Hong Kong Respiratory Medicine

Dr Stephanie Chu
Department of Medicine, Queen Elizabeth Hospital
Introduction
Despite the recent advances in the treatment of metastatic non-small cell lung cancer, management of Stage IIIA disease remains controversial. Patients with Stage IIIA tumours represent a heterogeneous group, which fit between the generally resectable stages I to II and the unresectable stage III disease. Treatment modalities include surgery, radiotherapy, and chemotherapy and often involve a combination of these. The debate is about the exact choice and sequence of different therapies. Large randomised studies are challenging to carry out due to the limited number of patients with wide variations of clinical presentation and prognosis within the Stage IIIA classification.

Careful pre-treatment evaluation and in particular the mediastinal nodal status is essential as findings will often not only affect the stage but also the choice of treatment. PET-CT scan and sometimes MRI brain is necessary to exclude unresectable metastatic disease. Where there is positive uptake of mediastinal lymph nodes on PET-CT scans in patients who are potential surgical candidates, mediastinoscopy or endobronchial ultrasound (EBUS) and endoscopic oesophageal ultrasound (EUS) is necessary to assess the status of various nodal stations and to exclude N3 disease. Multidisciplinary approach is the key to management.

Management of Different Disease Groups
1. N2 disease
A. Incidental disease discovered at surgery (T1-3 N2)
Despite adequate pre-operative staging with PET-CT scan, the metastatic lesions may occasionally be demonstrated intra-operatively on frozen section or come as a surprise days later in the histological examination of the surgical specimen. Microscopic disease was shown to occur in around 2.9-3.5% of patients with negative pre-operative PET-CT who subsequently underwent mediastinoscopy or EUS with fine needle aspiration (EUS-FNA).1 Routine use of these procedures for pre-operative staging in patients with negative PET-CT scan is currently not recommended. In general if only one single nodal station is unexpectedly found to be involved intra-operatively, and that both the involved node(s) and the primary tumour is technically resectable, then the surgeon should proceed with the planned resection surgery along with formal mediastinal lymph node dissection.2,3 The number of nodal involvement was found to be an independent predictor for survival and patients with single nodal disease do better.4

With negative resection margin adjuvant chemotherapy is recommended with 4 cycles of cisplatin-based doublet regime in combination with vinorelbine or etoposide, and gemcitabine or pemetrexed (for adenocarcinoma and large cell carcinoma) are acceptable alternatives.3,5,6 Carboplatin and paclitaxel for 4 cycles maybe used for patients with significant co-morbidities or for those who are unable to tolerate cisplatin.4 The 5-year survival for this group of patients with incidental N2 disease treated by surgery and adjuvant post-operative chemotherapy was reported to be around 35%.4 In patients with positive resection margin or residual disease, concurrent chemoradiation should be considered for those who are medically fit to decrease the rate of local recurrence and should be started as early as possible.3,7 The benefit of adjuvant chemotherapy aiming at elimination of micrometastatic disease was shown to improve survival irrespective of whether it was given together with post-operative radiotherapy or not.5

B. Potentially resectable disease (N2 disease confirmed before surgery)
The poor survival rates of this group of patients treated by surgery alone or even with adjuvant post-operative chemotherapy had prompted the use of pre-operative chemotherapy or radiation therapy, with a hope for debulking the tumour as well as potential nodal clearance with down-staging of disease to facilitate complete tumour resection at surgery. The decision of optimal choice or sequence of treatment should be discussed at a multidisciplinary meeting involving the cardiothoracic surgeons. After carefully excluding any distant metastatic disease by means of PET-CT scan (and sometimes MRI brain), induction (neoadjuvant) chemotherapy followed by surgical resection maybe considered, to be followed by post-operative chemotherapy with or without radiotherapy if not previously given.2,3
However it is still uncertain who will benefit from this approach i.e. neoadjuvant therapy followed by surgical resection, compared with definitive concurrent chemoradiation, which have similar survival outcome.2,3,9 What is known though, is that those patients with negative mediastinum after induction therapy may have a better prognosis.8 Decision to proceed to surgery should not be automatic, and whether only those with response to induction therapy should be selected for surgery remains controversial. Restaging following induction therapy is often difficult to interpret even with PET-CT scan or a repeat mediastinoscopy, and current evidence suggests that primary mediastinoscopy is the most accurate.11 Hence it may be preferable to use EBUS/EUS for the initial mediastinal sampling before treatment and reserve mediastinoscopy for restaging post induction therapy. In patients where pneumonectomy is anticipated, the role of neoadjuvant therapy remains controversial because of associated post-operative pulmonary toxicity.2,9,10

C. Unresectable tumour (Bulky N2 disease, T4 N 0-1)
For patients having bulky mediastinal disease with multiple pathologically proven lymph nodes, chemoradiation is recommended2,3 and is superior to radiation alone.12,13 Concurrent chemoradiation has also been shown to be superior to sequential therapy2,3,14,15. If patients are too frail for concurrent therapy then sequential chemoradiation can be considered.

2.Locally Advanced Disease
A. Superior sulcus (Pancoast) Tumour (T3 with invasion + N1-2, T4 with extension + N0-1)
Management of patients with superior sulcus tumours are frequently challenging because of the close proximity of the tumour to many vital structures, and usually require multimodality treatment. Invasion into adjacent important structures such as the brachial plexus, subclavian vessels and the spine is not uncommon. Thorough staging evaluation is warranted to assess the extent of the primary tumour and to exclude the presence of extra-thoracic lesions given the locally advanced nature of the disease. MRI is the imaging of choice for assessing the thoracic inlet including the subclavian vessels, spine and neural foramina.

For resectable tumours, preoperative concurrent chemoradiation should be offered followed by surgery and post-operative chemotherapy.2 For marginally resectable tumours pre-operative concurrent chemoradiation could be offered to be followed by surgical re-evaluation. If the tumour is considered resectable then surgery could be offered, to be followed by post-operative chemotherapy. For unresectable tumours management would be definite chemoradiation.2
With improved surgical techniques and the introduction of pre-operative chemoradiation followed by surgery, the overall 5 year survival rate was 44% for all patients and 54% who had complete resection.16 Data from the same study (n=110 patients) also showed that 95% of patients were able to complete pre-operative chemotherapy and 80% underwent thoracotomy. Post-operative mortality was 1.8% and 56% patients had complete resection. Pathological response (ie without any evidence of residual disease on resected specimen) rather than the tumour staging (T3 vs T4 disease) was found to predict overall survival.16 Disease progression when present mainly occurred at distant sites.

B. Tumours with chest wall invasion, proximal airway or mediastinum (T3 N0-1)
In some patients with bulky primary tumours which invade directly into the chest wall, long term survival can be achieved provided the primary tumour can be completely resected. Surgery followed by chemotherapy is the treatment of choice provided that the tumour can be resected en bloc at initial presentation.2 In some cases pre-operative concurrent chemoradiation or chemotherapy may be useful for initial control of the tumour followed by surgery.2 If the resection margin is positive, post-operative chemotherapy (if not given prior to surgery) with re-resection of tumour or chemoradiation followed by chemotherapy if not given as initial treatment can be offered.2 With radical surgery which includes chest wall resection, 5 year survival had been reported to be approximately 40-44%.17
For patients with T3 with invasion & N0-1 disease, optimal treatment would be pre-operative concurrent chemoradiation followed by surgery plus further cycles of post-operative chemotherapy.2 If the lesion is considered marginally resectable (T4 extension & N0-1) then surgical re-evaluation should be sought and if felt to be resectable then surgery should proceed as planned followed by post-operative chemotherapy. Where the lesion is unresectable then radiotherapy should be continued followed by further cycles of chemotherapy. For patients with N2 disease confirmed at mediastinoscopy then they should proceed with definitive concurrent chemoradiation.

3. Separate pulmonary nodule(s) (same lobe T3 N0 or ipslateral lung non-primary lobe T4N0)
Whenever surgery is feasible this would be the treatment of choice, followed by adjuvant chemotherapy if resection is complete with clear margins.2 For patients with evidence of residual tumour both microscopically or macroscopically, concurrent chemoradiation should be offered if clinical conditions allows.2

Conclusion
Patient selection and decision making as to the optimal choice and sequence of therapy continues to be challenging for patients with stage IIIA disease. The beauty of the complimentary effect of each treatment modality cannot be better demonstrated. We see how induction chemotherapy is able to reduce or downstage the disease making complete surgical resection feasible. At the same time, evidence is continually evolving as to the optimal sequence of combination therapy, for example, the optimal dose and regime of concurrent chemoradiation, the sequence and timing of each therapy, the role of surgery, and how best we can help to tailor made the best personalized therapy for our stage IIIA patients to improve the outcome.

References
1. Cerfolio RJ, Bryant AS, Eloubeid MA. Routine mediastinaopscopy and esophageal ultrasound fine-needle aspiration in patients with non-small cell lung cancer who are clinically N2 negative. Chest 2006; 130:1791-5
2. Robinson LA, Ruckdeschel JC, Wagner H Jr et al. Treatment of Non-small Cell Lung Cancer-Stage IIIA: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition). Chest 2007; 132:243S-265S
3. National Comprehensive Cancer Network
NCCN GuidelinesTM Non-Small Cell Lung Cancer Version 2.2012. www.nccn.com
4. Cerfolio RJ, Bryant AS. Survival of patients with unsuspected N2 (Stage IIIA) Non-small Cell Lung Cancer. Ann Thorac Surg 2008;86:362-367.
5. NSCLC Meta-analyses Collaborative Group Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small cell lung cancer: two meta-analyses of individual patient data. Lancet 2010;375(9722):1267-1277
6. The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin –Based Adjuvant Chemotherapy in Patients with Completely Resected Non-small Cell Lung Cancer. N Engl J Med 2004;350:351-360
7. Keller SM, Adak S, Wagner H et al. A randomised trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small cell lung cancer. Eastern Cooperative Oncology Group. N Engl J Med 2000; 343:1217-1222
8. Bueno R, Richards W, Swanson S et al. Nodal stage after induction therapy for stage IIIA lung cancer determines survival. Ann Thoraac Surg 2000;70:1826-1831
9. Albain KS, Swann RS, Rusch VW et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small cell lung cancer: a phase III randomised controlled trial. Lancet 2009;374:379-386
10. Thomas M, Rübe C, Hoffknecht P et al. Effect of preoperative chemoradiation in addition to preoperative chemotherapy: a randomised trial in stage III non-small cell lung cancer. Lancet Oncol 2008;9:636-648
11. de Cabanes Candela S, Detterbeck FC. A systematic review of restaging after induction therapy for stage IIIA lung ancer: prediction of pathologic stage. J Thorac Oncol 2010;5:389-398
12. Auperin A, Pechoux C, Rolland et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small cell lung cancer. J Clin Oncol 2010;28:2181-2190
13. O’Rouke N, Roque I, Fiuis M et al. Concurrent chemotherapy in non-small cell lung cancer. Cochrane Database Syst Rev 2010: CD 002140
14. Huber RM, Flentje M, Schmidt M et al. Simultaneous chemoradiotherapy compared with radiotherapy alone after induction chemotherapy in inoperable stage IIIA or IIIB non-small cell lung cancer: study CTRT99/97 by the Bronchial Carcinoma Therapy Group. J Clin Oncol 2006;24(27):4397-4404.
15. Zatloukal P, Petruzelka L, Zemanova M et al. Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study. Lung Cancer (2004)46, 87-98
16. Rusch VW, Giroux DJ, Kraut MJ et al. Induction Chemoradiation and Surgical resection for Superiour Sulcus Non-Small Cell Lung Carcinomas:Long-Term Results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol 2007; 25:313-318
17. Matsouka H, Nishio W, Okada M et al. Resection of chest wall invasion in patients with non-small cell lung cancer. Eur J Cardiothorac Surg 2004;26:1200-1204