Epidemiology, Survival

Data 2003-2009 from SEER: 5ys = 16.6%?! viel mehr 25%

Trends in Demographics and Overall Survival of Non–Small-Cell Lung Cancer Patients 1986-2008.[Schabath, 2014 #100], NSCLC pts aged > 70y increasing

The poor prognosis for lung cancer when surgery is not an option has been well described in the literature:
An early series of 1336 patients, who were not resection candidates due to stage or comorbidities, reported
a 6-month survival of 23%, 1-year survival of 8%, and 2-year survival of 3%.1
In a series of 273 unselected patients, the 5-year survival was 7% without treatment.2
A separate series reported a median survival of 25 months for clinical stage I lung cancer patients
who were not surgically treated if the cancer was screen detected, and 13 months if it was symptom
detected.3
A large screening trial found 5- and 10-year survival rates of 16.6% and 7.4% in nonsurgically treated,
clinical stage I lung cancer patients.4
In a report of individuals with squamous cell carcinoma on sputum cytology with negative chest imaging,
the study found that those who refused surgery had 5- and 10-year lung cancer survival rates of 53.2%
and 33.5%, respectively.5
In a series of 407 individuals with resectable cancer, the 346 who went to thoracotomy had a median
survival of 30.9 months compared with 15.6 months in the 57 who did not go to surgery.6
//Poonyagariyagorn H, 2008

Natural history of operable NSCLC:
![[Pasted image 20211014103255.png]]

Local recurrence

within the Z0030 cohort the local failure rate was 4% in the T1 patients
and 7% in the T2 patients at a median follow-up of 6.7 years. // (Su et al., 2014)

The overall 5‑year survival rate
is about 28% for patients with satellite nodules and 21% for
patients with ipsilateral pulmonary nodules. In patients with
brain metastases, surgical resection achieves 5‑year survival
rates between 11% and 30%, and those with adrenalectomy
for adrenal metastases have 5‑year survival rates of 26%.(Thippeswamy et al., 2013)

Survival according to surgical approaches

Lobectomy vs. Segmentectomy vs. wedge resection

One report found 5-year survivals of 92.4%, 96.7%, and 85.7% for lobectomy, segmentectomy, and wedge resection, respectively, in tumors 20 mm in diameter or smaller.106
For tumors larger than 20 mm, the survival gaps were wider at 87.4%, 84.6%, and 35.4% for lobectomy, segmentectomy, and wedge resection, respectively. None with a tumor larger than 30 mm who had a wedge resection survived at 5 years.(Poonyagariyagorn & Mazzone, 2008)

most commen metastasis of NSCLC: thorax, brain, adrenals

De Leyn, P., Dooms, C., Kuzdzal, J., Lardinois, D., Passlick, B., Rami-Porta, R., . . . Zielinski, M. (2014). Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac Surg, 45(5), 787-798. doi: 10.1093/ejcts/ezu028
Poonyagariyagorn, H., & Mazzone, P. J. (2008). Lung Cancer: preoperative pulmonary evaluation of the lung resection candidate. Semin Respir Crit Care Med, 29(3), 271-284. doi: 10.1055/s-2008-1076747
Su, S., Scott, W. J., Allen, M. S., Darling, G. E., Decker, P. A., McKenna, R. J., & Meyers, B. F. (2014). Patterns of survival and recurrence after surgical treatment of early stage non-small cell lung carcinoma in the ACOSOG Z0030 (ALLIANCE) trial. J Thorac Cardiovasc Surg, 147(2), 747-752: Discussion 752-743. doi: 10.1016/j.jtcvs.2013.10.001
Thippeswamy, R., Noronha, V., Krishna, V., Joshi, A., Bal, M. M., Purandare, N., . . . Prabhash, K. (2013). Stage IV lung cancer: Is cure possible? Indian J Med Paediatr Oncol, 34(2), 121-125. doi: 10.4103/0971-5851.116207

Screening

Koning NEJM 2020:
[[Koning-2020-Reduced Lung-cancer Mortality Volume CT Screening.pdf]]

• screening reduced lung cancer mortality
• stage I-II screening vs no screening : 80% vs 20% !!?
  (ps: in screeing group stage I-II in majority, in control group in minority, aber diese 80% vs. 20% von Gossot Zusammenfassung habe ich nicht verstand)

links to ESTS Gossot webinar

Abstract

Background: There are limited data from randomized trials regarding whether volume-based, low-dose computed tomographic (CT) screening can reduce lung-cancer mortality among male former and current smokers.

Methods: A total of 13,195 men (primary analysis) and 2594 women (subgroup analyses) between the ages of 50 and 74 were randomly assigned to undergo CT screening at T0 (baseline), year 1, year 3, and year 5.5 or no screening. We obtained data on cancer diagnosis and the date and cause of death through linkages with national registries in the Netherlands and Belgium, and a review committee confirmed lung cancer as the cause of death when possible. A minimum follow-up of 10 years until December 31, 2015, was completed for all participants.

Results: Among men, the average adherence to CT screening was 90.0%. On average, 9.2% of the screened participants underwent at least one additional CT scan (initially indeterminate). The overall referral rate for suspicious nodules was 2.1%. At 10 years of follow-up, the incidence of lung cancer was 5.58 cases per 1000 person-years in the screening group and 4.91 cases per 1000 person-years in the control group; lung-cancer mortality was 2.50 deaths per 1000 person-years and 3.30 deaths per 1000 person-years, respectively. The cumulative rate ratio for death from lung cancer at 10 years was 0.76 (95% confidence interval [CI], 0.61 to 0.94; P = 0.01) in the screening group as compared with the control group, similar to the values at years 8 and 9. Among women, the rate ratio was 0.67 (95% CI, 0.38 to 1.14) at 10 years of follow-up, with values of 0.41 to 0.52 in years 7 through 9.

Conclusions: In this trial involving high-risk persons, lung-cancer mortality was significantly lower among those who underwent volume CT screening than among those who underwent no screening. There were low rates of follow-up procedures for results suggestive of lung cancer. (Funded by the Netherlands Organization of Health Research and Development and others; NELSON Netherlands Trial Register number, NL580.).

Diagnostik

Histologische Sicherung

Schwierigkeit bei histologischer Sicherung:
zum Beispie Lokalisation (Segment 3), blutung bei Broncho, mehrfache nicht wegweisende Befunde, Patient nicht narkose-fähig
was kann man machen? Optionen?
EBUS, Media,
Biopsie extrathorakaler Befunde ? (PET)
LK an Hals?
Liquid Biopsy?
flexibel bleiben 🙂

Liquid biopsy

Untersuchung zellfreier DNA in Blut
gute Korrelation mit Molektularpathologie (man kann damit Mutationsanalyse machen!)
als ergänzende Untersuchung, wenn Biopsie nicht möglich ist
ggf. als Verlaufskontrolle nach Therapie

Subtypisierung NSCLC

![[Pasted image 20211014103453.png]]

histological classification of adenocarcinoma matters

LPA/lepidic predominant invasive adeno OS5/10y: 95%/92%, lymphatic spread rare
vs.
NLPA/Non-lepidic predominant invasive adeno OS5/10y: 88%/68%, lymphatic spread high risk!
Travis 2011 J thorac oncol


Immunhistochemie

Differenzierungsmarker für 3 Haupt-Subtypen

![[Pasted image 20211014103520.png]]

Klassische Marker für PEC: p63, p40, CK5/6 ==(p53 typisch für PEC in HNO!?)==
pseudozystisch eingeschmolzene Formation ist typisch für PEC

Klassische Marker für AdenoCa: TTF-1, Napsin A und ==CK 7 (cytokeratin 7)==

Klassische Marker für SCLC + Großzelliges neuroendokrines Lungenkarzinom:
CD56, Chromogranin, Synaptophysin

pulmonales enteritisches Adeno vs. Metastasen

positive für CDX2, CK20 (auch für Adenokarzinom in GI-Trakt), MUC2

![[Pasted image 20211014103605.png]]

Ausschluss GI (gastro-intestinalen) Primarius bei TTF-1 negativem Adenokarzinom in der Lunge
ÖGD + Koloskopie sind wichtiger als PET/CT

Tumormarker

肿瘤标志物是指肿瘤细胞在生长、发展甚至迁移的过程中产生并释放的化合物或机体本身对肿瘤细胞做出反应所产生的物质，它们具有、
的特显性。当机体产生肿瘤时、血液、细胞、组织或尿液等体液中的某比耀标志物就可能会相应地升高。肿瘤标志物分为很多种，有的只存在于题组织而不存在于成年个体中;有的在肿瘤惠老体内含量远超于正常人。它
的存在成县含量的改恋可以提示肿瘤的性质，从而帮助医生了解肿瘤的发
民细胞功能，从而对脚瘤的诊断、分类、预后判断和治疗提供一定的指导
助。肺癌相关的肿瘤标志物有哪此?它们有什么作用?

癌胚抗原(CEA)

CEA 在正常人体内含量很低，基本不会被测出、它是一种很重要的并
相关抗原，70%-90%的结肠癌患者在检测时都会出现高阳性现象，

CEA在其他恶性肿瘤中同样具有提示作用、在肺癌中其阳性率约为56%-80%。CEA 在胃液、唾液以及胸腹水的检测中阳性率会更高，因为这些环绕在宿附近的液体中可能会比血液更早地出现CEA。一般来说，CEA 的正常多考值为0~5ngml,
CEA测定主要用于指导各种肿瘤的治疗及随访效果，对肿瘤患者血液或其他体液中的CEA浓度进行连续观察，能对病情判断、预后及疗效观察提供重要的依据。CEA对肿瘤术后复发的敏感度极高，可达80%以上，往往早于病理检查及影像学检查。大量临床实践证实，患者术前CEA 浓度能明确预示肿瘤的状态、存活期及有无手术指征等。术前CEA 浓度越低，说明病期越早，肿瘤转移、复发的可能越小，其生存时间越长;反之，术前CEA浓度越高，说明病期较晚，难于切除，预后差。
在对恶性肿瘤进行手术切除时，连续测定CEA 将有助于疗效观察。手术完全切除的患者，CEA 一般在术后6周就恢复正常;术后有残留或有微转移灶的患者，CEA的含量会下降，但不恢复正常;手术无法完全切除而只能进行姑息治疗的患者，CEA 含量般会持续上升。CEA的浓度也能较好地反映放疗和化疗的效果。一般来说，只要 CEA 浓度能随治疗而下降，则说明治疗有效;若治疗后其浓度不变，甚至上升，则必须更换治疗方案。需要注意的是，吸烟人群CEA的含量也会稍微升高。同时，一些良性疾病也会影响CEA 的含量，比如当患者患有胰腺炎、直肠息肉、溃疡性结肠炎、胃炎、消化性溃疡病、慢性阻塞性肺疾病、肺部感染等各种急慢性炎症时，CEA 也会升高。不过，这些良性疾病一般只会导致CEA轻到中度升高，一般都小于20ug/L-一如果在体检中发现CEA 高得实在离谱，几百、上千的高，那还是需要提高警惕，尽早进行其他检查。

细胞角蛋白19片段(CYFRA 21-1)。

CYFRA 21-1是最有价值的判断非小细胞泡肺癌的肿瘤标志物，尤其是对于鳞状细胞癌患者来说，CYFRA 21-1对早期诊断、疗效观察和预后监测都
有重要意义。CYFRA 21-1在肺鳞癌中阳性率约为70%，肺鹗寒F如果肿糊治疗效果好，CYFRA60%，大细胞肺痹阳性率约为75%。
水平会很快下降或恢复到正常水平，在疾病的发展过程中，CYFRA
平的变化常常早于临环症状和影像学锆果的改变。CYFRA 21-1对于
良件肺视疾病(肺炎、结核、慢性支气管炎、支气管哮喘、肺气肿)
特异性比较好，其正常参考值为0.10~4ng/ml.## 神经元特异性烯醇化酶(NSE)
NSE 认为是监测小细胞肺癌的首选标志物，NSE在小细胞肺癌阳
性率约为91%。在锡解期，80%~96%的患者NSE含量正常，如NSE
升高，则提示惠者很可能复发小细胞肺癌。小细胞肺癌患者首轮化疗E
24-72小时内，由于肿瘤细胞的分解，NSE可能会出现一过性升高。因此NSE 是监测小细胞肺癌疗效与病程的有效标志物，并能提供有价值的预后息。NSE 的正常参考值约为0~16 ng/ml

鳞状细胞癌抗原(SCC)

SCC是一种特异性很好的肿瘤标志物，并且它是最早用于诊断鳞癌的肿瘤标志物。SCC在肿瘤细胞抱中参与肿瘤的生长，它对于所有鳞状上皮细施发源的恶性肿瘤都有一定的诊断和监测的作用。在这些肿瘤患者的血清中，
SCC 会升高，且浓度会随病期的加重而继续升高。临庆上可以用SCC监测这此肿瘤的疗效、复发、转移以及评价预后。SCC可辅助诊断肺鳞癌。在肺鳞癌患者中，SCC 的阳性率约为46.5%其水平与肿瘤的进展程度相关。同时，SCC还可预测食管鳞癌和鼻咽癌，阳性率随病情发展而上升，对于晚期患者，其灵敏性可达73%。SCC正常参者值一般低于1.5 mg/L。

癌抗原125 ( CA125)

CA125主要存在于卵巢组织中，上皮性卵巢癌患者的CA125水平会明显升高。卵巢癌中 CAI25升高的阳性率约为70%以上，而在肺癌中其阳性率约为44%。需要注意的是，一些良性疾病如子宫内膜异位症、盆腔炎、卵巢囊肿、胰腺炎、肝炎、肝硬化的患者，甚至是怀孕早期的正常孕妇，,CA125 也会升高，所以需要与恶性肿瘤患者仟细鉴别。

铁蛋白(SF)

铁蛋白水平的升高可发生于急性白血病、肺癌、结肠癌、肝癌和前列腺癌等肿瘤中。检测铁蛋白含量对肝脏转移性肿瘤有诊断价值，76%的肝转移患者铁蛋白含量高于400ug/L。SF的正常参考值为男性:30~400ug/L，女性:13~150ug/L。
血清中肿瘤标志物的水平-般与恶性肿瘤的生长、发展、消退、复发等状态具有良好的相关性，因此测定血清中肿瘤标志物的水平，可以在一定程度上帮助医生进行高危人群的筛查、鉴別肿瘤种类和临床分期、监测肿瘤的复发和判断预后、检测肿瘤的疗效以及更精准地进行个体化医疗。

Typische Tumormarker für Tumore:

Thyreoglobulin für Schilddrüsen-Ca
PSA für Prostata-Ca
Estrogen und Progesteron für Mamma-Ca
CA125 für Ovarial-Ca
Tumormarker4DiverseTumoren.pdf

Weiterdifferenzierung der neuroendokrinen Tumore

![[Pasted image 20211014103646.png]]

Chromogranin A, Synaptolysin und CD 56 sind klassische Marker für neuroendokrine Tumore.

Differenzierungsmarker für Mesotheliom

![[Pasted image 20211014103702.png]]

Molecular biology

[Herbst, 2008 #101]

Tyrosine kinase

inhibitor/Tarceva/erlotinib => overall survial benifit 2 months. EGFR+ pts 5 months

30% EFGR+ pts no response, accauired resistance[Lin, 2012 #102]

PD-L1

Quantitative Auswertung diagnostischer IHC-Ergebisse mittels verschiedener PD-L1-Scores

Studien und Zulassungen divergieren sowohl bezüglich der zu wertenden PD-L1-positiven Zellpopulationen (Tumorzellen/TC, Immunzellen/IC) als auch der jeweiligen Bezugsgrößen (vitale Tumorzellen, Tumorareal) sowie der Cut-offs. Um diesem Umstand Rechnung zu tragen, wurden unterschiedliche Algorithmen zur Bewertung der PD-L1-Expression in Tumorgeweben und dem umgebenden Mikromilieu entwickelt.

Der TC (vital Tumor Cells) Score/bzw. Tumor Proportion Score (TPS): Er gibt das Verhältnis der PD-L1-positiv gefärbten Tumorzellen bezogen auf alle vitalen Tumorzellen an und wird in Prozent ausgedrückt.
Der Combined Positive Score (CPS): Hierbei werden die positiv gefärbten Tumorzellen und Immunzellen in Bezug zu vitalen Tumorzellen gesetzt und mit 100 multipliziert, was einen errechneten Score-Wert (keinen Prozent-Wert!) ergibt, der theoretisch auch > 100 sein kann. Per Definition wurde der CPS auf einen Wert von 100 begrenzt. Als Immunzellen gelten hier Lymphozyten und Makrophagen. Granulozyten werden nicht miteinbezogen.
Der IC (Immune Cells) Score: Hier werden alle Immunzellen, die eine PD-L1-Färbung jeglicher Intensität aufweisen, und sich im Tumor oder in intratumoralem und benachbartem peritumoralem Stroma befinden, bei der Auswertung berücksichtigt. Der Wert wird in Prozent angegeben und ist auf das Tumorareal bezogen.

Prä-invasives Stadium

Adenokarzinom-Linie

AAH/atypische adenomatöse Hyperplasie
AIS/Adenokarzinom in situ: rein lepidisch wachsend, < 3 cm
MIA/minimal-invasives Adenokarzinom: lepidisch wachsend mit kleiner invasiver Areal (< 5mm). microinvasives Adenokarzinom gehört zu dieser Gruppe.
Adenokarzinom

Plattenepithel-Ca-Linie

Plattenepithel-Dysplasie
Carcinoma in situ von Plattenepithel-Ca
Plattenepithel-Ca

Neuroendokrineles Karzinom-Linie

DINEPCH: prä-invasive neuroendokrine Läsion.
Diagnose kann nur histologisch gestellt werden
Steroid-Therapie
oft bilateral multiple Herde

Tumorlet: präneoplatisches Stadium peropherer Karzinoide (< 5mm)
Konglumarat neuroendokriner Tumorzellen
keine Therapie erforderlich
symptom-orientierte Verlaufskontrolle erforderlich.

Paraneoplastische Syndrome

Karzinoid Syndrom, Cushing Syndrom
![[Pasted image 20211014103747.png]]

Staging

Klassifikation

UICC 8. Auflage auswendig?

口诀

einzigartige Stadien

IB
2aO
降级使用:-)

IIA
2b0
降级使用:-)

zweiteilig!

三菱(T3N0)两门(T2N1)是二逼
IIB /二逼

dreiteilig!

四菱(T4N0)四门(T4N1)双重(T2N2)
IIIA

一两对(T1/2N3)， 三四纵(T3/4N2)
IIIB

三四对(T3/4N3)
IIIC

Besonderheit

lappenübergreifende Tumore

Lunge cancer transgressing an adjacent fissure
soll als T3 gesehen werden, wenn Tumor < 5 cm
202407121626, 202407121627

Nodal staging

Station 1: low cervical, supraclavicular or sternal notch nodes = N3
Hals-lymphknoten = M1a?

• Revised ESTS guideline for preoperative medistinal lymph node staging:
• Extracasular extension
• minimal N1 or N2 disease

patients with clinical stage I NSCLC who underwent surgical resection report 29% to 35% pathologic upstaging at surgery.4,5 In the absence of pathologic staging, patients undergoing nonsurgical treatments are subject to clinical understaging! Starkes Argument gegen non-surgical therapy!!!
// (Su et al., 2014)

Revised ESTS guideline for preoperative medistinal lymph node staging:

Beschreibt exakte anatomische Grenze der einzelnen LK-Station

• Onkologische Mittelinie an der linken Rand der Trachea, aber endet oberhalb Hauptkarina
• Lymph node Zonen und Stationen: periphere Zone sind Station 12 -14
• In der rechten Lunge Station 11 unterscheid zwischen superior and inforior.
• Station 3a ist nun prävaskulär: links an Arteria subclavia, rechts auf V. cava. Sup.
• Station 3p: retrotracheal
• Station 8 paraösophageal. Die obere Grenze ist subkarinale Region
• Ursprung des LK => N1 oder N2
• In der rechten Lunge, Unterscheid St. 4 und 10 in der tracheobronchialen Winkel.
  // De Leyn et al., 2014)

Extracasular extension

![[Pasted image 20211014103938.png]]

minimal N1 or N2 disease

„minimal N2 disease“ defined as disease in only one metastatic level, intracapsular, macroscopically not suspect for metastasis at surgical exploration

With the term “limited N2 disease” (minimal N2 disease) we
indicate the patients with lung cancer and metastasis in only one group
of unilaterally mediastinal lymph nodes without rupture of their capsule
and extension in the surrounding soft tissues.

N3: mediastinale N3 vs kontralaterale N3

es gibt solche und solche N3.
bei mediastinale N3 ist der Tumor aus der Sicht Strahlentherapeuten noch kurativ (kombinierte CRT)
bei N3-Status mit Befall der kontralateralen hilären LK ist der Tumor nicht mehr kurativ. Es wird nur sequentielle CRT angeboten.

Leitlinien, Guide lines

S3-Leitlinie 2022

![[S3_Leitlinie_Lungenkarzinom_Langversion_2022m10.pdf]]
Über 600 Seiten lang ist das zweite Update der S3-Leitlinie „Prävention, Diagnostik, Therapie und Nachsorge des Lungenkarzinoms“, die jüngst im Rahmen des Leitlinienprogramms Onkologie erschienen ist. Zahlreiche Kapitel wurden in der neuen Fassung überarbeitet oder erweitert. Damit ist sie wesentlich umfassender als  noch die Version von 2018.

„Mit den neuen Erkenntnissen wird es möglich sein, die Behandlungen zu verbessern und die Überlebenschancen von Patienten zu steigern. Ein wichtiger Meilenstein für die Krebstherapie“,  betonte Torsten Bauer, Präsident der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin (DGP). Die Fachgesellschaft hat die Leitlinie federführend vorangetrieben.

CT-Screening für asymptomatische Risikopersonen

Neu hinzugekommen ist die Empfehlung für eine Computertomographie (CT) des Thorax bei asymptomatischen Risikopersonen für ein Lungenkarzinom. Dabei ist ein erhöhtes Risiko definiert durch ein Alter zwischen 50 und höchstens 75 Jahren, eine Raucheranamnese von ≥ 15 Zigaretten pro Tag für mindestens 25 Jahre oder ≥ 10 Zigaretten pro Tag für mindestens 20 Jahre sowie eine fehlende bzw. weniger als 10-jährige Nikotinkarenz.

Vorgehen  bei zufallsbefundlich diagnostizierten Lungenrundherden

Die Leitlinienautoren haben ebenfalls das Vorgehen bei Zufallsbefunden außerhalb des risikoadaptierten Screenings beschrieben. Neu ist hierbei, dass zur Abschätzung der Malignität eines neu aufgetretenen Lungenrundherdes auf ein validiertes Online-Wahrscheinlichkeits-Rechenmodell (z.B Mayo-Clinic, Herder, Brock) zurückgegriffen werden kann.

Bei Patienten ohne maligne (Vor-)Erkrankung und geringem Risiko für ein Lungenkarzinom mit einem Lungenrundherd <5 mm (oder <80 mm³) oder bei Patienten, deren Allgemeinzustand keine weitere Abklärung oder Therapie zulässt, sollte keine CT-Verlaufskontrolle durchgeführt werden, heißt es in der aktualisieren Fassung.

Neue oder aber modifizierte Empfehlungen liegen außerdem für die molekulare Testung aller nicht-kleinzelligen Lungenkarzinome (NSCLC) unabhängig vom Subtyp, für die Testung in frühen Stadien auf EGFR-Mutationen sowie für die molekulare Testung in der Rezidivsituation vor.

Immunchemotherapie in der Erstlinientherapie

Die Erweiterung des therapeutischen Spektrums hat ebenfalls zu zahlreichen Neuerungen in der Leitlinie geführt. Das betrifft auch die Immunchemotherapie als Erstlinientherapie bei Patienten mit fernmetastasiertem kleinzelligen Lungenkarzinom. Sofern keine Kontraindikationen bestehen, solle laut Leitlinie primär eine Chemo-Immuntherapie mit Platin/Etoposid und einem PD-L1-Antikörper (Atezolizumab oder Durvalumab) angeboten werden. Für Patienten mit Hirnmetastasen könne, so die Empfehlung, die Hinzunahme eines PD-L1 Antikörpers zur Chemotherapie angeboten werden.

„Mit der Überarbeitung der Leitlinie haben wir den aktuellsten Therapiestandard abgebildet, der in den vergangenen Jahren große Fortschritte gemacht hat“, sagte Wolfgang Schütte, Gesamtkoordinator der Leitlinie. Aufgrund der Vielfalt der Therapiemöglichkeiten komme es zu einer immer stärkeren Individualisierung in der Therapie des Lungenkarzinoms.

Die Autoren der Leitlinie schlagen vor, dass jeder Patient mit neu diagnostiziertem Lungenkarzinom in einem Thorax-Onkologischen Tumorboard vorgestellt werden soll, wo sich die Entscheidungen an den aktuell gültigen Leitlinien orientieren. Unter gewissen Bedingungen könne aber auch eine abweichende Therapieentscheidung getroffen werden, so Schütte.

Bereits im kommenden Jahr soll es weitere Überarbeitungen geben und die Lungenkarzinom-Leitlinie als  Living Guideline weitergeführt werden

NSCLC

Early-Stage

Early Stage NSCLC

Onkologische Überlegung bei der Entscheidung über Technik (VATS vs. Thkt) und Resektionsausmaß (Segmentektomie vs. Lobektomie)

Folgende Faktoren sollen berücksichtigt werden:

1. Histologie:
2. Größe

Es gibt Evidence über die folgendnen Empfehlung:
pure solid T1a AdenoCa (no GGO komponent ): Segmentektomie = Lobektomie
aber pure-solid cT1a (<2cm) Tumor: segmentectomy < lobectomy regarding locoregional recurrence. Aber selbst nur ein bißchen GGO-komponent dabei ist (consolidation tumour ratio/CTR zwischen 0,5 und <1,0): segmentectomy = lobectomy.
// Hattori, Aritoshi; Matsunaga, Takeshi; Takamochi, Kazuya; Oh, Shiaki; Suzuki, Kenji (2017): Locoregional recurrence after segmentectomy for clinical-T1aN0M0 radiologically solid non-small-cell lung carcinoma. In: European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 51 (3), S. 518–525. DOI: 10.1093/ejcts/ezw336.

Guidelines

NCCN 2015 guideline:

segmentectomy is an acceptable option for peripheral nodules < 2cm if they are a pure AIS histology, or nodules that have over 50% ground-glass opacity, or with a duplication time > 400 days.

ESMO guideline 2017:

segmentetomy equal to lobectomy bei pure solid cT1a adenocarcinoma #58
segmentectomy acceptable for pure GGO lesions or adenocarcinoma in situ or with minimal invasion
ESMO-2017-Early and locally advanced NSCLC.pdf

Lobektomie

1962 Shimkin

1995 Ginsberg: standard reference treatment

Segmentektomie (vs. Lobektomie)

prospective large series demonstrates equal long term outcome of open segmentectomy and lobectomy in pts with cT1 NSCLC

Nomori-Segmentektomie T1 NSCLC.pdf

Stage I (<= 3cm): VATS > Thkt
Tumor >= 2cm (ab T1c): Lobektomie > Segmentektomie

3. Lokalisation: eine sichere/saubere R0 (surgical margin) mit segmentektomie erreichbar?
4. Nodaler Status: N1/2 lieber Thorakotomie. Zum Beispiel Frau Hoffmann mit vergrößeten LK parastracheal und subkarinal. Lobektomie kann man mit VATS durchführen. Aber bei LAD wird man Problem haben, besonders bei schwieriger Abpräparation von der Vena cava. In dieser Phase zu konvertieren ist schade. Eine Entscheidung für Konversion ist schwierig. 騎虎難下。硬著頭皮weiter mit VATS, wird riskant. Deshalb viel besser von anfang an mit thorakotomie. Oder am Anfang der VATS Lobektomie die Schwierigkeit der LAD beurteilen!

Segmentektomie
Vorteile von segmentektomie
preserving lung tissue/function
providing chance for further resection for second lung cancer.

tumor free margin

89% of locoregional recurrences when margin < 2cm
Schuchert 2007 ATS


SBRT

Bei Rezidiv nach SBRT: palliative Lungenresektion

Visceral pleural invasion/VPI

Tian D. et al. Effect of viscral pleural invasion on the prognosis of patients with lymph node negative NSCLC. Thoracic Cancer 2017

VPI bedeutet T2a.
Die studie zeigt: VPI beeinflusst survival bei NSCLC < 2 cm oder > 3cm nicht.
nur bei NSCLC zwischen 2 -3 cm führt VPI zu schlechter survival, Autoren propagiert adjuvante Chemo bei VPI bei Tumor > 2cm

ich meine: bei NSCLC 2-3 cm und VPI: eher Lobektomie als Segmentektomie,
bei Tumor < 2 cm + VPI: Segmentektomie auch möglich.

Locally-advanced

Subgruppen von Stadium III

IIIA:
1) large tumor and no mediastinal nodal involvement (T4N0, T3/4N1). Should be approached linke stage II (surgery + adjuv. Chemo)
OR 2) smaller tumor and N2 disease (T1/2N2).

Evidence über multimodale Therapie für Stadium III

(Pless aus Schweiz, Stand 2015, SAMO ppt sehr gute Darstellung, repräsentative Publikation, siehe Anhang)
-immer multmodale Therapie, mindestens bimodal (Chemo + OP vs. RT) wenn es kurativ geht
-Chemo hilft immer
Chemo ist auch Radio-Sensitizer
simultane CRT besser als sequenziel, aber toxischer
Choice of Chemo does not matter, also for elderly
Induction chemo vor CRT hilft nicht
Consolidierungs-Chemo nach CRT controvers (SWOG S9504 pos., Meta-Analyse no difference)
-für resectable IIIA-N2: Operation + adjv. ChT als Therapie der Wahl, neoadjv Chemoradiatio + Surgery >> better OS in lobectomy vs. definitive Chemoradiation (intergroup trial 0139)
no difference betw surgical multimodality and definitive CRT in EORTC trial (unresectable N2,50% R1) and ESPATUE trial (IIIA, IIIB)
-für IIIB: simultane CRT als therapie der Wahl. aber es gibt auch resectable IIIB

Limitation Induction CRtx

Nach Induktiontherapie man kann nicht mehr significant dosis postop. Verabreichen. Was soll gemacht werden wenn R1 oder R2 resektion war?
Deshalb: Induktion therapie depend on, ob R0 achivable

Guidelines for LA NSCLC

ESMO guideline 2017

Postmus et al. Ann Onco 2017
benutzt UICC 8. edition
Therapiekonzepte hauptsächlich abhängig von N-Status und Resektablität:

• Resectable LA (single-station N2, T4N0 oder Downstaged nach neoadjv. Therapie): surgical multimodal treatment OR non-surgical multimodal treatment
• Non-resectable LA (multistation or bulky N2, N3): definitive CRT
  Es gibt 2 spezielle Subgruppen
• occult N2: nach Resektion adjv. ChT +/- PORT (postop. Radiation)
• Pancoast: neoadjv. CRT + OP
  Cave: cMRT soll bei Stage III Patienten vor der Lungenresektion gemacht werden. Sie kann bei stage I /II eventuell nach OP ergänzt werden.

NCCN guideline

Berücksichtigt sowohl N-Status als auch T-Status, teilt LA in 4 Subgruppen

1. Pancoast: onkologische Operabilität nur bei N0-1. Bei (potentiell) resektablen: neoadjv CRT + OP +/- ChT
   bei nicht resektablen Pancoast: definitive CRT
2. T1- noninvasive T3 (<7cm) N0-1: OP + ChT (if > 4cm or n1)
3. invasive T3/T4, N0-1: surgical multimodal treatment (neoadjv ChT/CRT + OP OR OP + adjv ChT when keine induktions Chemo)
4. T1-3, N2: surgical multimodal treatment mit neoadj ChT/CRT.

Multimodal surgical treatment/Trimodality

clinical trials:

intergroup 0139, ROTG 0229, 0617, ESPATUE, EORTC

Aussge von Intergroup 0139: bei Vermeidung einer Pneumonektomie die Operation für Patienten vorteilhaft sein kann. im Vergleich zu Chemoradiatio ohne OP.
Deshalb ist Manschettenresektion wichtig.

large single instutional study

Vyfhuis, Melissa A. L.; Bhooshan, Neha; Burrows, Whitney M.; Turner, Michelle; Suntharalingam, Mohan; Donahue, James et al. (2017): 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. In: Advances in radiation oncology 2 (3), S. 259–269. DOI: 10.1016/j.adro.2017.07.009. // paper in citaviNSCLCX1

Treatment algorithm

![[Pasted image 20211014104921.png]]

{Yun 2020 #2399: 61} in Citavi NSCLC-X1

Opinion of Donington on multimodal treatment

patients with complete pathologic responses to induction who can be resected by lobectomy have the best prognoses, while those with residual N2 disease should be considered for surgery on a case-by-case basis, with the knowledge that prognosis is relatively poor. Patients
//Bryan, Darren S.; Donington, Jessica S. (2019): The Role of Surgery in Management of Locally Advanced Non-Small Cell Lung Cancer. In: Curr. Treat. Options in Oncol. 20 (4), S. 7. DOI: 10.1007/s11864-019-0624-7.

Patientenselektion

die wichtigste Charakteristik für considering resection is extent of nodal disease!
Degree of N2: 1) occult 2) potentially resectable, 3) bulky or fixed unresectable

die onkologische prädiktoren für gute Prognose bei Patienten mit neoadjuvanten Therapie
1) MPR/major pathologic response (<10% residual viable tumor)
2) MDC/mediastinal disease clearence, ypN0

Erfahrung von Dartevelle über T4 Tumor

Pancoast, carinal involvement, SVC involvement, mediastinal involvement
4% mortality, 43% 5YS!
//Yildizeli, Bedrettin; Dartevelle, Philippe G.; Fadel, Elie; Mussot, Sacha; Chapelier, Alain (2008): Results of primary surgery with T4 non-small cell lung cancer during a 25-year period in a single center. The benefit is worth the risk. In: The Annals of thoracic surgery 86 (4), 1065-75; discussion 1074-5. DOI: 10.1016/j.athoracsur.2008.07.004.

Nodale status

Wichtigkeit von nodaler Downstaging

bei N2-IIIA 5YS 30-40% bei pN0 nach Induktionstherapie vs. 20% bei persistierenden pN2
Reich-Weinberger-2013-Chirurgie beim NSCLC im Stadium IIIA-N2.pdf

N2: single-level vs. multilevel

5YS 54% bei single level vs. 11% bei multilevel N2
Reich-Weinberger-2013-Chirurgie beim NSCLC im Stadium IIIA-N2.pdf

Szinarios und Entscheidungsfindung nach Induktionstherapie und Restaging

3 Faktoren muss man berücksichtigen:

• nodale clearence: N2 oder N0. bei persistierende N2 eher keine Operation
• Pneumonektomie vermeidbar?
• Funktionell, komorbidität operabel?
  Reich-Weinberger-2013-Chirurgie beim NSCLC im Stadium IIIA-N2.pdf ![[Pasted image 20211014105026.png]]
  ![[Pasted image 20211014105033.png]]

Induktionstherapie ja oder nein

limitation induction CRtx

Nach Induktiontherapie man kann nicht mehr significant dosis postop. Verabreichen. Was soll gemacht werden wenn R1 oder R2 resektion war?

Deshalb: Induktion therapie depend on, ob R0 achivable

Salvage OP bei Rezidiv nach Chemoradiatio

/storage/276F-7278/Daten2024-07-09Lexar/Thoracic_Disease/01_LungCancer/01B_LungCancer_NSCLC/Stadium-Locally-Advanced/Salvage Op Nach Chemoradiatio.pdf

Pancoast

• Das Leitsymptom
  ◇ Pancoast-Tobias-Triad:
• Staging, präop. Untersuchung
• Therapie
• Chirurgische Zugänge / Schnittführungen Dartevelle vs. Shaw-Paulson

1. April 2020.
   Der Pancoast-Tumor ist ein Lungenkarzinom mit Infiltration der oberen Thoraxapertur – beteiligt sind die ersten Rippen (auf jeden Fall T3), die kaudalen Wurzeln des Plexus brachialis, evtl. das Ganglion stellatum, die Wirbelsäule, die Subklaviagefäße.

Leitsymptom

ist der Schulterschmerz. Da sich die Ersttherapie gegen eine vermutete Osteoarthropathie richtet, wird die korrekte Diagnose häufig spät gestellt.

Pancoast-Tobias-Triad:

1. Horner-Syndrom: MEP= Miosis, Enophthalmus (Zurückweichen des gesamten Orbitainhaltes in die Orbitahöhle), Ptosis
2. Shoulder pain
3. Hand atrophy

Zwerchfellhochstand? >> Infiltration Phrenicus-Nerv

Staging, präop. Untersuchung

Der Erfolg der onkologischen Behandlung hängt von der genauen Einschätzung der Tumorausbreitung ab: Neben den Standarduntersuchungen (CT-Thorax, PET-CT, MRT-Schädel) sollen eine invasive Untersuchung des Mediastinums und eine MRT der oberen Thoraxapertur angeschlossen werden.

• Standarduntersuchungen: CT-Thorax, PET-CT, MRT-Schädel
• invasive Untersuchung des Mediastinums: EBUS-Bronchoskopie, Mediastinoskopie
• Funktionsdiagnostik wie üblich.

Therapie

Standardbehandlung des potentiell resektablen Pancoast-Tumors ist eine trimodale Therapie mit kombinierter Chemoradiotherapie und erweiterter Chirurgie.
==kontraindikation für OP: C8 Plexus involvment, N2/3 status. ==

Paulson recognised that the presence of a Horner’s syndrome, invasion of the brachial plexus and subclavian vessels or vertebrae all implied a poor prognosis even with aggressive treatment.
//BTS guidelines. guidelines on the selection of patients with lung cancer for surgery (2001). In: Thorax 56 (2), S. 89–108.

Bei inoperabler (z.B. Lufu zu schlecht), nicht metastatischer Erkrankung stellt die definitive Chemoradiotherapie die beste palliative Option dar. Falls nicht zumutbar, kommt die alleinige Bestrahlung in Betracht.

Guidelines von NCCN und ESMO über Pancoast

Dartevelle propagiert upfront resection, danach adjuvante Therapie
//Yildizeli, Bedrettin; Dartevelle, Philippe G.; Fadel, Elie; Mussot, Sacha; Chapelier, Alain (2008): Results of primary surgery with T4 non-small cell lung cancer during a 25-year period in a single center. The benefit is worth the risk. In: The Annals of thoracic surgery 86 (4), 1065-75; discussion 1074-5. DOI: 10.1016/j.athoracsur.2008.07.004. citavi

S3-Leitlinie

„Bei Pancoast-Tumoren im Stadium II-IIIB wird eine neoadjuvante Radiochemotherapie mit anschließender Resektion empfohlen. Bei Kontraindikationen zur Chemotherapie sollte eine neoadjuvante Strahlentherapie mit anschließender Resektion erfolgen. Bei einer R0-Resektion ist nach aktueller Datenlage keine postoperative Chemotherapie oder Ganzhirnbestrahlung erforderlich, kann aber im individuellen Fall zur Anwendung kommen.
Die Entscheidung zum bestmöglichen Vorgehen sollte interdisziplinär unter Beteiligung von Entscheidungsträgern mit hinreichender Erfahrung erfolgen (C).
Patienten mit technischer oder funktioneller Inoperabilität sollten eine definitive Radio-/Chemotherapie erhalten. Die Entscheidung zum bestmöglichen Vorgehen sollte interdisziplinär unter Beteiligung von Entscheidungsträgern (Thoraxchirurgie, Radioonkologie, Pneumologie) mit hinreichender Erfahrung erfolgen (D).“

![[Pasted image 20211014110125.png]]

//Goeckenjan, G.; Sitter, H.; Thomas, M.; Branscheid, D.; Flentje, M.; Griesinger, F. et al. (2011): Prävention, Diagnostik, Therapie und Nachsorge des Lungenkarzinoms. Interdisziplinäre S3-Leitlinie der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin und der Deutschen Krebsgesellschaft–Kurzfassung. In: Pneumologie (Stuttgart, Germany) 65 (8), S. 75. DOI: 10.1055/s-0030-1256562.

Zusammenfassung von Marra

//Modernes Management des Pancoast-Tumors
Alessandro Marra
Zentralbl Chir 2018; 143(03): 316-330
DOI: 10.1055/s-0043-109931

Chirurgische Zugänge / Schnittführungen Dartevelle vs. Shaw-Paulson

Dartevelle appoach (schnittführung) = cervicothoracic: sowohl für anterior sulcus superior tumor als auch für posterior tumor
transmanubrial, wenn keine Rippenresektion erforderlich,
transclavicular, wenn Rippenresektion doch erforderlich, aber ohne Resektion des medialen Anteils der Klavikular wie ursprunglich von Dartevelle beschrieben hat,
Shaw-Paulson = posterolaterale Thorakotomie: für posterior sulcus superior tumor, z.B. involvement Plexus brachialis, vertebral body

Cave: ZVK, Arterien-Zugang entweder kontralaterale Seite oder an der Leiste!!!
D:\Thoracic_Surgery\02_Lunge_Offene_Anatomische_Resektion\Pancoast Tumor\Dartevelle-2006-Anterior Approach to Superior Sulcus Tumors.pdf
D:\Thoracic_Surgery\02_Lunge_Offene_Anatomische_Resektion\Pancoast Tumor\Dartevelle-2006-Anterior Approach to Superior Sulcus Tumors.pdf
D:\Thoracic_Surgery\02_Lunge_Offene_Anatomische_Resektion\Pancoast Tumor\Dartevelle-2006-Anterior Approach to Superior Sulcus Tumors.pdf
D:\Thoracic_Surgery\02_Lunge_Offene_Anatomische_Resektion\Pancoast Tumor\Dartevelle-2006-Anterior Approach to Superior Sulcus Tumors.pdf

Pancoast-Syndrome: Triage

![[Pasted image 20211014110200.png]]

wenn C8 getroffen, ist eine komplette Resektion unwahrscheinlich

---

![[Pasted image 20211014110235.png]]

![[Pasted image 20211014110241.png]]

![[Pasted image 20211014110303.png]]

Prognose

5YS 46% bei T3N0, 13% bei T4N0 (overall survival einschließlich R1 resection)
//Rusch VW, Parekh KR, Leon L, et al. Factors determining outcome after surgical resection of T3 and T4 lung cancers of the superior sulcus. J Thorac Cardiovasc Surg. 2000
Jun;119(6):1147-53.

31% 5YS bei T4 Pancoast nach Dartevelle-Daten
//Dartevelle PG, Chapelier AR, Macchiarini P, et al. Anterior
transcervical-thoracic approach for radical resection of lung
tumors invading the thoracic inlet. J Thorac Cardiovasc Surg.
1993 Jun;105(6):1025-34.

Tumorprogress

Tumorprogress endobronchial
keine Möglichkeit für Re-Kanalisation:
kleinräimische Therapie (kryotherapie), erneute histologische Sicherung, danach Chemo oder Immuntherapie

Oligometastatic

Definition: < 5 [therapiebare] Fernmetastasen und < 2 (3) Organen

synchron (distant disease) vs. metachron (distant recurrence)

Patientenselektion

Lungenresektion im Rahmen der multimodalen Therapie bei selektierten Patienten:
NCCN guideline: solitäre Metastase (z.B. Hirn oder Nebenniere) M1b AND (T1/2N0/1 OR T3N0)

cN0-1 operabel, cN2/3 no go 🙁

Vorgehensweise

Sinnvolle Abfolge der OP und anderer Behandlungsmaßnahmen

wenn die oligo-Fernmetatase gut kontrolliert ist (z.B. Nebenniere-Metatase komplett reseziert) kann ggf. bei N2 oder N3 NSCLC eine definitive Radiochemo angeboten werden.

Pulmonale Metastase

DD: Zweittumor? andere Entitäten (> 80)?

Hirnmetatase

Lokale Kontrolle der Hirnmetastase (OP oder Radiatio) soll vor der Lungen-Op gemacht werden.

Nebenniere

Nebenniere-OP soll nach Lungen-OP gemacht werden wegen NN-Funktion.
25-35% 5YS nach Nebennierenresektion

//Opitz, Isabelle; Patella, Miriam; Payrard, Loic; Perentes, Jean Yannis; Inderbitzi, Rolf; Gelpke, Hans et al. (2020): Prognostic factors of oligometastatic non-small-cell lung cancer following radical therapy. A multicentre analysis. In: European Journal of Cardio-Thoracic Surgery 57 (6), S. 1166–1172. DOI: 10.1093/ejcts/ezz384.
Casiraghi, Monica; Bertolaccini, Luca; Sedda, Giulia; Petrella, Francesco; Galetta, Domenico; Guarize, Juliana et al. (2020): Lung cancer surgery in oligometastatic patients. Outcome and survival. In: European Journal of Cardio-Thoracic Surgery 57 (6), S. 1173–1180. DOI: 10.1093/ejcts/ezaa005.
beide in citaviNSCLC_X1

fließender Übergang

keine Metastase => kurativ
limited metastasis = oligo-metastase =>potentiell kurativ
disseminierte Metastasen => nicht kurativ

Metastastic

Synchronous multiple lung cancer

N2 neg. SMLC haben gute Prognose, unabhängig davon, ob bilateral oder ipsilaterl
Gründliche präoperative Staging einschließlich nodal assessment (Media vs. EBUS) ist sehr wichtig. Sonst werden solche Pat overstaged und untertherapiert.

Fabian-2011-Survival after resection of synchronous NSCLC.pdf

Es ist sicherlich schwierig, SMLC von der NSCLC mit pulmonaler Oligo-Metastase zu unterscheiden, besonders vor dem Hintergrund, dass Tumoren mit gleicher Histologie nicht nicht unbedingt die selben Tumoren sind!
Aber bei N2-neg. NSCLC mit pulmonaler Oligo-Metastase haben Patienten nach Resektion auch gute Prognose. Deshalb für das therapeutische Vorgehen spielt der Unterschied nicht so eine große Rolle. Für die Indikation eines operativen Vorgehen sind wichtig: N2/N3 negativ, funktionelle und technische Operabilität.

NET

SCLC

Stadium

Limited Disease = Stage I-III
Extended Disease = Stage IV

• Limited Disease Definition VLS (very limited stage) = T1-2 N0 LS (limited stage) = Stage I -III ES (extended stage) = Stage IV

Prognose

5YS for limited disease:
48% for stage I,
39% for II
15% for III
Low-2018-Thoracic Surgery in Early-Stage SCLC.pdf

Guideline

NCCN, ACCP, ASCO: surgical resection is superior to definitive chemoradiation for SCLC in clinical stage I.
Stage II/III: definitive Chemoradiatio
Stage IV: palliative Chemo
Low-2018-Thoracic Surgery in Early-Stage SCLC.pdf

Guideline ASCO 2015 ist gleich wie ACCP 2013

Therapiekonzepte Onkopedia

Very limited disease (Stadium I, II):

bei inzidentelem Befund bei OP: Lobektomie, adjuvante Chemo + PCI

bei gesichertem SCLC: entweder Lobektomie + adjuvante ChT+ PCI oder simultane CRT (ohne OP) + PCI

Limited disease (St. III): simultane CRTx + PCI. bei eingeschränktem AZ: sequenziell

Extensive Disease (St. IV): CTx mit CisEto (Cistplatin + Etoposid), ggf symptom-orierntierte Behandlung (Bestrahlung bei Schmerzen z.B.)

Operative Behandlung bei SCLC

Bei very limited diease T1-2 N0 (Stadium I), wenn OP soll man vorher pathologic mediastinal staging vornehmen. Postop ==auf jeden Fall adjuvante Chemotherapie==
Lobectomy is the preferred treatment (NCCN 2017)
Low-2018-Thoracic Surgery in Early-Stage SCLC.pdf

Prophylaktische Ganzhirnbestrahlung/PCI

• nur bei limited disease zusätzlich zu Chemoradiatio
• bei limited disease, wenn AZ gut und gute Remission nach Systemtherapie (so macht PCI onkologisch erst sinn)
• oder bei extended disease, wenn Tumor auf Chemotherapie gut anspricht.

SEZ6

is a transmembr´ane protein expressed in SCLC tumors that may be used as a therapeutic target. ABBV-011 is an antibody-drug conjugate (ADC) targeting SEZ6 with a calicheamicin payload, which has shown antitumor activity in preclinical models of SCLC.

Thracic radiation

Final survival data from a randomized phase II trial comparing high-dose with standard-dose twice-daily (BID) thoracic radiotherapy (TRT) in limited stage small-cell lung cancer (LS SCLC).

Conclusions:
Compared with LS SCLC patients who received standard TRT, patients receiving high-dose BID TRT of 60 Gy did not experience more toxicity, had a substantial prolongation of survival and a much higher long term survival rate. Clinical trial information: NCT02041845.

Citation

J Clin Oncol 41, 2023 (suppl 16; abstr 8512)

Convert trail for SCLC limited disease

Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial
Corinne Faivre-Finn et al. Lancet Oncol. 2017 Aug.

Interpretation: Survival outcomes did not differ between twice-daily and once-daily concurrent chemoradiotherapy in patients with limited-stage small-cell lung cancer, and toxicity was similar and lower than expected with both regimens. Since the trial was designed to show superiority of once-daily radiotherapy and was not powered to show equivalence, the implication is that twice-daily radiotherapy should continue to be considered the standard of care in this setting.

Wichtige study for SCLC Therapie: Turrisi T. Nejm 1999

Karzinoid

Treatment algorithm for lung carcinoid tumors

![[Pasted image 20211021195601.png]]
Noel-Savina E, Descourt R. Focus on treatment of lung carcinoid tumor. Onco Targets Ther. 2013;6:1533–1537. Published 2013 Oct 25. doi:10.2147/OTT.S32464 (fulltext article in PC)

Focus on treatment of lung carcinoid tumor.pdf

The main therapy for bronchial NETs is surgical resection. The surgical techniques of choice are lobectomy or sleeve resection. Pneumonectomy should be avoided except in selected cases. Systemic nodal dissection should be performed since lymphonodal metastases may be present in up to 25% of cases in TC and >50% in AC [15, 16]. Cytotoxic treatment combined with surgical resection when indicated has been the standard for metastatic bronchial and thymic NETs, although the available chemotherapy regimens demonstrate a rather poor effect (III OR A) [17,18]. hepatische Metastase: wenn oligo, lokale Therapie Leber, Lungen-OP. extrahepatische Metastasen: ChT

it is particularly important to avoid unnecessary pneumonectomies. we adhered to the recommendations of those authors who independent of the histological subtype and given a sufficient functional reserve OR prefer anatomical resections with radical lymphadenectomy because of the unclear pre- and intraoperative differentiation and a seamless transitions between neuroendocrine carcinomas of different malignancies [5], [11],[18]. //(Kyriss et al. 2006)

Unklarheit: Therapie-Option bei Rezidiv eines typischen Karzinoids nach OP? Chemo indiziert?

Epidemiology

Bronchial carcinoids are the second most common tumor arising in the tracheobronchial tree and account for 0 OR5 to 1 % of all tumours of bronchial origin and roughly 20 to 30 % of all carcinoid tumors. Male and female patients are almost equally distributed. Bronchial carcinoids are the most common primary lung neoplasm of children OR particularly presenting in late adolescence.
//(Modlin OR Lye OR & Kidd OR 2003; Quaedvlieg OR Visser OR Lamers OR Janssen-Heijen OR & Taal OR 2001)

Typical carcinoids (TCs) comprise ∼1%–2% and atypical carcinoids (ACs) only 0.1%–0.2% of pulmonary neoplasms.
Tumors are predominantly located in major OR lobar and segmental bronchi (more than 70 %) and less than a third in the periphery of the lung. Possibile symptoms are cough OR hemoptysis OR evidence of bronchial obstruction but many patients remain asymptomatic so that diagnosis is most often based on incidental ragiologic findings.
Bronchial carcinoids contain neurosecretory granules (serotonin OR histamine OR prostaglandins OR kallikrein and dopamine) whose systemic release can lead to the carcinoid syndrome. As they produce lesser quantities of serotonin than intestinal carcinoids they also account for a lower rate of carcinoid syndrome (1 to 5 % overall). However OR carcinoid syndrome can be seen in 80% of patients with liver metastases. Further rare manifestations are cushing’s syndrome and acrogemaly due to ectopic production of ACTH and GHRH.
As ca. 80 % of bronchial carcinoids express somatostatin receptors a detection of distant tumor sites is possibile by octreotide scintiscan.
//(K. Oeberg OR 2012)

that they represented the most common lung tumors in childhood

10–15% of cases the tumor can present with regional lymphonodal metastases OR and that is why they may be classified as malignant neoplasms OR even if with a low degree.
Distant metastases occur in 15% of cases OR and are typically
located in the liver OR bone OR adrenal gland and brain.
//[Bini OR 2008 #32]

TCs exhibit a good prognosis with a 5-year survival of 87%–90%. However OR distant metastases from TCs may occur many years even after radical resection of the primary tumor. A 15-year follow-up is therefore recommended.
ACs are regarded as intermediate in grade and are associated with poor prognosis and a 5-year survival of 44%–78%. The LCNEC is associated with a 5-year survival rate of 15%–57% and finally the 5-year survival rate for SCLC is ∼5% [6 OR 10].

Lung carcinoids are uncommon tumors OR so it’s hard to get accurate OR up-to-date survival
statistics for these cancers based on stage. The numbers below come from a study of more than 1400 people in the United States who were diagnosed with lung carcinoid tumors between 1990 and 2002 and were treated with surgery. They include some people who died from causes other than their cancer.
Stage 5-year Survival Rate
I 93%
II 85%
III 75%
IV 57%
These numbers include people with both typical and atypical carcinoids.

The 5-year survival
rate for the entire group was 94% and the 10-year
survival rate was 82%. In patients with typical carcinoid OR 5- and 10-year survival rates were 94% and 82% OR respectively OR
and in atypical carcinoid 92% and 62% OR respectively
(5-year survival n. s. OR 10-year survival p<0.01). 5- (10-)
year survival without lymph node involvement was 95%
(85%) OR with N1 involvement 88% (65%) OR with N2 involvement 67% (no 10-year survival).
//(Kyriss et al. OR 2006)

Even patients with TC who have lymph node metastases have an excellent survival [18].
//[Travis OR 2010 #9]

Sehr gute Zusammenfassung von allen Studien über Survival Tab3 in Kyriss 2006 paper!

Our own results have shown that it may be difficult to
preoperatively confirm the diagnosis or to differentiate
between the two types of carcinoid. Only in 50.5% (n=56)
of the patients OR preoperative bronchoscopy resulted in
the same classification as the postoperative analysis; in
7.2% of the cases OR a small cell or non-small cell carcinoma
was diagnosed preoperatively. The preoperatively correct
histologies reported in the literature range between 47%
and 83% (Barud et al.) [8] OR [9] OR [10] OR [13] OR [15].

//(Kyriss et al. OR 2006)

Diagnose

It is difficult to diagnose AC and LCNEC in small biopsies or cytology and a definitive diagnosis usually requires a surgical specimen. //[Travis OR 2010 #9]

Whether liver metastases originated from the lung in our case represents an important issue, because there is a possibility of the presence of another primary site. When liver metastases are demonstrated, CT of the chest and abdomen, abdominal ultrasonography, upper gastrointestinal endoscopy, and colonoscopy are performed to exclude primary tumors other than those of the lung

Karzinoid-Syndrom

NCCN: DOTATOC PET,
ESMO: Somatostatin imaging

Nachsorge und Rezidiv

The recurrence rate for typical carcinoid is lower (3.6%) than that of atypical carcinoid (33.3%) [5].
// https://doi.org/10.1155/2017/1564819
Chemo +/- Radiatio bei Rezidiv

Typical Carcinoid/TC: most central lesion
Atypical Carcinoid/AC: more commonly peripheral

Generally pulmonary TCs appear as central lesions, whereas ACs are more commonly located peripherally. most of them (90%) are confined to the bronchus (8) OR while the remaining 10% are located in the lung parenchyma OR rarely in the main carina or trachea. [Pusceddu 2010 #31]

Therapiemodalitäten

Chemotherapie

• adjuvante Chemo: verbesserung der Überlebenszeit um 5-10%

Zielgerichtete Therapie / TKI

Treibermutation

Treibermutation / Driver-Gene-Mutationen sind genetische Veränderungen, die direkt zur Entstehung und zum Wachstum eines Tumors beitragen. Diese Mutationen führen zu Aktivierung von Onkogenen oder zur Inaktivierung von Tumorsuppressor-Genen, wodurch die Zellproliferation unkontrolliert wird. Beispiele für Treibergene bei Lungenkrebs sind EGFR, KRAS und ALK.

EGFR and KRAS (红脸 和 白脸 🙂 )
drugable mutations

• Wild type = keine EGFR mutation!
• EGFR is normally found on the surface of epithelial cells and is often overexpressed in a variety of human malignancies. Presence of EGFR-activating mutations represents a critical biological determinant for proper therapy selection in patients with lung cancer.

TKI: Tarceva, Iressa…

• There is a significant association between EGFR mutations — especially exon 19 deletion, exon 21 mutation (L858R), and exon 18 (G719X) and response to TKIs.
• EGFR and KRAS mutations are mutually exclusive in patients with lung cancer.
• ==KRAS mutations are associated with intrinsic TKI resistance, ==and KRAS gene sequencing could be useful for the selection of patients as candidates for TKI therapy.
• The prevalence of EGFR mutations in adenocarcinomas is 10% of Western and up to 50% of Asian patients, with higher EGFR mutation frequency in non-smokers, women, and non-mucinous cancers. KRAS mutations are most common in non-Asians, smokers, and in mucinous adenocarcinoma. The most common EGFR mutations result in an arginine for leucine substitution at amino acid 858 in exon 21 (L858R) and in frame deletions at exon. Mutations are more common in non-mucinous lung adenocarcinoma with lepidic pattern (former BAC pattern) and in lung adenocarcinoma with papillary (and or micropapillary) pattern.
• Resistance to TKI therapy is associated with KRAS mutation and with secondary asquired EGFR mutations, such as T790M.
• EML4-ALK
  Anaplastic lymphoma kinases (ALK) gene rearrangements, in a subset of anaplastic large cell lymphomas (ALCL), have been recognized for over 15 years.The fusion between echinoderm microtubule—associated protein-like 4 (EML4) and ALK has recently been identified in a subset of patients with NSCLC. EML4-ALK NSCLC represents a unique subset of NSCLC patients for whom ALK inhibitors may represent a very effective therapeutic strategy. Crizotinib is an oral ALK inhibitor that was recently approved by the FDA for patients with locally advanced or metastatic NSCLC who have the ALK gene rearrangement. (ie, ALK positive).
  ALK-Inhibitor: Xalkori

ROS1 positive = TKI wirkungslos???

Zielgerichtete Therapie / Targettherapie als adjuvante Therapie

ADAURA study:

surgery + adjuvante TKI therapie (Osimertinib) vs placebo bei EGFRm (mutierte) NSCLC

---

• ADAURA final analysis
  Overall survival analysis from the ADAURA trial of adjuvant osimertinib in patients with resected EGFR‑mutated (EGFRm) stage IB–IIIA non-small cell lung cancer (NSCLC)

Adjuvant osimertinib demonstrated an unprecedented, highly statistically significant and clinically meaningful OS benefit in patients with EGFRm stage IB–IIIA NSCLC after complete tumor resection, with or without adjuvant chemotherapy. ADAURA is the first global Phase III study to demonstrate a statistically significant DFS and OS benefit with targeted treatment for patients with EGFRm stage IB–IIIA NSCLC. Clinical trial information: NCT02511106

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Weitere Publikationen über ADAURA
Wu YL, John T, Grohe C, Majem M, Goldman JW, Kim SW, Kato T, Laktionov K, Vu HV, Wang Z, Lu S, Lee KY, Akewanlop C, Yu CJ, de Marinis F, Bonanno L, Domine M, Shepherd FA, Zeng L, Atasoy A, Herbst RS, Tsuboi M. Postoperative Chemotherapy Use and Outcomes From ADAURA: Osimertinib as Adjuvant Therapy for Resected EGFR-Mutated NSCLC. J Thorac Oncol. 2022 Mar;17(3):423-433. doi: 10.1016/j.jtho.2021.10.014. Epub 2021 Nov 2. PMID: 34740861.

Wu YL, Tsuboi M, He J, John T, Grohe C, Majem M, Goldman JW, Laktionov K, Kim SW, Kato T, Vu HV, Lu S, Lee KY, Akewanlop C, Yu CJ, de Marinis F, Bonanno L, Domine M, Shepherd FA, Zeng L, Hodge R, Atasoy A, Rukazenkov Y, Herbst RS; ADAURA Investigators. Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer. N Engl J Med. 2020 Oct 29;383(18):1711-1723. doi: 10.1056/NEJMoa2027071. Epub 2020 Sep 19. PMID: 32955177.

ALK+ NSCLC adjuvante Therapie Alectinib / Alecensa

TKI vs. TKI plus Chemo,

also pem mono vs. Pem +pem

• AGAIN study
  A phase III study comparing EGFR tyrosine kinase inhibitor (EGFR-TKI) monotherapy and EGFR-TKI with inserted cisplatin (CDDP) plus pemetrexed (PEM) as a first-line treatment in patients (pts) with advanced non-squamous non–small-cell lung cancer (NSqNSCLC) harboring EGFR activating mutation (EGFR-NSqNSCLC): JCOG1404/WJOG8214L, AGAIN study. In patients with advanced EGFR-NSqNSCLC, the insertion of platinum-doublet chemotherapy after the initial response to EGFR-TKI could not prolong OS compared with EGFR-TKI, though that could prolong PFS. Clinical trial information: UMIN000020242.

Immuntherapie

Bei AdenoCa kann man nach Versagen TKI-Terhapie Immuntherapie (Nivolumab oder Pembrolizumab) machen.

Immuntherapie als Neoadjuvante Therapie

Princeps study:

Immuntherapie als neoadjuvante therapie, MPR (major pathological response not correlated with radiological respoonse /Recist)

Checkmate 816: neoadjuvante Immunchemo

In patients with resectable NSCLC, neoadjuvant nivolumab plus chemotherapy resulted in significantly longer event-free survival and a higher percentage of patients with a pathological complete response than chemotherapy alone. The addition of nivolumab to neoadjuvant chemotherapy did not increase the incidence of adverse events or impede the feasibility of surgery.
https://www.nejm.org/doi/full/10.1056/NEJMoa2202170

Keynote 671

https://meetings.asco.org/abstracts-presentations/225718
Pembro + chemo followed by resection and adjuvant pembro provided a statistically significant and clinically meaningful improvement in EFS, pCR and mPR in pts with resectable stage II, IIIA, and IIIB (N2) NSCLC.
Unabhängig von PDL1 Status
PCR 18,1%, mPR 30,2%

---

In the pembro arm 80.6% underwent definitive surgery compared to 75.5% in the placebo arm. ( 20% Patienten in Keynote 671 erreicht die OP NICHT! auch Stadium II und IIIA!!!)

AEGEAN trial: nroadjuvante Immunchemo Durvalumab

Perioperative Durvalumab for Resectable Non–Small-Cell Lung Cancer

N Engl J Med 2023;389:1672-1684
DOI: 10.1056/NEJMoa2304875
VOL. 389 NO. 18
METHODS
We randomly assigned patients with resectable NSCLC (stage II to IIIB [N2 node stage] according to the eighth edition of the AJCC Cancer Staging Manual) to receive platinum-based chemotherapy plus durvalumab or placebo administered intravenously every 3 weeks for 4 cycles before surgery, followed by adjuvant durvalumab or placebo intravenously every 4 weeks for 12 cycles. Randomization was stratified according to disease stage (II or III) and programmed death ligand 1 (PD-L1) expression (≥1% or <1%). Primary end points were event-free survival (defined as the time to the earliest occurrence of progressive disease that precluded surgery or prevented completion of surgery, disease recurrence [assessed in a blinded fashion by independent central review], or death from any cause) and pathological complete response (evaluated centrally).

RESULTS
A total of 802 patients were randomly assigned to receive durvalumab (400 patients) or placebo (402 patients). The duration of event-free survival was significantly longer with durvalumab than with placebo; the stratified hazard ratio for disease progression, recurrence, or death was 0.68 (95% confidence interval [CI], 0.53 to 0.88; P=0.004) at the first interim analysis. At the 12-month landmark analysis, event-free survival was observed in 73.4% of the patients who received durvalumab (95% CI, 67.9 to 78.1), as compared with 64.5% of the patients who received placebo (95% CI, 58.8 to 69.6). The incidence of pathological complete response was significantly greater with durvalumab than with placebo (17.2% vs. 4.3% at the final analysis; difference, 13.0 percentage points; 95% CI, 8.7 to 17.6; P<0.001 at interim analysis of data from 402 patients). Event-free survival and pathological complete response benefit were observed regardless of stage and PD-L1 expression. Adverse events of maximum grade 3 or 4 occurred in 42.4% of patients with durvalumab and in 43.2% with placebo. Data from 62 patients with documented EGFR or ALK alterations were excluded from the efficacy analyses in the modified intention-to-treat population.
CONCLUSIONS
In patients with resectable NSCLC, perioperative durvalumab plus neoadjuvant chemotherapy was associated with significantly greater event-free survival and pathological complete response than neoadjuvant chemotherapy alone, with a safety profile that was consistent with the individual agents. (Funded by AstraZeneca; AEGEAN ClinicalTrials.gov number, NCT03800134.)

202407142140.jpg

Immuntherapie als Adjuvante Therapie

IMpower010 study

(Atezolizumab für resektable NSCLC mit PDL1 >50% nach Resektion und postop. bzw. adjuvante Chemo): HR 0,43, bedeutet „Die Behandlung senkte das Risiko für ein Wiederauftreten der Erkrankung oder Tod um 57%“.

Pacific study:

Stadium III

The phase III PACIFIC trial compared durvalumab with placebo in patients with unresectable, stage III non–small-cell lung cancer and no disease progression after concurrent chemoradiotherapy.
Durvaluma für 2 Jahre
https://ascopubs.org/doi/full/10.1200/JCO.21.01308
https://www.nejm.org/doi/full/10.1056/nejmoa1709937

Keynote 091

Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB–IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial

Pembrolizumab significantly improved disease-free survival compared with placebo and was not associated with new safety signals in completely resected, PD-L1-unselected, stage IB–IIIA NSCLC. Pembrolizumab is potentially a new treatment option for stage IB–IIIA NSCLC after complete resection and, when recommended, adjuvant chemotherapy, regardless of PD-L1 expression.

https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(22)00518-6/fulltext

—

Keynote 091
Pempro als adjuvante Systemtherapie (1 Jahr) bei early stage NSCLC nach Lungenresektion (PDL1 Status?)
In the triple-blind, phase 3 PEARLS/KEYNOTE-091 study (NCT02504372), pembrolizumab (Keytruda) was shown to improve disease-free survival (DFS) vs placebo in patients with completely resected early-stage non–small cell lung cancer (NSCLC) regardless of surgical resection, tumor size, or the extent of adjuvant chemotherapy.

Data were presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting by Mary E.R. O’Brien, MD.

Within the study, patients with early-stage NSCLC were randomized 1:1 to receive pembrolizumab (n = 590) or placebo (n = 587). Pembrolizumab was administered at 200 mg every 3 weeks for a year while placebo was given at a matching rate. Participants enrolled in the trial were those with pathologically confirmed NSCLC who had previously had surgery, recovered from surgery, or received prior chemotherapy.

Findings revealed that in the patients receiving pembrolizumab as adjuvant therapy, median disease-free survival (DFS) was 53.6 months (95% CI, 39.2…

Keynote 789 , negativ für IO bei TKI versagen

Pemetrexed and platinum with or without pembrolizumab for tyrosine kinase inhibitor (TKI)-resistant, EGFR-mutant, metastatic nonsquamous NSCLC: Phase 3 KEYNOTE-789 study. EGFR-NSqNSCLC VI

Adults with histologically or cytologically confirmed stage IV nonsquamous NSCLC, ECOG PS of 0 or 1, documented DEL19 or L858R EGFR mutation, and ** progression after EGFR TKI treatment ** were enrolled.

In the KEYNOTE-789 study, addition of pembro to chemo in pts with TKI-resistant, EGFR-mutant, metastatic nonsquamous NSCLC **did not significantly prolong PFS and OS **in comparison to pbo + chemo. AEs were manageable in both arms, and no new safety signals were identified. Clinical trial information: NCT03820986.

J Clin Oncol 41, 2023 (suppl 17; abstr LBA9000)

nivolumab + relatlimab Aigner NEOprotect-Lung

Surgical outcomes of patients with resectable non-small-cell lung cancer receiving neoadjuvant immunotherapy with nivolumab plus relatlimab or nivolumab: Findings from the prospective, randomized, multicentric phase II study NEOpredict-Lung.

Relatlimab ist ein Arzneistoff aus der Gruppe der Checkpoint-Inhibitoren. Der monoklonale Antikörper wurde in fixer Kombination mit dem MAB Nivolumab unter dem Namen Opdualag im März 2022 in den USA und im September 2022 in der EU zugelassen zur Behandlung des schwarzen Hautkrebses.
lymphocyte-activation gene 3 (LAG-3) antibody, relatlimab,
anti-LAG-3 could be the third ICB pathway (after PD-1 and CTLA-4)

Surgery-induced immue dysfunction

Bakos O, Lawson C, Rouleau S, et al. Combining surgery and immunotherapy: turning an immunosuppressive effect into a therapeutic opportunity Journal for ImmunoTherapy of Cancer 2018;6:86. doi: 10.1186/s40425-018-0398
There is increasing mechanistic evidence to suggest primary tumor surgical resection disrupts the host immune system. These effects lie within the “postoperative period”, which lasts days [16] to weeks [16, 17] following tumor surgical resection and has been suggested to create an immunosuppressive window for the expansion and escape of occult tumors [11]. The postoperative period is a relatively short timeframe compared to the much longer duration of primary tumor development and progression. However, recent mechanistic studies demonstrate that this short period of surgery-induced immunosuppression is critically important in shaping the probability of postoperative metastatic disease [11, 14, 18]. This review will focus on the innate and adaptive immunological pathways that are disrupted by oncologic surgical stress and provide suggestions for rationally combining cancer surgery with immunotherapies to improve immune and treatment outcomes. immun

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On the other hand, the perioperative period potentially provides a window of opportunity
to strengthen the immune system and attenuate the development of cancer recurrences [16] .

Emerging treatments

oncolytic viruses
cancer vaccines

Strahlentherapie

radiatio

Port-c trail 2021

For patients with pIIIA-N2 NSCLC after complete resection and adjuvant chemotherapy, PORT does not improve disease-free or overall survival,

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2 comments
postoperative radiotherapy (PORT) for pIIIA-N2 non-small cell lung cancer (NSCLC) 1,2, no conclusive results have been established. Thus, PORT for pIIIA-N2 NSCLC has been a matter of debate for decades. Under these circumstances, Hui and colleagues conducted a phase 3 study (PORT-C study) evaluating the efficacy of PORT in patients with pIIIA-N2 NSCLC who underwent complete resection followed by adjuvant chemotherapy and reported their results recently in JAMA Oncology.3 The 3-year disease-free survival (DFS), which was the primary endpoint of the study, was 40.5% in the PORT arm and 32.7% in the observation arm (hazard ratio [HR] 0.84; p=0.20), indicating that PORT was not effective in this setting. In addition, the overall survival (OS) was not significantly different between the two arms. On the other hand, the 3-year locoregional recurrence only rates were 9.5% in the PORT arm and 18.3% in the observation arm (p = 0.04), suggesting that PORT was effective in terms of local control.

Palliative Therapie

In diesem Fall soll Lagedrainage oder CT-gesteuerte Drainageanlage in die Kaverne gemacht werden.as passiert, wenn die Drainage in der Kaverne stark fiestelt oder blutet? Was macht man, wenn Kaverne sich fortschreitet und Lungenarterien arodiert?
Kann man nicht die Lobektomie machen mit zentraler Kontrolle intraperikardial?
Man muss die CT genau anschauen!!!

Post ASCO 22.06.24

• sperling Pathologie: Laser Pathologische Beurteilung R-Klassifikation? Rauche als Schnellschnittuntersuchung?! Gerät Tübingen, intraoperative tissue identification using rapid evaporative iosnization mass spectrometry
• Forschung: upgrading rate bei single level N2?
• Hazard ration HR: used to estimate the treatment effect for time-to-event end points such as overall survival, PFS. HR = rate of patients dying in treatment arm / rate of patients dying in control arm for example 0,75. / HR = 1: equal efficacy, <1: treatemt ist better than control.
  Das Hazard Ratio (HR) ist ein statistisches Maß, das hauptsächlich in der Überlebensanalyse verwendet wird, um die Wahrscheinlichkeit des Eintretens eines Ereignisses zu einem bestimmten Zeitpunkt zwischen zwei Gruppen zu vergleichen.
  STATISTIK EINFACH LERNEN LOGO 2

Was ist: Hazard Ratio
Was ist das Hazard Ratio?
Das Hazard Ratio (HR) ist ein statistisches Maß, das hauptsächlich in der Überlebensanalyse verwendet wird, um die Wahrscheinlichkeit des Eintretens eines Ereignisses zu einem bestimmten Zeitpunkt zwischen zwei Gruppen zu vergleichen. Es ist besonders in der klinischen Forschung verbreitet, wo es hilft, die Wirksamkeit einer Behandlung oder Intervention zu bewerten. Das HR quantifiziert das Risiko, dass ein Ereignis in der Behandlungsgruppe im Vergleich zur Kontrollgruppe eintritt, und gibt Aufschluss über das relative Risiko, dem jede Gruppe während der Dauer einer Studie ausgesetzt ist.

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Die Berechnung des Hazard Ratio verstehen
Zur Berechnung des Hazard Ratio verwenden Forscher üblicherweise Daten aus Überlebensanalysetechniken, wie etwa dem Cox-Proportional-Hazards-Modell. Die Formel für das Hazard Ratio wird aus dem Verhältnis der Hazard-Funktionen der beiden verglichenen Gruppen abgeleitet. Mathematisch wird es als HR = h1(t) / h0(t) ausgedrückt, wobei h1(t) die Hazard-Funktion für die Behandlungsgruppe und h0(t) die Hazard-Funktion für die Kontrollgruppe ist. Ein HR größer als 1 weist auf ein höheres Risiko in der Behandlungsgruppe hin, während ein HR kleiner als 1 auf ein geringeres Risiko hindeutet.

Um das Hazard Ratio zu interpretieren, muss man seinen Kontext innerhalb der Studie verstehen. Ein Hazard Ratio von 1 bedeutet, dass es zwischen den beiden Gruppen keinen Unterschied im Risiko gibt. Ein Hazard Ratio von 2 bedeutet, dass das Ereignis in der Behandlungsgruppe doppelt so wahrscheinlich eintritt wie in der Kontrollgruppe, während ein Hazard Ratio von 0.5 bedeutet, dass die Behandlungsgruppe nur das halbe Risiko hat, das Ereignis zu erleben. Es ist wichtig, die mit dem Hazard Ratio verbundenen Konfidenzintervalle zu berücksichtigen, da sie Aufschluss über die Genauigkeit der Schätzung geben und darüber, ob der beobachtete Effekt statistisch signifikant ist.

• neoadjuvante Therapie: pCR (pathological complete remission) ca 20%, HR ca 0.6
• Stage III N2 vs. Stage III Non-N2 (T4N1/2 IIIA)

– N1 bedeutet die verbreitung diesease, N2 ist Spitze des Eisbergs, bedeutet noch nicht sichtbare Metatasen, circulating Tumorzellen

Laura study:

Osimertinib (TKI therapie) Significantly Improves PFS in Unresectable, Stage III, EGFR-Mutant NSCLC

• The LAURA trial, the first phase 3 study to assess a targeted agent following chemoradiotherapy (CRT) in unresectable stage III non–small cell lung cancer (NSCLC), found osimertinib significantly improves progression-free survival (PFS) over placebo (39.1 vs 5.6 months).
  Overall survival (OS) data were not fully mature, but an interim analysis favored osimertinib as well.
  Safety results were expected and manageable, consistent with the known profile of osimertinib plus CRT.

Adriatic Trial

• Durvalumab (D) as consolidation treatment (tx) for patients (pts) with limited-stage small-cell lung cancer (LS-SCLC).
• Background: The standard of care (SoC) for pts with LS-SCLC is concurrent platinum-based chemoradiotherapy (cCRT) ± prophylactic cranial irradiation (PCI). ADRIATIC (NCT03703297), a phase 3, randomized, double-blind, placebo (PBO)-controlled, multicenter, global study, assessed D ± tremelimumab (T) as consolidation tx for pts with LS-SCLC who had not progressed after cCRT. Here we report results for D vs PBO from the first planned interim analysis (IA).
• Conclusions: D as consolidation tx after cCRT demonstrated a statistically significant and clinically meaningful improvement in OS and PFS compared with PBO in pts with LS-SCLC. D was well tolerated and AEs were consistent with the known safety profile, with no new signals observed. These data support consolidation D as a new SoC for pts with LS-SCLC who have not progressed after cCRT. Clinical trial information: NCT03703297.
• Conclusions: D as consolidation tx after cCRT demonstrated a statistically significant and clinically meaningful improvement in OS and PFS compared with PBO in pts with LS-SCLC. D was well tolerated and AEs were consistent with the known safety profile, with no new signals observed. These data support consolidation D as a new SoC for pts with LS-SCLC who have not progressed after cCRT. Clinical trial information:
  NCT03703297.

Checkmate 77T:

A phase III trial of neoadjuvant nivolumab (NIVO) plus chemotherapy (chemo) followed by adjuvant nivo in resectable early-stage NSCLC.

Background: Although surgery for early NSCLC is potentially curative, 5-year overall survival (OS) rates for patients with stage IIA–IIIB disease are historically < 50%, representing a population of high unmet need. Conventional neoadjuvant or adjuvant chemo provides only a 5% absolute improvement in OS at 5 years. A rational approach to improve survival in these patients is to eradicate micrometastatic disease and potentially induce anti-tumor immunity to minimize the risk of relapse with peri-operative regimens including NIVO, a fully human anti–programmed death receptor-1 antibody.

Patients with EGFR/ALK mutations, brain metastasis, prior systemic anti-cancer treatment or radiotherapy, and autoimmune disease are excluded.

EVOKE-01

• Sacituzumab Govitecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non–Small Cell Lung Cancer: The Randomized, Open-Label Phase III EVOKE-01 Study
• The open-label, phase III EVOKE-01 study evaluated sacituzumab govitecan (SG) versus standard-of-care docetaxel in metastatic non–small cell lung cancer (mNSCLC) with progression on/after platinum-based chemotherapy, anti–PD-(L)1, and targeted treatment for actionable genomic alterations (AGAs). Primary analysis is reported.
• Although statistical significance was not met, OS numerically improved with SG versus docetaxel, which was consistent across histologies. Clinically meaningful improvement in OS was noted in mNSCLC nonresponsive to last anti–PD-(L)1–containing regimen. SG was better tolerated than docetaxel and consistent with its known safety profile, with no new safety signals.

OptiTROP-Lung01 study.

• in china
• Sacituzumab tirumotecan (SKB264/MK-2870) in combination with KL-A167 (anti-PD-L1) as first-line treatment for patients with advanced NSCLC from the phase II OptiTROP-Lung01 study.
• Background: Sacituzumab Tirumotecan (SKB264/MK-2870)is a TROP2 ADC developed with novel linker to conjugate the payload, a belotecan-derivative topoisomerase I inhibitor. The hydrolytically linker permits both extracellular pH-sensitive cleavage and intracellular enzymatic cleavage to release the membrane permeable payload enabling the “bystander effect”. Here, we report the initial results from a phase II study of SKB264 combined with KL-A167 in patients (pts) with advanced NSCLC (OptiTROP-Lung01, NCT05351788).

– SKB264 in combination with KL-A167 demonstrated promising efficacy results in treatment naive advanced NSCLC with manageable safety profile. SKB264 Q2W was recommended for further investigation. A Phase 3 study of SKB264 Q2W plus pembrolizumab vs pembrolizumab in 1L metastatic NSCLC with PD-L1 TPS ≥ 50% (NCT06170788) is ongoing.

HARMONi-A

• Ivonescimab combined with chemotherapy in patients with EGFR-mutant non-squamous non-small cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor treatment (HARMONi-A): A randomized, double-blind, multi-center, phase 3 trial.

CROWN Study 5y update

• gute Wirkung gegen hirnmetataste, wahrscheinlich neuer firstline therapie standard?
• Lorlatinib Versus Crizotinib in Patients With Advanced ALK-Positive Non–Small Cell Lung Cancer: 5-Year Outcomes From the Phase III CROWN Study
• Purpose
  Lorlatinib improved progression-free survival (PFS) and intracranial activity versus crizotinib in patients with previously untreated, advanced, ALK-positive non–small cell lung cancer (NSCLC) in the phase III CROWN study. Here, we report long-term outcomes from CROWN after 5 years of follow-up.

Conclusion
After 5 years of follow-up, median PFS has yet to be reached in the lorlatinib group, corresponding to the longest PFS ever reported with any single-agent molecular targeted treatment in advanced NSCLC and across all metastatic solid tumors. These results coupled with prolonged intracranial efficacy and absence of new safety signals represent an unprecedented outcome for patients with advanced ALK-positive NSCLC and set a new benchmark for targeted therapies in cancer.

KRYSTAL-12

• KRYSTAL-12: Phase 3 study of adagrasib versus docetaxel in patients with previously treated advanced/metastatic non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation.
• Background: Adagrasib (ADA) is a potent covalent inhibitor of KRASG12C with favorable properties such as long half-life (23 h), dose-dependent pharmacokinetics, and brain penetrance. In the phase 1/2 KRYSTAL-1 trial, ADA demonstrated deep and durable responses with promising PFS and OS in patients (pts) with previously treated KRASG12C-mutated NSCLC. Here, we report the primary analysis from KRYSTAL-12 (NCT04685135), a randomized, open-label phase 3 trial of ADA compared with docetaxel (DOCE) in pts with KRASG12C-mutated locally advanced or metastatic NSCLC who had previously received a platinum-based chemotherapy, concurrently or sequentially with anti-PD-(L)1 therapy.

– Conclusions: In the phase 3 KRYSTAL-12 trial, ADA demonstrated a statistically significant and clinically meaningful improvement in PFS and ORR over DOCE in pts with previously treated KRASG12C-mutated NSCLC. Safety profile of ADA was consistent with previous reports and with no new safety signals. These results further support ADA as an efficacious treatment option for pts with previously treated KRASG12C-mutated locally advanced or metastatic NSCLC. Fu

NRG-LU002

• Limited metatsastic NSCLC, OMG
• lokal additive ablative Therapie (Operation oder Radiatio) macht keine Differenz an PFS+OS (kombinierter Endpoint)
• poly-metastatic, oligo-metatastic
• Randomized phase II/III trial of maintenance systemic therapy versus local consolidative therapy (LCT) plus maintenance systemic therapy for limited metastatic non-small cell lung cancer (NSCLC).
• Background: First line therapy options for advanced NSCLC without actionable molecular alterations include immunotherapy (IO) -/+ chemotherapy or chemotherapy alone. NRG-LU002 was a randomized phase II/III study assessing the benefits of local consolidative therapy (LCT) when added to systemic therapy as maintenance in management of oligometastatic NSCLC.
• Methods: Eligible patients had metastatic NSCLC with 3 or fewer extracranial metastatic sites (excluding primary) exhibiting at least stable disease after 4 cycles of 1st line systemic therapy. Patients were randomized 1:2 to maintenance systemic therapy or LCT (radiation and/or surgery) followed by maintenance systemic therapy until progression, death, or intolerable toxicity. Stratification factors included histology and IO use. In the randomized phase II (RPhII) portion of the study, the primary endpoint was progression-free survival (PFS) with a planned decision analysis after 216 patients were enrolled and 138 PFS events observed. Secondary endpoints included overall survival (OS), quality of life, and toxicity. The RPhII portion was designed to provide at least 95% power to detect a PFS hazard ratio (HR) of 0.60 at 1-sided significance level of 0.15, and the phase III portion warranted only if the estimated HR was less than 0.83.

– Conclusions: LCT added to IO-based 1st line systemic therapy was associated with a PFS HR of 0.90. Reducing toxicity and increasing biologically-driven patient selection may optimize this therapeutic ratio. Clinical trial information: NCT03137771.

Cases

Frau Enns OMG Tumorprogress

Adonokarzinom im rechten mittellappen, pdl1 expression 90%. Singuläre hirnmetastase Pons , somit cT2 cN0 und cM1b. Zustand nach Hirnbestrahlung. In der tumorkonferenz Empfehlung lungenresektion versus definitive Chemo radiatio. Bei Ausschluss von N2 Status habe ich Lunge Resektion empfohlen. Patient kommt zur Operation mit laufender Dexamethason-therapie 12 mg pro Tag. Am aufnahmetag gib die Patientin brustwandschmerzen rechts an. Zusätzlich sehr hoher CRP 334 kommt von 0,8 innerhalb zwei Wochen beim normwertige leukozytenzahl. Daraufhin CT Untersuchung am Aufnahmetag. Deutlicher Tumorprogress bei Größenprogredienz des Tumors mit Infiltration bzw Kontakte an Brustinnenwand, Unregelmäßigkeit der Pleura sowie mediastinale Lymphadenopathie. Nach Diskussion mit Strahlentherapie und Onkologen wird die Operation storniert. Die Patientin bekommt Pott und anschließende Immuntherapie.
Reflexion: soll ich solche Fälle zügiger operieren? Sollte Dexomethason schneller pausiert werden? Timing

Terminologie

Event-free survival

Event-free survival (EFS) is defined as the time from randomization to an event which may include disease progression, discontinuation of the treatment for any reason, or death [24]. While EFS and DFS used to be interchangeable, the patient is not technically “disease-free” at the time of randomization in a neoadjuvant setting; EFS is now the clinical endpoint reserved for neoadjuvant settings while DFS is applied in adjuvant settings [24]. EFS is a surrogate endpoint that can be used in the place of a primary endpoint, such as OS, to reduce sample size, costs, and duration of follow-up [25]. Since EFS is a surrogate endpoint, it needs to be validated for each unique tumor type, treatment, and stage of disease.