Neoadjuvant Chemotherapy for Resectable Non–Small-Cell Lung Cancer
By Jhanelle Gray, MD1, Eric Sommers, MD2, Miguel Alvelo-Rivera, MD3, Lary Robinson, MD4,
Gerold Bepler, MD, PhD5 |
September 14, 2009
1 Assistant Professor of Medicine and Oncological Sciences, University of South Florida, Assistant Member, Thoracic Oncology
2 Assistant Professor of Surgery, University of South Florida, Assistant Member, Thoracic Oncology
3 Associate Professor of Surgery,
University of South Florida,
Professor of Surgery, University of South Florida, Senior Member, Thoracic Oncology
5 Professor of Medicine and Oncological Sciences, University of South Florida, Department Chair, Thoracic Oncology
Moffitt Cancer Center & Research Institute,
Randomized Trials of Neoadjuvant Therapy Followed by Surgery Compared With Definitive Chemoradiotherapy for Stage IIIA Non–Small-Cell Lung Cancer
Although surgery offers the best chance for survival to patients with limited-station N2 disease, not all patients with N2 disease are appropriate candidates for surgical resection. Neoadjuvant systemic chemotherapy may play a role in the management of this disease to help facilitate local surgical control. Many patients may have technically resectable disease but may not be curatively resectable. That is, they will have microscopic or macroscopic disease following their surgical procedure, solidifying their chances for relapse. For these patients, consideration must be given to concurrent chemoradiation for definitive treatment (Table 5). Although phase II studies did suggest a benefit to neoadjuvant concurrent chemoradiation therapy followed by surgery,[30-32] randomized trials found no additional benefit to surgery following bimodality induction therapy.[33-37]
Adjuvant vs Neoadjuvant Chemotherapy
Many studies have called for a randomized trial to evaluate and compare adjuvant vs neoadjuvant chemotherapy in patients with resectable cancer. In the Neoadjuvant/Adjuvant Taxol (paclitaxel) Carboplatin(Drug information on carboplatin) Hope (NATCH) trial from the Spanish Lung group, participants with stage I (> 2 cm), II, and T3, N1 NSCLC were randomized to either neoadjuvant or adjuvant carboplatin/paclitaxel and surgery. The preliminary results from the neoadjuvant arm, which was presented at the 2007 ASCO meeting, found neoadjuvant chemotherapy to be safe and feasible.
Final results of the NATCH trial were presented in August 2009 at the 13th World Congress on Lung Cancer, organized by the International Association for the Study of Lung Cancer (IASLC). Among the 624 participants in the study at the time of presentation, no significant difference in progression-free or overall survival was detected. With preoperative chemotherapy, adjuvant chemotherapy, and surgery alone, the 5-year progression-free survival rates were 38.3%, 36.6%, and 34%, and the 5-year overall survival rates were 46.6%, 45.5%, and 44%, respectively. This study was limited by the fact that a majority of participants had stage IA/IB NSCLC. Moreover, many participants in the adjuvant chemotherapy arm were unable to receive the planned three cycles of chemotherapy due to peri/postoperative morbidity. Both of these factors may have contributed to the difficulty in achieving statistical significance. Nevertheless, subset and exploratory analyses of the trial are currently underway to evaluate prognostic factors as well as prognostic and predictive molecular markers.
The Chinese Society of Lung Cancer has launched the Survival Study of Docetaxel(Drug information on docetaxel) and Carboplatin as Neoadjuvant vs Adjuvant Chemotherapy in Early-Stage NSCLC (NCT00321334). This investigation is set to enroll 410 participants and to be completed in March 2012. The trial may provide long-awaited answers to some key questions.
A systematic review of 31 randomized trials (21 postoperative and 10 preoperative chemotherapy) with over 10,000 subjects presented at ASCO 2008 is available. In this review, no differences in surgical morbidity/mortality, disease-free survival, or overall survival were found between the two groups. Based on these results, it would appear that the timing of chemotherapy administration has little impact on outcomes for patients with operable NSCLC.
To determine which chemotherapy regimens are ideal for which patient, molecular analysis is currently being studied in the metastatic and adjuvant setting. Molecular analysis for classification of NSCLC will play a key role as a tool for therapy-related decisions.
Lung cancer carries a poor prognosis. In efforts to improve that prognosis, the role of neoadjuvant chemotherapy has been studied extensively. From the type of surgical procedure performed to the type of chemotherapy used—not only within but also between studies—the data are difficult to analyze because of multiple heterogeneities. Nevertheless, potential advantages of neoadjuvant chemotherapy can be hypothesized. These include a decrease in tumor volume to improve curative surgical resection rates. With systemic administration of chemotherapy, micrometastatic disease is attended to earlier. In addition, there has been some argument for increased compliance with systemic administration of chemotherapy in the neoadjuvant setting. Whether these approaches translate into outcomes superior to those found when platinum-based chemotherapy is used in the adjuvant setting remains unknown.
Evidence about the role of neoadjuvant chemotherapy is inconclusive, as no large randomized trials comparing neoadjuvant chemotherapy to adjuvant chemotherapy in resectable NSCLC have determined any significant differences. The authors of this review believe that each patient needs to be evaluated individually by a multidisciplinary team of physicians.
Neoadjuvant chemotherapy may be beneficial to some patients, especially those who may otherwise have been unresectable. Patients must undergo adequate staging of the mediastinum via modalities such as mediastinoscopy and PET/CT. In addition to staging, the treating physician must pay close attention to the patients’ performance status, age, weight, and comorbidities when making these decisions. Finally, the addition of PORT to the treatment algorithms of patients with stage IIIA disease can be considered.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2008. CA Cancer J Clin 58:71-96, 2008.
2. Mountain CF: Revisions in the International System for Staging Lung Cancer. Chest 111:1710-1717, 1997.
3. Groome PA, Bolejack V, Crowley JJ, et al: The IASLC Lung Cancer Staging Project: Validation of the proposals for revision of the T, N, and M descriptors and consequent stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol 2:694-705, 2007.
4. Arriagada R, Bergman B, Dunant A, et al: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350:351-360, 2004.
5. Kato H, Ichinose Y, Ohta M, et al: A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med 350:1713-1721, 2004.
6. Winton T, Livingston R, Johnson D, et al: Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 352:2589-2597, 2005.
7. Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 311:899-909, 1995.
8. Pignon JP, Tribodet H, Scagliotti GV, et al: Lung adjuvant cisplatin evaluation: A pooled analysis by the LACE Collaborative Group. J Clin Oncol 26:3552-3559, 2008.
9. Scagliotti GV, Fossati R, Torri V, et al: Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell lung cancer. J Natl Cancer Inst 95:1453-1461, 2003.
10. Roth JA, Fossella F, Komaki R, et al: A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst 86:673-680, 1994.
11. Rosell R, Gomez-Codina J, Camps C, et al: Preresectional chemotherapy in stage IIIA non-small-cell lung cancer: A 7-year assessment of a randomized controlled trial. Lung Cancer 26:7-14, 1999.
12. Burdett S, Stewart LA, Rydzewska L: A systematic review and meta-analysis of the literature: Chemotherapy and surgery versus surgery alone in non-small cell lung cancer. J Thorac Oncol 1:611-621, 2006.
13. Depierre A, Milleron B, Moro-Sibilot D, et al: 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 20:247-253, 2002.
14. Gilligan D, Nicolson M, Smith I, et al: Preoperative chemotherapy in patients with resectable non-small cell lung cancer: Results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review. Lancet 369:1929-1937, 2007.
15. Pisters K, Vallieres, E, Bunn, PA, et al: S9900: Surgery alone or surgery plus induction (ind) paclitaxel/carboplatin (PC) chemotherapy in early stage non-small cell lung cancer (NSCLC): Follow-up on a phase III trial (abstract 7520). J Clin Oncol 25(18S):389s, 2007.
16. Lorent N, De Leyn P, Lievens Y, et al: Long-term survival of surgically staged IIIA-N2 non-small-cell lung cancer treated with surgical combined modality approach: Analysis of a 7-year prospective experience. Ann Oncol 15:1645-1653, 2004.
17. Sugarbaker DJ, Herndon J, Kohman LJ, et al: Results of cancer and leukemia group B protocol 8935. A multiinstitutional phase II trimodality trial for stage IIIA (N2) non-small-cell lung cancer. Cancer and Leukemia Group B Thoracic Surgery Group. J Thorac Cardiovasc Surg 109:473-485 (incl discussion), 1995.
18. Betticher DC, Hsu Schmitz SF, Totsch M, et al: 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. J Clin Oncol 21:1752-1759, 2003.
19. Migliorino MR, De Marinis F, Nelli F, et al: A 3-week schedule of gemcitabine plus cisplatin as induction chemotherapy for stage III non-small cell lung cancer. Lung Cancer 35:319-327, 2002.
20. Roberts JR, Eustis C, Devore R, et al: Induction chemotherapy increases perioperative complications in patients undergoing resection for non-small cell lung cancer. Ann Thorac Surg 72:885-888, 2001.
21. Venuta F, Anile M, Diso D, et al: Operative complications and early mortality after induction therapy for lung cancer. Eur J Cardiothorac Surg 31:714-717, 2007.
22. Mansour Z, Kochetkova EA, Ducrocq X, et al: Induction chemotherapy does not increase the operative risk of pneumonectomy! Eur J Cardiothorac Surg 31:181-185, 2007.
23. Martin J, Ginsberg RJ, Abolhoda A, et al: Morbidity and mortality after neoadjuvant therapy for lung cancer: The risks of right pneumonectomy. Ann Thorac Surg 72:1149-1154, 2001.
24. PORT Meta-analysis Trialists Group: Postoperative radiotherapy in non-small-cell lung cancer: Systematic review and meta-analysis of individual patient data from nine randomised controlled trials. Lancet 352:257-263, 1998.
25. Lally BE, Zelterman D, Colasanto JM, et al: Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the surveillance, epidemiology, and end results database. J Clin Oncol 24:2998-3006, 2006.
26. De Marinis F, Nelli F, Migliorino MR, et al: Gemcitabine, paclitaxel, and cisplatin as induction chemotherapy for patients with biopsy-proven stage IIIA(N2) nonsmall cell lung carcinoma: A phase II multicenter study. Cancer 98:1707-1715, 2003.
27. Abratt RP, Lee JS, Han JY, et al: Phase II trial of gemcitabine-carboplatin-paclitaxel as neoadjuvant chemotherapy for operable non-small cell lung cancer. J Thorac Oncol 1:135-140, 2006.
28. Garrido P, Gonzalez-Larriba JL, Insa A, et al: Long-term survival associated with complete resection after induction chemotherapy in stage IIIA (N2) and IIIB (T4N0-1) non small-cell lung cancer patients: The Spanish Lung Cancer Group Trial 9901. J Clin Oncol 25:4736-4742, 2007.
29. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92-98, 2002.
30. Weiden PL, Piantadosi S: Preoperative chemotherapy (cisplatin and fluorouracil) and radiation therapy in stage III non-small-cell lung cancer: a phase II study of the Lung Cancer Study Group. J Natl Cancer Inst 83:266-273, 1991.
31. Weitberg AB, Yashar J, Glicksman AS, et al: Combined modality therapy for stage IIIA non-small cell carcinoma of the lung. Eur J Cancer 29A:511-515, 1993.
32. Albain KS, Rusch VW, Crowley JJ, et al: Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: Mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 13:1880-1892, 1995.
33. Johnstone DW, Byhardt RW, Ettinger D, et al: 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 54:365-369, 2002.
34. Taylor NA, Liao ZX, Cox JD, et al: Equivalent outcome of patients with clinical stage IIIA non-small-cell lung cancer treated with concurrent chemoradiation compared with induction chemotherapy followed by surgical resection. Int J Radiat Oncol Biol Phys 58:204-212, 2004.
35. van Meerbeeck JP, Kramer GW, Van Schil PE, et al: Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst 99:442-450, 2007.
36. Albain KS, Swann RS, Rusch VR, et al: Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA (pN20 non-small cell lung cancer: Outcomes update of North American Intergroup 0139 (RTOG 9309) (abstract 7014). J Clin Oncol 23(16S):624s, 2005.
37. Robinson LA, Ruckdeschel JC, Wagner H Jr, et al: Treatment of non-small cell lung cancer-stage IIIA: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 132(3 suppl):243S-265S, 2007.
38. Felip E, Rosell R, Massuti B, et al: The NATCH trial: Observations on the neoadjuvant arm (abstract 7578). J Clin Oncol 25(18S):403s, 2007.
39. Felip E, Massuti B, Alonso G, et al: A phase III randomized trial of surgery alone, or preoperative (PREOP) paclitaxel/carboplatin (PC) followed by surgery, or surgery followed by adjuvant (ADJ) PC in early stage non-small cell lung cancer (NSCLC): NATCH follow-up data (abstract PRS.3). 13th World Conference on Lung Cancer, San Francisco, 2009.
40. Lim E, Harris G, Patel I, et al: Preoperative versus postoperative chemotherapy in patients with resectabley non-small cell lung cancer: Systematic review and indirect comparison meta-analysis of randomized trials (abstract 7546). J Clin Oncol 26(15S):408s, 2008.