These new guidelines, based on an exhaustive examination of the current literature, call for a number of recommendations. We have selected from among the guidelines below. For the full text and an explanation of the weighting of evidence, access the entire report here.
Recommendation 1: In the rare cases when stage III disease patients undergo primary surgical resection, there is a proposed definition of a surgically complete resection. In the majority of patients where stage III disease is confirmed by initial staging investigations, it is still of importance to classify them at baseline as resectable, potentially resectable with an increased risk for incomplete resection, or unresectable.
Recommendation 2.1: All patients planned for definitive stage III NSCLC treatment should undergo a diagnostic high-resolution CT followed by a PET or a combined positron emission tomography–computed tomography (PET-CT) with a CT technique with adequately high resolution for initial staging purposes in order to rule out detectable extra-thoracic extra-cranial metastasis and to assess potential mediastinal lymph node involvement, ideally within 4 weeks before the start of treatment. Single PET-positive distant lesions need pathological confirmation.
Recommendation 2.2: PET-positive mediastinal findings should be pathologically assessed. Invasive mediastinal staging may still be indicated despite PET negativity in case of suspicious lesions (primary tumor of >3 cm large axis, central tumors, cN1, CT-enlarged lymph nodes with small axis >1 cm).
Recommendation 2.3: All patients planned for curative stage III NSCLC treatment should receive brain imaging for initial staging. Contrast-enhanced brain MRI is the preferred method for staging of the brain in stage III disease. Alternatively, dedicated contrast-enhanced brain CT can be carried out.
Recommendation 3.1: Cardio-pulmonary functions are relevant for multidisciplinary treatment decisions including surgery or radiotherapy. Patients for whom a surgical intervention is planned must be functionally assessed for surgery.
Recommendation 3.2: Comorbidities are of paramount importance since the potential risk of toxicity/morbidity/mortality has to be balanced with the potential benefit of any aggressive curative-intent treatment strategy. The comorbidity profile of the patients has to be critically analyzed before any curative-intent treatment decision in stage III disease.
Recommendation 3.3: For curative-intent management, patients should be able to undergo platinum-based chemotherapy.
Recommendation 4.1: If, despite adequate mediastinal staging procedures, N2 disease is only documented intra-operatively, surgery should be followed by adjuvant chemotherapy. In case of complete resection, addition of post-operative radiotherapy is not routinely recommended, but may be an option following individual risk assessment.
Recommendation 4.2.2: In potentially resectable superior sulcus tumors, concurrent chemo-radiotherapy induction followed by definitive surgery is the treatment of choice.
Recommendation 4.3: Concurrent chemo-radiotherapy is the treatment of choice in patients evaluated as unresectable in stage IIIA and IIIB. If concurrent chemo-radiotherapy is not possible—for any reason—sequential approaches of induction chemotherapy followed by definitive radiotherapy represent a valid and effective alternative.
Recommendation 4.4: There is currently no role for prophylactic cranial irradiation in stage III NSCLC. Relapse pattern in stage III NSCLC patients has shown a high cumulative risk of developing brain metastases. Several trials have explored prophylactic cranial irradiation (PCI) within the multi-modality strategy. A significant impact on brain relapse as first site of failure and on overall-brain relapse rate has clearly been demonstrated.
Recommendation 5.3.1: In the stage III disease chemo-radiotherapy strategy, 2 to 4 cycles of concomitant chemotherapy should be delivered. There is no evidence for further induction or consolidation chemotherapy. In the perioperative setting, 3 to 4 cycles of platinum-based chemotherapy are recommended, aiming at a total cumulative dose of at least 300 mg/m2 in the adjuvant setting.
Recommendation 5.3.2: Regarding stage III disease chemo-radiotherapy, 2 to 4 cycles of concomitant chemotherapy should be delivered. There is no evidence for extended induction or consolidation beyond these 3 to 4 cycles.
Recommendation 6.1.1: Doses of 60–66 Gy in 30–33 daily fractions is recommended for concurrent chemo-radiotherapy. Maximum overall treatment time should not exceed 7 weeks. ‘Biological intensification’, such as treatment acceleration, is not standard practice in concurrent chemo-radiotherapy schedules.
Recommendation 6.1.2: Promising outcome is achieved with accelerated radiotherapy. A potential radiation schedule could be the delivery of 66 Gy in 24 fractions. Accelerated radiotherapy has resulted in improved 5-year survival rates compared with so-called conventional radiation schedules, i.e. 2 Gy per day five times per week.
Recommendation 6.1.3: Standard preoperative radiation doses within chemo-radiotherapy protocols should be between 40 and 50 Gy in conventional fractionation or 40 to 45 Gy in accelerated fractionation (bid application).
Recommendation 6.2: Elective mediastinal nodal irradiation—prophylactic irradiation of non-involved mediastinal nodes—is not recommended. Prophylactic irradiation of non-involved mediastinal nodes is no longer recommended when using modern diagnostic and chemo-radiotherapy strategies, neither in sequential nor in concurrent chemo-radiotherapy.
Recommendation 6.3: Quality assurance and dose constraints are required as a prerequisite. It is recommended that high-dose radiotherapy is prepared and executed according to standards such as those of the European Organisation for Research and Treatment of Cancer (EORTC). More and more centers use respiration-correlated CT scans (or ‘4D CT’), so as to take into consideration tumor movement in thoracic oncology.
Recommendation 7.1: The optimal surgical management aims at complete resection—preserving as much non-involved parenchyma as possible, preferably carried out by lobectomy/ sleeve resection. Complete resection necessarily includes systematic mediastinal nodal exploration. In selected patients, pneumonectomy must be carried out, but should be adequately selected and the procedure restricted to experienced centers.
Recommendation 7.2: Based on reported series, post-lobectomy and pneumonectomy mortality rates should not exceed 2% to 3% and 3% to 5%, respectively. Post-operative mortality resulting from stage III disease surgical resections should be evaluated in every thoracic center. Modern published series show that surgical 30-day mortality ranges between 2% to 3% for lobectomy and 3% to 8% for pneumonectomy
Recommendation 8.1: Age itself has not been shown to influence outcome following surgery plus adjuvant chemotherapy or definitive concurrent chemo-radiotherapy. However, data are limited for the elderly population and, in particular, in patients above 75 years of age. Age alone is not a good parameter to predict outcome in stage III disease after surgery and adjuvant chemotherapy.
Recommendation 10.1: Thoracic and upper abdominal CT scan (including adrenals) should be carried out every 6 months for 2 years, and yearly thereafter [III, C] for 3 years. No routine PET-CT is recommended. It might be considered only in the case of abnormalities detected by CT scale. No evidence from randomized trials is available to define optimal follow-up in treated stage III NSCLC patients. PET-CT—although of considerable value in initial staging for stage III disease patients —has no routine role for the follow-up of stage III NSCLC patients after surgical-based multi-modality treatment.
