DE GRUYTER Hormone Molecular Biology and Clinical Investigation.

2020; 20190028

Review Article
Aurélie Revaux1,2 / Marie Carbonnel2,3 / Frédéric Kanso4 / Iptissem Naoura2,3 / Jennifer Asmar2,3 /
Philippe Kadhel2,3,5 / Jean-Marc Ayoubi2,3

Hyperthermic intraperitoneal chemotherapy in

ovarian cancer: an update
1 Department of Gynecology and Obstetrics, Foch Hospital, 40 Rue Worth, 92150 Suresnes, France, E-mail:

aurelie.revaux@hopital-foch.com
2 Faculté de Médecine Paris Ouest (UVSQ), Versailles, France, E-mail: aurelie.revaux@hopital-foch.com
3 Department of Gynecology and Obstetrics, Foch Hospital, Suresnes, France
4 Department of Digestive Surgery, Foch Hospital, Suresnes, France
5 CHU de Pointe-à-Pitre, Univ Antilles, Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et

Travail) – UMR_S 1085, Pointe-à-Pitre, France

Abstract:
In the treatment of advanced-stage epithelial ovarian cancer (EOC)-associated surgery and chemotherapy with
intravenous platinum/taxane-based therapy most patients had early or late recurrence. Prevention of progres-
sion and recurrence is a major objective for the management of EOC. Recently, many clinical studies have
evaluated the strategy with hyperthermic intraoperative intraperitoneal (IP) drug delivery. This is an update
of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) in EOC and a view for future strategies.
Until recently studies on HIPEC in patients with EOC were mostly retrospective and heterogeneous. Thanks
to recent clinical trials, it is reasonable to conclude that surgical cytoreduction and HIPEC is an interesting
approach in the management of EOC without increasing morbidity.
Keywords: cytoreductive surgery, HIPEC, hyperthermic intraoperative intraperitoneal chemotherapy, ovarian
cancer, surgery
DOI: 10.1515/hmbci-2019-0028
Received: June 5, 2019; Accepted: December 3, 2019

Introduction
Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd

Epithemial ovarian cancer (EOC) is the second most common gynecological malignancy but the most lethal
gynecological cancer [1].
Most patients with EOC have peritoneal disease when the cancer is discovered. The standard therapy for
advanced EOC is debulking surgery and platinium-based chemotherapy. The natural history of advanced EOC
is one of clinical remission after this treatment followed by recurrence in most women. The 5-year survival rate
was less than 30% [2]. Thanks to optimal cytoreductive surgery and advances in chemotherapy, median overall
survival (OS) has improved in these patients in recent years [3].
In most advanced EOC patients, the peritoneal cavity is affected. In response to this diffusion to the peri-
toneum, hypotheses on the intraperitoneal (IP) administration of drugs have been evaluated in the management
of EOC. These studies show a pharmacological benefit of IP chemotherapy over intravenous (IV) chemother-
apy [4], [5], [6], [7]. Although IP treatment extends survival time and reduces the risk of death, it has its own
toxicity with difficult logistics and a high cost [8]. Hyperthermal IP chemotherapy (HIPEC) would allow direct
action on cancer cells, increase the cytotoxicity of chemotherapy by increasing the number of lysosomes and
their activity in cancer cells and have a role in angiogenesis [9], [10], [11], [12], [13], [14].
However, the role of HIPEC in patients with EOC remains controversial. Since the last randomized studies,
HIPEC has appeared to demonstrate its efficacy and safety in advanced EOC for patients managed in a neo-
adjuvant protocol [15]. The objective of this review is to provide an update on the use of HIPEC in EOC and to
identify the patient population most likely to benefit from this treatment.

Aurélie Revaux is the corresponding author.

© 2020 Walter de Gruyter GmbH, Berlin/Boston.

Brought to you by | Imperial College London

Authenticated 1
Download Date | 2/23/20 4:17 PM
 Revaux et al. DE GRUYTER

Physiopathology
HIPEC is a unique intraoperative chemotherapy treatment at the time of cytoreductive surgery. HIPEC has
several potential advantages:

1. High-dose chemotherapy can be used because the peritoneal barrier causes low absorption into the blood-
stream [16], [17].

2. By administering intraoperative chemotherapy, there is direct contact with the remaining microscopic cancer
cells without postoperative adhesions [18], [19].
3. Hyperthermia alone has cytotoxic effects and can increase the penetration depth of chemotherapy and can
also potentiate its antineoplastic effects [20], [21], [22].

The limitations of HIPEC are the morbidity and mortality described in the oldest studies.
Moreover, it was only performed when the surgery was classified as complete (no visible residual disease,
R0), which required extensive surgery and also explained the increase in mortality [23].
Morbidity and mortality have improved considerably in HIPEC expert centers [24]. A retrospective study
of 694 patients, treated between 2005 and 2011, showed a complication rate of 33% and a 30-day mortality rate
of 2.3% [25].
In EOC, HIPEC was evaluated in the primary and recurrent context. The majority of the data for this treat-
ment modality are retrospective, but recently some prospective data have been published.

Technique
Multiple studies have described different methods and protocols for HIPEC [26]. A study concerning the prac-
tices of 34 different French teams showed great heterogeneity in the HIPEC technique. There were differences
in techniques, equipment used, protection mechanisms and training [27].
In international studies, the type of chemotherapy, temperature and duration of treatment are very hetero-
geneous [28]. Platinum salts, most often cisplatin, oxaliplatin or carboplatin, are generally used [28], [29]. Some
teams use several molecules during the same procedure. The pharmacokinetics of the concomitant use of cis-
platin and paclitaxel for 90 min was studied but with significant morbidity (61.5%) [30]. For patients resistant
to platinum salts, attitudes differ between teams [31].
Surgical techniques can be open or closed and seem feasible. A laparoscopic or robotic surgical approach
Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd

to HIPEC treatment in patients with recurrent disease has been described by Fagotti on a series of 84 patients
with minimal complications [32].
A randomized Dutch study used cisplatin (100 mg/m2 ) at 40 °C with a nephroprotective agent, sodium
thiosulfate (9 g/m2 bolus then continuous infusion of 12 g/m2 over 6 h) [15]. Their results show identical
morbidity in the group with and without HIPEC and tend to impose this protocol.

HIPEC in primary disease treatment

The reference treatment for EOC is optimal cytoreduction surgery followed by platinum-based chemotherapy
if complete surgery is possible. If complete surgery does not seem possible (see section on resectability crite-
ria), neo-adjuvant chemotherapy (NACT) is preferred with interval surgery after three courses [33], [34]. The
response to this treatment is often good but with recurrences in most cases. The addition of HIPEC was there-
fore evaluated to improve progression-free survival (PFS) and overall survival (OS). Retrospective studies have
shown an improvement in overall survival [26], [31] (Table 1). In a retrospective study of 13 French institutions,
Bakrin found that first-line HIPEC-associated cytoreductive surgery resulted in a PFS at 12 months and an OS
at 35 months [35]. Those who had been able to have optimal surgery (residue less than 2.5 mm) had a median
survival of 41.5 months, compared to 21.2 months in subjects with residual disease greater than 2.5 mm [35].
One of the first meta-analyses showed that among patients with primary EOC, the median, 1-, 3-, and 5-year
overall survival rates are 46.1 months, 88.2%, 62.7% and 51% [29].
Some centers have proposed usinng HIPEC after NACT. A comparative Spanish study of 87 patients, 52 of
whom were HIPEC paclitaxel patients (23 primary and 29 post-NACT), found that HIPEC was associated with
prolonged PFS in the HIPEC group. All patients had complete cytoreductive surgery with no visible residual

Brought to you by | Imperial College London

2 Authenticated
Download Date | 2/23/20 4:17 PM
 DE GRUYTER Revaux et al.

disease (CC0). In the control group, respectively, the PFS was 66%, 33%, 18% and in the HIPEC arm, the PFS
was 81%, 67%, 63% at 1, 2 and 3 years (p < 0.01) [36].

Table 1: HIPEC primary trials [26].

Author Study type n Chemotherapy PFS OS
Van Driel [15] Prospective 245 Cisplatin 14.2 months 45.7 months
Bakrin [35] Retrospective 92 Cisplatin (80%) n/a CC0: 41.5 months
cohort
Cascales-Campos Retrospective 52 Paclitaxel 1 year: 81% 3 years: 63%
[36] series
Bae [37] Retrospective 67 Carboplatin or 3 years: 56.3% 3 years: 66.1%
case control paclitaxel

HIPEC, Hyperthermic intraoperative intraperitoneal chemotherapy; OS, Overall Survival; PFS, Progression-Free Survival.

The largest prospective randomized clinical trial demonstrated a survival benefit for patients who received
HIPEC in addition to surgical treatment and IV chemotherapy, for the treatment of primary EOC [15]. All
patients received neoadjuvant chemotherapy after having determined that they were not resectable. The control
group received standard IV chemotherapy before and after surgery (PFS = 10.7 months, OS = 33.9 months). The
experimental group received the same standard IV chemotherapy associated with HIPEC with cisplatin [PFS
= 14.2 months (p = 0.01), OS = 45.7 months (p = 0.02)]. A nephroprotective treatment (sodium thiosulfate)
was also administered, the pathophysiology of which was not specified in the study and which has temporary
authorisation in France.
More than 90% of patients have completed six complete cycles of IV chemotherapy in both arms. It should
be noted that this is a different patient population as all are not immediately resectable [15].
In addition to standardizing HIPEC’s procedure, the timing of HIPEC’s administration is another important
factor [38].

HIPEC in recurrent disease treatment

The interest of HIPEC in the recurrence of EOC has been studied by comparing different groups of patients
depending on the surgical treatment with or without HIPEC and the treatment with post-operative chemother-
apy.
Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd

Fagotti in 2012 compared patients with recurrent platinum-sensitive disease treated with cytoreductive
surgery and oxaliplatin-based HIPEC with similar patients with comparable clinical characteristics and treated
with cytoreductive surgery or systemic chemotherapy over the same period as controls [39]. The median follow-
up time was 46 months in cases and 36 months in controls. Twenty patients (66.6%) had secondary recurrence
in cases and 37 women (100%) in controls (p = 0.001). In addition, seven (23.3%) and 23 (62.2%) patients died
of disease in the cases and controls, respectively (p = 0.003). The duration of the secondary response was 26
months in cases and 15 months in controls (p = 0.004).
In 2015, they published their survival results at 5 and 7 years for 70 women treated with cytoreductive
surgery and HIPEC based on cisplatin or oxaliplatin for recurrent disease [19].
The median duration of the PFS was 27 months, and the 5-year and 7-year post-relapse survival rates (PRS)
were 52.8 and 44.7%, respectively (median 63 months).
A French study in 2013 compared patients treated with or without HIPEC who had undergone cytoreductive
surgery [40]. All patients had received preoperative chemotherapy. At 4 years, the overall survival rate was
75.6% in the HIPEC group and 19.4% in the control group (p = 0.013).
A systematic review of the use of HIPEC in recurrent EOC included 16 studies in 1168 patients, 82% of
whom were treated with cisplatin with HIPEC [28] (Table 2).
In patients undergoing cytoreductive surgery and HIPEC, overall survival ranged from 26.7 to 35 months,
with PFS ranging from 8.5 to 48 months. Morbidity related to HIPEC ranged from 13.6 to 30%, and toxicity was
haematological and renal [43]. Common complications of HIPEC include ileus, anastomotic leaks, intestinal
perforations, fistulas, abscesses, sepsis, bleeding and wound infections [28].

Brought to you by | Imperial College London

Authenticated 3
Download Date | 2/23/20 4:17 PM
 Revaux et al. DE GRUYTER

Table 2: HIPEC recurrent trials [26].

Author Study type n Chemotherapy PFS OS
Bakrin [35] Retrospective 470 Cisplatin (76%) n/a CC0: 51.5 months
cohort
Gonzalez Bayon [41] Prospective 27 Cisplatin and n/a 62.8 months for 1st
Doxorubicin recurrence
Cascales-Campos [36] Case control 39 Paclitaxel 21 months n/a
Fagotti [39] Case control 30 Oxaliplatin 26 months 5 years: 42.7%
Spiliotis [42] Prospective 60 Cisplatin or n/a 26.7 months
doxorubicin and
paclitaxel

HIPEC, Hyperthermic intraoperative intraperitoneal chemotherapy; OS, Overall Survival; PFS, Progression-Free Survival.

Spiliotis published a randomized trial on recurrent EOC and HIPEC in 120 patients operated on with or
without HIPEC [42]. The OS of the HIPEC group was significantly longer than that of the control group (26.7
vs. 13.4 months). But there were several biases in the study which decreased its power.

Discussion
EOC is the deadliest gynecologic malignancy. Currently there is increasing evidence that the combination of
CRS and HIPEC improves the prognosis of ovarian cancer significantly [39], [40], [44], [45], [46], [47], [48], [49].
However, a few years ago, some studies showed that HIPEC demonstrated no improvement in OS compared
to therapy without HIPEC [50], [51]. Thus, the therapeutic option with HIPEC offered to patients is always
discussed.
More studies have been published but most are small and retrospective. A primary critique of HIPEC ther-
apy in EOC is that there is not a standardized regimen. This was the same dose (cisplatin 100 mg/m2 ) utilized
in the primary EOC prospective trial [15].
Although a meta-analysis revealed that the association between CRS and HIPEC gave a better clinical prog-
nosis, the positive effect was only applied to primary EOC. This latest Chinese meta-analysis used HR instead
of OR to describe the prognostic effect of HIPEC [38]. Their meta-analysis demonstrated that HIPEC not only
improved OS significantly but also prolonged PFS throughout the population. Subgroup analysis showed that
HIPEC was associated with better clinical outcomes in primary disease or recurrence. EOC with stage III or IV
could benefit from HIPEC.
Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd

It would appear that some differences between studies have been reduced when incomplete resection pa-
tients are removed with a completeness of cytoreduction (CC) score at the end of the surgery equal to 3. In fact,
the CC score is a major prognostic factor for advanced ovarian cancer.
Factors including whether ovarian cancer resists platinum or not, pathological classification of ovarian can-
cer, the agency of chemotherapy medicine, the status of BRCA and the CC score were needed to be stratified
further to determinate the most suitable candidates for HIPEC. Additionally, in the meta-analysis among 13
included studies, only van Driel reported the information about adverse events between HIPEC arm and non-
HIPEC arm. There were no significant differences of complications between the two groups. For the HIPEC
treatment group, van Driel described abdominal pain, nausea, vomiting, fatigue, infection and ileus [15]. Kim
et al. [48] and Mendivil et al. [50] also reported a similar situation of toxicity and complications in HIPEC ther-
apy. Finally, the randomized controlled trials and well-designed observational studies are incorporated into
the meta-analysis to ascertain and evaluated the effect and the toxicity of HIPEC in ovarian cancer.
Another concern of HIPEC therapy is the increased cost associated with frequent intensive care unit (ICU)
admissions and length of hospital stay. There has been no cost analysis performed for HIPEC in EOC. The
addition of targeted or immunotherapies to IV regimens is another popular treatment option being considered.
The addition of bevacizumab or PARP inhibitor to BRCA mutated ovarian cancer has improved survival in
some subgroups of patients. This illustrates the importance of identifying appropriate patient populations for
specific treatment modalities.

Brought to you by | Imperial College London

4 Authenticated
Download Date | 2/23/20 4:17 PM
 DE GRUYTER Revaux et al.

Conclusion
Many randomized clinical trials are currently underway, recruiting patients with primary and recurrent disease,
as well as after NACT [38]. These studies will help us to validate HIPEC’s place in treatment and assess its
morbidity and cost.
In parallel, bevacizumab or nivaparib treatments are developing and have not been associated with HIPEC
treatment [52], [53].
Continuation of trials and association with new medical treatments is essential to find the best treatment
strategy for this type of cancer.
The combination of cytoreductive surgery and HIPEC in EOC seems to be an interesting therapeutic option
in view of the latest data in the literature and is one of the latest French recommendations [34].

Author statement

Research funding: Authors state no funding involved.

Conflict of interest: Authors state no conflict of interest.
Informed consent: Not applicable.
Ethical approval: Not applicable.

References
[1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.
[2] Morgan RJ, Alvarez RD, Armstrong DK, Burger RA, Chen L, Copeland L, et al. Ovarian cancer, version 2.2013. J Natl Compr Cancer Netw.
2013;11:1199–209.
[3] Holschneider CH, Berek JS. Ovarian cancer: epidemiology, biology, and prognostic factors. Semin Surg Oncol. 2000;19:3–10.
[4] Jones RB, Myers CE, Guarino AM, Dedrick RL, Hubbard SM, DeVita VT. High volume intraperitoneal chemotherapy (“belly Bath”) for
ovarian cancer. Pharmacologic basis and early results. Cancer Chemother Pharmacol. 1978;1:161–6.
[5] Miyagi Y, Fujiwara K, Kigawa J, Itamochi H, Nagao S, Aotani E, et al. Intraperitoneal carboplatin infusion may be a pharmacologically
more reasonable route than intravenous administration as a systemic chemotherapy. A comparative pharmacokinetic analysis of plat-
inum using a new mathematical model after intraperitoneal vs. intravenous infusion of carboplatin – a Sankai Gynecology Study Group
(SGSG) Study. Gynecol Oncol. 2005;99:591–6.
Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd

[6] Flessner MF, Dedrick RL, Rippe B. Estimation of lymphatic absorption and intraperitoneal volume during hypertonic peritoneal dialysis.
ASAIO Trans. 1989;35:178–81.
[7] Dedrick RL. Theoretical and experimental bases of intraperitoneal chemotherapy. Semin Oncol. 1985;12(3 Suppl 4):1–6.
[8] Wright AA, Cronin A, Milne DE, Bookman MA, Burger RA, Cohn DE, et al. Use and effectiveness of intraperitoneal chemotherapy for treat-
ment of ovarian cancer. J Clin Oncol. 2015;33:2841–7.
[9] González-Moreno S, González-Bayón LA, Ortega-Pérez G. Hyperthermic intraperitoneal chemotherapy: rationale and technique. World J
Gastrointest Oncol. 2010;2:68–75.
[10] Glehen O, Mohamed F, Gilly FN. Peritoneal carcinomatosis from digestive tract cancer: new management by cytoreductive surgery and
intraperitoneal chemohyperthermia. Lancet Oncol. 2004;5:219–28.
[11] Sugarbaker PH. Intraperitoneal chemotherapy and cytoreductive surgery for the prevention and treatment of peritoneal carcinomatosis
and sarcomatosis. Semin Surg Oncol. 1998;14:254–61.
[12] Panteix G, Beaujard A, Garbit F, Chaduiron-Faye C, Guillaumont M, Gilly F, et al. Population pharmacokinetics of cisplatin in patients with
advanced ovarian cancer during intraperitoneal hyperthermia chemotherapy. Anticancer Res. 2002;22:1329–36.
[13] van de Vaart PJ, van der Vange N, Zoetmulder FA, van Goethem AR, van Tellingen O, et al. Intraperitoneal cisplatin with regional hyper-
thermia in advanced ovarian cancer: pharmacokinetics and cisplatin-DNA adduct formation in patients and ovarian cancer cell lines. Eur
J Cancer. 1998;34:148–54.
[14] Ranieri G, Ferrari C, Di Palo A, Marech I, Porcelli M, Falagario G, et al. Bevacizumab-based chemotherapy combined with regional deep
capacitive hyperthermia in metastatic cancer patients: a pilot study. Int J Mol Sci. 2017;18:1458.
[15] van Driel WJ, Koole SN, Sikorska K, Schagen van Leeuwen JH, Schreuder HW, Hermans RH, et al. Hyperthermic intraperitoneal
chemotherapy in ovarian cancer. N Engl J Med. 2018;378:230–40.
[16] Sugarbaker PH, Graves T, DeBruijn EA, Cunliffe WJ, Mullins RE, Hull WE, et al. Early postoperative intraperitoneal chemotherapy
as an adjuvant therapy to surgery for peritoneal carcinomatosis from gastrointestinal cancer: pharmacological studies. Cancer Res.
1990;50:5790–4.
[17] Katz MH, Barone RM. The rationale of perioperative intraperitoneal chemotherapy in the treatment of peritoneal surface malignancies.
Surg Oncol Clin N Am. 2003;12:673–88.

Brought to you by | Imperial College London

Authenticated 5
Download Date | 2/23/20 4:17 PM
 Revaux et al. DE GRUYTER

[18] Sun X, Li X-F, Russell J, Xing L, Urano M, Li GC, et al. Changes in tumor hypoxia induced by mild temperature hyperthermia as assessed by
dual-tracer immunohistochemistry. Radiother Oncol. 2008;88:269–76.
[19] Petrillo M, De Iaco P, Cianci S, Perrone M, Costantini B, Ronsini C, et al. long-term survival for platinum-sensitive recurrent ovarian can-
cer patients treated with secondary cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC). Ann Surg Oncol.
2016;23:1660–5.
[20] Roti Roti JL, Kampinga HH, Malyapa RS, Wright WD, vanderWaal RP, Xu M. Nuclear matrix as a target for hyperthermic killing of cancer
cells. Cell Stress Chaperones. 1998;3:245–55.
[21] VanderWaal R, Thampy G, Wright WD, Roti Roti JL. Heat-induced modifications in the association of specific proteins with the nuclear
matrix. Radiat Res. 1996;145:746–53.
[22] El-Kareh AW, Secomb TW. A theoretical model for intraperitoneal delivery of cisplatin and the effect of hyperthermia on drug penetra-
tion distance. Neoplasia. 2004;6:117–27.
[23] Chua TC, Yan TD, Saxena A, Morris DL. Should the treatment of peritoneal carcinomatosis by cytoreductive surgery and hyperthermic
intraperitoneal chemotherapy still be regarded as a highly morbid procedure?: a systematic review of morbidity and mortality. Ann
Surg. 2009;249:900–7.
[24] Voron T, Eveno C, Jouvin I, Beaugerie A, Lo Dico R, Dagois S, et al. Cytoreductive surgery with a hyperthermic intraperitoneal chemother-
apy program: safe after 40 cases, but only controlled after 140 cases. Eur J Surg Oncol. 2015;41:1671–7.
[25] Jafari MD, Halabi WJ, Stamos MJ, Nguyen VQ, Carmichael JC, Mills SD, et al. Surgical outcomes of hyperthermic intraperitoneal
chemotherapy: analysis of the american college of surgeons national surgical quality improvement program. JAMA Surg. 2014;149:170–
5.
[26] Jewell A, McMahon M, Khabele D. Heated intraperitoneal chemotherapy in the management of advanced ovarian cancer. Cancers.
2018;10:296.
[27] Ferron G, Simon L, Guyon F, Glehen O, Goere D, Elias D, et al. Professional risks when carrying out cytoreductive surgery for peritoneal
malignancy with hyperthermic intraperitoneal chemotherapy (HIPEC): A French multicentric survey. Eur J Surg Oncol. 2015;41:1361–7.
[28] Hotouras A, Desai D, Bhan C, Murphy J, Lampe B, Sugarbaker PH. Heated intraperitoneal chemotherapy (HIPEC) for patients with recur-
rent ovarian cancer: a systematic literature review. Int J Gynecol Cancer. 2016;26:661–70.
[29] Huo YR, Richards A, Liauw W, Morris DL. Hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery (CRS) in ovar-
ian cancer: a systematic review and meta-analysis. Eur J Surg Oncol. 2015;41:1578–89.
[30] Ansaloni L, Coccolini F, Morosi L, Ballerini A, Ceresoli M, Grosso G, et al. Pharmacokinetics of concomitant cisplatin and paclitaxel ad-
ministered by hyperthermic intraperitoneal chemotherapy to patients with peritoneal carcinomatosis from epithelial ovarian cancer. Br
J Cancer. 2015;112:306–12.
[31] Cowan RA, O’Cearbhaill RE, Zivanovic O, Chi DS. Current status and future prospects of hyperthermic intraoperative intraperitoneal
chemotherapy (HIPEC) clinical trials in ovarian cancer. Int J Hyperthermia. 2017;33:548–53.
[32] Fagotti A, Petrillo M, Costantini B, Fanfani F, Gallotta V, Chiantera V, et al. Minimally invasive secondary cytoreduction plus HIPEC for
recurrent ovarian cancer: a case series. Gynecol Oncol. 2014;132:303–6.
[33] Wright AA, Bohlke K, Armstrong DK, Bookman MA, Cliby WA, Coleman RL, et al. Neoadjuvant chemotherapy for newly diagnosed, ad-
vanced ovarian cancer: society of gynecologic oncology and american society of clinical oncology clinical practice guideline. J Clin Oncol.
2016;34:3460–73.
[34] Lavoue V, Huchon C, Akladios C, Alfonsi P, Bakrin N, Ballester M, et al. Management of epithelial ovarian cancer. Short text drafted
from the French joint recommendations of FRANCOGYN, CNGOF, SFOG, GINECO-ARCAGY and endorsed by INCa. Bull Cancer (Paris).
Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd

2019;106:354–70.
[35] Bakrin N, Bereder JM, Decullier E, Classe JM, Msika S, Lorimier G, et al. Peritoneal carcinomatosis treated with cytoreductive surgery and
hyperthermic intraperitoneal chemotherapy (HIPEC) for advanced ovarian carcinoma: a french multicentre retrospective cohort study of
566 patients. Eur J Surg Oncol. 2013;39:1435–43.
[36] Cascales-Campos PA, Gil J, Gil E, Feliciangeli E, González-Gil A, Parrilla JJ, et al. Treatment of microscopic disease with hyperthermic
intraoperative intraperitoneal chemotherapy after complete cytoreduction improves disease-free survival in patients with stage IIIC/IV
ovarian cancer. Ann Surg Oncol. 2014;21:2383–9.
[37] Bae JH, Lee JM, Ryu KS, Lee YS, Park YG, Hur SY, et al. Treatment of ovarian cancer with paclitaxel- or carboplatin-based intraperitoneal
hyperthermic chemotherapy during secondary surgery. Gynecol Oncol. 2007;106:193–200.
[38] Zhang G, Zhu Y, Liu C, Chao G, Cui R, Zhang Z. The prognosis impact of hyperthermic intraperitoneal chemotherapy (HIPEC) plus cytore-
ductive surgery (CRS) in advanced ovarian cancer: the meta-analysis. J Ovarian Res. 2019;12:33.
[39] Fagotti A, Costantini B, Petrillo M, Vizzielli G, Fanfani F, Margariti PA, et al. Cytoreductive surgery plus HIPEC in platinum-sensitive recur-
rent ovarian cancer patients: a case-control study on survival in patients with two year follow-up. Gynecol Oncol. 2012;127:502–5.
[40] Le Brun J-F, Campion L, Berton-Rigaud D, Lorimier G, Marchal F, Ferron G, et al. Survival benefit of hyperthermic intraperitoneal
chemotherapy for recurrent ovarian cancer: a multi-institutional case control study. Ann Surg Oncol. 2014;21:3621–7.
[41] Gonzalez Bayon L, Steiner MA, Vasquez Jimenez W, Asencio JM, Alvarez de Sierra P, Atahualpa Arenas F, et al. Cytoreductive surgery
and hyperthermic intraperitoneal chemotherapy for the treatment of advanced epithelial ovarian carcinoma: upfront therapy, at first
recurrence, or later? Eur J Surg Oncol. 2013;39:1109–15.
[42] Spiliotis J, Halkia E, Lianos E, Kalantzi N, Grivas A, Efstathiou E, et al. Cytoreductive surgery and HIPEC in recurrent epithelial ovarian
cancer: a prospective randomized phase III study. Ann Surg Oncol. 2015;22:1570–5.
[43] Polom K, Roviello G, Generali D, Marano L, Petrioli R, Marsili S, et al. Cytoreductive surgery and hyperthermic intraperitoneal
chemotherapy for treatment of ovarian cancer. Int J Hyperthermia. 2016;32:298–310.
[44] Warschkow R, Tarantino I, Lange J, Müller SA, Schmied BM, Zünd M, et al. Does hyperthermic intraoperative chemotherapy lead to im-
proved outcomes in patients with ovarian cancer? A single center cohort study in 111 consecutive patients. Patient Saf Surg. 2012;6:12.
[45] Ryu KS, Kim JH, Ko HS, Kim JW, Ahn WS, Park YG, et al. Effects of intraperitoneal hyperthermic chemotherapy in ovarian cancer. Gynecol
Oncol. 2004;94:325–32.

Brought to you by | Imperial College London

6 Authenticated
Download Date | 2/23/20 4:17 PM
 DE GRUYTER Revaux et al.

[46] Gori J, Castaño R, Toziano M, Häbich D, Staringer J, De Quirós DG, et al. Intraperitoneal hyperthermic chemotherapy in ovarian cancer.
Int J Gynecol Cancer. 2005;15:233–9.
[47] Muñoz-Casares FC, Rufián S, Rubio MJ, Díaz CJ, Díaz R, Casado A, et al. The role of hyperthermic intraoperative intraperitoneal
chemotherapy (HIPEC) in the treatment of peritoneal carcinomatosis in recurrent ovarian cancer. Clin Transl Oncol. 2009;11:753–9.
[48] Kim JH, Lee JM, Ryu KS, Lee YS, Park YG, Hur SY, et al. Consolidation hyperthermic intraperitoneal chemotherapy using paclitaxel in
patients with epithelial ovarian cancer. J Surg Oncol. 2010;101:149–55.
[49] Safra T, Grisaru D, Inbar M, Abu-Abeid S, Dayan D, Matceyevsky D, et al. Cytoreduction surgery with hyperthermic intraperitoneal
chemotherapy in recurrent ovarian cancer improves progression-free survival, especially in BRCA-positive patients- a case-control study.
J Surg Oncol. 2014;110:661–5.
[50] Mendivil AA, Rettenmaier MA, Abaid LN, Brown JV, Mori KM, Lopez KL, et al. Consolidation hyperthermic intraperitoneal chemotherapy
for the treatment of advanced stage ovarian carcinoma: a 3 year experience. Cancer Chemother Pharmacol. 2017;80:405–10.
[51] Baiocchi G, Ferreira FO, Mantoan H, da Costa AA, Faloppa CC, Kumagai LY, et al. Hyperthermic intraperitoneal chemotherapy after sec-
ondary cytoreduction in epithelial ovarian cancer: a single-center comparative analysis. Ann Surg Oncol. 2016;23:1294–301.
[52] Chan JK, Herzog TJ, Hu L, Monk BJ, Kiet T, Blansit K, et al. Bevacizumab in treatment of high-risk ovarian cancer – a cost-effectiveness
analysis. Oncologist. 2014;19:523–7.
[53] Cohn DE, Kim KH, Resnick KE, O’Malley DM, Straughn JM. At what cost does a potential survival advantage of bevacizumab make sense
for the primary treatment of ovarian cancer? A cost-effectiveness analysis. J Clin Oncol. 2011;29:1247–51.
Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd

Brought to you by | Imperial College London

Authenticated 7
Download Date | 2/23/20 4:17 PM