Colorectal cancer: treatment of advanced disease

CANCER

TREATMENT

REVIEWS

1998: 24: I I9- I3 I

ANTITUMOUR TREATMENT

Colorectal disease

cancer: treatment

of advanced

M. T. Seymour ICRF Cancer Medicine

Research Unit, University of Leeds, Cookridge Hospital, Leeds, LS/6 6Q0, U.K.

Each year, colorectal cancer claims the lives of at least 18,000 patients in the U.K. and 55,000 in the U.S.A., with similar mortality rates (around 300/ million population) in other industrialized countries (1,2). Of these deaths, 40% are in patients under the age of 70 and 17% in the under-60s, indicating that the disease is a significant cause of early death (3). Most of these deaths are due not directly to the primary cancer but to metastases, the commonest sites of which are the liver, peritoneal surfaces, abdominal lymph node groups and lungs. Death from colorectal cancer is commonly preceded by a period of several months, or even longer, during which the patient and clinicians are aware of the presence of metastatic disease and may consider treatment strategies aimed at relieving symptoms or prolonging life. Good physical and psychological symptom control is an absolute requirement in advanced cancer. During the 1980s and 199Os, the quality and availability of expert palliative care services in hospitals, hospices and at home have improved rapidly in many countries and continue to develop. This is transforming the quality of remaining life for patients with incurable disease. This review will concentrate on those treatments aimed at controlling cancer and prolonging life but, without the complementary skills of palliative care, their value would be questionable.

RESECTION OF LIVER METASTASES Permanent cure of metastatic colorectal cancer is a rare event and is currently a realistic goal only for that small proportion of patients in whom complete surgical excision of metastases is possible. Published surgical series suggest that, depending on selection 0305-7372/98/020

I I9 + I 3 3 12.00/O

criteria, 20-40% of patients are disease free 5 years after liver resection (4-6). These series represent carefully selected patients whose prognosis without treatment is no doubt better than average, and there has never been a randomized trial of resection ZB alternative management. However, in the absence of ‘class 1’ evidence, the available data suggest that surgery offers a survival advantage over medical management for at least some subsets of operable patients (7-9). Resection has been estimated, by enthusiasts, to be feasible for around 10% of patients with synchronous liver metastases and 20-25% of patients with metachronous metastases (5,9), but current rates of liver resection surgery are only around 1% of the colorectal mortality rate. This reflects both the failure to detect metastatic disease at a potentially operable stage and general scepticism, born of the lack of randomized controlled evidence, as to the value of the approach for most patients. It is therefore important that the selection criteria for surgical referral are clarified and the value of surgery is properly assessed. Currently most resectionists regard one to three metastases confined to one hepatic lobe as operable, but opinions vary for patients with more metastases, bilateral disease or involvement of the major vessels, where more extensive operations are required such as trisegmentectomy or extracorporeal dissection. We need evidence on which to base these treatment decisions, ideally randomized trial comparing liver resection with the best alternative medical therapy, stratified for different extents of hepatic disease, a daunting task. A recent North American consensus statement concluded that, notwithstanding the lack of randomized evidence, resection is indicated for ‘a single accessible metachronous metastasis in a good patient 0

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with adequate control of the primary lesion and no evidence of extrahepatic disease’ but for patients with more advanced disease ‘it remains unclear where the threshold for surgical excision should be set. . . . This requires formal evaluation by controlled clinical trials based on uniform standards of staging’ (10). Similarly, alternative physical ablation techniques such as interstitial laser therapy and cryotherapy require controlled trials to define their role. The role of postoperative ‘adjuvant’ chemotherapy following potentially curative resection of metastatic disease was being evaluated in a collaborative European and Canadian controlled trial (EORTC, NCICCTG and GMO). However, because of slow accrual this trial has been closed early with only 140 of the planned 450 patients randomized. It seems that many clinicians feel confident to extrapolate the benefit of adjuvant chemotherapy in high-risk primary disease and do not see the need for a separate demonstration of its effect after resection of metastases.

CHEMOTHERAPY FOR METASTATIC COLORECTAL CANCER Cytotoxic chemotherapy for colorectal cancer has been intensively investigated over the past 10 years, both for primary resectable disease (as postoperative adjuvant therapy) and for advanced disease. For patients with established metastatic colorectal cancer there is no realistic prospect of cure using currently available drugs, and the two main goals of chemotherapy are to improve the duration and the quality of remaining life. The generally applied term ‘palliative chemotherapy’ should not obscure the first of these goals: even modest gains in life expectancy may be highly valued by patients (11). Chemotherapy

or no chemotherapy?

Among the huge world literature on the subject of chemotherapy for advanced colorectal cancer, only a handful of clinical trials have directly assessed the impact of chemotherapy by prospectively randomizing patients between chemotherapy or no chemotherapy, and there has never been a doubleblind placebo-controlled trial. The seven relevant trials are summarized in Table 1. In four, patients were randomized between an initial treatment policy involving systemic chemotherapy vs no chemotherapy (12-15). A further three trials have compared intrahepatic regional chemotherapy with ‘control which was supportive care alone for some patients but included systemic chemotherapy for others (16-18).

In every case, the patients randomized to receive either systematically or initial chemotherapy, regionally, had longer median survival than those randomized to control arms. The results were all statistically significant, although two of the trials were not restricted to colorectal cancer patients and not powered to analyse this subset separately (13, 14). The difference between median survival in treatment and control arms is around 6 months (range 3-9 months); however, given the high proportion of patients in the ‘control’ arms of these studies who subsequently received chemotherapy, and given the relatively low efficacy of some of the chemotherapy regimens used, 6 months is probably an underestimate of the true median survival advantage afforded by chemotherapy. Three trials included formal quality of life assessment using validated patient questionnaires (12,13, 18) and one other used ‘symptom-free survival’, as assessed by the doctor (15). All reported favourably for the effects of palliative chemotherapy on quality of life when compared with control. The favourable outcome was most often maintenance of quality of life combined with increased survival duration, rather than improved quality of life during treatment. Having demonstrated that chemotherapy may offer benefits to patients with this disease, we face several subsequent questions. l

l l l

Who is most likely to benefit from treatment, and who will not? How soon do we start treatment? How long do we carry on with treatment? What drugs do we use and in what schedule?

Who

do we treat? Patient and tumour

variables

Most trials have had a stated or unstated policy of excluding the very elderly, so our evidence base relates predominantly to patients under the age of 75 years. An Italian co-operative group compared chemotherapy versus supportive care alone in patients aged over 70 years. They reported a survival benefit, but this trial has not yet been published in full, and did not include formal quality of life measurement (14). Most oncologists do not use a fixed age cut-off but will take into account the patient’s age together with performance status and other prognostic variables when deciding whether to recommend chemotherapy. Perhaps not surprisingly, elderly patients are more likely to suffer severe toxicity with 5-fluorouracil(5FU) based chemotherapy when standard doses are used. Interestingly, female sex appears also to be an independent risk factor for 5-FU toxicity (19). It is

TREATMENT TABLE cancer Reference

(‘2)

(13)

I

OF

ADVANCED

Randomized

Patients 40

21 (subgroup)

trials

COLORECTAL

comparing

CANCER

chemotherapy

121

with

supportive

care (or a delayed

Eligibility

Trial

arms

Unselected

Chemotherapy vs supportive care

Increased months,

Unselected

Chemotherapy vs supportive care

Increased (median I2 vs 6 months, p =O. I subgroup, CO.0 I overall)

Better than control (p
Effect

chemotherapy

on survival (median p
option)

for advanced

Effect I I vs 5

on quality

Maintained for (patient-assessed life)

colorectal

of life longer quality

(14)

157

Aged over 70 years (median 75 years)

Chemotherapy vs supportive care

Increased (median 7.5 vs 5.5 months, p
Not

(‘5)

183

Asymptomatic only

Chemotherapy

Increased months;

(median ~~0.02)

I4 vs 9

Maintained for longer @
(median p
17 vs 8

Not

reported

I5 vs

Not

reported

patients

VS

expectancy*

(16)

60

Liver-only

metastases

HA occlusion + HPV chemotherapy vs supportive care

Increased months;

(17)

163

Liver-only

metastases

lntrahepatic chemotherapy vs supportive

Increased (median I I months; ~~0.02)

(18)

100

Liver-only

HA, hepatic artery; HPV, hepatic * Included systemic chemotherapy

metastases

portal vein. for symptomatic

lntrahepatic chemotherapy vs supportive

disease

of

reported

care* Increased (median 13.5 vs 7.5 months, ~~0.03)

Maintained for longer (p
care*

in some patients.

not known whether this is due to pharmacokinetic or pharmacodynamic differences. Several commonly measured clinical variables correlate with time to progression and survival of patients with metastatic colorectal cancer receiving chemotherapy. In a multivariate analysis of 141 patients who received chemotherapy, poor performance status, low serum albumin, high serum alkaline phosphatase and high percentage liver involvement predicted for disease progression, and low serum albumin, high y-glutamyl transferase and high carcinoembryonic antigen (CEA) predicted for poor survival (20). Not surprisingly, several other trials and meta-analyses have confirmed the importance of performance status as a predictor of survival (21, 22). However, while these variables may help in identifying patients with a poor prognosis, they do not necessarily predict who will or will not benefit from chemotherapy. There is much interest in tumour biological variables as predictors of response to chemotherapy. Candidates include expression of thymidylate synthase (TS), thymidine phosphorylase (TP) and bcl2, and deletion or mutation of ~53. TS is an essential enzyme in thymidine synthesis and is overexpressed

in response to DNA damage. It is a molecular target for 5-FIJ and antifolate antimetabolites such as raltitrexed. Low intratumoral TS mRNA levels have been found to predict for better survival and responsiveness to 5-FU, while TS mRNA levels above the median were associated with de-nova 5-m resistance, a potentially useful technique for selecting patients for treatment (23,24). The use of a second variable, TP n-RNA, may further refine this approach (25). However, these assays involve RT-PCR on fresh tissue and are currently only feasible in selected research units. Contradictory or negative results have been reported when TS, bcl-2 or p53 protein expression was measured immunohistochemically in paraffin-embedded tissue (26-33) and at this point we do not have a validated chemosensitivity prediction method which is applicable outside the research setting.

How soon do we start? Traditional teaching in oncology was that non-curative treatment should be reserved for patients with cancer-related symptoms; however, this approach

122

M. T. SEYMOUR

has been challenged in recent years. Early intervention with chemotherapy is potentially more effective for several reasons: less advanced tumours will have fewer drug-resistant clones; drug dosing may be more consistent in patients with less disease bulk, because there is less chance of organ dysfunction leading to unreliable drug clearance; patients with better overall performance status are more able to cope with chemotherapy side-effects, visits to hospital, etc. On the other hand, chemotherapy in asymptomatic patients may diminish otherwise normal quality of life. The ‘Nordic’ trial set out to balance this equation by looking specifically at patients with metastases discovered by palpation or ultrasonography at routine follow-up who had no cancer-related symptoms. One hundred and thirty-eight patients were randomized between immediate chemotherapy and ‘expectancy’, with the latter group reconsidered for chemotherapy at the time of developing symptoms. The results were in favour of immediate chemotherapy, with improved survival and symptom-free survival, although ‘symptom-free’ did not take account of chemotherapy side-effects. Contrary to expectations, few patients in the ‘expectancy’ arm remained asymptomatic for long periods: the median symptom-free period after randomization was only 2 months (15). The conclusions of this trial have been widely discussed and criticized. In particular, 43% of the patients assigned to expectancy died without having received chemotherapy, although it may be argued that this is a realistic reflection of the outcome of deciding to defer chemotherapy. The Nordic trial is useful in provoking debate on the issue of trading immediate chemotherapy sideeffects against potential longer-term gains. Different patients (and different health professionals) may have widely differing views on how to strike this balance (11). It also raises issues of follow-up after colorectal cancer surgery: should we be more actively screening patients for asymptomatic metastases in order to offer early chemotherapy and, when appropriate, resection? Previous small, underpowered, randomized trials showed no advantage for intensive follow-up (34-36); perhaps these should now be repeated with adequate numbers and defined surgical and medical intervention protocols for asymptomatic metastases.

When

do we stop?

The most important cytotoxic drug used for advanced colorectal cancer, 5-FU, is not limited by cumulative toxicity. An issue therefore arises as to how long to continue treatment: should this be indefinite, until

disease progression, or should we use shorter courses of fixed duration? In a recent survey of U.K. practice, oncologists were asked how long they routinely continue chemotherapy in patients with stable or responding disease. Half the respondents stop treatment at 6 months, 30% at 3 months and only 20% continue indefinitely until disease progression (37). A U.K. Medical Research Council (MRC) trial, CR06, is now underway in which patients whose disease is stable or responding after 12 weeks of chemotherapy are then randomized to continue chemotherapy indefinitely until progression or to stop, with further 3 month courses ‘as required’ in the future (38). End-points of this trial are survival, quality of life and health economics. The CR06 question has previously been asked in other advanced cancers, with various answers. In an almost identical trial design, an Australian group randomized 305 patients with metastatic breast cancer to receive chemotherapy (CMF or doxorubicincyclophosphamide) either indefinitely or for 3 months repeated ‘as required’. They found superior quality of life and a trend towards better survival with indefinite treatment (39). However, a French group randomized 176 patients between FEC given either indefinitely or intermittently and found no differences (40). In complete contrast, in a randomized trial in small-cell lung cancer, 18 weeks of chemotherapy gave equal survival and better quality of life when compared with 36 weeks (41). The result of the MRC CR06 trial will be helpful in guiding decisions in the future. Meanwhile practice varies, and economic and organizational considerations undoubtedly play a part.

CMOTOXIC DRUGS AND SCHEDULES Many of the drugs in standard clinical practice for other cancers are nearly or completely inactive in colorectal cancer. This may be due in part to physiologically high expression of cytoprotective mechanisms, such as membrane efflux pumps, in the colorectal epithelium (42). Until recently 5-FU was the only important cytotoxic agent, although some minor single-agent activity, of dubious clinical value, is seen with alkylating drugs such as nitrosoureas, mitomycin and cisplatin. Recent years-have seen an expansion of the arsenal, including drugs with similar activities to 5-FU and drugs with entirely new targets. 5-FU and other synthase

inhibiton

of thymidylate

In 1998, over 40 years after its invention, 5-FU remains the most important drug for colorectal cancer.

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It mimics native uracil in the pathways of nucleotide synthesis, with several consequences. The best studied is inhibition of TS, an essential enzyme in de-novo thymidine synthesis. During mitotic S phase, TS normally transfers a methyl group from a reduced folate cofactor onto the 5-position of the uridine ring, generating thymidine and dihydrofolate. However, with the 5-F substitution of 5-FU, this process fails, resulting in a covalently bound ternary complex of enzyme, cofactor and substrate (43). As a result, the nucleotide pools available for DNA replication and repair are disturbed, with reduced thymidylate, but also abnormal accumulations of deoxyuridine and deoxyfluorouridine which are misincorporated into DNA and then excised (44,45). However, inhibition of TS is temporary, overcome by dissociation of the ternary complex and transcriptional and posttranscriptional regulation of TS expression (46, 47), together with allosteric regulation of upstream enzymes in the pyrimidine pathway (48, 49). Effective TS inhibition therefore depends on several factors including baseline TS expression, the regulatory responses and cellular levels of folate cofactor. In addition to these variables, 5-FU activity is further complicated by its other (non-S-phase specific) effects as a false nucleotide (F-UTP) in RNA, where it disrupts the processing of ribosomal RNA and translation of mRNA (50). As a consequence of these different activities and interactions, the activity and toxicity of 5-FU may be affected not only by dose but also by the schedule of administration and by the concurrent use of modifying agents (‘biomodulators’), such as folinic acid (FA). With so many interdependent variables it is perhaps no surprise that a single method of administration of 5-FU has not emerged as the undisputed gold standard. Currently, clinicians may reasonably select between comparable schedules, taking into account their relative efficacy, toxicity, convenience and cost. Evidence to guide these choices is available from a large number of randomized trials and several meta-analyses examining particular issues.

Schedule

of 5-FU administration

123

including protracted venous infusion @‘VI) in which 5-FU is infused without interruption (53,54). These trials demonstrate, both individually and in a recent meta-analysis (55), that, as a single agent, 5-FU produces a higher response rate and different, usually more manageable, toxicity when given by slow infusion (56). Although significant survival advantage was not seen in all individual trials, a survival benefit was suggested by the meta-analysis (55). Infusion 5-FU schedules involve the substantial inconveniences, costs and morbidity associated with indwelling venous access lines and pumps. Perhaps mainly for these reasons, infusional 5-FU has remained a minority activity, with most clinicians concentrating their activity on the modulation of bolus 5-FU with leucovorin (see below). However, PVI of single-agent 5-FU remains a well-validated option for treatment of colorectal cancer and is also being investigated in the adjuvant setting. Chmnotherapy Another aspect of drug scheduling is the time of day. It is hypothesized that normal tissues conform to a circadian growth cycle, while malignant cell divisions occur randomly, providing an exploitable difference for scheduling phase-specific drugs such as 5-FU. After lengthy phase II development, this has been tested in two randomized trials, totalling 278 patients, comparing identical doses of three drugs (5-FU, leucovorin and oxaliplatin) given over 5 days every 3 weeks, using either a flat-rate infusion or a ‘chronomodulated’ infusion, in which the 5-FUleucovorin dose was given between 10p.m. and 10 a.m. with a peak at 4 a.m. Statistically significant advantages for the chronomodulated schedule were seen in terms of toxicity and response rate, but a small survival advantage seen in the first trial (57) did not hold up in the second, larger trial (58). These trials used bulky, expensive programmable infusion pumps, but there is potential to exploit the chronotherapy effect with simpler systems, and further randomized trials are ongoing.

Biomodulation

of 5-FU

The cytotoxicity of 5-FU is, in part, S-phase specific (51) and consequently shows marked schedule dependence in preclinical models (52). This, together with its short plasma half-life, provides the rationale for slow infusion schedules in cancer patients.

Many drugs, some with no independent cytotoxicity, affect the metabolism or target activity of 5-FU and influence its anticancer activity. The most extensively investigated in patients are folinic acid (FA, also known as calcium leucovorin), interferon-a (IFN-a) and methotrexate (MTX).

Infusional schedules

With interferon

A number of randomized trials have compared bolus 5-FU schedules with infusion of various durations,

EN-a has well-described synergistic with 5-FU and 5-FU-FA in preclinical

interactions models, and

124

this interaction has been extensively tested in phase 1,2 and 3 trials in patients with advanced colorectal cancer. Despite promising initial results, the conclusion of the phase 3 trials is clear: IFN-a has shown no evidence of clinical benefit for patients with advanced colorectal cancer (59-63). The data from these trials are currently being prepared for meta-analysis.

with methotrexate

MTX has little independent activity in colorectal cancer, but it interacts with 5-FU in a complex and sequence-specific manner in vitro, and several trials have investigated its use as a biomodulator of 5-FU therapy. A meta-analysis of nine randomized trials showed a significant increase in response rate (p
With fdinic acid

FA enhances 5-FU’s inhibition of T’S (see above), and the 5-FU-FA interaction has entered routine clinical practice. A series of nine trials comparing 5-FU alone with 5-FU-FA were reported between 1985 and 1992 and then subjected to meta-analysis (21). This showed a significantly higher objective response rate with 5FU-FA (23% vs ll%, pcO.OOl), but no increase in survival. Some of these studies used different schedules of 5-FU administration in the two arms, and most did not adjust the 5-FU doses to produce equal toxicity, so it is questionable whether they constitute evidence that FA improves the therapeutic index of 5-FU. A subsequent well-designed randomized trial compared 5-FU-FA with 5-F&placebo, with escalation of the 5-FU dose to achieve equal toxicity. The trial design was successful in that similar toxicity was seen in the two groups, with 12.5% higher 5-FU dose intensity in the 5-F&placebo arm. However, only small differences, not reaching statistical significance, were seen in response rate (23% vs 32%, p = 0.15) and time to treatment failure (median 16 weeks vs 22 weeks, p = 0.27), with survival longer in the placebo arm (65). Despite these doubts about the clinical benefit of FA, most clinicians worldwide now regard 5-FU-FA as the standard therapy for colorectal cancer. The dose of FA required also causes controversy, particularly as it is expensive in some countries. At least five randomized trials, involving 1614 patients,

M. T. SEYMOUR

have compared low-dose and high-dose FA as modulators of 5-FU in advanced colorectal cancer (66-70). In only one of these, involving a weekly administration schedule, did high-dose FA (500 mg/m’) show any benefit (66). However, when the same highdose regimen was tested in two subsequent larger trials, its advantage over low-dose FA did not hold up (68,69). Thus there is now no justification for the use of high-dose FA in association with bolus 5-FU regimens. As a result of all these trials, the ‘Mayo’ regimen of 5 day bolus 5-FU (425mg/m’) and low-dose FA (20mg/m’), repeated monthly, is currently widely regarded as the international comparitor for phase 3 trials, although it falls far short of being a ‘gold standard’.

Combinations

of biomodulation

and infusional

5-w Several groups have combined the approaches of infusional 5-FU administration and biomodulation with FA. The best assessed to date is the ‘de Gramont’ regimen involving a 48-h administration schedule of high-dose FA, bolus 5-FU and infusional 5-FU. This has been compared with ‘standard’ 5 day bolus 5FU-low-dose FA in a multicentre randomized trial involving 448 patients and demonstrated significantly better objective response rate and time to progression with significantly less toxicity, making it the current best-performing regimen in phase III trials (71). The survival advantage in this trial did not reach significance (p = 0.06), probably because of cross-over and second-line therapy. It is not known whether the high dose of FA used in this regimen is important for its efficacy. Another widely used regimen has been developed by the German Cancer Society @IO). This comprises high-dose infusional FA (500 mg/m’ over 2 h) and 5-FU (2600 mg/m* over 24 h) repeated weekly. This regimen is reported to give a high rate of response or stabilization when used second line after failure of standard first-line bolus 5-FU-FA (72). An ongoing EORTC randomized trial is comparing first-line therapy with the Mayo bolus 5-FU-FA regimen, weekly infusional 5-FU (2600 mg/m2 over 24 h) and the AI0 regimen of infusional 5-FU and FA.

lntrahepatic

artery administration

Spread from primary colorectal cancer to the liver is via the portal circulation, and intrahepatic portal 5-

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CANCER

FU is under continued evaluation as postoperative adjuvant therapy (73). However, established hepatic metastases are supplied almost entirely from the hepatic artery (74), making this a potential route for treatment of patients with inoperable metastases confined to the liver. Hepatic arterial infusion (HAI) of chemotherapy is feasible and gives an estimated pharmacokinetic advantage (I&, the ratio of hepatic to systemic exposure) of more than 50-fold for 5-FU, and even higher than this for the 5-FU analogue fluorodeoxyridine (FUDR) which is almost entirely extracted in first-pass hepatic clearance. HA1 chemotherapy consistently produces objective response rates higher than systemic therapy, but there is no evidence as yet that this improves survival. Seven randomized trials of IHA therapy, all with FUDR, have been meta-analysed: a survival advantage is seen for those using a supportive care or ‘ad Zibitum’ control (16-18) (see Table l), but not for those using a standard intravenous chemotherapy control (75). One reason for the failure of HA1 therapy with FUDR to improve survival could be its failure to control extrahepatic disease. For this reason, two more multicentre trials, ALM trial l/19 in Germany and MRC trial CR05 in the U.K. (76), are examining I-IA1 using 5-FU given at doses designed to achieve full systemic therapy levels, with equivalent systemic therapy controls. The results of these trials are awaited with interest.

5-FU prodrugs There may be two reasons for using a 5-FU prodrug: to allow more convenient administration (e.g. oral therapy) or to exploit a tumour-specific prodrug activating enzyme. The best-established 5-FU prodrug is ftorafur (Tegafur) which is 5-FU with a tetrahydrofuran substitution at the l-position of the pyrimidine ring. It is fully orally bioavailable (77) and is slowly converted to 5-FU by two pathways: hepatic PdsOmicrosomal cytochrome oxidation or more widespread soluble enzyme hydrolysis. Circulating 5-FU is barely detectable after ftorafur administration, but anticancer activity similar to that of 5-FU is reported, suggesting that intratumoral hydrolysis may be significant. Following initial single-agent use, ftorafur has been developed since the late 1970s in a fixed-ratio combination with uracil, named ‘WI”. Uracil inhibits 5FU catabolism by competition for dihydropyrimidine dehydrogenase (DPD), as a result of which oral UFT administration generates plasma 5-FU levels comparable with those seen after intravenous 5-FU infusion (78). Pooled phase II data from several Japanese centres gave a response rate of 25% in 56 evaluable patients with colorectal cancer (79). More

125

recently, a series of phase I, II and ongoing phase III studies in the U.S.A. and Europe are investigating the combination of oral UFT and FA in comparison with standard intravenous 5-FU-FA schedules. Other oral ftorafur combinations are being developed, including ‘Sl’, a combination of ftorafur with 5-chloro-2,4dihydroxypyridine (an inhibitor of DPD) and oxonic acid (which, by inhibiting the formation of F-UTP, increases the ratio of DNA to RNA effects). Sl is currently in phase II clinical evaluation WV Another promising 5-FU prodrug, capecitabine (XelodaTM), is also undergoing clinical phase III evaluation. Like ftorafur, capecitabine is orally bioavailable and is converted to 5-FU. However, the activating pathway involves the enzyme TP, which is over-expressed in some colorectal tumours, and is associated with 5-FU resistance (25). Initial phase I and II trials have defined a safe oral schedule (81) and phase III comparison with standard intravenous 5-FU-FA is underway.

Other inhibitors ofthymidylate synthase Raltitrexed (TomudexTM) is a potent and specific inhibitor of TS. It is a structural analogue of folate and is polyglutamated and retained within cells, making a three-weekly bolus administration schedule possible: an advantage over 5-FU therapy. Three separate randomized trials, of which one has been published, have compared raltitrexed with ‘standard 5 day bolus 5FU-leucovorm schedules in advanced colorectal cancer patients (82). The reported trial, in 439 patients, suggests a similar spectrum of activity and toxicity for raltitrexed compared with the control regimen of bolus 5-FU-FA. Mature results of the other two trials are awaited, together with those of further randomized trials in the advanced and adjuvant setting including the large U.K. MRC trial, CR06 (38). LY231514 is a ‘multitargeted antifolate’ (MTA) with activity against TS, dihydrofolate reductase and glycinamide ribonucleotide formyl transferase. Like raltitrexed and methotrexate, it requires polyglutamation for full activity and the polyglutamated form is retained in cells, allowing an intermittent (three-weekly bolus) schedule. Activity has been demonstrated in phase II studies (83), and further clinical evaluation is awaited.

CYTOTOXIC DRUGS WITH OTHER MECHANISMS: A NEW ERA OF COMBINATION CHEMOTHERAPY? Single-agent cytotoxic chemotherapy has only rarely produced substantial benefits in cancer treatment.

126

Progress has usually come from combining agents, each with good independent single-agent activity but differing mechanisms of action, different mechanisms of drug resistance and compatible toxicity profiles. Until recently, these demands have been impossible to satisfy for colorectal cancer: after 5FU, none of the available drugs with different mechanisms of activity and drug resistance satisfied the first condition of good independent activity. However, at last some interesting new agents are opening the door to rational combination chemotherapy for this disease. We are seeing clear evidence of activity, in patients with disease resistant to 5FU or other TS-targeted therapy, from drugs with completely different mechanisms. Furthermore, early indications are that first-line treatment with a combination of TS- and non-TStargeted drugs is feasible and may produce objective response rates substantially higher than we have seen previously with our best TS therapy. Oxaliplatin Cisplatin has some activity in colorectal cancer, but several randomized trials comparing 5-FU with 5FU-cisplatin have shown no overall clinical benefit from its use (54, 8487). On the other hand oxaliplatin, a novel diaminocyclohexane platinum compound with a different spectrum of activity to cisplatin in vitro, is showing promising clinical activity in colorectal cancer. When used as a single agent, oxaliplatin gave objective responses in 24% of 39 unpretreated patients (88) and in 10% of 106 patients with 5-FI-FA-resistant disease (89). Oxaliplatin is a relatively easy drug to use; like carboplatin, it is non-nephrotoxic so does not require pre- and post-hydration, and it is only moderately emetogenic. Cumulative peripheral sensory neuropathy is the dose-limiting toxicity. It is possible to combine oxaliplatin with 5-FU-FA with little or no compromise in dose, although 5-FU side-effects are slightly increased by concurrent oxaliplatin, possibly because of increased 5-FU anabolism (90). Furthermore, oxaliplatin and 5-FU show evidence of synergy in the laboratory and when 46 patients with disease progressing on 5-FU-FA were treated with oxaliplatin in combination with the same 5-FU-FA regimen, 46% responded, with an impressive overall median survival of 17 months from the initiation of second-line therapy (91). The 5-FU-FAoxaliplatin combination has now been assessed in a multicentre randomized trial as first line therapy. Two hundred and forty patients received the ‘de Gramont regimen’ of 5-FU-FA with or without oxaliplatin. Interim results of this trial are promising, the combination giving a significantly

M. T. SEYMOUR

improved radiological response rate (57% vs 26%) and median progression-free survival (40 weeks vs 28 weeks), with acceptable toxicity (92); mature results of this trial are awaited with interest. lrinotecan Irinotecan (CPT-11) is a semisynthetic camptothecin which acts though disruption of the nuclear enzyme topoisomerase-I. Phase II studies included 130 patients with assessable advanced colorectal cancer progressing after first-line 5-FU-FA, with an objective response rate of 18%, although surprisingly the response rate was no higher in a smaller unpretreated population (93). Two recent phase III trials have assessed the value of irinotecan as secondline palliative treatment by comparing it with supportive care alone (94) and with a more intensive infusion-based second-line 5-FU-FA regimen (95). Both trials show statistically significant survival advantages. A new trial comparing irinotecan with bolus 5-FU-FA as first-line treatment is now underway. Irinotecan may conveniently be given by threeweekly short infusion in the outpatient clinic. It carries significant toxicity, including neutropenia, alopecia and lethargy which may impact on quality of life in this patient group. Early trials had a high incidence of severe diarrhoea, nausea and vomiting, but these side-effects have been substantially mitigated by the development of effective supportive protocols, including high-dose loperamide. Given its novel mechanism of action and the lack of clinical cross-resistance with 5-FU, irinotecan is an interesting candidate for combination therapy, but the potential for additive toxicity is a concern. In-vitro studies of irinotecan with 5-FU or raltitrexed show variable sequence-dependent synergy and antagonism which may be of importance to clinical scheduling. Several pilot studies and randomized trials of irinotecan in concurrent and alternating schedules are underway: with 5-FU-FA, with protracted 5-FU infusion and with raltitrexed. Initial reports suggest that these combinations are feasible and less toxic than expected, raising the possibility of drug antagonism in normal-tissue targets. We must await mature results of the current trials, and larger randomized trials, to determine the antitumour efficacy of these combinations. Mitomycin-C Mitomycin as a single agent has low but definite activity in colorectal cancer, with the reported response rate averaging 16% in old, mainly uncontrolled trials (96). While not of major interest as

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a single agent, its relative ease of use and nonoverlapping toxicity, together with some in-vitro evidence of 5-FU-mitomycin synergy, prompted clinical trials of the combination. A small randomized trial of bolus 5-FU alone or together with mitomycin and methyl-CCNU showed no benefit for the combination (97). However, more recently a randomized trial in 200 patients has compared PVI 5-FU with or without bolus mitomycin-C every 6 weeks. The combination produced a significantly better objective response rate (54% ZG 38%, p =0.024) and failure-free survival (p = 0.033) (98). This trial should stimulate a fresh look at this previously discarded drug.

comparison, we are seeing response rates over 50% and median progression-free survival over 8 months in equivalent modern multicentre trials of optimum TS-non-TS combinations such as bolus + infusional 5-FU-FA with oxaliplatin (92) or protracted infusional 5-FU with mitomycin-C (98). Clearly, further comparative data are required, but there is understandable interest in how these new and apparently more effective regimens will perform in the adjuvant setting. Appropriate randomized trials of adjuvant combination chemotherapy are already underway in high-risk patients.

NEW DIRECTIONS The place for new active cytotoxic

drug

combinations These combination chemotherapy schedules are being developed as first- or second-line treatment for metastatic disease where the aim of treatment is to control the disease for as long as possible with acceptable side-effects. It is possible that sequential single-agent therapies will achieve this as well as, or better than, an intensive combination therapy with a high response rate. This question needs to be addressed in trials comparing different strategies of sequential or concurrent treatments, using overall survival and quality-adjusted survival as end-points. However, another purpose of research in patients with established metastatic disease is the prospect of improving postoperative adjuvant therapy, where the same drugs will be aimed at micrometastatic disease clones. We have no reliable laboratory models for adjuvant therapy, and to some extent treatment of patients with evaluable metastatic disease is an ‘experimental model’ for adjuvant therapy. We currently assume that treatments with a high initial objective response rate and longer progression-free survival in patients with established metastases are best able to eliminate micrometastases in the adjuvant setting. Current ‘gold standard’ regimens of 5 day bolus 5-FU with low- or high-dose FA are of proven, albeit modest, benefit in the curative adjuvant setting for high-risk postoperative patients (99-101). In their initial phase III trials, conducted during the 198Os, these regimens were reported to give objective response rates around 20-35% in patients with advanced metastatic disease (21, 67, 68). However, in more recent large, multicentre, randomized trials conducted to modern standards, reported since 1995, the same regimens regularly produce objective response rates below 20% and median progressionfree survival under 6 months (63, 70, 71, 82). By

Angiogenesis and invasion present new targets for small-molecule therapy. Of the numerous novel agents, marimastat is perhaps furthest into clinical development. It is a non-specific inhibitor of several matrix metalloproteinases, involved in both cancer cell invasion and tumour neovascularization. Current clinical trials are investigating the biological effects of marimastat and other matrix metalloproteinase inhibitors in patients with a range of solid turnours, including colorectal cancer (102). Other classes of inhibitor of angiogenesis are entering clinical trials; among the most promising is an inhibitor of basic fibroblast growth factor, tecogalen, which has produced responses in solid tumours during phase 1 testing (103). Immunological therapy is mainly of interest in the adjuvant setting, because micrometastases present better potential targets for host immune mechanisms than do bulky, established metastases. Hence current programmes using injected unconjugated monoclonal antibodies against tumour-associated antigens, or vaccination with autologous tumour conjugates or tumour antigen/promoter constructs, involve treatment of patients at risk after curative resection (104-106). Specific or non-specific immunotherapy has not been generally successful in patients with advanced colorectal cancer; trials or cytokine-stimulated immunity using interferons and interleukin-2 (IL-2) have produced a few definite antitumour responses, but at the cost of substantial toxicity (107). The same can be said of adoptive cellular immunotherapy with IL-2 and lymphokineactivated killer cells (108). Perhaps more promising in patients with established metastases, specific binding of monoclonal antibodies or fragments to tumour antigens is being exploited as a targeting vehicle for radionucleotides (radioimmunotherapy) and for prodrug converting enzymes (antibody-dependent enzyme-prodrug therapy, or ADEPT) (109). However, several obstacles remain to the therapeutic

128 effectiveness of antibody-targeted therapies in solid cancers. Gene therapy offers a wide variety of new potential therapies in colorectal cancer, full discussion of which is beyond the scope of this review. Perhaps the most immediate promise is from genetic enzyme-prodrug approaches (GDEI’T or VDEPT.), derived from the ADEPT concept of generating tumour-targeted prodrug converting enzyme activity. Instead of using antibody targeting, the gene for a non-human prodrug converting enzyme gene is linked to a tumour-specific promoter region, such as the CEA promoter. However, many other gene therapy approaches are under investigation, including attempts to correct p53 or AK tumour suppressor gene function (110) and the use of autologous tumour cells, transduced in vitro with cytokine genes, as cancer vaccines (111). Perhaps the greatest current challenge in gene and oligonucleotide therapy is the development of vectors and delivery systems to allow safe and effective transfer of genetic material to a sufficient proportion of cancer cells in patients. In almost every discipline of cancer research, significant progress has been made in colorectal cancer over the past decade. In concentrating on just one part of that process, cytotoxic chemotherapy in advanced disease, this article has highlighted some of the progress most relevant to current practice for patients with established metastatic colorectal cancer; but clearly this is just one aspect of a much broader movement. If the 1980s were ‘the decade of breast cancer’, we can reasonably claim the 1990s as the decade of colorectal cancer, but as we move past the millennium there is no sign of loss of momentum. The gains to patients so far have been modest but significant; there is every prospect of much more to come.

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