Therefore, the aim of the present study was to assess long-term outcomes within the LOLA arm of the international, multicentre, randomised LADIES trial, in which laparoscopic lavage was compared to sigmoidectomy in patients with perforated diverticulitis with purulent peritonitis.
Discussion
In the present long-term follow-up comparing laparoscopic lavage with sigmoidectomy in patients with perforated diverticulitis with purulent peritonitis (LOLA arm of the randomised LADIES trial), it was found that after 36 months overall morbidity and mortality did not differ between both procedures.
However, the number of patients who underwent a reoperation was lower if the patient had been treated with laparoscopic lavage. Additionally, the percentage of patients alive with stoma in situ was lower for those who underwent lavage compared with sigmoidectomy.
In line with these results, the DILALA trial did also show the benefit of lavage in terms of reoperations during a 24 month follow-up period (lavage 18/43 versus resection 27/40,
p = 0.01) [
13]. In addition, the long-term results of the SCANDIV trial did not show a significant difference in the number of reoperations (lavage 26/73 versus resection 24/69, p = 0·92) [
11]. In terms of overall morbidity, no differences between both groups were observed in the SCANDIV long-term outcomes and the present study [
11]. Importantly, in patients alive after 36 months fewer stoma rates were found in the lavage group compared to the sigmoidectomy group, which was confirmed by the long-term DILALA and SCANDIV results [
11,
13]. Although the difference was significant in the present study, this was mainly determent by the fact that in the lavage group the period of time with a stoma was lower as the majority never had a stoma. Eventually, stomas in the sigmoidectomy group were reversed which resulted in comparable rates after 36 months.
As described previously, leaving the affected sigmoid in situ resulted in more short-term complications in the LOLA 12 months follow-up. Although the SCANDIV- and DILALA trial did not find excessive short-term morbidity [
7,
16]. Failure to control sepsis in a patient with perforated diverticulitis might cause these short-term complications, especially since reoperations or percutaneous drainage could be indicated. The superior long-term outcomes of laparoscopic lavage need to be weighed against the potential increased short-term risks. Hence, reduction of short-term morbidity becomes of even greater importance as this might shift this balance. Preoperative characteristics (such as age, ASA grade, comorbidities, and inflammation parameters) might help to select patients that are prone to failure of lavage (e.g. short-term sigmoidectomy). In the present study, no discriminative analyses could be performed due to a lack of power. Moreover, improvement of pre- or perioperative diagnostics is of importance to better discriminate between Hinchey III diverticulitis and Hinchey IV or underlying carcinomas also. To our opinion, this could for example be achieved through the introduction of a CT-scan with rectal contrast in all patients suspected for complicated diverticulitis. Perioperative solutions might include a sigmoidoscopy, hydro-pneumatic testing or introduction of rectal contrast (e.g. methylene blue) to differentiate diverticulitis from perforated cancer and a Hinchey III from IV [
17‐
21].
The present study also focused on reoperations after index procedure with the inclusion of stoma reversals as this directly highlights the difference with sigmoidectomy with stoma construction, subsequent stoma reversal, and potential reversal- or stoma-related morbidity (e.g. parastomal/incisional hernia). Moreover, stoma reversal should not be underestimated in terms of associated risk of morbidity and mortality [
22]. The authors recognise that reoperations in lavage group are unplanned compared to planned reversals in the sigmoidectomy group. However, patients who underwent unplanned elective operations are not by definition more at risk than those undergoing colo/ileostomy reversals. Therefore, the number of emergency operations were considered which was higher in the lavage group. In the lavage group, the majority of these events occurred shortly after index procedure which confirms the short-term risk and the importance of patient selection.
Six of 77 (8%) patients were diagnosed with sigmoid carcinoma. The prevalence of colorectal carcinomas seems to be higher in patients suspected for complicated diverticular disease compared to uncomplicated disease [
23,
24]. Therefore, a colonoscopy (e.g. after at least 6 weeks) after the initial treatment is recommended for all patients with complicated diverticulitis and is even of more importance when treated with lavage [
23‐
25].
It has to be considered that leaving the sigmoid in situ could result in recurrent diverticulitis. In our study, 21% of patients treated with laparoscopic lavage had a recurrent episode within 36 months which included episodes of Hinchey I or II only. Eventually, 50% underwent elective sigmoidectomy with primary anastomosis. Long-term outcomes of the SCANDIV trial found a recurrence rate of 21% [
11]. Retrospective cohort studies following patients treated for perforated diverticulitis with laparoscopic lavage showed recurrence rates up to 30% [
12,
26].
Patients who suffered from ongoing abdominal complaints or recurrent diverticulitis on the long-term underwent an elective sigmoidectomy with primary anastomosis in most cases. This indicates that in selected patients, lavage could also be useful to overcome an emergent operation. If sigmoidectomy is still indicated on the long-term, an elective laparoscopic resection with primary anastomosis is the preferred treatment which preserve patients of stoma construction.
There were limitations to this study. Within the LADIES trial, a LOLA- and DIVA arm was included. Therefore, the sigmoidectomy group consisted of Hartmann’s procedure and sigmoidectomy with primary anastomosis (with or without ileostomy), which could have affected the stoma reversal rate and reoperation rate [
27]. Morbidity and mortality rates were not expected to be affected since no differences were found in previous randomised controlled trials [
27‐
29].
In addition, attrition bias might have been introduced due to General Data Protection Regulations requiring patients to provide approval for retrieval of data from patients records. However, loss to follow-up was relatively low and equally distributed among randomised groups. Therefore, any effects of loss to follow-up are likely not differential.
In conclusion, long-term outcomes showed that laparoscopic lavage was associated with less patients who underwent a reoperation and lower stoma rates in patients alive after 36 months compared to sigmoidectomy. No differences were found in terms of cumulative morbidity or mortality. These long-term benefits need to be weighed against the evidential risk of short-term complications, especially on going sepsis should be avoided as this could be a potentially fatal condition. These short-term complications could be further reduced by the optimisation of patient selection, pre-, and perioperative diagnostics. To define the optimal treatment, patients should be involved in the decision-making process after being informed about short- and long-term consequences regarding lavage. In that context, lavage could be valuable as treatment for perforated purulent diverticulitis.
Acknowledgements
If requested, deidentified data collected for the LADIES trial, the study protocol, and informed consent form can be made available. Please contact WAB (w.a.bemelman@amsterdamumc.nl) or JF (j.lange@erasmusmc.nl), who will review all requests with the members of the Dutch Diverticular Disease (3D) Collaborative Study Group and the LADIES trial investigators. Requests should fulfil the following access criteria: research can only be conducted in collaboration with and after approval of the members of the 3D Collaborative Study Group and the LADIES trial investigators, and with a signed data access and sharing agreement. The members of the 3D Collaborative Study Group and the LADIES trial investigators must approve all research done with the shared data.
The study was preregistered without an analysis plan, which can be assessed at ClinicalTrials.gov (NCT01317485). No preregistration exists for the reported second and third year data.
The LADIES trial collaborators: W C Hop, B C Opmeer, J B Reitsma, R A Scholte, E W H Waltmann, A Legemate,, J F Bartelsman, D W Meijer, M de Brouwer, J van Dalen, M Durbridge, M Geerdink, G J Ilbrink, S Mehmedovic, P Middelhoek, M J Boom (Department of Surgery, Flevo Hospital, Almere); E C J Consten, J D W van der Bilt, G D J van Olden, M A W Stam, M S Verweij (Department of Surgery, Meander Medical Centre, Amersfoort); Sandra Vennix, Gijsbert D Musters, Hilko A Swank, Marja A Boermeester, O R C Busch, C J Buskens, Y El-Massoudi, A B Kluit, C C van Rossem, M P Schijven, P J Tanis, C Unlu (Department of Surgery, Amsterdam University Medical Centre, University of Amsterdam, The Netherlands); Susan van Dieren (Clinical Research Unit, Amsterdam University Medical Centre, University of Amsterdam, The Netherlands); M F Gerhards, T M Karsten, L C de Nes, H Rijna (Department of Surgery, Onze Lieve Vrouwe Hospital, Amsterdam); B A van Wagensveld, G I Koff eman, E P Steller, J B Tuynman, (Department of Surgery, St Lucas Andreas Hospital, Amsterdam); S C Bruin (Department of Surgery, Slotervaart Hospital, Amsterdam); D L van der Peet (Department of surgery, VU Medical Center, Amsterdam); C F J M Blanken-Peeters (Department of Surgery, Rijnstate Hospital, Arnhem); H A Cense, E Jutte (Department of Surgery, Rode Kruis Hospital, Beverwijk); R M P H Crolla, G P van der Schelling, M van Zeeland (Department of Surgery, Amphia Hospital, Breda); E J R de Graaf, R P R Groenendijk (Department of Surgery, IJsselland Hospital, Capelle a/d IJssel); T M Karsten, M Vermaas, O Schouten, M R de Vries (Department of Surgery, Reinier de Graaf Hospital, Delft); H A Prins, D J Lips (Department of Surgery, Jeroen Bosch Hospital, Den Bosch); R J I Bosker (Department of Surgery, Deventer Hospital, Deventer); J A B van der Hoeven, J Diks, P W Plaisier (Department of Surgery, Albert Schweitzer Hospital, Dordrecht); P M Kruyt, C Sietses, M W J Stommel (Department of Surgery, Gelderse Vallei Hospital, Ede); S W Nienhuijs, I H J T de Hingh, M D P Luyer, G van Montfort, E H Ponten, J F Smulders (Department of Surgery, Catharina Hospital, Eindhoven); E B van Duyn, J M Klaase (Department of Surgery, Medical Spectrum Twente, Enschede); D J Swank, R T Ottow (Department of Surgery, Groene Hart Hospital, Gouda); H B A C Stockmann, J Vermeulen, R J C L M Vuylsteke (Department of Surgery, Kennemer Hospital, Haarlem); H J Belgers, S Fransen, E M von Meijenfeldt, M N Sosef (Department of Surgery, Atrium Medical Centre, Heerlen); A A W van Geloven, E R Hendriks, B ter Horst, M M N Leeuwenburgh, O van Ruler, J M Vogten, E J C Vriens, M Westerterp (Department of Surgery, Tergooi Hospital, Hilversum); Q A J Eijsbouts, A Bentohami, T S Bijlsma, N de Korte, D Nio (Department of Surgery, Spaarne Hospital, Hoofddorp); M J P M Govaert, J J A Joosten (Department of Surgery, Westfries Hospital, Hoorn); R A E M Tollenaar (Department of surgery, LUMC, Leiden); L P S Stassen (Department of Surgery, Maastricht University Medical Centre, Maastricht); M J Wiezer, E J Hazebroek, A B Smits, H L van Westreenen (Department of Surgery, St Antonius Hospital, Nieuwegein); J F Lange, A Brandt, W N Nijboer, Irene M Mulder (Department of Surgery, Erasmus Medical Centre University Hospital, Rotterdam); B R Toorenvliet, W F Weidema (Department of Surgery, Ikazia Hospital, Rotterdam); P P L O Coene (Department of Surgery, Maasstad Hospital, Rotterdam); G H H Mannaerts, D den Hartog, R J de Vos, J F Zengerink (Department of Surgery, St Franciscus Hospital, Rotterdam); A G M Hoofwijk, K W E Hulsewé, J Melenhorst, J H M B Stoot (Department of Surgery, Orbis Medical Centre, Sittard); W H Steup, P J Huijstee, J W S Merkus, J J Wever (Department of Surgery, Haga Hospital, The Hague); J K Maring, J Heisterkamp (Department of Surgery, Twee Steden Hospital, Tilburg); W M U van Grevenstein, M R Vriens, M G H Besselink, I H M Borel Rinkes, A J Witkamp (Department of Surgery, University Medical Centre, Utrecht); G D Slooter (Department of Surgery, Maxima Medical Centre, Veldhoven); J L M Konsten (Department of Surgery, VieCuri Hospital, Venlo); A F Engel (Department of Surgery, Zaans Medical Centre, Zaandam); E G J M Pierik, T G Frakking, D van Geldere, G A Patijn (Department of Surgery, Isala Hospital, Zwolle); Belgium A J L D’Hoore, A de Buck van Overstraeten, M Miserez, I Terrasson, A Wolthuis (Department of Surgery, University Hospital, Leuven); Italy S Di Saverio, M G De Blasiis (Department of Surgery, Hospital Maggiore, Bologna).
WC Hop, BC Opmeer, JB Reitsma, RA Scholte, EWH Waltmann, A Legemate,, JF Bartelsman, DW Meijer, M de Brouwer, J van Dalen, M Durbridge, M Geerdink, GJ Ilbrink, S Mehmedovic, P Middelhoek, MJ Boom, ECJ Consten, JDW van der Bilt, GDJ van Olden, MAW Stam, MS Verweij, Sandra Vennix, Gijsbert D Musters, Hilko A Swank, Marja A Boermeester, ORC Busch, CJ Buskens, Y El-Massoudi, AB Kluit, CC van Rossem, MP Schijven, PJ Tanis, C Unlu, Susan van Dieren, MF Gerhards, TM Karsten, LC de Nes, H Rijna, BA van Wagensveld, G I Koff eman, EP Steller, JB Tuynman, SC Bruin, DL van der Peet, CFJM Blanken-Peeters, HA Cense, E Jutte, RMPH Crolla, GP van der Schelling, M van Zeeland, EJR de Graaf, RPR Groenendijk, TM Karsten, M Vermaas, O Schouten, MR de Vries, HA Prins, DJ Lips, RJI Bosker, J A B van der Hoeven, J Diks, PW Plaisier, PM Kruyt, C Sietses, MWJ Stommel, SW Nienhuijs, IHJT de Hingh, MDP Luyer, G van Montfort, EH Ponten, JF Smulders, EB van Duyn, JM Klaase, DJ Swank, RT Ottow, HBAC Stockmann, J Vermeulen, RJCL M Vuylsteke, HJ Belgers, S Fransen, EM von Meijenfeldt, MN Sosef, AAW van Geloven, ER Hendriks, B ter Horst, MMN Leeuwenburgh, O van Ruler, JM Vogten, EJC Vriens, M Westerterp, QAJ Eijsbouts, A Bentohami, TS Bijlsma, N de Korte, D Nio, MJPM Govaert, J JA Joosten, RAEM Tollenaar, L P S Stassen, M J Wiezer, EJ Hazebroek, AB Smits, HL van Westreenen, JF Lange, A Brandt, WN Nijboer, Irene M Mulder, BR Toorenvliet, WF Weidema, PPLO Coene, GHH Mannaerts, D den Hartog, RJ de Vos, JF Zengerink, AGM Hoofwijk, K W E Hulsewé, J Melenhorst, JHMB Stoot, WH Steup, PJ Huijstee, JWS Merkus, JJ Wever, JK Maring, J Heisterkamp, WMU van Grevenstein, MR Vriens, MGH Besselink, IHM Borel Rinkes, AJ Witkamp, GD Slooter, JLM Konsten, AF Engel, EGJM Pierik, TG Frakking, D van Geldere, GA Patijn, BelgiumAJL D’Hoore, A de Buck van Overstraeten, M Miserez, I Terrasson, A Wolthuis, S di Saverio, MG de Blasiis