Vinblastine

Lung cancer is the leading cause of cancer-related mortality in the developed world. Non-small cell lung cancer (NSCLC) represents 85% of cases of lung cancer, and patients have a poor 5-year survival rate. Approximately one third of NSCLC patients present with early-stage disease that is amenable to potentially curative resection and multimodality therapy. Several randomized trials now have confirmed the survival benefit with adjuvant platinum-based chemotherapy, as seen in the 1995 meta-analysis from the NSCLC Collaborative Group. The International Adjuvant Lung Cancer Collaborative Group Trial demonstrated a 4.5% improvement in survival for patients with stage I to III NSCLC. Studies from Japan have reported an improvement of 15.4% in the 5-year survival rate among patients with T1N0 disease after they had received adjuvant therapy with a combination of platinum and uracil-tegafur, and an improvement in the 5-year survival of 11% rate favoring chemotherapy with uracil-tegafur in a subgroup analysis of patients with T2N0 disease. Two recently published metaanalyses have estimated a relative risk reduction in mortality of 11 to 13% at 5 years. Significant improvement in the long-term survival rate has been demonstrated for patients with stage IB and II disease by the Cancer and Leukemia Group B 9633 trial (4-year survival rate, 12%) and the The National Cancer Institute of Canada Clinical Trials Group BR.10 trial (5-year survival rate, 15%; risk reduction for recurrence, 40%). Thus, there is compelling evidence to now recommend adjuvant platinum-based combination chemotherapy for patients after resection of early-stage NSCLC.

Key words: drugs; lung cancer; thoracic surgery

Abbreviations: ALPI = Adjuvant Lung Project Italy; BLT = Big Lung Trial; CALGB = Cancer and Leukemia Group B; CAP = cyclophosphamide, doxorubicin, and cisplatin; ECOG = Eastern Cooperative Oncology Group; HR = hazard ratio; IALT = International Adjuvant Lung Cancer Collaborative Group Trial; LCSG = Lung Cancer Study Group; NCIC-CTG = National Cancer Institute of Canada Clinical Trials Group; NSCLC = non-small cell lung cancer; UFT = uracil-tegafur

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Lung cancer is the leading cause of cancer-related mortality in the developed world. Of the 1.2 million new cases of lung cancer that are diagnosed per year, approximately 1 million individuals will die. (1,2) Non-small cell lung cancer (NSCLC), the most common subtype of lung cancer, represents 85% of cases and has a poor 5-year survival rate. In a series (3) of > 4,000 patients in whom NSCLC had been diagnosed over 5 consecutive years, the estimated survival rates at 1 and 5 years were 60% and 19%, respectively, in women, and 51% and 15%, respectively, in men. Approximately one third of NSCLC patients present with early-stage disease that is amenable to potentially curative resection and multimodality therapy. However, even in early stage 1 disease, 30% of patients relapse and die within 5 years, (4) with systemic recurrence rates varying from 55 to 75%. (5,6)

The objective of this article was to provide a general overview of the evolution of adjuvant therapy for early-stage NSCLC, with special emphasis on recently reported randomized trials that have demonstrated improvements in survival and reductions in cancer recurrence with the use of adjuvant therapy. (7-10)

EARLIER STUDIES

In the 1980s and early 1990s, multiple studies of adjuvant chemotherapy in patients who have undergone resection for NSCLC showed conflicting results. The Lung Cancer Study Group (LCSG) evaluated cyclophosphamide, doxorubicin, and cisplatin (CAP) chemotherapy in four trials. As can be seen in Table 1, two trials (11,12) reported improvement in early relapse rates, but no benefits in long-term survival. The LCSG 772 trial compared immunotherapy with postoperative chemotherapy in patients with stage II and III adenocarcinoma and large cell carcinoma after complete surgical resection, and reported a 7-month improvement in both the median time to recurrence and survival favoring chemotherapy. (11) The LCSG 791 trial compared adjuvant chemotherapy and radiotherapy to adjuvant radiation therapy in patients with residual tumor in the resection margin or metastasis in the highest paratracheal lymph node (station 2). Although there was an improvement of 14% in the survival rate at 1 year, the relapse and death rates were similar at 2 years, with a median survival time of 17 months for the entire group. (12) The LCSG 801 trial randomized patients to CAP chemotherapy or observation after surgery, and no differences were seen. Only 53% of patients randomized to chemotherapy received all four courses, likely because of toxicity. (13) The LCSG 853 trial found similar survival and time to progression when comparing CAP chemotherapy administered immediately after surgery vs that administered at the first systemic recurrence. Immediate combination chemotherapy was associated with nonsignificant reductions of 12% and 18%, respectively, in the risk of recurrence and death. (14) A Finnish trial (15) reported an 11% improvement in the 5-year survival rate after adjuvant CAP chemotherapy in patients with T1-3N0 NSCLC, which was statistically significant. A 63% rate of therapy-related grade 3 to 4 GI toxicity prevented many patients from completing the planned chemotherapy.

These disparate results prompted a metaanalysis conducted by The Non-small Cell Lung Cancer Collaborative Group. (16) This included 9,387 completely resected NSCLC patients from 52 randomized trials performed between January 1, 1965, and December 31, 1991. With 7,151 deaths for analysis, the overall comparison of adjuvant chemotherapy vs no intervention after surgery demonstrated a 13% reduction in the risk of death, and a 5% improvement in the 5-year survival rate favoring adjuvant therapy. Adjuvant chemotherapy with alkylating agents appeared to produce an inferior survival rate and increased the risk of death by 15% (hazard ratio [HR], 1.15; p = 0.005). By contrast, adjuvant chemotherapy with platinum-based regimens improved the 5-year survival rate by 5% and reduced the risk of death by 13% (HR, 0.87; p = 0.08), which prompted ongoing studies of platinum-based combination therapy.

SECOND-GENERATION AND THIRD-GENERATION REGIMENS

Improvements in supportive care have led to better patient compliance in chemotherapy trials in the advanced NSCLC setting. Response rates of 30% and 1-year survival rates of 30 to 40% in stage IV NSCLC trials using newer platinum-based combinations (including the taxanes, vinorelbine, gemcitabine, or docetaxel) (17-20) encouraged further research in adjuvant chemotherapy for earlier stages of disease.

Several trials have suggested a survival benefit from adjuvant chemotherapy for completely resected early stage NSCLC. Table 2 describes details of second-generation and third-generation regimen trials, including patient distribution by stage, allocated arm, and outcomes. A randomized trial involving 66 patients with completely resected stage IB disease reported an 18% improvement in the 5-year survival rate after adjuvant chemotherapy with etoposide cisplatin, although the difference was not significant due to the small sample size. (21)

Two large negative studies (22,23) of adjuvant chemotherapy described an important lack of patient compliance to treatment. The Adjuvant Lung Project Italy (ALPI) randomized 1,209 patients with radically resected stage I to IIIA disease to three cycles of mitomycin, vindesine, and cisplatin every 3 weeks or to observation. Stratification included tumor size, lymph node involvement, center, and intended radiotherapy. There was no difference between the arms in survival time or recurrence with a 64.5-month median follow-up time. The main toxicity was grade 3 neutropenia in 16% of the patients and grade 4 in 12% of patients, Only one third of patients received all three cycles of chemotherapy; and radiotherapy was completed in only 65% of the 176 scheduled patients in the chemotherapy arm vs 82% of the 152 scheduled patients in the control arm. (22) The Big Lung Trial (BLT) randomized 381 patients to three courses of cisplatin-based chemotherapy (choosing from the following four combinations: vinorelbine/cisplatin; cisplatin/vindesine; mitomycin/ ifosfamide/ cisplatin; or mitomycin/vinblastine/cisplatin) before or after surgery, or to observation. (23) Approximately one third of patients had clinical stage IIIA or greater disease, and the other two thirds of patients had stage I-II disease. The patients in the arms of the study were well-balanced for risk factors. No improvement in overall survival rate or disease-free survival rate was seen. There were six treatment-related deaths, and 30% of patients experienced toxicity grade 3 or greater (mainly hematologic toxicity). Only 64% of the 192 patients who were allocated to chemotherapy received all three planned cycles, and just two thirds of them did so without modification or delays; 7% of patients received two cycles, 14% of patients received one cycle, and 13% received no chemotherapy.

The International Adjuvant Lung Cancer Collaborative Group Trial (IALT) (8) is the largest study of adjuvant chemotherapy that has been conducted to date. With a planned accrual of 3,300 patients, it was designed to have the statistical power to confirm a 5% absolute survival benefit for chemotherapy at 5 years (from 50 to 55%). (8) Patients were randomly assigned after surgery to receive either three to four cycles of cisplatin-based chemotherapy or to observation. Each center determined its policy for postoperative chemotherapy and radiotherapy before randomization. Due to slow accrual, the study closed after the enrollment of 1,867 patients. At least 74% of the patients received 240 mg/[m.sup.2] of cisplatin; and in more than half of patients, this regimen was combined with etoposide (56.5%) or vinorelbine (26.8%). Seven patients (0.8%) died of chemotherapy-induced toxic effects. With a median follow-up period of 56 months, there was a statistically significant improvement in overall survival with an absolute difference of 4.1% at 5 years favoring adjuvant chemotherapy. Several explanations have been proposed for the varying results of these trials. One is that a larger proportion of patients in the IALT (8) received a higher dose of cisplatin, while in the BLT and ALPI studies few patients completed the planned courses of chemotherapy. Two recent metaanalyses including trials published since 1995 have reported a consistent relative risk reduction for mortality at 5 years of 11% after postoperative platinum-based chemotherapy. (24,25)

STUDIES OF ADJUVANT TEGAFUR IN NSCLC

Uracil-tegafur (UFT) is an oral prodrug of fluorouracil that was administered in daily doses for up to 2 years, thereby offering a theoretical advantage of prolonged exposure to fluorouracil resembling a continuous infusion. (26) Table 3 describes details of adjuvant tegafur trials in patients with NSCLC, including patient distribution by stage, allocated regimens, and outcomes. A three-arm study in patients with resected stage I-IIIA NSCLC conducted by the West Japan Study Group for Lung Cancer Surgery described a significant 14% improvement in 5-year survival with adjuvant UFT therapy over 2 years and an 11% improvement with combined platinum-based chemotherapy and UFT over 1 year, compared to observation. (27) The same group described a trend toward better survival rates in patients with stage I and II NSCLC after platinum based chemotherapy followed by 1 year of UFT therapy compared to observation after surgery, with a 5.1% improvement in the 5-year overall survival rate and a 4.3% improvement in the disease-free survival rate. A subgroup analysis (28) of 116 T1N0 patients demonstrated a 15.4% improvement in the 5-year survival rate favoring chemotherapy over observation (p = 0.03). A study limited to completely resected stage I and II NSCLC patients that was conducted by the North-east Japan Study Group for Lung Cancer Surgery (29) described a nonsignificant 4% improvement in the survival rate after 2 years of oral adjuvant UFT therapy compared to observation. A larger study of patients with stage I adenocarcinoma comparing UFT therapy for 2 years vs observation by the Japan Lung Cancer Research Group in Post Surgical Adjuvant Chemotherapy found a significant 11% improvement in the 5-year survival rate favoring UFT therapy in a subgroup analysis of patients with pathologic state T2N0 disease (p = 0.04). Despite minimal toxicity, the treatment compliance dropped from 80% at 6 months to 61% at 24 months. (7) Two recent metaanalyses (24,25) have confirmed a survival benefit favoring postoperative UFT therapy, with a 17% risk reduction for mortality at 5 years. While one study (30) has suggested that the pharmacokinetics of tegafur are similar in Japanese and Western patients, there may be differences in 5-fluorouracil exposure based on differences in body size between different populations. Thus, it would be helpful to confirm the adjuvant benefits of tegafur in other populations before it is introduced in adjuvant regimens elsewhere.

CURRENT TRIALS OF EARLY-STAGE NSCLC (IB AND II) DISEASE

The Cancer and Leukemia Group B (CALGB) conducted a trial to evaluate adjuvant chemotherapy in completely resected stage IB NSCLC. (9) Three hundred forty-four patients with stage T2N0 disease, with negative lymph nodes proven by mediastinoscopy or thoracotomy, were randomized within 4 to 8 weeks after undergoing complete surgical resection to observation or to four cycles of therapy with paclitaxel (200 mg/[m.sup.2]) and carboplatin (area under the curve, 6) administered on day 1 every 3 weeks. The groups were well-balanced for known prognostic factors, including age, gender, race, ethnicity, histology, tumor differentiation, and resection type. The regimen was well-tolerated with no treatment-related deaths. The most commonly reported toxicity was grade 3 or 4 neutropenia in 36% of patients. The overall survival time was significantly longer in the chemotherapy arm (p = 0.028) with a 12% improvement in 4-year survival at a median follow-up time of 34 months.

The National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) conducted a study to evaluate adjuvant chemotherapy in completely resected stage IB NSCLC (T2N0) and stage II NSCLC (excluding T3N0 patients). Four hundred eighty-two patients were randomized to observation or to four cycles of therapy with vinorelbine (25 mg/[m.sup.2] weekly for 16 weeks) and cisplatin (50 mg/[m.sup.2] on days 1 and 8 every 4 weeks). The patients were stratified by nodal status (ie, N0 vs N1) and ras mutation status (ie, present vs absent vs unknown). The arms of the study were well-balanced for important prognostic factors. Toxicity included grade 4 neutropenia, with febrile neutropenia in 7% of patients receiving vinorelbine at 30 mg/[m.sup.2], which prompted a dose reduction to 25 mg/[m.sup.2] shortly after the study started. Two patients died of drug-related toxicity (febrile neutropenia, one patient; pulmonary fibrosis, one patient). In the long-term follow-up, the most common cause of death was NSCLC (including one patient with a second primary NSCLC). There was significant improvement in median survival time for patients in the adjuvant chemotherapy arm from 73 to 94 months (p = 0.011). There was also a 15% improvement in 5-year survival favoring adjuvant chemotherapy (HR, 0.7; p = 0.012). (10) The results of the CALBG 9633 trial, (9) the NCIC-CTG BR10 trial, (10) and the recently published metaanalyses (24,25) suggest that adjuvant chemotherapy improves survival time and the period free of disease in patients with early-stage NSCLC, and appears greater than the benefit of adjuvant therapy in cancer of other organs, such as the colon, (31) ovary, (32) and breast, (33) as demonstrated in Table 4.

CLOSING REMARKS

Recent data strongly support the use of adjuvant therapy in patients with early-stage completely resected NSCLC. Table 5 describes the evolving beneficial trend in favor of platinum-based adjuvant chemotherapy since the metaanalysis published in 1995. (16) The IALT (8) demonstrated a 4.5% improvement in survival time for patients with stage I to III NSCLC. Two metaanalyses (24,25) demonstrated an estimated 11 to 13% relative risk reduction in mortality at 5 years. Significant improvement in long-term survival has been demonstrated for patients with stage IB and II disease by the CALGB 9633 trial (improvement at 4 years, 12%) (9) and the NCIC-CTG JBR10 trial (improvement at 5 years, 15% [with a 40% risk reduction for recurrence]). (10) Thus, the evidence compels us to propose a paradigm shift in favor of recommending adjuvant chemotherapy for fit patients with NSCLC lung cancer in early stages IB and higher.

Systemic therapy for lung cancer has long been an area of therapeutic nihilism. The toxicity of the treatment was high, and the potential benefits were considered to be minimal. In the last decade, clinicians have increased the proportion of lung cancer patients to whom they offer systemic therapy. Novel combinations of third-generation agents have demonstrated better efficacy with response rates of [greater than or equal to] 30%, better tolerability, and, now, evidence to support second-line and even third-line systemic treatment (ie, docetaxel or pemetrexed, then erlotinib) to prolong survival and to improve symptoms and quality of life in patients with advanced NSCLC. Prior studies, including the IALT, (8) included older chemotherapy combinations, with potentially higher toxicity, less patient compliance, and lesser efficacy than presently used novel combinations. For example, regimens containing alkylating agents were associated with decreased survival time when administered in the adjuvant setting. Thus, while the IALT (8) confirms the modest benefits seen in the metaanalysis of adjuvant chemotherapy and is statistically significant, most patients received an older combination regimen (ie, etoposide and cisplatin). The results of the NCIC-CTG BR10 trial (10) and CALBG 9633 trial (9) are important as they are the first trials of third-generation platinum-based combination therapies to be reported, and both demonstrate a significant survival benefit when these newer agents, which are accepted as standard regimens around the world in patients with advanced disease, are administered in the adjuvant setting.

There are still areas for further research. The role of adjuvant chemotherapy for the treatment of stage IA NSCLC or for other stages of disease has not been established. Adjuvant studies (7,29) including only UFT have had negative results. Chemotherapy with platinum and UFT resulted in a 5-year survival rate improvement of 15.4% in a subgroup of 116 patients with TIN0 disease. (28) The IALT (8) demonstrated a trend for better survival after platinum-based adjuvant chemotherapy in 183 patients with T1N0M0 disease. (8) Thus, further studies are needed to clarify the best approach for adjuvant therapy in patients with stage IA NSCLC. A phase III chemoprevention trial of selenium supplementation in patients with resected stage IA and IB NSCLC (Eastern Cooperative Oncology Group [ECOG] study E5597) is underway and may provide valuable information in the near future.

It is not clear whether preoperative induction chemotherapy could confer benefits to adjuvant chemotherapy in early stage NSCLC. Induction chemotherapy has proven to be safe and feasible, with no increase in surgical complications. (34) Despite the possible advantages of induction chemotherapy (such as potentially better patient compliance and treatment delivery, early control of micrometastasis, and reduction in tumor size prior to surgery allowing complete resections to be performed more frequently), a phase III trial by the French Thoracic Cooperative Group reported no overall benefit in patients with early-stage NSCLC. (35) There was a nonsignificant improvement of 8.6% in survival rate at 4 years, and of 11% in disease-free survival at 3 years, favoring neoadjuvant therapy over surgery alone. (35) A randomized phase III trial comparing neoadjuvant paclitaxel/carboplatin chemotherapy to surgery alone in patients with clinical stage IB and II and T3N1 NSCLC (Southwest Oncology Group 9900 trial) was closed in view of the significant benefits seen in the NCIC-CTG JBR10 trial. (10) Open trials are evaluating the potential role of neoadjuvant therapy in patients with early-stage NSCLC. The NATCH in Spain allocates patients to three arms (ie, three courses of neoadjuvant paclitaxel plus carboplatin followed by surgery, vs surgery followed by three courses of adjuvant paclitaxel plus carboplatin, vs surgery alone). The CLINCH is a second Spanish trial comparing three courses of neoadjuvant paclitaxel plus carboplatin plus gemcitabine vs surgery alone. The CHEST trial in Italy compares three courses of neoadjuvant gemcitabine plus cisplatin vs surgery alone. The LU22 trial in the United Kingdom compares three courses of platinum-based neoadjuvant chemotherapy vs surgery alone (Table 6).

There are no data to support concurrent or sequential adjuvant radiation therapy in patients with completely resected early-stage NSCLC. In the IALT, (8) 572 patients received thoracic radiotherapy (chemotherapy arm, 284 patients [compliance rate, 70.4%]; control arm, 288 patients [compliance rate, 84.2%]), and established no interaction between treatment effect and patients' characteristics or the treatment options on overall or disease-free survival, and no significant interaction between the effect of chemotherapy and postoperative radiotherapy. (8) Radiation therapy provides local control when the mediastinum is involved by nodal disease. (36) The results of adjuvant radiation therapy trials diverge from the encouraging trend of adjuvant chemotherapy, as the Post Operative Radiation Therapy metaanalysis (37) yielded no survival benefit, adjuvant radiation therapy appeared to be detrimental in patients with stage I/II, N0-N1 disease, and no adverse effect in patients with stage III disease were described. The ECOG 3590 trial (38) (with pN2 disease in at least 53% of patients) found no reduction of intrathoracic recurrence within the radiation field, and no survival advantage in patients with completely resected stage II and IIIA NSCLC who had been treated with concurrent radiation therapy and adjuvant therapy with cisplatin-etoposide, as the regimen appeared more toxic than radiation therapy alone. Unreported and open trials such as ANITA-I trial (observation vs vinorelbine plus cisplatin), the ANITA-II trial (vinorelbine vs observation), and the Marseille trial (cisplatin combined with either gemcitabine or docetaxel) may yield important information regarding varied therapy combinations and quality of life (Table 6).

Future trials may include molecularly targeted agents, for example, as maintenance after adjuvant chemotherapy, particularly if they demonstrate activity in patients with advanced NSCLC. The use of orally administered drugs with potentially lower toxicity is an attractive option. This is particularly true from the patients perspective, in which patients have shown appreciation for oral medications as long as drug efficacy is not sacrificed. (39) For example, the NCIC-CTG BR 19 study is assessing the value of adjuvant gefitinib in patients with completely resected stage IB, II, or IIIA NSCLC. Patients are randomized to receive gefitinib, 250 mg/d for 2 years, or placebo after undergoing resection. Studies of epidermal growth factor receptor protein expression, gene copy number, and mutation status will be integral to this trial. In a similar phase III trial sponsored by Roche/Genetech, patients with completely resected stage IB to IIIA NSCLC will be randomized to receive erlotinib, 150 mg/d for 2 years, or to observation alone. Studies of vascular endothelial growth factor inhibitor are also being considered.

CONCLUSION

The results of a number of trials make a compelling case in favor of adjuvant chemotherapy in the treatment of patients with early-stage NSCLC as the new standard of treatment for patients with good performance status. In the future, molecularly targeted therapy may also be part of the protocols for adjuvant therapy in patients with early-stage NSCLC.

Manuscript received February 14, 2005; revision accepted April 18, 2005.

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Antonio L. Visbal, MD; Natasha B. Leighl; Ronald Feld, MD; and Frances A. Shepherd, MD

* From the Department of Medical Oncology, Princess Margaret Hospital/University Health Network, University of Toronto, Toronto, ON, Canada.

Correspondence to: Natasha B. Leighl, 5-222, 610 University Ave, Toronto ON, M5G 2M9 Canada; e-mail: Natasha.Leighl@ uhn.on.ca

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