Cancer Research UK Clinical Centre, Cookridge Hospital Leeds, Leeds LS16 6QB, UK
Received 18 September 2003; revised 18 November 2003; accepted 22 December 2003
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ABSTRACT |
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Current standard therapy following resection of high-risk colon cancer is intravenous bolus 5-fluorouracil (5-FU) with leucovorin (LV), but there is no consensus on the optimum regimen of these drugs: practice ranges from the high toxicity Mayo Clinic schedule to the very low toxicity weekly QUASAR schedule. We present data for a weekly schedule that aims to provide moderately dose-intense treatment with low toxicity.
Patients and methods:
One hundred and sixty-two patients were studied: 60% male; median age 65 years (36% over 70 years); 94% colorectal primary. Treatment was intravenous bolus (5 min) 5-FU 425 mg/m2 plus D,L-LV 45 mg flat rate once weekly, for a planned 24 weeks. Data for toxicity, dose-reductions, delays and stoppages were collected.
Results:
Overall, 20% of patients experienced any grade 3 toxicity, most commonly diarrhoea (14% patients). Dose reductions were made in 35% of patients (although only 21% required 20% or more reduction); toxicity contributed to a decision to stop treatment before 24 weeks in 16% of patients. Median delivered dose intensity (DI) was 96% of planned (407 mg/m2/week) during treatment, and 91% of planned (385 mg/m2/week) over the full 24 week treatment plan. Female sex and age >70 years were significantly associated with higher rates of toxicity and dose adjustment, and lower delivered DI.
Conclusions:
Weekly treatment at these doses is convenient and well-tolerated for the large majority of patients, and achieves DI comparable with the 5 days a month QUASAR schedule and other more toxic standard regimens.
Key words: adjuvant, colorectal, dose intensity, fluorouracil, leucovorin, toxicity
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Introduction |
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In late 1999, in the light of data recently reported from the large UK randomised trial, QUASAR [2, 3], we reviewed our institutions policy for non-trial adjuvant chemotherapy and decided to adopt a weekly schedule of 5-FU with low-dose folinic acid. However, rather than using the low 5-FU dose (370 mg/m2) and protracted schedule (30 weeks) that had been used in QUASAR, we opted instead to use a higher dose of 425 mg/m2 5-FU, and to reduce the planned treatment duration to 24 weeks. We anticipated that this modification would allow us to deliver treatment at a higher dose intensity (DI), more comparable to other standard regimens, but to retain the low toxicity and good patient acceptability that had characterised the QUASAR trial. We now present toxicity and tolerability data for the first 162 patients treated with this regimen.
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Patients and methods |
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Treatment
All treatment was administered by an appropriately trained nurse in a nurse-led chemotherapy clinic. Racaemic calcium D,L-LV was given at a flat-rate dose of 45 mg, regardless of patient surface area, as a slow intravenous injection over 5 min. This was followed by 5-FU at 425 mg/m2, also given over 5 min. Routine prophylactic antiemetics were not used, but all patients received supplies of p.r.n. oral metoclopramide, loperamide and a chlorhexidine mouthwash (CorsadylTM), with verbal and written instructions on their use. The total planned treatment duration was 24 weeks; doses omitted for toxicity or patient choice (e.g. holidays) during this period were not routinely added on at the end of the planned treatment period.
Evaluation of toxicity and treatment modification
Monitoring of toxicity was performed by the trained nursing staff, who also administered chemotherapy. Toxicity was routinely evaluated at each visit using the National Cancer Institute common toxicity criteria (version 2.0) grading system, and was summarised in the clinical notes on a pre-printed form every 6 weeks. For grade 2 toxicity, treatment was omitted until recovery and then restarted, either at the same dose or with a dose-reduction of 1025% at the discretion of the clinician responsible. In some cases, rather than continuing treatment at a reduced dose, a decision was made to stop adjuvant treatment altogether; this was more likely if the indication for treatment was uncertain (i.e. Dukes B cancer or non-colon primary), or if the patient was elderly.
Data collection
Data for treatment prescribed were collected from the Chemocare database, and for toxicity and adverse events from the clinical notes. The number of weeks of treatment received overall and the percentage dose reduction of 5-FU was recorded, so that the proportion of planned dose administered could be calculated. Reasons for dose reductions, delays and premature termination of treatment were noted.
Statistics
Toxicity and dose reduction evaluation in subgroups was performed using the 2 statistic. Previous studies have used different methods of reporting delivered DI. Therefore, for comparison, we calculated delivered DI in two ways: (i) in mg/m2/week, taken from the date of the first chemotherapy injection until 1 week after the final dose administered; and (ii) in mg/m2/week, taken from the date of first chemotherapy injection until 24 weeks later, i.e. the end of the planned course. The latter method gives reduced DI in patients stopping treatment earlier than planned. Comparison of DI in subgroups was assessed using the non-parametric MannWhitney test.
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Results |
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Rectal cancer patients who had received pre-operative radiotherapy or chemoradiotherapy appeared to tolerate post-operative adjuvant chemotherapy just as well as those who had not received pre-operative treatment. However, patients aged 70 years experienced significantly more grade
3 diarrhoea than younger patients (P = 0.05), and significantly more grade 2 or 3 watering of the eyes (P = 0.001). Female patients experienced toxicity more frequently than male patients, with 21% of women experiencing grade 2 or 3 nausea compared with 8% of males (P = 0.02). Female patients were also more likely to experience grade 2 or 3 lethargy and handfoot dermatitis (P = 0.06 and 0.06, respectively).
Dose reductions, stoppages and delays
In all, 59 of 162 (36%) patients received the entire 24-week planned course without any toxicity-related dose reductions or delays. The dose of 5-FU was reduced at some point in 57 (35%) patients, although only 34 (21%) patients underwent dose reduction of 20% or more. Pre-operative radiotherapy or chemoradiotherapy did not result in more dose reductions in subsequent adjuvant chemotherapy (P = 0.52). Female patients required more dose reductions than males (P = 0.02). These dose reductions were made at any time from week 4 to 22 (median 10.5 weeks) (Figure 1).
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Administration of chemotherapy was delayed for 1 week at some point in 70 (43%) patients, most commonly because of toxicity (35 patients, 22%) or holidays (18 patients, 11%). It was not unit policy to routinely add missed treatments to the end of the course after the planned 24 weeks treatment duration, although this was done in approximately half of these cases, usually at the patients request.
DI of chemotherapy administered
The regimen has a planned 5-FU DI of 425 mg/m2/week. Because of the relatively low rate of dose reductions and delays, the delivered DI calculated in the normal way, up to 1 week after stopping treatment, was median 96% of planned DI (407 mg/m2/week). The delivered DI exceeded 90% of planned DI in 67% of patients and exceeded 80% of planned DI in 90% of patients (Figure 2, upper line). If instead, DI is calculated over the full 24 weeks planned treatment course (10.2 g/m2/24 weeks), giving a reduced DI for patients who stop treatment early for any reason, the median delivered DI was still 91% of planned DI (9.23 g/m2/24 weeks, equivalent to 385 mg/m2/week) and exceeded 80% of planned DI in 71% patients (Figure 2, lower line).
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Discussion |
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However, these standard regimens, although effective, produce rates of serious toxicity that have sometimes exceeded normal definitions of maximum tolerable dose. The Mayo schedule was established in a trial in which 24% of patients had grade 34 diarrhoea and 36% had grade 34 mucositis; by the time cycle 6 was administered, fewer than 30% patients were still on treatment and receiving 80% or more of the planned dose [4]. Subsequently, nearly 1000 patients received the same regimen in INT-0089, and the rates of grade 3 and 4 toxicity were again high: mucositis in 18%, diarrhoea in 21% and neutropenia in 24% [9]. A recent retrospective review by Tomiak et al. [10] highlighted the problems of administering the Mayo Clinic schedule in routine clinical practice, with 35% of patients not receiving even the second cycle of treatment as planned because of toxicity. On the other hand, a recent phase III trial reported lower rates of toxicity, although 70% of patients still required dose modification at some point during treatment [11]. The Machover regimen appears less toxic than the Mayo schedule; rates of reported toxicity varied widely in the three trials making up the 1995 IMPACT report [7], but in a recent trial, 26% of 453 patients treated with this regimen experienced grade 3 or 4 toxicity [12]. The Roswell Park schedule, in the NSABP C-03 trial, produced grade 3 or 4 diarrhoea in 28% patients [8].
Two recent trials have looked at infusional regimens as potentially less toxic and/or more active than bolus 5-FU/LV in the adjuvant setting. Both showed reduced rates of grade 34 toxicity, although against this must be offset the risks, inconveniences and expense of infusional treatment; disappointingly, neither showed evidence of increased efficacy in the adjuvant setting [12, 13]. An ongoing industry trial of oral capecitabine will be of interest, since it presents a potentially more attractive method of protracted fluoropyrimidine dosing [14].
The large UK-based trial, QUASAR, has been important in identifying simple but better-tolerated regimens of bolus 5-FU and LV. It included 4929 patients randomised to receive adjuvant 5-FU at 370 mg/m2 (as in the Machover regimen [7]), together with either high- or low-dose L-leucovorin (175 versus 25 mg) and with either levamisole or placebo. This trial demonstrated, with high statistical power, that levamisole does not add to the activity of 5-FU/LV, and that low-dose LV is as effective as, and less toxic than, high-dose LV [2]. In QUASAR, participating centres chose to use a 5-day, 4-weekly schedule for six cycles (as in the Mayo and Machover regimens) or to give the same doses once weekly for 30 weeks. Similar numbers of patients received the two schedules (2559 and 2370, respectively), and, although not randomised, these groups were fortuitously very well matched for pre-treatment characteristics, including age and stage. The lack of randomisation means that comparisons must be interpreted with caution, but with this important proviso there was no evidence for any difference in relapse-free survival [hazard ratio (HR) 0.99; 95% confidence interval (CI) 0.901.08] or overall survival (HR 0.97; 95% CI 0.881.06) between patients receiving the two administration schedules. On the other hand, toxicity was markedly different, with highly significantly less diarrhoea (P <0.001), stomatitis (P <0.001), neutropenia (P <0.001) and dermatitis (P <0.001) in patients on the once-weekly schedule. Consequently, there were lower rates of dose reduction (P <0.001), and a higher percentage of planned dose was delivered (P <0.001) [3].
Reaction to these data has been mixed. Some oncologists now use the 5-day monthly treatment at 370 mg/m2 5-FU with low-dose LV, on the basis that the QUASAR trial randomly validated this schedule against a standard regimen. Others, reassured by the large size and well-balanced patient characteristics in QUASARs non-randomised comparison of schedules, have adopted the weekly regimen, which gives the same doses weekly for 30 weeks, so giving the same total planned dose (11.1 g/m2) but with lower planned DI (370 versus 462 mg/m2/week).
We reasoned that, given the low 5-FU dose used in the weekly QUASAR schedule and the near absence of toxicity for many patients, there was scope to increase the dose while maintaining acceptably low toxicity levels, and that this may allow for more dose-intensive treatment, comparable to other validated treatments. This report of our experience with this regimen must be interpreted with caution; as a non-randomised series it is subject to selection bias, and cannot provide evidence for efficacy. However, within this limitation the premise of the approach has been confirmed: weekly 5-FU at 425 mg/m2, with low dose D,L-LV 45 mg flat rate, for 24 weeks, is feasible, with minimal toxicity to patients. Consequently, even in this non-trial population where treatments were often omitted for patients holidays and the threshold for reducing or stopping treatment was relatively low, the median DI achieved was 96% of planned DI whilst on treatment (407 mg/m2/week), and 91% of planned DI over 24 weeks (385 mg/m2/week). Although dose modification or delay was used at some point in the majority of patients, this was usually for mild toxicity, and only 20% of patients experienced any grade 3 toxicity at any stage. Notably, 36% of our patients were over the age of 70 years, and, in common with previous studies [1517], we found that female sex and advanced age were significantly correlated with higher toxicity and lower delivered DI.
How does this compare with other schedules? The Mayo and Roswell Park schedules have planned DIs of 472 and 375 mg/m2/week, respectively; it is clear that the deliverable DI, particularly for the Mayo schedule, is well below planned DI, but trial reports have not provided these data. The Machover regimen was reported, in the three trials making up the IMPACT report, at variable median delivered DI from 85% to 98% of planned (393 to 454 mg/m2/week) [7]. Delivered DI data were reported for QUASAR: the median delivered DI was 398 mg/m2 for the 5-day monthly and 345 mg/m2 for the once weekly schedule [3]. Thus the higher dose weekly schedule described here achieved similar DI to the 5-days QUASAR schedule.
Does this represent an acceptable regimen for non-trial delivery of 5-FU? QUASAR firmly established its 5-day monthly schedule, with low-dose LV, to be as effective as the more toxic and expensive Machover schedule [2]; however, the status of QUASARs weekly schedule as a standard option is more contentious, depending as it does on a very large but non-randomised comparison [3]. The regimen we have described here delivers a similar DI to QUASARs 5-day monthly schedule. Its toxicity is low and acceptable: 20% of our patients underwent 20% dose reduction, which compares with 17% of patients in the QUASAR weekly and 42% in the 5-day monthly schedules. Comparison with trials using the Mayo, Machover and Roswell Park schedules would suggest that we have also achieved at least as high delivered DI, with lower toxicity, than those schedules.
With any adjuvant treatment regimen, certain proof of equivalent efficacy can only be achieved by an adequately powered randomised trial, involving several thousands of patients. Comparisons of different 5-FU schedules are, thankfully, no longer a priority for such large trials programmes, which are now rightly focused on novel therapies. However, we would suggest that the comparative toxicity and DI data presented here would support the use of 5-FU 425 mg/m2 plus low-dose LV, weekly for 24 weeks, as a simple, convenient and relatively low-toxicity treatment option for non-trial patients requiring 5-FU adjuvant therapy. Our subgroup analysis would, in common with others findings, suggest the need for caution in elderly female patients since, even with this low toxicity schedule, these patients have the highest risk of toxicity.
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Acknowledgements |
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FOOTNOTES |
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