Prognostic factors in carcinoma of the colon and rectum

Prognostic

Factors Colon

EDWARD

12. COPELAND,

in Carcinoma and Rectum

D. MILLER. M.D.. AND Philadelphia, Pennsyhumic~

M.D., LEONARD

From the Harrison Department of Surgical Research, .School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104. This work was supported in part by a Clinical Fellowship of the American Cancer Society

1968

S. JONES,

M.D.,

GENERAL

SURVEY

One thousand eighty-four patients with carcinoma of the colon and rectum treated between 19-ll and 1956 were studied. The disease was most prevalent in the sixth and seventh decade. (Fig. 1.) The majority of the lesions were in the sigmoid and rectum (Fig. 2). locations consistent with those reported by other observers. Seventy-six per cent of the patients

ILBERTSEN

Vol. 116, December

RAYFORD

tients in this group is stated for each parameter investigated.

[l] has pointed out that the apparent improvement in survival from cancer of the colon is related to the use of selected patients in statistical analysis. He reports an absolute five year survival rate of 32 per cent in an analysis of 840 unselected patients with carcinoma of the colon. Welch and Burke [Z] obtained a 38 per cent over-all five year survival rate in a similar group of patients from the New England area. Griffin, Judd, and Gage [3] reported a gross five year survival of 40.1 per cent for a series of patients with cancer of the ascending colon, and Glenn and McSherry [P] arrived at a similar figure (40.2 per cent) for carcinoma of the distal part of the descending colon. In an attempt to further elucidate the absolute five year survival rate for carcinoma of the colon and rectum, all patients with this disease seen at the Hospital of the University of Pennsylvania between 1941 and 1956 were studied. All parameters affecting gross yearly survival were examined. This time interval was chosen for completeness of follow up, and because chemotherapeutic agents, used sparingly throughout this period, can be eliminated as a cause of prolonged survival in any age group. Since carcinoma of the colon affects an older age group, many patients operated upon for cure die before a five year period and have no detectable disease at death. In other series, patients in this category have been handled in various ways. In this study, the number of pa-

G

of the

1. ;Ige distribution of 1,084 patierlts noma ot the colon or rectum

FIG. 2. Location of lesion. 875

with carci-

Copeland, Miller, and Jones

876 TABLE ESTIMATE

OF

CURABILITY

I AT

OPERATION

Status

L-0. of Patients

Per cent of Total

Curable Resectable but not curable Not resectable Not resected for clinical reasons

826 186 26 45

‘76.4 1’7.1 2.4 4.1

had disease which was estimated to be curable at the time of operation. (Table I.) All but 6.5 per cent of the patients underwent resection. One hundred eighty-six patients had palliative resection; results of follow-up in 1’77 patients in this group appears in Table II. One half of these patients died within the first twelve postoperative months and 87 per cent were dead at the end of three years. The 8.4 per cent of patients living at the end of five years did not have any evidence of recurrent disease clinically. It is probable that the tumor tissue thought left behind was inflammatory rather than neoplastic. The operative mortality was 4.0 per cent in those having palliative resection, which compares very favorably with present day mortality figures and with the mortality rate for the entire series (4.4 per cent). Patients who underwent exploration for palliation alone (with procedures including colostomy, side to side bypass, and the like) and who did not have resection had a somewhat less favorable prognosis. (Table II.) SURVIVAL

Figure 3 depicts the over-all five year survival after treatment with respect to anatomic site. These figures are somewhat more encour-

aging than other published results [I]. There has been a recurring debate in the literature concerning the relative effectiveness of abdominoperineal resection versus anterior resection for low-lying lesions. In our series, patients with lesions 5 to 14 cm. from the anus had an especially poor over-all prognosis. The lesions in this area were treated by both technics. The five year survival of those patients with lesions estimated curable, and who were treated by abdominoperineal resection, seemed somewhat better than that of a similar group treated by low anterior resection (Table III), results which conform with the observations of others [4,5]. The gross five year survival for all patients with carcinoma of the colon and rectum was 37.3 per cent. (Table IV.) Ten per cent of the patients were dead with no carcinoma before a five year period had elapsed. One cannot comment on whether recurrent disease would have appeared in these patients had they survived for the five year period. It is probable that the differing five year survival figures published by other observers result from the difference in handling of this category of patient. Five year TABLE SURVIVAL

OF

PATIENTS TIME

Survival

CURABLE

RESECTION

4.0% 53.5% 20.4% 9.0% 3.6% 1.1% 8.4%

7.0% 66.3’% 18.3Yo 5.6% 1.4% 0

FOR

OR

LOW

FIG. 3. Survival five years after treatment according anatomic site.

to

with with with with

no carcinoma carcinoma no carcinoma carcinoma

1.4%

III

PATIENTS

TREATED

Status Alive Alive Dead Dead

THE

Unresectable (Palliative Procedure) (71 patients)

SURVIVAL LESIONS

AT

Resectable but Not Curable (177 patients)

TABLE YEAR

INCURABLE

OF OPERATION

Operative deaths 1-12 mo. l-2 yr. 2-3 yr. 34 yr. 4-5 yr. 5 yr. or more

FIVE

II

THOUGHT

WITH

ESTIMATED

BY ABDOMINOPERINEAL

ANTERIOR

RESECTION

Abdominoperineal Resection

Low Anterior Resection

39.6% 3.8% 9.8% 45.0%

31.6% 1.7% 16.7% 50.0%

The American

Jouvnal of Suvnery

Carcinoma

>IIz,‘CS

Al-

FIVE

YEARS

AFTER

TREATMEST

Estimated Curable (8’6 patients)

Ciross

Survival

( 1,081

patients)

status

of Colon

AI1ivc;no details available .ilivc with no carcinoma Alive with carcinoma Dead with no carcinoma Ikad with carcinoma

TABLE ACCUMlJLATIVE DISTANI‘

TIME

v

OF POSTOPERATIVE

METASTASES ORIGINALLY

‘I’ime

IN

19;

PATIENTS

ESTIMATED

OCCURRENCE WITH

OF

LESIONS

CURABLE

Per cent __-

O-l” mo. l-2 yr. 2-3 yr. 3-4 yr. 4-5 yr. 5 yr. or more

survival for patients with estimated curable lesions was 48.1 per cent. Another 13.9 per cent of these patients died within five years after treatment with no manifestation of recurrent tumor. Only 3.4 per cent of all the patients were alive at five years with proved recurrent carcinoma of the colon. Consequently the disease can recur before the five year period and not be uniformly fatal by this time; this situation, however, is rare. The time of occurrence of later distant metastases in patients originally estimated curable is evaluated in Table V. If recurrent disease is to occur after a curative resection, fully three quarters of the cases will have appeared by the end of three years and 94 per cent by the end of five years. Thus a five year survival is virtually equivalent to a cure in this disease. The liver is the most frequent site of later distant metastases in patients estimated curable, followed by the lung and distant nodes. (Table VI.) Approximately one half of the patients with later distant. metastases have no nodal involvement at the time of the original procedure. However, i5 per cent of the patients with metastatic disease to the brain and vertebral column did have nodal involvement at the original procedure. (Table VI.) A significant Vol. 116,

lhrember

1968

and

Rectum

number oi patients in this bcries fell into a group undergoing an estimated curative qwrdtion Lvhere one margin of the re>ectetl specimen was measured at 1~s than 5 cm. from either or both edges of the tumor. The ensuing suture line recurrence rate was correspontlin~ly high (lS.4 per cent). Xs a result, perhaps, the survival in this group was significantly les\ than in a similar group of patients in whom at least 5 cm. of normal colon was excised proximal and distal to the lesion. (Table VII.) The suture line recurrence rate for the entire series of 1,CKGpatients was 10.1 per cent, essentially confirming Cole’s data [h’]. Welch and Burke [2] believe. that tumors which are highly malignant rapidly produce symptoms and demand urgent care. Those of his patients with long delays between onset of symptoms and treatment had a better prognosis, indicating that these lesions manifested lower malignant potential, and were more ‘I‘ABLE SITE

OF LATER LESIONS

DISTANT

ORIGINALLY

Site

ESTIMATED

Per

TABLE FEAR

LOCAL

FOLLO\V-UP

RESECTION

Status Alive with no carcinoma iZlive with carcinoma Dead with no carcinoma Dead with carcinoma

IN

PATIENTS

WITH

CURABLII

cent

64. ,!I’,;, ‘8.47; 10, “‘,;; Il.37 4 . 1 y:;, 14.2’<, 4.1”;. 11.2”;

Liver Lung \‘ertebral column Bowel Brain Distant no&s Adrenal Carcinomatosis

FIVE

VI

METASTASIS

FOR

DATA

VII IN

LESIOSS

PATIENTS ESTIMATED

Local Resection Margin Greater than 5 cm. (141 patients)

31.1<; 5.7“~c 10.6’:;, 3L’.6C,’ c

CNDERGOING CURABLE

Local Resection Margin Less than .5 cm. (‘_‘OA patients)

878

TIME

Copeland, Miller, and Jones TABLE VIII OF FIRST SYMPTOM TO OPERATION* WITH FIVE YEAR SURVIVAL

CORRELATED

Duration

Status Alive with no carcinoma Alive with carcinoma Dead; no details available Dead with no carcinoma Dead with carcinoma

0 to 5 Months (493 patients)

6 to 12 Months (335 patients)

12 Months or More (152 patients)

3lY0 3 Yc

37% 2%

36% 2%

1%

1%

1%

10% 55%

19% 59%

8% 53Y0

* The median was 5 months.

amenable to surgical cure. A similar pattern was noted in this series, in that 37 per cent of the patients having symptoms for six months or longer survived five years without recurrence, whereas only 31 per cent of those with symptoms existing six months or less were alive without recurrence at the end of a five year period. (Table VIII.) Obviously a purposeful delay in treatment would not increase survival, but it does seem that the innate virulence of the tumor and the resistance of the host are at least as important as “early diagnosis and treatment.” An abdominal mass, obstruction, and anemia have been correlated with a rapidly progressing tumor. The presence of a palpable mass or anemia (symptomatic or asymptomatic) in this series, was not indicative of a poorer prognosis. (Table IX.) Thus a tumor present long enough to produce symptomatic anemia or a mass does not necessarily possess a greater tendency to metastatic spread. Obstructing carcinoma, however, uniformly carried a poor prognosis. (Table IX.) TABLE FIVEYEARSURVIVALCORRELATEDWITHTHEPRESENTINGSIGNS

Status Alive Alive Dead Dead

with with with with

no carcinoma carcinoma no carcinoma carcinoma

Vein invasion, nodal and bowel wall involvement, and pathologic differentiation have a direct effect upon the five year survival of patients with carcinoma of the colon. The resected specimens were examined microscopically for venous invasion by special staining technics (Verhoeff-Van Gieson) in 597 instances. Only 19 per cent of the patients with vein invasion were alive at five years and free of tumor, whereas 40 per cent of those free of vein invasion survived for five years without recurrence. (Table x.) Thus vein invasion, as an isolated phenomenon, carries a poor prognosis, and when correlated with other evidence of local spread, further decreases the chance for a five year cure. The over-all five year survival for patients with no nodal involvement was 51.5 per cent. (Table XI.) Having one node involved reduced the chances of survival to 30.3 per cent, but a further fall in survival rate was not noted until five or more nodes were involved. (Table XI.) Depth of penetration of the bowel wall with or without nodal spread, as delineated by an Astley-Coller classification, is integrally related to prognosis. (Table XII.) Extension of the tumor was most frequently through the muscle of the bowel wall (379 cases), with a five year survival of 43 per cent when no nodes were involved, and 15 per cent when nodal metastasis was present. Similarly, bowel penetration alone was an important FIVE YEAR

SURVIVAL

with with with with

TO VEIN INVASION

Without Vein Invasion (482 patients)

Status Alive Alive Dead Dead

TABLEX RELATED

no carcinoma carcinoma no carcinoma carcinoma

With Vein Invasion (115 patients) 19% 3% 3%

49% 3% 12% 45%

75Yo

Ix AND

SYMPTOMSOFMASS,OBSTRUCTION,ANDANEMIA

Mass (220 patients)

Obstruction (133 patients)

Symptomatic Anemia (115 patients)

Asymptomatic Anemia (197 patients)

33% 2% 3% 57%

21% 3% 13% 63%

35Y0 2% 8% 55%

31% 2% 14% 53%

The American

Jouvnal

of Surgery

Carcinoma of Colon and Rectum

579

TABLE XI CI,RKELATIUS

UF NODAL

INVOLVEMENT

AND

so Nodes Involved (584 patients)

Status

FIVE

YEAR

One Node Involved (112 patients)

SURVIVAL

OF PATIENTS

Two Sodek Involved (68 patients I

WITH

Three Nodes Involved

(40 patients)

CARCINOMA

OF THE

Four Xodes Involved

(‘4 patients)

COLON

Five or More Nodes Involved (ll0 patients)

.klive with no carcinoma &Uive with carcinoma Dead with no carcinoma

rhd

with carcinoma

TABLE BOWEL

WALL

INVOLVEMENT

WITH

Involve-

Status at Five Years Alive; no details available Alive with no carcinoma Alive with carcinoma Dead ; no details available Dead with no carcinoma Dead with carcinoma

ment of Mucosa without Nodes (66 patients) 0

71% 3% 0

2%

6%

AND

WITHOUT

NODAL

0

67%

AS RELATED

15; 6lC;

0 3i% 0

COMMENTS

It seems to us that the gross five year survival rate is the most accurate indicator of the true virulence of carcinoma of the colon and rectum. The absolute five year survival of 1968

METASTASIS

Involvement Involvement Involveinto but not into but not ment of through through Mucosa Muscle Muscle with Nodes without Xodes with Nodes (3 patients) (150 patients / (58 patients)

prognostic factor. Tumors that had penetrated into but not through the muscle carried a 65 per cent five year survival, as compared to 43 per cent when the entire muscular coat was invaded. Well differentiated lesions were relatively rare in this series, but when they occurred, they carried a good prognosis. (Table XIII.) The majority of the well differentiated lesions were confined to the mucosa with no nodal involvement. The more poorly differentiated the lesion, the greater was the correlation with nodal involvement and bowel wall penetration. These lesions generally produced more disturbing symptoms, shortening the time interval between the first onset of symptoms and definitive therapy. Despite this, as indicated previously, the five year survival was relatively poor.

Vol. 116, December

XII

167, ? 18“,

TO FIVE

YEAR

Involvement through Muscle without Nodes (379 patients)

SURVI\-AL

Involvement through Muscle with Nodes (329 patients)

0 48% 5% 0 4icT,(

37.3 per cent in this series is somewhat higher than that reported by Gilbertsen [I] and significantly higher than that reported by Grinnell [7] and Floyd, Stirling, and Cohn (.!?I. The results are consistent with the 38 per cent overall five year survival reported by Welch and TABLE XIII FIVE YEAR SURVIVAL BASED ON THE PATHOLOGIC DIFFERENTIATION OF LESION FOUND AT SURGERY Lesion

Status

Alive with no carcinoma Alive with carcinoma Dead with no carcinoma Dead with carcinoma

Well Differentiated (33 cases)

Moderately U’ell Differentiated (462 cases)

Poorly Diff erentiated (159 cases)

51.54;

39.4:;,

20.1%

6.1%

3.0%

1.3%

15.2%

12.3%

9.4%

27.2%

45.3%

69.2%

880

Copeland, Miller, and Jones

Burke [Z]. The over-all five year survival for each anatomic site was somewhat better than that reported by Gilbertsen [I]. The reason for this apparent improvement resides in the difference in resectability rates between the two series. The resectability rate in our series was 93.5 per cent, whereas during a similar chronologic period (1940-195(J), the resectability rate for patients in Gilbertsen’s series was only 76 per cent. The patients in our series had lesions seemingly more amenable to surgical correction when they first presented themselves for treatment. It is also conceivable that a more aggressive approach to resection may yield a significant increment in survival without a concomitant increase in operative mortality. Often, fixation of these lesions to other structures is on the basis of inflammation rather than neoplasm, giving rise to undue pessimism as to curability [9]. The liver was the most frequent site of later distant metastases in patients with or without local spread at the time of operation. Lymph node involvement, vein invasion, or penetration of the tumor through to the serosa halved the five year survival in patients otherwise operated upon for cure. It is in these patients with tumor spread to the pericolonic fat and mesenteric lymph nodes that the resection for cure by the no-touch isolation technic of Turnbull et al. [IO] has doubled the five year survival for lesions proximal to the rectum. There can be little question that once tumor has invaded venous channels, dissemination by surgical manipulation is likely. Since it is impossible to determine venous invasion, and frequently lymph node involvement, at the time of operation, the no-touch isolation technic appears to be a logical and potentially productive refinement of operative technic. It seems unfortunate, therefore, that it is most difficult to apply notouch principles to lesions of the true rectum, the most common single site of occurrence of carcinoma and the area from which the poorest prognosis may be expected. It seems feasible to us to attempt at least a partial application of the technic for lesions amenable to abdominoperineal resection. Although many patients with rectal carcinoma die of local recurrence and ureteral obstruction, a significant group in our series have died of liver metastases after a seemingly curative procedure. Although tumor embolization through venous channels emptying directly into the systemic circuit is difficult,

if not impossible, to control, it is possible that early ligation of the inferior mesenteric vein at the level of the bifurcation of the inferior mesenteric artery would be an aid in preventing dissemination through the portal system. SUMMARY

The clinical and pathologic findings in 1,084 patients with carcinoma of the colon and rectum have been analyzed. The five year survival for the entire group of patients was 37.3 per cent. The five year survival for patients operated upon for cure was 48.1 per cent. The resectability rate was 93.5 per cent, and the over-all operative mortality 4.4 per cent. If recurrent disease was to occur after curative resection, 94 per cent of the cases appeared by the end of five years. In patients operated upon for cure, sutureline recurrence was high unless 5 cm. or more of normal colon was excised proximal and distal to the lesion. The presence of a palpable mass or symptomatic anemia was not indicative of a poorer prognosis. Vein invasion, nodal involvement, and deep penetration of the bowel wall halved the five year survival in patients operated upon for cure. A plea is made for widespread application of Turnbull’s no-touch isolation technic, and for partial application of it in abdominoperineal resection. REFERENCES

1. GILBERTSEN, V. A. Adenocarcinoma of the large bowel; factors seemingly responsible for unrealistically optimistic appraisals of current curative achievements, and a suggestion for improvement of therapeutic results. J.A.M.A., 174: 1789, 1960. 2. WELCH, C. E. and BURKE, J. F. Carcinoma of the colon and rectum. New England J. Med., 266: 211, 1962. 3. GRIFFIN, G. D. J., JUDD, E. S., and GAGE, R. P. Carcinoma of the right side of the colon: operability, resectability, and survival rates. Ann. SW;., 143: 330, 1656. 4. GLENN. F. and MCSHERRY. C. K. Carcinoma of the distal large bowel: 32 year review of 1,026 cases. Ann. Surg., 163: 838, 1966. 5. GILBERTSEN,V. A. The results of surgical treatment of cancer of the rectum. Surg. Gynec. 6’ Obst., 114: 313, 1962. 6. COLE, W. H. Recurrence in carcinoma of the colon and proximal rectum following resection for carcinoma. Arch. Surg., 65: 264, 1952. The American

Journal o.f Surgery

Carcinoma

Vol. 116, Detemher 1968

of Colon and Rectum

SSI