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J Thorac Cardiovasc Surg 2001;122:796-802
© 2001 The American Association for Thoracic Surgery
General Thoracic Surgery |
From the Thoracic Department, Institut Mutualiste Montsouris,a Paris; the Departments of Medicineb and Radiotherapy,c Institut Gustave Roussy, Villejuif; the Intensive Care Unit, Institut Mutualiste Montsouris,d Paris; and the Department of Biostatistics,e Institut Gustave Roussy, Villejuif, France.
Received for publication Dec 20, 2000. Revisions requested Feb 27, 2001; revisions received March 27, 2001. Accepted for publication April 13, 2001. Address for reprints: D. H. Grunenwald, MD, Head, Thoracic Department, Institut Mutualiste Montsouris, 42 bld Jourdan, 75674 Paris cedex 14, France (E-mail: thorax{at}imm.fr).
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Abstract |
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 Top Abstract IntroductionPatients and methodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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1-3 An analysis of relapse sites has shown that locoregional failure is the major stumbling block in these patients 4 because the 1-year locoregional control rate was only 17% for patients treated with chemoradiotherapy. In the same trial, chemotherapy dramatically decreased the rate of distant metastasis from 67% to 45%. Since then, postinduction surgery has been investigated as a possible alternative means of improving locoregional control of stage IIIB disease. Postinduction surgery was reported to be feasible and complete resection possible in more than 50% of cases. Only a few studies, 5-7 however, included more than 20 patients, and the median follow-up was short in all of them. The long-term evaluation of postinduction surgery in a large phase II study has yet to be attempted. The aim of the present phase II study was to evaluate the long-term efficacy of postinduction surgery for patients with stage IIIB non–small cell lung cancer (NSCLC), particularly focusing on patients with viable tumor cells after induction treatment. |
Patients and methods |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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8 diagnosed at mediastinoscopy or thoracotomy were included in the present prospective clinical trial. Potentially resectable disease after induction treatment was mandatory for inclusion. Table 1 describes the patient population selected. Further eligibility criteria included a Karnofsky index above 70%, weight loss of less than 10%, age below 70 years, a granulocyte and platelet count of more than 2000/mm3 and more than 100,000/mm3, respectively, a hemoglobin value of more than 10 g/dL, a serum creatinine value of less than 100 µm/L, a predicted postoperative forced vital capacity of more than one third the value in theory, no previous malignancy (except basocellular cutaneous cancer), and no prior treatment for lung cancer. This study was approved by the ethical committee and all patients had to sign a written informed consent form before inclusion. During the same period, a total of 210 patients with stage IIIB NSCLC have been seen in our institutions.
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Preoperative chemoradiotherapy (Figure 1)
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Two cycles of chemotherapy were to be administered on days 1 and 31; the first of the two chemotherapy cycles was delivered concomitantly with radiotherapy, but not the second cycle. Chemotherapy consisted in 5-fluorouracil, 1 g/m2 in 24 hours over a 72-hour period in a continuous infusion (D1 and D31), cisplatin, 100 mg/m2 given 2 to 6 hours after the start of 5-fluorouracil, and vinblastine, 4 mg/m2. The second chemotherapy course on day 31 was postponed if patients had a granulocyte count of less than 1500/mm3 or a platelet count of less than 100,000/mm3 and until these values were reached.
Response and toxicity of chemoradiotherapy
Response to induction treatment was assessed by means of the standard World Health Organization (WHO) criteria. Complete response to induction treatment was defined as the complete eradication of tumor. Partial response was defined as a 50% reduction in the sum of the products of all measurable lesions or a decrease (50%) in the size of assessable but nonmeasurable lesions. Stable disease was defined as a change in the sum of the products of all measurable lesions, between less than a 50% reduction and less than 25% progression. Definitive progressive disease was defined as a 25% increase in the sum of the products of tumor parameters or the appearance of new tumor lesions. Toxicity induced by preoperative treatment was assessed by means of WHO criteria.
Postchemoradiotherapy staging
At day 65, restaging was done in all patients with a chest x-ray film, CT scan of the thorax, the upper part of the abdomen, and brain, and examination with a fiberoptic bronchoscope. This new staging procedure was performed to assess the clinical tumor response and to select patients for surgery. Lung function tests and ventilationperfusion nuclide scintiscans were performed to assess whether examination results did not contraindicate surgery.
Surgery (Figure 1
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All patients treated with induction chemoradiotherapy and having a clinical response were selected for surgery. The surgical approach was a midline sternolaparotomy in most of the cases. When the lower part of the trachea or the carina was involved at the first staging procedure, the surgical approach was a right thoracotomy. A right thoracotomy associated with a laparotomy or a sternolaparotomy was the surgical option in cases of vena caval involvement. For left-sided tumors, particularly from the left lower lobe, or when a great vessel was involved on the left side (pulmonary artery), the surgical approach was a left thoracotomy in association with either a laparotomy or a sternolaparotomy, according to the nodal status (N2 or N3). The objective of surgery was to completely remove all tumor tissue. Lymph node dissection consisted in the resection of all ipsilateral mediastinal lymph node stations in all cases. In case of N3 disease, a bilateral mediastinal lymph node dissection was performed. After lung resection, the bronchial stump was wrapped in a pedicled omental flap in all cases, to avoid bronchial complications resulting from preoperative chemoradiotherapy and particularly stump insufficiency.
After surgery and according to pathologic findings, patients were classified as having had a complete or an incomplete response to induction treatment and a complete or a partial resection. The status of mediastinal lymph nodes after induction treatment was also recorded.
Follow-up
All patients were monitored every 3 months for the first 2 years from the end of the treatment and every 6 months during the next 3 years. Tests conducted during follow-up visits included a physical examination, a complete blood cell count and serum chemistry assessment, and a chest x-ray film. A CT scan of the thorax was obtained every 6 months after the end of the treatment, and examination with a fiberoptic bronchoscope was performed every year after the end of the treatment.
Statistical analysis
Survival was measured from the first day of radiotherapy until death or the last follow-up visit. The postoperative death and morbidity rates are defined as events occurring before hospital discharge. The locoregional control rate is defined as the percentage of patients free of tumor in the ipsilateral lung, the mediastinum, or the supraclavicular area. This definition is derived from that proposed by Arriagada and associates. 4 Relapse-free survival was the time from radiotherapy until disease progression. Survival curves were evaluated by the Kaplan-Meier method. 9 Median follow-up was calculated by the method of Schemper and Smith. 10 Multivariate analysis of prognostic factors for survival and relapse was performed by the Cox model. Multivariate analysis included 4 parameters (10% of the number of patients): pretreatment T, pretreatment N, postinduction N, and postinduction T.
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Results |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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A clinical tumor response was obtained in 29 patients (73%) during chemoradiotherapy (2 clinical complete responses). Disease was stable in 1 patient but progressed in 6 patients. The 29 (73%) patients who had a clinical tumor response after induction treatment were therefore eligible for surgery. Patients who did not have a tumor response (n = 7) or who had mediastinitis (n = 1) were not eligible for surgery.
Surgery
The median time from the first day of chemoradiotherapy to surgery was 77 days (range 63-90 days). Twenty-nine patients underwent a thoracotomy, which revealed unresectable disease in 5 patients. Tumor resection was therefore feasible in 24 (60%) patients. A pneumonectomy was performed on 18 patients and a lobectomy on 6. Twenty-one patients, including all patients with N3 disease at initial staging, underwent a bilateral mediastinal lymphadenectomy and 3 an ipsilateral mediastinal lymph node dissection. The postchemoradiotherapy mediastinal lymph node status was therefore assessable in all patients treated with surgery. The vena cava was resected in 4 patients, a great vessel in 3 patients, the left atrium in 7 patients, the trachea in 3 patients, and the carina in 3. In 18 patients treated with pneumonectomy, the bronchial stump was wrapped in a pedicled omental flap. The postoperative death rate was 7% (2 patients). Postoperative morbidity affected 7 patients (24%) and included acute respiratory distress syndrome (n = 2), phrenic nerve paralysis (n = 1), prolonged assisted ventilatory support (n = 1), cardiac failure during surgery (n = 1), persistent pleural effusion (n = 1), and omental flap necrosis (n = 1). No stump insufficiency nor morbidity related to laparotomy was noted. The median duration of the postoperative hospital stay was 20 days.
Pathologic findings
A histologic complete resection was achieved in 23 (58%) patients. A histologic complete response was obtained in 4 (10%) patients. Ten patients with N2/N3 disease (30%) had a complete disappearance of mediastinal lymph node involvement (mediastinal lymph node down staging) after chemoradiotherapy. Twenty-five patients who had a clinical objective tumor response and who had persistent viable tumor cells in the thorax were submitted to surgery. These 25 patients were defined as partial responders. Thirteen partial responders were classified as postinduction N0/N1. Resection was complete in 20 of these partial responders.
Survival analysis
Of the 40 patients, 7 (17.5%) were alive at 48, 53, 54, 67, 72, and 73 months, and 5 (12.5%) of them were free of disease at 48, 53, 67, 72, and 73 months. All these 7 patients had persistent viable tumor cells after induction treatment and 6 of them had no mediastinal lymph node involvement at the time of surgery (postinduction N0/N1).
In 8 patients the disease progressed during chemoradiotherapy. Progression occurred in the primary site (n = 5), bone (n = 3), brain (n = 2), and liver (n = 1). Of the 29 patients who underwent thoracotomy, 19 (65%) have had a relapse. Thirteen (45%) had a distant metastasis as the first relapse event. The first site of distant metastasis was the contralateral lung (n = 5), liver (n = 1), bone (n = 3), brain (n = 6), distant lymph node (n = 1), or another site (n = 2). Five patients had multiple sites of metastasis. Seven (24%) patients had a locoregional relapse after surgery. Five (20%) partial responders had a locoregional relapse. When overall patients are considered, 12 (30%) have had a locoregional relapse. Twenty-three percent of the overall population (95% confidence interval [CI]: 11%-41%) had not had a relapse at 5 years. When only partial responders were considered (n = 25), 22% (95% CI: 10%-34%) had not had a relapse at 5 years.
Thirty-three deaths occurred. Of these, 8 (24%) occurred in patients with no evidence of recurrent disease. These 8 patients died of thrombocytopenia and neutropenia (n = 1), myocardial infarction (n = 2), and lung insufficiency (n = 5). Lung insufficiency was related to acute respiratory distress syndrome (n = 3), pulmonary embolism plus interstitial pneumonitis (n = 1), and postradiation pneumonitis (n = 1). Of these, 4 (10%) were directly related to treatment.
The 5-year overall survival for the 40 patients is 19% (CI 95%: 10%-34%) (Figure 2). The 5-year overall survival is 23% (11%-40%) and 17% (6%-39%) for patients with T4 NX and TX N3, respectively. The 5-year overall survival is 42% for postinduction N0/N1 treated with complete resection, 12% for postinduction N2/N3 treated with complete resection, and 0% for patients who were not treated with complete resection (P < .001) (Figure 3). A multivariate analysis (Table 4) showed that postinduction mediastinal lymph node status was the only prognostic factor for survival and relapse (relative risk for death, 3.1; relative risk for relapse, 4.9; P = .005 and .001, respectively).
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Discussion |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Chemoradiotherapy is considered the standard treatment for stage IIIB NSCLC. 1-3 Nevertheless, the locoregional control rate, defined as the percentage of patients free of residual tumor in the thorax after treatment, is a modest 17% at 1 year. 4 The persistence of viable tumor cells in the primary tumor site or in the mediastinum after chemoradiotherapy is a valid marker of treatment failure and death, whatever the clinical response. 11 This was demonstrated in a series of 63 patients with stage III disease treated with chemoradiotherapy who had persistent viable tumor cells at bronchoscopy. In this prospective study, the 3-year operative survival was only 3% for these patients. Because locoregional control is determinant in the outcome of stage III disease, it was the rationale behind the inclusion of surgery in a multimodality treatment approach. In this setting, postinduction surgery is considered a salvage procedure aimed at achieving locoregional control. Previous studies of multimodality treatment reported 3-year operative survivals ranging from 24% to 26%, complete resection rates from 50% to 70%, and locoregional failure rates of only 20% to 38%. 5-7 Our results are in the same range, with a 3-year operative survival of 28%, a 58% complete resection rate, and a 30% locoregional failure rate. All together, these results are encouraging when compared with the large phase III chemoradiotherapy studies conducted by Le Chevalier, 2 Sause, 3 and their coworkers, but not convincing when compared with phase III trials of chemoradiotherapy performed in well-selected populations. 12,13
Because the persistence of viable tumor cells after chemoradiotherapy is considered a marker of treatment failure, we looked at the effect of surgery in patients who only partially responded to chemoradiotherapy. Surprisingly, surgery successfully salvaged a population rarely considered curable and obtained an interesting 28% long-term survival. A comparable result was achieved in the Southwest Oncology Group (SWOG) study, 5 which reported a similar outcome for patients with a pathologic complete response after chemoradiotherapy and those with persistent viable tumor after chemoradiotherapy and treated by surgery. In the German study, 6 the 4-year survival was 46% for patients treated with surgery and having persistent viable tumor cells after chemoradiotherapy. These data suggest that surgery is an efficient salvage treatment for patients with stage IIIB NSCLC with viable residual disease after chemoradiotherapy alone. On the other hand, none of the 4 patients who had a histologic complete response after induction treatment are alive. The rationale for surgery is questionable in these patients in whom preoperative evaluation of a pathologic complete response, with the use of new staging techniques such as positron emission tomographic scanning, is probably required.
Previous studies 5,6,13 have reported that the mediastinal lymph node status after induction treatment had a prognostic significance for patients treated with postinduction surgery. In a study including 42 patients with stage IIIAN2 disease treated with multimodality therapy, Choi and colleagues 14 reported that the degree of lymph node down staging was translated into a survival benefit since the 5-year survivals were 79%, 42%, and 18% for postoperative tumor stages 0/I, II, and III, respectively. In the SWOG study, 5 the strongest predictor of long-term survival after thoracotomy was the absence of tumor in the mediastinal nodes (3-year survival 44% vs 18%; P = .0005). In the German study, 4-year survivals were 38% and 15% (P = .11) for postinduction N0/N1 and N2/N3 patients, respectively. Multivariate analysis performed in our study fully confirms these data since it shows that the presence of mediastinal lymph node involvement after induction treatment is the most relevant prognostic indicator. Altogether these studies suggest that the postinduction N2/N3 status is a marker of microscopic metastatic disease and that surgery is not associated with a significant long-term survival in these patients. On the other hand, the absence of mediastinal lymph node involvement after induction therapy for patients with stage III disease is always associated with a long-term survival of more than 30% after surgery, whatever the initial T stage.
Specific procedures such as bilateral lymphadenectomy, extrapulmonary resections, and median sternotomy are required for postinduction surgery for patients with stage IIIB NSCLC. Initial reports 14 documented high rates of postoperative complications (46%) and mortality (8.6%) in patients treated with preoperative chemoradiotherapy. In their respective studies, Albain, 5 Eberhardt, 6 and their associates reported high rates of non–cancer-related deaths (25% and 26% of the overall population). Our study confirms this finding inasmuch as 8 (20%) deaths occurred in patients in complete remission. Five of these deaths were due to lung insufficiency and 2 to myocardial infarction. Our study and others reported a higher rate of acute respiratory distress syndrome or pneumonitis after multimodality treatment compared with standard lung resection alone. These data indicate that patient management needs to be improved to decrease toxicities. In particular, radiotherapy schedules, surgical procedures, and postoperative care (intensive care and long-term follow-up) need to be reappraised and redefined to avoid these complications. Previous studies suggested that preoperative chemotherapy and/or radiotherapy could increase the rate of bronchial stump insufficiency. 15 Some teams 16,17 perform omentoplasty to avoid this complication. In the present study, the bronchial stump was wrapped in a pedicled omental flap in 18 cases. No stump insufficiency was noted with this procedure, which suggests that it is an efficient way of avoiding stump insufficiency.
Stage IIIB NSCLCs are classified as "unresectable locally advanced NSCLC" in the current TNM staging system. 18 Nevertheless, our study and previous studies (Table 5) show that surgery makes it possible both to achieve a high rate of complete remission and to salvage patients with residual disease after chemoradiotherapy. This argues for a change in the TNM classification. In a recently published proposition, 19,20 selected patients with stage IIIB disease and clinically detectable N2 disease were classified in a subgroup designated "potentially resectable." Further studies are needed to confirm the relevance of this new subclassification.
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Acknowledgments |
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References |
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