At the 2nd European Society of Medical Oncology (ESMO) Consensus Meeting on Lung Cancer, held in Lugano, Switzerland, May 11-12, 2013, 35 experts discussed some issues of non-small cell lung cancer (NSCLC) and developed corresponding recommendations (with recommended grading and level of evidence). The consensus was published online in Annals of Oncology (Ann Oncol) on April 20, 2015, and is partially translated below.
Stage III non-small cell lung cancer (NSCLC) sub-stage
In the minority of stage III patients who undergo direct surgical resection, a definition of complete surgical resection is now proposed. In the majority of patients with stage III confirmed by initial staging evaluation, classification as potentially resectable, potentially resectable with increased risk of incomplete resection, or unresectable at baseline remains important.
Positron emission tomography (PET)/CT
All patients planned for definitive stage III NSCLC treatment should undergo diagnostic high-resolution CT followed by PET for the purpose of initial staging or combined PET/CT with CT technology and appropriate resolution [I, A] to exclude detectable extra-pulmonary extra-cranial metastases and to assess potential mediastinal lymph node involvement; the examination should preferably be performed within 4 weeks before the start of treatment [III, B]. Pathological confirmation of a single PET-positive distant lesion is required [V, B].
Minimally invasive mediastinal staging (TBNA/EBUS/EUS/mediastinoscopy)
PET-positive mediastinal lesions are subject to pathologic evaluation [I, A]. In cases with concomitant suspicious lesions (primary tumor >3 cm long axis, central tumor, cN1, CT enlarged lymph nodes >1 cm short axis), indications for invasive mediastinal staging exist despite PET negativity [III, B]. When feasible, an endoscopic approach should be preferred as the initial intervention [I, A]. When endoscopic findings are negative and mediastinal lymph node involvement is highly suspicious, indications for surgical staging exist [I, A].
Magnetic resonance imaging (MRI)/cerebral CT of the brain
All patients scheduled for curative stage III NSCLC treatment should undergo initial brain imaging staging [III, B]. In stage III disease, contrast-enhanced brain MRI is the preferred brain staging method [III, A]. Dedicated contrast-enhanced brain CT may be performed as an alternative [III, B].
Cardiopulmonary function has implications for multidisciplinary treatment decision making including surgery [II, A] and radiotherapy [III, C].
Co-morbidity is of critical importance as any aggressive treatment strategy aimed at cure requires a balance of potential risks of toxicity/morbidity/mortality and potential benefits [III, A].
For treatment with curative intent, patients should be able to receive platinum-based chemotherapy (cisplatin preferred) [I, A].
Incidental IIIA (N2)
If the N2 lesion is found only intraoperatively despite the implementation of an adequate mediastinal staging operation, it should be followed by adjuvant chemotherapy after surgery [I, A]. In the case of complete resection, additional postoperative radiotherapy is not routinely recommended, but it is one of the options after individual risk assessment [V, C].
Potentially resectable IIIA(N2)
Preoperative diagnosis of IIIA(N2)
Possible strategies include the following options: induction chemotherapy followed by surgery, induction radiotherapy followed by surgery, or concurrent definitive radiotherapy [I, A]. No recommendation can be made at this time; however, an experienced multidisciplinary team is essential in any complex multimodal treatment strategy decision. If induction chemotherapy alone is given preoperatively, postoperative radiotherapy is not the standard of care, but may be one of the options based on an important assessment of the risk of local recurrence [IV, C].
Potentially operable IIIA (N2) disease and selective IIIB disease
In potentially resectable supratentorial tumors, concurrent radiotherapy induction followed by definitive surgery is one of the treatment options [III, A]. In highly selective cases and in experienced medical centers, the same strategy can be used for potentially resectable T3 or T4 central tumors [III, B]. In both cases, surgery should be performed within 4 weeks after the last radiotherapy [III, B].
Patients with unresectable IIIA (N2) disease and IIIB disease
In patients with unresectable stage IIIA and IIIB disease who have been evaluated, concurrent radiotherapy is one of the optional treatments [I, A]. If concurrent radiotherapy cannot be administered for some reason, sequential therapy with induction chemotherapy followed by definitive radiotherapy represents a definite and effective alternative [I, A].
Prophylactic brain irradiation (PCI)
There is no role for PCI in stage III NSCLC [II, A].
Cisplatin or carboplatin in combination with radiotherapy
When there are no contraindications, the optimal chemotherapy in combination with radiotherapy in stage III NSCLC should be based on cisplatin. There are no definitive conclusions to support the use of single-agent carboplatin as a sensitizing agent for radiotherapy [I, A].
Chemotherapy combinations
Most studies comparing concurrent radiotherapy with sequential application have used cisplatin + etoposide or cisplatin + vincristine (typical: cisplatin + vincristine). There are no comparative phase III trials applying the paclitaxel/carboplatin regimen. In perioperative applications, cisplatin-based combination therapy may be considered as one of the optional treatments in the absence of contraindications. [I, A].
Number of chemotherapy cycles
In a radiotherapy strategy for stage III disease, two to four cycles of parallel chemotherapy should be given [I, A]. There is no evidence for induction or consolidation chemotherapy. In the perioperative setting, 3 to 4 cycles of cisplatin-based chemotherapy are recommended [I, A]; a total cumulative dose of at least 300 mg/m2 cisplatin is targeted in adjuvant chemotherapy [II, B].
Dose and fractionation in concurrent radiotherapy
In concurrent radiotherapy it is recommended to divide 60-66 Gy into 30-33 days, once daily [I, A]. The total treatment duration should not exceed a maximum of 7 weeks [III, B]. In concurrent radiotherapy regimens, “biological intensification” such as treatment acceleration is not the standard protocol [III, B].
Dose and fractionation in sequential radiotherapy
Accelerated radiotherapy has shown promising regression [I, A].66 Gy in 24 fractions is a potential radiotherapy regimen [II, C].
Preoperative radiotherapy dose
The standard preoperative radiotherapy dose in radiotherapy regimens should be 40-50 Gy in conventional fractionation or 40-45 Gy in accelerated fractionation (applied twice daily) [I, B].
Selective mediastinal lymph node irradiation
Selective mediastinal lymph node irradiation (prophylactic irradiation of non-involved mediastinal lymph nodes) is not recommended [I, B].
Radiotherapy technique
Both quality assurance and dose restraint are required [I, A].
Type and extent of surgery
Optimal surgical treatment is aimed at complete resection – preserving as much of the uninvolved lung parenchyma as possible, with lobectomy/sleeve resection preferred [I, A]. Complete resection must include exploration of the mediastinal lymph node system. In elective patients, total pneumonectomy must be performed, but the procedure should be adequately selected and limited to an experienced medical center [III, B].
Postoperative mortality associated with surgical interventions
Based on reporting series, mortality rates after lobectomy and total pneumonectomy should not exceed 2% to 3% and 3% to 5%, respectively [IV, B].
Age
Age per se does not affect regression after surgery combined with adjuvant chemotherapy or definitive concurrent radiotherapy [I, A]. However, the data are limited to the elderly population, especially to patients over 75 years of age.
Physical status (PS)
After the implementation of a surgical combined adjuvant treatment strategy, a reduction in PS is a significant negative predictor in terms of OS outcome. Therefore, treatment planning needs to be individualized [III, B].
Targeted agents
Except for clinical trials, there is no role for targeted agents in stage III NSCLC.
After radical treatment
CT scans of the chest and upper abdomen (including the adrenal glands) should be performed at 6-month intervals for 2 years and annually for 3 years thereafter [III, C]. Routine PET/CT examinations are not recommended. It is considered only in cases where abnormalities are detected on CT scan [III, C].
Brain imaging methods
Patients with stage III disease accompanied by a high risk of brain recurrence after multimodal therapy. Elective patients with a high risk of brain recurrence may be followed up with brain imaging, leading to early detection and treatment of single site recurrence with the aim of cure [V, C].
Smoking cessation
Patients treated for stage III disease should be strongly encouraged to quit smoking and/or participate in a smoking cessation program [I, A].