Colorectal peritoneal metastases: Optimal management review

Table 1 Risk factors for metachronous peritoneal metastases

Risk factors for metachronous peritoneal metastases
Advanced T stage
Lymph node metastases
Synchronous ovarian metastases
Poor differentiation
Colon origin (versus rectal origin)
Uncomplete primary tumor resection
Mucinous adenocarcinoma
Signet ring histology
Emergency surgery at diagnosis
Young age

Table 2 Patient and operative factors associated with cytoreductive and hyperthermic intraperitoneal chemotherapy morbidity (modified from Newton et al[70])

Patients characteristics	Operative factors
Age > 60-70 yr	Pancreatic resections
Performance status	Bowel resection and anastomosis
Hypoalbuminemia	Surgeon experience
	Peritoneal carcinomatosis index

Table 3 Survival of patients with peritoneal metastases from colorectal cancer treated by cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy

Author/ Years/ Country	1-yr SR (%)	3-yr SR (%)	5-yr SR (%)	Mortality rate (%)	Morbidity rate (%)	Median OS (mo)	OS 95%CI (mo)	PFS 95%CI (mo)	DFS/RFS 95%CI (mo)	Follow-up times (range) (mo)
Controlled studies
Franko/2010/America[109]	92	51	28	NR	NR	34.7	NR	NR	NR	NR
Gervais/2013/Canada[110]	92	61	36	4	20	54	NR	NR	8	22.8 (2-81)
Goéré/2015/France[111]	90	52	32	5.8	29.5	35	NR	NR	NR	60 (47-74)
Huang/2014/China[112]	63.6	16	NR	0	28.6	13.7	10.0-16.5	NR	NR	41.5 (11.5-70.9)
HIPEC single arm studies
Cao/2009/Australia[113]	83.6	51.4	32.1	NR	NR	37.0	1-72	NR	NR	19 (1-72)
Ceelen/2014/Belgium[61]	75 (NNT) 75 (NCA) 96 (NCB)	39 (NNT) 30 (NCA) 71 (NCB)	25 (NNT) 13 (NCA)	NR	NR	25 (NNT) 22 (NCA) 39 (NCB) 30 (AC) 22 NAC)	19.1-30.9 (NNT) 12.9-31.1 (NCA) 17.6-60.4 (NCB) 20.7-39.3 (AC) 14.2-29.8 (NAC)	NR	NR	18
Elias/2014/France[53]	91.4	54	36.5	4.2	17	41	NR	NR	NR	62.4 (55.6-77.6)
Frøysnes/2016/Norway[114]	93	65	36	0	15.5	47	42-52	NR	10 (7-12)	45 (35-55)
Hamilton/2011/Canada[115]	79	38	34	NR	NR	27	0-87	NR	9 (0-87) 3-yr 34% 5-yr 26%	28 (0-119) (all)
Hompes/2012/Belgium[116]	97.9	84	NA	0	52.1	NA	NA	NR	19.8 (RFS)	22.7 (3.2- 55.7)
Passot/2016/France[117]	83	51	31	NR	30	36	NR	NR	11	NR
Prada-Villaverde/2014/Spain[118]	85	45	35	NR	NR	31.4	NR	NR	NR	NR
Quenet/2011/France[119]	92	36	44	4.1	47.2	41	32-60	NR	10.9 3-yr 15%	30.3 (2-88)

Adapted from Huang et al[112]. SR: Survival rate; OS: Overall survival; PFS: Progression-free survival; RFS: Recurrence-free survival; DFS: Disease-free survival; NA: Not achieved; NR: Not reported; NNT: Non-neoadjuvant therapy; NCA: Neoadjuvant chemotherapy alone; NCB: Neoadjuvant chemotherapy + bevacizumab; AC: Adjuvant chemotherapy; NAC: Non-adjuvant chemotherapy; CI: Confidence interval.

Table 4 Studies on the ClinicalTrials.gov registry investigating the role of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy on high risk patients for preventing peritoneal metastases from colorectal origin

ClinicalTrials.gov ID	Phase	High risk criteria	Control vs Treatment arms
NCT01226394 ProphyloCHIP trial	Phase III	Complete resection of minimal abdominal synchronous metastases or perforated tumors	Surveillance vs second-look laparotomy with HIPEC (intraperitoneal oxaliplatin and intravenous 5-FU) after primary resection
NCT02231086 COLOPEC trial	Phase III	T4, N0-2M0 or perforated colon cancer	Adjuvant systemic therapy only vs adjuvant systemic therapy + HIPEC, without resection of target organs
NCT02974556 PROMENADE trial	Phase III	T3-T4 tumors	Resection of target organs for peritoneal implants, plus HIPEC with oxaliplatin and concomitant i.v., 5-fluorouracil/leucovorin
NCT02179489	Phase III	T4M0 and complete resection of minimal abdominal synchronous metastases or perforated tumors	Surgery vs surgery and HIPEC with mitomycin C (without preventive excision of target organs)
NCT02965248 APEC trial	Phase II	T4NanyM0 and T3-NanyM0 + mucinous or signet ring cells histology	Adjuvant systemic chemotherapy alone (arm A) vs systemic chemo + HIPEC with raltitrexed (arm B) or oxaliplatin (arm C)
NCT02614534 HIPEC T4	Phase III	Complete resection of T4a, bNanyM0	Surgery vs prophylactic HIPEC with mitomycin plus target organs excision
NCT03413254 COLOPEC-II	Phase III	Complete resection of T4a, bN0-2M0	Routine follow-up (arm A) vs a second exploratory laparoscopy (arm B) and third exploratory laparoscopy (arm C) if the work-up is negative
NCT02974556	Phase III	Complete resection of T3-4NanyM0	Systemic chemotherapy alone vs CRS/HIPEC with oxaliplatin and systemic therapy
NCT02758951	Phase II/III	Complete resection of colorectal tumors with ≤ 50% of signet ring cells.	Upfront CRS-HIPEC alone vs pre/post perioperative systemic chemotherapy and CRS-HIPEC
NCT02830139	Phase II	Complete resection of T3-4NanyM0	CRS + systemic chemotherapy vs CRS + HIPEC with paclitaxel + 5-FU + postoperative chemotherapy

CRS: Complete cytoreductive surgery; HIPEC: Hyperthermic intraperitoneal chemotherapy.

Table 5 Studies on the ClinicalTrials.gov registry investigating the role of pressurized intraperitoneal aerosol chemotherapy

Number Clinical Trial	Experimental therapy	Malignant origin	Cytotoxic drugs	Primary outcomes
NCT03280511 The PIPAC-OPC3 CC Trial	Exploratory Laparoscopy + biopsies + 1st PIPAC 2 mo after radical primary resection+/-adyuvant chemo + 2nd PIPAC 5 wk later	High risk colorectal cancer patients	Oxaliplatin (92 mg/m²)	Peritoneal recurrence
NCT03246321 CRC-PIPAC	ePIPAC + leuvocorin + 5-FU iv	Colorectal / appendiceal carcinomas	Oxaliplatin (92 mg/m²)	Major toxicity
NCT03210298	PIPAC/PITAC	Peritoneal metastasis of various origins	Depends on tumor origin	Overall survival
NCT02604784 PI-CaP	PIPAC fixed repeated dose vs PIPAC increasing single dose	Gastric, colorectal and ovarian cancers or primary peritoneal tumors	Cisplatin + doxorubicin or oxaliplatin (92 mg/m²)	Overall response rate

PIPAC: Pressurized intraperitoneal aerosol chemotherapy; ePIPAC: Electrostatic pressurised intraperitoneal aerosol chemotherapy.