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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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Predictingg the survival of patients with
peritoneall carcinomatosis
off colorectal origin treated by aggressive cytoreduction
andd hyperthermic intraperitoneal chemotherapy
Vicc J. Verwaai
1, Harm van Tinteren
2, Serge van Ruth
1and Frans A.N. Zoetmulder
111
Department of Surgery and
2Department of Biometrics
Thee Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
Amsterdam,, the Netherlands
BackgroundBackground Peritoneal carcinomatosis in the absence of distant metastasis occurs in approximately 8% of patientss with colorectal cancer. Cytoreduction followed by hyperthermic intraperitoneal chemotherapy
(HIPEC)) is a new treatment option. Patient selection is crucial to outcome.
Methods:Methods: Cytoreduction followed by HIPEC was performed in 102 patients with peritoneal carcinomatosis. Thee following factors were studied for association with survival: perforation and obstruction of the primary lesion,, location of the primary lesion, obstruction associated with carcinomatosis, presentation, tumour dif-ferentiationn and histological type. Extent of disease and completeness of cytoreduction were also studied. Hazardd ratios (HRs) were used to study these factors.
Results:Results: Location of the primary tumour in rectum (HR 3.14 (95% confidence interval c.i. 1.11 to 8.91); PP = 0.069), poor differentiation (HR 1.73 (95% c.i. 1.04 to 2.88); P = 0.031) and signet cell histological type (HRR 2.24 (95% c.i. 1.21 to 4.16); P - 0.008) were associated with shorter survival. Important factors predict-ingg survival were the number of affected regions (HR 1.38 (95% c.i. 1.20 to 1.59); P < 0.001), the simplified peritoneall cancer score (HR 1.19 (95% c.i. 1.12 to 1.26); P < 0.001) and completeness of cytoreduction (HRR 8.54 (95% c.i. 4.01 to 18.18); P < 0.001). N o other factor correlated with survival.
Conclusion:Conclusion: The survival of patients with peritoneal carcinomatosis of colorectal origin is dominated by the extentt of disease and the amount of residual tumour after cytoreduction.
Introduction n
Peritoneall carcinomatosis is present in approximately 10% of patients with colorectal cancer at thee time of first diagnosis and in about 25% of patients with recurrent disease.1-3 Although perito-neall carcinomatosis is frequently found in combination with distant metastases, it appears to be the onlyy site of disease in 25-35% of patients, even after extensive diagnostic investigations.4'5 If peri-toneall carcinomatosis is the only site of metastasis, it is considered to be an established regional diseasee rather than a systemic malignancy.6
Effectivee elimination of regional disease may cure some patients with carcinomatosis, and lead to prolongedd survival in others. Sugarbaker and others have pioneered the technique of aggressive cy-toreductionn in combination with hyperthermic intraperitoneal chemotherapy (HIPEC).78
Encouragingg results for this approach have been published in nine studies,7"15 in which the me-diann survival usually exceeded two years with 20—30% of patients living for five years or longer. Similarr survival is rarely observed following systemic chemotherapy alone. A randomized phase III studyy has confirmed this prolonged survival after cytoreduction and HIPEC.1 6
Cytoreductionn with HIPEC is known to carry a considerable risk of serious complications and relatedd death.17 Despite the intensive treatment, a substantial proportion of patients have early
re-currencee and die from the disease without experiencing any benefit. It is therefore important to se-lectt patients who are expected truly to benefit. A prospective database of patients with peritoneal carcinomatosiss who underwent cytoreduction and HIPEC was analysed to identify the factors that predictt long-term survival.
Patientss a n d m e t h o d s
Betweenn November 1995 and October 2002, 102 patients with peritoneal carcinomatosis of colo-rectall origin were treated by cytoreduction and HIPEC at the Netherlands Cancer Institute. As this institutee is a tertiary referral hospital, all but two patients were referred from regional hospitals. The firstt 36 patients were entered into phase I and II studies, the subsequent 48 patients were entered intoo a randomized phase III study, and the remaining 18 were treated afterwards. All patients were treatedd according to the same protocol.
Patientss with histologically proven peritoneal carcinomatosis with no evidence of liver or lung metastasis,, up to the age 70 years and fit to undergo major surgery, were eligible for the protocol. Patientss with either synchronous or metachronous carcinomatosis were eligible. Written informed consentt was required for patients who participated in the trials.
Treatmentt consisted of laparotomy for cytoreduction combined with intraperitoneal chemother-apy,, followed by adjuvant systemic chemotherapy.
CytoreductiveCytoreductive surgery
Thee aim of cytoreduction was to remove all macroscopic tumour. If this was not feasible, efforts weree made to leave no residual tumour deposits thicker than 2.5 mm, as this is the maximum
pre-Chapterr 3
dietedd penetration of intraperitoneal chemotherapy. Peritoneal resection was carried out as de-scribedd by Sugarbaker.18 If rumour had infiltrated the viscera, the affected part was resected. The
greaterr omentum was removed routinely, as were the ovaries in women. Reconstruction of bowel continuityy was always postponed until after intraperitoneal chemotherapy to prevent the entrap-mentt of tumour cells in suture lines.
HyperthermicHyperthermic intraperitoneal chemotherapy
Thee perfusion circuit consisted of a centrally placed inflow catheter, three outflow catheters placedd in the pelvis and below the left and right diaphragm, tubing, a roller pump, a reservoir and a heatt exchanger. Four temperature probes were placed in the abdomen close to the inflow and out-floww catheters. Perfusion was started with three litres of perfusate, at a rate of 1-2 1/min and an in-flowflow temperature of 4 1 ^ 2 ° C . Mitomycin C was added to the perfusate as soon as the temperature inn the abdomen was stable above 40°C at all four probes. In the first procedures performed, the dosee of mitomycin C was increased stepwise from 15 to 35 mg/m2. The dose was limited to a maximumm of 70 mg. The total dose of mitomycin C was given in three divided fractions: 50% ini-tiallyy and 25% after 30 and 60 min. The perfusion fluid was drained from the abdomen after 90 minutes. .
PostoperativePostoperative care
Patientss were managed in the intensive care unit until stable. Evidence of abdominal sepsis was ann indication for relaparotomy. Jejunal tube feeding was started on day one and normal oral nutri-tionn was resumed as soon as possible. During the postoperative period all side-effects were re-corded. .
SystemicSystemic chemotherapy
Thee modified Laufman regimen was used as adjuvant therapy (5-fluorouracil 400 mg/m2 and leu-covorinn 80 mg/m2 weekly).19 Systemic chemotherapy was not started until at least six weeks after
HIPEC,, and was continued for 26 weeks or until tumour progression or unacceptable toxicity had occurred. .
Follow-up Follow-up
Patientss were seen every three months for two years and at 6-month intervals thereafter. Physical examinationn and determination of carcinoembryonic antigen and CA19.9 levels were undertaken at eachh visit. Computed tomography (CT) was performed after three months and repeated every six monthss for three years, then yearly.
DataData collection
Thee following potential prognostic factors were recorded prospectively: sex, age, site of primary lesionn (appendix versus colon versus rectum), histological appearance of the primary lesion (signet celll carcinoma versus non-signet cell carcinoma), tumour differentiation (good or moderate versus poor),, clinical presentation of primary lesion (obstruction versus no obstruction, and perforation versuss no perforation), presentation of carcinomatosis (synchronous versus metachronous), clinical
presentationn of carcinomatosis (obstruction versus no obstruction).
Informationn on the extent of carcinomatosis (primary lesion site versus ovarian metastases versus extensive)) was obtained from the operating notes of the preceding laparotomy.
Thee spread and thickness of tumour was recorded in seven regions: pelvis, right lower abdomen, omentum—transversee colon, small bowel—mesentery, subhepatic space—stomach, right subphrenic spacee and left subphrenic space. For each region a semiquantitative score was allocated by measur-ingg the maximum thickness of the largest nodules (none, 0; less than 20 mm, 1; 20-50 mm, 2; more thann 50 mm, 3). When the nodules were confluent, the maximum thickness of the resulting plaque wass used.
AA simplified peritoneal cancer (SPC) score was designed to calculate tumour load, reflecting the peritoneall spread and tumour thickness, with a maximum score of 21.
Afterr cytoreduction, the residual tumour load in each region was recorded. Residual tumour was categorizedd as: none, 0; less than 2.5 mm, 1; 2.5—20 mm, 2; more than 20 mm, 3. The overall result off cytoreduction was summarized by recording the maximum thickness of any tumour left behind: noo macroscopic tumour, R-l; less than 2.5 mm, R-2a; 2.5 mm or more, R-2b.
StatisticalStatistical analysis
Alll potential prognostic factors were analysed for their impact on survival, which was determined fromm die date of HIPEC until death or date of last follow-up. Patients who were alive at the time off analysis were entered as censored observations. Survival differences between categories were testedd with the log rank test. Continuous variables were tested for linearity and proportionality, and thee relative hazard was calculated by means of Cox proportional regression analysis. In this analysis thee number of affected regions and SPC score were taken as discrete variables. A Cox-based model wass constructed based on all patient and tumour characteristics known directly after exploration of thee abdomen.
Results s
Dataa on 102 consecutive patients were analysed. Sixty patients had synchronous and 42 had metachronouss peritoneal carcinomatosis. There were 44 women and 58 men of median age 53 (rangee 24—75) years. The primary cancer site was the appendix in 15 patients, colon in 78 and rec-tumm in five. In four patients the site of the primary lesion was not detectable owing to a large amountt of tumour in the abdomen. These patients were assumed to have had colonic carcinoma. Thee median follow-up was 41.6 (range 2.7-83.2) mondis and the median survival 19.9 (95% confi-dencee interval c.i. 17.0 to 24.4) months (figure 1).
Thee distribution of tumour as found at exploration of the abdomen is shown in table 1. The
mostt frequendy affected regions were pelvis and omentum—transverse colon. The distribution of thee number of regions affected by carcinomatosis and the SPC scores are given in figures 2 and 3. Theree was a wide variation in tumour load. The distribution of residual tumour following cytore-ductionn is shown in table 2. The small bowel—mesentery and the subhepatic space—stomach were
Chapterr 3
Figuree 1. Kaplan Meier curve of overall survival in 102 patients with perito-neall carcinomatosis of colorectal origin treated by cytoreduction and HIPEC
1.00 0 0.80 0 .& 0.60 !a a 03 3 -Q Q O O Q-- 0.40 0.20 0 0.00--1>> 6 12 18 24 30 36 42 48 54 60 survivall in months
mostt frequently involved. The right lower abdominal region, omentum and pelvis were cleared in almostt all patients.
Univariatee analysis of all potentially prognostic patient and tumour characteristics is given in table 3.. Poor differentiation and signet cell histological type were significandy associated with poor sur-vival.. Both the number of regions and the SPC score were linearly associated with worsening prog-nosiss (Hazard ratio 1.38 (95% c.i. 1.20 to 1.59) and 1.19 (1.12-1.26) respectively). Residual tumour afterr cytoreduction was found to be an even more significant prognostic factor.
Figuree 4 depicts a multivariate analysis of the Hazard ratios of pre-cytoreduction characteristics, andd shows that the number of involved regions was the strongest prognostic factor. In addition, tumourr located in the rectum was also associated with a worse prognosis in the multivariate analy-sis.. In this model the number of affected regions was used, as this is easier to calculate and has a similarr hazard ratio in the univariate analysis.
Fourr factors were included in the final model: location of the primary tumour, tumour differen-tiation,, histological appearance and number of affected regions (linearly fitted). These factors were combinedd to create a prognostic score (PS) by multiplying every coefficient by its corresponding factorr and adding these up:
Tablee 1. T h e seven regions as affected by t u m o u r in 102 patients with peritoneal carcinomato-siss of colorectal origin
Region n Nott affected < 2 cm 2 - 5 cm > 5 cm 00 points 1 point 2 points 3 points
%% of patients in which regionn is affected Pelvis s
Rightt lower abdomen Omenrum/transverse-colon n Smalll bowel/mesentery Subhepatic/stomach h Rightt subphrenic space Leftt subphrenic space
12 2 32 2 15 5 24 4 65 5 65 5 77 7 10 0 21 1 24 4 33 3 14 4 22 2 19 9 41 1 26 6 39 9 33 3 18 8 12 2 12 2 39 9 23 3 29 9 12 2 5 5 3 3 3 3 90 0 70 0 87 7 78 8 37 7 37 7 25 5
Tablee 2. T h e 7 regions as affected with residual t u m o u r after cytoreduction in 102 patients withh peritoneal carcinomatosis of colorectal origin, categorised by thickness
Region n Nott affected < 2.5mm 2.5 - 20mm > 20mm % of patients with thicknesss thickness thickness residual rumour Pelvis s
Rightt lower abdomen Omentum/transversee colon Smalll bowel/mesentery Subhepatic/stomach h Rightt subphrenic Leftt subphrenic 85 5 95 5 87 7 59 9 79 9 81 1 90 0 15 5 6 6 12 2 33 3 14 4 17 7 10 0 1 1 --1 --1 7 7 6 6 1 1 --1 --1 1 1 2 2 3 3 3 3 3 3 2 2 17 7 7 7 15 5 43 3 23 3 21 1 12 2 Figuree 2. Histogram of n u m b e r of affected
re-gionss in 102 patients treated by cytoreduction andd H I P E C
Figuree 3. Histogram of SPC score out-comess in 102 patients treated by cytore-ductionn and H I P E C 25 5 in in i_ _ (1) ) m m D. . CD D n n F F
-> >
!_ _
?0 0 15 5 10 0 5 5 0--00 1 2 3 4 5 6 7 numberr regions 15 5 II 10 Q. .tt 5
3 3 0--- 1 — i — i — i — i — i — i — i — i — i — i — r r 00 2 4 6 8 10 12 14 16 18 20 22 SPCC scoreChapterr 3
Tablee 3. Univariate analysis of prognostic factors for survival in patients with peritoneal tosiss of colorectal origin and treated by cytoreduction and HIPEC
Factor r Age e Sex x Presentationn PC Locationn CRC Malignancyy grade CRC' Histologyy CRC2 Obstructionn at CRC Perforationn at CRC Obstructionn at PC Tumourr extent
Numberr affected regions SPCC score Resultt cyto-reduction Male e Female e Primary y Recurrence e Colon n Appendix x Rectum m Goodd / Moderate Poor r
Nonn signet cell Signett cell N o o Yes s N o o Yes s N o o Yes s Locally y Ovary--Extensive e 0-7 7 1-21 1 Rll (no residual) R-2aa ( < 2.5mm) R-2bb ( > 2.5mm) Number r 102 2 58 8 44 4 60 0 42 2 82 2 15 5 5 5 66 6 27 7 86 6 15 5 59 9 43 3 88 8 14 4 60 0 42 2 52 2 14 4 36 6 102 2 102 2 50 0 37 7 15 5 Mediann Survival (Months) ) 19.9 9 19.6 6 19.9 9 19.2 2 21.4 4 21.6 6 19.2 2 16.0 0 21.6 6 15.6 6 21.4 4 13.0 0 20.8 8 18.6 6 19.9 9 23.7 7 20.8 8 19.7 7 19.2 2 21.6 6 21.9 9 19.9 9 19.9 9 39.0 0 17.4 4 5.0 0 HRR (95% CI) 1.00(0.97-1.02) ) 1.00 0 0.86(0.52-1.44) ) 1.00 0 0.866 (0.52-1.43) 1.00 0 0.933 (0.44-1.96) 3.14(1.11-8.91) ) 1.00 0 1.73(1.04-2.88) ) 1.00 0 2.24(1.21-4.16) ) 1.00 0 1.19(0.72-1.97) ) 1.00 0 0.75(0.34-1.65) ) 1.00 0 1.16(0.70-1.19) ) 1.00 0 0.45(0.19-1.07) ) 0.744 (0.43-1.26) 1.38(1.20-1.59) ) 1.19(1.12-1.26) ) 1.00 0 3.555 (1.93-6.55) 8.54(4.01-18.18) ) carcinoma--pp value 0.989 9 0.569 9 0.573 3 0.069 9 0.031 1 0.008 8 0.489 9 0.473 3 0.564 4 0.145 5 <0.001 1 << 0.001 << 0.001
'dataa of 9 patients missing; 2data of one patient missing,
Figuree 4. Hazard ratio and multilevel confidence bars of prognostic factors of survival known after exploringg the abdominal cavity
Agee - 60:45
Genderr - Female : Male
Locationn - Appendix: Colon
Locationn - Rectum : Colon
0.55 0 _11 I L 2.00 8.0 14.0 _ || i l l l l l l l 0.99 9 0.99 9 0.95 5 0.95 5
Presentationn - Recurrence : Primary
Differentationn - Poor: Good/Moderate
Affectedd regions - 6-7:0-5
Figuree 5. Kaplan Meier curve of survival in peritoneal carcinomatosis of colorectal origin forr each prognostic index group
1.00 0 0.80 0 jg11 0.60 CO O .a a o o o.. 0.40 0.20 0 0.00 0 I I .. . , , H-L L '"\\
^
^
' - I J L . . 1 1 k k '' i —— i i i — 1 1 LL — 1 1 —— PI < = 2.65 -- 2.66<PI<3.34 - P I ^ - 3 3R1 1
1 1 1 1 : : 122 18 24 30 s u r v i v a ll in m o n t h s 36 6Chapterr 3
wheree C (colon) and R (rectum) represent the location of the primary tumour (colon or rectum, 1;; otherwise, 0), D is the grade of malignancy (good or moderate, 1; poor, 2), H is the histological appearancee (signet cell, 2; non signet cell, 1) and Re is the number of affected regions (1-7), This modell was developed on die present data set and should be validated on an independent prospec-tivetive database.
Too visualize the combined effect of the four factors, the study population was divided in three prognosticc index (PI) groups of roughly equal size on the basis of the prognostic score: PI = 1 whenn PS was 2.65 or less; PI = 2 when PS was 2.66—3.34; PI = 3 when PS was 3.35 or more. The correspondingg survival curves are displayed in figure 5.
Discussion n
Theree is now considerable evidence that aggressive cytoreduction combined with HIPEC pro-longss survival and can potentially cure peritoneal carcinomatosis of colorectal origin. This does not necessarilyy mean that all patients suffering from peritoneal carcinomatosis benefit. The results of thiss study, as well as those of odier published series, show high morbidity and mortality rates after treatment.. Progression of cancer occurs in around 30% of patients.20'21 It seems clear that these pa-tientss do not derive a significant benefit from this aggressive approach. To be able to exclude poor candidatess for this treatment it is important to identify characteristics that predict an unfavourable outcome.. This should preferably be done before operation but, if this is impossible, at least at an earlyy stage of the operation, before major resection.
Off the factors known before surgery, only poor differentiation, signet cell histological type and primaryy location in the rectum had an impact on survival. However, some patients with these char-acteristicss were long-term survivors, making it difficult to deny this treatment based solely on these factors. .
Thee most important factors predicting poor outcome proved to be extent of disease found at laparotomyy and die tumour residue remaining after cytoreduction. None of the patients who had sixx or seven involved regions survived for longer than two years. Of course, extent of disease was closelyy related to ability to reach a macroscopically complete or nearly complete cytoreduction. Abilityy to resect tumour is clearly related not only to the number of regions involved, but also to thee anatomical site and the nature of the tumour at that site. For instance, extensive tumour infil-trationn of small bowel mesentery, porta hepatis or pancreas may be technically irresectable, irre-spectivee of involvement elsewhere.
N oo patient with substantial residual tumour (diickness of 2 5 mm or more) after cytoreduction survivedd for long. This appears to confirm that hyperthermic intraperitoneal lavage with mitomycin CC can eliminate only very small deposits of residual tumour. The conclusion seems valid diat pa-tientstients with six or seven involved regions, and those who have technically irresectable disease, shouldd not receive this therapy.
thiss respect is the low sensitivity of CT or magnetic resonance imaging for peritoneal carcinomato-sis.222 Only exploration of the abdomen can provide reliable information on the number of regions involved.. This information is often poorly recorded in the operative notes of previous laparoto-mies.. It would be of great help, and prevent unnecessary laparotomies, if surgeons finding perito-neall carcinomatosis would accurately record the extent of disease over the regions of the abdomen. Portillaa et al. proposed a rather complicated peritoneal cancer index, based on 13 regions and the volumee of tumour per region.23 This index is difficult to use as it is based on division of the
abdo-menn by artificial straight lines that do not easily match with surgical anatomy during exploration of thee abdomen. The seven-region system used in the present study was based on anatomical findings. Thee addition of tumour volume to the number of regions involved, as expressed in the SPC score,, would, theoretically, add predictive value to the count of regions affected. However, this provedd not to be the case, probably due to the fact that volume is not an appropriate prognostic factor.. For instance, a patient with 100 1-mm nodules over seven regions will have a SPC score of seven,, but is unlikely to undergo a complete cytoreduction. By contrast, a patient with a large local recurrencee in the right lower abdomen, large metastases in the ovaries, and a few large nodules in thee omentum will have a SPC score of nine, but is more likely to have a complete cytoreduction. If completenesss of cytoreduction is the ultimate factor determining outcome, it seems likely that the secondd patient will do better, despite a higher SPC score. This emphasizes the point that it is not 'howw much' but 'whether' tumour is left behind. As a result, the question arises as to whether mito-mycinn C actually penetrates tumour nodules or merely kills free-floating tumour cells thereby pre-ventingg reseeding.
Alll four scoring systems — Sugerbaker's peritonealcancer index, the regional number count, the SPCC score and the mathematical model — work well. For practical reasons, a useful scoring system hass to be simple to apply. This study showed that the addition of tumour volume to the scoring doess not give a more predictive hazard ratio. Therefore, the authors have opted to use the most practicall system, the region count.
Fromm the data in this study, a model has been developed to predict the likelihood of survival. Thiss model was built on all factors known at the time of exploration of die abdomen. A model basedd solely on preoperative factors is not very predictive. All of the models described above indi-catee survival when patients with peritoneal carcinomatosis of colorectal origin are treated by cy-toreductionn and HIPEC. They do not predict survival in patients who are treated otherwise, and thuss can be used only to 'deselect' patients for the aggressive treatment.
Explorationn of the abdominal cavity gives the best information for selecting patients for cytore-ductionn and HIPEC, which should be undertaken only when it is judged feasible to achieve a com-pletee resection of all macroscopic tumour, or the maximum thickness of residual tumour nodules is 2.55 mm. Otherwise, the procedure should be aborted. Patients with signet cell histological type, poorr differentiation or rectal location of the primary lesion have a limited survival span, as do pa-tientss with more than five affected regions.
Chapterr 3
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