Efficacy and safety in the use of intraperitoneal hyperthermia chemotherapy and peritoneal cytoreductive surgery for pseudomyxoma peritonei from appendiceal neoplasm: A systematic review

Floriano, Idevaldo; Silvinato, Antônio; Reis, João C.; Cafalli, Claudia; Bernardo, Wanderley Marques

doi:10.1016/j.clinsp.2022.100039

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Review articles • Clinics 77 • 2022 • https://doi.org/10.1016/j.clinsp.2022.100039 copy

Efficacy and safety in the use of intraperitoneal hyperthermia chemotherapy and peritoneal cytoreductive surgery for pseudomyxoma peritonei from appendiceal neoplasm: A systematic review

Authorship SCIMAGO INSTITUTIONS RANKINGS

Highlights

Hyperthermia chemotherapy and cytoreductive surgery in patients with peritoneal pseudomyxoma.

Abstract

The objective of this systematic review is to provide efficacy and safety data in the application of Intra-Abdominal Hyperthermia Chemotherapy (HIPEC) and Cytoreductive Surgery (CRS) in patients with Peritoneal Pseudomyxoma (PMP) of origin in the cecal appendix. The databases Medline and Central Cochrane were consulted. Patients with PMP of origin in the cecal appendix, classified as low grade, high or indeterminate, submitted to HIPEC and CRS. The results were meta-analyzed using the Comprehensive Metanalysis software. Twenty-six studies were selected to support this review. For low-grade PMP outcome, 60-month risk of mortality, Disease-Free Survival (DFS), and adverse events was 28.8% (95% CI 25.9 to 32), 43% (95% CI 36.4 and 49.8), and 46.7% (95% CI 40.7 to 52.8); for high-grade PMP, 60-month risk of mortality, Disease-Free Survival (DFS) and adverse events was 55.9% (95% CI 51.9 to 59.6), 20.1% (95% CI 15.5 to 25.7) and 30% (95% CI 25.2 to 35.3); PMP indeterminate degree, 60-month risk of mortality, Disease-Free Survival (DFS) and adverse events was 32.6% (95% CI 30.5 to 34.7), 61.8% (95% CI 58.8 to 64.7) and 32.9% (95% CI 30.5 to 35.4). The authors conclude that the HIPEC technique and cytoreductive surgery can be applied to selected cases of patients with PMP of peritoneal origin with satisfactory results.

Keywords
Pseudomyxoma peritonei; Intra-abdominal hypertermic chemotherapy; Cecal appendix; Appendiceal; Cytoreductive surgery; HIPEC; CRS; Abdominal carcinomatosis

Study	Reason for exclusion
Austin 2015	Follow-up time 24-months
Auer 2020	Systematic review
Bratt 2017	Follow-up time 15-months
Bartoška 2020	Full article not found
Goslin 2012	Follow-up time 14-months
Hovath 2018	Follow-up time 18-months
Järvinen 2014	Did not apply HIPEC to all patients
Kusamura 2006	Phase II study
Kusamura 2019	Compares HIPEC infusion pressure
Kusamura 2014	Outcome evaluates learning curve
Leigh 2019	Outcome evaluates learning curve
Murphy 2007	Perioperative primary outcome
Mizumoto 2012	Follow-up time 30-days
Narasimhan 2019	Follow-up of 104 and 120-months
Narasimhan 2020	Follow-up time 18-months
Sugarbaker 2006	Intraoperative morbidity and mortality
Tabrizian 2014	Does not meet inclusion criteria
Van 2019	Outcome assesses prognostic factors
Van Leeuwen 2007	Follow-up time 24-months

Study	Design	Patient	Intervention	Comparison	Outcome	Follow-up
Alzahrani 2015	Case series (n = 675)	Patients undergoing CRS+HIPEC with peritoneal carcinomatosis of different origins	CRS+HIPEC (Source-dependent CT).	Index of carcinomatosis	Morbidity and mortality	60 months
Alzahrani 2015	Case series (n = 675)		CRS+HIPEC (Source-dependent CT).	Grading of malignancy	Morbidity and mortality	60 months
Azzam 2017	Case series (n = 38)	Patients with PMP undergoing CRS + HIPEC	CRS+HIPEC (Mitomycin, some CT before or after CRS)	Gender, PCI, SC, surgical time, histological grade, and blood loss.	Disease-free survival, mortality, and complications	Average of 54 months (1‒84)
Brandley 2006	Case series (n = 101)	Patients with PMP of origin in cecal appendix	CRS+HIPEC (mitomycin)	Prognosis in relation to histopathological classification	Mortality	36 and 60 months
Deraco 2006	Case series (n = 75)	Patients with PMP of origin in cecal appendix	CRS + HIPEC (mytomicin + cisplatinun)	Prognostic factors	Morbidity and mortality	Average of 37 months
Elias 2008	Case series (n = 105)	Patients with PMP of origin cecal appendix (88%) and another 12%	CRS+HIPEC (oxaliplatin or oxiplatin + irinotecan and 5 FU + leucovorin pre HIPEC)	PCI, Histopathologic and markers	Morbidity and mortality	Average of 48 months
Elias 2010	Case series (n = 301)	Patients with PMP in appendix (91%) and ovary 7%	CRS+HIPEC (mitomycin and oxaliplatin) and some cases EPIC (fluorouracil for 4 days) intraperitonandal)	Surgical classification, histology, sex, institution and HIPEC	Morbidity and mortality	Average of 88 months
Huang 2016	Case series (n = 250)	Patients with low-grade PMP submitted to CRS + HIPEC	CRS+HIPEC (mitomycin)	EPIC (CT post operation, 5-fluoracil, 2‒6 days)	Disease-free survival, mortality, and complications	60-months
Huang 2017	Case series (n = 185)	Patients with peritoneal adenocarcinoma of cecal appendix	CRS+HIPEC or CRS + HIPEC + EPIC (CT)	HIPEC + EPIC	Disease-free survival, mortality, and complications	60-months
Iversen 2013	Case series (n = 80)	Patients with peritoneal carcinomatosis (Colorectal, mesum and appendix origin) submitted to CRS + HIPEC	CRS + HIPEC (mitomycin or cisplatin)	Types of origin of carcinomatosis	Morbidity and mortality	Average of 26 months
Jimenez 2014	Case series (n = 202)	Patients with peritoneal carcinomatosis of appendix	CRS + HIPEC (does not inform chemotherapy used)	Histological type, PCI, lymph node involvement and surgery classification	Morbidity and mortality	60-months
Lansom 2016	Case series (n = 345)	Patients with pseudomyxoma from cecal appendix	CRS+HIPEC (Mitomycin, se PMCA) (oxaliplatin + folinic acid + 5FU[IV])	Surgical classification	Morbidity and mortality	60-months
Li 2020	Case series (n = 254)	Patients with pseudomyxoma from cecal appendix	CRS+HIPEC (cisplatin and mitomycin or cisplatin and docetaxel)	HIPEC, PCI, transfusion, and intra-operative blood loss	Morbidity and mortality	60-months
López-López 2017	Case series (n = 17)	Patients over 74 years old with PMP undergoing CRS + HIPEC	CRS+HIPEC (Mitomycin (by itself or in combination with Doxorubicin, paclitaxel and oxaliplatin))	Degree of complications, CRS efficacy	Disease-free survival, mortality, and complications	36-months
Lord 2015	Case series (n = 512)	Patients with PMP originating from perforation of mucinous tumor from cecal appendix	CRS+HIPEC (mitomycin)	Patients without recurrence. Patients with recurrence and reoperated. Patients with non-operated recurrence	Morbidity and mortality	60-months
Marcotte 2014	Case series (n = 58)	Patients with appendix carcinomatosis and PMP	CRS+HIPEC (oxaliplatin) + CT for PMCA (5-fluorouracil with irinotecan or oxaliplatin)	Histological types	Morbidity and mortality	Average of 33.7 months
Marcotte 2014	Case series (n = 58)	Patients with appendix carcinomatosis and PMP		Results post-first intervention.	Morbidity and mortality	Average of 33.7 months
Masckauchan 2019	Case series (n = 92)	Peritoneal appendix carcinomatosis	Peritonectomy + HIPEC (Oxiplatin)	Histological type	Morbidity and mortality	Average of 42 months
Munoz Zuluaga 2018	Case series (n = 151)	Patients with peritoneal carcinomatosis of high-grade from appendix origin	CRS + HIPEC (mitomycin)	Histological type (signet and non-signet) and abdominal lymph nodes	Morbidity and mortality	Average of 50 months
Nikiforchin 2020	Case series (n = 121)	Patients with low-grade appendix neoplasms	CRS + HIPEC (mitomycin)	Cellularity in low-grade PMP mucin	Mortality	120 months
Polanco 2016	Case series (n = 97)	Patients with mucinous neoplasms of high-grade cecal appendix and large volume of carcinomatosis	CRS+HIPEC (mitomycin + EPIC)	Volume of disease in high-grade PMP:	Morbidity and mortality	Average of 50.8 months
Polanco 2016	Case series (n = 97)		CRS+HIPEC (mitomycin + EPIC)	High Volume Results (SPCI) ≥ 12 vs. Low Volume (SPCI) < 12	Morbidity and mortality	Average of 50.8 months
Sinukumar 2019	Case series (n = 91)	Peritoneal pseudomyxoma	Peritonectomy + HIPEC (Mitomycin and/or CT (oxaliplatin and 5-FU-based)	Histological types of origin (appendix, ovary, colorectal, mesus)	Morbidity and mortality	36 months
Smeenk 2007	Case series (n = 103)	Patients with peritoneal pseudomyxoma with appendix (92%) and others (11%)	CRS + HIPEC (mitomycin), CT carcinoma (5 FU + leucovorin)	Prognostic factors	Disease-free survival, Morbidity, and mortality	Average of 51 months
Stewart 2006	Case series (n = 110)	Patients with cecal appendix carcinomatosis	CRS + HIPEC (mitomycin)	Prognostic factors	Morbidity and mortality	Average of 34.8 months
Sugarbaker 1999	Case series (n = 385)	Patient with peritoneal tumor dissemination of cecal appendix	CRS + HIPEC (mitomycin), systemic CT (5 FU + leucovorin)	CRS + HIPEC (mitomycin), EPIC (5 FU + leucovorin)	Morbidity and mortality	Average of 37 months
Vaira 2009	Case series (n = 53)	Patients with peritoneal pseudomyxoma	CRS+HIPEC ([mitomycin and cisplatinum] in cases of adeno-carcinomatosis, pre-surgical CT)	Surgical classification, histopathological type, and systemic CT.	Morbidity and mortality	60 months
Virzì 2012	Case series (n=26)	Patients with PMP	CRS + HIPEC (cisplatin + mitomycin)	Histological types	Morbidity and mortality	60 months
Youssef 2011	Case series (n = 456)	Patients with peritoneal pseudomyxoma from appendix cecal origin	CRS+HIPEC (mitomycin and some cases-5-fluorouracil for 4-days intraperitoneal)	Surgical classification	Morbidity and mortality	Average of 32 months

Study	Alzahnani	Azzam	Brandley	Deraco	Elias	Elias	Huang	Huang	Iversen	Jimenez	Lansom J	Li XB	Lopes	Lord	Marcotte E	Masckauchan	Munoz-Zuluaga	Nikiforchin	Poçaco PM	Sinukumar	Smeenk	Stewart	Sugarbaker	Vaira	Virzi	Youssef
Checklist	2015	2017	2006	2006	2008	2010	2016	2017	2013	2014	2016	2020	207	2015	2014	2019	2018	2020	2016	2019	2017	2006	1999	2009	2012	2011
Were there clear criteria for inclusion in the case series?	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y
Was the condition measured in a standard, reliable way for all participants induced in the case series?	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	U	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	U	Y	Y	Y
Were valid methods used for identification of the condition for all participants included in the case series?	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	U	Y	Y	Y
Did the case series have consecutive inclusion of participants?	U	Y	U	U	Y	Y	Y	Y	U	U	U	U	U	N	Y	Y	U	Y	Y	U	Y	U	U	U	U	U
Did the case series have complete inclusion of participants?	Y	U	Y	Y	Y	Y	Y	Y	U	U	Y	U	U	N	Y	Y	U	N	Y	U	U	Y	U	U	Y	U
Was there clear reporting of the demographist of the participants in the study?	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	U	Y	Y	Y	Y	Y	Y	Y	Y	Y	U	Y	N	N	Y	Y
Was there clear reporting of clinical information of the participants?	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	U	Y	N	N	Y	Y
Were the outcomes or follow up results of cases clearly reported?	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y
Was there clear reporting of the presenting site(s)/clink(s) demographic information?	U	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	N	Y	N	Y	N	Y	N	Y	N	N	Y	N
Was statistical analysis appropriate?	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	S	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y

N° of studies	Study design	Risk of bias	Inconsistency	Indirect ness	Imprecision	Other considerations	Risk of event	Quality	Importance
Low-grade PMP. Mortality (follow-up: 36 months average)
3	Observational study	Not serious	Record^a a Heterogeneity of 68.61%	Not serious	Not serious	None	34.4% (95% CI 28.6 to 40.7; I² 2 heterogeneity. Explanations: = 68.61%)	⨁◯◯◯ Very low	Important
Low-grade PMP. Mortality (follow-up: 60 months average)
11	Observational study	Not serious	Very serious^b b Heterogeneity 92.1%	Not serious	Not serious	None	28.8% (95% CI 25.9 to 342; I² 2 heterogeneity. Explanations: = 92.1%)	⨁◯◯◯ Very low	Important
Low-grade PMP. SLD (follow-up: 60 months. average)
4	Observational study	Not serious	Not serious	Not serious	Not serious	None	57% (95% CI 50.2 and 63.6; I² 2 heterogeneity. Explanations: = 25.57%)	⨁⨁◯◯ Low	Important
Low-grade PMP. Adverse events (follow-up: 60 months average)
4	Observational study	Not serious	Very serious^c c Heterogeneity 94.7%	Not serious	Not serious	None	24.2% (95% CI 19.7 to 29.3; I² 2 heterogeneity. Explanations: = 94.7%)	⨁◯◯◯ Very low	Important
Pmp high grade. Mortality (follow-up: 36 months average)
5	Observational study	Not serious	Serious^d d Heterogeneity 89.2%	Not serious	Not serious	None	48.5% (95% CI 43 to 54.1%; I² 2 heterogeneity. Explanations: = 89.2%)	⨁◯◯◯ Very low	Important
Pmp high grade. Mortality (follow-up: mean 60 months)
8	Observational study	Not serious	Grave^e e Heterogeneity 89%	Not serious	Not serious	None	55% (95% CI 51.9 to 59.5; I² 2 heterogeneity. Explanations: = 89%)	⨁◯◯◯ Very low	Important
Pmp high grade. SLD (follow-up: 36 months average)
3	Observational study	Not serious	Very serious^f f Heterogeneity 94.13%	Not serious	Not serious	None	45.6% (95% CI 25.7 to 67; I² 2 heterogeneity. Explanations: = 94.13%)	⨁◯◯◯ Very low	Important
Pmp high grade. SLD (follow-up: 60 months average)
3	Observational study	Not serious	Very serious^g g Heterogeneity 70.84%	Not serious	Not serious	None	20.1% (95% CI 15.5 to 25.7; I² 2 heterogeneity. Explanations: = 70.84%)	⨁◯◯◯ Very low	Important
Pmp high grade. Adverse events (follow-up: 60 months average)
4	Observational study	Not serious	Very serious^h h Heterogeneity 91.8%	Not serious	Not serious	None	33.1% (95% CI 16 to 56.3; I² 2 heterogeneity. Explanations: = 91.8%)	⨁◯◯◯ Very low	Important
PMP without histopathological classification. Mortality (follow-up: 36 months average)
10	Observational study	Not serious	Very seriousⁱ i Heterogeneity 88.91%	Not serious	Not serious	None	28.4% (95% CI 21 to 37.2; I² 2 heterogeneity. Explanations: = 88.91%)	⨁◯◯◯ Very low	Important
PMP without histopathological classification. Mortality (follow-up: 60 months average)
14	Observational study	Not serious	Very serious^j j Heterogeneity 94.45%	Not serious	Not serious	None	29.2% (95% CI 21 to 39.2; I² 2 heterogeneity. Explanations: = 94.45%)	⨁◯◯◯ Very low	Important
PMP without histopathological classification. SLD (follow-up: 36 months average)
5	Observational study	Not serious	Very serious^k k Heterogeneity 94.29%	Not serious	Grave^l I Confidence interval with wide amplitude; greater than two standard deviation	None	35.1% (CI 95% 17 to 58.9; I² 2 heterogeneity. Explanations: = 94.29%)	⨁◯◯◯ Very low	Important
PMP without histopathological classification. SLD (follow-up: 60 months average)
9	Observational study	Not serious	Very serious^m m Heterogeneity 93.51%	Not serious	Not serious	None	56% (95% CI 41.7 to 69.3; I² 2 heterogeneity. Explanations: = 93.51%)	⨁◯◯◯ Very low	Important
PMP without histopathological classification. Adverse events (follow-up: 60 months average)
13	Observational study	Not serious	Very seriousⁿ n Heterogeneidade 93.58%.	Not serious	Not serious	None	35% (95% CI 25.2 to 46.1; I² 2 heterogeneity. Explanations: = 93.58%)	⨁◯◯◯ Very low	Important

Outcomes	Low-grade PMP	High-grade PMP	PMP without histopathological classification
RM 36 months	34.4% (95% CI 28.6 to 40.7; I²= 68.61%)	48.5% (95% CI 43 to 51.1%; I²= 89.2%)	28.4% (95% CI 21 to 37.2; I²= 88.91%)
RM 60 months	28.8% (95% CI 25.9 to 32; I²= 92.1%)	55% (95% CI 52.1 to 59.6; I²= 89.1%)	29.2% (95% CI 21 to 39.2; I²= 94.45%)
SLD 36 months		45.6% (95% CI 25.7 to 67; I²= 94.13%)	35.1% (95% CI 17 to 58.9; I²= 94.29%)
SLD 60 months	57% (95% CI 50.2 to 63.6; I²= 25.57%)	20.1% (95% CI 15.5 to 25.7; I²= 70.84%)	56% (95% CI 41.7 to 69.3; I²= 93.51%)
EAD 60 months	24.2% (95% CI 19.7 to 29.3; I²= 94.7%)	33.1% (95% CI 16 to 56.3; I²= 92.8%)	35% (95% CI 25.2 to 46.1; I²= 93.58%)

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[1] ⁎Corresponding author. E-mail address:idfloriano@hotmail.com (I. Floriano).