Neoadjuvant strategies for non-small cell lung cancer

Lung Cancer 34 (2001) S145– S150

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Neoadjuvant strategies for non-small cell lung cancer Nico van Zandwijk * Department of Thoracic Oncology, The Netherlands Cancer Institute, Plesmanlann 121, 1066 CX, Amsterdam, The Netherlands

Abstract During the last 15–20 years, several phase II trials have investigated the use of chemotherapy and chemoradiation prior to surgery in the management of stage IIIA non-small cell lung cancer (NSCLC). The results of these studies, in contrast to insignificant outcomes of comparative studies with chemotherapy in the postoperative setting, have been encouraging. Moreover, phase III trials comparing surgery alone with chemotherapy plus surgery have confirmed the efficacy of this multimodality approach. In recent years, newer and more effective chemotherapy combinations have become available and are now being used prior to surgery. One focus of ongoing research is to confirm that preoperative chemotherapy followed by complete resection is a better treatment approach than surgery alone, even for patients with early-stage NSCLC. Recent data suggest that induction chemotherapy in this category of patients yields high response rates and does not compromise the outcome of surgery. Given the systemic nature of lung cancer it is estimated that systemic therapy before local treatment will play an increasingly important role for patients with early-stage NSCLC. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: NSCLC; Induction therapy; Neoadjuvant therapy

1. Introduction

2. Adjuvant chemotherapy

Surgical resection is the treatment of choice for patients with localized NSCLC. Unfortunately, at the time of diagnosis, fewer than 25% of all NSCLC patients are considered candidates for surgical therapy. Cure after resection is highly dependent on the stage of disease present and whether lymph nodes are involved. Patients with stages II and III disease have a much poorer prognosis than those with stage I disease (Table 1). Patients without lymph node metastases who have been completely resected have a 5-year survival rate of more than 70%. This rate decreases to 50 and 15%, respectively, if hilar or mediastinal nodes are involved [1]. Analyses of sites of recurrence, revealed that twothirds of all recurrences following a complete resection occurred distantly. In a fair number of occasions, the brain was the first metastatic site to be recognized [2]. The urgent need for better treatment of a disease with such a systemic nature has led to several studies employing chemotherapy in addition to local (surgical) treatment.

In an attempt to improve survival outcomes in patients with completely resected NSCLC, much time and effort have been spent exploring the role of postoperative adjuvant therapy. Fourteen adjuvant trials, comprising 4357 patients randomized to receive either postoperative chemotherapy or no treatment, have been re-analyzed by the Non-Small Cell Collaborative Group [3]. An unfavorable effect was associated with the use of alkylating agents, whereas a slight improvement in survival was noted, with the use of platinumbased chemotherapy. The latter difference, however, failed to reach statistical significance (P= 0.08). A recently published study by the Eastern Cooperative Oncology Group (ECOG) [4] that, compared postoperative radiotherapy with chemoradiotherapy, in completely resected stages II and IIIA NSCLC patients, did not show significant differences between the two treatment arms. The authors concluded that in the locally advanced (node positive) resected patients, adjuvant therapy with the ‘older’ cytotoxic drugs did not seem to enhance survival. It has been argued that this study might have benefited from the inclusion of two additional study arms: one with adjuvant chemotherapy alone and one observation-only control arm.

* Tel.: +31-20-512-2958; fax: +31-20-512-2572. E-mail address: [email protected] (N. van Zandwijk).

0169-5002/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 0 1 ) 0 0 3 5 9 - 2

N. 6an Zandwijk / Lung Cancer 34 (2001) S145 – S150

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Table 1 Staging criteria and 5-year survival rate for non-small cell lung cancer Stage

Grouping

5-year survival (%)

IA IB IIA IIB

T1N0M0 T2N0M0 T1N1M0 T2N1M0 T3N0M0 T1–3N2M0 T3N1M0 T1–3N3M0 T4anyNM0

75 55 50 40

IIIA IIIB

15 35 5–10 5–10

An important additional observation in many studies with postoperative adjuvant therapy was that a significant proportion of patients did not receive the full, intended dose of chemotherapy. The lack of beneficial effect of postoperative adjuvant therapy so far might be partly explained by the poor tolerance of chemotherapy in the postoperative period. Despite these observations, there continues to be interest in the use of adjuvant chemotherapy. Several large-scale, randomized, multicenter chemotherapy trials in the postoperative setting have been initiated in the last decade and will soon produce final results. On the basis of the available data, however, postoperative chemotherapy in patients with completely resected NSCLC cannot be recommended as the standard of care.

3. Induction chemotherapy before surgery (neoadjuvant therapy) The use of systemic therapy before definitive local-regional therapy is generally referred to as induction or neoadjuvant therapy. Initial studies used chemotherapy or chemoradiotherapy prior to surgery primarily as a means to render unresectable disease resectable. Today, however, the rationale for induction therapy in resectable NSCLC is based on the considerations that chemotherapy may prevent the growth of systemic disease and, at the same time, shrink the locoregional macroscopic disease, which may then be adequately treated by surgery. Thus, a successful induction program should include optimal cyto-reduction of metastatic and local disease at the same time, for an early eradication of micro-metastases and an ‘easier’ resection of the primary tumor. These advantages must be weighed against concerns regarding increased morbidity and mortality of a combined modality approach and, in case of an ineffective induction regimen, progression of local disease in patients whose tumor could have been resected initially.

There have been several phase II feasibility trials of induction chemotherapy followed by surgical resection [5–8]. The first studies were small, frequently lacked surgical staging, and accrued a wide variation of stage subsets. Although most of the more recent trials of preoperative chemotherapy required pathologic documentation of N2 disease, the definition of stage III disease still allowed the inclusion of patients with vastly different disease characteristics. Moreover, different chemotherapeutic regimens were used and some of the trials had both combination chemotherapy and radiation as induction regimens. Despite the significant variability of these studies, however, a number of general conclusions can be made. The response rates resulting from chemotherapy in patients with good performance scores and stage III and early-stage disease are significantly higher than those seen in patients with stage IV disease; complete pathologic responses occurred in 5–15% of patients and median survival ranged from 9 to 30 months, with an average median of approximately 17 months. Furthermore, it became apparent that downstaging of mediastinal lymph nodes and complete surgical resection are reliable predictors of long-term survival [9]. On the other hand, it was also noted that survival of patients with persistent N2 disease or incompletely resected tumors remains disappointing.

4. Randomized trials of induction chemotherapy A small number of phase III trials comparing induction chemotherapy to surgery alone has been reported. A summary of the results of five trials randomizing patients to induction chemotherapy followed by surgery9 radiation or surgery9radiation is given in Table 2. Four of these studies, albeit small and using different induction regimens, showed similar outcomes with superior survival rates in the treatment arm that included chemotherapy [10–12,14]. In two of these studies, the survival differences were so impressive that the decision was made to stop them prematurely [10,11]. In one small study from the CALGB [13], there was no advantage observed with induction therapy. Updated survival data from the Rosell and MD Anderson studies have become available (Table 2). In both studies, the survival in the preresectional study arm stabilized at longer follow-up. The 3- and 5-year survival rates for perioperative chemotherapy in the MD Anderson study were 43 and 36%, respectively [15]. In the Rosell study, the overall median survival in the combined study arm was 20 versus 10 months for patients who received surgery alone [16]. So it appears that induction therapy of short duration is able to alter the natural development of NSCLC, that has spread to the mediastinum.

N. 6an Zandwijk / Lung Cancer 34 (2001) S145 – S150

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Table 2 Randomized trials of induction chemotherapy and surgerya Author

Treatment

No. of patients

Pass [10]

EP+Surg Surg+RT MIC+Surg (RT) Surg (RT) CEP+Surg Surg EP+Surg−RT Surg−RT MIC+Surg+MIC Surg

13 14 30 30 28 32 23 24 187 186

Rossell [11] Roth [12] Elias [13] Depierre [14]b

No. resected

23 27 17 21

169 174

Median survival (months)

Long-Term survival (%)

28.7 15.6 26 8 21 14 19 23 36 26

42 (3-year) 18 30 (3-year) 0 36 (5-year) 15 NR NR 49 (3-year) 41 (3-year)

a

For NSCLC patients using etoposide and cisplatin (EP); mitomycin C ifosfamide and cisplatin (MIC); or cyclophosphamide, etoposide, and cisplatin (CEP). Surg, Surgery; RT, radiotherapy; NR, not reported. b Preliminary data.

A large French study that randomized patients with resectable (IB–IIIA) NSCLC to two cycles of MIP (mitomycin, ifosfamide, cisplatin) induction chemotherapy (and two more cycles after surgery) or surgery alone has recently published preliminary results [14]. Interestingly, a favorable effect of the combined modality approach was noted among patients presenting with the earliest stages of disease. In the same study, there was a suggestion of increased morbidity in the combined study arm. The specific composition of the induction regimen (mitomycin) might have been responsible for this observation. In general, induction therapy does not seem to significantly increase the morbidity of chest surgery.

5. New induction regimens Newer chemotherapeutic agents, such as gemcitabine and the taxoids, have shown activity in patients with advanced NSCLC. Because platinum is still being regarded as the backbone of chemotherapy for NSCLC, new platinum-based combinations were the first to be tested as induction regimens [17]. Three platinum-based chemotherapy combinations recently have been tested. The European Organisation for the Research and Treatment of Cancer (EORTC) Lung Cancer Group was the first to study gemcitabine/cisplatin (GC) as an induction regimen. Early suggestions of increased efficacy of this combination in patients with advanced disease [18] prompted the EORTC to initiate a phase II trial in patients with stage IIIA, biopsy-proven, N2 disease [19]. Fortyseven patients, all except one with (gross) clinical N2 disease, were registered to receive three cycles of the GC combination. This chemotherapy regimen was tolerated rather well and produced a high response rate [19]. Independent evaluation of CT scans of all re-

sponding patients, excluding those patients who received less than the three prescribed GC courses (intent-to-treat analysis), revealed a 70.2% objective response rate. Ninety-four percent of the patients who underwent surgery were deemed resectable, of whom 71% had complete resection. Mediastinal nodes were rendered free of tumor in 53% of cases (Table 3). Overall median survival was 18.9 months and 1-year survival was 69% (95% CI, 56–82%). The Lung Cancer Project Group of the Swiss Group for Clinical Cancer Research (SAKK) has performed a similar trial designed to analyze the docetaxel/cisplatin (DC) combination as an induction regimen in patients with stage IIIA disease. To date, preliminary results (no intent-to-treat analysis) show a radiographic response in 66% of the patients, with negative first mediastinal lymph node upon surgery occurring in 60% [20]. In a multicenter United States phase II study, 94 patients with T2N0, T1–2N1, and T3N0–1 earlystage NSCLC and negative mediastinoscopy received two cycles of induction paclitaxel/carboplatin followed by surgery and then three additional cycles of the same chemotherapy combination [21]. After induction therapy, 53 (56%) of 94 patients had an objective response, 88 (94%) underwent surgical exploration, and 81 (86%) underwent complete resection. All three studies with the newer combinations reported few postoperative complications. A comparison of the old (three-drug) regimens, such as MVP (mitomycin, vinblastine, and cisplatin) and MIC (mitomycin, ifosfamide, and cisplatin), and the new doublets suggests that the new doublets have a milder toxicity profile. Another important finding in the EORTC and SAKK studies was the low percentage of patients who progressed during induction therapy, which encourages the use of these combinations in patients with early-stage disease.

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Regimen

No. of patients

Stage

No. of courses

PR/CR rate (%)

PD (%)

Complete resection (%)

Mediastinum downstaging (%)

Median survival months

Gemcitabine/cisplatin EORTC [19] Carboplatin/taxol BLOT [21]

47 94

6 3

71 86

53 Not applicable

18.9 Not yet reached

34

3 2 (+three cycles after surgery) 3

64/6 50/6

Docetaxel/cisplatinb SAKK [20]

IIIA IB–II+( few) IIIA IIIA

53/12

6

70

60

NR

a

NR, not reported; PR, partial response; CR, complete response; EORTC, European Organisation for the Research and Treatment of Cancer; BLOT, Bimodality Lung Oncology Team; SAKK, Swiss Group for Clinical Cancer Research. b Interim results: no intent-to-treat response data.

N. 6an Zandwijk / Lung Cancer 34 (2001) S145 – S150

Table 3 Induction therapy studies with newer chemotherapy combinationsa

N. 6an Zandwijk / Lung Cancer 34 (2001) S145–S150

6. Ongoing studies in resectable NSCLC Surgery unquestionably plays an important role in the multimodality approach to stage III disease. It is still important to clarify, however, whether surgery is preferred over radiotherapy after induction therapy, especially in patients who cannot be completely resected. Since December 1994, the EORTC Lung Cancer Cooperative Group has been randomizing patients with stage IIIA disease who respond to platinum-based chemotherapy to receive surgery or radiotherapy (EORTC 08941) [22]. The High Priority North American Intergroup Trial (0139) attempts to address this issue slight differently by comparing concurrent etoposide/cisplatin and radiotherapy followed by randomization to surgery or continuation of radiotherapy. Several comparative studies, frequently employing new drug combinations, are ongoing in patients with resectable early-stage disease. In the UK and the EORTC, the LU22 study comparing induction versus no induction therapy has been started. In Italy, a similar (ChEST) study comparing gemcitabine/cisplatin vs no induction therapy in T2– 3N0, T1 – 2N1, and T3N1 is underway, while, in France, gemcitabine/cisplatin is being compared with paclitaxel/carboplatin as a perioperative chemotherapy regimen. Another approach that can be taken parallel to the induction therapy studies is the assessment of predictive molecular markers of chemotherapy resistance. The Spanish Lung Cancer Group will soon start a prospective study of predictive molecular markers in patients with resectable disease. Ideally, it will become possible to customize chemotherapy according to individual tumor profiles. Finally, the time has come to add so-called targeted agents to existing chemotherapy doublets. Many candidates are available, including the epidermal growth factor inhibitors and vascular endothelial growth factors (VEGF) antibodies, that already have shown some promising results [23,24]. The EORTC Lung Cancer Group will soon start a study of the combination of gemcitabine/cisplatin with the tyrosine kinase inhibitor ZD 1839 in patients with stage IIIA N2 disease.

7. Conclusion Apart from a minority of patients with very earlystage disease, most NSCLC patients who are candidates for surgical treatment suffer from systemic disease. Randomized studies in patients with stage III disease have revealed a survival advantage for patients receiving preoperative chemotherapy, and induction therapy has become an accepted approach for this group of patients.

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