Phase II Trial of Neoadjuvant Chemotherapy Using Alternating Doublets in Non-Small-Cell Lung Cancer

original contributio n Phase II Trial of Neoadjuvant Chemotherapy Using Alternating Doublets in Non−Small-Cell Lung Cancer Renato G. Martins,1 Rodrigo Dienstmann,2 Paulo de Biasi,2 Karina Dantas,2 Valdelice Santos,2 Edson Toscano,2 Walter Roriz,2 Mauro Zamboni,2 Aureliano Sousa,2 Isabele A. Small,2 Denise Moreira,2 Carlos G. Ferreira,2 Mauro Zukin2 Abstract PURPOSE: Lung cancer is an epidemic disease in developing countries. Incorporation of new active drugs in the neoadjuvant treatment of operable patients might lead to improved outcomes. Postchemotherapy mediastinal-based treatment decisions allow for in vivo testing of activity and could help to determine the ideal local treatment. PATIENTS AND METHODS: This phase II trial enrolled patients with documented non–small-cell lung cancer, clinically staged IB-IIIA, and considered candidates for surgical resection. Patients received 3 cycles of neoadjuvant chemotherapy with alternating doublets: cisplatin/gemcitabine; gemcitabine/vinorelbine, and cisplatin/vinorelbine. After neoadjuvant treatment, clinical restaging was performed. Patients without evidence of progression underwent mediastinoscopy. Those with negative mediastinal nodes were taken to surgery whereas those with positive nodes were treated with radiation therapy. RESULTS: Between January 2001 and August 2002, 30 patients were included. The median age was 56 years, 66% of the patients were men, 43% of the patients had adenocarcinoma, and 34% had squamous cell carcinoma. Clinical staging was IB in 9 patients (30%), IIB in 7 (23%), and IIIA in 14 (47%). Median tumor size was 6.5 cm (range, 3-11 cm). Twenty-three patients (77%) had clinical response to neoadjuvant chemotherapy. Eight of 12 patients (67%) with N2 disease had clinical downstaging. Twenty-two patients (73%) were taken to surgery. Complete resection rate was achieved in 21 patients (70%). Treatment was well tolerated. CONCLUSION: Localized non–small-cell lung cancer is very sensitive to chemotherapy. Postchemotherapy mediastinal-based treatment decision led to a high complete resection rate, even in patients with large tumors. This strategy deserves further investigation. Clinical Lung Cancer, Vol. 8, No. 4, 257-263, 2007

Key words: Cisplatin, Gemcitabine, Mediastinal downstaging, Vinorelbine

Introduction

decreasing smoking rates, particularly among the youth. However, developing countries face the difficult task of helping the patients already afflicted by this disease. The past decade brought to the clinic a number of new active agents in non–small-cell lung cancer (NSCLC). Their impact in increasing survival for patients with advanced-stage disease has been limited. However, in patients with curable tumors, their impact is yet to be fully explored. Neoadjuvant chemotherapy has gained acceptance for patients with mediastinal compromise.2,3 Recent data suggest that the benefit of preoperative chemotherapy might be extended to less advanced cases.4 Conventionally, when 3 agents are given, they are used together as a triplet combination, with all 3 drugs given every cycle. This strategy usually requires dose reduction of the agents because of overlapping and mostly hematologic

Lung cancer is a worldwide epidemic, with increasing smoking rates in developing countries. In Brazil, 40% of men aged > 15 years and 25% of women are current smokers.1 Lung cancer is already the leading cause of cancerrelated death among men. The most important strategy to decrease the number of deaths is to invest resources in 1Division 2Instituto

of Medical Oncology, University of Washington, Seattle Nacional de Câncer - Brazil, Rio de Janeiro

Submitted: Sept 11, 2006; Revised: Jan 11, 2007; Accepted: Jan 29, 2007 Address for correspondence: Mauro Zukin, MD, Division of Medical Oncology, Instituto Nacional de Câncer - Brazil, Praça Cruz Vermelha 23/ 8o andar, Rio de Janeiro, Brazil, 22230-130 Fax: 31-3011-2809; e-mail: [email protected]

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Clinical Lung Cancer January 2007

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Alternating Doublets in Lung Cancer Figure 1

Treatment Schema

Cycle, Every 21 Days

Chemotherapy and Dose

One

Gemcitabine 1200 mg/m2 on days 1 and 8 Cisplatin 100 mg/m2 on day 1

Two

Gemcitabine 1200 mg/m2 on days 1 and 8 Vinorelbine 30 mg/m2 on days 1 and 8 Vinorelbine 30 mg/m2 on days 1 and 8 Cisplatin 100 mg/m2 on day 1

Three

to the level of the adrenal glands, bone scan, CT scan of the brain, complete blood cell count, and biochemistry evaluation of renal and liver functions. Positron emission tomography (PET) scans were not available at the time this study was conducted. After chemotherapy, patients without evidence of disease progression had a mediastinoscopy performed. Clinical T and N stage was defined by CT imaging. Lymph nodes with a short axis diameter ≥ 1 cm were considered to be involved. All toxicities were graded according to Southwest Oncology Group (SWOG) toxicity criteria.

Mediastinoscopy (4-6 weeks after last cycle)

(PD or node positive) RT (60 cGy)

or

(PD or node positive) Surgery

toxicities. One alternative way of incorporating 3 agents would be the use of alternating doublets. With this strategy, higher doses of the agents would be used, and the patients would be exposed to each agent twice in a 3-cycle treatment course. Furthermore, we have learned that the efficacy of cytotoxic drugs might be driven by very specific mechanisms of resistance. Although cisplatin resistance is related to ERCC1 and BRCA1, sensitivity to gemcitabine is influenced by RRM1.5 Therefore, the use of alternating schedules that contain gemcitabine and platinum might circumvent RRM1 and ERCC1 expression, at least partially, in patients who were not analyzed a priori. This current study investigated the response rate (RR) of neoadjuvant alternating doublets, using cisplatin, gemcitabine, and vinorelbine and the maximum phase II doses of their doublets.6-8 With the objective of optimizing resource utilization in a developing country and regarding the limitations of remediastinoscopy, we performed the mediastinoscopy only after neoadjuvant chemotherapy and made local treatment decisions based on its results.

Patients and Methods Eligibility Criteria This was a phase II institutional trial. Patients were eligible if they: had stage IB (except for T1 N0), IIB, or IIIA histologically or cytologically proven NSCLC; had resectable disease as defined by our surgical team, including absence of direct mediastinal tumor invasion; were aged ≥ 18 years; World Health Organization Performance Status (PS) of 0/1; had adequate hematologic, renal, and hepatic function to safely undergo chemotherapy and surgery; and had bidimensionally measurable disease. Patients were also required to have predicted postresection forced expiratory volume in 1 second of ≥ 0.8 L. Exclusion criteria were previous malignancy or cancer treatment and coexisting serious illness. The internal review board of our institution, the Brazilian National Cancer Institute, approved this protocol, and signed informed consent was obtained from all patients. Pre-enrollment studies included a chest radiograph, computed tomography (CT) scan of the chest, with sections down

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Chemotherapy Eligible patients received 3 cycles of preoperative chemotherapy (Figure 1). Cycle 1 included gemcitabine (1200 mg/m2 on days 1 and 8) and cisplatin (100 mg/m2 on day 1). In cycle 2, vinorelbine (30 mg/m2 on days 1 and 8) and gemcitabine (1200 mg/m2 on days 1 and 8) were given; in cycle 3, vinorelbine (30 mg/m2 on days 1 and 8) and cisplatin (100 mg/m2 on day 1) were administered. Response Evaluation and Postchemotherapy Treatment Plan Radiologic response was assessed according to the Response Evaluation Criteria in Solid Tumors.9 Pathologic response was evaluated by mediastinoscopy before surgery and by pathologic analysis of surgical specimens. Histologic diagnosis and assessment of mediastinal lymph nodes were performed using American Thoracic Society mapping in all patients.10 Complete pathologic response was defined as ≥ 95% of necrosis and fibrosis in the surgical specimen. For patients with clinical partial response or complete response, surgery was performed 4-6 weeks after the last cycle of chemotherapy. If there was evidence of progressive disease (PD) or positive lymph node at the mediastinoscopy, surgery was not performed and the patient received 60 Gy of radiation therapy (RT) to the primary tumor and mediastinum, as long as no distant metastatic disease was identified. Surgery Patients without evidence of PD by CT scan and a negative mediastinoscopy underwent thoracotomy. The standard surgical procedures were lobectomies or pneumonectomies. The attending surgeon chose the most appropriate approach to assure the complete removal of the primary lesion with negative gross and microscopic margins (R0), according to the decision on the basis of the CT scan before chemotherapy. All accessible hilar lymph nodes were dissected from the specimen, and a complete mediastinal lymph node dissection was performed in all patients. For right-sided lesions, this included 2R, 4R, 7, 8, 9 and 10R. For left-sided lesions, this included 4L, 5, 6, 7, 8, 9 and 10L. Follow-Up Follow-up procedures included physical examination and chest radiograph every 3 months and chest CT scan every 12 months for the first 2 years. From the third to the sev-

Renato G. Martins et al Table 1

Patient Characteristics Characteristic

Median Age (Years) Sex, Male (%)

Table 2 Number of Patients 56 20 (66)

Performance Status (%)

Chemotherapy Toxicity

Nonhematologic Grade 3/4 Toxicity

Patients (%)

Vomiting

5 (17)

Nausea

5 (17)

Ototoxicity

1 (3)

0

13 (43)

Asthenia

2 (7)

1

17 (57)

Constipation

1 (3)

Infection

2 (7)

Histology (%)

Hematologic Grade 3/4 Toxicity

Adenocarcinoma

13 (43)

Squamous cell carcinoma

10 (34)

Neutropenia

4 (13)

NSCLC, not specified

7 (23)

Thrombocytopenia

1 (3)

Anemia

1 (3)

Clinical Stage (%) IB

9 (30)

IIB

7 (23)

IIIA

14 (47)

Tumor Size (cm) Median (range)

6.5 (3-11)

enth years, follow-up consisted of a chest radiograph every 6 months and CT scan of the chest every year. Statistical Analysis The main objective of this trial was to establish the RR of alternating doublets as neoadjuvant chemotherapy in patients with clinical stage IB, II, and IIIA NSCLC. The secondary objectives were to evaluate mediastinal downstaging and resectability after neoadjuvant chemotherapy, toxicity of regimen, progression-free survival (PFS), and overall survival (OS). Progression-free survival and OS times were calculated as the elapsed time between the date of registration in the study and the first documentation of recurrence or death. Postoperative treatment deaths were defined as deaths that occurred in the first 100 days after surgery, as long as the patient had no evidence of recurrence. Survival was estimated using the Kaplan-Meier method.11 We chose to evaluate PFS when all patients were rendered disease free, because those treated with RT had radiologic residual lesions. All analyses were based on intent-to-treat.

Results Patients Between January 2001 and August 2002, 30 patients were included in the trial. This represents all but 1 patient who met the inclusion criteria and was considered for surgery at the Brazilian National Cancer Institute during the study period. Patient characteristics are described in Table 1. The median age was 56 years, 66% were men, and 43% had adenocarcinoma. Thirteen patients had a PS of 0 and 17 patients had a PS of 1. Clinical staging was IIIA in 14 patients (46%). Twelve patients had mediastinal nodes > 1 cm in the

shortest axis in their CT scan (N2) and 2 patients had T3 tumors with hilar lymph nodes (N1). The median tumor size was 6.5 cm, ranging from 3 cm to 11 cm. Toxicity The treatment was relatively well tolerated. Table 2 describes grade 3/4 toxicities related to the chemotherapy. Nausea and vomiting were common and related to the high doses of cisplatin used. Fever and neutropenia developed in 5 patients (17%); however, only 1 case was associated with admission to the Intensive Care Unit for aggressive support, and this patient recovered. No patient required > 1 week of delay in the cycle because of cytopenia and none had dose modifications because of toxicity. One patient developed a myocardial infarction related to cocaine abuse. Another patient had normal platelet count at the beginning of treatment but developed marked reactive thrombocytosis, with platelet count > 1,000,000, concomitant with recurrent deep vein thrombosis. A third patient responded to the chemotherapy but had a drop of his clinical performance during treatment, with a PS of 3 at the completion of chemotherapy. As a consequence of his PS compromise, he was treated with RT. There was 1 treatment-related death during chemotherapy. After the third cycle, the patient presented with increasing dyspnea and bilateral pulmonary infiltrates. He had no fever or neutropenia. His dyspnea evolved to respiratory failure and he died of this progressive bilateral pulmonary process without a clear diagnosis. Of note, his admitting chest radiograph showed complete resolution of the pulmonary mass. Response to Neoadjuvant Chemotherapy Twenty-three patients responded to the chemotherapy, leading to an overall RR of 77% (95% confidence interval, 62%-93%). No patient met criteria for PD during the treatment. Eight of 12 subjects (67%) with clinical N2 disease at baseline had radiologic downstaging (a controversial term considering that a patient does not change his/her initial staging during his/her disease) comparing the pretreatment CT scan and the CT scan before Clinical Lung Cancer January 2007

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Alternating Doublets in Lung Cancer Figure 2

Computed Tomography Images of Large Tumor Mass Substituted by a Large Cavity

The surgical morbidity and mortality were comparable to our experience without the use of neoadjuvant chemotherapy. Two patients had prolonged postoperative time on ventilatory support. Both patients had right-side resections, 1 upper lobe lobectomy and 1 pneumonectomy. Surgery-related mortality was 4% (1 patient). This patient died 94 days after surgery of delayed postoperative complications, including empyema and bronchopleural fistula.

Progression and Survival After a median estimated follow-up of 36 months, median PFS was 21 months, as shown in Figure 3. Eighteen patients experienced progression: 12 (40%) had locoregional recurrence, 1 with concomitant hepatic progression; 5 (17%) developed brain metastasis, and 1 had progression in bone. All patients treated with RT experienced progression. The actuarial 1-, 2-, and 3-year PFS were 43%, 33%, and 33%, respectively. Median Upper left and right panels: prechemotherapy and postchemotherapy CT scans, respectively, of one patient that had substitution of a large tumor mass by a cavity. Lower left and right panels: same response in another patient. PFS of the small subgroup of patients with initial N2 disease (n = 12) was 21 months. Those who exhibited mediastinal radiologic downsurgery, which showed resolution of the lymph nodes in the staging (n = 8) had a median estimated PFS of 22 months, mediastinum. Four patients (13%) had a tumor decrease compared with 10 months in those without downstaging > 90% in their postchemotherapy CT scan. In 2 patients, (n = 4; log rank, P = 0.02). the large tumor mass was substituted by a large cavity, as Median survival was 36 months, as shown in Figure 4. The shown in Figure 2. actuarial 1-, 2-, and 3-year OS rates were 60%, 53%, and Postchemotherapy Treatment 43%, respectively. As described in Table 3, 22 patients (73%) underwent surgery. The reasons for not having surgery were as follows: death during chemotherapy, myocardial infarction, recurDiscussion rent deep venous thrombosis, drop in the PS, and posiOur main objective at study initiation was to evaluate if the tive mediastinoscopy, each in 1 patient. Three additional use of maximum phase II doses of alternating chemotherapy patients had CT scan changes that made the surgical team doublets would lead to a high RR in the neoadjuvant setting. consider them inoperable; 1 had involvement of main pulWe also wanted to analyze the results of a postchemotherapy monary artery and 2 had functional inability for pneumecmediastinal-based treatment decision. tomy. None of these 3 cases had a tumor volume increase Our findings support the conclusion that localized NSCLC that would qualify as PD. Among patients in whom a is a highly sensitive tumor to chemotherapy. Other groups thoracotomy was performed, 21 (95% of operated patients treating patients with clinical stages IB-IIIA and using cisplaand 70% of the entire study population) had a complete tin-based4 or carboplatin-based12,13 treatments have shown microscopic surgical resection. Among patients with cliniRRs > 60%. Compared with these studies, our patients had cal IIIA disease, 9 (64%) had radiologic response and were diseases in more advanced stages. For example, in the study considered for surgical resection. One patient in this group by Pisters et al, 45% of patients had clinical stage IB;12 this had positive mediastinoscopy and was treated with RT and stage represented only 26% of cases in our trial. However, another patient had a false-negative mediastinoscopy, with in our study, mediastinoscopy was not performed until after 1 positive microscopic lymph node on his final surgical pathe chemotherapy, leading to imprecise staging of the medithology. Four patients (13%) had no cancer at their surgical astinum. This inaccurate staging would occur in both direcspecimen (pathologic complete response). tions and would cause overestimation and underestimation

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Renato G. Martins et al

Clinical Stage

Treatment

Pathologic Stage

Reason for Nonsurgical Treatment

1

T2 N2, IIIA

Surgery

T0 N1

–

2

T3 N0, IIB

Surgery

T3 N0

–

3

T3 N1, IIIA

Surgery

T2 N0

–

4

T3 N0, IIB

Surgery

T3 N1

–

5

T3 N2, IIIA

RT

–

Unresectable

6

T2 N0, IB

Surgery

T2 N2

–

7

T3 N0, IIB

Surgery

T3 N0

–

8

T2 N0, IB

Surgery

Complete response

–

9

T2 N0, IB

Surgery

T2 N0

–

10

T3 N0, IIB

RT

–

Unresectable

11

T3 N0, IIB

Surgery

Complete response

–

12

T2 N2, IIIA

RT

–

Positive mediastinoscopy

13

T2 N0, IB

Surgery

T1 N0

–

14

T3 N0, IIB

Surgery

Complete response

–

15

T3 N2, IIIA

Surgery

T1 N0

–

16

T2 N0, IB

Surgery

T2 N0

–

17

T3 N2, IIIA

Surgery

T4 N0

–

18

T2 N2, IIIA

Surgery

T2 N0

–

19

T2 N0, IB

Surgery

T1 N0

–

Progression-Free Survival (%)

Patient

Figure 3

Initial Staging and Results of Treatment in 30 Patients with NSCLC Receiving Neoadjuvant Chemotherapy

100 80 60 40 20 0

Figure 4

20

T3 N0, IIB

RT

–

21

T2 N2, IIIA

Surgery

T1 N0

–

22

T3 N1, IIIA

RT

–

Unresectable

23

T3 N0, IIB

RT

–

Myocardial infarction

24

T2 N2, IIIA

Surgery

T2 N0

–

25

T2 N0, IB

Surgery

T1 N0

–

26

T3 N2, IIIA

–

–

Death during therapy

27

T3 N2, IIIA

RT

–

Drop in performance status

28

T3 N2, IIIA

Surgery

Complete response

–

29

T2 N0, IB

Surgery

T1 N1

–

Surgery

T4 Nx positive margins

–

30

T2 N2, IIIA

of nodal involvement; however, underestimation is a more common occurrence.14 Furthermore, our patients had large primary tumors, with a median tumor size of 6.5 cm, and more frequent underestimation by CT scan would be expected. Despite these large tumors, we observed a high RR. A possible explanation for this high RR includes the size of the trial, considering that the lower end of our 95% confidence interval does include the findings of other groups.

12

24

36

48

60

Overall Survival of 30 Patients with Resectable NSCLC Receiving Neoadjuvant Chemotherapy

100 80 60 40 20 0

Recurrent thrombosis

Progression-Free Survival of 30 Patients with Resectable NSCLC Receiving Neoadjuvant Chemotherapy

Months

Overall Survival (%)

Table 3

12

24

36

48

60

Months

Another explanation might be the dose of cisplatin used in 2 chemotherapy cycles. This influence of cisplatin dose in the RR might be particularly relevant in patients with diseases in less advanced stages.15 Finally, vinorelbine and gemcitabine are active drugs in NSCLC. Both agents have shown higher RRs and survival improvement when combined with cisplatin versus single-agent cisplatin.16,17 This improvement in survival with the combination of a new agent plus cisplatin versus cisplatin alone might not be true for all drugs.18 The use of 3 drugs, combined in alternating doublets, does allow higher dose per infusion. It is possible that this higher dose is the reason for the high RR we observed. However, this question can only be addressed in a randomized trial. Chemotherapy has gained an increasingly important role in surgically curable NSCLC, both in neoadjuvant and adjuvant settings. In the study by Depierre et al, the survival benefit of neoadjuvant chemotherapy seemed more significant in patients with stage I/II when compared with patients with stage III NSCLC.4 Although the survival differences in the initial report of the study were not statistically significant, a recent update showed that the survival difference at 3 years is now significant and the absolute benefit at 5 years approaches 10%.19 Another landmark study in this area is the International Adjuvant Lung Cancer Trial.20 Despite the negative results of previous studies,21,22 the number of patients included in Clinical Lung Cancer January 2007

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Alternating Doublets In Lung Cancer this worldwide effort and the survival difference observed made the results of this study compelling. Since the International Adjuvant Lung Cancer Trial publication, 3 other studies confirmed the survival benefits of adjuvant chemotherapy for patients with IB-IIIA NSCLC, with magnitude of absolute increase in survival estimated to be between 5% and 15%.23-25 However, considering recent data, survival benefit for adjuvant chemotherapy in IB patients is still controversial.26 Based on the results of a phase II trial that showed that preoperative carboplatin/paclitaxel was safe, feasible, and possibly increased survival,27 SWOG designed a phase III trial (SWOG 9900) to compare neoadjuvant chemotherapy with surgery alone for patients with resectable IB, II, and IIIA (N2 negative) NSCLC. The trial closed early because adjuvant therapy became the standard of care; surgery alone became unethical. Recently, Pisters presented the preliminary results of a trial with a planned sample size of 600 patients, with 354 patients accrued. Major radiographic response to 3 cycles of neoadjuvant paclitaxel/carboplatin was 41% in 180 patients. Compliance with induction chemotherapy was 77%. With a median follow-up of 28 months, PFS and OS favored the chemotherapy arm, but without statistical significance (31 months vs. 20 months; P = 0.26 and 47 months vs. 40 months; P = 0.47, respectively).28 Two-year survival in the neoadjuvant arm of this study was 69% compared with 59% in the Depierre trial4 and 53% in our trial. Taken together, these studies suggest that most candidates for surgical cure of NSCLC should be considered for chemotherapy. For years, confronted by the negative results of previous adjuvant trials and the positive results of small neoadjuvant studies, many in the lung cancer community believed that the chemotherapy would only improve survival if given before surgery. A metaanalysis of randomized trials evaluating neoadjuvant chemotherapy in early-stage NSCLC is under way. Phase III trials comparing neoadjuvant and adjuvant chemotherapy in resectable NSCLC are also in progress, and the results will be presented soon. The response to neoadjuvant chemotherapy might predict the outcome of the surgical procedure in NSCLC. Patients with positive mediastinal nodes after induction platinum agent–based chemotherapy have a poor prognosis, with median survivals after surgery comparable with those with unresectable disease.29,30 The strategy of surgical decision after neoadjuvant chemotherapy allows patients with no mediastinal clearance to be spared from a surgical procedure from which they are unlikely to benefit. It is possible that some of our patients had stage IIIB–based or N3 disease before chemotherapy; these patients would not have been treated with surgery. However, different groups have shown that these patients can have prolonged disease-free survivals with surgery as long as they have clearance of their mediastinal nodes with neoadjuvant chemotherapy.31,32 As well, positron emission tomography (PET) is becoming an integral part of NSCLC staging.33 Positron emission tomography can also be used to evaluate the response of chemotherapy.34,35 It is very likely that our strategy of a

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postchemotherapy treatment decision would be improved with the information gained from a PET scan. However, PET is not a reality in most developing countries, where a progressively larger proportion of the world’s patients with lung cancer will be treated in the coming years. One possible disadvantage of the neoadjuvant chemotherapy would be the increase in the surgical morbidity and mortality. Besides the substantial toxicity of high-dose chemotherapy used in this study (neutropenic fever, 17%), our results suggest that this is not the case. Two patients (9%) had prolonged time on ventilatory support. Both had right-side resections, which is associated with higher rates of postoperative complication after neoadjuvant chemotherapy. Only 1 patient (4%) in our study died because of delayed surgical complications. This surgical mortality is compatible with recent literature on preoperative chemotherapy.36 A recent retrospective analysis of 242 patients treated with induction chemotherapy showed no increase in the surgical mortality when compared with patients treated with primary surgery.37 The only exception for the choice of neoadjuvant chemotherapy might be patients believed to require a right pneumonectomy. These patients have a higher postoperative morbidity and mortality, which seems to be worsened by neoadjuvant chemotherapy.28 Among our 2 severe postoperative complications, 1 had a right pneumonectomy. Our study shows that the strategy of neoadjuvant alternating doublets using cisplatin, gemcitabine, and vinorelbine is highly active in localized NSCLC. A postchemotherapy-based mediastinal treatment decision is feasible and associated with a high rate of complete resection among patients taken to surgery. Morbidity and mortality of this combined approach are acceptable and in line with the current literature. At our institution, neoadjuvant chemotherapy in resectable NSCLC has a major advantage, considering the high volume of patients and the consequent delay in definitive surgery. With the preoperative chemotherapy, patients start their treatment immediately and the surgery date can be planned in advance. Most of these patients would have been candidates to receive chemotherapy after surgery, based on the survival benefits of adjuvant treatment previously described. We conclude that this strategy deserves further investigation, and randomized trials comparing neoadjuvant and adjuvant chemotherapy in resectable NSCLC are expected.

Acknowledgements This study was supported in part by grants from Eli Lilly and Company and ASTA Medica. Our thanks to Jeffrey Slater, MFA, for assistance.

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