Overzicht van systematic reviews en meta-analyses

Studie, jaar	Opzet	Aantal studies	Lokalisatie keratose	Interventie	Controle	Participant complete clearance rate	Lesion clearance rate % per area/patient	Pigmentveranderingen en Lokale huidreacties	Overige uitkomstmaten per review
Gupta, 2012	Studietype: Cochrane review	83 RCTs met een totale sample size van 10,036 patienten. Een deel van de vergelijkingen is in deze richtlijn geëxcudeerd.	Lesions were located on the head only (i.e. face, forehead, temples, cheeks, scalp, ear, lips, and neck) in 59 studies, on only non-head locations (up- per and lower extremities, legs, arms, elbow, forearms, hands, dorsa of hands, shoulder, décolleté, chest, trunk, and back) in 9 studies, and on both head and non-head locations (including the term ”other“) in 22 studies. One study did not specify the location of the lesions. In general, lesions were more often located on the face and scalp, which are easy to reach.	The RCTs betroffen 18 topicale behandelingen, 1 orale behandeling, 2 mechanische interventies, en 3 chemische interventies, incl. photodynamic therapy (PDT)	A significant number of participants withdrew because of adverse events with 144 participants affected out of 1000 taking 3% diclofenac in 2.5% hyaluronic acid, compared to 40 participants affected out of 1000 taking 2.5% hyaluronic acid alone, and 56 participants affected out of 1000 taking 5% imiquimod compared to 21 participants affected out of 1000 taking placebo.	The primary outcome ’participant complete clearance’ significantly favoured four field-directed treatments compared to vehicle or placebo: 3% diclofenac in 2.5% hyaluronic acid (RR 2.46, 95% CI 1.66 to 3.66; 3 studies with 420 participants), 0.5% 5-fluorouracil (RR 8.86, 95% CI: 3.67 to 21.44; 3 studies with 522 participants), 5% imiquimod (RR 7.70, 95% CI 4.63 to 12.79; 9 studies with1871 participants), and 0.025% to 0.05% ingenol mebutate (RR 4.50, 95% CI 2.61 to 7.74; 2 studies with 456 participants). The corresponding comparative risks in terms of number of participants completely cleared per 1000 were as follows: 313 with 3% diclofenac compared to 127 with 2.5% hyaluronic acid; 136 with 0.5% 5-fluorouracil compared to 15 with placebo; 371 with 5% imiquimod compared to 48 with placebo; 331 with ingenol mebutate compared to 73 with vehicle; 527 to 656 with ALA/MAL-PDT treatment compared to 89 to 147 for placebo-PDT; and 580 with ALA-PDT compared to 443 with cryotherapy. 5% 5-fluorouracil efficacy was not compared to placebo, but it was comparable to 5% imiquimod (RR 1.85, 95% Cl 0.41 to 8.33)	It also significantly favoured the treatment of individual lesions with photodynamic therapy (PDT) compared to placebo-PDT with the following photosensitisers: aminolevulinic acid (ALA) (blue light: RR 6.22, 95% CI 2.88 to 13.43; 1 study with 243 participants, aminolevulinic acid (ALA) (red light: RR 5.94, 95% CI 3.35 to 10.54; 3 studies with 422 participants), and methyl aminolevulinate (MAL) (red light: RR 4.46, 95% CI 3.17 to 6.28; 5 studies with 482 participants). ALA-PDT was also significantly favoured compared to cryotherapy (RR 1.31, 95% CI 1.05 to 1.64).	Based on investigator and participant evaluation, imiquimod treatment and photodynamic therapy resulted in better cosmetic outcomes than cryotherapy and 5-fluorouracil.
Heppt, 2019	Studietype: systematische review Land: Duitsland Financiering: geen	8 studies met totale sample size van 242 patiënten (range 8-81) A. Dragieva, 2004 B. Helsing, 2013 C. Perrett, 2007 D. Togsverd-Bo, 2018 E. Togsverd-Bo 2015 F. Ulrich, 2007 G. Ulrich, 2010 H. Wennberg, 2008	Face, scalp, romp, extremiteiten	A. MAL-PDT B. AFXL+PDT C. MAL-PDT (2 cycli) D. MAL-PDT (1-2 cycli) E. AFXL F. IMQ G. DIC H. MAL-PDT (2 cycli)	A. placebo-PDT B. AFXL C. 5-FU D. IMQ E. AFXL+ DL-PDT, cPDT, DL-PDT F. vehicle G. vehicle H. alle andere therapie (wv 83% cryotherapie)	A. 76.4% vs. 0% na 16 weken (RR 27.00; 1.73-420.67) B. niet gerapporteerd C. 89% vs. 11% na 6 maanden (RR 8.00; 1.24-51.51) D. 40% vs. 27.5% na 2 behandelingen (RR 1.45; 0.69-3.10) E. niet gerapporteerd F. 62.1% vs. 0% (RR 18.50; 1.19-286.45) G. 41% vs. 0% (RR 5.78; 0.38-87.35) H. niet gerapporteerd	A. 90% vs. 0% (RR 121.97; 7.70-1932.51) B. 73% vs. 31% (RR 2.35; 1.99-2.80) C. 99% vs. 79% relatieve reductive (RR 1.26; 1.23-1.30) D. 78% vs. 61% na 2 behandelingen E. 5% (AFXL), vs. 74% (AFXL-DLPDT), vs. 46% (DL-PDT), vs. 50% (cPDT) na 3 maanden F. 73.7% vs niet gerapporteerd G. 53% vs. 17% H. 77% vs. 74%	Primair: remissie laesies en rejectie transplantaat Secundair: locale huidreacties en pigmentveranderingen Nergens rejectie van transplantaat	-
Liew, 2020	Studietype: systematische review en meta-analyse Land: Singapore FInanciering: geen	8 studies met totale sample size van 234 patiënten A. Wennberg, 2008 B. de Graaf, 2006 C. Wulf, 2005 D. Togsverd-Bo, 2017 E. Togsverd-Bo, 2014 F. Helsing, 2013 G. Perrett, 2007 H. Dragieva, 2004	Niet nader toegelicht	A. MAL-PDT 6 maandelijks B. ALA-PDT C. MAL-PDT D. MAL-PDT E. AF laser+DL-PDT F. AF laser+DL-PDT G. MAL-PDT H. MAL-PDT	A. PDT/5-FU/IMQ B. geen behandeling C. geen behandeling D. IMQ E. AF laser, DL-PDT, cPDT F. AF laser G. 5-FU H. Placebo	NIEUWE LAESIES A. PDT: 253 vs. Ctrl: 312 (AK) B. PDT: 206 vs. Ctrl: 383 (AK) C. PDT: 94 vs. Ctrl: 221 (NMSK) AK COMPLETE REMISSIE D. PDT: 78% vs. IMQ: 61% E.v AFL-DL-PDT: 74% vs. DL-PDT: 46% vs. cPDT: 50% vs. AFL: 5% F. AFL-PDT: 73% vs. AFL 31% G. PDT: 89% vs. 5-FU: 11% (epidermale dysplasie) H. PDT: 76% vs. Placebo: 0%	-	Pijn, erytheem, brandend gevoel	Meta-analyse PDT in preventie van AK/PCC: pooled RD 0.14 (95% CI: 0.19-0.08) I²: 69.2 (p=0.039) à statistisch significante voorkeur voor PDT Meta-analyse behandeleffect PDT op AK’s: RD 0.77 (95% CI: 0.60-0.94) I²: 98.69% (p<0.001) à statistisch significante voorkeur voor PDT
Mei, 2019	Studietype: systematische review en meta-analyse Land: China Financiering: geen informatie	6 studies met totale sample size van 369 patiënten en 5556 AK laesies A. Wiegell, 2008 B. Rubel, 2014 C. Togsverd-Bo, 2015 D. Lacour, 2015 E. Neittaanmaki, 2016 F. Sotiriou, 2018	Face, scalp, romp, extremiteiten	Allen DL-PDT	Allen cPDT	-	Pooled data 6 studies: CR niet significant verschillend voor de twee groepen (RR 0.93, 95% CI: 0.86-1.01, p=0.07) I²: 85% Pooled data na exclusie Neittaanmaki 2016 (open label en geen intra-individueel design) geen significantie (RR 0.97, 95% CI: 0.91-1.04, p=0.42) I²: 80% In pooled data voor studies met inclusie graad I-III laesies werd significant lagere CR gezien voor dPDT vs cPDT. Bij gepoolde data met graad I-II laesies verdween de significantie	Gepoolde data 6 studies significant lagere pijnscore DL-PDT tov cPDT: MD = -4.51 (95% CI: -5.12 - -3.89, p<0.001)	Gepoolde data 6 studies significant lager aantal AE’s DL-PDT tov cPDT: RR 0.70 (95% CI: 0.58-0.85, p<0.001, I²: 0)
Thomás-Velázquez, 2016	Studietype: systematische review en meta-analyse Land: Spanje Financiering: geen informatie	3 studies (split-site design) met totale sample size van 237 patiënten A. Wiegell, 2008 B. Rubel, 2014 C. Lacour, 2015	Gelaat en scalp	Allen DL-PDT	Allen cPDT	-	Pooled data studie B+C: voor PP analyse en cPDT DL-PDT resp. -3.69% (95% CI, -6.54 tot -0.84) voor ITT analyse cPDT en DL-PDT resp. -3.40% (95% CI, -6.10 tot -0.70)	AE’s erytheem, crustvorming	-
Zhao, 2018	Studietype: systematische review en meta-analyse Land: China Financiering: geen informatie	8 studies met totale sample size van 424 patiënten A. Rubel, 2014 B. Sotiriou, 2017 C. Lacour, 2015 D. Togsverd-Bo, 2014 E. Fargnoli, 2015 F. Neittaanmaki, 2016 G. Wiegell, 2008 H. Wiegell, 2012	Niet nader toegelicht	Allen DL-PDT	Allen cPDT	Pooled data van 4 studies (B, C, F, H) laten geen significant verschil zien tussen DL-PDT en cPDT (n=244; RR 0.892; 95% CI, 0.818-0.973, p=0.01)	Pooled data van 5 studies (A, B, D, E, H) laten een SMD lesion response zien voor DL-PDT van -0.221 (n=237; 95% CI, -0.395 tot -0.027, p=0.024)	-	Patient tevredenheid pooled data 5 studies (A, B, C, E, G) laat zien dat mensen meer tevreden waren over DL-PDT dan cPDT (n=318; RR 4.001; 95% CI, 2.017-7.938, p <0.001 Patiënt-gerapporteerde pijn pooled data 8 studies (A t/m H) laat zien dat er een lagere pijnscore was voor DL-PDT vs cPDT (n=424; SMD -2.544; 95% CI -3.57 tot -1.632, p<0.001)

Observationele studies - Intra- en extramurale veldbehandelingen Actinische Keratose (2021)

Beoordeling van Risk of Bias voor cohortstudies (Newcastle-Ottawa Scale)

		Selection				Comparability	Outcomes
Studie	Study design	Representativeness of the intervention cohort	Selection of the non intervention cohort	Ascertainment of intervention	Demonstration that outcome of interest was not present at start of study	Comparability of cohorts on the basis of the design or analysis	Assessment of outcome	Was follow up long enough for outcomes to occur	Adequacy of follow up of cohorts	Explanations
Neugebauer, 2018 (5-FU + Imiquimod)	Retrospective cohort study	«	-	-	«	-	-	«	«	Adequate selection of subjects with AK, excluding variate factors Two treatments (5-FU and IMQ) compared. No non-intervention cohort Outcomes were not blinded. No specification on assessment method. Adequate follow-up period of 2 and 5 years.
Van Rijsingen, 2016 (5-FU + IMQ + PDT)	Multicentre, 1 year observational study	«	-	-	«	-	«	«	«	significant baseline selection bias was observed in all groups. Patients were analyzed following ITT analysis Cost-effectiveness correctly calculated Investigator-reported outcome measures.