VATS vs. RATS NSCLC Stadium III resektabel

1

mVATS lobectomy may be associated with improved overall survival compared to open lobectomy.

C-LD

II-B

2

mVATS may have similar disease-free survival when compared to open lobectomy.

C-LD

II-B

3

mVATS may be associated with a lower recurrence rate, primarily related to distant recurrence when compared to open lobectomy.

C-LD

II-B

4

rVATS has no difference in overall survival and recurrence when compared to mVATS lobectomy.

C-EO

II-B

5

Open lobectomy results in an increase in nodal upstaging when compared to mVATS.

C-LD

II-A

6

mVATS, uVATS, and rVATS may be equivalent in terms of number of lymph nodes harvested and nodal upstaging.

B-NR

II-B

7

mVATS may facilitate the completion of adjuvant chemotherapy when compared to open lobectomy.

C-LD

II-B

8

mVATS lobectomy for the treatment of NSCLC is associated with a decreased risk of adverse events when compared to open lobectomy.

C-LD

II-A

9

mVATS, uVATS, and rVATS may be associated with similar rates of adverse events.

C-LD

II-B

10

mVATS can improve postoperative pain (Class IIA, Level B-R), and may be associated with improved quality of life (Class IIB, Level B-R), and overall function (Class IIB, Level C-EO) when compared to open lobectomy.

B-R und C-EO

II-A und B

11

uVATS lobectomy may reduce early postoperative pain and analgesic requirements compared with mVATS.

C-LD

II-B

12

mVATS and rVATS may be associated with a decreased length of stay when compared to open lobectomy.

C-LD

II-B

13

There is no significant difference in length of stay between mVATS, uVATS, and rVATS.

C-LD

II-B

14

mVATS is associated with reduced costs when compared to open lobectomy.

B-NR

II-A

15

rVATS is associated with higher costs when compared to mVATS lobectomy.

B-NR

II-A

mVATS: multiport video-assisted thoracic surgery; rVATS: robotic video-assisted thoracic surgery; uVATS: uniportal video-assisted thoracic surgery

Evidenzgrade:

B-R: randomized (moderate-quality evidence from 1 or more RCTs or meta-analyses of moderate-quality RCTs)

B-NR: nonrandomized (moderate-qaulity evidence from 1 or more well-designed, well-executed nonrandomized studies, observational studies, or registry studies or meta-analyses of such studies)

C-LD: limited data (randomized or nonrandomized observational or registry studies with limitations of design or execution, meta-analyses of such studies or physiological or mechanistic studies in human subjects)

C-EO: expert opinion (consensus of expert opinion based on clinical experience

Empfehlngsgrade:

IIa: moderate Empfehlung (benefit>>risk)

IIb: schwache Empfehlung (benefit≥risk)

Batihan Ergebn2020

(40)

01/2014-12/2018

Retrospective study with confounder adjustment

Comparision of intraoperative and post-operative results of VATS and thoracotomy in patients NSCLC with tumors > 5 cm (≥T3)

Inclusion criteria:

· patients who underwent anatomic lung resection for lung cancer with tumors > 5 cm (≥ T3)

· Tumor size was defined according to the maximum diameter in the pathological specimens

Exclusion criteria:

· Patients who underwent neoadjuvant CT/RT, chest wall resection, tracheobronchoplasty, and angioplasty

n=849 screened, n=60 included

characteristics (VATs vs. Thoracotomy):

62.2±1.6 vs. 63.2±2.1 yrs

Males: 91.7 vs. 97.2 %

Co-morbidities: none: 62.5 vs. 52.5 %

Heart disease: 42. Vs. 11.1 %

Hypertension: 8.3 vs. 8.3 %

Diabetes: 8.3 vs. 11.1 %

COPD: 16.7 vs. 16.7 %

Pathology:

adeno: 58.3 vs. 63.9 %

squamous cell: 29.2 vs. 30.6 %

large cell: 12.5 vs. 5.6 %

Operation:

Lobectomy: 91.6 vs. 72.2 %

Bilobectomy: 4.2 vs. 27.8 %

Postoperative p staging:

Stage II: 37.5 vs. 38.9 %

Stage III: 62.5 vs. 61.1 %

Thorax computed tomography (CT), PET-CT, and bronchoscopy

if mediastinal lymph node enlargement or high FDG uptake first mediastinal lymph node sampling via endobronchial ultrasound with real-time guided transbronchial needle aspiration (EBUS-TBNA) or mediastinoscopy was performed

VATS (n=24)

vs.

Thoracotomy (n=36)

postoperative complication (any

complication occurring ≤30 days after surgery)

prolonged air leakage (air leak > 7 days after surgery)

recurrence-free survival

postoperative mortality (≤30 days after surgery)

Perioperative data: no differences shown

· Operation durations:228.7±91.9 vs. 260.2±102.8 min)

· Intraoperative complications: 1 vs. 2

· Drainage time: shorter with VATS (5.0±3.4 vs. 8.1±5.0 days)

· Lengths of stay: shorter with VATS (5.4±2.3 vs. 9.1±5.3 days)

Postoperative complications (%):

Total: 8 (33.3) vs. 14 (38.9)

· Prolonged air leakage: 4(16.7) vs. 9 (25)

· Hemorrhage: 1 (4.1) vs. 1(2.8)

· Pneumonia: 3 (12.5) vs. 2 (5.6)

· Empyema: 0 vs. 1

· Bronchopleural fistula: 0 vs. 1

Recurrence-free survival: better with VATS:

· Median:  53.3 vs. 37.6 months (p=0.031)

· 1-year recurrence: 81.2 vs. 78.8 %

· 3-year recurrence: 81.2 vs. 50.2 %

HR_a: 7.211 (95%CI 1.309-40.83) (p=0.023)*

Overall survival: no difference shown

· Median: 52.3 vs. 38.5 months

· 1-year OS: 77.6 vs. 82.9 % (p=0.056)

· 3-year OS: 77.6 vs. 57.2 %

HR_a: 1.609 (95%CI 0.978-3.812) (p=0.064)*

*Adjustierung erfolgte für Charakteristika des Patienten (Alter, Geschlecht, FEV1, Komorbiditäten), der Tumorerkrankung (Tumorgröße, Stadium, pathologischer Subtyp, die Länge des krankheitsfreien Intervalls, Nodalstatus) und der Behandlung (VATs vs. Thoraktomie, Zeit zwischen der Operation und der adjuvanten Therapie, Anzahl der sezierten Lymphknoten).

2b-

Abwertung aufgrund geringer Präzision

Zusammenfassende Beurteilung

Schlussfolgerungen der Autoren der Studie: „In conclusion, this current study demonstrates significant differences in drainage time, length of hospital stays, overall and recurrence-free survival in favor of VATS. Therefore, according to these results, we emphasize that VATS is a feasible surgical procedure for tumors larger than 5 cm. Difficulties may be experienced in the retraction of the lung and providing adequate exposure for safe dissection but this kind of issue can be overcome with the proper placement of ports, the use of appropriate surgical instruments, and teamwork.”

Schlussfolgerung der Begutachterin: Monozentrische türkische retrospektive Studie unter konsekutivem Einschluss aller 60 NSCLC-Patienten mit einem Tumordurchmesser über 5 cm (62 % im Stadium III), bei denen von eine pulmonare Resektion in den Jahren 2014-2018 durchgeführt wurde. Die Durchführung von VATS nahm bei diesen Patienten mit zunehmender Erfahrung der Operateure zu. Die Datenerhebung basiert auf vorliegenden Krankenakten. Es wurden geringe Unterschiede in den Charakteristika der Patienten festgestellt. Die Ergebnisse zum Einflus der Operationstechnik auf das Gesamt- und progressionsfreie Überleben basieren auf konfounderadjustierten Analysen. In der Gruppe mit VATS waren die Zeiten mit Drainage und im Krankenhaus kürzer. Unterschiede im Auftreten von peri- und postoperativen Komplikationen wurden nicht nachgewiesen. In konfounderadjustierten Analysen konnte ein verlängertes krankheitsfreies Überleben nachgewiesen werden. Unterschiede im Gesamtüberleben konnten, evtl. auf Grundlage der geringen Fallzahlen nicht nachgewiesen werden (daher Abwertung aufgrund geringer Präzision).

Huang 2019

(41)

ChiCTR-INR-17012777

01/2016-12/2018

Shanghai

RCT

Non-inferiority of RATS for cN2 stage NSCLC on short-term outcomes

Inclusion criteria:

· patients 18 to 75 yrs with clinically diagnosed c-N2 NSCLC

· exhibited as a suspicious pulmonary lesion with enlarged mediastinal lymph nodes (diameter > 1 cm on CT scan)

· adequate organ function to tolerate pulmonary resection

Exclusion criteria:

· invasion into neighboring organs, extensive pleural adhesion,

· earlier thoracotomy, high dose radiation on the chest,

· history of other malignancies in the past 5 years (except for nonmelanoma skin cancer, cervix cancer in situ, or early-stage prostate cancer)

· predicted postoperative FEV1 or diffusing capacity of lung for carbon monoxide value

· pregnant or lactating female patients, inability to obtain consent

· intraoperative pleural adhesion or technical challenge to achieve hemostasis needed conversion from RATS to thoracotomy

· occult pleural metastasis

· major protocol violation; clinician decides the patient should not continue the trail according to individual condition; patients withdraw from the trial

· histologic finding is not NSCLC

n=113

males: 71 %

age: 61.2±8.2 yrs

smoking history: 51.3 %

no comorbidities: 65 %

adeno/aquamous /large cell carcinoma: 66/23/3.5 %

Tumour size: 3.45±1.4 cm

Pathologic stage IIIA/B: 29/11.5 %

IV: 3.5 %

radical lobectomy combined with mediastinal lymph node dissection (hilar and mediastinal lymph nodes were routinely dissected, and ≥ 3 mediastinal lymph nodes (N2) stations was harvested)

RATS using the da Vinci Surgical System followed the strict definition of the Cancer and Leukemia Group B 39802, (anatomic

lobectomy, visualization only by thoracoscope and non-ribspreading technique) (n=58)

vs.

conventional lobectomy with a rib-spreading

thoracotomy of 15 to 20 cm (n=55)

Within the first 2 years patients were reviewed in outpatient clinic in 3-month intervals. Then, the surveillance was scheduled on a 6-month basis for the next 3 years

Short-term perioperative outcomes (not specified)

RATS surgery was converted to thoracotomy in 5 subjects due to extensive pleural adhesion (2 cases) and equipment issues (3 cases), thus 53 RATS (91.4 %) cases were analysed

perioperative outcomes:

no difference shown in:

distribution of different pulmonary resections )Lobectomy, bilobectomy, sleeve lobectomy)

Operative time: 108±39 vs. 103±30 minutes

POD1 drainage: 300 (95-840) vs. 320 (50-979) ml

In all cases, the mediastinal lymph node was completely dissected.

R0 resection: 98.2 vs. 94.3 %

Benefit of RATS in:

Intraoperative blood loss: less with RATS (86.3±41.1 vs. 165.7±46.4 ml; p<0.001)

Chest tube duration: less with RATS (4 [2-63] vs. 5 [3-66]; p<0.01)

Total drainage: less with RATS (820 [220-2460] vs. 960[320-4630]; p=0.05)

Lower VAS on postoperative days 1-5 (no further explanations, all with p<0.001)

Costs:

Higher with RATS (100 367±19 251 vs. 82 002POD1-520 434 ¥

Length of hospital stay:

No difference shown (10 [7-31] vs. 11 [6-44] days; p=0.07)

Complications:

Mortality: 1 (1.7 %) vs. 0

Any complications: no differences shown (27.6 vs. 38.2 %

2b

Abwertung aufgrund eingeschränkter Übertrag-barkeit und fehlender Präzision, es liegen bisher ausschließlich Ergebnisse bis zur Entlassung aus dem Krankenhaus vor

Zusammenfassende Beurteilung

Schlussfolgerungen der Autoren der Studie: “In conclusion, RATS is safe and effective to treat patients with cN2 NSCLC owing to its similar shortterm outcomes of thorough dissection of lymph node and occurrence of postoperative complications compared to axillary thoracotomy and may be superior due to its lesser intraoperative blood loss. However, long-term follow-up is warranted to verify the superior or equivalent oncologic outcome of RATS lobectomy. The report could be expected by the end of 2020.“

Schlussfolgerung der Begutachterin: Multizentrische chinesische Nicht-unterlegenheits-RCT unter Einschluss und Randomisierung von 113 NSCLC-Patienten (c-N2, davon 40.1 % im Stadium III), (daher Abwertung aufgrund von eingeschränkter Übertragbarkeit der Ergebnisse) von denen 108 (91.4 % ohne Konversation zur konventionellen Lobectomy ausgewertet wurden (aufgrund der Fallzahl Abwertung augrund geringer Präzision). Für den Vergleich zwischen RATS und konventioneller Lobektomie werden ausschließlich Ergebnisse bis zum Zeitpunkt der Entlassung aus dem Krankenhaus berichtet, langfristige Ergebnisse sollen Ende 2020 veröffentlicht werden (nicht gefunden).

Randomisierung und Zuweisung wird adäquat beschrieben, keine verblindete Endpunkterhebung oder Beschreibung des primären Endpunktes, Protokoll existiert in chinesischer Sprache.

Ng 2019

(9)

Search from 2000-01/2018

Systematic review

optimal surgical approach

for lobectomy (multiport

video-assisted thoracic surgery (mVATS), uniportal video-assisted thoracic surgery (uVATS), robotic video-assisted

thoracic surgery (rVATS)) compared to conventional open lobectomy to improve clinical and resource outcomes

Inclusion criteria:

· RCTs and non-randomized observational studies (prospective or retrospective cohort and case–control studies)

· Adult patients undergoing upfront lobectomy for stages I–III NSCLC

· Studies comparing VATS (mVATS, rVATS, or uVATS) to conventional open thoracotomy, as well as studies that compared mVATS to rVATS or uVATS

· any VATS lobectomy using more than one port was considered to be multiport VATS

· studies reporting mixed lung resection procedures, whe data  extraction and analysis of outcomes for lobectomy for NSCLC patients could be segregated out.

Exclusion criteria:

· Studies that assessed other types of surgery (segmentectomy, bilobectomy, sleeve lobectomy, pneumonectomy, and wedge resection)

· studies where patients received neoadjuvant chemotherapy or radiation

· studies that included patients with advanced lung cancer

· studies that included patients with benign neoplasm or infectious disease

N=145 studies, n=369793

N=7 RCTs with n=1276

N=138 n-RCTs (cohort and case-control studies) with n=368517

142 studies published in English

N=13 with propensity score matching

Most studies

were conducted in the United States, China, Japan, and South Korea, but also in several European countries and one South American country

Risk of bias:

All RCTs were rated as high risk of bias

for blinding.

N=138 nRCTs were rated with Newcastle-Ottawa scale (range 0-9, 9 indicats high methodological quality). Most studies have reasonably good quality, all studies were at risk for

performance or detection bias because it was not possible to blind physicians, patients and personnel to the intervention,

many of the outcomes are objective in nature,

no clear evidence of publication bias, but inadequate power for some clinical outcomes

minimally invasive surgical (MIS) approaches (multiport

video-assisted thoracic surgery (mVATS), uniportal video-assisted thoracic surgery (uVATS), and robotic video-assisted

thoracic surgery (rVATS))

vs.

conventional open lobectomy

mVATS vs. open lobectomy (N=115)

mVATS vs. rVATS (N=9)

mVATS vs. uVATS (N=13)

rVATS vs. open lobectomy (N=1)

mVATS to rVATS vs. open lobectomy (N=4)

combined mVATS / rVATS vs. open lobectomy (N=2)

Primary:

Overall survival. Secondary: Recurrence-free survival

local or distant

tumor recurrence

lymph node evaluation, pathological upstaging

adverse events

length of stay

postoperative pain

scores

quality of life

ability to return to normal activities

respiratory function*

cost-effectiveness*

*not extracted

mVATS vs. open lobectomy:

Survival and recurrence:

· 5-year-survival (N=30, n=16200): higher with mVATS (72 % vs. 67 %; OR 1.35; 95%CI 1.17 to 1.56) with substantial heterogeneity between studies (I²=60 %)

· 5-year DFS (N=14, n=4108): no difference shown (no recurrence in 65 vs. 61%; OR 1.15; 95%CI 0.94 to 1.40) with moderate heterogeneity between studies (I²=48 %)

· Overall disease recurrence (N=22, n=6176): lower with mVATS (15 vs. 19 %; OR 0.73; 95%CI 0.61 to 0.87) with small heterogeneity between studies (I²=24 %)

· Local recurrences (N=14, n=3691): no differences shown (5 vs. 6 %; OR 0.77; 95%CI 0.58 to 1.03) with small heterogeneity between studies (I²=0 %)

· Distant recurrences (N=14, n=3691): lower with mVATS (6 vs. 10 %; OR 0.67; 95%CI 0.52 to 0.85) with small heterogeneity between studies (I²=0 %)

Lymph node evaluation and pathological upstaging:

No difference in lymph nodes (N=28; n=29341) and lymph node stations (N=15; n=6714) dissected

· Reduced odds of nodal upstaging with mVATS (11 vs. 14%; OR 0.71; 95%CI 0.58 to 0.97) with moderate heterogeneity between studies (I²=57 %)

Complications and adverse events:

All less frequent with mVATS:

· Complications (N=53, n=88 460): (36 vs. 42 %; OR 0.64; 0.59 to 0.71) with substantial heterogeneity between studies (I²=64 %)

· Cardiopulmonary (N=17, n=143 390): (OR 0.60; 0.48 to 0.75) with substantial heterogeneity between studies (I²=74 %)

· Atrial fibrillation (N=23, n=12 246): (OR 0.62; 0.45 to 0.84) with moderate heterogeneity between studies (I²=46 %)

· Prologed air leak (N=33, n=18 762): (OR 0.78; 0.67 to 0.90) with small heterogeneity between studies (I²=12 %)

· Wound infection (N=13, n=52 234): (OR 0.50; 0.36 to 0.68) with small heterogeneity between studies (I²=0 %)

· 30-day mortality (N=15, n=23 629): (OR 0.77; 0.62 to 0.95) with small heterogeneity between studies (I²=0 %)

· No differences shown for 90-day mortality (N=6, n=12 479): (OR 0.78; 0.56 to 1.07) with small heterogeneity between studies (I²=13 %)

Pain and quality of life:

Less postoperative pain (measured with VAS) with mVATS on days 1,7,14,30 and 90

Higher quality of life (1 RCT, n=201, EQ5D) at week 2, 8, 12, 26 and 52 and higher quality of life (N=3, n=332, Global QoL tool) at 1 year and better activities of daily lifing (N=1, n=103)

Length of hospital stay (N=35, n=36 776):

· shorter with mVATS (MD -1.95; 95%CI -3.1 to 0.73) with substantial heterogeneity between studies (I²=97 %)

mVATs vs. rVATS:

Survival and recurrence:

· 5-year-survival (N=1, n=313): no difference shown (OR 0.79; 95%CI 0.47 to 1.33)

· 5-year DFS (N=1, n=313): no difference shown (OR 0.71; 95%CI 0.44 to 1.14)

· Similar results after 2 years

Lymph node evaluation and pathological upstaging:

No difference in lymph nodes detection (N=5; n=7814), lymph node stations detection (N=2; n=179) and nodal upstaging  (N=6; n=18 216) with substantial and small heterogeneity between studies (I²=74, 69 and 18 %)

Complications and adverse events:

No differences shown for complications (N=1-6, n=999 to 24 513), atrial fibrillation, prologed air leak, pneumonia and 30-day mortality 

Length of hospital stay:

No difference shown (N=6; n=7752)

mVATs vs. uVATS:

Survival and recurrence:

· 3-year-survival (N=1, n=160): no difference shown (OR 0.57; 95%CI 0.20 to 1.64)

Lymph node evaluation and pathological upstaging:

No difference in lymph nodes detection (N=10; n=1789) and nodal upstaging  (N=1; n=106) with substantial heterogeneity between studies (I²=67 %)

Complications and adverse events:

No differences shown for complications (N=1 to 5, n=106 to 930, prologed air leak, pneumonia, perioperative and 30-day mortality 

Pain and quality of life:

Less postoperative pain analgetics per months with uVATS (MD 4.2;95%CI 3.8 to 4.6) with small heterogeneity between studies (I²=0 %)

less pain (measured with VAS) with uVATS on days 1,3, 7 and 30

Length of hospital stay:

No difference shown (N=7; n=1269)

2a-

Abwertung aufgrund von Indirektheit und Studienlimitationen, Aufwertung aufgrund hoher Präzision

 Zusammenfassende Beurteilung

Schlussfolgerungen der Autoren der Studie: “In conclusion, we have performed an extensive systemic review and meta-analysis comparing mVATS to open lobectomy, and the most popular MIS approaches to each other. mVATS has been reported for over 25 years and a large number of studies with several thousand patients have been included in comparisons between mVATS and open lobectomy. However, only 7 of the 145 included studies were randomized trials. In addition to the general limitations of meta-analysis, it is hard to control for surgeon specific biases (e.g., treating smaller and peripheral tumors with an MIS approach), and institutional biases where some surgeons will use an open and others an MIS approach. With these limitations in mind, our analysis suggests that the mVATS approach is superior to thoracotomy, particularly with respect to adverse events, pain control and perhaps improved survival. With respect to the optimal MIS approach, fewer studies are available to make definitive statements. Robotic VATS may be more expensive than mVATS, but otherwise does not demonstrate superiority or inferiority compared to mVATS. There is a suggestion that uVATS may be associated with lower adverse events and pain. It is our goal that the extensive analysis provided in the manuscript and appendix will assist future investigators in planning new trials to explore differences between these techniques.”

Schlussfolgerung der Begutachterin: Systematische Übersicht zum Vergleich minimal invasiver Operationstechniken (mVATS, uVATS, rVATS) mit einer offenen Thorektomie unter Einschluss von RCTs und vergleichenden Beobachtungsstudien (Kohorten- und Fall-Kontrollstudien) mit einer Suche bis Januar 2018. Einschluss von 145 Studien mit 369 793 Studienteilnehmern mit NSCLC der Grade I-III (davon 7 randomisierte Studien und 13 Studien mit Propensity-Score-Matching), von denen die meisten in Asien durchgeführt wurden und viele Patienten in einem frühen Erkrankungsstadium einschließen (deshalb und wegen Einbezug der Grade I-III Abwertung aufgrund von eingeschränkter Übertragbarkeit).

Die systematische Übersichtsarbeit weist eine moderate Einschränkung der Qualität auf (fehlendes Protokoll, Informationen zur Suche in Registern und zum Screenen der Referenzen, keine Heterogenitätsbetrachtungen), die Studien sind nicht verblindet (Durchführungs- und Beobachtungsbias kann nicht ausgeschlossen werden (daher Abwertung aufgrund von Studienlimitationen). Es wird die Wirksamkeit einer minimal invasiven Operation auf das Überleben (substantielle Heterogenität, aber 25/30 Studien zeigen Vorteil von mVATS) und krankheitsfreie Überleben sowie das Auftreten von Rekurrenzen,  ein Upstaging aufgrund der Lymphknotenuntersuchung, dem Auftreten postoperativer Komplikationen (auch hier substantielle Heterogenität, aber in 51/53 Studien weniger Komplikationen mit mVATS im Vergleich zur Thorektomie), das Auftreten von Schmerzen, die Lebensqualität und die Länge des Krankenhausaufenthaltes gezeigt. Insgesamt wird die Qualität der Evidenz aufgrund der aus der hohen Anzahl von Studien und Teilnehmern und der aussagekräftigen Ergebnisse zu Überleben und Komplikationen um einen Grad von 2a (Systematische Übersicht auf Grundlage von Kohortenstudien) auf 2a- abgewertet.

CG: Control group; CI: Confidence interval; d: Tag; DCR: Disease control rate; ECOG: Eastern Cooperative Oncology Group; HR: Hazard ratio; IG: Intervention group; MIS: minimally invasive surgery; mVATS: multiport video-assisted thoracic surgery; N: Number of studies; n: Number of participants;RATS: robot-assisted thoracoscopic surgery;  rVATS: robotic video-assisted thoracic surgery; uVATS: uniportal video-assisted thoracic surgery; VAS: Visual analogue scale; wks: weeks; yrs: years