UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl)
UvA-DARE (Digital Academic Repository)
Cytoreduction and hyoerthermic intraperitoneal chemotherapy in peritoneal
carcinomastosis of colorectal origin
Verwaal, V.J.
Publication date
2004
Link to publication
Citation for published version (APA):
Verwaal, V. J. (2004). Cytoreduction and hyoerthermic intraperitoneal chemotherapy in
peritoneal carcinomastosis of colorectal origin.
General rights
It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s)
and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open
content license (like Creative Commons).
Disclaimer/Complaints regulations
If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please
let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material
inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter
to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You
will be contacted as soon as possible.
Toxicityy of cytoreductive surgery
andd hyperthermic intraperitoneal chemotherapy
Vicc J. Verwaai
1, Harm van Tinteren
2, Serge van Ruth
1andd Frans A.N. Zoetmulder
1d e p a r t m e n tt of Surgery and
2Department of Biometrics
Thee Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital,
Amsterdam,, the Netherlands
BackgroundBackground and Objectives: Cytoreduction with hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatmentt with a high morbidity. Optimal patients selection can possible reduce toxicity and complications.
Pa(ientSPa(ientS and Methods: Complications and toxicity of 102 patients were studied. Toxicity was graded accord-ingg National Cancer Institute Common Toxicity Criteria (NCI CTC) classification. A complication was de-finedfined as any post-operative event that needed re-intervention. Potential patients, tumor, and treatment fac-torss were studied on their relation to complications.
Results:Results: Grade 3, 4, or 5 toxicity was observed in 66 patients (65%). Eight patients died of treatment-relatedd causes. Surgical complications occurred in 36 patients (35%). Fistulae were frequendy encountered (188 patients). The risk of a complicated recovery was higher in recurent colorectal cancer with carcinomato-siss (P =0.009) and in the case of more than five regions affected (P = 0.044), who had a Simplified Perito-neall Cancer (SPC) score of 13 (P = 0.012) and with an incomplete initial cytoreduction (P - 0.035). Patients withh blood loss exceeding 6 1 (P = 0.028) and those with three or more anastomoses also had an increased post-operativee complication rate (P = 0.018).
Conclusions:Conclusions: Toxicity of cytoreduction followed by HIPEC was 65% (Grade 3-5 NCI CTC), with a surgical complicationn rate of 35%. Patients with six or seven regions involved and those in whom complete
cytore-ductionn cannot be reached are probably better off without this treatment.
I n t r o d u c t i o n n
Cytoreductivee surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is a novell treatment for patients with peritoneal carcinomatosis of colorectal origin. In recent years, severall phase II studies and one phase III study have shown that this therapy improves survival to aa median of two years and that approximately 20% of patients live longer then five years and are
probablyy cured.1-10 This potential improvement in survival has to be balanced against the side
ef-fectss of this intensive treatment.,A number of studies report complication rates as high as 30%,n'12
mostlyy surgery related.13
Patientss with peritoneal carcinomatosis often have wide-spread disease.14 Surgeons tend to push
too the limits to resect all macroscopic tumor, knowing that best results can be achieved if the
cy-toreductionn is complete.15 This aggressive approach leads to a considerable incidence of
surgery-relatedd complications. These observations taken together with bone marrow toxicity, which fre-quendyy occurs after intraperitoneal instillation of Mitomycin C (MMC) in combination with
hyper-thermia,, imply that the post-operative period can be hazardous.13
Itt seems obvious that patients who suffer serious postoperative complications and have grim chancee of long survival would have been better off if they had been excluded from this therapy. Onn the other hand, this treatment offers a chance of long-term survival for selected patients.
Inn this study, we analyzed the complications and toxicities of patients with peritoneal carcinoma-tosiss of colorectal origin treated with cytoreduction and HIPEC at The Netherlands Cancer Insti-tute.. The aim was to identify characteristics that cause toxicity and complications of HIPEC in or-derr to optimize patient selection.
Patientss and Methods
Betweenn November 1995 and October 2002, 102 patients with peritoneal carcinomatosis of colo-rectall origin were treated with cytoreduction and HIPEC at The Netherlands Cancer Institute. The firstt 36 patients were entered in phase I and II studies. The following 48 patients were entered in a randomizedd phase III study and the remaining 18 patients were treated after this study. All patients weree treated according to the same protocol.
Patientss with histologically proven peritoneal carcinomatosis without evidence of Over or lung metastases,, up to 70 years of age and fit to undergo major surgery, were eligible for this therapy. Peritoneall carcinomatosis both at primary presentation and at recurrence were included. Patients hadd to be followed for at least six months to be eligible for the study. Written informed consent waswas required for patients who participated in the trials.
Treatment Treatment
CytoreductiveCytoreductive surgery
Thee objective of cytoreduction was to leave no macroscopic tumor behind. If this was found im-possible,, the aim was to leave no deposits thicker than 2.5 mm, as this is the maximum penetration
Chapterr 4
depthh at which a dose advantage of intraperitoneal MMC is expected.
Maximumm exposure was obtained by opening the abdominal cavity from xyphoid to pubis and
dividingg all adhesions. Resection of the peritoneum was carried out as described by Sugarbaker.16
Infiltratedd viscera were (partly) resected. The only reasons for not proceeding to a complete cytore-ductionn were extensive involvement of small bowel or its mesentery and tumor infiltration in the portaa hepatis and pancreas. In these cases, the amount of tumor was resected as far as was judged too be compatible withi sufficient post-operative function. No further restrictions were made on the extentt of surgery. Cytoreduction could include for example: gastrectomy, splenectomy, cholecys-tectomy,, peritonectomies of diaphragms, omentectomy, partial small and large bowel resections, rectall resection, resection of uterus and ovaries, and partial bladder or ureter resections. Of course, inn many cases only a selection of these techniques was needed.
HIPEC HIPEC
Ourr perfusion method is described in detail elsewhere by Witkamp et al.17 The open carrousel
methodd was used in all patients. The perfusion circuit consisted of a centrally placed inflow cathe-ter,, three outflow catheters placed in the pelvis and below left and right diaphragm, tubing, a roller pump,, a reservoir, and a heat exchanger. Four temperature probes were placed in the abdomen closee to in- and outflow catheters. A plastic sheet covered the laparotomy opening to reduce heat losss and to avoid drug spilling. A central aperture was made to allow manipulation to achieve opti-mall drug and heat distribution and prevent hot spots. Three liters of perfusate were used at an in-floww temperature of 41—42°C. As soon as the temperature in the abdomen was stable above 40°C,
MMCC was added in three fractions with a 30-min interval (V2, , % of the total dose, respectively).
Duringg the perfusion the patients in the phase II study, the dose of MMC was increased stepwise
fromm 25 to 40 mg/m2. All other patients were treated with 35 mg/m2 MMC. After the completion
off 90-minutes perfusion, the fluid was drained from the abdomen via the outflow catheters. These catheterss were left in place for drainage of the abdomen during the first five post-operative days.
Reconstruction Reconstruction
Thee continuity of the gastro-intestinal tract was restored after finishing the perfusion. Single-layer hand-suturedd anastomoses were used. A colostomy was routinely made in case of a rectum resec-tion.tion. A gastrostomy was used to allow the stomach to drain, and a trans-gastric jejunal feeding tube wass placed for enteral nutrition.
Post-operativePost-operative care
Patientss stayed in the intensive care unit until they were stable with respect to cardiac and pulmo-naryy function. Close watch was kept for any sign of abdominal sepsis, which was an indication for relaparotomyy at an early stage. Jejunal tube feeding was started at day 1, and normal oral nutrition wass resumed as soon as possible.
AdjuvantAdjuvant chemotherapy
Systemicc adjuvant chemotherapy was given for six months, using the modified Laufman regimen
(5-Fluorouracill 400 mg/m2 and Leucovorin 80 mg/m2, weekly).18 If patients had been treated with
5-Fluororuracill within a year prior to HIPEC, they were treated with irinotecan (350 mg/m2,
weekly)) instead of 5-fluroruracil.
DataData Collection
Thee following factors, potentially related to a complicated recovery, were prospectively recorded. Patientt and tumor characteristics. Gender, presentation of peritoneal carcinomatosis (associated withh primary colorectal cancer vs. recurrence), location of primary lesion (appendix vs. colon vs. rectum),, malignancy grade (good/moderate vs. poor), histology of adenocarcinoma (signet cell car-cinomaa vs. non-signet cell carcinoma), clinical presentation (obstruction vs. no obstruction), extent off carcinomatosis (primary tumor site vs. ovarian metastasis vs. more extensive). These factors weree based on the medical history and on operative notes from the laparotomy in which the diag-nosiss of peritoneal carcinomatosis was made.
Dataa on cytoreduction and HIPEC. The abdomen was divided into seven anatomic regions (pelvis;; right lower abdomen; small bowel and mesentery; omentum and transverse colon; sub-hepaticc space and stomach; right subphrenic space; left subphrenic space). The number of affected regionss was recorded, as was the Simplified Peritoneal Cancer score (SPC score). This score was determinedd by the maximum tumor thickness in each of the seven regions, using a grading system (noo residue: 0; < 20 mm: 1; 20 - 50 mm: 2; > 50 mm: 3). The SPC score was calculated by adding thesee numbers (minimum zero and maximum 21). The overall result of cytoreduction was deter-minedd according to maximum thickness of tumor nodules left behind at any place in the abdomen. Noo residual macroscopic tumor was graded as an Rl resection, residual macroscopic tumor < 2.5 mmm was recorded as R-2a resection and if more disease was left behind as R2b resection. The total operationn time, blood loss, number of bowel and organ resections, and the number of anastomoses weree recorded.
Dataa on post-operative period. During the postoperative period, all side effects and complica-tionss were recorded, as well as re-operations, duration of stay in the intensive care unit, total hospi-tall stay, survival time, and cause of death.
DefinitionDefinition and Criteria of Endpoints
Treatment-relatedd death was defined as death due to toxicity following cytoreduction and HIPEC withoutt time interval restrictions. Toxicity was recorded in accordance to the National Cancer
In-stitutee Common Toxicity Criteria (NCI CTC).19 Surgical complications were seen as a component
off the total toxicity and were also registered in accordance of the NCI CTC. Surgical failure was definedd as any bowel fistulae resulting in abdominal infection for which invasive therapy was needed. .
Results s
Sixtyy of the 102 patients presented with colorectal cancer with simultaneous peritoneal carcino-matosiss and 42 presented with peritoneal carcinomatosis as a recurrence. There were 45 female and 577 male patients, with a median age of 53 years (range 24—75). The primary cancer sites were the
Chapterr 4
Tablee 1. Resection in 102 patients treated by cytoreduction and H I P E C Numberr patients
Gastrectomyy 11 Smalll bowel resection 52'
Cecumm resection 102 Colonn resection 41 Rectumm resection 53 Splenectomyy 12
Hysterectomyy 202
Mediann number of small bowel resections 2 (range 0 - 7 ) , 2in 45 women
appendixx in 15 patients, colon in 78 patients, and rectum in 5. In four patients the site of the pri-maryy lesion could not b e determined because of massive tumor growth t h r o u g h o u t the a b d o m e n .
T h ee distribution of the t u m o r over the abdomen expressed in n u m b e r of involved regions and SPCC score showed a wide variation. T h e median n u m b e r of affected regions was four and the me-diann S P C score was eight.
T a b l ee 1 summarizes the organ resections performed during cytoreduction. T h e median operation durationn was 7 hr 30 min (range, 4 hr 35 m i n - 1 4 hr), with a median blood loss of 3.5 L (range 0.4 — 30). .
Forty-threee percent of the patients remained without serious toxicity (Grade 2). Toxicity Grades 3,, 4, and five are listed in table 2. Often, patients had G r a d e 3 o r 4 toxicity in m o r e than one cate-gory.. T h r e e patients died within 30 days, o n e due t o post-operative hemorrhage and two due in
in-Tablee 2. G r a d e 3, 4 and 5 toxicity in 102 patients treated for peritoneal carcinomatosis o f colorectall cancer by cytoreduction and H I P E C
Bonee marrow Heart t Skin n Gastrointestinall tract Hemorrhage e Liver r Infections s Nervee system Lung g Kidney y All l Gradee 3 16 6 2 2 3 3 7 7 1 1 1 1 15 5 3 3 8 8 3 3 59 9 Gradee 4 3 3 5 5 --152 2 1 1 --2 --2 2 2 28 8 Gradee 5' --1 --1 --1 --1 --62 2 --8 --8 'gradee 5 refers to toxicity related deaths, 2patients who died of abdominal sepsis due to fistula were 52coredd as gastrointestinal grade 4 and infections grade 5
Tablee 3. Relationship between patient- and treatment-related factors and complicated recovery inn 102 patients with peritoneal carcinomatosis of colorectal cancer origin treated by cytoreduc-tiontion and HIPEC
Factor r Gender r Presentationn PC Locationn CRC Malignancyy grade CRC2 Histologyy CRC Obstructionn at PC Tumorr extent on PC
Numberr affected regions
SPCC score3
Resultt cytoreduction
Bloodd loss
Operationn time
Numberr suture lines
Male e Female e Primary y Recurrence e Appendix x Colon n Rectum m NS S Goodd / moderate Poor r Signett cell Non-signett cell Yes s N o o Locally y Ovary y Extensive e 0 - 5 5 6 - 7 7 << 13 >> 13 R-l l R-2a a R-2b b < 6 1 1 > 6 1 1 << 10 h >> l O h < 2 2 > 2 2 Numberr of patients s 57 7 45 5 60 0 42 2 15 5 78 8 5 5 4 4 67 7 27 7 15 5 87 7 42 2 60 0 52 2 14 4 36 6 77 7 25 5 25 5 11 1 50 0 37 7 15 5 68 8 34 4 71 1 31 1 69 9 33 3 Percentage e Complications s 40 0 28 8 25 5 50 0 40 0 32 2 40 0 75 5 33 3 41 1 27 7 37 7 38 8 33 3 40 0 14 4 36 6 30 0 52 2 30 0 61 1 28 8 35 5 60 0 28 8 50 0 30 0 48 8 28 8 35 5 pp value' 0.229 9 0.009 9 0.346 6 0.468 8 0.449 9 0.620 0 0.594 4 0.044 4 0.012 2 0.035 5 0.028 8 0.067 7 0.018 8
'uni-variatee Chi square test, 2data of 6 patients missing, 'Simplified Peritoneal Carcinoma score, NS: not
Chapterr 4
tra-abdominall sepsis. Five other patients died after more than 30 days as a result of complications, onee because of pulmonary emboli and four due to uncontrollable abdominal sepsis.
Surgicall failures occurred in 35 patients (35%). In 16 patients, this resulted into an abdominal sepsiss for which extensive ICU treatment was necessary. All patients with abdominal sepsis under-wentt relaparotomy. Five of these patients received open-abdomen treatment after recurrent leak-age.. Twenty-one patients had an intra-abdominal abscess, which was drained percutaneously.
Tablee 3 lists pre- and intra-operative factors related to surgical complications. The risk of a com-plicatedd recovery was significantly increased if carcinomatosis was part of a recurrence and if there
Figuree 1. Probability of a surgical complica-tiontion related to SPC score in 102 patients treatedd by cytoreduction and HIPEC for peri-toneall carcinomatosis of colorectal origin
Figuree 2. Probability of complicated recovery relatedd to operation time in 102 patients treatedd by cytoreduction and HIPEC for peri-toneall carcinomatosis of colorectal origin
a. a.
E E
0 1 2 3 4 5 6 7 88 910111213141516171821 SPCC score
Operationn time (min)
Figuree 3. Probability of complicated recovery relatedd to blood loss in 102 patients treated by cytoreductionn and HIPEC for peritoneal carcinomatosiss of colorectal origin
Figuree 4. Probability of complicated recovery andd number of suture lines in 102 patients treatedd by cytoreduction and HIPEC for peri-toneall carcinomatosis of colorectal origin
Numberr of suture line
wass a large tumor burden (SPC score >13).
Figuree 1 shows that the chance of a surgical failure was generally increased, with an increasing SPCC score. In patients in whom the small bowel was heavily involved, the chance of a complicated post-operativee course was 83%.
Figuress 2-4 show the modeled relationships between the risk of a complicated recovery and, re-spectively,, operation time, blood loss, and number of suture lines. The graph for operation time showss a pronounced increase in post-operative complications if the procedure exceeded 10 hr. Af-terr blood loss of more than five 1, the chance of a complicated recovery increased steeply to 100%. Thee chance of a complicated recovery was 32% when up to two suture lines were needed, but this increasedd to 56% if more were required.
Discussion n
Resultss of cytoreduction followed by HIPEC are generally expressed in terms of survival. A me-diann survival increase of one year compared to systemic chemotherapy alone has been reported and
aboutt 20% of these patients can be considered to be cured.10 Unfortunately, this achievement
comess with surgical side effects of 27—35% and a mortality of 1.5—5%.n-12
Analyzingg side effects of a combination therapy, such as cytoreduction and HIPEC, is difficult. Onn one hand, there is toxicity, which can be classified by NCI CTC. Although made for chemo-therapyy evaluation, this scale can cope in some way with surgical complications.
However,, even normal post-operative recovery would in this way be regarded as toxicity. For in-stance,, postoperative nausea would be classified as Grade 4 toxicity. It is clear that this does not makee sense. On the other hand, surgical complications of cytoreduction are not easily graded be-causee they are not easy to separate from toxicity caused by intraperitoneal chemotherapy. We opted too score all toxicity and surgical complications in the NCI CTC, and surgical failures were analyzed separatelyy as well.
Inn contrast to most other investigators, we use the term "treatment-related deaths" instead of 30-dayy or inhospital mortality. It reflects all treatment related deaths whether they occurred within or beyondd 30 days. Only three (3%) patients died within 30 days. Four patients died after more than 300 days but still because of abdominal sepsis. Intensive treatment certainly postponed death but did nott prevent it.
Thee overall toxicity was relatively high, as 65% of the patients had at least Grade 3 toxicity in one orr more categories. Major surgical complications were an important part of toxicity. Of all patients, 35%% needed a re intervention because of complications, fistula resulting from bowel leakage being thee most frequent. This complication is clearly related to tumor load and the extent of
cytoreduc-tion.tion.2020 The magnitude of cytoreduction directly influences the operation duration, blood loss, and
numberr of anastomoses. This explains the increased probability of complications with an increased numberr of regions affected and an increased SPC score. On the other hand, we found that when moree disease is left behind (R2b resections), the complication rate also increases. This can best be
Chapterr 4
explainedd by our stringent attempts to reach complete cytoreduction, even in those patients who hadd tumor nodules in every nook and cranny of the abdomen. Limited peritoneal carcinomatosis cann be resected without major surgical problems, resulting in a situation without macroscopic resi-due,, with only a small risk of post-operative complications, a low risk of early death, and a relative goodd long-term survival. At the other end of the spectrum, extensive peritoneal carcinomatosis in-volvingg many regions demands extensive surgery, with a considerable risk of leaving macroscopic diseasee behind, which leads to early progression and to a high risk of post-operative complications.
Ass surgical complications are responsible for the bulk of the morbidity, and almost all treatment relatedd mortality, it is of utmost importance to identify the patients who are prone to these events inn order to spare them aggressive surgery that is unlikely to prolong their survival. The most import indicatorr for this is tumor load. Tumor load was directly or indirectly associated with almost all fac-torss we found correlated with a higher probability of a complicated recovery.
Wee scored the tumor load in seven anatomic regions. Based on this partition, we analyzed the numberr of regions and the SPC score. Theoretically, the SPC score should give more insight in the loadd of tumor, as this also considers the thickness of tumor. In our data, the SPC score as well as thee count of regions predicted the probability of complications. It seems that distribution predicts complicationss as accurate as distribution and thickness combined do.
Previouss studies showed that patients with substantial tumor load derive little or no survival
benefitt from cytoreduction and HIPEC.10'21 The prognostic factors in these studies concur with the
factorss predicting an increased probability of major complications in the current study. The com-plicationss are another reason that why patients with a major tumor load do not benefit from cy-toreductionn followed by HIPEC. This study shows that the possibility of benefit from HIPEC is markedlyy reduced for patients with five involved regions with peritoneal carcinomatosis or a SPC scoree of 13 or higher.
Iff it has been possible to select patients with a maximum of five affected regions, 77 instead of 1022 patients would have been treated. The percentage of surgical failures was 52% in patients with sixx or seven regions involved and 30% in patients with less extensive disease. Unfortunately, nei-therr a CT scan nor a PET scan can reliably visualize the extent of peritoneal carcinomatosis. Both techniquess derive information from tumor density per volume. Typical carcinomatosis is spread outt on surfaces and has therefore a relative low volume density. It is like a paper: if you look at it fromm the front side it is clearly visible, in cross-section it hardly can be seen. Perhaps in the near fu-ture,, immunological marker will become available to allow better imaging to determine the extent off tumor. Most certainly more biological information determining outcome will be available from micro-arrayss and proteomics. But at this moment, the only possibility to avoid unnecessary compli-cationss is to abandon the procedure after full exploration of the abdomen and before any resection.
Att this moment only a limited number of institutions, worldwide, has embarked on cytoreduction withh HIPEC. Therefore, the number of patients who could benefit from this new treatment option
outnumberss present capacity.14-2223 Efforts should be made to increase the capacity of the present
institutionss and to increase the number of institutions that are able to apply this specialized treat-mentt option. However, as patient selection improves, resources can be used more effectively for
t h o s ee patients w h o may b e expected to benefit m o s t in terms of survival with the least risk o f ma-jorr complications.
I nn conclusion, morbidity of cytoreduction and H I P E C in patients with peritoneal carcinomatosis off colorectal origin can be substantial. T h e morbidity is mainly related to surgical complications. T u m o rr load is the m o s t important factor for surgical complications. T h e a m o u n t o f t u m o r was pre-viouslyy described as the m o s t important factor for survival. Considering b o t h toxicity and survival, cytoreductionn followed by H I P E C should be restricted to patients with t u m o r load involving u p to fivefive of the seven regions.
References s
1.. Beaujard AC, Glehen O, Caillot JL, et al. Intraperitoneal chemohyperthermia with mitomycin C for di-gestivee tract cancer patients with peritoneal carcinomatosis. Cancer 2000; 88: 2512-2519.
2.. Cavaliere F, Perri P, Di Filippo F, et al.: Treatment of peritoneal carcinomatosis with intent to cure. / SurgSurg Oncol 2000; 74: 41^14.
3.. Elias D , Blot F, El Otmany A, et al. Curative treatment of peritoneal carcinomatosis arising from colo-rectall cancer by complete resection and intraperitoneal chemotherapy. Cancer 2001; 92: 71-76.
4.. Fujimura T, Yonemura Y, Fujita H, et al.: Chemohyperthermic peritoneal perfusion for peritoneal dis-seminationn in various intraabdominal malignancies. Int Surg 1999; 84: 60-66.
5.. Loggie BW, Fleming RA, McQuellon RP, et al. Cytoreductive surgery with intraperitoneal hyperthermic chemotherapyy for disseminated peritoneal cancer of gastrointestinal origin. Am Surg 2000; 66: 561-568.
6.. Piso P, Bektas H, Werner U, et al.: Improved prognosis following peritoneotomy procedures and hy-perthermicc intraperitoneal chemotherapy for peritoneal carcinomatosis from appendiceal carcinoma. EurJ SurgSurg Oncol 200\; 27: 286-290.
7.. Rey Y, Porcheron J, Talabard J N , et al. [Peritoneal carcinomatosis treated by cytoreductive surgery and intraperitoneall chemohyperthermia] Carcinoses peritoneales traitees par chirurgie de reduction tumorale et chimiohyperthermiee intraperitoneale. Ann Chir 2000; 125: 631-642.
8.. Sugarbaker PH, Chang D. Results of treatment of 385 patients with peritoneal surface spread of appen-diceall malignancy. Ann Surg Oncol 1999; 6: 727-731.
9.. Witkamp AJ, de Bree E, Kaag MM, et al. Extensive cytoreductive surgery followed by intra-operative hyperthermicc intraperitoneal chemotherapy with mitomycin-C in patients with peritoneal carcinomatosis of colorectall origin. Eur J Cancer 2001; 37: 9 7 9 - 984.
10.. Verwaai VJ, van Ruth S, de Bree E, et al. Randomized trial of cytoreduction and hyperthermic intrap-eritoneall chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal car-cinomatosiss of colorectal cancer. J Clin Oncol 2003; 21: 3737-3743
11.. Loggie BW, Fleming RA. Complications of heated intraperitoneal chemotherapy and strategies for prevention.. Cancer Treat Res 1996; 82: 221-233.
12.. Stephens AD, Alderman R, Chang D, et al. Morbidity and mortality analysis of 200 treatments with cytoreductivee surgery and hyperthermic intraoperative intraperitoneal chemotherapy using the coliseum technique.. Ann Surg OnC0h999; 6: 790-796.
13.. Witkamp AJ, Muller SH, de Bree E, et al. Impact of mitomycin-C kinetics on surgical complications afterr hyperthermic intraperitoneal chemotherapy (HIPEC). EurJSurg Oncol 2000; 26: 3 0 6 - 307.
14.. Jayne D G , Fook S, Loi C, et al. Peritoneal carcinomatosis from colorectal cancer. Br JSurg 2002; 89: 1545-1550. .
15.. Portilla AG, Sugarbaker PH, Chang D. Second-look surgery after cytoreduction and intraperitoneal chemotherapyy for pentoneal carcinomatosis from colorectal cancer: Analysis of prognostic features. World J SurgSurg 1999; 23: 23-29.
Chapterr 4
16.. Sugarbaker PH. Peritoneotomy procedures. Ann Surg 1995; 221: 29-42.
17.. Witkamp AJ, van Coevorden F, Kaag MM, et al. Dose finding study of hyperthermic intraperitoneal chemotherapyy with mitomycin C in patients with carcinosis of colorectal origin [abstract]. Eur J Surg Oncol 1998;; 24: 214.
18.. Laufman LR, Krzeczowski KA, Roach R, et al. Leucovorin plus 5-fluorouracil: An effective treatment forr metastatic colon cancer. / Clin Oncol \9%1; 5: 1394—1400.
19.. National Cancer Institute. Common toxicity criteria manual. Washington, DC: National Cancer Institute, 1997.. pp 1-25.
20.. Jacquet P, Stephens AD, Averbach AM, et al. Analysis of morbidity and mortality in 60 patients with peritoneall carcinomatosis treated by cytoreductive surgery and heated intraoperative intraperitoneal chemo-therapy.. Cancer 1996; 77: 2622-2629.
21.. Verwaal VJ, Zoetmulder FAN, Ruth S, et al. Prognostic factors in peritoneal carcinomatosis of colo-rectall origin. EurJSurg One 2002; 28: 284.
22.. Carraro PG, Segala M, Cesana BM, et al. Obstructing colonic cancer: Failure and survival patterns overr a ten-year follow-up after one-stage curative surgery. Dis Colon Rectum 2001; 44: 2 4 3 - 250.
23.. Russell AH, Pelton J, Reheis CE, et al. Adenocarcinoma of the colon: An autopsy study with implica-tionss for new therapeutic strategies. Cancer 1985; 56: 1446—1451.
