Preoperative Therapy for Early-Stage NSCLC: Opportunities and Challenges

The treatment of early-stage non–small-cell lung cancer (NSCLC) has undergone a paradigm shift recently with the addition of systemic therapy to local therapy. The use of cisplatin-based chemotherapy following surgery is now a standard approach for patients with stage II–IIIA disease. In this issue of ONCOLOGY, Gray et al present an overview of neoadjuvant approaches to the treatment of early-stage NSCLC. The paper outlines various advantages associated with earlier initiation of systemic therapy for patients with surgically resectable disease. In addition to those mentioned by the authors, we would like to highlight two important areas that make the neoadjuvant approach more attractive for the treatment of lung cancer.

Advantages of Neoadjuvant Therapy
The first issue relates to the better ability to deliver chemotherapy in the preoperative setting. In the randomized clinical trials conducted in the postoperative setting, only about 60% to 70% of patients were able to receive the planned courses of chemotherapy.[1,2] This is likely due to the invasive nature of the surgery and longer recovery times with lung cancer surgery. In addition, the presence of smoking-related comorbid illness in a majority of lung cancer patients contributes to the difficulty in completion of planned chemotherapy. Notably, the meta-analysis of adjuvant chemotherapy studies found the dose of cisplatin to be an important determinant of outcome.[3]

Therefore, the preoperative setting might be more suited for delivery of optimal dose and number of cycles of chemotherapy. In the Southwest Oncology Group (SWOG) 9900 study, 80% of patients received all three cycles of planned chemotherapy in the preoperative setting.[4]

The second major advantage of the preoperative approach is the ability to evaluate novel molecularly targeted agents to obtain additional insights into the mechanism(s) of action and assess the degree of target modulation in the tumor. Agents that target specific molecular pathways such as inhibitors of the epidermal growth factor receptor are already in routine clinical use. A variety of other novel compounds are in various phases of development. For targeted agents, it is important to establish target modulation and determine any dose-response effects before large-scale clinical trials are initiated to evaluate efficacy. This requires paired tumor biopsies before and after administration of a novel agent, which is often not feasible in lung cancer. The risk of pneumothorax, unfavorable tumor location and presence of comorbid illness are major limiting factors in lung cancer patients for obtaining paired biopsies.

As an alternative, administration of a novel agent for a brief of period of time in the preoperative period, followed by evaluation of the molecular effects on the harvested tumor tissues (at surgery) is an attractive approach. Nikolinakos and colleagues reported on a study that involved the administration of pazopanib, a vascular endothelial growth factor receptor inhibitor, for 2 to 6 weeks before surgery for NSCLC patients with resectable disease.[5] This study identified a variety of circulating angiogenic factors that were correlated with reduction in tumor size. The molecular studies on the tumor tissues have not yet been reported. Notably, only 19 patients were included in this trial.

Our group is conducting a similar study with everolimus (Afinitor), an inhibitor of the mammalian target of rapamycin (mTOR) pathway, in patients with resectable disease. Following a diagnostic baseline tumor biopsy, patients are treated with 3 weeks of oral therapy with everolimus and then undergo surgical resection. Molecular events that are both upstream and downstream of mTOR are evaluated and compared between the baseline and the posttreatment specimens.

These biomarker-driven “window of opportunity” studies require a relatively small sample size, but yield a great deal of mechanistic insights into the targeted pathways relevant to novel agents. For proven agents such as erlotinib (Tarceva), a brief duration of therapy in selected patients might achieve tumor downstaging when used as preoperative therapy. It is our view that this approach should be aggressively pursued to guide drug development in lung cancer.

Challenges
Gray and colleagues rightly point out the limitations to the routine use of preoperative therapy despite the availability of supportive data from phase III studies in their paper. The results of the Neoadjuvant/Adjuvant Taxol (paclitaxel) Carboplatin Hope (NATCH) study, the first randomized comparison of preoperative vs postoperative chemotherapy in early-stage NSCLC were presented recently.[6] Approximately 600 patients were randomized to the regimen of carboplatin and paclitaxel for three cycles administered either before or after surgery. The third arm of the trial was surgery alone. Though patients with stage I, II, or IIIA NSCLC were eligible, approximately 75% had stage I disease. The investigators found a trend toward superior 5-year disease-free survival-the primary endpoint of the study-in the neoadjuvant arm. In particular, delivery of chemotherapy was achieved in 90% of patients in the neoadjuvant arm compared to only 66% in the adjuvant therapy arm. The lack of a clear survival advantage to systemic therapy in this study is not surprising given the high proportion of stage I patients enrolled, in whom the benefit with adjuvant chemotherapy is still not firmly established.

A phase III study that was initiated in the United States to compare adjuvant vs neoadjuvant therapy was unfortunately closed early due to poor accrual. This study was designed to compare the administration of cisplatin-docetaxel for three cycles either before or after surgery for early-stage NSCLC. One of the main hurdles to accrual was the prevailing practice of taking patients with suspected lung cancer to surgery without a preoperative diagnostic biopsy. Since a diagnosis of lung cancer was necessary for patients to be enrolled in this study, many of the potentially eligible patients were unable to participate due to the lack of a diagnostic biopsy. It is important to arrive at a consensus regarding the need for a diagnostic biopsy before surgery to facilitate the conduct of future studies in the preoperative setting.

Three-Drug Combinations
Gray et al describe data from the use of combinations of three cytotoxic agents. Such regimens are associated with a higher degree of toxicity and did not result in a clear survival advantage in studies conducted in patients with advanced-stage disease.[7] In the Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis, the use of three-drug combinations was shown to result in a lower dose of cisplatin being administered as adjuvant therapy. Since cisplatin remains the cornerstone of therapy for lung cancer, the three-drug combinations would not be ideal for adjuvant or neoadjuvant therapy.

Alternatively, the addition of a rational molecularly targeted agent might be more suited for combination with platinum-based doublet regimens. The Eastern Cooperative Oncology Group is conducting a phase III study (ECOG 1505) to evaluate the utility of adding bevacizumab (Avastin), a monoclonal antibody against the vascular endothelial growth factor, to cisplatin-based doublets for patients with surgically resected NSCLC (stages IB–IIIA). The emergence of cisplatin/pemetrexed (Alimta) as an efficacious regimen for nonadenocarcinoma histology in advanced NSCLC[8] has led to the inclusion of this as one of the chemotherapy backbones for the ECOG 1505 study. It is hoped that better tolerated regimens such as cisplatin/pemetrexed would be more suited for combination with molecularly targeted agents both in the preoperative and neoadjuvant settings.

Though not described in the article, Zheng and colleagues from the authors’ group have pursued novel biomarker-driven strategies to define patient populations susceptible to platinum-based chemotherapy.[9] Their work on the use of ERCC1 and RRM1 as both predictive and prognostic markers has led to a prospective phase II study by the Southwest Oncology Group for biomarker-based treatment selection in patients with resected NSCLC.

Conclusion
In summary, a number of new approaches to eradicate micrometastasis in early-stage NSCLC are currently being pursued. The neoadjuvant approach has many potential advantages and has been proven to improve survival compared to surgery alone. Individualization of treatment based on risk of recurrence and susceptibility to specific chemotherapeutic agents are other highly promising avenues toward improved outcome for patients with early-stage NSCLC.

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.

References:

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4. Pisters KM, 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.
5. Nikolinakos P, Altorki N, Guarino M, et al: Analyses of plasma cytokine/angiogenic factors (C/AFs) profile during preoperative treatment with pazopanib (GW786034) in early-stage non-small cell lung cancer (abstract 7568). J Clin Oncol 26(15S):414s, 2008.
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9. Zheng Z, Chen T, Li X, et al: DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer. N Engl J Med 356:800-808, 2007.