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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.
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Chapterr five
Peritoneall carcinomatosis without distant metastasis
off colorectal origin:
Resultss of conventional surgery and
systemicc chemotherapy
Byy Vic J. Verwaai
1, Serge van Ruth
1, Henk Boot
2andd Frans A.N. Zoetmulder
1d e p a r t m e n tt of Surgery and
2Department of Gastroenterology
Thee Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
Amsterdam,, the Netherlands
Background:Background: Cytoreduction combined with intraperitoneal chemotherapy enhances survival in patients with
isolatedd peritoneal carcinomatosis. However, little is known about the results of the conventional approach, whichh consists of conventional surgery and systemic chemotherapy.
Method:Method: Fifty patients with proven peritoneal carcinomatosis of colorectal origin were treated with
conven-tionall surgery and 5-fluorouracil (400mg/m2) and leucovorin (80mg/m2) once weekly, or irinotecan
(350mg/m2)) every three weeks in patients treated by 5-fluorouracil within 12 months prior to entry. Survival andd progression-free survival were studied by using the Kaplan Meier method. Prognostic factors were ana-lyzed. .
Results:Results: The median survival time of these patients was 12.8 months. The median time to progression was
7.66 months. Location of primary tumor and result of conventional surgery were prognostic factors related to survival. .
Conclusion:Conclusion: The survival time of patients with peritoneal carcinomatosis of colorectal origin is short when
treatedd by conventional surgery and systemic chemotherapy. Patients do better after adequate surgical de-bulking. .
Standardd treatment
Introduction n
AA growing number of non-randomized studies are being published on cyto-reductive surgery combinedd with some form of hyperthermic intraperitoneal chemotherapy in patients with perito-neall carcinomatosis of colorectal origin.16 These papers emphasize encouraging results compared too the poor results of standard management.7 This increasing number of publications is in contrast too the limited knowledge of the results of conventional surgery and systemic chemotherapy. The latterr approach is at this moment more or less standard in most western countries.
Inn many studies published on the effects of chemotherapy in advanced colorectal cancer, patients withh carcinomatosis have been lumped together with patients with systemic metastases.8-9 Studies
focusingg on carcinomatosis often combine results of patients with and without distant metasta-ses.10-111 They also describe the results in patients treated in a variety of ways or not treated at all. Therefore,, it is not possible to determine whether the particular characteristics that distinguish peritoneall carcinomatosis from metastases at other sites have implications for survival.12 Nor is it possiblee to compare these results with outcomes of phase II studies dealing with cytoreductive sur-geryy and intraperitoneal chemotherapy.
Recentt editorials call for randomized trials examining the potential benefit of cytoreduction fol-lowedd by hyperthermic intraperitoneal chemotherapy.1314 However, there is still much to be learnedd from the results of the standard treatment of peritoneal carcinomatosis.
Patientss with isolated peritoneal carcinomatosis of colorectal origin have been treated at The Netherlandss Cancer Institute within a trial comparing standard therapy to cytoreductive surgery followedd by hyperthermic intraperitoneal chemotherapy. The first analysis of this trial has been performedd in 2002 with a median follow-up of 21.6 months.15 The prospective database of this trial iss continuously updated. The present study concerns the patients treated by palliative surgery and systemicc chemotherapy, with a current median follow-up of 42 months.
Patientss and methods
Betweenn April 1997 and August 2001, 105 patients were treated in a single-institution random-izedd trial comparing conventional surgery and systemic chemotherapy to cytoreductive surgery fol-lowedd by hyperthermic intraperitoneal chemotherapy. Within this trial, 51 patients were random-izedd to standard therapy. Two of these patients rejected the result of the randomization and were treatedd by cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy. In the ex-perimentall arm, one patient refused experimental therapy shortly after entering the study and was treatedd by standard therapy. Thus, 50 patients were treated according to the control arm of the pro-tocol,, 25 were female and 25 were male with median age of 55 years (range 29-70 years). All these patientss remained in follow-up until the writing of this report and their data were prospectively col-lected. .
metasta-C h a p t e rr 5
ses,, age 7 0 years or younger, fit t o u n d e r g o major surgery and written informed consent. T h e study wass o p e n for both patients with synchronic and metachronic peritoneal carcinomatosis.
T i m ee between first diagnosis o f colorectal cancer and the diagnosis of peritoneal carcinomatosis, locationn o f the primary t u m o r , malignancy grade, histological type, presentation with or without o b s t r u c t i o nn or perforation, type o f initial surgery and extent of peritoneal carcinomatosis were re-c o r d e dd as pre-study data.
Systemicc chemotherapy, often given in the referring hospital, was started as s o o n as possible after enteringg the study using the slighdy modified Laufman regimen.16 This consisted of a one-hour i n t r a v e n o u ss infusion of leucovorin (80 m g / m2) followed by an intravenous p u s h dose of
5-fluoro-uracill (400 m g / m2) in a weekly schedule for 26 weeks or till progression or intolerable toxicity. Patientss w h o had been treated with 5-fluorouracil within 12 m o n t h s prior to entering the protocol weree treated with irinotecan, 350 m g / m2 for nine c y c l e s . 'J r
D a t aa o n type of c h e m o t h e r a p y , n u m b e r of courses and reasons for stopping were registered. Any second-linee therapy was allowed after progression of the disease. This could include both surgical p r o c e d u r e ss to overcome obstruction or o t h e r cancer related problems and second-line or third-line c h e m o t h e r a p y .. Follow-up consisted of medical history and physical examination with C E A and CA19.99 measurements every three m o n t h s . Every six m o n t h s , a C T of the a b d o m e n and a chest X-rayy were made. Progressive disease was defined as 2 5 % growth of C T - or palpable findings, ap-pearancee o f new lesions or rise of t u m o r markers above normal values.
T i m ee to progression and overall survival were taken from the m o m e n t of entering. T h e n u m b e r off hospital admissions and the n u m b e r of operations during follow-up were also registered.
Parameterss were tested for a possible effect o n survival by using the Log rank test, in which P << 0.05 was considered to be significant.
T a b l ee 1. Peritoneal carcinomatosis of colorectal cancer by location of origin in 50 patients
Locationn Synchronic Metachronic All Appendixx 4 3 7 Rightt colon 11 5 16 Ixftt colon 3 1 4 Sigmoidd 6 10 16 Rectumm 2 3 5 N o tt specified 2 - 2
Standardd treatment
Tablee 2. E x t e n t of peritoneal carcinomatosis of colorectal origin in 50 patients (largest distancee from primary t u m o r )
Synchronicc Metachronic All l Nearr primary tumor
Ovaries s Douglass pouch
Minorr involvement mesentery Majorr involvement mesentery Sub-hepaticc space 12 2 7 7 3 3 4 4 2 2 20 0 10 0 9 9 7 7 2 2 2 2
Tablee 3. Operations performed in 50 patients with peritoneal carcinomatosis of colo-rectall origin
Operation n Synchronic c Metachronic c All l
Explorationn only Bypass s Palliativee resection Radicall resection 4 4 5 5 14 4 5 5 9 9 3 3 8 8 2 2 13 3 8 8 22 2 7 7
Figuree 1. Kaplan Meier curves for survival and progression-free survival in 50 patients affectedd by peritoneal carcinomatosis of colorectal origin
1.00 0 0.80 0 >>> 0.60 .a a to o -Q Q O O Q-- 0.40 0.20 0 0.00 0 overall l diseasee free 12 2 188 24 survivall in months
Chapterr 5
Results s
Twenty-eightt of the 50 patients had peritoneal carcinomatosis synchronic with the colorectal can-cerr and in 22 patients this was metachronic. The median time between the primary carcinoma and thee carcinomatosis was 36 mondis (range 15-107 months) for patients with metachronic disease. Thee location of die original colorectal tumor is shown in table 1. In two female patients the loca-tionn of the primary tumor was not clear. They had an immuno-histological marker pattern consis-tentt with colorectal cancer and were classified accordingly.
Off the 28 synchronic patients, three (11%) presented with tumor perforation and eighteen (63%) withh bowel obstruction. Four of the 22 patients (17%) wifii metachronic carcinomatosis had previ-ouss a perforation and four (17%) had an obstruction.
Thee diagnosis of peritoneal carcinomatosis was made during laparotomy in all patients. In 27 pa-tientss (54%), it was found during surgery for an abdominal emergency, mostly obstruction. In 20
Tablee 4. Median surviv tients s
All l Gender r
Presentation n
locationn primary tumor
Malignancyy grade
Sitee of PC
Resection n
all after recurrence of colorectal peritoneal
female e male e synchronic c metachronic c appendix x colon n rectum m ns s goodd / moderate poor r local l ovarian n extensive e no o palliative e radical l Numberr of patients s 50 0 25 5 25 5 28 8 22 2 7 7 36 6 5 5 2 2 24 4 13 3 20 0 10 0 20 0 21 1 22 2 7 7 carcinomatosiss in 50 pa-Mediann survival (SE) ) 12.88 (2.6) 17.77 (1.2) 10.11 (1.7) 12.8(1.9) ) 12.66 (2.3) 21.7(0.8) ) 12.811 (1.9) 16.33 (2.1) 0.8 8 16.33 (1.5) 9.77 (1.2) 14.22 (0.5) 17.66 (2.9) 10.11 (0.8) 8.33 (0.2) 17.77 (2.1) 16.3(1.1) ) PP value1 0.05 5 0.85 5 <0.01 1 0.09 9 0.25 5 <0.01 1
Standardd treatment
patientss (40%), peritoneal carcinomatosis occurred near the location of the primary colorectal tu-mor.. The extent of the tumor spread is listed in table 2. Table 3 describes the surgical procedures performedd at the laparotomy during which the carcinomatosis was found. Because most of these proceduress were undertaken in the referring hospital, the reason why a particular procedure was performedd could not always be ascertained.
Fourr of the 50 patients (8%) never started the chemotherapy they were scheduled to receive. One refusedd systemic treatment after entering the study and two deteriorated rapidly and died of pro-gressivee disease. In the remaining patient, the reason why systemic chemotherapy was not given re-mainedd unknown.
Twenty-fivee patients (50%) completed the full 26-week schedule. Fifteen patients (33%) had pro-gressionn during the 26 weeks and, consequently, the treatment was stopped. In three patients (6%) thee treatment was stopped because of toxicity and three other patients refused further treatment as theyy found the impact on their quality of life unacceptable.
Thee median follow-up was 43 months (range 21-64 months) and was completed in all patients untill June 2003. Forty-six patients had progression of disease within the follow-up period. Progres-sionn was located only intraperitoneally in 38 patients, in the liver in four patients and both intra-peritoneallyy and hepatic or distant in four patients. The median time to progression was 7.6 months (SEE 0.7).
Twelvee patients were still alive at the last follow-up update. The median survival time was 12.8 monthss (SE 2.6). Figure 1 shows overall and progression-free survival. The two patients with carci-nomatosiss of unknown colorectal location had a poor survival (0.3 and 2.5 months). Table 4 shows thee impact of patient-, tumor- and treatment-related factors on survival. In patients in whom it was possiblee to perform either a radical or a palliative resection, the median survival was 16.3 months (SEE 1.1) and 17.7 months (SE 2.1) respectively. The median survival of the four patients who did nott start systemic chemotherapy was 0.8 months (SE 0.1). In patients who did receive chemo-therapyy survival was 14.8 months (SE1.9) and 8.3 months (SE 0.9) for 5-fluorouracil / leucovorin andd irinotecan respectively.
Thee majority of the patients developed serious medical problems during follow-up. The average numberr of hospital admissions was 1.4 (range 0-7). They spent on average 15.2 days in the hospital, upp to 93 days. One out of every two patients had to undergo further surgery, usually because of re-currentt bowel obstruction.
Discussion n
Thiss study shows a longer survival of patients with peritoneal carcinomatosis of colorectal origin afterr conventional surgery and systemic chemotherapy than is reported by other investigators,1011 butt die median survival is still limited to 12.6 months. The observed difference is probably due to a positivee selection of patients entering this study, e.g. no distant metastases, fit to undergo major surgeryy and potential resectable disease.
Chapterr 5
Sadeghii et al s h o w e d a lower overall survival of only 5.2 m o n t h s . " In their study, patients with lesss extensive regional disease and widiout distant metastases were n o t distinguished and these pa-d e n t ss in particular are subjectepa-d to the new therapeutic strategies.iH-V) Therefore, a comparison be-tweenn phase II studies of the novel therapeutic strategies and the Sadeghi study is inappropriate.
T h ee p r e s e n t study s h o w s interesting basic characteristics of peritoneal carcinomatosis. It confirms thee earlier observation t h a t peritoneal carcinomatosis originates m o r e often in appendiceal cancer andd right-sided colon cancer c o m p a r e d to left colon cancer and rectal cancer.20*21 A substantial
n u m b e rr of patients p r e s e n t e d with either tumor perforation or bowel obstruction initially, suggest-ingg t h a t these events can stimulate the spread of t u m o r cells to the peritoneal surface.
Survivall time in this study varies widely and appears to be related to multiple factors. A p o o r dif-ferentiationn grade of the primary t u m o r results in a shorter survival. Ovarian metastases have a relativelyy g o o d prognosis, while extensive involvement of the bowel mesentery translates to a short survival.. T h e s e differences are n o t significant, probably due to the small n u m b e r s . Female patients havee a better survival. T h i s may be related to the observed relatively g o o d prognosis of ovarian me-tastases.2 22 Patients w h o u n d e r w e n t resection of the involved lesions fared significantly better than
t h o s ee w h o had a by-pass p r o c e d u r e only or were just o p e n e d and closed. Marcus et al did similar observations.1 22 It is difficult to determine the value of this observation into clinical practice. We are n o tt i n f o r m e d about the reasons why in some patients a choice for resection was made, while in o t h e r ss a bypass was performed. Clearly this decision was pardy dictated by the extent of t u m o r in-v o l in-v e m e n t .. Limited peritoneal seeding adjacent t o the colorectal t u m o r or oin-varian metastases will t e m p tt m o s t surgeons to resect. Patients with extensive mesenteric involvement, o n the other hand, willl almost always have an explorative laparotomy only. Preferences of die surgeon may also play a role.. T h e accuracy of the operative notes describing the situation found at laparotomy often leaves m u c hh to be desired. C o m p a r i n g operative notes of previous laparotomies with the observations d u r i n gg a second laparotomy showed unexplained discrepancies. F o r this reason, a multivariate analysiss including these factors was not performed. T h e survival benefit of resection of all macro-scopicc t u m o r s suggests that this is the best option, even in regionally disseminated disease.
T h ee impact of systemic c h e m o t h e r a p y is difficult to determine. Imaging response to chemother-apyy by C T or ultrasonography is often unreliable in peritoneal carcinomatosis, leaving serum mark-erss ( C E A and CA 19.9) as tool for response measurement,2 3 a clinical situation not different from
m a n a g e m e n tt of stage III ovarian cancer. T h e value of this latter tool is also limited as only 6 0 % of patientss with metastatic colorectal cancer have increased serum marker levels.
T h ee time to progression in this series is barely seven m o n t h s . T h e a b d o m e n remains in the vast majorityy of patients the main site of t u m o r activity7. In m o s t patients, this leads to recurrent bowel o b s t r u c t i o nn and half of all patients u n d e r w e n t an additional laparotomy to overcome this problem. Itt is clear that peritoneal carcinomatosis patients lay a major claim on health care resources.
Inn conclusion, this study confirms the p o o r outcome of patients with peritoneal carcinomatosis off colorectal origin treated with conventional surgery and systemic chemotherapy. T h e response of peritoneall carcinomatosis t o systemic chemotherapy seems to be limited. At present no data are availablee o n newer schedules such as oxaliplatin - fluorouracil - leucovorin or irinotecan -
5-Standardd treatment
fluorouracill - leucovorin. I n selected patients with this grave disease cytoreduction combined with hyperthermicc intraperitoneal chemotherapy is a promising treatment option.1 5
References s
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Chapterr 5
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