| Japanese Journal of Clinical Oncology | Pages |
Introduction
Patients And Methods
Portal Embolization and Hepatic Resection
Results
Case 1
Case 2
Discussion
Acknowledgments
References
A Pilot Study of Multimodality Therapy for Initially Unresectable Liver Metastases from Colorectal Carcinoma: Hepatic Resection after Hepatic Arterial Infusion Chemotherapy and Portal Embolization
INTRODUCTION
The treatment strategy for liver metastases from colorectal carcinoma is still controversial. In the case of surgically resectable tumors, hepatic resection is generally recommended (1 -6 ). Five-year survival rates after curative resection of hepatic metastases are reported to be 25-48% (1 ,2 ,4 ,6 ). These results are still not satisfactory, but also not entirely disappointing and some patients can be cured (1 ,2 ,4 -6 ).
On the other hand, unresectable liver metastases are difficult to treat. In general, hepatic arterial infusion chemotherapy (HAI) is offered to patients without extrahepatic disease and systemic chemotherapy is used for patients with extrahepatic disease (7 ). Nevertheless, the effectiveness of these treatments is so limited that patients with unresectable liver metastases have very little chance of cure (6 -13 ). Indeed, there are at best only one or two 5-year survivors in each HAI trial (6 ,8 -10 ). Therefore, some breakthrough in therapy is needed.
The purpose of this pilot study was to evaluate the feasibility and efficacy of a multimodality therapy with hepatic resection after HAI with 5-fluorouracil (5-FU) and mitomycin C, followed by portal embolization, in patients with initially unresectable hepatic metastases from colorectal carcinoma.
PATIENTS AND METHODS
From October 1988 to June 1990, eight patients with primary colorectal adenocarcinoma and synchronous unresectable liver metastases underwent complete resection of the primary tumor, hepatic arterial catheterization and placement of an Infusaid model 400 pump (Infusaid, Norwood, MA, USA). Informed consent was obtained from each patient. The patients' characteristics are shown in Table 1 . All of the patients had five or more hepatic metastases involving three or four hepatic segments, which were detected by computed tomography and ultrasonography and confirmed by intraoperative ultrasonography, inspection, palpation and biopsy. These metastases were considered unresectable because the remaining functional parenchymal volume of the liver after resection was estimated to be too small (less than one segment) to maintain normal liver function, and/or because the tumors were contiguous to essential intrahepatic vascular structures (cases Nos 2, 4, 6 and 7).
Cholecystectomy and ligation of the right gastric artery, gastroduodenal artery and the small branches supplying the stomach and duodenum were performed. A hepatic arterial catheter was inserted through the gastroduodenal artery. The primary tumor, involved lymph nodes, and, in case No.7, a few peritoneal implants near the primary tumor were removed completely. Whole liver perfusion was confirmed during the operation with the injection of indigo carmine.
Post-operatively, a technetium-99m macroaggregated albumin scan through the sideport was performed to ascertain the adequacy of liver perfusion. HAI was initiated 2-3 weeks after the operation. 5-FU was administered by continuous infusion through the Infusaid pump for 21 days, alternating with normal saline for 7 days. We used 5-FU instead of floxuridine (FUDR), which is generally used for HAI (7 -13 ), because FUDR is not permitted in Japan. Mitomycin C was given by injection through the sideport of the pump once a month. The starting doses of 5-FU and mitomycin C were 0.3 mg/kg/day and 0.1 mg/kg/month, respectively. This treatment cycle was repeated as many times as possible. The patients underwent a physical examination, complete blood count and blood biochemistry profile every 2 weeks. When abdominal symptoms or abnormal values in the blood test attributable to HAI were noted, HAI was discontinued until the side-effects were resolved. After resolution of the side-effects, subsequent doses were administered at half of the starting dose. When severe complications such as bleeding from a duodenal ulcer, sclerosing cholangitis, occlusion of the hepatic artery or extravasation occurred, HAI was terminated.
All of the patients were examined before the initiation of HAI and every 2 months thereafter with computed tomography and ultrasonography of the abdomen and chest x-ray. Serum carcinoembryonic antigen was measured every 2 weeks. The tumor response was evaluated with computed tomography and ultrasonography and was defined according to WHO criteria (14 ).
Since the tumors of two patients reduced in size and number and became resectable, but still did not disappear after HAI, they became candidates for surgical resection. Extended right hepatic lobectomy was needed to resect these tumors completely. To prevent post-operative hepatic failure, portal embolization (15 ,16 ) was performed before hepatectomy. In both cases, the right main portal branch was embolized with a mixture of 0.5-1.0 g of minced Gelfoam (Upjohn, Kalamazoo, MI, USA), 2500-5000 units of thrombin (Green Cross, Osaka, Japan), 10-20 ml of 60% diatrizoate sodium meglumine and 40 mg of gentamicin, as described elsewhere (15 ,16 ).
After portal embolization, both patients underwent extended right hepatic lobectomy. During the operation, intraoperative ultrasonography was used to determine the exact number and location of tumors and the correct plane of dissection.
RESULTS
During a median period of 196 days (range 68-352 days), a median total 5-FU dose of 22.3 g (range 11.1-34.5 g) and a median total mitomycin C dose of 36 mg (range 12-60 mg) were given to the patients. HAI was terminated because of the appearance of extrahepatic lesions in four patients and because of complications in the other four patients.
The treatment results are summarized in Table 2 . Of the eight patients who received HAI, one patient (13%) showed a complete response, five (63%) showed a partial response and two (25%) had progressive disease. The overall response rate was 75%.
Complications were observed in five patients (63%), including hepatic arterial occlusion in three patients (38%), sclerosing cholangitis in two (25%) and duodenal ulcer in three (38%) (Table 2 ). Two patients with sclerosing cholangitis developed liver abscess and received ultrasonography-guided drainage. Two patients with duodenal ulcer developed bleeding and underwent emergency surgery. There were no complication-related deaths.
Table 1
| Case No. | Age (yr)/ sex | Site of primary tumor | pTN classification* | Number of liver metastases | Involved liver segments[dagger] | Other metastases[Dagger] | Pre-HAI CEA levels (ng/ml) |
| 1 | 46/M | Colon | T3N0 | 14 | PAML | None | 53.5 |
| 2 | 40/M | Rectum | T4N0 | 5 | PAM | None | 247 |
| 3 | 77/M | Rectum | T3N1 | 10 | PAML | None | 5.4 |
| 4 | 60/M | Colon | T3N3 | 6 | PAML | Paraaortic node | 1320 |
| 5 | 64/M | Rectum | T3N1 | 8 | PAML | None | 29.1 |
| 6 | 50/M | Rectum | T3N3 | 5 | PAML | Paraaortic node | 1880 |
| 7 | 58/F | Colon | T3N3 | 30 | PAML | Peritoneum | 556 |
| 8 | 68/M | Colon | T3N0 | 7 | PAML | None | 674 |
Table 2
| Case No. | Tumor response | Post-HAI CEA levels (ng/ml) | HAI-related major complications | Hepatectomy after HAI | Survival from initiation of HAI (months) | Outcome |
| 1 | PR | 4.1 | HAO, SC | Yes | 81 | ANED |
| 2 | PR | 1.5 | HAO | Yes | 77 | ANED |
| 3 | CR | 2.4 | HAO, SC, duodenal bleeding |
No | 40 | DOD |
| 4 | PR | 30.9 | None | No | 19 | DOD |
| 5 | PR | 2.4 | Duodenal bleeding | No | 58 | DOD |
| 6 | PD | 17800 | None | No | 11 | DOD |
| 7 | PD | 600 | None | No | 17 | DOD |
| 8 | PR | 7.2 | Duodenal ulcer | No | 20 | DOD |
Overall, the median survival time after the initiation of HAI was 30 months (Table 2 ). Of the six patients who responded to HAI, one patient with a complete response finally developed multiple metastases and died, three patients with a partial response relapsed into progressive disease and died and the two other patients with a partial response underwent additional hepatectomy after HAI. Details of these last two cases are described below.
Case 2
The patient underwent low anterior resection and HAI-pump placement for rectosigmoid cancer and synchronous liver metastases: three nodules in the right lobe and two in the left lobe. Owing to the bilobar spread of the metastases and involvement of the root of the right hepatic vein by a 6*5 cm tumor in the anterior segment (Fig. 2 ), the metastatic tumors were considered unresectable. After seven cycles of HAI, a 91% decrease in the sum of the areas of the five lesions was observed. At that time, since the patient developed hepatic arterial occlusion, HAI was terminated. Shrinkage of the tumors, including the lesion that previously involved the root of the right hepatic vein, made complete resection of the metastases feasible (Fig. 2 ). However, since the left lobe represented only 15% of the functioning liver tissue, extended right hepatic lobectomy after portal embolization was planned. Soon after portal embolization, the patient showed a local recurrence and underwent abdominoperineal resection for complete clearance. Five months after portal embolization, the patient underwent extended right hepatic lobectomy. The right lobe of the liver became remarkably atrophied, while the left lobe became markedly hypertrophied and represented 57% of the functioning liver tissue. The resected specimen contained five metastatic tumors with clear surgical margins. These tumors showed complete necrosis in three and partial necrosis in two. The post-operative course was uneventful and the patient was discharged on the 17th post-operative day. The patient is alive at 77 months after the initiation of HAI and is free of disease at 63 months after hepatic resection.AB
DISCUSSION
Surgical resection is currently the only treatment that can provide long-term survival and a possible cure for patients with liver metastasis from colorectal carcinoma (1 ,2 ,4 ,6 ). However, only 27-38% of such patients can undergo resection (6 ,17 -19 ). For patients with unresectable metastases, there is substantially no therapy that can provide long-term survival. HAI can significantly prolong the survival of patients with metastases confined to the liver, compared with systemic chemotherapy or no chemotherapy (8 ). However, there are still very few 5-year survivors receiving HAI (6 ,8 -10 ). Therefore, a treatment that is more effective than HAI alone is needed.
There are two main reasons why hepatic metastases would be technically unresectable. First, the remaining functional parenchymal volume of the liver after resection may be too small to maintain normal liver function. Second, the tumor may be contiguous to essential intrahepatic vascular structures. In both cases, there is a chance that complete surgical resection may become feasible if HAI has sufficiently reduced the size and number of the tumors. HAI can decrease the total tumor area by more than 50% in 41-62% of patients with liver metastases (7 -13 ). However, the rate of complete response is as low as 2-8% (7 -13 ). Therefore, there is a rationale for surgical resection after HAI, if morbidity and long-term results are acceptable.
The present study showed the possibility that some initially unresectable liver metastases may become resectable if HAI effectively reduces the volume and/or number of metastatic tumors. Complete surgical resection in such cases is feasible without significant morbidity. Portal embolization (15 ,16 ) may enhance the safety of extended liver resection in this setting. Although the exact cause of the remarkable effect of portal embolization in our cases is not known, prior hepatic arterial occlusion resulting from the side-effect of HAI may cause a marked reduction in blood flow into the embolized hepatic lobe and cause a marked expansion of the non-embolized lobe and shrinkage of the embolized lobe. The two patients described here who received such multimodality therapy survived more than 6 years and may in fact be cured. Therefore, this approach warrants further investigation.
Hodgson et al. (20 ) reported a multimodality therapy using partial removal of the metastatic disease, peripheral presinusoidal embolization and portal vein branch ligation, followed by HAI. They suggested that multimodality therapy was superior to HAI alone. Our aggressive approach is similar to theirs. However, complete surgical resection after HAI is thought to be preferable to partial removal before HAI because, in the latter case, if HAI is not effective, resection may not be beneficial and it is difficult to predict the effectiveness of HAI in individual patients.
Since the use of FUDR is not permitted in Japan, we used 5-FU. Also, a monthly bolus of mitomycin C was added because additional mitomycin C may enhance the efficacy of HAI (21 ). The response rate with the present regimen is comparable to those of regimens using FUDR (7 -13 ). In addition, the incidence of sclerosing cholangitis and duodenal ulcer in our study is consistent with the incidence in studies using FUDR (8 -12 ). However, improvement of the regimen and/or management of HAI is necessary, since one of the long-term survivors in our series still suffers from sclerosing cholangitis.
In conclusion, the present results suggest that a multimodality therapy with hepatic resection after HAI and portal embolization is feasible and may be beneficial in selected patients with initially unresectable liver metastases from colorectal carcinoma.
Acknowledgments
This study was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare and a Grant-in-Aid for the Comprehensive 10-year Strategy for Cancer Control in Japan.
References
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Copyright© Japanese Journal of Clinical Oncology, 1997.
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