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.

Neoadjuvant Therapy

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%.[4] 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.[10] 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.[11] 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.

Metastatic NSCLC

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.[12] Although several combination treatments are available, no one combination has emerged as the first-line treatment of choice for metastatic NSCLC.[13]

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.[14] 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).[15]

Conclusions

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.

Disclosures:

The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1.

Roth JA, Atkinson EN, Fossella F, et al:Long-term follow-up of patients enrolled in arandomized trial comparing perioperative chemotherapyand surgery with surgery alone inrespectable stage IIIA non-small cell lung cancer.Lung Cancer 21:1-6, 1998.

2.

Rosell R, Gomez-Godina J, Camps C, etal: Preresectional chemotherapy in stage IIIAnon-small cell lung cancer: A 7-year assessmentof a randomized controlled trial. LungCancer 26:7-14, 1999.

3.

Depierre A, Milleron B, Sibilot DM, et al:Preoperative chemotherapy followed by surgerycompared with primary surgery in respectablestage I (except T1N0), II, and IIIAnon-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. BimodalityLung Oncology Team. J ThoracCardiovasc Surg 119:429-439, 2000.

5.

Dillman RO, Seagren SL, Propert KJ, etal: A randomized trial of induction chemotherapyplus high dose radiation versus radiationalone in stage III non-small cell lung cancer. NEngl J Med 323:940-945, 1990.

6.

Dillman RO, Herndon J, Seagren SL,et al: Improved survival in stage III nonsmallcell lung cancer: Seven year follow-upof 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: RadiationTherapy Oncology Group (RTOG) 88-08and Eastern Cooperative Oncology Group(ECOG) 4588: Preliminary results of a phaseIII trial in regionally advanced unresectablenon-small cell lung cancer. J Natl Cancer Inst87:198-205, 1995.

8.

Furuse K, Fukuoka M, Kawahara M, et al:Phase III study of concurrent versus sequentialthoracic radiotherapy in combination with mitomycin,vindesine, and cisplatin in unresectablestage III non-small cell lung cancer. J ClinOncol 17:2692-2699, 1999.

9.

Curran WJ, Scott C, Langer C, et al: PhaseIII comparison of sequential versus concurrentchemoradiation for patients with unresectedstage III non-small cell lung cancer: Initial reportof radiation therapy oncology group(RTOG) 9410 (abstract 1891). Proc Am SocClin Oncol 19:484a, 2000.

10.

Choy H, Curran WJ, Scott CB, et al:Preliminary report of locally advanced multimodalityprotocol (LAMP): ACR 427: Arandomized phase II study of three chemoradiationregimens with paclitaxel, carboplatin, andthoracic radiation (TRT) for patients with locallyadvanced non-small cell lung cancer (abstract1160). Proc Am Soc Clin Oncol 21:291a,2002.

11.

Gaspar L, Gandara D, Chansky K, et al:Consolidation docetaxel following concurrentchemoradiotherapy in pathologic stage IIIBnon-small cell lung cancer (SWOG 9504): Patternsof failure and updated survival (abstract1255). Proc Am Soc Clin Oncol 20:315a,2001.

12.

Lilenbaum RC, Herndon J, List M, et al:Single-agent versus combination chemotherapyin advanced non-small cell lung cancer: ACALGB randomized trial of efficacy, qualityof life, and cost-effectiveness (abstract 2). ProcAm Soc Clin Oncol 21:1a, 2002.

13.

Schiller JH, Harrington D, Belani CP, etal: Comparison of four chemotherapy regimensfor advanced non-small cell lung cancer. NEngl J Med 346:126-128, 2002.

14.

Shepherd FA, Dancey J, Ramlau R, et al:Prospective randomized trial of docetaxel versusbest supportive care in patients with nonsmallcell lung cancer previously treated withplatinum-based chemotherapy. J Clin Oncol18:2095-2103, 2000.

15.

Kris MG, Natale RB, Herbst RS, et al: Aphase II trial of ZD1839 (Iressa) in advancednon-small cell lung cancer patients who hadfailed platinum- and docetaxel-based regimens(IDEAL 2) (abstract 1166). Proc Am Soc ClinOncol 21:292a, 2002.

16.

Johnson DH, Herbst R, Giaccone G,et al: ZD1839 (Iressa) in combination withpaclitaxel and carboplatin in chemotherapynaivepatients with advanced non-small celllung cancer (NSCLC): Results from aphase III clinical trial (INTACT 2) (abstract468). Program and abstracts of the 27thCongress of the European Society forMedical Oncology, Oct 18-22, 2002; Nice,France.