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© 2003 American Society for Clinical Oncology Mediastinal Lymph Node Clearance After Docetaxel-Cisplatin Neoadjuvant Chemotherapy Is Prognostic of Survival in Patients With Stage IIIA pN2 Non–Small-Cell Lung Cancer: A Multicenter Phase II Trial
From the Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland. Address reprint requests to Daniel Betticher, MD, Institute of Medical Oncology, University of Bern, 3010 Bern, Switzerland; email: daniel.betticher{at}insel.ch.
Purpose: A multicenter, phase II trial investigated the efficacy and toxicity of neoadjuvant docetaxel-cisplatin in locally advanced non–small-cell lung cancer (NSCLC) and examined prognostic factors for patients not benefiting from surgery. Patients and Methods: Ninety patients with previously untreated, potentially operable stage IIIA (mediastinoscopically pN2) NSCLC received three cycles of docetaxel 85 mg/m2 day 1 plus cisplatin 40 mg/m2 days 1 and 2, with subsequent surgical resection. Results: Administered dose-intensities were docetaxel 85 mg/m2/3 weeks (range, 53 to 96) and cisplatin 95 mg/m2/3 weeks (range, 0 to 104). The 265 cycles were well tolerated, and the overall response rate was 66% (95% confidence interval [CI], 55% to 75%). Seventy-five patients underwent tumor resection with positive resection margin and involvement of the uppermost mediastinal lymph node in 16% and 35% of patients, respectively (perioperative mortality, 3%; morbidity, 17%). Pathologic complete response occurred in 19% of patients with tumor resection. In patients with tumor resection, downstaging to N0–1 at surgery was prognostic and significantly prolonged event-free survival (EFS) and overall survival (OS; P = .0001). At median follow-up of 32 months, the median EFS and OS were 14.8 months (range, 2.4 to 53.4) and 33 months (range, 2.4 to 53.4), respectively. Local relapse occurred in 27% of patients with tumor resection, with distant metastases in 37%. Multivariate analyses identified mediastinal clearance (hazard ratio, 0.22; P = .0003) and complete resection (hazard ratio, 0.26; P = .0006) as strongly prognostic for increased survival. Conclusion: Neoadjuvant docetaxel-cisplatin is effective and tolerable in stage IIIA pN2 NSCLC. Resection is recommended only for patients with mediastinal downstaging after chemotherapy.
THE MAJORITY of patients with locally advanced lung cancer, and particularly those with mediastinal lymph node involvement, will develop distant metastases within several months of local therapy. Early administration of chemotherapy may eradicate micrometastases, leading to improved survival.1 Although complete resection for patients with stage IIIA, bulky, N2-positive disease is technically feasible, the 5-year survival is only approximately 10%, mainly because of the development of distant metastases.2 This poor outcome has prompted the investigation of additional chemotherapy given before or after resection. In contrast to the adjuvant approach, the feasibility and activity of neoadjuvant chemotherapy has been demonstrated in the phase II and III settings. Response rates in the range of 30% to 70% have been achieved, depending on the chemotherapy administered and disease stage (according to the tumor-node-metastasis [TNM] classification system, T3, N0–1; Tx, N2–3), with radical resection feasible in approximately two thirds of patients.1 Results from randomized trials assessing neoadjuvant chemotherapy in stage IIIA disease are inconsistent because of small sample sizes, short follow-up periods, and unacceptable toxicity for certain of the chemotherapy regimens administered.3–7 Nevertheless, the recent randomized trial of Depierre et al3 showed a significant reduction in the development of distant metastases in the chemotherapy arm compared with the control group. However, because the overall survival (OS) did not differ between the two arms, further study of chemotherapy combinations incorporating new, active drugs is required in this setting. Docetaxel-platinum combination regimens are established in the management of non–small-cell lung cancer (NSCLC). Recently, two phase III randomized trials assessed first-line docetaxel-cisplatin in stage IIIB-IV NSCLC.8,9 In the first of these studies, a 2-year survival rate of 21% was demonstrated for docetaxel-cisplatin versus 14% for vinorelbine-cisplatin (P = .035).8 Docetaxel-cisplatin was also the better-tolerated regimen, with improved quality of life versus the standard doublet.10 In the second study, which allowed patients with stable brain metastases, a 17% response rate and median survival of 7.4 months was demonstrated for docetaxel-cisplatin.9 The primary objective of this multicenter trial was to assess the activity and toxicity of neoadjuvant docetaxel-cisplatin in patients with mediastinoscopically proven stage IIIA (pN2) NSCLC. The secondary objective comprised the identification of prognostic factors for patients who would not benefit from tumor resection.
Patient Characteristics Patients with potentially operable stage IIIA pN2 NSCLC were enrolled in a prospective, multicenter, phase II trial of docetaxel-cisplatin induction chemotherapy. At each center a medical panel comprising a thoracic surgeon, radiologist, chest physician, radio-oncologist, pathologist, and medical oncologist confirmed the stage of disease and whether patients should be enrolled. Patients were required to have mediastinoscopically proven, previously untreated, operable stage IIIA (T1–3, pN2, M0) NSCLC. Eligibility criteria included: age 18 to 75 years; World Health Organization (WHO) performance status (PS)  2; forced expiratory volume  1.2 L/sec; normal cardiac and bone marrow (leukocytes > 4.0 x 109/L, platelets > 100 x 109/L) function; and adequate hepatic (bilirubin within normal limits, AST and ALT 1.5 x upper limit of normal [ULN], alkaline phosphatase 2.5 x ULN) and kidney (creatinine clearance > 60 mL/min) function. Exclusion criteria were prior malignancy other than nonmelanoma skin cancer or adequately treated stage I in situ cervical cancer; coexisting serious illness such as unstable cardiac disease, severe hypercalcemia, insulin-treated diabetes mellitus, gastric ulcer, or peripheral neuropathy (> grade 1); history of significant neurologic or psychiatric disorder; active uncontrolled infection; or patients receiving concurrent prednisone or in whom corticosteroid premedication was contraindicated.
Trial Design and Treatment Plan Patients were planned to receive cisplatin 40 mg/m2 as a 1-hour infusion on days 1 to 2 plus docetaxel 85 mg/m2 as a 1-hour infusion on day 1 every 3 weeks for three cycles as long as hematologic function was adequate (neutrophils > 1.5 x 109/L, platelets > 100 x 109/L). Cisplatin was given over 2 days because at the trial’s initiation there was some indication that docetaxel might have been nephrotoxic. This was subsequently not demonstrated to be the case. Dexamethasone (8 mg) was administered orally 1, 7, and 13 hours before chemotherapy and twice daily on days 1 to 3. If the leukocyte nadir during the previous cycle was less than 1.0 x 109/L, granulocyte colony-stimulating factor (G-CSF; 34 million IE/d) was administered until the leukocyte count was more than 15 x 109/L. The dose of docetaxel was reduced if grade 3 impaired hepatic function, diarrhea, peripheral neuropathy, or severe fluid retention occurred. If creatinine clearance decreased to less than 50 mL/min, the subsequent dose of cisplatin was omitted.
Surgery
Postoperative Therapy
Evaluations
The trial aims were to assess the efficacy and toxicity of the docetaxel-cisplatin combination and to investigate the benefit of tumor resection, in terms of OS, for patients responding to chemotherapy versus nonresponders. Response to chemotherapy was evaluated by WHO criteria and complete pathologic response was defined as Histologic diagnosis and assessment of mediastinal lymph nodes were performed using American Thoracic Society mapping criteria in all patients. Histologic diagnoses were reviewed centrally by an experienced pneumopathologist (M.T.), in consultation with local pathologists. CT scan results, mediastinoscopy, and surgical procedures were also analyzed centrally (by reviewing the reports of C.J.). We assessed the association of OS, event-free survival (EFS; an event-comprised disease progression, relapse, or death), risk of local relapse, and risk of distant metastases with each of 12 potential prognostic factors: age, sex, PS, histology, tumor stage, differentiation, involvement of mediastinal lymph node, serum lactate dehydrogenase (LDH), clinical response, type of surgery performed, pathologic response, mediastinal downstaging, resection margin, and complete resection (negative margin and clearance of the uppermost mediastinal lymph node).
Statistical Analysis
Continuous variables were depicted by descriptive statistics and categoric variables were illustrated by frequency tables. Time-to-event variables (OS, EFS, TTLR, TTDM) were all calculated from the time of enrollment. Analyses were calculated to death for OS; PD, relapse, or death for EFS; documented local relapse or death caused by tumor for TTLR; and documented distant metastasis or death caused by tumor for TTDM. Time-to-event variables were estimated using the Kaplan-Meier method. Comparisons between groups were performed using the Wilcoxon rank sum test for continuous variables, the The predictive or prognostic impact of certain variables was investigated using multiple logistic regression for binary outcomes and the Cox proportional hazards model for time-to-event outcomes. The association between an outcome (eg, clinical response, OS, and so on) and a potential predictive or prognostic factor was investigated separately for each individual factor (univariate analysis). The prognostic impact of mediastinal downstaging (N0–1 v N2) and complete resection on survival in patients with tumor resection was also investigated in multivariate analyses including four additional established factors (age, PS, tumor stage, and LDH). All P values are two-sided. No correction was performed for multiple evaluations.
Patients Between April 1997 and September 2000, 90 patients with mediastinoscopically proven stage IIIA pN2 NSCLC were enrolled at nine Swiss centers. The baseline patient characteristics are shown in Table 1  . One patient was receiving steroids at trial entry and was therefore ineligible. The majority of patients had good PS (59% PS = 0) and the median age was 60 years. Squamous cell carcinoma was the predominant (38%) initial histologic subtype. All patients had mediastinoscopically proven stage IIIA pN2 disease. In a minority of patients (18%), the CT scan revealed no enlargement of the mediastinal lymph nodes at baseline. Multilevel nodal involvement, assessed by mediastinoscopy, was present in 20 of 62 patients (32%; detailed mediastinoscopy data were unavailable for review in 28 patients). For all except three patients the initial histology diagnoses were reviewed centrally. The reviewed diagnoses differed from the initial NSCLC subtype in 30 patients; in particular, several initially undifferentiated and large-cell NSCLC were reclassified as squamous cell carcinomas and adenocarcinomas. In three patients, a diagnosis other than NSCLC (small-cell lung cancer in two patients and lymphoma in one patient) was reported by the local pathologists after enrollment.
Treatment Administration After a high response rate and low toxicity were observed in the first 36 patients, the protocol was amended in July 1998 to increase the sample size to 71 patients and to increase the cisplatin dose to 100 mg/m2/cycle (from patient 37). A second amendment in April 2000 increased the sample size again to 90 patients to allow additional analyses of pathologic outcomes. In total, 90 patients received 265 cycles of chemotherapy. Four patients received fewer than three cycles: three patients because of PD (brain, bone, and liver metastases) while receiving therapy, and one patient died during cycle 1 from gastric bleeding (ie, the ineligible patient who received steroids at baseline). Chemotherapy was delayed in eight cycles of seven patients because of pneumonia (three cycles), diarrhea (one cycle), neutropenic fever (one cycle), hospital bed unavailable (one cycle), and patient’s request (two cycles). The median dose-intensity per administered cycle was 84.7 mg/m2 (range, 53 to 96; targeted dose 85.0 mg/m2) for docetaxel and 94.6 mg/m2 (range, 0 to 104; targeted dose 80.0 mg/m2 for the first 36 patients, then 100.0 mg/m2) for cisplatin. The docetaxel dose was reduced because of grade 3 diarrhea in four cycles (two patients). The cisplatin dose was reduced because of atrial fibrillation in one cycle and omitted because of ototoxicity in two cycles.
Toxicity
Response to Neoadjuvant Chemotherapy The overall clinical response rate (ORR) for all 90 patients was 66% (95% confidence interval [CI], 55% to 75%), including seven (8%) complete remissions (CRs), 52 (58%) partial remissions (PRs), 22 (24%) no change (NC), and nine (10%) PDs (which included the ineligible patient). No patient characteristics were predictive for overall clinical response. There were two PRs and one NC in the three patients with review histology other than NSCLC. After excluding these patients, the ORR and 95% CI remained unchanged.
Surgery and Perioperative Complications
Incomplete resection with positive margin, involvement of the uppermost mediastinal lymph node, or both, occurred in six (8%), 20 (27%), and six (8%) patients with tumor resection, respectively. The median overall cisplatin dose-intensity in patients with negative resection margin was higher than that in patients with positive margin (96 v 80 mg/m2/cycle; P = .034). The proportion of patients with complete resection was significantly higher for those with a clinical response (CR, PR) versus NC (67% v 30%; P = .007). It was also higher in patients with a
Radiotherapy Thirty-three patients received mediastinal adjuvant radiotherapy (median total dose 60 Gy [range, 22 to 70 Gy]). Reasons for receiving radiotherapy included positive resection margin (n = 3), involvement of the uppermost mediastinal lymph node (n = 14), or both (n = 6), in addition to the medical panel’s decision even in the absence of the uppermost mediastinal lymph node involvement and a negative resection margin (n = 10). Nine patients did not receive radiotherapy despite a positive tumor resection margin (n = 3) or involvement of the uppermost mediastinal lymph node (n = 6).
Pathologic Response and Nodal Downstaging The proportion of patients with nodal downstaging was significantly higher in patients with a clinical response (CR, PR) versus those with NC (73% v 40%; P = .015). It was also higher in patients with complete pathologic response than in patients with less activity in the primary tumor (93% v 57%; P = .013). Squamous cell carcinomas had improved pathologic responses compared with adenocarcinomas or large cell/undifferentiated NSCLC (median 80% necrosis plus fibrosis in squamous NSCLC v 35% in adenocarcinomas v 50% in large-cell/undifferentiated NSCLC; P = .0077). Furthermore, squamous NSCLC had a higher frequency of mediastinal nodal downstaging compared with adenocarcinomas or large-cell/undifferentiated NSCLC (62% v 55% v 31%; P = .049).
Relapse and Survival
Among the 75 patients with tumor resection, 35 (47%) had died and median OS was 33.0 months (range, 2.4 to 53.4). In total, 44 patients (59%) experienced an event and the median EFS was 14.8 months (range, 2.4 to 53.4), with progression or relapse occurring in 38 patients (51%; 10 local disease, 18 distant metastases, 10 both). Among the 28 patients (37%) with distant metastases, 12 had brain metastases. The median time to local disease (n = 20) or death caused by tumor (n = 14) was 31.7 months (range, 2.4 to 53.4). The median time to distant metastases (n = 28) or death caused by tumor (n = 11) was 18.9 months (range, 2.4 to 53.4). After those three patients with negative NSCLC histology were excluded, the OS and EFS results remained unchanged.
Prognostic Factors for Survival in Patients Undergoing Tumor Resection
Patients without pathologic mediastinal downstaging had poor survival rates (35% at 2 years, 11% at 3 years; median, 16.2 months; range, 2.4 to 37 months; Fig 2 ). This contrasts with a 2-year survival rate of 73% and 3-year rate of 61% (median not reached; range, 3.6 to 53.4 months) for patients with N0–1 downstaging. Results of the multivariate analyses are summarized in Table 5. Mediastinal downstaging (N0–1 v N2) proved to be the most powerful positive prognostic factor for survival (hazard ratio, 0.22; P = .0003; Table 5, model 1; Fig 2), after the four established prognostic factors (age, PS, tumor stage, and LDH) were taken into account. Although multilevel disease, resection margin, and complete resection were associated with OS in the univariate analyses, they also correlated with each other and with mediastinal downstaging. Therefore, it was not possible to include all of these factors in the same multivariate model. If mediastinal downstaging was replaced with complete resection in the multivariate model, complete resection proved to be the most powerful positive prognostic factor for survival (hazard ratio, 0.26; P = .0006; Table 5, model 2; Fig 3), after age, PS, tumor stage, and LDH were taken into account. If both mediastinal downstaging and complete resection were included, their prognostic impact remained, but with larger P values (Table 5, model 3) because of the correlation between the factors. After those three patients with negative NSCLC histology were excluded, the above-found associations, particularly those between survival and mediastinal downstaging or complete resection, remained true.
Our trial conducted in 90 patients with stage IIIA pN2 NSCLC revealed that docetaxel-cisplatin neoadjuvant chemotherapy was both active and well tolerated, with the majority of patients able to receive the planned dose. Moreover, the incidences of both perioperative morbidity (17%) and mortality (3%) after neoadjuvant therapy were low. Several prognostic factors were associated with OS; clearance of mediastinal lymph node involvement after chemotherapy was identified as the most powerful prognostic factor for survival (hazard ratio, 0.22; P = .0003). Surgical resection after neoadjuvant docetaxel-cisplatin treatment was also well tolerated after right pneumonectomy (49% of patients with tumor resection), which has previously been associated with unacceptable morbidity and mortality.14,15 Our results endorse the recent M.D. Anderson Cancer Center (Houston, TX) retrospective analysis in 380 NSCLC patients, which found no significant difference in the overall incidence of postoperative morbidity and mortality in patients who received neoadjuvant chemotherapy plus surgery versus surgery alone.16 Preliminary results from the Bimodality Lung Oncology Team phase II multicenter trial also demonstrate excellent tolerability and a low complication rate for neoadjuvant chemotherapy in a multicenter setting.17 In contrast, other institutions have demonstrated high rates of perioperative morbidity and mortality,18–22 which makes generalizations difficult. The good tolerability in our trial was not offset by a loss of activity, with an ORR of 66% achieved. Our pathologic CR rate of 15% in patients with tumor resection is comparable to the 14% reported by Martini et al23 for neoadjuvant mitomycin, vindesine, vinblastine, and cisplatin in stage IIIA (N2) disease. In our trial, complete resection with a negative resection margin and no involvement of the uppermost lymph node was achieved in 48% of all patients and 57% of patients with tumor resection. The resection margin and the uppermost lymph node were involved in 16% and 35% of patients with tumor resection, respectively. The median EFS and OS for patients with tumor resection were promising at 15 and 33 months, respectively. Although 33 patients received adjuvant radiotherapy, local relapse was high and occurred in 27% of patients with tumor resection. To date, the role of adjuvant radiotherapy in this setting remains undefined and further progress is required to reduce the high local relapse rate. Notwithstanding these results, the major problem for this patient population remains the high risk of distant metastases, which occurred in 37% of patients with tumor resection in our trial. The secondary objective of our trial was to identify prognostic factors for survival that have therapeutic implications. PS, weight loss, and disease stage (IIIA v IIIB) have historically been considered the key prognostic factors for survival in patients with locally advanced disease treated with either surgery or radiotherapy alone.1 Consequently, trials of surgery plus chemoradiotherapy have focused on patients with good PS (0 to 1) minimal weight loss (< 5% to 10%), and stage IIIA disease. Tumor size has also been identified as a prognostic factor for survival in some trials23,24 but not in others.25,26 The most powerful prognostic factor identified in our trial was clearance of mediastinal lymph nodes. Patients with remaining lymph node involvement had a poor 3-year survival rate of 11%, similar to that in stage IIIB-IV disease. In contrast, patients with N0–1 downstaging had a 73% survival rate at 3 years, similar to that expected for stage I disease. An association between survival and mediastinal lymph node clearance in locally advanced NSCLC has also been reported in a retrospective trial in 103 patients.27 In 29 patients downstaged to N0, a 5-year survival rate of 36% was achieved, with median OS of 21 months. In contrast, 74 patients with persistent lymph node tumor (N1 or N2) had a 9% survival rate at 5 years, with median OS of 16 months (P = .02). In the Southwest Oncology Group trial 8805, nodal downstaging was the only independent favorable prognostic factor identified in a multivariate model that included complete resection rate and pathologic complete response, among other factors.26 However, the Southwest Oncology Group trial included patients with stage IIIB disease and mediastinal radiotherapy was given, rendering assessment of chemotherapy on mediastinal downstaging difficult. A second strong prognostic factor for survival in our trial was complete resection, the significant impact of which remained evident even after adjustment for mediastinal downstaging. This observation is in agreement with other trials in locally advanced disease.28,29 No other factors reached statistical significance in our multivariate analyses. In our trial, tumor size was not predictive of response, probability of complete resection, EFS, or survival. Histology (in particular, squamous cell carcinomas) correlated with a better pathologic response after three cycles of docetaxel-cisplatin (P = .013). A similarly improved response for patients with nonadenocarcinoma histology was recently reported by Georgoulias et al,30 and may reflect the more frequent p53 mutation status in squamous cell carcinoma. Overall, these data support surgical resection for patients with mediastinal downstaging from N2 to N0–1 after chemotherapy. Conversely, patients with positive mediastinal lymph nodes after three cycles of docetaxel-cisplatin neoadjuvant chemotherapy do not benefit from resection. Efforts should therefore concentrate on improving the accuracy of restaging after neoadjuvant therapy by using the dual-modality positron-emission tomography and CT imaging technique or invasive staging. The Cancer and Leukemia Group B has an ongoing study assessing the efficacy of invasive restaging of lymph nodes after neoadjuvant therapy for stage IIIA NSCLC using thoracoscopy. Other modalities, such as lymph node biopsy via esophageal ultrasound and mediastinoscopy, may prove useful in identifying the optimal candidates for resection after neoadjuvant therapy. In conclusion, this multicenter phase II trial shows that neoadjuvant docetaxel-cisplatin is effective and well tolerated in stage IIIA N2 NSCLC, with mediastinal clearance and complete resection being strong prognostic factors for increased survival. The design of further trials in poor-prognosis, locally advanced NSCLC should ideally take into account the mediastinal lymph node response before thoracotomy. Because a second mediastinoscopy is difficult, we suggest further trials in which mediastinoscopy be performed once, after neoadjuvant chemotherapy, which should ideally be administered to patients with locally advanced disease as assessed by CT and positron-emission tomography scan. In the event of resistant disease in mediastinal lymph node biopsies obtained by mediastinoscopy, tumor resection should not be performed and patients may benefit from additional palliative chemoradiotherapy.
We thank Aventis Pharmaceuticals, Zurich, Switzerland, for providing the drug docetaxel.
Supported by an unrestricted grant used for part of the trial data management from Aventis Pharmaceuticals, Zurich, Switzerland.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 or Fisher’s exact test for categoric variables, and the log-rank test for time-to-event variables. 
