JOURNAL

OF SURGICAL

RESEARCH 18, 1-7 (1975)

Rectal Physician’s

and Rectosigmoid Prediction

Carcinoma

:

of Local Recurrence

PETER C. REE, M.D., JAMES E. MARKS, M.D., A. RAHIM MOOSA, MB. ChB., FRCS,* BERNARD LEVIN, M.D., AND CHARLES E. PLATZ, M.D. Department of Radiology, Pathology, Surgery, and Medicine, and the Franklin McLean Memorial Research Institute, University of Chicago, Chicago, Illinois 60637t Submitted for publication July 25, 1974

Cancer of the rectum and rectosigmoid affects 37,000 patients each year in the United States. Abdominoperineal resection is the treatment of choice for lesions at or below the peritoneal reflection. Unfortunately, lO-20% of these patients later develop local recurrence, with concomitant adverse effects on the quality of their life if not on their survival. Little has been done to decrease this high rate of local recurrence. Fear of complications and uncertainty about the efficacy of radiotherapy has drastically limited its use in these patients. In several large series of patients randomized according to preoperative radiation followed by surgery versus surgery alone, it has been found that doses of up to 5000 rad given in eight weeks resulted in no increase in operative complications [l] or mortality [14]. Radiotherapy has been found effective in diminishing the incidence of local recurrence after surgery in carcinoma of the cervix [7], cancers of the head and neck [8], and endometrial carcinoma [3], to name a few. We need to determine whether it can be equally effective in carcinoma of the rectum and rectosigmoid.

Clearly, it would be advisable to irradiate only those patients who are likely to have a local recurrence. Toward this end, several authors have examined the factors that predict local recurrence. Morson [12] and others [4-61 have reported that the stage within Duke’s classification, the amount of local extension, grade of malignancy, mucin production, and level in the rectum were related to the incidence of pelvic recurrence. Morson [I I] has suggested that patients with tumors in the lower and middle third of the rectum who are in Duke’s Class B and C could benefit from postoperative radiotherapy. He noted, retrospectively, for his sample that this group of patients which constituted 58% of the total number studied, had 85% of all pelvic recurrences. If physicians were able to predict postoperatively which patients are likely to have local recurrences, it would be possible to avoid the acute morbidity, time, and expenseof pre- or postoperative irradiation to those patients who do not benefit from it. We examined the ability of some physicians to predict local recurrence in patients with rectal and rectosigmoid carcinoma.

*Address all correspondence to Dr. A. R. Moossa, Department of Surgery, University of Chicago, Chicago, Illinois 60637. toperated by the University of Chicago for the United States Atomic Energy Commission. This work was supported in part by U.S.P.H.S. Cancer Research Grants TO1 CA05204 and IPOl CA 14599. We are grateful to Dr. David B. Skinner for his invaluable help and advice in the preparation of this manuscript.

METHODS Four physicians at The University of Chicago Hospitals and Clinics were selected to make predictions of local recurrence. The group consisted of physicians who would be expected to make decisions about patients with this kind of carcinoma: a gastroenterology oncologist, a pathologist, a general surgeon, and a radiotherapist.

Copyright o 1975by Academic Press, Inc. All rights of reproduction in any form reserved. Printed in the United States.

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One hundred and fourteen patients underwent abdominoperineal resection for cancer of the rectum and rectosigmoid at this institution from 1943through 1972.The records of 94 of these patients could be located. Eleven cases were eliminated because of previous surgical treatment, such as anterior resection; 7 or 8.4% died during the first 30 days after surgery and were also excluded since there was insufficient time for the development of a local recurrence. Two patients who had received postoperative radiotherapy were also excluded. None received preoperative radiotherapy. This left 74 patients who underwent abdominoperineal resection as their initial treatment, had no radiation, and survived more than 30 days. All of these patients were followed until death or for a minimum of two years, so that the majority of recurrences could be detected. It was our intention to duplicate for the four physicians the amount of information which would be available to clinicians at the end of the postoperative period, the time at which additional therapy might be instituted. Copies of reports on the operation, barium enema, surgical pathology, intravenous pyelogram, and proctoscopy were made and submitted to our physicians. The patients’ demographic data and actual outcome were recorded separately from information in the medical charts and from tumor registry records. A local recurrence was judged to have occurred if (I) there was clinical evidence of pain in the perineum, buttocks, groin, leg, or sacrum, or (2) a mass was detected in the vagina, abdominal wall, pelvis, or perineum. The operative report and pathologist’s report were available in every case. The barium enema, intravenous pyelogram, and proctoscopist’s report were available in 84, 32, and 74% of cases, respectively. The physicians were asked to give a yes or no decision as to whether each patient would have a local recurrence. They were instructed to use their clinical judgment; in addition, each was given copies of Morson’s work [ 11, 121

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as a guide. To focus their thinking further on variables that might be related to local recurrence, we asked them to evaluate each patient according to six parameters: grade of malignancy, Duke’s Class, level in rectum, tumor present in resected margin, blood vessel invasion, and lymphatic involvement. The observers worked independently; no joint meetings were held. RESULTS Our cases included 7 1 adenocarcinomas, two squamous cell carcinomas, and one mixed adenosquamous carcinoma. The number of male and female patients was 37 each, and the average age for both sexeswas 60 years. There were 18 local recurrences among the 74 patients surviving the postoperative period, giving an incidence of 24.3%. Twelve of the 18 had tumor masses and 11 noted pain (Table 1). The median time from operation to local recurrence was 9.5 mo, with a range of 2-87 mo. The median time from local recurrence to death was 14 mo, with a range of 2-47 mo. There was considerable variation-from 39 to 68%-among our observers on the percentage of patients for whom they predicted local recurrence (Table 2). Unfortunately, for no observer was the discrimination as to which patients would have a local recurrence significantly better than random. The observers who detected the largest number of recurrences also predicted the largest number (seeTable 2). Local spread, as mentioned in the operative report, tumor in the lymph nodes as indicated by the pathologist’s report, and TABLE 1 Signs and Symptoms of Local Recurrence Location of tumor mass Vaginal Pelvic Perineal Abdominal

No. of cases 5 3 2

wall

2 12

Location of pain Sacral Perineal Buttock Groin Thigh

No. of cases 3 4 2 1 1 11

REE ET AL.: RECTAL AND RECTOSIGMOID

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CARCINOMA

TABLE 2 Prediction and Incidence of Local Recurrence Observer No.

Number of casespredicted to have a local recurrence Percent of total casespredicted to have a local recurrence Number of local recurrences correctly predicted Percent of local recurrences correctly predicted Chi-square

1

2

3

4

41

30

50

29

55%

44%

68%

39%

13

8

14

10

72% 2.72 NSa

44% 0.15 NS

78% 0.88 NS

57% 2.67 NS

Total number of cases-74 Total number of local recurrences-l 8 ‘NS = Not significant.

age below 60 years at time of operation (Table 3) were significantly related to higher local recurrence by the chi-square test (significance level 0.05). In seeking an explanation for the lower incidence of local recurrence in older patients, we compared several parameters in older and younger groups: level in the rectum, grade of malignancy, local spread, and state of the lymph nodes. No difference was found. Survival was also longer in the older than in the younger patients.

Table 4 shows factors that seemed to show a trend to local recurrence, but were not significantly related to it. Lower rectal level of tumors, mucin production, female sex, and Duke’s Class C were associated with a higher incidence of local recurrence. The two patients in Duke’s Class A, and three patients with lesions above the peritoneal reflection (“upper l/3”), had no local recurrence. In Table 5, factors found to be unrelated to local recurrence are listed. These factors

TABLE 3 Factors Significantly Related to Local Recurrence No. of patients

No. with local recurrence

% with local recurrence

Local spread Yes No Total

12 62 74

7 11 18 (x2 = 9.OO;P < 0.01)

58.3 17.7

Involvement of lymph nodes Positive Negative Total

33 37 70

11 5 16 (x2 = 3.88;P < 0.05)

33.3 13.5

Age at time of operation Below 60 yr Above 60 yr Total

31 43 74

12 6 18 (x2 = 5.99; P < 0.02)

38.7 13.9

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TABLE 4 Factors with a Trend to Local Recurrence

Level in rectum Upper l/3 Middle l/3 Lower l/3 Total Mucin production Positive Negative Total Patient’s sex Female Male Total Duke’s Class A B C Total

were (1) extension of tumor through the full thickness of the bowel wall, (2) perforation No. % of the bowel wall by the tumor or by the surof Local with local geon, (3) volume of tumor in resected specpatients recurrence recurrence imen, (4) grade of malignancy, and (5) the range of years when the operation was 3 0 0 performed. For evaluation of the last 15 3 20.0 parameter, the patients were divided ac56 15 26.8 cording to five-year periods (except for the 14 18 first interval), and the incidence of local re(x2 = 0.5580, df= 2; NS) currence in each period was computed. No significant change in local recurrence was 13 4 30.8 noted over the duration of the study. 61 14 22.9 Calculated actuarial survivals are pre74 18 sented in Table 6, and survival curves for (x2 = 0.358; NS) patients with and without local recurrence 31 12 32.4 are shown in Fig. 1. For patients without 37 6 16.2 local recurrence, the five-year survival was 74 18 65% and the ten-year survival 41%. The five(x2 = 2.642;NS) and ten-year survivals for patients with local recurrence were 31 and 8%, respectively. 2 0 0 The overall five- and ten-year survivals were 35 5 14.2 57 and 33’96,respectively. 33 11 33.3 70

16

DISCUSSION Local recurrence rates have remained high at this institution. Our data have shown

(x2 = 0.5704, df = 2; NS)

TABLE 5 Factors Not Related to Local Recurrence No. of patients

No. with local recurrence

% with local recurrence

23

5

21.7

48

12

25.0

71

17 (x2 = 0.0907, df= 2; NS)

Perforation of bowel wall by tumor or surgeon Perforation No perforation Total

14 60 14

3 15 18 (x2 = 0.0786;NS)

Volume of tumor in surgical specimen O-l.0 cm3 1.1-10.0 cm3

1 21

Penetration through bowel wall by tumor Nonpenetrated (Duke’s A, Br, Cl)* Penetrated (Duke’s B2, C2) Total

21.4 25.0

1

100.0

6

28.6

REE ET AL.: RECTAL AND RECTOSIGMOID

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CARCINOMA

TABLE 5 (continued) Factors Not Related to Local Recurrence No. of patients

No. with local recurrence

% with local recurrence

10.1-100.0 cm3 >lOO.l cm3 Total

20 9 51

4 3 15 (x2 = 1.398, df= 3; NS)

20.0 33.3

Grade of malignancy Well differentiated Moderately well differentiated Poorly differentiated Total

28 24 8 60

6

21.4 25.9 12.5

Time of operation 1943-1957 1958-1962 1963-1967 1968-1972 Total

16 18 25 15 14

1

1 14 (x2 = 0.295; df= 2; NS) 2 6 I 3 18 (x2 = 0.617, df= 3; NS)

12.5 33.3 28.0 20.0

that local recurrence is a bad prognostic modes, such as irradiation or chemotherapy, factor, with death often occurring within one should be tested. Morson [lo] reports that a year. The failure of the surgeon to lower the trial of postoperative radiotherapy at St. local recurrence rate during the last few Mark’s Hospital in London, was disdecades may indicate that the current tech- continued because patients did not want the niques have reached their limits. Analysis of additional inconvenience of radiotherapy the operative reports and pathological spec- after major surgery. We have found that this imens indicates that the extent of surgical has not been a problem in cases such as dissection has been very radical over the past gynecological malignancies, which require ten years. Twenty-two of the last 25 patients irradiation after surgery. underwent high ligation of the inferior Local spread of tumor, positive lymph mesenteric artery and extensive aortoiliac nodes, and low age are related to a high inciand pelvic node dissection en bloc with the dence of local recurrence. The higher incimain cancer. Our thesis is that additional therapeutic TABLE 6 Actuarial Survivals % survival Group All patients 18 patients with local recurrence 56 patients without local recurrence Pre-1963 1963-1972

5 yr

10 yr

Median survival (yr)

51

33

6.0

31

8

3.3

6.5 58 55

41 31 29

6.8 5.9 6.1

0

2

4 6 YEARS

6

IO

FIG. 1. Actuarial survival of patients with local recurrence (L.R.) vs those without local recurrence (no L.R.) in rectal and rectosigmoid carcinoma.

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dence in young compared to older patients cannot be accounted for on the basis of longer survival, poorer histology, location, state of nodes, or greater local spread. Perhaps tumors in young patients are biologically more aggressive. The relationship of mutinous tumors, low level in the rectum, and Duke’s Class with an increased incidence of local recurrence has been reported previously, [4-6, 121.The finding that, in our series, females had a higher incidence of local recurrence than males was surprising. On reviewing the types of recurrences in the female patients, we noted that five involved the vagina, This finding would seem to indicate that our surgeons too often attempt to preserve. the vagina. If vaginal recurrences are disregarded (excluded), the male and female recurrence rates are approximately equal. Several unexpected results were found in the group of factors unrelated to local recurrence. One might expect a greater likelihood of seeding due to full-thickness and perforated tumors than due to partial-thickness or nonpenetrating tumors; however, this did not seem to be the case in our patients. It might also be assumed that larger tumors have grown faster or longer than small lesions, and that this would predispose them to be more advanced locally; this was not the case, however, since the local recurrence rate for tumors smaller than 10 cc was as in larger tumors. It has been reported [12] that less well-differentiated tumors have a higher local recurrence rate, but our study failed to demonstrate this fact, perhaps because our sample was too small. The possible effect of local wound infection on the recurrence rate could not be evaluated since none of the patients studied sustained major wound sepsis. Our data showed significantly poorer survival for patients with local recurrence compared to those without. It would be presumptuous to state on the basis of these data that reduction of local recurrence will lead to improved survival in patients with rectal and rectosigmoid carcinoma, because

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we do not know the true cause of death in these patients. If, as in head and neck cancer, the most frequent causeof death was the local recurrence, improved survival would be likely to result from improved local control. On the other hand, if death were most often due to distant metastases, as in lung cancer, survival would not be improved by better local control. Unfortunately, because the available records are inadequate, the true cause of death in many of the cases is unknown. We also do not know whether there was an increased incidence of distant disease in patients with local recurrence. Perhaps patients with rectal and rectosigmoid carcinoma tend to die from distant metastases; in that case, prevention of local recurrence would improve quality, but not the length of life. Some interesting data collected by Floyd and his associates [6] show that early recurrence of many adenocarcinomas of the large bowel tends to be localized-“distant metastases were only responsible for 9 of 41 deaths.” Proof that prevention or treatment of local recurrence leads to improved survival can be obtained only from prospective scientific investigation. Meaningful data on retreatment for recurrence of colorectal cancer are scant for three reasons: (1) the general attitude of doctors is usually one of pessimism, (2) the exact extent of recurrence is rarely evaluated, (3) the adequacy of treatment can often be questioned. Polk and Spratt [13] have advocated a careful follow-up program with a view to early diagnosis of recurrence or persistence of colorectal cancer after primary surgery. The aim is to seek recurrent diseasewhich is sufficiently limited to allow retreatment. We agree with their aggressive approach but feel that the follow-up strategies should be even more stringent in the first postoperative year when all patients should be reexamined at monthly intervals. In our experience, perineal pain may precede detectable recurrence in the perineum or presacral spaceby several months. Anorexia and weight loss are less

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RECTOSIGMOID

CARCINOMA

7

noma. Amer. J. Roentgenology. Rad. Therapy reliable predictors of tumor recurrence. Nucl. Med. 114: 506508,1972. Careful perineal and vaginal examinations 2. Bacon, H. E., and Berkley, J. L. The Rationale of are mandatory at each visit. Sinus tracts re-resection for recurrent cancer of the colon and should be probed and curetted, the material rectum. Diseases Colon Rectum 2: 549-554, 1959. obtained being sent for histology. Needle 3. Beiler, D. D., Schmutz, D. A., and O’Rourke, T. L. Carcinoma of the endometrium: Radiation and surbiopsy is advised for any suspicious area. If gery versus surgery alone. Radiol. 102: 159-1964, the index of suspicion is still high an early 1972. second look laparotomy is recommended. 4. Butcher, H. R. Carcinoma of the rectum-Choice Kiselow et al. [9] have successfully treated between anterior resection and abdominal perineal resection of the rectum. Cancer 28: 204-207,197 1. patients with recurrent cancer after sigmoid 5. Floyd, C. E., Corley, R. G., and Cohn, I., Jr. Local or abdominoperineal resection by total recurrence of carcinoma of the colon and rectum. pelvic exenteration. They record a 30% fiveAmer. J. Surg. 109: 153-159,1965. year survival rate. Bacon and Berkley [2] 6. Gilchrist, R. K., and David, V.,C. A consideration also advocate an aggressive surgical apof pathological factors influencing five-year survival in radical resection of the large bowel and rectum proach to recurrent colorectal neoplasms. for carcinoma. Ann. Surg. 126: 421-435, 1947. Seventy-nine patients with pelvic recurrence were reoperated upon with no death, and 32 7. Guttman, R. Significance of postoperative irradiation in carcinoma of the cervix: A ten-year survey. of these had a curative resection. Twenty Amer. J. Rad. 108: 102-108,197O. patients lived for more than two years, 16 8. Henschke, U. K., Frazell, E. L., Hilaris, B. S., more than three years, and 11 for more than Nickson, J. J., Tollefsen, H. S., and Strong, E. W. Value of preoperative X-ray therapy as an adjunct five years. to radical neck dissection. Radiology 86: 450-543, Since we have demonstrated that phy1966. sicians are not able to predict the cases of 9. Kiselow, M., Bricker, H. R., and Butcher, E. M. rectal and rectosigmoid carcinoma in which Results of radical surgical treatment of advanced local recurrences will appear, we suggest the pelvic cancer. Ann. Surg. 166: 428-434, 1967. following alternative strategy. All such 10. Morson, B. C. Personal communication. patients, except those with lesions in Duke’s 11. Morson, B. C., and Bussey, H. J. R. Surgical pathology of rectal cancer in relation to adjuvant Class A and those with lesions located above radiotherapy. Brit. J. Rad. 40: 161-165, 1967. the peritoneal reflection, be subjected to a 12. Morson, B. C., Vaughan, E. G., and Bussey, controlled trial of postoperative radioH. J. R. Pelvic recurrence after excision of rectum therapy. Careful follow-up examinations and for carcinoma. Brit. Med. J. 2: 13-18, 1963. early retreatment may well show that the 13. Polk, H. C., and Sprat& J. S. Recurrent colorectal gloomy prognosis for recurrent colorectal carcinoma: Detection, treatment and other cancer is not warranted. considerations. Surgery 69: 9-23, 1971.

REFERENCES 1. Alien, C. V., and Fletcher, W. S. A Pilot study on preoperative irradiation of rectosigmoid carci-

14. Roswit, B., Higgins, G. A., and Keehn, R. J. A con-

trolled study of preoperative irradiation in cancer of the sigmoid colon and rectum. Radiology 97: 133140, 1970.