for Cancer Research from the Ministry of Health and Welfare of Japan. This study was presented at the 35th General Meeting of the Japan Lung Cancer Society, Nagasaki, November 8, 1994. Katsuya Fujimori, MD, Currently at Niigata Prefectural Shibata Hospital. Manuscript received December 23, 1995; revision accepted October 10, 1996. Reprint requests: Dr. Fujimori, Department of Internal Medicine, Niigata Prefectural Shibata Hospital, Ote-cho, 4-5-48, Shibata 957, Japan.

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