Commentary (Brahmer): Chemotherapy for Non–Small-Cell Lung Cancer
Commentary (Brahmer): Chemotherapy for Non–Small-Cell Lung Cancer
Drs. Novello and Le Chevalier have written a comprehensive review on the role of chemotherapy in the treatment of non-small-cell lung cancer (NSCLC). Their review spans chemotherapy's controversial use in early-stage disease to its mainstream use in late-stage disease. The authors highlight the controversies in the treatment and research of all stages of NSCLC and discuss ongoing research in combining chemotherapy with the new molecularly targeted agents.
Chemotherapy can be used in early-stage NSCLC as adjuvant or neoadjuvant treatment. Unfortunately, to date, it has not improved survival when used in the adjuvant setting. However, we anxiously await the results of trials conducted by the National Cancer Institute of Canada and Cancer and Leukemia Group B (CALGB), in which newer agents (vinorelbine [Navelbine] and paclitaxel) have been combined with a platinum following surgery. Hopefully, the results of these trials will finally resolve the issue of adjuvant chemotherapy.
Chemotherapy can also be used in early-stage disease as neoadjuvant treatment. In theory, the use of chemotherapy in this setting makes more sense than in the adjuvant setting, potentially controlling micrometastatic disease prior to surgery. Moreover, delivery of chemotherapy to the tumor should be enhanced when the blood supply has not been disrupted by surgery. The hope is to downstage the disease before surgery, making the tumor easier to resect. Small studies have shown a trend toward improvement in overall survival with the use of neoadjuvant chemotherapy, but the results have not demonstrated a statistical advantage over surgery alone.[1-3]
The Bimodality Lung Oncology Team (BLOT) study showed the feasibility of neoadjuvant therapy with the newer combination of paclitaxel and carboplatin (Paraplatin). The response rate with this combination was 56%, and the 2-year survival was 56%. This trial led to initiation of the phase III randomized Southwest Oncology Group (SWOG) trial (S9900) of neoadjuvant paclitaxel and carboplatin followed by surgery vs surgery alone. We await the results of SWOG S9900 before we can characterize the use of chemotherapy in the neoadjuvant setting as routine.
Locally Advanced Disease
Drs. Novello and Le Chevalier also review the use of chemotherapy in locally advanced NSCLC. In this situation, chemotherapy improves survival especially when given concurrently with radiation. Both CALGB 8433 and the Radiation Therapy Oncology Group (RTOG) trial 8808 proved that sequential chemotherapy followed by radiation improved survival over radiation alone.[5-7] A Japanese study and RTOG 9410 showed that concurrent chemotherapy and radiation therapy improves both response and survival rates[8,9] but also increases toxicities—in particular, esophagitis. Thus, potentially enhanced toxicities must be considered when selecting patients for this regimen.
More recently, investigators have presented interesting trial results at the last two American Society of Clinical Oncology (ASCO) meetings. In 2002, Dr. Hak Choy presented the results of the Locally Advanced Multi-Modality Protocol (LAMP) trial, which compared different ways of combining paclitaxel and carboplatin with radiation, ie, sequentially or concurrently. The investigators closed the study arm receiving induction chemotherapy followed by concurrent chemotherapy and radiation earlier than planned because of decreased survival (median: 12.8 months). They next compared concurrent chemotherapy and radiation followed by consolidation chemotherapy vs chemotherapy given sequentially followed by radiation therapy, and found no differences in outcome. The results demonstrated a trend toward improved median survival with concurrent chemotherapy followed by consolidation chemotherapy (16 months) compared to chemotherapy followed by radiation therapy (13 months).
Data from SWOG 9504 were presented at the 2001 ASCO meeting. In this trial, cisplatin and etoposide were given concurrently with radiation and followed by docetaxel (Taxotere) consolidation in patients with stage IIIB disease (without a pleural effusion). These phase II results are unprecedented in the literature. The median survival was 27 months, and the 3-year survival rate was 40%. SWOG plans to use the same regimen, with or without ZD1839 (Iressa), in a follow-up phase III study (S0023).
Thus, many questions remain about combining chemotherapy and radiation. Most importantly, the exact combination of chemotherapy to be given with radiation and the timing of chemotherapy (as consolidation or induction therapy) have yet to be determined.
Chemotherapy is the mainstay of treatment for metastatic NSCLC, but we have been unable to break through the glass ceiling of an 8- to 10-month median survival in these patients. Clearly, newer agents combined with platinum therapy have improved survival compared to single-agent chemotherapy. Dr. Rogerio Lilenbaum reported that paclitaxel combined with carboplatin improved survival in patients with advanced NSCLC compared to patients who received paclitaxel alone. Although several combination treatments are available, no one combination has emerged as the first-line treatment of choice for metastatic NSCLC.
Second-line treatment of advanced NSCLC with docetaxel was approved in 2001, based in part on Dr. Francis Shepherd's trial, which demonstrated an improved survival and quality of life in patients treated with docetaxel vs those who received best supportive care. In 2003, we are talking about the possible approval of a third-line agent, ZD1839 (Iressa), based partly on the results of Dr. Mark Kris's trial comparing two doses of Iressa in patients who had failed two previous therapies (platinum-based and docetaxel).
The excitement surrounding new targeted therapies has been dampened slightly by the recent results of a phase III trial of ZD1839 in combination with chemotherapy as firstline treatment of advanced NSCLC, reported at the 2002 meeting of the European Society for Medical Oncology.[ 16] The question of how to optimally combine chemotherapy with molecularly targeted therapies remains to be answered. We all wish we could develop treatments with fewer side effects and better efficacy than chemotherapy alone, but for now, chemotherapy remains the backbone of treatment in patients with advanced NSCLC.
2. Rosell R, Gomez-Godina 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.
3. Depierre A, Milleron B, Sibilot DM, et al: Preoperative chemotherapy followed by surgery compared with primary surgery in respectable stage I (except T1N0), II, and IIIA non-small cell lung cancer. J Clin Oncol 20:247- 253, 2002.
4. Pisters KM, Ginsberg RJ, Giroux DJ, et al: Induction chemotherapy before surgery for early- stage lung cancer: A novel approach. Bimodality Lung Oncology Team. J Thorac Cardiovasc Surg 119:429-439, 2000.
5.Dillman RO, Seagren SL, Propert KJ, et al: A randomized trial of induction chemotherapy plus high dose radiation versus radiation alone in stage III non-small cell lung cancer. N Engl J Med 323:940-945, 1990.
6. Dillman RO, Herndon J, Seagren SL, et al: Improved survival in stage III nonsmall cell lung cancer: Seven year follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst 88:1210-1215, 1996.
7. Sause WT, Scott C, Taylor S, et al: Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: Preliminary results of a phase III trial in regionally advanced unresectable non-small cell lung cancer. J Natl Cancer Inst 87:198-205, 1995.
8. Furuse K, Fukuoka M, Kawahara M, et al: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small cell lung cancer. J Clin Oncol 17:2692-2699, 1999.
9. Curran WJ, Scott C, Langer C, et al: Phase III comparison of sequential versus concurrent chemoradiation for patients with unresected stage III non-small cell lung cancer: Initial report of radiation therapy oncology group (RTOG) 9410 (abstract 1891). Proc Am Soc Clin Oncol 19:484a, 2000.
10. Choy H, Curran WJ, Scott CB, et al: Preliminary report of locally advanced multimodality protocol (LAMP): ACR 427: A randomized phase II study of three chemoradiation regimens with paclitaxel, carboplatin, and thoracic radiation (TRT) for patients with locally advanced non-small cell lung cancer (abstract 1160). Proc Am Soc Clin Oncol 21:291a, 2002.
11. Gaspar L, Gandara D, Chansky K, et al: Consolidation docetaxel following concurrent chemoradiotherapy in pathologic stage IIIB non-small cell lung cancer (SWOG 9504): Patterns of failure and updated survival (abstract 1255). Proc Am Soc Clin Oncol 20:315a, 2001.
12. Lilenbaum RC, Herndon J, List M, et al: Single-agent versus combination chemotherapy in advanced non-small cell lung cancer: A CALGB randomized trial of efficacy, quality of life, and cost-effectiveness (abstract 2). Proc Am Soc Clin Oncol 21:1a, 2002.
13. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small cell lung cancer. N Engl J Med 346:126-128, 2002.
14. Shepherd FA, Dancey J, Ramlau R, et al: Prospective randomized trial of docetaxel versus best supportive care in patients with nonsmall cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18:2095-2103, 2000.
15. Kris MG, Natale RB, Herbst RS, et al: A phase II trial of ZD1839 (Iressa) in advanced non-small cell lung cancer patients who had failed platinum- and docetaxel-based regimens (IDEAL 2) (abstract 1166). Proc Am Soc Clin Oncol 21:292a, 2002.
16. Johnson DH, Herbst R, Giaccone G, et al: ZD1839 (Iressa) in combination with paclitaxel and carboplatin in chemotherapynaive patients with advanced non-small cell lung cancer (NSCLC): Results from a phase III clinical trial (INTACT 2) (abstract 468). Program and abstracts of the 27th Congress of the European Society for Medical Oncology, Oct 18-22, 2002; Nice, France.