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Regional hepatic chemotherapy using an implantable drug infusion pump
Regional Hepatic Chemotherapy Using an Implantable Drug Infusion Pump
Alfred M. Cohen, MD, Boston, Massachusetts Sheldon D. Kaufman, MD, Boston, Massachusetts William C. Wood, MD, Boston, Massachusetts Alan J. Greenfield, MD, Boston, Massachusetts
Regional infusion of chemotherapeutic agents in the treatment of liver cancer can greatly increase the tumor exposure to the drugs when compared with the exposure when the peripheral intravenous route is employed. Hepatic arterial chemotherapy, primarily with the fluoropyrimidines, has been shown to produce objective response rates of 50 to 80 percent in patients with metastatic colorectal cancer [l-5]. Using carefully stratified historical control subjects, it appears that floxuridine, continuously administered into the hepatic artery, can increase the survival of such patients twofold to threefold over the survival for untreated patients [2]. The discomfort, inconvenience, and complications associated with extracorporeal drug infusion pumps have limited their use in patients receiving chemotherapy. A totally implantable and percutaneously refillable biomedical device has recently been developed for long-term intravascular drug infusions [6]. The initial application of this pump (Infusaida, Infusaid Corp., Norwood, MA) has been for long-term heparin infusion [7]. The same pump has recently been used with floxuridine chemotherapy for long-term infusion into the hepatic artery [S-10]. We recently reported the successful integration of the Infusaid pump with transaxillary angiographic hepatic arterial catheterization [/1,12]. Herein we report our experience with the first 50 patients who have had pump implants for regional chemotherapy, including those patients who underwent either direct surgical or anziozraohic catheterization. From the DeparbTlents of Surgery, Mediiine, and Ftadiilogy. Harvard Medical School and the Massachusetts General Hospital, Boston. Massachusetts. Requests for reprints should be addressed to Alfred M. Cohen, MD, Cox Cancer Center. Massachusetts General Hospital, Boston, Massachusetts 02114. Presented at the 63rd Annual Meeting of the New England Surgical Society, Bretton Woods, New Hampshire, October 15-17, 1982.
Volume 145, April 1983
Patients and Methods Over the 2iJzyear period which ended in March 1982,50 patients with liver cancer underwent implantation of an Infusaid drug infusion pump. In all patients, benzyl alcohol-preserved water containing 1,000 units/ml of heparin was used in the pump. Of the first 50 patients who received pump implants, 3 had primary hepatocellular carcinoma and 47 had metastatic cancer to the liver; 41 of these 47 patients had metastatic colorectal cancer. The primary sites for the remaining six patients were the stomach, small bowel carcinoid, breast, kidney, nasopharynx, and one unknown primary site. A minimum 6 month follow-up was carried out on all patients reported. Of the 41 patients with colorectal cancer metastatic to the liver, 8 had concomitant lung metastases. The extent of hepatic metastases using technetium sulfur colloid liver scan evaluation was as follows: less than 10 percent in 5 patients, 10 to 25 percent in 6,25 to 50 percent in 17, and more than 50 percent in 9. Eleven of the 50 patients underwent laparotomy for catheterization; in 9 the catheter was implanted into the hepatic artery and in 2 into the portal vein. Thirty-nine patients underwent angiographic catheterization; a transaxillary hepatic artery catheter was placed in 38 and an angiographic transhepatic portal vein catheter was placed in 1. Hepatic artery catheterization at laparotomy was performed through the gastroduodenal artery. Angiographic catheterization of the hepatic artery through the transaxillary route was performed as previously described [11,12]. The only drug used in the pump reservoir was floxuridine. It was used at an appropriate concentration within the pump so that the patient received 0.3 mg/kg per day. The drug was kept in the pump for 2 weeks at a time, followed by a 2 week period without the drug to minimize the chance of hepatitis. The alkylating agents mitomycin C and 1,3-bis-(2 chloroethyl) I-nitrosourea (BCNU) were given through the pump sideport as a 1 hour intraarterial infusion every 6 weeks at 15 mg/M2 and 150 mg/M2, respectively.
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Cohen et al
TABLE I
Hepatic Arterial Chemotherapy of Metastatic Colorectal Cancer in 41 Patients
Agents FUdR FUdR + RT Mitomycin FUdR + mitomycin FUdR, mitomycin, BCNU
Therapeutic Response
Stable Disease
3 1 2 2 13
7 1 1 0 4
Progres- Not sive EvalDisease uable 3 1 0 0 1
2 1 0 1 2
BCNU = 1,3-his-(2 chloroethyl) 1-nitrosouria; FUdR = floxuridine; RT = radiotherapy.
Satisfactory response to the chemotherapeutic program was determined by a reduction of at least 50 percent of the
sum of products of measurable lesions on the liver scan and no increase in any other indicator lesion and no new area of malignant disease in the liver. If hepatomegaly was used as the primary indicator, there had to be a reduction in the sum of the measurements below the costal margin at the midclavicular lines and the xyphoid process by at least 30 percent. To be considered a partial response, the above criteria had to be met for at least 3 months. The disease was considered stable if the patient had minimal responses but insufficient regression to meet the above criteria. Progression was defined as an increase in any measurable lesion of more than 25 percent or the appearance of new areas of metastatic disease in the liver. Regular plain roentgenograms of the abdomen were used to check on catheter placement. If there appeared to be any migration of the catheter, the perfusion pattern of the liver was then determined either by digital subtraction angiography or radionuclide flow studies, both performed through the pump sideport. In the latter case, 1 mCi of technetium-99m aggregated albumin microspheres injected slowly through the pump sideport confirmed catheter position and flow to the liver [13].
Results Catheter and pump complications: There were no pump malfunctions in over 260 patient-months. Of more than 600 percutaneous refills, only one infection resulted; it was Escherichia coli infection of the pump pocket which occurred 1 year after the pump was implanted. It necessitated removal of the system. There were no episodes of systemic septicemia or infections of the fluid within the pump reservoir. Of the 38 transaxillary hepatic arterial catheter systems, no problems related to peripheral emboli or to the brachial or axillary arteries occurred. There was no case of catheter occlusion or documented hepatic artery thrombosis. Three hepatic arteries were studied at postmortem examination, the longest one of the three was studied 18 months after death (longest postmortem time of the three) with an angiographic catheter in place. The arteries remained patent with only a very small clot present. In the group that underwent transaxillary angiography, 7 of the 38 patients had withdrawal of the
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TABLE II
Effect of Prior Chemotherapy on Response to Hepatic Arterial Chemotherapy
Prior Chemotherapy
Therapeutic Response (n)
Disease Stable (n)
Progressive Disease (n)
No Yes
12 9
7 6
2 3
catheter which necessitated four episodes of cracking of which required exchanges. eter could not be replaced patic artery.
replacement. There were the polyethylene catheter In two patients the cathsuccessfully into the he-
Chemotherapeutic responses: There was no response to floxuridine in the three patients with primary hepatocellular carcinoma. Responses at six months in the patients with both stomach cancer and carcinoid were excellent. The patient with metastatic gastric cancer had had progression of her cancer while receiving fluorouracil and chloroethyl cyclohexyl nitrous urea (CCNU). However, an excellent objective response was achieved with floxuridine, mitomycin C and BCNU. The patient with carcinoid metastases to the liver responded to floxuridine. The experience in the 41 patients with metastatic colorectal cancer is outlined in Table I. The effects of previous chemotherapy on the response to hepatic arterial chemotherapy is shown in Table II. Side effects of chemotherapy: Of the 50 patients, symptomatic ulcers or gastritis developed in 8. Two of the eight patients required gastrectomy. Hepatitis that was thought to be chemically induced developed in five patients. One patient remained grossly jaundiced for a year despite the discontinuation of floxuridine. Survival: With a minimum follow-up of 6 months, the survival of the 16 patients with colorectal cancer with only liver metastases was 2.5,4,4.5,, 5,8,8.5,9, 10 (2 patients), 11,12 (2 patients), 13,18 (2 patients), and 21 months. An additional nine patients were alive at 8 (two patients), 9,10,12,13 (two patients), 17, and 18 months after implantation. Comments Until recently, long-term ambulatory regional chemotherapy involved the use of an extracorporeal pump device. This work was pioneered at the Lahey Clinic by Watkins et al [14] using a spring activated pump, More recently, battery powered devices have come into widespread use, not only for constant infusion chemotherapy but also for insulin infusion. However, the quality of life for patients attached to an extracorporeal pump device for many months has been found to be unsatisfactory. In addition, septic complications due to transcutaneous catheterization are unavoidable. The Infusaid pump is an entirely implantable and refillable drug infusion system (now
The American Journalof Surgery
Implantable Drug Pump
approved by the Food and Drug Administration) for chemotherapy with floxuridine. Our experience with 50 patients has confirmed the reliability, safety, and convenience of this medical device. The hepatic artery can be catheterized by laparotomy and surgical implantation of the catheter or by techniques employing angiographic fluoroscopy. The initial approach by Watkins ‘et al [14] was through laparotomy with the catheter threaded into the hepatic artery through the gastroduodenal artery. We have implanted pumps in 12 of our 50 patients in that fashion. An advantage of direct surgical catheterization of the hepatic artery is that it allows for complete abdominal exploration to rule out nonhepatic metastases and to quantitate the extent of liver involvement. However, in patients with extensive liver metastases, recovery from laparotomy may be slow. In patients with marked hepatomegaly, exposure difficulties may make it impossible to directly catheterize the hepatic artery. The technique of percutaneous transbrachial or transaxillary hepatic arterial catheterization has allowed patients to be treated on a prolonged ambulatory basis without the necessity for laparotomy [14,15]. However, catheter-related sepsis and dislodgement of the catheter were the limiting features of this technique [16,17]. We have recently reported the integration of the implantable Infusaid pump with transaxillary hepatic arterial catheterization [11,12]. The surgery is relatively minimal, being performed under local anesthesia. The disadvantages of this system are primarily related to catheter withdrawal which necessitates replacing the catheter. In the 38 patients treated there were no vascular complications in the arm and there were no peripheral emboli. We did have seven patients whose catheters moved out of the ideal area for perfusion and required replacement under local anesthesia. We believe this report confirms the safety and efficacy of the transaxillary approach. Although there is no randomized trial of long-term hepatic arterial chemotherapy with floxuridine, the response rates of patients so treated and their survival strongly suggest a benefit. In the extensive experience at the Lahey Clinic, 71 percent of patients with metastatic colorectal cancer who were treated with long-term administration of floxuridine into the hepatic artery did demonstrate objective therapeutic responses [I]. Pettavel et al [2] used a similar program and reported remissions in 82 percent of 44 patients. This group has pioneered in the staging of hepatic tumors, and using carefully stratified historical control subjects, has demonstrated what appears to be considerably prolonged survival using this regimen. Mitomycin C has some activity in colorectal cancer when given intravenously (an approximately 15 percent objective response rate) [18]. Mitomycin C, like floxuridine [191, is metabolized in the liver, which
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145, April 1993
may provide an approximately sixfold increase in tumor exposure when given by the hepatic arterial route [20,21]. In a series of 13 patients with metastatic colorectal cancer treated with the administration of mitomycin C into the hepatic artery, 6 patients responded [22]. Fluorouracil and mitomycin C were combined and administered as a hepatic arterial infusion at the Cleveland Clinic with 10 of 14 patients responding [23]. In a limited experience at the M.D. Anderson Hospital with hepatic arterial infusion of floxuridine and mitomycin C, 10 of 12 patients responded [5]. The nitrosoureas are another group of alkylating agents which have some activity in metastatic colorectal cancer when given intravenously [24]. The drug is actively metabolized in the liver and has a half-life of approximately 5 minutes [25]. Our initial experience with hepatic arterial combination chemotherapy with floxuridine, mitomycin C, and BCNU has been quite encouraging. Excluding 2 nonevaluable patients, 17 of 18 patients with metastatic colorectal cancer responded to this three-drug program; 72 percent of these patients had objective responses which lasted for at least 4 months. Based on the preliminary results, we have embarked on a randomized trial in patients with metastatic colorectal cancer of the liver in which we compare chemotherapy with hepatic arterial infusion of floxuridine with the three-drug chemotherapeutic program of floxuridine, mitomycin C, and BCNU. Summary Regional infusion of chemotherapeutic agents in the treatment of liver cancer can greatly increase tumor exposure to certain drugs. Exposure is 100 times greater with floxuridine, 6 times greater with mitomycin C, and 6 times greater with BCNU. The Model 400 Infusaid implantable, refillable drug infusion pump overcomes much of the discomfort and inconvenience associated with previously employed extracorporeal systems. Our experience with our first 50 patients has been presented herein. Forty-one patients had metastatic colorectal cancer, 3 primary cancers, and 6 other metastatic cancers. Eleven pumps and 11 catheters were implanted at laparotomy. Thirty-nine patients had their pumps integrated to angiographically placed catheters. In over 260 patient months there were no pump malfunctions and only one infection. There were no vascular complications in the patients with angiographically placed catheters. Chemotherapeutic programs included floxuridine, floxuridine and radiotherapy, or floxuridine with mitomycin C and BCNU. In 18 patients with evaluable metastatic colorectal cancer who received hepatic arterial combination chemotherapy, there were therapeutic responses in 13 and disease stabilization in 4. The pumps were well tolerated by patients. They offer a reasonable approach to long-term ambulatory regional hepatic chemotherapy.
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References 1. Oberfield RA, McCaffrey JA, Polio J, et al. Prolonged and continuous percutaneous intraarterial hepatic infusion chemotherapy in advanced metastatic liver adenocarcinoma from colorectal primary. Cancer 1979;44:414-23. 2. Pettavel J. Morgenthaler F. Protracted arterial chemotherapy of liver tumors: an experience of 107 cases over a 12 year period. Prog Clin Cancer 1978;7:217-33. 3. Ansfield FJ, Guillermo R, Davis HL, et al. Further clinical studies with intrahepatic arterial infusion with 5-fluorouracil. Cancer 1975;36:2413-7. 4. Burrows JH, Talley RW, Drake EH, et al. Infusion of fluorinated pyrimidines into hepatic artery for treatment of metastatic carcinoma of the liver. Cancer 1967;20:1886-92. 5. Patt YZ, Mavligit GM, Chuang VP, et al. Percutaneous hepatic arterial infusion (HAI) of mitomycin C and floxuridine (FWR): an effective treatment for metastatic colorectal carcinoma in the liver. Cancer 1980:46:261-5. 6. Blackshear PJ, Dorman FD, Blackshear PL Jr, et al. The design and initial testing of an implantable infusion pump. Surg Gynecol Obstet 1972;134:51-6. 7. Rohde TD, Blackshear PJ, Varco RL, et al. One year of heparin anticoagulation: an ambulatory subject using a totally implantable infusion pump. Minn Med 1977;60:719-22. 8. Buchwald H, Grage TB, Vassilopoulos PP, et al. Intraarterial infusion chemotherapy for hepatic carcinoma using a totally implantable infusion pump. Cancer 1980;45:866-9. 9. Frankel S, O’Mary S. Byfield JE, et al. Regional intraarterial chemotherapy using a totally implantable infusion pump (abstr). American Assoc Cancer Res 1981;22:C-331. 10. Keller J, Ensminger W, Niederhuber J, et al. Effective prolonged hepatic arterial chemotherapy using a totally implanted delivery system (abstr). Assoc Cancer Res 1981;22:C-87. 11. Cohen AM, Wood WC, Greenfield A, et al. Transbrachial hepatic arterial chemotherapy using an implanted infusion pump. Dis Colon Rectum 1980;23:223-7. 12. Cohen AM, Greenfield A. Wood WC, et al. Treatment of hepatic metastases by transaxillary hepatic artery chemotherapy using an implanted drug pump. Cancer 1983 (in press). 13. Kaplan WD, D’Orsi CJ, Ensminger WD, et al. Intraarterial radionuclkfe infusion:a new technique to assess chemotherapy perfusion patterns. Can Treat Rep 1978;62:699-703. 14. Watkins E, Khazei AM, Nahra KS, Surgical basis for arterial infusion chemotherapy of disseminated carcinoma of the liver. Surg Gynecol Obstet 1970;130:581-605. 15. Petrek JA, Minton JP. Treatment of hepatic metastases by percutaneous hepatic arterial infusion. Cancer 1979;43: 2182-8. 16. Tandon RN, Bunnell IL, Cooper RG. The treatment of metastatic carcinoma of the liver by the percutaneous selective hepatic artery infusion of 5fluorouracil. Surgery 1973;73:118-21. 17. Clouse ME, Ahmed R, Ryan R, et al. Complications of long-term transbrachial hepatic arterial infusion chemotherapy. AJR 1977; 129:799-803. 18. Goldman ML, Bilbao MK, Rosch J, et al. Complications of indwelling chemotherapy catheters. Cancer 197536: 1983-90. 19. Krauss S, Sonoda T, Solomon A. Treatment of advanced gastrointestinal cancer with 5-fluorouracil and mitomycin C. Cancer 1979;43: 1598-603. 20. Tseng MH, Luch J. Mittelman A, et al. Chemotherapy of advanced colorectal cancer with regional arterial mitomycin C infusionand concomitant measurement of serum drug level (abstr). Amer Assoc Cancer Res 1981;22:C-104. 21. Hashimdto Y. Fundamental investigations on local chemotherapy for liver cancer. Arch Jap Chir 1978;47:302-18. 22. Fcrtunv IE, Theologides A, Kennedy BJ. Hepatic arterial infusion for iiver metastases from colon cancer: comparison of mitomycin C (NSC-26980) and 5-fluorouracil (NSC-19893). Cancer Chemother Rep 1975;59:401-4. 23. Misra NC, Jaiswal MSD, Singh RV, et al. lntrahepatic arterial
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infusion of combination of mitomycin C and 5-fluorouracil in treatment of primary and metastatic liver carcinoma. Cancer 1977;39: 1425-29. 24. Moertel CG, Reitemeier RJ, Hahn RG. Therapy of advanced gastrointestinal cancer with 1-3-his-(2-chloroethyl)-l-nitrosourea (BCNU). Clin Pharmacol Ther 1968;9:652-6. 25. Ensminger WD, Thompson M, Come S. et al. Hepatic arterial BCNU: a pilot clinical-pharmacologic study in patients with liver tumors. Cancer Treat Rep 1978;62:1509-12.
Discussion Robert Crichlow (Hanover, NH): Metastasis to the liver from colorectal carcinoma is a very common problem which has long awaited a satisfactory management solution. Metastatic carcinoma of the liver is seldom resectable in its entirety, and the tolerance of the liver to ionizing radiation is insufficient to permit satisfactory palliation with radiotherapy. Systemic chemotherapy, conventionally with 5-fluorouracil, has yielded low (10 to 15 percent) response rates of disappointingly short duration. Regional infusion into the hepatic artery through an external pump vastly improved the quality of palliation but brought significant interference to patients’ life-styles, annoying pump problems, and complications of mycotic aneurysms and sepsis related to the transcutaneous passage of the catheter. The present availability of a totally implantable delivery system has obviated many of the problems inherent in the extracorporeal systems while it has retained the substantial therapeutic advantages of protracted regional infusion. Dr. Cohen and his co-workers have demonstrated the practicality of transbrachial catheter placement without laparotomy, which offers a significant advantage to the patient. Many technical problems have been resolved, including the directing of flow by selective embolization. The delivery system in their hands has been relatively trouble-free and the response rates, especially with the threedrug combination, are impressive. The incidence of ulcer and gastritis complications seems high. I wonder if Dr. Cohen has been able to relate the problem to choice of drug or to catheter position. We have seen uneven responses within the liver which we could relate to laminar flow and uneven drug distribution. I wonder if Dr. Cohen has observed this phenomenon in his patients. Robert Osteen (Boston, MA): At the Brigham and Women’s Hospital, we have explored 34 patients from the Sidney Farber Cancer Institute who were believed to have liver-only metastases. Eleven of those patients were found to have unexpected extrahepatic metastases which indicated the efficacy or the inefficacy of computerized tomography for the evaluation for this problem. We had 17 patients who had evaluable metastases from colorectal carcinoma treated with floxuridine. Our technique involved intraoperative demonstration of bilobar flow using fluorescein dye and postoperative demonstration with radionuclide injections. Of the 17 evaluable patients, we have had partial responses in only 5, defined as a 50 percent reduction in tumor size as measured by the scan. This 29 percent response rate corresponded exactly with the 30 percent response rate reported from Chicago for a threedrug protocol, substituting a methotrexate derivative for the nitrosourea described by Dr. Cohen. We believe that this 29 percent response rate is not significantly different from the response rate that can be obtained with systemic high-dose 5-fluorouracil. There may be a trade-off between
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Implantable Drug Pump
the morbidity of a major abdominal operation and the systemic toxicity of the intravenous chemotherapy. We believe that even though the Infusaid pump is an excellent device for delivery of regional chemotherapy, we have temporarily stopped using the pump until more promising chemotherapy is available. We are currently experimenting with other drugs given for a short time through a percutaneously placed angiographic catheter. We agree with the authors that percutaneously placed polyethylene angiographic catheters malfunction about 30 percent of the time. Transabdominal insertion of the Silastice catheter has fewer catheter-related complications. The abdominal approach allows identification of extrahepatic metastasis, and perfusion of the pancreas, stomach, and duodenum can be avoided by ligating the branches of the hepatic artery. John Braasch (Burlington, MA): Our experience with pumps and catheterization has included considerable trouble with migration of the catheter in the hepatic artery and occlusion of the hepatic artery. Has it been shown that the implantable pump is associated with fewer catheter problems in the hepatic artery? Alfred Cohen (closing): Is this whole thing worth it? Is it worth it to the patients in terms of the modest prolongation of survival, and is it worth it to our society? This group of patients will all ultimately die from their cancer and most are elderly. In terms of randomized trials, there is only one randomized trial (run by the Central Oncology Group) which involved only a 3 week infusion of 5-fluorouracil (which is less effective than floxuridine that
Volume 145, April 1993
showed no benefit. As yet there have been no other controlled trials and there need to be. The group at Michigan is seeking federal funding to do a trial in which all study patients will have a pump implanted and then half the patients will receive 5-fluorouracil intravenously until their condition improves and then hepatic arterial chemotherapy will be added. It will be difficult to decipher the incremental benefit of the pump and there will be no control subjects. Gastritis has been a big problem. The group in Michigan implanted over 100 pumps surgically and made sure that they ligated all right gastric arteries; they had a 60 percent incidence of gastritis as measured by endoscopy. An important advance in detecting laminar flow has been technetium microspheres. Using the sideport of the pump, one can slowly inject over about 1 minute 1 mCi of technetium microspheres and then scan the liver. In this way the distribution of flow and drug to the liver can be seen. The interesting thing is that although liver metastases are hypovascular angiographically, one can see hypervascular and hypovascular metastases by this technique. This may, in fact, be an excellent way of predicting which patients are going to respond to chemotherapy. Dr. Osteen presented a 29 percent response rate with floxuridine. That is about what I’m getting and is at quite considerable variance with the 82 percent that the Michigan group is now talking about. We study catheter flow every 2 to 3 months in our patients. Perhaps because the patients get about 2,500 units of heparin a day, we have seen minimal hepatic artery problems and, in fact, not one documented case of hepatic artery thrombosis.
533
Alfred M. Cohen, MD, Boston, Massachusetts Sheldon D. Kaufman, MD, Boston, Massachusetts William C. Wood, MD, Boston, Massachusetts Alan J. Greenfield, MD, Boston, Massachusetts
Regional infusion of chemotherapeutic agents in the treatment of liver cancer can greatly increase the tumor exposure to the drugs when compared with the exposure when the peripheral intravenous route is employed. Hepatic arterial chemotherapy, primarily with the fluoropyrimidines, has been shown to produce objective response rates of 50 to 80 percent in patients with metastatic colorectal cancer [l-5]. Using carefully stratified historical control subjects, it appears that floxuridine, continuously administered into the hepatic artery, can increase the survival of such patients twofold to threefold over the survival for untreated patients [2]. The discomfort, inconvenience, and complications associated with extracorporeal drug infusion pumps have limited their use in patients receiving chemotherapy. A totally implantable and percutaneously refillable biomedical device has recently been developed for long-term intravascular drug infusions [6]. The initial application of this pump (Infusaida, Infusaid Corp., Norwood, MA) has been for long-term heparin infusion [7]. The same pump has recently been used with floxuridine chemotherapy for long-term infusion into the hepatic artery [S-10]. We recently reported the successful integration of the Infusaid pump with transaxillary angiographic hepatic arterial catheterization [/1,12]. Herein we report our experience with the first 50 patients who have had pump implants for regional chemotherapy, including those patients who underwent either direct surgical or anziozraohic catheterization. From the DeparbTlents of Surgery, Mediiine, and Ftadiilogy. Harvard Medical School and the Massachusetts General Hospital, Boston. Massachusetts. Requests for reprints should be addressed to Alfred M. Cohen, MD, Cox Cancer Center. Massachusetts General Hospital, Boston, Massachusetts 02114. Presented at the 63rd Annual Meeting of the New England Surgical Society, Bretton Woods, New Hampshire, October 15-17, 1982.
Volume 145, April 1983
Patients and Methods Over the 2iJzyear period which ended in March 1982,50 patients with liver cancer underwent implantation of an Infusaid drug infusion pump. In all patients, benzyl alcohol-preserved water containing 1,000 units/ml of heparin was used in the pump. Of the first 50 patients who received pump implants, 3 had primary hepatocellular carcinoma and 47 had metastatic cancer to the liver; 41 of these 47 patients had metastatic colorectal cancer. The primary sites for the remaining six patients were the stomach, small bowel carcinoid, breast, kidney, nasopharynx, and one unknown primary site. A minimum 6 month follow-up was carried out on all patients reported. Of the 41 patients with colorectal cancer metastatic to the liver, 8 had concomitant lung metastases. The extent of hepatic metastases using technetium sulfur colloid liver scan evaluation was as follows: less than 10 percent in 5 patients, 10 to 25 percent in 6,25 to 50 percent in 17, and more than 50 percent in 9. Eleven of the 50 patients underwent laparotomy for catheterization; in 9 the catheter was implanted into the hepatic artery and in 2 into the portal vein. Thirty-nine patients underwent angiographic catheterization; a transaxillary hepatic artery catheter was placed in 38 and an angiographic transhepatic portal vein catheter was placed in 1. Hepatic artery catheterization at laparotomy was performed through the gastroduodenal artery. Angiographic catheterization of the hepatic artery through the transaxillary route was performed as previously described [11,12]. The only drug used in the pump reservoir was floxuridine. It was used at an appropriate concentration within the pump so that the patient received 0.3 mg/kg per day. The drug was kept in the pump for 2 weeks at a time, followed by a 2 week period without the drug to minimize the chance of hepatitis. The alkylating agents mitomycin C and 1,3-bis-(2 chloroethyl) I-nitrosourea (BCNU) were given through the pump sideport as a 1 hour intraarterial infusion every 6 weeks at 15 mg/M2 and 150 mg/M2, respectively.
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Cohen et al
TABLE I
Hepatic Arterial Chemotherapy of Metastatic Colorectal Cancer in 41 Patients
Agents FUdR FUdR + RT Mitomycin FUdR + mitomycin FUdR, mitomycin, BCNU
Therapeutic Response
Stable Disease
3 1 2 2 13
7 1 1 0 4
Progres- Not sive EvalDisease uable 3 1 0 0 1
2 1 0 1 2
BCNU = 1,3-his-(2 chloroethyl) 1-nitrosouria; FUdR = floxuridine; RT = radiotherapy.
Satisfactory response to the chemotherapeutic program was determined by a reduction of at least 50 percent of the
sum of products of measurable lesions on the liver scan and no increase in any other indicator lesion and no new area of malignant disease in the liver. If hepatomegaly was used as the primary indicator, there had to be a reduction in the sum of the measurements below the costal margin at the midclavicular lines and the xyphoid process by at least 30 percent. To be considered a partial response, the above criteria had to be met for at least 3 months. The disease was considered stable if the patient had minimal responses but insufficient regression to meet the above criteria. Progression was defined as an increase in any measurable lesion of more than 25 percent or the appearance of new areas of metastatic disease in the liver. Regular plain roentgenograms of the abdomen were used to check on catheter placement. If there appeared to be any migration of the catheter, the perfusion pattern of the liver was then determined either by digital subtraction angiography or radionuclide flow studies, both performed through the pump sideport. In the latter case, 1 mCi of technetium-99m aggregated albumin microspheres injected slowly through the pump sideport confirmed catheter position and flow to the liver [13].
Results Catheter and pump complications: There were no pump malfunctions in over 260 patient-months. Of more than 600 percutaneous refills, only one infection resulted; it was Escherichia coli infection of the pump pocket which occurred 1 year after the pump was implanted. It necessitated removal of the system. There were no episodes of systemic septicemia or infections of the fluid within the pump reservoir. Of the 38 transaxillary hepatic arterial catheter systems, no problems related to peripheral emboli or to the brachial or axillary arteries occurred. There was no case of catheter occlusion or documented hepatic artery thrombosis. Three hepatic arteries were studied at postmortem examination, the longest one of the three was studied 18 months after death (longest postmortem time of the three) with an angiographic catheter in place. The arteries remained patent with only a very small clot present. In the group that underwent transaxillary angiography, 7 of the 38 patients had withdrawal of the
530
TABLE II
Effect of Prior Chemotherapy on Response to Hepatic Arterial Chemotherapy
Prior Chemotherapy
Therapeutic Response (n)
Disease Stable (n)
Progressive Disease (n)
No Yes
12 9
7 6
2 3
catheter which necessitated four episodes of cracking of which required exchanges. eter could not be replaced patic artery.
replacement. There were the polyethylene catheter In two patients the cathsuccessfully into the he-
Chemotherapeutic responses: There was no response to floxuridine in the three patients with primary hepatocellular carcinoma. Responses at six months in the patients with both stomach cancer and carcinoid were excellent. The patient with metastatic gastric cancer had had progression of her cancer while receiving fluorouracil and chloroethyl cyclohexyl nitrous urea (CCNU). However, an excellent objective response was achieved with floxuridine, mitomycin C and BCNU. The patient with carcinoid metastases to the liver responded to floxuridine. The experience in the 41 patients with metastatic colorectal cancer is outlined in Table I. The effects of previous chemotherapy on the response to hepatic arterial chemotherapy is shown in Table II. Side effects of chemotherapy: Of the 50 patients, symptomatic ulcers or gastritis developed in 8. Two of the eight patients required gastrectomy. Hepatitis that was thought to be chemically induced developed in five patients. One patient remained grossly jaundiced for a year despite the discontinuation of floxuridine. Survival: With a minimum follow-up of 6 months, the survival of the 16 patients with colorectal cancer with only liver metastases was 2.5,4,4.5,, 5,8,8.5,9, 10 (2 patients), 11,12 (2 patients), 13,18 (2 patients), and 21 months. An additional nine patients were alive at 8 (two patients), 9,10,12,13 (two patients), 17, and 18 months after implantation. Comments Until recently, long-term ambulatory regional chemotherapy involved the use of an extracorporeal pump device. This work was pioneered at the Lahey Clinic by Watkins et al [14] using a spring activated pump, More recently, battery powered devices have come into widespread use, not only for constant infusion chemotherapy but also for insulin infusion. However, the quality of life for patients attached to an extracorporeal pump device for many months has been found to be unsatisfactory. In addition, septic complications due to transcutaneous catheterization are unavoidable. The Infusaid pump is an entirely implantable and refillable drug infusion system (now
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approved by the Food and Drug Administration) for chemotherapy with floxuridine. Our experience with 50 patients has confirmed the reliability, safety, and convenience of this medical device. The hepatic artery can be catheterized by laparotomy and surgical implantation of the catheter or by techniques employing angiographic fluoroscopy. The initial approach by Watkins ‘et al [14] was through laparotomy with the catheter threaded into the hepatic artery through the gastroduodenal artery. We have implanted pumps in 12 of our 50 patients in that fashion. An advantage of direct surgical catheterization of the hepatic artery is that it allows for complete abdominal exploration to rule out nonhepatic metastases and to quantitate the extent of liver involvement. However, in patients with extensive liver metastases, recovery from laparotomy may be slow. In patients with marked hepatomegaly, exposure difficulties may make it impossible to directly catheterize the hepatic artery. The technique of percutaneous transbrachial or transaxillary hepatic arterial catheterization has allowed patients to be treated on a prolonged ambulatory basis without the necessity for laparotomy [14,15]. However, catheter-related sepsis and dislodgement of the catheter were the limiting features of this technique [16,17]. We have recently reported the integration of the implantable Infusaid pump with transaxillary hepatic arterial catheterization [11,12]. The surgery is relatively minimal, being performed under local anesthesia. The disadvantages of this system are primarily related to catheter withdrawal which necessitates replacing the catheter. In the 38 patients treated there were no vascular complications in the arm and there were no peripheral emboli. We did have seven patients whose catheters moved out of the ideal area for perfusion and required replacement under local anesthesia. We believe this report confirms the safety and efficacy of the transaxillary approach. Although there is no randomized trial of long-term hepatic arterial chemotherapy with floxuridine, the response rates of patients so treated and their survival strongly suggest a benefit. In the extensive experience at the Lahey Clinic, 71 percent of patients with metastatic colorectal cancer who were treated with long-term administration of floxuridine into the hepatic artery did demonstrate objective therapeutic responses [I]. Pettavel et al [2] used a similar program and reported remissions in 82 percent of 44 patients. This group has pioneered in the staging of hepatic tumors, and using carefully stratified historical control subjects, has demonstrated what appears to be considerably prolonged survival using this regimen. Mitomycin C has some activity in colorectal cancer when given intravenously (an approximately 15 percent objective response rate) [18]. Mitomycin C, like floxuridine [191, is metabolized in the liver, which
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may provide an approximately sixfold increase in tumor exposure when given by the hepatic arterial route [20,21]. In a series of 13 patients with metastatic colorectal cancer treated with the administration of mitomycin C into the hepatic artery, 6 patients responded [22]. Fluorouracil and mitomycin C were combined and administered as a hepatic arterial infusion at the Cleveland Clinic with 10 of 14 patients responding [23]. In a limited experience at the M.D. Anderson Hospital with hepatic arterial infusion of floxuridine and mitomycin C, 10 of 12 patients responded [5]. The nitrosoureas are another group of alkylating agents which have some activity in metastatic colorectal cancer when given intravenously [24]. The drug is actively metabolized in the liver and has a half-life of approximately 5 minutes [25]. Our initial experience with hepatic arterial combination chemotherapy with floxuridine, mitomycin C, and BCNU has been quite encouraging. Excluding 2 nonevaluable patients, 17 of 18 patients with metastatic colorectal cancer responded to this three-drug program; 72 percent of these patients had objective responses which lasted for at least 4 months. Based on the preliminary results, we have embarked on a randomized trial in patients with metastatic colorectal cancer of the liver in which we compare chemotherapy with hepatic arterial infusion of floxuridine with the three-drug chemotherapeutic program of floxuridine, mitomycin C, and BCNU. Summary Regional infusion of chemotherapeutic agents in the treatment of liver cancer can greatly increase tumor exposure to certain drugs. Exposure is 100 times greater with floxuridine, 6 times greater with mitomycin C, and 6 times greater with BCNU. The Model 400 Infusaid implantable, refillable drug infusion pump overcomes much of the discomfort and inconvenience associated with previously employed extracorporeal systems. Our experience with our first 50 patients has been presented herein. Forty-one patients had metastatic colorectal cancer, 3 primary cancers, and 6 other metastatic cancers. Eleven pumps and 11 catheters were implanted at laparotomy. Thirty-nine patients had their pumps integrated to angiographically placed catheters. In over 260 patient months there were no pump malfunctions and only one infection. There were no vascular complications in the patients with angiographically placed catheters. Chemotherapeutic programs included floxuridine, floxuridine and radiotherapy, or floxuridine with mitomycin C and BCNU. In 18 patients with evaluable metastatic colorectal cancer who received hepatic arterial combination chemotherapy, there were therapeutic responses in 13 and disease stabilization in 4. The pumps were well tolerated by patients. They offer a reasonable approach to long-term ambulatory regional hepatic chemotherapy.
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References 1. Oberfield RA, McCaffrey JA, Polio J, et al. Prolonged and continuous percutaneous intraarterial hepatic infusion chemotherapy in advanced metastatic liver adenocarcinoma from colorectal primary. Cancer 1979;44:414-23. 2. Pettavel J. Morgenthaler F. Protracted arterial chemotherapy of liver tumors: an experience of 107 cases over a 12 year period. Prog Clin Cancer 1978;7:217-33. 3. Ansfield FJ, Guillermo R, Davis HL, et al. Further clinical studies with intrahepatic arterial infusion with 5-fluorouracil. Cancer 1975;36:2413-7. 4. Burrows JH, Talley RW, Drake EH, et al. Infusion of fluorinated pyrimidines into hepatic artery for treatment of metastatic carcinoma of the liver. Cancer 1967;20:1886-92. 5. Patt YZ, Mavligit GM, Chuang VP, et al. Percutaneous hepatic arterial infusion (HAI) of mitomycin C and floxuridine (FWR): an effective treatment for metastatic colorectal carcinoma in the liver. Cancer 1980:46:261-5. 6. Blackshear PJ, Dorman FD, Blackshear PL Jr, et al. The design and initial testing of an implantable infusion pump. Surg Gynecol Obstet 1972;134:51-6. 7. Rohde TD, Blackshear PJ, Varco RL, et al. One year of heparin anticoagulation: an ambulatory subject using a totally implantable infusion pump. Minn Med 1977;60:719-22. 8. Buchwald H, Grage TB, Vassilopoulos PP, et al. Intraarterial infusion chemotherapy for hepatic carcinoma using a totally implantable infusion pump. Cancer 1980;45:866-9. 9. Frankel S, O’Mary S. Byfield JE, et al. Regional intraarterial chemotherapy using a totally implantable infusion pump (abstr). American Assoc Cancer Res 1981;22:C-331. 10. Keller J, Ensminger W, Niederhuber J, et al. Effective prolonged hepatic arterial chemotherapy using a totally implanted delivery system (abstr). Assoc Cancer Res 1981;22:C-87. 11. Cohen AM, Wood WC, Greenfield A, et al. Transbrachial hepatic arterial chemotherapy using an implanted infusion pump. Dis Colon Rectum 1980;23:223-7. 12. Cohen AM, Greenfield A. Wood WC, et al. Treatment of hepatic metastases by transaxillary hepatic artery chemotherapy using an implanted drug pump. Cancer 1983 (in press). 13. Kaplan WD, D’Orsi CJ, Ensminger WD, et al. Intraarterial radionuclkfe infusion:a new technique to assess chemotherapy perfusion patterns. Can Treat Rep 1978;62:699-703. 14. Watkins E, Khazei AM, Nahra KS, Surgical basis for arterial infusion chemotherapy of disseminated carcinoma of the liver. Surg Gynecol Obstet 1970;130:581-605. 15. Petrek JA, Minton JP. Treatment of hepatic metastases by percutaneous hepatic arterial infusion. Cancer 1979;43: 2182-8. 16. Tandon RN, Bunnell IL, Cooper RG. The treatment of metastatic carcinoma of the liver by the percutaneous selective hepatic artery infusion of 5fluorouracil. Surgery 1973;73:118-21. 17. Clouse ME, Ahmed R, Ryan R, et al. Complications of long-term transbrachial hepatic arterial infusion chemotherapy. AJR 1977; 129:799-803. 18. Goldman ML, Bilbao MK, Rosch J, et al. Complications of indwelling chemotherapy catheters. Cancer 197536: 1983-90. 19. Krauss S, Sonoda T, Solomon A. Treatment of advanced gastrointestinal cancer with 5-fluorouracil and mitomycin C. Cancer 1979;43: 1598-603. 20. Tseng MH, Luch J. Mittelman A, et al. Chemotherapy of advanced colorectal cancer with regional arterial mitomycin C infusionand concomitant measurement of serum drug level (abstr). Amer Assoc Cancer Res 1981;22:C-104. 21. Hashimdto Y. Fundamental investigations on local chemotherapy for liver cancer. Arch Jap Chir 1978;47:302-18. 22. Fcrtunv IE, Theologides A, Kennedy BJ. Hepatic arterial infusion for iiver metastases from colon cancer: comparison of mitomycin C (NSC-26980) and 5-fluorouracil (NSC-19893). Cancer Chemother Rep 1975;59:401-4. 23. Misra NC, Jaiswal MSD, Singh RV, et al. lntrahepatic arterial
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infusion of combination of mitomycin C and 5-fluorouracil in treatment of primary and metastatic liver carcinoma. Cancer 1977;39: 1425-29. 24. Moertel CG, Reitemeier RJ, Hahn RG. Therapy of advanced gastrointestinal cancer with 1-3-his-(2-chloroethyl)-l-nitrosourea (BCNU). Clin Pharmacol Ther 1968;9:652-6. 25. Ensminger WD, Thompson M, Come S. et al. Hepatic arterial BCNU: a pilot clinical-pharmacologic study in patients with liver tumors. Cancer Treat Rep 1978;62:1509-12.
Discussion Robert Crichlow (Hanover, NH): Metastasis to the liver from colorectal carcinoma is a very common problem which has long awaited a satisfactory management solution. Metastatic carcinoma of the liver is seldom resectable in its entirety, and the tolerance of the liver to ionizing radiation is insufficient to permit satisfactory palliation with radiotherapy. Systemic chemotherapy, conventionally with 5-fluorouracil, has yielded low (10 to 15 percent) response rates of disappointingly short duration. Regional infusion into the hepatic artery through an external pump vastly improved the quality of palliation but brought significant interference to patients’ life-styles, annoying pump problems, and complications of mycotic aneurysms and sepsis related to the transcutaneous passage of the catheter. The present availability of a totally implantable delivery system has obviated many of the problems inherent in the extracorporeal systems while it has retained the substantial therapeutic advantages of protracted regional infusion. Dr. Cohen and his co-workers have demonstrated the practicality of transbrachial catheter placement without laparotomy, which offers a significant advantage to the patient. Many technical problems have been resolved, including the directing of flow by selective embolization. The delivery system in their hands has been relatively trouble-free and the response rates, especially with the threedrug combination, are impressive. The incidence of ulcer and gastritis complications seems high. I wonder if Dr. Cohen has been able to relate the problem to choice of drug or to catheter position. We have seen uneven responses within the liver which we could relate to laminar flow and uneven drug distribution. I wonder if Dr. Cohen has observed this phenomenon in his patients. Robert Osteen (Boston, MA): At the Brigham and Women’s Hospital, we have explored 34 patients from the Sidney Farber Cancer Institute who were believed to have liver-only metastases. Eleven of those patients were found to have unexpected extrahepatic metastases which indicated the efficacy or the inefficacy of computerized tomography for the evaluation for this problem. We had 17 patients who had evaluable metastases from colorectal carcinoma treated with floxuridine. Our technique involved intraoperative demonstration of bilobar flow using fluorescein dye and postoperative demonstration with radionuclide injections. Of the 17 evaluable patients, we have had partial responses in only 5, defined as a 50 percent reduction in tumor size as measured by the scan. This 29 percent response rate corresponded exactly with the 30 percent response rate reported from Chicago for a threedrug protocol, substituting a methotrexate derivative for the nitrosourea described by Dr. Cohen. We believe that this 29 percent response rate is not significantly different from the response rate that can be obtained with systemic high-dose 5-fluorouracil. There may be a trade-off between
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the morbidity of a major abdominal operation and the systemic toxicity of the intravenous chemotherapy. We believe that even though the Infusaid pump is an excellent device for delivery of regional chemotherapy, we have temporarily stopped using the pump until more promising chemotherapy is available. We are currently experimenting with other drugs given for a short time through a percutaneously placed angiographic catheter. We agree with the authors that percutaneously placed polyethylene angiographic catheters malfunction about 30 percent of the time. Transabdominal insertion of the Silastice catheter has fewer catheter-related complications. The abdominal approach allows identification of extrahepatic metastasis, and perfusion of the pancreas, stomach, and duodenum can be avoided by ligating the branches of the hepatic artery. John Braasch (Burlington, MA): Our experience with pumps and catheterization has included considerable trouble with migration of the catheter in the hepatic artery and occlusion of the hepatic artery. Has it been shown that the implantable pump is associated with fewer catheter problems in the hepatic artery? Alfred Cohen (closing): Is this whole thing worth it? Is it worth it to the patients in terms of the modest prolongation of survival, and is it worth it to our society? This group of patients will all ultimately die from their cancer and most are elderly. In terms of randomized trials, there is only one randomized trial (run by the Central Oncology Group) which involved only a 3 week infusion of 5-fluorouracil (which is less effective than floxuridine that
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showed no benefit. As yet there have been no other controlled trials and there need to be. The group at Michigan is seeking federal funding to do a trial in which all study patients will have a pump implanted and then half the patients will receive 5-fluorouracil intravenously until their condition improves and then hepatic arterial chemotherapy will be added. It will be difficult to decipher the incremental benefit of the pump and there will be no control subjects. Gastritis has been a big problem. The group in Michigan implanted over 100 pumps surgically and made sure that they ligated all right gastric arteries; they had a 60 percent incidence of gastritis as measured by endoscopy. An important advance in detecting laminar flow has been technetium microspheres. Using the sideport of the pump, one can slowly inject over about 1 minute 1 mCi of technetium microspheres and then scan the liver. In this way the distribution of flow and drug to the liver can be seen. The interesting thing is that although liver metastases are hypovascular angiographically, one can see hypervascular and hypovascular metastases by this technique. This may, in fact, be an excellent way of predicting which patients are going to respond to chemotherapy. Dr. Osteen presented a 29 percent response rate with floxuridine. That is about what I’m getting and is at quite considerable variance with the 82 percent that the Michigan group is now talking about. We study catheter flow every 2 to 3 months in our patients. Perhaps because the patients get about 2,500 units of heparin a day, we have seen minimal hepatic artery problems and, in fact, not one documented case of hepatic artery thrombosis.
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