Research

JAMA Surgery | Original Investigation

Survival After Hyperthermic Intraperitoneal Chemotherapy

and Primary or Interval Cytoreductive Surgery in Ovarian Cancer
A Randomized Clinical Trial
Myong Cheol Lim, MD, PhD; Suk-Joon Chang, MD, PhD; Boram Park, PhD; Heon Jong Yoo, MD, PhD; Chong Woo Yoo, MD, PhD;
Byung Ho Nam, PhD; Sang-Yoon Park, MD, PhD; for the HIPEC for Ovarian Cancer Collaborators

Invited Commentary page 383

IMPORTANCE Ovarian cancer has the highest mortality rate among gynecologic malignant Supplemental content
tumors. Data are lacking on the survival benefit of hyperthermic intraperitoneal
chemotherapy (HIPEC) in women with ovarian cancer who underwent primary or interval
cytoreductive surgery.

OBJECTIVE To assess the clinical benefit of HIPEC after primary or interval maximal
cytoreductive surgery in women with stage III or IV primary advanced ovarian cancer.

DESIGN, SETTING, AND PARTICIPANTS In this single-blind randomized clinical trial performed at
2 institutions in South Korea from March 2, 2010, to January 22, 2016, a total of 184 patients
with stage III or IV ovarian cancer with residual tumor size less than 1 cm were randomized
(1:1) to a HIPEC (41.5 °C, 75 mg/m2 of cisplatin, 90 minutes) or control group. The primary end
point was progression-free survival. Overall survival and adverse events were key secondary
end points. The date of the last follow-up was January 10, 2020, and the data were locked on
February 17, 2020.

EXPOSURES Hyperthermic intraperitoneal chemotherapy after cytoreductive surgery.

MAIN OUTCOMES AND MEASURES Progression-free and overall survival.

RESULTS Of the 184 Korean women who underwent randomization, 92 were randomized to
the HIPEC group (median age, 52.0 years; IQR, 46.0-59.5 years) and 92 to the control group
(median age, 53.5 years; IQR, 47.5-61.0 years). After a median follow-up of 69.4 months (IQR,
54.4-86.3 months), median progression-free survival was 18.8 months (IQR, 13.0-43.2
months) in the control group and 19.8 months (IQR, 13.7-55.4 months) in the HIPEC group
(P = .43), and median overall survival was 61.3 months (IQR, 34.3 months to not reported) in
the control group and 69.5 months (IQR, 45.6 months to not reported) in the HIPEC group
(P = .52). In the subgroup of interval cytoreductive surgery after neoadjuvant chemotherapy,
the median progression-free survival was 15.4 months (IQR, 10.6-21.1 months) in the control
group and 17.4 months (IQR, 13.8-31.5 months) in the HIPEC group (hazard ratio for disease
progression or death, 0.60; 95% CI, 0.37-0.99; P = .04), and the median overall survival was
48.2 months (IQR, 33.8-61.3 months) in the control group and 61.8 months (IQR, 46.7
months to not reported) in the HIPEC group (hazard ratio, 0.53; 95% CI, 0.29-0.96; P = .04).
In the subgroup of primary cytoreductive surgery, median progression-free survival was 29.7
(IQR, 17.2-90.1 months) in the control group and 23.9 months (IQR, 12.3-71.5 months) in the
HIPEC group, and the median overall survival was not reached in the control group and 71.3
months (IQR, 45.6 months to not reported) in the HIPEC group.

CONCLUSIONS AND RELEVANCE The addition of HIPEC to cytoreductive surgery did not
improve progression-free and overall survival in patients with advanced epithelial ovarian
Author Affiliations: Author
cancer. Although the results are from a subgroup analysis, the addition of HIPEC to interval
affiliations are listed at the end of this
cytoreductive surgery provided an improvement of progression-free and overall survival. article.

TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01091636 Group Information: A complete list

of the members of the HIPEC for
Ovarian Cancer Collaborators appears
in Supplement 3.
Corresponding Author: Sang-Yoon
Park, MD, PhD, Center for
Gynecologic Cancer, National Cancer
Center, 323 Ilsan-ro, Ilsandong-gu,
JAMA Surg. 2022;157(5):374-383. doi:10.1001/jamasurg.2022.0143 Goyang, Gyeonggi 10408, South
Published online March 9, 2022. Korea (parksang@ncc.re.kr).

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 Survival After Hyperthermic Intraperitoneal Chemotherapy and Primary or Interval Cytoreductive Surgery in Ovarian Cancer
W
omen with ovarian, fallopian, and primary perito-
neal cancer are frequently diagnosed with perito-
neal carcinomatosis, which has the highest mortal-
ity rate among gynecologic malignant tumors with an
age-standardized, 5-year net survival rate of 37% to 43%.1,2 The
standard treatment involves maximal cytoreductive surgery fol-
lowed by adjuvant chemotherapy to minimize the residual tu-
mor size.3 Moreover, neoadjuvant chemotherapy can also be
used in selected patient populations with severe medical ill-
ness or unresectable tumor burden.3 Intraperitoneal chemo-
therapy increases progression-free and overall survival among
patients with ovarian cancer who undergo cytoreductive sur-
gery for a residual tumor size of less than 1 cm.3,4 The survival
benefits of intraperitoneal chemotherapy extend for more than
10 years.5 However, despite the long-term survival benefits, port-
related adverse effects, abdominal pain, and additional effort
required for the management of an intraperitoneal catheter limit
the use of intraperitoneal chemotherapy.6
Hyperthermic intraperitoneal chemotherapy (HIPEC) in-
volves intraperitoneal chemotherapy, which does not require
a postoperative intraperitoneal port and is accompanied with
heated chemotherapeutic agents that are administered im-
mediately after cytoreductive surgery. The intraoperative ad-
ministration of HIPEC before any surgical adhesions can con-
fer several potential treatment benefits. Several retrospective
studies7,8 have suggested the survival benefits of HIPEC in pri-
mary and recurrent ovarian cancer. The results from a ran-
domized trial9 (Interval Debulking Surgery +/− Hyperthermic
Intraperitoneal Chemotherapy in Stage III Ovarian Cancer
[OVHIPEC-01]) indicated the clinical benefit of HIPEC after in-
terval cytoreductive surgery subsequent to neoadjuvant che-
motherapy for stage III primary ovarian cancer with regard to
decreased recurrence and mortality rates. However, further evi-
dence from a clinical trial is needed to resolve several issues,
including the lack of a selection flowchart after neoadjuvant
chemotherapy, disproportionate histologic types, a bias in sur-
gical radicality, or underreported adverse events, found in a
previous study.10 Furthermore, the clinical benefit of HIPEC
in an extended study population, including patients with stage
IV primary ovarian cancer and those who have undergone pri-
mary cytoreductive surgery, needs to be investigated.
Following the confirmation of the feasibility and safety of
HIPEC after primary or interval maximal cytoreductive sur-
gery from a phase 2 study11 in 2009, the current randomized
clinical trial was initiated in 2010. This trial was conducted to
assess the clinical benefit of HIPEC after primary or interval
maximal cytoreductive surgery in women with stage III or IV
primary advanced ovarian cancer.
Methods
Study Design
This single-blind randomized clinical trial was conducted at
2 institutions in South Korea (National Cancer Center and Ajou
University Hospital) from March 2, 2010, to January 22, 2016.
The date of the last follow-up was January 10, 2020, and the
data were locked on February 17, 2020. This trial was
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Original Investigation Research
Key Points
Question Does hyperthermic intraperitoneal chemotherapy
(HIPEC) after primary or interval cytoreductive surgery increase
survival in patients with ovarian cancer?
Findings In this randomized clinical trial of 184 women with
ovarian cancer, among those who underwent interval
cytoreductive surgery after neoadjuvant chemotherapy, the
addition of HIPEC decreased recurrence and increased overall
survival; however, in patients undergoing primary cytoreductive
surgery, progression-free survival and overall survival were not
improved. No unresolved serious HIPEC-related adverse events
were found in either group.
Meaning These results suggest that HIPEC after interval
cytoreductive surgery may increase progression-free and overall
survival in patients with ovarian cancer who receive neoadjuvant
chemotherapy.
approved by the institutional review boards of both institu-
tions. The study was conducted in accordance with the Dec-
laration of Helsinki.12 Written informed consent for this trial
was preoperatively obtained from women who were eligible
for primary or interval cytoreductive surgery. The trial proto-
col can be found in Supplement 1. This study followed the Con-
solidated Standards of Reporting Trials (CONSORT) reporting
guideline.
Study Participants
Eligible patients were younger than 75 years with newly diag-
nosed advanced (Internal Federation of Gynecology and Ob-
stetrics stage III or IV) epithelial ovarian, primary peritoneal,
or fallopian tube cancer. Neoadjuvant chemotherapy was of-
fered based on the judgment of the surgeon in conformance
with the institutional criteria using computed tomographic
findings and performance.13 Randomization of the study par-
ticipants is shown in Figure 1. After 3 cycles of neoadjuvant che-
motherapy with carboplatin (area under the curve of 5 mg/mL
per minute) and paclitaxel (175 mg/m2 of the body surface area),
patients were assessed for a partial response and stable dis-
ease. All patients who had an Eastern Cooperative Oncology
Group performance status of 0 or 1, residual tumor smaller than
1 cm, age older than 75 years, and adequate hematologic func-
tion (white blood cell count of ≥3000/μL [to convert to ×109/L,
multiply by 0.001] and platelet count of ≥100.0 × 103/μL [to
convert to ×109/L, multiply by 1]), liver function (serum bili-
rubin level ≤1.5 mg/dL [to convert to micromoles per liter, mul-
tiply by 17.104] and alanine aminotransferase, aspartate ami-
notransferase, and alkaline phosphatase levels ≤80 IU/L [to
convert to microkatals per liter, multiply by 0.0167]), and re-
nal function (creatinine level ≤1.5 mg/dL [to convert to micro-
moles per liter, multiply by 88.4]) were included in this study.
The main exclusion criteria were unresectable extraperito-
neal metastasis (brain, bone, lung parenchyma, or lymph node);
residual tumor 1 cm or larger; previous other malignant tu-
mors; serious heart, kidney, or pulmonary insufficiency; preg-
nant or breastfeeding; considered unsuitable by a physician;
or no pathological diagnosis of cancer during cytoreductive sur-
gery after neoadjuvant chemotherapy.
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 Research Original Investigation Survival After Hyperthermic Intraperitoneal Chemotherapy and Primary or Interval Cytoreductive Surgery in Ovarian Cancer
Figure 1. Flowchart of Enrollment and Randomization
274 Patients enrolled
46 Excluded before surgery
49 Excluded intraoperatively 10 Screening failure
4 Residual disease 27 Suspected early-stage disease
1 Severe adhesion 7 Suspected extraperitoneal
2 Technical issue with HIPEC disease
28 No cancer on frozen section 2 Withdrawal of consent
biopsy
14 Incidental intraoperative
complications
184 Randomized
92 Randomized to undergo 92 Randomized to undergo
cytoreductive surgery cytoreductive surgery
without HIPEC with HIPEC
3 Loss to 1 Loss to
follow-up follow-up
92 Included in the intention-to-treat 92 Included in the intention-to-treat
analysis and safety analysis analysis and safety analysis
HIPEC indicates hyperthermic intraperitoneal chemotherapy.
Both primary and interval cytoreductive surgical proce-
dures were offered as treatment options in these patients.11,13
The vaginal stump and resected diaphragm were closed to en-
sure a water-tight fit, and bowel anastomosis was completed
before randomization.
Setting
An independent statistical center randomly assigned the par-
ticipants to the HIPEC group or the control group. Partici-
pants were blinded to the group allocation. Patients were in-
traoperatively randomized into the HIPEC and control groups
in a 1:1 manner at the completion of cytoreductive surgery if
the estimated residual tumor size was less than 1 cm. Intraop-
erative HIPEC (75 mg/m2 of cisplatin) was perfused through a
closed technique with a target temperature of 41.5 °C for 90
minutes using the Belmont Hyperthermia Pump system
(Belmont Instrument Corporation), as previously reported.11
Women randomized to the HIPEC group received blanket cool-
ing, intravenous cold fluid hydration, and ice pack applica-
tion over the head before and during HIPEC procedures. Af-
ter the cytoreductive and reconstructive surgical procedures,
2 inflow and 2 outflow tubes were placed in the pelvic cavity
and in the subdiaphragmatic space, respectively. The abdomi-
nal wall was closed in layers with a water-tight fit, and 0.9%
normal saline was injected into the closed abdominal cavity.
After smooth circulation to and from the HIPEC pump was con-
firmed, the chemotherapeutic agent was mixed with the cir-
culating fluid. During the 90-minute HIPEC perfusion proce-
dure, the patients were gently shaken from side to side to
ensure even distribution of the chemotherapeutic agent within
the peritoneal cavity. Sodium thiosulfate was not used in the
initial 71 cases, given the low incidence of serum creatinine
elevation in the phase 2 study.11 However, in the remaining 21
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patients, 4 g/m2 of sodium thiosulfate was administered as a
bolus infusion immediately before HIPEC, and 12 g/m2 was ad-
ministered over 6 hours during and after the HIPEC proce-
dures. Four intraperitoneal thermometer readings for each ab-
dominal quadrant, a nasopharyngeal temperature probe, and
manual tube checks were undertaken at 5-minute intervals to
monitor the peritoneal and core body temperatures. During
postoperative recovery, if the patients could tolerate a gen-
eral diet without evidence of active infection and with an ac-
ceptable clinical condition to sustain chemotherapy, we ad-
ministered 6 cycles of intravenous paclitaxel and carboplatin
in both groups. After completion of adjuvant chemotherapy,
follow-up with the CA125 test and computed tomography was
conducted every 3 months for 2 years, every 6 months for up
to 5 years, and yearly thereafter.
Outcomes
Progression was defined by a clinical decision that was based
on radiologic findings of tumor growth (Response Evaluation
Criteria in Solid Tumors criteria 1.1) or biochemical assess-
ment of the Gynecologic Cancer InterGroup CA125 criteria,
whichever occurred first.14,15 The primary end point was pro-
gression-free survival, which was defined as the time from the
date of randomization to the date of disease progression or
death from any cause, whichever occurred first. Secondary end
points included overall survival and adverse events. Overall
survival was defined as the time from randomization to the
date of death from any cause. Survival data were censored at
the date of the last follow-up. An adverse event was evalu-
ated using the Common Terminology Criteria for Adverse
Events from randomization to the initiation of the first adju-
vant chemotherapy and thereafter to 6 weeks after the last
adjuvant chemotherapy.
Sample Size
A log-rank test with an overall sample size of 184 individuals
(92 in the control group and 92 in the treatment group) achieves
55.1% and 81.0% power at a P < .05 significance level to de-
tect hazard ratios (HRs) of 0.75 and 0.66 when median sur-
vival time of the control group is 18.0 months.16 The number
of events required is 150 patients in the total set (80 in the con-
trol group and 70 in the treatment group). The total study pe-
riod was 8 years, allowing 6 years as an accrual period and 2
years as a follow-up period after the last patients were
accrued.
Statistical Analysis
All analyses were performed on the intention-to-treat popula-
tion. The Kaplan-Meier method and log-rank test were used to
estimate and compare survivals between the 2 groups. The Cox
proportional hazards regression model was used to estimate HRs
and 95% CIs in univariable and multivariable models. Sub-
group analysis was performed according to the use of neoad-
juvant chemotherapy. The additional subgroup analysis re-
sults were reported with HRs (95% CIs) using a forest plot.
Differences for adverse events were calculated using the pro-
portion of the HIPEC group minus the proportion of the con-
trol group. Differences and 95% CIs were presented as
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 Survival After Hyperthermic Intraperitoneal Chemotherapy and Primary or Interval Cytoreductive Surgery in Ovarian Cancer Original Investigation Research

Table 1. Baseline Patient Characteristics and Treatment-Related Variablesa

Total Cytoreductive surgery

Primary Interval
Control HIPEC
Variable (n = 92) (n = 92) Control (n = 49) HIPEC (n = 58) Control (n = 43) HIPEC (n = 34)
Age, median (IQR), y 53.5 (47.5-61.0) 52.0 (46-59.5) 53.0 (47.0-61.0) 51.0 (45.0-58.0) 54.0 (48.0-61.0) 55.0 (47.0-64.0)
Serum albumin, median (IQR), g/dL 4.3 (4-4.5) 4.3 (4-4.6) 4.1 (3.9-4.4) 4.1 (3.8-4.6) 4.4 (4.1-4.6) 4.4 (4.1-4.7)
FIGO stageb
III 51 (55.4) 60 (65.2) 34 (69.4) 45 (77.6) 17 (39.5) 15 (44.1)
IV 41 (44.6) 32 (34.8) 15 (30.6) 13 (22.4) 26 (60.5) 19 (55.9)
Histologic type
Serous 79 (85.9) 85 (92.4) 41 (83.7) 53 (91.4) 38 (88.4) 32 (94.1)
Endometrioid 5 (5.4) 3 (3.3) 3 (6.1) 3 (5.2) 2 (4.7) 0
Clear cell 4 (4.4) 0 3 (6.1) 0 1 (2.3) 0
Others 4 (4.4) 4 (4.4) 2 (4.1) 2 (3.5) 2 (4.7) 2 (5.9)
Neoadjuvant chemotherapy
No 49 (53.3) 58 (63.0) 49 (100) 58 (100) 0 0
Yes 43 (46.7) 34 (37.0) 0 0 43 (100) 34 (100)
Peritoneal carcinomatosis index scorec
0-5 29 (31.5) 22 (23.9) 16 (32.7) 14 (24.1) 13 (30.2) 8 (23.5)
6-10 63 (68.5) 70 (76.1) 33 (67.4) 44 (75.9) 30 (69.8) 26 (76.5)
Residual disease after
cytoreductive surgery
Microscopic 80 (87.0) 75 (81.5) 43 (87.8) 48 (82.8) 37 (86.0) 27 (79.4)
Macroscopic 12 (13.0) 17 (18.5) 6 (12.2) 10 (17.2) 6 (14.0) 7 (20.6)
Bowel surgery
No 24 (26.1) 19 (20.7) 11 (22.5) 7 (12.1) 13 (30.2) 12 (35.3)
Yes 68 (73.9) 73 (79.4) 38 (77.6) 51 (87.9) 30 (69.8) 22 (64.7)
Rectosigmoid resection
No 30 (32.6) 28 (30.4) 15 (30.6) 15 (25.9) 15 (34.9) 13 (38.2)
Yes 62 (67.4) 64 (69.6) 34 (69.4) 43 (74.1) 28 (65.1) 21 (61.8)
Time of operation, 405.0 525.0 426.0 529.5 384.0 506.5
median (IQR), min (330.5-476.5) (463.5-575.0) (340.0-500.0) (486.0-577.0) (328.0-437.0) (449.0-570.0)
Duration of hospital stay, 14 (12-23.5) 17 (13-23) 15 (13-29) 16 (14-22) 14 (12-20) 17 (13-27)
median (IQR), d
Time between surgery and initiation 20 (18-27) 22 (19-25) 23 (19-27) 21 (19-26) 20 (16-24) 22 (19-24)
of the adjuvant chemotherapy,
median (IQR), d
Time between end of first 111 (105-123) 112 (106-122) 113 (105-123) 113 (107-122) 108 (105-120) 111 (105-119)
chemotherapy session and initiation
of the adjuvant chemotherapy,
median (IQR), d
b
Abbreviations: FIGO, Federation of Gynecology and Obstetrics; Details on the International FIGO staging system are provided in eTable 1 in the
HIPEC, hyperthermic intraperitoneal chemotherapy. Supplement.
c
SI conversion factor: To convert albumin to grams per liter, multiply by 10. Details on the peritoneal carcinomatosis index are provided in eTable 2 in the
a
Data are presented as number (percentage) of patients unless otherwise Supplement.
indicated.

percentiles. A 2-sided P < .05 was considered statistically sig-
nificant, and all statistical analyses were conducted using SAS
software, version 9.4 (SAS Institute Inc) and R software, ver-
sion 3.6.2 (R Foundation for Statistical Computing).
Results
Patients and Cytoreductive Surgery With or Without HIPEC
Of the 184 Korean women who underwent randomization, 92
were randomized to the HIPEC group (median age, 52.0 years;
IQR, 46.0-59.5 years) and 92 to the control group (median age,
53.5 years; IQR, 47.5-61.0 years). The baseline demographic and
clinical characteristics were similar in the 2 groups (Table 1),
with the exception of an additional 2 hours of operative time
for the HIPEC procedures (405 vs 525 minutes). eTable 3 in
Supplement 2 lists the operative procedures undertaken for
ovarian cancer. No intergroup differences in operative proce-
dures and surgical outcomes were found. Ileostomy was per-
formed in 7 patients (7.6%) in the HIPEC group and 6 patients
(6.5%) in the control group.
Outcomes
In the current analysis, 145 progressions occurred in the
overall cohort, in 71 of 92 patients (77.2%) in the HIPEC
group and 74 of 92 patients (80.4%) in the control group.

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 Research Original Investigation Survival After Hyperthermic Intraperitoneal Chemotherapy and Primary or Interval Cytoreductive Surgery in Ovarian Cancer

Figure 2. Kaplan-Meier Estimates of Progression-Free Survival and Overall Survival as Preplanned Intention to Treat

A Progression-free survival B Overall survival

100 100
Hazard ratio, 0.88 (95% CI, 0.63-1.21) Hazard ratio, 0.87 (95% CI, 0.58-1.32)
P = .43 by log-rank test P = .52 by log-rank test
80 80
Survival, %

Survival, %
60 60
HIPEC
Control
40 40

HIPEC
20 20
Control
0 0
0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10
Follow-up, y Follow-up, y
No. at risk No. at risk
Control group 92 70 33 24 18 10 7 4 1 0 0 Control group 92 89 81 68 51 28 18 12 6 1 0
HIPEC group 92 74 38 31 24 12 10 7 4 2 0 HIPEC group 92 90 82 75 60 31 20 13 6 3 0

A, Events of progression or death were observed in 74 patients (80.4%) in the 41.3% in the HIPEC group. B, A total of 47 patients (51.1%) in the surgery group
control group and in 71 patients (77.2%) in the hyperthermic intraperitoneal and 45 (48.9%) patients in the HIPEC group died. The Kaplan-Meier estimate of
chemotherapy (HIPEC) group. The Kaplan-Meier estimate of patients who were patients who were alive at 60 months was 52.3% in the control group and
without progression and alive at 24 months was 36.3% in the control group and 57.5% in the HIPEC group.

The median follow-up duration at the time of data cutoff
was 69.4 months (IQR, 54.4-86.3 months) for all patients in
the intention-to-treat population and was similar for the
HIPEC (69.4 months; IQR, 55.6-92.1 months) and control
(70.8 months; IQR, 53.6-85.8 months) groups. The longest
follow-up at the time of the database locking was 115.7
months. Moreover, among the randomized patients, 87
(94.6%) underwent HIPEC. The median progression-free
survival was 19.8 months (IQR, 13.7-55.4 months) in the
HIPEC group and 18.8 months (IQR, 13.0-43.2 months) in the
control group, and the median overall survival was 69.5
months (IQR, 45.6 months to not reported) in the HIPEC
group and 61.3 months (IQR, 34.3 months to not reported) in
the control group (Figure 2).
In patients who underwent interval cytoreductive sur-
gery after neoadjuvant chemotherapy, the median progression-
free survival was 17.4 months (IQR, 13.8-31.5 months) in the
HIPEC group and 15.4 months (IQR, 10.6-21.1 months) in the
control groups (HR for disease progression or death, 0.60; 95%
CI, 0.37-0.99; P = .04). The median overall survival was 61.8
months (IQR, 46.7 months to not reported) in the HIPEC group
and 48.2 months (IQR, 33.8-61.3 months) in the control group
(HR, 0.53; 95% CI, 0.29-0.96; P = .04). In patients who under-
went primary cytoreductive surgery (Figure 3), the median pro-
gression-free survival was 23.9 months (IQR, 12.3-71.5 months)
in the HIPEC group and 29.7 months (IQR, 17.2-90.1 months)
in the control groups. The median overall survival was 71.3
months (IQR, 45.6 months to not reported) in the HIPEC group
and was not reached in the control group.
Assessment of the predefined subgroup of the total pa-
tients with postneoadjuvant chemotherapy HIPEC and an in-
terval of 3 weeks or less between surgery and initiation of the
adjuvant chemotherapy yielded HRs of 0.60 (95% CI, 0.37-
0.99) and 0.59 (95% CI, 0.37-0.94) in the HIPEC group com-
pared with the control group (eFigure 2 in Supplement 2). In
patients with primary cytoreductive surgery, no subgroup
differences were meaningful for progression-free and overall
survival (eFigure 3 in Supplement 2). In the assessment of pa-
tients with postneoadjuvant chemotherapy HIPEC (eFigure 4
in Supplement 2), the results of the subgroup analyses for pro-
gression-free survival showed a benefit for younger age (HR,
0.39; 95% CI, 0.19-0.83; P = .01), high-grade serous histo-
logic type (HR, 0.49; 95% CI, 0.28-0.88; P = .02), lower peri-
toneal carcinomatosis index (HR, 0.22; 95% CI, 0.06-0.79;
P = .02), lower residual tumor (HR, 0.52; 95% CI, 0.30-0.91;
P = .02), no bowel surgery (HR, 0.35; 95% CI, 0.14-0.88;
P = .03), and no rectosigmoid resection (HR, 0.38; 95% CI, 0.16-
0.91; P = .03). Baseline characteristics, including age, serum
albumin, stage, histologic type, bowel surgery, or rectosig-
moid resection, were not significant for survival outcomes in
the multivariable Cox proportional hazards regression model
(eTable 5 in Supplement 2).
Safety
At least 1 adverse event of any grade occurred in all study par-
ticipants after randomization until 6 weeks after the last che-
motherapy (Table 2). During HIPEC, no intraprocedural ad-
verse events occurred that necessitated the discontinuation
of the procedure. In addition, no HIPEC-related deaths oc-
curred. Grade 3 or 4 adverse events were reported in 86 pa-
tients (93.5%) in the HIPEC group and 80 patients (87.0%) in
the control group.
With regard to any-grade adverse events, increased pro-
thrombin time (75 [81.5%] vs 60 [65.2%]; P = .01) and acute
kidney injury (19 [20.7%] vs 6 [6.5%]; P = .005) were preva-
lent in the HIPEC group compared with the control group. Elec-
trolyte disturbance (74 [80.4%] vs 41 [44.6%]; P < .001) was
prevalent as a grade 3 or 4 adverse event in the HIPEC group.
Amifostine use decreased the incidence of elevated serum cre-
atinine level (82% to 24%; P < .001) and acute kidney injury
(27% to 0%; P = .005) in the HIPEC group (eTable 4 in Supple-
ment 2).

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 Survival After Hyperthermic Intraperitoneal Chemotherapy and Primary or Interval Cytoreductive Surgery in Ovarian Cancer Original Investigation Research

Figure 3. Kaplan-Meier Estimates of Progression-Free Survival and Overall Survival According to the Primary Treatment
as Preplanned Intention to Treat

A Progression-free survival in patients undergoing primary B Overall survival in patients undergoing primary cytoreductive surgery
cytoreductive surgery
100 100
Hazard ratio, 1.16 (95% CI, 0.74-1.83) Hazard ratio, 1.38 (95% CI, 0.75-2.54)
P = .51 by log-rank test P = .29 by log-rank test
80 80

Control
Survival, %

Survival, %
60 60

HIPEC
40 40
Control
HIPEC
20 20

0 0
0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10
Follow-up, y Follow-up, y
No. at risk No. at risk
Control group 49 42 28 22 17 10 7 4 1 0 0 Control group 49 47 43 37 31 21 17 11 6 1 0
HIPEC group 58 44 29 24 18 10 8 6 3 1 0 HIPEC group 58 56 51 46 38 23 14 10 4 2 0

C Progression-free survival in patients undergoing interval cytoreductive D Overall survival in patients undergoing interval cytoreductive surgery
surgery after neoadjuvant chemotherapy after neoadjuvant chemotherapy
100 100
Hazard ratio, 0.60 (95% CI, 0.37-0.99) Hazard ratio, 0.53 (95% CI, 0.29-0.96)
P = .04 by log-rank test P = .04 by log-rank test
80 80
Survival, %

Survival, %
60 60

40 40
HIPEC
20 HIPEC 20
Control
Control
0 0
0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10
Follow-up, y Follow-up, y
No. at risk No. at risk
Control group 43 28 5 2 1 0 0 0 0 0 0 Control group 43 42 38 31 20 7 1 1 0 0 0
HIPEC group 34 30 9 7 6 2 2 1 1 1 0 HIPEC group 34 34 31 29 22 8 6 3 2 1 0

Among the patients undergoing primary cytoreductive surgery prespecified
subgroup analysis, the Kaplan-Meier estimate of patients who were free of
progression and death at 24 months was 57.1% in the control group and 50% in
the hyperthermic intraperitoneal chemotherapy (HIPEC) group (A), and the
Kaplan-Meier estimate of patients who were alive at 60 months was 68.7% in
the control group and 61% in the HIPEC group (B). Among the patients
undergoing interval cytoreductive surgery after neoadjuvant chemotherapy
prespecified subgroup analysis, the Kaplan-Meier estimate of patients who
were free of progression and death at 24 months was 11.9% in the control group
and 26.5% in the HIPEC group (C), and the Kaplan-Meier estimate of patients
who were alive at 60 months was 32.2% in the control group and 52% in the
HIPEC group (D).

40.0 °C), dose of the chemotherapeutic agent (75 mg/m2 with

Discussion
This randomized clinical trial in patients with stage III or IV
epithelial ovarian, fallopian tubal, and primary peritoneal can-
cer who underwent primary or interval cytoreductive sur-
gery did not find a significant improvement of progression-
free survival or overall survival between the HIPEC and control
groups. This is the first trial, to our knowledge, to identify the
clinical benefit of HIPEC after primary or interval cytoreduc-
tive surgery in primary advanced ovarian cancer (eFigure 1 in
Supplement 2). In this study, a survival benefit from HIPEC was
identified in women with primary stage III and IV epithelial
ovarian cancer who underwent interval cytoreductive sur-
gery after neoadjuvant chemotherapy. The current findings are
consistent with the survival benefit reported in the OVHIPEC-01
trial despite the different setting of HIPEC with regard to the
HIPEC technique (closed vs open), temperature (41.5 °C vs
100% of the dose perfused initially vs 100 mg/m2 with 50%
of the dose perfused initially [25% at 30 minutes and 25% at
60 minutes]), and time of bowel anastomoses (before vs after
HIPEC).9 The median duration of surgery was longer in this trial
(507 minutes) compared with OVHIPEC-01 (338 minutes) be-
cause of the extensiveness of cytoreductive surgery. How-
ever, the adjuvant chemotherapy was initiated earlier in the
current trial than in OVHIPEC-01 (22 vs 33 days). However, this
trial did not identify a survival benefit of HIPEC in women with
primary stage III and IV epithelial ovarian cancer who under-
went primary cytoreductive surgery.
Hyperthermic intraperitoneal chemotherapy is consid-
ered a regional treatment for intraperitoneal disease. A previ-
ous randomized study16 of HIPEC focused on stage III ovar-
ian cancer. From the merged analysis 17 of 3 Gynecologic
Oncology Group studies, residual tumor in the peritoneal cav-
ity is the most important prognostic factor for progression-

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 Research Original Investigation Survival After Hyperthermic Intraperitoneal Chemotherapy and Primary or Interval Cytoreductive Surgery in Ovarian Cancer

Table 2. Adverse Events From Randomization to the 6 Weeks After Postoperative Adjuvant Chemotherapya

Any grade Grade 3 or 4

No. (%) No. (%)
Difference, Difference,
Adverse event Control (n = 92) HIPEC (n = 92) % (95% CI)b Control (n = 92) HIPEC (n = 92) % (95% CI)b
Anemia 92 (100) 92 (100) 0 44 (47.8) 52 (56.5) 8.7 (−5.7 to 23.1)
Electrolyte disturbance 92 (100) 92 (100) 0 41 (44.6) 74 (80.4) 35.9 (22.9 to 48.9)
Abdominal pain 92 (100) 92 (100) 0 0 0 0
Hyperaminotransferase 77 (83.7) 78 (84.8) 1.1 (−9.4 to 11.6) 18 (19.6) 8 (8.7) −10.9 (−20.8 to −0.9)
Peripheral sensory neuropathy 79 (85.9) 78 (84.8) −1.1 (−11.3 to 9.1) 0 0 0
Lymphocele 84 (91.3) 76 (82.6) −8.7 (−18.3 to 1) 12 (13) 16 (17.4) 4.3 (−6 to 14.7)
INR increased 60 (65.2) 75 (81.5) 16.3 (3.7 to 28.9) 2 (2.2) 1 (1.1) −1.1 (−4.7 to 2.6)
Pulmonary 63 (68.5) 69 (75) 6.5 (−6.5 to 19.5) 5 (5.4) 8 (8.7) 3.3 (−4.1 to 10.7)
Nausea 63 (68.5) 68 (73.9) 5.4 (−7.6 to 18.5) 0 0 0
WBC count decreased 62 (67.4) 67 (72.8) 5.4 (−7.8 to 18.6) 22 (23.9) 24 (26.1) 2.2 (−10.3 to 14.7)
Neutrophil count decreased 53 (57.6) 63 (68.5) 10.9 (−3 to 24.7) 26 (28.3) 31 (33.7) 5.4 (−7.9 to 18.8)
Creatinine increased 44 (47.8) 63 (68.5) 20.7 (6.7 to 34.6) 2 (2.2) 2 (2.2) 0 (−4.2 to 4.2)
Anorexia 58 (63) 54 (58.7) −4.3 (−18.4 to 9.7) 2 (2.2) 5 (5.4) 3.3 (−2.2 to 8.8)
Cardiac event 46 (50) 48 (52.2) 2.2 (−12.3 to 16.6) 0 2 (2.2) 2.2 (−0.8 to 5.2)
Infection 43 (46.7) 47 (51.1) 4.3 (−10.1 to 18.8) 25 (27.2) 27 (29.3) 2.2 (−10.8 to 15.2)
Insomnia 36 (39.1) 47 (51.1) 12 (−2.3 to 26.2) 1 (1.1) 2 (2.2) 1.1 (−2.6 to 4.7)
Diarrhea 38 (41.3) 43 (46.7) 5.4 (−8.9 to 19.8) 17 (18.5) 20 (21.7) 3.3 (−8.3 to 14.8)
Vomiting 35 (38) 38 (41.3) 3.3 (−10.9 to 17.4) 3 (3.3) 1 (1.1) −2.2 (−6.4 to 2)
Constipation 40 (43.5) 35 (38) −5.4 (−19.6 to 8.7) 1 (1.1) 0 −1.1 (−3.2 to 1)
Platelet count decreased 26 (28.3) 33 (35.9) 7.6 (−5.8 to 21.1) 8 (8.7) 8 (8.7) 0 (−8.1 to 8.1)
Hypertension 36 (39.1) 29 (31.5) −7.6 (−21.4 to 6.2) 9 (9.8) 11 (12) 2.2 (−6.8 to 11.2)
Ileus 26 (28.3) 26 (28.3) 0 (−13 to 13) 8 (8.7) 9 (9.8) 1.1 (−7.3 to 9.5)
Blood bilirubin increased 28 (30.4) 26 (28.3) −2.2 (−15.3 to 11) 4 (4.3) 2 (2.2) −2.2 (−7.3 to 2.9)
Lymphedema 25 (27.2) 23 (25) −2.2 (−14.9 to 10.5) 0 0 0
Wound dehiscence 25 (27.2) 22 (23.9) −3.3 (−15.9 to 9.3) 10 (10.9) 14 (15.2) 4.3 (−5.4 to 14.1)
Acute kidney injury 6 (6.5) 19 (20.7) 14.1 (4.4 to 23.8) 3 (3.3) 2 (2.2) −1.1 (−5.8 to 3.6)
Urticaria 19 (20.7) 19 (20.7) 0 (−11.7 to 11.7) 4 (4.3) 4 (4.3) 0 (−5.9 to 5.9)
Febrile neutropenia 10 (10.9) 9 (9.8) −1.1 (−9.9 to 7.7) 10 (10.9) 9 (9.8) −1.1 (−9.9 to 7.7)
Thromboembolic event 5 (5.4) 8 (8.7) 3.3 (−4.1 to 10.7) 0 1 (1.1) 1.1 (−1 to 3.2)
Depression 8 (8.7) 8 (8.7) 0 (−8.1 to 8.1) 1 (1.1) 0 −1.1 (−3.2 to 1)
Fistula, perforation, or leakage 0 7 (7.6) 7.6 (2.2 to 13) 0 5 (5.4) 5.4 (0.8 to 10.1)
of bowel
Anal hemorrhage 2 (2.2) 6 (6.5) 4.3 (−1.5 to 10.2) 0 1 (1.1) 1.1 (−1 to 3.2)
Intra-abdominal hemorrhage 0 3 (3.3) 3.3 (−0.4 to 6.9) 0 1 (1.1) 1.1 (−1 to 3.2)
Sepsis 0 3 (3.3) 3.3 (−0.4 to 6.9) 0 3 (3.3) 3.3 (−0.4 to 6.9)
Fall 2 (2.2) 3 (3.3) 1.1 (−3.6 to 5.8) 0 1 (1.1) 1.1 (−1 to 3.2)
Colonic fistula 0 2 (2.2) 2.2 (−0.8 to 5.2) 0 2 (2.2) 2.2 (−0.8 to 5.2)
Colonic perforation 0 2 (2.2) 2.2 (−0.8 to 5.2) 0 2 (2.2) 2.2 (−0.8 to 5.2)
Large intestinal anastomotic leak 0 2 (2.2) 2.2 (−0.8 to 5.2) 0 1 (1.1) 1.1 (−1 to 3.2)
Delirium 2 (2.2) 2 (2.2) 0 (−4.2 to 4.2) 0 1 (1.1) 1.1 (−1 to 3.2)
Syncope 1 (1.1) 2 (2.2) 1.1 (−2.6 to 4.7) 1 (1.1) 2 (2.2) 1.1 (−2.6 to 4.7)
Urinary fistula 1 (1.1) 1 (1.1) 0 (−3 to 3) 0 1 (1.1) 1.1 (−1 to 3.2)
Duodenal perforation 0 1 (1.1) 1.1 (−1 to 3.2) 0 0 0
Jejunal hemorrhage 0 1 (1.1) 1.1 (−1 to 3.2) 0 1 (1.1) 1.1 (−1 to 3.2)
Seizure 0 1 (1.1) 1.1 (−1 to 3.2) 0 1 (1.1) 1.1 (−1 to 3.2)
Postoperative hemorrhage 1 (1.1) 0 −1.1 (−3.2 to 1) 1 (1.1) 0 −1.1 (−3.2 to 1)
Abbreviations: HIPEC, hyperthermic intraperitoneal chemotherapy; of frequency in the HIPEC group. The adverse events were graded according
INR, international normalized ratio; WBC, white blood cell. to the National Cancer Institute Common Terminology Criteria for Adverse
a
Data are given for adverse events that occurred in at least 1 patient in either Events, version 4.
b
trial group during the trial intervention or up to 6 weeks after adjuvant Differences were calculated using the proportion of HIPEC group minus the
chemotherapy after cytoreductive surgery and are listed in descending order proportion of control group.

free survival and overall survival in patients with stage IV ovar- neal disease control with cytoreductive surgery and locore-
ian cancer. Disease control within the intraperitoneal disease gional treatment, including HIPEC, is important to improve
is consistently important in stage IV ovarian cancer, as iden- survival outcome. In addition, regional hyperthermia might
tified from the recent investigations. Therefore, intraperito- induce activation of systemic immune response by activating

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 Survival After Hyperthermic Intraperitoneal Chemotherapy and Primary or Interval Cytoreductive Surgery in Ovarian Cancer
heat shock protein, which is a potent immune modulator that
stimulates innate and adaptive immune responses.18 Hyper-
thermic intraperitoneal chemotherapy can increase systemic
antitumor response by the maturation of dendritic cells via heat
shock protein. With these backgrounds, locoregional disease
control in the peritoneal cavity, including radical surgery and
HIPEC, is an important and reasonable treatment strategy in
stage IV ovarian cancer.
This finding engenders the question of why HIPEC is ef-
fective only after recent exposure of chemotherapy and not in
chemotherapy-naive women with ovarian cancer. From the
first randomized trial of HIPEC for recurrent ovarian cancer,
there was an observable profound survival benefit of HIPEC
after recent exposure to chemotherapy and survival improve-
ment in platinum-resistant recurrent disease (HR, 0.4 for over-
all survival; estimated from the 1-year survival curve).19 A ret-
rospective study20 showed that, in primary ovarian cancer, the
effect of HIPEC after adjuvant chemotherapy is maximized (HR,
0.2–0.4 for overall survival). In platinum-sensitive recurrent
ovarian cancer, surgery with carboplatin HIPEC was well tol-
erated but not superior to the surgery in the Memorial Sloan
Kettering team ovary phase 2 study (progression-free sur-
vival, 12.3 vs 15.7 months; P = .05).21 There could be several ex-
planations for the consistent findings, including the effect of
HIPEC only after recent exposure of chemotherapy. First, even
normal-appearing peritoneum during interval cytoreductive
surgery after neoadjuvant chemotherapy could have micro-
scopic residual tumor cells, thereby potentially harboring a sub-
population of cancer cells, including chemotherapy-resistant
cancer stem cells.22,23 After neoadjuvant chemotherapy, con-
densed and subpopulated chemotherapy-resistant cancer stem
cells within the effective penetrating depth of cisplatin by
HIPEC provide an actionable space wherein the therapeutic ef-
fect of HIPEC is demonstrable.24 Second, the chemotherapy-
sensitive subgroup could be selected for neoadjuvant chemo-
therapy. Women with BRCA mutations respond well to
neoadjuvant chemotherapy, and the BRCA mutation is a good
predictive biomarker for better survival outcomes after intra-
peritoneal chemotherapy.25-27 In a randomized trial of intra-
peritoneal chemotherapy for ovarian cancer, the survival ben-
efit was observed only in women with aberrant BRCA1 (OMIM
113705) expression.4,27 Third, hyperthermia induces degrada-
tion of BRCA2 (OMIM 600185) and inhibits homologous
recombination.28 Therefore, hyperthermia could induce a sub-
populated chemotherapy-resistant cancer cell line in the peri-
toneum, whereby a homologous recombination-proficient tu-
mor changes into a homologous recombination-deficient
tumor. Fourth, after neoadjuvant chemotherapy, quiescent
cells within the hypoxic and nutrient-deprived tumor re-
gions could be targeted by hyperthermia through the reposi-
tioning of the cell cycle and reoxygenation of the hypoxic tu-
mor, thereby triggering the immune system through the
production of heat shock proteins and improving the micro-
ARTICLE INFORMATION Published Online: March 9, 2022.
Accepted for Publication: December 27, 2021. doi:10.1001/jamasurg.2022.0143
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Original Investigation Research
environment that is symbiotically related to the cancer stem
cell.18 In the current trial, 9 patients with pathological com-
plete remission on intraoperative frozen histopathological ex-
amination (Figure 1) were excluded, and their inclusion may
have indicated maximization of the treatment benefit of HIPEC.
In a previous randomized trial4 of intraperitoneal chemo-
therapy, left colon surgery, including low anterior resection,
was a predictive factor for the likelihood of noncompletion of
the planned intraperitoneal chemotherapy. In this trial, HIPEC
was safely administered after anastomosis during low ante-
rior resection in approximately two-thirds of the women. A
colostomy or ileostomy after bowel surgery was more fre-
quently performed in the HIPEC group (72% vs 43%, P = .04)
of OVHIPEC-1. However, in the current trial, ileostomy after
bowel surgery was less frequently and similarly performed in
both the groups, without intergroup differences in the anas-
tomosis leakage.
Most toxic effects, including anemia and neuropathy, in
this trial were related to the surgery and adjuvant chemo-
therapy. Acute kidney toxic effects and electrolyte imbalance
were observed more frequently in the HIPEC group because
of the absence of sodium thiosulfate use in most patients
(n = 71). With the use of sodium thiosulfate in 21 patients, the
incidence of these adverse events decreased significantly, with-
out any intergroup differences between the HIPEC and con-
trol groups (eTable 4 in Supplement 2).
Limitations
This study has several limitations, including small sample size.
The enrollment into the trial was not stratified by the pri-
mary or interval cytoreductive surgery, stage, and BRCA sta-
tus or homologous recombination deficiency. Although there
is no statistical difference, the current treatment outcomes still
need to be carefully interpreted because of the potential im-
balance between 2 groups in terms of stage and type of pri-
mary treatment. An advantage of this trial is that the results
provide preliminary clues to ascertain a possible benefit of
HIPEC based on the primary treatment of primary advanced
epithelial ovarian cancer.
Conclusions
The addition of HIPEC after interval cytoreductive surgery fol-
lowing neoadjuvant chemotherapy was observed to reduce re-
currence and mortality rates in women with primary stage III
or IV epithelial ovarian cancer. Hyperthermic intraperitoneal
chemotherapy could be performed safely after maximal cyto-
reductive surgery, including left colon surgery, without any de-
lay in the initiation of adjuvant chemotherapy. The survival
benefit of HIPEC immediately after primary cytoreductive
surgery has not been identified in this trial and needs to be
further investigated in future clinical trials.
Open Access: This is an open access article
distributed under the terms of the CC-BY License.
© 2022 Lim MC et al. JAMA Surgery.
(Reprinted) JAMA Surgery May 2022 Volume 157, Number 5 381
 Research Original Investigation Survival After Hyperthermic Intraperitoneal Chemotherapy and Primary or Interval Cytoreductive Surgery in Ovarian Cancer
Author Affiliations: Center for Gynecologic Cancer,
National Cancer Center, Goyang, South Korea (Lim,
H. J. Yoo, C. W. Yoo, S.-Y. Park); Center for Clinical
Trial, National Cancer Center, Goyang, South Korea
(Lim); Division of Rare and Refractory Cancer,
Research Institute, National Cancer Center, Goyang,
South Korea (Lim); Department of Cancer Control
and Policy, National Cancer Center, Goyang, South
Korea (Lim); Department of Obstetrics and
Gynecology, Ajou University School of Medicine,
Suwon, South Korea (Chang); Biostatistics
Collaboration Team, National Cancer Center,
Goyang, South Korea (B. Park, Nam); Biomedical
Statistics Center, Research Institute for Future
Medicine, Samsung Medical Center, Seoul, South
Korea (B. Park); Chungnam National University
School of Medicine, Dajeon, South Korea (H. J. Yoo);
HERINGS, Seoul, South Korea (Nam).
Author Contributions: Drs Lim and S.-Y. Park had
full access to all the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: Lim, Chang, C.W. Yoo, Nam,
S.-Y. Park.
Acquisition, analysis, or interpretation of data: Lim,
Chang, B. Park, H.J. Yoo, C.W. Yoo, S.-Y. Park.
Drafting of the manuscript: Lim, Chang, B. Park,
H.J. Yoo, C.W. Yoo, S.-Y. Park.
Critical revision of the manuscript for important
intellectual content: Lim, Chang, H.J. Yoo, C.W. Yoo,
Nam, S.-Y. Park.
Statistical analysis: Lim, Chang, B. Park, C.W. Yoo,
Nam, S.-Y. Park.
Obtained funding: Lim, C.W. Yoo, S.-Y. Park.
Administrative, technical, or material support: Lim,
H.J. Yoo, C.W. Yoo, S.-Y. Park.
Supervision: H.J. Yoo, C.W. Yoo, S.-Y. Park.
Conflict of Interest Disclosures: Dr Lim reported
having a consulting or advisory role for
AstraZeneca, Boryung, CKD Pharm, Genexine,
Hospicare, GI Innovation, and Takeda and receiving
research funding from AbbVie, Amgen, Astellas,
AstraZeneca, BeiGene, Cellid, CKD Pharm, Clovis,
Eisai, Genexine, GSK, Incyte, Merck, MSD,
OncoQuest, Pfizer, and Roche outside the
submitted work. Dr Chang reported receiving
research funding from AstraZeneca and Clovis
outside the submitted work. Dr S.-Y. Park reported
having a consulting or advisory role for Boryung
and Takeda and receiving research funding from
AbbVie, Amgen, Astellas, AstraZeneca, BeiGene,
Cellid, CKD Pharm, Clovis, Eisai, Genexine, GSK,
Incyte, Merck, MSD, OncoQuest, Pfizer, and Roche
outside the submitted work. No other disclosures
were reported.
Funding/Support: The study was funded by grants
NCC1010112, 1310312, 1610070, and 2110790 from
the National Cancer Center of Korea.
Role of the Funder/Sponsor: The funder had
no role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Group Information: A complete list of the
members of the HIPEC for Ovarian Cancer
Collaborators appears in Supplement 3.
Data Sharing Statement: See Supplement 4.
Additional Contributions: The maintaining of the
study and collection of the data was provided by
Yohan Woo, RN, and Kyojin Bae, RN, and the
382 JAMA Surgery May 2022 Volume 157, Number 5 (Reprinted)
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medical illustrations were provided by Su Hyun
Chae, MFA, and Ji Hyun Kim, MD, National Cancer
Center of Korea. We thank all participants, their
families, their caregivers, the cytoreductive and
hyperthermic intraperitoneal chemotherapy team,
study sites, and investigators who participated in
this clinical study. None of these individuals were
compensated for their work.
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Invited Commentary

Hyperthermic Intraperitoneal Chemotherapy for the Treatment

of Epithelial Ovarian Cancer
Stephanie L. Wethington, MD, MSc; Deborah K. Armstrong, MD; Fabian M. Johnston, MD, MHS

Hyperthermic intraperitoneal chemotherapy (HIPEC) has
been a treatment modality of interest for more than 40 years;
initially focusing on the treatment of gastrointestinal malig-
nant tumors, HIPEC was sub-
sequently used to treat a clas-
Related article page 374 sic peritoneal malignant
tumor—epithelial ovarian
cancer (EOC).1 Intraperitoneal chemotherapy for advanced EOC
has been a focus of research and debate for more than 30 years.2
Support peaked with the publication of the Gynecologic
Oncology Group (GOG) 172 trial,3 the seventh randomized clini-
cal trial comparing standard intravenous chemotherapy with
intraperitoneal chemotherapy, and a rare National Cancer
Institute clinical announcement in 20064 and nadired with the
publication of the negative findings of GOG-252.5
In this issue of JAMA Surgery, Lim et al6 present the re-
sults of a randomized clinical trial of HIPEC for patients with
newly diagnosed EOC. The study showed no difference in out-
come with the addition of HIPEC. The results confirmed ex-
tensive prior literature documenting better outcomes for in-
dividuals who underwent successful primary debulking
surgery (PDS) compared with those who underwent neoadju-
vant chemotherapy (NACT) and interval cytoreductive sur-
gery (ICS), regardless of HIPEC use.
The authors present subgroup data that indicate a better out-
come for patients who underwent NACT and ICS with HIPEC
compared with the control group. However, PDS vs NACT and
ICS does not appear to have been a stratification variable, and the
numbers in these groups are small and not balanced. As is always
the case, in a study in which outcomes are similar, identification
of a subgroup with a benefit (NACT and ICS) necessitates that an-
other subgroup has a detriment (PDS). The subgroup data indi-
cate that in a cohort enriched for a good prognosis (ie, optimal
PDS), the addition of HIPEC resulted in an inferior outcome.
Several issues of this subgroup analysis raise concern for im-
balance and possible bias, including a lack of criteria for which
patients were enrolled, equivalent peritoneal carcinomatosis in-
dex in the PDS group as well as the NACT and ICS group, stage,
and the use of frozen section to identify complete response at
ICS, leading to exclusion of 9% of cases. The authors postulate
multiple reasons for the difference between PDS and ICS, most
plausibly the effect of cisplatin and hyperthermia on selected
platinum-resistant cells remaining after NACT.
The best-supported conclusion we are left with is the criti-
cal need for well-designed studies of HIPEC in EOC. The stud-
ies must carefully define the patient population and enroll-
ment process, including criteria for PDS or NACT and IDS and
balancing stage, grade, and histologic type. The HIPEC proce-
dure must specify the drug, volume of irrigation, time to dwell,
as well as supportive approaches used. More difficult consid-
erations are the use of a sham HIPEC and/or use of the same
chemotherapy intravenously for the control group. Contempo-
rary maintenance strategies, such as poly(adenosine diphos-
phate–ribose) polymerase inhibitors, must be considered
for inclusion in the study design. Lastly, data on toxic effects
must be reported fully to address concerns regarding the
toxic effects of HIPEC and tolerability of subsequent chemo-
therapy.

ARTICLE INFORMATION REFERENCES chemotherapy for ovarian cancer. Accessed

Author Affiliations: Department of Gynecology
and Obstetrics, The Johns Hopkins University
School of Medicine, Baltimore, Maryland
(Wethington); Department of Oncology, The Johns
Hopkins University School of Medicine, Baltimore,
Maryland (Armstrong); Division of Surgical
Oncology, Department of Surgery, The Johns
Hopkins University School of Medicine, Baltimore,
Maryland (Johnston).
Corresponding Author: Deborah K. Armstrong,
MD, Department of Oncology, The Johns Hopkins
University School of Medicine, 201 N Broadway,
Viragh Room 10293, Baltimore, MD 21287
(armstde@jhmi.edu).
Published Online: March 9, 2022.
doi:10.1001/jamasurg.2022.0156
Conflict of Interest Disclosures: None reported.
1. van Driel WJ, Koole SN, Sikorska K, et al.
Hyperthermic intraperitoneal chemotherapy in
ovarian cancer. N Engl J Med. 2018;378(3):230-240.
doi:10.1056/NEJMoa1708618
2. Jaaback K, Johnson N, Lawrie TA. Intraperitoneal
chemotherapy for the initial management of
primary epithelial ovarian cancer. Cochrane
Database Syst Rev. 2011;(11):CD005340.
doi:10.1002/14651858.CD005340.pub3
3. Armstrong DK, Bundy B, Wenzel L, et al;
Gynecologic Oncology Group. Intraperitoneal
cisplatin and paclitaxel in ovarian cancer. N Engl J
Med. 2006;354(1):34-43. doi:10.1056/
NEJMoa052985
4. Cancer Therapy Evaluation Program, National
Cancer Institute. January 5, 2006. Intraperitoneal
January 10, 2022. https://ctep.cancer.gov/
highlights/docs/clin_annc_010506.pdf
5. Walker JL, Brady MF, Wenzel L, et al.
Randomized trial of intravenous versus
intraperitoneal chemotherapy plus bevacizumab in
advanced ovarian carcinoma: an NRG
Oncology/Gynecologic Oncology Group study. J Clin
Oncol. 2019;37(16):1380-1390. doi:10.1200/JCO.18.
01568
6. Lim MC, Chang SJ, Park B, et al; HIPEC for
Ovarian Cancer Collaborators. Survival after
hyperthermic intraperitoneal chemotherapy and
primary or interval cytoreductive surgery in ovarian
cancer: a randomized clinical trial. JAMA Surg.
Published online March 9, 2022. doi:10.1001/
jamasurg.2022.0143

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