Elsevier

Lung Cancer

Volume 42, Supplement, December 2003, Pages S29-S34
Lung Cancer

CONFERENCE
Adjuvant therapy for locally advanced non-small cell lung cancer

https://doi.org/10.1016/j.lungcan.2003.08.008Get rights and content

Introduction

Successful removal of all intrathoracic non-small cell lung cancer (NSCLC) does not always translate into cure. In fact, the majority of patients with intrathoracic lymph node involvement will die form recurrent disease. Recurrent disease is, perhaps, a misnomer. Patients die from tumors that represent the growth of previously undetected micrometastatic disease. In order to improve patient survival following complete tumor resection, adjuvant therapy has been employed to eradicate or control micrometastases.

Though eradication of the last remaining tumor cell might be preferable, control of tumor growth would likely be equally effective. Various therapeutic options are available, as are means of administration (Table 1). The most commonly employed has been parenteral cytotoxic therapy administered for a brief interval.

Locally advanced NSCLC is generally defined as tumors that involve other intrathoracic structures or, more commonly, tumors that have spread to intrathoracic lymph nodes. The poor survival of patients with locally advanced disease was quickly recognized by the pioneers of lung cancer surgery. Overholt reported a 24% 5-year survival for patients with mediastinal lymph node disease in 1956 [1], not very different than the current figures of 40 and 25% for patients with stages II and IIIa, respectively.

Radiotherapy and chemotherapy have been utilized in the adjuvant setting since the inception of surgical treatment of NSCLC. Brachytherapy seed were implanted during the first successful pneumonectomy for cancer [2]. Nitrogen mustard was employed as the treatment arm of the first randomized phase III trial of adjuvant chemotherapy [3]. During the past three decades, numerous phase III adjuvant therapy trials have been conducted in an effort to identify effective postoperative treatment (Table 2). With rare exception, no advantage for adjuvant chemotherapy has been demonstrated.

Section snippets

Short-term cytotoxic therapy

A meta-analysis of adjuvant chemotherapy was published in 1995 [23]. Nine phase III trials containing 1394 patients compared surgery alone to surgery plus adjuvant chemotherapy. The difference in the survival curves was not significant (P=0.08). Six additional randomized prospective trials containing 668 patients compared adjuvant chemoradiotherapy to adjuvant therapy alone. Once again, no survival advantage was demonstrated (P=0.46).

The Post Operative Radiotherapy Trialists (PORT) Group

Long-term administration of cytotoxic therapy

Long-term oral administration of cytotoxic chemotherapy appears more promising than traditional short course treatment. Investigators have utilized daily administration of the oral drug, UFT which consists of uracil and tegafur in 4:1 molar ratio [27], [28], [29], [30]. The latter is a prodrug of 5-FU and the former inhibits the metabolism of 5-FU, resulting in sustained levels of 5-FU in the tumor tissue. UFT is well tolerated and diarrhea is the dose limiting toxicity.

Wada randomized 310

Immunotherapy

Immunotherapy has been investigated as an alternative to cytotoxic therapy with mixed results [31], [32], [33]. Most recently, Kato utilized Ubenimex, a non-specific orally administered immuno-stimulant, as adjuvant therapy for patients who had undergone resection of stage I squamous cell NSCLC [33]. Patients were randomized to receive Ubenimex or placebo daily for 2 years. The 5-year survival was 81% for those patients in the treatment arm and 74% for those who had received placebo (P<0.02).

Current trends

The ongoing adjuvant therapy trials sponsored by the large cooperative groups reflect the traditional approach of short-term cytotoxic therapy (Table 3). Though newer agents and combinations are utilized, the results are unlikely to differ from those previously published. At the present time, we are unable to control or eradicate undetected micrometastatic disease.

Effective, individualized adjuvant therapy based upon the patient’s proven ability to respond to treatment and the tumor’s

Conclusion

Short-term cytotoxic adjuvant therapy following resection of NSCLC has proved ineffective. Long-term cytotoxic therapy with oral agents appears promising but requires further investigation. New paradigms regarding methods of targeting the cancer cell and length of therapy are needed. Confirmation of technology that permits identification of patients likely to develop recurrent disease and likely to respond to therapy will permit targeting of appropriate cohorts. I believe that the resources of

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