Cancer TreatmentReviews ( 1991) 18, 213-224

Regional infusion chemotherapy for colorectal hepatic m e t a s t a s e s - - W h e r e is it going? Michael J. Dworkin and Timothy G. Allen-Mersh Department of Surgoy, Westminster and Charing ()ross Medical School, Horseferry Road, Dean Ryle Street, London SW1P 2AP, U.K.

Colorectal cancer is the second most frequent cause of cancer death in the U.K. responsible for 22,000 deaths per annum. The incidence of hepatic metastases in those relapsing after 'curative' surgery is at least 50°,~, and there is clearly a need tbr more effective treatment. Interest in regional inliasion chemotherapy arose because of the failure of systemic therapy to influence the course of the disease. Regional infusion chemotherapy to the liver was first attempted over 30 years ago. Initially, treatment was carried out using percutaneously placed angiographic catheters. However, this was associated with cracked and blocked catheters as well as gastroduodenal and hepatic toxicity. However, since 1980, interest has been rekindled due to the development of the implantable pump. The accuracy and reliability of these pumps means that patients can now receive continuous treatment as an outpatient without interfering with daily activities. The main limitations of the system are the requirement for low volume chemotherapy in a stable solution, the cost of the p u m p and its implantation. The requirements for regional infusion therapy for liver metastases are: • a drug with appropriate pharmacokinetics, • catheter placement to infuse the entire turnout • a safe and reliable drug delivery system.

Rationale for regional infusion chemotherapy Dose response relationship The aim of hepatic artery infusion (HAI) is to increase drug concentration in the liver while sparing other organs from excessive toxicity. Although the relationship between dose and toxicity is clear, evidence for a dose relationship with tumour response is less obvious. In vitro such a relationship has been demonstrated but *.he multitude of trials with their variety of regimens and doses make comparison between trials difficult. Hyrniuk et al. have attempted to overcome this by using the concept of dose intensity (28). This is the a m o u n t of drug received per unit time as mg/m2/week. It allows for time delays and dose reductions but assumes that scheduling is more important in reducing toxicity than in effecting tumour kill. From an analysis of published trials they demonstrated a steep dose 0305-7372/91/040213 + 12 $08.00/0

,~) 1991 Academic Press Limited 213

214

M.J. DWORKIN AND T. G. ALLEN-MERSH

response relationship for 5FU in advanced colorectal cancer which has been confirmed by others (19).

The regional advantage The benefit of regional delivery over systemic infusion is known as the regional advantage (Rd) and can be expressed as: Rd-

1 + CLtb Qt(1 - E t )

where CLtb is the total body clearance, Qt is the blood flow through the perfused artery and Et is the extraction ratio of the perIhsed organ (9). This advantage will vary according to the individual pharmacokinetics of each agent. There is a greater regional advantage with drugs which have short plasma half-lives and high clearance from the circulation such as 5 fluorouracil (5FU) and fluorodeoxyuridine (FUdR) while agents with low total body clearance such as methotrexate have virtually no regional advantage (10). The first pass extraction ratios for 5FU and F U d R are around 50 and 90°/'0 respectively (15) and their plasma half-lives are only a few minutes. It is thus possible to achieve a regional advantage of several hundred fold using these drugs. Other agents have been used although the pharmacokinetics are rarely as well suited to regional treatment. The regional advantage can be further increased by decreasing the blood flow (Qt) to the organ and this is the basis of treatment with arterial ligation or embolization combined with regional cytotoxic therapy.

Infusion or bolus? Prolonged infusion appears to be the optimal method of drug administration. Most cytotoxic agents act only on the proliferating cell fraction and continuous exposure may induce other cells into the proliferating part of the cycle and increase tumour cell kill (51). Prolonged infusion may also decrease the drug toxicity as shown by Seiffert et al. who randomized 70 patients to receive either bolus or infusion therapy and noted a reduction in myelotoxicity as well as an increased response in the infusion group (54). A similar randomized study by Lokich et al. reached the same conclusions (38).

Which route of administration? The rationale behind the route of hepatic artery chemotherapy is based on the vascular pattern of hepatic metastases. This is more complex than at other sites due to the dual blood supply via the hepatic artery and portS,1 vein. Hepatic metastases are thought to develop t)om portal vein tumour emboli (63). Dukes found evidence of venous spread in 17 °/o of operative rectal cancer specimens (13) and it is known that malignant cells may pass into the portal circulation at the time of tumour mobilization (17). Established metastases within the liver are predominantly supplied by the hepatic arter~rather than the portal vein (6, 36). Ackermann carried out studies on tumours of varying sizes and found that tumours less than 1 mm in diameter showed no new vessel formation. Above this size new vessels developed around the tumour which derived from arterial or portal circulations in a random manner. Finally, as the tumours

REGIONAL INFUSION CHEMOTHERAPY FOR COLORECTAL HEPATIC METASTASES 215 increased in size up to and above 5 mm they developed a circulation which was predominantly derived from the arterial side with little portal contribution (1). From these studies and others, it would seem logical to deliver chemotherapy tbr established hepatic metastases via the hepatic arterial rather than portal vein route. This has been confirmed in a number of studies (11) some of which have demonstrated superior response rates after hepatic artery administration compared with portal vein infusion.

Experience with hepatic artery infusion Although hepatic artery chemotherapy has been in use for 30 years, improvement in survival or quality of life has not been demonstrated. Lokich stated in 1983 that one of the main reasons why hepatic artery chemotherapy is not the standard treatment for established hepatic metastases is the inability to demonstrate that it prolongs survival more than systemic chemotherapy as well as concern about cost (37). This is still true today. Numerous reports in the literature have demonstrated response rates of 40-88% (4, 42, 53). Although response criteria vary, this is higher than that reached by systemic chemotherapy (15 20~{/o) and is also higher than response rates achieved when agents such as folinic acid are added (16-45%) (3). However, these have largely been reports of series rather than randomized trials. It is therefore not possible to say fi'om these studies if survival is prolonged and quality of life has rarely been measured. There are a few prospective controlled trials which assess whether hepatic artery chemotherapy is superior to systemic therapy. An early study by Grage compared a loading course of HAI (21 days) with systemic chemotherapy both followed by weekly systemic bolus therapy. Response criteria relied on abdominal palpation. This study showed an increased response rate in the HAI arm although survival was similar (21). Kemeny et al. randomized 99 patients to receive HAI (48 patients) or systemic (51 patients) FUdR. All patients had a laparotomy and were given a 14-day infusion F U d R alternating with normal saline. The dose administered in the intra-arterial group was twice that of the systemic group due to the limitation of systemic toxicity. Patients in the HAI group had a higher response rate (50 vs 20°/O). Survival analysis showed increased median survival in the HAI group, 17 vs. 12 months but this was not statistically significant and was difficult to interpret as many non-responding patients were crossed over from the systemic into the HAI arm (30, 31). A similar study by the Northern California Oncology group showed response rates of 42 vs. 10°/jo (25). They also crossed over patients into the HAl arm and found a further response of 11 o~ in those not responding to systemic therapy. They initially noted a high incidence ofbiliary toxicity for which it was necessary to discontinue treatment but found that this could be avoided by early dose reduction when the alkaline phosphatase was elevated. Once again, crossover into the HAI arm prevented survival analysis. Chang et al. performed a study with no crossover (8). They showed improved response rates of 62 vs. 17°'o in the HAI group but at 2 years survival was not significantly different; 22 and 15°/~ in the HAI and systemic arms respectively. In this study patients randomized to HAI therapy had a staging laparotomy and in 9 out of 32 patients HAI therapy was not given due to extrahepatic disease. As analysis excluded these patients this means that the HAI group was a more favourably selected group than the systemic group who did not receive a laparotomy. Kirk Martin et al. randomized 74 patients to continuous HAI FUdR or weekly bolus

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M.J. DWORKIN AND T. G. ALLEN-MERSH

Table 1. Randomized trials of hepatic artery infusion chemotherapy

Study

Treatment arms

No

Response rate ('~"i,)

Median survival

Cross over

13.5 15.4

No

Grage 1979 (COG) (21)

HAI 5FU loading then IV Bolus IV bolus 5FU

31 30

34~'o 23%

Chang 1987 (8)

HAI FUdR IV FUdR

21 32

62~o 17%

Kemeny 1987 (30, HA1 FUdR 31) IV FUdR

48 51

50'~;, 19.6%

17 12

31/51

Hohn 1989 (NCOG) (25)

HAI FUdR IV FUdR

50 65

42'~o 10".~,

16.3 16.1

High biliary toxicity 28/65 Diarrhoea

Kirk Martin 1990 (34)

HAl FUdR IV bol. 5FU

33 36

48~)~ 21'~,

12.6 10.5

No

Rougier 1990 (48) HAI FUdR IV 5FU or symptomatic

81

14

No

Sail 1989 (50)

HAl FUdR HA1 + IV FUdR

2 y survival 22"; 15%

No

82

10*

23 21

1 and 3 year survival 86'I~, 43°.~, 89°~o0°,~,

52°i~ 48%

Response by palpation

Extrahepatic relapse 56%

Extrahepatic relapse No

6 l '~, 33%

5 F U a n d found increased response rate (48 vs. 21¢!{,) in the HA1 a r m with a slight but not significant increase in m e d i a n survival (12.6 vs. 10.5 months) (34). So far no fully published trials have d e m o n s t r a t e d significant increased survival in treated patients vs. controls receiving s y m p t o m a t i c t r e a t m e n t alone although one abstract by R o u g i e r reports a modest survival increase of 4 months (48). A few conclusions emerge a b o u t hepatic artery c h e m o t h e r a p y . First, the response rate after H A l is consistently higher within the liver than with other tbrms of c h e m o t h e r a p y . A l t h o u g h there m a y be some survival a d v a n t a g e c o m p a r e d with systemic c h e m o t h e r a p y this has not been d e m o n s t r a t e d by the studies to date. W h e r e relapse occurs in patients receiving hepatic artery infusions it is frequently e x t r a h e p a t i c whereas i n t r a h e p a t i c progression leading to d e a t h is often the case with systemic c h e m o t h e r a p y . O n e w a y a r o u n d this d i l e m m a m a y be to combine the systemic a n d regional approaches. Sail (50) did this by infusing F U d R both systemically a n d regionally. A similar a p p r o a c h was used by Stagg who c o m b i n e d shorter cycles of H A l F U d R with systemic 5 F U (55). A l t h o u g h the p r i m a r y aim was to reduce biliary toxicity they also noticed a lower incidence o f e x t r a h e p a t i c failure (see T a b l e ) .

Problems with hepatic artery infusion chemotherapy Toxicity

Unlike systemic t h e r a p y the toxic effects of F U d R infhsion c h e m o t h e r a p y are almost entirely confined to the liver due to high local d r u g levels c o m b i n e d with a high first pass

REGIONAL INFUSION CHEMOTHERAPY FOR COLORECTAL HEPATIC METASTASES 217 extraction. In this regard H A I is similar to radiotherapy, as the dose-limiting factor is of local turnout host tissue toxicity (14). FUdR-induced cholecystitis is prevented by cholecystectomy at the time of p u m p insertion (not possible when percutaneously placed catheters are used) and gastritis is rarely problematic if patients are placed in H2 antagonists. The most significant toxicity encountered is biliary sclerosis but as pointed by Hohn, this can be reduced by carefhl enzyme monitoring and early dose reduction (24). Many trials have reported a high incidence of biliary toxicity due to a lack of awareness of this approach. Most cases are reversible by early detection and dose reduction. Corticosteroids may be of benefit in patients with hepatic toxicity or cholestatic jaundice and these may also be given through the inthsion pump. There is also evidence that fluoropyrimidine metabolism is subjected to a circadian rhythm with metabolism higher in the late afternoon and evening. In a randomized study using a time modified regimen of systemic F U d R those receiving the time modified regimen tolerated 50°,~, more F U d R with less toxicity (60).

Anatomical variation The hepatic arterial supply of the liver varies in 25°'/o of persons. The major variations that commonly occur are when the left hepatic artery originates from the left gastric artery or when the right hepatic arises from the superior mesenteric artery. While the use of two separate catheters has been advocated, we have found that ligation of the aberrant vessel results in perthsion of both lobes by the remaining artery and this can be easily checked by the infusion of methylene blue into the catheter at the time of surgery.

Adjuvant chemotherapy Adjuvant systemic therapy Occult micrometastatic disease is present in 20 30~)~o of patients undergoing apparently curative resection and may be particularly sensitive to chemotherapy due to a shorter cell cycle time and increased growth fraction (51). A variety of single and combination agents have been used. A meta-analysis of systemic adjuvant therapy by Buyse et al. analysed published data on 6791 patients. Although it did not show any overall survival advantage it showed a slight advantage (3Uo) among those receiving prolonged 5FU-based regimens (7). The addition of the immunomodulator levamisole appears to have a beneficial efl'ect when given with 5FU as adjuvant therapy following colonic resection. Recent studies have shown a survival advantage in Dukes C patients (35, 41). However, the decrease in hepatic metastases is not as apparent as the decrease in systemic disease and this may indicate that this form of adjuvant therapy is less effective in eliminating occult liver metastases.

Adjuvant intraportal therapy Several studies ofintraportal 5FU have been carried out. Taylor randomized 244 patients to either 1 week of 5FU starting at the time of surgery or no adjuvant therapy and found

218

M.J. DWORKIN AND T. G. ALLEN-MERSH

a highly significant increase in median survival in Dukes C and B patients with a reduction in hepatic recurrence (57). However, when repeated by the NSABP in 1158 patients there was an increase in disease-free but not overall survival (64). They found a higher relapse rate in the liver in the intraportal arm and speculated that the increase in disease-free interval may be due to 5FU acting systemically rather than regionally. Other trials (5) have produced similar conflicting results and a meta-analysis performed by Gray demonstrates that there is still a need to evaluate the question of whether adjuvant portal vein chemotherapy does lead to a reduction in mortality (22). The A X I S multicentre trial currently underway in the U K has been designed to answer this question. While the idea of adjuvant therapy is attractive it is not without related morbidity and mortality. One of the problems with this approach is that the majority of patients will not fit; either because they would never have developed metastases or because they develop disease despite adjuvant therapy. One possible refinement is to select high risk rather than treating all patients. Selection may be by risk factors such as histology, DNA ploidy, oncogene expression or allelic loss. An alternative strategy is that of an early diagnostic approach using perioperative ultrasound or enhanced CT scan so that patients with confirmed low bulk metastases can be identified and treated while disease is minimal. It would allow for more radical treatment in the knowledge of definite disease rather than a probability and may be easier for patients to accept. No trial has yet been carried out specifically investigating treatment of low bulk disease.

Hepatic artery infusion adjuvant to hepatic resection Long-term survival may be achieved in around 25°/'o of those undergoing curative hepatic resection. This implies that 75C~o of those whose metastases are resected will die due to a recurrence of their disease. An analysis of the site of recurrence after liver resection demonstrates that the liver is the primary site of treatment failure in about one-third of those with recurrence (26). Experimental evidence in animals suggests that the development of occult tumours is enhanced by liver resection possibly by the release of growth factor involved in liver regeneration (43). Adjuvant therapy may therefore be of benefit in patients undergoing curative hepatic resection. One randomized study ofintra-arterial chemotherapy as an adjunct to resection of multiple hepatic metastases showed a trend to increased survival in the resected group (29) although this was not seen at a later analysis (61). Resection of large metastases leaving low bulk residual disease may be of benefit when combined with infusion chemotherapy. Patt et al. found that with adjuvant HAI chemotherapy there was no survival difference between patients with positive resection margins (normally a poor prognostic indicator) and those with clear margins (44). He suggested that this may indicate the benefit of adjuvant regional chemotherapy in patients with positive margins or residual tumour.

Alternative strategies Ligation and embolization Hepatic artery ligation has been used in an attempt to decrease the growth of hepatic metastases. The potential benefit is reduced by revascularization of the tumour from portal

REGIONAL INFUSION CHEMOTHERAPY FOR COLORECTAL HEPATIC METASTASES 219 or collateral arterial sources. This has led some to develop methods of intermittent arterial occlusion in which the hepatic artery can be repeatedly occluded for short periods (46). The combination of hepatic artery ligation and infusion chemotherapy into portal or arterial routes has been investigated. One randomized study of ligation and portal vein infusion in 24 patients did show a survival benefit although group numbers were small (58). Other studies have combined hepatic artery ligation with infusion through the distal artery and some achieve high response rates (12) but once again meaningful advantage is difficult to determine due to a lack of randomized studies. More recently there has been interest in degradable starch microspheres. These commercially prepared spheres have a half-life in the region of 20-30 min and provide a very effective way of temporarily reducing hepatic arterial flow. Administration of these spheres causes regional stasis in the tumour and this has been shown to increase the uptake of 5FU or F U d R experimentally (18) and clinically (59) and to decrease the peak plasma drug levels. A number of Phase II studies have been undertaken combining starch microspheres with a number of cytotoxic drugs and these report response rates of between 20-50o/o. One randomized controlled trial compared a combination of starch microspheres and 5FU with non-reversible hepatic artery embolization and a no treatment control arm (27). 'This showed a slight, but non-significant, increase in the median survival of the microsphere/5FU group. An alternative approach is to use longer acting microparticles which have the cytotoxic agent encapsulated within (33). This approach can alter the pharmacokinetic profile of a drug so that its regional advantage can be enhanced and combined with the effect of short-term ischaemia. Another vehicle for selectively delivering treatment to tumours is to use lipiodol, an oily contrast medium which is retained within tumours. Lipiodol can be emulsified with several cytotoxic drugs or used to deliver iodine- 131 or yttrium-90. This has been extensively used in the treatment of hepatocellular carcinoma but less frequently for colorectal metastases which are less well vascularized.

Vasoactive agents

Sigurdson et al. (55) have reported that the uptake of F U d R into tumour is less than into liver. This is likely to be a function of the poor vascular perfusion of the tumour and a relatively poorer extraction by tumour than liver. Clinically, liver uptake is the factor that limits against further dose increase. One approach to increase the therapeutic index is to alter the proportion of blood flow to favour the tumour. Vasoconstrictors, such as vasopressin and angiotensin have been used to exploit the absence of smooth muscle around the tumour vessels and to constrict selectively normal vessels increasing the proportion of drug delivered to the tumour. The absence of smooth muscle means that the tumours are less able to autoregulate their flow and induced hypertension has also been used to try to increase uptake into a variety of tumours. Goldberg et al. have used regionally delivered angiotensin to target potentially cytotoxic microspheres to liver tumours and have shown an increase in the relative delivery to tumours up to threetbld (20). However, whether these agents have any potential to enhance the delivery of cytotoxic drugs given by infusion is unknown although it may be that the beneficial effect is a short-term phenomenon and not possible over a prolonged period (52).

220

M.J. DWORKIN AND T. G. ALLEN-MERSH

Regional antibody therapy The concept of tumour-associated antigens as a target for immunotherapy dates ti'om the 1960s. Monoclonal antibodies are attractive because of their high speciiicity compared to conventional chemotherapy. Several problems remain including heterogeneity of antigen expression, development of high affinity antibodies and antigenic modulation. They may be used to induce host-mediated toxicity or labelled with toxins or radio pharmaceuticals. A number of Phase I and Phase II studies have been carried out such as that by Riva et al. (49) in which a monoclonal directed against CEA or similar turnout antigens, was used and labelled with a therapeutic dose of 113'. Four responses out of 15 patients were achieved including two complete responses. Animal studies suggest that compared to systemic administration, there may be some regional advantage tbr antibodies administered into the hepatic artery although this is only likely to be small. However, the addition of histamine to the infusion increased the uptake ratio in the tumour threefold (23). Radiotherapy One randomized study of H A I chemotherapy using 5FU with or without external beam radiotherapy I~ailed to show any increase in response rates in those receiving additional radiotherapy (62) although regionally delivered radiolabelled microspheres may have a more selective action if delivered into the hepatic artery as discussed above.

Biological response modifiers Tumour necrosis factor Experimental work with tumour necrosis factor has suggested a wide range of anti-turnout activity. However, clinical tumour response has been disappointing. There have also been severe limiting side-effects ofhypotension, CNS dystunction and cardiopulmonary toxicity (32). Mavligit el al. carried out a Phase I trial of hepatic artery infusion o f r T N F (39) and tbund that by using a regional approach, doses of six times the intravenous dose could be tolerated. They also demonstrated a partial response in some previously chemoresistant patients. Despite the improved regional delivery advantage, response rates were poor. An adequate therapeutic index may not be achieved and approaches such as isolated perfusion may be required if improved response rates are to be achieved. Interleukin- 2 T cell growth factor II,-2 may have a synergistic effect with fluorouracil and may act by increasing LAK cells or tumour-infiltrating lymphocytes. Mavligit el al. (40) randomized 28 patients to receive IL-2 into hepatic or splenic artery with partial responses in only one in each group (7%). Marked dose-related toxicity was noted and four complications at the site of femoral puncture. Moreover, eight patients developed allergic reactions ti'om contrast due to repeated percutaneous catheterizations. There was no systemic treatment arm and it is therefore not possible to compare regional with systemic delivery although there was probably a lower incidence ofcardiopulmonary toxicity when compared with other trials.

REGIONAL INFUSION CHEMOTHERAPY FOR COLORECTAL HEPATIC METASTASES

221

Biochemical response modifiers Folinic acid

Because of the low response of metastatic disease to systemic 5FU strategies are being developed to enhance its anti-turnout effect through biochemical modulation. Folinic acid increases the stability of the F d U M P ternary complex necessary to inhibit thymidylate synthetase within the t u m o u r cell and can increase the cytotoxicity of the fluoropyrimidines. Several randomized trials have been carried out of 5FU vs. 5FU/Folinic acid given systemically. Most show an increased response rate but in only two of seven studies was a survival advantage demonstrated (16, 47). Two regional infusion studies have included tblinic acid in the regimen. Pattet al. carried out a Phase I trial of H A l F U d R and escalating doses of folinic acid (45). T h e y had a partial response rate of 58~I{~ but had to terminate treatment in 35°i~ of patients because ofhepatobiliary toxicity which occurred more frequently than from F U d R alone. K e m e n y carried out a pilot study to evaluate administration of F U d R and fblinic acid through the Inlhsaid p u m p in a variety of doses and showed an overall response rate of 72°4 with a median survival of greater than 27 months. However, once again, the combination of folinic acid and F U d R caused greater hepatic toxicity than with F U d R alone (31 ).

The future Hepatic artery chemotherapy is currently the most effective treatment for unresectable hepatic colorectal metastases. Response rates are higher than for any other treatment although there is no clear survival advantage compared with systemic chemotherapy. This may be because of extrahepatic disease progression in the presence of a hepatic infusion of F U d R . Better vascular perthsion and drug uptake into small metastases may mean that they are more sensitive to chemotherapy. Intraoperative ultrasound and C T portography are now able to detect small metastases of around 5 mm. The use of H A I as a treatment fbr early metastases needs to be addressed within a controlled clinical trial (2). Occult residual disease is present in the livers of m a n y patients undergoing apparently curative resection of liver metastases and therefore a similar argument holds true concerning H A l as an adjuvant therapy to hepatic resection. With established metastatic disease there are two main problems to solve. First, to improve response in terms of both n u m b e r of responders and the extent of response. T h e combination of biological response modifiers with established drugs holds some hope fbr this. Second, the problem of extrahepatic relapse ill those responding intrahepatically needs to be addressed. One possible approach is to place separate catheters to deliver both regional and systemic therapy. An alternative method may be to utilize the varying pharmacokinetic properties of different cytotoxic agents to combine treatment with a drug that has a high regional advantage with one that has not. This would allow both intra and extrahepatic sites to be treated utilizing one delivery system via the hepatic artery. However, the viability of the transhepatic route to deliver chemotherapy to systemic sites has not been evaluated. Finally, it is important to stress that well-organized controlled studies are the only way of making progress.

222

M . J . D W O R K I N AND T. G. ALLEN-MERSH

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26.

27.

28. 29.

30.

31.

32. 33. 34.

35.

36.

37. 38.

39.

40.

41.

42. 43. 44.

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