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Eur J Cardiothorac Surg 2006;30:184-189
© 2006 Elsevier Science NL

Results of pulmonary resection following neoadjuvant therapy for locally advanced (IIIA–IIIB) lung cancer

Shin-ichi Takeda * , Hajime Maeda, Tatsuya Okada, Toshihiko Yamaguchi, Masaru Nakagawa, Soichiro Yokota, Noriyoshi Sawabata 1 , Mitsunori Ohta 2

Department of General Thoracic Surgery and Pulmonary Medicine, Toneyama National Hospital, Toneyama 5-1-1, Toyonaka City, Osaka 560-8552, Japan

Received 3 March 2006; accepted 29 March 2006.

* Corresponding author. Tel.: +81 6 6853 2001; fax: +81 6 6850 1750. (Email: stakeda{at}toneyama.hosp.go.jp).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussions
 References
 
Objective: We performed this study to determine the role and prognostic factors of neoadjuvant therapy followed by surgery for locally advanced non-small cell cancer. Methods: One hundred patients with clinical stage III non-small cell lung cancer (79 IIIA, 21 IIIB; 78 males, 22 females; average age 60.5 years) received neoadjuvant therapy, of whom 84 received two cycles of platinum chemotherapy combined with an average radiation dose of 41.5 Gy, and 16 patients underwent chemotherapy alone. The mean follow-up duration was 80.9 months. Survival rate was estimated by the Kaplan–Meier method, and a Cox proportional hazards model was applied to determine the prognostic factors. Results: The operative procedures included 74 lobectomies, 7 bi-lobectomies, and 19 pneumonectomies. Two patients died within 30 days due to adult respiratory distress syndrome and acute pulmonary embolism, respectively. The overall 5-year survival rate was 39.7% with a median survival time (MST) of 39.6 months. The 5-year survival rate for downstaged (pN1,2) patients was 53.5% while it was 16.3% for patients with residual N2. There was no difference in survival between lobectomy and pneumonectomy (MST 38 months vs 42 months). Univariate and multivariate analyses revealed that nodal status and tumor size after neoadjuvant therapy were independent prognostic factors. Conclusions: Neoadjuvant therapy was shown to deliver the optimal effect for surgery for cIIIA/IIIB NSCLC with acceptable mortality. Re-staging to exclude the residual multiple nodal metastasis can lead to the proper patient selection. A pneumonectomy, as a last option, following neoadjuvant therapy did not affect the mortality.

Key Words: Locally advanced lung cancer • Neoadjuvant therapy • Pneumonectomy • Downstaging • Survival


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussions
 References
 
Locally advanced stage III non-small cell lung cancer (NSCLC) cases is a therapeutic challenge with variable options. To establish a rationale, many attempts were done in recent years, and promising multidisciplinary setting and regimen await investigation. Recently, preoperative chemoradiotherapy and chemotherapy (neoadjuvant therapy) have contributed to increase the resectability for locally advanced stage III NSCLC, and two small randomized trials [1,2] confirmed the superiority of neoadjuvant therapy followed by surgery as compared to surgery alone. The drawbacks of neoadjuvant therapy are high rates of operative morbidity and mortality [3–5], which we have also experienced at our institution [6]. In addition to the adverse effects in the immediate postoperative period [3–6], additional large number of other randomized studies [7–11] have not established clear evidence of the superiority of neoadjuvant therapy.

On the other hand, the prognosis of patients with clinical N2 [12] and mediastinoscopically proven N2 [13] is not satisfactory with a 5-year survival of 9–16%. Therefore, multimodality therapy is required to treat micrometastasis that cannot be detected clinically, and to downstage the unresectable disease. Following the initial promising results of induction therapy for stage III lung cancer [1,2,7,8], further efforts are necessary to determine which patients can benefit from surgery in terms of nodal status [14,15]. In addition, the indications of a pneumonectomy following neoadjuvant therapy have not been fully established because of their high mortality and unclear survival benefits [4,16].

In the present study, we therefore retrospectively reviewed our surgical results following neoadjuvant therapy to determine prognostic factors and the significance of residual N2, as well as indications of pneumonectomy.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussions
 References
 
Over a period of 12 years until December 2003, pulmonary resections were performed at our hospital for 100 consecutive patients with clinical stage III NSCLC (78 males, 22 females; average age 60.5 years), each of whom received neoadjuvant therapy followed by surgery. The histological subtypes included 55 adenocarcinomas, 37 squamous cell carcinomas, and 8 large cell carcinomas. Clinical staging by the TNM classification [17] was performed as follows; evaluation of M1 disease that included results from abdominal computed tomogram (CT), bone scan, brain CT, or magnetic resonance imaging (MRI) examinations as well as laboratory tests. There were 79 patients with c-IIIA (75 with N2, 4 with T3N1), and 21 patients with c-IIIB [15 with T4 (invasion into the mediastinum or great vessels), 6 with N3] (Table 1 ). Among the 93 patients with c-N2/c-N3, 60 were proven cyto-histologically by mediastinoscopy, transbronchial needle aspiration (TBNA) or later surgery results, while positive N2/N3 nodes were determined on the basis of CT scan finding (a cross-sectional diameter of 1.5 cm or greater) in 33 patients. For the present study, patients with T4 lesions due to the malignant effusion or separate pulmonary nodules in the same lobe were excluded from analysis.


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  		Table 1. Characteristics of population
 
Eighty-four patients received chemoradiotherapy, and 16 underwent chemotherapy alone. Preoperative chemoradiotherapy consisted of more than two cycles of cisplatin/vindesine/mitomycin C (MVP) for 40 patients, cisplatin/vindesine (PV) for 30 patients, and cisplatin/vinorelbine for 11 patients and 3 others, with conventional radiation therapy applied with an average radiation dose of 41.5 Gy. Preoperative chemotherapy consisted of two cycles of carboplatin/docetaxel for 10 patients, cisplatin/docetaxel for 4, and carboplatin/paclitaxel for 2. The operative procedures included 74 lobectomies, 7 bi-lobectomies (including 14 sleeve resection and 2 complex carinoplasty procedures), and 19 pneumonectomies, including 3 sleeve pneumonectomies, which included 94 R0 and 6 R1 resections (Table 1). Informed consent of induction chemotherapy and chemoradiotherapy as well as operative risks were obtained from all patients. The protocols of induction therapy were approved by IRB at our hospital.

Hospital mortality included 30-day mortality and operation-related deaths during the same hospitalization. Cancer recurrence was carefully divided into two categories according to the site of initial relapse, i.e., locoregional recurrence was defined as any site within the ipsilateral hemithorax, and all other sites of recurrence were considered to be distant metastases. Mean follow-up duration until December 2005 was 80.9 months (23–154 months).

Data are reported as mean ± standard deviation or as a proportion. Survival rates were estimated by the Kaplan–Meier method, and a log-rank test was used to compare survival rates between two groups. A Cox proportional hazards model was fitted to examine and adjust for the effects of surgical treatment and other covariates on survival Variables significantly related to the morbidity (p < 0.05) in univariate analyses were analyzed by multivariate analysis. Significance was accepted as a p value of less than 0.05 (StatView 5.0 Abacus Concepts; Berkeley, CA, USA).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussions
 References
 
The present 100 patients who underwent subsequent surgery were treated using different regimens, thus this is not a randomized protocol study. Those patients who failed to undergo surgery following neoadjuvant therapy due to apparently progressive and unresectable diseases were excluded from analysis.

Of the 100 patients who underwent surgery for clinical stage III, a clinical response was observed in 64% [complete response (CR) 9, partial response (PR) 55], while 30 had stable disease (SD), and 6 progressive disease (PD). Recent patients were pathologically restaged by mediastinoscopy, TBNA, or VATS in addition to the radiologic findings. None underwent an exploratory thoracotomy. Ninety-four patients underwent R0 resection (no microscopic residual tumor), and six were treated with an R1 resection (no gross residual tumors). The resections were performed based on radiographic findings from initial radiographic imaging, thus primarily scar tissues remaining after neoadjuvant therapy were also completely removed.

Two patients who received neoadjuvant chemoradiotherapy died within 30 days after surgery (30-day mortality 2%), 1 due to an acute pulmonary embolism 2 days after a right middle and lower lobectomy, and 1 due to an acute respiratory distress syndrome (ARDS) 6 days after a right pneumonectomy for residual N3 disease. In addition, two other patients died of respiratory failure (ARDS and pneumonia, respectively) within 90 days. Further, one patient developed empyema as a sequelae of radiation pneumonitis 11 months after surgery, and eventually died of abrupt bleeding due to a rupture of the pulmonary artery.

Fifty-one of the patients died of cancer including 46 from distant metastasis (33 of whom were initially discovered with brain metastasis), while 8 patients showed local recurrence initially. Six patients were died of causes unrelated to cancer, including one due to cardiorespiratory failure 71 months after pneumonectomy. At the time of writing, 34 patients were alive without relapse with a mean follow-up duration of 59.4 months (23–154 months). The overall 3-year and 5-year survival rates for all 100 patients were 50.1% and 39.7%, respectively, with a median survival time (MST) of 39.6 months (Fig. 1 ). Univariate analysis (Table 2 ) revealed that age, gender, histology, location, clinical stage, radiation, clinical response rate, presence of complication, type of chemotherapy regimen, and pneumonectomy did not have a significant effect on prognosis. In contrast, tumor size following neoadjuvant therapy and p-N status were found to be significant prognostic factors by univariate analysis, and the p-N status (p = 0.0004) was shown to be a strong independent prognostic factor followed by tumor size after neoadjuvant therapy (p = 0.0117) using multivariate analysis.


Figure 1
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  		Fig. 1. Overall survival rates for 100 patients with c-IIIA (n = 79)/c-IIIB (n = 21) who underwent neoadjuvant therapy. Three-year and five-year survivals were 50.1% and 39.7%, respectively, with a median survival time of 39.6 months.

 

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  		Table 2. Hazard ratios for covariates of survival after resection for stage III NSCLC after neoadjuvant therapy
 
The 5-year survival rate of patients with tumors sized ≤3 cm after neoadjuvant therapy (n = 41) rates was 55.1% with an MST of 71 months, while it was 29.1% for patients with tumors sized >3 cm (n = 59) with an MST of 33 months (p = 0.0076) (Fig. 2 ). The 5-year survival rate of the 64 patients with p-N0 or p-N1 (including 57 mediastinal down-staged c-N2/c-N3 patients) was 53.5% with an MST 67 months, while that of 33 patients with residual N2 was 16.3% with an MST of 23 months (Fig. 3 ). After subdividing the residual N2 patients, single residual p-N2 patients (n = 17) exhibited a 5-year survival of 34.8% (MST 46 months), whereas there were no 5-year survivors with multiple p-N2 (n = 16, MST 11 months) (Fig. 4 ) or p-N3 (n = 3, MST 6 months) patients (Fig. 3). Our analysis also showed that a pneumonectomy (16 patients with c-N2, and 3 patients with T4 N0,1) did not cause any disadvantage in regards to survival as compared a lobectomy or sleeve resection following neoadjuvant therapy (Fig. 5 ).


Figure 2
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  		Fig. 2. Five-year survival rate of patients with tumor size ≤3 cm after neoadjuvant therapy (n = 40) rates was 55.1% with a MST of 71 months, and it was 29.1% of patients with tumor size >3 cm with a MST of 33 months (p < 0.0076).

 

Figure 3
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  		Fig. 3. Five-year survival rate of down-staged p-N0, PN1 (n = 64) rates was 53.5% (MST, 67 months), and it was 16.3% (MST, 23 months) of persistent p-N2 (n = 33) patients (p < 0.0001), and 0% (MST, 6 months) of p-N3 (n = 3) patients.

 

Figure 4
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  		Fig. 4. Five-year survival rate of persistent N2 patients, five-year survival rate of single p-N2 (n = 17) was 34.8% with a MST of 46 months; however, no 5-year survivors of multiple p-N2 with a MST of 11 months (n = 16) (p = 0.0007).

 

Figure 5
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  		Fig. 5. Overall survival rates for 81 patients who underwent lobectomy or bi-lobectomies (L group) and 19 pneumonectomy patients (PN group) who received induction therapy for stage III disease. No significant difference was found between the groups.

 

   4. Discussions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussions
References
 
Because of poor 5-year survival rate in patients with complete resection for stage III disease [12,13], neoadjuvant therapy has been partly effective for locally advanced NSCLC in terms of rendering them the tumors to be resectable, and improving the survival of patients with resectable N2 disease [7,8,18]. However, in other reports [9,10,14,16], neoadjuvant therapy with or without radiation did not result in such survival benefits for stage III disease, and it also has been noted that a poor outcome can be expected in those patients requiring pneumonectomy [16]. In addition, meta-analysis based on the published trials has not confirmed the benefits for stage IIIA N2 disease [19,20] except for stage IB, II [9,19] or for T4 N0,1 stage IIIB [20].

Stage III disease was complex and was composed of heterogenous components ranging bulky to surgery proven N2 initially assessed as cN0,1 [21], and encompassed T3N1 or T4. In our institution, 5-year survival following a complete resection for p-N2 (surgery proven) stage IIIA NSCLC is 28.1% [22]. As for our initial patients with bulky (≥2 cm) cN2/cN3 who were treated with chemoradiotherapy followed by surgery, no survivors were found among those with residual p-N2, whereas patients with mediastinal downstaged patients seemed to obtain a survival benefit [23]. In an earlier report by Martini et al. [18], the overall survival of 136 clinical stage IIIA (bulky N2) patients who received curative resection was 17% at 5 years, while the 5-year survival rate for 19 patients who showed complete pathologic response was 56%.

The critiques exist regarding the staging, namely, clinically staged N2 was based on the finding of CT image that a disappearance of mediastinal lymph node enlargement was regarded as downstaged in 33 patients. However, we have recently been performing systematic pathological staging and restaging with transbronchial needle aspiration cytology (TBNA) and/or mediastinoscopy. Taking into account for the potential limitations, we retrospectively reviewed our surgical results to determine the prognostic factors for and the efficacy of the neoadjuvant therapy as a multimodality treatment for stage IIIA/IIIB disease that can be treated surgically.

Our overall 5-year survival rate after resection was 39.7% with an MST of 39.6 months, which was acceptable and encouraging, as compared to our previous historical study for p-N2 IIIA disease that found a 5-year survival rate of 28.1% [22]. Different from our initial report [23], the present study found a 5-year survival rate of 34.8% in patients with single residual N2, which indicated that residual N2 was not necessarily contraindicated unless the patients was determined to be multiple N2 or N3 by re-staging. Univariate and multivariate analyses revealed that nodal downstaging and shrinkage of the main tumor were independent prognostic factors, regardless of the initial clinical stage, which is informative, and implies a pathological response. Therefore, accurate re-staging with regard to the nodal status as well as tumor size should lead to the appropriate patient selection. Recent institutional reports [24,25] with regard to the impact of nodal and pathological downstaging on survival are consistent with our contentions. As for the relapse pattern, a local recurrence rate of 8% is acceptable, however, 34% of our patients had brain metastasis as a first relapse site, which must be solved [20].

Our institutional results showed an overall 30-day mortality for pulmonary resection of 0.5% [6], and 2% (2/100) in patients undergoing pulmonary resection including 19 pneumonectomies and 16 tracheo-bronchoplasties after neoadjuvant therapy, which are acceptable. Different from the previous reports, we did not see any drawbacks of with the pneumonectomy procedures, which have been reported to be associated with a high mortality and poor outcome [4,16]. As we reported previously [6], chemotherapy and chemoradiotherapy had impact on diffusing capacity and its relationship to respiratory complications following lung resections. In that sense, the predictive postoperative DLco value was more important than lung volumes such as VC and %FEV1. The risks of surgery were carefully assessed and individualized for surgical candidates following neoadjuvant therapy. In addition, our 19 pneumonectomy patients were composed of 16 with N2 disease and 3 with T4 without N2, the survival was not different compared to those who received a lobectomy with the matched clinical stage (Fig. 5). This favorable result was different from the negative outcomes for pneumonectomy following neoadjuvant therapy reported in the previous studies [4,16].

In summary, neoadjuvant therapy potentially delivers an optimal effect for surgical resection of cIIIA/IIIB NSCLC with an acceptable mortality. Re-staging for exclusion of patients with residual multiple nodal metastases can provide the proper selection of those who will benefit survival following surgery. Further, a pneumonectomy as a last surgical option aimed at curative resection following neoadjuvant therapy showed acceptable level of mortality and survival for selected patients with locally advanced NSCLC.


   Acknowledgments
 
The authors wish to thank Dr Osamu Kuwahara, Dr Masayoshi Inoue, Dr Masaru Koma, Dr Keiji Inada, Dr Yasunobu Funakoshi, Dr Shigeru Nakane, Dr Yoshihisa Kadota, and Dr Masanobu Hayakawa, former and present attending surgeons, for their contributions to this project, and Miss Yukari Hirai and Miss Machico Ioue for their secretarial assistance.


   Footnotes
 
1 Present address: Department of General Thoracic Surgery, Osaka University, Graduate School of Medicine, Yamadaoka 2-2 Suita, Osaka 565-0847, Japan. Back

2 Present address: National Hospital Organization, Department of General Thoracic Surgery, Kinkichuo Chest Medical Center, Nagasonecho 1180, Sakai, Osaka 591-8555, Japan. Back


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussions
 References
 

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