More questions about neoadjuvant chemotherapy in lung cancer.

Not the Same Populations! When one compares the published meta-analysis of modern day induction and adjuvant chemotherapy trials, similar hazard ratios of just above 0.80 are seen with both strategies.[1,2] It is probably dangerous to conclude that these approaches have a similar efficacy, however, as the populations studied in induction trials are different from those in adjuvant studies. The most obvious difference is that induction trials rely on clinical staging to select patients, whereas adjuvant trials rely on pathologic staging: We all know that despite modern day imaging, including computed tomography–positron-emission tomography (CT-PET) staging, the concordance between clinical and pathologic staging is relatively poor.[3] Another important difference is that in induction trials, all eligible patients at presentation are randomized to either get chemotherapy or not. In the postoperative setting, patients who have had a complicated or difficult recovery from their surgery are often not considered for adjuvant studies. The postoperative population attrition rate has been estimated to be around 25% (personal communication, D. Gandara). Operative Risks After Induction Chemotherapy? The potential increased risks of operating on patients who have received preoperative chemotherapy are often touted as a reason to avoid induction chemotherapy. This fear, however, is based entirely on retrospective single-institution series.[4,5] The authors rightly point to the fact that prospective, randomized phase III studies that have compared the strategies of surgery alone or after preoperative chemotherapy without radiation therapy have failed to show such an increment in operative risks. Compliance to Systemic Chemotherapy The optimal dose of perioperative chemotherapy has never been clearly established. Nevertheless, largely based on the experience in more advanced-stage disease, it is believed that a minimum of three cycles of chemotherapy should be the goal. One of the pitfalls of adjuvant or postoperative chemotherapy is the inability to give our patients the intended dose of chemotherapy. On trial, one-third to one-quarter of our patients are not receiving what most would consider adequate systemic therapy after surgery. One of the theoretical advantages of a preoperative chemotherapy approach is better delivery of the systemic treatment. The phase III Chemotherapy for Early Stages Trial (Ch.E.S.T.) reported by Scagliotti at the 2007 annual meeting of the American Society of Clinical Oncology (ASCO) indeed documented that 99% of the patients in the preoperative chemotherapy arm received at least two of three cycles of cisplatin and vinorelbine and 85% received all three.[6] The results of the Neoadjuvant/Adjuvant Taxol (paclitaxel) Carboplatin Hope (NATCH) trial were recently presented at ASCO 2009. The three-arm trial randomized patients to surgery alone, or surgery with induction or adjuvant carboplatin/paclitaxel chemotherapy. The investigators found a significant difference in the ability to deliver chemotherapy favoring the induction chemotherapy group: In an intent-to-treat analysis, 90% of the induction chemotherapy patients received all three cycles as planned, whereas only 66% of the patients in the adjuvant arm actually received any chemotherapy. Even if one eliminates from the adjuvant chemotherapy group those patients who