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• W2923070502 abstract "“What cannot be cured with medicaments is cured by the knife, what knife cannot cure is cured with the searing iron, and whatever this cannot cure must be considered incurable”–Hippocrates of Kos (c.460-370 BC)1Hyppocrates: Aphorisms. 7:87. cit: Haeger K: The Illustrated History of Surgery. Hauld Starke London, London, England1988: 40Google Scholar The case series report referencing crizotinib in a neoadjuvant setting for the locally advanced NSCLC of Zhang et al.2Zhang C. Li S.L. Nie Q. et al.Neoadjuvant crizotinib in resectable locally advanced non–small cell lung cancer with ALK rearrangement: a brief report.J Thorac Oncol. 2019; 14: 726-731Abstract Full Text Full Text PDF Scopus (43) Google Scholar unveils far more questions regarding preoperative targeted therapy in comparison to its ability in answering existing dilemmas. Hippocrates’ triad of drugs, surgery, and radiotherapy covers the entire armamentarium of oncopulmonology. Neoadjuvant therapy, a per se contextual definition, positions itself in a sequential relationship to surgery and is in sharp contrast to the adjuvant treatment concept. Distinctly, both cited forms of combined modalities assume surgery in the role fixated within the hub. The term neoadjuvant refers to the indirect admission for which, when considering locally advanced NSCLC, there is no real chance of longer survivals, not to speak about cure, without focal destruction and tumor cell eradication of the malignant tissue mass. The most recent turns of the scalpel versus ray contest are beyond our present horizon, yet do not affect the conceptual need for the destruction of the primary focus.3Weder W. Moghanaki D. Stiles B. et al.The great debate flashes: surgery versus stereotactic body radiotherapy as the primary treatment of early-stage lung cancer.Eur J Cardiothorac Surg. 2018; 53: 295-305Google Scholar, 4Jaklitsch M.T. Strauss G.M. Healey E.A. et al.An historical perspective of multi-modality treatment for resectable non–small cell lung cancer.Lung Cancer. 1995; 12: S17-S32Abstract Full Text PDF PubMed Scopus (16) Google Scholar In the heart of the matter, NSCLC is a systemic disease without a defined cause which would fulfill the carcinogenesis adjusted Koch postulates and, as a logic-dictated consequence, systemic approach should bear priority, at least theoretically.5Molnar T.F. Tuberculosis: mother of thoracic surgery then and now, past and prospectives: a review.J Thorac Dis. 2018; 10: S2628-S2642Crossref PubMed Google Scholar The idea is not entirely new. Even the very first lung cancer chemotherapies back in the 1950s were applied in a neoadjuvant, or more correctly perioperative manner.6Katsuki H. Shimada K. Koyama A. et al.Long-term intermittent adjuvant chemotherapy for primary, resected lung cancer.J Thorac Cardiovasc Surg. 1975; 70: 590-605Abstract Full Text PDF PubMed Google Scholar Cisplatinum, the queen of the second-generation chemotherapeutics in the 1980s, resulted in a renaissance of the neoadjuvant concept throughout the early 1990s.7Fennell D.A. Summers Y. Cadranel J. et al.Cisplatin in the modern era: the backbone of first-line chemotherapy for non–small cell lung cancer.Cancer Treat Rev. 2016; 44: 42-50Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 8Murren J.R. Buzaid A.C. Hait W.N. Critical analysis of neoadjuvant therapy for stage IIIa non–small cell lung cancer.Am Rev Respir Dis. 1991; 143: 889-894Crossref PubMed Google Scholar While the members of the third-generation anticancer drugs, such as the taxanes and the camptothecins, joined to the existing medicines against NSCLC up until the turn of the millennium, two external factors reshaped the treatment strategy landscape.9Cullen M. Lung cancer 4: chemotherapy for non–small cell lung cancer: the end of the beginning.Thorax. 2003; 58: 352-356Crossref PubMed Scopus (14) Google Scholar The first was the general acceptance in the significance to the chain of N2 lymph nodes, introduced into the conceptually topographical TNM system back in 1974 and the formation of a mental thin red line in oncological operability. The second factor was the new concept in shared decision-making associated with the form of multidisciplinary tumor boards (often referred to as an oncoteam) which emerged in the late 1980s to became more or less the standard of care by the mid-1990s.10Gross G.E. The role of the tumor board in a community hospital.CA Cancer J Clin. 1987; 37: 88-92Crossref PubMed Scopus (35) Google Scholar Herein describes the field of reception, in which the fourth-generation of the anticancer medical treatment, biologic therapy, landed and made its debut in the first decade of the twenty-first century. Not without its antecedents, as blood serum therapy and Bacillus Calmette-Guerin–boosting treatments to increase immune response were attempted in NSCLC long ago, they had little if any effect.11Lewiecki E.M. Biological therapy: chronicling 15 years of progress.Expert Opin Biol Ther. 2015; 15: 619-621Google Scholar The umbrella-like terminology referencing biologic therapy encapsulates both immunotherapy and targeting therapy. Diagnostic monoclonal tumor antibodies common to the 1970s entered their adulthood as potential pharmaceuticals in the late 1990s and became applicable against advanced NSCLC by the middle of the first decade of 2000s.12Yarden Y. Sliwkowski M.X. Untangling the ErbB signalling network.Nat Rev Mol Cell Biol. 2001; 2: 127-137Crossref PubMed Scopus (5609) Google Scholar Targeting therapy usually in the tyrosine kinase inhibition (TKI) domain implies a promise for one of four to five NSCLC patients. Only 1% to 7% percent of NSCLC patients show some form of ALK receptor tyrosine kinase (ALK) fusion gene, making these individuals eligible for crizotinib therapy.13Lynch T.J. Bell D.W. Sordella R. et al.Activating mutations in the epidermal growth factor receptor underlying responsiveness of non–small-cell lung cancer to gefitinib.N Engl J Med. 2004; 350: 2129-2139Crossref PubMed Scopus (10000) Google Scholar, 14Soda M. Choi Y.L. Enomoto M. et al.Identification of the transforming EML4-ALK fusion gene in non–small-cell lung cancer.Nature. 2007; 448: 561-566Crossref PubMed Scopus (4304) Google Scholar TKI therapy, having followed the standard cancer drug testing patterns, was offered in the most advanced cases in the first pilot-type clinical trials. Moderate yet well-established effect of targeted therapy witnessed in the advanced-stage NSCLC aroused the idea of usage of the drug in earlier stages.15McCoach C.E. Bivona T.G. Blakely C.M. et al.Neoadjuvant oncogene-targeted therapy in early stage non–small-cell lung cancer as a strategy to improve clinical outcome and identify early mechanisms of resistance.Clin Lung Cancer. 2016; 17: 466-469Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar The 72% to 74% response rate posed a challenge to secure and establish the supposedly stabilized tumor-body relation: eliminating the primary focus.16Shaw A.T. Ou S.H. Bang Y.J. et al.Crizotinib in ROS1-rearranged non–small-cell lung cancer.N Engl J Med. 2014; 371: 1963-1971Crossref PubMed Scopus (1412) Google Scholar A promising scenario, a room for neoadjuvant setting was spontaneously generated for selected cases. The meta-analysis of 15 neoadjuvant chemotherapy trials, all using second- and third-generation drugs, with a significant benefit in 5-year survival, time to distant metastasis and recurrence-free survival across all stages of resectable NSCLC (IB-IIIA) supported the drug-before-surgery concept.17NSCLC Meta-analysis Collaborative GroupPreoperative chemotherapy for non–small-cell lung cancer: a systematic review and meta-analysis of individual participant data.Lancet. 2014; 383: 1561-1571Abstract Full Text Full Text PDF PubMed Scopus (461) Google Scholar Today, the present situation is marked by the fact that the drug element listed in Hippocrates’ aphorism consists of three competing but not mutually excluding composites: chemotherapy, targeting therapy, and biological response modifier (immuno-) therapy. The ALK inhibitor TKI crizotinib 75% response rate versus 45% of chemotherapy in a first-line setting provoked the idea of usage the substance in earlier stages and/or as a primary drug in the neoadjuvant setting.18Solomon B.J. Mok T. Kim D.W. et al.First line crizotinib versus chemotherapy in advanced ALK-positive lung cancer.N Engl J Med. 2014; 371: 2167-2177Crossref PubMed Scopus (2439) Google Scholar Paradoxically enough, the well-documented tendency to develop resistance against TKIs is a strong argument in support of surgery in properly responding patients as a consolidating procedure in the time window of the state of grace.19McCoach C.E. Le A.T. Gowan K. et al.Resistance mechanisms to targeted therapies in ROS1+ and ALK+ non–small cell lung cancer.Clin Cancer Res. 2018; 24: 3334-3347Crossref PubMed Scopus (148) Google Scholar The fact that the incomplete response increases the subsequent therapy resistance rate must function as a whistleblowing mechanism against the far too liberal inclusion criteria regarding subsequent surgery.20Bivona T.G. Doebele R.C. A framework for understanding and targeting residual disease in oncogene-driven solid cancers.Nat Med. 2016; 22: 472-478Crossref PubMed Scopus (109) Google Scholar In general, although the questions relating to biologic induction therapy are numerous, the answers are few and understandably cautious.21Blumenthal G.M. Bunn Jr., P.A. Chaft J.E. et al.Current status and future perspectives on neoadjuvant therapy in lung cancer.J Thorac Oncol. 2018; 13: 1818-1831Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar Patients undergoing surgery while receiving TKI had no increased complication rates.22Rizvi N.A. Rusch V. Pao W. et al.Molecular characteristics predict clinical outcomes: prospective trial correlating response to the EGFR tyrosine kinase inhibitor gefitinib with the presence of sensitizing mutations in the tyrosine binding domain of the EGFR gene.Clin Cancer Res. 2011; 17: 3500-3506Crossref PubMed Scopus (56) Google Scholar Naturally, these new agents are playing a part of NSCLC neoadjuvant therapy settings. One might question the value of anecdotic reports or retrospective case series, in particular, because there are highly sophisticated trials underway such as the ALCHEMIST, the Swiss SAKK 16-14, and the NCTO 1857271, 2201992, and 2347839 trials among others.15McCoach C.E. Bivona T.G. Blakely C.M. et al.Neoadjuvant oncogene-targeted therapy in early stage non–small-cell lung cancer as a strategy to improve clinical outcome and identify early mechanisms of resistance.Clin Lung Cancer. 2016; 17: 466-469Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 23Govindan R. Mandrekar S.J. Gerber D.E. et al.ALCHEMIST trials: a golden opportunity to transform outcomes in early-stage non–small cell lung cancer.Clin Cancer Res. 2015; 21: 5439-5444Crossref PubMed Scopus (84) Google Scholar, 24Van Schil P.E. Berzenji L. Yogeswaran S.K. et al.Surgical management of stage IIIA non-small cell lung cancer.Front Oncol. 2017; 7: 249Crossref PubMed Scopus (23) Google Scholar Indisputably, a trilogy that resonates includes the epistemological, the evidence-seeking statistical, and the moral issues. Building knowledge requires the first bricks, even in our current litigation-infested, risk-averse age. The problem is not the underweight of the retrospective anecdotal reports, but with the general lack of negative results counterbalancing the bias generated by the single-sided report/publication policies. Application of a theoretically justifiable off-label method/substance, if all the standard modalities failed, is a scenario where no time is left to wait for cohort-level data from running trials. All interim observations are inevitably anecdotal, but can we afford the luxury of ignoring them? The slowly, yet steadily shaping potential of TKI in a neoadjuvant setting highlights former unfinished work. The jury is still out regarding the varied questions even among the good old neoadjuvant chemotherapy setting. Should we (and if yes, to what extent) resect the site of the former lesion after a complete remission? Should we follow the magical 6-week interval rule, or do we have a more reliable indicator in response accurately predicting the timing of surgery? What is the best way, the most cost-effective, regarding surgery? How and when do we consider the factor of accessibility? And, specifically, how and when do we verify the effectiveness of neoadjuvant therapy? The question of remediastinoscopy or the value of image-guided endoscopic biopsy specimens is far from settling down. The long-term comparative survival data with regard to the intensity of preoperative diagnostic aggressiveness are still awaited. The optimal duration of neoadjuvant treatment and the postoperative consolidation drug treatment are all defined through institutional protocols, guidelines, and advices, yet strong supportive evidence is, as of yet, rather scanty. The very nature of the approach of the oncopulmonologic community is a bifocal one. The biological features of the tumor are in one spot, whereas the therapeutic options and technologies intent on destruction are poised in another location. The different therapeutic modalities steered by the most recent TNM staging are gyrating around one another revealing our mindset in the form of treatment-centered care. Seemingly, often the individual patient receives the less attention, not to speak in reference to the socioeconomic environment around him/her. Personalized treatment (targeting therapy included) of early- and locally advanced stages means not only optimizing sequence of modalities, but resource optimization as well. Affordability and availability of anticancer drugs are key words yet not interchangeable. Targeting therapy bears a distinct advantage over immunotherapy because half of the existing drugs in the second group are more expensive than 100,000 USD annually, a cost few health insurance systems likely can afford. Onco-economy, rich with a plethora of yet unresolved moral issues, is considerably a new aspect in which the shared decisions regarding specifically what modalities are beneficial in which the sequence are to be applied. We have no other choice but to properly portray our role in the assigned scene while we are “waiting for Godot.” Zhan et al.2Zhang C. Li S.L. Nie Q. et al.Neoadjuvant crizotinib in resectable locally advanced non–small cell lung cancer with ALK rearrangement: a brief report.J Thorac Oncol. 2019; 14: 726-731Abstract Full Text Full Text PDF Scopus (43) Google Scholar made their bit. Neoadjuvant Crizotinib in Resectable Locally Advanced Non–Small Cell Lung Cancer with ALK RearrangementJournal of Thoracic OncologyVol. 14Issue 4PreviewLocally advanced NSCLC is one of the most heterogeneous conditions, with multidimensional treatments involved. Neoadjuvant therapy had been commonly considered an optimal management strategy for patients with operable locally advanced. However, as targeted therapy has been widely applied in advanced NSCLC, neoadjuvant targeted therapy has remained poorly explored in locally advanced disease. Full-Text PDF Open Archive" @default.
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• W2923070502 title "Neoadjuvant Crizotinib for ALK Re-arranged NSCLC?" @default.
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