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Adjuvant Chemotherapy for Non–Small Cell Lung Cancer: Contribution of the International Adjuvant Lung Trial

Authors' Affiliation: Departments of Biostatistics and Epidemiology (AD, JPP) and Medicine (TLC), Institut Gustave-Roussy, Villejuif, France

Requests for reprints: Ariane Dunant, Institut Gustave-Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France; E-mail: adunant{at}igr.fr.

	Abstract

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The recently reported International Adjuvant Lung Cancer Trial (IALT) was designed to assess the potential benefit of three to four cycles of adjuvant cisplatin-based chemotherapy after complete resection of non–small cell lung cancer (NSCLC). Each center predetermined the cisplatin dose (total 300-400 mg/m²), the combined drug (etoposide or a Vinca alkaloid), and the radiotherapy policy. From 1995 to 2000, 1,867 patients were randomized in 148 centers from 33 countries. On September 1, 2002, median follow-up was 56 months and >98% of patients had an updated follow-up. Overall survival was significantly different between the two arms: 5-year survival rate was 44.5% in the chemotherapy arm versus 40.4% in the control arm [relative risk = 0.86 (0.76-0.98), P < 0.03]. Disease-free survival, incidence of local recurrence, and incidence of distant metastases (but not brain metastases) were likewise significantly different, with an advantage for the chemotherapy arm. We concluded that adjuvant cisplatin-based chemotherapy in resected NSCLC should become part of the standard management of operable NSCLC. Two other recently reported randomized prospective studies also showed a significant benefit for postoperative platin-based doublets in stage IB and II NSCLC and confirmed the role of adjuvant chemotherapy as part of the treatment of these patients. The Lung Adjuvant Cisplatin Evaluation program, a pooled analysis of all recent platin-based adjuvant trials, and the IALT-Bio study, which will investigate over 30 markers in the IALT patients' specimens, should allow us to better define the populations more likely to benefit from postoperative chemotherapy.

	Materials and Methods

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A detailed report of the design and methods of the IALT study has been presented elsewhere (2). Briefly, the IALT was a large-scale study designed to show a 5% benefit in 5-year survival of cisplatin-based chemotherapy compared with no adjuvant chemotherapy after complete resection of NSCLC. Before randomization, each center had to determine the candidate population for inclusion (stage I, II, and/or III), the dose of cisplatin (80, 100, or 120 mg/m² per cycle for three to four cycles, with a total dose ranging between 300 and 400 mg/m²), the drug to be combined with cisplatin (etoposide, vindesine, vinblastine, or vinorelbine), and the use, or not, of postoperative thoracic radiotherapy.

The primary end point was overall survival. All analyses were done according to the intention-to-treat principle. For all analyses of time-to-event data, a Cox model was used and adjusted according to previously defined stratification factors. All tests were two sided. Estimation of event incidence was based on the Kaplan Meier method with censoring at death (as in the corresponding Cox models).

	Results

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The study closed after enrollment of 1,867 patients of the 3,300 planned because of a slow down in accrual. In the last semester after >5 years accrual, the accrual rate had decreased to one third of its maximum and it became clear that the target sample size would not be achieved. At the time of the analysis, the median follow-up was 56 months. In all, 74% of the patients in the chemotherapy arm received at least 240 mg/m². The toxicity-associated death rate was 0.8%. No interaction was observed with gender, age, pathologic stage, histology, type of surgery, dose of cisplatin, drug combined with cisplatin, or radiotherapy. Further details have been published previously (2).

Table 1 summarizes the results concerning death and cancer-related events, and Table 2 describes the causes of death. Overall and disease-free survivals were significantly higher in the chemotherapy arm compared with the control arm, as reported previously (2). Incidence of recurrence, either local or distant, was significantly lower in the chemotherapy arm compared with the control arm (P < 0.003 local and P < 0.03 distant recurrence). Brain alone was the most frequent metastatic site (30%). The incidence of brain metastasis was not significantly different between the two arms (P = 0.61), whereas the incidence of other metastases was significantly lower in the chemotherapy arm compared with the control arm (P < 0.003). Incidence of a second cancer was not significantly different between the two arms (P = 0.64).

	Discussion

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The results observed in the IALT were very close to those reported in the meta-analysis, in which findings for a total of 1,394 patients from eight studies were analyzed (1). The large number of patients in the IALT analysis may explain the significance of the results, compared with smaller, inconclusive trials of adjuvant therapy. Table 3 summarizes the results of the NSCLC meta-analysis and those of the recently randomized adjuvant platin-based trials. The large Adjuvant Lung Project Italy trial failed to show the superiority of three cycles of postoperative mitomycin/vindesine/cisplatin compared with no adjuvant chemotherapy in the same population (3); however, the use of mitomycin C and the smaller number of analyzed patients may explain the negativity of this trial. The adjuvant arm of the Big Lung Trial also did not find any benefit from adjuvant cisplatin-based chemotherapy, but the population of the trial seems to have been more heterogeneous because a proportion of patients did not have a complete microscopic resection of their tumor (4). More recently, two other randomized studies were reported on selected populations. The BR10 study led by the National Cancer Institute of Canada excluded resected patients with stage IA and those with a mediastinal involvement (5). The Cancer and Leukemia Group B 9633 study selected only pathologic stage IB patients (6). These two studies showed a 12% to 15% benefit at 4 to 5 years from modern chemotherapeutic doublets (vinorelbine/cisplatin and paclitaxel/carboplatin, respectively). This higher benefit may be related to the selection of earlier stages and also to the use of more contemporary drugs. Another factor that may account for the variation in the results between trials is the poor compliance observed in most of these adjuvant studies, in which a high proportion of patients did not receive the total planned doses of chemotherapy (Table 4). In summary, the better results observed in some trials may be related to a selected population, lack of maturity in the follow-up, early stopping, or a more efficient drug; however, the results of all these trials are consistent with those of the meta-analysis, as the confidence intervals of their hazard ratios overlap with that of the meta-analysis.

Ongoing analyses will clarify the role of adjuvant chemotherapy and its indications. They include (a) the planned Lung Adjuvant Cisplatin Evaluation program, a pooled analysis of the recent platin-based adjuvant studies, to better characterize the clinical subgroups of patients most likely to benefit from adjuvant chemotherapy; (b) the update of the NSCLC meta-analysis, which will include all adjuvant trials (>20 trials and 8,000 patients) and give the best possible estimation of the effect of adjuvant chemotherapy in the general population; (c) the IALT-Biology program, which will analyze >30 tumor markers from the pathologic specimens of over 800 patients who were included in the IALT. In addition, several ongoing trials compare neoadjuvant chemotherapy and observation, in particular the Italian Chemotherapy for Early Stages study and the Spanish Neoadjuvant/Adjuvant Taxol Carboplatin Hope trial, which will also address the issue of neoadjuvant versus adjuvant therapy. The French IFCT0002 study examines the optimal timing of chemotherapy: all four cycles before surgery versus two before and two after.

The role of third-generation cytotoxic agents (taxanes and gemcitabine in particular) will be evaluated through ongoing and future trials. Biologically targeted therapies may also hold promise in the management of early-stage NSCLC. Because of their activity in the management of advanced disease, both gefitinib and celecoxib are currently being investigated in the adjuvant setting (9).

In conclusion, sufficient data are now available to convince clinicians to adopt adjuvant chemotherapy as a standard of care. The more skeptical clinicians will await the results of the pooled studies.

	Open Discussion

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Dr. Thomas Lynch: One of the questions that we are left with now is the relationship between stages I, II, and III in terms of who benefits from adjuvant chemotherapy. We have gotten slightly different messages from the three trials. Stage I patients seem to do better in the CALGB results. Stage III patients seem to do better in IALT. Why do you think there are differences in which stage might benefit, and what do you think the real story will be here?

Dr. Le Chevalier: I would like to know why stage III patients were not included in the other studies, just to look at the difference. The problem with the IALT is that it is not a sophisticated study. We see an overall benefit but we cannot be certain of subgroups. Although we made site visits, we do not know much about the management of patients in Argentina or in the Philippines. Complete resection was part of the inclusion criteria, but we don't know, for example, about the mediastinal dissection outside of Europe. Why did stage III do better than the others? I cannot explain it.

Dr. Joan Schiller: My impression after talking to Frances Shepherd about the Intergroup JRB.10 study was that all of the benefits were seen in stage II and none is seen in stage I. So, if the IALT group would have just chosen to do the same patient population as the CALGB, you would have had one positive and one negative trial.

Dr. Le Chevalier: Our staging system was the unrevised 1987 International Staging System, so that T₃ N₁ were stage III, etc. When we look at the N status, we didn't see any difference between N₀ and N₁ and N₂. For the Ts, it is even more obvious than with the stage. T₁ does not benefit and T₃ benefit the most.

Dr. Thatcher: Looking at it strictly, then, you would include stage I with stage IIIA patients in places of your data. On the basis of your trial, the go away message was that there is no statistically significant subgroup that would benefit greater or less. Therefore, we should strictly include stage I.

Dr. Giorgio Scagliotti: In the analysis presented in the New England Journal of Medicine, most of the benefit in IALT was seen in the subgroup of patients below age 64. This is another piece of information that is extremely important because today up to 40% of patients are above age 55.

Dr. Le Chevalier: I agree with you, but you speak like a clinician and my presentation is from a statistician's viewpoint. So, no interaction, no difference. Now that's the problem. If there is no interaction, we must consider that it is an overall benefit.

Dr. Bruce Johnson: I wanted to ask Dr. Scagliotti and Dr. LeChevalier how many patients with stage IA were in their studies. That's not in your publications and you didn't present it today. Did you have any stage IA patients?

Dr. Scagliotti: None.

Dr. Le Chevalier: We have just one T₁. We do not have the ability to differentiate between IA and IB by our trial design. The study enrollment form asked for T₁, T₂, T₃, T₄, so we do not have data on IA and IB.

Dr. James Jett: The corollary to the issue of stage is the question raised by Dr. Scagliotti about age groups and selection for adjuvant chemotherapy. We are seeing a lot of people in their 70s. I have taken the attitude that I am not treating the stage IA patients with adjuvant therapy, based on the fact that there are no data to support it. But then what about the 75-year olds, and if that's okay then what about the 70-year-olds?

Dr. Le Chevalier: I agree with you. You can set a threshold for a minimal benefit, age 73, stage IB, something like that. You can consider that. You must just realize that in our countries, unlike in Japan, the 70% 5-year survival rate in stage I is not very good; 30% of patients will die from cancer within 5 years. So, even if we are not convinced by this chemotherapy I think that we have to work on that because the data are not so good.

Dr. Lynch: Question for the surgeons, Dr. Wood and Dr. DeCamp. We have been referring to a 60% to 70% cure rate in stage I. In the thoracic surgical literature, what do you feel the appropriate outcome in stage IA and IB lung cancer would be in the most modern series from a surgical standpoint, not the control groups of the adjuvant trial? Is there a feeling that surgery is improving outcome beyond 60% or 65% in this setting?

Dr. Douglas Wood: I don't think surgery has become more sophisticated in the past couple of decades for stage IA disease or stage I disease overall, but staging has become much more sophisticated, and so clinical staging, which overall tends to underestimate stage, has improved its accuracy. The staging data used by Mountain in the 1997 revision of the International System are not anything that any of us would consider adequate for our patients today, so I think that we are really dated when we use those numbers as a prognostic guide for how a clinical stage IA patient who has had a PET scan and mediastinoscopy will do. They have had a current CT, and maybe a series of screening CT scans that followed them even before they were diagnosed. Because of stage migration, survival in early stage disease is much better. So I would say that at stage IA 80% of patients should be cured surgically.

Dr. Malcolm DeCamp: I would agree with that. The other caveat with stage IA is that we are now finding smaller IA tumors, which brings up the issue about whether we need to carve up stage IA into subgroups based on tumor size. In the original lobectomy versus limited resection study, the average size of those tumors was 2.8 cm [Ann Thorac Surg 1993;56:825–32]. Now, we are regularly seeing 0.8 cm tumors. With contemporary, thorough, and homogenous staging, stage IA survival should be 80%. Then, you've got to decide if you are going to treat eight people who don't need to be treated. If I can do it with Gary Strauss' regimen and not hurt anybody, it may be worth it.

Dr. Wood: But then I would say, is there a biological difference between a 2.9 cm lesion and a 3.1 cm lesion? There is none, but where do you draw the line? Although I am probably the biggest skeptic for adjuvant therapy, it is hard for me to draw the line in telling patients with stage IA that they shouldn't be considered for adjuvant chemotherapy. I think they should.

Dr. Glenwood Goss: My guess is that stage I, II, and III would all respond to chemotherapy, although maybe not equally. By the time you have a 1 cm lesion, the tumor is already far advanced in its half-life. It has already undergone many divisions and there are not a lot of divisions left before it clinically kills its host. So, there is not that much room for clonal evolution from the time we get a clinically treatable tumor to the time the patient dies. Resistance develops as the tumor grows, but the majority of tumor growth has already taken place. I think that the effect that we see with chemotherapy is probably a ubiquitous effect in clinically relevant tumors, but that's just an opinion.

	Footnotes

 
Presented at the International Conference on Early-Stage Lung Cancer: New Approaches to Evaluation and Treatment, October 1-2, 2004, Cambridge, Massachusetts.

	References

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1. 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 randomised clinical trials. BMJ 1995;311:899–909.[Abstract/Free Full Text]
2. The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small cell lung cancer. N Engl J Med 2004;350:351–60.[Abstract/Free Full Text]
3. Scagliotti GV, Roldano F, Torri V, et al. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small cell lung cancer. J Natl Cancer Inst 2003;95:1453–61.[Abstract/Free Full Text]
4. Waller D, Peake RJ, Stephens RJ, et al. Chemotherapy for patients with non-small cell lung cancer: the surgical setting of the Big Lung Trial. Eur J Cardiothorac Surg 2004;26:173–82.[Abstract/Free Full Text]
5. Winton TL, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin compared with observation in resected non-small cell lung cancer. N Engl J Med. In press 2005.
6. Strauss GM, Herndon J, Maddaus MA, et al. Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in Stage IB non-small cell lung cancer (NSCLC): report of Cancer and Leukemia Group B (CALGB) protocol 9633 [meeting abstracts]. J Clin Oncol 2004;22:7019.
7. Kato H, Tsuboi M, Ohta M, et al. A randomized phase III trial of adjuvant chemotherapy with UFT for completely resected pathological stage I (T1N0M0, T2N0M0) adenocarcinoma of the lung [abstract 2498]. Proc Am Soc Clin Oncol 2003;22:621.
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