Adjuvant or neoadjuvant chemotherapy in minimal N2 stage IIIA nonsmall cell lung cancer Sofie De Craenea, Veerle Surmonta,b and Jan P. van Meerbeeck Current Opinion in Oncology 2010, 22:

INTRODUCTION Stage IIIA NSCLC patients represent a heterogeneous group of patients whose tumor extension is restricted to the affected lung (T3N1), but also include patients with metastatic disease to the ipsilateral mediastinal lymph nodes (T1-3 N2). Approximately 10–15% of newly diagnosed cases with NSCLC will be classified as stage IIIA-N2 2

Treatment of stage III NSCLC requires both local and systemic disease control. The role of surgery in patients with subset IIIA3 : controversial poor survival with surgery alone has led to efforts at adding adjuvant chemotherapy and/or radiotherapy Unresectable stage IIIA-N2 : Platinum-based concurrent chemoradiotherapy is considered the standard current approach. Several randomized trials have shown an improved survival with postoperative chemotherapy in completely resected NSCLC improving 5-year survival rate with 13–15% Postoperative radiotherapy (PORT) in pN2 patients : No clear improvement in overall survival, but a small but significant reduction in local recurrence 3

4 Neoadjuvant chemotherapy Theoretical advantages Decrease in tumor size to allow more readily resection Potential nodal clearance of tumor with downstaging Decreased surgical seeding In-vivo chemosensitivity testing of the chemotherapy regimen Increased patient acceptance and compliance Disadvantages Delaying resection Increasing the surgical morbidity and mortality Twelve randomized trials have compared neoadjuvant chemotherapy followed by surgery versus surgery alone significant benefit in favor of neoadjuvant chemotherapy is present ranging at 5 years from 6 to 14%, though weakened by several confounding factors

5 This article will review the recent evidence with regard to (neo-)adjuvant chemotherapy in stage IIIA3 NSCLC.

RESULTS – NEOADJUVANT CHEMOTHERAPY 6

Mansour et al. Suggest that pneumonectomy is justified even in patients with persistent N2 disease after induction chemotherapy Carretta et al. // Yap et al. There is no benefit of chemoradiotherapy over chemotherapy alone as induction treatment Edelman et al. Hyperfractionated radiation and chemotherapy followed by surgery in stage IIIA and IIIB NSCLC was safe and well tolerated Feasibility for an aggressive trimodality approach to treat locally advanced NSCLC. 7

Dudek et al. : Assessed the clinical activity of neoadjuvant therapy with carboplatin, gemcitabine, and thalidomide in 8 patients with stage IIB and 14 patients with IIIA NSCLC. Response rates : PR (70%), SD(20%), PD(10%) Downstaging : 14 patients (70%), 10 lobectomies (45.5%), one bilobectomy (4.5%), and three pneumonectomies (13.64%). Thomas et al. : compared the intensity of the induction regimen => Neoadjuvant concurrent chemoradiation versus chemotherapy alone in 524 patients. Severe toxicity and mortality rate : CCRT > CTx Pathologic CR(pCR) rate : CCRT > CTx Outcome : not significantly different => casting a doubt on the value of pCR as a surrogate marker of outcome 8

Albain et al. Pathologically documented stage IIIA-pN2 NSCLC CCRT (two cycles of cisplatin 50 mg/m2 on day 1, 8, 29, and 36 and etoposide 50 mg/m2 on days 1–5 and 29–33//45 Gy) followed by surgery (trimodality treatment), versus chemotherapy with definitive radiotherapy (uninterrupted radiotherapy up to 61 Gy) and without surgery. Progression free survival : trimodality > bimodality Overall survival : not significantly improved High mortality rate after pneumonectomy, mainly attributable to acute respiratory distress syndrome and other respiratory causes. Inadequate study power Reduced delivery of the adjuvant chemotherapy in the surgical group 9

Felip et al. Three cycles of adjuvant or preoperative paclitaxel/carboplatin improve 5-year disease-free survival (DFS) compared with surgery alone in clinical stage IA (T>2 cm), IB, II, and T3N1. Preoperative chemotherapy had a nonsignificant trend toward improved DFS when compared with surgery The only subgroup benefiting from preoperative chemotherapy had stage T3N1 Westeel et al. Compared preoperative and perioperative chemotherapy (2 cycles + 2 cycles in responders before surgery versus 2 cycles before + 2 cycles after surgery in responders) Compliance : preoperative > perioperative Postoperative mortality, DFS : no significant difference 10

RESULTS – ADJUVANT CHEMOTHERAPY 11

Carretero et al. Evaluated the clinical efficacy and toxicity profile of platinum-based and taxane-based adjuvant chemotherapy in 41 patients with completely resected IB-IIIA NSCLC(stage IIIA : 27 pts) Platinum–taxane-based adjuvant chemotherapy in pIB-IIIA NSCLC following complete resection is feasible, well tolerated, and can be delivered in most patients in the adjuvant setting. Tibaldi et al. Evaluate postoperative drug delivery and toxicity of cisplatin and gemcitabine in patients with radically resected stage pIB-III NSCLC.(stage IIIA : 50%) Combination of cisplatin/gemcitabine is a feasible and well tolerated regimen 12

Stinchcombe et al. Postoperative carboplatin and docetaxel(n=72, stage IIIA : 22%) Grade 4 neutropenia 42% and febrile neutropenia 11% of patients. Toxicity profile with the use of granulocyte colony-stimulating factor (G-CSF) supportive therapy was acceptable and that the majority of patients completed four cycles of therapy within 12 weeks. Felip et al. Compared three cycles of adjuvant paclitaxel/carboplatin to surgery alone Postoperative mortality : similar across arms. Patients with T3N1 did not benefit from adjuvant chemotherapy 13

DISCUSSION Whereas the role of surgery in the management of stage IIIA-N2 is controversial When comparing the available evidence regarding both strategies (neoadjuvant versus adjuvant therapy), the following conclusions can be drawn : The patient populations of the trials with neoadjuvant and adjuvant therapy are different due to the clinicopathological stage migration as a result of the inaccuracy of our clinical staging The use of new staging techniques such as PET, integrated CT/PET, endoscopic ultrasound with fine needle biopsy improves the clinical staging and restaging. There is a lack of a standardized definition of what is considered a technically resectable N2 disease. As only downstaged patients seem to benefit from multimodality treatment, mediastinal restaging by both imaging and endoscopic techniques will increasingly become of interest Our present systemic induction treatment is still poor. 14

CONCLUSION 15

Although numerous trials have evaluated the benefits of (neo- )adjuvant therapy in NSCLC, their accumulated evidence does not allow to change the current recommendation Recommendation for the routine use of adjuvant cisplatin- based chemotherapy in case of unforeseen pN2 (subsets IIIA-1 and IIIA-2) is unanimously given PORT is controversial and only recommended when the resection is considered potentially incomplete US and Canadian oncological societies do not advocate PORT after complete resection 16

British National Collaborating Centre for Acute Care guidance Recommends chemotherapy and radical radiotherapy as first choice for eligible patients with stage IIIA Surgery with or without PORT or adjuvant chemotherapy as suitable Does not recommend preoperative chemotherapy European Society of Medical Oncology Recommends preoperative cisplatin-based combination chemotherapy in patients with stage IIIA-N2 disease Surgery is considered questionable in patients with persistent N2 disease after chemotherapy Does not specifically address the role of definitive chemoradiation 17

American College of Chest Physicians (ACCP) NSCLC patients with stage IIIA-N2 disease identified preoperatively, induction therapy followed by surgery is not recommended except as part of a clinical trial US National Comprehensive Cancer Network (NCCN) practice guidelines in oncology Category 1 evidence to definite concomitant chemoradiation for patients with clinical T1-3N2 NSCLC Category 2B evidence to surgery in case of nonprogression after an induction with either chemotherapy or chemoradiation for clinical T1-2N2 NSCLC 18

Taken together these guidelines Suggest a limited role for immediate surgery in patients with stage IIIA-N2 Recommend a combined approach with a systemic induction treatment Surgical resection after induction treatment : remains unproven There is a strong conviction that modern radiotherapy as part of a multimodality approach of stage III patients will further improve the outcome 19

Finally… The use of surgery in stage IIIA-N2 should not be uncritically recommended Radically resected pIIIA-subsets 0–2 should be followed by adjuvant chemotherapy Surgical resection after induction treatment for cIIIA-subset 3 can be radical but whether this approach is superior to modern definitive thoracic radiotherapy remains unproven. Patients should be given a balanced view of both treatment options 20