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Ann Thorac Surg 2002;74:164-169
© 2002 The Society of Thoracic Surgeons

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Original article: general thoracic

Surgery as part of combined modality treatment in stage IIIB non-small cell lung cancer

^a Department of Pulmonology, St. Antonius Hospital Nieuwegein, Nieuwegein, The Netherlands
^b Department of Thoracic Surgery, St. Antonius Hospital Nieuwegein, Nieuwegein, The Netherlands
^c department of Thoracic Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
^d department of Radiotherapy, University Medical Center Utrecht, Utrecht, The Netherlands

Accepted for publication March 28, 2002.

* Address reprint requests to Dr Schramel, Department of Pulmonology, St. Antonius Hospital, PO Box 2500, 3430 EM Nieuwegein, The Netherlands
e-mail: f.schramel{at}antonius.net

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. The role of surgery after neoadjuvant chemotherapy in patients with stage IIIB non-small cell lung cancer (NSCLC) remains unclear.

Methods. A prospective multicenter trial of neoadjuvant chemotherapy followed by surgery or radiotherapy or both was conducted with 41 patients with stage IIIB NSCLC. End points were toxicity, response, downstaging, complete resectability, and survival. The diagnostic value of repeat mediastinoscopy after neoadjuvant chemotherapy (three courses of gemcitabine/cisplatin) was also studied.

Results. Response rate after neoadjuvant chemotherapy was 66% (27 of 41). Fifteen patients underwent repeat mediastinoscopy, which proved to be inadequate in 6 patients. Two repeat mediastinoscopies were false negative. Resection was performed in 18 patients, of which 10 proved to be radical. Hospital mortality was 2.4% (n = 1). Major complications occurred in 6 patients (fistula, empyema, hemorrhage). Histopathologically proven downstaging was seen in 16 patients (39%). Twenty-five patients underwent radiotherapy of whom 14 were diagnosed with stable/progressive disease and 9 with partial/complete response. Median survival for all patients was 15.1 months, for nonresponders 8.4 months and for responders 16.8 months (p = 0.11). Patients with partial/complete response had a mean survival of 21.5 months after resection and 13.0 months after radiotherapy (p = 0.0003).

Conclusions. Radical surgery can be performed in 37% (10 of 27) of the responders resulting in a prolonged survival. Surgery as part of combined modality treatment is feasible in stage IIIB NSCLC. Results of a repeat mediastinoscopy are disappointing and proved to be a not-so-effective restaging tool because of the high number of incomplete procedures and because it yields false negative results.

	Introduction

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At presentation, 25% to 35% of all patients with non-small cell lung cancer (NSCLC) have tumors that have not yet metastasized systemically. However these tumors are locally too advanced to allow complete resection. Even though it could not cure the majority of patients, radiotherapy used to be the standard treatment in locally unresectable tumors [1].

Recently multimodality treatment has become the standard therapy used for these patients [2]. In combined modality treatment, the main goal of chemotherapy is to eradicate micrometastases and mediastinal lymph node metastases and to diminish the size of the primary tumor.

So far most clinical trials of neoadjuvant chemotherapy followed by surgery or radiotherapy or both have focused on patients with stage IIIA N2 disease [3]. In this group neoadjuvant chemotherapy did achieve improved survival. However, the role of surgery after neoadjuvant chemotherapy in patients with stage IIIB disease remains unclear.

In this prospective phase II multicenter trial we evaluated the role of surgery after neoadjuvant chemotherapy in patients with stage IIIB NSCLC. The diagnostic value of repeat mediastinoscopy after neoadjuvant chemotherapy for mediastinal staging was also analyzed.

	Material and methods

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Patients
All patients with stage IIIB NSCLC were eligible: patients were staged as IIIB because of contralateral mediastinal lymph node metastases, or invasion of the mediastinum, heart, great vessels, trachea, esophagus, vertebral body, or carina. N3 nodes or T4 primary lesions were confirmed either by means of cervical mediastinoscopy, thoracotomy or by anterior mediastinotomy. Futher eligibility criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; platelet count 100 x 10⁹/L; leukocyte count 3 x 10⁹/L; normal liver and renal functions; unidimensionally or bidimensionally measurable disease; no active infections; no pregnancy or lactation; no other malignancies except carcinoma in situ of the cervix or basal cell carcinoma of the skin and no malignant pleural effusion or positive supraclavicular lymph nodes. Staging procedures included routine blood tests, thoracic computed tomography (CT), ultrasonography of the upper abdomen, bronchoscopy, mediastinoscopy, and pulmonary function tests. Computed tomography of the brain and bone scintigraphy was performed only in case of clinical suspicion of metastatic disease.

The study has been approved by the ethics committee in all participating centers. All patients were entered after written consent had been obtained. Multimodality treatment consisted of neoadjuvant chemotherapy, which was followed by surgery or radiotherapy or both.

Chemotherapy
Neoadjuvant chemotherapy consisted of three cycles of gemcitabine and cisplatin. Gemcitabine was administered on a weekly basis on days 1, 8, and 15 at a dose of 1,000 mg/m² (intravenously over 30 minutes) for 3 weeks followed by a 1-week rest throughout 28-day cycles. Cisplatin 100 mg/m² (intravenously over 4 hours) was administered on day 2 of each 28-day course. Dose escalations were not allowed during this study. Treatment was stopped in those cases in which the disease progressed or unacceptable toxicity occurred. A complete blood cell count and differential cell count, serum electrolytes, renal and liver function were measured on day 1, 8, and 15 of each cycle. Doses for both gemcitabine and cisplatin were reduced to 75% if the leukocyte count was 2.0 to 2.9 x 10⁹/L or platelet count was 50 to 99 x 10⁹/L. Chemotherapy was not given when the leukocyte count was less than 2.0 x 10⁹/L or the platelet count less than 50 x 10⁹/L. The cisplatin dose was reduced to 50% if patients showed peripheral neurotoxicity grade 2. Cisplatin was omitted in case of peripheral neurotoxicity grade 3 to 4. The dose of cisplatin was reduced to 50% when the creatinine clearance was 40 to 60 mL/min. Cisplatin was not given in patients with a creatinine clearance less than 40 mL/min.

Tumor assessment
Response to neoadjuvant chemotherapy was assessed after three cycles of chemotherapy. Restaging procedures included routine blood tests and thoracic CT. Other investigations were performed on indication.

Complete response throughout this study was defined as the complete disappearance of all evidence of malignant disease as assessed by CT. Partial response was defined as at least 50% reduction in the product of the two largest perpendicular diameters in bidimensional measurable disease or at least a 30% reduction of the largest diameter in unidimensional disease. Progressive disease was defined as at least a 25% increase of the product of the two largest perpendicular diameters in bidimensional measurable disease or the largest diameter in unidimensional disease or the appearance of any new lesion not previously identified. All other patients were considered to have stable disease .

Surgery and radiotherapy
Repeat mediastinoscopy was performed if mediastinal lymph node metastases were present at diagnosis in patients with complete, or partial response. Biopsies were taken at five different levels (Naruke numbers: 2 right and left, 4 right and left, and 7). In case repeat mediastinoscopy showed no mediastinal lymph node metastases, surgical exploration was performed within 4 to 5 weeks after finishing chemotherapy. A pneumonectomy was performed in cases in which the tumor was located in the lower or middle lobe. In case the tumor was located in the upper lobe, a lobectomy was performed. Postoperative radiotherapy was given at a dose of 5,640 cGy when resection margins were not free at histopathology, the tumor was not resectable, or ipsilateral mediastinal lymph nodes were found to be positive.

When repeat mediastinoscopy showed mediastinal lymph node metastasis, patients were treated with radiotherapy alone at a dose of 5,640 cGy with daily fractions of 235 cGy if only ipsilateral nodes were positive and at a dose of 3900 cGy in 13 fractions if contralateral nodes were involved. Follow-up visits were made every 3 months.

Statistics
Survival was estimated from the date of inclusion using the Kaplan-Meier survival analysis method [4]. Survival comparisons were analyzed by means of the log rank test [5]. The difference was considered statistically significant when the p value was less than 0.05.

The follow-up was complete as of February 1, 2002. Follow-up data were obtained from hospital files and from questionnaires to referring pulmonary physicians and general practitioners.

	Results

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From January 1997 until September 1999, 41 patients with stage IIIB NSCLC were entered into this trial. Ages ranged from 39 to 73.6 years with a mean of 60.5 years. Thirty-one patients were male. Twenty-six tumors were located on the right side. Cervical mediastinoscopy proved to be positive in 29 patients (70.7%). In this group, eight patients showed positive N2 nodes and 21 positive N3 nodes. Clinical TNM classification is shown in Table 1. The histologic diagnosis was adenocarcinoma in 17 patients (41.5%), squamous cell carcinoma in 15 patients (36.6%), and large cell carcinoma in 9 patients (21.9%).

The radiologic response to neoadjuvant chemotherapy is presented in Table 2. The response rate after neoadjuvant chemotherapy was 66% (27/41). Two patients showed a complete response.

Survival
After a median follow-up of 46 months, 36 patients had died. The estimated median survival for the whole group was 15.1 months (95% confidence interval [CI] = 11.2 to 19.1 with an estimated 1-year, 2-year, and 3-year survival of 60%, 25%, and 15%, respectively (Fig 1).

View larger version (8K): [in this window] [in a new window]   Fig 1. Median survival of all patients (n = 41). (Cum = cumulative.)

View larger version (11K): [in this window] [in a new window]   Fig 2. Median survival of patients with stable/progressive disease (PD/SD) (n = 14; dashed line) and patients with complete/partial response (CR/PR) (n = 27; solid line). (Cum = cumulative.)

View larger version (11K): [in this window] [in a new window]   Fig 3. Median survival in responders treated with surgery (n = 18; solid line) or radiotherapy (n = 9; dashed line). (Cum = cumulative.)

Distant metastases developed in 8 of 27 patients with complete or partial response (29.6%). Brain metastases occurred in 6 (22.2%). Eight patients had local recurrence (29.6%). Two patients had combined local and distant recurrence (7.4%).

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Surgery is the treatment of choice in patients with NSCLC but resectability is closely related to the stage of the disease [6]. Whereas stage I and II tumors are considered to be resectable, the role of surgery for stage IIIB NSCLC remains controversial [7]. In the series by Mountain [8] 5-year survival is 6% for clinical T4 and 3% for N3 disease. Death of patients with stage III NSCLC is more often caused by distant metastases rather than local disease and patients are rarely cured with local treatment modalities alone. Therefore multimodality treatment has surfaced as the treatment of choice in a selected group of patients with stage III NSCLC [2, 9]. However, it is still unclear which treatment modality (surgery or radiotherapy or both) will result in prolonged survival after neoadjuvant chemotherapy.

Over the years the optimal chemotherapy has proved hard to define. Meta-analyses has indicated that the chance of survival increases when a platinum-based regimen is being used [9, 11]. Numerous combinations of cisplatin and older drugs have been used with no single mix emerging as the superior combination. Although several single agents have been producing response rates of 15% to 20% combination chemotherapy is still considered the standard of care [12]. The combination of cisplatin and gemcitabine has shown significant activity in advanced non-small cell lung cancer with response rates as high as 70% in several phase II studies [13].

The optimal duration of induction chemotherapy remains controversial als well. The American Society of Clinical Oncology guidelines proposed a duration of 2 to 8 cycles [2]. Crino and associates [14] who studied the gemcitabine/cisplatin regimen as induction chemotherapy in 42 patients with stage IIIA (n = 11) and IIIB (n = 31) achieved an overall response rate of 62%. Complete resection could be achieved in 10 patients, with tumor downstaging in 9. Similar results have been reported by Van Kooten and colleagues [15] and Abratt and coworkers [16].

Our study showed a response rate of 66% after induction chemotherapy. Two patients responded completely. Albain and coworkers [17] found in their research an even higher response rate when using a trimodality approach of concurrent chemotherapy and irradiation followed by surgery in patients with stage IIIA and IIIB NSCLC. Resectability in their case was 80% for the entire IIIB group.

In the past, repeat mediastinoscopy has been considered to be contraindicated as it was perceived to be too hazardous to dissect the scarred mediastinum [18]. Between 1976 and 1990, 140 patients underwent repeat mediastinoscopy in our hospital as a routine staging procedure. No mortality occurred. Sensitivity was 74%, and accuracy 94% [19].

Mediastinal structures become differently affected after neoadjuvant chemotherapy. The cytotoxic drugs change the normal inflammatory response and adhesions. Additionally nodal tissue can be seriously distorted. During our research, the 15 patients who underwent repeat mediastinoscopy, did not show complications, such as described by Pauwels and associates [20] and Mateu-Navarro and colleagues [21]. However, 40% remained incomplete owing to fibrosis and adhesions. Beside that, 2 out of 7 proved to be false negative. Comparable figures were reported by Pauwels and coworkers [20] (25%) and Mateu-Navarro and associates (40%) [21]. Hence this paper argues that repeat mediastionoscopy after neoadjuvant chemotherapy is a not the most effective restaging tool. The promising results of PET-scanning in staging NSCLC [22, 23] make it an attractive alternative for selecting patients with negative mediastinal lymph nodes after neoadjuvant chemotherapy. A prospective pilot study of FDG-positron emission tomography scan after neoadjuvant chemotherapy in stage IIIA NSCLC of Vansteenkiste showed an accuracy of 100% [22].

In this study a thoracotomy was performed on 20 patients. In 2 cases the tumor proved to be unresectable. Although 8 patients underwent a pneumonectomy, hospital mortality was low (2.4%). Complications occurred in 6 patients and 4 of them underwent a pneumonectomy. Three patients had from a hemorrhage and 3 a bronchopleural fistula with an empyema. A complete resection was performed in 10 responders (24.4%). Survival in this group was better than survival among patients with stable or progressive disease. However, this difference was not significant. For all responders survival proved significantly better among patients who underwent surgery than among patients treated with radiotherapy.

The brain is a major site of distant metastases [17]. In this study 6 responders developed brain metastases (22.2%). Few studies have routinely used prophylactic cranial irradiation. Eberhardt and colleagues [24] did not perform a randomized investigation of prophylactic cranial irradiation in their study but the overall brain relapse was remarkably reduced in the group that received prophylactic cranial irradiation even though no impact on survival was noted. Large prospective randomized studies are necessary to evaluate the role of prophylactic cranial irradiation.

In conclusion these data show that radical surgery can be performed in 37% (10 of 27) of the responders and can result in prolonged survival. Surgery as part of combined modality treatment is feasible for patients with stage IIIB NSCLC. Results of repeat mediastinoscopy are disappointing and proved to be a not-so-effective restaging tool because of the high number of incomplete procedures and because it yields false negative results.[10]

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
We thank the following pulmonologists for contributing eligible patients to this study: Dr N. Schlösser (University Medical Center, Utrecht, The Netherlands), Drs H. Dik and J. Kersbergen (Rijnland Hospital Leiderdorp, The Netherlands), and Dr B. Biesma (Bosch Medical Center Den Bosch, The Netherlands). We also thank Dr P. Zanen for his help with the statistical analysis.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Aart Brutel de la Rivière Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pitz, C. C.M. Articles by Schramel, F. M.N.H. Search for Related Content PubMed PubMed Citation Articles by Pitz, C. C.M. Articles by Schramel, F. M.N.H. Related Collections Lung - cancer