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Cytoreduction and hyoerthermic intraperitoneal chemotherapy in peritoneal
carcinomastosis of colorectal origin
Verwaal, V.J.
Publication date
2004
Document Version
Final published version
Link to publication
Citation for published version (APA):
Verwaal, V. J. (2004). Cytoreduction and hyoerthermic intraperitoneal chemotherapy in
peritoneal carcinomastosis of colorectal origin.
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Cytoreductionn and
hyperthermicc intraperitoneal chemotherapy
i n n
peritoneall carcinomatosis
off colorectal origin
Cytoreductionn and hyperthermic intraperitoneal chemotherapy in
peritoneall carcinomatosis of colorectal origin
Byy Vic J Verwaai
Thiss study has been performed in
T h ee Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital,
Amsterdam,, the Netherlands.
T h ee publication of this thesis was made possible by financial support of
T h ee Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
Stichtingg Bevordering Kanker onderzoek
Universiteitt van Amsterdam
Nutriciaa BV
Thycoo Healthcare BV
Johnsonn & Johnson Medical BV
ISBNN 90 6464 580 9
Coverr design: Dustin Remmé
Cytoreductionn and
hyperthermicc intraperitoneal chemotherapy
inn peritoneal carcinomatosis
off colorectal origin
Academischh proefschrift
terr verkrijging van de graad van doctor aan de Universiteit van Amsterdam
opp gezag van de Rector Magnificus
prof.. mr. P.F. van der Heijden
tenn overstaan van een door het college voor promoties ingestelde commissie,
inn het openbaar te verdedigen in de Aula der Universiteit
opp donderdag 30 september 2004, te 10.00 uur
doorr Victor Jilbert Verwaal
Promotiecommiss sie:
Promotor:: prof. dr. B.B.R. Kroon
Co-promotor:: dr. F.A.N. Zoetmulder
Overigee leden: prof dr. JJ.B. van Lanschot
prof.. dr. DJ. Richel
prof.. dr. Th. Wobbes
dr.. A. Cats
prof.. dr. J. Jeekel
prof.. dr. S.J.H, van Deventer
Contents s
Chapterr one ' Introductionn and outline of the thesis
Chapterr two 15 Randomizedd trial of cytoreduction, hyperthermic intraperitoneal chemotherapy and
systemicc chemotherapy versus systemic chemotherapy and palliative surgery in patients withh peritoneal carcinomatosis of colorectal cancer
QQ Clin Oncol 2003; 21:3737-3743)
Includingg communication 0 Clin Oncol 2004; 22:1527-1529)
Chapterr three 33 Predictingg survival of peritoneal carcinomatosis of colorectal origin treated by aggressive
cytoreductionn and hyperthermic intraperitoneal chemotherapy
(Br(Br J Surg 2004; 91: 739-746)
Chapterr four 47 Toxicityy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy
00 Surg Oncol 2004; 85:61-67)
Chapterr five 59 Peritoneall carcinomatosis without distant metastasis of colorectal origin:
Resultss of conventional surgery and systemic chemotherapy
(Submitted) (Submitted)
Chapterr six 69 Follow-upp of patients treated by cytoreduction and chemotherapy for peritoneal
carcinomatosiss of colorectal origin
(Eur(Eur J Surg Oncol 2004; 30:280-285)
Chapterr seven 79 Recurrencess after peritoneal carcinomatosis of colorectal origin treated by cytoreduction
andd hyperthermic intraperitoneal chemotherapy: Location, treatment and outcome
(Ann(Ann Surg Oncol; 2004; 11:375-379)
Chapterr eight 89 Costt effectiveness and quality of life analysis
Contents s
Chapterr nine 97 Long-termm survival of patients with peritoneal carcinomatosis of colorectal origin
(Submitted) (Submitted)
Chapterr ten 109 Generall discussion and final analysis
Chapterr eleven 121 Summary,, Nederlandse samenvatting
Ackownlagementss (Dankwoord) 131
Chapterr one
Introduction n
Inn November 1995, The Netherlands Cancer Institute embarked on the treatment of peritoneal carcinomatosiss of colorectal cancer by means of cytoreduction followed by hyperthermic intraperi-toneall chemotherapy. Peritoneal carcinomatosis is a manifestation of colorectal cancer in which in-traperitoneall seeding of tumour cells occurs. After implantation on the peritoneal surfaces, the ma-lignantt cells may form tumour nodules throughout the abdominal cavity, which can cause bowel obstructions.. Peritoneal carcinomatosis occurs commonly in colorectal cancer patients and is the second-mostt frequent cause of death after metastatic disease to the liver. In an estimated 25% of patients,, no other tumour locations can be found, even if a detailed diagnostic work-up is per-formed.133 Sugarbaker and others have suggested that peritoneal carcinomatosis of colorectal can-cer,, like liver metastases, should probably not be equated with generalised disease, but can be seen ass a first step of further dissemination.4'5
Thee treatment - cytoreduction followed by hyperthermic intraperitoneal chemotherapy - consists off two elements. The first element is cytoreduction. The objective of the cytoreduction is to re-movee all macroscopic tumours or at least to have only limited residual disease (< 2.5 mm thick-ness).. This is achieved by a surgical procedure in which a maximum exposure of the abdominal cavityy is obtained, followed by resection of the affected peritoneum and infiltrated viscera. Reasons forr not reaching a complete cytoreduction are extensive involvement of small bowel or its mesen-tery,, and tumour infiltration in the porta hepatis or pancreas. In the latter cases, the tumour depos-itss are resected as far as is judged to be compatible with sufficient post-operative function. There aree no further restrictions on the extent of surgery. Cytoreduction can include for example gastrec-tomy,, splenectomy, cholecystectomy, peritonectomies of diaphragms, omentectomy, partial small andd large bowel resections, rectal resection, resection of uterus and ovaries, and partial bladder or ureterr resections. Of course, in many cases only a selection of these resections is needed.
Thee second element of the treatment is the hyperthermic intraperitoneal chemotherapy itself. Sprattt was the first to describe this technique in 1980.6 The theoretical background has been stud-iedd well.7 The concept of intraperitoneal cytotoxic drug administration was developed from the ideasideas on peritoneal dialysis. A mathematical outline of intraperitoneal drug administration is based onn the findings of Dedrick.8 He postulated that the intraperitoneal-to-plasma concentration ratio dependss on molecular weight and the permeability of the peritoneal surfaces. He also concluded thatt a large proportion of the absorbed cytotoxic drug would pass through the portal system, which wouldd result in high liver concentrations. Both situations are advantageous in peritoneal carcinoma-tosis.. Brenner has provided guidelines for intraperitoneal drug selection.9 These guidelines consist off four points: (1) the drug should be capable of killing carcinoma cells either directly or by meta-bolicc activation within tumour tissue, (2) it should possess a limited peritoneal permeability, (3) it shouldd be rapidly cleared from plasma, and (4) there should be a dose-response relationship. Loss ett al studied a rat model in which the temperature was increased to 41 °C by means of submersion off the animal.10 They found that heat administration combined with intraperitoneal chemotherapy favourss the response of solid intra-abdominal tumour cells to cytoreductive drugs.11 Although this modell does not correspond completely with the method used in human beings, it supports the idea thatt hyperthermia is useful. The penetration depth after intraperitoneal administration was also
Chapterr 1
studied.122 They found that therapeutic concentrations were only reached within two mm from the exposedd surface. Based on these observation, a complete or nearly complete cytoreduction is neededd before intraperitoneal chemotherapy is started. It explains also why most intraperitoneal applicationss of cytotoxic drugs fail if applied without surgery.
Thee initiation of The Netherlands Cancer Institute project was based on the data known in 1995. Beforee that year, a number of institutes had started to treat patients affected by peritoneal carcino-matosiss by the above described novel approach.13 Sugarbaker, as important promoter of this treat-ment,, described the first clinical results in 1985.14 In that study, he and his co-workers found a sig-nificantt decrease in recurrence when intraperitoneal 5-fluorouracil was given in comparison to in-travenouss use. They presented the clinical features of 66 patients affected by carcinomatosis in 19911 is They briefly described the procedure of cytoreduction and hyperthermic intraperitoneal chemotherapy.. The procedure has been explained in more detail in 1995 without providing survival dataa or other outcome features.16 These results were reported elsewhere that same year.17 A three-yearr survival rate of 6 1 % was found. The study consisted mainly of patients with low-grade tu-mourss and had a median follow-up of two years. Results of selected patients with carcinomatosis off appendiceal carcinomas had been reported two years earlier.18 This evaluation of 69 patients showedd a good survival rate in patients who were affected by pseudomyxoma peritonei (89% three-yearr survival) and a worse survival in adenocarcinoma patients (38% three-year survival). The latter groupp consisted of only six patients. A considerable toxicity was mentioned. Currently, Sugar-baker'ss group is working on an evaluation of the treatment of peritoneal carcinomatosis by hyper-thermicc intraperitoneal chemotherapy around the world.
Inn Japan Yamaguchi treated eight patients with peritoneal carcinomatosis in a similar way and foundd a two-year survival of 18%.19 Another feasibility study was performed by Schneebaum et al.200 They encountered severe pulmonary and renal toxicity in one of their fifteen patients. In Europe,, Gilly and colleagues treated 28 patients with various digestive cancers and reached a one-yearr survival rate of 54%.21-22
Thee above-mentioned studies up to 1995 provide only circumstantial evidence of the effective-nesss of cytoreduction and hyperthermic intraperitoneal chemotherapy. The degree of evidence shouldd be seen as level V.23>24 This was mainly because of the lack of information on other treat-mentt options.
Thee initiating project at The Netherlands Cancer Institute ran between November 1995 and De-cemberr 1997. This part consisted of a feasibility study of intraperitoneal Mitomycin C.25 The study containedd 29 patients. From the experience of this study is that a dose above 35 mg/m2 give severe toxicity. .
Inn the period of the feasibility study, a number of other institutes also started to treat peritoneal carcinomatosiss by means of cytoreduction and hyperthermic intraperitoneal chemotherapy. Loggie ett al in the USA treated 20 patients with peritoneal carcinomatosis of various origins in this fash-ion.. Their main finding was that more patients were alive at six months when the cytoreduction wass complete than when it was incomplete.26 Also, cytology of the peritoneal fluid became tumour-negativee in case of successful cytoreduction. One year later, his group reported on 39 patients with
Introduction n
aa one-year survival of 74% and a two-year survival of 48.5%.27 Their median survival time was 18.2 months.. In this study, gastrointestinal and ovarian cancer were lumped together. Complete or near-completee cytoreduction was reached in only eight of the 36 patients. Complications were reported separately.288 The Sugarbaker group produced a large number of reports containing important clini-call information, but did not provide new survival data.2933
Inn Europe, Elias et al reported on their successes. They described their approach in 1996 and the resultss the year thereafter.34-35 The two-year survival was 50%. The study population consisted of patientss with sarcomas, neuroendocrine tumours, pseudomyxoma, various gastrointestinal tu-mours,, a patient with ovarian cancer and another with testicular carcinoma.
Inn Japan, Nishimura et al treated fourteen patients successfully. These patients had a three-year survivall rate of 25%.36 AU patients had colorectal cancer. Fujimura treated eight patients, two with gastricc cancer and six with colorectal cancer, of whom only one died within a year.37
Fromm the data available in 1997, one may gather that the two-year survival after cytoreduction andd hyperthermic intraperitoneal chemotherapy is approximately 50% and the three-year survival 25%.. Although these studies provided an abundance of useful information, there were also a num-berr of flaws. Data were collected from patients with a wide variety of diseases and the populations weree highly selected. There was also a lack of data on results of other treatments, such as systemic chemotherapyy or debulking operations without chemotherapy. With the latter in mind, the degree off evidence was not improved above level V.
Partlyy based on the promising results of the above-mentioned reports and on our own results in thee dose-finding study, a randomised trial was started. The trial was supported by the "College voorr Zorgvoorzieningen (CVZ)", a Dutch organisation that funds the development of new thera-piess and the research of their efficacy. The aim of this study was to provide level II evidence of the benefitt of cytoreduction and hyperthermic intraperitoneal chemotherapy.
Thiss thesis contains the results of this phase III study (Chapter 2), an evaluation of prognostic factorss for survival and for toxicity (Chapters 3 and 4), the long-term results of peritoneal carcino-matosiss when treated by conservative surgery and systemic chemotherapy (Chapter 5), the results off treatment of recurrence after the first management of peritoneal carcinomatosis (Chapter 6) and thee evaluation of the follow-up (Chapter 7). The cost and quality of live consequences are given (Chapterr 8). The survival data are updated until autumn 2003 (Chapter 9). This thesis closes with ann general discussion in which remaining question are discussed and the lay-put for futures plans aree given.
References s
1.. Minsky BD, Mies C, Rich TA, et al.: Potentially curative surgery of colon cancer: patterns of failure and survival.. J Clin Oncol 1988; 6: 106-118.
2.. 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.
3.. Tong D, Russell AH, Dawson LE, et al.: Adenocarcinoma of the cecum: natural history and clinical pat-ternss of recurrence following radical surgery. MJ Radiat Oncol Biol Phys 1983; 9: 357-360.
treat-Chapterr 1
mentt of peritoneal carcinomatosis and sarcomatosis. Semin Surg Oncol 1998; 14: 254-261.
5.. Sugarbaker PH: Management of peritoneal-surface malignancy: the surgeon's role. Langenbecks Arch Surg 1999;384:576-587. .
6.. Spratt JS, Adcock RA, Sherrill W, Travathen S: Hyperthermic peritoneal perfusion system in canines. CancerCancer Res WW; 40: 253-255.
7.. Myers CE, Collins JM: Pharmacology of intraperitoneal chemotherapy. Cancer Invest 1983; 1: 395-407. 8.. Dedrick RL, Myers CE, Bungay PM, DeVita VT, Jr.: Pharmacokinetic rationale for peritoneal drug ad-ministrationn in the treatment of ovarian cancer. Cancer Treat Rep 1978; 62: 1-9.
9.. Brenner DE: Intraperitoneal chemotherapy: A review. / Clin OncoJ 1986; 4: 1135-1147.
10.. Los G, Smals OA, van Vugt Mj, et al.: A rationale for carboplatin treatment and abdominal hyperther-miaa in cancers restricted to the peritoneal cavity. Cancer Res Res 1992; 52: 1252-1258.
11.. Los G, van Vucht MJ, Pinedo HM: Response of peritoneal solid tumors after i.p. chernohyperthermia treatmentt with cisplatin or carboplatin. Br J Cancer 1994; 69: 235-241.
12.. Los G, Mutsaers PH, Lenglet WJ, et al.: Platinum distribution in intraperitoneal tumors after intraperi-toneall cisplatin treatment. Cancer Chemother Pharmacol 1990; 25: 389-394.
13.. Ceelen WP, Hesse U, de Hemptinne B, Pattyn P: Hyperthermic intraperitoneal chemoperfusion in the treatmentt of locally advanced intra-abdominal cancer. Br JSurg 2000; 87: 1006-1015.
14.. Sugarbaker PH, Gianola FJ, Speyer JC, et al.: Prospective, randomized trial of intravenous versus in-traperitoneall 5-fluorouracil in patients with advanced primary colon or rectal cancer. Surgery 1985; 98: 414-422. .
15.. Sugarbaker PH: Cytoreductive surgery and intraperitoneal chemotherapy with peritoneal spread of cys-tadenocarcinoma.. Eur J Surg 1991; 561: 75-82.
16.. Sugarbaker PH: Peritonectomy procedures. Ann Surg 1995; 221: 29-42.
17.. Sugarbaker PH, Jablonski KA: Prognostic features of 51 colorectal and 130 appendiceal cancer pa-tientss with peritoneal carcinomatosis treated by cytoreductive surgery and intraperitoneal chemotherapy.
AnnAnn Surg 1995; 221: 124-132.
18.. Sugarbaker PH, Zhu B, Banez Sese G, Shmookler BM: Peritoneal Carcinomatosisi from Appendiceal Cancer:: Results in 69 patients treated by cytoreductive surgery and intraperitoneal chemotherapy. Dis Colon RectumRectum 1993; 36: 323-329.
19.. Yamaguchi A, Tsukioka Y, Fushida S et al.: Intraperitoneal Hyperthermic treatment for peritoneal dis-seminationn of colorectal cancers. DiS Colon Rectum 1992; 35: 964-968.
20.. Schneebaum S, Arnold MW, Staubus A, et al.: Intraperitoneal hyperthermic perfusion with mitomycin CC for colorectal cancer with peritoneal metastases. Ann Surg Oncol 1996; 3: 44-50.
21.. Gilly FN, Sayag AC, Carry PY, et al.: Intraperitoneal chemo-hyperthermia (CHIP): A new therapy in thee treatment of the peritoneal seedings. Int Surg 1991; 76: 164-167.
22.. Gilly FN, Carry PY, Sayag A et al.: Regional chemotherapy (with mitomycin C and intra-operative hy-perthermiaa for digestive cancers with peritoneal carcinomatosis. Hepato-Gastroenterol 1994; 41: 124-129.
23.. Cook DJ, Guyatt G H , Laupacis A, et al: Rules of evidence and clinical recommendations on the use of antithromboticc agents. Chest \992; 102: 305S-311S.
24.. Sackett DL: Rules of evidence and clinical recommendations for the management of patients. Can J CardiolCardiol 1993; 9: 487-489.
25.. 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: 979-984.
26.. Loggie BW, Fleming RA, Geisinger KR: Cytologic assesment before and after intraperitoneal hyper-thermicc chemotherapy for peritoneal carcinomatosis. Acta Cytol 1996; 40: 1154-1158.
Introduction n
withh disseminated intraperitoneal malignancies by aggressive combined-modality therapy. Am Surgeon 1997; 63:: 137-143.
28.. Loggie BW, Fleming RA: Complications of heated intraperitoneal chemotherapy and strategies for prevention.. Cancer Treat Res Res 1996; 82: 221-233.
29.. Fernandez-Trigo V, Stuart OA, Stephens A D , et al.: Surgically directed chemotherapy: heated intrap-eritoneall lavage with mitomycin C. Cancer Treat Res 1996; 81: 51-61.
30.. Gomez Portilla A, Deraco M, Sugarbaker PH: Clinical pathway for peritoneal carcinomatosis from co-lonn and rectal cancer: guidelines for current practice. Tumori 1997; 83: 725-728.
31.. 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.
32.. Sugarbaker PH, Schellinx MET, Chang D, et al.: Peritoneal carcinomatosis from adenocarcinoma of thee colon. World J Surg 1996; 20: 585-592.
33.. Sugarbaker PH, Chang D, Koslowe P: Prognostic features for peritoneal carcinomatosis in colorectal andd appendiceal cancer patients when treated by cytoreductive surgery and intraperitoneal chemotherapy. CancerCancer Treat Res Res 1996; 81: 89-104.
34.. Elias D, Damia E, Puizillout J, et al.: Thermic homogeneity and standardization of intraperitoneal chemohyperthermiaa for peritoneal carcinomatosis. Reg Cancer Treat 1996; 9: 54-59.
35.. Elias D, Dubé P, Blot F, et al.: Peritoneal carcinomatosis treatment with curative intent: the Institut Gustave-Roussyy experience. Eur J Surg One 1997; 23: 317-321.
36.. Nishimura G, Fushida S, Fujimura T, et al.: Intraperitoneal treatment for peritoneal dissemination of colorectall cancer. Reg Cancer Treat 1996; 9: 60-62.
37.. Fujimura T, Yonemura Y, Nishimura G, et al: Treatment strategy for peritonitis carcinomatosa in gas-troentericc cancer. Reg Cancer Treat 1996; 9:103-106.
Chapterr two
Randomizedd trial of cytoreduction, hyperthermic
intraperitoneall chemotherapy and systemic chemotherapy
versuss systemic chemotherapy and palliative surgery in
patientss with peritoneal carcinomatosis of colorectal cancer
Vicc J. Verwaai
1, Serge van Ruth
1, Eelco de Bree
1, Gooike W van Slooten
1,
Harmm van Tinteren
2, Henk Boot
3and Frans A.N. Zoetmulder
111
Department of Surgery,
2Department of Biometrics,
33
Department of Gastroenterology
Thee Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
Amsterdam,, the Netherlands
Purpose:Purpose: To confirm the findings from uncontrolled studies that aggressive cytoreduction in combination withh hyperthermic intraperitoneal chemotherapy (HIPEC) is superior to standard treatment in patients with peritoneall carcinomatosis of colorectal cancer origin.
PatientsPatients and Methods: Between February 1998 and August 2001, 105 patients were randomly assigned to re-ceivee either standard treatment consisting of systemic chemotherapy (fluorouracil-leucovorin) with or with-outt palliative surgery, or experimental therapy consisting of aggressive cytoreduction with HIPEC, followed byy the same systemic chemotherapy regime. The primary end point was survival.
Results:Results: After a median follow-up period of 21.6 months, the median survival was 12.6 months in the stan-dardd therapy arm and 22.3 months in the experimental therapy arm (log-rank test, P - 0.032). The treat-ment-relatedd mortality in the aggressive therapy group was 8%. Most complications from HIPEC were re-latedd to bowel leakage. Subgroup analysis of the HIPEC group showed that patients with 0 to 5 of the 7 regionss of the abdominal cavity involved by tumor at the time of the cytoreduction had a significantly better survivall than patients with 6 or 7 affected regions (log-rank test, P < 0.0001). If the cytoreduction was macroscopicallyy complete (R-l), the median survival was also significant better than in patients with limited (R-2a),, or extensive residual disease (R-2b; log-rank test, P < 0.0001).
Conclusion:Conclusion: Cytoreduction followed by HIPEC improves survival in patients with peritoneal carcinomatosis off colorectal origin. However, patients with involvement of six or more regions of the abdominal cavity,
orr grossly incomplete cytoreduction, had still a grave prognosis.
Randomizedd trial
Introduction n
Peritoneall carcinomatosis (PC) of colorectal origin is common and is the second-most frequent causee of death in colorectal cancer after metastatic disease to the liver. In an estimated 25% of patients,, no other tumor locations can be found, even when a detailed diagnostic work-up is per-formed.11 3 Sugarbaker45 has suggested that PC of colorectal origin should probably not be equated withh generalized disease, but can be a first step of dissemination, not unlike the situation with liver metastasess of colorectal origin. ,
Basedd on this concept, attempts have been made to achieve long-term survival in patients with PCC by combining surgery and intraperitoneal chemotherapy to eradicate microscopic residual dis-ease.. Advances in surgical techniques and improved anesthesiology have made it possible to re-movee most or all macroscopic tumor in PC.6 In theory, intraperitoneal chemotherapy could eradi-catee limited residual tumor and should have an optimal chance to succeed if it would immediately followw surgery (to avoid regrowth of tumor cells), and if exposure of the peritoneal surface at risk couldd be guaranteed. To achieve these goals, peritoneal lavage, as part of the surgical procedure, hass been developed.7 Others and our group have shown that peritoneal lavage containing Mitomy-cinn C (MMC) results in a drug exposure to the peritoneal surface that is 20 times higher than else-wheree in the body.8-9 This degree of pharmacokinetic advantage is thought to result in optimal cir-cumstancess for tumor cell kill. In addition, enhancement of MMC cytotoxity at temperatures higherr than 39°C has been demonstrated in animals and in vitro models.10-11 The addition of intra-peritoneall hyperthermia has been shown to be technically feasible in the surgical setting.12-13 This approachh of aggressive cytoreduction in combination with intraperitoneal chemotherapy, often em-ployingg MMC and hyperthermia, has been studied in 11 phase II studies on patients with PC of co-lorectall origin.12-1423 The results of these studies show a strikingly long median survival and, more importantly,, a 20% to 30% long-term (5-year) survival rate, reminiscent of that of surgery for iso-latedd liver metastases. It has been advocated that these favorable results justify such an aggressive treatment,, particularly since long-term survival is hardly ever seen after systemic chemodierapy alone.. It remains to be shown that these encouraging results of uncontrolled studies are not the re-sultt of patient selection. The need for a controlled study was recently re-emphasized in an editorial inn the Journal of Clinical Oncology by Sugarbaker,24 who originally pioneered the approach. This needd is particularly urgent because HIPEC is associated with significant morbidity and treatment-relatedd mortality. In this article, we report the results of a randomized single-institution phase III study,, and present data that may aid in better selection of patients for aggressive treatment of peri-toneall carcinomatosis.
Patientss and methods
PatientPatient Selection and Study Design
Patientss with histologically proven peritoneal metastases of colorectal adenocarcinoma (CRC) or positivee cytology of ascites, who were diagnosed either at first presentation or at recurrence of CRC,, were eligible. No signs of distant metastases (liver, lung) on computed tomography (CT-scan)
Chapterr 2
off abdomen and chest x-ray were allowed. Patients had to be younger than 71 years and fit for ma-jorr surgery (normal bone marrow indices, and normal renal and liver functions). Initially, patients whoo had received fluorouracil (FU) within 12 months before random assignment were excluded. In thee first year of the study, an amendment to the protocol was made to allow inclusion of these pa-tients. .
Patientss were randomly allocated to either standard treatment or to the experimental treatment. Thee randomization was performed centrally by computer, and stratified for presentation (primary orr recurrence) and site (appendix, colon or rectum). The medical ethical committee of the Nether-landss Cancer Institute approved the study, and written informed consent was obtained from all pa-tients. .
StandardStandard Treatment
Surgeryy was only performed in cases of symptoms of intestinal obstruction, and consisted of ei-therr bypass or stoma surgery. Often, this type of surgery had already been performed before refer-rall for random assignment. Patients started chemotherapy immediately after random assignment or afterr recovery from surgery. Chemotherapy was given in the local setting, usually by the patients' ownn medical oncologist, and consisted of FU (intravenous (IV) push-dose of 400 mg/m2) and leu-covorinn (TV 80 mg/m2) on an outpatient basis (modified Laufman regimen).25 Treatment was given weeklyy for 26 weeks, or until progression, death, or unacceptable toxicity. Patients who had already beenn treated with FU within 12 months before random assignment were treated with irinotecan (3500 mg/m2) at three-weekly intervals for six months or until progression or intolerable toxicity.
ExperimentalExperimental Treatment
CytoreductiveCytoreductive surgery
Alll procedures were carried out in the Netherlands Cancer Institute. Laparotomy under general anesthesiaa was performed from xyphoid to pubis. After opening the abdomen, the presence of macroscopicc tumor deposits was recorded in seven abdominal regions: pelvis and sigmoid; right lowerr abdomen; small bowel and mesentery; omentum and transverse colon; subhepatic space and stomach;; right subphrenic space; and left subphrenic space. The maximal tumor size was recorded inn each region as: none, less than one cm, one to five cm, or more than five cm.
Thee objective of cytoreduction was to leave no macroscopic tumor behind, or at least to have limitedd residual tumor (< 2.5 mm in thickness). To achieve this, the stripping of the parietal perito-neumm was carried out as described by Sugarbaker et al.26 Infiltrated viscera were resected if this was compatiblee with retaining function. Most often this concerned the rectum, parts of small bowel and colon,, the gall bladder, parts of the stomach, and the spleen. The greater omentum was routinely removed.. Reconstruction of gastrointestinal continuity was postponed until after the lavage, to pventt entrapment of tumor cells in suture lines. At completion of cytoreduction, the absence of siduall tumor was recorded as R-l. If the largest residual tumor was smaller than 2.5 mm, it was re-gardedd as an R-2a resection. In cases of residual tumor larger than 2.5 mm, cytoreductive surgery wass scored as R-2b. The total length of the operation, and blood loss were also recorded.
Randomizedd trial
HyperthermicHyperthermic intraperitoneal chemotherapy (HIPEC)
Too increase the volume of the abdominal cavity and to prevent spillage of lavage fluid, the skin of thee laparotomy wound was pulled up against a retractor. A plastic sheet covered the laparotomy openingg to reduce heat loss and to avoid drug spilling. A central aperture was made to allow ma-nipulationn to achieve optimal drug and heat distribution. The perfusion circuit consisted of a cen-trallyy placed inflow catheter, outflow cadieters, placement in the pelvis below left and right dia-phragm,, a roller pump, and a heat exchanger. Temperature probes were attached to inflow and outfloww catheters. Perfusion was started with a minimum of three liter of isotonic dialysis fluid, at onee to two 1/min, and an inflow temperature of 41 °C to 42°C. As soon as the temperature in die abdomenn was stable above 40°C, MMC was added to the perfusate at a dose of 17.5 mg/m2 fol-lowedd by 8.8 mg/m2 every 30 minutes. The total dose was limited to 70 mg at maximum. If the coree temperature exceeded 39°C, the inflow temperature was reduced. After 90 minutes, the perfu-sionn fluid was drained from the abdomen, and bowel continuity was restored. A temporary colos-tomyy was made in most cases if the rectum was resected. A draining gastrostomy and transgastric jejunall feeding tube were inserted. The outflow catheters were used for postoperative drainage of thee abdomen cavity.
PostoperativePostoperative Care
Patientss stayed in the intensive care unit for three days. In cases of abdominal sepsis (faecal flora inn drain fluid, high fever, sepsis), a laparotomy was performed to correct bowel leakage at an early stage.Jejunall tube feeding was begun on day 1. Parenteral nutrition was given until jejunal feeding couldd cover all nutritional needs. Oral fluid and food intake was resumed as soon as the gas-trostomyy production dropped below 500 raL per 24 hours.
AdjuvantAdjuvant Chemotherapy
Systemicc chemotherapy was intended to start after six weeks beyond cytoreduction followed by HIPEC,, and before three months after cytoreduction followed by HIPEC. The regimens as de-scribedd in the standard therapy arm were used.
Toxicity'/ComplicaToxicity'/Complica tions
Chemotherapy-relatedd toxicity was recorded using the World Health Organization (WHO) scale. Alll postoperative complications were noted, and were graded as toxicity according to the WHO scale. .
Follow-Up Follow-Up
Alll patients were seen at the outpatient clinic once every three months for two years, and every sixx months thereafter. The follow-up consisted of physical examination and serum CEA every threee months and an abdominal CT scan of the abdomen every six months, starting three months afterr randomization in the standard arm and three months after cytoreduction followed by HIPEC inn the experimental arm.
StatisticalStatistical Analysis
Chapterr 2
Patientss alive at the time of analysis were censored at their last follow-up examination. The survival wass estimated by the Kaplan Meier method and tested with the log-rank test following the inten-tion-to-treatt principle. The analysis was planned at a median follow-up of two years to have 80% powerr to detect a 20% absolute difference in survival. To detect this difference, with P<0.05 (two-tailedd test), at least 100 patients had to be entered.
Too improve patient selection in the future, additional exploratory analyses were performed to identifyy potential prognostic factors. Presentation (primary v recurrence), site (appendix vs colon vs rectum),, number of regions involved (<5 regions vs >5 regions), and completeness of cytoreduc-tionn (R-l vs R-2a vs R-2b) were included in a Cox proportional hazards regression model in order too obtain hazard ratios and 95% confidence intervals. All P values are two-sided.
Results s
Figuree 1. Trial profile
Randomized d 105 5 Standardd treatment 511 patients
I I
I I Startedd chemotherapy 444 patients 3at t ents s E E xperimentall therapy 544 patients l lI I
Treatedd by HIPEC 499 patientsI I
Betweenn January 1998 and August 2001, 105 patients were randomlyy assigned in this study 51 to standard therapy and 544 patients to experimental therapy. Two patients proved in-eligiblee one patient with pseudomyxoma peritonei in the standardd arm and one with peritoneal mesothelioma in the experimentall arm. Figure 1 shows the trial profile. All pa-tients,, including the ineligible ones, were included in the in-tention-to-treatt analysis. The patient group included 58 men startedd adjuvant therapy a n d 4 7 women, with a median age of 54 years (range, 28 to 355 patients 70 years). Fifty-eight patients had PC at their primary presen-tation,, and 47 patients had the disease at recurrence. The pri-maryy sites were appendix in 18 patients, colon in 75, and rectum in 12. The patient and tumor char-acteristicss were well balanced within both arms, except for a nonsignificant overrepresentation of maless in the "HIPEC" arm (63% vs 47%; P =0.11). Tumor size and differentiation grade were equallyy distributed in both arms. The majority of the patients (95.8% standard arm; 98.0% HIPEC arm)) had large tumors (T3 and T4). All patients with small tumors (3.1%; Tl and T 2) were pa-tientss with PC at recurrence of CRC (table 1).
StandardStandard Arm
Sevenn patients never started systemic chemotherapy: five patients withdrew their consent; two patientss had severe progressive disease before they could start, and deteriorated rapidly. Thirty-eightt patients started with FU-leucovorin, of whom 21 received treatment for at least 5.4 months (median,, 5.8 months; range, 5.4 to 6.7); 12 stopped because of progression of disease; two stopped becausee of toxicity; and three were still on treatment. Six patients started with irinotecan, of whom twoo completed treatment.
Randomizedd trial Tablee 1. Characteristics of 105 Alll patients Gender r male e female e
Agee (Median, range) Performancee status Nott recorded 0 0 1 1 2 2 Presentationn at randomization Att primary presentation Att as recurrence Primaryy tumor Appendix x Colon n Rectum m Differentiationn grade1 Good d Moderate e Poor r
TT status of primary tumor2
T l l T2 2 T3 3 T4 4 patients s randomizedd in Arm m Standard d N N 51 1 24 4 27 7 55 5 19 9 23 3 7 7 2 2 28 8 23 3 11 1 34 4 6 6 .. 3 27 7 18 8 1 1 1 1 17 7 29 9
(%) )
(100.0) ) (47.1) ) (52.9) ) (29-70) ) (37.3) ) (45.1) ) (13.7) ) (3.9) ) (54.9) ) (45.1) ) (21.6) ) (66.7) ) (11.8) ) (6.3) ) (56.3) ) (37.5) ) (2.1) ) (2.1) ) (35.4) ) (60.4) ) thee trial HIPEC C N N 54 4 34 4 20 0 53 3 15 5 30 0 9 9 --30 0 24 4 7 7 41 1 6 6 5 5 33 3 15 5 --1 --1 19 9 29 9(%) )
(100.0) ) (63.0) ) (37.0) ) (28-69) ) (27.8) ) (55.6) ) (16.7) ) --(55.6) ) (44.4) ) (13.0) ) (75.9) ) (11.1) ) (9.43) ) (62.3) ) (28.3) ) --(2.0) ) (38.8) ) (59.2) ) N N 105 5 58 8 47 7 54 4 34 4 53 3 16 6 2 2 58 8 47 7 18 8 75 5 12 2 8 8 60 0 33 3 1 1 2 2 36 6 58 8 All l(%) )
(100.0) ) (55.2) ) (44.8) ) (28-70) ) (32.4) ) (50.5) ) (15.2) ) (1.9) ) (55.2) ) (44.8) ) (17.1) ) (71.4) ) (11.4) ) (7.9) ) (59.4) ) (32.7) ) (1.0) ) (2.1) ) (37.1) ) (60.0) )Chapterr 2
ExperimentalExperimental Arm
Fivee patients did not undergo cytoreduction followed by HIPEC treatment. While waiting for surgery,, one died due to rapid tumor progression; two patients developed lung and liver metastases, forr which they were treated with palliative chemotherapy; and in one patient, a primary lung cancer wass detected shortly after randomization. This patient died shortly after randomization. One pa-tientt withdrew consent. The median time between randomization and surgery was six weeks (range, 66 days to 14 weeks). The median hospital stay of the 49 patients operated on was 29 days (range, 6 too 166 days). The median duration of the cytoreduction and HIPEC was 485 minutes (range, 315 too 765 minutes), while the median blood loss was 3.9 L (range, 0.5 to 30.0 L; for seven patients, dataa were not available). Of the seven possible affected regions, six or seven were involved in 16 patients.. Those patients had a median operation time of 585 minutes (range, 440 to 765 minutes) andd a median blood loss of 6.0 L (range, 3.5 to 30.0 L). In two patients, no macroscopic tumor was foundd at all, and peritoneal metastases had been resected at a previous laparotomy. Both received HIPECC without cytoreduction. The median hospital admission duration was 23 days (range, 13 to 900 days) for zero to five affected regions, and 38 days (range, 6 to 166 days) for six to seven re-gions. .
Ann average of 1.8 visceral resections were performed per patient. Most often, parts of small bowell (45 patients) and rectum (25 patients) were resected. Twenty-four patients needed a colos-Tablee 2. Major toxicity and complications of 48 patients1 with peritoneal carcinomatosis treated by cytoreductionn plus HIPEC
gradee 3 grade 4 33 (6%) 77 (15%) 1 (2%) 22 (4%) 22 (4%) 11 (2%) 22 (4%) 11 (2%) 33 (6%) 22 (4%) 11 (2%) 44 (8%) 2 (4%) 77 (15%) 11 (2%) 33 (6%) 33 (6%) 4 (8%) 33 (6%) 2 (4%) dataa of complications missing in one patient, GI: gastro-intestinal
Fever r Leukopenia a Thrombocytopenia a Neuropathyy (paresis) Pleurall effusion
Pulmonaryy embolus (within 3 months after surgery) Pneumonia a
Anuriaa (acute tubular necrosis) Renall obstruction Cardiacc arrhythmia Heartt failure GII Fistula Pancreatitis s Catheterr infections Haemorrhage e Psychologicall disorders
Randomizedd trial
tomy.. The median number of bowel anastomoses was two (range, zero to seven anastomoses). In 188 patients, no macroscopic residual disease was left behind (R-l); in 21, the residual deposits were smallerr than 2.5 mm (R-2a); and in 10 cases, residual deposits were < 2.5 mm (R-2b).
Gradee 3 and 4 toxicity, as well as complications, are shown in table 2. The surgical complications aree recorded as toxicity, as described in the WHO criteria. Only bone marrow toxicity (14% grade 3,, and 5% grade 4) is definitely attributable to MMC. The nadir was between 10 and 12 days. AH otherr toxicity is most likely due to surgery or to an interaction between MMC and major surgery. Thee most important complications were small bowel leakage and abdominal sepsis. Four patients (8%)) died as a result of the treatment. Two patients (4%) died of abdominal sepsis within 30 days afterr cytoreduction followed by HIPEC. Two other patients (4%) never recovered and died of a complicatedd postoperative course.
Fourteenn patients never started adjuvant chemotherapy after cytoreduction followed by HIPEC. Thiss was because of early progression (seven patients), toxicity due to HIPEC (four patients) or refusall (three patients). All 35 patients who started chemotherapy received FU-leucovorin. Twenty completedd six months of therapy, five stopped early because of disease progression, two stopped becausee of toxicity, and one withdrew consent. At the time of closing the database, seven patients weree still receiving the treatment..
Survival Survival
Onee patient was lost during follow-up after seven months, while the follow-up was complete for alll other patients. After a median follow-up of 21.6 months, 20 patients were still alive in the stan-dardd treatment group, compared with 30 patients in the HIPEC group. Cytoreduction followed by HIPECC significantly reduced the risk of dying (hazard ratio, 0.55; 95% CI, 0.32 to 0.95; log-rank
Figuree 2. Kaplan Meier survival curve, comparing standard treatment to HIPEC
0.80--to o
0.00--^ " 0.00--^ 0.00--^
\ \ _ _
L L i. . i i 1 1 j _ _ —— standard treatment - -- HIPEC L L 122 18 24 survivall in months 30 0 36 6Chapterr 2
PP = 0.032). Median survival in the standard arm was 12.6 months, compared with 22.4 months in thee HIPEC arm (P = 0.032; figure 2). Exploratory subgroup analysis did not reveal any particular subgroupp in which the effect of cytoreduction followed by HIPEC was better or worse compared withh standard treatment (figure 3). When the data of the patients who underwent cytoreduction
Figuree 3. Explorative subgroup analysis on survival of all 105 patients randomized
Forestt plot shows the hazard ratio for various subgroups of patients. The diamond indicating the overalll result corresponds with the 95% confidence interval
Subgroupp estimates 9 9 % , Overall 9 5 % contidence interval-S u b g r o u p p S e x x m^ln n female e A g e e «=== 50 yrs 511 - 60 yrs >> 60 yrs K i t ee of t u m o r appendix x colon n rectum m O r i g i n n primary y recurrence e O v e r a l ll result HIPEC C events/N N 17/34 4 7/20 0 10/22 2 9/16 6 5/16 6 2 / 7 7 20/41 1 2 / 6 6 14/30 0 10/24 4 2 4 / 5 4 4 Contro' ' events/f\ \ 18/24 4 13/27 7 9/16 6 12/20 0 10/15 5 7/11 1 21/34 4 3 / 6 6 16/28 8 15/23 3 3 1 / 5 1 1
0.555
(0.321
,0.951
Figuree 4. Kaplan Meier survival curve of 49 patientss with peritoneal carcinomatosis treated byy cytoreduction followed by HIPEC, compar-ingg number of regions affected with PC
Figuree 5. Kaplan Meier survival curve of 49 pa-tientss with peritoneal carcinomatosis treated by cytoreductionn followed by HIPEC, comparing numberr of regions with residual tumor
1.00-- 0.75--probabilit y y o o o o
0.25--
o.oo--jj
L_ l l i i L _ _ 1 1 1 1 12 2 0-55 regions - 6 - 77 regions\ \
— i — — 24 4 36 6 survivall in months 1.00 0 0.75 5 SS 0.50-O 0.50-O 0.25 5 0.00 0 R-1 1 R-2a a R-2b b ii 1 122 24 36 6Randomizedd trial
followedd by HIPEC were further analyzed, they showed that patients with six to seven regions still hadd a very poor survival (median, 5.4 months) compared with those with zero to five regions in-volvedd (median, > 29 months; P < 0.0001, figure 4; ). The success of the surgical procedure also hadd prognostic value. After complete resection (R-l), only one of 18 patients died. Fourteen of the 211 patients with limited residual disease (R-la) died, compared with seven of the 10 patients with extensivee residual disease (R-2b) (P < 0.0001). The median times to death in the latter two groups weree 20 and five months, respectively (figure 5).
Discussion n
Thiss study was designed to answer the question of whether the addition of aggressive cytoreduc-tionn and HIPEC with MMC improves survival in patients with PC of colorectal origin. In this analysis,, the results of all 105 randomly assigned patients are reported. The median follow-up at the timee of analysis was 21.6 months, which is more than twice the median survival in the standard arm.. At the time of this writing, an event (either recurrence or death) had occurred in 6 1 % of the patients,, almost two-thirds of what had been experienced in the standard arm. Follow-up, there-fore,, is long enough to demonstrate any impact of this new therapy on survival. The analysis was carriedd out according to the intention-to-treat principle, irrespective of the actual treatment re-ceived.. Protocol violations, including ineligibility of enrolled patients and treatment alterations, shouldd have a negative impact on the experimental arm. Nevertheless, Kaplan-Meier survival analy-siss showed a statistically significant survival benefit for the experimental therapy. The effect is of a remarkablee size. The median duration of survival almost doubled, while the 2-year survival was evenn more than twice as high. The difference between the patient groups withstands selection bias, ass in the control arm, life expectancy exceeded six months known from literature.27'28 Nevertheless, thesee relative good results suggest positive selection before random assignment.
Althoughh the longest survivor is at present only four years after randomization, the Kaplan-Meier survivall curve suggests a 5-year survival rate in the order of 20%, which is comparable to survival foundd in phase II studies. Together with die results of published phase II studies12-14"23 (table 3), ourr results provide compelling evidence of the effectiveness of aggressive cytoreduction and HIPEC. .
Thiss effect was associated with considerable morbidity and mortality (8%), which is similar to thatt reported by others.21 Most of the serious complications seem to be related to the extent of sur-gery,, and may be related to the extent of peritoneal involvement, rather than to the HIPEC proce-dure.. The median blood loss of almost four liter is high. The most extreme blood loss measure-mentss were found in patients with six and seven regions involved. Characteristically, these patients wouldd undergo a partial gastrectomy, splenectomy, resection of the tail of the pancreas, omentec-tomy,, multiple small bowel resections, ileocecal resection, rectosigmoid resection, and uterus with adnexx extirpation combined with multiple peritonectomy procedures, leaving an enormous intra-abdominall wound bed. Exhaustion of coagulations factors, though replaced with fresh frozen plasmaa and thrombocytes if measurably low, has probably contributed to the blood loss.
Chapterr 2
Itt is n o t e w o r t h y that in the first six m o n t h s , the period in which the treatment-related deaths oc-curred,, survival was identical in b o t h treatment arms. This emphasizes one of the problems of this s t u d y — t h ee inclusion of many patients with extensive peritoneal disease. This was due partly to our lackk of u n d e r s t a n d i n g of the impact of extent o f the disease on morbidity and survival, which m e a n tt that w e did not exclude any patients based on the extent of the disease. E v e n if w e had de-signedd the study t o exclude patients with extensive disease (six or seven regions), we would not havee b e e n very successful in predicting the extent of the disease based o n preoperative findings. C T - s c a n ss failed because typical P C is a like a coating that projects as a thin line o n a cross-section. M o r ee m o d e r n positron emission tomography scans are based on t u m o r density per volume unit, w h i c hh is low in these circumstances. T h e only trustworthy m o m e n t o f predicting o u t c o m e occurs afterr exploration of the a b d o m e n .
T h ee analysis of prognostic factors in the H I P E C arm shows that patients with cancer deposits in sixx or seven regions o f the a b d o m e n d o poorly, b o t h in respect to direct postoperative complica-tionss and long-term survival. Eighty percent of all incidences of grade 4 toxicity (postoperative complicationss included) and all treatment-related deaths were in this patient group. These are the samee patients in w h o m w e failed to obtain a complete cytoreduction. These patients have clearly n o tt benefited from cytoreduction and H I P E C . Both Sugarbaker et al, and Elias and Ouellet have
r e p o r t e dd very similar findings.26-29 Patients in whom six o r seven regions were affected by t u m o r
alsoo had p o o r survival (median, 5.4 m o n t h s ) . Patients with a high t u m o r load could be spared un-necessaryy toxicity since there is litde chance of improved survival. Such patients should be identi-fiedfied before surgery by standardization of explorations in every patient affected by PC.
M a n yy questions remain unanswered. T h e experimental arm o f this study combined two treatment elements:: aggressive cytoreduction and H I P E C . W h e t h e r the combination of these treatment m o -dalitiess was required for the survival benefit is unclear. Complete o r nearly complete resection seemss to be a prerequisite for a favorable outcome. This is consistent with our understanding that intraperitoneall c h e m o t h e r a p y only leads to drug delivery advantages to the superficial layers below thee peritoneal surface, and can therefore only be effective in minimal-residue disease. Nevertheless, itt c a n n o t be excluded that the observed effect was exclusively or mainly caused by the aggressive cytoreductionn alone.
I nn this study, a moderately dosed regimen of FU-leucovorin was used, as this is a convenient
out-patientt regimen with only minimal gastrointestinal toxicity or other toxicity.25 Recendy, somewhat
m o r ee aggressive schedules of combination chemotherapy have been introduced in advanced
colo-rectall cancer, which may be associated with a small survival benefit.w-31 It is possible that the use of
thesee c o n t e m p o r a r y chemotherapy schedules would have slighdy prolonged survival in b o t h treat-m e n tt artreat-ms. H o w e v e r , it seetreat-ms unlikely that it would have had any influence on the survival differencess found in this study. T h e combination of cytoreduction and H I P E C with continuous F U / -leucovorin,, irinotecan, a n d / o r oxaliplatin seems certainly promising for further o u t c o m e improve-m e n t . .
Q u e s t i o n ss concerning other aspects of H I P E C , for instance, the role of hyperthermia and die b e s tt choice of drug or dosage for intraperitoneal therapy, remain completely open. O t h e r drugs
Randomizedd trial
suchh as oxaliplatin32 and floxuridine33 have been studied and may be incorporated alone or i n novel
combinations. .
I nn this study, the open coliseum technique is used. This o p e n system presents the possibility to maintainn optimal distribution by manual stirring. Recently, this system has been tested for safety by
operatingg r o o m personnel.3 4 In this study, M M C was found neither in the operating r o o m air, nor in
thee urine of the surgeon or perfusionist, and is therefore safe.
Thiss study shows that the therapeutic nihilism that has dominated the care for patients with PC for suchh a long time may not be appropriate. Limited PC may represent a situation analogous to that of isolatedd liver metastases, in which long-term survival can be achieved in s o m e patients by the surgical removall of macroscopic disease and by systemic treatment to deal with microscopic residual disease. Withh the appropriate patient selection and a determined locoregional treatment effort, P C o f colo-rectall origin may even be a potentially curable disease in patients with limited peritoneal involve-ment. .
References s
1.. Minsky BD, Mies C, Rich TA, et al: Potentially curative surgery of colon cancer: Patterns of failure and survival.. J Clin Oncol 1988: 6: 106-118.
2.. Russell AH, Tong D, Dawson LE, et al: Adenocarcinoma of the retroperitoneal ascending and descend-ingg colon: Sites of initial dissemination and clinical patterns of recurrence following surgery alone. Int J Radiat OncolOncol Biol Phys 1983; 9: 361-365.
3.. Tong D, Russell AH, Dawson LE, et al: Adenocarcinoma of the cecum: Natural history and clinical pat-ternss of recurrence following radical surgery. Int J Radiat Oncol Biol Phys 1983; 9: 357-360.
4.. Sugarbaker PH: Intraperitoneal chemotherapy and cytoreductive surgery for the prevention and treat-mentt of peritoneal carcinomatosis and sarcomatosis. Semin Surg Oncol 1998; 14: 254-261.
5.. Sugarbaker PH: Management of peritoneal-surface malignancy: The surgeon's role. Langenbecks Arch Surg 1999;; 384: 576-587.
6.. Sugarbaker PH: Peritonectomy procedures. Ann Surg 1995; 221: 29-42.
7.. Spratt JS, Adcock RA, Muskovin M, et al: Clinical delivery system for intraperitoneal hyperthermic che-motherapy.. Cancer Res 1980; 40: 256-260.
8.. Fernandez-Trigo V, Stuart OA, Stephens AD, et al: Surgically directed chemotherapy: Heated intraperito-neall lavage with mitomycin C. Cancer Treat Res 1996; 81: 51-61.
9.. Witkamp AJ, van Coevorden F, Kaag MM, et al: Dose finding study of hyperthermic intraperitoneal che-motherapyy with mitomycin C in patients with carcinosis of colorectal origin. Eur J Surg Oncol 1998; 24: 214, (abstrr F74).
10.. Cavaliere R, Ciocatto EC, Giovanella BC, et al: Selective heat sensitivity of cancer cells: Biochemical and clinicall studies. Cancer \961; 20: 1351-1381.
11.. Isacoff WH, Borud K: Chemotherapy for the treatment of patients with metatastic colorectal cancer: An overview.. WorldJSutg 1997; 21: 748-762.
12.. Fujimura T, Yonemura Y, Fujita H, et al: Chemohyperthermic peritoneal perfusion for peritoneal dis-seminationn in various intra-abdominal malignancies. Int Surg 1999; 84: 60-66.
13.. Storm FK: Clinical hyperthermia and chemotherapy. Radiol Clin North Am 1989; 27: 621-627,
14.. 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.
Chapterr 2
SurgSurg Oncol 2000; 74: 41-44.
16.. Elias D , Blot F, El Otmany A, et at: Curative treatment of peritoneal carcinomatosis arising from colo-rectall cancer by complete resection and intraperitoneal chemotherapy. Cancer 2001; 92: 71-76.
17.. Loggie BW, Fleming RA, McQuellon RP, et al: Cytoreductive surgery with intraperitoneal hyperther-micc chemotherapy for disseminated peritoneal cancer of gastrointestinal origin. Am Surg 2000; 66: 561-568. 18.. Piso P, Bektas H, Werner U, et al: Improved prognosis following peritonectomy procedures and hy-perthermicc intraperitoneal chemotherapy for peritoneal carcinomatosis from appendiceal carcinoma. Eur J SurgSurg Oncol'2001; 27: 286-290.
19.. Rey Y, Porcheron J, Talabard J N , et al: Peritoneal carcinomatosis treated by cytoreductive surgery and intraperitoneall chemohyperthermia. Ann Chir2000; 125: 631-642.
20.. Schneebaum S, Arnold MW, Staubus A, et al: Intraperitoneal hyperthermic perfusion with mitomycin CC for colorectal cancer with peritoneal metastases. Ann Surg Oncol 1996; 3: 44-50.
21.. Shen P, Levine EA, Hall J, et al: Factors predicting survival after intraperitoneal hyperthermic chemo-therapyy with mitomycin C after cytoreductive surgery for patients with peritoneal carcinomatosis. Arch Surg 2003;; 138: 26-33.
22.. Sugarbaker PH, Chang D: Results of treatment of 385 patients with peritoneal surface spread of ap-pendiceall malignancy. Ann Surg Oncol \999; \999; 6: 727-731.
23.. 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. EurJ Cancer-2001; 37: 979-984.
24.. Sugarbaker PH: Carcinomatosis: Is cure an option? J Clin Oncol 2003; 21: 762-764.
25.. Laufman LR, Krzeczowski KA, Roach R, et al: Leucovorin plus 5-fluorouracil: An effective treatment forr metastatic colon cancer. J Clin Oncol\981; 5: 1394-1400.
26.. Sugarbaker PH, Schellinx ME, Chang D, et al: Peritoneal carcinomatosis from adenocarcinoma of the colon.. World J Surg \996; 20: 585-591.
27.. Jayne D G , Fook S, Loi C, et al: Peritoneal carcinomatosis from colorectal cancer. Br J Surg 2002; 89: 1545-1550. .
28.. Sadeghi B, Arvieux C, Glehen O, et al: Peritoneal carcinomatosis from non-gynecologic malignancies: Resultss of the EVOCAPE 1 multicentric prospective study. Cancer 2000; 88: 358-363.
29.. Elias DM, Ouellet JF: Intraperitoneal chemohyperthermia: Rationale, technique, indications, and re-sults.. Surg Oncol Clin North Am 2001; 10: 915-933.
30.. Andre T, Louvet C, Maindrault-Goebel F, et al: CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorinn and bolus and continuousinfusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancerr GERCOR. Eur J Cancer \999\ 35: 1343-1347.
31.. de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-linee treatment in advanced colorectal cancer. J Clin Oncol 2000; 18: 2938-2947.
32.. Elias D, Bonnay M, Puizillou JM, et al: Heated intra-operative intraperitoneal oxaliplatin after com-pletee resection of peritoneal carcinomatosis: Pharmacokinetics and tissue distribution. Ann Oncol 2002; 13: 267-272. .
33.. Culliford AT, Brooks A D , Sharma S et al.: Surgical debulking and intraperitoneal chemotherapy for establishedd peritoneal metastases from colon and appendix cancer. Ann Surg Oncol 2001; 8: 787-795.
34.. Stuart OA, Stephens A D , Welch L, Sugarbaker PH: Safety monitoring of the coliseum technique for heatedd intraoperative intraperitoneal chemotherapy with mitomycin C. Ann Surg Oncol 2002; 9: 186-191.
Randomizedd trial
Communicationn in the Journal of Clincal Oncology after publication of the
randomi2edd trial.
Letterr to the editor by Maurie Markman
Verwaall et al1 are to be congratulated for their efforts to evaluate in a phase III randomized trial thee clinical utility of "aggressive surgical cytoreduction" followed by hyperthermic intraperitoneal chemotherapyy (HIPEC) as a management strategy for peritoneal carcinomatosis resulting from a colorectall malignancy.
Unfortunately,, a major conceptual flaw in the study's design prevents any meaningful conclusions too be drawn from the results of this otherwise interesting study. The investigators elected to com-paree a strategy that combined aggressive surgery with HIPEC versus standard intravenous chemo-therapyy plus palliative surgery (if necessary). However, if the aim of the study was to evaluate the highlyy experimental, complex, costly, and potentially very morbid regional chemotherapy strategy, thiss trial has failed to address this important question.
AA more appropriate trial design would have been to randomly assign patients with peritoneal car-cinomatosiss to aggressive surgical cytoreduction with or without HIPEC. With the present study design,, the demonstrated survival benefit may have been due principally, if not totally, to the exten-sivee surgery, with the regional chemotherapy only adding toxicity. The favorable impact on survival associatedd with an attempt at "interval surgical cytoreduction" (without the subsequent administra-tionn of intraperitoneal chemotherapy) has been documented in ovarian cancer,2 and the major influencee of the volume of residual disease on survival has been clearly shown in the current study (mediann survival of 20 months versus 5 months for patients with "limited" versus "extensive" resi-duall cancer, respectively).
Ass appropriately noted by the authors: "... it cannot be excluded that the observed effect was ex-clusivelyy or mainly caused by the aggressive cytoreduction alone." In sum, this study fails to provi-dee any support for the routine (as opposed to investigative) use of HIPEC in this clinical setting.
Itt is hoped that these investigators will follow their important initial efforts with a phase III ran-domizedd trial that directly addresses the unique contribution (if any) of the regional chemotherapy componentt of this intensive management strategy.
References s
1.. Verwaal VJ, van Ruth S, de Bree E, et al: Randomized trial of cytoreduction and hyperthermic intraperi-toneall chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carci-nomatosiss of colorectal cancer. J Clin Oncol 2003; 21: 3737-3743.
2.. Van der Burg MEL, Van Lent M, Buyse M, et al: The effect of debulking surgery after induction che-motherapyy on the prognosis in advanced epithelial ovarian cancer. N Engl J Med1995; 332: 629-634.
Chapterr 2
Letterr to the editor bv Bert Hildebrandt, Beate Rau Johanna, Gellermann, Peter
Wustt and Hanno Riess
Vicc }. Verwaai and colleagues1 demonstrated that an improvement of survival is achieved in
colo-rectall cancer patients with peritoneal carcinosis treated by surgical cytoreduction and hyperthermic intraperitoneall chemotherapy ( H I P E C ) when compared with schedules with palliative chemothera-pyy (with or without surgery) alone. This study, for the first time, demonstrated a survival benefit forr adjunctive H I P E C in the scope o f a randomized trial, but this result was counterbalanced by a 1 6 %% early death rate and an excessively high rate of severe side effects in the experimental arm ( W H OO 3: 6 5 % of patients; W H O 4: 4 5 % of patients). In our opinion, such high complication rates aree hardly acceptable in a palliative treatment concept that yielded an overall survival benefit of 10 m o n t h ss for the entire patient population. In addition, there was virtually n o clinically relevant im-p r o v e m e n tt in subgrouim-ps of im-patients with far advanced disease. Indeed, a median survival of less thann 6 m o n t h s was reported in 3 3 % of patients treated in the experimental arm.
Itt is plausible that a n u m b e r of side effects associated with surgery plus H I P E C have been caused orr p r o m o t e d by either the intraperitoneal application of mitomycin C or the hyperthermic conditi-onss of its administration (eg, hematotoxicity, 27%; fistuke, 1 5 % ; infection, 6%; pancreatitis, 2 % of patientss treated). Certain o t h e r complications may rather be assigned to the surgical procedure or rapidd disease progression (eg, pulmonary embolism within 3 m o n t h s after surgery). However, 2 4 % off patients treated with H I P E C suffered from severe or life-threatening complications that caused damagee to vital organs (heart failure/arrhythmia, 14%; terminal renal failure, 6%; paresis: 4 % o f pa-tients),tients), and it is difficult to ascribe these events t o any of the single modality applied. Therefore, thesee high rates of severe ad-verse events appear to result from the topical application of surgery andd adjunctive chemotherapy under hyperthermic conditions. Unfortunately, the study was not de-signedd to precisely define the role of H I P E C by comparing treatment with surgery alone with sur-geryy plus H I P E C .
W ee would like to emphasize that it is largely unknown if elevated (eg, > 37°C) temperatures actu-allyy contribute to the efficacy of intraperitoneal chemotherapy. O n the one hand, 10 randomized trialss o n different locoregional hyperthermia approaches have already demonstrated a benefit when hyperthermiaa is added to standard radiotherapy a n d / o r chemotherapy. Most of these studies have b e e nn performed with radiofrequency hyperthermia techniques in patients with superficial or pelvic t u m o r s ,, and a n u m b e r of c o n c o m i t a n t analyses have revealed a clear-cut correlation between
ther-mall dose and clinical o u t c o m e .2 O n the other hand, such a dose-response relationship has never
b e e nn duplicated for any of the " c o n v e c t i v e " hyperthermia techniques H I P E C or hyperthermic iso-latedd limb perfusion (HIEP), respectively. In addition, a randomized comparison o n n o r m o t h e r m i c versuss hyperthermic chemotherapy in the scope of H I P E C or H I E P has never been performed. T h ee occurrence of organ failure in the context of H I P E C raises suggestions o n the experiences withh chemotherapy and whole-bod)- hyperthermia (WBH). In particular extracorporal W B H , in whichh the patient's core body temperature is raised bv convective heating of blood, bears the risk
R a n d o m i z e dd trial
o ff severe renal failure,3 but heart failure, arrhythmias, multiorgan failure, or pareses have also been
reportedd with the use of m o d e r n radiant-heat W B H devices.4
Inn our opinion, it cannot be ruled o u t that intraoperative H I P E C may produce additional toxicity withoutt being m o r e effective than n o r m o t h e r m i c intraperitoneal chemotherapy. O n e strategy to resolvee the question of whether the efficacy of intraperitoneal chemotherapy is actually enhanced byy application as H I P E C may be a randomized comparison between n o r m o t h e r m i c and hyperther-micc intraperitoneal drug application. A n o t h e r policy may be the application of hyperthermic che-motherapyy in the postoperative or palliative setting by employing novel regional radiofrequency hy-perthermiaa (RHT) applicators that enable effective heat delivery to the entire a b d o m e n ("partbody hyperthermia").. After a phase of preclinical evaluation, such magnetic resonance— guided R H T de-vicess have recently been introduced into clinical practice in o u r institution, as well as a very few others.. First clinical experience and phase I-data indicate that effective hyperthermia can be safely
deliveredd to patients with peritoneal masses by this technology, with only little additional toxic-ity.5
AA first phase II trial on intravenous chemotherapy (folinic acid/nuorouracil/oxaliplatin) plus R H T inn patients with peritoneal carcinosis has recently b e e n initiated.
References s
1.. Verwaai VJ, van Ruth S, de Bree E, et al: Randomized trial of cytoreduction and hyperthermic intraperi-toneall chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carci-nomatosiss of colorectal cancer. / Clin Oncol 2003; 21: 3737-3743.
2.. Wust P, Hildebrandt B, Sreenivasa G, et al: Hyperthermia in combined treatment of cancer. Lancet Oncol 2002;; 3: 487-497.
3.. Wiedemann GJ, Robins HI, Gutsche S, et al: Ifosfamide, carboplatin and etoposide (ICE) combined withh 41.8 degrees C whole body hyperthermia in patients with refractory sarcoma. Eur J Cancer 1996; 32A: 888-892 2
4.. Kerner T, Hildebrandt B, Ahlers O, et al: Anaesthesiological experiences with whole body hyperther-mia.. Int J Hyperthermia 2003; 19: 1-12.
5.. Gellermann J, Wlodarczyk W, Seebass M, et al: MR-thermometry during radiofrequeny hyperthermia (part-bodyy hyperthermia) in pelvic tumors. Radiology 2002; 225(P): 510 (abstr).
I nn r e p l y b y V i c J V e r w a a i
T h ee c o m m e n t s in the letters to the editor are well taken. We agree with b o t h writers that our stu-dyy could n o t answer the question of whether adding hyperthermic, intraperitoneal chemotherapy to cytoreductionn is better than cytoreduction alone. T o answer this question, an appropriate study d e -signn would, indeed, be a randomized trial comparing cytoreduction alone with cytoreduction plus hyperthermicc intraperitoneal chemotherapy.
Att the current state of art in the treatment o f carcinomatosis, neither cytoreduction alone nor hyperthermiaa plus chemotherapy is c o m m o n practice or a proven treatment. This means that a studyy design comparing single elements of the treatment would be a comparison of two new
Chapterr 2
therapiess and would not answer the question whether either treatment is better than the regular treatment. .
Att this moment, the gold standard in the treatment of peritoneal carcinomatosis has not yet been established.. In practice, most patients affected by peritoneal carcinomatosis face a therapeutic nihi-lismm and do not undergo major treatments. In this perspective, a novel therapy like cytoreduction withh hyperthermic intraperitoneal chemotherapy should be compared with a nihilistic treatment re-gime,, as being the standard.
N o ww that our randomized trial has been completed, the question of which element of the combi-nedd treatment is effective becomes relevant, as suggested in both letters. The design proposed in thee first letter is an excellent suggestion. In such a study, cytoreduction plus hyperthermic intraperi-toneall chemotherapy is seen as standard treatment. Therefore, this would be a noninferiority study design.. A study of this nature is currendy being prepared.
Thee suggestions in the second letter could follow if the oncoming trial will prove a benefit of hy-perthermicc intraperitoneal chemotherapy after cytoreduction. This trial would compare cytoreduc-tionn plus hyperthermic intraperitoneal chemotherapy, with cytoreduction plus intraperitoneal che-motherapyy without hyperthermia.
Ourr randomized trial showed a survival benefit of cytoreduction plus hyperthermic intraperito-neall in patients affected by peritoneal carcinomatosis of colorectal origin. The value of any other neww therapies should be tested either with the standard therapy or with cytoreduction plus hy-perthermicc intraperitoneal chemotherapy in a phase III setting. Only in this way we will be able to determinatee which treatment or combination of treatments is optimal.
