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Hyperthermic intraperitoneal chemotherapy in peritoneal surface malignancy
Witkamp, A.J.
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Citation for published version (APA):Witkamp, A. J. (2003). Hyperthermic intraperitoneal chemotherapy in peritoneal surface malignancy.
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Download date: 19 Jun 2020
X X
Generall discussion
\ \
Thiss thesis describes the first experiences in The Netherlands Cancer Institute with
cytoreductivee surgery followed by intra-operative HIPEC with MMC. The work pre-
sentedd is a reflection of the evolution of the HIPEC procedure in The Netherlands
Cancerr Institute towards a reliable treatment modality with acceptable morbidity
andd mortality. The treatment of peritoneal carcinomatosis from colorectal origin
andd pseudomyxoma peritonei were chosen as objects of main emphasis of this the-
sis. .
Techniquee and toxicity
Thee pharmacokinetic advantage of intraperitoneal chemotherapy is the most impor-
tantt rationale for HIPEC in peritoneal surface malignancy. The peritoneal-plasma
barrierr creates a concentration gradient, strongly favouring the intra-peritoneal
concentrationn after intraperitoneal drug administration. Despite the stripping of
largee surfaces of the peritoneum in most patients, we found a mean AUC ratio
(plasma/perfusionn fluid) of 13 when MMC was used. This finding confirms that the
peritoneal-plasmaa barrier remains effective even after large peritonectomy proce-
dures.. Unfortunately it is not possible to measure the penetration depth of MMC
intoo tumour tissue. The only data on MMC penetration are from animal studies
afterr bladder instillation chemotherapy. Therapeutic concentrations were found in
alll layers of the bladder suggesting a penetration depth of at least a few millimetres
[1] .. In our studies we used a MMC dosage based on body surface, however we
foundd a wide and partly unpredictable inter-individual variation of drug concentra-
tionss in perfusion fluid and plasma. Consequently, dosage according body surface
alonee appears to be inaccurate. A dosage per body surface and volume of perfusion
fluidfluid (mg /m2 / L ) , as also proposed by Cavaliere, is probably more accurate [2] .
Almostt all reports on aggressive cytoreductive surgery and HIPEC show relatively
highh treatment related morbidity rates [3-8]. Number of previous laparotomies,
durationn of surgery, number of peritonectomy procedures, number of visceral
resectionss and number of suture lines were found to be associated with major mor-
bidityy [9] . Our studies largely underwrite these findings with an overall morbidity
ratee of 41%. Especially the number of previous laparotomies appears to be an
importantt factor in causing surgery related complications (i.e. bowel perforations).
Wee found that bowel perforations are probably caused by surgical trauma of the
bowell surfaces, maybe enhanced by thermal and chemotherapeutic damage.
Whetherr MMC itself impairs suture line healing could not be concluded from our
studies,, however we found no relation between higher intraperitoneal MMC con-
centrationss and the occurrence of bowel perforations or suture line leakage.
Anotherr important finding was the significant negative effect of pre-operative
bowell obstruction on the occurrence of postoperative morbidity. Leucocytopenia
1222 occurred in 42% of patients and could be fully attributed to MMC.
ChapterChapter X General discussion inn i n
Survivall and quality of live
Althoughh survival is not an important issue in this thesis, first results in patients
wit hh peritoneal metastases from colorectal cancer and pseudomyxoma peritonei are
promising.. In colorectal cancer patients we found a 2-year survival rate of 45% at a
mediann follow-up of 38 months. This is comparable with other studies on HIPEC
inn patients with intraperitoneal disseminated colorectal cancer, where 2 year sur-
vivall rates of 35-50% are described [10]. This seems an important improvement
whenn compared to standard therapy (i.e. systemic chemotherapy and palliative sur-
gery)) where 2 year survival rates of 10-20% are reported. More important might be
thatt we found a group of relatively long-term survivors, with a 5 year survival rate
off approximately 20%, which is very rare after standard therapy. The studies
describedd in this thesis suggest that intra-operative HIPEC with MMC may con-
tributee to long-term survival. However, a survival benefit can not be proven by
thesee phase II studies in a relatively small group of patients. Therefore a randomised
phasee II I trial has been performed in The Netherlands Cancer Institute to study the
effectt of cytoreductive surgery and intra-operative HIPEC in patients with per i-
toneall metastases from colorectal origin. Inclusion of this study has recently been
closedd (after 104 patients were included) and the first results of this study are soon
expected. .
Thee 3 year survival rate of 81% that was found after cytoreductive surgery and
HIPECC in patients with pseudomyxoma peritonei after a median follow-up of 12
monthss is more difficul t to interpret. First off all pseudomyxoma peritonei is a dis-
easee with a relatively benign character. Retrospective studies showed a 5 year sur-
vivall rate of approximately 50% after surgery alone. This means that prospective
survivall studies must have a relatively long median follow-up (probably at least 5
years).. Secondly, pseudomyxoma peritonei is a very rare disease, which makes it
difficul tt to investigate treatment strategies in larger groups of patients. In patients
wit hh pseudomyxoma peritonei pre-operative histological assesment of the tumour
seemss an important prognostic parameter, both in our group of patients and in the
Sugarbakerr analysis of 385 patients [11]. Benign cellular phenotype and small num-
berr of cells in comparison to mucus predict a better outcome. The separation of
benignn pseudomyxoma from intermediate or malignant pseudomyxoma is however
farr from clear. This also goes for the separation between pseudomyxoma peritonei
andd well differentiated mucinous carcinoma. The completeness of cytoreduction
playss an important role in survival after HIPEC. It is not clear whether this observa-
tionn is caused by the more complete exposure to heated chemotherapy if only small
residuee is left or that we simply observe the effect of better surgery (or both).
Theree is off course also a selection factor. Less tumour to start with and less infiltra-
tivee disease wil l make complete resection easier, but also may have prognostic
meaningg itself. Early detection of the disease (before increase of the abdominal
girth)) is therefore important to limi t the extension of the tumour. For that reason 123
surgeonss and gynaecologists should be aware of the clinical signs of the disease
becausee diagnosis is often made at abdominal surgery performed for a different rea-
sonn (39% of women present during evaluation of an ovarian mass, 27% of both
malee and female patients present during surgery for suspected acute appendicitis
andd 27% of the male patients present during surgery for inguinal hernias) [12,13].
Whenn survival can be improved, the quality of live becomes an important issue.
Extensivee cytoreductive surgery followed by intra-operative HIPEC is a very aggres-
sivee treatment schedule with a considerable treatment related morbidity. There are
nott many data on the quality of live after this treatment modality. However,
recentlyy a study was published by McQuellon et al. [14]. They performed an assess-
mentt study to the functional status and the quality of live of patients with dissemi-
natedd peritoneal cancer before and after cytoreductive surgery and HIPEC with
MMC.. Their conclusion was that the described treatment was well tolerated in a
groupp of 64 patients. Most patients returned to baseline or better levels of function-
ingg within 3 months post-treatment. The experience in The Netherlands Cancer
Institutee underwrites these findings.
Patientt selection
Cytoreductivee surgery followed by intra-operative HIPEC is associated with relative-
lyy high morbidity and mortality rates. Careful selection is important, both regarding
riskk factors for post HIPEC morbidity and with a view on the chances for long term
success.. Patients in a poor medical condition (e.g. pre-operative bowel obstruction)
orr that are heavily pre-treated by surgery (> 2 previous laparotomies) or patients
thatt are of high age, should be excluded because of the high risk of postoperative
complicationss (see chapter 4). Although the studies herein described found no direct
relationn between the extension of the tumour spread and postoperative morbidity,
otherr studies have described such an effect [9] . Moreover, one of the prerequisites
forr effective HIPEC is a limited tumour residue which is unlikely to be reached if
alll areas of the abdomen are extensively involved. Pre-operative screening by CT-
scann is important to distinguish inoperable disease or tumour spread in patients
wit hh peritoneal carimomatosis. However it remains extremely difficul t to judge
tumourr extent on CT in most cases. Better registration of tumour extend during
laparotomyy or laparoscopy can provide more accurate information. In most cases,
bothh pseudomyxoma peritonei and peritoneal carcinomatosis of colorectal origin,
thee diagnosis was made by laparotomy. The information of these operations is
howeverr often very disappointing. Better registration wil l improve selection of
thosee patients who can realistically undergo a complete cytoreduction, reducing the
postoperativee morbidity and improving long-term outcome. This probably dimin-
ishess the postoperative morbidity because surgery can be limited, while theoretical-
1244 ly long term survival can be improved.
ChapterChapter X General discussion
Thee work described in this thesis has a strong emphasis on technique, feasibility and
short-termm survival in patients with proven intraperitoneal metastases. More (ran-
domised)) clinical studies are needed to proof the effect of extensive surgical cytore-
ductionn and HIPEC on the long-term survival in patients with peritoneal surface
malignancies.. However, further studies (both experimental and clinical) are also
neededd to proof the contribution of the different components of the treatment, to
searchh for new chemotherapeutic agents and combinations that can be used in
HIPECC procedures. Better understanding may also open this approach to other peri-
toneall surface malignancies, notably ovarian cancer, gastric cancer and peritoneal
mesothelioma. .
125 5
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126 6