Synchronous versus metachronous onset of peritoneal metastases of colorectal carcinoma does not independently impact survival outcomes after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). A multi-center study of 390 patients found no significant difference in disease-free survival or overall survival based on synchronous versus metachronous onset after adjusting for other factors. Higher peritoneal cancer index, poor primary tumor differentiation, and positive nodal stage were independently associated with worse overall survival. Synchronous onset was associated with more extensive surgery but metachronous onset was associated with more severe postoperative complications.

1. Survival Outcomes After Cytoreductive Surgery with
Hyperthermic Intraperitoneal Chemotherapy in
Patients with Synchronous Versus Metachronous
Onset of Peritoneal Metastases of Colorectal
Carcinoma
Dr. Pradip Thapa
MCh Resident 1st Year

2. Dietz et al
Department of Surgical Oncology, Erasmus MC Cancer Institute,
Rotterdam
Department of Surgery, Radboud University Medical Center, Nijmegen
The Netherlands
October, 2022
Impact Factor: 13.78

3. ■ Colorectal cancer (CRC) is the 2nd most common malignancy worldwide.
■ 4-6 % presents with synchronous peritoneal metastasis.
■ 4% has localized metastasis to peritoneum only.
■ Anther 4-6% develops metachronous lesions in peritoneum.
INTRODUCTION
Bakkers et al. Ann Surg Oncol. 2021

4. ■ Poor prognosis with median overall survival of 5-7 months.
■ Administration of systemic chemotherapeutic regimens have slightly
increased median overall survival to 16 months.
■ Prognosis of peritoneal only metastasis is poor than liver only or lung only
metastasis ( 16.3 vs 19.1 vs 24.6 months).
Franko et al. Lancet Oncol 2016
INTRODUCTION

5. ■ Surgical management of peritoneal metastases of colorectal origin has
evolved.
■ Hyperthermic intraperitoneal chemotherapy (HIPEC) has been added to
cytoreductive surgery (CRS).
■ CRS plus HIPEC is superior to systemic chemotherapy with increased median
disease-free survival (DFS) and overall survival (OS) up to 20 and 41 months,
respectively.
Verwaal et al. J Clin Oncol 2003
INTRODUCTION

6. ■ CRS is an approach to cancer treatment that aims to reduce the number of
cancer cells via resection of primary tumor along with metastatic deposits.
■ Peritonectomy along with resection procedure of primary are combined to
complete the cytoreductive surgery in cases of peritoneal carcinomatosis.
INTRODUCTION
Quenet et al. PRODIGE 7 trial, Lancet Oncol. 2021

7. CRS depends on the distribution and extent of invasion of the malignancy
disseminated within the peritoneal space. The peritoneum, only that which is
implanted by cancer is excised.
INTRODUCTION

8. ■ HIPEC delivers high local concentrations of antineoplastic drugs, the
cytotoxic effects of which are enhanced by hyperthermia.
INTRODUCTION

9. INTRODUCTION
Sugarbaker et al. Turk J Colorectal Dis 2020

10. ■ CRS-HIPEC is associated with severe postoperative morbidity.
■ Only selected patients who are likely to benefit from this treatment should
be offered with this extensive treatment strategy.
■ Previous studies have identified the peritoneal cancer index (PCI) and
completeness of cytoreduction (CCR) among many as predictors of survival
after CRS-HIPEC.
Hompes et al. Ann Surg Oncol. 2012
Hallam et al. BJS. 2019
INTRODUCTION

11. ■ A recent study in metastatic CRC patients reported impaired survival in
patients with synchronous onset of peritoneal metastases.
■ A few groups have published conflicting data on the impact of s-PM versus
m-PM on survival outcomes in patients undergoing CRS-HIPEC.
INTRODUCTION
Coloca et al. Clin Transl Oncol. 2020

12. Hypothesis
■ Synchronous onset of colorectal PM is a negative prognostic
factor. More information about prognostic factors contributes to
a better estimation of the prognosis and could aid in shared
decision making.

13. Methods

14. Study Design
■ Retrospective study with prospectively collected data
■ Multi centre study
■ Study duration: March 2014 and June 2020

15. ■ Synchronous onset of PM (s-PM) was defined as a diagnosis of colorectal
PM at the time of presentation, during routine staging, or at primary
surgery.
■ If Colorectal PM were diagnosed in the follow-up period, the patients were
stratified in the metachronous onset (m-PM) group.
■ Disease-free interval (DFI) was defined as the time between diagnosis of the
primary tumor and the diagnosis of the PM. A cutoff value of 12 months
was used to stratify the DFI as short or long.
Definitions

16. Inclusion criteria:
■ Patients who underwent a complete CRS-HIPEC procedure for
colorectal PM in that study period.
Exclusion criteria:
■ Patients with appendiceal carcinomas or without histologically proven
PM.

17. Excluded:
Four patients in whom colorectal PM were not
histologically proven in the preoperative workup or
at CRS-HIPEC
394 patients who underwent a first CRS-HIPEC
procedure for colorectal PM
390 patients were included
Study flow chart
s-PM: 179 (45.9%) p-PM: 211 (54.1%)

18. ■ After referral for CRS-HIPEC, all patients were preoperatively screened.
■ Dedicated radiologists reviewed preoperative CT scans to determine the
extent of the disease.
■ If possible, patients underwent diagnostic laparoscopy (DLS).
■ The Patients were eligible for CRS-HIPEC if they were fit and had an estimated
PCI below 20 according to Jacquet and Sugarbaker without extra-abdominal
metastasis.
■ The presence of liver metastases was no definite contra-indication for CRS-
HIPEC.
Preoperative Course

19. ■ Performed by a specialized surgical team, in accordance with the Dutch CRS-
HIPEC protocol.
■ Postoperatively treated following standard of care for CRS-HIPEC procedures.
■ Severe postoperative complications were defined as Clavien–Dindo grade III
or higher.
■ The postoperative period was defined as the 30 days after CRS-HIPEC or the
duration of the entire hospital stay when exceeding 30 days.
Perioperative Course

20. In the Erasmus Medical Center:
■ CEA every three months and a CT scan six months, or as needed in case of rising
CEA levels, during the first 2 years of follow-up.
■ When patients were disease-free after 2 years, CEA every 6 months and a CT scan
every 12 months, or in case of rising CEA levels.
■ Follow-up was completed after a disease-free interval of 5 years following CRS-
HIPEC.
In the Radboud University Medical Center:
■ CEA and CT scans every 6 months during the 5 years of follow-up.
Follow-Up

21. ■ The primary outcomes of this study were DFS and OS.
■ DFS was defined as the time interval in months between CRS-HIPEC and
date of recurrence or date of last follow-up visit.
■ OS was defined as the time interval in months between CRS-HIPEC and
date of death or date of the last update of survival status.
Outcomes

22. ■ The primary outcomes of this study were DFS and OS.
■ DFS was defined as the time interval in months between CRS-HIPEC and
date of recurrence or date of last follow-up visit.
■ OS was defined as the time interval in months between CRS-HIPEC and
date of death or date of the last update of survival status.
Outcomes

23. Quantitative
Data
Qualitative
Data
Median with interquartile range
(IQR)
Mann-Whitney U test
Percentage
Chi square test or Fisher exact
test
Kaplan Meier test
The log-rank test
P < 0.05 was considered statistically significant
STATISTICAL ANALYSIS
To determine predictive factors for OS and DFS multivariable
cox regression analyses

24. Results

25. Baseline characteristics

26. Baseline characteristics: Contd

27. Baseline characteristics: Contd

28. Intraoperative characteristics and postoperative outcomes

29. Intraoperative characteristics and postoperative outcomes

30. Kaplan–Meier curves for DFS (A) and OS (B)
28 vs 33 months
9 vs 8 months

31. Cox proportional regression analysis for predictors of DFS

32. Cox proportional regression analysis for predictors of DFS:
Contd

33. Cox proportional regression analysis for predictors of OS

34. DISCUSSION

35. ■ Median OS was shorter for s-PM (28 months) compared to m-PM patients
(33 months, p = 0.045). However, the onset of PM was not associated
with OS in multivariable analysis (p = 0.193).
■ Factors that were independently associated with OS in multivariable
analysis were:
■ N stage (HR 1.76, 95% CI 1.9–2.84, p = 0.020),
■ poor differentiation of the primary tumor (HR 1.95, 95% CI 1.32–
2.90), and
■ PCI (HR 1.07, 95% CI 1.03–1.10, p=0.001)

36. ■ A study by Hentzen et al. in the Netherlands reported a decreased DFS (15
months for s-PM vs. 11 months for m-PM patients) , but not OS, after CRS-
HIPEC, in contradictory of the hypothesis that synchronous onset would
predict poor survival.
■ This is probably explained by the use of perioperative chemotherapy.
■ In this study the use of perioperative chemotherapy was associated with
longer DFS in univariable, but not in multivariable analysis as there is no
consensus in the field regarding the use of perioperative systemic
chemotherapy around CRS-HIPEC.
Hentzen et al. Ann Surg Oncol. 2019

37. ■ An ongoing randomized controlled trial, CAIRO-6 trial in the
Netherlands, comparing perioperative systemic therapy and CRS-HIPEC
with CRS-HIPEC alone will give clarity about the role of perioperative
chemotherapy
Rovers et al. BMC Cancer. 2019

38.  A total of 287 patients (77.2%) had a recurrence of disease during follow-up .
Majority (37.6%) had peritoneal recurrence.
 For the s-PM patients, the median DFS was 9 months, compared with 8
months for the m-PM patients (p = 0.962).
 Multivariable analysis showed that age (HR 0.99, 95% CI 0.97–1.00, p =
0.035) and PCI (1.05, 95% CI 1.02–1.07, p = 0.001) were independently
associated with DFS.

39. ■ For patients with metachronous onset of PM, the time interval between
diagnosis of the primary tumor and the diagnosis of PM (DFI) was neither
associated with DFS, nor with OS.
■ This supports the hypothesis that the time of onset of PM is not an
independent prognostic factor.

40. ■ As CRS-HIPEC was more often the primary treatment for s-PM patients,
bowel resections, and the creation of an anastomosis and/or stoma were
more often performed in this group.
■ However, significantly more severe complications (i.e., Clavien-Dindo C III)
and reoperations after CRS-HIPEC were reported in m-PM patients.
■ Several previous studies showed that extensive prior surgery is a risk factor
for the occurrence of complications after CRS-HIPEC.
Baumgartner et al. Ann Surg Oncol.
2016

41. ■ In the current study, severe postoperative complications (Clavien- Dindo C III) were
associated with poorer OS in univariate but not in multivariate analysis.
■ This is probably explained by the association of postoperative complications with higher PCI,
reflecting extensive surgery.
■ PCI was the only variable that was independently associated with both DFS and OS.
■ A currently ongoing trial, DISCO-trial in Netherlands,, was initiated to determine the role of
MRI in detecting colorectal PM in patients who are considered for CRS-HIPEC, which may
come up with improved preoperative PCI estimation.
Baumgartner et al. Ann Surg Oncol.

42. CONCLUSION
■ Synchronous onset of colorectal PM was associated with impaired
overall survival.
■ Tumor differentiation, lymph node status, and PCI were more valuable
predictors for survival after CRS-HIPEC and are important factors that
could aid in shared decision making

43. Strength
 Prospectively maintained data
 Multi center study
 Enough sample size

44. Limitation
 Retrospective nature
 Patient characteristics were not comparable with lots of confounding
factors influencing overall outcomes.
 Relatively short follow-up for surviving patients.

45. Author/Jour
nal/
Year
Methodology Title Result
Hentzen et
al Ann Surg
Oncol 2019
Retrospective study of
433 Patients with
histologically proven
colorectal PM who
underwent CRS with
HIPEC between Feb
2006 and Dec 2017 in
two Dutch tertiary
referral hospitals.
Impact of Synchronous
Versus Metachronous
Onset of Colorectal
Peritoneal Metastases on
Survival Outcomes After
CRS with HIPEC: A
Multicenter, Retrospective,
Observational Study
53% had s-CRPM and 47% had M-
CRPM. The major postoperative
complication rate and median OS were
similar (26.8% vs 29.7%; p = 0.693
and 34 vs 33 months, respectively; p =
0.819). The median DFS was
significantly decreased for the patients
with m-CRPM (11 vs 15 months).
m-CRPM is associated with early
recurrence after CRS with HIPEC
compared with s-CRPM, without a
difference in OS or major postoperative
complications.
.
Literature review

46. Literature review
Author/Journa
l
Methodology Title Result
Wong et al.
World Journal
of Surgical
Oncology
A retrospective analysis of
102 CPM patients treated
with CRS and HIPEC at the
National Cancer Centre,
Singapore over 15 years.
.
The importance of
synchronicity in the
management of
colorectal peritonea
metastases with CRS and
HIPEC.
19.6% patients had s-CPM and 80.4%
had m-CPM.
Recurrences occurred in 45% of s-CPM
and in 54% of m-CPM (p = 0.619).
Median overall survival was prolonged
in patients with m-CPM (45.2 versus
26.9 months, p = 0.025).
A survival advantage was seen a
subset of m-CPM patients, possibly
representing differences in disease
biology.
.

47. Literature review
Author/Jour
nal
Methodology Title Result
Bakers et
al. Ann Surg
Oncol. 2021
743 patients from the
Netherlands Cancer Registry
with the diagnosis of CPM,
including 409 patients with
synchronous CPM and 334
patients with metachronous
CPM.
Treatment Strategies and
Prognosis of Patients
With Synchronous or
Metachronous Colorectal
Peritoneal Metastases: A
Population- Based Study
The median OS was 8.1 months for the
patients with s-CPM vs 12 months for
the patients with m-CPM (p = 0.003).
After multivariable correction, OS no
longer differed (HR 1.03).
The two groups did not differ
statistically in terms of DFS (median
DFS, 21.5 vs 14.1 months, p = 0.094).
This suggests that a similar prognosis
may be expected for patients selected
for treatment regardless of the onset
of CPM.
.

48. ■ Regardless of the time of occurrence of peritoneal metastasis,
synchronous or metachronous, selected patients with CRPM with
low PCI and favorable tumour biology can be undertaken for CRS-
HIPEC, in high volume dedicated centers to have improved survival.
Take Home message

49. Thank you