Unresectable Stage III NSCLC Can Be Reevaluated for Resectability After Initial Treatment
2023; Elsevier BV; Volume: 18; Issue: 9 Linguagem: Inglês
10.1016/j.jtho.2023.06.002
ISSN1556-1380
AutoresChris Dickhoff, David J. Heineman, Idris Bahce, Suresh Senan,
Tópico(s)Esophageal Cancer Research and Treatment
ResumoNSCLC represents a major disease burden, with the highest cancer-related death rate worldwide.1Sung H. Ferlay J. Siegel R.L. et al.Global cancer statistics 2020: GLOBOCAN. Estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2021; 71: 209-249Crossref PubMed Scopus (38026) Google Scholar Tumors are classified according to the IASLC staging committee, with stage III accounting for approximately 25% of patients.2Siegel R.L. Miller K.D. Wagle N.S. Jemal A. Cancer statistics, 2023.CA Cancer J Clin. 2023; 73: 17-48Crossref PubMed Scopus (1098) Google Scholar Current TNM staging groups are derived from patients treated some decades ago, who shared a similar prognosis on the basis of treatments available at that time. For example, the eighth edition of the TNM staging of NSCLC is based on data collected from 1999 until 2010 but was implemented worldwide in 2017.3Detterbeck F.C. Boffa D.J. Kim A.W. Tanoue L.T. The eighth edition lung cancer stage classification.Chest. 2017; 151: 193-203Abstract Full Text Full Text PDF PubMed Scopus (943) Google Scholar Since then, new neoadjuvant and adjuvant treatment strategies have emerged, leading to changes in guidelines for stage III NSCLC. As a result, the current edition of TNM staging does not take into account the potential benefits of these newer adjuvant and neoadjuvant therapies. Stage III NSCLC represents a very heterogenous patient group, with varying T- and N-descriptors at diagnosis, resulting in the use of a range of treatment strategies, including local treatments such as radiotherapy and surgery, combined with systemic therapy (Fig. 1).4Simone 2nd, C.B. Bradley J. Chen A.B. et al.ASTRO radiation therapy summary of the ASCO guideline on management of Stage III non-small cell lung cancer.Pract Radiat Oncol. 2023; 13: 195-202Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar However, the optimal combination and sequence of these therapies for subgroups of stage III disease, are not yet well defined. Current treatment pathways are presented in Figure 1 (black arrows). At present, the recommended approach for patients with unresectable stage III NSCLC who are fit for radical treatment, is definitive chemoradiotherapy followed by consolidation with durvalumab. For those with resectable disease, one treatment option is induction therapy (either chemotherapy, chemoradiotherapy to 46 to 50 Gy, or more recently, chemo-immunotherapy) followed by resection in patients without disease progression. When the feasibility of a complete resection is unclear (borderline resectable), another strategy taken is to initiate treatment with definitive chemoradiotherapy to 60 Gy, usually after recommendation by a multidisciplinary tumor board (MDT).5Postmus P.E. Kerr K.M. Oudkerk M. et al.Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2017; 28: iv1-iv21Abstract Full Text Full Text PDF PubMed Scopus (1154) Google Scholar,6Ramnath N. Dilling T.J. Harris L.J. et al.Treatment of stage III non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.Chest. 2013; 143: e314S-e340SAbstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar Although guidelines can help distinguish between resectable and unresectable stage III NSCLC, resectability is not uniformly defined, making it highly dependent on the experience of the local thoracic surgical team and on the interpretation of diagnostic imaging (e.g., T-size and T-invasion), leading to varying treatment recommendations between centers, and countries.7Putora P.M. Leskow P. McDonald F. Batchelor T. Evison M. International guidelines on stage III N2 nonsmall cell lung cancer: surgery or radiotherapy?.ERJ Open Res. 2020; 6 (00159–2019)Crossref Scopus (29) Google Scholar,8Hoeijmakers F. Heineman D.J. Daniels J.M. et al.Variation between multidisciplinary tumor boards in clinical staging and treatment recommendations for patients with locally advanced non-small cell lung cancer.Chest. 2020; 158: 2675-2687Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar Current recommendations for treating fit patients with unresectable stage III are largely based on the PACIFIC study regimen, consisting of definitive chemoradiotherapy, which is followed by consolidation durvalumab for patients without progressive disease. Until recently, guideline recommendations for resectable disease are based on the results of trials completed over a decade ago in a heterogenous population, including different T- and N- subsets treated with a range of induction strategies.9Albain K.S. Swann R.S. Rusch V.W. 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: 379-386Abstract Full Text Full Text PDF PubMed Scopus (1192) Google Scholar, 10Eberhardt W.E. Pöttgen C. Gauler T.C. et al.Phase III study of surgery versus definitive concurrent chemoradiotherapy boost in patients with resectable stage IIIA(N2) and selected IIIB non-small-cell lung cancer after induction chemotherapy and concurrent chemoradiotherapy (ESPATUE).J Clin Oncol. 2015; 33: 4194-4201Crossref PubMed Scopus (249) Google Scholar, 11König D. Schär S. Vuong D. et al.Long-term outcomes of operable stage III NSCLC in the pre-immunotherapy era: results from a pooled analysis of the SAKK 16/96, SAKK 16/00, SAKK 16/01, and SAKK 16/08 trials.ESMO Open. 2022; 7100455Google Scholar Studies performed before the era of immunotherapy indicate that outcomes of definitive chemoradiotherapy were comparable to those achieved with induction therapy and surgery, with 2-year locoregional and distant failure rates ranging from 10% to 31% and 39% to 57%, respectively.9Albain K.S. Swann R.S. Rusch V.W. 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: 379-386Abstract Full Text Full Text PDF PubMed Scopus (1192) Google Scholar, 10Eberhardt W.E. Pöttgen C. Gauler T.C. et al.Phase III study of surgery versus definitive concurrent chemoradiotherapy boost in patients with resectable stage IIIA(N2) and selected IIIB non-small-cell lung cancer after induction chemotherapy and concurrent chemoradiotherapy (ESPATUE).J Clin Oncol. 2015; 33: 4194-4201Crossref PubMed Scopus (249) Google Scholar, 11König D. Schär S. Vuong D. et al.Long-term outcomes of operable stage III NSCLC in the pre-immunotherapy era: results from a pooled analysis of the SAKK 16/96, SAKK 16/00, SAKK 16/01, and SAKK 16/08 trials.ESMO Open. 2022; 7100455Google Scholar, 12Bradley J.D. Paulus R. Komaki R. et al.Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study.Lancet Oncol. 2015; 16: 187-199Abstract Full Text Full Text PDF PubMed Google Scholar Besides, previous trials have also not taken into account the molecular profiling features and biological behavior of individual tumors. This, and data from ongoing trials evaluating tumor genomic profiles and detecting minimal residual disease, either before, or after initial induction therapy, may influence strategies for patients with initially inoperable stage III NSCLC. These considerations indicate a need for the thoracic oncological community to urgently reevaluate resectability in stage III NSCLC in light of the availability of more effective systemic agents, such as immunotherapy combined with chemotherapy in the neoadjuvant setting, and to determine whether the assessment of resectability should be made only at baseline, or also reconsidered in patients considered unresectable at initial presentation. Resectability of stage III NSCLC is preferably determined during a MDT discussion, after accurate staging that includes a positron emission tomography-computed tomography and magnetic resonance imaging of the brain, plus if indicated, invasive mediastinal staging.5Postmus P.E. Kerr K.M. Oudkerk M. et al.Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2017; 28: iv1-iv21Abstract Full Text Full Text PDF PubMed Scopus (1154) Google Scholar To be considered resectable, there must be a reasonable probability of achieving a complete resection of the primary tumor and involved lymph nodes (technical resectability), and also a low probability of occult distant metastases (oncological resectability). It is mainly determined by the T-descriptor, and it depends on the experience and composition of the surgical team. For instance, patients with tumors invading the spine, may be judged unresectable at one institution, but not at centers where neurosurgeons and orthopedic surgeons closely collaborate in decision making and treatment of such malignancies. In a recent study on agreement of staging and recommended treatment for patients with stage IIIA, the authors identified considerable variation in T-staging (k = 0.55, 95% confidence interval: 0.34–0.75), in particular in patients with suspected primary tumor invasion of surrounding structures, with significant impact on treatment recommendation such as induction therapy and resectability.8Hoeijmakers F. Heineman D.J. Daniels J.M. et al.Variation between multidisciplinary tumor boards in clinical staging and treatment recommendations for patients with locally advanced non-small cell lung cancer.Chest. 2020; 158: 2675-2687Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar Specialized thoracic radiology expertise is indispensable to improve the determination of technical resectability, and patients should be discussed in, or referred to, MDT's where experienced surgical teams participate. This is an important consideration as treatments including surgery offer improved disease control, even when extended resections are needed.13Unal S. Winkelman J.A. Heineman D.J. et al.Long term outcomes following chemoradiotherapy and surgery for superior sulcus tumors.JTO Clin Res Rep. 2023; 4100475PubMed Google Scholar,14Furrer K. Weder W. Eboulet E.I. et al.Extended resection for potentially operable patients with stage III non-small cell lung cancer after induction treatment.J Thorac Cardiovasc Surg. 2022; 164: 1587-1602.e5Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar It is mainly determined by lymphatic (N-descriptor) and hematological (M-descriptor) tumor spread. Invasive mediastinal procedures, such as endoscopic ultrasound, endobronchial ultrasound, and mediastinoscopy, are instruments to determine the extent of nodal involvement. Common categories of nodal involvement are hilar (N1), N2-single station, N2-multistation, N2-bulky, N2-invasive or N3.5Postmus P.E. Kerr K.M. Oudkerk M. et al.Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2017; 28: iv1-iv21Abstract Full Text Full Text PDF PubMed Scopus (1154) Google Scholar,6Ramnath N. Dilling T.J. Harris L.J. et al.Treatment of stage III non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.Chest. 2013; 143: e314S-e340SAbstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar Although these subsets are well defined, treatment recommendations can vary considerably between current guidelines, and variations of clinical practice may be even greater. In general, patients with a resectable primary tumor with limited mediastinal nodal involvement, are candidates for a surgical approach, when systemic therapies to address possible occult metastases are incorporated. Surgical resection is generally considered only for patients with limited mediastinal nodal involvement, or after downstaging of mediastinal nodal disease after induction.15Cerfolio R.J. Maniscalco L. Bryant A.S. The treatment of patients with stage IIIA non-small cell lung cancer from N2 disease: who returns to the surgical arena and who survives.Ann Thor Surg. 2008; 86: 912-920Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar However, the results of recent trials such as NADIM and CheckMate-816, suggest that the addition of surgery can result in good outcomes, even in patients with multilevel N2.16Provencio M. Nadal E. Insa A. et al.Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial.Lancet Oncol. 2020; 11: 1413-1422Abstract Full Text Full Text PDF Scopus (365) Google Scholar,17Forde P.M. Spicer J. Lu S. et al.Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer.N Engl J Med. 2022; 386: 1973-1985Crossref PubMed Scopus (482) Google Scholar Although in these trials, and in others such as AEGEAN and Neotorch, no details on postneoadjuvant mediastinal nodal evaluation and N2 subtypes were reported, they have paved the way for inclusion of immunotherapy into neoadjuvant strategies for patients with resectable NSCLC without targetable mutations, such as EGFR-mutant tumors.16Provencio M. Nadal E. Insa A. et al.Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial.Lancet Oncol. 2020; 11: 1413-1422Abstract Full Text Full Text PDF Scopus (365) Google Scholar, 17Forde P.M. Spicer J. Lu S. et al.Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer.N Engl J Med. 2022; 386: 1973-1985Crossref PubMed Scopus (482) Google Scholar, 18Heymach J.V. Mitsudomi T. Harpole D. et al.Design and rationale for a phase III, double-blind, placebo-controlled study of neoadjuvant durvalumab + chemotherapy followed by adjuvant durvalumab for the treatment of patients with resectable stages II and III non-small-cell lung cancer: the AEGEAN trial.Clin Lung Cancer. 2022; 23: e247-e251Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 19Lu S. Wu L. Zhang W. et al.Perioperative toripalimab + platinum-doublet chemotherapy vs chemotherapy in resectable stage II/III non-small cell lung cancer (NSCLC): interim event-free survival (EFS) analysis of the phase III Neotorch study.J Clin Oncol. 2023; 36 (425126–425126)Google Scholar The NADIM investigators reported a striking rate of complete pathologic response in patients with resectable stage IIIA, treated with induction chemo-immunotherapy (63%).16Provencio M. Nadal E. Insa A. et al.Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial.Lancet Oncol. 2020; 11: 1413-1422Abstract Full Text Full Text PDF Scopus (365) Google Scholar The results of the randomized phase 3 CheckMate-816 trial, in which patients with resectable tumors (≥4 cm), including stage IIIA, were randomized for induction chemotherapy plus nivolumab or the control group (chemotherapy alone), led to recent approval by the US Food and Drug Administration of this regimen.17Forde P.M. Spicer J. Lu S. et al.Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer.N Engl J Med. 2022; 386: 1973-1985Crossref PubMed Scopus (482) Google Scholar Although all these studies were designed to include "resectable tumors" at baseline, resectability was not clearly defined. Multilevel mediastinal nodal involvement represented a considerable proportion of enrolled patients in both trials, whereas this patient subgroup is often considered unresectable. Thus, by combining more effective systemic treatments (immunotherapy, targeted therapy, chemotherapy) in patients without distant metastases on restaging after induction, further improvement in outcomes may be achieved, even in patients presenting with initially multilevel, bulky or invasive N2, as long as complete removal of tumor and involved lymph nodes is anticipated. In the era of improved systemic treatments and precision medicine, there is a clear need for reconsidering the definition of resectable stage III, not only to improve agreement between treatment recommendations and clinical practice, but also to compare results of trials investigating the optimal treatment for patients within well-defined subgroups of stage III NSCLC. A better classification of patients (e.g., T- and N-descriptor, tumor biology) may identify benefits for different treatment approaches, and it is essential to implement results from studies into clinical practice. Currently, there are several initiatives, both at national and international level, including one from the European Organisation for Research and Treatment of Cancer, aiming to establish a much needed consensus on definitions of resectability in stage III.20Lee V.H. Au J.S.K. Mu J.W. et al.Real-world perspectives from surgeons and oncologists on resectability definition and multidisciplinary team discussion of Stage III NSCLC in People's Republic of China, Hong Kong, and Macau: a physician survey.JTO Clin Res Rep. 2022; 3100308Google Scholar,21Scherpereel A. Martin E. Brouchet L. et al.Reaching multidisciplinary consensus on the management of non-bulky/non-infiltrative stage IIIA N2 non-small cell lung cancer.Lung Cancer. 2023; 177: 21-28Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar A widely endorsed, uniform definition of resectability will help in the design of future multicenter, clinical trials, and facilitate interpretation of trial results. Patients with unresectable stage III NSCLC, may become resectable during, or after completing, chemotherapy or chemoradiotherapy (Fig. 1, red arrows). For example, patients with large tumors (T3 and T4) and multilevel mediastinal nodal involvement (N2-multilevel), who respond well to chemoradiotherapy, may become amenable to a complete resection before proceeding to consolidative durvalumab, potentially reducing considerable locoregional failure rates. Currently, there is little evidence to support beneficial oncological outcomes with this strategy. Surgery was traditionally avoided after high-dose radiotherapy because of concerns of increased morbidity, when compared with surgery after lower doses of induction radiotherapy. Recent data from studies investigating high-dose radiotherapy in the setting of trimodality therapy for locally advanced NSCLC, have shown that surgery after radiotherapy doses exceeding 60 Gy can be performed safely, without increased rates of complications.22Vyfhuis M.A.L. Bhooshan N. Burrows W.M. et al.Oncological outcomes from trimodality therapy receiving definitive doses of neoadjuvant chemoradiation (≥60 Gy) and factors influencing consideration for surgery in stage III non-small cell lung cancer.Adv Radiat Oncol. 2017; 2: 259-269Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar,23Liu K.X. Sierra-Davidson K. Tyan K. et al.Surgical complications and clinical outcomes after dose-escalated trimodality therapy for non-small cell lung cancer in the era of intensity-modulated radiotherapy.Radiother Oncol. 2021; 165: 44-51Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Several studies have reported surgery for locoregional failure after radical intent, definitive chemoradiotherapy, to be feasible and safe. In patients without distant metastases and completely resectable tumors, 5-year overall survival rates of up to 75% can be achieved, even when a pneumonectomy is performed.24Dickhoff C. Otten R.H.J. Heymans M.W. Dahele M. Salvage surgery for recurrent or persistent tumour after radical (chemo)radiotherapy for locally advanced non-small cell lung cancer: a systematic review.Ther Adv Med Oncol. 2018; 101758835918787989Google Scholar,25Joosten P.J.M. Dickhoff C. van der Noort V. et al.Is pneumonectomy justifiable for patients with a locoregional recurrence or persistent disease after curative intent chemoradiotherapy for locally advanced non-small cell lung cancer?.Lung Cancer. 2020; 150: 209-215Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar The extent to which improved locoregional control rates will contribute to overall survival in stage III NSCLC is currently unknown. Survival is mainly determined by distant metastases, which usually present earlier than, or simultaneously with, locoregional recurrences. Historically, improving locoregional control by adding surgery to conventional chemoradiotherapy did not result in overt survival increase.9Albain K.S. Swann R.S. Rusch V.W. 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: 379-386Abstract Full Text Full Text PDF PubMed Scopus (1192) Google Scholar,10Eberhardt W.E. Pöttgen C. Gauler T.C. et al.Phase III study of surgery versus definitive concurrent chemoradiotherapy boost in patients with resectable stage IIIA(N2) and selected IIIB non-small-cell lung cancer after induction chemotherapy and concurrent chemoradiotherapy (ESPATUE).J Clin Oncol. 2015; 33: 4194-4201Crossref PubMed Scopus (249) Google Scholar However, with more effective systemic treatments, locoregional control may become increasingly important in the absence of distant disease. Surgery in this setting may result in improved locoregional control and potentially improve overall survival, in particular for those patients without pathologic complete response to nonsurgical treatment. Another consideration is that locoregional recurrences are often difficult to treat, with high risks of fatal bleeding for re-irradiation, and a higher rate of morbidity for salvage surgery when compared with planned surgery. In the current era of improved systemic treatments, a clear definition of resectable stage III NSCLC is essential to improve agreement in treatment recommendations by the multidisciplinary tumor board, and to compare results of trials investigating multimodal approaches for the treatment of patients within the different subsets of stage III NSCLC. Furthermore, unresectable stage III NSCLC may become resectable during or after effective (induction) treatment, and surgery may add to survival by increasing locoregional control rates. Tumor characteristics will become increasingly important for individualized treatment selection for patients with stage III NSCLC in particular.
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