Chemotherapy for Metastatic Rectal Cancer

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Introduction

Many modalities have been evaluated for the treatment of metastatic colorectal cancer: systemic chemotherapy, regional chemotherapy, ablative therapies, surgery and combined strategies. Systemic chemotherapy is the most widely used approach and for many years has been considered only in a palliative setting. After four decades 5-fluoruracil remains the mainstay of treatment with its different biomod- ulations and infusional regimens. However the availability of active new drugs such as irinotecan, oxaliplatin and raltitrexed, oral agents such as capecitabine and uracil-tegafur (UFT), and more recently the development of targeted molecular therapies such as cetuximab and bevacizumab has permitted the oncologist to leave behind nihilism and enter a promising new age.

About50% of patients diagnosed with colorectal carcinoma have metastatic disease at the time of diagnosis or will develop metastases or local recur- rences after diagnosis.

Rectal cancer requires a different approach to colon cancer in the pre-operative and adjuvant set- tings: metastatic diseases have the same treatment and randomised or phase II trials include both tumours.

This chapter reviews the evidence and focuses on state of the art research and everyday treatment of patients with metastatic rectal cancer.

5-Fluorouracil (FU)

Fluorouracil (FU), discovered in 1957 [1], has been considered to be the standard therapy for the palliative treatment of metastatic colorectal cancer for about40 years. The overall response rate when used as the single agent is about 20% and complete responses are extremely rare with a median survival less than 12 months. One review of trials of new agents in colorectal cancer between 1960 and 1990 found that none of the 72 compounds evaluated pro-

duced a higher response rate than FU [2]. One way to attempt to increase the mechanisms of action of FU was biomodulation. A number of biomodulation strategies have been used with FU: methotrexate with a higher response rate (19% vs. 10%) and a 1.6- month survival advantage (p=0.024) [3]; interferon- α without any documented advantage [4]; and final- ly leucovorin calcium (LV), which has been the most widely used agent for biomodulation. When compared with the best supportive care, the combination FU–LV showed a significantly longer survival (11 vs.

5 months) [5].

The best known regimens, Machover (a daily⫻5 schedule of FU 370 mg/m²with LV 200 mg/m²every4 weeks), Roswell Park (a weekly schedule of FU 600 mg/m² with LV 500 mg/m²) and Mayo Clinic (a daily×5 schedule of FU 425 mg/m²with LV 20 mg/m² every 4 weeks), showed 20–30% increased response rates with different kinds of toxicity: mucositis in the first and diarrhoea in the second [6, 7].

At least a dozen randomised trials have addressed the question of whether FU plus LV is superior to FU alone. The updated meta-analysis has show the advantage of FU-LV over FU alone is not limited to tumour response (21% for the combination and 11%

for FU alone) but also applies to overall survival, with a median survival time of 10.5 months for patients treated with FU alone and 11.7 months for patients treated with FU–LV (p=0.004) [8].

A North Central Cancer Treatment Group study compared two leucovorin schedules: Mayo Clinic low-dose, daily⫻5 and the Roswell Park weekly high dose. There were no significant differences in therapeutic efficacy between the two regimens tested with respect to the following parameters: objective tumour response (35% vs. 31%), survival (median 9.3 vs.10.7 months) and palliative effects (as assessed by relief of symptoms, improved performance status and weight gain). There were significant (p<0.05) differences in toxicity, with more leukopenia and stom- atitis seen with the intensive-course regimen, and more diarrhoea and requirement for hospitalisation to manage toxicity with the weekly regimen. Finan-

Maurizio Cantore, Alfonso Del Freo, Andrea Mambrini, Giammaria Fiorentini

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cial cost was also higher with the weekly regimen [9].

FU has been shown to have a short plasma half-life of 8–20 min following a bolus injection and these observations led to the development of different infusional schedules classically divided in two cate- gories: protracted intravenous (IV) and high-dose intermittent infusions. These have been compared with bolus schedules in randomised trials.

FU continuous infusion (CI) is superior to FU bolus in terms of tumour response and achieves a slight increase of overall survival. The haematologic toxicity is much less important in patients who receive FU CI, but hand-foot syndrome is frequent in this group of patients [10].

The intermittent high dose was more effective and less toxic than the monthly regimen and definitely increased the therapeutic ratio. However, there was no evidence of increased survival [11] (Table 1).

New Drugs

In the late 1990s the incorporation of irinotecan (CPT-11) and oxaliplatin in the management of advanced colorectal cancer generated further improvement in survival. Combinations of FU and LV with irinotecan (FOLFIRI, IFL) or oxaliplatin (FOLFOX4, FOLFOX6) are considered to be standard first-line chemotherapy treatment.

Irinotecan

Irinotecan (CPT-11) is a campthotecin derivative with anti-tumour activity via inhibition of topoiso- merase-I, a nuclear enzyme that facilitates DNA uncoiling for replication and transcription by bind- ing to DNA and causing reversible single-stranded DNA breaks. Because of the different mechanism of

action from that of FU, at the beginning it was evaluated in FU-refractory disease.

A total of 304 patients with FU-refractory colorectal tumour had a major response rate of 13% with 49% of minor response or stable disease when treated with weekly doses of 125 mg/m²for4 weeks followed by a 2-week break. Diarrhoea and neutropenia were the major dose-limiting toxicities [12].

In two European trials CPT-11 has been compared to best supportive care or retreatment with FU CI in patients with colorectal cancer refractory to FU bolus. The CPT-11 schedule of 350 mg/m² every 3 weeks was used for these trials.

In the first study the overall survival was significantly better in the CPT-11 group (1-year survival of 36.2% and 13.8% respectively in CPT-11 and sup- portive care arms, p=0.0001). In a quality of life (QoL) analysis, all significant differences, except on the diarrhoea score, were in favour of the CPT-11 group [13].

In the second study, patients treated with CPT-11 lived for significantly longer than patients treated with FU (p=0.035). Survival at 1 year was increased from32 to 45% and median survival from 8.5 to 10.8 months in the CPT-11 group. Median progression- free survival was longer with CPT-11 (4.2 vs. 2.9 months, p=0.030). Both treatments were equally well tolerated and QoL was similar in both groups [14].

Another phase III trial has investigated the efficacy and tolerability of two CPT-11 dosing regimens (weekly 125 mg/m² for 4 weeks or once 300–350 mg/m²every3 weeks) in patients with FU-refractory colorectal cancer. There was no significant difference in1-year survival (46% vs. 41%, respectively, p=0.42), median survival (9.9 vs. 9.9 months, p=0.43) or medi- an time to progression (4.0 vs. 3.0 months, p=0.54) between the two regimens. Every 3-week regimen was associated with a significantly lower incidence of severe diarrhoea (p=0.002). Treatment-related mor- Table 1.FU evolution in the treatment of metastatic colorectal cancer

Author Trial Response rate Median survival 1-year survival

(%) (months) (%)

Scheitauer et al. [5] FU+LV 11 pS –

BSC 5 –

Meta-analysis [3] FU+LV 21 pS 11.7 47 pS

FU 11 10.5 37

Buroker et al. [9] FU+HDLV 35 9.3 –

FU+LDLV 31 10.7 –

Meta-analysis [10] FU CI 22 pS 12.1 pS –

FU 14 11.3 –

De Gramont et al. [11] FU+LV2 32 pS 15.5 –

FU+LV 14.5 14.2 –

pS, p value statistically significant

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tality occurred in 5.3% receiving weekly CPT-11 and in1.6% receiving CPT-11 every 3 weeks [15].

CPT-11 was then introduced in the first line for the treatment of previously untreated colorectal cancer.

Three phase III prospective randomised trials were designed to compare the efficacy and toxicity of the combination of FU, LV and CPT-11 to FU and LV alone.

The American trial compared bolus FU–LV–CPT- 11 (IFL) to bolus FU-LV and to CPT-11 alone. The trial demonstrated significant benefit in terms of confirmed response rates, progression-free survival and overall survival. IFL showed confirmed responses in 39% of patients, compared with 21% in patients treated with FU–LV and 18% in patients treated with CPT-11 (p<0.001). In addition, progression-free sur- vival was significantly prolonged with IFL (7.9 vs. 4.3 months, p=0.004). Median survival was also improved:14.8 months for IFL and 12.6 months for FU–LV (p=0.042) [16].

The first European trial compared CPT-11, using AIO or Douillard regimen (weekly or every 2 weeks infusion) with infusional FU–LV using the same schedule. The CPT-11 regimen had a significantly longer time-to-progression (median 6.7 months vs.

4.4 months, p<0.001), a higher response rate (49% vs.

31%, p<0.001) and a higher overall survival (median 17.4 vs. 14.1 months, p=0.031) [17] (Table 2).

Oxaliplatin

Oxaliplatin is a novel diaminocyclohexane platinum analogue that acts mainly by causing interstrand and intrastrand cross-links in DNA. Alone or combined with FU and LV, it has shown promising activity in previously treated and untreated patients with metastatic colorectal cancer and in patients with FU refractory disease.

Three phase III prospective randomised trials compared the efficacy of the combination OXA–FU–

LV to FU–LV.

The first study compared FOLFOX regimen (oxali- platin85 mg/m²as a 2-hour infusion on day 1 and 2- hour infusion of LV 200 mg/m²/day followed by a FU bolus 400 mg/m²/day and 22-hour infusion 600 mg/m²/day for 2 consecutive days every 2 weeks) to the same regimen of infusional FU-LV alone in previously untreated patients with advanced colorectal cancer. Patients treated with FOLFOX4 had a significantly longer progression-free survival (9.0 vs. 6.2 months, p=0.0003) and response rate (50.7% vs.

22.3%, p=0.0001), but no improvement in overall survival (16.2 vs. 14.7 months, p=0.12). Grade 3 and 4 toxicity (neutropenia, diarrhoea and neuropathy) were more common in the oxaliplatin arm but this did not result in impairment of QoL. Survival without disease progression or deterioration in global health status was longer in patients allocated to oxali- platin treatment (p=0.004) [18].

Similar results were observed in a second randomised trial using a chronomodulated schedule.

Sixteen percent of the patients receiving FU-LV had an objective response, compared with 53% of those receiving additional oxaliplatin (p<0.001). The median progression-free survival time was 6.1 months with FU–LV and 8.7 months with oxalipaltin and FU–LV (p=0.048). Median survival times were 19.9 and19.4 months, respectively [19].

A third phase III study randomised between FU bolus425 mg/m², LV 20 mg/m², on days 1–5, repeated every 4 weeks; and oxaliplatin 50 mg/m²,2-h infusion, FU 2000 mg/m²,24-h infusion, LV 500 mg/m²on days1, 8, 15, 22, repeated every 5 weeks (FUFOX regimen). Response rate was more than doubled in FUFOX with 48.3% vs. 22.6% (p<0.0001) and 8.8% of complete response in FUFOX. After a median follow- up of 27.3 months, progression-free survival is signif- Table 2.Phase III randomised trials of CPT-11 in patients with metastatic colorectal cancer

Authors Trial Response rate Progression-free survival Median survival

(%) (months) (months)

Cunningham et al. [13] CPT+BSC – – 9.2

vs. BSC – – 6.5

Rougier et al. [14] CPT-11 – – 10.8

FU CI – – 8.5

Saltz et al. [16] CPT-11+FU+LV 39 pS 7.9 pS 14.8 pS

FU+LV 21 4.3 12.6

CPT-11 18 4 12

Douillard et al. [17] CPT-11+FU+LV 49 pS 6.7 pS 17.4 pS

FU+LV 31 4.4 14

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icantly longer in the oxaliplatin arm: 7.9 vs. 5.3 months (p<0.0001). Median overall survival is 20.4 and16.1 months respectively [20] (Table 3).

Two North American randomised phase III trials have evaluated a second chemotherapeutic line with a regimen containing oxaliplatin in patients with progressive metastatic colorectal cancer after front- line treatment with CPT-11, bolus FU–LV. In the first FOLFOX was found to be superior in response rate (9.6%) to oxaliplatin (1.1%) and FU–LV (0.7%) alone. Mature data from this study, however, failed to show a statistically significant improvement in median survival. Toxic effects, particularly neutropenia and neuropathy, were higher in the FOLFOX arm but these toxicities were predictable and did not result in a higher rate of treatment discontinuation or 60-day mortality rate [21].

In the second, FU–LV with or without oxaliplatin was evaluated in patients with metastatic colorectal cancer after disease progression on sequential fluoropyrimidine and CPT-11. FOLFOX was found to be superior to FU–LV in terms of: response rates (13%

vs.2%, p=0.0027), median time to disease progression (4.8 vs. 2.4 months, p<0.0001) and median sur- vival (11.4 vs. 9.9 months, p=0.20). Symptomatic improvement was significantly better for FOLFOX (32% vs. 18%, p=0.05) [22].

The next generation of studies compared CPT-11- based to oxaliplatin-based chemotherapy in patients with newly diagnosed advanced colorectal cancer.

GERCOR group compared FOLFOX with FOLFIRI in patients with advanced colorectal cancer. In this study, patients were crossed over from 1 regimen to the other at the time of progression.

These 2 first-line treatments for metastatic and advanced colorectal cancer have demonstrated similar response rates and acceptable toxic effects pro- files with no differences in median time-to-first progression (8 vs. 8.5 months) or overall survival (20.6 vs.21.5 months) for FOLFOX followed by FOLFIRI regimen vs. FOLFIRI followed by FOLFOX regimen.

A response rate of 15% and a median progression-

free survival of 4.5 months were seen in patients who progress to FOLFIRI chemotherapy when treated with FOLFOX, and a response rate of 4% with a median progression-free survival of 2.5 months for the reverse sequence [23].

The US Cooperative Groups completed a randomised intergroup clinical trial for the first treatment of advanced colorectal cancer. This trial was originally launched to compare IFL, FOLFOX and a combination of oxaliplatin and CPT-11 with Mayo regimen. A total of 795 patients were randomised.

With a median follow-up of 20.4 months, all outcome measures for FOLFOX were significantly better than IFL, including a significantly better time-to-tumour progression (8.7 vs. 6.9 months, p=0.0014), a higher response rate (45% vs. 31%, p=0.002) and an improved overall survival (19.5 vs. 15 months, p=0.0001). Patients treated with irinotecan and oxaliplatin (IROX) had a significantly lower median time- to-progression (6.5 months) and response rate (35%) compared to FOLFOX (p=0.001 and p=0.03, respec- tively); median survival, however, did not differ significantly between the 2 regimens (19.5 vs. 17.4 months, p=0.09).

The results of this study establish the FOLFOX regimen as the first-line treatment in advanced colorectal cancer [24].

The last generation of trials evaluated the triplet combination of CPT–oxaliplatin–FU in patients with newly diagnosed or pretreated metastatic colorectal cancer. A biweekly regimen with oxaliplatin, CPT-11, infusional FU and LV (FOLFOXIRI) showed a response rate of 71.4% and 26% of patients were downstaged and surgical resection could be performed; median progression-free and overall survival times were 10.4 and 26.5 months, respectively.

The pharmacokinetics parameters of the agents used and their metabolites did not seem to be influenced by the concomitant use of the other drugs. The most relevant toxicities were diarrhoea and neutropenia [25] (Table 4).

Table 3.Phase III randomised trials of oxaliplatin in patients with metastatic colorectal cancer

Author Trial Response rate Progression-free survival Median survival

(%) (months) (months)

De Gramont et al. [18] FOLFOX 50.7 pS 9 pS 16.2

FU–LV 22.3 6.2 14.7

Giacchetti et al. [19] FU–LV+OXA chrono 53 pS 8.7 pS 19.9

FU–LV 16 6.1 19.4

Grothey et al. [20] FUFOX 48.3 pS 7.9 pS 20.4

FU–LV 22.6 5.3 16.1

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Tomudex

Raltitrexed is a specific thymidylate synthase inhibitor which has demonstrated activity similar to that of bolus FU and LV for the first-line treatment of advanced colorectal cancer. The recommended dose is3.0 mg/m²every three weeks. Median survival and response rate were comparable to that of bolus or infusional FU–LV. As with other cytotoxic agents, serious and potentially life-threatening side effects can occur: particularly diarrhoea and neutropenia.

The incidence of serious side effects may be min- imised with the assessment of renal function before and after every treatment and dosage adjustment in the presence of renal impairment [26].

Oral Chemotherapy

A protracted continuous infusion of FU has the advantages of a different and milder toxicity, but there is the drawback of the need of a central venous system for infusion and the discomfort of carrying an infusion pump. Oral regimens using prodrugs of FU pharmacologically simulate continuous infusion and are under clinical evaluation. Furthermore, patients receiving therapy for late-stage disease prefer oral rather than IV chemotherapy (IVC) but are unwilling to accept a lower response rate or a shorter duration of response to their preferred choice of oral chemotherapy.

Capecitabine

Capecitabine is an oral fluoropyrimidine carbamate that is converted by thymidine phosphorylase (TP) into FU: because TP levels may be higher in tumour than in normal tissue, a specific therapeutic advantage was possible [27]. A substantial efficacy with an acceptable toxicity profile was documented in a phase II study [28].

A total of 1207 patients with previously untreated metastatic colorectal cancer were randomised to either oral capecitabine (1250 mg/m² twice daily, days1–14 every 21 days) or IV bolus FU–LV (Mayo regimen). Capecitabine demonstrated a statistically significant superior response rate compared with FU–LV (26 vs. 17%, p<0.0002). The median time to response, duration of response, time to progression and overall survival were equivalent in the two arms (median 12.9 vs. 12.8 months); an improved safety profile was observed and improved convenience compared with IV FU–LV as first-line treatment for metastatic colorectal cancer [29].

Uracil–Tegafur (UFT)

Another oral agent is a combination of uracil and the fluoruracil prodrug tegafur. Uracil is a competitive inhibitor of dihydropyrimidine dehydrogenase that is the rate-limiting enzyme in the catabolism of FU.

UFT has been studied in combination with oral leucovorin.

A total of 380 patients were randomised to receive either UFT (300 mg/m²/day) and LV (90 mg/day), administered for 28 days every 35 days, or FU (425 g/m²/day) and LV (20 mg/m²/day), given IV for 5 days every 35 days. There were no statistically significant differences in survival, tumour response, duration of response and time to response. Substantial safety benefits were observed in patients treated with UFT-LV [30].

Targeted Therapy

Interference with the activation of growth factor receptors and/or with the intracellular growth factor- activated signal transduction pathways represents a promising strategy for the development of novel and selective anti-cancer therapies.

Two of the most promising new targets in the Table 4.Comparative, sequential and integrated trials of CPT and OXA

Author Trial Response rate Progression-free survival Median survival

(%) (months) (months)

Tournigand et al. [23] FOLFOX–FOLFIRI 56 8.1 20.4

FOLFIRI–FOLFOX 57.5 8.5 21.5

Goldberg et al. [24] IFL 31 6.9 15

FOLFOX 45 pS 8.7 pS 19.5

IROX 34 6.5 17.4

Falcone et al. [25] FOLFOXIRI 71.4 10.4 26.5

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treatment of colorectal cancer are the epithelial growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF). Agents that inhib- it the EGFR or bind to VEGF have demonstrated clinical activity as single agents and in combination with chemotherapy in phase II and phase III clinical trials.

Cetuximab

Cetuximab is a monoclonal antibody that specifically blocks the EGFR. The efficacy of cetuximab in combination with CPT-11 or alone was evaluated in a randomised trial in metastatic colorectal cancer refractory to treatment with CPT-11. Three hundred and twenty-nine patients whose disease had progressed during or within three months after treatment with a CPT-11-based regimen were randomly assigned to receive either cetuximab and CPT-11 (at the same dose and schedule as in a pre-study regimen) or cetuximab monotherapy. The rate of response in the combination therapy was significantly higher than that in the monotherapy (22.9% vs. 10.8%, p=0.007).

The median time to progression was significantly greater in the combination therapy (4.1 vs. 1.5 months, p<0.001). The median survival time was 8.6 months for the combination-therapy and 6.9 months for the monotherapy (p=0.48). Toxic effects were more frequent in the combination therapy group, but their severity and incidence were similar to those that would be expected with CPT-11 alone. Cetuximab has clinically significant activity when given alone or in combination with CPT-11 in patients with CPT-11- refractory colorectal cancer [31].

Bevacizumab

Bevacizumab is a humanised variant of the anti- VEGF monoclonal antibody that has been studied as an anti-angiogenic cancer therapeutic as a single agent and in combination with chemotherapy in patients with stage III and IV colon cancer. In addition to its direct anti-angiogenic effects, bevacizumab may allow more efficient delivery of chemotherapy by altering tumour vasculature and decreasing the elevated interstitial pressure common in tumours.

Eight hundred and thirteen patients with previously untreated metastatic colorectal cancer were randomly assigned to receive IFL plus bevacizumab (5 mg/kg body weight every two weeks) or to receive IFL plus placebo. The primary end-point was overall survival.

Secondary end-points were progression-free survival, response rate, duration of the response, safety and QoL. Median survival was 20.3 months for IFL plus bevacizumab and 15.6 months for IFL plus

placebo (p<0.001). Median progression-free survival was10.6 months for IFL plus bevacizumab, and 6.2 for IFL plus placebo (p<0.001); response rates were 44.8 and 34.8% (p=0.004) in favour of the patients treated with IFL plus bevacizumab. The addition of bevacizumab to FU-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer [32].

Liver Metastases

Unlike most other malignancies, colorectal cancer has a potential to metastasise to an isolated distant site, of which the liver is the most common. These locoregional metastases may be treated with surgical or ablative procedures or hepatic arterial chemotherapy (HAC).

Only about 20% of patients presenting with liver metastases are suitable for surgical resection. An adequate response to chemotherapy in advanced colorectal cancer with initially unresectable liver metastases may permit resection of the metastases and the 5-year survival rate is similar to that of initially re- sectable metastases. In a retrospective analysis of 701 patients with initially unresectable liver metastases, surgery with curative intent was performed in 35%

of patients following FU–LV and OXA; the 5-year survival rate was 35% with long-term survival, similar to that in initially curative resection [33]. Liver resection seems associated with a poor outcome if there is tumour progression under chemotherapy and metastatic disease is not controlled prior to surgery [34].

HAC delivers high concentrations of cytotoxic agents directly to liver metastases with minimal systemic toxicities. Randomised trials comparing HAC with systemic chemotherapy have demonstrated superior response rates and times to hepatic progression for unresectable disease. A meta-analysis based on seven trials compared HAC with floxuridine (FUDR) vs. IVC with FUDR or FU vs. best supportive care: tumour response rate was 41% and 14% for patients allocated to HAC and IVC respectively (p<0.0001); survival analyses showed a statistically significant advantage for HAI compared with control when all the trials were taken into account (p=0.0009) but not when survival analysis was restricted to trials comparing HAC and IVC (p=0.14) [35].

A recent randomised trial compared HAI with the standard IV de Gramont regimen for patients with metastases confined to the liver. There is no evidence of advantage in overall survival (14.7 and 14.8 months) or progression-free survival (7.7 and 6.7

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months). Thus, clinical use of this regimen cannot be recommended and other prospective clinical trials should be conducted to more definitively answer this question [36].

According to the clinical response rate and median survival obtained with the new systemic regimen, phase I and II studies of HAI with oxaliplatin or CPT- 11 have already been published. They have demonstrated tolerability and an interesting efficacy in heavily pretreated patients [37, 38].

Elderly Patients

A significant proportion of patients presenting with colorectal cancer are elderly (over the age of 70 years). The Comprehensive Geriatric Assessment, which subdivides the population of elderly cancer patients into three groups, can help to guide treatment decisions. The group of “fit” elderly patients (good performance status or no significant comor- bidity) can tolerate a cytotoxic treatment and the use of systemic FU-based chemotherapy has been shown to be of clinical benefit for these patients with metastatic disease in terms of survival, control of symptoms and QoL.

A European analysis of 22 trials with 5-FU-containing treatment found the same survival and response rate in elderly and in younger patients, while progression-free survival was marginally prolonged in the elderly [39]. In a North American analysis of 4 trials testing 5-FU with or without LV, performance status, not age, has been predictive of time to tumour progression and overall survival; elderly patients treated with 5-FU have modestly higher rates of severe toxicity, mainly diarrhoea and stom- atitis [40].

Data from the first clinical trials regarding the use of new drugs (oxaliplatin, irinotecan, raltitrexed, oral fluoropyrimidines) in selected elderly patients are limited but indicate an activity comparable to that observed in younger patients, with overall manage- able toxicity.

In conclusion, standardised palliative chemotherapy should generally be offered to fit elderly patients and they should not be excluded from clinical trials in order to gain information about new treatments.

The Therapeutic Strategy

Generally, patients with a large tumour and several metastatic sites with an ECOG performance status of 2 or greater have a lower chance of response to chemotherapy. For many of these patients the atten- dance or supportive care is the recommended treat-

ment choice. On the other hand, patients who are in a good general condition with a small tumour, not previously exposed to chemotherapy, have response rates of approximately 50% when treated with CPT- 11 and oxaliplatin. The cases in between the two con- ditions described are more difficult to manage and the approach must be individualised. If the patient is elderly, his general condition is not very good or he does not seek particular medical attention, it is rea- sonable to wait a month or two, check the rate of disease progression and withhold treatment until later in the course [41].

More debatable is the issue of treatment of the non- symptomatic patient. As the end-point of treatment is palliation, should we wait until symptoms develop (so that there is something to palliate) or should treatment be instituted right away? Several phase III studies concluded that patients who are treated at diagnosis of metastatic disease with conventional FU-based regimens live significantly longer (by 3–6 months) than patients in whom chemotherapy is delayed until symptoms develop; even if the overall response rate to standard chemotherapeutic regimens is low in unse- lected patients with advanced colorectal cancer, the subjective benefit is substantial [42].

At this time, there is a role for combination chemotherapy as a first-line treatment in fit patients.

Standard systemic chemotherapy for advanced colorectal cancer is the use of combination therapy with oxaliplatin or CPT-11. Only in some cases can FU-LV be considered the best choice. In general there is agreement that bolus FU alone is ineffective and that biochemical modulation is needed for bolus FU activity whereas it is not for protracted infusional FU.

Biochemical modulation is also required when using intermittent high-dose infusional FU.

In fit patients chemotherapy is also indicated for second- and in some cases thirdline therapy. Treat- ment of patients who progress after first-line chemotherapy is guided by which treatment was used for first-line treatment. Patients who were treated with a FOLFOX-based regimen should be treated with a CPT-11-based regimen and patients who already received a CPT-11-based regimen should be treated with a FOLFOX-based regimen.

The GERCOR Group achieved 26-month median overall survival with the sequential use of continuous infusional FU–LV, oxaliplatin and CPT11 combinations in metastatic patients.

The analysis of large phase III trials using FU, CPT11 and oxaliplatin revealed that the higher proportion of patients was treated with all three drugs, the longer overall survival was achieved; the use of combination protocols as first-line chemotherapy was associated with a significant improvement in median survival of 3.5 months (p=0.0083) [43].

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The anti-VEGF bevacizumab increases the efficacy of first-line CPT-11 therapy, while the addition of cetuximab restores CPT-11 sensitivity in second-line treatment.

Regarding the duration of chemotherapy for these patients, as long as there are no other factors that contraindicate treatment, chemotherapy should be recommended for approximately 2 months and then their outcome must be evaluated. If the treatment is fairly well tolerated and there is at least a stabilisation of the disease, chemotherapy should be continued until progression or toxicity. Usually in clinical prac- tice chemotherapy is stopped after a maximum of 6 months. A recent trial has compared effectiveness of continuous and intermittent chemotherapy in patients who responded or had stable disease after receiving 12 weeks of the regimens described by de Gramont and Lokich, or raltitrexed chemotherapy:

they were randomised to either intermittent (a break in chemotherapy, re-starting on the same drug on progression) or continuous chemotherapy until progression. Patients on intermittent chemotherapy had significantly fewer toxic effects and serious adverse events than those in the continuous group. There was no clear evidence of a difference in overall survival [44]. Another strategy may be the so-called “stop and go therapy”. In the OPTIMOX study reintroduction of oxaliplatin was feasible and achieved a response or stabilisation in 73% of patients. These results support the concept that intensified, repeated short courses of FOLFOX are efficacious and less toxic [45].

References

1. Heidelberger C, Chanakary NK, Daneberg PV et al (1957) Fluorinated pyrimidines: a new class of tumor inhibitory compounds. Nature 179:663–666

2. Haskel CM, Selch MT, Ramming KP (1990) Colon and rectum. In: Haskel CM (ed) Cancer treatment. WB Saunders, Philadelphia, pp 232–254

3. Advanced Colorectal Cancer Meta-Analysis Project (1994) Meta-analysis of randomised trial testing the biochemical modulation of fluoruracil by methotrexate in metastatic colorectal cancer. J Clin Oncol 12:960–969

4. Corfu – A study group (1995) Phase III randomised study of two fluoruracil combination with either interferon alfa-2a or leucovorin for advanced colorectal cancer. J Clin Oncol 13:921–928

5. Scheithauer W, Rosen H, Kornek GV et al (1993) Ran- domised comparison of combination chemotherapy plus supportive care with supportive care alone in patients with metastatic colorectal cancer. BMJ 306:752–755

6. Machover D, Scharzenberger L, Goldschmidt T et al (1982) Treatment of advanced colorectal and gastric adenocarcinomas with FU combined with high dose

folinic acid: a pilot study. Cancer Treat Rep 66:

1803–1807

7. Madajewicz S, Petrelli N, Rustum YM et al (1984) Phase I/II trial of high dose calcium leucovorin and fluouracil in advanced colorectal cancer. Cancer Res 44:4667–4669

8. The Meta-Analysis Group in Cancer (2004) Modula- tion of fluorouracil by leucovorin in patients with advanced colorectal cancer: an updated meta-analysis.

J Clin Oncol 22:3766–3775

9. Buroker TR, O’Connel MJ, Wieand HS et al (1994) Randomised comparison of two schedules of fluoruracil and leucovorin in the treatment of advanced colorectal cancer. Am J Clin Oncol 12:14–20

10. Meta-analysis Group in Cancer (1998) Efficacy of intravenous continuous infusion of fluoruracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 16:301–308

11. De Gramont A, Bosser JF, Milan C et al (1997) Ran- domised trial comparing monthly low dose leucovorin and fluoruracil bolus with bimonthly high dose leucovorin and fluoruracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol 15:808–815

12. Von Hoff DD, Rothemberg ML, Pitot HC et al (1997) Irinotecan therapy for patients with previously treated metastatic colorectal cancer. Proc Am Soc Clin Oncol 16:803a

13. Cunningham D, Pyrhonen S, James RD et al (1998) Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:1413–1418

14. Rougier P, Van Cutsem E, Bajetta E et al (1998) Ran- domised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352:

1407–1412

15. Fuchs CS, Moore MR, Harker G et al (2003) Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol21:807–814

16. Saltz LB, Cox JV, Blanke C et al (2000) Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343:905–914

17. Douillard JY, Cunningham D, Roth AD et al (2000) Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial.

Lancet355:1041–1047

18. de Gramont A, Figer A, Seymour M et al (2000) Leu- covorin and fluoruracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938–2947

19. Giacchetti S, Perpoint B, Zidani R et al (2000) Phase III multicenter randomised trial of oxaliplatin added to chronomodulated fluoruracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 18:136–147

20. Grothey A, Deschler B, Kroening H et al (2002) Phase III study of bolus 5-fluoruracil/folinic acid (Mayo) vs weekly high-dose 24h 5-fu + oxaliplatin (FUFOX) in

(9)

advanced colorectal cancer. Proc Am Soc Clin Oncol 21:129a, [abstract 512]

21. Rothenberg ML, Oza AM, Bigelow RH et al (2003) Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol 21:2059–2069

22. Kemeny N, Garay CA, Gurtler J et al (2004) Ran- domised multicenter phase II trial of bolus plus infusional fluorouracil/leucovorin compared with fluorouracil/leucovorin plus oxaliplatin as third-line treatment of patients with advanced colorectal cancer. J Clin Oncol 22:4753–4761

23. Tournigand C, Andre T, Achille E et al (2004) FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomised GERCOR study. J Clin Oncol 22:229–237

24. Goldberg RM, Sargent DJ, Morton RF et al (2004) A randomised controlled trial of fluoruracil plus leucovorin, irinotecan and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23–30

25. Falcone A, Masi G, Allegrini G et al (2002) Biweekly chemotherapy with oxaliplatin, irinotecan, infusional Fluorouracil, and leucovorin: a pilot study in patients with metastatic colorectal cancer. J Clin Oncol 20:4006–4014

26. Cunningham D, Zalcberg J, Maroun J et al (2002) Effi- cacy, tolerability and management of raltitrexed (Tomudex) monotherapy in patients with advanced colorectal cancer. A review of phase II/III trials. Eur J Cancer38:478–486

27. Schuller J, Cassiday J, Dumont E (2000) Preferential activation of capecitabine in tumor following oral administration to colorectal carcinoma patients. Can- cer Chemother Pharmacol 45:291–297

28. Van Cutsem E, Findlay M, Osterwalder B (2000) Capecitabine, an oral fluorinated pyrimidine with substantial activity in advanced colorectal cancer: results of a randomised phase II study. J Clin Oncol 18:1337–1345

29. Van Cutsem E, Hoff PM, Harper P et al (2004) Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer 90:1190–1197

30. Carmichael J, Popiela T, Radstone D et al (2002) Ran- domised comparative study of tegafur/uracil and oral leucovorin versus parenteral fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 20:3617–3627

31. Cunningham D, Humblet Y, Siena S et al (2004) Cetux- imab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337–345

32. Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leu-

covorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342

33. Adam R, Avisar E, Ariche A et al (2001) Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal liver metastases.

Ann Surg Oncol 8:347–353

34. Adam R, Pascal G, Castaing D et al (2004) Tumor progression while on chemotherapy: a contraindication to liver resection for multiple colorectal metastases? Ann Surg Oncol 6:1052–1061

35. Meta-Analysis Group in Cancer (1996) Reappraisal of hepatic arterial infusion in the treatment of nonresectable liver metastases from colorectal cancer. J Natl Cancer Inst 88:252–258

36. Kerr DJ, McArdle CS, Ledermann J et al (2003) Intra- hepatic arterial versus intravenous fluoruracil and folinic acid for colorectal cancer liver metastases: a multicentre randomised trial. Lancet 361:368–373 37. van Riel JMG, Groeningen CJ, Kedde MA et al (2002)

Continuous administration of irinotecan by hepatic arterial infusion. A phase I and pharmacokinetic study.

Clin Cancer Res 8:405–412

38. Fiorentini G, Rossi S, Dentico P et al (2004) Oxaliplatin hepatic arterial infusion chemotherapy for hepatic metastases from colorectal cancer: a phase I–II clinical study. Anticancer Res 24:2093–2096

39. D’Andre S, Sargent DJ, Cha SS et al (2005) 5-Fluo- rouracil-based chemotherapy for advanced colorectal cancer in elderly patients: a north central cancer treatment group study. Clin Colorectal Cancer 4:325–331 40. Folprecht G, Cunningham D, Ross P et al (2004) Effi-

cacy of 5-fluorouracil-based chemotherapy in elderly patients with metastatic colorectal cancer: a pooled analysis of clinical trials. Ann Oncol 15:1330–1338 41. Kohne CH, Cunningham D, Di CF et al (2002) Clinical

determinants of survival in patients with 5-fluoruracil- based treatment for metastatic colorectal cancer:

results of a multivariate analysis of 3825 patients. Ann Oncol13:308–317

42. Simmonds PC (2000) Palliative chemotherapy for advanced colorectal cancer: systematic review and meta-analysis. Colorectal Cancer Collaborative Group.

BMJ321:531–535

43. Grothey A, Sargent DJ, Goldberg RM, Schmoll HJ (2004) Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil- leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 22:1209–1214

44. Maughan TS, James RD, Kerr DJ et al (2003) Compar- ison of intermittent and continuous palliative chemotherapy for advanced colorectal cancer: a multicentre randomised trial. Lancet 361:457–464

45. Maindrault-Goebel F, Tournigand C, Andre T et al (2004) Oxaliplatin reintroduction in patients previously treated with leucovorin, fluorouracil and oxaliplatin for metastatic colorectal cancer. Ann Oncol 15:1210–1214