Key words
ovarian cancer - statement - HIPEC - AGO
Schlüsselwörter
Ovarialkarzinom - Empfehlung - HIPEC - AGO
Some hospitals in Germany offer HIPEC (hyperthermic intraperitoneal chemotherapy) to
treat patients with a primary diagnosis of ovarian cancer or recurrent ovarian
cancer. As this procedure is currently not indicated for the treatment of patients
with ovarian cancer, there is a risk that patients will be denied established
procedures that have been proven to be effective, putting patients at risk. We
therefore formulated the following statement after analysing the currently available
data.
The standard therapy to treat advanced ovarian cancer consists of initial surgery
with the goal of achieving for macroscopic complete resection, followed by
platinum-based intravenous combination chemotherapy [1], [2], [3], [4].
This concept was established based on data from several prospective studies and
10 000 patients and it is the accepted standard worldwide [5]. Recently, the therapy options for patients with FIGO stage IIIB, IIIC
and IV cancer have been expanded with the postoperative intravenous administration
of the combination carboplatin-paclitaxel with the angiogenesis inhibitor
bevacizumab.
The preclinical rationale for hyperthermic chemotherapy is based on studies which
reported an increased cytotoxicity of cisplatin and other cytostatic drugs in human
cell lines and animal models [6], [7], [8], [9], [10]. To explain this increased cytotoxicity it was
suggested that higher temperatures could overcome cisplatin resistance [11]. Moreover, increased penetration of cisplatin
administered intraperitoneally was described when combined with hyperthermia [12]. These theoretical approaches and preclinical
observations are the basis for the clinical application of HIPEC. There are
currently 3 published randomised studies on the use of HIPEC to treat advanced colon
and gastric cancer. A randomised phase III trial for recurrent colorectal cancer in
105 patients investigated the efficacy of systemic therapy alone compared to a
combination of cytoreductive surgery and HIPEC (mitomycin C), followed by systemic
therapy. The trial demonstrated a significant benefit of combined therapy with
respect to mean progression-free survival (7.7 vs. 12.6 months; p = 0.020) and mean
disease-specific survival (12.6 vs. 22.2 months; p = 0.028). The strongest
prognostic factor in this trial was postoperative residual tumour. Only patients
with complete tumour resection benefited, while patients with residual tumour
intraoperatively showed no benefit from HIPEC. Postoperative mortality in the
experimental HIPEC arm was 8 % [13], [14]. A further randomised study investigated the efficacy
of surgery combined with HIPEC (cisplatin and mitomycin C) compared to surgery alone
for peritoneal carcinomatosis of gastric cancer (n = 68). The rate of complete
resections was 58 % in both study arms. A significant benefit with regard to
disease-specific survival (6.5 vs. 11.0 months; p = 0.046) was observed for surgery
combined with HIPEC. No data was provided for overall survival. The strongest
predictors in this study were the presence or absence of postoperative complications
and completion of 6 cycles of postoperative chemotherapy. In absolute terms,
patients who only underwent surgery with complete or almost complete resection (max.
residual tumour 2.5 mm) had the best prognosis with a mean disease-specific survival
of 31 months, while the mean disease-specific survival for patients with complete
resection and HIPEC was 12 months [15]. A three-arm
randomised study of 139 patients with a primary diagnosis of locally advanced
gastric cancer stage T2–T4 compared surgery alone vs. surgery + HIPEC vs. surgery +
intraperitoneal chemotherapy. Peritoneal carcinomatosis was not a prerequisite
condition for inclusion in the study. Subgroup analysis (serosa invasion or lymph
node metastasis) found a benefit for HIPEC [16].
The use of HIPEC is primarily discussed for the therapy of peritoneal carcinomatosis.
The different tumour biologies and therapeutic concepts make a highly differentiated
approach necessary to take account of the different diagnoses. Studies have shown
that peritoneal carcinomatosis from primary ovarian cancer has a different tumour
biology and a significantly better overall prognosis compared to metastasised
gastrointestinal tumours [17]. As the choice of systemic
therapies to treat peritoneal metastases of gastrointestinal tumours is limited,
HIPEC offers an additional option. But all studies to date have also highlighted an
increase in postoperative complications such as infections, and the current S3
guideline on the treatment of gastric cancer therefore only recommends using HIPEC
as part of a study (GoR A, LoE I) [18]. An update of the
S3 guideline on colorectal cancer which includes an evaluation of HIPEC for this
disease entity is still lacking.
Early peritoneal metastasis often occurs with ovarian cancer, and most patients are
only diagnosed at an advanced stage of disease [19]. For
primary surgery, postoperative residual tumour is the strongest independent
predictor in addition to tumour stage [4]. The presence of
peritoneal carcinomatosis often limits the efficacy of complete resection [20], [21]. However, it has not
been shown that peritoneal carcinomatosis is in itself an independent predictor
[22]. Peritoneal carcinomatosis has been shown to be
a negative predictor for complete resection in recurrent ovarian cancer. However, if
complete resection of the tumour is achieved, then peritoneal carcinomatosis no
longer serves as a prognostic factor [23], [24]. Thus, peritoneal carcinomatosis of ovarian, fallopian
tube or primary peritoneal cancer appears to be a technical obstacle to complete
resection (and in this context has prognostic importance), but by itself it does not
appear to be of biological importance and therefore does not require specific
treatment – with the exception of the appropriate surgical technique.
To date, there are no randomised studies on HIPEC in the context of primary surgery
for ovarian cancer or surgery for recurrent ovarian cancer. Some retrospective data
has been published as well as a few phase I/II trials with different, mostly
platinum-based regimens, dosages and administration times [25]. There are no systematic studies on dosages. None of the studies to
date have demonstrated a benefit of HIPEC with regard to overall survival times
compared to surgery alone [26], and many studies reported
significantly increased complication rates. In contrast to the limited data
currently available on HIPEC, results of randomised phase III trials are available
for normothermic intraperitoneal chemotherapy. A somewhat higher efficacy was
observed for normothermic intraperitoneal chemotherapy regimens but this was
accompanied by significantly increased side-effects, particularly for doses
repeatedly administered intraperitoneally [27]. Due to
the increased side-effects and the lower associated benefit as measured by the much
lower rates of therapy completion, intraperitoneal therapy is not currently
recommended as a standard option [28], [29].
In summary, there is currently no data available which shows an improvement in
progression-free survival or overall survival after the use of HIPEC combined with
cytoreductive surgery. Based on the available data, the increased rate of surgical
complications means that HIPEC cannot be classified as practicable and safe. HIPEC
should therefore not be used to treat ovarian, fallopian tube or primary peritoneal
cancer outside prospective controlled studies, neither for primary therapy or
to treat recurrence. This clear recommendation against the use of HIPEC has also
been included in the most recent S3 guideline on the diagnosis and therapy of
ovarian cancer and is based on an interdisciplinary consensus.
