new surgical treatments for recurrent colorectal cancer

8
New Surgical Treatments for Recurrent Colorectal Cancer GLENN STEELE JR, MD, PHD, T. S. RAVIKUMAR, MD, AND PETER N. BENOTTI, MD Currently, only two areas of recurrence in patients with colorectal cancer are potentially surgically curable: isolated liver and isolated lung metastases. Regional recurrence from rectal cancer, although probably not resectable for cure, offers an appropriate palliative goal because symptoms in such patients are in- tolerable. We review several new diagnostic and therapeutic techniques that have allowed wider application of surgical approaches for cure or palliation in patients with recurrent colorectal cancer. Cancer 65:723-730, 1990. URING THE PAST FOUR decades there has been no D change in the 5-year survival of patients with colon and rectum carcinoma. Of the 140,000 new cases of pri- mary colon and rectum carcinoma diagnosed in 1988, 67,000 patients will die. The most effective treatment is surgical removal of the primary tumor, and the most ef- fective time to test multimodality therapy is when primary tumor treatment is performed. Several exciting new ad- juvant protocol results in colon and rectum carcinoma may foreshadow increasing survival rate in high-risk pri- mary disease patients who are treated with surgery and adjuvant chemotherapy or chemo/radiotherapy. Nev- ertheless, at present approximately 50% of all colorectal cancer patients will die within 5 years of their diagnosis. Eighty percent of patients destined to experience recur- rences will do so within the first 2 years after what ap- peared to be adequate primary tumor therapy. Half will have recurrences distantly and half will have recurrences regionally. Treatment for recurrent colon and rectum adenocar- cinoma is limited by the lack of effective systemic che- motherapy. Treatment is further limited by the lack of any curative regional chemotherapy for recurrent colo- rectal carcinoma. We have, therefore, investigated the ap- plication of surgical therapy or multimodality therapy for a select group of patients with isolated regional or distant tumor recurrence after adequate primary colorectal cancer excision. In this article we summarize our selection cri- teria, report on the application of conventional and new Presented at the National Conference on Advances in Cancer Man- From the Department of Surgery, New England Deaconess Hospital. Supported by National Cancer Institute Grant POlCA44704. Address for reprints: Glenn Steele, Jr, MD, PhD, 110 Francis Street, Accepted for publication June 15, 1989. agement, Los Angeles, California, December 7-9, 1988. Harvard Medical School, Boston, Massachusetts. Suite 3A, Boston, MA 022 15. surgical techniques, and describe methods to decrease the morbidity of extensive regional surgery for such patients. Numerous retrospective reviews have investigated which patients with recurrent colorectal carcinoma can be cured surgically. In only two categories is resection justified. Patients with isolated pulmonary metastases or liver metastases fall into one category, whereas patients with isolated local or regional recurrence fall into a second category. Only in the former group has cure been docu- mented. However, even in the most highly selected pa- tients with liver or lung metastases, no more than 20% to 30% are cured by complete surgical resection.’ In patients with regional recurrence (usually after unsuccessful low anterior or abdominoperineal resection for rectal carci- nomas), numerous investigations of surgical “salvage” have not shown surgery to be effective in effecting a cure, but have demonstrated significant operative morbidity.2 Until recently, therefore, little justification for exenterative reexcision has existed. Our justification for approaching these two categories of patients and our preliminary results are presented. Liver Metastases from Colorectal Carcinoma In 1978 Welch and Donaldson reviewed their patients with documented recurrence of colon and rectum carci- noma. In only 10% to 12% of patients, primarily those with isolated liver or lung metastases, could resection be justified as “c~rative.”~ Numerous follow-up studies, starting with the original Wangensteen second-look sur- gery series of the late 1940s and early 1950s and reviewed in 1974 by Gunderson and S ~ s i n , ~ showed the same lim- ited results and extended the indications for curative re- section of recurrence to only a very few patients with iso- lated regional recurrences, particularly from distal sigmoid and rectal carcinoma. Recent study of carcinoembryonic antigen (CEA)-ini- tiated second-look surgery again focused surgery on sal- 723

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New Surgical Treatments for Recurrent Colorectal Cancer

GLENN STEELE JR, MD, PHD, T. S. RAVIKUMAR, MD, AND PETER N. BENOTTI, MD

Currently, only two areas of recurrence in patients with colorectal cancer are potentially surgically curable: isolated liver and isolated lung metastases. Regional recurrence from rectal cancer, although probably not resectable for cure, offers an appropriate palliative goal because symptoms in such patients are in- tolerable. We review several new diagnostic and therapeutic techniques that have allowed wider application of surgical approaches for cure or palliation in patients with recurrent colorectal cancer.

Cancer 65:723-730, 1990.

URING THE PAST FOUR decades there has been no D change in the 5-year survival of patients with colon and rectum carcinoma. Of the 140,000 new cases of pri- mary colon and rectum carcinoma diagnosed in 1988, 67,000 patients will die. The most effective treatment is surgical removal of the primary tumor, and the most ef- fective time to test multimodality therapy is when primary tumor treatment is performed. Several exciting new ad- juvant protocol results in colon and rectum carcinoma may foreshadow increasing survival rate in high-risk pri- mary disease patients who are treated with surgery and adjuvant chemotherapy or chemo/radiotherapy. Nev- ertheless, at present approximately 50% of all colorectal cancer patients will die within 5 years of their diagnosis. Eighty percent of patients destined to experience recur- rences will do so within the first 2 years after what ap- peared to be adequate primary tumor therapy. Half will have recurrences distantly and half will have recurrences regionally.

Treatment for recurrent colon and rectum adenocar- cinoma is limited by the lack of effective systemic che- motherapy. Treatment is further limited by the lack of any curative regional chemotherapy for recurrent colo- rectal carcinoma. We have, therefore, investigated the ap- plication of surgical therapy or multimodality therapy for a select group of patients with isolated regional or distant tumor recurrence after adequate primary colorectal cancer excision. In this article we summarize our selection cri- teria, report on the application of conventional and new

Presented at the National Conference on Advances in Cancer Man-

From the Department of Surgery, New England Deaconess Hospital.

Supported by National Cancer Institute Grant POlCA44704. Address for reprints: Glenn Steele, Jr, MD, PhD, 110 Francis Street,

Accepted for publication June 15, 1989.

agement, Los Angeles, California, December 7-9, 1988.

Harvard Medical School, Boston, Massachusetts.

Suite 3A, Boston, MA 022 15.

surgical techniques, and describe methods to decrease the morbidity of extensive regional surgery for such patients.

Numerous retrospective reviews have investigated which patients with recurrent colorectal carcinoma can be cured surgically. In only two categories is resection justified. Patients with isolated pulmonary metastases or liver metastases fall into one category, whereas patients with isolated local or regional recurrence fall into a second category. Only in the former group has cure been docu- mented. However, even in the most highly selected pa- tients with liver or lung metastases, no more than 20% to 30% are cured by complete surgical resection.’ In patients with regional recurrence (usually after unsuccessful low anterior or abdominoperineal resection for rectal carci- nomas), numerous investigations of surgical “salvage” have not shown surgery to be effective in effecting a cure, but have demonstrated significant operative morbidity.2 Until recently, therefore, little justification for exenterative reexcision has existed. Our justification for approaching these two categories of patients and our preliminary results are presented.

Liver Metastases from Colorectal Carcinoma

In 1978 Welch and Donaldson reviewed their patients with documented recurrence of colon and rectum carci- noma. In only 10% to 12% of patients, primarily those with isolated liver or lung metastases, could resection be justified as “c~ra t ive .”~ Numerous follow-up studies, starting with the original Wangensteen second-look sur- gery series of the late 1940s and early 1950s and reviewed in 1974 by Gunderson and S ~ s i n , ~ showed the same lim- ited results and extended the indications for curative re- section of recurrence to only a very few patients with iso- lated regional recurrences, particularly from distal sigmoid and rectal carcinoma.

Recent study of carcinoembryonic antigen (CEA)-ini- tiated second-look surgery again focused surgery on sal-

723

Vol. 65 724 CANCER February 1 Supplement 1990

vaging patients with recurrent colorectal carcinoma. As in earlier studies, patients with a chance for disease-free survival after surgery were those with liver only recurrence, particularly when the liver metastasis was diagnosed long after the primary tumor, when the liver recurrence was unaccompanied by symptoms, when the tumor could be removed completely by the surgeon, and when the disease seen in the liver did not foreshadow distant failure. Even in this best subset of patients, only 50% in the more highly selected series' and 20% to 25% from the larger less biased studies were shown to be alive 5 years after surgery.' There is no question that most patients alive 5 years after surgery will also be alive 10 years after surgery. This is encouraging because there are no alternative therapeutic approaches; however, one must examine just how select this subset of cured patients is. Approximately 70,000 deaths from colon and rectum carcinoma occur each year. Sixty percent to 70% of these patients will die with the liver as a part of their pattern of failure.6 Although one might think that many such patients would be amenable to surgical resec- tion of liver metastases, an important determinant of any regional therapy is the timing of liver metastases. As shown in several of the recently completed adjuvant colon and rectum treatment protocol^,'^^ only 12% to 15% of patients who fail after resection of high risk colon and rectum carcinoma will fail first or predominantly in the liver. An additional exclusion occurs when one examines how many patients have liver metastases that can be removed. Those patients with more than three liver metastases have a high probability of additional tumor in the portal watershed, in other areas of the liver, and elsewhere in distant sites. They should not undergo major resection, because they are likely to fail shortly from regional or systemic disease recurrence.' If one further selects only those patients whose three or fewer liver metastases are technically re- sectable, and who have no comorbid disease, probably only 3000 to 4000 potential candidates for surgery will be found each year. Because the mortality of a major liver resection was reported as 3% to 10% in a recent series" and the outcome was 25% to 30% for 5- and 10-year dis- ease-free survival, very few patients are truly benefited by this approach.

An important but unanswerable consideration is whether the selection process outlined above defines a group of patients with good biology no matter what ther- apy is offered. The exact impact of surgery will remain unknown because no surgeon would consent to randomly denying patients resection once resectable disease was found in the liver at operation. However, neither natural history data nor alternative therapy approaches in such patients have shown a plateau in survival curves. There- fore, it must be assumed that some patients are benefited by surgery and are, in fact, cured.

Our justification for using intraoperative ultrasound

monitoring of hepatic cryosurgery is to attempt applica- tion of regional therapy to a wider group of patients with liver only, nonresectable colorectal carcinoma metastases.

A major limitation in our staging of patients who have liver metastases is the inadequacy of our preoperative di- agnostic imaging techniques. Despite the addition of magnetic resonance imaging (MRI), external ultrasound, and refinements in computed tomography (CT) scanning, resolution threshold for liver metastases remains 1 cm at best and considerably larger in the left lobe. One third of the patients on whom we operate expecting to perform liver resection are found at surgery to have previously undiagnosed additional liver lesions or previously undi- agnosed extrahepatic metastases that obviate resection. Routine application of intraoperative ultrasound has in- creased the number of patients in whom we found pre- viously unsuspected liver nodules. Resolution thresholds for lesions of 3 to 5 mm can now be achieved, even in the left lobe of the liver. Recent studies from our own group and from others suggested that intraoperative ul- trasound should be a part of staging at the time of primary tumor resection. Because benefit from treatment of these small liver metastases (once found) remains unproven, there is no therapeutic imperative to such intraoperative ultrasound staging at present. The main justification would be, therefore, to establish better natural history data.

We applied intraoperative ultrasound for three reasons. First, it gives us better staging. This allows for more ra- tional selection of patients for resection of liver metastases. Better selection of patients with limited liver only disease will affect patterns of failure after resection. Because the resolution capacity for diagnosing smaller, insidious met- astatic disease in the liver will be increased, failure in the residual liver after resecting the sentinal liver metastasis should decrease. The intraoperative ultrasound increased our capacity to diagnose liver metastases (Table 1). U1- trasound is performed after initial freeing of the liver from its diaphragmatic attachments. The sterile transducer is moved over the entire anterior and posterior surface of the right and the left lobe including lateral and medial segments of the liver. In patients found to have small lesions deep within the liver parenchyma, needle place- ment for biopsy can be guided by the intraoperative ul- trasound. More rational decisions concerning resection as opposed to systemic therapy can then be made.

TABLE 1. Preoperative Imaging of the Liver versus Intraoperative Ultrasound (IOUS)

Preoperative

Variable IOUS US CT Angiogram

Patients 54 54 48 35 Lesions 167 1271167 91/150 561107

(76%) (6 190) (52%)

No. 3 NEW SURGICAL TREATMENTS Steele et al. 725

A second important application of the intraoperative ultrasound is to define the anatomy of the liver and the tumor to be resected. It is no longer necessary to estimate contiguity between a large liver metastasis in the right lobe of the liver and the vena cava, or possible involvement of the right hepatic vein as it leaves the vena cava, or possible extension of the tumor across the midline in- cluding the middle hepatic vein. Previously, these surgical speculations often resulted in a frantic hepatic parenchy- mal transection as the surgeon neared the vena cava. With intraoperative ultrasound the precise relationship between the tumor and adjacent structures at the base of the liver are apparent before hepatic transection (Fig. 1).

The third reason for applying intraoperative ultrasound is to monitor the placement of probes that deliver liquid nitrogen and to monitor the adequacy of the freezing margin. Our development of cryosurgical ablation oc- curred in three phases.

First, five patients with metastatic colon carcinoma to the liver were studied to explore the safety of cryoablation, to evaluate the ability of intraoperative ultrasound to de- tect occult liver metastases, to monitor the freezing pro- cess, and to obtain clinicopathologic correlation of frozen tumor and normal liver. In this early phase, all patients had resectable disease by the usual criteria. Their lesions were frozen and then resected by standard operative tech- nique. Tumors and adjacent normal liver were examined to determine the adequacy of intraoperative ultrasound prediction of margins and the overall safety of the tech- nique.

In the second phase of clinical application, patients with metastatic liver tumors underwent cryoablation and their lesions were left in situ and followed. This second group of patients was chosen for one of several reasons. Either they had more than three liver metastases or they had

FIG. 1. Intraoperative photograph to show placement of 8-mm trocar

significant comorbid disease we believe ruled out any ma- jor hepatic resection. At this writing, a third group of pa- tients is being treated with cryosurgical ablation as a sub- stitute for resection. These patients earlier would have been considered good candidates for surgical removal of liver-only metastases.

All patients underwent preoperative studies to exclude extrahepatic disease. Routine staging now includes CT of the chest and abdomen, external ultrasound, and MRI. Hepatic angiography was obtained only if resection was contemplated and only to define the arterial anatomy.

Typically, a right subcostal incision was used. Explo- ration of the peritoneal cavity was carried out to rule out extrahepatic disease not previously suspected on the basis of the preoperative staging. All ligamentous attachments to the liver were released. An intraoperative Ultrasound unit (OR330 Technicare, Johnson and Johnson, New Brunswick, NJ) was used to obtain real-time ultrasound scan of the entire liver. An array of trocar and disc probes for hepatic cryoablation were available for use. Trocar probes of 8 to 12 mm are commonly used. Either a Fri- gitronic Inc. or an ERBE (Tubigen, Germany) cryosurgical delivery system is used. These units circulate liquid ni- trogen to the probe at - 196°C. Freezing was accomplished by placing the probe in the center of the lesion to be frozen under ultrasound guidance with continuous monitoring of the freeze-thaw process. Before freezing, the liver was isolated from surrounding structures by placing lap pads to protect the contiguous viscera. The initial application of cryosurgery was done with three repeated freeze-thaw cycles; however, during the latter part of our study we found that only two complete freeze-thaw cycles were needed to achieve complete necrosis of frozen tumor tis- sue.

Postoperative evaluation included several plasma CEA levels, liver enzymes, white blood cell count, and a baseline postoperative CT scan and ultrasound. The median hos- pitalization for the 25 patients thus far treated with cryo- surgery has been 5 days.

Results of Intraoperative Ultrasound in Detection of Liver Metastases

A prospective comparison of preoperative imaging techniques with intraoperative ultrasound was camed out in 54 consecutive patients. A total of 167 lesions was seen by the intraoperative ultrasound. Preoperative ultrasound, CT scan, and angiography detected 76%, 61%, and 52% of these lesions, respectively. The intraoperative ultra- sound was especially good in detecting lesions in the lateral segment of the left lobe and in identifying metastases smaller than 2 cm in diameter. Lesions as small as 3 or 4 mm, deep in the parenchyma of the liver, were routinely

probe into the liver tumor under intraoperative ultrasound monitoring. detectable by the intraoperative ultrasound.

726 CANCER February 1 Supplement 1990 Vol. 65

Intraoperative Ultrasound Monitoring of Cryosurgery

Intraoperative ultrasound was used to guide the cryo- probe to the correct position within the hepatic tumor without injuring major vascular or biliary structures (Fig. 2). Cryoablation was visualized by the intraoperative ul- trasound's depiction of an hyperechoic rim with posterior acoustic shadowing emanating from the freeze front as it advanced through the normal liver. In contrast, frozen- thawed tumor does not change in echogenecity during monitoring by the cryoprobe. Thus, delineation of ade- quate margin between frozen tumor and frozen liver as- sures completeness of cryoablation. The largest ice ball generated using a single 8-mm cryoprobe was approxi- mately 3 cm in diameter.

Frozen tissue showed a coagulum of necrosis with loss of nuclear and cytoplasmic detail. " In the five patients whose frozen metastases were resected, there was excellent clinico-pathologic correlation between freeze margin predicted by intraoperative ultrasound and pathologically defined margin. Several patients were reexplored 6 months

FIG. 2. Intraoperative ultrasound of liver showing a 2-cm metastasis straddling the confluence of right hepatic vein, middle hepatic vein, and inferior vena cava.

after initial cryosurgery. Excision of the site where tumors had previously been cryoablated showed focal collapse of subcapsular architecture and mild diffuse fibrosis without evidence of residual tumor.

Postoperative Complications

During the first phase of our patient study we proved that hepatic cryosurgery was safe. There was no mortality and there were no significant complications. Intraopera- tive bleeding from the probe was effectively controlled by application of pressure 10 minutes after removal of the nitrogen delivery system. Transient elevation of liver en- zyme levels and leucocyte counts was observed. These normalized by the 5th postoperative day, which was the median day of hospital discharge. A single patient who underwent right hepatic lobectomy and freezing of a left lobe metastasis developed a right subphrenic abscess. An- other patient, with a solitary right lobe metastasis in whom cryoablation rather than resection was opted for due to severe comorbid disease, developed a partial wound de- hiscence on his 5th postoperative day.

Tumor Response to Cryoablation

The follow-up on our 25 patients who underwent cryo- surgical ablation ranged from 4 to 36 months with a me- dian of 20 months. Patterns of failure, serial evaluation of CT scans, external ultrasound and tumor markers, and overall and disease-free survival have been analyzed.

Because one goal of this study was to ascertain the tech- nical feasibility and antitumor response of cryosurgery, attempts were made in some patients to freeze dominant lesions with gross untreated residual disease left behind. The tumor response demonstrated in these patients by CT scan evidence of necrosis and shrinkage after tumor was compared with progressive growth in the nonfrozen lesions. As early as 5 to 7 days after cryoablation, CT scans showed evidence of necrosis with gas bubbles in the treated lesions. Thereafter the serial CT scans demon- strated gradual shrinkage of the cryoablated tumor over a period of several months. Even in the context of pro- gressive growth of nontreated lesions in other areas of the liver, the frozen tumors remained stable or continued to shrink.

Serial CEA estimations were available in 15 patients. The kinetics of fall in CEA were quite different from pa- tients undergoing liver resection for isolated metastases. After cryoablation, CEA levels fell gradually over a period of 6 weeks to 3 months. Changes in CEA levels were very sensitive indicators of tumor response or recurrence. Characteristics of the plasma CEA levels in patients with gross untreated residual tumor and in patients with no evidence of disease were published previously. ' ' Several patients whose functional neuroendocrine tumors were

No. 3 NEW SURGICAL TREATMENTS - Steele et ul. 727

successfully cryoablated and who are still asymptomatic after this treatment have been followed during normal- ization of their endocrine tumor markers.

Of our 25 patients, seven had gross residual disease left untreated at the time of cryosurgery. Of this group, five have died. All of the remaining patients who had no gross untreated cancer at the time of cryoablation are alive, seven without any evidence of tumor recurrence. Among patients in whom we have documented rerecurrence, 50% have failed both in and outside the liver. Patients who failed in the liver failed only in sites not treated by cryo- surgery.

Discussion

The initial hypothesis in applying cryosurgery was to define a group of patients in whom regional therapy for isolated colon and rectum carcinoma occurrence could be offered when surgical resection was not applicable. We therefore applied this new approach to patients with more than three but fewer than six isolated liver metastases. Our postulation that cryosurgical ablation of tumors would allow complete and effective treatment when the metastasis was adjacent to major blood vessels such as the vena cava or a major hepatic vein proved wrong. Be- cause the thermal dilution caused by rapid blood flow prevents adequate freezing of tumor adherent to the vena cava or major hepatic venous branches, if surgical resec- tion is impossible, then cryosurgical ablation is also in- adequate. Before application of cryosurgical ablation to patients who now undergo conventional resection of re- sectable liver metastases is possible, we will need more mature disease-free and overall survival data in our group of patients. At present, however, it appears that the sur- vival in these patients will be at least as good after appro- priate and effective cryosurgical ablation as it is after sur- gical resection. Obviously, morbidity is lessened and hos- pital stay is significantly shorter after cryosurgery. Present limitations include a lack of appropriately designed probes for access to metastases in the dome of the right lobe of the liver, and a lack of multiple probes that would allow cryosurgical freezing of tumor metastases of large size. Additional limitations include the time involved in achieving two complete freeze-thaw cycles in patients who have multiple liver metastases.

Extra-Hepatic Isolated Regional Recurrence

The track record of surgical attempts to save patients with regionally recurrent colorectal carcinoma, particu- larly patients who have recurrences after low anterior re- section or abdominoperineal resection of rectal carci- noma, is not g ~ o d . ' ~ , ' ~ Expectation of achieving cure in these patients is small. Nevertheless, because of severe symptomatology at recurrence until death in patients with

isolated regional recurrence, we attempted to develop new operative indications and new surgical techniques to save such patients. Although the goal is cure, our more realistic expectation is to decrease operative morbidity and achieve durable palliation.

Since 1982 we have operated on approximately 50 pa- tients with regionally recurrent abdominal and pelvic tu- mors; this is a consecutive series. Colorectal carcinoma recurrence predominant (36 patients). Other diagnoses included in the group were reported in an earlier follow- up at the New England Surgical Society' and are sum- marized in Table 2. In all these patients pelvic recurrence was unaccompanied by other disease after preoperative staging. For this article only patients with isolated pelvic recurrence were considered. They formed the majority (84%) of the series.

All patients had symptoms that subsequently led to the diagnosis of their recurrence after CT scan, endoscopy, MRI, or ultrasound. Most had percutaneous CT or ultra- sound-guided needle biopsy. Many were treated by ex- ternal beam irradiation or by a variety of chemotherapy approaches before referral for surgery. Nonsurgical ap- proaches were of no help in attempts to cure or to palliate. Pain was the predominant symptom in the series and oc- curred in more than three quarters of the patients. Tumors were palpable in 27% of the patients. Genitourinary symptoms, intestinal fistulae, and pelvic sepsis were com- mon. Patients most often had multiple symptoms of long duration. That all of these patients had their diagnosis of tumor recurrence established after long-term and often severe symptoms and not by routine tumor surveillance studies is interesting. This may have selected for patients whose tumor biology was unique. Although their recur- rences were large, they were isolated. Our ability to palliate or even cure these patients may be more a function of this selection process than the particular surgical approach used. Thus, the biology here may be somewhat analogous to that in patients who undergo liver or pulmonary re- section for isolated colorectal carcinoma distant metas- tases.

CEA levels were obtained preoperatively for all of our patients and were obtained postoperatively in a serial

TABLE 2. Primary Tumor ~~

Variable Number Percent

Colorectal Ovarian Cervical Anal Sacral chordoma Bladder Uterus Melanoma

36 13 4 8 3 6 2 4 1 2 1 2 1 2 1 2

N = 49.

728 CANCER February 1 Supplement 1990 Vol. 65

fashion. Preoperative CEA levels ranged from 0.4 ng/ml to up 963 ng/ml, with a median level that was quite low (3.6 ng/ml). Thus, although the CEA was elevated, our series supports other CEA surveillance studies in which it was shown that CEA surveillance is not particularly valuable in patients who fail first or only with regional disease.

Extensive intraoperative staging was performed before regional exenteration. In six patients, conservative pro- cedures were carried out because of previously unsus- pected extrapelvic or unresectable pelvic tumor found at surgery. Conservative procedures included biopsy only or colonic or ureteral diversion. Nine patients underwent what we have termed “completion” abdominoperineal resection. Seventeen patients underwent radical resection of tumor recurrence involving either the abdominal wall, the perineum, or additional adjacent viscera. Eighteen patients underwent pelvic exenteration, 13 of which were extended total exenterations. Preoperative signs of incur- ability include fixation to the pelvic sidewall, fixation of the tumor to the sacrum as defined by sacral nerve root pain, and swelling of the leg implying extension into the hypogastric and common iliac lymphatics. Because of these clinical indicators and our operative experience in this set of patients, we will no longer attempt to cure and will rarely attempt to surgically palliate, as the only jus- tification for major exenteration is to surgically encompass all the tumor. The possibility of cure and the effectiveness of palliation are limited if gross tumor is left behind. Un- fortunately, the determination of resectability by frozen- section biopsy of margins was impossible. Most often areas to be biopsied were in operative scar or in tissue previously irradiated, or at sites of septic tumor necrosis. Operability and resectability were usually clinical decisions. The clin- ical definition of success in circumscribing the tumor was subsequently confirmed or denied by permanent histo- logic examination of surgical margins. Fixed tumors in the pelvis precluded en bloc dissection, and all such tumors were deemed unresectable. Any attempt to excise such tumors in piecemeal fashion invariably led to early re- currence and was not justifiable even for palliation.

Of our patients, 88% underwent recurrent tumor re- section. In 32 patients the surgeon believed all gross tumor was removed. In 1 1 patients a major resection was camed out with residual tumor left behind, usually fixed to pelvic side walls. This invariably occurred because there was no turning back once the technical commitment to exenterate had been made. In nine patients intraoperative radiation therapy was used as a boost to a subsequent or a preceding course of external beam irradiation. Areas of tumor ad- herence in the retroperitoneum and on the pelvic sidewall were irradiated only if intraoperative irradiation could be combined with external beam irradiation. Thus, most of our patients who had already had a complete course of

external beam therapy long before referral were not eligible for additional intraoperative radiation because there was no synergistic effect of the two treatment courses and be- cause the radiation toxicity threshold to adjacent bowel, bone, and nerves would have been exceeded. Intraoper- ative radiation therapy was given only when frozen section confirmed the presence of microscopic residual tumor.

Three significant technical considerations in the treat- ment of these patients may have affected the decreased length of stay after such major procedures. First, patients often underwent staged operative procedures. A number had ureteral and colonic diversions done with drainage of pelvic abscesses from necrotic tumor recurrence. Sub- sequent exenteration of the tumor and pelvic soft tissue reconstruction was performed 1 or 2 weeks later. Other patients had ureteral and colonic diversions at the time their tumor was exenterated but with packs left in the pelvis for subsequent soft tissue reconstruction performed a week to 10 days after the initial procedure. The ureteral and colonic bypass and tumor exenteration often took 6 to 10 hours. If vascularized musculocutaneous pedicle flaps were used to reconstruct the pelvis, an additional 4 to 6 hours, depending on unilateral or bilateral flap place- ment, could make any operative procedure unacceptably lengthy, particularly in elderly patients who had nutri- tional deficits or pelvic sepsis before their referral.

A second important technical consideration was the design of ureteral diversion. Initially, Bricker-type ure- teroileal loops were routinely constructed. However, be- cause most of these patients had pelvic and lower abdom- inal irradiation, predicting which segment of small bowel had been irradiated was impossible. To avoid anasto- mosing ureters to small bowel that was previously irra- diated, we now construct ureterocolonic loops, often using the already fashioned colostomy in patients who have had recurrences after a previous abdominoperineal resection. A second more proximal colostomy is fashioned for fecal diversion. The opposite quadrant of the anterior abdom- inal wall is used as the exit site. Since initiating this large bowel bypass, there have been no healing problems with ureteral reconstructions.I4

A third technical consideration has been the manage- ment of the open pelvis after exenteration in patients who have had previous pelvic surgery and external beam ir- radiation. Healing in such a pelvis is suboptimal. Routine reconstruction of the pelvis using vascularized tissue has significantly reduced early and late morbidity. Our usual reconstructive technique is either a unilateral or a bilateral posterior thigh myocutaneous flap.I5

We believe that the three technical improvements summarized above have been responsible for the decrease in hospital length of stay (median stay between 2 and 3 weeks). Despite the long list of minor complications (Table 3), postoperative death has occurred in only one patient

No. 3 NEW SURGICAL TREATMENTS - Steele et al. 729

TABLE 3. Complications

Variable Number Percent

Mortality Prolonged ileus Hemorrhage Superficial wound infection Bowel obstruction Deep venous thrombosis Renal failure Respiratory failure Sepsis (perineal/pelvic) Miscellaneous None

1 6 4 4 2 2 2 2 3

10 21

2 12 8 8 4 4 4 4 6

20 43

in the entire series. Most important, full rehabilitation is achieved quickly for discharged patients. l 6

Results

All patients have been followed until death or until publication of this article. Median follow-up was 17 months with a range of 3 to 74 months. The overall sur- vival of this group of patients was 4 1 %. Ten patients were disease free with a median follow-up of 19 months. The single operative mortality occurred early in the series and involved resection of a recurrent infected uterine carci- noma in the pelvis of a debilitated patient. The fatality was related to failure of the small bowel/ureteral anas- tomosis in an irradiated pelvis. This case led us to consider the change in ureteral reconstruction technique described

FIG. 3. Algorithm for managements with locoregional recurrence of colorec- tal carcinoma.

above. Our mortality rate compares favorably with that described in other published series2

In the patients who underwent curative resection (as defined by the surgeon), 44% are surviving with a median follow-up of 15 months. Ten are disease free, and four are alive with regional recurrence. Our single 5-year dis- ease-free survivor is a 28-year-old patient with regionally recurrent colorectal carcinoma that was successfully cir- cumscribed at reresection. Eighteen of our patients died, with a median survival of 16 months. Of these, 15 rere- curred in the site of their initial regional failure. One pa- tient died at 6 months free of tumor, and two patients died with distant disease outside of the pelvis.

Of the patients who underwent palliative resection, 73% died, including the single postoperative death in our entire group. Median survival in this group was 18 months. Thus, with the present follow-up there is no difference in the median survival of patients who underwent palliative versus patients who underwent curative resection.

Analysis of survival after major resection in these pa- tients must continue and must focus on the subset of pa- tients that is defined as cured by the surgeon and con- firmed as having disease-free margins by the pathologist. This is the only group of patients having some chance of being cured by such regional surgery and among our entire series represents approximately half of the patients who underwent an exenterative approach.

Although it is too early to be definitive about whether some of our patients were cured, we can say that the high- est probability of failing a second time is in the region of

ROUTINE

SURVEILLAt4CE

hlatory -D- ptiyalcsl exam

hemoccult CT

CEA

uni

AEGIONAL AECURRENCE dlagnoaed

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L PnE OPERATIVE f lAUIATIUN 300 - 5000 c G y t 5 F U

, MAJOR RESECTION

INTRAOPERATIVE RADIATION

7 30 CANCER February 1 Supplement 1990 Vol. 65

that after a first failure. If patients can be identified pre- operatively in whom both the surgeon and the pathologist confirm complete reexcision of recurrence, our ability to limit application of these procedures to more appropriate patient subsets will increase the probability of cure.

At present our palliative goal seems achievable. Thus, with the low mortality and decreased morbidity, the de- creased hospital length of stay after these complex pro- cedures, and the 80% to 85% of patients in our series reporting complete rehabilitation ( i e . , normalization of living and working habits after hospitalization), the con- trast between postoperative quality of life and patient symptomatology at presentation is startling.

Because our experience with intraoperative radiation therapy in this series is limited to nine patients, the precise impact of radiation added to exenterative surgery is un- clear. Overall, however, six of the nine patients who re- ceived intraoperative radiation therapy were surviving at a median of 27 months, four of whom were disease free. Our intuition is that intraoperative radiation therapy can be used only in combination with external beam radiation therapy, either preoperatively or postoperatively. This has preempted intraoperative radiation therapy use in most patients referred to us after external beam irradiation has failed to control either tumor growth or symptoms. In addition, intraoperative radiation therapy seems most useful only when all gross tumor is removed. Ideally, if patients are referred before external beam or shortly after external beam radiation is performed, intraoperative ra- diation therapy is a potential adjuvant consideration at the time of surgical reresection.

A proposed algorithm for the care of patients suspected of having regional recurrence is summarized in Figure 3.16 We hope improved MRI will offer the potential for earlier diagnosis and will help us select patients who are most suitable for successful surgical reexcision of regional recurrence. In the future, an increasing potential for mul- timodality combinations using effective systemic adjuvant therapy and external beam or intraoperative radiation combined with surgery at the time of primary tumor re- section should obviate the need to deal with these difficult problems once regional recurrence becomes obvious. At

present, however, we continue to be limited by marginally effective systemic therapy for bowel cancers. Surgery, therefore, remains the most important mode for primary as well as recurrent colorectal cancer therapy.

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