ABSTRACT: Non-small-cell lung cancer (NSCLC) accounts for approximately 80% of all lung tumors. Patients diagnosed with early-stage disease generally undergo surgery, but up to 50% develop local or distant recurrences. The benefit of chemotherapy in this disease is modest, but new drugs and combined strategies offer hope of improved survival rates. Because the disease recurs outside the chest in 70% of cases, one of the foremost goals of therapy is to prevent distant dissemination. To this end, chemotherapy may be administered preoperatively or after resection of the tumor. The first part of this article, which concludes next month, will address adjuvant and neoadjuvant chemotherapy in early-stage non-small-cell lung cancer.
Lung cancer remains a major public health problem, accounting for more than 1 million new cases per year worldwide. In the United States, lung cancer is the third most common malignancy after prostate and breast cancer, and the leading cause of cancer death in both men and women. In Eastern Europe, lung cancer is the most frequent cause of cancer-related mortality among men and the third among women. Mortality rates in women are rising, due to the increasing use of tobacco. Despite advances in surgical and nonsurgical therapy, overall 5-year survival rates have only increased modestly over the last 25 years, remaining at approximately 14%.
Non-small-cell lung cancer (NSCLC) accounts for approximately 80% of all lung tumors. For earlystage disease, surgery remains the most common treatment and can be considered curative. However, only 20% to 30% of all patients with NSCLC are diagnosed at an early stage, and up to 50% of these patients will develop local or distant recurrences. The prognosis of patients with clinical stage IIIA or IIIB disease (ie, with radiologically documented involvement of the mediastinum or a technically unresectable tumor) continues to be poor, with 5-year survival rates ranging from 5% to 10% and median survivals from 12 to 15 months.
The outcome of untreated patients with advanced NSCLC is predictable: The median survival is 4 months, and the 1-year survival rate ranges from 10% to 15%. The role of chemotherapy in this disease is generally modest, but new drugs and combined strategies offer hope of improved survival rates in the near future. In this two-part article, which concludes next month, we review the role of chemotherapy in the various presentations of NSCLC.
Surgery remains the primary curative treatment for patients with early- stage NSCLC, ie, stage I, II, and minimal IIIa. Nevertheless, approximately half of these patients will die of tumor progression after complete surgical resection. Because the disease recurs outside the chest in 70% of cases, one of the foremost goals of therapy is the development of systemic treatments-mainly chemotherapy- to prevent distant dissemination. Chemotherapy may be administered preoperatively or after resection of the tumor.
• Radiation—The first adjuvant treament explored after complete resection of lung tumors was radiation. Several trials have compared surgery alone to surgery plus postoperative radiotherapy, and a meta-analysis of those trials-the postoperative radiotherapy (PORT) meta-analysis, which included 2,128 patients-was recently reported. Results show the significantly detrimental effect of postoperative radiotherapy on survival with an absolute reduction at 2 years of 7%. However, a subgroup analysis suggests that this effect occurs mainly in patients with N0/1 disease, whereas there is no evidence of a detrimental effect in patients with N2 disease.
The results of this meta-analysis should be considered with caution, as many patients were treated with equipment, doses, and irradiation fields that are now considered suboptimal. In addition, there are insufficient data on mediastinal lymph node dissection, and the surgical procedure differed among studies and centers. Thus, the role of radiotherapy in patients with N2 disease remains unclear, and new randomized studies are necessary to clarify its impact on local control and the survival of patients with resected N2 disease.
• Chemotherapy—The role of adjuvant chemotherapy has been highly controversial for years: The first chemotherapeutic agents studied in the postoperative setting, alone or in combination, were alkylating agents. From 1980 on, most trials used cisplatin- containing chemotherapy regimens, and the most well-known were those conducted by the Lung Cancer Study Group.
Holmes et al reported the first efficacy trial of postoperative chemotherapy in patients who had undergone complete resection for stage II/III NSCLC. Participants were randomized to either four cycles of adjuvant CAP (cyclophosphamide [Cytoxan, Neosar], doxorubicin [Adriamycin], cisplatin [Platinol]) or immunotherapy with bacillus Calmette- Gurin (BCG). The median recurrence- free period was significantly longer for the chemotherapy group (7 months), and a survival benefit was demonstrated for adjuvant chemotherapy vs immunotherapy, but the difference was not statistically significant significant (P = .078). In a second study, adjuvant CAP chemotherapy did not improve survival compared with surgery alone in patients with stage I NSCLC, but this lack of efficacy could be explained by the suboptimal chemotherapy regimen.
A survival benefit was reported by Niiranen et al in patients with T1-3, N0 tumors treated with adjuvant CAP chemotherapy. The 5-year survival rate increased from 56% to 67% (P = .05) in the group that received adjuvant therapy compared to those who underwent surgery alone. Wada et al found the 5-year survival rate increased from 49% to 61% with the use of postoperative cisplatin/vindesine/UFT (uracil and tegafur) chemotherapy in patients with completely resected stage I-III NSCLC (P = .04). In another Japanese study, VP (vindesine/platinum) was reported to be more effective than CAP in the treatment of resected stage IIIA patients, but there was no difference in recurrence-free or overall survival between untreated patients and those in the VP group. Several other studies also reported negative results. The main platinumbased randomized trials are summarized in Table 1.[6-10]
• Meta-Analysis of Cumulative Data—Given the limited number of patients enrolled in these and other trials, it was not possible to clearly establish the role of adjuvant chemotherapy in early-stage NSCLC. Therefore, the Medical Research Council (MRC) and Institut Gustave-Roussy (IGR) conducted a large meta-analysis using updated data. More than 9,000 patients from 52 randomized trials fulfilled the selection criteria. The group comparing surgery alone to surgery followed by adjuvant chemotherapy encompassed 14 trials, with an overall accrual of 4,357 patients (2,574 of whom died).
The results of the five trials that used long-term alkylating agents (2,145 patients, 1,670 deaths) showed a 15% 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), the risk of death was reduced by 13%, suggesting an absolute benefit of 5% with adjuvant chemotherapy at 5 years (P = .08). The group comparing surgery and radiotherapy to surgery, radiotherapy, and chemotherapy included 807 patients, 619 of whom died. Cisplatin-based chemotherapy provided 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 the effect of chemotherapy.
Even if the potential advantage of adjuvant chemotherapy in NSCLC is small, the high incidence of the disease would translate this benefit into a prolongation of life for more than 10,000 patients worldwide each year. The findings of the above trials provided the rationale for several large-scale trials of cisplatin-based regimens in the late 1990s.
• Intergroup Trial 0115—The North American Intergroup Trial INT-0115 is the only recent adjuvant trial that has already been published.[ 12] It 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 28 days, plus concomitant thoracic radiotherapy to a total dose of 50.4 Gy delivered in 28 daily fractions, was superior to 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 either systemic sampling or complete dissection of mediastinal lymph nodes. The results failed to show any advantage for adjuvant chemotherapy plus radiotherapy over radiotherapy alone in preventing local recurrences or increasing survival. A 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 recurrences within the radiotherapy field was 12% for the combined treatment group vs 13 % for the adjuvant radiotherapy alone treatment group (P = .84). The pattern of recurrences and the median time to recurrence were not significantly different in the two groups. Median survival also did not differ significantly between groups (39 months with chemotherapy and radiotherapy vs 38 months with radiotherapy alone [P = .56]).
In a multivariate analysis, the factors that significantly influenced overall survival were the extent of lymph node involvement, the type of lymph node dissection, the histologic subtype, and the patient's gender. The side effects of treatment were more common and severe in the chemoradiotherapy arm. An analysis of the impact of K-ras and p53 on the activity of chemotherapy also failed to demonstrate any interaction between overexpression of these genes and efficacy of treatment. 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) concomitantly with radiotherapy. Even if the combination of cisplatin and etoposide is not the most effective regimen in NSCLC, this study demonstrated that it is easily administered concurrently with radiotherapy.
• Adjuvant Lung Project Italy Trial—Among the adjuvant studies recently completed, the Adjuvant Lung Project Italy (ALPI) trial aimed to assess the effectiveness of adjuvant chemotherapy, with or without radiotherapy. It was initiated in 1994 with the participation of 66 Italian centers and 5 from the European Organization for Research and Treatment of Cancer (EORTC). The study was coordinated by the Laboratory of Cancer Clinical Research at the Mario Negri Institute in Milan.
After surgery, patients with stage I, II, and IIIa NSCLC were randomized to receive either three courses of MVP (mitomycin [Mutamycin], 8 mg/m2 on day 1; vindesine, 3 mg/m2 on days 1 and 8; cisplatin, 100 mg/m2 on day 1, every 3 weeks for three cycles) or no adjuvant treatment. Patient referral to radiotherapy was left to the discretion of the participating centers and, if given, thoracic irradiation (50 to 54 Gy over 5 to 6 weeks) was initiated after completion of chemotherapy.
Overall, 1,209 patients were enrolled in the study between January 1994 and February 1998. A total of 602 patients were randomized to chemotherapy and 594 to the control group; 13 patients were excluded from the analysis due to protocol violations. Radiotherapy was delivered in 482 patients, of whom 5% were stage I, 45% stage II, and 50% stage IIIa. (These data were obtained from Dr. Scagliotti's slide presentation at the American Society of Clinical Oncology [ASCO] website.)
Of the 327 evaluable patients (69%) who completed chemotherapy, 166 required modification of the planned regimen and 100 (21%) discontinued treatment, mainly due to toxicity. Overall, 127 (30%) and 79 (18%) patients receiving chemotherapy, respectively, experienced grade 3 and 4 toxicity, and 47 patients never started chemotherapy. Results were presented at the 2002 ASCO meeting.
• Ongoing and Recently Completed Trials—The International Adjuvant Lung Cancer Trial (IALT) was a randomized study designed to determine the impact on overall survival of a chemotherapy regimen including cisplatin and either a vinca alkaloid or etoposide vs no chemotherapy after complete surgical resection in patients with stage I, II, or III NSCLC. The total dose of cisplatin in this trial was 300 to 400 mg/m2 administered in three or four cycles of 80 to 120 mg/m2. The vinca alkaloid was either vindesine at 3 mg/m2/wk, vinblastine at 4 mg/m2/wk, or vinorelbine (Navelbine) at 30 mg/m2/wk, given up to the last dose of cisplatin. The dose of etoposide was 100 mg/m2/d for 3 consecutive days every 3 to 4 weeks with cisplatin. Thoracic radiotherapy was given according to the preregistration policy of each center. A total of 1,867 patients were enrolled in the study, and the results will be presented at the next ASCO meeting in Chicago.
In the Adjuvant Navelbine International Trial Association (ANITA1) study, which is also evaluating treatment of patients with completely resected NSCLC, chemotherapy consists of four cycles of cisplatin at 100 mg/m2 every 4 weeks and 16 cycles of vinorelbine at 30 mg/m2/wk compared to a control arm. The trial enrolled 831 patients between October 1994 and December 2000. At the same time, the ANITA2 trial was initiated for patients who were unable to receive cisplatin and were instead randomized to either vinorelbine alone (30 mg/m2/wk for a total of 16 administrations) or the control arm.
The National Cancer Institute of Canada recently completed accrual of 482 patients into a phase III trial comparing surgery alone to surgery followed by adjuvant chemotherapy with cisplatin and vinorelbine in patients with stage T1/2, N0/1 disease. The Cancer and Leukemia Group B (CALGB) is also sponsoring an intergroup study (CALGB 9633) in patients with high-risk stage I NSCLC randomized to surgery alone or surgery followed by treatment with carboplatin (Paraplatin)/paclitaxel. Finally, adjuvant chemotherapy is part of the Big Lung Trial led by the MRC; 481 patients were included in the corresponding subgroup.
In conclusion, randomized postoperative chemotherapy trials have to date provided inconclusive results and have failed to demonstrate a significant benefit in survival. The results and an overview of all recently completed studies will clarify the role of chemotherapy after complete resection of early-stage NSCLC. Notably, there have been no published results of studies using recent cytotoxic or cytostatic agents as adjuvant chemotherapy in patients with early-stage NSCLC. Parameters such as angiogenesis, expression of oncogenes, mutations in tumorsuppressor genes, and presence of a drug-resistance mechanism might be taken into consideration in future protocols.
1. Parkin DM, Pisani P, Ferlay J: Global
cancer statistics. CA Cancer J Clin 49:33-64, 1,
2. Jemal A, Thomas A, Murray T, et al:
Cancer statistics, 2002. CA Cancer J Clin 52:23-
3. Levi F, Lucchini F, Negri E, et al: Cancer
mortality in Europe, 1990-1994, and an overview
of trends from 1955 to 1994. Eur J Cancer
4. Wingo P, Ries L, Rosenberg HM, et al:
Cancer incidence and mortality, 1973-1995: A
report card for the US. Cancer 82:1197-1207,
5. PORT Meta-analysis Trialists Group:
Postoperative radiotherapy in non-small-cell
lung cancer: Systematic review and meta-analysis
of individual patient data from nine randomised
controlled trials. Lancet 352:257-263,
6. 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.
7. Feld R, Rubinstein L, Thomas PA: Adjuvant
chemotherapy with cyclophosphamide,
doxorubicin, and cisplatin in patients with completely
resected stage I non-small-cell lung cancer.
The Lung Cancer Study Group. J Natl
Cancer Inst 85:299-306, 1993.
8. Niiranen A, Niitamo-Korhonen S, Kouri
M, et al: Adjuvant chemotherapy after radical
surgery for non-small-cell lung cancer: A randomised
study. J Clin Oncol 10:1927-1932,
9. Wada H, Hitomi S, Teramatsu T: Adjuvant
chemotherapy after complete resection in
non-small-cell lung cancer. West Japan Study
Group for Lung Cancer Surgery. J Clin Oncol
10. Ohta M, Tsuchiya R, Shimoyama M, et
al: Adjuvant chemotherapy for completely resected
stage III non-small-cell lung cancer. The
Japan Clinical Oncology Group. J Thorac Cardiovasc
Surg 106:703-708, 1993.
11. 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,
12. Keller SM, Adak S, Wagner H, et al: A
randomized trial of postoperative adjuvant therapy
in patients with completely resected stage
II or IIIA non-small-cell lung cancer. Eastern
Cooperative Oncology Group. N Engl J Med
13. Schiller J, Adak S, Feins RH, et al: Lack
of prognostic significance of p53 and K-ras mutations in primary resected non-small-cell lung cancer on E4592: A
Laboratory Ancillary Study on an Eastern Cooperative Oncology Group
Prospective Randomised Trial of Postoperative Adjuvant Therapy. J
Clin Oncol 19:448-457, 2001.
14. Tonato M, on behalf of the ALPI/EORTC-LCG investigators:
Final report of the Adjuvant Lung Project Italy (ALPI): An Italian/
EORTC-LCG randomised trial of adjuvant chemotherapy in completely
resected non-small cell lung cancer (NSCLC) (abstract 1157). Proc
Am Soc Clin Oncol 21:290a, 2002.
15. Shields T, Higgins GA Jr, Lawton R, et al: Preoperative x-ray
therapy as an adjuvant in the treatment of bronchogenic carcinoma. J
Thorac Cardiovasc Surg 59:49-61, 1970.
16. Warram J: Preoperative irradiation of cancer of the lung: Final
report of a therapeutic trial. Cancer 36:914-925, 1975.
17. Martini N, Kris MG, Flehinger BJ, et al: Preoperative chemotherapy
for stage IIIa (N2) lung cancer: The Sloan-Kettering experience
with 136 patients. Ann Thorac Surg 55:1365-1373, 1993.
18. Rosell R, Gomez-Codina J, Camps C, et al: A randomized trial
comparing preoperative chemotherapy plus surgery with surgery alone
in patients with non-small-cell lung cancer. N Engl J Med 330:153-158,
19. Roth JA, Fossella F, Komaki R, et al: A randomized trial comparing
perioperative chemotherapy and surgery with surgery alone in
resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst
20. Roth JA, Atkinson EN, Fossella F, et al: Long-term follow-up of
patients enrolled in a randomised trial comparing perioperative chemotherapy
and surgery with surgery alone in resectable stage IIIA nonsmall-
cell lung cancer. Lung Cancer 21:1-6, 1998.
21. Rosell R, Gomez-Godina J, Camps C, et al: Preresectional chemotherapy
in stage IIIA non-small-cell lung cancer: A 7-year assessment
of a randomised controlled trial. Lung Cancer 26:7-14, 1999.
22. Depierre A, Milleron B, Moro-Sibilot D, et al: Preoperative
chemotherapy followed by surgery compared with primary surgery in
resectable stage I (except T1N0), II, and IIIa non-small-cell lung cancer.
J Clin Oncol 20:247-253, 2002.
23. André F, Grunenwald D, Pignon JP, et al: Survival of patients
with resected N2 non-small cell lung cancer: Evidence for a subclassification
and implications. J Clin Oncol 18(16):2981-2989, 2000.
24. Pisters KM, Ginsberg RJ, Giroux DJ, et al: Induction chemotherapy
before surgery for early-stage lung cancer: A novel approach.
Bimodality Lung Oncology Team. J Thorac Cardiovasc Surg 119:429-
25. Rosell R: The integration of newer agents into neoadjuvant
therapy. Semin Oncol 25:24-27, 1998.
26. Van Zandwijk N, Smit EF, Kramer GW, et al: Gemcitabine and
cisplatin as induction regimen for patients with biopsy-proven stage
IIIA N2 non-small-cell lung cancer: A phase II study of the European
Organization for Research and Treatment of Cancer Lung Cancer Cooperative
Group (EORTC 08955). J Clin Oncol 18:2658-2664, 2000.
27. Albain KS, Rusch VW, Crowley JJ, et al: Concurrent cisplatin/
etoposide plus chest radiotherapy followed by surgery for stages IIIA
(N2) and IIIB non-small-cell lung cancer: Mature results of Southwest
Oncology Group phase II study 8805. J Clin Oncol 13:1880-1892,
28. Thomas M, Rube M, Semik H, et al: Randomized trial of
chemotherapy (CT) and twice-daily chemoradiation (hfRT/CT) versus
chemotherapy (CT) alone before surgery in stage III non-small
cell lung cancer (NSCLC): Interim analysis of toxicity (abstract 1769).
Proc Am Soc Clin Oncol 18:458a, 1999.