Ann Surg Oncol (2014) 21:4218–4225 DOI 10.1245/s10434-014-3869-1
ORIGINAL ARTICLE – GASTROINTESTINAL ONCOLOGY
Predictive and Prognostic Survival Factors in Peritoneal Carcinomatosis from Appendiceal Cancer After Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy William Jimenez, MD, Armando Sardi, MD, FACS, Carol Nieroda, MD, Michelle Sittig, RN, Vladimir Milovanov, MD, Maria Nunez, MD, Nail Aydin, MD, and Vadim Gushchin, MD, FACS Institute for Cancer Care, Mercy Medical Center, Baltimore, MD
ABSTRACT Background. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has survival benefit in the treatment of selected patients with peritoneal carcinomatosis (PC) from appendiceal cancer (AC). We evaluated factors affecting the survival of patients with PC from AC after CRS/HIPEC. Methods. A retrospective analysis of 387 CRS/HIPEC procedures performed between February 1998 and February 2013 identified 202 patients with PC from AC. Tumor histopathology, complete cytoreduction (CC 0–1), Peritoneal Cancer Index (PCI), and lymph node (LN) status were related to overall survival (OS) and progression-free survival (PFS) using the Kaplan–Meier method. Results. Overall, 129 women (64 %) and 73 men (36 %), mean age 54 years (range 25–81), with a mean follow-up of 36 months were included in the study. Seventy-seven lowgrade tumors (disseminated peritoneal adenomucinosis [DPAM]; 38 %) and 125 high-grade tumors (peritoneal mucinous carcinomatosis [PMCA]; 62 %) were identified. Five- and 10-year OS was 56 % and 47 %, respectively, with PFS of 44 % at 5 and 10 years. Five-year OS in DPAM patients was 83 %, with a 5-year OS significant difference related to CC 0–1 versus CC 2–3 (incomplete cytoreduction) [p = 0.021]. Five-year OS in PMCA patients was 41 %, with a 5-year OS significant difference Electronic supplementary material The online version of this article (doi:10.1245/s10434-014-3869-1) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2014 First Received: 23 April 2014; Published Online: 2 July 2014 A. Sardi, MD, FACS e-mail:
[email protected]
related to CC 0–1 versus CC 2–3 (p \ 0.001), PCI \20 versus PCI C20 (p = 0.002), and (–)LN versus (?)LN (p \ 0.001). Grade III/IV complications were 16 %. No perioperative mortality was reported. Conclusion. Positive LN, PMCA histopathology, and PCI C20 are negative prognostic factors, while CC 0–1 is a positive survival predictor in PC from AC treated with CRS/HIPEC. However, in patients with PMCA and PCI C20 in whom CC 0–1 was a potential outcome should not be denied CRS/HIPEC.
The incidence of appendiceal cancer (AC) is 0.1–1 in 1,000,000 people annually,1,2 and symptoms are frequently not manifested until aggressive peritoneal dissemination (peritoneal carcinomatosis [PC]) has been established (stages III–IV). Multiple publications have demonstrated the long-term survival benefit of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in selected AC patients.3–9 As CRS/HIPEC is an extensive and complex procedure, specialized centers have performed careful patient selection in an attempt to decrease postoperative morbidity and mortality. Reported variables affecting survival in PC from AC after CRS/HIPEC, such as high-grade histopathology and high peritoneal cancer index (PCI) score10–12 have been considered as exclusion criteria in specialized centers. In contrast, other factors have evidenced survival benefit, such as complete cytoreduction (CC 0–1), low-grade histopathology, good performance status, and careful perioperative care.3,13–17 The presence of lymph node (LN) metastasis has not been consistently considered as a prognostic factor.7,13,18–20 In an attempt to define the patient subpopulation who will benefit most from CRS/HIPEC, this analysis addresses predictive and prognostic survival factors in PC from AC
Survival Factors of Appendiceal Carcinomatosis
4219
after CRS/HIPEC in a medical center specializing in peritoneal surface malignancies.
TABLE 1 Clinicopathologic characteristics of the study population Variable
Result
PATIENTS AND METHODS
Gender (male/female) [n (%)]
73/129 (36/64)
A retrospective analysis of a prospective database of 387 CRS/HIPEC procedures performed identified 202 patients with PC from AC between February 1998 and February 2013. The predictive and prognostic factors, such as tumor histopathology, PCI, LN status, and completeness of cytoreduction (CC), were measured and correlated with overall survival (OS) and progression-free survival (PFS). All histopathology from the CRS/HIPEC, as well as the histopathology from previous biopsies or surgeries was reviewed at our institution, according to the Ronnett et al.21,22 classification for peritoneal disseminated AC. This included disseminated peritoneal adenomucinosis (DPAM) and peritoneal mucinous carcinomatosis (PMCA).21,22 PCI score at the time of the CRS/HIPEC was used to determine the extent of PC, from a scale of 0–39 as previously described by Jacquet and Sugarbaker23 Patients with a PCI score of 0–19 were considered to have low tumor loads (PCI \20), and those with a score of 20–39 were considered to have large tumor loads (PCI C20). LN status was obtained from patients’ previous surgeries and/ or at the time of CRS/HIPEC. During surgery, resections were carried out as needed to achieve complete cytoreduction (CC 0–1), defined as no visible tumor nodules or nodules less than 2.5 mm in size. Incomplete cytoreduction (CC 2–3) was considered when tumors or nodules of 2.5 mm or more in size were left behind, as recommended by peritoneal surface malignancy experts.24–26 For each patient, a computed tomography (CT) scan of the chest, abdomen, and pelvis, as well as tumor markers (CEA, CA19-9 and CA-125) were obtained prior to CRS/ HIPEC. The CRS/HIPEC (closed) surgical technique and the perioperative care used for the patient have been previously described by our group.7,14,27 A total of 29 patients underwent a second CRS/HIPEC due to tumor recurrence based on the CT scan, elevated tumor markers, and/or clinical presentation (bowel obstruction), and analysis was performed only from the first CRS/HIPEC procedure. Grade III/IV surgical complications were defined according to Dindo’s Classification of Surgical Complications.28 Patients with extra-abdominal metastatic disease were excluded. All patients participated in a protocol approved by the Institutional Review Board and preoperative informed consent was obtained. Statistical Analysis OS and PFS were analyzed using survival analyses displayed as Kaplan–Meier curves. The log-rank test for
Mean age at diagnosis, years (range)
52 (24–79)
Mean age at surgery, years (range)
53 (25–80)
Status [% (n)] Alive
67 (135)
NED
53 (106)
AWD
14 (29)
Deceased
32 (65)
DOC
5 (10)
DOD
27 (55)
Unknowna Mean follow-up from CRS/HIPEC, months (range)
1 (2) 36 (0–178)
Mean time to CRS/HIPEC, months (range)
18 (0–182)
Multiple surgeries, yes/no [% (n)]
19 (39)/81 (163)
Tumor markers, negative/positive [% (n)]b
48 (89)/52 (95)b
Histology, DPAM/PMCA [% (n)]
38 (77)/62 (125)
PCI \20/C20 [% (n)]
28 (56)/72 (140)d 85 (170)/15 (30)c
CC 0–1/2–3 [% (n)] e
LN status, negative/positive [% (n)]
62 (77)/37 (42)e
NED no evidence of disease, AWD alive with disease, DOC dead of other cause, DOD dead of disease, CRS cytoreductive surgery, HIPEC hyperthermic intraperitoneal chemotherapy, DPAM disseminated peritoneal adenomucinous, PMCA peritoneal mucinous adenocarcinoma, CC completeness of cytoreduction, PCI Peritoneal Cancer Index a
Two patients with unknown status, range since last follow up: 12–25 months
b
Tumor markers for 18 patients were not available
c
Two CC scores were unavailable
d
Six PCI scores were unavailable Only applies for PMCA histopathology, 6 LN status unavailable
e
the equality of survival curves was used to compare the survival distributions for PCI, CC, LN status, and tumor histopathology. Statistically significant results were those with p values B0.05. RESULTS Mean age at diagnosis and surgery was 52 and 54 years, respectively, and 64 % (129) of patients were female. Mean time from diagnosis to CRS/HIPEC was 18 months, and mean follow-up was 36 months. Table 1 depicts the population clinicopathologic characteristics. At the end of the study, 67 % (135) of the patients were alive and 32 % (65) were deceased. Table 1 shows specific survival distribution. CC 0–1 was achieved in 85 % (170) of the entire population and 91 % (68/75) and 82 % (102/125) of DPAM
95
58
CC 0–1
CC C2
79
PMCA
63
86
45
68
NA
NA
48
68
3-year PFS (%)
41
83
NA
NA
18
59
54
67
34
58
NA
NA
43
48
RC
58
NA
NA
43
RC
10-year PFS (%)
RC
83
NA
NA
RC
51
45
RC
\0.001
NA
\0.001
0.029
26
NR
NA
NA
36
51
0.003
NA
0.117
p Value
NA
NA
NA
NA
69
92
88
100
NA
NA
NA
NA
69
88
84
100
90
NA
NA
NA
NA
84
NA
NA
NA
NA
46
88
80
100
72
NA
NA
NA
NA
64
36
NA
NA
NA
NA
60
NA
NA
NA
NA
60
RC
10-year PFS (%)
NA
NA
NA
NA
RC
88
80
RC
NA
NA
0.021
0.145
48
NA
NA
NA
NA
NR
97
NA
NA
0.696
p Value
NA
NA
82
91
55
97
84
NA
NA
68
82
71
89
1-year PFS (%)
NA
NA
43
76
33
68
50
82
NA
NA
11
61
0
44
36
60
63
NA
NA
14
58
32
51
NA
NA
7
48
26
NA
NA
RC
RC
RC
RC
10-year PFS (%)
NA
NA
RC
RC
RC
RC
RC
RC
NA
NA
17
51
20
NR
MPFS (months)
NA
NA
35
NR
16
53
38
76
10-year OS MS (%) (months)
5-year PFS (%)
5-year OS (%)
3-year PFS (%)
3-year OS (%)
PMCA [n = 125] p Value 1-year OS (%)
MPFS (months)
NA
NA
NA
NA
48
NR
NR
NR
10-year OS MS (%) (months)
5-year PFS (%)
5-year OS (%)
3-year PFS (%)
3-year OS (%)
1-year PFS (%)
p Value 1-year OS (%)
MPFS (months)
47
NR
NA
NA
18
NR
90
NR
10-year OS MS (%) (months)
5-year PFS (%)
5-year OS (%)
DPAM [n = 77]
NA
\0.001
0.008
p Value
NA
\0.001
\0.001
\0.001
p Value
OS overall survival, MS median survival, NR not reached, RC right censoring, NA not applicable, PFS progression-free survival, PCI Peritoneal Cancer Index, CC completeness of cytoreduction, LN lymph node, DPAM disseminated peritoneal adenomucinosis, PMCA peritoneal mucinous carcinomatosis, MPFS median progression-free survival
86
DPAM
79
PCI C20
NA
90
PCI \20
NA
1-year PFS (%)
Variable
(?) LN
90
PMCA
(–) LN
90
DPAM
NA
(?) LN
NA
NA
NA
(–) LN
41
76
86
66
86
PCI C20
3-year OS (%)
PCI \20 98
1-year OS (%)
Variable Overall (all population) [n = 202]
TABLE 2 Overall survival of the entire study population and by histopathology related to relevant predictive and prognostic factors
4220 W. Jimenez et al.
Survival Factors of Appendiceal Carcinomatosis
The 5-year OS related to PCI \20 versus PCI C20 was 67 % versus 54 %, respectively (p = 0.029) [Table 2]. The 5-year OS related to CC 0–1 versus CC 2–3 was 59 % versus 18 %, respectively (p \ 0.001) [Table 2]. The MS related to PCI \20 and CC 0–1 was not reached, while the MS related to patients with PCI C20, and CC 2–3, was 90 months and 18 months, respectively.
0.25
0.50
0.75
1.00
(a)
4221
0.00
p < 0.001 0
2
4
6
8
10
26
14
5
3
30
11
1
0
Years
Number at risk histology = 0
77
50
histology = 1
125
71
PMCA
0.50
0.75
1.00
DPAM
(b)
Survival and Outcomes by Tumor Histopathology The 5-year OS of DPAM versus PMCA patients was 83 % versus 41 %, respectively (p \ 0.001) [Fig. 1a; Table 2]. The MS for DPAM patients was not reached, while in PMCA, MS was 47 months. The 5-year PFS of DPAM versus PMCA patients was 58 versus 34 %, respectively (p = 0.003) [Fig. 1b; Table 2]. The MPFS in DPAM was not reached, while in PMCA patients the MPFS was 26 months.
0.25
Disseminated Peritoneal Adenomucinosis and Survival Factors
0.00
p = 0.003
0
2
4
6
8
Years
Number at risk* histology = 0
68
42
15
8
2
histology = 1
100
40
15
6
1
DPAM
PMCA
FIG. 1 Kaplan–Meier curves showing (a) overall survival and (b) progression-free survival of patients undergoing CRS/HIPEC for peritoneal carcinomatosis from appendiceal cancer by histopathology (PMCA vs. DPAM). *Thirty patients were never considered at risk of recurrence (CC 2–3), and two patients had unknown recurrence dates and were excluded from the analysis. CRS cytoreductive surgery, HIPEC hyperthermic intraperitoneal chemotherapy, PMCA peritoneal mucinous adenocarcinoma, DPAM disseminated peritoneal adenomucinous
and PMCA patients, respectively. Moreover, CC 0–1 was achieved in 100 % (56/56), and 78 % (109/140) in patients with PCI \20 and PCI C20, respectively. Survival and Outcomes The general OS at 1, 3, 5, and 10 years was 90, 71, 56, and 47 %, respectively, with median survival (MS) of 90 months. The PFS at 1, 3, 5, and 10 years was 81, 54, 44, and 44 %, respectively, with median PFS (MPFS) of 40 months. TM expression (positive vs. negative) at CRS/HIPEC was not significantly correlated to OS (p = 0.227) and PFS (p = 0.873), nor to OS of PCI C20 (p = 0.403), CC 2–3 (p = 0.201), or (?)LN (p = 0.538) patients.
The 5-year OS of DPAM patients related to PCI \20 versus PCI C20 was 100 versus 80 %, respectively (p = 0.145) [Table 2]. The 5-year OS of DPAM patients with CC 0–1 versus CC 2–3 was 88 versus 46 %, respectively (p = 0.021) [Table 2]. The MS of DPAM patients with CC 0–1 was not reached, while CC 2–3 was 48 months
Peritoneal Mucinous Carcinomatosis and Survival Factors The 5-year OS of PMCA patients with PCI \20 versus PCI C20 was 60 versus 36 %, respectively (p = 0.002) [Table 2]. MS related to PCI\20 and PCI C20 was 76 and 38 months, respectively. The 5-year OS of PMCA patients with CC 0–1 versus CC 2–3 was 44 versus 0 %, respectively (p \ 0.001) [Table 2]. MS according to CC 0–1 and CC 2–3 was 52 and 15 months, respectively. PMCA patients’ 5-year OS related to (–)LN versus (?)LN status was 61 versus 11 %, respectively (p \ 0.001) [Table 2]. The MS of (–)LN was not reached, while for (?)LN the MS was 34 months. Subpopulation Analysis In patients with CC 0–1, the 5-year OS related to (?)LN versus (–)LN was 10 versus 62 % (p \ 0.001) [Fig. 2]. In patients with (?)LN, the 3 and 5-year OS related to CC 0–1 was 46 and 10 %, respectively, while in CC 2–3 it was
W. Jimenez et al. 1.00
4222
0.00
0.25
0.50
0.75
p = 0.001
Complications and Mortality 0
Number at risk* In = 0 In = 1
status was 2.7 (95 % CI 1.6–4.7) over (–)LN status, and PMCA was 3 (95 % CI 1.4–6.1) over DPAM. The disease recurrence HR related to PCI C20 was 2 (95 % CI 1.1–3.6) over PCI \20, (?)LN status was 2.4 (95 % CI 1.4–4.1), and PMCA was 2.1 (95 % CI 1.2–3.7). CC score does not apply for recurrence HR (CC 2–3 were never disease free).
2
4
6
8
8 3
1 0
Years 66 35
44 19
21 5 LN Negative
LN Positive
1.00
FIG. 2 Kaplan–Meier curve showing overall survival of PMCA patients with complete cytoreduction (CC 0–1) related to LN status. *One LN status unavailable. PMCA peritoneal mucinous carcinomatosis, LN lymph node
0.50
CRS/HIPEC has gained popularity as a treatment option for patients with PC from AC, and is considered by many the standard of care for this condition,5,7–9,27,29–32 producing meaningful 5 and 10-year OS results of 38–78 % and 21–63 %, respectively.3,7,8,11,31–33 These results are similar to our outcomes of 56 and 47 %, respectively, for the same survival intervals. Of interest, the rate of our highgrade tumor histopathology (PMCA) population was 62 % compared with 25–50 % from other reports,3,8,11,32 affecting OS. CRS/HIPEC is an acceptable, safe therapeutic option for PC,34 with reported morbidity and mortality rates at 12–67 %, and 0–9 %, respectively. 5,7,9,34 Our series reported grade III/ IV morbidity of 16 % and no mortality. Moreover, this procedure is an effective approach with disease recurrence even after initial CRS/HIPEC (repeated CRS/HIPEC).27,35 However, appropriate patient selection is a pre-determinant for a successful CRS/HIPEC completion.3,16,36 In the challenging process of patient selection, prognostic and predictive variables become instrumental in gaining the most benefit from this procedure. Reported measurable survival factors in PC undergoing CRS/HIPEC include tumor histopathology (DPAM vs. PMCA),3,8,13,37 PCI scores,5,7,8,13,14,35 LN positivity,12,38 and CC.3,8,13,15 The pathologic subtype has been suggested as the dominant factor in survival.8 In our series, the 5-year OS of PMCA versus DPAM patients was 41 versus 83 %, respectively (p \ 0.001), with 5-year PFS of 34 versus
0.00
DISCUSSION
0.25
0.75
p = 0.019
Grade III/IV complications were present in 15.8 % (32) of the population, represented by a total of 38 different complications (four patients had two complications and one patient had three complications). The most common complication observed was pancreatic leak/abscess (9/38), followed by aspiration pneumonia (6/38), pulmonary embolism (5/38), and pleural effusions (4/38). Other complications included deep vein thrombosis, anastomotic leak, pneumonia, and acute respiratory distress syndrome (13/38). No peri-hospital mortality was seen (grade V complication) after CRS/HIPEC.
0
Number at risk cc = 0 cc = 1
2
4
6
8
Years 56
32
13
4
1
23
8
4
0
0
CC 0 or 1
CC 2 or 3
FIG. 3 Kaplan–Meier survival curve showing the overall survival of PMCA patients with PCI C20 by completeness of cytoreduction (CC 0–1 vs. CC 2–3). PMCA peritoneal mucinous carcinomatosis, PCI Peritoneal Cancer Index, CC 0–1 complete cytoreduction, CC 2–3 incomplete cytoreduction
20 % and not available (right censoring), respectively (p = 0.109). Considering only PMCA patients with a PCI C20, a CC 0–1 was achieved in 71 % (56/79) of cases, with 5-year OS of 38 % compared with 0 % for CC 2–3 (p = 0.019) [Fig. 3]. The 5-year OS in PMCA patients with CC 0–1 by PCI \20 versus PCI C20 was 56 versus 38 % (p = 0.026). Multivariate Analysis of Survival and Recurrence The survival hazard ratio (HR) for PCI C20 was 2.2 (95 % confidence interval [CI] 1.4–6.1) over PCI \20, CC 2–3 was 1.8 (95 % CI 0.9–3.5) over CC 0–1, a (?)LN
Survival Factors of Appendiceal Carcinomatosis
58 %, respectively (p = 0.003). PMCA histopathology negatively impacts patient OS and PFS after CRS/HIPEC. Considering only DPAM patients, the 5 and 10-year OS after CRS/HIPEC was constant at 83 %, and when CC 0–1 was achieved, a higher OS of 88 % remained stable at 3, 5, and 10 years (p = 0.021), evidencing its survival benefit . Additionally, the PFS in DPAM patients remained at 58 % at both 5 and 10 years, suggesting a curative outcome once DPAM patients reach 5-years post-CRS/HIPEC and remain free of disease. These findings suggest CRS/HIPEC should be offered as the standard of care for PC from AC with DPAM histopathology regardless of tumor load (PCI \20 vs. C20; p = 0.145), with a potential curative outcome if CC 0–1 is achieved. In PMCA patients, previous studies showed that survival has not been influenced by LN positivity, and prognostic significance could not be determined.13,18 In 2004, Gonzalez-Moreno et al.18 reported that LN metastasis in PC from AC does not reduce survival (p = 0.15). However, their sampling was unequally balanced [25 (?)LN patients vs. 476 (–)LN or unassessed], and also reported four DPAM patients with (?)LN.18 More recently, in 2012, Van Sweringen et al.,13 reported no difference in survival of (?)LN versus (–)LN patients (p = 0.65) in their work about predictors of survival, which included 36 patients with PC and CRS/HIPEC from a variety of histopathologies (72 % appendiceal primary).13 They compared the LN status at CRS/HIPEC, without consideration of LN status of previous surgeries. In contrast, our series included the LN status from previous surgeries (before CRS/HIPEC) and only PMCA histopathology. Our results showed a 61 versus 11 % 5-year OS between negative and positive LN, respectively (p \ 0.001), supporting the significant negative impact of (?)LN on long-term survival, consistent with our previous study and demonstrated by others.7,12,19,39 Therefore, the primary surgeon should address, identify, resect and/or biopsy local and regional LN at the first diagnostic procedure, surgery, or CRS/HIPEC, since this could represent a useful prognostic factor for long-term survival. It is known that tumor load impacts survival.7,40 Our series showed a 5-year OS of PCI \20 versus PCI C20 of 67 % versus 54 %, respectively (p = 0.029). Moreover, PMCA patients showed an increased association between PCI C20 and worse survival (5-year OS of 36 vs. 60 % of PCI \20 [p = 0.002]), indicating that PMCA survival is affected by tumor load (PCI C20).13 Therefore, one might deduce that PMCA patients with PCI C20 undergoing CRS/HIPEC will have limited benefit due to poor prognosis. Some authors have mentioned that high-grade histology and PCI C20 should be excluded from CRS/HIPEC.3,4,13,31 However, survival is impacted by CC 0–1, as high PCI scores can often be completely
4223
cytoreduced during CRS/HIPEC.31 In our series, CC 0–1 was achieved in 78 % of all PCI C20 patients. In addition, PMCA patients in whom CC 0–1 was achieved (82 % of all PMCA patients) reported a 5-year OS of 44 % (MS 53 months) compared with 0 % (MS 15 months) for CC 2–3 (p \ 0.001). Furthermore, PMCA patients with PCI C20 and a 5-year OS of 38 %, compared with 0 % of CC 2–3 patients (p = 0.019). These findings support that CC 0–1 is crucial for long-term survival, 13–15,27,31 even with unfavorable histopathology (PMCA) and large tumor loads (PCI C20). Overall, CC 0–1 significantly improved OS despite tumor histopathology (DPAM [p = 0.021], PMCA [p [ 0.001]), or tumor load (PCI C20 [p = 0.029]). High tumor loads and PMCA histopathology may suggest worse prognosis and require extensive surgical procedures; however, these negative survival prognostic factors will not predict the CC during CRS/HIPEC. Furthermore, extensive CRS has acceptable morbidity and mortality, without association to negative impact on oncologic outcomes.41 Therefore, every attempt should be made to achieve a CC 0–1, avoiding large bowel resections, when possible, to preserve quality of life. If achieved, CC 0–1 will provide a better OS regardless of all other negative prognostic variables in PC from AC undergoing CRS/HIPEC. Preoperatively, weighing all of the factors that simultaneously affect patient survival and outcomes is a complex process. Often accurate PCI, CC scores, or LN status cannot be determined before CRS/HIPEC is attempted. Other presurgical strategies, such as clinical findings, tumor markers,42,43 and imaging studies (positron emission tomography-CT and magnetic resonance imaging)44–47 define patient eligibility for CRS/HIPEC, even though tumor burden and resectability often cannot precisely be determined preoperatively.42,47 In our series, no correlation was achieved between TM positivity and survival by PCI C20, CC 2–3, or (?)LN. Diagnostic laparoscopy has been proposed to address the difficulty in selecting patients for CRS/HIPEC;48 however, these patients frequently have multiple previous surgeries, inhibiting accurate laparoscopic assessments. Although more patients are presenting to specialized centers following appendectomy (19 % of our population), the majority of patients often have already undergone major debulking/multiple procedures and chemotherapy treatments (42 % of our population). Additionally, in many instances, 2–4 h of lysis of adhesions is required to determine if CRS/HIPEC will be feasible. This may lead the surgeon to reconsider or abort the CRS/HIPEC, increasing our selectivity, which is a limitation in our study, while the challenges of appropriate selection remain. In other words, the experience of the operating surgeon makes a great difference in the outcome. Considering all patient parameters, the most important
4224
factors—prognostic and predictive–become apparent during the CRS/HIPEC procedure itself (LN, CC score, and PCI). CONCLUSIONS Positive LN status, PMCA histopathology, PCI C20, and CC 2–3 are significantly related to worse prognosis in PC from AC undergoing CRS/HIPEC. However, CRS/ HIPEC should be offered to this population irrespective of tumor histopathology and after careful consideration of tumor extent in an attempt to achieve CC 0–1, which is frequently attainable, even with high tumor loads (PCI C20). AKNOWLEDGMENT The authors will like to thank Ryan MacDonald, PhD, For providing the statistics and for data analysis, and Roy Hatch for literature and data gathering. DISCLOSURE William Jimenez, Armando Sardi, Carol Nieroda, Michelle Sittig, Vladimir Milovanov, Maria Nunez, Nail Aydin, and Vadim Gushchin declare there are no financial or commercial interests in this study.
REFERENCES 1. Omohwo C, Nieroda CA, Studeman KD, et al. Complete cytoreduction offers longterm survival in patients with peritoneal carcinomatosis from appendiceal tumors of unfavorable histology. J Am Coll Surg. 2009;209(3):308–312. 2. McCusker ME, Cote TR, Clegg LX, Sobin LH. Primary malignant neoplasms of the appendix: a population-based study from the surveillance, epidemiology and end-results program, 1973-1998. Cancer. 2002;94(12):3307–3312. 3. Chua TC, Moran BJ, Sugarbaker PH, et al. Early- and long-term outcome data of patients with pseudomyxoma peritonei from appendiceal origin treated by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. J Clin Oncol. 2012;30(20):2449–2456. 4. Elias D, Honore C, Ciuchendea R, et al. Peritoneal pseudomyxoma: results of a systematic policy of complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Br J Surg. 2008;95(9):1164–1171. 5. Elias D, Gilly F, Quenet F, et al. Pseudomyxoma peritonei: a French multicentric study of 301 patients treated with cytoreductive surgery and intraperitoneal chemotherapy. Eur J Surg Oncol. 2010;36(5):456–462. 6. Miner TJ, Shia J, Jaques DP, Klimstra DS, Brennan MF, Coit DG. Long-term survival following treatment of pseudomyxoma peritonei: an analysis of surgical therapy. Ann Surg. 2005;241(2):300–308. 7. Shankar S, Ledakis P, El Halabi H, Gushchin V, Sardi A. Neoplasms of the appendix: current treatment guidelines. Hematol Oncol Clin North Am. 2012;26(6):1261–1290. 8. Smeenk RM, Verwaal VJ, Antonini N, Zoetmulder FA. Survival analysis of pseudomyxoma peritonei patients treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Ann Surg. 2007;245(1):104–109. 9. Votanopoulos KI, Shen P, Stewart JH, Levine EA. Current status and future directions in appendiceal cancer with peritoneal dissemination. Surg Oncol Clin N Am. 2012;21(4):599–609.
W. Jimenez et al. 10. Baratti D, Kusamura S, Nonaka D, Cabras AD, Laterza B, Deraco M. Pseudomyxoma peritonei: biological features are the dominant prognostic determinants after complete cytoreduction and hyperthermic intraperitoneal chemotherapy. Ann Surg. 2009;249(2):243–249. 11. Baratti D, Kusamura S, Nonaka D, et al. Pseudomyxoma peritonei: clinical pathological and biological prognostic factors in patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). Ann Surg Oncol. 2008;15(2):526–534. 12. Halabi HE, Gushchin V, Francis J, et al. Prognostic significance of lymph node metastases in patients with high-grade appendiceal cancer. Ann Surg Oncol. 2012;19(1):122–125. 13. Van Sweringen HL, Hanseman DJ, Ahmad SA, Edwards MJ, Sussman JJ. Predictors of survival in patients with high-grade peritoneal metastases undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Surgery. 2012;152(4): 617–624. 14. Halabi HE, Gushchin V, Francis J, et al. The role of cytoreductive surgery and heated intraperitoneal chemotherapy (CRS/HIPEC) in patients with high-grade appendiceal carcinoma and extensive peritoneal carcinomatosis. Ann Surg Oncol. 2012;19(1):110–114. 15. Omohwo C, Nieroda CA, Studeman KD, et al. Complete cytoreduction offers longterm survival in patients with peritoneal carcinomatosis from appendiceal tumors of unfavorable histology. J Am Coll Surg. 2009;209(3):308–312. 16. Bell JC, Rylah BG, Chambers RW, Peet H, Mohamed F, Moran BJ. Perioperative management of patients undergoing cytoreductive surgery combined with heated intraperitoneal chemotherapy for peritoneal surface malignancy: a multi-institutional experience. Ann Surg Oncol. 2012;19(13):4244–4251. 17. Levine EA, Stewart JH, Shen P, Russell GB, Loggie BL, Votanopoulos KI. Intraperitoneal chemotherapy for peritoneal surface malignancy: experience with 1,000 patients. J Am Coll Surg. 2013;218(4):573–85. 18. Gonzalez-Moreno S, Brun E, Sugarbaker PH. Lymph node metastasis in epithelial malignancies of the appendix with peritoneal dissemination does not reduce survival in patients treated by cytoreductive surgery and perioperative intraperitoneal chemotherapy. Ann Surg Oncol. 2005;12(1):72–80. 19. Halabi HE, Gushchin V, Francis J, et al. Prognostic significance of lymph node metastases in patients with high-grade appendiceal cancer. Ann Surg Oncol. 2012;19(1):122–125. 20. Arjona-Sanchez A, Munoz-Casares FC, Casado-Adam A, et al. Outcome of patients with aggressive pseudomyxoma peritonei treated by cytoreductive surgery and intraperitoneal chemotherapy. World J Surg. 2013;37(6):1263–1270. 21. Ronnett BM, Zahn CM, Kurman RJ, Kass ME, Sugarbaker PH, Shmookler BM. Disseminated peritoneal adenomucinosis and peritoneal mucinous carcinomatosis. A clinicopathologic analysis of 109 cases with emphasis on distinguishing pathologic features, site of origin, prognosis, and relationship to ‘‘pseudomyxoma peritonei’’. Am J Surg Pathol. 1995;19(12):1390–1408. 22. Ronnett BM, Yan H, Kurman RJ, Shmookler BM, Wu L, Sugarbaker PH. Patients with pseudomyxoma peritonei associated with disseminated peritoneal adenomucinosis have a significantly more favorable prognosis than patients with peritoneal mucinous carcinomatosis. Cancer. 2001;92(1):85–91. 23. Jacquet P, Sugarbaker PH. Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis. Cancer Treat Res. 1996;82:359–374. 24. Esquivel J, Elias D, Baratti D, Kusamura S, Deraco M. Consensus statement on the loco regional treatment of colorectal cancer with peritoneal dissemination. J Surg Oncol. 2008;98(4):263–267. 25. Sugarbaker PH. Peritonectomy procedures. Surg Oncol Clin N Am. 2003;12(3):703–27, xiii.
Survival Factors of Appendiceal Carcinomatosis 26. Sugarbaker PH. New standard of care for appendiceal epithelial neoplasms and pseudomyxoma peritonei syndrome? Lancet Oncol. 2006;7(1):69–76. 27. Sardi A, Jimenez WA, Nieroda C, Sittig M, Macdonald R, Gushchin V. Repeated cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal carcinomatosis from appendiceal cancer: analysis of survival outcomes. Eur J Surg Oncol. 2013;39(11):1207–1213. 28. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240(2): 205–213. 29. Kuijpers AM, Mirck B, Aalbers AG et al. Cytoreduction and HIPEC in the Netherlands: nationwide long-term outcome following the Dutch protocol. Ann Surg Oncol. 2013;20(13): 4224–4230. 30. Sugarbaker PH. Technical handbook for the integration of cytoreductive surgery and perioperative intraperitoneal chemotherapy into the surgical management of gastrointestinal and gynecologic malignancy. 4th ed. Michigan: The Ludman Company; 2005. 31. Teo MC, Tan GH, Tham CK, Lim C, Soo KC. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in Asian patients: 100 consecutive patients in a single institution. Ann Surg Oncol. 2013;20(9):2968–2974. 32. Virzi S, Iusco D, Bonomi S, Grassi A. Pseudomyxoma peritonei treated with cytoreductive surgery and hyperthermic chemotherapy: a 7-year single-center experience. Tumori. 2012;98(5):588–593. 33. Iversen LH, Rasmussen PC, Hagemann-Madsen R, Laurberg S. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis: the Danish experience. Colorectal Dis. 2013;15(7):e365–e372. 34. Canda AE, Sokmen S, Terzi C, et al. Complications and toxicities after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Ann Surg Oncol. 2013;20(4):1082–1087. 35. Esquivel J, Sugarbaker PH. Second-look surgery in patients with peritoneal dissemination from appendiceal malignancy: analysis of prognostic factors in 98 patients. Ann Surg. 2001;234(2): 198–205. 36. Jafari MD, Halabi WJ, Stamos MJ, et al. Surgical outcomes of hyperthermic intraperitoneal chemotherapy: analysis of the american college of surgeons national surgical quality improvement program. JAMA Surg. 2014;149(2):170–175. 37. Votanopoulos KI, Ihemelandu C, Shen P, Stewart JH, Russell GB, Levine EA. Outcomes of repeat cytoreductive surgery with
4225
38. 39.
40.
41.
42.
43.
44.
45.
46.
47. 48.
hyperthermic intraperitoneal chemotherapy for the treatment of peritoneal surface malignancy. J Am Coll Surg. 2012;215(3): 412–417. Sugarbaker PH. Epithelial appendiceal neoplasms. Cancer J. 2009;15(3):225–235. Arjona-Sanchez A, Munoz-Casares FC, Casado-Adam A, et al. Outcome of patients with aggressive pseudomyxoma peritonei treated by cytoreductive surgery and intraperitoneal chemotherapy. World J Surg. 2013;37(6):1263–1270. Dayal S, Taflampas P, Riss S, et al. Complete cytoreduction for pseudomyxoma peritonei is optimal but maximal tumor debulking may be beneficial in patients in whom complete tumor removal cannot be achieved. Dis Colon Rectum. 2013;56(12): 1366–1372. Wagner PL, Austin F, Maduekwe U, et al. Extensive cytoreductive surgery for appendiceal carcinomatosis: morbidity, mortality, and survival. Ann Surg Oncol. 2013;20(4):1056–1062. Wagner PL, Austin F, Sathaiah M, et al. Significance of serum tumor marker levels in peritoneal carcinomatosis of appendiceal origin. Ann Surg Oncol. 2013;20(2):506–514. Ross A, Sardi A, Nieroda C, Merriman B, Gushchin V. Clinical utility of elevated tumor markers in patients with disseminated appendiceal malignancies treated by cytoreductive surgery and HIPEC. Eur J Surg Oncol. 2010;36(8):772–776. Klumpp B, Aschoff P, Schwenzer N, et al. Correlation of preoperative magnetic resonance imaging of peritoneal carcinomatosis and clinical outcome after peritonectomy and HIPEC after 3 years of follow-up: preliminary results. Cancer Imaging. 2013;13(4): 540–547. Klumpp BD, Schwenzer N, Aschoff P, et al. Preoperative assessment of peritoneal carcinomatosis: intraindividual comparison of 18F-FDG PET/CT and MRI. Abdom Imaging. 2013;38(1): 64–71. Low RN, Barone RM, Lee MJ. Surveillance MR imaging is superior to serum tumor markers for detecting early tumor recurrence in patients with appendiceal cancer treated with surgical cytoreduction and HIPEC. Ann Surg Oncol. 2013;20(4): 1074–1081. Patel CM, Sahdev A, Reznek RH. CT, MRI and PET imaging in peritoneal malignancy. Cancer Imaging. 2011;11:123–139. Iversen LH, Rasmussen PC, Laurberg S. Value of laparoscopy before cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis. Br J Surg. 2013;100(2):285–292.
