- Email: [email protected]
Current advances in the treatment of gastrointestinal malignancy
127
1993; 14: 127-l 52 0 1993 Elsevier Scientific Publishers Ireland Ltd. All rights reserved. 1040-8428/93/%24.00 Critical
Reviews
in Oncology/Hematology,
ONCHEM 00066
Current advances in the treatment of gastrointestinal malignancy Michael Findlay and David Cunningham Department
of Medicine,
Royal
Marsden
Hospital,
Downs
Road,
Sutton,
Surrey,
SM2
SPT,
UK
(Accepted 18 December 1992)
Contents I.
Introduction
.................................................
II.
Treatment of unresectable or metastatic colorectal cancer .........
128
III.
Adjuvant treatment of colorectal cancer .........................
134
IV.
Non-invasive monitoring
136
V.
Molecular biology of colorectal cancer ..........................
139
VI.
Treatment of advanced and metastatic gastric cancer .............
140
VII.
Neo-adjuvant chemotherapy for gastric cancer ...................
145
VIII.
Conclusions
147
of drug metabolism in colorectal cancer
.................................................
References ...........................................................
I. Introduction Colorectal and gastric cancers are two of the four most common tumours worldwide [l]. These two tumour types are the most widely studied gastrointestinal malignancies in oncology, hence are in need of frequent review. The range of potential outcomes for these two diseases provides both the scientist and clinician with a variety of challenges, thus demanding a multidisciplinary approach. Advanced metastatic incurable disease is the ultimate outcome in about half of all new cases of colorectal cancer. This large population of patients have historically received relatively ineffective cytotoxic treatment driven by anecdote and frustration on the part of the clinician and by desperation in the patient. The advances in preclinical science and a Correspondence to: Dr. David Cunningham, Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK.
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148
more structured format for conducting clinical trials has yielded important results in this area. The renewed interest in treating colorectal cancer is based on several relatively recent advances. 5-Fluorouracil is the cornerstone of treatment and although over 30 years old is still being keenly studied to optimise both its own schedule and to combine it with the increasing variety of modulators. These studies have yielded clinical results showing prolongation of life and reduction of tumour related symptoms - important endpoints in palliative treatment. Advances in non-invasive monitoring of chemotherapy and tumour metabolism using positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) shows promise in providing early predictors of outcome thus enabling a more individualized treatment programme. Anti-tumour activity, determined from studies in metastatic disease can indicate appropriate schedules for use in the adjuvant setting - perceived by many to be a more useful place for these relatively inactive schedules. Beyond optimiz-
128
ing the use of established treatments, new drugs and novel therapies are needed. Much of the emphasis in this area is based on the increasing understanding of the molecular carcinogenesis of this disease. Gastric cancer more frequently presents at an advanced stage consequently with poor final outcome, yet can be cured if surgically resected at an early stage. Screening and prevention strategies are important in this disease, however, treatment of advanced gastric cancer again relies on the development of new drugs or schedules. Application of active regimens to the adjuvant and neo-adjuvant settings currently offer the best opportunity to improve long term survival. II. Treatment of unresectable or metastatic colorectal cancer After lung cancer in men and breast cancer in women, colorectal carcinomas are the next most common tumour type in the United States [2]. Overall approximately 50% of the 140 000 cases diagnosed each year are ultimately cured [2] while 200/o of patients have metastatic disease at first presentation. Despite the potential to reduce the incidence of metastatic disease with primary prevention, with screening for early stage disease and with the use of adjuvant treatments [3,4], there remains an urgent need to develop more effective treatment for disseminated colorectal cancer. Short of curing metastatic disease, oncologists must focus on maximizing length and quality of life ensuring active treatment is significantly better than best supportive care. Randomised studies with a best supportive care arm however are difficult to conduct due to patient and oncologist acceptance. A recent study from the Nordic Gastrointestinal Tumour Adjuvant Therapy Group [5] has randomised patients with asymptomatic metastatic colorectal cancer to immediate chemotherapy or chemotherapy when symptoms develop. Using this design the investigators have shown chemotherapy given before symptoms arise is more likely to prolong life while maintaining a longer symptomfree period. This study encourages the practice of giving early chemotherapy however only partly supports the use of treatment over best supportive care. Successful treatment of other disseminated malignancies has been with combination chemotherapy however in colorectal cancer this has been unrewarding and recent emphasis has been on 5-fluorouracil (5-FU), its scheduling and its modulation by agents such as leucovorin, interferon-a, PALA or cisplatin. Although the manipulation of 5-FU may enhance activity enough to influence survival when applied to the adjuvant set-
ting, its combination with new agents having different mechanisms of action are needed to greatly impact on metastatic disease. With the Intergroup study showing a survival advantage with adjuvant 5-FU and levamisole in Dukes C colon cancer [4] there has been renewed interest in optimising new regimens in metastatic disease that may also have application in the adjuvant setting. II-A. 5Fluorouracil
Since its introduction in 1957 by Heidelberger et al. [6], 5-FU continues to be the mainstay of cytotoxic treatment in colorectal cancer. 5-FU given orally results in highly variable absorption [8] however in a trial comparing i.v. to oral 5-FU, even though both arms had equivalent haematological toxicity the intravenous route gave a higher response rate (26% vs. 19%) [7]. As 5-FU given by the oral route is not indicated based on the current experience, most of the recent work with 5-FU has been determining the best intravenous schedule and exploring intra-arterial treatment. The most recent issue in intravenous 5-FU treatment is that of schedule. Based on in vitro data showing enhanced inhibition of colony formation in human colon cancer cells with prolonged drug exposure [9] and the known short plasma half-life of 5-FU [6], intravenous infusions have entered clinical evaluation. Although short (l-5 day) and prolonged ambulatory infusions appear to give better responses than bolus schedules, there has been no comparison of short and long infusions. In a multicentre study, Lokich et al. from the Mid Atlantic Oncology Program, compared continuous i.v. 5-FU at a dose of 300 mg/m2/day for 10 weeks or more, to five daily bolus injections (500 mg/m2) given for 1 week in every 5 [lo]. The results show an enhanced response rate (30% vs. 7%) with infusional treatment however no overall difference in survival. Infusional 5-FU gave less haematological toxicity and stomatitis however was uniquely associated with plantar-palmar erythema requiring dose reductions in 23% of patients. Plantar-palmar erythema usually requires reduction of 5-FU dose however pyridoxine 50 mg per oral t.d.s. does ameliorate the condition [ll]. Another problem with ambulatory infusions is that of the central venous catheter - mainly with thrombosis. In a randomised trial, Bern et al. [12] have shown that warfarin 1 mg orally daily, a dose very unlikely to measurably alter the patients prothrombin time, reduces the incidence of indwelling line induced venous thrombosis. Our own unpublished observations have shown a reduced incidence in this complication since the introduction of warfarin prophylaxis from 31% to 18%. The pattern of toxicity to some extent depends on the
129
5-FU schedule, with weekly boluses giving predominantly diarrhoea, short-term infusions (2-5 days) mucositis and long-term infusions (weeks) plantar-palmar erythema. Ultimately the best 5-FU schedule may depend on the type of modulator being employed with it. The best standard single agent control arm for phase III studies will be influenced by the modulated arm. However, with quality of life in mind we believe long term infusional treatment may be preferable. The drawback with the infusional schedule is the cost of the pump and of central line insertion [ 131, although the cost of pumps can be reduced by reusing them and is offset by savings in the management of toxicity [14]. The increased understanding of intravenous 5-FU scheduling provides a greater variety of methods to investigate the optimum therapeutic index of modulated 5-FU. Martin et al. [15], have compared intravenous 5-FU to intra-arterial floxuridine in a randomised multi-centre study of patients with hepatic metastases. No survival difference between the intraarterial and intravenous treatment groups was found. While response rates are superior with i.a. treatment, these patients relapse outside the liver, Progress in regional treatment relies on randomised trials investigating its additive effect to systemic treatment.
II-B. 5-FU plus folinic acid This combination is a good example of biochemical pharmacology providing a mechanism of enhancing the activity of an established cytotoxic with a successful translation into the clinic. Although many questions have been answered there is still a need for further schedule investigation. A detailed review of the mechanism of folinic acid modulation of 5-FU is found elsewhere [ 161. Thymidylate synthase (TS) is a key enzyme in the de novo synthesis of deoxythymidine triphosphate (dTTP) a direct substrate of DNA (see Fig. 1). Fluorodeoxyuridine monophosphate (FdUMP), an active anabolite of 5-FU competes with cellular deoxyuridine monophosphate (dUMP) for TS binding sites. The dUMP-TS complex requires the reduced folates to complete the conversion of dUMP to deoxythymidine monophosphate (dTMP). When FdUMP binds TS it does so less reversibly than dUMP and the substituted fluorine atom prevents the reaction proceeding forward. There is therefore a TS-FdUMP binary complex formed. This complex is stabilized by reduced folates from folinic acid and forms a ternary complex [ 161. These findings led to the addition of folinic acid (leucovorin calcium) to 5-FU in patients whose tumours were resistant to 5-FU alone. Reversal of 5-FU resistance was noted with second responses in some tumours [17]. The
DHFU + FUPA -+ FBAL -+ FDHUDH
CATABOLITES
_______.____. _.._. ..._.. _- .__...__.__.._ ._..__.- _.._.- _.._.___...__..__.._._.._. . .._..__...__......__... t 5-Fluorouracil
.._.-_.._-...-..--.-.-..... _...._.._......._.
Nucleosldes Thvmidinc
F-deoxwridine
\
F-uridinc
TK
Nucleotides
TS _
FUMP
FdUMP
UDP reductase 4
dTDP
dlTP
1
FdUTP
DNApiymerase
DNA
1
FU-DNA
I FUDP
FUTP
I
RNA polymerase
F&RNA
Fig. 1. 5-Fluorouracil metabolism. The various routes by which 5-FU is metabolised: (1) by catabolism to non-cytotoxic components DHFU, FUPA, FBAL and F-; (2) anabolism to FUMP with eventual incorporation into RNA; (3) anabolism to FdUMP with inhibitory effects on enzyme thymidylate synthase (TS); and (4) incorporation into DNA. Abbreviations: DHFU, dihydrofluorouracil; FUPA, fluoroureido propionic acid; FBAL, fluoro-beta-alanine; DHUDH, dihydrouracil dehydrogenase; TP’ase, thymidine phosphosylase; UrdP’ase, uridine phosphosylase; TK, thymidine kinase; Urd K, uridine kinase; FUMP, fluorouridine monophosphate; FUDP, fluorouridine diphosphate; FUTP, fluorouridine triphosphate; FdUMP, fluorodeoxyuridine monophosphate; FdUDP, fluorodeoxyuridine diphosphate; FdUTP, fluorodeoxyuridine triphosphate; dUTP OH’lase, deoxyuridine triphosphate hydroxylase; dUMP, deoxyuridine monophosphate; TS, thymidylate synthase; CH,THF, methylene tetrahydrofolate; dTMP, deoxythymidine monophosphate; dTMPK, dTMP kinase; dTDP, deoxythymidine diphosphate; dTTP, deoxythymidine triphosphate.
5-FU-leucovorin
combination
was however more toxic
WI. Subsequent phase II studies confirmed clinical eficacy using a variety of different 5-FU and folinic acid schedules. The 5-FU schedules ranged from weekly i.v. bolus (300-750 mg/m2) [19], to two weekly 2-day infusions (600 mg/m2/day) [20], five daily boluses (340-400 mg/m2/day) for 1 week every 3-5 weeks [21] to a continuous ambulatory i.v. infusion (300 mg/m*/day) [22]. The dose of folinic acid ranged from 15 mg to 1000 mg a week and was generally given intravenously as a bolus or infusion although oral administration was used in
130
some (see below). The DeGramont regimen [20], while not studied in a phase III trial with single agent 5-FU, appears active with a 51% objective response rate and low toxicity. The regimen, i.v. folinic acid 200 mg/m2 over 2 h followed by 5-FU 300 mg/m2 bolus then 300 mg/m2 infused over 22 h is given on days 1 and 2 every 2 weeks. The problem with the schedule is the frequent inpatient stay which can only be avoided by using a indwelling central venous line and infusing the 5-FU via an ambulatory pump. Continuous ambulatory infusion of 5-FU at 300 mg/m2/day has been modulated with weekly i.v. folinic acid (20-75 mg/m2) [22]. The study found 7 of 10 patients treated with 20 mg/m2/week folinic acid completed 4 weeks of 5-FU with 3 needing a treatment break for toxicity. Doses higher than this were less well tolerated. The dose limiting toxicity was stomatitis not plantar/palmar erythema as for single agent infusional 5-FU. Eight of the 19 evaluable patients (42%) in this study had a tumour response. A phase III trial is being carried out by the South West Oncology Group [22]. Phase III studies of folinic acid have been performed using various weekly and monthly 5-FU schedules. Two major studies performed by collaborative groups have each investigated optimum folinic acid dosage for a specific 5-FU schedule [23,24]. The Gastrointestinal Tumour Study Group (GITSG) [23] randomised 343 patients to: (a) a control arm of 5-FU alone (500 mg/m2 daily for 5 days every 4 weeks with 25 mg/m2 escalation); (b) weekly 5-FU 600 mg/m2 plus folinic acid 500 mg/m2 for 6 weeks with 2 weeks rest; or (c) 25 mg/m2 folinic acid given with the same weekly 5-FU schedule. The response rate for the high dose FA arm (30.3%) was statistically significantly better than control 5-FU (12.1%). The low dose FA arm (18.8%) was not significantly different to the high dose arm. Toxicity in the modulated 5-FU patients was predominantly in the form of diarrhoea with 11 patients (7 high dose FA, 4 low dose FA) dying as a result. Ten of these were over age 63 years. However, a protocol change ensured treatment was withheld for any (as opposed to grade 2) diarrhoea, mucositis or stomatitis until it had resolved. Although responses favoured the 5-FU plus high dose FA arm there was no difference in median survival partly due to the toxic deaths. The second collaborative study, that of the North Central Cancer Treatment Group (NCCTG) has recently been updated [241. The original study [25] of 429 patients randomised patients to either: (a) 5-FU 500 mg/m2 for 5 consecutive days every 5 weeks; (b) 5-FU 300 mg/m2/day and cisplatin 20 mg/m2/day for 5 consecutive days every 5 weeks; (c) 5FU 1000 mg/m2 7 h after a 4-h infusion of methotrexate
200 mg/m2 and folinic acid 14 mg/m2 orally in eight 6-h doses starting 24 h after initiating methotrexate-courses every 3 to 4 weeks; (d) 5-FU 700 mg/m2 preceded 24 h by methotrexate 40 mg/m2 i.v. on days 1 and 8 every 28 days; (e) 5-FU 370 mg/m2/day preceded by FA 200 mg/m2/day for 5 consecutive days every 4-5 weeks; and (f) 5-FU 425 mg/m2/day preceded by FA 20 mg/m2/day for 5 consecutive days 4-5 times weekly. This earlier study confirmed that the low and high dose FA arms were superior to 5-FU alone; the high dose methotrexate arm was the only other, possibly conferring some advantage. Based on this a further 259 patients were randomised to 5-FU plus low dose FA, 5-FU plus high dose FA or 5-FU plus high dose methotrexate and FA rescue. 5-FU plus low dose FA gave a significant survival benefit over 5-FU plus high dose MTX (12.7 vs. 8.4 months; P I 0.01) but 5-FU with high dose FA was unable to do so (see Fig. 2). There was however no significant difference in survival between the two FA arms. Objective tumour response was seen in 14% on 5FU plus high dose MTX, 31% on 5-FU plus high dose FA and 42% on 5-FU plus low dose FA. Leucopenia was the dose limiting toxicity in the 5-FU plus high dose MTX arm while mucocutaneous toxicity was dose limiting in the FA arms. Stomatitis was more frequent (28%) than diarrhoea (16-19%). Rates of hospitalization for toxicity were highest in the low dose FA arm (15%) 6.5% for the MTX arm and 5.4% for the high dose FA arm. There was one toxic death in each arm. From the results of the GITSG and NCCTG studies a further trial was initiated comparing weekly 5-FU plus high dose FA with 5-FU plus low dose FA on the 5-day schedule, The preliminary results reported in abstract form [26], show that of the 3 15 evaluable patients there was no difference in median survival (10 months) or response (28% GITSG and 33O/oNCCTG). The dose limiting toxicities were stomatitis for the NCCTG regimen and diarrhoea for the GITSG regimen. Although the incidence of life-threatening toxicity was similar, because of diarrhoea, the GITSG regimen had induced more toxicity inpatient days (430 vs. 3 17; P = 0.07). This and the cost of FA favours use of the NCCTG regimen. While current results suggest that low dose FA given with five day bolus 5-FU regimens offers the best tumour response, patient survival and palliative-effect, further investigation of FA modulation will continue. Oral administration of FA may offer an advantage over iv. by selective absorption of the active L-isomer to the exclusion of the inactive D-isomer which may compete with it at the target site [27]. Similarly, an intravenous preparation of the purified L-isomer is available for
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80 -
60 s ai ,r a 40 -
0 I
0
6
I
I
12
18
Time from RadomiZMiOn,
24
mo
Fig. 2. Survival of patients with metastatic colorectal cancer on chemotherapy: - - -, 5-FU + high dose methotrexate, n = 155; . . . . 5-FU + high dose leucovorin, n = 149 (P vs. 5-FU + high dose methotrexate; 0.04, unadjusted; 0.44, Cox model); -.-.-, 5-FU + low dose Ieucovorin, n = 153 (P vs. 5-FU + high dose methotrexate; 0.01, unadjusted;
study. While the role of continuous infusion 5-FU and FA remains unresolved it provides another opportunity to explore the therapeutic window provided by these two drugs [22]. II-C. 5-FU plus interferon (IFN)
As early as 1982 the combination of 5-FU and interferon has been shown to be synergistic in human tumour cell lines [28] although another early report found that by altering the timing of interferon a protective effect on 5-FU cytotoxicity could be demonstrated in mice [29]. Synergy with 5-FU is seen both with alpha- and gammainterferon although in some cell lines IFN does not affect 5-FU cytotoxicity [30]. Although literature is accumulating, the exact mechanism(s) of the 5-FU-IFN synergy is not resolved. This is partly due to the uncertainty as to the relative importance of thymidylate synthase inhibition by FdUMP and the incorporation of FUTP into RNA as mechanisms of 5-FU cytotoxicity [3 11. Current evidence suggests interferon may: increase
intracellular FdUMP levels [32] perhaps by favouring its formation or interfering with its catabolism; prevent the 5-FU induced upregulation of TS thereby maintaining adequate levels of inhibition [33]; or impair thymidine transport and thymidine kinase activity which is a potential rescue mechanism for the 5-FU treated cell [34]. &huller et al. [35] provide additional evidence with a pharmacokinetic study suggesting IFN reduces 5-FU clearance, increasing its AUC by 80% [35]. This can increase delivery of 5-FU to the cell thus contributing to any cellular synergy. Our own experience using in vivo “F-magnetic resonance spectroscopy to monitor 5-FU metabolism in tumours in situ suggests the addition of interferon-o to a continuous 5-FU infusion at a time of 5-FU resistance results in increased 5-FU and 5-FU anabolite tissue levels. These changes may predict reversal of 5-FU resistance [36]. These findings also raise the possibility that interferon may alter 5-FU uptake or efflux or interfere with 5-FU catabolism, encouraging anabolism. A clinical study by O’Connell et al. [37], investigating
132
the activity of interferon-gamma alone in patients with advanced colorectal cancer showed minimal effect with only 1 patient having a response out of 16 treated. Clark et al. [38] treated 36 patients with interferon-a alone on two schedules: either 50 million units/m2 i.v. on 5 consecutive days every 4 weeks or 20 million units/m2 S.C. three times per week. Toxicity was unacceptable and there were no tumour responses. In the second part of the same study 29 patients received interferon in similar schedules but at reduced doses (20 million units/m2 i-V./day; 5 million units/m2 S.C.three times per week and were given 5-FU 250-500 mg/m2 for 5 consecutive days on a 4-weekly cycle. Toxicity was acceptable but there was only one response of short duration. The doses of 5-FU used were however lower than currently recommended. Wadler et al. [39] investigated the feasibility of interferon-o doses ranging from 6 to 18 million units while patients received 5-FU 750 mg/m2/day infusion for 5 days then weekly boluses. Responses were seen in 5 of 9 patients given the lowest dose levels of interferon while none were seen in the 9 patients at higher dose levels. Toxicity was acceptable at 15-18 million units, but greater than at lower levels. Following this a phase II study was performed using 5-FU 750 mg/m2/day infused for 5 days then weekly as an iv. bolus with interferon-cr-2a, 9 million units S.C.three times per week [40]. This study confirmed activity of the combination in previously untreated patients with 13 of 17 achieving a response. There were no responses in previously treated patients. 5-FU toxicity was evident with no suggestion of interferon offering preferential protection of normal tissue. Subsequent attempts to reproduce this data yielded response rates of 26-35% but with up to 84% of patients requiring dose reduction for toxicity [41,42]. Most recently a multi-institutional confirmatory trial was performed by the Eastern Co-operative Oncology Group (ECOG) [43], in which a 42% response rate was seen in 36 evaluable patients. Eight patients had grade 4 toxicities (sepsis, diarrhoea, neutropenia) and 2 patients experienced grade 3 neurological toxicity. The median time to treatment failure was 8 months. Using a different study design we have been able to show interferon-a, has activity in 5-FU resistant tumours [36]. Patients were treated with 5-FU (300 mg/m2/day) as an ambulatory infusion and at maximum response, defined as no change over 12 weeks or increase in tumour size or CEA levels, interferon-a 5 million units S.C.three times per week was added. Twenty one percent of patients showed evidence of further response to the addition of interferon albeit with some increase in toxicity. Although the present evidence points to a modulatory
effect of interferon-o on 5-FU action and in 5-FU resistance, the results of ongoing randomised phase III studies based at the Royal Marsden Hospital, comparing 5-FU + interferon-a to 5-FU alone, will provide the strongest indication of the clinical utility of the current schedules. Further preclinical research is needed to elucidate the mechanisms of action involved in the combination. In particular the most appropriate 5-FU schedule needs to be determined, the precise timing and the dose of interferon established to maximise any normal tissue cytoprotective effects while optimising 5-FU biochemical modulation. II-D. 5-Fluorouracil plus N-phosphon-acetyl+aspartate
(PALA) N-phosphor+acetyl+aspartate (PALA) is an inhibitor of de novo pyrimidine synthesis. By inhibiting aspartate transcarbamylase the formation of erotic acid (OA) from carbamyl phosphate is reduced. This leads to a reduction in UMP and subsequently UTP incorporation into RNA. Similarly dUMP binding to thymidylate synthase is reduced. Simultaneously phosphoribosyl pyrophosphate levels increase due to reduced OA and enhance anabolic metabolism of 5-FU if present. Overall this leads to enhanced FUTP incorporation into RNA and FdUMP binding to TS [31,44]. Phase II trials using PALA as a single agent show no significant antitumour effect, possibly because the activity of the target enzyme aspartate transcarbamylase is much higher in tumour than normal tissue [45]. Although animal results suggested that only moderate PALA induced uridine nucleotide depletion was needed to maximize PALA modulation of 5-FU [46], the first clinical studies used maximum PALA doses and reduced doses of 5-FU [47]. Consequently the results were disappointing underlining the need to keep 5-FU, the active agent, at maximum tolerable dose and adjust the modulator instead. Subsequent studies have shown more encouraging results [48,49,50]. Ardalan et al. [48] studied 52 patients using a weekly 24-h infusion of 5-FU (750-3400 mg/m2) preceded 24 h by PALA 250 mg/m2 and a 5-FU only (1300-5200 mg/m2) control arm. The maximum tolerated dose of 5-FU in each arm was 2600 mg/m2 with ataxia being the dose limiting side-effect both with 5-FU/PALA and 5-FU alone. Eleven of 28 patients (39%) responded to 5-FU/PALA while 4 of 19 (21%) to 5-FU alone. O’Dwyer et al. [49] using PALA 250 mg/m2 and a weekly 24-h infusion of 5-FU (2600-3250 mg/m2) noted tumour response in 16 of 37 (43%) patients. The maximum tolerated dose of 5-FU was 2600 mg/m2.
133
Kemeny et al. [50] report the use of PALA (250 mg/m2) followed 24 h later by bolus 5-FU at three dose levels - 600, 700 and 800 mg/m* - weekly for 6 weeks in every 8. Forty-five patients were treated and of the 43 evaluable for response 15 (35%) had either a CR or PR. Toxicity (diarrhoea and neutropenia) was largely seen in the highest 5-FU dose level. An interesting observation in this study, detailed in a separate publication [51] was of the development of ascites, hyperbilirubinaemia and hypoalbuminaemia generally in patients responding to 5-FU/PALA. The investigators postulate the enhanced incorporation of 5-FU into RNA may inhibit protein synthesis in the liver and that PALA induced reduction in uridine pools inhibits bilirubin glucuronidation. From the clinical standpoint however, it is important to differentiate this syndrome from tumour progression. Overall these results show PALA has potential as a well tolerated form of modulation. Both the Eastern Co-operative Oncology Group and the South West Oncology Group are testing PALAS-FU in phase III trials. II-E. 5Fluorouracil
plus methotrexate
platin combination [61] randomised trials fail to confer its clinical advantage. Kemeny et al. [62], studied 122 patients randomised to receive either 5-FU (1000 mg/m2/day) as a continuous infusion for 5 days every 4 weeks or cisplatin 20 mg i.v. bolus daily for 5 days during the 5-FU infusion. Although the response rate was better with 5-FU and cisplatin (25% vs. 3%, P = 0.001) the toxicity was worse and the median duration of response and survival were no different. In a Mid-Atlantic Oncology Program study, Lokich et al. [63] randomised treatment to either ambulatory infusional 5-FU (300 mg/m2/day) for 10 weeks of every 12 or this with weekly cisplatin (20 mg/m2 i.v.). Neither the response rate (35% vs. 33%) nor median survival (11.8 vs. 11.2 months) differed in the two groups. Hansen et al. [64], of the Eastern Co-operative Oncology Group report protracted infusion 5-FU with or without cisplatin gives a superior response rate to bolus 5-FU however 5-FU/cisplatin was not better than infusional 5-FU alone. There were no statistical differences in survival between the groups.
(MTX) II-G. S-Fluorouracil plus other modulators
Preclinical studies show by inhibition of the purine de novo pathway, MTX increases the concentration of PRPP which enhances anabolism of 5-FU inducing cytotoxicity via an RNA effect [52,53]. Translation of this mechanism into the clinic has led to disappointing results despite extensive study. One factor that might explain these findings is the time interval between administration of the MTX and 5-FU. Most earlier studies used intervals of between l-7 h with no randomised trials demonstrating either an advantage in tumour response rates or patient survival when compared to 5-FU alone [25,54,55]. Several studies used a 24-h dose interval in the MTX arm [24,56,57] however, only one of these was associated with a survival advantage [57]. Other studies have failed to find a response or survival advantage with this schedule [58,59]. II-F. SFluorouracil
plus cisplatin
Interest in cisplatin and 5-FU combinations stems from preclinical evidence of synergy. Although the interaction is incompletely understood at the cellular level Scanlon et al [60] found cisplatin increased the intracellular reduced folate levels which enhanced FdUMP binding to TS. The mechanism may relate to the cisplatin induced inhibition of methionine transport and subsequent methionine deprivation leading to an enhanced intracellular synthesis of reduced folates. Despite phase II studies suggesting enhanced activity of the 5-FU/cis-
5-FU has been combined with several other agents in clinical studies with mixed success. Allopurinol has been shown to prevent 5-FU toxicity to normal tissues in animals [65] probably by inducing a rise in erotic acid which competes with 5-FU for the enzyme erotic acid phosphoribosyl transferase. It was used clinically on the basis that normal tissues would be more affected by allopurinol and tumour would activate 5-FU by alternative mechanisms thus maintaining a cytotoxic effect. While Fox et al. [66] were unable to show an improved therapeutic ratio the use of an allopurinol mouthwash may reduce 5-FU-induced stomatitis (671. Dipyridamole is an inhibitor of nucleotide transport which does not affect uptake of 5-FU into the cell but inhibits efflux of the active nucleotides of 5-FU [68]. Remick et al. [69], however, found the combination appeared to have no advantage over 5-FU alone. The complete reversal of 5-FU cytotoxicity by uridine implies 5-FU was working via RNA effects, conversely successful thymidine rescue would imply a DNA effect was predominant [31]. A uridine infusion of 1 h failed to protect from 5-FU toxicity [70] but alternating a 3-h infusion with 3 h rest for 3 days, adequate uridine levels could be maintained without developing high fevers the major problem seen with prolonged infusions [71]. Using the intermittent infusion schedule uridine could protect from 5-FU induced leucopenia but not thrombocytopenia [72]. As the infusions are inconvenient, oral
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preparations have been tested, however, diarrhoea and poor bioavailability have been problematic [73]. Coadministration of oral uridine with a uridine phosphorylase inhibitor reversed 5-FU induced toxicity [74]. Although these results are preliminary they do show potential to increase the therapeutic index of 5-FU. Thymidine, by being catabolized to thymine competes with 5-FU for the catabolic enzyme dihydro-uracil dehydrogenase (see Table 1). In addition thymidine facilitates the production of dTTP which both bypasses the inhibitory effect of FdUMP on DNA synthesis and by negative feedback inhibits ribonucleotide reductase diminishing FdUMP formulation from FUMP. This favours FUTP incorporation into RNA [75]. These effects greatly lengthen the plasma half life of 5-FU and increase its toxicity, Because of these actions, further investigation of scheduling or combination with other modulators is needed before the true usefulness of thymidine can be assessed. II-H. Double modulation of 5-jluorouracil
With increased knowledge of the mechanisms of 5-FU modulation and the clinical experience now available, more interest has been directed to using two modulating agents of 5-FU in one schedule. Kemeny et al. report the use of PALA, methotrexate and 5-FU in combination [76]. PALA 250 mg/m2 and MTX 250 mg/m2 were administered on day 1 and a 5-FU bolus on day 2, with folinic acid 10 mg q.d.s. for eight doses starting 24 h after the MTX. Using an alternate week schedule the MTD of 5-FU was 900 mg/m2 but only 600 mg/m2 on the weekly for 2 weeks then 2 weeks break schedule. The dose limiting toxicity was diarrhoea. This regimen is being further evaluated with the addition of uridine. The combination of 5-FU, folinic acid and interferon alpha has been evaluated in several studies to date reported in abstract form. Seymour et al. [77] using a modified DeGramont schedule (2-day 5-FU infusion plus FA with interferon-a 6 million units S.C.three times weekly every 2 weeks) report a modest increase in toxicity but improved response rate (52%) compared to previous phase II studies of 5-FU/FA in this schedule [20]. This regimen is the subject of a randomised trial in the United Kingdom testing the additive effect of interferon. Other studies suggest toxicity is not a major problem but response rates were sometimes very poor [78,79,80]. The study by Schuller et al. [35] showed that interferon increased the plasma AUC of 5-FU (80%) but when FA was added this resulted in a reduction of the AUC to near single agent 5-FU levels. If this data is
reproducible then until there is a better understanding of the intracellular effects of double modulation, attempts at combining these agents should be made with caution. II-I. Newer cytotoxic agents and combinations
Combination chemotherapy for colorectal cancer has generally been very disappointing. Mitomycin C, cisplatin, 5-FU and vincristine appears an active combination with a 44% response rate compared to a control arm of cisplatin and 5-FU (12%) [81]. Toxicity and poor overall survival suggest this regimen is not clinically useful in advanced disease. High dose melphalan (L-PAM) plus misonidazole and autologous marrow rescue [82] gives a response rate of 42% with significant toxicity. Unfortunately the responses were short lived (median 17 weeks). The use of cisplatin and Ara-C in combination has yielded a 42% response rate in a small study [83]. All these newer combinations appear to enhance response for short periods at the cost of increased toxicity. Newer agents acting via novel targets for example the ~21”” protein (see molecular biology section) or topoisomerase 1 show potential in colorectal cancer. Shimada et al. [84] demonstrated a partial response in 6113 (46%) patients with colorectal cancer treated with a campothecin analogue CPT-11 - a topoisomerase 1 inhibitor. The main toxicities were of vomiting, leucopenia and diarrhoea. CPT-11 is undergoing .further evaluation in Japan in combination with 5-FU. Topotecan, another camptothecin analogue has undergone extensive phase I study [85-881 revealing myelosuppression as the dose limiting toxicity. Diarrhoea, fever, nausea, rash, cystitis and alopecia also occur and are mild to moderate. Although there is no phase II information available at present, many of the patients in the phase I studies had colorectal tumours with none showing tumour responsiveness to topotecan. Phase II studies are awaited to determine the efficacy of topotecan in this tumour. III. Adjuvant treatment of colorectal cancer III-A.
Colon cancer
Since the Intergroup study of Moertel et al. [4] set the precedent in the United States for adjuvant chemotherapy in Duke’s C colon cancer, the treatment of resectable colon cancer has undergone major re-evaluation. Prior to this study there was no standard recommended adjuvant treatment. In 1988, Buyse et al. reported the results of a meta analysis of the adjuvant trials published up to December 1986 [89]. A total of 17 trials compared
chemotherapy with control groups. Results from these showed that administration of 5-FU for periods of 1 year or longer reduced the odds of death by about 17% (odds ratio 0.83 95% C.I. 0.70-0.98, P = 0.03) and gave a 3-4% higher 5-year survival. This study was done prior to the completion of three major trials: INT-0035 [4], NSABP R-01 [90] and NSABP C-01 [91]. Gray et al. [92] reviewed the Buyse et al. data with the results of these three trials included. Overall, there was a 14% (odds ratio 0.86 95% C.I. 0.81-0.90 2P < 0.003) reduction in mortality in 20 studies of various single agent and multiple agent schedules of various durations (5 weeks to indefinite). This updated review however did not present an analysis of the impact of 5-FU ( f other agent) given for 1 year or longer - the group that appeared to derive the maximum benefit in the earlier review. Results of detailed subset analysis in overviews can however be misleading. The available published data from these two overview analyses shows at least encouraging evidence for the efficacy of 5-FU in the adjuvant setting. This benefit may be small but in terms of patient numbers in this common tumour the benefit is significant. Further information could be obtained by performing a large collaborative meta-analysis on the scale of the recently published breast cancer study [93]. The Intergroup study [4] randomised 1296 patients, 325 with stage B2 disease and 971 with stage C disease. The stage B2 patients were randomized to surgery only or surgery with 5-FU plus levamisole for I year. The results after 3.5 years follow-up show no significant difference between the two arms. This group will be observed for at least another two years before drawing conclusions. The 971 patients with stage C disease were randomised to either surgery alone, surgery plus levamisole or surgery plus levamisole and 5-FU. 5-FU plus levamisole reduced the risk of recurrence by 41% (95% C.I. 23-540/o). At 3.5 years, 63% of patients receiving 5FU plus levamisole and 47% of controls were free of recurrence. The rate of recurrence was reduced at all sites in particular those outside the abdominal cavity (lungs, retroperitoneal and peripheral nodes and abdominal wall). The estimated reduction in the death rate by treatment with 5-FU/levamisole compared with control was 33% (95% C.I. lo-SO%). The 3.5 year survival estimates were 71% for the 5-FLVlevamisole arm and 55% for control (P = 0.0064) (see Fig. 3). Toxicity was generally mild with the majority of side effects being consistent with 5-FU alone (nausea, vomiting, diarrhoea, stomatitis, dermatitis and leucopenia). Compliance with the levamisole arm was good with 92% of patients taking at least 90°/ of the planned course. 5-FU/levamisole patients, experiencing more toxicity, had a 30% rate of
100
25 40 -2= a” 20
0
...... -
Lev + 5FU Levamisole Observat~n
12
At risk 304 310 315
24
Months
Dead 78 109 114
3s
4s
since Enrollment
Fig. 3. Survival of patientsfollowing resectionof Dukes’s C colon cancer. A comparison of the effects of levamisole and 5-FU + levamisole over surgery alone. From Moertel CG et al. N Engl J Med 322:352-358, 1990 (with permission).
early treatment discontinuation. The final report on this study was presented by Moertel at the 1992 American Society of Clinical Oncology meeting. With a median follow up of 5 years the results of the earlier report were confirmed-Duke’s C patients could achieve a 31% reduction in their chances of death due to cancer. Whilst this study has produced the most convincing data for adjuvant treatment of Stage C colon cancer the ommision of an arm using 5-FU alone casts doubt over the role of levamisole in this combination. Although there is a lack of clinical and preclinical supportive evidence for levamisole’s activity in established disease, it is possible synergism is seen only in vivo and only in states of minimum disease. Despite these uncertainties this regimen is currently the best available considering the additional supportive evidence from the overview analysis of 5-FU based regimens. An important lesson learnt from other adjuvant studies was the use of agents that are leukaemogenic. The NSABP study [91] for colon tumours found some marginal overall survival advantage but the use of methyl-CCNU in combination with 5-FU and vincristine increased the incidence of leukaemia. Ongoing analysis of this study has suggested a weakening of the survival benefit. Intraportal5-FU given as a short post-operative infusion has been tested in several trials following the study by Taylor et al. [94] from the United Kingdom. 5-FU (1 g/day) was given as a continuous infusion for the first 7 post-operative days with heparin 5000 units/day. Of the 127 control patients, 22 (18%) developed liver metastases compared to only 5 of 117 (4%) in the treatment arm. There was a survival benefit in Duke’s B
136
tumours only. A subsequent trial [95] from the NSABP of 1158 patients with Duke’s A, B and C colon cancer suggested a borderline improvement in overall survival (P = 0.07). Methodological problems with this study reviewed by O’Connell [96] include a high proportion (18.7%) of pre-operatively randomized patients being excluded, and the inclusion of Duke’s A tumours in the study. Exclusion of the patients with Duke’s A tumours removed the advantage in disease free and overall survival seen with the intraportal 5-FU. Although the overview analysis of Gray et al. [92] suggests some overall benefit from intraportal post operative 5-FU the use of this modality should be in clinical trials with a systemic chemotherapy arm. While 5-FU/levamisole remains the standard arm for ongoing trials the results of these studies will determine the role of 5-FU (in various schedules) with high or low dose leucovorin f levamisole as the future optimum combination [97]. With these trials in progress, further development of other modulators of 5-FU (PALA and interferon-a: see metastatic disease section) will provide further options for future adjuvant treatment schedules. III-B. Rectal Cancer
Rectal carcinomas have a different pattern of spread to colon carcinomas so adjuvant treatment requires different design. Below the peritoneal reflection lymphatic and vascular drainage of the rectum is often not through the mesenteric system as with colon but via haemorrhoidal and pudendal systems [98]. This in part may explain the increase in local recurrence (25-50%) and pulmonary metastases seen with rectal carcinoma [99]. The majority of the initial adjuvant rectal cancer studies therefore concentrated on radiation therapy (pre- or post-operative) to reduce local recurrence. In an overview of these studies [92], Gray et al. note that there is good evidence that local radiotherapy reduces the local recurrence rate but the evidence for improved survival is lessconvincing. Nevertheless, a 10% estimated improved survival combined with the results of recent trials containing chemotherapy arms provides a useful structure for future clinical trials. One study performed by the GITSG [lOO] randomized patients to receive surgery alone, radiotherapy, 5-FU plus methyl-CCNU or both radiotherapy with 5-FU and methyl-CCNU. The results showed a significant reduction in recurrence rate (55% control and 33% combined radiotherapy-chemotherapy) with time to recurrence also significantly favouring the combination arm. In a later report of this study [loll a survival advantage was evident with the combined treatment arm. The NSABP R-01 study [90] randomized patients to surgery alone, post-operative radiotherapy or
post operative chemotherapy with 5-FU, methyl-CCNU and vincristine. The results showed a reduction in local recurrence with radiotherapy (25-16%) though no impact on disease-free interval or survival compared to surgery alone. Chemotherapy however, resulted in an improvement in disease free survival and overall survival. The finding on subset analysis that this chemotherapy advantage was limited to males is difficult to explain though may be due to chance. A study published in 1991 by Krook et al. [3] has provided the strongest evidence for efficacy of combined modality treatment in rectal cancer. Two hundred-four patients with local invasion or nodal spread were randomized to receive post operative radiation (4500-5050 Gy) or radiation plus fluorouracil, which was preceded then followed by a cycle of systemic fluorouracil plus methyl-CCNU. After a median follow-up of 7 years, combined therapy had reduced recurrence by 34% (95% C.I. 12-50%: P = 0.0016) and overall death rate by 29% (95% C.I. 7-45%: P = 0.025). The reduction of local recurrence from 25% to 13.5% (P = 0.036) by combined modalities suggests some synergy, however, the reduction in metastatic relapse with chemotherapy (45% to 28.8%: P = 0.011) is of similar order. The apparent superiority of these results over the GITSG study may relate to an overall higher dose of radiation administered (5040 vs. 4200 cGy) and to the earlier administration of systemic chemotherapy which appears to have given a lower systemic relapse rate. A further GITSG trial [102], conducted to test the value of methyl-CCNU in the 5-FU-methyl-CCNU combination, suggests no benefits over 5-FU alone. Adjuvant treatment of rectal cancer, therefore, is divided into the control of local recurrence and of systemic disease. Radiation alone has an impact on local recurrence, possibly with the help of radiosensitization by 5-FU while chemotherapy alone (mainly 5-FU) can influence metastatic disease. The two modalities together can improve overall survival in rectal cancer. Future developments in adjuvant treatment of rectal cancer lies in the scheduling of radiotherapy (pref post-operative) with radiosensitizers and the development of newer chemotherapy regimens using 5-FU and Levamisole as the standard. IV. Non-invasive colorectal cancer
monitoring
of drug metabolism
in
Until recently the intracellular fate of cytotoxic agents in humans had to be inferred from analysis of body fluids (plasma, urine, faeces) or from tissue samples obtained via an invasive procedure. The opportunity to ethically obtain tissue for this purpose is uncommon and
137 often meets with disapproval from the patient. With the development of clinical magnetic resonance systems and positron emission tomography (PET) there is now unmeasurable potential to more accurately assess the tissue pharmacology of drugs in vivo, non-invasively and repeatedly with greater convenience and safety than before. Because 5-FU remains the major active drug in colorectal cancer and for various reasons (described below) the Fluorine nucleus in 5-FU is ideal for use in magnetic resonance spectroscopy (MRS) and PET studies, some of the pioneering work using these systems has been done in colorectal cancer patients. IV-A. 19F magnetic resonance spectroscopy
Nuclear magnetic resonance spectroscopy has been used to study the structure of a range of chemicals and tissues in vitro using 'H, i3C 19F> 31P 23Na and 15N techniques. The clinical application mosi widely known is the use of ‘H NMR for imaging patients. With the advent of these clinical systems it is now possible to observe signal from various nuclei giving detailed biochemical information. The 19F nucleus is detectable using MRS. Its advantages are that it is very sensitive to detection (83% that of ‘H), is naturally 100% abundant in the 19F form and has a large range of chemical shifts - that is, its resonant frequency is clearly altered by changes in the structure of the molecule attached to it. This enables detection of various metabolites of fluorine containing drugs such as 5-FU. The other added advantage is that in animals (including humans) there is not naturally more than a minute amount of fluorine in the body to act as background ‘noise’. 5-FU is catabolized to non-cytotoxic metabolites (FBAL, FUPA, F-) or anabolised to cytotoxic metabolites (FdUMP, FUTP, FdUR, FUR) (see Fig. 1). Because r9F-MRS used in vivo increases the width of the spectral peaks and as 5FU metabolites resonate at a similar frequency this technique is not as specific as biochemical assay but is more specific than PET techniques. Despite this, peaks fall into three groups; the cytotoxic anabolites; the noncytotoxic catabolites, and 5-FU itself. Despite these difficulties much information can be obtained from animal and, more recently, human studies on the intracellular metabolic fate of 5-FU. McSheehy et al. [103] demonstrated that the Walker carcinosarcoma grown S.C.in rats rapidly anabolised 5-FU to its nucleotides. HPLC used on tumour extracts confirmed about 50% of the anabolite signal was FUTP. In addition, by pre-treating with allopurinol the anabolite signal reduced. The size of the anabolite peak predicted the cytotoxic effect. Lutz et al. [104] have presented data to suggest that 5-FU is largely catabolized and inactivated
in liver while much less so in tumour. They hypothesize that catabolites seen in tumour may be there due to recirculation from liver. Additionally they note that the best tumour response is seen when the product of the nucleotide peak and infusion time is high but that systemic toxicity is worse when large amounts of nucleotide are seen in liver. Translation of the MRS technique to humans involves several technical problems. Because patients cannot be submitted to very high magnetic fields, 0.5 to 3 Tesla systems are generally used as opposed to 4.7 + Tesla in animals. This factor, the wide bore of the magnet and the variations of the human form lead to inhomogeneity of the magnetic field used for the examination. The i9F nucleus can overcome this problem providing adequate dose is given, however overall one must expect to lose some sensitivity compared to in vitro or animal systems. A further problem is that of localisation of the tissue of interest. When the 19F signal is abundant then smaller fields of interest may be employed thus enabling, for example, a small metastasis to be isolated from surrounding liver. When the signal intensity is lower one can allow for this problem by using patients with large tumours. Earlier work from our unit [ 1051 has demonstrated the liver metabolism of 5-FU when given both intraperitoneally and intravenously. The achievement of actually measuring 5-FU and FBAL in tissue over time and the results of a study correlating tumour response with with tumour 5-FU ‘trapping’ [106] led to a pilot study of a clinical protocol using interferon-a [36]. This protocol used an ambulatory infusion of 5-FU (300 mg/m*/day) until maximum response then interferon-a was added to clinically evaluate reversal of 5-FU resistance and monitor the changes using MRS. The preliminary results suggest that a detectable 5-FU peak (often transient) in liver metastases predicts response and that after the addition of interferon the recurrence of a 5-FU peak may predict further response. An example of these findings is shown in Fig. 4. While the biochemical explanations are varied (and discussed in the section on metastatic colorectal cancer) the important feature of this and other studies is that they demonstrate the feasibility of repeated in vivo measurements and their application to optimising 5-FU scheduling. These studies must initially be verified with standard plasma pharmacokinetics and tissue biopsies but ultimately the technique will be non-invasive. Currently the limitations of MRS are that it cannot measure tumour blood flow or the uptake of drug into the tumour, however complementary clinical studies using PET scanning techniques will build a much more detailed picture of 5-FU tissue metabolism.
138
CATABOLITI
Al \BO LITES
!
I
I
I
1
I
I
15.
10.
5.
0.
-5.
-10.
Chemical
shift
/
I
ppm
.15.
I 10.
Chemical
I 5.
I 0.
shift
I -5.
/
I -10. Ppm
I
Fig. 4. These two separate 19FMRS studies of a patient with large volume liver metastases show the three major peaks seen with 5-FU. The inactive non-cytotoxic catabolites; the active cytotoxic anabolites; and 5-FU itself (see text for details).
IV-B. Positron emission tomography
Initial clinical PET studies have concentrated on monitoring cerebral and myocardial metabolism using various positron emitting agents, however, more recent work has extended to tumour blood flow, metabolism and 5-FU uptake [107]. PET is complementary to 19F MRS in the study of 5-FU metabolism. It cannot offer detailed information of the intracellular metabolism of 5-FU because the 18F label is attached to all metabolites, but preliminary studies have shown tumour [**F]SFU uptake and retention can be assessed using PET and that high uptake may predict response [ 1071. Fluoro-deoxyglucose (FDG) is a general metabolic marker for tumour activity. It is currently being evaluated for its ability to: monitor general tumour metabolism and thus predict prognosis, to predict response to treatment, and to detect early relapse [108]. In patients with residual colorectal cancer PET studies using FIDG before and after radiotherapy showed a general
follow-up FDG activity was still measurable despite normal plasma CEA levels {107]. These results if confirmed suggest FDG-PET may be useful in detecting early relapse amenable to second-look surgery. Additionally FDG could be used to more accurately stage patients prior to surgery. We are currently investigating the role of FDG PET in predicting tumour response in patients with colorectal cancer treated with infusional 5FU (Fig. 5). Use of FDG PET after surgery or chemotherapy may however be problematic in that FDG will be taken up by inflammatory cells in a post-operative abcess or in tumours with a large inflammatory activity. The correct timing of the scans may however minim&e this factor. This potential problem can be circumvented by labelling components of more specific processes for example thymidine, which is being examined as an indicator of tumour DNA synthesis. In vivo metabolic monitoring of drugs like 5-FU in normal and malignant tissues will enable earlier use of new drugs in the clinic, will help optimize clinical
Fig. 5. Tumour metabolism measured using fluorodeoxyglucose (FDG) and Positron Emission Tomography (PET). The transaxial CT image indicating two metastasesin liver (top left) with PET image (below left) showing high FDG uptake in these two plus one other smaller lesion. Repeat studies following treatment with infusional 5-FU (300 mg/m2/d) show tumour reduction after I2 weeks on CT (above right) and decreased tumour metabolism (below right) after 4 weeks using FDG-PET. The reduction in metabolism of the metastases relative to the baseline metabolism in kidney is demonstrated by the now visible superior pole of the left kidney on the PET scan.
convenient, non-invasive means of predicting response at an early stage in treatment. V. Molecular biology of colorectal cancer Genetic alterations of two types have been documented in colorectal cancer. Mutations in cellular proto-oncogenes, (e.g. the ras oncogene) and deletions on chromosomes whose deleted sequences may include tumour suppressor genes [109]. Mutations in the c-Ki
ras-2 gene occur in approximately 40% of colorectal carcinomas [ 1 lo]. The ras proto-oncogene encodes a 21kDa p21 ‘(Is protein. This protein undergoes a series of post translational modifications including polyisoprenylation and palmitoylation - the latter significantly increasing the membrane binding capacity of p21 ‘as [ 1111. Once modified the p21 rasprotein is able to attach to the inner surface of the plasma membrane and bind GTP. The p2 1‘““-GTP complex activates signal transduction probably via several mechanisms in addition to
140
protein kinase C. Hydrolysis of bound GTP to GDP by GTPase gives rise to an inactive p2 1““-GDP complex. Some human tumours have point mutations in ras resulting in a protein complex with reduced GTPase activity thus locking the complex in the activated p21’““GTP state. Increased understanding of this has provided new targets for anti-cancer treatment, for example the post-translational modification step which is necessary for the ~21”’ protein to bind to the inner plasma membrane in turn enabling activation. Deletions in chromosomal regions have been noted on the long arm of chromosome 5 which contains the gene for familial adenomatous polyposis, the short arm of chromosome 17 and the long arm of chromosome 18 [109]. It is hypothesised that these sections of the genome contain tumour suppressor genes whose products normally inhibit neoplastic transformation. On the long arm of chromosome 5 the MCC (mutated in colorectal cancer) gene has been identified and is thought to be the tumour suppressor gene located in this region [ 1121. The deletion on chromosome 18 [ 1091 involves the DCC (deleted in colorectal cancer) gene which may be involved in cell adhesion [ 1131. The p53 tumour suppressor gene appears to be located where deletions on chromosome 17 occur in colorectal cancer. The p53 gene product is associated with control of cell division and immortality. Vogelstein et al. [ 1141 postulate deletions on chromosome 5 and point mutations in the ras protooncogene are relatively early events in the sequence of carcinogenesis while deletions on chromosome 18 and chromosome 17 occur later. This new understanding of colorectal carcinogenesis will provide the basis for a new generation of novel therapies and help identify high risk populations for screening or adjuvant treatment. VI. Treatment of advanced and metastatic gastric cancer Gastric cancer remains one of the leading causes of cancer deaths globally despite a decline in its incidence [I]. In 1980 it was the most common new tumour worldwide - second only to cervical cancer in the developing world and in the developed world only to lung and colorectal cancers. Although the incidence is reducing at a rate of about 2.2% per year, there is an increase in the incidence of proximal tumours which are technically more difficult to resect [ 1151. The epidemiology of this disease is notable for marked geographical differences in incidence with higher rates in the Far East, Europe and Russia and lower in the US, Australia, New Zealand and Africa [ 11. Evaluation of dietary factors revealed that pickled foods confer increased risk and allium vegetables, ascorbic acid, vitamin E and carotene are protective [ 116,117]. Most
interest has been in the carcinogenic effects of N-nitroso compounds formed from dietary nitrites [ 1181. The reduction in incidence of gastric cancer may be related to improved refrigeration which led to a reduction in use of meat preservatives containing such nitrites. Infection with helicobacter pylori - a known causative factor in atrophic gastritis, has been recently linked with gastric cancer [ 1191. The reduction in intraluminal acid production may allow bacterial overgrowth producing increased nitrite formation. These factors provide new targets for directing prevention strategies. With up to 80% of gastric cancers presenting too far advanced for curative resection [ 1201, screening for early stage disease in high risk populations is needed. This has been successfully implemented both in Japan [121] and in parts of the United Kingdom [122]. In a UK study, patients 40 years or over presenting to their family practitioner with dyspepsia were referred to a specialist endoscopy unit [122]. Two percent of all those referred had gastric cancer, with 1 in 177 being an early lesion. These figures compare favourably with breast mammography and cervical cancer screening programmes, however the success of screening may be determined by its use in high risk populations. Despite introduction of screening for early stage tumours there will still be a need for better systemic treatment for use in locally advanced and metastatic disease. Combinations showing activity can be applied to the adjuvant or neo-adjuvant settings. VI-A. Single agent cytotoxic activity
While it appears that greater anti-tumour activity in gastric cancer can be achieved with combination chemotherapy, the testing place for new drugs is in single agent Phase II studies. The activity of the more commonly used drugs in gastric cancer are summarised in Table 1. Direct comparisons on these responses are always difficult because of the patient selection factors and also the different measurement criteria for response. It is now generally accepted for studies of this type that the definition of partial response is a 50% reduction in the product of the longest tumour dimension and its widest perpendicular, and in the case of multiple lesions a 50% reduction in the sum of these products in the absence of a new or increasing lesion. Complete response is defined as complete disappearance of all evidence of disease. This can be confirmed histologically in some instances, however, this is often not practical. Any response should be sustained for at least 1 month. With the recognised difficulty in accurate clinical measurement of disease, particularly the degree of hepatomegaly, this method
141
TABLE 1 Single agent activity in gastric cancer Dw
No. responding pts/total
%
Reference
Adriamycin (doxorubicin) BCNU Carboplatin Cisplatin Epirubicin (bolus) (protracted infusion) Etoposide 5-FU (bolus) (protracted infusion) 5-FU + moderate dose FA. 5-FU + methotrexate 5-FU + PALA + thymidine Methotrexate Methyl-CCNU Mitomycin-C Triazinate
17168 4123 3157 441129 8122 4126 2131 841392 4113 13127 4122 9136 3128 3131 631211 4126
25 17 5 19 36 15 6 21 31 48 18 25 11 8 30 15
Moertel and Levin [ 13I] Kovach et al. [137] Einzig et al. [136] Leichman and Berry [135] Cazap et al. [I331 de Vries et al. [134] O’Dwyer [ I381 Comis [123] Moynihan et al. [I251 Machover et al. [126] Blijham et al. [127] Windshitl et al. [I291 Bruckner et al. [I281 Moertel et al. (1421 Comis [I231 Bruckner et al. [I281
FA, folinic acid; PALA, iv-phosphon-acetyl-L-aspartate.
should now be replaced with one of the many available imaging techniques. S-Fluorouracil is the most commonly used drug in gastric cancer. It has, until recently, been used as an intravenous bolus or short infusion yielding a response rate of 21% from collective studies [ 1231. The dose limiting toxicity for 5-FU on this schedule, is myelosuppression. Because 5-fluorouracil is cell cycle specific and has a plasma half life of approximately lo-20 min and because at any time, approximately 3% of tumour cells are cycling, investigation of a protracted continuous intravenous infusion of this drug seemed justified [8]. This work was piloted in colorectal cancer by Lokich et al. [124] who went on to show in a randomised study that a continuous low dose infusion of 5-FU (300 mg/m2 per day) given for up to 10 weeks at a time, yielded an improved response rate compared to an intravenous bolus schedule given 5 days for 1 week in every 5 [lo]. The improved response rate, a result of the higher dose intensity of the drug delivered was not associated with increased patient toxicity. On the contrary, the toxicity was less marked because of the low dose rate infusion. Myelosuppression became less evident while plantar palmar erythroderma, was the most prevalent, but generally mild side effect. Although there has been no randomised study in gastric cancer, there has been one study of 13 patients using a protracted infusion of 5-FU in which 4 patients (31%) responded [125]. Another technique for improving the efficacy of 5-FU is the addition of a modulator which has been discussed
earlier in the section on treatment of metastatic colorectal cancer. In gastric cancer the most active of the variety of 5-FU plus folinic acid schedules appears to be that of 5-FU 340-400 mg/m2 per day, i.v. over 15 min and folinic acid 200 mg/m2, i.v. bolus for 5 consecutive days, every 3 weeks [126]. This yielded responses in 13 of 27 (48%) patients. Toxicity included stomatitis, diarrhoea and myelosuppression. The modulatory effect of methotrexate on 5-FU as a single agent has been explored yielding a modest response rate of 18% in one study [127]. Methotrexate itself appears less active as a single agent [128]. Attempts at double modulation of 5fluorouracil with PALA and thymidine yielded significant toxicity probably due to the thymidine effect of reducing 5-FU catabolism [ 1291. Mitomycin C has been extensively studied as a single agent giving a 30% response rate overall [ 1231. The main toxicity is that of cumulative myelosuppression, largely thrombocytopenia, which when the drug is given as an intravenous bolus requires a dose interval of at least 6 weeks. Mitomycin C has also been associated with the haemolytic-uraemic syndrome, being reported in 8.5% of 251 patients receiving adjuvant Mitomycin C and 5FU [130]. Various anthracyclines have been used in gastric cancer - the most widely used, being Doxorubicin (Adriamycin) [ 1311. This gives a response rate of approximately 25% making it one of the more active agents. Epirubicin, a derivative of Adriamycin is thought to be less cardiotoxic and produces less
142 TABLE 2 Combination chemotherapy regimens in gastric cancer Combination
Non-randomised
Number of responses/ number of patients
Percent response
Median survival (months)
Reference
1511453
33
5.5-1.2
Gohmann & Macdonald [147]
8-9
Moettel et al. [154] Rougier et al. [155]
12
Levi et al. (1431
6
Wils et al. [151]
studies
FAM (S-FU, Adriamycin, mitomycin) FAP (S-FU, Adriamycin, cisplatin)
24158 (k
FAB (S-FU, Adriamycin, BCNU)
CR)
18/35 (ita CR)
FAMTX (S-FU, Adriamycin, methotrexate) EAP (etoposide, Adriamycin, cisplatin) ELF (etoposide, leucovotin, 5-FU) FAM-CF (S-FU, Adriamycin, mitomycin, leucovorin)
22161 (ii,/, CR)
7.5-10
Wilke et al. [158] Lernet et al. [159]
11
Wilke et al. [I581
6.8
Arbuck et al. [161]
42 (11% CR)
9.2
Lopez et al. [162]
33%
NS
Taal et al. [163]
25170
36 (16% CR)
9
Dehino et al. [I651
951133
71 (11% CR)
8.2
Findlay et al. [166]
3137 12/30 219 6129 8128 4123 14134 2118 4117 9170 30175 2lll 3/11 5113 6144 1l/39 18146 13146 5133 6131 6/30
8 40 22 21 29 17 41 11 24 13 40 18 27 38 14 29 39 29 15 19 20
3.2 5.0 4.5 4.5 1.4 3.5 7.7 4 5.5 4.7 8.25 1.2 1.2 1.2 3.2 5.5 1.5 4.5 26 7.5 7.8
Moertel et al. 11421
95/181 (:i% CR) 27151
53 (12% CR)
10126 (%o CR)
FEB (S-FU, epirubicin, BCNU) FEMTX-C S-FU-methotrexate, epirubicin and cisplatin CEF (cisplatin, epirubicin, 5-FU) ECF (epirubicin, cisplatin, protracted infusion 5-FU) Ranabmised
19145
II21
studies
Methyl-CCNU VS 5-FU + methyl-CCNU 5-FU VS 5-FU + methyl-CCNU S-FU VS BCNU VS 5-FU + BCNU 5-FU + BCNU VS 5-FU + Adriamycin + BCNU Adriamycin VS 5-FU + Adriamycin + BCNU S-FU VS 5-FU + Adriamycin VS 5-FU + Adr + mitomycin C S-FU + Methyl-CCNU VS S-FU + Adr + methyl-CCNU VS S-FU + Adr + mitomycin VS Adriamycin + mitomycin S-FU + Adr + methyl-CCNU VS S-FU + Adriamycin + ttiazinate VS 5-FU + Adriamycin + cisplatin
Baker et al. [141] Kovach et al. [137] Schnitzler et al. 1145) Levi et al. (1441 Cullinan et al. [148] Douglass et al. [149]
Stablein et al. [156]
143
TABLE 2 (continued) Combination
5-FU + Adr + mitomycin-C VS 5-FU + Adr + methotrexate 5-FU + Adr + mitomycin-C VS Cisplatin + epirubicin + leucovorin + 5-FU 5-FU + Adr + methotrexate VS Etoposide + Adr + cisplatin Abbreviations: Adr - Adriamycin; NS -
Percent response
Median survival (months)
Reference
II79 33/81 813 1
9 41 26
7.2 10.5 5.1
Wits et al. [I521
20145
44 33 20
8.2 I.3 6.1
Number of responses/ number of patients
10130 6130
Cocconi et al. [I641 Kelsen et al. [160]
Not stated
stomatitis [ 1321. It has been shown in some studies to be active when given as an intravenous bolus (36% response rate) though less so when given as a protracted infusion [133,134]. Cisplatin has now been shown to have significant activity in gastric cancer equivalent to SFU, mitomycin C and the anthracyclines [135]. Despite this activity, it has the disadvantages of nephrotoxicity, requiring hydration, and marked emesis - both acute and delayed. In a disease where most chemotherapy is palliative, this drug has to be given with optimal supportive care to be acceptable. The less nephrotoxic and emetogenic analogue of cisplatin, carboplatin has not been found active in gastric cancer to date [136]. Despite showing modest activity, the nitrosoureas BCNU and methyl-CCNU have been used in various cytotoxic combinations in a number of studies in gastric cancer. BCNU appears to be the more active of the two drugs however in a controlled study was less active than 5-FU [ 1371. While these agents may be justifiable in combination regimens, a major problem is of delayed myelosuppression requiring dose intervals of 6-8 weeks. This interval may give fast growing gastric cancers a biological advantage. In recent years, etoposide has been used extensively in combination with other agents despite its relatively poor activity as a single agent [ 1381. This is based on pre-clinical evidence of synergy between etoposide and cisplatin [ 1391. Triazinate has shown activity in gastric cancer and represents one of many folate antagonists destined to be tested in gastrointestinal tumours [140]. The camptothecin analogue CPT-11 has shown activity in colorectal cancer [84] leading to some optimism that when tested, this new class of cytotoxic may be useful in carcinoma of the stomach. VI-B Combination chemotherapy
Cytotoxic combinations in gastric cancer have been derived from active single agents and scheduled to max-
imise the anti-tumour effect while minimising the recruitment of toxicity. While giving an important indication of anti-tumour activity and toxicity, Phase II studies of new combinations should be compared to other studies with great caution (see Table 2). One of the earlier combinations was of 5-FU and methyl-CCNU which showed an initial response rate of 40%, however, a subsequent study failed to demonstrate any benefit over 5-FU alone [141,142]. Levi et al. [143] treated 35 evaluable patients with 5-FU, Adriamycin and BCNU (FAB), demonstrating 18 (51%) responses. When they subsequently studied FAB in a randomised trial against single agent Adriamycin, they found no difference in the survival between the two groups [144]. Schlitzler et al. [145] random&d 77 patients to either FAB or 5-FU plus BCNU (FB), finding only 24% of patients responding to FAB and 11% to FB with no survival difference. Until recently the most extensively used combination in gastric cancer was of 5-FU, Adriamycin and mitomytin C (FAM) developed by Macdonald et al. [ 1461. Preliminary results suggested response rates in excess of 50%, however, the now quite extensive experience in over 400 patients suggests a response rate of 33%, with acceptable toxicity [147]. The results of two early randomised studies gave conflicting results. Cullinan et al., from the North Central Cancer Treatment Group [148] randomised patients to 5-FU alone, 5-FU plus Adriamycin, or 5-FU plus Adriamycin plus mitomycin. Although the response rate in the FAM arm was greater than the other two arms there was no difference in survival. The authors concluded that FAM was of no advantage over single agent 5-FU although the study had relatively small numbers in each arm. Douglass et al., from the Eastern Co-operative Oncology Group [149] randomised patients to one of four arms: 5-FU plus methyl CCNU; 5-FU plus Adriamycin plus methyl CCNU; 5-FU plus Adriamycin plus mitomycin C; and Adriamycin plus mitomycin C. This study found FAM to be
144
superior to the other arms in both response and survival-achieved with acceptable toxicity. Based on pre-clinical studies [53] Klein et al., from Germany, developed a further modification of the FAM regimen [ISO]. This was based on substituting high dose methotrexate for mitomycin C (FAMTX). The methotrexate was given an hour prior to 5-FU in an attempt to modulate its action. This initially resulted in a response rate of 65%, although on a subsequent contirmatory Phase II study from the EORTC Gastrointestinal Group, 33% of 67 patients responded [151]. Included in this were 13% complete responses. Wils et al. from the EORTC Gastrointestinal Group subsequently performed a study randomising patients to either FAM or FAMTX [ 1521. They found a significantly superior response rate for the FAMTX regimen (41 vs. 9%) and a median survival of 42 weeks vs. 29 weeks. There was no major difference in the nonhaematological toxicity although mucositis was more a pronounced FAMTX. There was no difference in leucocyte nadirs, however, there was cumulative thrombocytopenia with the FAM arm. Although the response rate seen with the FAM regimen is substantially less than seen in previous studies, these results support the place of FAMTX as the best standard therapy for further randomised studies. Further attempts at refining the scheduling of FAMTX have been initiated [153], namely by changing the dose interval between the methotrexate and 5-FU. These regimens will also need testing in the Phase III setting. The other drug that has been used to replace mitomytin C in the FAM regimen is cisplatin. The Phase II experience with this combination shows a 41% response rate in 58 patients including 10% complete responses [ 154,155]. A Gastrointestinal Tumour Study Group study randomised patients to receive: 5-FU plus Adriamycin plus methyl CCNU (FAMe); 5-FU plus Adriamycin plus triazinate (FAT); 5-FU, Adriamycin and cisplatin (FAP) [ 1561. The study found that FAP and FAT were superior to FAMe, both in response and in median survival. A further cisplatin containing regimen developed in the latter 1980s by Preusser et al. [139], based on preclinical evidence of synergy between etoposide and cisplatin, combined etoposide and Adriamycin with cisplatin (EAP). The original Phase II study of 67 patients demonstrated a response rate of 64% including 21% complete responses. The main toxicity was of myelosuppression, with 64% of patients experiencing this at a WHO grade of 3 or 4. The median survival was 9 months with 6 (9%) patients surviving 2 years. A parallel study using EAP in patients with locally advanced disease, demonstrated that previously unresectable locally advanced tumours could be successfully
resected [ 1571. The subsequent cumulative experience from different centres confirms the activity of this regimen with a response rate of approximately 50”/;, including 14% complete responses [ 158,159]. This regimen however, did appear to be more toxic than others. This was confirmed by Kelsen et al. in a randomised trial comparing EAP to FAMTX. The trial was ceased early because of no apparent difference in response (EAP 20%, FAMTX 33%), but a significantly higher toxic death rate with EAP (13% vs. 0) [160]. More recent combination chemotherapy regimens have focused on optimising 5-FU efficacy, either with modulation or alterations in schedule and in substitution of Adriamycin for epirubicin. Wilke et al. [ 1581 combined etoposide with 5-FU and leucovorin (ELF) in 51 patients, achieving a response rate of 53% including 12% complete responses. The regimen was designed as the default study for patients with cardiac or other medical conditions or of advanced age, who were thought not likely to tolerate EAP. Arbuck et al. [ 1611 combined the FAM regimen with calcium leucovorin (FAM-CF) in an attempt to modulate the 5-FU. The response rate overall in this study was 38%, however, with progressive courses, the amount of 5-FU the patient could tolerate decreased suggesting it would be unlikely that a randomised study would detect any difference between FAM and FAM-CF. Lopez et al. [162] modified the FAB regimen to include epirubicin instead of Adriamycin, in combination with 5-FU and BCNU. In 45 patients a response rate of 42% was seen with 11% complete response - appearing little different to the original FAB. Four recent studies have investigated the role of 5FU, cisplatin and epirubicin in combination. Taal et al. [ 1631, examined an alternating schedule of methotrexate 300 mg/m2 followed 7 h later by 5-FU 900 mg/m2 with leucovorin rescue starting 24 h after the methotrexate. Epirubicin 60 mg/m2 and cisplatin 75 mg/m2 were given on day 15 (FEMTX-C). The results from the study of 21 patients revealed a 33% response rate and relatively little toxicity. A randomised study comparing cisplatin, epirubicin, 5-FU and leucovorin (PELF) to FAM is currently in progress. An interim report by Cocconi et al. [ 1641 suggests a superior response rate and survival in the PELF arm, although neither reaches statistical significance. Delfino et al. [165], studied 70 patients using cisplatin (70 mg/m2), epirubicin (60 mg/m2) and 5-FU (600 mg/m2) given once every 28 days. This resulted in a 36% response rate with 16% complete responses. Our experience [166] using the same drugs, but at different doses and schedules (5-FU protracted infusion 200 mg/m2 per day for 21 weeks with eight 3-weekly cycles of epirubicin 50 mg/m2 and cisplatin 60 mg/m2; ECF).
145
Ninety-five of the 133 patients with evaluable disease (71%) achieved a response. Responses were seen both in small and large volume disease in a variety of sites (see Fig. 6). There were 11% complete responses. Assuming no major differences in case selection or response criteria, the results of our study and that of Delfino et al. [165] suggests there may be a role for protracted infusion 5-FU, with its high dose intensity, in this disease, as it is unlikely the differences in dose or schedule of cisplatin and epirubicin explain the different response rates. Current evidence suggests that there is no standard cytotoxic combination for general use in advanced gastric cancer. The FAMTX regimen appears to be established as the best treatment for control arms in future Phase III studies. The results of the FAMTX vs. EAP study [160] emphasize the need for randomised comparisons to establish comparative toxicity and antitumour activity.
VII. Neo-adjuvant chemotherapy for gastric cancer With the generally disappointing results from studies using post-operative surgical adjuvant chemotherapy in gastric cancer there is an increasing interest in prescribing pre-operative chemotherapy. The rationale for this is to offer earlier treatment to micrometastatic disease and to potentially downstage the primary tumour. This approach however does provide some methodological difficulties. Firstly, in order to determine the effect of a regimen on survival, randomised studies with a nonchemotherapy arm need to be performed in patients with advanced, but resectable disease. The difficulty with this is that patients with surgically curable nonadvanced disease are difficult to exclude by clinical staging. The risk to these patients in a surgery delaying preoperative chemotherapy programme, is that, unless the chemotherapy is a 100% effective in preventing disease progression, there is a possibility of a surgically curable
Fig. 6. Tumour response to ECF chemotherapy in metastatic gastric cancer [ 1661. The left hand set of CT images show the complete radiological resoiution of liver metastases. The right hand set of CT images show a partial response in bulky bilateral Kruckenberg tumours.
146
tumour becoming unresectable. This obviously requires better methods of staging early gastric cancer and also necessitates very active chemotherapy regimens which not only have a high probability of inducing a response, but can also prevent frank progression of disease during the pre-operative period. An alternative approach is to look at patients with inoperable tumours determined either by a failed surgical procedure or by clinical criteria of locally advanced disease. Patients would then be offered chemotherapy with subsequent attempted resection. The difficulty with this approach is that there is no ability to randomise to a non-treatment arm, thus interpretation of results would rely on historical controls. The other difficulty is
that of no reliable criteria for clinically defining locally advanced disease. Cumulative patient morbidity will occur if exploratory laparotomy for staging is required in addition to chemotherapy and a second laparotomy for definitive resection. With either approach, investigators must be wary of inducing significant toxicity with the chemotherapy which will both increase the perioperative risks and delay definitive surgery. Recent pre-operative chemotherapy studies are summarized in Table 3. Wilke, Preusser and colleagues [ 1571 treated 34 patients with unresectable gastric cancer as determined by failed laparotomy. Using the EAP regimen, 23 patients had a major response, 2 a minor response to treatment and there was one early death.
TABLE 3 Neoadjuvant chemotherapy for locally advanced gastric cancer Regimen
Resectability
Evaluable patients
Responses (CR and PR)
Patients having surgery
Number of resection achieved
Complete Pathologic complete response
Etopside, adriamycin cisplatin [ 1571
Unresectable
33
23133 (70%)
l9+
15120 (75%)
5120
Etopside, adriamycin, cisplatin [I671
Potentially resectable
48
l5/48 (31%) ‘major responses’
41
37/4 I (90%)
0141
Etopside, 5FU, cisplatin 11681
Potentially resectable
25
6125 (24%) ‘major responses’
25
18/25 (72%)
O/25
Etopside, 5FU, cisplatin [ 1691
Potentially resectable
35
17/35 (49%) ‘major responses’
32
25/32 (78%)
l/32
5FU, leucovorin, cisplatin [I351
Not stated
25
l6/25 (64%)
25 ‘signtiicant
Not stated
O/25
Epirubicin, cisplatin, 5FU [166]
Unresectable or clinically LAD
36
29/36 (8 I%)
21
12121 (57%)
512I
cisplatin, 5FU [170]
Clinically LAD
26
15126 (58%)
I5 + IINC + INE
21127 (78”/u)
Not stated
Epirubicin, tegafur u731 vs no chemotherapy
Potentially resectable T2-3 NOM0
9212
Not stated
9212
Not stated
Not stated
5FU, leucovorin, epirubicin, cisplatin [ 1721
Unresectable
Methotrexate, 5FU I1711 5FU, adriamycin, methotrexate [ 1521
I NC
(increased disease free survival with chemotherapy) 5/lO (50%)
5
515 (100%)
015
Unresectable (2 clinically LAD)
Not stated
I3
7113 (54%)
Not stated
Unresectable
Not stated
317 (43”/u)
Not stated
147
Nineteen of the major responders and one minor responder went forward to surgery. Fifteen were completely resected, 5 having pathological complete responses. In 3 patients complete resection was attempted but microscopically the proximal resection margin was positive. Two patients remained unresectable. In all, of the 20 patients submitted to further surgery three quarters were successfully resected. At a median followup of 20 months the relapse rate was 12/20 (60%) and the median survival for all patients 18 months while 24 months in disease free patients. Ajani et al. 11671, from the MD Anderson Cancer Centre, recently reported the results of perioperative EAP in potentially resectable gastric cancer. The response to EAP was 31% and despite 90% of patients tumours being successfully resected, there were no histological complete responses noted in the resection specimen. In two earlier reports, Ajani et al. describe the use of pre-operative etoposide, 5-FU and cisplatin (EFP) in both gastric [ 1681, oesophago-gastric and oesophageal adenocarcinoma [169]. In 25 patients with potentially resectable gastric cancer [ 1681, two cycles of EFP were given pre-operatively and then post-operatively in those who had an initial response. Major responses assessed using a barium oesophagram, was seen in 6 patients and minor response in 16. All 25 patients had surgery with 18 (72%) achieving complete resection. None of the resected specimens were histologically free of disease. The second study, using EFP in proximal tumours [ 1691, reports 17 major responses in 35 patients (49%). Of the 32 patients having surgery, 25 (78%) had a curative resection although only 1 had no residual tumour in the resected specimen. In our experience of 36 patients with unresectable or clinically locally advanced disease 29 responded to ECF chemotherapy (81%) [166]. Twenty-one patients had surgery while 8 did not due to patient refusal, poor operative risk factors or early relapse. Of the patients having surgery 12 (57%) had their tumours completely resected. A histological complete response in the primary was confirmed in 5 patients. Six patients tumours were not resectable whilst 3 had their tumours incompletely resected (positive resection margin). From France, Lasser et al. [ 1701, using a 5-day infusion of 5-FU (1 gm/m*/day) and single dose cisplatin (100 mg/m* day 2) for 2-3 cycles found 15/26 responded while the other 11 remained unchanged after chemotherapy. Three further patients were not evaluable (toxic death, lost to follow-up and cardiac toxicity) for tumour response however one of these was submitted to reoperation. In all 21/27 (78O/4)patients submitted to surgery were resected completely. The high rate of resec-
tability in the non-responding group suggests theclinical staging used was overestimating disease extent or conversely that minor responses may be adequate to permit successful resection. The number of histological CRs was not stated. The EORTC study comparing FAM to FAMTX, Wils et al. [ 1521, reported 19 patients with unresectable disease randomised to FAMTX, 7 of whom went to second laparotomy. Three of these were able to be completely resected. Verschueren et al. [ 1711 using methotrexate and 5-FU in 17 patients with unresectable disease demonstrated 7113 having further surgery were able to have a complete resection. Similarly a small Japanese study of 10 patients [ 1721 using 5-FU and leucovorin i.v. with cisplatin and etoposide IA (FLEP) achieved an objective response in 5 patients all of whom were successfully resected. None of the resected specimens however confirmed histological CR. In a review paper Leichman and Berry [ 1351 discuss their experience of 25 patients given infusional S-FU plus leucovorin and cisplatin (FLC) before surgery and i.p. cisplatin and floxuridine post-operatively. Although they do not detail the specific patient group they are studying or the subsequent resection rates, histological examination of the resected specimens revealed there had been no complete responses to this regimen. Roberts et al. [173] in a study from Finland, report 92 patients randomised to surgery alone or pre- and postoperative chemotherapy using epirubicin and Tegafur (Ftorafur). While not all the details are outlined in the abstract, this trial was examining the impact of chemotherapy on resectable locally advanced disease in comparison to a surgery only control arm. The disease free interval favoured the chemotherapy arm but there was no difference in overall survival at 3 or 5 years. Studies of pre-operative chemotherapy in gastric cancer are still few and small. The design of future studies will have to address the issues of non-surgical assessment of resectability and the use of surgery only control arms. Adjuvant chemotherapy has, to date, generally failed and in most populations its application is limited because the majority of patients’ tumours are unresectable at presentation. One way forward is to investigate the ability of current combination chemotherapy regimens to treat micrometastatic disease, to downstage locally advanced tumours, improve resection rates and ultimately impact on survival. VIII. Conclusions This review has focused on the two most common tumour types in gastrointestinal malignancy which is
148
where the opportunity for small advances to have the greatest impact on population survival and quality of life. The approach to forwarding the treatment of these diseases must be a mixture of maximizing the efficacy of established modalities while searching for new agents. With the continued presentation of patients with advanced disease, treatment remains a regular challenge, however, the longer term impact of prevention and screening strategies should continue to be investigated. Biographies Michael Findlay is a Medical Oncologist and Senior Research Fellow in the GI Unit at the Royal Marsden Hospital, Sutton, Surrey, UK. David Cunningham is a consultant Medical Oncologist and head of the GI and Lymphoma Units at the Royal Marsden Hospital, Sutton, Surrey, UK.
Reviewer This paper was reviewed by John S. MacDonald M.D., Temple University, Comprehensive Cancer Center, Philadelphia, Pennsylvania, USA. References I
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1993; 14: 127-l 52 0 1993 Elsevier Scientific Publishers Ireland Ltd. All rights reserved. 1040-8428/93/%24.00 Critical
Reviews
in Oncology/Hematology,
ONCHEM 00066
Current advances in the treatment of gastrointestinal malignancy Michael Findlay and David Cunningham Department
of Medicine,
Royal
Marsden
Hospital,
Downs
Road,
Sutton,
Surrey,
SM2
SPT,
UK
(Accepted 18 December 1992)
Contents I.
Introduction
.................................................
II.
Treatment of unresectable or metastatic colorectal cancer .........
128
III.
Adjuvant treatment of colorectal cancer .........................
134
IV.
Non-invasive monitoring
136
V.
Molecular biology of colorectal cancer ..........................
139
VI.
Treatment of advanced and metastatic gastric cancer .............
140
VII.
Neo-adjuvant chemotherapy for gastric cancer ...................
145
VIII.
Conclusions
147
of drug metabolism in colorectal cancer
.................................................
References ...........................................................
I. Introduction Colorectal and gastric cancers are two of the four most common tumours worldwide [l]. These two tumour types are the most widely studied gastrointestinal malignancies in oncology, hence are in need of frequent review. The range of potential outcomes for these two diseases provides both the scientist and clinician with a variety of challenges, thus demanding a multidisciplinary approach. Advanced metastatic incurable disease is the ultimate outcome in about half of all new cases of colorectal cancer. This large population of patients have historically received relatively ineffective cytotoxic treatment driven by anecdote and frustration on the part of the clinician and by desperation in the patient. The advances in preclinical science and a Correspondence to: Dr. David Cunningham, Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK.
127
148
more structured format for conducting clinical trials has yielded important results in this area. The renewed interest in treating colorectal cancer is based on several relatively recent advances. 5-Fluorouracil is the cornerstone of treatment and although over 30 years old is still being keenly studied to optimise both its own schedule and to combine it with the increasing variety of modulators. These studies have yielded clinical results showing prolongation of life and reduction of tumour related symptoms - important endpoints in palliative treatment. Advances in non-invasive monitoring of chemotherapy and tumour metabolism using positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) shows promise in providing early predictors of outcome thus enabling a more individualized treatment programme. Anti-tumour activity, determined from studies in metastatic disease can indicate appropriate schedules for use in the adjuvant setting - perceived by many to be a more useful place for these relatively inactive schedules. Beyond optimiz-
128
ing the use of established treatments, new drugs and novel therapies are needed. Much of the emphasis in this area is based on the increasing understanding of the molecular carcinogenesis of this disease. Gastric cancer more frequently presents at an advanced stage consequently with poor final outcome, yet can be cured if surgically resected at an early stage. Screening and prevention strategies are important in this disease, however, treatment of advanced gastric cancer again relies on the development of new drugs or schedules. Application of active regimens to the adjuvant and neo-adjuvant settings currently offer the best opportunity to improve long term survival. II. Treatment of unresectable or metastatic colorectal cancer After lung cancer in men and breast cancer in women, colorectal carcinomas are the next most common tumour type in the United States [2]. Overall approximately 50% of the 140 000 cases diagnosed each year are ultimately cured [2] while 200/o of patients have metastatic disease at first presentation. Despite the potential to reduce the incidence of metastatic disease with primary prevention, with screening for early stage disease and with the use of adjuvant treatments [3,4], there remains an urgent need to develop more effective treatment for disseminated colorectal cancer. Short of curing metastatic disease, oncologists must focus on maximizing length and quality of life ensuring active treatment is significantly better than best supportive care. Randomised studies with a best supportive care arm however are difficult to conduct due to patient and oncologist acceptance. A recent study from the Nordic Gastrointestinal Tumour Adjuvant Therapy Group [5] has randomised patients with asymptomatic metastatic colorectal cancer to immediate chemotherapy or chemotherapy when symptoms develop. Using this design the investigators have shown chemotherapy given before symptoms arise is more likely to prolong life while maintaining a longer symptomfree period. This study encourages the practice of giving early chemotherapy however only partly supports the use of treatment over best supportive care. Successful treatment of other disseminated malignancies has been with combination chemotherapy however in colorectal cancer this has been unrewarding and recent emphasis has been on 5-fluorouracil (5-FU), its scheduling and its modulation by agents such as leucovorin, interferon-a, PALA or cisplatin. Although the manipulation of 5-FU may enhance activity enough to influence survival when applied to the adjuvant set-
ting, its combination with new agents having different mechanisms of action are needed to greatly impact on metastatic disease. With the Intergroup study showing a survival advantage with adjuvant 5-FU and levamisole in Dukes C colon cancer [4] there has been renewed interest in optimising new regimens in metastatic disease that may also have application in the adjuvant setting. II-A. 5Fluorouracil
Since its introduction in 1957 by Heidelberger et al. [6], 5-FU continues to be the mainstay of cytotoxic treatment in colorectal cancer. 5-FU given orally results in highly variable absorption [8] however in a trial comparing i.v. to oral 5-FU, even though both arms had equivalent haematological toxicity the intravenous route gave a higher response rate (26% vs. 19%) [7]. As 5-FU given by the oral route is not indicated based on the current experience, most of the recent work with 5-FU has been determining the best intravenous schedule and exploring intra-arterial treatment. The most recent issue in intravenous 5-FU treatment is that of schedule. Based on in vitro data showing enhanced inhibition of colony formation in human colon cancer cells with prolonged drug exposure [9] and the known short plasma half-life of 5-FU [6], intravenous infusions have entered clinical evaluation. Although short (l-5 day) and prolonged ambulatory infusions appear to give better responses than bolus schedules, there has been no comparison of short and long infusions. In a multicentre study, Lokich et al. from the Mid Atlantic Oncology Program, compared continuous i.v. 5-FU at a dose of 300 mg/m2/day for 10 weeks or more, to five daily bolus injections (500 mg/m2) given for 1 week in every 5 [lo]. The results show an enhanced response rate (30% vs. 7%) with infusional treatment however no overall difference in survival. Infusional 5-FU gave less haematological toxicity and stomatitis however was uniquely associated with plantar-palmar erythema requiring dose reductions in 23% of patients. Plantar-palmar erythema usually requires reduction of 5-FU dose however pyridoxine 50 mg per oral t.d.s. does ameliorate the condition [ll]. Another problem with ambulatory infusions is that of the central venous catheter - mainly with thrombosis. In a randomised trial, Bern et al. [12] have shown that warfarin 1 mg orally daily, a dose very unlikely to measurably alter the patients prothrombin time, reduces the incidence of indwelling line induced venous thrombosis. Our own unpublished observations have shown a reduced incidence in this complication since the introduction of warfarin prophylaxis from 31% to 18%. The pattern of toxicity to some extent depends on the
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5-FU schedule, with weekly boluses giving predominantly diarrhoea, short-term infusions (2-5 days) mucositis and long-term infusions (weeks) plantar-palmar erythema. Ultimately the best 5-FU schedule may depend on the type of modulator being employed with it. The best standard single agent control arm for phase III studies will be influenced by the modulated arm. However, with quality of life in mind we believe long term infusional treatment may be preferable. The drawback with the infusional schedule is the cost of the pump and of central line insertion [ 131, although the cost of pumps can be reduced by reusing them and is offset by savings in the management of toxicity [14]. The increased understanding of intravenous 5-FU scheduling provides a greater variety of methods to investigate the optimum therapeutic index of modulated 5-FU. Martin et al. [15], have compared intravenous 5-FU to intra-arterial floxuridine in a randomised multi-centre study of patients with hepatic metastases. No survival difference between the intraarterial and intravenous treatment groups was found. While response rates are superior with i.a. treatment, these patients relapse outside the liver, Progress in regional treatment relies on randomised trials investigating its additive effect to systemic treatment.
II-B. 5-FU plus folinic acid This combination is a good example of biochemical pharmacology providing a mechanism of enhancing the activity of an established cytotoxic with a successful translation into the clinic. Although many questions have been answered there is still a need for further schedule investigation. A detailed review of the mechanism of folinic acid modulation of 5-FU is found elsewhere [ 161. Thymidylate synthase (TS) is a key enzyme in the de novo synthesis of deoxythymidine triphosphate (dTTP) a direct substrate of DNA (see Fig. 1). Fluorodeoxyuridine monophosphate (FdUMP), an active anabolite of 5-FU competes with cellular deoxyuridine monophosphate (dUMP) for TS binding sites. The dUMP-TS complex requires the reduced folates to complete the conversion of dUMP to deoxythymidine monophosphate (dTMP). When FdUMP binds TS it does so less reversibly than dUMP and the substituted fluorine atom prevents the reaction proceeding forward. There is therefore a TS-FdUMP binary complex formed. This complex is stabilized by reduced folates from folinic acid and forms a ternary complex [ 161. These findings led to the addition of folinic acid (leucovorin calcium) to 5-FU in patients whose tumours were resistant to 5-FU alone. Reversal of 5-FU resistance was noted with second responses in some tumours [17]. The
DHFU + FUPA -+ FBAL -+ FDHUDH
CATABOLITES
_______.____. _.._. ..._.. _- .__...__.__.._ ._..__.- _.._.- _.._.___...__..__.._._.._. . .._..__...__......__... t 5-Fluorouracil
.._.-_.._-...-..--.-.-..... _...._.._......._.
Nucleosldes Thvmidinc
F-deoxwridine
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FUMP
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UDP reductase 4
dTDP
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1
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DNA
1
FU-DNA
I FUDP
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Fig. 1. 5-Fluorouracil metabolism. The various routes by which 5-FU is metabolised: (1) by catabolism to non-cytotoxic components DHFU, FUPA, FBAL and F-; (2) anabolism to FUMP with eventual incorporation into RNA; (3) anabolism to FdUMP with inhibitory effects on enzyme thymidylate synthase (TS); and (4) incorporation into DNA. Abbreviations: DHFU, dihydrofluorouracil; FUPA, fluoroureido propionic acid; FBAL, fluoro-beta-alanine; DHUDH, dihydrouracil dehydrogenase; TP’ase, thymidine phosphosylase; UrdP’ase, uridine phosphosylase; TK, thymidine kinase; Urd K, uridine kinase; FUMP, fluorouridine monophosphate; FUDP, fluorouridine diphosphate; FUTP, fluorouridine triphosphate; FdUMP, fluorodeoxyuridine monophosphate; FdUDP, fluorodeoxyuridine diphosphate; FdUTP, fluorodeoxyuridine triphosphate; dUTP OH’lase, deoxyuridine triphosphate hydroxylase; dUMP, deoxyuridine monophosphate; TS, thymidylate synthase; CH,THF, methylene tetrahydrofolate; dTMP, deoxythymidine monophosphate; dTMPK, dTMP kinase; dTDP, deoxythymidine diphosphate; dTTP, deoxythymidine triphosphate.
5-FU-leucovorin
combination
was however more toxic
WI. Subsequent phase II studies confirmed clinical eficacy using a variety of different 5-FU and folinic acid schedules. The 5-FU schedules ranged from weekly i.v. bolus (300-750 mg/m2) [19], to two weekly 2-day infusions (600 mg/m2/day) [20], five daily boluses (340-400 mg/m2/day) for 1 week every 3-5 weeks [21] to a continuous ambulatory i.v. infusion (300 mg/m*/day) [22]. The dose of folinic acid ranged from 15 mg to 1000 mg a week and was generally given intravenously as a bolus or infusion although oral administration was used in
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some (see below). The DeGramont regimen [20], while not studied in a phase III trial with single agent 5-FU, appears active with a 51% objective response rate and low toxicity. The regimen, i.v. folinic acid 200 mg/m2 over 2 h followed by 5-FU 300 mg/m2 bolus then 300 mg/m2 infused over 22 h is given on days 1 and 2 every 2 weeks. The problem with the schedule is the frequent inpatient stay which can only be avoided by using a indwelling central venous line and infusing the 5-FU via an ambulatory pump. Continuous ambulatory infusion of 5-FU at 300 mg/m2/day has been modulated with weekly i.v. folinic acid (20-75 mg/m2) [22]. The study found 7 of 10 patients treated with 20 mg/m2/week folinic acid completed 4 weeks of 5-FU with 3 needing a treatment break for toxicity. Doses higher than this were less well tolerated. The dose limiting toxicity was stomatitis not plantar/palmar erythema as for single agent infusional 5-FU. Eight of the 19 evaluable patients (42%) in this study had a tumour response. A phase III trial is being carried out by the South West Oncology Group [22]. Phase III studies of folinic acid have been performed using various weekly and monthly 5-FU schedules. Two major studies performed by collaborative groups have each investigated optimum folinic acid dosage for a specific 5-FU schedule [23,24]. The Gastrointestinal Tumour Study Group (GITSG) [23] randomised 343 patients to: (a) a control arm of 5-FU alone (500 mg/m2 daily for 5 days every 4 weeks with 25 mg/m2 escalation); (b) weekly 5-FU 600 mg/m2 plus folinic acid 500 mg/m2 for 6 weeks with 2 weeks rest; or (c) 25 mg/m2 folinic acid given with the same weekly 5-FU schedule. The response rate for the high dose FA arm (30.3%) was statistically significantly better than control 5-FU (12.1%). The low dose FA arm (18.8%) was not significantly different to the high dose arm. Toxicity in the modulated 5-FU patients was predominantly in the form of diarrhoea with 11 patients (7 high dose FA, 4 low dose FA) dying as a result. Ten of these were over age 63 years. However, a protocol change ensured treatment was withheld for any (as opposed to grade 2) diarrhoea, mucositis or stomatitis until it had resolved. Although responses favoured the 5-FU plus high dose FA arm there was no difference in median survival partly due to the toxic deaths. The second collaborative study, that of the North Central Cancer Treatment Group (NCCTG) has recently been updated [241. The original study [25] of 429 patients randomised patients to either: (a) 5-FU 500 mg/m2 for 5 consecutive days every 5 weeks; (b) 5-FU 300 mg/m2/day and cisplatin 20 mg/m2/day for 5 consecutive days every 5 weeks; (c) 5FU 1000 mg/m2 7 h after a 4-h infusion of methotrexate
200 mg/m2 and folinic acid 14 mg/m2 orally in eight 6-h doses starting 24 h after initiating methotrexate-courses every 3 to 4 weeks; (d) 5-FU 700 mg/m2 preceded 24 h by methotrexate 40 mg/m2 i.v. on days 1 and 8 every 28 days; (e) 5-FU 370 mg/m2/day preceded by FA 200 mg/m2/day for 5 consecutive days every 4-5 weeks; and (f) 5-FU 425 mg/m2/day preceded by FA 20 mg/m2/day for 5 consecutive days 4-5 times weekly. This earlier study confirmed that the low and high dose FA arms were superior to 5-FU alone; the high dose methotrexate arm was the only other, possibly conferring some advantage. Based on this a further 259 patients were randomised to 5-FU plus low dose FA, 5-FU plus high dose FA or 5-FU plus high dose methotrexate and FA rescue. 5-FU plus low dose FA gave a significant survival benefit over 5-FU plus high dose MTX (12.7 vs. 8.4 months; P I 0.01) but 5-FU with high dose FA was unable to do so (see Fig. 2). There was however no significant difference in survival between the two FA arms. Objective tumour response was seen in 14% on 5FU plus high dose MTX, 31% on 5-FU plus high dose FA and 42% on 5-FU plus low dose FA. Leucopenia was the dose limiting toxicity in the 5-FU plus high dose MTX arm while mucocutaneous toxicity was dose limiting in the FA arms. Stomatitis was more frequent (28%) than diarrhoea (16-19%). Rates of hospitalization for toxicity were highest in the low dose FA arm (15%) 6.5% for the MTX arm and 5.4% for the high dose FA arm. There was one toxic death in each arm. From the results of the GITSG and NCCTG studies a further trial was initiated comparing weekly 5-FU plus high dose FA with 5-FU plus low dose FA on the 5-day schedule, The preliminary results reported in abstract form [26], show that of the 3 15 evaluable patients there was no difference in median survival (10 months) or response (28% GITSG and 33O/oNCCTG). The dose limiting toxicities were stomatitis for the NCCTG regimen and diarrhoea for the GITSG regimen. Although the incidence of life-threatening toxicity was similar, because of diarrhoea, the GITSG regimen had induced more toxicity inpatient days (430 vs. 3 17; P = 0.07). This and the cost of FA favours use of the NCCTG regimen. While current results suggest that low dose FA given with five day bolus 5-FU regimens offers the best tumour response, patient survival and palliative-effect, further investigation of FA modulation will continue. Oral administration of FA may offer an advantage over iv. by selective absorption of the active L-isomer to the exclusion of the inactive D-isomer which may compete with it at the target site [27]. Similarly, an intravenous preparation of the purified L-isomer is available for
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80 -
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0 I
0
6
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12
18
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Fig. 2. Survival of patients with metastatic colorectal cancer on chemotherapy: - - -, 5-FU + high dose methotrexate, n = 155; . . . . 5-FU + high dose leucovorin, n = 149 (P vs. 5-FU + high dose methotrexate; 0.04, unadjusted; 0.44, Cox model); -.-.-, 5-FU + low dose Ieucovorin, n = 153 (P vs. 5-FU + high dose methotrexate; 0.01, unadjusted;
study. While the role of continuous infusion 5-FU and FA remains unresolved it provides another opportunity to explore the therapeutic window provided by these two drugs [22]. II-C. 5-FU plus interferon (IFN)
As early as 1982 the combination of 5-FU and interferon has been shown to be synergistic in human tumour cell lines [28] although another early report found that by altering the timing of interferon a protective effect on 5-FU cytotoxicity could be demonstrated in mice [29]. Synergy with 5-FU is seen both with alpha- and gammainterferon although in some cell lines IFN does not affect 5-FU cytotoxicity [30]. Although literature is accumulating, the exact mechanism(s) of the 5-FU-IFN synergy is not resolved. This is partly due to the uncertainty as to the relative importance of thymidylate synthase inhibition by FdUMP and the incorporation of FUTP into RNA as mechanisms of 5-FU cytotoxicity [3 11. Current evidence suggests interferon may: increase
intracellular FdUMP levels [32] perhaps by favouring its formation or interfering with its catabolism; prevent the 5-FU induced upregulation of TS thereby maintaining adequate levels of inhibition [33]; or impair thymidine transport and thymidine kinase activity which is a potential rescue mechanism for the 5-FU treated cell [34]. &huller et al. [35] provide additional evidence with a pharmacokinetic study suggesting IFN reduces 5-FU clearance, increasing its AUC by 80% [35]. This can increase delivery of 5-FU to the cell thus contributing to any cellular synergy. Our own experience using in vivo “F-magnetic resonance spectroscopy to monitor 5-FU metabolism in tumours in situ suggests the addition of interferon-o to a continuous 5-FU infusion at a time of 5-FU resistance results in increased 5-FU and 5-FU anabolite tissue levels. These changes may predict reversal of 5-FU resistance [36]. These findings also raise the possibility that interferon may alter 5-FU uptake or efflux or interfere with 5-FU catabolism, encouraging anabolism. A clinical study by O’Connell et al. [37], investigating
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the activity of interferon-gamma alone in patients with advanced colorectal cancer showed minimal effect with only 1 patient having a response out of 16 treated. Clark et al. [38] treated 36 patients with interferon-a alone on two schedules: either 50 million units/m2 i.v. on 5 consecutive days every 4 weeks or 20 million units/m2 S.C. three times per week. Toxicity was unacceptable and there were no tumour responses. In the second part of the same study 29 patients received interferon in similar schedules but at reduced doses (20 million units/m2 i-V./day; 5 million units/m2 S.C.three times per week and were given 5-FU 250-500 mg/m2 for 5 consecutive days on a 4-weekly cycle. Toxicity was acceptable but there was only one response of short duration. The doses of 5-FU used were however lower than currently recommended. Wadler et al. [39] investigated the feasibility of interferon-o doses ranging from 6 to 18 million units while patients received 5-FU 750 mg/m2/day infusion for 5 days then weekly boluses. Responses were seen in 5 of 9 patients given the lowest dose levels of interferon while none were seen in the 9 patients at higher dose levels. Toxicity was acceptable at 15-18 million units, but greater than at lower levels. Following this a phase II study was performed using 5-FU 750 mg/m2/day infused for 5 days then weekly as an iv. bolus with interferon-cr-2a, 9 million units S.C.three times per week [40]. This study confirmed activity of the combination in previously untreated patients with 13 of 17 achieving a response. There were no responses in previously treated patients. 5-FU toxicity was evident with no suggestion of interferon offering preferential protection of normal tissue. Subsequent attempts to reproduce this data yielded response rates of 26-35% but with up to 84% of patients requiring dose reduction for toxicity [41,42]. Most recently a multi-institutional confirmatory trial was performed by the Eastern Co-operative Oncology Group (ECOG) [43], in which a 42% response rate was seen in 36 evaluable patients. Eight patients had grade 4 toxicities (sepsis, diarrhoea, neutropenia) and 2 patients experienced grade 3 neurological toxicity. The median time to treatment failure was 8 months. Using a different study design we have been able to show interferon-a, has activity in 5-FU resistant tumours [36]. Patients were treated with 5-FU (300 mg/m2/day) as an ambulatory infusion and at maximum response, defined as no change over 12 weeks or increase in tumour size or CEA levels, interferon-a 5 million units S.C.three times per week was added. Twenty one percent of patients showed evidence of further response to the addition of interferon albeit with some increase in toxicity. Although the present evidence points to a modulatory
effect of interferon-o on 5-FU action and in 5-FU resistance, the results of ongoing randomised phase III studies based at the Royal Marsden Hospital, comparing 5-FU + interferon-a to 5-FU alone, will provide the strongest indication of the clinical utility of the current schedules. Further preclinical research is needed to elucidate the mechanisms of action involved in the combination. In particular the most appropriate 5-FU schedule needs to be determined, the precise timing and the dose of interferon established to maximise any normal tissue cytoprotective effects while optimising 5-FU biochemical modulation. II-D. 5-Fluorouracil plus N-phosphon-acetyl+aspartate
(PALA) N-phosphor+acetyl+aspartate (PALA) is an inhibitor of de novo pyrimidine synthesis. By inhibiting aspartate transcarbamylase the formation of erotic acid (OA) from carbamyl phosphate is reduced. This leads to a reduction in UMP and subsequently UTP incorporation into RNA. Similarly dUMP binding to thymidylate synthase is reduced. Simultaneously phosphoribosyl pyrophosphate levels increase due to reduced OA and enhance anabolic metabolism of 5-FU if present. Overall this leads to enhanced FUTP incorporation into RNA and FdUMP binding to TS [31,44]. Phase II trials using PALA as a single agent show no significant antitumour effect, possibly because the activity of the target enzyme aspartate transcarbamylase is much higher in tumour than normal tissue [45]. Although animal results suggested that only moderate PALA induced uridine nucleotide depletion was needed to maximize PALA modulation of 5-FU [46], the first clinical studies used maximum PALA doses and reduced doses of 5-FU [47]. Consequently the results were disappointing underlining the need to keep 5-FU, the active agent, at maximum tolerable dose and adjust the modulator instead. Subsequent studies have shown more encouraging results [48,49,50]. Ardalan et al. [48] studied 52 patients using a weekly 24-h infusion of 5-FU (750-3400 mg/m2) preceded 24 h by PALA 250 mg/m2 and a 5-FU only (1300-5200 mg/m2) control arm. The maximum tolerated dose of 5-FU in each arm was 2600 mg/m2 with ataxia being the dose limiting side-effect both with 5-FU/PALA and 5-FU alone. Eleven of 28 patients (39%) responded to 5-FU/PALA while 4 of 19 (21%) to 5-FU alone. O’Dwyer et al. [49] using PALA 250 mg/m2 and a weekly 24-h infusion of 5-FU (2600-3250 mg/m2) noted tumour response in 16 of 37 (43%) patients. The maximum tolerated dose of 5-FU was 2600 mg/m2.
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Kemeny et al. [50] report the use of PALA (250 mg/m2) followed 24 h later by bolus 5-FU at three dose levels - 600, 700 and 800 mg/m* - weekly for 6 weeks in every 8. Forty-five patients were treated and of the 43 evaluable for response 15 (35%) had either a CR or PR. Toxicity (diarrhoea and neutropenia) was largely seen in the highest 5-FU dose level. An interesting observation in this study, detailed in a separate publication [51] was of the development of ascites, hyperbilirubinaemia and hypoalbuminaemia generally in patients responding to 5-FU/PALA. The investigators postulate the enhanced incorporation of 5-FU into RNA may inhibit protein synthesis in the liver and that PALA induced reduction in uridine pools inhibits bilirubin glucuronidation. From the clinical standpoint however, it is important to differentiate this syndrome from tumour progression. Overall these results show PALA has potential as a well tolerated form of modulation. Both the Eastern Co-operative Oncology Group and the South West Oncology Group are testing PALAS-FU in phase III trials. II-E. 5Fluorouracil
plus methotrexate
platin combination [61] randomised trials fail to confer its clinical advantage. Kemeny et al. [62], studied 122 patients randomised to receive either 5-FU (1000 mg/m2/day) as a continuous infusion for 5 days every 4 weeks or cisplatin 20 mg i.v. bolus daily for 5 days during the 5-FU infusion. Although the response rate was better with 5-FU and cisplatin (25% vs. 3%, P = 0.001) the toxicity was worse and the median duration of response and survival were no different. In a Mid-Atlantic Oncology Program study, Lokich et al. [63] randomised treatment to either ambulatory infusional 5-FU (300 mg/m2/day) for 10 weeks of every 12 or this with weekly cisplatin (20 mg/m2 i.v.). Neither the response rate (35% vs. 33%) nor median survival (11.8 vs. 11.2 months) differed in the two groups. Hansen et al. [64], of the Eastern Co-operative Oncology Group report protracted infusion 5-FU with or without cisplatin gives a superior response rate to bolus 5-FU however 5-FU/cisplatin was not better than infusional 5-FU alone. There were no statistical differences in survival between the groups.
(MTX) II-G. S-Fluorouracil plus other modulators
Preclinical studies show by inhibition of the purine de novo pathway, MTX increases the concentration of PRPP which enhances anabolism of 5-FU inducing cytotoxicity via an RNA effect [52,53]. Translation of this mechanism into the clinic has led to disappointing results despite extensive study. One factor that might explain these findings is the time interval between administration of the MTX and 5-FU. Most earlier studies used intervals of between l-7 h with no randomised trials demonstrating either an advantage in tumour response rates or patient survival when compared to 5-FU alone [25,54,55]. Several studies used a 24-h dose interval in the MTX arm [24,56,57] however, only one of these was associated with a survival advantage [57]. Other studies have failed to find a response or survival advantage with this schedule [58,59]. II-F. SFluorouracil
plus cisplatin
Interest in cisplatin and 5-FU combinations stems from preclinical evidence of synergy. Although the interaction is incompletely understood at the cellular level Scanlon et al [60] found cisplatin increased the intracellular reduced folate levels which enhanced FdUMP binding to TS. The mechanism may relate to the cisplatin induced inhibition of methionine transport and subsequent methionine deprivation leading to an enhanced intracellular synthesis of reduced folates. Despite phase II studies suggesting enhanced activity of the 5-FU/cis-
5-FU has been combined with several other agents in clinical studies with mixed success. Allopurinol has been shown to prevent 5-FU toxicity to normal tissues in animals [65] probably by inducing a rise in erotic acid which competes with 5-FU for the enzyme erotic acid phosphoribosyl transferase. It was used clinically on the basis that normal tissues would be more affected by allopurinol and tumour would activate 5-FU by alternative mechanisms thus maintaining a cytotoxic effect. While Fox et al. [66] were unable to show an improved therapeutic ratio the use of an allopurinol mouthwash may reduce 5-FU-induced stomatitis (671. Dipyridamole is an inhibitor of nucleotide transport which does not affect uptake of 5-FU into the cell but inhibits efflux of the active nucleotides of 5-FU [68]. Remick et al. [69], however, found the combination appeared to have no advantage over 5-FU alone. The complete reversal of 5-FU cytotoxicity by uridine implies 5-FU was working via RNA effects, conversely successful thymidine rescue would imply a DNA effect was predominant [31]. A uridine infusion of 1 h failed to protect from 5-FU toxicity [70] but alternating a 3-h infusion with 3 h rest for 3 days, adequate uridine levels could be maintained without developing high fevers the major problem seen with prolonged infusions [71]. Using the intermittent infusion schedule uridine could protect from 5-FU induced leucopenia but not thrombocytopenia [72]. As the infusions are inconvenient, oral
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preparations have been tested, however, diarrhoea and poor bioavailability have been problematic [73]. Coadministration of oral uridine with a uridine phosphorylase inhibitor reversed 5-FU induced toxicity [74]. Although these results are preliminary they do show potential to increase the therapeutic index of 5-FU. Thymidine, by being catabolized to thymine competes with 5-FU for the catabolic enzyme dihydro-uracil dehydrogenase (see Table 1). In addition thymidine facilitates the production of dTTP which both bypasses the inhibitory effect of FdUMP on DNA synthesis and by negative feedback inhibits ribonucleotide reductase diminishing FdUMP formulation from FUMP. This favours FUTP incorporation into RNA [75]. These effects greatly lengthen the plasma half life of 5-FU and increase its toxicity, Because of these actions, further investigation of scheduling or combination with other modulators is needed before the true usefulness of thymidine can be assessed. II-H. Double modulation of 5-jluorouracil
With increased knowledge of the mechanisms of 5-FU modulation and the clinical experience now available, more interest has been directed to using two modulating agents of 5-FU in one schedule. Kemeny et al. report the use of PALA, methotrexate and 5-FU in combination [76]. PALA 250 mg/m2 and MTX 250 mg/m2 were administered on day 1 and a 5-FU bolus on day 2, with folinic acid 10 mg q.d.s. for eight doses starting 24 h after the MTX. Using an alternate week schedule the MTD of 5-FU was 900 mg/m2 but only 600 mg/m2 on the weekly for 2 weeks then 2 weeks break schedule. The dose limiting toxicity was diarrhoea. This regimen is being further evaluated with the addition of uridine. The combination of 5-FU, folinic acid and interferon alpha has been evaluated in several studies to date reported in abstract form. Seymour et al. [77] using a modified DeGramont schedule (2-day 5-FU infusion plus FA with interferon-a 6 million units S.C.three times weekly every 2 weeks) report a modest increase in toxicity but improved response rate (52%) compared to previous phase II studies of 5-FU/FA in this schedule [20]. This regimen is the subject of a randomised trial in the United Kingdom testing the additive effect of interferon. Other studies suggest toxicity is not a major problem but response rates were sometimes very poor [78,79,80]. The study by Schuller et al. [35] showed that interferon increased the plasma AUC of 5-FU (80%) but when FA was added this resulted in a reduction of the AUC to near single agent 5-FU levels. If this data is
reproducible then until there is a better understanding of the intracellular effects of double modulation, attempts at combining these agents should be made with caution. II-I. Newer cytotoxic agents and combinations
Combination chemotherapy for colorectal cancer has generally been very disappointing. Mitomycin C, cisplatin, 5-FU and vincristine appears an active combination with a 44% response rate compared to a control arm of cisplatin and 5-FU (12%) [81]. Toxicity and poor overall survival suggest this regimen is not clinically useful in advanced disease. High dose melphalan (L-PAM) plus misonidazole and autologous marrow rescue [82] gives a response rate of 42% with significant toxicity. Unfortunately the responses were short lived (median 17 weeks). The use of cisplatin and Ara-C in combination has yielded a 42% response rate in a small study [83]. All these newer combinations appear to enhance response for short periods at the cost of increased toxicity. Newer agents acting via novel targets for example the ~21”” protein (see molecular biology section) or topoisomerase 1 show potential in colorectal cancer. Shimada et al. [84] demonstrated a partial response in 6113 (46%) patients with colorectal cancer treated with a campothecin analogue CPT-11 - a topoisomerase 1 inhibitor. The main toxicities were of vomiting, leucopenia and diarrhoea. CPT-11 is undergoing .further evaluation in Japan in combination with 5-FU. Topotecan, another camptothecin analogue has undergone extensive phase I study [85-881 revealing myelosuppression as the dose limiting toxicity. Diarrhoea, fever, nausea, rash, cystitis and alopecia also occur and are mild to moderate. Although there is no phase II information available at present, many of the patients in the phase I studies had colorectal tumours with none showing tumour responsiveness to topotecan. Phase II studies are awaited to determine the efficacy of topotecan in this tumour. III. Adjuvant treatment of colorectal cancer III-A.
Colon cancer
Since the Intergroup study of Moertel et al. [4] set the precedent in the United States for adjuvant chemotherapy in Duke’s C colon cancer, the treatment of resectable colon cancer has undergone major re-evaluation. Prior to this study there was no standard recommended adjuvant treatment. In 1988, Buyse et al. reported the results of a meta analysis of the adjuvant trials published up to December 1986 [89]. A total of 17 trials compared
chemotherapy with control groups. Results from these showed that administration of 5-FU for periods of 1 year or longer reduced the odds of death by about 17% (odds ratio 0.83 95% C.I. 0.70-0.98, P = 0.03) and gave a 3-4% higher 5-year survival. This study was done prior to the completion of three major trials: INT-0035 [4], NSABP R-01 [90] and NSABP C-01 [91]. Gray et al. [92] reviewed the Buyse et al. data with the results of these three trials included. Overall, there was a 14% (odds ratio 0.86 95% C.I. 0.81-0.90 2P < 0.003) reduction in mortality in 20 studies of various single agent and multiple agent schedules of various durations (5 weeks to indefinite). This updated review however did not present an analysis of the impact of 5-FU ( f other agent) given for 1 year or longer - the group that appeared to derive the maximum benefit in the earlier review. Results of detailed subset analysis in overviews can however be misleading. The available published data from these two overview analyses shows at least encouraging evidence for the efficacy of 5-FU in the adjuvant setting. This benefit may be small but in terms of patient numbers in this common tumour the benefit is significant. Further information could be obtained by performing a large collaborative meta-analysis on the scale of the recently published breast cancer study [93]. The Intergroup study [4] randomised 1296 patients, 325 with stage B2 disease and 971 with stage C disease. The stage B2 patients were randomized to surgery only or surgery with 5-FU plus levamisole for I year. The results after 3.5 years follow-up show no significant difference between the two arms. This group will be observed for at least another two years before drawing conclusions. The 971 patients with stage C disease were randomised to either surgery alone, surgery plus levamisole or surgery plus levamisole and 5-FU. 5-FU plus levamisole reduced the risk of recurrence by 41% (95% C.I. 23-540/o). At 3.5 years, 63% of patients receiving 5FU plus levamisole and 47% of controls were free of recurrence. The rate of recurrence was reduced at all sites in particular those outside the abdominal cavity (lungs, retroperitoneal and peripheral nodes and abdominal wall). The estimated reduction in the death rate by treatment with 5-FU/levamisole compared with control was 33% (95% C.I. lo-SO%). The 3.5 year survival estimates were 71% for the 5-FLVlevamisole arm and 55% for control (P = 0.0064) (see Fig. 3). Toxicity was generally mild with the majority of side effects being consistent with 5-FU alone (nausea, vomiting, diarrhoea, stomatitis, dermatitis and leucopenia). Compliance with the levamisole arm was good with 92% of patients taking at least 90°/ of the planned course. 5-FU/levamisole patients, experiencing more toxicity, had a 30% rate of
100
25 40 -2= a” 20
0
...... -
Lev + 5FU Levamisole Observat~n
12
At risk 304 310 315
24
Months
Dead 78 109 114
3s
4s
since Enrollment
Fig. 3. Survival of patientsfollowing resectionof Dukes’s C colon cancer. A comparison of the effects of levamisole and 5-FU + levamisole over surgery alone. From Moertel CG et al. N Engl J Med 322:352-358, 1990 (with permission).
early treatment discontinuation. The final report on this study was presented by Moertel at the 1992 American Society of Clinical Oncology meeting. With a median follow up of 5 years the results of the earlier report were confirmed-Duke’s C patients could achieve a 31% reduction in their chances of death due to cancer. Whilst this study has produced the most convincing data for adjuvant treatment of Stage C colon cancer the ommision of an arm using 5-FU alone casts doubt over the role of levamisole in this combination. Although there is a lack of clinical and preclinical supportive evidence for levamisole’s activity in established disease, it is possible synergism is seen only in vivo and only in states of minimum disease. Despite these uncertainties this regimen is currently the best available considering the additional supportive evidence from the overview analysis of 5-FU based regimens. An important lesson learnt from other adjuvant studies was the use of agents that are leukaemogenic. The NSABP study [91] for colon tumours found some marginal overall survival advantage but the use of methyl-CCNU in combination with 5-FU and vincristine increased the incidence of leukaemia. Ongoing analysis of this study has suggested a weakening of the survival benefit. Intraportal5-FU given as a short post-operative infusion has been tested in several trials following the study by Taylor et al. [94] from the United Kingdom. 5-FU (1 g/day) was given as a continuous infusion for the first 7 post-operative days with heparin 5000 units/day. Of the 127 control patients, 22 (18%) developed liver metastases compared to only 5 of 117 (4%) in the treatment arm. There was a survival benefit in Duke’s B
136
tumours only. A subsequent trial [95] from the NSABP of 1158 patients with Duke’s A, B and C colon cancer suggested a borderline improvement in overall survival (P = 0.07). Methodological problems with this study reviewed by O’Connell [96] include a high proportion (18.7%) of pre-operatively randomized patients being excluded, and the inclusion of Duke’s A tumours in the study. Exclusion of the patients with Duke’s A tumours removed the advantage in disease free and overall survival seen with the intraportal 5-FU. Although the overview analysis of Gray et al. [92] suggests some overall benefit from intraportal post operative 5-FU the use of this modality should be in clinical trials with a systemic chemotherapy arm. While 5-FU/levamisole remains the standard arm for ongoing trials the results of these studies will determine the role of 5-FU (in various schedules) with high or low dose leucovorin f levamisole as the future optimum combination [97]. With these trials in progress, further development of other modulators of 5-FU (PALA and interferon-a: see metastatic disease section) will provide further options for future adjuvant treatment schedules. III-B. Rectal Cancer
Rectal carcinomas have a different pattern of spread to colon carcinomas so adjuvant treatment requires different design. Below the peritoneal reflection lymphatic and vascular drainage of the rectum is often not through the mesenteric system as with colon but via haemorrhoidal and pudendal systems [98]. This in part may explain the increase in local recurrence (25-50%) and pulmonary metastases seen with rectal carcinoma [99]. The majority of the initial adjuvant rectal cancer studies therefore concentrated on radiation therapy (pre- or post-operative) to reduce local recurrence. In an overview of these studies [92], Gray et al. note that there is good evidence that local radiotherapy reduces the local recurrence rate but the evidence for improved survival is lessconvincing. Nevertheless, a 10% estimated improved survival combined with the results of recent trials containing chemotherapy arms provides a useful structure for future clinical trials. One study performed by the GITSG [lOO] randomized patients to receive surgery alone, radiotherapy, 5-FU plus methyl-CCNU or both radiotherapy with 5-FU and methyl-CCNU. The results showed a significant reduction in recurrence rate (55% control and 33% combined radiotherapy-chemotherapy) with time to recurrence also significantly favouring the combination arm. In a later report of this study [loll a survival advantage was evident with the combined treatment arm. The NSABP R-01 study [90] randomized patients to surgery alone, post-operative radiotherapy or
post operative chemotherapy with 5-FU, methyl-CCNU and vincristine. The results showed a reduction in local recurrence with radiotherapy (25-16%) though no impact on disease-free interval or survival compared to surgery alone. Chemotherapy however, resulted in an improvement in disease free survival and overall survival. The finding on subset analysis that this chemotherapy advantage was limited to males is difficult to explain though may be due to chance. A study published in 1991 by Krook et al. [3] has provided the strongest evidence for efficacy of combined modality treatment in rectal cancer. Two hundred-four patients with local invasion or nodal spread were randomized to receive post operative radiation (4500-5050 Gy) or radiation plus fluorouracil, which was preceded then followed by a cycle of systemic fluorouracil plus methyl-CCNU. After a median follow-up of 7 years, combined therapy had reduced recurrence by 34% (95% C.I. 12-50%: P = 0.0016) and overall death rate by 29% (95% C.I. 7-45%: P = 0.025). The reduction of local recurrence from 25% to 13.5% (P = 0.036) by combined modalities suggests some synergy, however, the reduction in metastatic relapse with chemotherapy (45% to 28.8%: P = 0.011) is of similar order. The apparent superiority of these results over the GITSG study may relate to an overall higher dose of radiation administered (5040 vs. 4200 cGy) and to the earlier administration of systemic chemotherapy which appears to have given a lower systemic relapse rate. A further GITSG trial [102], conducted to test the value of methyl-CCNU in the 5-FU-methyl-CCNU combination, suggests no benefits over 5-FU alone. Adjuvant treatment of rectal cancer, therefore, is divided into the control of local recurrence and of systemic disease. Radiation alone has an impact on local recurrence, possibly with the help of radiosensitization by 5-FU while chemotherapy alone (mainly 5-FU) can influence metastatic disease. The two modalities together can improve overall survival in rectal cancer. Future developments in adjuvant treatment of rectal cancer lies in the scheduling of radiotherapy (pref post-operative) with radiosensitizers and the development of newer chemotherapy regimens using 5-FU and Levamisole as the standard. IV. Non-invasive colorectal cancer
monitoring
of drug metabolism
in
Until recently the intracellular fate of cytotoxic agents in humans had to be inferred from analysis of body fluids (plasma, urine, faeces) or from tissue samples obtained via an invasive procedure. The opportunity to ethically obtain tissue for this purpose is uncommon and
137 often meets with disapproval from the patient. With the development of clinical magnetic resonance systems and positron emission tomography (PET) there is now unmeasurable potential to more accurately assess the tissue pharmacology of drugs in vivo, non-invasively and repeatedly with greater convenience and safety than before. Because 5-FU remains the major active drug in colorectal cancer and for various reasons (described below) the Fluorine nucleus in 5-FU is ideal for use in magnetic resonance spectroscopy (MRS) and PET studies, some of the pioneering work using these systems has been done in colorectal cancer patients. IV-A. 19F magnetic resonance spectroscopy
Nuclear magnetic resonance spectroscopy has been used to study the structure of a range of chemicals and tissues in vitro using 'H, i3C 19F> 31P 23Na and 15N techniques. The clinical application mosi widely known is the use of ‘H NMR for imaging patients. With the advent of these clinical systems it is now possible to observe signal from various nuclei giving detailed biochemical information. The 19F nucleus is detectable using MRS. Its advantages are that it is very sensitive to detection (83% that of ‘H), is naturally 100% abundant in the 19F form and has a large range of chemical shifts - that is, its resonant frequency is clearly altered by changes in the structure of the molecule attached to it. This enables detection of various metabolites of fluorine containing drugs such as 5-FU. The other added advantage is that in animals (including humans) there is not naturally more than a minute amount of fluorine in the body to act as background ‘noise’. 5-FU is catabolized to non-cytotoxic metabolites (FBAL, FUPA, F-) or anabolised to cytotoxic metabolites (FdUMP, FUTP, FdUR, FUR) (see Fig. 1). Because r9F-MRS used in vivo increases the width of the spectral peaks and as 5FU metabolites resonate at a similar frequency this technique is not as specific as biochemical assay but is more specific than PET techniques. Despite this, peaks fall into three groups; the cytotoxic anabolites; the noncytotoxic catabolites, and 5-FU itself. Despite these difficulties much information can be obtained from animal and, more recently, human studies on the intracellular metabolic fate of 5-FU. McSheehy et al. [103] demonstrated that the Walker carcinosarcoma grown S.C.in rats rapidly anabolised 5-FU to its nucleotides. HPLC used on tumour extracts confirmed about 50% of the anabolite signal was FUTP. In addition, by pre-treating with allopurinol the anabolite signal reduced. The size of the anabolite peak predicted the cytotoxic effect. Lutz et al. [104] have presented data to suggest that 5-FU is largely catabolized and inactivated
in liver while much less so in tumour. They hypothesize that catabolites seen in tumour may be there due to recirculation from liver. Additionally they note that the best tumour response is seen when the product of the nucleotide peak and infusion time is high but that systemic toxicity is worse when large amounts of nucleotide are seen in liver. Translation of the MRS technique to humans involves several technical problems. Because patients cannot be submitted to very high magnetic fields, 0.5 to 3 Tesla systems are generally used as opposed to 4.7 + Tesla in animals. This factor, the wide bore of the magnet and the variations of the human form lead to inhomogeneity of the magnetic field used for the examination. The i9F nucleus can overcome this problem providing adequate dose is given, however overall one must expect to lose some sensitivity compared to in vitro or animal systems. A further problem is that of localisation of the tissue of interest. When the 19F signal is abundant then smaller fields of interest may be employed thus enabling, for example, a small metastasis to be isolated from surrounding liver. When the signal intensity is lower one can allow for this problem by using patients with large tumours. Earlier work from our unit [ 1051 has demonstrated the liver metabolism of 5-FU when given both intraperitoneally and intravenously. The achievement of actually measuring 5-FU and FBAL in tissue over time and the results of a study correlating tumour response with with tumour 5-FU ‘trapping’ [106] led to a pilot study of a clinical protocol using interferon-a [36]. This protocol used an ambulatory infusion of 5-FU (300 mg/m*/day) until maximum response then interferon-a was added to clinically evaluate reversal of 5-FU resistance and monitor the changes using MRS. The preliminary results suggest that a detectable 5-FU peak (often transient) in liver metastases predicts response and that after the addition of interferon the recurrence of a 5-FU peak may predict further response. An example of these findings is shown in Fig. 4. While the biochemical explanations are varied (and discussed in the section on metastatic colorectal cancer) the important feature of this and other studies is that they demonstrate the feasibility of repeated in vivo measurements and their application to optimising 5-FU scheduling. These studies must initially be verified with standard plasma pharmacokinetics and tissue biopsies but ultimately the technique will be non-invasive. Currently the limitations of MRS are that it cannot measure tumour blood flow or the uptake of drug into the tumour, however complementary clinical studies using PET scanning techniques will build a much more detailed picture of 5-FU tissue metabolism.
138
CATABOLITI
Al \BO LITES
!
I
I
I
1
I
I
15.
10.
5.
0.
-5.
-10.
Chemical
shift
/
I
ppm
.15.
I 10.
Chemical
I 5.
I 0.
shift
I -5.
/
I -10. Ppm
I
Fig. 4. These two separate 19FMRS studies of a patient with large volume liver metastases show the three major peaks seen with 5-FU. The inactive non-cytotoxic catabolites; the active cytotoxic anabolites; and 5-FU itself (see text for details).
IV-B. Positron emission tomography
Initial clinical PET studies have concentrated on monitoring cerebral and myocardial metabolism using various positron emitting agents, however, more recent work has extended to tumour blood flow, metabolism and 5-FU uptake [107]. PET is complementary to 19F MRS in the study of 5-FU metabolism. It cannot offer detailed information of the intracellular metabolism of 5-FU because the 18F label is attached to all metabolites, but preliminary studies have shown tumour [**F]SFU uptake and retention can be assessed using PET and that high uptake may predict response [ 1071. Fluoro-deoxyglucose (FDG) is a general metabolic marker for tumour activity. It is currently being evaluated for its ability to: monitor general tumour metabolism and thus predict prognosis, to predict response to treatment, and to detect early relapse [108]. In patients with residual colorectal cancer PET studies using FIDG before and after radiotherapy showed a general
follow-up FDG activity was still measurable despite normal plasma CEA levels {107]. These results if confirmed suggest FDG-PET may be useful in detecting early relapse amenable to second-look surgery. Additionally FDG could be used to more accurately stage patients prior to surgery. We are currently investigating the role of FDG PET in predicting tumour response in patients with colorectal cancer treated with infusional 5FU (Fig. 5). Use of FDG PET after surgery or chemotherapy may however be problematic in that FDG will be taken up by inflammatory cells in a post-operative abcess or in tumours with a large inflammatory activity. The correct timing of the scans may however minim&e this factor. This potential problem can be circumvented by labelling components of more specific processes for example thymidine, which is being examined as an indicator of tumour DNA synthesis. In vivo metabolic monitoring of drugs like 5-FU in normal and malignant tissues will enable earlier use of new drugs in the clinic, will help optimize clinical
Fig. 5. Tumour metabolism measured using fluorodeoxyglucose (FDG) and Positron Emission Tomography (PET). The transaxial CT image indicating two metastasesin liver (top left) with PET image (below left) showing high FDG uptake in these two plus one other smaller lesion. Repeat studies following treatment with infusional 5-FU (300 mg/m2/d) show tumour reduction after I2 weeks on CT (above right) and decreased tumour metabolism (below right) after 4 weeks using FDG-PET. The reduction in metabolism of the metastases relative to the baseline metabolism in kidney is demonstrated by the now visible superior pole of the left kidney on the PET scan.
convenient, non-invasive means of predicting response at an early stage in treatment. V. Molecular biology of colorectal cancer Genetic alterations of two types have been documented in colorectal cancer. Mutations in cellular proto-oncogenes, (e.g. the ras oncogene) and deletions on chromosomes whose deleted sequences may include tumour suppressor genes [109]. Mutations in the c-Ki
ras-2 gene occur in approximately 40% of colorectal carcinomas [ 1 lo]. The ras proto-oncogene encodes a 21kDa p21 ‘(Is protein. This protein undergoes a series of post translational modifications including polyisoprenylation and palmitoylation - the latter significantly increasing the membrane binding capacity of p21 ‘as [ 1111. Once modified the p21 rasprotein is able to attach to the inner surface of the plasma membrane and bind GTP. The p2 1‘““-GTP complex activates signal transduction probably via several mechanisms in addition to
140
protein kinase C. Hydrolysis of bound GTP to GDP by GTPase gives rise to an inactive p2 1““-GDP complex. Some human tumours have point mutations in ras resulting in a protein complex with reduced GTPase activity thus locking the complex in the activated p21’““GTP state. Increased understanding of this has provided new targets for anti-cancer treatment, for example the post-translational modification step which is necessary for the ~21”’ protein to bind to the inner plasma membrane in turn enabling activation. Deletions in chromosomal regions have been noted on the long arm of chromosome 5 which contains the gene for familial adenomatous polyposis, the short arm of chromosome 17 and the long arm of chromosome 18 [109]. It is hypothesised that these sections of the genome contain tumour suppressor genes whose products normally inhibit neoplastic transformation. On the long arm of chromosome 5 the MCC (mutated in colorectal cancer) gene has been identified and is thought to be the tumour suppressor gene located in this region [ 1121. The deletion on chromosome 18 [ 1091 involves the DCC (deleted in colorectal cancer) gene which may be involved in cell adhesion [ 1131. The p53 tumour suppressor gene appears to be located where deletions on chromosome 17 occur in colorectal cancer. The p53 gene product is associated with control of cell division and immortality. Vogelstein et al. [ 1141 postulate deletions on chromosome 5 and point mutations in the ras protooncogene are relatively early events in the sequence of carcinogenesis while deletions on chromosome 18 and chromosome 17 occur later. This new understanding of colorectal carcinogenesis will provide the basis for a new generation of novel therapies and help identify high risk populations for screening or adjuvant treatment. VI. Treatment of advanced and metastatic gastric cancer Gastric cancer remains one of the leading causes of cancer deaths globally despite a decline in its incidence [I]. In 1980 it was the most common new tumour worldwide - second only to cervical cancer in the developing world and in the developed world only to lung and colorectal cancers. Although the incidence is reducing at a rate of about 2.2% per year, there is an increase in the incidence of proximal tumours which are technically more difficult to resect [ 1151. The epidemiology of this disease is notable for marked geographical differences in incidence with higher rates in the Far East, Europe and Russia and lower in the US, Australia, New Zealand and Africa [ 11. Evaluation of dietary factors revealed that pickled foods confer increased risk and allium vegetables, ascorbic acid, vitamin E and carotene are protective [ 116,117]. Most
interest has been in the carcinogenic effects of N-nitroso compounds formed from dietary nitrites [ 1181. The reduction in incidence of gastric cancer may be related to improved refrigeration which led to a reduction in use of meat preservatives containing such nitrites. Infection with helicobacter pylori - a known causative factor in atrophic gastritis, has been recently linked with gastric cancer [ 1191. The reduction in intraluminal acid production may allow bacterial overgrowth producing increased nitrite formation. These factors provide new targets for directing prevention strategies. With up to 80% of gastric cancers presenting too far advanced for curative resection [ 1201, screening for early stage disease in high risk populations is needed. This has been successfully implemented both in Japan [121] and in parts of the United Kingdom [122]. In a UK study, patients 40 years or over presenting to their family practitioner with dyspepsia were referred to a specialist endoscopy unit [122]. Two percent of all those referred had gastric cancer, with 1 in 177 being an early lesion. These figures compare favourably with breast mammography and cervical cancer screening programmes, however the success of screening may be determined by its use in high risk populations. Despite introduction of screening for early stage tumours there will still be a need for better systemic treatment for use in locally advanced and metastatic disease. Combinations showing activity can be applied to the adjuvant or neo-adjuvant settings. VI-A. Single agent cytotoxic activity
While it appears that greater anti-tumour activity in gastric cancer can be achieved with combination chemotherapy, the testing place for new drugs is in single agent Phase II studies. The activity of the more commonly used drugs in gastric cancer are summarised in Table 1. Direct comparisons on these responses are always difficult because of the patient selection factors and also the different measurement criteria for response. It is now generally accepted for studies of this type that the definition of partial response is a 50% reduction in the product of the longest tumour dimension and its widest perpendicular, and in the case of multiple lesions a 50% reduction in the sum of these products in the absence of a new or increasing lesion. Complete response is defined as complete disappearance of all evidence of disease. This can be confirmed histologically in some instances, however, this is often not practical. Any response should be sustained for at least 1 month. With the recognised difficulty in accurate clinical measurement of disease, particularly the degree of hepatomegaly, this method
141
TABLE 1 Single agent activity in gastric cancer Dw
No. responding pts/total
%
Reference
Adriamycin (doxorubicin) BCNU Carboplatin Cisplatin Epirubicin (bolus) (protracted infusion) Etoposide 5-FU (bolus) (protracted infusion) 5-FU + moderate dose FA. 5-FU + methotrexate 5-FU + PALA + thymidine Methotrexate Methyl-CCNU Mitomycin-C Triazinate
17168 4123 3157 441129 8122 4126 2131 841392 4113 13127 4122 9136 3128 3131 631211 4126
25 17 5 19 36 15 6 21 31 48 18 25 11 8 30 15
Moertel and Levin [ 13I] Kovach et al. [137] Einzig et al. [136] Leichman and Berry [135] Cazap et al. [I331 de Vries et al. [134] O’Dwyer [ I381 Comis [123] Moynihan et al. [I251 Machover et al. [126] Blijham et al. [127] Windshitl et al. [I291 Bruckner et al. [I281 Moertel et al. (1421 Comis [I231 Bruckner et al. [I281
FA, folinic acid; PALA, iv-phosphon-acetyl-L-aspartate.
should now be replaced with one of the many available imaging techniques. S-Fluorouracil is the most commonly used drug in gastric cancer. It has, until recently, been used as an intravenous bolus or short infusion yielding a response rate of 21% from collective studies [ 1231. The dose limiting toxicity for 5-FU on this schedule, is myelosuppression. Because 5-fluorouracil is cell cycle specific and has a plasma half life of approximately lo-20 min and because at any time, approximately 3% of tumour cells are cycling, investigation of a protracted continuous intravenous infusion of this drug seemed justified [8]. This work was piloted in colorectal cancer by Lokich et al. [124] who went on to show in a randomised study that a continuous low dose infusion of 5-FU (300 mg/m2 per day) given for up to 10 weeks at a time, yielded an improved response rate compared to an intravenous bolus schedule given 5 days for 1 week in every 5 [lo]. The improved response rate, a result of the higher dose intensity of the drug delivered was not associated with increased patient toxicity. On the contrary, the toxicity was less marked because of the low dose rate infusion. Myelosuppression became less evident while plantar palmar erythroderma, was the most prevalent, but generally mild side effect. Although there has been no randomised study in gastric cancer, there has been one study of 13 patients using a protracted infusion of 5-FU in which 4 patients (31%) responded [125]. Another technique for improving the efficacy of 5-FU is the addition of a modulator which has been discussed
earlier in the section on treatment of metastatic colorectal cancer. In gastric cancer the most active of the variety of 5-FU plus folinic acid schedules appears to be that of 5-FU 340-400 mg/m2 per day, i.v. over 15 min and folinic acid 200 mg/m2, i.v. bolus for 5 consecutive days, every 3 weeks [126]. This yielded responses in 13 of 27 (48%) patients. Toxicity included stomatitis, diarrhoea and myelosuppression. The modulatory effect of methotrexate on 5-FU as a single agent has been explored yielding a modest response rate of 18% in one study [127]. Methotrexate itself appears less active as a single agent [128]. Attempts at double modulation of 5fluorouracil with PALA and thymidine yielded significant toxicity probably due to the thymidine effect of reducing 5-FU catabolism [ 1291. Mitomycin C has been extensively studied as a single agent giving a 30% response rate overall [ 1231. The main toxicity is that of cumulative myelosuppression, largely thrombocytopenia, which when the drug is given as an intravenous bolus requires a dose interval of at least 6 weeks. Mitomycin C has also been associated with the haemolytic-uraemic syndrome, being reported in 8.5% of 251 patients receiving adjuvant Mitomycin C and 5FU [130]. Various anthracyclines have been used in gastric cancer - the most widely used, being Doxorubicin (Adriamycin) [ 1311. This gives a response rate of approximately 25% making it one of the more active agents. Epirubicin, a derivative of Adriamycin is thought to be less cardiotoxic and produces less
142 TABLE 2 Combination chemotherapy regimens in gastric cancer Combination
Non-randomised
Number of responses/ number of patients
Percent response
Median survival (months)
Reference
1511453
33
5.5-1.2
Gohmann & Macdonald [147]
8-9
Moettel et al. [154] Rougier et al. [155]
12
Levi et al. (1431
6
Wils et al. [151]
studies
FAM (S-FU, Adriamycin, mitomycin) FAP (S-FU, Adriamycin, cisplatin)
24158 (k
FAB (S-FU, Adriamycin, BCNU)
CR)
18/35 (ita CR)
FAMTX (S-FU, Adriamycin, methotrexate) EAP (etoposide, Adriamycin, cisplatin) ELF (etoposide, leucovotin, 5-FU) FAM-CF (S-FU, Adriamycin, mitomycin, leucovorin)
22161 (ii,/, CR)
7.5-10
Wilke et al. [158] Lernet et al. [159]
11
Wilke et al. [I581
6.8
Arbuck et al. [161]
42 (11% CR)
9.2
Lopez et al. [162]
33%
NS
Taal et al. [163]
25170
36 (16% CR)
9
Dehino et al. [I651
951133
71 (11% CR)
8.2
Findlay et al. [166]
3137 12/30 219 6129 8128 4123 14134 2118 4117 9170 30175 2lll 3/11 5113 6144 1l/39 18146 13146 5133 6131 6/30
8 40 22 21 29 17 41 11 24 13 40 18 27 38 14 29 39 29 15 19 20
3.2 5.0 4.5 4.5 1.4 3.5 7.7 4 5.5 4.7 8.25 1.2 1.2 1.2 3.2 5.5 1.5 4.5 26 7.5 7.8
Moertel et al. 11421
95/181 (:i% CR) 27151
53 (12% CR)
10126 (%o CR)
FEB (S-FU, epirubicin, BCNU) FEMTX-C S-FU-methotrexate, epirubicin and cisplatin CEF (cisplatin, epirubicin, 5-FU) ECF (epirubicin, cisplatin, protracted infusion 5-FU) Ranabmised
19145
II21
studies
Methyl-CCNU VS 5-FU + methyl-CCNU 5-FU VS 5-FU + methyl-CCNU S-FU VS BCNU VS 5-FU + BCNU 5-FU + BCNU VS 5-FU + Adriamycin + BCNU Adriamycin VS 5-FU + Adriamycin + BCNU S-FU VS 5-FU + Adriamycin VS 5-FU + Adr + mitomycin C S-FU + Methyl-CCNU VS S-FU + Adr + methyl-CCNU VS S-FU + Adr + mitomycin VS Adriamycin + mitomycin S-FU + Adr + methyl-CCNU VS S-FU + Adriamycin + ttiazinate VS 5-FU + Adriamycin + cisplatin
Baker et al. [141] Kovach et al. [137] Schnitzler et al. 1145) Levi et al. (1441 Cullinan et al. [148] Douglass et al. [149]
Stablein et al. [156]
143
TABLE 2 (continued) Combination
5-FU + Adr + mitomycin-C VS 5-FU + Adr + methotrexate 5-FU + Adr + mitomycin-C VS Cisplatin + epirubicin + leucovorin + 5-FU 5-FU + Adr + methotrexate VS Etoposide + Adr + cisplatin Abbreviations: Adr - Adriamycin; NS -
Percent response
Median survival (months)
Reference
II79 33/81 813 1
9 41 26
7.2 10.5 5.1
Wits et al. [I521
20145
44 33 20
8.2 I.3 6.1
Number of responses/ number of patients
10130 6130
Cocconi et al. [I641 Kelsen et al. [160]
Not stated
stomatitis [ 1321. It has been shown in some studies to be active when given as an intravenous bolus (36% response rate) though less so when given as a protracted infusion [133,134]. Cisplatin has now been shown to have significant activity in gastric cancer equivalent to SFU, mitomycin C and the anthracyclines [135]. Despite this activity, it has the disadvantages of nephrotoxicity, requiring hydration, and marked emesis - both acute and delayed. In a disease where most chemotherapy is palliative, this drug has to be given with optimal supportive care to be acceptable. The less nephrotoxic and emetogenic analogue of cisplatin, carboplatin has not been found active in gastric cancer to date [136]. Despite showing modest activity, the nitrosoureas BCNU and methyl-CCNU have been used in various cytotoxic combinations in a number of studies in gastric cancer. BCNU appears to be the more active of the two drugs however in a controlled study was less active than 5-FU [ 1371. While these agents may be justifiable in combination regimens, a major problem is of delayed myelosuppression requiring dose intervals of 6-8 weeks. This interval may give fast growing gastric cancers a biological advantage. In recent years, etoposide has been used extensively in combination with other agents despite its relatively poor activity as a single agent [ 1381. This is based on pre-clinical evidence of synergy between etoposide and cisplatin [ 1391. Triazinate has shown activity in gastric cancer and represents one of many folate antagonists destined to be tested in gastrointestinal tumours [140]. The camptothecin analogue CPT-11 has shown activity in colorectal cancer [84] leading to some optimism that when tested, this new class of cytotoxic may be useful in carcinoma of the stomach. VI-B Combination chemotherapy
Cytotoxic combinations in gastric cancer have been derived from active single agents and scheduled to max-
imise the anti-tumour effect while minimising the recruitment of toxicity. While giving an important indication of anti-tumour activity and toxicity, Phase II studies of new combinations should be compared to other studies with great caution (see Table 2). One of the earlier combinations was of 5-FU and methyl-CCNU which showed an initial response rate of 40%, however, a subsequent study failed to demonstrate any benefit over 5-FU alone [141,142]. Levi et al. [143] treated 35 evaluable patients with 5-FU, Adriamycin and BCNU (FAB), demonstrating 18 (51%) responses. When they subsequently studied FAB in a randomised trial against single agent Adriamycin, they found no difference in the survival between the two groups [144]. Schlitzler et al. [145] random&d 77 patients to either FAB or 5-FU plus BCNU (FB), finding only 24% of patients responding to FAB and 11% to FB with no survival difference. Until recently the most extensively used combination in gastric cancer was of 5-FU, Adriamycin and mitomytin C (FAM) developed by Macdonald et al. [ 1461. Preliminary results suggested response rates in excess of 50%, however, the now quite extensive experience in over 400 patients suggests a response rate of 33%, with acceptable toxicity [147]. The results of two early randomised studies gave conflicting results. Cullinan et al., from the North Central Cancer Treatment Group [148] randomised patients to 5-FU alone, 5-FU plus Adriamycin, or 5-FU plus Adriamycin plus mitomycin. Although the response rate in the FAM arm was greater than the other two arms there was no difference in survival. The authors concluded that FAM was of no advantage over single agent 5-FU although the study had relatively small numbers in each arm. Douglass et al., from the Eastern Co-operative Oncology Group [149] randomised patients to one of four arms: 5-FU plus methyl CCNU; 5-FU plus Adriamycin plus methyl CCNU; 5-FU plus Adriamycin plus mitomycin C; and Adriamycin plus mitomycin C. This study found FAM to be
144
superior to the other arms in both response and survival-achieved with acceptable toxicity. Based on pre-clinical studies [53] Klein et al., from Germany, developed a further modification of the FAM regimen [ISO]. This was based on substituting high dose methotrexate for mitomycin C (FAMTX). The methotrexate was given an hour prior to 5-FU in an attempt to modulate its action. This initially resulted in a response rate of 65%, although on a subsequent contirmatory Phase II study from the EORTC Gastrointestinal Group, 33% of 67 patients responded [151]. Included in this were 13% complete responses. Wils et al. from the EORTC Gastrointestinal Group subsequently performed a study randomising patients to either FAM or FAMTX [ 1521. They found a significantly superior response rate for the FAMTX regimen (41 vs. 9%) and a median survival of 42 weeks vs. 29 weeks. There was no major difference in the nonhaematological toxicity although mucositis was more a pronounced FAMTX. There was no difference in leucocyte nadirs, however, there was cumulative thrombocytopenia with the FAM arm. Although the response rate seen with the FAM regimen is substantially less than seen in previous studies, these results support the place of FAMTX as the best standard therapy for further randomised studies. Further attempts at refining the scheduling of FAMTX have been initiated [153], namely by changing the dose interval between the methotrexate and 5-FU. These regimens will also need testing in the Phase III setting. The other drug that has been used to replace mitomytin C in the FAM regimen is cisplatin. The Phase II experience with this combination shows a 41% response rate in 58 patients including 10% complete responses [ 154,155]. A Gastrointestinal Tumour Study Group study randomised patients to receive: 5-FU plus Adriamycin plus methyl CCNU (FAMe); 5-FU plus Adriamycin plus triazinate (FAT); 5-FU, Adriamycin and cisplatin (FAP) [ 1561. The study found that FAP and FAT were superior to FAMe, both in response and in median survival. A further cisplatin containing regimen developed in the latter 1980s by Preusser et al. [139], based on preclinical evidence of synergy between etoposide and cisplatin, combined etoposide and Adriamycin with cisplatin (EAP). The original Phase II study of 67 patients demonstrated a response rate of 64% including 21% complete responses. The main toxicity was of myelosuppression, with 64% of patients experiencing this at a WHO grade of 3 or 4. The median survival was 9 months with 6 (9%) patients surviving 2 years. A parallel study using EAP in patients with locally advanced disease, demonstrated that previously unresectable locally advanced tumours could be successfully
resected [ 1571. The subsequent cumulative experience from different centres confirms the activity of this regimen with a response rate of approximately 50”/;, including 14% complete responses [ 158,159]. This regimen however, did appear to be more toxic than others. This was confirmed by Kelsen et al. in a randomised trial comparing EAP to FAMTX. The trial was ceased early because of no apparent difference in response (EAP 20%, FAMTX 33%), but a significantly higher toxic death rate with EAP (13% vs. 0) [160]. More recent combination chemotherapy regimens have focused on optimising 5-FU efficacy, either with modulation or alterations in schedule and in substitution of Adriamycin for epirubicin. Wilke et al. [ 1581 combined etoposide with 5-FU and leucovorin (ELF) in 51 patients, achieving a response rate of 53% including 12% complete responses. The regimen was designed as the default study for patients with cardiac or other medical conditions or of advanced age, who were thought not likely to tolerate EAP. Arbuck et al. [ 1611 combined the FAM regimen with calcium leucovorin (FAM-CF) in an attempt to modulate the 5-FU. The response rate overall in this study was 38%, however, with progressive courses, the amount of 5-FU the patient could tolerate decreased suggesting it would be unlikely that a randomised study would detect any difference between FAM and FAM-CF. Lopez et al. [162] modified the FAB regimen to include epirubicin instead of Adriamycin, in combination with 5-FU and BCNU. In 45 patients a response rate of 42% was seen with 11% complete response - appearing little different to the original FAB. Four recent studies have investigated the role of 5FU, cisplatin and epirubicin in combination. Taal et al. [ 1631, examined an alternating schedule of methotrexate 300 mg/m2 followed 7 h later by 5-FU 900 mg/m2 with leucovorin rescue starting 24 h after the methotrexate. Epirubicin 60 mg/m2 and cisplatin 75 mg/m2 were given on day 15 (FEMTX-C). The results from the study of 21 patients revealed a 33% response rate and relatively little toxicity. A randomised study comparing cisplatin, epirubicin, 5-FU and leucovorin (PELF) to FAM is currently in progress. An interim report by Cocconi et al. [ 1641 suggests a superior response rate and survival in the PELF arm, although neither reaches statistical significance. Delfino et al. [165], studied 70 patients using cisplatin (70 mg/m2), epirubicin (60 mg/m2) and 5-FU (600 mg/m2) given once every 28 days. This resulted in a 36% response rate with 16% complete responses. Our experience [166] using the same drugs, but at different doses and schedules (5-FU protracted infusion 200 mg/m2 per day for 21 weeks with eight 3-weekly cycles of epirubicin 50 mg/m2 and cisplatin 60 mg/m2; ECF).
145
Ninety-five of the 133 patients with evaluable disease (71%) achieved a response. Responses were seen both in small and large volume disease in a variety of sites (see Fig. 6). There were 11% complete responses. Assuming no major differences in case selection or response criteria, the results of our study and that of Delfino et al. [165] suggests there may be a role for protracted infusion 5-FU, with its high dose intensity, in this disease, as it is unlikely the differences in dose or schedule of cisplatin and epirubicin explain the different response rates. Current evidence suggests that there is no standard cytotoxic combination for general use in advanced gastric cancer. The FAMTX regimen appears to be established as the best treatment for control arms in future Phase III studies. The results of the FAMTX vs. EAP study [160] emphasize the need for randomised comparisons to establish comparative toxicity and antitumour activity.
VII. Neo-adjuvant chemotherapy for gastric cancer With the generally disappointing results from studies using post-operative surgical adjuvant chemotherapy in gastric cancer there is an increasing interest in prescribing pre-operative chemotherapy. The rationale for this is to offer earlier treatment to micrometastatic disease and to potentially downstage the primary tumour. This approach however does provide some methodological difficulties. Firstly, in order to determine the effect of a regimen on survival, randomised studies with a nonchemotherapy arm need to be performed in patients with advanced, but resectable disease. The difficulty with this is that patients with surgically curable nonadvanced disease are difficult to exclude by clinical staging. The risk to these patients in a surgery delaying preoperative chemotherapy programme, is that, unless the chemotherapy is a 100% effective in preventing disease progression, there is a possibility of a surgically curable
Fig. 6. Tumour response to ECF chemotherapy in metastatic gastric cancer [ 1661. The left hand set of CT images show the complete radiological resoiution of liver metastases. The right hand set of CT images show a partial response in bulky bilateral Kruckenberg tumours.
146
tumour becoming unresectable. This obviously requires better methods of staging early gastric cancer and also necessitates very active chemotherapy regimens which not only have a high probability of inducing a response, but can also prevent frank progression of disease during the pre-operative period. An alternative approach is to look at patients with inoperable tumours determined either by a failed surgical procedure or by clinical criteria of locally advanced disease. Patients would then be offered chemotherapy with subsequent attempted resection. The difficulty with this approach is that there is no ability to randomise to a non-treatment arm, thus interpretation of results would rely on historical controls. The other difficulty is
that of no reliable criteria for clinically defining locally advanced disease. Cumulative patient morbidity will occur if exploratory laparotomy for staging is required in addition to chemotherapy and a second laparotomy for definitive resection. With either approach, investigators must be wary of inducing significant toxicity with the chemotherapy which will both increase the perioperative risks and delay definitive surgery. Recent pre-operative chemotherapy studies are summarized in Table 3. Wilke, Preusser and colleagues [ 1571 treated 34 patients with unresectable gastric cancer as determined by failed laparotomy. Using the EAP regimen, 23 patients had a major response, 2 a minor response to treatment and there was one early death.
TABLE 3 Neoadjuvant chemotherapy for locally advanced gastric cancer Regimen
Resectability
Evaluable patients
Responses (CR and PR)
Patients having surgery
Number of resection achieved
Complete Pathologic complete response
Etopside, adriamycin cisplatin [ 1571
Unresectable
33
23133 (70%)
l9+
15120 (75%)
5120
Etopside, adriamycin, cisplatin [I671
Potentially resectable
48
l5/48 (31%) ‘major responses’
41
37/4 I (90%)
0141
Etopside, 5FU, cisplatin 11681
Potentially resectable
25
6125 (24%) ‘major responses’
25
18/25 (72%)
O/25
Etopside, 5FU, cisplatin [ 1691
Potentially resectable
35
17/35 (49%) ‘major responses’
32
25/32 (78%)
l/32
5FU, leucovorin, cisplatin [I351
Not stated
25
l6/25 (64%)
25 ‘signtiicant
Not stated
O/25
Epirubicin, cisplatin, 5FU [166]
Unresectable or clinically LAD
36
29/36 (8 I%)
21
12121 (57%)
512I
cisplatin, 5FU [170]
Clinically LAD
26
15126 (58%)
I5 + IINC + INE
21127 (78”/u)
Not stated
Epirubicin, tegafur u731 vs no chemotherapy
Potentially resectable T2-3 NOM0
9212
Not stated
9212
Not stated
Not stated
5FU, leucovorin, epirubicin, cisplatin [ 1721
Unresectable
Methotrexate, 5FU I1711 5FU, adriamycin, methotrexate [ 1521
I NC
(increased disease free survival with chemotherapy) 5/lO (50%)
5
515 (100%)
015
Unresectable (2 clinically LAD)
Not stated
I3
7113 (54%)
Not stated
Unresectable
Not stated
317 (43”/u)
Not stated
147
Nineteen of the major responders and one minor responder went forward to surgery. Fifteen were completely resected, 5 having pathological complete responses. In 3 patients complete resection was attempted but microscopically the proximal resection margin was positive. Two patients remained unresectable. In all, of the 20 patients submitted to further surgery three quarters were successfully resected. At a median followup of 20 months the relapse rate was 12/20 (60%) and the median survival for all patients 18 months while 24 months in disease free patients. Ajani et al. 11671, from the MD Anderson Cancer Centre, recently reported the results of perioperative EAP in potentially resectable gastric cancer. The response to EAP was 31% and despite 90% of patients tumours being successfully resected, there were no histological complete responses noted in the resection specimen. In two earlier reports, Ajani et al. describe the use of pre-operative etoposide, 5-FU and cisplatin (EFP) in both gastric [ 1681, oesophago-gastric and oesophageal adenocarcinoma [169]. In 25 patients with potentially resectable gastric cancer [ 1681, two cycles of EFP were given pre-operatively and then post-operatively in those who had an initial response. Major responses assessed using a barium oesophagram, was seen in 6 patients and minor response in 16. All 25 patients had surgery with 18 (72%) achieving complete resection. None of the resected specimens were histologically free of disease. The second study, using EFP in proximal tumours [ 1691, reports 17 major responses in 35 patients (49%). Of the 32 patients having surgery, 25 (78%) had a curative resection although only 1 had no residual tumour in the resected specimen. In our experience of 36 patients with unresectable or clinically locally advanced disease 29 responded to ECF chemotherapy (81%) [166]. Twenty-one patients had surgery while 8 did not due to patient refusal, poor operative risk factors or early relapse. Of the patients having surgery 12 (57%) had their tumours completely resected. A histological complete response in the primary was confirmed in 5 patients. Six patients tumours were not resectable whilst 3 had their tumours incompletely resected (positive resection margin). From France, Lasser et al. [ 1701, using a 5-day infusion of 5-FU (1 gm/m*/day) and single dose cisplatin (100 mg/m* day 2) for 2-3 cycles found 15/26 responded while the other 11 remained unchanged after chemotherapy. Three further patients were not evaluable (toxic death, lost to follow-up and cardiac toxicity) for tumour response however one of these was submitted to reoperation. In all 21/27 (78O/4)patients submitted to surgery were resected completely. The high rate of resec-
tability in the non-responding group suggests theclinical staging used was overestimating disease extent or conversely that minor responses may be adequate to permit successful resection. The number of histological CRs was not stated. The EORTC study comparing FAM to FAMTX, Wils et al. [ 1521, reported 19 patients with unresectable disease randomised to FAMTX, 7 of whom went to second laparotomy. Three of these were able to be completely resected. Verschueren et al. [ 1711 using methotrexate and 5-FU in 17 patients with unresectable disease demonstrated 7113 having further surgery were able to have a complete resection. Similarly a small Japanese study of 10 patients [ 1721 using 5-FU and leucovorin i.v. with cisplatin and etoposide IA (FLEP) achieved an objective response in 5 patients all of whom were successfully resected. None of the resected specimens however confirmed histological CR. In a review paper Leichman and Berry [ 1351 discuss their experience of 25 patients given infusional S-FU plus leucovorin and cisplatin (FLC) before surgery and i.p. cisplatin and floxuridine post-operatively. Although they do not detail the specific patient group they are studying or the subsequent resection rates, histological examination of the resected specimens revealed there had been no complete responses to this regimen. Roberts et al. [173] in a study from Finland, report 92 patients randomised to surgery alone or pre- and postoperative chemotherapy using epirubicin and Tegafur (Ftorafur). While not all the details are outlined in the abstract, this trial was examining the impact of chemotherapy on resectable locally advanced disease in comparison to a surgery only control arm. The disease free interval favoured the chemotherapy arm but there was no difference in overall survival at 3 or 5 years. Studies of pre-operative chemotherapy in gastric cancer are still few and small. The design of future studies will have to address the issues of non-surgical assessment of resectability and the use of surgery only control arms. Adjuvant chemotherapy has, to date, generally failed and in most populations its application is limited because the majority of patients’ tumours are unresectable at presentation. One way forward is to investigate the ability of current combination chemotherapy regimens to treat micrometastatic disease, to downstage locally advanced tumours, improve resection rates and ultimately impact on survival. VIII. Conclusions This review has focused on the two most common tumour types in gastrointestinal malignancy which is
148
where the opportunity for small advances to have the greatest impact on population survival and quality of life. The approach to forwarding the treatment of these diseases must be a mixture of maximizing the efficacy of established modalities while searching for new agents. With the continued presentation of patients with advanced disease, treatment remains a regular challenge, however, the longer term impact of prevention and screening strategies should continue to be investigated. Biographies Michael Findlay is a Medical Oncologist and Senior Research Fellow in the GI Unit at the Royal Marsden Hospital, Sutton, Surrey, UK. David Cunningham is a consultant Medical Oncologist and head of the GI and Lymphoma Units at the Royal Marsden Hospital, Sutton, Surrey, UK.
Reviewer This paper was reviewed by John S. MacDonald M.D., Temple University, Comprehensive Cancer Center, Philadelphia, Pennsylvania, USA. References I
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