Surgery remains the cornerstone of treatment for patients with early stage non-small cell lung cancer (NSCLC) and provides the best hope for cure. Operable patients with stages IA through IIIA disease are candidates for complete resection with curative intent. Patients diagnosed with these stages represent approximately one third of all lung cancer cases.¹ However, despite complete surgical resection, a large number of patients will relapse after surgery. Five-year survival rates in patients with completely resected NSCLC average 78% and 58% for stages IA and IB, 46% and 36% for stages IIA and B, and 24% for stage IIIA, respectively.² The most frequent cause of death for patients with NSCLC after complete resection is the development of distant metastases. Although the frequency of intrathoracic recurrence averages 10% to 15% across stages, the frequency of distant metastasis as site of first relapse increases from 15% in stage IA over 40% in stage II to 60% in stage IIIA.³,⁴,⁵,⁶ Relapse at distant sites is thought to be a result of occult micrometastatic disease, undetected at the time of preoperative staging.

Eradication of early metastatic disease by chemotherapy may theoretically translate into a decreased incidence of recurrence in distant sites, and thereby improve survival. This chemotherapy can be administered before (neoadjuvant or induction) or after (postoperative or adjuvant) surgery. Several randomized trials and metaanalyses have recently demonstrated an overall survival benefit with adjuvant platinum-based chemotherapy in early stage NSCLC.⁷,⁸,⁹ These results have lead to the adoption of surgery and adjuvant chemotherapy as the new standard of care in selected patients.¹⁰ This chapter will focus on the administration of chemotherapy prior to surgery as an alternate approach to adjuvant chemotherapy in early stage resectable NSCLC.

The term neoadjuvant chemotherapy was coined by Frei¹¹ to refer to the specific strategy of using a drug treatment at the earliest time possible. Neoadjuvant chemotherapy has several potential advantages over immediate surgery and adjuvant therapy. The most important is the systemic treatment of occult microscopic metastatic disease at the earliest possible time, with an improved progression-free and overall survival as compared to the local treatment only. The former is thought to be the result of a better control of the cytokines released by the wound repair, the latter by an improved sterilization of the occult metastases. Besides its potential systemic effects, chemotherapy induces cytotoxic effects at the level of the primary tumor, resulting in clinical and even pathological remissions. A reduction in the primary tumor mass may theoretically lead to less extensive surgery and possibly renders borderline unresectable lesions resectable (e.g., by downstaging of involved mediastinal lymph nodes). Another potential advantage of neoadjuvant chemotherapy is its better compliance. Only 45% to 60% of the patients are able to complete the adjuvant chemotherapy without dose reductions or delays, whereas the induction chemotherapy was shown to be administrated in more than 80% of the patients in most phase II induction trials.¹² Other potential advantages include the in vivo assessment of tumor chemosensitivity, a lower risk of developing drug resistance, and the selection of responsive patients, as patients with disease progression on chemotherapy will most likely not benefit from surgery.

The potential disadvantages of neoadjuvant chemotherapy include a delay in potentially curative surgery, less accurate staging—as the pathological staging is confounded by the induction treatment—and increased surgical morbidity and mortality after chemotherapy with decrease in quality of life. Lastly, a benefit of neoadjuvant chemotherapy is well established for the treatment of invasive bladder cancer and endothoracic esophageal cancer.¹³,¹⁴

Enthusiasm for the use of neoadjuvant chemotherapy for treating early stage NSCLC was generated by positive survival results from two small randomized studies in patients with
stage IIIA. Roth et al.¹⁵ randomized patients with potentially resectable clinical stage IIIA NSCLC between perioperative chemotherapy followed by surgery and a control arm of surgery alone. Patients allocated to chemotherapy were to receive three cycles of chemotherapy with cyclophosphamide, etoposide, and cisplatin before surgery; an additional three cycles were given after surgery to patients with preoperative radiographic response. Following an interim analysis, the trial was closed after 60 patients had been accrued because of a clinically meaningful survival benefit in favor of the induction chemotherapy arm. Long-term follow-up of this trial, after a median time from randomization of 82 months, confirmed the beneficial effect of induction chemotherapy. Median and 5-year survival rates were 21 months and 36% versus 14 months and 15% for surgery alone.¹⁶

In a similar randomized trial conducted by Rosell et al.,¹⁷ clinical stage I to IIIA NSCLC patients were randomized to immediate surgery or surgery preceded by three cycles of mitomycin, ifosfamide, and cisplatin chemotherapy. Both treatment groups received postoperative mediastinal radiation therapy to 50 Gy. Interim analysis after 24 months follow-up with 60 eligible patients showed a significant difference in survival favoring induction chemotherapy and enrollment was stopped. Reassessment with 7-year follow-up found median and 5-year survival rates of 22 months and 17% in the chemotherapy arm compared to 10 months and 0% in the surgeryalone arm.¹⁸ The outcome of patients treated with immediate surgery was, however, disappointingly low.

Pass et al.¹⁹ randomized 27 patients between surgical resection either preceded by cisplatin-etoposide chemotherapy or followed by radiotherapy and observed median survival rates of 29 versus 16 months. The results of this trial are, however, difficult to interpret because of the asymmetry in randomization. Four other small randomized series did not observe a difference in outcome between an approach with or without preoperative chemotherapy.²⁰,²¹,²²,²³

These earlier trials have a number of weaknesses in their design: (a) a variable use of adjuvant chemotherapy and radiotherapy; (b) the use of first-and second-generation drugs, of which some have been associated with a detrimental effect on survival²⁴; and (c) the use of the 1986 staging classification, in which stage III is even more heterogenous than in the present one.²⁵

In 2001, the results of a French phase III randomized trial of induction mitomycin, ifosfamide, cisplatin chemotherapy in resectable stages IB, II, and IIIA were reported.²⁶ Three hundred fifty-five eligible patients were randomized to surgery alone or combined modality therapy consisting of two cycles of chemotherapy followed by surgery. Responding patients (radiographically or pathologically) received two additional cycles of adjuvant chemotherapy. The arms were well balanced for patient characteristics with the exception that less clinical N2-assigned patients were assigned to the surgery-only arm (28% vs. 40%; p = 0.65). A nonsignificant excess of postoperative morbidity in the chemotherapy arm was seen (24/167 vs. 22/171). Postoperative mortality was 6.7% in the chemotherapy arm and 4.5% in the surgery arm (p = 0.38). Median survival was improved by 11 months (37 vs. 26 months) and at 4 years, there was an 8.6% increase in survival in the chemotherapy arm, but this did not achieve statistical significance. In a subset analysis, the benefit of chemotherapy was confined to patients with N0 and N1 disease with a relative risk of death of 0.68 (p = 0.027). After a nonsignificant excess of deaths in the combined modality arm during the treatment period, the effect of induction chemotherapy was favorable on survival. No difference was seen in local recurrence rates. A significant decrease in distant metastases was observed, favoring the chemotherapy arm with a relative risk of 0.54 (p = 0.01). Followup data on this trial, when minimal follow-up exceeded 60 months, showed that the 3- to 5-year survival differences were stable around 10% (p = 0.04 at 3 years and p = 0.06 at 5 years).²⁷ Statistically significant benefits in the N0-1 subgroup were confirmed with 5-year survival rates of 49% compared to 34% in the N2 subgroup (p = 0.02)

The use of preoperative chemotherapy may increase surgical complication rates. Several large retrospective series have addressed this issue. Siegenthaler et al.²⁸ reported data from 335 patients undergoing lobectomy or greater resection for NSCLC, of whom 76 received induction chemotherapy. The use of preoperative chemotherapy did not significantly affect morbidity or mortality overall, based on clinical stage, postoperative stage, or extent of resection. No significant differences in overall or subset mortality or morbidity, including pneumonia, acute respiratory distress syndrome, reintubation, tracheostomy, wound complication, or length of hospitalization, were seen.

Four hundred and seventy patients treated with induction chemotherapy and surgery from 1993 through 1999 at Memorial Sloan-Kettering Cancer Center were reviewed.²⁹ Univariate and multivariate methods for logistic regression model were used to identify predictors of adverse events. Overall, a surgical mortality rate of 3.8% was observed, which compared favorably to other primary surgery studies. Total morbidity and major complication rates were 38% and 27%, similar to previous primary surgery studies. The authors concluded that overall morbidity rates were not significantly affected by the use of induction therapy. They did find an operative mortality rate of 24% for patients undergoing right pneumonectomy following induction therapy. This number was higher than previous mortality rates seen in trials wherein patients did not have induction therapy. The authors recommended that right pneumonectomy after induction therapy be performed very selectively and only when no alternative resection is possible.

A third French series reviewed 114 patients who underwent thoracotomy following induction chemotherapy.³⁰ In this series, there was only one death following pneumonectomy in 55 patients. Overall morbidity rate was 29%, similar to other surgical series. The authors concluded that preoperative chemotherapy did not increase postoperative morbidity and mortality.

The conclusion from these series is that induction chemotherapy is likely to be a feasible and safe procedure, not impacting on complication and hospitalization rates, with the possible exception of right-sided pneumonectomy.

The feasibility and safety of preoperative chemotherapy using third-generation drugs in early stage NSCLC, classified according to the 1997 staging classification, was prospectively established in the Bimodality Lung Oncology Team (BLOT) trial.³¹ This phase II trial enrolled two sequential cohorts of patients with clinical stage IB, II, and IIIA patients. Clinical staging was defined by computed tomography (CT) imaging, and all patients were required to undergo mediastinoscopy. Positron emission tomography (PET) imaging was not routinely performed in this study. Patients with mediastinoscopy proven N2 disease or superior sulcus tumors were excluded from this trial. Patients were treated with paclitaxel and carboplatin before and after surgery (number of cycles in cohort I: 2 pre and 3 post; cohort 2: 3 pre and 4 post). For the two cohorts combined, the radiographic response rate was 51%, complete resection rate was 86%, and pathologic complete response rate was 5%. Three-and five-year survival rates were 61% and 45%, respectively, and comparable with historical series.²,²⁷ There were no significant differences in patient characteristics or outcome between the two cohorts. A detailed analysis of the radiological and pathological responses showed a lack of correlation between both, with 50% of, patients who were found to have equivalent or more extensive disease at surgery, having major chemotherapy responses. Two postoperative deaths occurred. A total of 96% of patients received the planned preoperative chemotherapy versus 45% receiving postoperative chemotherapy.