distribution of metastases at necrospy in colorectal cancer

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CLIN. EXPL. METASTASIS, 1983, VOr.. 1, XO. 2, 97--101 Distribution of metastases at necrospy in colorectal cancer JONATHAN M. GILBERT+ Department of Surgery, Stoke Mandeville Hospital, Aylesbury, Buckinghamshire, United Kingdom (Received 26 February 1982; accepted 10 March 1982) A series of 372 necropsies on patients with colorectal cancer (CRC) was examined retrospectively. Patients were excluded if the primary tumour was not removed, if the operation was palliative or if death occurred within three months of operation. Only 43 cases remained after these exclusions and of these six died ofintercurrent disease. The 37 remaining patients were all thought to have undergone a curative resection, following which they died with recurrent tumour. They represent the group of patients who might have benefited from adjuvant chemotherapy. The pattern of metastases and the cause of death was examined in these 37 patients. Local recurrence was found more commonly (25 cases, 68 per cent) than hepatic metastases (21 cases, 57 per cent) or metastases at other sites. This finding indicates that excision of the primary tumour must be as complete as possible and that adjuvant therapies must be directed both locally as well as systemically. Introduction Surgery alone fails to cure a significant proportion of patients with colorectal cancer (CRC), even when the primary tumour is resectable. In order to define the reasons for the failure of surgery, the pattern of metastases and the cause of death were examined in those patients who survived resection of the primary tumour, who had no macroscopic evidence of metastases at operation, but who were found to have recurrent tumour at subsequent necropsy. In these patients it is presumed that micrometastases were present at the time of operation, but were clinically undetectable. These are the patients for whom adjuvant chemotherapy would have been appropriate, and the necropsy findings indicate how their treatment might have been improved. Patients and methods The necropsy records at a district general hospital were examined retrospectively for the period 1951-79. All patients in whom a primary tumour of the colon or rectum had been removed and who survived for more than three months and then came to necropsy were included. This excluded patients in whom the primary turnour was not removed and those dying from operative complications. Patients with evidence of metastases at operation who underwent a palliative resection were also excluded. The patients remaining after these exclusions are those in whom the operation was thought to be curative. Patients were only included if the pathology reports were available from both the resected primary and any subsequent tumour resections. The clinical case note8 were examined. t Clinical Research Centre, Watford Road, Harrow, Middlesex, HA1 3UJ, U.K. 0262~)898/83/0102 0097 S02'00 i' 1983 Taylor & Francis l,td

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CLIN. EXPL. METASTASIS, 1983, VOr.. 1, XO. 2, 97--101

D i s t r i b u t i o n o f m e t a s t a s e s at n e c r o s p y i n c o l o r e c t a l c a n c e r

J O N A T H A N M. G I L B E R T +

Department of Surgery, Stoke Mandeville Hospital, Aylesbury, Buckinghamshire, United Kingdom

(Received 26 February 1982; accepted 10 March 1982)

A series of 372 necropsies on patients with colorectal cancer (CRC) was examined retrospectively. Patients were excluded if the primary tumour was not removed, if the operation was palliative or if death occurred within three months of operation. Only 43 cases remained after these exclusions and of these six died ofintercurrent disease. The 37 remaining patients were all thought to have undergone a curative resection, following which they died with recurrent tumour. They represent the group of patients who might have benefited from adjuvant chemotherapy.

The pattern of metastases and the cause of death was examined in these 37 patients. Local recurrence was found more commonly (25 cases, 68 per cent) than hepatic metastases (21 cases, 57 per cent) or metastases at other sites.

This finding indicates that excision of the primary tumour must be as complete as possible and that adjuvant therapies must be directed both locally as well as systemically.

Introduct ion Surgery alone fails to cure a significant p ropor t ion of pat ients with colorectal

cancer (CRC), even when the p r ima ry t u m o u r is resectable. In order to define the reasons for the failure of surgery, the pa t t e rn of metastases and the cause of death were examined in those pa t ients who survived resect ion of the p r i ma r y t umour , who had no macroscopic evidence of metastases at operat ion, b u t who were found to have r ecu r ren t t u m o u r at s u b s e q u e n t necropsy. In these pat ients it is p r e sumed that micrometas tases were presen t at the t ime of operat ion, bu t were cl inical ly unde tec tab le . These are the pat ients for w h o m ad juvan t chemothe rapy would have been appropr ia te , and the necropsy f indings indicate how their t r ea tmen t m i gh t have been improved .

Patients and m e t h o d s T h e necropsy records at a distr ict general hospital were examined ret rospect ively

for the per iod 1951-79. All pa t ients in whom a p r i ma r y t u m o u r of the colon or rec tum had been removed and who survived for more than three m o n t h s and then came to necropsy were inc luded. T h i s excluded pat ients in whom the p r imary tu rnour was no t removed and those dy ing from operat ive compl ica t ions . Pa t ients with evidence of metastases at opera t ion who u n d e r w e n t a pall iat ive resect ion were also excluded. T h e pa t ients r ema in ing after these exclusions are those in w h o m the opera t ion was though t to be curat ive.

Pa t ients were only inc luded if the pathology reports were available from both the resected p r i m a r y and any s u b s e q u e n t t u m o u r resections. T h e clinical case note8 were examined .

t Clinical Research Centre, Watford Road, Harrow, Middlesex, HA1 3UJ, U.K.

0262~)898/83/0102 0097 S02'00 i ' 1983 Taylor & Francis l , td

98 J. M. Gilbert

R e s u l t s During the 29 years reviewed, 372 necropsies were performed on patients with

CRC. In 155 necropsies (42 per cent) no operation had been performed, either because CRC was an incidental finding (41 cases, 11 per cent) or because the patient was too ill from other diseases, or the tumour too far advanced (115 cases, 31 per cent). There had been a palliative operation in 87 cases (23 per cent) and radical surgery (with the intention of cure) had been possible in the remaining 130 (35 per cent). Of these 130 patients, 87 (23 per cent) had come to necropsy within three months of operation. Only the remaining 43 necropsies were in patients who had survived a 'curative' resection of a CRC for three months or more. Six of these died of intercurrent disease without evidence of metastases, leaving 37 patients who died with recurrent turnout. These patients form the basis of this study.

The 37 patients had a mean age at first resection of 65'7 years (median 70, range 37-83) and a mean age at death of 67"2 years (median 70, range 38-84). They survived for an average of 20"8 months from the first operation (median 16, range 3-93) but the majority of patients died within a year of this operation as shown in the figure.

Sixteen of the tumours were in the rectum and the other 21 in the remainder of the colon. Fifteen of the rectal tumours were treated by abdomino-perineal excision and only one by anterior resection. According to the pathological reports, two of the tumours were in Dukes ' group A, 16 in Dukes ' group B and 19 in group C.

Analysis of the site of metastases (table 1) shows that local spread was commonest followed closely by spread to the liver. Analysis by site of primary tumour (table 2) shows that rectal tumours most commonly spread locally whereas those of the more proximal bowel spread most commonly to the liver but almost as frequently to local tissues. The pattern of metastases according to Dukes' grouping is shown in table 3 and it is seen that Dukes ' group B were found to have considerably more local spread than hepatic, and Dukes ' C turnouts mainly hepatic metastases with nearly as much local involvement.

The cause of death in the majority of patients was stated to be broncho- pneumonia, cardiac failure or gastric aspiration, although the majority of these

2C

09

~o

d Z

Survival from Resection of Colorectal Cancer to Post- mortem

/,2

n = 37

[ - - 1 1 '1 2 3 4 5 6 7 8

Years

Survival after resection of colorectal cancer in 37 patients with recurrent tumour at necropsy.

Colorectal cancer; necropsies 99

Local Peritoneal Nodes Liver Lungs Other

25 11 10 21 8 5

Table 1. Pattern of metastases in 37 necropsies.

No. Site Local Peri- Nodes Liver Lung Other toneal

16 Rectum 14 4 3 8 4 4 21 Rectosigmoid

to caecum 11 7 7 13 4 1

Totals 37 25 11 10 21 8 5

Table 2. Pattern of metastases by site of tumour.

No. Dukes' Local Peritoneal Nodes Liver Lung Other Group

2 A 2 1 0 1 0 1 16 B 11 5 3 5 3 1 19 C 12 5 7 15 5 3

Totals 37 25 11 10 21 8 5

Table 3. Pattern of metastases by Dukes' grouping.

pa t ien ts died in a cachetic ca rc inomatous state. On ly a mino r i t y of cases died for reasons which were specifically identif iable and related to their ma l i gna n t state or the i r metastases. Five pa t ients developed bilateral ureter ic obs t ruc t ion , four died from signif icant p u l m o n a r y emboli , and three had such massive hepat ic r ep lacement by secondaries that liver func t ion was compromised .

Discuss ion T h i s s tudy has shown that after resect ion of a CRC, local recurrence is

numer i ca l l y more c o m m o n and cl inically more signif icant than hepatic or other metastases. T h i s f ind ing relates to a selected group of pa t ients that represent the late failures of surgery. By us ing evidence f rom necropsy examinat ion , the in fo rma t ion is more accurate than can be ob ta ined from clinical data alone, a l though the pat ients who come to necropsy are a selected group and only a small p ropor t ion of all those with CRC.

In a clinical series, Morson et al. [6] found evidence for pelvic recurrence in on ly 9"7 per cent of 1596 pa t ients after radical non- res to ra t ive opera t ions on the rec tum. T h i s was based on clinical examina t ion and invest igat ion and the authors concede that "the true incidence isprobably higher". Dis t an t metastases were no t examined in this s tudy, and so the relative f requency of d is tant and local recurrence canno t be judged .

A more accurate result migh t be expected from studies in which clinical examina t ion was combined with the more complete in format ion obta inable from

100 J. M. Gilbert

laparotomy. The results of a programme of planned reoperation showed that local and/or regional lymph node metastases were more common than distant metastases. Local recurrence and regional lymph node metastases are sequential events in a single process and were combined to form a 'locoregional' group. 'Locoregional ' tumour was the only recurrence present in 50 per cent of the long-term failures of surgery and was found as some component in 92 per cent of failures. By contrast distant metastases occurred in isolation (i.e. without locoregional recurrence) in only 7'7 per cent of cases [4].

These studies confirm that CRC is a disease in which local spread is of prime importance and distant metastases usually follow later. This was recognized by Dukes and is the basic precept of the Dukes' classification. Dukes' group D which denotes systemic spread was not even included in the original paper [3] and is a later addition of convenience.

There are several implications from these findings. They emphasize the need for adequate local excision but show that surgery alone is still inadequate. This result was not the result of a trend towards less extensive surgery, as 15 of the 16 patients with rectal lesions had undergone an abdomino-perineal excision, despite which local recurrence occurred in 14 of them.

After local recurrence, the liver was the commonest site for secondaries .Twenty- one of the 37 patients (57 per cent) had metastases in the liver but in only seven cases (19 per cent) was the liver the sole site of disease. This is further evidence that the importance of hepatic metastases has been over-emphasized and contrasts with the much higher incidence of hepatic secondaries in series derived from advanced cases which are incurable at presentation and in whom the primary tumour is still in situ [9].

Only in those necropsy series where an indication is given of which of the patients had undergone surgery is it possible to extract information which may be compared with this series. The Malm6 study [2] included 267 necropsies after operation for cure of a CRC, and of the 207 with residual cancer, 110 (53 per cent) had local recurrence. The frequency of recurrence at other sites is not stated specifically for this group.

Mayo and Schlicke [5] reviewed 334 necropsies on patients with CRC of which only 38 were on patients surviving operation for more than 21 days. Only 18 patients had metastases and these were in the liver in six cases (33 per cent), the nodes in 10 (55 per cent) and 'other sites' in 13 (72 per cent). Taylor 's series [7] consisted of 180 deaths in patients with CRC, the majority of whom had a necropsy. Thir ty-three died of the cancer after operations performed with the hope of cure and 24 of these (72 per cent) were deemed to be due to 'local continuance or recurrence' compared with eight (25 per cent) dying due to liver metastases, although these figures do include peri-operative deaths.

The patients in this series are those in whom surgery alone failed and the pattern of their metastases indicates how the results of treatment might be improved. Firstly, excisional surgery must be as extensive as is reasonable and should include precautions against local dissemination. Further local disease might be prevented by pre-or post-operative radiotherapy where this is anatomically possible. Distant metastases would require treatment by an adjuvant therapy which was systemically effective. I f the chemotherapeutic agent were also a radiosensitizer, an opt imum treatment might be achieved, by giving radiotherapy at the same time as chemotherapy.

Colorectal cancer; necropsies 101

H e p a t i c pe r fu s ion o f d r u g s as p r ac t i c ed by T a y l o r [8] and Ansf ie ld [1] wou ld seem to have some basis in v iew o f the subs tan t i a l inc idence o f hepa t i c metas tases . H o w e v e r , these d r u g s wou ld have to exer t an effect sys t emica l ly as well as in the l iver in o r d e r to m a t e r i a l l y inf luence the course o f the disease, because o f the inc idence o f local r ecu r rence .

Ana lys i s o f the causes o f dea th has shown tha t even when hepa t i c me tas t a ses are presen t , the hepa t i c reserve is such tha t t hey do no t of ten d i r ec t ly cause the actual dea th of the pa t i en t . Pa t i en t s wi th hepa t i c me tas t a ses seem to die with the i r me tas tases ra the r than from t hem. In contras t , local r ecu r rence caused b i la te ra l u re t e r i c o b s t r u c t i o n and the dea th o f five pa t ien ts .

Because the l iver is of ten easi ly p a l p a b l e when metas tases are p resen t , and is r o u t i n e l y and eas i ly inves t iga ted by ve ry sensi t ive me thods , me tas t a s t i c disease o f the l iver is easy to de tec t . Cl in ica l i m p r e s s i o n s are the re fo re d i r ec t ed at the i m p o r t a n c e o f hepa t i c metas tases , and local r ecu r r ence which is d i f f icul t to de tec t c l in ica l ly is p r e s u m e d to be o f lesser i m p o r t a n c e .

T h i s series has d e m o n s t r a t e d the oppos i t e o f the cl inical impres s ion . Loca l r ecu r r ence is m o r e c o m m o n and more i m p o r t a n t than hepa t i c metas tases in pa t i en t s su i tab le for t r e a t m e n t s a d j u v a n t to su rge ry .

Conclusions F o l l o w i n g successful resec t ion o f a CRC, local r ecu r rence is m o r e f r equen t than

hepa t i c or o the r metas tases . I t is also m o r e i m p o r t a n t as a cause o f death , and hepa t ic me tas t a ses ra re ly cause dea th d i rec t ly . T h e s e f indings ind ica te tha t exc is ional su rge ry m i g h t be i m p r o v e d i f c o m b i n e d wi th fu r the r local t h e r a p y and sys t ema t i - cal ly act ive c h e m o t h e r a p y .

Acknowledgments I wou ld like to t hank M r G. J. Hadf ie ld for help, advice and p e r m i s s i o n to r epo r t

on pa t i en t s u n d e r his care. I wou ld also like to thank the late M r R. R. Pryer , M r P. N I c A r t h u r and M r C. J. S m a l l w o o d for p e r m i s s i o n to r e p o r t on the i r pa t i en t s .

References [1] ANSFIELD, F. J., RAMIREZ, G., SKIBBA, J. L., BRYAN, G. T., DAVIES, H. L., and WIRTANEN,

G. W., 1971, Intrahepatic arterial infusion with 5-fluorouracil. Cancer, 28, 1147-1151. [2] BERGE, r . , EKELUND, G., MELLNER, C., PIHL, B., and WENCKERT, A., 1973, Carcinoma of

the colon and rectum in a defined population. Acta Chirurgica Scandinavica Supplementum, 438, 4 5 4 9 .

[3] DUKES, C. E., 1940, Cancer of the rectum: an analysis of 1000 cases. Journal of Pathology and Bacteriology, 50, 527-539.

[4] GI'XDERSOX, L. L., and SosIN, H., 1974, Areas of failure found at reoperation (second or symptomatic look) following "curative surgery" for adenocarcinoma of the rectum. Cancer, 34, 1278-1292.

[5] MAYO, C. W., and SCVlLICKE, C. P., 1942, Carcinoma of the colon and rectum. Surgery, Gynaecology and Obstetrics, 74, 83-91.

[6] MORSON, B. C., VAUGHAN, E. G,, and BUSSEY, H. J. R., 1963, Pelvic recurrence after excision of rectum for carcinoma. British Medical Journal, 13 18.

[7] TAYLOR, F. W., 1962, Cancer of the colon and rectum: A study of routes of metastases and death. Surgery, 52, 305-308.

[8] TAYLOR, I., ROWLING, J., and WEST, C., 1979, Adjuvant cytotoxic liver perfusion for colorectal cancer. British Journal of Surgery, 66, 833-837.

[9] WILLIS, R. A., 1960, In Pathology of Turnouts. Third edition (London: Butterworths), p. 427.