Keywords
cytoreductive surgery - hyperthermic intraperitoneal chemotherapy - gastric cancer
- peritoneal carcinomatosis - palliative chemotherapy
Introduction
We analyze the results of the treatment with cytoreductive surgery (CRS) and hyperthermic
intraperitoneal chemotherapy (HIPEC) for patients with gastric cancer and peritoneal
carcinomatosis in Indian patients.
Methods
This is as retrospective single institutional study of patents diagnosed with gastric
carcinoma and peritoneal metastasis and treated with CRS and HIPEC from February 2015
to December 2019. All the patients with resectable peritoneal disease and no metastatic
disease, Eastern Cooperative Oncology Group (ECOG) 0/1, < 70 years of age, and preoperative
serum albumin > 3 g% were included in the study ([Table 1]). To be considered for CRS and HIPEC, patients should have a normal organ function
(serum creatinine < 1.5 × the upper limit of normal [ULN] or calculated creatinine
clearance of ≥ 50 mL/min; bilirubin less than 1.5 mg/dL; hepatic enzymes < 3 times
the ULN; white blood cell count ≥ 4,000/mm3; and platelet count ≥ 100,000/mm3). The patient cohort included cases undergoing upfront surgery, interval cytoreduction
after neoadjuvant chemotherapy (NACT), and those undergoing surgery for recurrent
disease. Patients with limited peritoneal dissemination (peritoneal cancer index [PCI] < 7)
confirmed by laparoscopy or laparotomy were subjected to CRS/HIPEC. Patients with
high disease burden and massive ascites were referred for NACT. Informed consent was
obtained from all patients. Ethics committee (EC) approval and Institutional Review
Board (IRB) approval was obtained. All patients were treated by a team of two surgeons,
anesthesiologist, intensivist, and medical oncologist having expertise in peritoneal
surface malignancy. The extent of intraperitoneal tumor manifestation is determined
using the PCI and a combined numerical score of lesion size (LS-0 to LS-3) and tumor
localization (region 0–12).[1] The aim of CRS is to obtain optimal cytoreduction (defined as CCR-0/1) as a precondition
for the application of HIPEC. Following cytoreduction, all patients underwent HIPEC
by semiopen technique with a dedicated HIPEC machine (RanD Biotech) using injection
mitomycin 35 mg/m2. Patient baseline demographics and perioperative details like PCI,[2] prior surgical score (PSS), the average blood loss, operative time, hospital stay,
and ICU stay were recorded prospectively in all patients. Adverse events are graded
according to common terminology criteria for adverse events (CTCAE). Clavien–Dindo
classification was used to grade surgical complications. In-hospital mortality was
recorded. Histopathology was assessed by dedicated oncopathologist. The patients were
followed up with regular upper gastrointestinal (GI) endoscopy and radiological monitoring
for any recurrence.
Table 1
Perioperative patient characteristics
|
Variable
|
n
|
|
Age (years) median
|
55.5
|
|
Hemoglobin (g/dl) mean
|
11.5
|
|
Albumin (g/dl) mean
|
3.8
|
|
Performance status
|
|
|
ECOG 0
|
12
|
|
ECOG 1
|
4
|
|
Comorbidity
|
4
|
|
Prior surgical score
|
|
|
0
|
16
|
|
1
|
0
|
|
2
|
0
|
|
3
|
0
|
|
NACT
|
|
|
Yes
|
6
|
|
Interval
|
10
|
Abbreviations: ECOG, Eastern Cooperative Oncological Group; NACT, neoadjuvant chemotherapy.
Statistical Analysis
Continuous variables are presented as mean with standard error of the mean or median
with range or interquartile range (IQR), as appropriate. Adverse events were recorded
and graded according to the CTCAE version 4.0. Survival was calculated in a Kaplan–Meier
survival curve. Progression-free survival (PFS) and overall survival (OS) both were
calculated from date of surgery.
Results
A total of 16 patients with gastric cancer and peritoneal carcinomatosis were operated
from February 2015 to December 2019 at Manipal Comprehensive Cancer Center. The median
age of our patients was 55.5 years. Prior surgical score was 0 for all 16 patients.
Six patients underwent upfront CRS, while 10 patients underwent interval CRS after
NACT. The mean number of cycles of NACT was 4.
The mean PCI was 3.5 (range 1–7), and adequate complete cytoreduction (CC) score of
0/1 was achieved in all patients. The mean duration of surgery was 8.5 hours; mean
intraoperative blood loss was 575 mL. Total gastrectomy and D2 lymphadenectomy were
performed in all patients. Total peritonectomy was performed in two patients; pelvic
peritonectomy was performed in 6 patients; and total omentectomy and lesser omentectomy
were performed in all patients. Bilateral salpingo-oophorectomy was performed in two
patients. Multivisceral resection (> 4 organs' resection) was done in one patient.
All patients received HIPEC with 35 mg/m2 of mitomycin C.
Seven patients were extubated in OT. Median intensive care stay was 2 days. Major
surgical complications were observed in 2 patients (12.5%) who had major surgical
site infections. Grade I surgical site infection was present in two patients. Six
patients had prolonged GI recovery. The 30-day mortality was zero.
Median follow-up time was 39 months. The median OS was 12 months (95% CI 6.86–17.13].
The median PFS was 17 months (95% CI 6.36–27.64) ([Fig. 1]).
Fig. 1 Overall survival (OS) curve and progression-free survival (PFS) curve.
Discussion
Systemic chemotherapy has improved the prognosis of patients with metastatic gastric
cancer, reaching survival of 8 to 14 months in selected series.[3] However, the response rate of measurable gastric peritoneal carcinomatosis to systemic
chemotherapy is only 14 to 25%, most likely attributable to poor penetration of systemic
chemotherapy across the blood-peritoneal barrier.[4]
A meta-analysis by Yan et al[5] on adjuvant regional chemotherapy for resectable gastric cancer has shown a survival
benefit from addition of intraperitoneal chemotherapy. A significant improvement in
survival was associated with HIPEC (hazard ratio [HR] = 0.60; 95% CI = 0.43 to 0.83;
p = 0.002) or HIPEC combined with early postoperative intraperitoneal chemotherapy
(HR = 0.45; 95% CI = 0.29 to 0.68; p = 0.0002). They also noted that Intraperitoneal chemotherapy was also found to be
associated with higher risks of intra-abdominal abscess (RR = 2.37; 95% CI = 1.32
to 4.26; p = 0.003) and neutropenia (RR = 4.33; 95% CI = 1.49 to 12.61; p = 0.007).
In the early 1990s, Sugarbaker et al introduced CRS and HIPEC as a new innovative
therapeutic option for selected patients with peritoneal carcinomatosis.[6]
A recent randomized control trial by Rudloff et al[7] comparing CRS-HIPEC with systemic chemotherapy demonstrated an overall survival
of 11.3 months in CRS-HIPEC arm versus 4.3 months in the chemotherapy alone arm.
Despite several studies reporting encouraging survival results with CRS + HIPEC in
patients with gastric cancer and peritoneal carcinomatosis,[3]
[8]
[9]
[10] its use has not been standardized. PCI and CC scores are known to be independent
prognostic factors after CRS plus perioperative chemotherapy.
From a systematic review and meta-analysis of data from 748 patients with peritoneal
metastasis, Coccolini et al[11] concluded that the PCI cutoff level can be 12 for better or worse prognosis. Accordingly,
peritonectomy and CRS are not recommended in patients with PCI higher than the cut-off
level. Yonemura et al[12] could show in a multivariate analysis that the completeness of cytoreduction is
a highly significant factor for the prediction of patient survival. He also determined
that the best results are obtained with PCI < 6.
The optimal cytoreduction, measured as CC score showed a survival benefit, according
to a systematic review by Coccolini et al. The OS increased by CC0-CC1 cytoreduction
in patients with peritoneal carcinomatosis of gastric origin.
Our study results, despite limited number of patients with a mean follow-up of 38
months, show recurrence-free and OS rates comparable with earlier published studies.
Mean PCI of our study was 3.5, which is a good prognostic factor, and optimal cytoreduction
(CC score 0/1) that we were able to achieve in all our patients may have contributed
to this.
Therefore, the use of CRS-HIPEC for selected patients with gastric cancer and peritoneal
carcinomatosis seems to improve survival, as evidenced by other systematic reviews.[13] Although the survival benefit is less encouraging than those obtained for other
peritoneal surface malignancies, a multidisciplinary approach for physically fit,
low burden disease with complete cytoreduction can be benefited.
Conclusion
Multidisciplinary treatment of perioperative chemotherapy with CRS and HIPEC is a
promising treatment option, which may prolong survival in selected patients (low peritoneal
disease burden, physically fit patients) with gastric carcinomatosis. Large randomized
clinical trials are warranted to prove its efficacy and become a standard of care.
