Table 5 summarizes clinicopathological characteristics of the PMP-patients, stratified according to treatment. Sixty-two patients were treated with CRS-HIPEC, comprising 36 women (58%) and 26 men (42%), median age was 56 years (27-78). Fifteen patients were treated with surgery only, comprising 12 women (80%) and 3 men (20%). Median age in the surgery only group was 64 years (38-82). Median PCI was 22 (3-39) in the CRS-HIPEC group and 35 (14-39) in the surgery-only group. With the exception of one case with urachus as the primary site, all cases had verified (n=71) or probable (n=5) appendiceal origin.
Histopathological classification in the CRS-HIPEC group showed low grade histology in 48 patients (77%) and high grade in 14 (23%). In the surgery only group histopathological classification showed low grade in 9 patients (60%) and high grade in 6 (40%). In the CRS-HIPEC group, 17 patients (27%) experienced disease recurrence; with PM only (n=15) and PM and distant metastasis (n=2) as the first registered recurrence. Eight patients (13%) died within the follow-up period in the CRS-HIPEC group, and 9 (60%) in the surgery only group.
Table 5 - Patient characteristics for the PMP patients, stratified according to treatment
CRS-HIPEC Surgery only
Distant metastasis only 0 (0)
*CRS, cytoreductive surgery, DFS disease-free survival, HIPEC, hyperthermic intraperitoneal chemotherapy, OS, overall survival, PCI, peritoneal cancer index, PM, peritoneal metastasis, PMP-pseudomyxoma peritonei
13 Table 6 summarizes survival data. For the group receiving CRS-HIPEC, the estimated 5-and 10-year OS were 88% and 73%, respectively, with a follow-up time of 51 months (95%CI 38-64). Median follow-up time was 25 months (95% CI 17-33) for DFS. Estimated median OS and estimated median DFS was not reached in the CRS-HIPEC group, because of a low mortality and recurrence rate within the follow-up period. In the surgery only group, the estimated 5-year and 10-year OS were 0%, estimated median OS was 27 months (95% CI 7-47), with a median follow-up time of 39 months (95% CI 17-61). Univariable analyses using the Kaplan Meier method in the CRS-HIPEC group showed statistically significant
association between OS and histopathological subtype (p=0.01), PCI when stratified in to the groups 0-10, 11-20, 21-30 and >30 (p=0.02) and gender (p=0.02).
Table 6 – survival data and univariable analysis of OS in the PMP group
No. of patients OS (%) P
Histopathological classification 0.01
Low grade 48 90 90
High grade 14 78 46
*CRS, cytoreductive surgery, HIPEC, hyperthermic intraperitoneal chemotherapy, OS, overall survival, PCI, peritoneal cancer index, PM, peritoneal metastasis, PMP, pseudomyxoma peritonei
14
Fig. 4. Overall survival (OS) and histopathological differentiation after cytoreductive surgery (CRC) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with pseudomyxoma peritonei (PMP)
15
4 Discussion
This project thesis describes long-term outcome and associated prognostic factors for a selected group of patients in which tumor tissue samples were collected and stored in a biobank for molecular analyses. This method of selection differ somewhat from what is most common for cohort studies; consecutive patient series including all patients treated in a certain time period. By selecting patients based on availability of tumor samples, all PM-CRC and PMP patients at our institution were not included and we cannot exclude that there could be a potential selection bias. However, the present results are in line with previous cohort studies on PM-CRC and PMP from the same institution, supporting that our patient cohort is representative.
The survival analysis in this project thesis has mainly focused on the group undergoing CRS-HIPEC, implicitly having achieved complete cytoreduction. Patients (both PMP and PM-CRC) with too extensive disease to undergo CRS-HIPEC may not always be recognized by pre-operative work-up. This may lead to surgery where the aim or hope is to do CRS-HIPEC, but where the surgeons during assessment of peritoneal distribution or later recognize that complete cytoreduction is not achievable and the procedure is thus converted to explorative and/or debulking surgery. These patients may also have other comorbid factors that will affect their prognosis negatively. If these patients were included in survival analyses using an intention-to treat approach, the efficacy of CRS-HIPEC would be underestimated [20]. For this reason we have separated the CRS-HIPEC patients from the surgery only patients, and the difference in outcome is in line with what we expected, with a median OS of 42 months for CRS-HIPEC, vs. 16 months for surgery only (PM-CRC group). In the PMP group the five-year OS for the CRS-HIPEC was 88 %, vs 0% in the surgery only group.
In the PM-CRC group treated with CRS-HIPEC the five-year OS was 36 % with a median OS of 42 months, which is in line with results from a previous publication from our institution [13]. This previous publication included PM-CRC patients undergoing CRS-HIPEC, where 22 out of 119 patients overlap with our present PM-CRC CRS-HIPEC group (N=79). Other tertiary referral centers have reported similar OS [9, 12, 24]. This survival rate is considerably longer than for patients receiving contemporary systemic chemotherapy where a median OS of 17 months has been reported [11].
16
Although CRS-HIPEC has improved outcome in PM-CRC, recurrence of disease will occur in approximately 50 % of the patients within the first year [25-27]. Estimated median DFS in our cohort was 11 months for PM-CRC patients undergoing CRS-HIPEC. This is also in line with previous reports [8, 13]. Despite the relatively short DFS, the improvement in OS remains high in patients who completed CRS-HIPEC. This supports that CRS-HIPEC can be beneficial to PM-CRC patients despite high recurrence rates.
Follow-up time for DFS was relatively short, with an estimated median of 18 months. This may affect the significance and reliability of these results. For OS follow-up time was considerably longer, with an estimated median follow-up of 32 months.
In our analyses of the PM-CRC group PCI was the only parameter associated with OS using Cox-regression analysis, and was also borderline significantly associated with DFS. However, when stratifying patients according to PCI, we saw a relatively similar OS (42 vs 43 months) and DFS (10 vs 14 months) in the PCI 11-20 group and PCI >20 group. Other studies have reported PCI as a prognostic factor in PM-CRC patients, and many centers have regarded PCI>20 as a relative contraindication to CRS-HIPEC for PM-CRC [25, 28, 29]. One study that found a linear correlation between PCI and OS has suggested PCI 12-17 and PCI>17 as relative and absolute contraindications [30]. Authors at our institution previously found that a cut-off value of PCI >12 corresponded to 100 % specificity for prediction of recurrence, and also points out that there is no difference in the long-term outcome for patients with PCI 11-20 and PCI>11-20 [13], which is in line with the present study. Although the finding of
association between PCI and long-term outcome is in line with most of the literature in this field, the similar OS and DFS found in the PCI > 20 group is somewhat unexpected and has no obvious explanation. The PCI>20 group is however relatively small (n=12), and it is possible that the long survival of these patients could be related to a high prevalence of
favorable prognostic factors in the group, such as age, low comorbidity and good performance status, making them eligible for CRS-HIPEC despite a high PCI.
Another factor that could influence the PCI/survival association is the heterogeneity of the cancer types in the group, as we have included primary tumors from different locations in the intestine, including appendix and two cases of tumors in the distal ileum. Four out of twelve cases in the PCI>20 group were appendiceal primary tumors. It will be interesting to see the awaited molecular analyses, hoping that they can provide some more insight regarding
17 variation in tumor biology and location in the intestine, and implications this may have on survival.
For the PMP CRS-HIPEC group, the estimated 5-and 10-year OS were 88% and 73 %, which is in line with published results from our institution [20] and others [19, 31]. Low-grade histopathological differentiation (p=0.01), low PCI when stratified into four groups (p=0.02), and female gender (p=0.02) were all found to be positively associated with OS in univariable analyses. Although the findings are in line with what we expected, the reliability of these findings is however of some uncertainty, as we only have uni- and not multivariable analyses.
It is possible that the factors confound each other. However, follow-up time in the PMP group was relatively long, with an estimated median of 51 months for OS and 25 months for DFS.
Histopathological differentiation has been regarded as the most important prognostic factor in patients with PMP treated with CRS-HIPEC [20, 32, 33]. Although the terminology and classification may vary in the literature, it is a common finding that disease with high-grade histologic features has a less favorable prognosis than disease with low-grade histologic features. Some therefore argue that in patients with a high-grade histopathology one should use a similar approach for surgery and apply PCI cut-off values as in PM-CRC [34]. Others have concluded that the acceptable OS found in the high grade group with PCI>20 should advocate that PCI>20 should not be used as an exclusion criterion for CRS-HIPEC [20, 35]
given that they present clinically with PMP and that complete CRS is achievable.
In this study, PCI when stratified into four groups was associated with OS (p=0.02) for the PMP group. However as noted above, this is not adjusted for histopathological differentiation.
A recent multi-center study looking at peritoneal dissemination from high-grade appendiceal primaries, found that PCI was not predictive of survival after CRS-HIPEC [36]. This is in contrast to our finding, but the results are not completely comparable as the patient groups are different regarding burden of high grade histological differentiation. The literature is divided when it comes to PCI as a prognostic factor in PMP, and although we find a significant association between PCI and OS in the present study, this must be interpreted with caution because of a small cohort (N=62) and for this reason, multivariable analysis was not performed.
18
The observation of female gender as a factor positively associated with OS in PMP has been shown before [20, 34], and although it is an interesting observation we see no obvious explanation for this finding.
This present study has the limitations of a single-institutional cohort analysis, including potential selection bias, institutional learning curves, and to some extent retrospective data-collection. Although most data was prospectively registered in our database, some missing data had to be obtained from charts or remained missing. The extent of patient characteristics, outcome data and statistical analyses presented in the project thesis is limited. This is mostly due to the purpose being data collection for a molecular study, and the timeframe of the project thesis. Nonetheless, the overall results that have been presented correspond well with previously published studies from our institution on similar patient cohorts [13, 20].
19
5 Conclusions
Patients with PM-CRC and PMP treated with CRS-HIPEC achieved satisfactory long-term outcome in accordance with results from previous reports. Patients in the surgery only group had a much less favorable outcome. PCI was the only prognostic factor significantly
associated with OS in PM-CRC patients treated with CRS-HIPEC. OS was considerably longer than DFS in the PM-CRC group. The strongest prognostic factors in PMP patients treated with CRS-HIPEC were PCI and histopathological differentiation. Further studies are needed to establish common selection criteria for CRS-HIPEC.
20
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