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Ann Thorac Surg 2009;87:1676-1683. doi:10.1016/j.athoracsur.2009.03.068
© 2009 The Society of Thoracic Surgeons
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Right arrow Lung - cancer

Original Articles: General Thoracic

Trimodal Therapy for Histologically Proven N2/3 Non–Small Cell Lung Cancer: Mid-Term Results and Indicators for Survival

Volker Steger, MDa,*, Thorsten Walles, MDa, Bora Kosan, MDa, Tobias Walker, MDb, Thomas Kyriss, MDa, Stefanie Veit, MDa, Jürgen Dippon, PhDc, Godehard Friedel, MDa

a Department of Thoracic Surgery, Schillerhöhe Hospital, Gerlingen, Germany
b Department of Thoracic, Cardiac and Vascular Surgery, Tübingen University, Tübingen, Germany
c Department of Mathematics, Stuttgart University, Stuttgart, Germany

Accepted for publication March 25, 2009.

* Address correspondence to Dr Steger, Department of Thoracic Surgery, Schillerhöhe Hospital, Solitudestr 18, Gerlingen, 70839, Germany (Email: vrsteger{at}gmx.de).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 References
 
Background: Surgery alone for stage III non–small cell lung cancer provides a 5-year survival of 20% and competes with multimodal treatments. In 1999, a trimodal protocol was implemented at the Schillerhöhe Clinic. The aim of this study was to verify the feasibility and outcome of this trimodal protocol including survival, risk factors for survival, and comorbidity in a single institution.

Methods: Included were all patients with potentially resectable, previously untreated stage III non–small cell lung cancer operated on between February 1999 and May 2006 in the General Thoracic Surgery Unit of the Schillerhöhe Clinic following the same neoadjuvant protocol. Treatment-related morbidity, recurrence, survival after R0 resection, and risk factors for survival (pN0 after trimodal therapy, downstaging of International Union Against Cancer stage, T downstaging, N downstaging, regression rate, and histologic type of tumor) were analyzed.

Results: From 107 patients with stage III non–small cell lung cancer, 55 patients with mediastinoscopy-positive N2 or N3 were eligible for this study. Forty patients (72%) had the effect of International Union Against Cancer downstaging. Treatment-related comorbidity was 54% with hospital and 120-day mortality of 3.6% and 5.4%, respectively. Overall mean survival (Kaplan-Meier) was 43 months (95% confidence interval, 35 to 52) with an estimated 5-year survival rate of 49%. In multivariate testing, International Union Against Cancer downstaging after trimodal therapy achieved a level of significance (p = 0.031), and patients with UICC-downstaging after trimodal therapy had a mean survival of 53 months (95% confidence interval, 44 to 63) with an estimated 5-year survival rate of 60%.

Conclusions: Neoadjuvant trimodal treatment for histologically proven N2 or N3 stage III non–small cell lung cancer is promising and can, like no other approach at present time, considerably improve 5-year survival rates up to 63% in selected patients.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 References
 
For stage III non–small cell lung cancer (NSCLC), no satisfactory treatment has yet been established. Single-modality treatment with surgery alone in locally advanced NSCLC stage III results in disappointing 5-year survival rate of up to 20% [1]. Other single-modality therapy protocols result in more disappointing 3-year survival of 5% to 15% [2, 3]. Recently, multimodality approaches combining radiotherapy, chemotherapy, and surgery have been introduced in the neoadjuvant setting. Unfortunately, the results of currently available randomized prospective studies addressing these issues are not consistent. However, there is evidence that neoadjuvant approaches may offer superior results in selected patients with locally advanced NSCLC [4–11], although the "ideal" treatment regimen is still subject of ongoing trials and controversies. For example, there are concerns that neoadjuvant radiochemotherapy may raise the patient's morbidity and mortality without increasing long-term survival [12–14]. So far, the comparability of published neoadjuvant studies is hampered by either varying protocols [15, 16], incomplete invasive mediastinal staging [4, 17], possible mediastinal affection [18], or analysis of a heterogeneous group of patients with different, hardly comparable TNM subsets [19]. Independently, numerous studies have shown an unfavorable outcome in mediastinal affected stage III NSCLC versus nonaffected stage III disease. In 1999 we started to treat patients with advanced stages of NSCLC with an aggressive neoadjuvant trimodality protocol. Here we report risk factors for survival after neoadjuvant chemotherapy and radiation therapy followed by surgery in patients with mediastinoscopy-positive pN2 or pN3 NSCLC based on our single-center experience.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 References
 
Study Design
The study design was a retrospective single-center cohort analysis. The study was approved by the ethics committee of the University of Tübingen.

Study Population
Included in this study were all patients with potentially resectable, previously untreated stage III NSCLC operated on between February 1999 and May 2006 in the General Thoracic Surgery Unit of the Schillerhöhe Clinic following the same neoadjuvant protocol. Treatment decisions were made on the basis of a recommendation by the institutional multidisciplinary tumor board. Inclusion criteria were (1) pathologically confirmed stage III NSCLC, (2) World Health Organization performance scale of 0 to 1, and (3) potentially resectable disease after chemoradiotherapy. No discrimination was made among single, multilevel, or bulky mediastinal effect. Patients with contralateral hilar mediastinal N3 or both contralateral bulky N3 and bulky N2 were excluded.

Staging
Oncologic staging included (1) chest computed tomography (CT) scan to determine primary tumor localization and extension, (2) cranial CT or magnetic resonance imaging, (3) 99m-technetium bone scan, and (4) abdominal CT or ultrasound to rule out distant metastasis as well as bronchoscopy to obtain cytologic or histologic specimen and to rule out endobronchial disease. All patients underwent standard cervical mediastinoscopy to confirm or rule out mediastinal nodal disease. Functional staging included (1) spirometry, (2) whole body plethysmography, and (3) electrocardiography. Since 2003 additional pulmonary diffusion capacity (DLCO) measurements were performed. The entire set of staging procedures except mediastinoscopy was repeated after chemoradiotherapy and before surgery. Patients were eligible for surgery if forced expiratory volume after 1 second (FEV1) was greater than 70% and DLCO greater than 60%. A perfusion scan of the lung was done to estimate postoperative FEV1 and DLCO if FEV1 was less than 70% or DLCO was less than 60%. Operation was declined if postoperative FEV1 or postoperative DLCO was less than 40%. Since 2005, spiroergometry was routinely applied to determine peak oxygen consumption, with peak oxygen consumption less than 10 mL · kg–1 · min–1 resulting in declining the operation, and a peak oxygen consumption ranging between 10 and 20 mL · kg–1 · min–1 limiting patient acceptance to those necessitating only lobectomies.

Neoadjuvant Protocol
The trimodality protocol consisted of four courses of polychemotherapy applying carboplatin to the area under the curve times two and paclitaxel (100 mg/m2) once weekly. Subsequently, accelerated hyperfractionated radiotherapy with two treatments per day (each 1.5 Gy) on a daily basis (five times per week) and a cumulative dose of 45 Gy (representing 50 to 90 Gy standard fractionations) was started on week 6 targeting tumor, mediastinum, and the supraclavicular region with a margin of 1.5 cm. Finally, two additional concurrent cycles of chemotherapy (carboplatin [area under the curve times two] and paclitaxel [50 mg/m2]) were administered (Fig 1). Prophylactic cerebral radiation (30 Gy cumulative dose) was offered to 30 patients. Operations were then carried out if R0 resection was deemed technically feasible.


Figure 1
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  		Fig 1. Neoadjuvant protocol. (AUC = area under the curve.)

 
Operative Strategy
The primary objective was to realize an R0 resection in all patients. Operations were performed through a posterolateral thoracotomy. Bronchial and vascular reconstructions were performed to decrease the amount of resected lung tissue when feasible. Systematic lymphadenectomy included positions 5, 6, 7, 8, and 9 on the left and positions 2, 4, 7, 8, and 9 on the right side. All patients were extubated immediately after surgery and monitored routinely for 4 days in the intermediate care unit. To avoid pulmonary complications, a thorough physiotherapeutic workup was applied. After pneumonectomy or bronchoplasty, bronchoscopy for stump healing was performed during the first and second postoperative week.

Outcome Measures
For each patient, treatment-related comorbidities, relapse, survival, and risk factors for survival after resection were analyzed. The disease-free interval was defined as the time from R0 resection to histologically proven relapse or unambiguous radiologic findings with consecutive appropriate therapy. In case of no recurrence, the date of the last contact was used. The survival end point was the date of death defined as the time between the date of operation and the date of death. Follow-up was obtained from our own outpatient files, the attending family doctor's files, or the central death registry. Risk factors analyzed were (1) sterile mediastinal lymph nodes (ypN0), (2) formal T and N downstaging, (3) Junker regression score [20], (4) International Union Against Cancer (UICC) downstaging, (5) histologic type of primary tumor (adenocarcinoma, squamous cell carcinoma), and (6) pneumonectomy.

Statistical Analysis
All statistical calculations were performed with the SPSS software package for Windows (SPSS for Windows 13, SPSS Inc, Chicago, IL). The Kaplan-Meier method was used to analyze survival after operation. Risk factors for survival were first analyzed using univariate log-rank test. Factors with probability values less than or equal to 0.05 were considered to be significant. Multivariate testing using Cox regression was performed with factors reaching level of significance in univariate testing. Survival plots with 95% confidence intervals (CI) were created with R 2.7.0 Software (R Foundation for Statistical Computing, Vienna, Austria).


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 References
 
Patient Characteristics
During the study period, 107 patients with stage III NSCLC were identified. Of these, 52 patients had absent mediastinal lymph node involvement. Therefore, 55 patients with mediastinoscopy-positive pN2 or pN3 NSCLC were included into this analysis. Patient characteristics as well as T and N stage and UICC stage at admission are listed in Tables 1 and 2, Go respectively. The entire trimodal protocol was completed by 40 patients (72%). Of those, 2 patients received 60 Gy radiotherapy with traditional dose and fractionation (5 x 2 Gy/week) by an external institution. The remaining 15 patients completed at least the initial four cycles of chemotherapy and the full radiotherapeutic treatment. The mean time between first diagnose of NSCLC and completion of chemoradiotherapy was 137 days. All operations were performed within a mean of 40 days (range, 17 to 230 days) after radiotherapy.


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  		Table 1 Patient Characteristics
 

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  		Table 2 International Union Against Cancer Stage, N Stage, and T Stage at Admission
 
Operative Procedures
To obtain an R0 resection, 26 lobectomies (47%), 3 bilobectomies (5%), and 26 pneumonectomies (47%) were performed (Table 1). Extended resections were performed in 42 patients (76%), including 12 sleeve resections, 10 tangential esophagectomies, 2 chest wall resections, 6 atrial resections, and 24 intrapericardial resections. Histologic classification revealed 27 patients (49%) with squamous cell carcinoma, 22 patients (40%) with adenocarcinoma, 2 patients (3.6%) with giant cell carcinoma, and 4 patients (7.2%) with mixed type NSCLC.

Pathologic Response
A formal T downstaging was achieved in 44 patients (80%), whereas 7 patients (13%) maintained T stage and 4 patients (7%) had formal upstage. The latter 4 patients were initially graded T2 and finally classified as pathologic T3 after trimodal therapy (ypT3; n = 2) and pathologic T4 after trimodal therapy (ypT4; n = 2), respectively. All upstaged ypT4 cases were satellite tumors within the same lobe. Formal N downstaging was present in 38 patients (69%), whereas 17 patients (31%) remained in their initial N stage. N upstaging was not observed. A sterile mediastinum (pathologic N0 after trimodal therapy; ypN0) was present in 28 (51%) patients. UICC downstaging was achieved in 40 patients (72%), whereas 10 patients (18%) maintained UICC stage and 5 patients (9%) were upstaged. Two were upgraded from IIIa to IIIb and 3 were finally classified as stage IV with separate ipsilateral tumor in another lobe. In our cohort 19 patients (35%) were staged pathologic UICC stage 0 after trimodal therapy (ypUICC) stage 0, indicating absence of viable tumor tissue after chemoradiotherapy (Table 3). Applying the Junker regression score [20], 1 patient was regression score I (1.8%) representing no regression at all by chemoradiotherapy, 17 patients (31%) were classified regression score IIa, 16 patients (29%) were score IIb, indicating less than 10% vital tumor tissue, and 19 patients (35%) were regression score III, indicating no vital tumor tissue detectable (Table 4).


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  		Table 3 Downstaging Effect
 

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  		Table 4 Junker Regression Score [20] After Trimodality Therapy
 
Recurrences
Tumor relapse was detected in 24 patients (44%). Most frequent site of relapse was distant and multiple (12 patients, 50%), followed by local or mediastinal (6 patients, 25%) and brain (6 patients, 25%). Overall, estimated mean and median time for relapse was 42 months (95% CI, 33 to 51) and 45 months (95% CI, not available), respectively.

Survival
Follow-up was complete for all 55 patients (100%). Perioperative morbidity was 54.5% which included rhythm disturbances, heart attack, stump insufficiency, pneumonia, adult respiratory distress syndrome, acute lung injury, pulmonary embolism, respiratory insufficiency, atelectasis, prolonged air leakage, and pleural empyema (Table 5). The mean follow-up time was 30 months. Overall hospital and 120-day mortality was 3.6% (2 of 55 patients) and 5.4% (3 of 55 patients), respectively. The Kaplan-Meier method with 28 censored cases (49%) showed an overall estimated mean and median survival of 43 months (95% CI, 35 to 52) and 48 months (95% CI, 9 to 87), respectively (Fig 2). Persistent N2/N3 after trimodal therapy (ypN2/N3) resulted in a mean survival of 27 months (95% CI, 16 to 38), 19 months (95% CI, 8 to 30) median survival, and a 5-year-survival-rate of 16%. In cases of nominal T downstaging, regression score at least IIb, N downstaging, UICC downstaging, and ypN0, mean survival improved to 47 months (95% CI, 37 to 56), 49 months (95% CI, 38 to 59), 51 months (95% CI, 41 to 61), 53 months (95% CI, 44 to 62), and 54 months (95% CI, 42 to 66), respectively (Figs 3, 4). Go With univariate log-rank test, risk factors for survival were UICC downstaging (p < 0.001), ypN0 (p = 0.014), and ypN downstaging (p = 0.004). In multivariate testing only UICC downstaging remained significant (p = 0.031; 95% CI, 0.075 to 0.883). In our analysis, formal T downstaging (p = 0.072) as well as regression scores of at least IIb (p = 0.072), histologic type of cancer (squamous cell carcinoma, p = 0.484; adenocarcinoma, p = 0.162), and pneumonectomy failed to be significant predictors (Table 6).


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  		Table 5 Postoperative Comorbidity
 

Figure 2
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  		Fig 2. Cumulative (Cum) Kaplan-Meier survival plot with 95% confidence intervals indicated by stippled area.

 

Figure 3
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  		Fig 3. Cumulative (Cum) Kaplan-Meier survival plot for pathologic node status after neoadjuvant radiochemotherapy (ypN0) with 95% confidence intervals indicated by stippled area.

 

Figure 4
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  		Fig 4. Cumulative (Cum) Kaplan-Meier survival plot for International Union Against Cancer downstaging after neoadjuvant radiochemotherapy (yUICC) with 95% confidence intervals indicated by stippled area.

 

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  		Table 6 Survival Rates in Months and Risk Factors for Survival
 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
References
 
As yet, no promising therapy for patients with UICC stage III NSCLC has been found. The tremendous research efforts of the past 4 decades and numerous clinical studies demonstrate that adjuvant radiotherapy after tumor resection yields improved local control, but does not improve long-term survival. Even worse, some evidence suggests that improved local control accounts for higher mortality in certain subsets of patients [21]. Moreover, adjuvant chemotherapy has been identified to result in only a 5% survival benefit for the patients [22]. To overcome these limitations and in analogy to positive experiences in different tumor entities, multimodal approaches were introduced in a neoadjuvant setting preceding surgery. For neoadjuvant chemotherapy, initial results in stage III NSCLC were conflicting: although Roth and coworkers [5] and Rosell and associates [4] and later on Betticher and colleagues [23] and Lorent and associates [24] reported improved survival, these findings were not confirmed by larger prospective randomized trials [7, 8]. Hence varying neoadjuvant protocols, applied agents, dosing, and inclusion criteria are jointly responsible for these inconclusive results. Combined neoadjuvant radiotherapy and chemotherapy showed on one hand a small survival benefit in prospective studies for pN2 or T4 stage III NSCLC [12], on the other an increase of treatment-related mortality after pneumonectomy, rising from 10% to 43% [13]. However, additional nonprospective and nonrandomized studies demonstrated less mortality in selected patients with stage III NSCLC and neoadjuvant chemoradiotherapy [25]. Currently, most trimodal therapy reports in stage III NSCLC share the lack of survival benefit corresponding to the achieved downstaging level.

In 1999, an aggressive trimodal therapy protocol was implemented at the Schillerhöhe Clinic. For our protocol, we applied carboplatin and paclitaxel [26, 27], being established agents in treatment of advanced NSCLC and the known radiosensitizing effect of paclitaxel. Weekly administration has demonstrated similar efficiency with slightly fewer side effects and foremost better tolerability than traditional applications [28, 29]. To maximize radiosensitization and numbers of completed radiochemotherapy before surgery, sequential application of chemoradiotherapy was chosen. Accelerated hyperfractionated radiotherapy with 1.5 Gy twice daily up to 45 Gy was selected to minimize time delay by neoadjuvant protocol and enhance toxicity, representing 50 to 90 Gy if converted to standard fractionation of 2 Gy once daily. To identify treatment efficiency and impact on patient survival, we analyzed the subgroup of patients with mediastinoscopy-positive pN2 or pN3 NSCLC operated on between 1999 and 2006.

The clinical applicability and patient tolerability of our aggressive multimodal regimen is illustrated by the high rate of completed neoadjuvant protocols (72%). Neoadjuvant chemoradiotherapy took an average of 137 days from first diagnosis. While intentionally the operation should have followed chemoradiotherapy within 30 days, it took on average 40 days until surgery because of radiotherapy-induced esophagitis. This delay may account for the detected upstaging of 3 patients from stage III to stage IV owing to ipsilateral tumor in another lobe.

Neoadjuvant chemoradiotherapy resulted in major pathologic response rates with less than 10% vital tumor tissue in almost two thirds (n = 35, 63%) of our patients, with 19 patients (35%) having no detectable tumor tissue at time of surgery. Moreover, 28 patients (51%) achieved a sterile mediastinum (ypN0). Therefore, the applied regimen is superior to most reported less-aggressive neoadjuvant protocols [9, 30–33]. However, because of the chance of viable tumor residues after chemoradiotherapy, surgery is still mandatory to improve long-term patient survival [34–36].

After neoadjuvant chemoradiotherapy, we could not prevent pneumonectomy in 47% of patients despite the high pathologic response rate of 72% UICC downstaging and 80% T downstaging. This high proportion is well founded by numerous T4 tumors (44%) and cicatrization after radiation therapy of the hilar structures. Therefore, our treatment-related perioperative comorbidity is 54% and mirrors the impact of neoadjuvant therapy and surgery on the patients' general condition. However, meticulous postoperative care including intensive physiotherapeutic support, nursing, and precocious bronchoscopy in case of postoperative secretion retention resulted in a perioperative mortality rate of 3.6% (3.8% after pneumonectomy and 3.5% after lobectomy/bilobectomy). As a consequence, postoperative hospital stay was long (21 ± 9.7 and 23 ± 22 days after pneumonectomy and lobectomy or bilobectomy, respectively).

In our study, the overall mean survival was 43 months (calculated from 50% censored events and 28 patients still alive). Based on these data, the estimated overall 5-year survival rate for stage III NSCLC is 46%, which at present time surpasses any single-modality treatment protocol for comparable stage III NSCLC. In the literature, overall 5-year survival rates after neoadjuvant chemotherapy have been reported to be 35% but with less local control [23, 24, 31, 37]. Patients with persistent mediastinal effects (ypN2 or ypN3) showed less favorable results with a mean survival of 27 months and an estimated 5-year survival of 16%. Formal UICC downstaging emerged as a major risk factor for survival, corroborating both a cleared mediastinum and a responding primary lesion as a pillar in neoadjuvant therapy. For the more than two thirds (38 of 55) of patients with at least formal N downstaging, a remarkable improvement in survival can be expected: according to our data patients who achieved formal N downstaging, sterile mediastinum (ypN0), or UICC downstaging after trimodal therapy showed a mean survival up to 53 months and a 5-year survival rate up to 63%, which is at the upper level of known survival rates after histologically confirmed N2 or N3 NSCLC.

We are not able to predict pathologic response rate after neoadjuvant chemoradiotherapy in the individual patient. However, we did show that we are able to achieve complete pathologic response (yUICC0) in 35% of patients, resulting in superior survival rates compared with those obtained using multimodal protocols without surgery [35, 38, 39]. Therefore, patients with histologically confirmed pN2- or pN3-positive UICC stage III NSCLC should be offered multimodal therapies including surgery. Because of the complexity involved in patient selection, logistics of the multimodal concept, surgical approach, and postoperative care, these multimodal treatments will only be realizable in specialized thoracic surgery units.

This study is limited by its retrospective design and statistical power, but we do demonstrate that for selected pN2 or pN3 NSCLC this trimodal protocol is safe, promising, and superior to most other neoadjuvant approaches with chemotherapy alone [9, 30, 31, 36] or multimodal protocols without surgery.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 

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