Int J Clin Oncol (2013) 18:439–446 DOI 10.1007/s10147-012-0397-5
ORIGINAL ARTICLE
Comparative analysis of perioperative intraperitoneal chemotherapy regimen in appendiceal and colorectal peritoneal carcinomatosis Terence C. Chua • Winston Liauw Jing Zhao • David L. Morris
•
Received: 12 September 2011 / Accepted: 21 February 2012 / Published online: 14 March 2012 Ó Japan Society of Clinical Oncology 2012
Abstract Background Perioperative intraperitoneal chemotherapy (PIC) is delivered by intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) and early postoperative intraperitoneal chemotherapy (EPIC). The relative survival benefits of each or both regimens are explored in this large series of patients undergoing cytoreduction at a single institution. Methods Patients with a complete (CCR0) or optimal (CCR1) cytoreduction who received intraperitoneal chemotherapy for appendiceal and colorectal peritoneal carcinomatosis were included for analysis. PIC regimens were delivered according to the treatment protocol. Standardized statistical analyses were performed. Results Of 262 patients, 98 patients (37%) had colorectal peritoneal carcinomatosis, 108 patients (41%) had lowgrade pseudomyxoma peritonei and 56 patients (21%) had appendiceal peritoneal carcinomatosis. For pseudomyxoma peritonei, recurrence-free survival (RFS) did not vary with PIC regimen, 5-year survival was 86% in the HIPEC and EPIC group and 64% in the HIPEC or EPIC group (P = 0.070). For appendiceal peritoneal carcinomatosis, RFS and overall survival (OS) did not vary with PIC regimen. For colorectal peritoneal carcinomatosis, the median RFS was 33 months in the HIPEC and EPIC group,
T. C. Chua J. Zhao D. L. Morris (&) Hepatobiliary and Surgical Oncology Unit, Department of Surgery, St George Hospital, University of New South Wales, Level 3 Pitney Building, Gray Street, Kogarah, Sydney, NSW 2217, Australia e-mail:
[email protected] W. Liauw Department of Medical Oncology, Cancer Care Centre, St George Hospital, Kogarah, Sydney, NSW 2217, Australia
19 months in the HIPEC alone group and 20 months in the EPIC alone group (P = 0.046). OS did not vary with PIC regimen. Conclusion From our experience, without compromising the perioperative morbidity and mortality, PIC consisting of HIPEC and EPIC appears to be associated with potential survival benefits of improved OS in pseudomyxoma peritonei and RFS in colorectal peritoneal carcinomatosis. Keywords Colorectal cancer Appendiceal cancer Intraperitoneal chemotherapy
Introduction The locoregional patterns of spread of gastrointestinal and gynecological malignancies within the peritoneal cavity are some of the most difficult problems in oncology. This disease manifestation is only partially sensitive to radiotherapy or chemotherapy. As part of a multimodality approach, surgery by cytoreduction combined with intraperitoneal chemotherapy provides an integrated regional management for this disease that is likely to be more effective than a single modality treatment [1]. Cytoreductive surgery (CRS) allows removal en masse of tumor nodules within the disease peritoneal cavity and allows regional intraperitoneal chemotherapy to eradicate microscopic residual disease. This strategy allows for high regional concentration of chemotherapy without exposing the systemic circulation to drug toxicity [2]. The delivery of intraperitoneal chemotherapy for peritoneal surface malignancies has been continuously refined. It may be delivered using either an open-coliseum or a closed-abdomen approach [3]. Its delivery may also be augmented using hyperthermia. Experimental and clinical
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data have shown that at a temperature of 41–43°C, there is enhanced cytotoxic destruction [4] and potential synergistic effects on the efficacy of cytotoxic drugs [5]. Further, there is also variability in the perioperative intraperitoneal chemotherapy regimen by which regional chemotherapy may be delivered in combination with cytoreduction. The most common approaches today include hyperthermic intraperitoneal chemotherapy (HIPEC) and normothermic intraperitoneal chemotherapy that may be delivered early in the postoperative period (EPIC) or as an outpatient schedule as adjuvant intraperitoneal chemotherapy. A dual modal approach of HIPEC and EPIC is often referred to as perioperative intraperitoneal chemotherapy (PIC). As reported by Gonzales-Moreno et al. [6], there is now a variety of intraperitoneal chemotherapy regimens employed in the management of peritoneal carcinomatosis, including HIPEC alone or HIPEC with EPIC. In this retrospective analysis, we report our experience of PIC regimens and their influence on survival after cytoreduction for appendiceal and colorectal peritoneal carcinomatosis, to identify the relative benefits of each intraperitoneal chemotherapy regimen.
Methods Patient selection Between January 1996 and January 2011, a total of 287 consecutive patients with peritoneal carcinomatosis from appendiceal or colorectal cancer underwent CRS and PIC. All patients were followed prospectively and included in a prospective electronic database. No patients were lost to follow-up. Patients were [18 and B80 years old, with good performance status (World Health Organization Performance Status B2) and had a confirmed histological diagnosis. A signed informed consent was obtained from every patient. The exclusion criteria for this study included the presence of extraabdominal metastasis, re-operative procedures and patients who had incomplete cytoreduction (CCR2/3). Curative intent regional surgery A standardized treatment protocol based on a curative intent treatment combining CRS and intraperitoneal chemotherapy was performed by the same surgical team. An initial assessment of the volume and extent of disease was recorded using the Peritoneal Cancer Index (PCI) at laparotomy [7]. Surgery was then conducted to remove all visible intraperitoneal and visceral tumour deposits. CRS was performed using Sugarbaker’s techniques [8]. After surgery, residual disease was scored prospectively using the completeness of cytoreduction (CCR) score [7]. CCR0
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indicates that no macroscopic residual cancer remained; CCR1, that no nodule [2.5 mm in diameter remained; CCR2, that nodules between 2.5 mm and 2.5 cm in diameter remained; and CCR3, that nodules [2.5 cm in diameter remained. Intraperitoneal chemotherapy regimen All patients were treated with an intention to deliver both HIPEC and EPIC as a PIC regimen. However, in circumstances where high-risk surgical procedures were performed and there was a reasonable risk of complications, leakage of intraperitoneal chemotherapy, major organ impairment, inability to tolerate intraperitoneal pressures with compromise of urine output and in patients with haemodynamic instability, EPIC was withheld. In the last 6 years, these policies on EPIC dose reduction for patients with high risk of perioperative mortality and morbidity have been implemented. A dose reduction was also permitted by omitting 1–4 days of EPIC for the following clinical situations: suboptimal preoperative condition, extensive prior treatment, duration of surgery more than 12 h, and unprotected bowel anastomoses. In patients treated without the availability of HIPEC due to resource limitation, EPIC was delivered as the sole intraperitoneal chemotherapy regimen. In summary, there are three potential groups of patients within the treatment cohort: HIPEC and EPIC, HIPEC alone, and EPIC alone. HIPEC was performed by instillation of a heated chemoperfusate into the abdomen using the coliseum technique at approximately 42°C for 90 min. The chemoperfusate was made up of the cytotoxic drug diluted in 3 L of 1.5% dextrose peritoneal dialysis. For gastrointestinal malignancies, mitomycin C (10–12.5 mg/m2) or oxaliplatin (460 mg/m2) was used. In patients receiving oxaliplatin HIPEC, an intravenous perfusion of 5-fluorouracil (400 mg/m2) with leucovorin (20 mg/m2) was administered 30 min prior to commencing HIPEC [9]. EPIC was delivered via a subcutaneous implanted abdominal peritoneal port. EPIC was made up of 5-fluorouracil (650–800 mg/m2 per day) in 1 L of 1.5% dextrose peritoneal dialysis solution. This was administered in either the intensive care unit or the high dependency unit. The intraperitoneal chemotherapy was allowed to dwell for 23 h before it was removed by closed suction drains over the course of 1 h. The next instillation was commenced once the abdomen was cleared of fluid as completely as possible. This was performed for 5 days. Statistical analysis Relevant clinical data were retrieved from the peritoneal surface malignancy database for patients with low-grade
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pseudomyxoma, appendiceal (non-mucinous and highgrade mucinous histology) cancer and colorectal cancer. The patients were categorized by diagnosis and intraperitoneal chemotherapy regimen. Postoperative complications were graded I–V with increasing severity based on the National Cancer Institute’s Common Toxicity Criteria. All patients were followed prospectively at monthly intervals for the first 3 months and at 6-monthly intervals thereafter. Survival was calculated from the date of CRS to last follow-up or death. Categorical variables were compared using v2 analysis or Fisher’s exact test where appropriate. Normally distributed variables were compared using the t test or one-way ANOVA as appropriate. Survival analysis was performed using the Kaplan–Meier method. All statistical analyses were performed using SPSSÒ for Windows version 16.0 (SPSS, Munich, Germany). P \ 0.05 was considered significant.
Results During the study period, 287 patients underwent treatment. Cytoreduction was suboptimal (CCR2/3) in 16 patients (6%) and nine patients (3%) did not receive intraperitoneal chemotherapy. These 25 patients were excluded from further analysis. The final study cohort consisted of 262 patients: 158 females (60%) and 103 males (40%) with a median age of 56 (range 18–83) years. There were 98 patients (37%) with colorectal peritoneal carcinomatosis; 45 patients (46%) received HIPEC and EPIC, 30 patients (31%) received HIPEC and 23 patients (23%) received EPIC. There were 108 patients (41%) with low-grade pseudomyxoma peritonei; 87 patients (81%) received HIPEC and EPIC, 15 patients (14%) received HIPEC and six patients (5%) received EPIC. There were 56 patients (21%) with appendiceal peritoneal carcinomatosis; 37 patients (66%) received HIPEC and EPIC, 11 patients (20%) received HIPEC and 8 patients (14%) received EPIC. Four patients (1.5%) died as a result of treatment-related mortality and were excluded from survival analyses. Table 1 demonstrates the group characteristics of patients according to diagnosis and intraperitoneal chemotherapy regimen. Owing to the number of patients receiving each intraperitoneal chemotherapy type, patients with pseudomyxoma peritonei and appendiceal peritoneal carcinomatosis were dichotomized into a HIPEC and EPIC group (n = 87 and n = 37) and a HIPEC or EPIC group (n = 21 and n = 19), respectively. There were no differences in baseline clinical and treatment-related characteristics between groups in both these diagnoses. For patients with colorectal peritoneal carcinomatosis, patients were trichotomized into a HIPEC and EPIC group (n = 45), a HIPEC group (n = 30) and an EPIC group (n = 23).
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Baseline clinical and treatment-related characteristics were similar, apart from more patients with mucinous tumors in the HIPEC and EPIC group (P = 0.046) and a longer duration of operation in patients in the HIPEC and EPIC group and HIPEC group (P \ 0.001). Comparison of morbidity and mortality There were 4 patients (1.5%) who died within 30 days of surgery. One patient suffered a perioperative cardiac arrest and the remaining three patients developed intra-abdominal sepsis that required reoperations. As shown in Table 2, per PIC regimen, there was no difference in incidence of major complications (grade III/IV/V) between the types of intraperitoneal regimens. When the cohort of 262 patients was compared by HIPEC and EPIC group (n = 169) and HIPEC or EPIC group (n = 93), the following charted complications were identified from the database: there were higher rates of pleural effusion (P = 0.030), intra-abdominal collection (P = 0.036) and pneumothorax (P \ 0.001) observed in the HIPEC and EPIC treatment group. There were higher rates of bleeding (P = 0.005) and reoperation (P = 0.019) in the HIPEC or EPIC alone treatment group. Survival analysis for pseudomyxoma peritonei The median follow-up time for patients with pseudomyxoma peritonei was 36 (range 2–170) months. For patients receiving HIPEC and EPIC, the median follow-up time was 35 (range 2–111) months and for patients receive HIPEC or EPIC alone, the median follow-up time was 42 (range 2–170) months. The median recurrence-free survival was 72 [95% confidence interval (CI) 68.0–76.6] months for the HIPEC and EPIC group and 97 (95% CI 30.5–164.4) months in the HIPEC or EPIC group (P = 0.389). The median overall survival was not reached in the HIPEC and EPIC group and was 97 (95% CI 10.1–184.8) months in the HIPEC or EPIC group. The 5-year survival was 86% in the HIPEC and EPIC group and 64% in the HIPEC or EPIC group (P = 0.070) (Fig. 1). Survival analysis for appendiceal peritoneal carcinomatosis The median follow-up time for patients with appendiceal peritoneal carcinomatosis was 25 (range 3–132) months. For patients receiving HIPEC and EPIC, the median follow-up time was 26 (range 3–109) months and for patients receive HIPEC or EPIC alone, the median follow-up time was 20 (range 2–170) months. The median recurrence-free survival was 44 (95% CI 24.3–64.3) months for the HIPEC and EPIC group and 35 (95% CI 0.0–78.8) months in the HIPEC or EPIC group (P = 0.303). The median overall
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Table 1 Clinical characteristics of patients with pseudomyxoma peritonei, appendiceal peritoneal carcinomatosis and colorectal peritoneal carcinomatosis treated by perioperative intraperitoneal chemotherapy Pseudomyxoma peritonei
Appendiceal PC
Colorectal PC
HIPEC ? EPIC
HIPEC/ EPIC
P value
HIPEC ? EPIC
HIPEC/ EPIC
P value
HIPEC ? EPIC
HIPEC
EPIC
Number of patients (n)
87
21
–
37
19
–
45
30
23
Age (years) [mean (SD)]
53 (11)
55 (13)
0.418
52 (11)
57 (11)
0.119
54 (14)
59 (11)
60 (15)
Sex
0.804
1.000
33
12
16
8
16
10
12
Female
54
9
21
11
29
20
11
Well/mod differentiated
–
–
29
12
34
28
21
Poor differentiated
–
–
8
7
11
2
2
Yes
–
–
16
7
21
9
4
No
–
–
21
12
24
21
19
–
Mucinous histology
0.339
–
Duration from initial diagnosis
0.046
0.244
0.549
B12 months
52
9
26
10
21
11
9
[12 months
35
12
11
9
24
19
15
24 (8)
22 (10)
22 (9)
19 (11)
11 (7)
11 (9)
8 (5)
Peritoneal Cancer Index (PCI) Completeness of cytoreduction (CCR) CCR0 CCR1
0.508 0.183
0.265 0.703
17 2
–
37
5
–
0
6
0.363 0.429
64 23
12 9
Mitomycin C
87
13
Oxaliplatin
0
2
Duration of surgery (h)
10 (3)
10 (5)
0.551
10 (3)
10 (3)
0.415
8 (2)
9 (3)
4 (1)
\0.001
Duration of ICU stay (days)
5 (10)
9 (17)
0.352
5 (8)
8 (12)
0.404
4 (7)
4 (6)
2 (1)
0.409
Duration of hospital stay (days) Major complications (grade III/IV/V)
32 (23)
35 (34)
0.666
36 (28)
50 (66)
0.393
30 (33)
22 (15)
23 (11)
0.361
Type of HIPEC
30 7
0.100
0.067
0.777
0.220
– 0.315
Male Tumor grade
P value
–
44 1
29 1
21 2
–
45
18
–
–
–
0
12
–
–
–
0.809
–
0.578
0.430
Yes
38
10
20
12
16
13
6
No
49
11
17
7
29
17
17
PC peritoneal carcinomatosis, SD standard deviation, ICU intensive care unit
survival was 56 (95% CI 39.1–73.6) months in the HIPEC and EPIC group and 104 (95% CI 17.4–190.5) months in the HIPEC or EPIC group. The 5-year survival was 23% in the HIPEC and EPIC group and 54% in the HIPEC or EPIC group (P = 0.515). Survival analysis for colorectal peritoneal carcinomatosis The median follow-up time for patients with colorectal peritoneal carcinomatosis was 18 (range 3–102) months.
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The median follow-up time was 22 (range 5–88) months for the HIPEC and EPIC group, 12 (range 4–48) months in the HIPEC alone group and 18 (range 3–102) months in the EPIC alone group. The median recurrence-free survival was 33 (95% CI 22.4–43.8) months for the HIPEC and EPIC group, 19 (95% CI 13.8–24.3) months for the HIPEC alone group, and 20 (95% CI 15.9–24.1) months in the EPIC alone group (P = 0.046) (Fig. 2). Between groups, the recurrence-free survival was significantly different when the HIPEC and EPIC group was compared to the HIPEC alone group (P = 0.012) and there was a trend to
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Table 2 Specific complication profile between intraperitoneal chemotherapy regimens Complication
Perioperative intraperitoneal chemotherapy regimen
P value
HIPEC and EPIC (%)
HIPEC or EPIC (%)
Major morbidity (grade III/IV/V)
44
44
1.00
Sepsis
15
12
0.465
Reoperation
11
23
0.019
Pulmonary embolus
3
4
0.725
Infection
38
39
0.895
Bleeding Cardiac
4 8
14 7
0.005 0.807
Pneumonia
5
8
0.591
Pleural effusion
40
26
0.030
Fistula
13
14
0.851
Perforation
3
4
0.725
Disseminated intravascular coagulation
0
1
0.355
Collection Renal impairment
46 0
33 1
0.036 0.355
Pneumothorax
21
4
\0.001
Pancreatic leak
7
8
1.000
Fig. 2 Recurrence-free survival analysis of patients with colorectal peritoneal carcinomatosis stratified according to receiving HIPEC and EPIC, HIPEC alone or EPIC alone
CI not reached) months in the HIPEC alone group and 28 (95% CI 16.2–39.4) months in the EPIC alone group. The 5-year survival was 41% in the HIPEC and EPIC group, 46% in the HIPEC alone group and 44% in the EPIC alone group (P = 0.380). Between groups, there was no difference in median overall survival.
Discussion
Fig. 1 Survival analysis of patients with pseudomyxoma peritonei stratified according to receiving HIPEC and EPIC compared to HIPEC or EPIC alone
statistical significance in the difference between the HIPEC and EPIC group compared to the EPIC alone group (P = 0.084). There was no difference in recurrence-free survival between the HIPEC alone or EPIC alone group (P = 0.658). The median overall survival was 38 (95% CI 21.1–54.9) months in the HIPEC and EPIC group, 19 (95%
The role of intraperitoneal chemotherapy for managing peritoneal-based cancers is increasingly accepted owing to the body of data available in the literature that demonstrate encouraging survival rates. In colorectal peritoneal carcinomatosis, a meta-analysis concluded that there were significant improvements in survival associated with CRS combined with HIPEC over surgery and systemic chemotherapy (P \ 0.0001), but not for CRS combined with EPIC over surgery and systemic chemotherapy (P = 0.35), with an overall effect of PIC being superior to the control group (P = 0.0002) [10]. Critiques of this combined modality therapy have continuously questioned the role of intraperitoneal chemotherapy in the setting of CRS [11]. This question will be answered in the currently accruing Fe´de´ration Nationale des Centres de Lutte Contre le Cancer trial (NCT00769405). The purpose of this study is a retrospective analysis of our experience of offering various intraperitoneal chemotherapy regimens according to a curative intent-to-treat approach in patients with appendiceal and colorectal peritoneal carcinomatosis, in an attempt to delineate the relative benefits of each intraperitoneal regimen. The important finding of this study is that combination intraperitoneal chemotherapy is potentially associated with overall survival benefits in
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pseudomyxoma peritonei and improves recurrence-free survival in patients with colorectal peritoneal carcinomatosis. To avoid a biased patient cohort, patients with incomplete cytoreduction (CCR2/3) were excluded. This was because complete cytoreduction has become recognised as one of the strongest prognostic indicators in patients with carcinomatosis [12]. This study cohort consisted only of patients with a complete or optimal cytoreduction who received HIPEC and EPIC, HIPEC alone or EPIC alone. In our unit, there is a limit for HIPEC treatment on a week-byweek basis. With a large referral base, waiting times are protracted and patients may elect to undergo CRS plus EPIC alone. This unique setting puts us in a clinical equipoise to examine the survival benefits of each intraperitoneal regimen. This topic is important given that there is an increasing push towards using an oxaliplatin-based HIPEC regimen that would not include EPIC treatment [13]. In low-grade pseudomyxoma peritonei, there appeared to be no difference in recurrence-free survival, but a trend of improved 5-year survival of 86% compared to 64% for patients receiving HIPEC and EPIC compared to HIPEC or EPIC alone was observed. Recurrence in pseudomyxoma peritonei may not be the most suitable endpoint as this disease has a long clinical course and patients alive with a small amount of disease may continue to survive for a period of time. Further analysis of our data also showed that 26 of 87 patients (30%) in the HIPEC and EPIC group compared to seven of 14 patients (50%) in the HIPEC or EPIC alone group developed recurrence. The higher risk of recurrence in the HIPEC or EPIC alone group may explain the poorer overall survival in the longterm. It has been proposed that CRS in combination with intraperitoneal chemotherapy should be a standard of care in the management of pseudomyxoma peritonei [14]. Importantly, it has also been shown that undergoing CRS as definitive treatment without other prior operations is an important factor predicting recurrence-free survival [15]. In patients undergoing complete cytoreduction alone without any intraperitoneal chemotherapy, Miner et al. [16] reported a potential for 10-year survival in patients undergoing complete cytoreduction. However, this must be interpreted with caution as the survival was measured from date of initial operation rather than from date of cytoreduction (commonly reported in the literature), given that a proportion of patients may have undergone successive debulking as previous therapy. Given that our data appears to show that EPIC in addition to HIPEC is associated with favourable long-term survival benefits, a trial of cytoreduction or without HIPEC and EPIC examining the endpoints of risk of recurrence and overall survival may be appropriate to determine whether intraperitoneal chemotherapy improves survival. However, the rarity of this
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disease may lead to an accrual failure and the body of clinical evidence reporting the survival data of CRS in combination with HIPEC and EPIC supports its role as a treatment standard. In appendiceal peritoneal carcinomatosis, there were no observed differences in recurrence-free and overall survival between intraperitoneal chemotherapy regimens. This disease is distinct from colorectal peritoneal carcinomatosis owing to the distinct difference in survival outcomes. However, the management strategy of this disease has often been extrapolated from trials conducted for colorectal cancer. There are at present no known published reports of survival data examining the outcomes for appendiceal peritoneal carcinomatosis treated by chemotherapy alone. Shapiro et al. [17] reported a Cox regression model of a mixed cohort of patients with pseudomyxoma and appendiceal peritoneal carcinomatosis who were treated by chemotherapy and reported that moderate to poorly differentiated tumors and signet ring histology were negative prognostic indicators for overall survival, but survival data was not presented. These authors further identified treatment with cytoreduction and HIPEC as conferring significant survival advantage in patients who underwent surgery after chemotherapy. Therefore, we believe that in appendiceal peritoneal carcinomatosis, the most important factor for outcome is the complete cytoreduction rather than the chemotherapy regimen. It must be recognised that the prognosis following CRS is different between patients with appendiceal peritoneal carcinomatosis compared to colorectal peritoneal carcinomatosis, where 5-year survival rates of 63 and 30%, respectively, are achieved, as demonstrated in the French registry [18]. There are potential pharmacological explanations as to why the combination of HIPEC and EPIC might be superior to EPIC alone. Firstly, 5-fluorouracil exposure in the EPIC regimen is extremely high, with peritoneal to plasma ratios of 5-fluorouracil of 444 (±360) [19]. This in turn results in high tumour nodule penetration of 9.9 (±9.8) and 5.2 (±4.7) for peritoneal fluid to tumour nodule and plasma to tumour nodule AUC ratios, respectively. Despite the high 5-fluorouracil Cmax achieved by intraperitoneal administration, the more important issue may be the maintenance of high peritoneal concentrations over an extended time period, in this case the total (5-day) duration of the EPIC regimen. The concentration time profile may mimic the effect of infusional 5-fluorouracil. Infusional 5-fluorouracil has a pharmacological advantage over bolus 5-fluorouracil which translates into superior response rates, progression-free and overall survival [20]. A further pharmacological consideration relates to the synergy that occurs with polychemotherapy. Neither mitomycin C (MMC) nor oxaliplatin are routinely used as monotherapy in colorectal cancer due to their low overall response rates
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[21, 22]. Typically these agents are co-administered with 5-fluorouracil and most commonly it is with infusional regimens [23, 24]. As such, the MMC HIPEC plus 5-fluorouracil-based EPIC regimen may be analogous to the optimal systemic regimens in metastatic colorectal cancer. In contrast, the bidirectional regimen advocated by Elias et al. [9] may in turn out to be inferior to MMC plus EPIC due to the lack of an equivalent to infusional 5-fluorouracil exposure, as it employs bolus 5-fluorouracil. Nonetheless, an increasing trend towards performing CRS with oxaliplatin-based HIPEC has gradually led to PIC that includes HIPEC and EPIC becoming a less favoured option. Opponents of EPIC have raised concerns about the prolonged hospital stay, increase in rates of fistulas and postoperative complications. However, in our study, the complication rates were similar between groups. The important finding of this study was that HIPEC and EPIC conferred significant recurrence-free survival benefit compared to HIPEC alone or EPIC alone. However, there was no difference in overall survival. This was likely associated with the palliative nature of the disease course in patients who develop recurrences after this radical surgical therapy. There are two currently accruing trials of CRS plus HIPEC in patients with colorectal peritoneal carcinomatosis, both without the use of EPIC. Sugarbaker et al. [25] conceptualized the advantages of delivering EPIC after CRS and HIPEC at the time of minimal residual tumor burden to enhance further intraperitoneal targeted therapy to eliminate cancer cells prior to the formation of postoperative fibrinous adhesions. Furthermore, a matched case–control study comparing HIPEC and repeated postoperative intraperitoneal chemotherapy demonstrated that HIPEC was associated with improved overall survival and disease-free survival [26]. It appears from our data, therefore, that an intensified intraperitoneal dosing of chemotherapy through the use of both HIPEC and EPIC may contribute to improved recurrence-free survival in colorectal peritoneal carcinomatosis. The strategy of HIPEC and EPIC to provide intraperitoneal treatment may be more appropriate than long-term repeated intraperitoneal injections, a chemotherapy schedule that was previously investigated in several pharmacokinetic studies [27, 28] and utilized in trials of ovarian cancer that showed limited tolerability [29]. There was no difference in major complication rates when patients receiving HIPEC and EPIC were compared to patients who received HIPEC or EPIC alone. However, it appeared that patients who received two forms of intraperitoneal chemotherapy (HIPEC and EPIC) did have a higher incidence of pleural effusion, intra-abdominal collections and pneumothorax development. The resultant higher rates of pneumothorax may be related to the effect of chest tube placement to treat the pleural effusion. The
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observed lower rate of bleeding and reoperations in the HIPEC and EPIC group reflects our strict and careful postoperative monitoring to withhold EPIC in patients who were haemodynamically unstable during the early postoperative period or in those who had developed early complications. In conclusion, we show that the various regimens, including double dosing with HIPEC and EPIC, did not result in an increased rate of major morbidity postoperatively. Combining HIPEC and EPIC as a PIC appears to be associated with overall survival benefits in pseudomyxoma peritonei and recurrence-free survival benefit in colorectal peritoneal carcinomatosis. The clinical results support the conceptualized benefits of EPIC in the early postoperative setting in targeting minimal residual disease. Conflict of interest
None declared.
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