There have been many attempts to develop effective

Postoperative Chemotherapy for Non-Small-Cell Lung Cancer* E. Carmack Holmes, M.D. The Lung Cancer Study Group has performed a number of postoperative adjuvant trials in patients with resectable DOD-small-ceO lung cancer (NSCLC). Adjuvant cyclophosphamide, cloxorubicio, and cisplatio (CAP) chemotherapy was compared with immunotherapy in the treatment of 13 patients with stage ll or ill adenocarcinoma or large ceo undifferentiated carcinoma. Careful intraoperative staging was performed in all patients. Disease-free interval was signi&cantly prolonged in the chemotherapy group (p=.32). After 7.5 years of follow-up, the difference in time to recurrence and cancer deaths remains statistically sigoi&caot. Another study compared CAP chemotherapy plus radiotherapy with radiotherapy alone in advanced stagei ll and ill resected NSCLC. Again, the chemotherapy arm had sigoi6cantly increased disease-free surviv81. In a third study, patients with high-risk stage I NSCLC were nmdomized after surgery to CAP chemotherapy or s e r vatioo. In this study there was oo difference in recurrencefree survival or overall survival. (Cheat 1993; 13:3S-34S) There have been many attempts to develop effective postoperative adjuvant therapy for patients with resected non-small-cell lung cancer (NSCLC). Most previous studies have suffered from problems in protocol design. Many of these trials were not randomized or stratified for important risk factors like cell type, nodal involvement, performance status, age, or other prognostic variables. Careful intraoperative staging was not performed in most of these studies, which makes it difficult to determine whether patients had stage I, stage II, or, in some cases, occult stage III disease. In addition to these problems, many clinical trials included chemotherapeutic agents that were only marginally effective or ineffective (Table 1). - 7 However, with the development of platinum-based regimens, the effectiveness of combination chemotherapy for NSCLC has significantly increased. Patients with stage IliA or IIIB disease con&ned to the thorax have had particularly high response rates (6 to 7 percent) to these regimens. s-ll Considering response rates of this magnitude, it seems logical to deduce that the likelihood of success with adjuvant chemotherapy has increased greatly (Table 2). s- 11 The National Cancer Institute funded a cooperative group of thoracic surgeons, medical oncologists, radiotherapists, statisticians, nurse data managers, and pathologists to perform surgical adjuvant studies in patients with lung cancer. The Lung Cancer Study Group (LCSG) has performed a number of prospective randomized trials over the past 12 years evaluating adjuvant chemotherapy and radiotherapy. *From the Department of Surgery, Divisi<>n of Oncology, UCLA Medical Center, Los Angeles. PosTOPERATIVE ADJUVANT THERAPY TRIALS Stages II and Ill Adenocarcinoma and Large CeU Undifferentiated Carcinoma The &rst of these trials evaluated surgical adjuvant therapy in patients with resectable stage II or III adenocarcinoma or large cell undifferentiated carcinoma of the lung. 7 Patients underwent surgery with careful intraoperative staging that included lymph node sampling. Following pathologic staging, all patients were stratified based on the presence or absence of preoperative arrhythmia, regardless of disease stage and prior weight loss. Following stratification, patients were randomized to two groups: one group received intrapleural bacillus Calmette-Guerin (BCG) and orallevamisole and the other adjuvant chemotherapy consisting of cyclophosphamide (4 mg!m ), doxorubicin (4 mg,tm ), and cisplatin (4 mglm ) (CAP). The latter regimen was administered monthly for 6 months beginning 2 to 3 days following surgery. The BCG was given via an intrapleural injection of 1 7 tice BCG organisms into the chest tube of lobectomy patients or by thoracentesis in patients with pneumonectomy; levamisole, 2.5 mgllcg, was given orally for 3 consecutive days every o t hweek e for 18 months. Immunotherapy was given in lieu of no treatment considering the poor prognosis of these patients following surgery. Table 1-Buul.t. of Adjuvant Chemotherapy Adminimt-ed A/Ur Complete Heaection ofnsclc* Reference Agent Results Brunner et al 1 Cyclophosphamide Negative Hughes and Higgins (VA) Nitrogen mustard Negative Slaclc' Nitrogen mustard Negative Shields et al (VA)' Cyclophosphamide + Negative methotrexate Shields et al (VA}' Lomustine + hydroxyurea Negative Newman et ajo CAMP Positive LCSG 7 CAP Positive *NSCLC =non-small-cell lung cancer; CAMP= cyclophosphamide/ doxorubicin/methotrexate/procarbazine; LCSG = Lung Cancer Study Group; CAP= cyclophosphamide/doxorubicinlcisplatin. Table 2-veraU Reaponae (CH + PH) to Chemotherapy in lbtienta With Stagea lila or lllb NSCLC* Author Bonomi et al Bltran et al" Strauss et al Martini et al 11 Regimen Cisplatin + mitomycin or 5-FU Cisplatin + vindesine/etoposide Cisplatinlvindesine Mitomycinlvindesine/cisplatin %Overall Response 6 7 45 7 *CR =complete response; PR =partial response; NSCLC =nonsmall-cell lung cancer; 5-FU = 5-fluorouracil. 38

1 8 Log rank p =.32 c ;;;, :; 6 = E 4 ll. ------------------ CAP 2 BCGIINH FIGURE 1. Kaplan-Meier disease-free survival of 13 patients with completely resected adenocarci noma or large cell undifferentiated lung cancer treated with chemotherapy (CAP) or immunother 12 36 48 6 72 84 96 18 12 apy ( B C G ICAP= I N cyclophosphamide/doxoru H bicinlcisplatin; BCGIINH =bacillus Calmette-Guerinlisoniazid. Follow-up examinations were scheduled monthly for 6 months, then quarterly for 6 months, and semiannually thereafter. Chest x-ray, alkaline phosphatase levels, and liver function tests were among the required laboratory evalua tions. No statistically significant treatment imbalances were noted for stratification factors or other baseline covariants such as nodal status, performance status, race, gender, or history ofheart disease. Ninety percent of patients had hilar or mediastinal lymph node involvement. A total of 141 patients were randomized, 13 of whom were considered to fulfill all eligibility criteria. Of the 13 eligible patients, 67 received CAP and 63 received immunotherapy. Most ineligible patients had histologic results other than adenocarcinoma or large cell undifferentiated lung cancer. Dis ease-free survival was significantly prolonged in the chemotherapy group (p=.32). There was no evidence that immunotherapy had either a positive or a negative effect on survival. After 7 years of follow-up, the d i f f e in r e time c e to recurrence as well as cancer deaths remains statistically significant in favor of the chemotherapy group (Fig 1). lf the 15 patients who were randomized to but did not receive CAP are excluded from the analysis, the difference in favor of the chemotherapy group is enhanced (log rank, p =. 5 for recurrence and p =.13 for survival). Although this comparison is not protected by the randomization and may be affected by unidentified selection factors, the comparison of performance status, prior weight loss (greater or less than 1 percent of normal weight) and initial stage of disease did not suggest that those who received CAP had a better initial prognosis than those who did not. It must be emphasized, however, that all patients randomized to CAP were included in the analysis regardless of whether they received the assigned treatment. A few patients in the BCG/ levamisole arm also failed to receive the assigned treatment. The survival of these patients was similar to the survival of both patients who received postoperative immunotherapy and those randomized to receive CAP who, for a variety of reasons, did not. This evidence suggests strongly that there was no deleterious effect of postoperative immunotherapy. This study shows quite clearly that postoperative platinum-based chemotherapy can prolong cancel"free survival in patients with resected stage II or III adenocarcinoma and large cell undifferentiated carcinoma of the lung. The 1 c:: ;;;, e :; j E e Q)... 8 6 4 2 Log rank p =.2 FIGURE 2. Kaplan-Meier disease-free survival of 164 patients with resected non-small-cell lung cancer treated with radiotherapy only () or radiotherapy plus chemotherapy (). CAP= cyclophosphamide/doxorubicinlcisplatin. 9 18 27 36 45 54 63 72 81 9 CHEST I 13 I 1 I JANUARY, 1993 I Supplement 318

I i 1 8 Log rank p =.45 6 J 4 2 ---------- 9 18 27 36 45 54 63 FIGURE 3. Kaplan-Meier disease-free survival of patients with squamous cell histologic findings treated with radiotherapy alone () or radiotherapy plus chemotherapy () postopera- 72 tively. CAP= cyclophosphamideldoxorubicinlclsplatin. treatment effect remains statistically significant after more than 7 years of f o l l o In addition, u p. the data indicate that almost au recurrences in both groups occurred within the flnt 18 months after surgery (Fig 1}. Long-term survival is 18 percent for the immunotherapy group and 32 percent for the chemotherapy group. Locally Advanced NSCLC The LCSG also evaluated postoperative chemotherapy and radiotherapy in patients with resected locally advanced NSCLC.ta Patients who underwent resection and had microscopic residual disease or extensive lymph node involvement were randomized to receive CAP chemotherapy plus radiotherapy or radiotherapy alone postoperatively. Again, patients were carefully staged intraoperatively with lymph node sampling. Fbllowing pathologic staging, they were stratified for significant prognostic factors, which included histology (squamous vs nonsquamous), extent of residual disease (macroscopic vs microscopic}, and performance status. Treatment was begun within 7 days of randomization. Thoracic irradiation was administered in a split-course schedule, with two courses of 2 cgy given in five fractions over 5 days; each course was separated by 3 weeks' rest. The CAP regimen was administered every 4 weeks for six cycles and consisted of cyclophosphamide, 4 mglm ; doxorubicin, 4 mglm 1 ; and cisplatin, 4 mglm 1 ; the first two cycles were given on day 1 of each radiotherapy course. One hundred seventy-two patients were randomized and 164 (95 percent) were eligible for analysis. Ineligibility was due to histologic &ndings, death within 2 weeks of randomization, and stage M1 disease in four patients. Distribution of prognostic factors was similar within the two groups. The majority of patients had N2 disease (7 percent in the radiotherapy only arm and 76 percent in the chemotherapy plus radiotherapy arm}. Figure 2 shows time to recurrence for au 164 evaluable patients (log rank, p=.2 favoring the radiation and chemotherapy group). As noted in the previous study, most recurrences took place within the first 18 months following surgery; thereafter, the survival curves for both groups are fairly stable. Figure 3 shows time to recurrence in patients with nonsquamous cell histologic findings. Again, there Is a statistically significant difference favoring the radiotherapy plus chemotherapy group (log rank, p=.45}. In au the studies, patients with squamous cell histologic findings survived much longer than patients with nonsquamous cell histologic findings. Figure 4 1 8 Log rank p =.13 6 4 FlcURE 4. Kaplan-Meier disease-free survival of patients with nonsquamous cell or mixed histologic findings treated with radiotherapy alone () or ndiotherapy plus chemotherapy () postoperatively. CAP"' cyclophosphamideldoxorubiclnl clsplatin. 2 9 18 27 36 45 54 63 72 81 Po8loperaiNe Chemolher8py for NSCLC (E. Cermack HoirNs)

Within 1 yr 1-2 yr >2yr 32 (6) 15 6 No. Recurrences (% Patients) 55 (8) 9 5 p.1.512 * =radiotherapy; CAP= cyclophosphamideldoxorubicinlcisplatin. shows time to recurrence in patients with nonsquamous cell histologic findings. Again, the radiotherapy plus chemotherapy group experienced longer disease-free survival than did the radiotherapy only group (log rank, p=.13). Once again, the majority of recurrences in both patients with squamous and patients with nonsquamous cell histologic findings occurred within the first 18 months. Thble 3 indicates the recurrence rate according to postoperative year; 6 percent of recurrences in the combined-modality group and 8 percent of recurrences in the radiotherapy group occurred within the first year; only six and five recurrences, respectively, occurred after the second year. When the pattern of recurrences is evaluated, it is clear that chemotherapy played a major role in significantly reducing systemic recurrences ('Ihble 4). Local recurrences occurred with equal frequency in both the radiotherapy plus chemotherapy group and the radiotherapy only group. Thus, the differences in disease-free survival can be attributed to the significant reduction in systemic recurrences achieved with the combined modalities. Stage I NSCLC A final surgical adjuvant chemotherapy study was performed by the I..CSG in patients with resectable stage I (1'2NO and TlN1) NSCI..C. 13 Patients again were staged carefully by lymph node mapping at the time of surgery, stratified for important risk factors, and after pathologic staging randomly assigned to receive postoperative CAP chemotherapy or no further treatment. Chemotherapy included cyclophosphamide, 4 mg/m 1 ; doxorubicin, 4 mg/ m 1 ; and cisplatin, 6 mg/m 1 administered at 3-week intervals for four courses. Two hundred eighty-three patients were entered into this study; only 92 recurrences and 92 deaths have been observed. There were no differences between the chemotherapy and control groups with regard to survival or disease-free survival. Of interest, disease did not recur in more than 6 percent of patients in this study. With such a high survival rate, the effect of chemotherapy would have to be profound to demonstrate a beneficial effect. Therefore, based on these studies, one cannot recommend adjuvant CAP chemotherapy in patients with TlN1 or T2NO disease. DISCUSSION These studies indicate that CAP chemotherapy has a significant impact on disease-free survival and death from cancer in patients with advanced, resectable NSCI..C. Two studies in patients with predominately positive lymph nodes and poor projected survival indicate that the addition of platinum-based chemotherapy to radiotherapy improves CAP= cyclophosphamideldoxorubicinlcis * =radiotherapy; platin. tp=.6. No. Recurrences 4t 53 disease-free survival and decreases the likelihood of death due to cancer. In the study using immunotherapy, careful analyses revealed no deleterious effects associated with such therapy. At the time the study was designed, Mountain and Gail had suggested that BCG might be effective in such patients and that studies with levamisole had been promising. Subsequent studies, however, showed that neither levamisole nor BCG had a beneficial effect on survival in patients with resected NSCI..C. 14 13 One study 13 actually suggested that levamisole was associated with a higher death rate because of postoperative complications. However, in that study, there was no evidence of increased risk of recurrent cancer in patients receiving levamisole; thus, the excessive death rate in that group was indeed due to noncancer-related causes. The second study showed that adding CAP chemotherapy to radiotherapy in patients having incomplete resection improves relapse-free survival. In this study both arms were identical with respect to staging and prognostic factors. The only variable was the addition of CAP chemotherapy, which proved to be advantageous in both patients with squamous and those with nonsquamous cell histologic findings. Patients given both modalities experience significantly fewer deaths during the first year of follow-up. It was originally hypothesized that the benefit of such therapy in terms of delaying recurrence and death would be seen only in the first year after treatment, when the more aggressive tumors would be expected to be more responsive to chemotherapy. Thus, it was anticipated that treatment would have a greater impact on these tumors than on those with a slow growth rate. This theory is supported by the fact that the survival curves were relatively stable after 18 months of follow-up. In both of these studies, systemic chemotherapy reduced systemic recurrences without significantly affecting local recurrence. It has been shown that radiotherapy alone following resection of squamous cell carcinoma diminishes local recurrences without affecting overall survival or systemic recurrences. 18 Thus, these data considered together strongly suggest that the addition of chemotherapy to radiotherapy has a significant effect on systemic recurrences. Finally, patients with TlN1 and T2NO disease have a high probability (6 percent or greater) of cure with surgical resection. In this setting, adjuvant chemotherapy has not improved survival. Indeed, more effective chemotherapeutic regimens are needed to prolong survival in these relatively good-risk patients. Since the studies of the I..CSG have been reported, new and more effective chemotherapeutic regimens have produced higher response rates than those achieved with the CAP regimen. It is reasonable to assume that the use of CHEST I 13 I 1 I JANUARY, 1993 I Supplement 338

..... these regimens will enhance the adjuvant effect of chemotherapy in patients with resected NSCLC. REFERENCES 1 Brunner Kw, Marthaler T, Muller W. Effects of long-term adjuvant chemotherapy with cyclophosphamide (NSC-26271) for radically resected bronchogenic carcinoma. Cancer Chemother Rep 1973; 4:1.25-32 2 Hughes RA, Higgins GA. Veterans surgical adjuvant lung cancer chemotherapy study: present status. J Thorac Cardiovasc Surg 1962; 44:295-38 3 Slack HH. Bronchogenic carcinoma: nitrogen mustard as a surgical adjuvant and factors inhuencing survival: University Surgical Adjuvant Lung Cancer Project. Cancer 197; 25:987-12 4 Shields Tw, Robinette CD, Kuhn MS. Bronchial carcinoma treated by adjuvant cancer chemotherapy. Arch Surg 1974; 19:329-33 5 Shields TM, Higgins GA, Humphrey EW, et al. Prolonged intermittent adjuvant chemotherapy with CCNU and hydroxyurea after resection of carcinoma of the lung. Cancer 1982; 5:1713-21 6 Newman SB, DemeesterTR, Golomb HM, eta!. The treatment of modified stage II (T1N1MO, T2N1MO) non-small cell bronchogenic carcinoma. J Thorac Cardiovasc Surg 1983; 86:18-85 7 Holmes EC, Gail M. Surgical adjuvant therapy for stage II and stage III adenocarcinoma and large cell undifferentiated carcinoma. J Clin Oncol1986; 4:71-15 8 Bonomi R, Sandler S, Busby J, et al. Adjuvant chemotherapy of locally advanced squamous cell bronchogenic carcinoma [abstract}. Proc Am Soc Clin Oncol1984; 3:228 9 Bitran J, Golomb H, Hoffinan P, et al. Neoadjuvant chemother- apy in non-small cell lung cancer (NSCLC) stage III MO (T3N2): an attempt to increase surgical resectability [abstract}. Proc Am Soc Clin Oncol1985; 4:175 1 Strauss G, Sherman D, Schwartz J, et al. Combined modality approach to regionally advanced stage III non-small cell carcinoma of the lung (NSCLC) employing neoadjuvant chemotherapy (CI') with vindesine and high-dose platinum, radiotherapy (R'lj and surgery (S): a preliminary report [abstract}. Proc Am Soc Clin Oncol1985; 4:175 11 Martini N, Kris MG, Gralla RJ, et al. The effects of preoperative chemotherapy on the resectability of non-small cell lung cancer with mediastinal lymph node metastases (N2MO). Ann Thorac Surg 1988; 45:37-79 12 Lad T, Rubenstein L, Sadeghi A, and The Lung Cancer Study Group. The benefit of adjuvant treatment for resected local advanced non-small cell lung cancer. J Clin Oncol1988; 6:125-9J.YT 13 Thomas P, Felt R, for the Lung Cancer Study Group. Preliminary report of a clinical trial comparing postresection adjuvant chemotherapy vs no chemotherapy for T1N1, T2NO non-small cell lung cancer. Lung Cancer, vol 4. Fifth World Conference, Interlaken, Switzerland, 1988 14 Mountain CF, Gail MF. Surgical adjuvant intrapleural BCG treatment fur stage I non-small cell lung cancer: preliminary report of the National Cancer Institute Lung Cancer Study Group. J Thorac Cardiovasc Surg 1981; 82:649-57 15 Anthony HM, Mearns AJ, Mason MK, et al. Levamisole in surgery of bronchogenic carcinoma patients: increased deaths from cardiorespiratory failure. Thorax 1979; 34:4-12 16 The Lung Cancer Study Group. Effects of postoperative mediastinal radiation on completely resected stage I and II epidermoid carcinomas of the lung. N Eng) J Med 1986; 315:1377-81 348 Postopetallve Chemotherapy for NSCLC (E. Cennaclc HolmN)