HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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): Stefano Margaritora Alfredo Cesario Domenico Galetta Pierluigi Granone Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Margaritora, S. Articles by Granone, P. Search for Related Content PubMed PubMed Citation Articles by Margaritora, S. Articles by Granone, P. Related Collections Lung - cancer

Eur J Cardiothorac Surg 2001;19:894-898
© 2001 Elsevier Science NL

Ten year experience with induction therapy in locally advanced non-small cell lung cancer (NSCLC): is clinical re-staging predictive of pathological staging?

^a General Thoracic Surgery, Department of General Surgery, Catholic University, Rome, Italy
^b Department of Radiology, Catholic University, Rome, Italy
^c Department of Radiotherapy, Catholic University, Rome, Italy

Received 7 October 2000; received in revised form 20 March 2001; accepted 21 March 2001.

Corresponding author. Tel.: +39-0335-8366161; fax: +39-06-3051162
e-mail: alfcesario{at}yahoo.com

	Abstract

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion 5. Conclusion Appendix A. Conference... References

 
Objective: To verify if in our experience with ‘induction therapy’ in non-small cell lung cancer (NSCLC) the clinical re-staging is really predictive of pathological staging. Materials and methods: From January 1990 to February 2000, 136 patients with locally advanced NSCLC underwent a protocol of induction therapy according to three different treatment plans: Carboplatin+radiotherapy – study A; Cisplatin+5-Fluorouracil+radiotherapy – study B; Gemcitabine+radiotherapy – study C. Results: Clinical re-staging showed in the patients enrolled in study A a clinical Complete Response rate (cCR) of 2.3%; a clinical Partial Response rate (cPR) of 50%; a clinical Stable Disease (cSD) rate of 44.3%; a clinical Disease Progression (cDP) rate of 3.4%. In study B, cCR was 0%; cPR: 71.4%; cSD 10.7%; cDP: 17.9%. In study C, cCR was 0%; cPR: 23.5%; cSD: 11.8%; cDP: 64.7%. After clinical re-staging, 76 patients (47 group A; 23 group B; 6 group C) were judged to be resectable and underwent a surgical operation. Pathological staging showed no tumour in eight patients (10.5%; 8/76) (three in study A, four in study B, one in study C) and microscopic neoplastic remnants in seven (9.2%; 7/76). Thirty-nine patients were pN0. Overall downstaging rate in the operated patients was 51%. No precise correlation was found among clinical re-staging and pathological staging. We had two cCRs and eight pCRs, and all of these pCRs had been re-staged as cPR except in one case (cSD). In seven cases, where only microscopic remnants have been found, six had been clinically restaged as cPR and one as cSD. Conclusions: Our experience confirmed how often the clinical re-staging data are unreal. Accordingly surgery should be indicated in any case where an induction therapy has been administered, if it is reasonably possible.

Key Words: Non-small cell lung cancer • Induction therapy • Clinical staging • Clinical restaging • Pathological staging

	1. Introduction

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion 5. Conclusion Appendix A. Conference... References

 
The neoadjuvant or induction therapy (IT) is a cytoreductive treatment, given to a patient with a diagnosis of cancer in a pre-operative setting. In the last ten years, many studies concerning induction therapy in non-small cell lung cancer (NSCLC) with mediastinal lymph node involvement have been realized, on the basis of the encouraging preliminary results. These tumours are classified as N2 and staged IIIa or IIIb according to the dimensional and infiltrative characteristics of the tumour mass: this classification remained unchanged in the recent revision by Mountain [1].

The patients enrolled in an induction therapy protocol must follow a strictly uniform plan: clinical staging, induction therapy, clinical re-staging with the evaluation of response to the treatment, surgery, and pathological staging in the resected cases. The comparison of the results for patients enrolled in a neoadjuvant protocol is based on the respect of the precise classification according to the TNM staging of each tumour inside the three different staging procedures: clinical, clinical post induction therapy and pathological. Looking at the wide literature report on this issue the general idea is that the clinical re-staging procedure is somewhat limited by the bias associated with imaging procedures (accuracy).

This paper describes retrospectively our experience with neoadjuvant therapy to verify if the clinical re-staging is really predictive of pathological staging, evaluating the results of a wide, homogeneous and methodologically uniform experience.

To do this we reviewed three induction therapy protocols: one previously described [2] and now terminated (study A); the second (study B) and the third (study C) still in progress. It is to be underlined that, in this paper, no comparison between the specific results of the three protocols has been attempted and no analysis of the survival has been carried out.

	2. Patients and methods

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion 5. Conclusion Appendix A. Conference... References

 
In the period between January 1990 and February 2000, 136 patients with locally advanced NSCLC underwent IT according to three different protocols. Male/female ratio was 122:14, with an average age of 61 years (range 42–77). The population was normally distributed.

The clinical staging has been obtained by means of chest X-ray, bronchoscopy, CT scan of the thorax, brain and upper abdomen, liver ultra-sonography, and whole bone radionuclide scan. Respiratory function was assessed with standard spirometry, blood gases analysis, CO diffusion testing and pulmonary perfusion scan.

Cyto/histological confirmation of the primitive tumour has been obtained by fine needle aspiration biopsy (FNAB) and/or endo/trans-bronchial biopsy. In all the patients mediastinal lymph node involvement has been histologically or cytologically confirmed by mediastinoscopy in 83 cases (61%), FNAB in 41 patients (30%) and left anterior mediastinotomy in 22 patients (16%). Patients characteristics are summarized in Table 1.

Induction treatment protocols details are described in Table 2. We remind the lector that while study A has been terminated, study B and C are still in progress. This very last, moreover, is a phase I, ‘dose finding’ study.

In all patients a re-evaluation of the pulmonary function has been realized.

	3. Results

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion 5. Conclusion Appendix A. Conference... References

 
Clinical re-staging has been carried out on 133 patients. One patient died for acute haemathological toxicity, one patient died for a massive bleeding from the tumour inside the bronchial tree (and considered as a direct effect of the treatment) and one patient developed multiple symptomatic brain metastases. Treatment-related mortality rate was 1.5% (2/136). Re-do mediastinoscopy to confirm the absence of tumour at the N3 level has been performed in two patients. Data on clinical re-staging are summarized in Tables 3 and 4. The overall clinical downstaging (staging at clinical re-staging more favorable than the initial one) was 51% (68/133). After the induction treatment 78 patients have been judged to be resectable. Two patients refused surgery. Due to the intra-operative finding of an extensively infiltrating tumour, in three cases an explorative thoracotomy has been performed. Seventy-three patients underwent major pulmonary resection and homolateral hilar and mediastinal lymph-node dissection (a mean number of 20 lymph-nodes have been dissected and examined). Only one patient had an incomplete resection (evidence of microscopic (R1) tumour infiltration of the bronchial margin). Data on surgical details are summarized in Table 5. The overall resectability index has been 54% (72/133). The resectability index referred to the patients clinically judged to be resectable and operated upon is 96% (73/76). With regards to the pathological staging data are summarized in Tables 6 and 7. The overall pathological downstaging was 48.6% (37/76).

So, in our experience, we report a discrepancy rate among clinical re-staging and pathological re-staging of 22% (17/76).

	4. Discussion

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion 5. Conclusion Appendix A. Conference... References

 
In this paper the authors have voluntarily not addressed the very large number of discussion opportunities present when neo-adjuvant therapy in NSCLC is approached. So, subjects as the possible ways of clinical staging, the mediastinal lymph node identification, their cyto or histological confirmation, the post-surgical therapy, etc. have not been addressed. The general idea is that the clinical re-staging procedure based essentially on CT and NMR imaging is limited according to the limited accuracy of these methods, especially in a neoadjuvant setting where the effects of therapy confuses the chance to distinguish between scar and residual tumour tissue.

The focus of this paper is, in fact, in the assessment of the value of clinical re-staging in predicting the real extent of the response to an induction therapy protocol, in a methodologically uniform and homogeneous experience.

Locally advanced NSCLC is accordingly considered as a systemic disease and the chance of cure given by a single treatment option (chemotherapy or radiotherapy or surgery) are very low [3,4].

Chemotherapy combined with thoracic radio-therapy has emerged as a primary treatment option for locally advanced NSCLC [5].

When this type of approach is used in neoadjuvant setting (systemic spread prevention and loco-regional macroscopic shrinkage) and a complete or major response is achieved prior to surgery (i.e. at the clinical restaging) a better long term outcome can be anticipated [5–11].

In the last 10 years, the neoadjuvant therapy treatment plans have been mainly used in the NSCLC with homolateral mediastinal lymph node involvement, clinically staged IIIa or IIIb. The efficacy of the various neoadjuvant treatment plans protocols adopting chemo or radio-chemotherapy is firstly evaluated at the moment of the clinical re-staging.

When only the bigger reported experiences are analysed, we observe clinical ‘Major Response’ (cMR) rates that are somewhat different.

For chemotherapy-only based regimens, the range of cMR obtained is 54% (Kirn [12]) to 87% [13]; for radio-chemotherapy protocols it is 51% [14] to 85% [15]. In the cases of cMR the cCR and cPR ratio is variable with differences sometimes low (Kirn [12] reported a 10% value of cCR versus 44% of cPR) and sometimes higher (Rush [15] reported a 80% value of cPR versus 5% of cCR, Strauss [14] a 51% value of cPR versus 0% of cCR and Andre [3] recently reported value of 70% of cPR versus 2% of cCR).

The results are different when the pathological staging is compared too. In fact the 4% value of pCR in the Kirn [12] and Rosell [16] experiences is not confirmed in that of Faber [17] where a 27% value of pCRs is reported.

Anyway, it is really interesting to make a comparison between the clinical re-staging and the pathological staging data. Pujol [18] alone, in fact, reports a precise correlation of cCRs with pCRs: in the five patients where no radiological remnants of tumour were detected at the moment of clinical re-staging, the pathological examination confirmed the absence of tumour. In the other evaluated experiences, significant differences are, on the contrary, reported.

Rush [15] reports a 5% cCR value versus a 23% of pCR while Rosell reports a 7% of cCR value versus a 4% of pCR. Sometimes the values are equivalent by chance: Burkes [19], in fact, obtained three pCRs and three cCRs but only one cCR was confirmed to be a pCR because in the other two cases some neoplastic remnants (as microscopic foci) were found at the moment of the pathological examination. The other pCR cases, at the moment of clinical re-staging, had been classified as cPR.

In our experience, a discrepancy ratio of 22% (17 out of 76 cases) is reported. Several authors agree about the very little predictive value on the index of tumour reduction of the clinical re-staging. In fact, the precise difference in the number of cCRs when compared with the number of pCRs is sometimes only reported [16], and sometimes investigated [20]. In this experience, Yashar reports how, in four of the ten cases of pCR, some radiological findings of tumour remnants had been reported. Martini [21] puts the focus on the fact that on the whole number of 19 pCRs, only five were cCRs, and the remaining 14 were cPRs. Strauss [14], who didn't report any cCR, got four pCRs (three in patients who achieved a cPR and one in a cSD case). Moreover, in the three unresectable cases discovered at the time of operation for the extent of the presumed neoplastic mass, only biopsies were undertaken. No tumour was found at the moment of the pathologic examination of the biopsies, but fibrosis and necrosis, only.

All these observations demonstrate how difficult it is to distinguish, after an induction treatment is administered, among neoplastic tissue, fibrosis and scar, not only by means of the radiological evaluation at the moment of clinical re-staging, but at the time of the operation by means of the surgeon's hands, too.

	5. Conclusion

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion 5. Conclusion Appendix A. Conference... References

 
At the light of the reported evidences we can conclude that:

• Three different but comparable staging procedures must be scheduled when an induction treatment protocol is planned: clinical staging, clinical re-staging after induction therapy, pathological staging.
  
• The bias in the comparison of the results of the different experiences is represented mainly by the fact that often the staging procedures are not homogeneous. In our opinion a not uniform staging procedure makes the different induction therapy trials results data not much, if not at all, comparable.
  
• Considering clinical re-staging and pathological staging, nowadays, we don't think it can be considered incorrect to indicate surgery for the most of the patients enrolled in the IT protocols including the patients, where a clinical No Change has been evidenced. In fact several experiences, including ours, demonstrated how very often the clinical re-staging overesteems the real extent of the residual disease, with imaging that very hardly distinguish among neoplastic tissue, fibrosis and scar. In this way, in fact, it is possible to judge as unresectable patients who have a residual disease that is, actually, minimal.
  

For these reasons we feel comfortable to conclude recommending to indicate surgery where an induction therapy has been administered when it is reasonably possible. The re-staging procedure results, in fact, seem to be often unreal.

	Footnotes

 
Presented at the 14th Annual Meeting of the European Association of Cardio-thoracic Surgery, Frankfurt, Germany, October 7–11, 2000.

	Appendix A. Conference discussion

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion 5. Conclusion Appendix A. Conference... References

 
Dr P. Macchiarini (Hannover, Germany): Could you please tell us how you did your staging?

Dr Margaritora: All patients included in this protocol had non-invasive procedures; CT scan of the whole body, later with sonography, bone scintigraphy. And all of these patients were histologically-proven N2 patients. I mean that we did obtain histology by means of mediastinoscopy or anterior median sternotomy or in eight cases fine-needle aspiration biopsy of N2 stations.

Dr Macchiarini: That means that the mediastinum was correctly staged through mediastinoscopies almost always?

Dr Margaritora: Yes. Because only these patients were included in this study.

Dr F. Rea (Padova, Italy): Did you have a group of patients with combined chemotherapy and radiotherapy?

Dr Margaritora: All patients. We changed the chemo scheme in the last 2 years, but all patients had radiotherapy already.

Dr Rea: In the last group of patients where you changed with the new drugs, do you have some difference in results?

Dr Margaritora: Currently, no, because it is a small number, the last 28 patients out of 136. So I do not have results yet.

	References

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion 5. Conclusion Appendix A. Conference... References

 

1. Mountain C.F. Revisions in the international system for staging lung cancer. Chest 1997;111:1710-1717.[Abstract/Free Full Text]
2. Granone P., Margaritora S., Cesario A., Galetta D., Bonatti P.L., Picciocchi A. Concurrent radiochemotherapy for N2 NSCLC. Interim analysis. Eur J Cardio-thorac Surg 1997;12:366-371.[Abstract]
3. Andre F., Grunenwald D., Pignon J.P., Dujon A., Pujol J.L., Brichon P.Y., Brouchet L., Quoix E., Westeel V., Le Chevalier T. Survival of patients with resected N2 non-small-cell lung cancer: evidence for a subclassification and implications. J Clin Oncol 2000;16:2981-2989.
4. Mattson K. Docetaxel (Taxotere) in the neo-adjuvant setting in non small cell lung cancer. Ann Oncol 1999;10(Suppl 5):S69-S72.
5. Rosell R., Felip E. Role of multimodality treatment for lung cancer. Semin Surg Oncol 2000;18(2):143-151.[Medline]
6. Lilembaum R.C., Green M. Multimodality therapy for non small cell lung cancer. Oncology 1994;8:25-31.[Medline]
7. Rosell R., Gomez-Codina J., Camps C., Maestre J., Padille J., Canto A., Mate J.L., Li S., Roig J., Olazabal 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(3):153-158.[Abstract/Free Full Text]
8. Roth J.A., Fossella F., Komaki R., Ryan M.B., Putnam J.B., Jr, Lee J.S., 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(9):673-680.[Abstract/Free Full Text]
9. Pass H.I., Pogrebniak H.W., Steinberg S.M., Mulshine J., Minna J. Randomized trial of neoadjuvant therapy for lung cancer: interim analysis. Ann Thorac Surg 1992;53(6):992-998.[Abstract]
10. Depierre A., Milleron B., Moro D. Phase III trial of neo-adjuvant chemotherapy (NCT) in resectable stage I (except T1N0), II, Iia non-small cell lung cancer (NSCLC): The French experience. Proc Am Soc Clin Oncol 1999;18:465a (abstract 1792).
11. Schilder R.J., Goldberg M., Millenson M.M., Movsas B., Rogatko A., Rogers B., Langer C.J. Phase II trial of induction high-dose chemotherapy followed by surgical resection and radiation therapy for patients with marginally resectable non-small cell carcinoma of the lung. Lung Cancer 2000;27(1):37-45.[Medline]
12. Kirn D.H., Lynch T.J., Mentzer S.J., Lee T.H., Strauss G.M., Elias A.D., Skarin A.T., Sugarbaker D.J. Multimodality therapy of patients with stage IIIa N2 non small cell lung cancer. Impact of pre-operative chemotherapy on resectability and downstaging. J Thorac Cardiovasc Surg 1993;106:696-702.[Abstract]
13. Mathisen D.J., Wain J.C., Wright C., Choi N., Carey R., Hilgenberg A., Grossbard M., Lynch T., Grillo H. Assessment of preoperative accelerated radiotherapy and chemotherapy in stage IIIa (N2) non small cell lung cancer. J Thorac Cardiovasc Surg 1996;111(1):123-131.[Abstract/Free Full Text]
14. Strauss G.M., Herndon J.E., Sherman D.D., Mathisen D.J., Carey R.W., Choi N.C., Rege V.B., Modeas C., Green M.R. Neoadjuvant chemotherapy and radiotherapy followed by surgery in stage IIIa non small cell carcinoma of the lung: report of a Cancer and Leukemia Group B phase II study. J Clin Oncol 1992;10:1237-1241.[Abstract/Free Full Text]
15. Rush V.W. Resection of stage III non small cell lung cancer following induction therapy. World J Surg 1995;19:817-822.[Medline]
16. Rosell R., Font A., Pifarre A., Canela M., Maurel J., Arellano A., Izquierdo J. The role of induction therapy (neoadjuvant) chemotherapy in stage IIIa NSCLC. Chest 1996;109(Suppl 5):102S-106S.[Medline]
17. Faber L.P., Kittle C.F., Warren W.H., Bonomi P.D., Taylor S., IV, Reddy S., Lee M.S. Pre-operative chemotherapy and irradiation for stage III non small cell lung cancer. Ann Thorac Surg 1988;45:370-379.[Abstract]
18. Pujol J.L., Rossi J.F., Le Chevalier T., Daures P., Rouanet P., Douillard J.I., Dubois J.B., Arriagada R., Mary H., Godard P., Michel F.B. Pilot study of neoadjuvant ifosfamide, cisplatin and etoposide in locally advanced non small cell lung cancer. Eur J Cancer 1990;26(7):798-801.
19. Burkes R.L., Ginsberg R.J., Sheperd F.A., Blackstein M.E., Goldberg M.E., Waters P., Patterson A., Todd T., Pearson F.G., Cooper J., Jones D., Lockwood G. Induction chemotherapy with mitomicin, vindesine and cisplatin for stage III unresectable non small cell lung cancer: results of the Toronto phase II trial. J Clin Oncol 1992;10:580-586.[Abstract/Free Full Text]
20. Yashar J., Weitberg A.B., Glicksmann A.S., Posner M.R., Feng W., Wanebo H.J. Preoperative chemotherapy and radiation therapy for stage IIIa carcinoma of the lung. Ann Thorac Surg 1992;53:445-450.[Abstract]
21. Martini N., Kris M.G., Flehinger B.J., Gralla R.J., Bains M.S., Burt M.E., Heelan R., McCormack P., Pisters K.M.W., Rigas J., Rusch V.W., Ginsberg R.J. Preoperative chemotherapy for stage IIIa (N2) lung cancer: the Sloan Kettering experience with 136 patients. Ann Thorac Surg 1993;55:1365-1374.[Abstract]

This article has been cited by other articles:

				L. A. Robinson, J. C. Ruckdeschel, H. Wagner Jr, and C. W. Stevens Treatment of Non-small Cell Lung Cancer-Stage IIIA: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition) Chest, September 1, 2007; 132(3_suppl): 243S - 265S. [Abstract] [Full Text] [PDF]

				M. Serra, L. Occhionero, and D. Galetta Complete Response Following Preoperative Chemotherapy for Resectable Non-small Cell Lung Cancer. Chest, October 1, 2006; 130(4): 1284 - 1285. [Full Text] [PDF]

				B. Milleron, V. Westeel, E. Quoix, D. Moro-Sibilot, D. Braun, B. Lebeau, A. Depierre, and for the French Thoracic Cooperative Group Complete Response Following Preoperative Chemotherapy for Resectable Non-Small Cell Lung Cancer: Accuracy of Clinical Assessment Using the French Trial Database Chest, September 1, 2005; 128(3): 1442 - 1447. [Abstract] [Full Text] [PDF]

				A. Cesario, S. Margaritora, D. Galetta, V. Porziella, P. Granone, R. M. D'Angelillo, L. Trodella, V. Cardaci, S. Sterzi, and P. Russo Correspondence re L. J. Wirth et al., Induction Docetaxel and Carboplatin Followed by Weekly Docetaxel and Carboplatin with Concurrent Radiotherapy, Then Surgery in Stage III Non-Small Cell Lung Cancer: a Phase I Study. Clin Cancer Res 2003;9:1698-704. Clin. Cancer Res., April 15, 2004; 10(8): 2902 - 2903. [Full Text] [PDF]

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): Stefano Margaritora Alfredo Cesario Domenico Galetta Pierluigi Granone Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Margaritora, S. Articles by Granone, P. Search for Related Content PubMed PubMed Citation Articles by Margaritora, S. Articles by Granone, P. Related Collections Lung - cancer