Interactive Cardiovascular and Thoracic Surgery 2:558-562(2003)
© 2003 European Association of Cardio-Thoracic Surgery
Institutional review - Thoracic general |
Survival and postoperative complication in daily practice after neoadjuvant therapy in resectable stage IIIA-N2 non-small cell lung cancer
Fabrice Barlésia,*,
Christophe Doddolib,
Bruno Chetaillec,
Jean-Philippe Torred,
Roger Giudicellib,
Pascal Thomasb,
Jean-Pierre Kleisbauera and
Pierre Fuentesb
a Department of Thoracic Oncology, Sainte Marguerite Hospital, University of Méditerranée, Faculty of Medicine, Assistance Publique - Hôpitaux de Marseille, Marseille, France
b Department of Thoracic Surgery, Sainte Marguerite Hospital, University of Méditerranée, Faculty of Medicine, Assistance Publique - Hôpitaux de Marseille, Marseille, France
c Department of Pathology, Sainte Marguerite Hospital, University of Méditerranée, Faculty of Medicine, Assistance Publique - Hôpitaux de Marseille, Marseille, France
d Department of Medical Information, Timone Hospital, University of Méditerranée, Faculty of Medicine, Assistance Publique - Hôpitaux de Marseille, Marseille, France
* Corresponding author. Service d'Oncologie Thoracique, Département des Maladies Respiratoires, Hôpital Sainte-Marguerite, 270 Bd Sainte-Marguerite, 13274 Marseille Cedex 09, France. Tel.: +33-491-74-47-36; fax: +33-491-74-55-24
Fabrice.Barlesi{at}mail.ap-hm.fr
Received April 23, 2003;
received in revised form June 30, 2003;
accepted July 3, 2003
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Abstract
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Regarding persisting controversies about neoadjuvant treatment (NT), we studied the impact of neoadjuvant therapy in daily practice. Patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) resected after NT were eligible. Data on preoperative treatments, surgical procedure, postoperative complications and survival were collected. Overall, 71 (60 men, median age of 60 years) patients met inclusion criteria. All patients received a two-drug platinum-based regimen (median of 2.5 cycles [2–4 cycles]) and 15 (21%) had an associated radiotherapy (20–40 Gy). Nine complete and 27 partial responses were achieved. Surgical procedure principally was a lobectomy (44%), a left (15.5%) or a right (27%) pneumonectomy. Operative mortality was 4.2% while 21 patients (29%) experienced postoperative complications. Median survival was 17 months (95% CI, 13–21 months) with 3- and 5-year survival rates of 24 and 13%, respectively. Five-year survival was worse if postoperative complication occurred (18 versus 0%,  ). Multivariate analysis showed male gender ( , 95% CI, 0.16–0.81,  ) and postoperative positive lymph node ( , 95% CI, 1.4–5.2,  ) to influence survival. In conclusion, achievement of a clinical and pathological response after NT for stage IIIA-N2 NSCLC patients enables a better survival. More efficient but also less toxic regimens of chemotherapy should be developed regarding its impact on long-term survival.
Key Words: Non-small cell lung cancer; Neoadjuvant chemotherapy; Pathological response; N2; Surgery; Postoperative complication
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1. Introduction
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Stage IIIA-N2 non-small cell lung cancer (NSCLC) remains of poor prognosis despite the changes in therapeutic strategies. Indeed, two randomized trials [1,2] suggested a significant survival benefit with the use of chemotherapy before surgery when compared to results obtained with surgery alone. Based on these results, most teams currently integrate neoadjuvant chemotherapy in their clinical practice. However, use of chemotherapy in this setting is still controversial given the results provided by three other trials [3–5]. Besides, adjunction of radiotherapy to neoadjuvant chemotherapy was investigated with similar median survival times. Conflicting issues with the multimodality approach and thus difficulties in determining the optimal treatment strategy in NSCLC patients with stage IIIA-N2 disease are explained in part by the heterogeneity of the staging methods used at the initial work-up, the pivotal fact that whether or not lymph node biopsies were required, the nature of chemotherapy drug combinations and adjuvant treatments applied in all these published trials.
Nevertheless, the poor results obtained with surgery alone in advanced stage patients explain the great attention given worldwide to the place of induction therapy during the past decade.
The aim of the present study was to depict the clinical impact of neoadjuvant therapy in daily practice for patients with stage IIIA-N2 NSCLC treated at our institution with emphasis on the patients' outcome.
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2. Material and methods
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2.1. Patients
The medical records of all patients who underwent surgery following induction therapy for a clinical stage IIIA-N2 NSCLC at diagnosis were reviewed for the period from 1990 to 2000. Patient charts were identified by screening of a database into which data were entered prospectively for any patient undergoing surgery for lung malignancy at our institution. All patients were staged on the basis of clinical examination, chest X-rays, bronchoscopy, abdominal ultrasound, nuclear bone scan, and finally body CT-scan findings, considering any mediastinal lymph node greater than 10 mm in its shortest diameter as pathologic. Patients with equivocal CT-scan findings or a lymph node disease supposed to be limited to one mediastinal station underwent cervical mediastinoscopy. Other patients were staged as cN2 provided that controlateral lymph node stations were supposed disease-free.
2.2. Treatments
Data on chemotherapy drugs, number of cycles, adjunction of radiotherapy and grade III–IV toxicity were collected. Clinical response to neoadjuvant chemotherapy was assessed on the same basis than the pre-treatment work-up using the WHO criteria (Table 1). Patients in whom local disease progression was suspected were reviewed for resectability and considered as candidates for surgery only if a complete resection was thought to be possible. Re-mediastinoscopy was not performed. The extent of the performed lung resection was tailored on the intraoperative assessment of the residual disease. Completeness of resection, pathologic stage, mediastinal lymph node stations and pathological features such as vascular or lymphatic invasion, involvement of visceral pleura and tumor grade were reported using internationally available criteria. Operative morbidity and mortality was defined as any event occurring during the first 30 days following surgery or during the same hospitalization. Postoperative treatment when appropriate was recorded. Date and site (local or general) of the first cancer recurrence were collected. Date of death was collected.
2.3. Statistical analysis
Survival was estimated using the product limit method of Kaplan–Meier from the date of the diagnosis and included the operative mortality as well as any cancer-related and unrelated death. The following variables were considered as potential prognosticators: age under 65 years, sex, clinical stage, carrying out of mediastinoscopy, clinical stage, preoperative chemotherapy and radiotherapy, response to neoadjuvant chemotherapy, type of resection, pathological lymph node status, number of resected lymph node, histology, grade, vascular or lymphatic invasion, pleural involvement, postoperative complications and adjuvant chemotherapy or radiotherapy. Factors potentially influencing postoperative complications were analyzed by the Pearson's  2 and Fisher's exact test. Kaplan–Meier log-rank and Cox regression analyses were used for univariate analyses. Proportional hazards regression (Cox model) was used to incorporate in the same model any explanatory variables with a p-value less than 0.20. Forward stepwise procedure and likelihood ratio tests were used to select the variables with the greatest prognostic value ( ). This statistical analysis was performed by using the SPSS V10.0 software package (SPSS Inc., Chicago, Illinois).
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3. Results
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From 1990 to 2000, 71 patients underwent surgery after neoadjuvant chemotherapy for an NSCLC staged as cIIIA-N2. There were 60 men and 11 women whose median age was 60 years (range 22–76 years). Forty-two patients (59%) underwent mediastinoscopy and had positive node biopsies while 29 patients were staged as having N2 disease on the basis of CT-scan findings only. Further clinical information is listed in Table 2.
3.1. Neoadjuvant treatment
All patients received a platinum-based regimen. Combination was done with vinorelbine in 33 (46.4%), etoposide in 18 (25.3%), paclitaxel in nine (12.7%), gemcitabine in nine (12.7%) and ifosamide plus mitomycine in two cases. A median of 2.5 cycles was administered (range 2–4 cycles). Fifteen patients (21%) received thoracic radiotherapy with neoadjuvant chemotherapy at doses ranging from 20 to 45 Gy. Eleven patients (15.5%) experienced a grade III/IV hematological toxicity and 18 (25%) a grade III/IV non-hematological toxicity essentially nausea and vomiting grade III (10 patients, 14%). Clinical response to the neoadjuvant treatment (NT) is summarized in Table 2.
3.2. Surgical treatment
Open and close thoracotomy was performed in five patients (7%): pleural metastasis (two cases), carena invasion (one case), controlateral nodule (one case) and chest wall invasion (one case). Type of resection and pathological staging are listed in Table 2. Histological features are as follows with a majority of adenocarcinoma (45%) and squamous cell carcinoma or large cell carcinoma in 38 and 17%, respectively. There were nine pathological complete responses. The median number of resected mediastinal lymph nodes was 14 (range 0–46). Sixty-one patients underwent a complete R0 resection while three and two patients had an R1 (microscopically invaded bronchial margin) or R2 (gross residual disease) incomplete resection, respectively.
3.3. Postoperative complications
One patient died intraoperatively from myocardial infarction. Two patients died postoperatively from ARDS. Operative mortality was thus 3/71 (4.2%). Twenty-one patients (29%) experienced a non lethal postoperative complication. One patient recovered from ARDS, 11 patients experienced infectious pneumonia and four a broncho-pleural fistula. Three were reoperated. Three patients presented with a recurrent nerve palsy. Another one presented with arrhythmia and the last one a stroke. No factor associated with the neoadjuvant as well as adjuvant treatments (i.e. drugs, number of cycles, radiotherapy, etc.) was significantly associated with occurrence of postoperative complication. Beyond the first 30 postoperative days, six patients experienced complications with two pulmonary embolism, two COPD exacerbations, one digestive bleeding and one febrile neutropenia.
3.4. Survival
Overall survival (Fig. 1A>) was 24% at 3 years (95% CI, 0–47%) and 13% at 5 years (95% CI, 0–45%) with median survival of 17 months (95% CI, 13–21 months). The recurrence was local, general or both in 22, 44 and 34% of relapsing patients, respectively. Factors influencing survival in univariate and multivariate analysis are summarized in Table 3. Survival was not influenced by carrying out mediastinoscopy (mean survival, 15 versus 17 months,  ). Survival curves for clinical response, positive postoperative lymph node and postoperative complications are shown in Fig. 1B–D, respectively. Responders as well as pN0 patients had the best survival figures. At multivariate analysis, female sex and persistence of an N2 disease were found as independent prognosticators of poor outcome.
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Fig. 1 A. Overall survival. B. Survival depending on clinical response to preoperative treatment. C. Survival depending on postoperative lymph node status. D. Survival depending on occurrence of postoperative complication.
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4. Discussion
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Despite controversial results of available randomized trials, combined strategies with induction therapy are currently applied for the management of stage IIIA-N2 NSCLC patients. Our single-institution experience typified some of the main pitfalls of such process: undefined place of invasive staging methods, wide variety of chemotherapy drug combinations, no guidelines concerning the selection of candidates for surgery as well as for the type of resection to be performed, and undefined role of adjuvant treatment. Of interest, however, is the fact that we observed very similar survival figures to those of currently available studies (median survival of 13–36.6 months and 3-year survival of 23–50% [6,7], and recently, Martin et al. [8] reported a median survival of 22 months and a 3-year survival of 34%). Our results showed that treatment-related risks of such combined treatment strategies may be quite low, as testified by our 4.2% of operative mortality. A word of caution is however required given that the occurrence of postoperative complications seemed to affect negatively the long-term outcome, although not reaching statistical significance (5-year survival of 18 versus 0%, ). Moreover, survival was strongly influenced by the clinical response (5-year survival of 24 versus 0%,  ) or achievement of a complete pathological mediastinal lymph node response (5-year survival of 25.5 versus 0%,  ). Presence of pathological N1 or N2 disease after neoadjuvant therapy presented a relative risk of death of 2.7 (95% CI, 1.4–5.2, ) at multivariate analysis.
Thus, presence of involvement of mediastinal lymph nodes at surgery was one of the strongest predictor factor reported in this study. Indeed, none of the patients were alive at 5 years in the case of persistent N1 or N2 disease. This finding is consistent with previous reports disclosing differences in median survival between pathological N2 and N0/N1 disease after neoadjuvant therapy (30–21.3 versus 10–15.9 months) [9,10]. This dramatically poor outcome for patients with pN2 disease after neoadjuvant chemotherapy suggests the need for an accurate mediastinal lymph node staging at operation in order to plane adjuvant treatment. Clearly, it argues in favor of an invasive preoperative staging by re-mediastinoscopy as suggested by Van Schil et al. [11] who reported a sensitivity of 73% with positive and negative values of 100 and 75%, respectively, for this technique. In the same area, clinical evaluation could be improved by new tools such as PET scanning which shows interesting results in mediastinal lymph node [12] and response [13] evaluation. Anyway, an accurate staging may avoid a potentially unnecessary thoracotomy in patients with persistent pathologic mediastinal lymph nodes, and to switch towards radiotherapy as it was recently suggested [14] and currently tested in an international setting (EORTC-08941 trial).
Our results showed a favorable prognosis for male gender (hazard ratio of 0.37, 95% CI 1.4–5.2, ). Sex was occasionally examined as a potential prognostic factor in operable NSCLC with conflicting results. Indeed, some authors reported a positive effect of female gender on survival [8] while others did not find any prognostic impact for sex [15]. However, favorable impact of male gender on survival was never reported before and none of the factors studied here could explain this difference. A molecular analysis (K-Ras, p53) could perhaps have shown an imbalance in genetic alterations between men and women included in this study.
Results of this study reinforced the current knowledge about the outcome of stage IIIA-N2 NSCLC patients submitted to NT in the daily practice setting, even if its size and its retrospective design did not allow us to draw formal conclusions. The heterogeneity of chemotherapy regimens is a serious drawback. It reflects the heterogeneity of NTs through a 10-year period and choice of various teams where patients were treated before being referred to us. However, "modern" regimens were used in more than 70% of cases (combination of platinum with either vinorelbine, paclitaxel or gemcitabine), a feature not widely reported in the available literature and type of chemotherapy did not influence patients' outcome in terms of response, complications or survival. Indeed, equivalence of these newer platinum-based regimens is attested by their results in advanced NSCLC patients. Besides, combinations without platinum seem to reach a good activity in advanced NSCLC and have also to be randomly tested in this setting. At last, we are also waiting for an ongoing trial interesting for part on neoadjuvant chemotherapy (UK MRC LU22).
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5. Conclusion
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In summary, NT is one of the possible ways to improve the management of stage IIIA-N2 NSCLC patients. Achievement of a clinical and above all pathological response is an important goal to be reached. Efforts should be made towards not only more efficient but also less toxic chemotherapy (and/or radiotherapy) regimen given that treatment-related risks have an impact on long-term survival.
doi:10.1016/S1569-9293(03)00138-5
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References
|
|---|
- Rosell R, Gomez-Codina J, Camps C, Maestre J, Padille J, Canto A, Mate JL, Li S, Roig J, Olazabal A, Canela M, Ariza A, Skacel Z, Morera-Prat J, Abad A. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med. 1994;330:153–158[Abstract/Free Full Text]
- Roth JA, Fossella F, Komaki R, Ryan MB, Putnam JB Jr., Lee JS, Dhingra H, De Caro L, Chasen M, McGavran M. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst. 1994;86:673–680[Abstract/Free Full Text]
- Pass HI, Pogrebniak HW, Steinberg SM, Mulshine J, Minna J. Randomized trial of neoadjuvant therapy for lung cancer: interim analysis. Ann Thorac Surg. 1992;53:992–998[Abstract]
- Yoneda S, Hibino S, Gotoh I, Sakai H, Noguchi Y, Yamamoto M. A comparative trial on induction chemotherapy followed by surgery (CRS) or immediate surgery (IS) for stage III NSCLC. Proc Am Soc Clin. 1995;14:A1128
- Depierre A, Milleron B, Moro-Sibilot D, Chevret S, Quoix E, Lebeau B, Braun D, Breton JL, Lemarie E, Gouva S, Paillot N, Brechot JM, Janicot H, Lebas FX, Terrioux P, Clavier J, Foucher P, Monchatre M, Coetmeur D, Level MC, Leclerc P, Blanchon F, Rodier JM, Thiberville L, Villeneuve A, Westeel V, Chastang C, French Thoracic Cooperative Group. Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non-small-cell lung cancer. J Clin Oncol. 2002;20:247–253[Abstract/Free Full Text]
- Perry MC, Deslauriers J, Albain KS, Choi NC, Depierre A, Johnston MR, Lacquet LK, Payne DG, Putnam JB, Sculier JP, Shepherd FA. Induction treatment for resectable non-small cell lung cancer. Lung Cancer. 1997;17:S15–S18[Medline]
- Eberhardt W, Hepp R, Korfee S, Stamatis G. Current status of adjuvant and neoadjuvant chemotherapy in resectable nonsmall cell lung cancer. Eur Respir Rev. 2002;84:196–207
- Martin J, Ginsberg RJ, Venkatraman ES, Bains MS, Downey RJ, Korst RJ, Kris MG, Rusch VW. Long-term results of combined-modality therapy in resectable non-small-cell lung cancer. J Clin Oncol. 2002;20:1989–1995[Abstract/Free Full Text]
- Choi NC, Carey RW, Daly W, Mathisen D, Wain J, Wright C, Lynch T, Grossbard M, Grillo H. Potential impact on survival of improved tumor downstaging and resection rate by preoperative twice-daily radiation and concurrent chemotherapy in stage IIIA non-small-cell lung cancer. J Clin Oncol. 1997;15:712–722[Abstract/Free Full Text]
- Bueno R, Richards WG, Swanson SJ, Jaklitsch MT, Lukanich JM, Mentzer SJ, Sugarbaker DJ. Nodal stage after induction therapy for stage IIIA lung cancer determines patient survival. Ann Thorac Surg. 2000;70:1826–1831[Abstract/Free Full Text]
- Van Schil P, van der Schoot J, Poniewierski J, Pauwels M, Carp L, Germonpre P, De Backer W. Remediastinoscopy after neoadjuvant therapy for non-small cell lung cancer. Lung Cancer. 2002;37:281–285[CrossRef][Medline]
- Pieterman RM, Van Putten JW, Meuzelaar JJ, Mooyaart EL, Vaalburg W, Koeter GH, Fidler V, Pruim J, Groen HJ. Preoperative staging of non-small-cell lung cancer with positron-emission tomography. N Engl J Med. 2000;343:254–261[Abstract/Free Full Text]
- Hoekstra CJ, Hoekstra OS, Stroobants SG, Vansteenkiste J, Nuyts J, Smit EF, Boers M, Twisk JW, Lammertsma AA. Methods to monitor response to chemotherapy in non-small cell lung cancer with 18F-FDG PET. J Nucl Med. 2002;43:1304–1309[Abstract/Free Full Text]
- Johnstone DW, Byhardt RW, Ettinger D, Scott CB. Phase III study comparing chemotherapy and radiotherapy with preoperative chemotherapy and surgical resection in patients with non-small-cell lung cancer with spread to mediastinal lymph nodes (N2); final report of RTOG 89-01. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys. 2002;54:365–369[CrossRef][Medline]
- Choi YS, Shim YM, Kim J, Kim K. Recurrence-free survival and prognostic factors in resected pN2 non-small cell lung cancer. Eur J Cardiothorac Surg. 2002;22:695–700[Abstract/Free Full Text]
- Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer. 1981;47:207–214[CrossRef][Medline]
- Mountain CF. Revisions in the International system for staging lung cancer. Chest. 1997;111:1710–1717[Abstract/Free Full Text]
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Abstract
1. Introduction