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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

Referencee List

1.. Wientjes MC, Badalament RA, Wang RC, Hassan F, Au /£. Penetration of mitomycin C in human bladder.

Cancerr Res 1993; 53: 3314.

2.2. Cavaliere F et al. Peritonectomy and hyperthermic antiblast perfusion in the treatment of peritoneal

carcinomatosis.. Eur | Surg One 2000; 26: 486-91.

3.. Koga S et al. Prophylactic therapy for peritoneal recurrence of gastric cancer by continuous

hyperthermicc peritoneal perfusion with mitomycin-C. Cancer 1988; 61: 232-7.

4.. Tsiftis D et al. Peritoneal expansion by artificially produced ascites during perfusion chemotherapy. Arch

Surgg 1999; 134: 545-9.

5.. Beaujard AC et al. Intraperitoneal chemohyperthermia with mitomycin C for digestive tract cancer

patientss with peritoneal carcinomatosis. Cancer 2000; 88: 2512-9.

6.. jacquet P et al. Analysis of morbidity and mortality in 60 patients with peritoneal carcinomatosis treated

byy cytoreductive surgery and heated intraoperative intraperitoneal chemotherapy. Cancer 1996; 77:

2622-9. .

7.. Ikeguchi M et al. Effects of continuous hyperthermic peritoneal perfusion on prognosis of gastric cancer

withh serosal invasion. Eur | Surg 1995; 161: 581-6.

8.. Yonemura Y et al. Prophylaxix with intraoperative chemohyperthermia against peritoneal recurrence of

serosall invasion-positive gastric cancer. World ] Surg 1995; 19: 450-5.

9.. Stephens AD et al. Morbidity and mortality analysis of 200 treatments with cytoreductive surgery and

hyperthermicc intraoperative intraperitoneal chemotherapy using the coliseum technique. Ann Surg

Oncoll 1999; 6: 790-6.

10.. Benson AB3. Therapy for advanced colorectal cancer. Sem Oncol 1998; 25: 2-11.

11.. Sugarbaker PH, Chang D. Results of treatment of 385 patients with peritoneal surface spread of

appendiceall malignancy. Ann Surg Oncol 1999; 6: 727-31.

11 2. EsquivelI, Sugarbaker PH. Pseudomyxoma peritonei in a hernia sac: analysis of 20 patients in whom

mucoidd fluid was found during hernia repair. Eur | Surg Oncol 2001; 27: 54-8.

11 3. Esquivel I, Sugarbaker PH. Clinical presentation of the pseudomyxoma peritonei syndrome. Br | Surg

2000;; 87: 1414-8.

14.. McQuellen RP et al. Quality of live after intraperitoneal hyperthermic chemotherapy (IPHC) for peritoneal

carcinomatosis.. Eur J Surg Oncol 2001; 27: 65-73.

126 6