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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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Long-termm survival of patients with
peritoneall carcinomatosis of colorectal origin
Vicc J. Verwaai
1, Serge van Ruth
1, Arjen Witkamp
1,
Henkk Boot
2, Gooike van Slooten
1,
Franss 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
Introduction:Introduction: Peritoneal carcinomatosis of colorectal cancer is probably best treated by cytoreduction and hyperthermicc intraperitoneal chemotherapy. In The Netherlands Cancer Institute this treatment is
per-formedformed since 1995. The long tradition of this treatment enabled us to study long-term survival in detail. PatientsPatients and method: Between 1995 and 2003 117 patients affected by peritoneal carcinomatosis of colorectal originn were treated by cytoreduction combined witli hyperthermic intraperitoneal chemotherapy. The aim of thee cytoreduction was to remove all visible tumor. Mitomycin C (35 mg/m2) was given intraperitoneally at a
temperaturee of 40 to 41 °C during 90 minutes. Overall survival was calculated by the Kaplan Meier method. Survivall was also analyzed for the following subgroups: patients with no residual tumor; with residual tu-morr < 2.5 mm and with residual tumor > 2.5 mm. Hazard ratios for each of the 7 abdominal regions were calculatedd to determine the influence on survival.
Results:Results: The median survival of peritoneal carcinomatosis of colorectal cancer once treated by cytoreduc-tionn and hyperthermic intraperitoneal chemotherapy was 21.8 months. The 1-year, 3-year and 5-year survival ratee were 75%, 28%, 19% respectively. The Kaplan Meier curve shows a consistent survival rate after 54 monthss of 18%. In 59 patients a complete cytoreduction was achieved, and in 41 patients there was minimal residuall disease. The median survival of these patients groups was 42.9 and 17.4 months respectively. When grosss macroscopic tumor was left behind, which was the case in 17 patients, the median survival was five months.. Involvement of the small bowel prior to the cytoreduction was associated with poorer outcome.
Conclusion:Conclusion: Cytoreduction followed by intraperitoneal chemotherapy showed a median survival of 21 months.. From three year on a consistent group of 18% stays alive.
Introduction n
Peritoneall carcinomatosis is a manifestation of colorectal cancer in which tumor cells float throughh the abdominal cavity and reseed in peritoneal surface. After implantation on the peritoneal surfaces,, the malignant cells may form tumor nodules throughout the abdominal cavity.1 Peritoneal carcinomatosiss is present in approximately 10% of patients with colorectal cancer at the time of firstt diagnosis and in approximately 25% of patients with recurrent disease.24 Although peritoneal carcinomatosiss is frequendy found in combination with distant metastases, it appears to be the only sitesite of disease in about 25% - 35% of the patients, even after an extensive diagnostic work-up.5-6
Thee treatment of peritoneal carcinomatosis of colorectal origin is shifting from a nihilistic ap-proachh to a very active management.78 Cytoreduction followed by hyperthermic intraperitoneal chemotherapyy (HIPEC) is the most pro-active way of dealing with peritoneal carcinomatosis. This treatmentt has been established by a number of phase II studies and even a phase III study.6-912 In thee phase III study a significant better survival was found when this treatment is compared to pal-liativee surgery and systemic chemotherapy.
Thiss potential improvement in survival has to be balanced against the side effects of diis inten-sivee treatment.13 A number of studies report complication rates as high as 30%.1415 Although most complicationss are surgery related, hyperthermic intraperitoneal chemotherapy probably increases thee impact of the complications.
Thee above-mentioned complication rates are only acceptable if a long-term survival can be ex-pected.. In The Netherlands Cancer Institute this treatment is performed since 1995. The long tra-ditionn of this treatment enables to study long-term survival.
Patientss a n d m e t h o d s
Betweenn November 1995 and August 2003, 117 patients with peritoneal carcinomatosis of colo-rectall origin were treated with cytoreduction and HIPEC at The Netherlands Cancer Institute. Sixty-fourr patients were male and 53 women with a median age of 53 years. The first 36 patients weree entered in phase I and II studies. The following 48 patients were entered in a randomized phasee HI study and the remaining 33 patients were treated after this study.
Patientss with histologically proven peritoneal carcinomatosis of colorectal origin without evi-dencee of liver or lung metastases, up to 70 years of age and fit to undergo major surgery were eligi-blee for this therapy. Both synchronic and metachronic carcinomatosis was included. Written in-formedd consent was required for patients who participated in the trials.
TreatmentTreatment schedule
Thee entire treatment consisted of surgical cytoreduction plus intraperitoneal chemotherapy, fol-lowedd by adjuvant systemic chemotherapy.
Thee objective of cytoreduction was to leave no macroscopic tumor behind. If this was not feasi-ble,, the aim was reframed to "no thicker than 2.5 mm", as this is the maximum penetration depth
Chapterr 9
att which a dose advantage of intraperitoneal Mitomycin C can be 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. Restrictions were made on the extent of surgery as far as it wass compatible with sufficient post-operative function.
Thee perfusion method used for the hyperthermic intraperitoneal chemotherapy is described in detaill elsewhere by Witkamp et al17. The inflow temperature of the perfusate was 41-42° C. As soonn as this temperature was reached, Mitomycin C was added in three fractions with a 30-minute intervall (Vz, 'A, VA of the total dose respectively). For patients in the phase II study, the dose of Mi-tomycinn C was increased step-wise from 25 mg/m2 to 40 mg/m2. All other patients were treated withh 35 mg/m2 Mitomycin C. After completion of 90 minutes perfusion, the fluid was drained fromm the abdomen.
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.. A gastrostomy was used to allow the stomach to drain, and a trans-gastric jejunal feeding tube wass placed for enteral nutrition.
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.
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 hyperthermic intraperitoneal chemotherapy, they were treated withh Irinotecan (350 mg/m2, three-weekly) instead of 5-FIuroruracil.19-20
GradingGrading tumor amount
Thee spread and thickness of tumor was measured in seven regions of the abdomen: pelvis, right lowerr abdomen, omentum / transverse colon, small bowel / mesentery, subhepatic space / stom-ach,, right subphrenic space and left subphrenic space. For each region a semi-quantitative score wass allocated by measuring maximum thickness of the largest nodules (none = 0; < 20 mm = 1; 20-500 mm = 2; >50 mm = 3). In case of confluent nodules the maximum thickness of the resulting plaquee was used.
Thee result of cytoreduction was determined according to maximum thickness of tumor nodules leftt behind at any place in the abdomen. No residual macroscopic tumor was graded as an R-l re-section,, residual macroscopic tumor < 2.5 mm was recorded as R-2a resection and if more disease wass left behind as R-2b resection.
StatisticalStatistical analyses
Survivall was measured from the date of cytoreduction and hyperthermic intraperitoneal chemo-therapyy until death or date of last follow-up in censored cases. The median survival as well as the one-,, two-, three-, four- and five-years survival rates were determined for the entire patients popu-lationn and for each cytoreduction category. The survival differences between categories were tested
usingg the log rank test. Potential prognostic factors were analyzed for their impact on survival by usingg the log rank test. The relation between affected region and survival was analyzed by using the Coxx regression analysis.
Results s
Figuree 1. Follow-up of 117 patients treated for peritoneall carcinomatosis of colorectal origin by cytoreductionn plus hyperthermic intraperitoneal chemotherapy y
15 5
|| 10 as s a. . Dataa on 117 consecutive patients were ana-lyzedd with a median follow-up of 46 months. Thee distribution of the follow-up is shown in figurefigure 1. The colorectal cancer was in ninety-fivefive patients located in the colon. Thirty-three patientss had a right-sided colon cancer, 15 pa-tientss had a left-sided colon cancer and in 47 patientss the tumor was located in the sigmoid. Inn 15 patients the carcinomatosis was based on ann appendix cancer and in five patients on rec-tall cancer. The location of the primary tumor waswas not known in two patients. Sixty-seven pa-tientss had synchronic carcinomatosis and 50 hadd carcinomatosis metachronic with the colo-rectall cancer.
Thee TNM classification of the primary tu-morr showed a Tt tumor in 61 patients and in
522 patients had a T3 tumor. In two patients the primary tumor was T2. In 24 patients the primary tumorr was graded as No, in 34 patients as Ni and in 12 patients as N2. In the remaining 47 patients thee N-status could not be determined.
Tablee 1. Percentage of affection with peritoneal carcinomatosis per region before and after cytoreductionn and percentage of clearance per region in 117 patients treated by cytoreduc-tiontion plus hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis
CD D . 0 0 E E 5 --~ 1 — — 12 2 T T T T ~r ~r 244 36 48 60 72 B4 96 follow-UDD in months Pelvis s Ileocecal l
Omentumm /transverse colon Smalll bowel / mesentery Subhepaticc space Subphrenicc space left Subphrenicc space right
Percentage e Before e 90.6 6 67.5 5 83.8 8 78.6 6 34.2 2 23.1 1 34.2 2 affected d After r 15.4 4 6.0 0 12.0 0 40.2 2 19.7 7 9.4 4 18.0 0 Percentagee cleared 83.0 0 91.1 1 85.7 7 48.9 9 42.5 5 59.3 3 47.5 5
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Tablee 1 shows the percentage in which a region is affected before and after the cytoreduction. Thee pelvis and the omentum were affected in almost all patients. The ileocecal region was cleared inn most patients. If tumor deposits had to be left behind, this was in the subhepatic space, on the mesenteryy of the small bowel and in the right subphrenic space.
AA large number of organs were resected. Omentum and ovaries were resected in female patients. Thee rectum was resected in 51.3% of the patients, parts of the colon were resected in 4 1 % patients andd ileocecal resections were done in 58% of the patients. Forty-eight percent of the patients neededd a colostomy. In the upper abdomen, partial stomach resections were performed in 10% of thee patients and 56% needed one or more small bowel resections. A splenectomy was performed in 9%% patients.
Thee cytoreductions were in 59 patients macroscopically complete (R-l), in 44 patients there was minimall residual tumor left behind (R-2a) and in 14 patients there was gross macroscopic tumor leftt behind (R-2b).
Off the 117 treated patients, seven (6%) died of treatment related causes. Three of these patients hadd gross incomplete resections (R-2b), the other four had minimal residual disease.
Thee median survival of the entire study population was 21.8 months (CI 19.0 — 25.5). The one-year,, three-year and five-year survival probability was 0.75 (CI 0.65 - 0.82), 0.28 (CI 0.18 - 0.38) andd 0.19 (CI 0.10 - 0.29) respectively.
Figuree 2. Kaplan Meier curve by result of cytoreduction of 117 treated for peritoneal car-cinomatosiss of colorectal origin by cytoreduction plus hyperthermic intraperitoneal che-motherapy y 1.00 0 0.80 0 >-- 0.60 JO O CO O - Q Q O O Q-- 0.40 0.20 0 0.00 0 ~[~[ 1 1 1 1 1 1 1 1 1 1 1 1 1 r 66 12 18 24 30 36 42 48 54 60 66 72 78 84 90 survivall in months
Patientss in whom six or all seven regions were affected had a median survival time of only 11.2 monthss (CI 5.0 - 20.8), while this was 25.5 months (CI 19.7 - 33.4) when less regions were af-fected. .
Thee survival was also strongly correlated with the degree of completeness of the cytoreduction (figuree 2). In patients in whom the cytoreduction was macroscopically complete die median sur-vivalvival was 42.9 months (CI 22.8 - not reached). In this group the one-year, three-year and five-year survivall probability was 0.94 (CI 0.83 - 0.98), 0.56 (CI 0.38 - 0.71) and 0.43 (CI 0.25 - 0.60) respectively.. When there was residual tumor left behind, which was not thicker then 2.5 mm the mediann survival was 17.4 months (CI 12.0 - 20.8). The one-year and three-year survival was 0.66
Tablee 2. Hazard ratios for survival per affected region in 117 patients treated by completee cytoreduction plus hyperthermic intraperitoneal chemotherapy for peri-toneall carcinomatosis
Pelvis s Ileocecal l
Omentumm / transverse colon Smalll bowel / mesentery Subhepaticc space Subphrenicc space left Subphrenicc space right
Hazardd ratio 3.1 1 0.6 6 2.3 3 5.7 7 2.3 3 1.0 0 0.9 9 0.6 6 0.2 2 0.5 5 1.7 7 0.5 5 0.2 2 0.3 3 CII 9 5 % -- 16.6 1.8 8 -- 10.1 -- 23.7 -- 11.2 -- 5.6 -- 3.0
Tablee 3. Hazard ratios for survival per region with residual tumor in 1177 patients after treatment by cytoreduction plus hyperthermic intrap-eritoneall chemotherapy for peritoneal carcinomatosis
Pelvis s Ileocecal l
Omentumm / transverse colon Smalll bowel / mesentery Subhepaticc space Subphrenicc space left Subphrenicc space right
Hazardd ratio 1.4 4 0.7 7 0.8 8 1.1 1 0.7 7 2.2 2 1.5 5 CII 95% 0.66 - 3.0 0.33 - 1.8 0.44 - 1.9 0.44 - 2.7 0.33 - 1.4 0.99 - 5.8 0.77 - 3.4
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(CII 0.49 - 0.79) and 0.09 (CI 0.02 - 0.20). Only one patient survived more then five years. One pa-tient,, who had a gross incomplete cytoreduction survived three years. The median survival was only 5.00 months (CI 2.7 - 9.5) in patients in whom the cytoreduction gross was incomplete.
Inn patients in whom a complete cytoreduction was reached involvement of the small bowel prior too the cytoreduction was related to decreased survival. Hazard ratios per region of patients with completee cytoreduction are shown in table 2. On the other hand, if tumor was left behind in the abdomen,, no specific region dominates the effect on survival. Table 3 provides the hazard ratios forr regions with residual disease.
Discussion n
Inn the past decade, a number of groups have reported on results of cytoreduction with some formm of intraperitoneal chemotherapy. The Sugarbaker-group has been the most productive. They publishedd a paper on 385 patients affected by appendiceal malignancies showing a five-year sur-vivall rate of 30% in 1999.21 In a similar study Loggie et al made a clear distinction between patients whoo had a complete cytoreduction and patients who had an incomplete cytoreduction.10 Patients withh a complete cytoreduction had a median survival of 28 months and those who had an incom-pletee cytoreduction survived median 10 months. A comparable result was found by Shen et al, showingg an improved survival after complete cytoreduction.6 The three-year survival rate in their studyy was 68% for those who underwent a complete cytoreduction versus 2 1 % for die others. In Europe,, Piso et al found a remarkable four-year survival rate of 7 5 % .u Even in incomplete cytore-ducedd patients the four-year survival rate was 40%, whereas after complete cytoreduction this was 90%.. Elias and co-workers concluded from their experience in Paris that a 50% two-year survival couldd be reached9 and the group of Beaujard in Lyon found a median survival of 16 months in pa-tientss who underwent a successful cytoreduction.22 The Roman study of Cavaliere et al showed a two-yearr survival of 61 %.23 At The Netherlands Cancer Institute a median survival of 22 months wass found in a randomized trial comparing cytoreduction plus hyperthermic intraperitoneal che-motherapyy followed by systemic adjuvant chemotherapy to palliative surgery and systemic chemo-therapy.122 In the presented study a median survival of 42.9 months and a five-year survival rate of 4 3 %% was found in patients in whom a complete cytoreduction could be reached.
Selectingg patients for cytoreduction and hyperthermic intraperitoneal chemotherapy is difficult. Inn prospective to survival and to complication rates, it is obvious that the key issue is to select pa-tientss in whom it is feasible to reach a complete cytoreduction. The best information to select these patientss is gathered during the laparotomy in which the diagnosis peritoneal carcinomatosis is made.13-244 It is therefore, of utmost importance that the operative notes provide full details of the proceduree during which the carcinomatosis is found. This means that a description of the findings shouldd be accompanied by an explanation of the attempts made to reach ever)' part of the abdo-men.. A standardized form on which operative findings can be reported would be of help. An ex-amplee of such a form is displayed in figure 3.
Althoughh surgical groups conduct most studies, the studies provide full data on the hyperthermic intraperitoneall chemotherapy itself, while data on the surgery done to reach the cytoreduction is oftenn poorly presented. In the current study, the extent of surgery is given. Unfortunately, we did nott record the extent of the peritoneal stripping. Our data indicate that small bowel and its mesen-teryy is the limiting factor for survival. Once it has been affected and cleared from tumor, it still re-mainss the region, which indicates poor outcome.
Itt is obvious mat the large number of resected organs does not only result in high complication rates,, but will also have impact on the remaining function. McQuellon et al studied quality of live afterr cytoreduction plus hyperthermic intraperitoneal chemodierapy.25-26 They found, however, no longg lasting impairment of the quality of live after cytoreduction plus hyperthermic intraperitoneal chemotherapy.. This probably means that the remaining abdominal function is adequate for a
Figuree 3. Registration form
Registrationn form peritoneal carcinomatosis Namee patient:
Datee of birth: Number: :
Datee diagnosis colorectal cancer: Location colorectal cancer. N u m b e rr affected regions: Proceduress done: Resections: : 1 1 2 2 3 3 4 4 5 5 6 6 7 7 Pelvis s lleo-colic c O m e n t u mm / Transverse colon n
Smalll bowel / Mesentery Subhepatic// Subgastric Subphrenicc left Subphrenicc right
N oo tumor << 2 cm 2 - 55 cm >> 5 cm
Explorationn only / Bypass / Ostomy / Debulking [ complete / incomplete j Stomach h Smalll bowel lleo-colic c Largee bowel Rectum m Peritoneum m Ovaries s Uterus s Remarks: :
Regionn residual tumor:.
Lengthh small bowel not affected : cm Lengthh large bowel not affected : cm Histology: :
Chapterr 9
"normal"" well-being.
Thee question remains which part of the combination treatment "cytoreduction plus hyperthermic intraperitoneall chemotherapy" is effective. From the presented analysis it is clear that a macro-scopicc complete resection (R-l) is a basic necessity for good outcome. Nevertheless, this does not excludee that hyperthermic intraperitoneal chemotherapy is the condition making an R-l resection worthwhile.. A randomized study in which one arm consists of cytoreduction and the other arm of cytoreductionn and hyperthermic intraperitoneal chemotherapy would answer the question if an ele-mentt of the treatment can be left out.
References s
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