Surgical management of patients with primary operable colorectal cancer and synchronous liver metastases

Surgical Management of Patients with Primary Operable Colorectal Cancer and Synchronous Liver Metastases Harold J. Wanebo, MD,* New York, New York Christopoulos Semoglou, MD, New York, New York Fadi Attiyeh, MD, New York, New York Maus J. Stearns, Jr, MD, New York, New York

Approximately 10 per cent of the patients in American series who present with primary operable colorectal cancer have associated synchronous liver metastases [I]. The surgical management of these patients varies according to the philosophy and personal experience of individual surgeons, and in some cases reflects the philosophy of a specialized service or institution. The general philosophy of the Rectum and Colon Service at Memorial Hospital has been to perform palliative resection of the primary cancer, as this affords maximal relief from tumor-related symptoms, such as bleeding and obstruction, and permits optimal quality to remaining life. An additional approach in selected patients with solitary liver metastases has been to resect the liver metastases in combination with the primary lesion. The present report analyzes the surgical results in the management of 217 patients who were operated on for primary colorectal cancer and were found at laparotomy to have synchronous liver metastases. Material and Methods The charts of patients with primary rectal colon cancer who were surgically treated between the years 1951 and 1974 at Memorial Hospital were reviewed. There were 217 patients (126 male, 91 female) with synchronous liver metastases demonstrated at the time of primary surgery who were culled from this twenty-four year experience. The mean age was sixty-one years (range, 38 to 85 years). Major signs and symptoms were related to the primary tumor (rectal bleeding, 43 per cent; change in bowel habits, 31 per cent; pain, 27 per cent; abdominal distension, 16 per cent). Approximately 10 to 12 per cent had symptoms and findings possibly related to the liver metastases, that is, weight loss and an abdominal mass. The primary cancer was located in the rectum or rectosigmoid colon in 172 patients

From the Oepartmentof Surgery,MemorialSloan-KetteringCancer Center, New York, New York. Reeented at the Eiieenth AnnualMeeting of the Society for Surgery of the AlimentaryTract, Toronto,Ontario,Canada, May 24-25. 1977. of Swgery, univef5ii ‘Presmltaddressandreprblteprtntrequests:DeparhT of Virginia Medical Center, Charlottesville,Virginia 22901.

Volume 136, January 1978

(77 per cent) and in the right colon in 25 patients (12 per cent). The hepatic and splenic flexures were involved in 20 patients. Although only a limited number had preoperative laboratory studies, 42 per cent of 130 patients had abnormal alkaline phosphatase levels, and 35 per cent of patients with recorded hemoglobin or hematocrit values were anemic. Additional sites of disease or metastases besides the liver were recorded in sixty patients. Ten patients had direct extension of disease to other pelvic (7 patients) or abdominal (3) viscera. Fifty patients had metastases to other sites in the abdomen: adrenal, 3 patients; ovary, 6; omenturn, 10; peritoneum, 19; retroperitoneal nodes, 7; serosa of bowel, 6. Distant sites of metastases included lung in 18 patients, bone in 4, skin and abdominal wall in 3, and multiple sites in 4. The sites and extent of liver metastases are noted in Table I. In forty-eight patients the right lobe only was involved, and in twenty-four patients there was involvement of the left lobe only. The majority of patients had metastases to both lobes. There were fifty patients who had solitary metastases recorded; the remainder had multiple metastases to one or both lobes. Seventy patients had replacement of more than 50 per cent of the liver. Surgical Management of Primary Lesions. Surgical management of the primary lesion was resection in 202 patients. Fifteen patients had laparotomy only or COCOStomy. Most of the resections were sphincter-preserving, although an abdominal perineal resection was done in twenty-six patients and a Hartmann type resection in twelve patients. (Table II.) Colostomy or laparotomy only was performed in patients with extensive intraabdominal disease or obvious end-stage disease. Surgical Management of Liver Metastases. Sixty-three patients underwent liver biopsy, and twenty-seven underwent resection of a solitary liver metastasis (excision only of a small metastasis, 13 patienta; resection of segment or wedge, 10; lobectomy, 4-l right, 3 left). In two patienta resection of more than two metastases was performed. In 125 patients there was no surgical attack or biopsy, but inspection by the surgeon confirmed the presence of liver metastases (ultimately documented by the demise of the patient within a 3 year period). Two patients died postoperatively (1 from hemorrhage in the first 36 hours and the other, 38 days after surgery in the hospital).

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TABLE I

TABLE II

Site and Extent of Liver Metastases Left Lobe

Right Lobe

Patients

Both Lobes

>4 cm

Multlple (number) 2-4 34 Replacement (>50%) Total

3

5

2

18 6

16 1

1

72

7

1

13 1

2 -

48

24

Abdominal perineal resection Anterior resection Anterior resection (Hartmann) Sigmoid resection Lefl hemicolectomy Resection transverse colon Right hemicolectomy Subtotal colectomy Local excision or fulguration

70 145

No Resectionof Primary Laparotomyonly Colostomy

Operative Mortality. The thirty day operative mortality in patients who had palliative resection of their primary cancer was 10 per cent (17 of 175 patients), in patients having resection of the primary cancer and excision or resection of synchronous liver metastases 7 per cent (2 of 27), and in patients having only laparotomy or colostomy 7 per cent (1 of 15). The overall mortality was 9 per cent (20 of 217 patients). The extent of the primary cancer (Dukes’ classification) as determined by routine pathologic examination was available in only 150 of the charts reviewed. There were two patients (1 per cent) classified as Dukes’ A. Twenty-two patients (15 per cent) had invasion through the muscularis propria without nodal metastases (Dukes’ B) and 126 patients (84 per cent) had nodal metastases (Dukes’ C). Although grading was done on many of the patients, it was not consistent enough to warrant evaluation. Survival after Surgery of the Primary Cancer. (Table ZZZ.) There were 197 patients who were

available for follow-up from two to twenty-four years after surgery of the primary lesion (excluding 20 patients who died within 30 days of surgery). The survival was directly related to the extent of liver metastases. The median and mean survivals were TABLE Ill Liver Metastases

Survival after Resection of Primary Cancer Patients 6-11

Sofltary Resected

25

Unresected

18

12-23

Survival (mo) 24-35 36-47

23 92% 15 83%

21 84% 13 72%

17 68% 6 33 %

9 36% 3 17%

149

93 62%

37 25%

10 7%

2 1%

15

4 27%

1 6%

Multiple Unresected

Primary unresected

82

48-59

7 28%

202

Primary Resectlon

Solltary Metastases

(2 cm 2-4 cm

Surgical Management of the Primary Lesions

60

7 26%

26 75 12 35 13 5 32 2 2

15 7 8

seven and nine and a half months, respectively (range 1 to 47 months), in 149 patients who had nonresectable liver metastases. One of these patients survived forty-seven months after resection of the primary cancer and essentially no treatment for the bilobed liver metastases. Survival was much better in eighteen patients who had solitary liver metastases which for various reasons were not resected. The median and mean survivals were each 19 months (range, 4 to 36 months). None of the patients in these two groups survived five years. Survival was significantly better in twenty-five patients with solitary metastases which were resected at the time of the primary surgery (or within a 3 month period in the few staged cases). Seven of twenty-five patients (28 per cent) who underwent resection of a synchronous liver metastasis survived free of disease at five years. The median and mean survivals in this group were thirty-six and fifty-eight months, respectively (range, 3 to 300 months). The comparison between the patients with resected versus nonresected solitary liver metastases cannot be exact because of personal variations in judgment and philosophy at the time of the primary surgery, but the two groups are reasonably matched by age, sex, and the common factor that all had resection of their primary rectal colon cancer. The difference in survival between the patients with resected versus nonresected liver metastases is significant (p CO.001; Fisher exact test). Patients treated by laparotomy or colostomy only did poorly, and only one of fifteen survived one year (this patient died at 13 months). This only attests to the extent of disease found at the time of the laparotomy and reflects the surgeon’s judgment that even a palliative resection was not feasible. Recurrences after Primary Treatment. There were 183 patients who had resection of the primary cancer who were followed until death (or in the case of seven survivors, were free of disease at 5 years).

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There were sixty-five patients who developed recurrence or had progression of liver disease. Twenty-one developed pelvic recurrence and ten had signs of intraabdominal recurrence (masses, ascites, obstruction). Seventeen patients had progressive symptomatic liver disease, which was treated for the most part by radiation. The remaining patients had relatively asymptomatic distant metastases to lung (19 patients), bone and soft tissue (S), and multiple sites (5). Comments

Several factors of prognostic importance have emerged from this review of patients with primary colorectal cancer and synchronous liver metastases. Although the treatment of these patients reflects the philosophy of the surgeons and service involved, there are some differences in treatment that warrant comparison. Patients who have primary cancer limited to the rectocolon and have solitary liver metastases do significantly better than patients with multiple or nonresectable liver metastases. The results of treatment in patients with solitary metastases indicate that of all patients who have had resection of the primary lesion, only those who had resection of the liver metastases had opportunity for long-term cure (28 per cent survived 5 years). There was also a significant difference in the median survivalnineteen months in the nonresected patients versus thirty-six months in those who had resection of the metastases. Although these two treatment groups cannot be exactly matched (not a randomized study), they are similar in type and extent of liver metastases. It appears that the liver metastases are exerting the major influence on survival in our overall material. There was a group of patients with extensive disease who had laparotomy or colostomy only, in whom the surgeon believed palliative resection of the primary lesion was not warranted. These patients had the worst prognosis: only one of fifteen was alive at thirteen months. There are other reports that suggest the primacy of the influence of liver metastases on prognosis compared with other factors such as local extent of disease [2,4,5]. Some reports do point out the prognostic importance of other factors in addition to liver metastases [1,2]. Cady, Monson, and Swinton [I] found that certain factors related to the primary tumor have a significant influence on survival in addition to the presence of liver metastases. These factors included presence of intestinal symptoms, a palpable liver, demonstration of direct extension to other organs, ascites, peritoneal seeding, depth of invasion, and presence of nodal metastases. Overall, they also found that survival was immea-

vohmo 196. JMuary 1978

Cancer and Synchronous Liver Metastases

surably better in patients having resection of the primary cancer than in those who had bypass or laparotomy. They did not compare all of these factors with the extent of liver metastases, however, and one would question whether many of the important prognostic factors they reviewed were just indirect reflections of the extent of liver metastases. Another major factor in this series is the benefit of palliative resection in the presence of synchronous liver metastases [1,4]. This would appear to permit a better quality of life for the patient. Only a relatively small number of patients (10 per cent) developed clinically significant local recurrence in the pelvis. Progression of liver disease in approximately 10 per cent was generally treated with local radiation for additional palliation. The development of distant metastases (that is; lung) in these patients did not appear to be associated with serious clinical symptoms and appeared to be relatively well tolerated compared with the symptoms usually associated with pelvic recurrence or persistence of a nonresected rectal cancer in the pelvis. Although the overall operative mortality in this series was 9 per cent and is much higher than the mortality for resectional colorectal surgery in this institution, it appears to be related in part to the extent of the liver metastases. Seventy of these patients had total liver replacement by metastases). The mortality in other series has ranged from 4.5 per cent [I] to 18 per cent [4] and in general has been more than 9 per cent [1,2,4]. The results of surgical attack on solitary metastases have been reported by several authors [5,6]. Wilson and Adson [5] reported a remarkable series of sixty patients who had resection of hepatic metastases secondary to colorectal cancer. Two-thirds were synchronous metastases. Multiple lesions were removed from twenty patients (none survived 5 years) and solitary metastases were removed from forty patients. Fifteen of thirty-six patients eligible for five year follow-up have survived five years. Only eight of these patients had synchronous lesions removed at the time of primary surgery. In Foster’s review [3] of resected metastases to the liver there was a correlation of survival with the interval between surgery of primary cancer and diagnosis of hepatic metastases. In his series the five year survival after resection of hepatic metastases was 12.5 per cent in patients with synchronous metastases, 22 per cent in those in whom the free interval was less than two years, and 31 per cent in those in whom the interval was more than two years. This most likely is related to the influence of host factors which may

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al

limit extent and growth of such hepatic metastases and thus permit a potentially curative resection of a solitary nodule. An additional factor of comparison of our series with the Mayo Clinic series is that most of the resections of hepatic metastases could be accomplished by simple excision or wedge resection (23 of our 27 cases). A general treatment policy can be formulated from this series. Patients with primary operable colorectal cancer who undergo laparotomy and are found to have synchronous liver metastases should undergo adequate resection of the primary cancer. A sphincter-saving procedure is advised whenever possible. In some patients local excision or possibly fulguration in more advanced cases may be indicated. If the primary disease is resectable for cure and there are solitary hepatic metastases, then excision of these seems warranted. In most cases simple excision or wedge resection is adequate, although a few cases may require lobectomy. In the latter instance judgment regarding personal experience with the procedure, availability of blood, adequate assistance, or informed consent may warrant doing the hepatic resection as a later, staged procedure. The additional questions of the role of systemic chemotherapy or hepatic artery ligation and infusional chemotherapy in these patients is not answered from this review. There are numerous reports of infusional therapy via the hepatic artery [7-101, although there are no concrete data suggesting that this is superior to systemic chemotherapy [8-121. Additional therapy to the liver by radiation is required in some of these patients for palliation of symptoms [13]. Improved follow-up of these patients is currently available by use of serum or plasma CEA [14] and liver enzymes [15] and facilitates evaluation of the above mentioned therapeutic adjuncts.

SUMMARY

The surgical results were analyzed of 217 patients who had undergone operation for primary colorectal cancer and were found to have synchronous liver metastases. It is recommended that patients with primary operable colorectal cancer who are found to have synchronous liver metastases should at least have an adequate resection of the primary lesion. If the primary lesion is resectable for cure and there are solitary hepatic metastases, then excision of these seems warranted. In most cases this can be accomplished by simple excision or wedge resection, although occasional cases may require lobectomy.

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References 1. Cady B, Monson DO, Swinton NW: Survival of patients after colonic resection for carcinoma with simultaneous liver metastases. SurgGynecolObsfet 131: 697, 1970. 2. Jaffe BM, Donegan WL, Watson F, Spratt JS: Factors influencing survival in patients with untreated hepatic metastases. Surg Gynecol Obstet 127: 1, 1968. 3. Foster JA: Survival after liver resection for cancer. Cancer 26: 493.1970. 4. Nielson J, Balslev I, Jensen HE: Carcinoma of the colon with liver m&stases. Acfa Chir Stand 137: 463, 1971. 5. Wilson SM, Adson MA: Surgical treatment of hepatic metastases from colorectal cancers. Arch Surg 111: 330, 1976. 6. Starzl TE, Putnam CW: Surgical approaches to primary and metastatic liver neoplasms. /ntJ Radiat Viol 1: 959, 1976. 7. Almersjo 0, Bengmark S, Rudenstam CM, Hafstrom L, Nilsson LAV: Evaluation of hepatic dearterialization in primary and secondary cancer of the liver. Surgery 124: 5, 1972. 8. Freckman HA: Chemotherapy for metastatic colorectal liver carcinoma by intraaortic infusion. Cancer 28: 1152, 1971. 9. Ansfield FJ, Ramirez G, Skibba JL, Bryan GT, Davis HL, Wirtanen GW: lntrahepatic arterial infusion of !i-ftuorouracil. Cancer28: 1147, 1971. 10. Ramming KP, Sparks FC, Eilber FR, Holmes EC, Morton DL: Hepatic artery ligation and 5-fluorouracil infusion for metastatic colon carcinoma and primary hepatoma. Am J Surg 132: 236, 1976. 11. Ma&man S, Ansfield FJ, Ramirez G, Curreri AR: A second look at the second look operation in colonic cancer after the administration of ftuorouracil. Am J Surg 128: 763, 1974. 12. Hahn RG, Moertet CG, Schutt AJ, Bruckner HW: A double-blind comparison of intensive course 5-fluorouracit by oral vs. intravenous route in the treatment of colorectal carcinoma. Cancer 35: 1031, 1975. 13. Maischeider-Turek M, Kazem I: Palliative irradiation for liver metastases. JAMA 232: 625, 1975. 14. Mackay AM, Pate1 S, Carter S, Stevens U, Laurence DJR, Cooper EH, Neville AM: Role of serial plasma CEA assays in detection of recurrent and metastatic colorectal carcinomas. Br Med J 4: 382, 1974. 15. Almersjo 0, Bengmark S, Hafstrom L: Liver metastases found by follow-up of patients operated on for colorectal cancer. Cancer 37: 145. 1976.

Discussion

James H. Foster (Hartford, CT): Although this study is very impressive for one institution, your numbers are not very large, and I rise to give support to your thesis by adding some recently collected data. In 19’74 I collected information on 126 patients who had liver resection for metastatic colorectal carcinoma. Using these and an additional 109 cases reported in the literature, for a total experience of approximately 230 patients with primaries in the bowel, I studied survival, operative death, and so on. In that experience there was approximately a 6 per cent operative mortality, mostly due to failure to control hemorrhage in the operating room. Surprisingly, there was a 19 per cent five year survival rate in these patients; giving support to the authors’ attitudes about resection. An attempt was made to correlate clinical factors with favorable outcome. ‘rhe larger lesions did not do as well, as might be expected, but the number of metastases (as long as they were in the same lobe), the interval between liver resection and resection of the primary bowel tumor, the

The American Journal of Surgery

Colorectal Cancer and Synchronous

status of the mesenteric lymph nodes, and whether or not the primary tumor was in the cecum, sigmoid, or rectum did not correlate with the five year survival rate of these patients. The extent of liver resection did not correlate either, so that local resection of metastases is probably as effective as major lobectomy, if tumor anatomy allows. No patient with a liver metastasis that was palpable before colon resection survived five years, so that is a very bad sign. I agree with the authors that a surgeon should not give up on a real chance of cure in a patient who has localized liver metastases from colon and rectum. The same cannot be said for resection of liver metastases from other primary sites. The available evidence would speak against resection of liver secondary metastases from stomach, pancreas, breast, melonoma, and lung. Another important factor to consider is the natural history of patients with liver metastases. Did any of the seven patients who lived five years subsequently die of their colon carcinoma? Theodore R. Schrock (San Francisco, CA): Most studies of colorectal cancer report that some patients with distant metastases or locally nonresectable cancer will survive five years. In an ordinary series of this sort, the five year survival rate for patients with Dukes’ D lesions would be 1 or 2 per cent. We have all seen patients with metastases living in apparent harmony with the tumor for many months or even years. The biologic behavior of these cancers is apparently different from the norm. It is possible that the authors’ patients have segregated themselves into two groups. Those with aggressive tumors have very extensive and unremovable liver metastases and are doomed to die of those metastases very soon. Patients with nonaggressive tumors are a different group; they have localized hepatic metastases and are destined to survive for longer periods, perhaps, regardless of how the liver metastases are handled. Since the metastases were removed in these patients, that procedure was credited with the survival. The fundamental and actually unanswerable question is this: Does a small metastatic deposit in the liver represent an early stage in a uniform natural history, or do small, localized metastases reflect a difficult, more benign biologic behavior? Bernard Gardner (Brooklyn, NY): We have a series of patients who have had primary resections of colon cancer. Approximately I50 of these patients were untreated after resection of the colon cancer and had simultaneously bilateral liver metastases. The average survival in that group was eight months. With the adjuvant use of chemotherapy in similar patients we could extend the average survival to approximately sixteen months (this is in approximately sixty patients with simultaneous liver metastases). Using a combination of radiation therapy to the liver with long-term infusion chemotherapy, we were able to extend the survival to twenty months in fifteen patients. None of the patients lived longer than four years when they had this very dire complication of cancer. In my opinion and in the opinion of my coauthors, there is no question that the cure of cancer will depend on removing the cancer at the time of the initial operation. vohuno lS,

Janwy 1878

Liver Metastases

Edgar C. White (Houston, TX): What is your opinion on the necessity of giving therapy in conjunction with lobectomy for a solitary metastasis? William L. Donegan (Milwaukee, WI): My question concerns the comparability of the two groups with the solitary metastasis either resected or nonresected. Were these comparable in size and location in the liver? Blake Cady (Boston, MA): We published a series of more than 300 cases of colon cancer metastatic to the liver some years ago. Patients were followed up without any operation, and the number of patients surviving more than five years (all of them dying of disease) was only about 1 per cent. I would merely back up Doctor Wanebo’s and Doctor Foster’s attempt to be aggressive with these metastatic lesions in selective patients. Harold J. Wanebo (closing): The fact of the natural history and the host resistance that was raised by Doctor Schrock is due consideration. Although it may be possible for a patient to survive up to five years with unresected liver metastasis, this is a very rare event. Doctor Cady mentioned one or two such patients in a series of more than 300. The longest such survivor in our series of 217 patients lived forty-four months. In general, only patients who had resection of liver metastases have enjoyed five year survival. Patients who had resection of metachronous metastasis appeared to survive longer than those with synchronous metastasis, as reported in different series. Doctor Foster has pointed this out, and Wilson and Adson [5] from the Mayo Clinic also demonstrated this-they reported a five year survival of 40 per cent of patients with resected liver metastases from colorectal cancer. However, many of these were patients with metachronous rather than synchronous metastases. Doctor Gardner’s comments are pertinent. Certainly many of our patients had extensive liver metastases that might have benefited from an aggressive therapeutic approach postoperatively, such as infusional chemotherapy. Most of these patients did not have any systematic approach with chemotherapy. The question about chemotherapy is important, and we certainly do not have the answer. Even of the patients who had resection of a solitary metastasis, 70 per cent died from their disease. This would suggest that some aggressive approach with chemotherapy is probably warranted. The question of the comparability of the two groups that had solitary liver metastases is difficult to answer. We tried to match these patients according to age and stage of the lesion. We selected patients who had solitary lesions which appeared to be resectable and which were not associated with any other lesion besides the colon cancer. As far as we could see the groups were reasonably comparable although it would be impossible to have truly comparable groups from our material, anyway. We have relied on Doctor Cady’s series [I] quite heavily. His is one of the largest in the literature of synchronous liver metastases from colorectal cancer. As he mentioned, there were very few survivors without an aggressive approach with liver metastases. a5