Seminars in Oncology
Volume 32, Issue 3 , Pages 279-283, June 2005

Adjuvant Chemotherapy in Early-Stage Non-Small Cell Lung Cancer

Department of Medicine, Institut Gustave-Roussy, Villejuif, France

Article Outline

Approximately 80% of lung malignancies are non-small cell lung carcinoma (NSCLC). Patients diagnosed with early-stage disease (about 30% of patients) undergo surgery, but up to 50% develop local or distant recurrence. In an effort to improve survival for patients with resectable NSCLC, chemotherapy has been explored in the adjuvant setting. Several adjuvant trials were launched in the mid 1990s after an individual data-based meta-analysis suggested a 5% survival benefit at 5 years. Among those, the International Adjuvant Lung Cancer Trial (IALT) study, with 1,867 patients included, confirmed the benefit of postoperative chemotherapy in resected NSCLC. More recently, modern platinum-containing doublets showed a 10% to 15% overall benefit compared to no adjuvant treatment. In this article, the current status of adjuvant chemotherapy is reviewed, and future prospects are discussed.

 

Lung cancer is a major cause of mortality worldwide, with an estimated annual incidence of more than 1.2 million cases and an overall mortality of about 1.1 million cases.1 Approximately 80% of lung tumors are of the non-small cell histologic subtype. Surgery remains the best treatment modality for potential cure in patients with stage I-IIIa non-small-cell lung cancer (NSCLC), but only 20% to 30% of patients with lung cancer are suitable for potentially curative resection. When complete resection is achieved, 5-year survival rates range from 67% for T1N0 disease to 23% for patients with T1-3N2 disease2 (Table 1). In fact, both local and distant recurrences limit the curative ability of surgery alone. Indeed, the majority of resected patients will show distant relapse, suggesting that the predominant factor affecting survival is the presence of occult micrometastatic disease. In an effort to improve survival of patients with resectable NSCLC, chemotherapy has been explored in the adjuvant setting.

Table 1. Five-Year Survival for Surgically Resected Early-Stage NSCLC2
StageClinicalPathologic
Ia61%67%
Ib38%57%
IIa34%55%
IIb22–24%38–39%
IIIa9–13%23–25%

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First Generation Randomized Trials 

The first cytotoxic drugs widely studied in the postoperative setting were alkylating agents, which have been studied alone or in combination regimens. These agents had no major side effects, but they never demonstrated any survival benefit.3, 4, 5, 6, 7 Since 1980, most trials have used cisplatin-containing chemotherapy regimens. The most well known are those conducted by the Lung Cancer Study Group. Holmes8 reported the first efficacy trial of postoperative chemotherapy in patients who had undergone complete resection for stage II and III NSCLC. Patients were randomized to either four cycles of adjuvant chemotherapy including cyclophosphamide 400 mg/m2, doxorubicin 40 mg/m2, cisplatin 40 mg/m2 (CAP regimen) or to immunotherapy using bacille Calmette-Guérin (BCG) or to a control group. The median recurrence-free survival period was significantly longer for the chemotherapy group (7 months) than for the immunotherapy group. An overall survival benefit for adjuvant chemotherapy was also demontrated, but the difference was not statistically significant (P = .078). In a second study, adjuvant CAP chemotherapy did not improve survival as compared with surgery alone in patients with stage I NSCLC, but this lack of efficacy could be explained by the suboptimal chemotherapy regimen.9

Niiranen et al10 reported a trial in which 110 patients with completely resected T1-3N0 NSCLC were randomized to postoperative chemotherapy (CAP regimen at the same doses as in the Holmes study) for six cycles or to no additional therapy. After 10 years of follow-up, overall survival and disease-free survival were significantly better in the chemotherapy arm than in the control arm (61% v 48% and 69% v 52%, P = .005 and P = .001, respectively). This trial has been criticized because a major imbalance in randomization occured, which resulted in the assignment of twice as many pneumonectomies to the control arm.

In a Japanese study,11 vindesine/platinum (VP) was reported to be more effective than CAP in the treatment of stage IIIA patients who had undergone a complete resection, but there was no difference in the disease-free or overall survival rates between untreated patients and the VP group. The main platinum-based randomized trials are summarized in Table 2.

Table 2. Platin-Based Postoperative Chemotherapy Trials Performed Between 1965 and 1993
AuthorNo. of PatientsStageTreatmentP Value
Holmes8141II,IIICAP v BCG.78
Feld9169T1N1, T2N0CAP v noneNS
Niiramen10110T1-T3N0CAP v none.05
Ohta11209IIIVP v noneNS

Abbreviations: C, cisplatin; BCG, bacille Calmette-Guérin; CAP, cyclophosphamide, doxorubicin, cisplatin; VP, vindesine and cisplatin; NS, not significant.

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Meta-analysis 

In view of the inconclusive results observed in most trials addressing the role of chemotherapy in NSCLC, the Medical Research Council and Institut Gustave-Roussy decided to perform a large overview using updated individual data.12 In the studies comparing surgery alone to surgery followed by adjuvant chemotherapy, 14 trials were recorded with an overall accrual of 4,357 patients (of whom 2574 died). The results of the five trials that used long-term alkylating agents (2,145 patients, 1,670 deaths) showed an increase in the risk of death, which corresponds to a 5% absolute negative effect of chemotherapy on survival at 5 years (P = .005). In the eight trials that used a cisplatin-based regimen (1,394 patients, 614 deaths), a 13% reduction in the risk of death was observed, suggesting an absolute benefit of 5% with adjuvant chemotherapy at 5 years with survival increasing from 50% to 55% (P = .08). When chemotherapy was randomly added to surgery and radiotherapy in a total of 807 patients (619 deaths), there was a 6% reduction in the risk of death, suggesting a 2% absolute benefit at 5 years. Sex, performance status, age, and histologic subtype had no impact on this effect. The above findings constitued the rationale for large-scale trials using cisplatin-based regimens. These studies started in the mid 1990s and the results of some of them have already been reported.

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Recent Randomized Trials 

The North American Intergroup trial13 INT-0115 was designed to determine whether a combination of four cycles of chemotherapy with cisplatin at 60 mg/m2 on day 1 and etoposide at 120 mg/m2 on days 1 to 3 every 4 weeks plus concomitant thoracic radiotherapy to a total dose of 50.4 Gy delivered in 28 daily fractions was superior to adjuvant radiotherapy alone given at the same dose. A total of 488 patients with stage II/IIIa NSCLC from 121 centers were randomized. All patients underwent systematic sampling or complete dissection of mediastinal lymph nodes. The results failed to show any advantage for adjuvant chemotherapy plus radiotherapy over radiotherapy alone on local recurrence or survival. Recurrence was documented in 56% of patients who received chemotherapy plus radiotherapy and in 53% of patients who received radiotherapy alone. The rate of intrathoracic recurrence within the radiotherapy field was 12% for the combined arm versus 13% for the adjuvant radiotherapy alone arm (P = 0.84). The pattern of recurrence and the median time to recurrence were not significantly different in the two groups. Also, median survival did not differ significantly between the two groups (38 months with chemoradiotherapy v 39 months with radiotherapy alone, P = .56). There was also no significant difference in survival between the two arms when they were analyzed according to age (<60 years v >60 years), sex, race, stage II versus IIIa, Eastern Cooperative Oncology Group (ECOG) performance status (1 v ≥1), and the number of operations performed per surgeon (1 v ≥2). The simultaneous administration of chemotherapy and radiotherapy postoperatively caused a higher incidence of serious side effects than did the postoperative administration of radiotherapy alone. For the combination regimen, sepsis caused two of the four deaths; the other two patients died of pneumonitis and esophagitis, respectively. For the adjuvant radiotherapy alone group, two of the three deaths were due to radiation-induced pneumonitis. The third was due to esophagitis. The lack of a significant difference in survival rates in this study may be due to the chemotherapy regimen used, as cisplatin was given at a low dose (60 mg/m2). Also the detrimental role of radiotherapy14 may have been enhanced by the concomitant chemotherapy.

The second large recent adjuvant study was the Adjuvant Lung Project Italy (ALPI) trial launched in Italy in January 1994 and completed in February 1998 with the participation of 66 Italian centers and five centers from the European Organization for Research and Treatment of Cancer (EORTC).15 After surgery, patients with stage I, II, and IIIa NSCLC were randomly allocated to receive either three courses of MVP (mitomycin C, 8 mg/m2 day 1; vindesine, 3 mg/m2 day 1 and 8; cisplatin, 100 mg/m2 day 1 every 3 weeks) or no adjuvant therapy. Delivery of postoperative radiotherapy (total dose of 50–54 Gy in 5–6 weeks, beginning at least 4 weeks after the completion of chemotherapy) was left to the policy of the participating centers. A total of 1,209 patients were enrolled into the study, of which 1,197 were eligible and 1,088 analyzed. With a median follow-up of 63 months, no significant differences were observed between the two arms in terms of overall survival (hazards rate [HR] = 0.96; 95% confidence interval [CI], 0.81–1.13) and event-free survival (HR = 0.89; 95% CI, 0.76–1.03). An analysis of the prognostic implication of p53, K-ras, and Ki67 was unable to find any impact of these parameters on survival. The lack of a significant difference in survival rates may be due to the number of patients enrolled and to the choice of the specific chemotherapy (mitomycin-containing).

The International Adjuvant Lung Cancer (IALT)16 trial was a large worldwide randomized study that aimed to determine the impact on overall survival of three to four cycles of a chemotherapy regimen including cisplatin and either a vinca alkaloid or etoposide compared to no chemotherapy after complete surgical resection in patients with stage I, II, or III NSCLC. The total dose of cisplatin was 300 to 400 mg/m2 given in three or four cycles of 80 to 120 mg /m2. The vinca alkaloid could be vindesine (3 mg/m2/wk for 6 weeks and then every 2 weeks up to the last dose of cisplatin) or vinblastine (4 mg/m2/wk for 6 weeks and then every 2 weeks up to the last dose of cisplatin) or vinorelbine (30 mg/m2/wk up to the last dose of cisplatin). Thoracic radiotherapy was given according to the pre-registration policy of each center. A total of 1,867 patients were included and the two arms did not show any significant differences in characteristics (Table 3).

Table 3. Baseline Characteristic of Patients in the IALT Randomized Trial
Adjuvant (n = 932)Control Arm (n = 935)
Age, mean (yr)5959
Male/female (%)81/1980/20
Pathologic stage I (%)3637
Pathologic stage II (%)2524
Pathologic stage III (%)3939
Pneumonectomy (%)3534
Lobectomy (%)6465
Segmentectomy (%)1<1
Radiotherapy (%)7185

There were 932 patients allocated to chemotherapy and 67% received at least 300 mg/m2 of cisplatin; 935 patients were allocated to the control arm. The drug combined with cisplatin was etoposide in 56%, vinorelbine in 27%, vinblastine in 11%, and vindesine in 6% of patients. Median follow-up was 56 months. Overall survival rates were significantly different between the two arms: 2- and 5-year survival rates were 70% and 45% in the chemotherapy arm versus 67% and 40% in the control arm (HR = 0.86; CI, 0.76–0.98; P = .03). Disease-free survival was also significantly different: 61% and 39% in the chemotherapy arm versus 55% and 34% in the control arm at 2 and 5 years, respectively (HR = 0.83; CI, 0.74–0.94; P = .003). No significant interaction was observed with age, performance status, type of surgery, pathologic stage, histology, cisplatin dose, and combined drug or radiotherapy. Side effects of the treatment were acceptable, with 23% of patients having at least one episode of grade 4 toxicity, mainly neutropenia (18%). Seven patients (0.8%) died of chemotherapy-related toxicity.

Kato et al17 reported a phase III trial of adjuvant chemotherapy with uracil tegafur (UFT) for completely resected pathologic stage I (T1-T2N0M0) adenocarcinoma of the lung. A total of 979 patients were eligible for analysis and the median follow-up was 70 months. Five-year overall survival was significantly different between the two groups: 87.9% in the UFT arm versus 85.4% in the control arm (P = .036). A subgroup analysis showed that the benefit was restricted to the population of T2 disease patients (84.9% versus 73.5%, P = .005), while the T1 disease patients did not have any advantage from UFT (P = .867). This study is consistant with the trial reported in 1996 by Wada et al.18 At the 2004 American Society of Clinical Oncology (ASCO) meeting, the Japanese adjuvant UFT meta-analysis19 confirmed a significant advantage of the drug compared to control in 2,003 patients (P <.001).

In the Big Lung trial20 led by the Medical Research Council (MRC), 381 patients were included. There was no survival difference (HR = 1; CI, 0.75–1.35; P = .98), but the lack of significance can be explained by the unspecified quality of resection and the poor compliance (16% of patients never received chemotherapy, 64% received three cycles, of whom only 63% received the planned dose).

The National Cancer Institute-Canada also conducted a phase III trial comparing surgery alone to surgery followed by adjuvant chemotherapy with cisplatin and vinorelbine in 459 eligible patients with stage Ib and II resected NSCLC.21 They showed a 15% benefit at 5 years (P = .012).

The Cancer and Leukemia Group B (CALGB) also conducted a randomized trial in 344 patients with stage Ib NSCLC (CALGB 9633).22 A 12% absolute benefit at 5 years was reported with adjuvant paclitaxel-carboplatin compared to no adjuvant treatment (P <.03).

In the Adjuvant Navelbine International Trialist Association (ANITA1) trial, which also concerned patients with completely resected NSCLC, chemotherapy consisted of four cycles of cisplatin at 100 mg/m2 every 4 weeks and 16 cycles of vinorelbine at 30 mg/m2 weekly compared to a control arm (Pierre Fabre and Asta Medica, oral communication). A total of 831 patients were included from October 1994 to December 2000, and the analysis is planned in 2005. ANITA2 was started at the same time for patients unable to receive cisplatin and who are randomized to receive either vinorelbine alone (30 mg/m2 weekly for a total of 16 administrations) or to be in the control arm. The recent adjuvant randomized trials of chemotherapy in resected NSCLC are summarized in Table 4.

Table 4. Recent Adjuvant Trials of Chemotherapy in Resected NSCLC
TrialCountryCT RegimenNResults
INT 011513USA4× VP16-P462Negative
ALPI-EORTC15Italy/Europe3× MVP1197Negative
NCI-C20Canada/USA4× NVB-P482Negative
BLT19International3× V-P481Completed
IALT16International3/4× V-P1867Positive
Wada18JapanVP/UFT323Positive
JLCRG17JapanUFT ×2y999Positive
ANITA 01International4× NVB-P831Completed
ANITA 02International16 NVB195Ongoing
CALGB 963320USA4× Taxol-Carbo196/504Ongoing

Abbreviations: VP, vindesine and platinum; MVP, mitomycin, vindesine, cisplatin; NVB, vinorelbin; UFT, uracil tegafur; INT, International; ALPI, Adjuvant Lung Project Italy; EORTC, European Organization for Research and Treatment of Cancer; NCIC, National Cancer Institute of Canada; CALGB, Cancer and Leukemia Group B; BLT, Big Lung Trial; JLRCG, Japan Lung Cancer Research Group; ANITA, Adjuvant Navelbine International Trialist Association.

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Molecular Markers 

Pharmacogenomics encompass studies where genomics are applied to pharmaceutical research and drug discovery. Due to a better understanding of the molecular mechanisms of disease and response to therapy, biomarkers have been identified in an effort to define clinical outcome, therapeutic efficacy, or treatment-related toxicity. The expression of some of these molecular markers has been found to be linked to enhanced response to chemotherapy and therefore survival. Cancer patients now require a reliable method to determine which chemotherapy combinations are most likely to improve survival based on genetic markers.23, 24 Low ERCC1 (excision repair cross complementing 1) expression may be predictive of therapeutic efficacy and survival in the advanced NSCLC patients treated with a ciplatin-gemcitabine combination.25 An ongoing study is analyzing expression of beta-tubulin III, stathmin, ribonucleotide reductase M1 (RRM1), cyclooxygenase-2 (COX-2), and glutathione S-transferase P1 (GSTP1) in mRNA isolated from tumor biopsies of 75 NSCLC patients treated within a large randomized trial26 is ongoing. Predictive markers are also emerging for molecular targeted agents. In that regard, epidermal growth factor receptor (EGFR) mutations and at a lower level immunohistochemical evaluation of phosphorylated AKT (pAKT) appear to be promising markers to predict the benefit of EGFR inhibitors such as gefitinib and erlotinib.27, 28, 29, 30 The next step will be the integration of the best markers in prospective trials and the inplementation of pharmacogenomic-based clinical trials.

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Molecular Targeted Therapies 

Targeted therapies are supposed to target only the cancer cells, sparing normal tissues and therefore reducing toxicity while simultaneously increasing the eradication of cancer cells. The promise of targeted therapy is illustrated by the success of drugs like trastuzimab and imatinib in, respectively, breast carcinoma and gastrointestinal stromal tumors.31, 32 Ichinose et al33 published their results of a trial comparing 2 years of postoperative bestatin to placebo in 400 patients with completely resected stage I squamous cell cancer of the lung. Bestatin is a potent inhibitor of aminopeptidases and is believed to have immunomodulatory activity. Five-year overall and cancer-free survivals favored the bestatin arm (81% and 71% v 74% and 62%, P = .033 and P = .017, respectively).

Vaccine therapy, another targeted therapy, is designed to activate the immune system in order to develop a response against tumor and prevent the recurrence of cancer. Two phase I studies with EP2101 and EGFRvIII peptide vaccines are ongoing for patients with completely resected NSCLC. A summary of the ongoing adjuvant trials of targeted therapies is shown in Table 5. Nevertheless, the negative results of the combination of chemotherapy with gefitinib in the Iressa NSCLC Trial Assessing Combination Treatment (INTACT) trials34, 35 in the setting of advanced NSCLC highlights the need to carefully plan the sequence of treatment between moleculer targeted therapies and standard chemotherapy if such a conbination is envisioned.

Table 5. Ongoing Clinical Trials of Targeted Therapies in Early-Stage NSCLC Randomized Adjuvant Trials
TherapyStageGroupStatus
GefitinibI-IIIaNCIC-CTGOngoing
EP2101III-IIIaEpimuneOngoing
EGFRvIII peptide vaccineIIb-IIIaNCI-SWOGOngoing
HMFG vaccineI-IIIaEORTCOngoing
GefitinibI-IIIaJCOGClosed

Abbreviations: EORTC, European Organization for research and Treatment of Cancer; NCIC-CTG, National Cancer Institute of Canada Clinical Trials Group; JCOG, Japanese Clinical Oncology Group; SWOG, Southwest Oncology Group.

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Conclusion 

In conclusion, the results of the recently reported large randomized studies of adjuvant chemotherapy, and particularly the IALT study,16 suggest a 4% to 5% improvement of survival at 5 years, a benefit comparable to that observed in breast and colon cancer. Such a performance may seem small or even derisory; however, based on current epidemiologic data, roughly 7,000 deaths would be avoided annually if adjuvant cisplatin-based chemotherapy is routinely administered. The apparent contrasting results between the two recent largest trials performed in the postoperative setting of NSCLC (ALPI and IALT) could be explained by the detrimental effect of mitomycin-based chemotherapy in the ALPI trial. In fact, the higher mortality during the first year in the adjuvant arm as compared to the control arm (90 deaths v 69 deaths) remains to be better documented.

The planned Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis of the new generation of trials will include more than 4,000 patients and will be of major importance for the community. In the future, a predictive model using a panel of molecular markers may be able to more accurately identify subgroups of patients who would benefit most from adjuvant treatment: the promise of personalized cancer treatment is one of the greatest expectation of patients and health care professionals.

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PII: S0093-7754(05)00088-6

doi:10.1053/j.seminoncol.2005.02.018

Seminars in Oncology
Volume 32, Issue 3 , Pages 279-283, June 2005

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