Challenges and State of the Art: The early stage patient

Surgery: How aggressive should it be?

Surgical treatment of patients with early lung cancer is often a challenging task that requires robust preoperative risk assessment as a first step. Wherever possible, pneumonectomy should be avoided, in an attempt to maximally preserve functional capacity, as Khosro Hekmat, MD, Department of Cardiothoracic Surgery, University Hospital of Cologne, emphasized. To decide whether surgery is possible at all, and how radical it might need to be, not only the tumor stage needs to be considered, but also the preoperative risk assessment, which includes clinical factors, spirometry, gas exchange parameters, exercise testing, and radionuclide studies to differentially examine each lung. For many stage IIIA cancers and nearly all stage IIIB cancers, the tumor might be difficult, and sometimes impossible, to remove. In such cases, the thoracic surgeon can recommend chemotherapy combined with radiotherapy prior to further considering surgery.

The complex anatomy of the bronchial tree and its intimate connection with neighboring tissues, and especially the pulmonary vessels, require the use of intricate surgical resection techniques, which include bronchial sleeve resections and vascular sleeve resections. Bronchial sleeve resection includes resection of infested bronchial sections, together with the contaminated parts of the parenchyma, and the subsequent anastomosis of the remaining bronchial segments [1]. Where large pulmonary vessels are also affected, a more complicated procedure can be applied, known as vascular sleeve resection. Here, small affected parts of the vascular wall are removed and grafted with patches of tissue. Where large areas are affected, the respective part of the artery can be removed, and the remaining ends rejoined surgically, or the gap can be replaced using an extravascular graft [2].

Oligometastatic lung cancer is defined as the synchronous presentation of a primary lung tumor and a distant site of extrapulmonary metastasis. This represents stage IV according to the International Union for Cancer Control (UICC) classification, but in selected cases, it can be amenable to surgical treatment with curative intention. According to the TNM staging system, UICC stage IV is subdivided as follows: Stage M1a is defined by – in addition to the primary tumor – the presence of a separate tumor in a contralateral lobe, or pleural or pericardial nodules, or malignant pleural or pericardial effusion. In stage M1b, a single extrathoracic metastasis is present, and in stage M1c, the patient has multiple extrathoracic metastases in one or more organs. About one third of oligometastases are located in the brain or lungs. Prognosis is strongly dependent on intrathoracic versus extrathoracic localization of the oligometastases. In a literature review, patients with intrathoracic disease (stage IVA) showed median survival of 11.5 months, and 2-year and 5-year survival rates of 23 % and 10 %, respectively, whereas for patients with extrathoracic disease (stage IVB) these were 6.0 months, 10 %, and 0 %, respectively [3].

Adjuvant chemotherapy: how to balance benefit and toxicity

In patients with solid tumors, surgical removal of the primary malignancy is essential, although this might not be sufficient for cure. A malignant tumor has to contain about 10⁸ cancer cells to be detectable by computed tomography (CT), and 10⁹ cells to be clinically palpable; therefore, even the most radical operation does not guarantee freedom from small (micro-)metastases, especially in locally advanced stages. Real-world data suggest that even in stage I NSCLC, 5-year survival rates are only about 35 %, and for all patients with NSCLC together, this becomes only about 10 %.

Therefore, there clearly is a rationale for adjuvant treatment of patients with lung cancer after surgical resection, and several trials have been conducted to this end. Ten years ago, a meta-analysis of five large trials with more than 4,500 patients with stage I–III NSCLC already showed significant improvement in overall survival (OS) with postoperative cisplatin-based chemotherapy, as Matthias Scheffler, MD, Department of Internal Medicine I, University Hospital of Cologne, stated [4]. After a median follow-up of 5.2 years, the hazard ratio (HR) for death was 0.89 in favor of adjuvant chemotherapy, with a 5-year absolute survival benefit of 5.4 %. This benefit was independent of type of chemotherapy (which always included cisplatin), although it appeared not to apply to patients with stage IA disease and those with an Eastern Cooperative Oncology Group (ECOG) performance status of 2. Otherwise, parameters like sex, age, histology, type of surgery, planned radiotherapy, and planned total dose of cisplatin did not influence the results. Postoperative cisplatin-based chemotherapy therefore significantly improves survival in patients with NSCLC.

A more recent Cochrane meta-analysis of 47 trials with more than 11,000 patients also demonstrated clear benefit of adjuvant chemotherapy for these patients, irrespective of whether chemotherapy was given in addition to surgery alone (HR, 0.86; 95 % confidence interval [CI], 0.81–0.92; p < 0.0001) or to surgery plus radiotherapy (HR, 0.88; 95 % CI, 0.81–0.97; p = 0.009) [5]. For both situations (i.e., adjuvant chemotherapy after surgery alone or after surgery plus radiotherapy), there were similar benefits for recurrence outcomes, and the benefits were largely independent of the type of chemotherapy or other characteristics. The effects of adjuvant chemotherapy on quality of life and adverse events were not investigated in this meta-analysis, because quality of life information had not routinely been collected during all of the trials included. As far as toxicity was assessed and mentioned in these publications, it was thought to be manageable.

Novel combinations with chemotherapy

The future of chemotherapy of early stage NSCLC, as Scheffler mentioned, will be mainly characterized by the use of more individualized approaches. A glimpse of this future can already be gained from the results of the phase III PACIFIC trial, in which treatment of patients with stage III disease with the anti-PD-L1 antibody durvalumab for 2 years after chemoradiotherapy achieved a tripling of median progression-free survival (PFS), from 5.6 to 16.8 months (HR, 0.52; 95 % CI, 0.42–0.65; p < 0.001) (Fig. 1; [6]). This effect was similar for all of the subgroups investigated. 

Figure 1: The PACIFIC trial. There was a tripling of progression-free survival by durvalumab versus placebo in patients with stage III NSCLC. Modified from [6].

REFERENCES

1. Dienemann HC, Hoffmann H, Detterbeck FC (Eds.). Chest Surgery 2014. Springer-Verlag Berlin Heidelberg 2015.
2. Patterson GA et al. (Eds.). Pearson´s Thoracic Surgery. Churchill Livingstone 2008, 3rd edition.
3. Lanuti M et al. Surgical management of oligometastatic non-small cell lung cancer. Thorac Surg Clin 2016; 26: 287-94.
4. Pignon JP et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008; 26: 3552-9.
5. Burdett S et al. Adjuvant chemotherapy for resected early-stage non-small cell lung cancer. Cochrane Database Syst Rev 2015, Issue 3. Art. No.: CD011430. DOI: 10.1002/14651858.CD011430.
6. Antonia SJ et al. Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. N Engl J Med 2017; 377: 1919-29.

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