S eminars in Vol 28, No 3, Suppl 9 Oncology June 2001

New Drug and Multimodality Combinations in the Treatment of Advanced Non-Small Cell Lung Cancer

Masaaki Kawahara, Mark G. Kris, Mark Green, and Hideo Kunitoh

I N THE 1980s and 1990s platinum-based che-

motherapy was shown to improve survival in patients with metastatic non-small cell lung can-

cer (NSCLC), those with locally advanced disease treated by radiotherapy, and, as preoperative che-

motherapy for stage III resectable disease.‘-3 Over the last decade a range of new agents has

become available for the treatment of patients

with NSCLC. These include antimetabolites such as gemcitabine and multi-targeted antifolate, an-

titubulin (vinorelbine), tubulin-stabilizing taxanes (docetaxel and paclitaxel), and topoisomerase- 1

inhibitors such as irinotecan. Taxanes have contributed substantially to the

progress that has been made. Docetaxel, in partic- ular, is the first drug shown to be beneficial in the second-line setting (ie, in patients with NSCLC

refractory or resistant to platinum therapy). The focus of a symposium held in Tokyo as part of the Ninth World Conference on Lung Cancer was the

role of docetaxel in the evolution of more effective therapy and as a potential foundation for new combination treatments in advanced disease and

in the induction setting.

DOCETAXEL AND SURVIVAL: FIRST AND SECOND LINE

Used first line in NSCLC, single-agent do- cetaxel produces a pooled response rate of approx- imately 31% with median survivals exceeding 9 months and 39% overall one-year survival.4xs

These results are similar to those reported previ- ously with combination regimens. Used second- line, the response rate to single agent docetaxel in

phase II trials is approximately 2O%.6 In the first-line setting, a randomized phase III

trial has shown that single-agent docetaxel leads to significantly improved survival relative to best supportive care.7 At 1 year, 25% of docetaxel-

Seminars in Oncology, Vol 28, No 3, Suppl 9 tune), 200 I : pp I-4

treated patients were alive, compared with 16% in

the control arm.

In the year 2000, the Journal of Clinical Oncology

published two papers reporting phase III studies of

docetaxel in the second-line setting.s,9 At the

Tokyo meeting, Thomas Lynch reviewed these

two studies. In the trial versus best supportive care,

docetaxel 75 mg/m2 produced survival advantages

compared with the control patients who received

supportive care only.s Importantly, treatment also

brought clinical benefit: patients treated with do-

cetaxel required less opioid analgesia and pallia-

tive radiotherapy, lost less weight, and suffered less

fatigue.

In the second phase III study, docetaxel at two

doses was compared with a standard regimen of

vinorelbine or ifosfamide.9 The response rate and

time to progression with docetaxel were signifi-

cantly higher than with either of the comparator

agents. One-year survival in the patients treated

with docetaxel 75 mg/m2 was 32%. One-year sur-

vival in patients receiving vinorelbine or ifos-

famide was 19%. These data confirm that the

survival benefit was achieved without compromis- ing quality of life.

From the National Kinki Central Hospital, Japan; the Thomcic

Oncology Service, Department of Medicine, Memorial Sloan Ket- tering Cancer Center, New York, NY; the Department of Medi-

cine, Hematology/Oncology Division, Medical University of South Carolina, Charleston; and the National Cancer Center Hospital, Japan.

Drs Kru and Green serve as consultants to and have received

research grant support and honoraria from Auentis Pharmaceuticals Inc.

Address reprmt requests to Mark G. Kris, MD, Memorial Sloan Kettering Cancer Center-, 1275 York Awe, New York, NY 10021.

Copyright 0 2001 by W.B. Saunders Company

0093-7754/Oi/Z803-0901$35.00/O doi:10.1053/sonc.2001.24600

2

COMBINATION REGIMENS WITH AND WITHOUT PLATINUM

Docetaxel also has been extensively studied in

combination regimens, particularly with cisplatin, carboplatin, gemcitabine, and vinorelbine. These combinations have shown substantial activity.ia+iz

Dr Chandra Belani presented preliminary anal- ysis of the TAX 326 study comparing docetaxel

plus cisplatin with docetaxel plus carboplatin and vinorelbine plus cisplatin.13 The full toxicity and

efficacy analysis from this study should be available for the American Society of Clinical Oncology

meeting in 2001. Together with the results of the Eastern Cooperative Oncology Group compari-

son11 between paclitaxel/cisplatin, docetaxel/cis- platin, gemcitabine/cisplatin, and paclitaxel/car- boplatin, the TAX 326 results should provide

considerable guidance for choosing among plati- num-containing combinations in advanced dis-

ease. The meeting heard a full review by Dr James

Rigas covering the rapidly evolving field of non- platinum combination chemotherapy. A random-

ized trial has already shown that the combination of docetaxel and gemcitabine is equivalent to that

of docetaxel and cisplatin in efficacy while being superior in tolerability. 14 A controlled trial also

has shown that the combination of docetaxel with irinotecan achieves response rates and l-year sur-

vival similar to that seen with docetaxel/cispla- tin.15 Toxicity, in this instance, had a different

profile than seen with cisplatin or carboplatin- based regimens.

The increased range of therapeutic options

opens up the possibility of customizing therapy to the individual patient. Chemotherapy choices can

or will be made based on comorbidities and char- acteristics of the disease shown in biological mark- ers.

Those attending were reminded that expanding choice concerns not only the single or multiple agents selected for chemotherapy but also their

scheduling. Dr John Hainsworth presented data supporting the use of weekly docetaxel and achiev- ing toxicity benefits that are not bought at the

expense of antitumor efficacy.16p17 The reduction in myelosuppression, which switches from being the most prominent every 3 week docetaxel-re- lated toxicity to being the least prominent with weekly docetaxel, is particularly dramatic. This

KAWAHAM ET AL

opens up the possibility of combinations with other potentially myelosuppressive agents. It also renders eligible for therapy patients who are el-

derly, who are of poor performance status, or sim- ply those who wish to receive chemotherapy but want treatment to have the smallest possible im-

pact on their daily (and frequently their working) lives.

The data presented showing the efficacy of a wide range of combinations in advanced disease

sets the stage for their introduction at earlier stages in the treatment of NSCLC. These novel combi- nations are ripe for testing pre- and postopera-

tively in patients with resectable tumors and con- currently with radiation therapy. The new doublets also appear well suited for use in combi- nation with the next generation of agents such as

those targeted at vascular epithelial growth factor, bcl-2, or epidermal growth factor receptor.

MULTIMODALITY AND NEOADJUVANT THERAPY

The integration of docetaxel into multimodality therapy for stage III NSCLC was discussed by Dr

David Gandara. He focused on the Southwest Oncology Group 9504 trial, which shows that concurrent chemoradiotherapy with cisplatin plus etoposide followed by three cycles of consolidation with full-dose docetaxel results in a l-year survival rate of 76% and a 2-year survival rate of 53%.1s

Dr Karin Mattson presented data showing that it is feasible to use docetaxel as induction therapy and that such use of the drug does not compromise

later radical radiotherapy.19 Phase II trials of do- cetaxel plus platinum in the induction setting have produced response rates of up to 82% and complete resection rates of up to 79%.20-22

The area of induction therapy provoked lively discussion.

Several important questions remain unan- swered. In stage IIIA disease, should induction therapy be chemotherapy or chemoradiotherapy? Is surgery still indicated in all such patients? Stage IIIA N2 patients with a positive initial scan which normalizes following induction therapy may have a very good prognosis. I f it is assumed that the

good outcome in these patients results from the eradication of micrometastases by systemic ther- apy, the need f or surgery is called into question.

Even among patients who have had induction chemoradiotherapy, the proportion who achieve a

NEW CHEMOTHERAPIES FOR LUNG CANCER

pathologic complete response is small, the local failure rate remains substantial, and the cure rate is no more than 20% to 25%. For patients of good performance status, surgery remains a viable mo- dality. Indeed, its importance may grow as a means of monitoring biological endpoints. These ques- tions will become of increasing interest with the introduction of agents such as the angiogenesis and tyrosine kinase inhibitors that have novel mechanisms of action.

In Japan, many patients with stage IIIA N2 disease undergo surgery without preoperative che- motherapy. Survival data are provocative. How- ever, there is a need to be clear about how these patients are staged. Worldwide, the results follow- ing surgery alone in N2 patients are not good, and there is a clear case for induction treatment. Data from the Eastern Cooperative Oncology Group adjuvant trial suggest that these patients cannot be successfully managed by leaving chemotherapy un- til after surgery has been performed. Data from the Southwest Oncology Group study of stage IIIA N2 and IIIB patients show that use of chemotherapy and radiotherapy together can achieve a patho- logic complete or near-complete response in a higher proportion of patients. These data led them to the on-going trial of chemoradiotherapy with or without surgery in locally advanced NSCLC.

Intriguing questions are posed by the French study suggesting that stage IB and II patients achieve a greater benefit from induction therapy than stage III patients. If this is so, there is a case for treating every candidate for surgery with induc- tion therapy followed by mediastinoscopy, decid- ing only at that point whether to go ahead and perform surgery. This issue is now being addressed in part by the US trial in which patients are randomized to three cycles of carboplatin plus pac- litaxel induction followed by surgery or to surgery alone.

It is important to note that the majority of induction chemotherapy studies use immediate surgery as the control arm. An exception is the Spanish trial of Rose11 et al in which induction chemotherapy followed by surgery is being com- pared both with surgery alone and with surgery plus postoperative therapy. The results of this study will establish whether it is chemotherapy per se that confers benefit or chemotherapy specifi- cally in the induction setting.

There was much discussion on the resolution of

3

positron emission tomography, such as the diffi- culties in interpretation of the scans following chemoradiotherapy and the possibility that a “neg- ative” scan may be found even with substantial residual disease in mediastinal nodes.

Overall, the meeting heard a wealth of data confirming advances in efficacy among treatments for NSCLC and suggestions for a range of ap- proaches that may bring further progress. The search for a more effective and better tolerated treatment of lung cancer will need to continue until the cigarette smoking that causes this disease is eradicated.

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