Results: Median operating theatre time was 5 hours and median blood loss was. 1500 ml .... stage of the primary for this subgroup are displayed in Table 3.
HEPATIC RESECTION FOR METASTASES IN COLORECTAL CARCINOMA (title)
Re se cti on of colore cta l live r m e ta sta se s (short title)
Jean-Luc Jourdan MD Surgical Fellow, The W akefield Clinic for Gas trointes tinal Diseas es, W ellington.
Rebecca Cannan MSc Sc ientific Officer, The W akefield Clinic for Gas trointes tinal Diseas es, W ellington.
Richa rd S tubbs MD FRCS(Eng) FRACS Director, The W akefield Clinic for Gas trointes tinal Diseas es, W ellington.
Correspondence to: Mr Richard S tubbs , Direc tor, The W akefield Clinic for Gastrointes tinal Diseases , Private Bag 7907, W ellington. Phone: 04 381 8110,
Fax: 04 381 8111
Su m m a ry
Aims: To outline the role of liver resec tion in the t r e atm ent of colorectal liver metastases with particular reference to hos pital morbidity, mortality and subs equent survival. Me thods: Seventy m ajo r l iver resec tions were performed in W ellington by t he senior author (RSS) b e t w e e n 1987 and 1997 for colorectal metast ases . Fifty three entailed resection alone with intent to cure, 9 were as s o c iated with additional cryotherapy, and in 8 hepatic arter i a l chem otherapy was subs equently given. Resec tion w a s t h e init ial form of liver treatment in all 70 patient s. P atient s were aged between 29 and 7 6 y e ars with a median of 60.0 years . A ll patients were judged pre-operatively to have tumour confined to a resec table p ortion of the liver. Data was collected prospectively and held in a com p uterised database. Follow-up was available on all patients. Re sul ts: Median operating theatre time was 5 hours and medi a n b l ood loss was 1500 ml (60ml-25litres). Eighty percent of resec tions entailed 4 or more liver segments. Pos t-operative m orbidity occurred in 26 (37.1%) and 30-day mortality was 5.7% . Median hospital stay w a s 1 1 days (2-67). In the 53 patients who underwent resection alone the 3 and 5-year actuarial s u r vi val rates, including the 30-day mortality, were 62.0% and 27.9% r e s p e c t i vely. Duk es stage of the prim ary was the only significant prognost ic factor found in this sub-group of patients (p < 0.05). Conclusions: Resec tion of colorec tal liver metas tas es can ac hieve extension of life and
long-term
survival
in sel e ct ed
patients .
However,
it
remains
a
major
un d e rt ak i ng and is probably bes t performed in units with appropriate expertise and experience.
Ke y w ords: hepatect om y , neoplasms metast asis , outc ome analy sis , prognostic fact ors, s urvival.
Introduction
C olorectal canc er is one of the comm onest canc ers found in western count r i es throughout the W orld. S o m e 5 0 % of those affected will ultimately present with met ast atic diseas e but perhaps because of its unique route of spread via the portal vein the metas tas es will, in many instances , be c onfined to the liver for quite som e period of tim e. Thi s fe at u re distinguis hes c olorectal liver metas tas es from most other ty pes
of
liver metas tas es and provides the rationale for considering
m a nagement by loc al treatment such as resection, c ryotherapy, s elect ive internal radiation therapy or hepatic arterial chem otherapy.
P r o g n osis without ac tive treatment is determined by a number of independen t fact ors including, ext ent of liver invo lvement, grade of primary tumour, presence of ext rahepatic diseas e, m esent eric lymph node s tatus , s erum CEA and age
1
.
Combinations of these independent fact ors define subgroups with medi a n s u r vival tim es varying from 3.8 to 21.3 months. Yet despite som e patient groups s urviving quite long periods of time, death remains the inevi t a b l e outcome and is chiefly related to progression of tum our within the liver its elf. W hile the anatom ical and phys iological basis of liver resec tion has now been well desc ribed
2-7
, the procedure
remains a potentially dangerous one and o p e rative mortality of up to 5-10% c an be ex p e c t e d e ven in spec ialist units. A lthough no randomised studies have ever been p erformed, reported 5-year survival figures of 20-52%
3,8-13
are generally taken t o
indicate the procedure is worthwhile for selected patients.
W hile W orld experience with liver resec tion has grown substantially over the last 15 years, its p ractic e remains confined to a relatively lim ited number of centres in any
o n e country, where interest and expertise has been developed. As a c onsequenc e , the proportion of potential patients so treated remains sm all as does the experience of most individual centres and surgeons. The aim of this report is to emphasiz e the role of liver resec tion, whic h is the only potentially c urative t r e atment for patients with colorectal liver metas tas es, while detaili n g t h e risk s and results of the proc edure in a New Zealand unit spec ialising in the m anagement of liver canc er.
Me thods
The present report is of 70 pati e n t s with colorectal liver metas tas es treated by liver resec tion between April 198 7 a n d Decem ber 1997 by a s ingle s urgeon (RSS). In these patients, resec tion was the initial form of treatment for the liver metas tas es and operations were performed either at W ellington Hospit al o r W akefield Hospital, W ellington. F i ft y three patients received resection alone with curative intent, 9 received resection with as soc iated cryotherapy to resec t io n m argins or residual lesions, and 8 i n vo l ved resection with s ubsequent hepatic artery chemot herapy. This report exam ines the morbidity and the mortality of the surgery in all 70 patients and, the tum our characteristic s and s urvival of the 53 patients whos e t reatment involved liver resec tion alone.
Patients were referred from a n u m ber of sources t hroughout New Zealand. Preoperative evaluation with chest X-ray and CT scan (abdominal ± pelvic) was util is e d to c onfirm localisation of tum our to the liver. Routine ches t CT and bone scans were not performed. All patients were judged fit for surgery a n d w e re aware of the major and potentially dangerous n a ture of the operation. Liver resec tion was undertaken b y est ablished m ethods. W henever possible hilar diss ect ion was performed together with is o l ation of the relevant hepatic vein (prior to division of liver subs tance). Parenchym al division was performed using a mo d ified finger fracture tec hnique with Roberts forceps, during temporary inflow occ lusion.
A detailed prospective database is held on all patients covering aspec t s o f the clinic al and operative
h istory inc luding, pres entation, previous bowel surgery ,
laboratory investigations, details of operative findings, p r o c edures employed, intraoperative and post-operative com plications, and subs equent follow-up. Th e l atter
has been collected in the c ours e of clinical visits performed every 3 - 6 months for the first 18 months and a t variable times thereafter. In some instances follow-up inform a t ion on patients has been obtained by correspondenc e from referring doc tors or phone calls with doctors or patients . M edian follow-up was for a period of 41.6 months (range 6.2 - 131.3). No patient has been lost to follow up.
Survival rates have b e e n e s tim ated using the Kaplan-Meier method. Trial time was calc ulated from the date o f diagnosis of liver lesions. S urvival differences between s u b g r oups have been evaluated by univariate analysis with the log-rank test. A p value of less than 0.05 was taken to indicate statistical significance.
Results
The study g r o u p included 32 fem ales and 38 males aged from 29 to 76 y ears (median 60.0 years). In all but 2 of the 70 patients the liver resection was performed at a separate operation, a m edian of 18.4 months (range 0 - 91.7) after resection of the primary. The extent of the liver resec tion is shown in Tabl e 1 . T h ea t re time, including anaesthet ic t ime, ranged from 160 to 600min (median 300min). E st imat ed intra-operative blood loss rang e d from 60ml to 25 litres (median 1500ml) and led to a transfusion of a median number of 2 units of blood (range 0 - 37) pe r patient for that hos pitalisation. Twenty seven patients (38.6%) required no blood transfusion.
Pos t-operative morbidity of varying degrees of seriousness occurred in 26 patients (37.1% ) and is s hown in Table 2. In many patients the comp l i cat ions were minor and did not affect the duration of hospitalisation. However, a total of 8 patients (11.4% ) did require re-operation for complications within the s ame adm iss ion. Median hos pital s tay was 11 days (range 2-67).
Four patients died within 30 days of surgery, giving a mortality of 5 .7% . The circ ums tanc es leading to death (which have be e n included in the m orbidity figures) were as follows: 1 pulmonary em bolus at 36 hours, 1 cardiac arrest in the contex t of su dden septicaem ia at 10 days , 1 death at 16 day s following severe CVA, and 1 death after hospital disc harge oc c u r ri n g at 29 days , in a patient with non-resolving jaundice (? biliary strict ure) and an acute upper GI bleed at home.
The subgr o u p o f 5 3 patients whose treatment involved resection alone included 22 females and 31 males aged between 29 and 76 y ears (median 61). Site and Dukes’ st age of the primary for this s ubgroup are display ed in Ta b le 3. The patients had
between 1 and 10 met as tas es in the resec ted liver (m edian 1) ranging fro m 2 to 16 cm in size (median 6). In 18 patie n t s the sec ondaries were found sy nchronously with the primary and in 35 they were diagnosed later (metachronous), afte r a median of 24.4 months (range 2 - 89.6).
In these 53 patients the estim ated survival ± standard error (S E ) including the 30day mortality i s 6 2 . 0 ± 1.6% at 3 years and 27.2 ± 2.4% at 5 years (Fig 1a). Five potential predic tors of s u r vi va l were submitted to univariate analysis (Table 4). Of these o n l y t h e original lymph node status showed a significant correlation with su rvival (X2=5. 04, df=1, p < 0.05). The relevant survival curves are displayed in Fig 1 b . Th e e s t i m ated survival ± SE is 76.7 ± 2.6% at 3 years and 41.4 ± 3.6% a t 5 years for patients with negative lym ph nodes, and 49.1 ± 2.4% at 3 years and 0% at 5 years for patients with positive lymph nodes.
Disc uss ion
The known poor prognosis of colorectal liver metas ta ses 1,10,14-16,27 has been a st imulus to develop and promot e safe liver surgery for those in whom the diseas e is solit ary or at least confined to a resectable portion of the liver. Sus tained interest in t h e s u b j ect was first s een in the late 1970s and a number of sm all experiences followed in the literature attesting to the safety of major liver resection 1 0, 17-1 9, and the apparent efficac y of the surg ery , w ith reported five year survival figures ranging from 20 to 52% 3,8-13.
Since the appearance of these reports, W orld experience and i nterest in the area has certainly grown, and although a randomis ed, controlled trial of liver resec tion for solit ary colorectal metas tas es has never been carried out, a cons ensus view is certainly held that the procedure is worthwhile 3,8-13,1 7 , 2 0 , 21. Furthermore, many units employ resection for a limited number of multiple metast ases , providing t h ese can be resected completely 22-24. S ome units, including o ur own, see a place for pall i a t ive debulking of colorectal liver metas tas es, and employ this in selec ted circumstances, often in association with adjuvant treatm ents suc h as c ryotherapy or hepatic artery chemot herapy 25-26. In spite of this increased interest and activity worldwide, the numbers of p a t i e nts being treated in mos t c entres, or by any one surgeon remains relatively s mall an d it is therefore pertinent to ask what is the mortality and morbidity of liver resection performed in these circumstances.
The reported ex perience is of a modes t s eries of liver res e c t io n s for colorectal met ast ases ca rri ed ou t by a s ingle surgeon, with a s pecial interest in the managem ent of hepatobiliary m alignancy . The resec tion policy has
becom e
increasingly aggressive over a number of yea r s a n d t his is reflect ed in the number
and siz e of the tum ours in the resec ted livers, t he extent of the liver resec tions and the ages of th e p atients treated. In the interests of enabling some comparison with o t her published results, 17 patients who underwent hepatic resection but w h o receive d a dditional cryotherapy or arterial chem otherapy have been exc luded from the survival calculations.
The est imat ed 3-year and 5-year survival figures of 61.8% and 27.2% are in keep i n g with other published reports 3,8-13 and compare favourably with the natural history of this dis ease, which y ields figures of 5-15% and 0-1% for the same tim e periods 1,27. Thus not only can a s mall but significant group of patients expec t prolonged survival after liver resec tion, but mos t c an expec t to live longer than if the resec tion had not been perfo rmed. A s reported by m any others 3,10,13,21,28 our experience was that the i n vo lvement of lym ph nodes at the time of primary resec tion was
predictive of survival after liver resection.
Published literature
suggests predictive value for other fact ors such as ; resec tion margin of 1cm 27 - 3 1, no sat ellite l esions 12,32,33 and metachronous secondary diseas e 21,23,32,34 although not a l l report s confirm these findings. A ge, sex, s ite of the prim ary, preoperative CEA levels, number and siz e of met ast ases a n d e x tent of resection are
less
in
question
and
have
not
been
shown
to
affect
survival
3,12,13,21,22,28,35.
Even in ex peri enced s urgical hands, liver resec tion must be regarded as a m ajor undertaking and is as soc iated with appreciable morbidity . If one includes both major and minor morbidity, figures rangi n g fr o m 2 5 to 50% can be found in the lit erature and are known to be influenced by the extent of the resection 8,36. Given that 80% of our procedures were either hemi-hepatec tom ies or e x t e n d ed hepatectom ies, our mobidity of 37.1% is not unreaso n a b le, especially when it is appreciated that
approximately half of this entailed relatively m inor problems w h ich neither affect ed hospital stay, nor threatened life.
Publis hed mortality fi g u res range between 2 and 20% 3,7,10,12,17,22,28. W hile intra-operative mortality i s usually a cons equence of uncontrolled bleeding 37 and should be avoidable, 30-day mortality is re lated to ex tent of resection, s kill of the surgical team, and age and fitnes s of the patient 4,8,17,38,39. It is note w orthy t hat 2 of the 4 deat hs reported in this paper were not direc t l y related to the liver condition (CV A and P E).
W e believe the results ac hieved by this aggress ive s urg ical approach to colorectal liver metas tas es jus tify the polic y. However, the mortality and morbidity of the proc edure, e ve n i n the hands of a relatively ex perienced liver surgeon, point to the advisability of the surgery being undertaken by units wi t h particular interest and experience in the surgical treatment of liver cancer.
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3
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M , et al. Long-term s urvival following
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Fong Y, Cohen A M, F ortner J G , et al Liver resec tion for colorectal met ast ases . J Clin Oncol 1997; 15: 938-46
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13
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14
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16
Jaffe B M, Donegan W L, Watson F , S p ratt J S. Fac tors influencing survival in patients with untreated hepatic metas t as e s . Surg Gy necol Obst et 1968; 127: 1-8.
17
Ads on M A, Van Heerden J A. Major hepatic re s e c t ions for metas tatic colorectal cancer. A nn Surg 1980; 191: 576-83.
18
Fortn e r J G, Silva J S, Cox E B, Golbey R B, Gallowitz H, Maclean B A. Multivariate ana l ysis of a personal series of 247 consecutive patients with liver
metastas e s
from
c olorectal
c ancer:
treatment
by
intrahepatic
chem otherapy. Ann S urg 1984;199: 3017-24. 19
Bengm ark S , H a fs t r om L, Jeppsson B, et al. M etas tatic diseas e in the liver from colorectal canc er: an apprais al of liver surgery . W orld J Surg 1982; 6: 61-5.
20
Bengm ark S, Ek berg H, Tranberg K G. M etas tatic tum ours of t he liver. In: Blum gart L H (ed. ) Surgery of the Liver and Biliary Tract. Edinburgh: Churchill Livingst on, 1988; pp 1179-89.
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Hohenberger P, S chlag P M, Gernet h T, Herfarth C. Pre and postoperative carc inoe mbry onic antigen determinations in hepatic resection for colorectal met ast ases . A nn Surg 1994; 2: 135-143.
22
Rees M, Plant G, and Bygrave S. L a t e results justify resect ion for multiple hepatic met ast ases from colorectal c ancer. B r J Surg 1997; 84: 1136-40
23
L o g a n S E, Meier S J, Ramming K P, Morton D L, Longmire W P. H ep at i c resec tion of metas tatic colorectal carcinoma. A rch Surg 1982; 117: 25-8.
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Fong Y, Bl umgart L H, Cohen A M. S urgical treatm ent of colorectal met ast ases to the liver. Ca Cancer J Clin 1995; 45: 50-62.
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Mc Call J L, Ross W B, M orris D L. Cryotherapy with liver resection for th e treatm ent of liver tumours. Gut 1994; 35 (Suppl 2): S15.
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W agner J S, Ads on M A , V an Heerden J A, A dson M H, Ilstrup D M. The n atural history of hepatic met ast ases from colorectal c ancer; a c ompari s on with respec tive treatment. A nn Surg 1984; 199: 502-7.
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But ler J, At tiy eh F F, Daly J M. Hepatic resection for metas tas es of the colon and rectum . S urg Gynec ol Obstet 1986; 162: 109-13.
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Eckberg H. Colorectal liver cance r: resection and regional chemotherapy. Bulletin 1986 no. 61. Department of Surgery, Lund University , Lund, S weden.
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Fos ter J H, Lundy J. Liver metas tas es. Curr Probl Surg 1981; 18: 157-202.
31
Cady B, Mc Dermott W V. Major hepatic resection
for met achronous
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Sc heele J, Sta n g l R, Altendorf-Hofman A , Gall F P. Indicators of prognosis after liver resec tion for colorectal secondaries. S urgery 1991; 110: 13-29.
33
Ekberg M, Tranberg K G, A ndersson R, et al. Determinants of survival in liver resec tion for colorectal secondaries. Br J Surg 1986; 73: 727-31.
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Hughes K S , S imon R, Sonhorabodi S, et al. Res ect ion of the liver for colorectal carcinoma metastases: a multi-institut i o nal study of indications for resec tion. Surgery 1988; 103: 278-88.
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Table 1 :
Ex tent of liver resec tion
n extended right hepatectomy extended left hepatectomy right hepatectomy
18 3 27
left hepatectomy
7
segmentectomy
14
other
1
Table 2:
Post-operative morbidity seen in 26 patients
Minor
Major
ches t infection
3
post -op bleeding
5 (4)
wound infect ion
2
abdominal s epsis
5 (3)
pleural effusion
3
pulmonary embolus
3
st ress ulcer
2
prolonged bile leak
4 (1)
rapid AF
1
air embolus
1
renal "failure"
2
CVA
1
liver "failure"
3
cardiac arrest
1
( ) Figures in parentheses denote numbers of patients requiring re-operation.
Table 3:
site
Site and stage of init ial primary tumours
n
st age
n
colon
14
Dukes A
1
sigm oid
16
Dukes B
19
7
Dukes C
31
16
unknown
2
recto-s igmoid rectum
Table 4 : Analy sis of potential prognostic fact ors
n
significance
resec tion margin 1 cm
29
no*
num ber of tumours =1
27
>1
26
no*
blood transfusion < 4 units
28
> 4 units
25
no*
negative
20
yes
posit ive
31
(p 0.05
Figure legends
Fig 1: Life table for the patients who received resection alone without as soc iated cryotherapy or subs equent adjuvant chemot herapy: (a) for all patients ; the num ber of patients st ill alive and under obs ervation at entry and annually thereafter were 53, 42, 29, 17, 7, 4, 1; (b) for 2 subgroups of patients acc ording to the lym ph node status at the tim e of primary resect ion; the number of patients st ill alive and under observation at entry and annually thereafter were: 31, 22, 14, 5, 0 for the node positive group (¶) and 20, 19, 14, 11, 6, 4, 1 for the node negative group (®).
