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Severe Sequence-Specific Toxicity When Capecitabine Is Given After Fluorouracil and Leucovorin

Ivo M. Hennig, Jay D. Naik, Sarah Brown, Alex Szubert, David A. Anthoney, David P. Jackson, Alan M. Melcher, S. Michael Crawford, Christopher Bradley, Julia M.B. Brown, Matthew T. Seymour

From the St James's Institute of Oncology, St James's University Hospital; Clinical Trials Research Unit, University of Leeds, Leeds; Airedale General Hospital, Keighley; Bradford Royal Infirmary, Bradford; and York District Hospital, York, United Kingdom

Corresponding author: Matthew Seymour, MA, MD, FRCP, Cancer Research UK Centre, St James's Institute of Oncology, St James's University Hospital, Leeds LS9 7TF, United Kingdom; e-mail: matt.seymour{at}leedsth.nhs.uk

	ABSTRACT

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Purpose Options for single-agent fluoropyrimidine adjuvant therapy after bowel cancer resection include intravenous fluorouracil with leucovorin (FU/LV) or oral capecitabine. These treatments have similar efficacy but differ in convenience and toxicity. We therefore wished to compare their overall acceptability to patients.

Patients and Methods Patients scheduled for adjuvant single-agent fluoropyrimidine therapy were randomly assigned to receive once-weekly FU/LV (425 mg/m² FU, 45 mg LV) for 6 weeks, followed by two 3-week cycles of capecitabine (1,250 mg/m² twice daily, days 1 through 14), or the same treatments but in reverse order. After 12 weeks, the patients were asked which treatment they preferred, and received the preferred treatment for an additional 12 weeks. The primary end point was patient preference.

Results After 40 of the planned 74 patients had been randomly assigned, real-time adverse event monitoring led to early trial closure because of excess sequence-specific toxicity. Eleven of 14 patients (79%) receiving capecitabine as their second treatment experienced grade 3 toxicity. This compared with five of 18 patients (28%) receiving capecitabine as the first treatment, and no patients receiving FU/LV as the first treatment (zero of 16) or the second treatment (zero of 12). Similar imbalances were seen in the proportion of patients requiring interruption of treatment.

Conclusion In chemotherapy-naïve patients, capecitabine produced more toxicity than FU/LV, but at levels in line with previously reported data. However, treatment with capecitabine after FU/LV caused markedly increased toxicity, indicating a sequence-specific interaction. The mechanism has not been determined, but interaction with intracellularly retained folate after FU/LV therapy is a possibility. Oncologists need to be aware of this risk if considering crossing patients over from FU/LV to capecitabine-based regimens.

	INTRODUCTION

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Fluoropyrimidines are the backbone of adjuvant therapy for bowel cancer. Currently, treatment options after resection of stage III (Dukes' C) colon cancer include single-agent fluoropyrimidine or an oxaliplatin/fluoropyrimidine combination for 6 months. Fluoropyrimidine therapy is also commonly prescribed after resection of stage II (Dukes' B) colon cancer and stage II or III rectal cancer.

Early trials established intravenous fluorouracil with leucovorin (FU/LV) as the standard fluoropyrimidine therapy in the adjuvant setting. Subsequent studies comparing different FU/LV schedules^1-9 identified differences in toxicity but no major differences in efficacy. The largest of these trials was the United Kingdom Quick and Simple and Reliable Collaborative Group trial, which demonstrated that high-dose LV is not superior to low-dose LV, and that levamisole does not add efficacy. It also showed in a large but nonrandomized comparison that—at an FU dose of 370 mg/m²—once-weekly treatment for 30 weeks is better tolerated than a 5-day treatment given monthly for 6 months.¹⁰ After publication of United Kingdom Quick and Simple and Reliable Collaborative Group trial, we assessed higher-dose once-weekly FU/LV for 24 weeks, with FU at 425 mg/m². This regimen was also well tolerated; toxicity rates were low and 90% of the patients received more than 80% of the planned dose. Consequently, delivered dose intensity compared favorably with the more toxic 5-day schedules.¹¹ This was therefore adopted as our standard adjuvant fluoropyrimidine regimen.

Capecitabine, an orally bioavailable prodrug of fluorouracil, is an attractive alternative to intravenous FU/LV. Patients consider oral therapy generally to be preferable to injections,^12,13 and hospital administration costs for oral therapy are lower. A Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) phase III trial compared capecitabine with the Mayo Clinic FU/LV regimen (425 mg/m² FU plus 20 mg/m² LV, days 1 to 5 of a 28-day cycle) after resection of Dukes' C colon cancer. Capecitabine was at least as effective as FU/LV, with lower rates of National Cancer Institute Common Toxicity Criteria grade 3 stomatitis and neutropenia.^14,15 However, the Mayo Clinic regimen is substantially more toxic than other FU/LV schedules,^9,16-18 so X-ACT did not establish whether capecitabine would be preferable to a less toxic, weekly FU/LV schedule.

Many factors affect the overall acceptability of different treatments to patients, including practicalities, toxic effects, and psychological impact. Patients who have experienced both treatments are uniquely well placed to distill these factors into a single overall preference.

	PATIENTS AND METHODS

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The Patient Preference in Adjuvant Colorectal Therapy (PACT) trial aimed to determine if patients receiving single-agent fluoropyrimidine adjuvant therapy after bowel cancer resection prefer oral capecitabine or intravenous FU/LV. It was conducted in accordance with the Declaration of Helsinki and its amendments. The protocol was approved by the ethics committees of each participating center, externally peer reviewed, adopted by the United Kingdom National Cancer Research Network, and registered as ISRCTN35708246 [controlled-trials.com] .

Patient Selection
Patients older than age 18 years with resected Dukes' C or B colonic or rectal carcinoma and no clinical or radiologic evidence of metastatic disease were eligible, as were chemotherapy-naïve patients with fully resected colorectal metastases. Patients had to begin adjuvant chemotherapy within 12 weeks of surgery, have a good performance status (WHO 0 to 2), and have adequate hematologic and biochemical function, including a calculated or measured glomerular filtration rate of more than 50 mL/min. Exclusion criteria were planned postoperative radiotherapy, severe uncontrolled comorbidities, psychiatric or neurologic conditions compromising the ability to give consent or to comply with oral medication, another cancer diagnosis in the preceding 3 years, pregnancy, or breast feeding.

Trial Design and Treatment
PACT was a multicenter, open-label, prospective, randomized, controlled, unblinded cross-over trial assessing patient preference for standard intravenous weekly FU/LV treatment or oral capecitabine treatment. After written informed consent was received, patients were randomly assigned by center, sex, and presence of a stoma to either group A (intravenous FU 425 mg/m² and intravenous LV 45 mg once weekly for 6 weeks,¹¹ followed by two 3-week cycles of capecitabine 1,250 mg/m² twice daily on days 1 through 14¹⁵); or to group B (the same two treatments but in reverse order).

Crossover from the first treatment period (start period) to the second treatment period (switch period) occurred without a time gap. After 12 weeks, patients were asked to state which treatment they preferred, and received this treatment in the third treatment period (preference period) for the final 12 weeks (Fig 1).

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Patient Preference in Adjuvant Colorectal Therapy trial design. FU/LV, fluorouracil with leucovorin.

Assessments
Prerandomization assessment for each patient comprised a medical history, physical examination, performance status, hematology, biochemistry, carcinoembryonic antigen, and—where indicated—pregnancy test. Metastatic disease was excluded by computed tomographic scans of the chest, abdomen, and pelvis. During treatment, patients underwent a clinical assessment every 3 weeks, including evaluation of hematologic and nonhematologic toxicities using Common Terminology Criteria for Adverse Events, version 3.0 (CTCAEv3).

Dosing and Adjustments
Capecitabine was administered to the nearest achievable dose using tablets of 500 and 150 mg. If glomerular filtration rate decreased below 50 mL/min, capecitabine was reduced by 25%. For patients whose weight was 15% more than ideal body weight, surface area was calculated using ideal body weight plus 15%.

With both regimens, CTCAEv3 grade 1 was managed symptomatically. Grade 2 nonhematologic toxicity, persisting despite symptomatic measures, was managed by pausing chemotherapy for a week, then resuming treatment at the same dose. Doses were reduced by 20% for grade 3 toxicity, or in the event of persistent grade 2 toxicity requiring two or more delays. With both regimens, CBC was checked every 3 weeks, and the next treatment cycle delayed for hematologic toxicity of CTCAEv3 grade 2. A dose reduction was mandated after two treatment delays or one treatment delay of 2 weeks occurred.

Statistical Methods
The planned statistical comparison of patient preference 12 weeks after starting treatment is not reported here because the observation of sequence-specific toxicity invalidates this comparison (see Discussion). The principle focus of this report is therefore safety.

Toxicity data (maximum toxicity experienced within each period, per patient, for each toxicity) were summarized according to both the intention-to-treat and safety populations, and are presented here for the latter. The safety population included all patients who received at least 3 weeks of trial medication during any given treatment period. The requirement for treatment delays or dose reductions was also summarized. CIs for differences in grade 3 toxicity and dose delays were calculated including a continuity correction.

	RESULTS

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From October 2005 to July 2006, 40 of the planned 74 patients at six institutions were randomly assigned to one of two treatment groups before the early trial closure. Patient characteristics are summarized in Table 1. One enrolled patient with poor venous access withdrew before the first treatment was administered. Because of early trial closure, five patients (three in group A and two in group B) either did not start treatment or withdrew during the first 3 weeks, and are not included in this analysis. At final analysis, 34 patients (85%) had received at least 3 weeks of the first 6-week period of trial treatment. Twenty-six patients (65%) had begun the second 6-week period of trial treatment.

After trial closure, the patients completed 24 weeks of adjuvant therapy. However, crossover from FU/LV to capecitabine was disallowed, and patients receiving capecitabine at the time of closure were offered the choice of continuing oral chemotherapy or crossing over to FU/LV. Overall toxicity and dose delay, or stoppage results for the safety population are listed in Table 2. A graphic illustration of grade 2, 3, or 4 toxicities is shown in Figure 2.

View this table: [in this window] [in a new window]   Table 2. Grade 3 Toxicity Experienced and Dose Adjustments Due to Toxicity in the PACT Trial Safety Population, Comparing Start and Switch Periods

View larger version (22K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. For each drug treatment, a histogram demonstrates the percentage of patients experiencing National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 (CTC AEv3.0) grade 2, 3, or 4 toxicity when receiving the treatment either as start period, switch period, or preference period. The period of treatment is the same as shown in Figure 1. The panels show the adverse events of (A) any toxicity; (B) lethargy; (C) diarrhea; (D) Palmar-Plantar syndrome; and (E) mucositis. FU/LV, fluorouracil with leucovorin.

Switch Period (weeks 7 to 12)
During the second treatment period, 14 patients in group A received capecitabine, and 12 patients in group B received FU/LV. An unexpectedly high rate of toxicity was observed in the group A patients, with grade 3 toxicity in 11 (79%) of 14 patients, compared with zero (0%) of 12 patients in group B. Grade 3 toxicities during capecitabine treatment included diarrhea (six patients), Palmar-Plantar syndrome (three patients), lethargy (two patients), neutropenic sepsis (one patient), and angina (one patient). Only two of the 14 patients who received capecitabine after FU/LV tolerated full-dose chemotherapy without delays, whereas all 12 patients who received FU/LV after capecitabine tolerated full-dose treatment without delays.

Preference Period (weeks 13 to 24)
At the time of trial closure, 20 patients had passed the 12-week choice point. Of those, three patients (all in group A) had already permanently discontinued chemotherapy because of capecitabine toxicity during the switch period. Seventeen patients started preference period treatment, five choosing capecitabine and 12 choosing FU/LV.

All five patients who chose capecitabine were in group B. They had therefore received capecitabine (start period) then FU/LV (preference period) prior to making their choice. Four of these patients (80%) developed grade 3 toxicities despite having tolerated capecitabine well during the start period. This reinforces our observation of increased toxicity with capecitabine after FU/LV in the switch period. Of the 12 patients choosing FU/LV, two patients (17%) developed toxicities of grade 3 (one patient developed leukopenia; the other patient developed shortness of breath).

There was one treatment-related death. After trial closure, crossover from FU/LV to capecitabine was stopped but one group B patient, who had tolerated treatment in both the start and switch periods well but had poor venous access, demanded capecitabine after week 12 to avoid the need for an in-dwelling central venous cannula. One cycle was given at 50% dose and was well tolerated. A second cycle was given at 75% dose. However, the patient developed grade 3 toxicities (diarrhea, lethargy, and anorexia), and then suffered a fatal myocardial infarction.

	DISCUSSION

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We have identified previously unreported excessive toxicity with capecitabine when given immediately after FU/LV. Overall, 19 patients in our study received capecitabine immediately after FU/LV; of these, 15 patients (79%) developed grade 3 toxicity. This observation is of direct importance to patient safety, with significant clinical implications for patient management.

Oral capecitabine is an attractive alternative to intravenous FU/LV. In general, patients prefer oral therapy provided other factors are equal,¹⁹ and health economic comparisons have shown that the higher cost of capecitabine compared with FU/LV can be offset by reduced drug administration costs.²⁰ The X-ACT trial demonstrated with high statistical certainty that capecitabine is at least as effective as the Mayo Clinic FU/LV regimen in the adjuvant setting¹⁵ and, in that trial, capecitabine compared favorably with the Mayo Clinic regimen with regard to toxicity. However, the Mayo Clinic regimen is recognized to be among the most toxic regimens with FU administration.¹⁸

We therefore wished to compare patient preference for capecitabine with our standard low-toxicity FU/LV schedule.¹¹ We chose a randomized cross-over trial design using patient preference as the primary end point. This design allows patients to take into account factors such as convenience and location of treatment, its perceived benefits, and its effects on daily activities, as well as toxicity. Random allocation also allows a balanced assessment of the order in which treatments are received and any influence this may have on acceptability.

One hazard of this trial design, however, is sequence-specific interaction. An observation that pre-exposure to one drug affects the toxicity of the second drug may invalidate any cross-over comparison, in this case our principal research question of patient preference.

Our results are consistent with the X-ACT trial in showing significant but manageable levels of toxicity when capecitabine is given as first-line treatment. But crucially, we saw a marked and unexpected increase in toxicity when patients were switched from FU/LV to capecitabine. Grade 3 toxicity occurred in 11 of 14 patients receiving capecitabine after FU/LV in the switch period; furthermore, of the five patients who had FU/LV in the switch period and opted to complete their treatment with capecitabine, four developed grade 3 toxicity in the preference period. These patients had already been given capecitabine in the start period without significant toxicity. Finally, after trial closure, one patient who received reduced-dose capecitabine after FU/LV suffered a treatment-related death.

Patient safety dictated early closure of the trial, even though this limited the statistical support for our observations. In view of this previously unreported sequence-specific effect, patient preference for either fluoropyrimidine could not be reliably assessed; however, the finding of a clinically evident increase in toxicity affecting patient safety requires dissemination.

Two previous randomized cross-over design trials have compared capecitabine and FU/LV treatments. Pfeiffer et al,²¹ using a trial design very similar to ours, compared capecitabine with the Nordic regimen (FU 500 mg/m² plus LV 60 mg/m², days 1 and 2 every 2 weeks) in 60 patients. Forty-nine patients completed both treatments; of these, 30 patients (61%) expressed a preference for FU/LV. In patients randomly assigned to FU/LV first, only two patient cases (9%) of grade 3 toxicity were reported, but 11 patient cases (48%) were observed during capecitabine treatment after FU/LV. This compared with the 19% grade 3 toxicity among patients receiving capecitabine first. However, in their report the authors did not indicate that the treatment sequence may have influenced toxicity.

Another cross-over study of patients with metastatic disease compared capecitabine with FU/LV treatment using either the Mayo Clinic FU/LV schedule, the de Gramont regimen given on an inpatient basis (LV 200 mg/m² over 2 hours, FU 400 mg/m² bolus and 600 mg/m² 22-hour infusion, days 1 and 2 every 2 weeks), or a modified de Gramont regimen given on an outpatient basis (LV 175 mg over 2 hours, FU 400 mg/m² bolus and 2,800 mg/m² 46-hour infusion, every 2 weeks). After patients received both treatments, preference was dependent on the FU/LV regimen that had been given, with 50% of patients preferring FU/LV if the outpatient LV5FU2 regimen had been used. The authors did not report any substantial difference in the safety profile subject to treatment sequence.¹⁹

Leucovorin affects the maximum tolerated dose (MTD) of fluoropyrimidines and there is good evidence that patients receiving protracted fluoropyrimidine regimens may be especially sensitive to even low-level folate supplementation. During the clinical development of capecitabine, a phase I study investigating continuous capecitabine with once-weekly LV reached a 40% lower MTD than the same schedule without LV.^22,23 Capecitabine given in a 2-out-of-3-week cycle, when assessed in combination with LV, reached a 33% lower MTD than with capecitabine alone.²⁴ Similarly, a trial of continuous ambulatory infusional FU with once-weekly low-dose oral LV reached MTD at only 100 mg/m² per 24 hours, approximately 67% lower than single-agent FU.²⁵ Based on these findings, one possible explanation for the sequence-specific toxicity of capecitabine after FU/LV observed in our trial is retention of intracellular polyglutamated folates. LV administration produces high levels of circulating folates, including leucovorin itself (5-formyl-tetrahydrofolate) and 5-methyl-tetrahydrofolate. Short-lived plasma folates are actively transported into cells, and chains of up to five glutamate residues are added by the enzyme folylpolyglutamate synthase. Intracellular half-life increases with the length of this polyglutamated chain,³⁰ therefore patients may retain intracellular polyglutamated folates for prolonged periods after LV dosing. Furthermore, methylene-tetrahydrofolate, the active cofactor for FU inhibition of thymidylate synthase, is most active in its pentaglutamate form.^26-29

Dose-intensity and rate of LV may affect the accumulation and retention of polyglutamated folates, but experimental model data are inconsistent,^30-33 and it is not clear to what extent weekly bolus LV increases folate pools in patients. However, preclinical and clinical data support the suggestion that continuous infusion or repeated oral leucovorin administrations are effective in generating higher polyglutamated forms of methylene-tetrahydrofolate.³⁴

Interestingly, recent evidence has emerged that suggests that the tolerability of fluoropyrimidines, including capecitabine, show regional differences, with the highest rates of toxicity observed in the United States.³⁵ This may be because of ethnic variation in gene polymorphisms, but another contributing factor could be differences in dietary folic acid intake. Notably, mandatory fortification of cereal grain with folic acid, as a preventive measure against neural tube birth defects, has been in force in the United States since 1998. The same measure is planned in the United Kingdom and elsewhere.

In conclusion, from a clinical viewpoint, we have identified a significant and potentially life-threatening, sequence-specific toxicity when switching patients from FU/LV to capecitabine. The mechanism is currently undetermined, but one possible reason is persisting intracellular folate repletion following LV dosing. Our experience and current knowledge preclude us from recommending a specific safe washout period or dose reduction for patients switching from FU/LV to capecitabine. However, oncologists wanting to switch patients from FU/LV to capecitabine need to be aware of this risk and should exercise due caution. This caution should also be extended to switching patients from combination regimens containing FU/LV to capecitabine-containing equivalents (eg, from infusional FU/LV with oxaliplatin to capecitabine with oxaliplatin).

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: S. Michael Crawford, Hoffman-La Roche (C) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: Christopher Bradley, Roche Ltd; Matthew T. Seymour, Roche Ltd

	AUTHOR CONTRIBUTIONS

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Conception and design: Jay D. Naik, Ivo M. Hennig, Sarah Brown, Matthew T. Seymour

Provision of study materials or patients: David A. Anthoney, David P. Jackson, Alan M. Melcher, S. Michael Crawford, Christopher Bradley, Matthew T. Seymour

Collection and assembly of data: Ivo M. Hennig, Jay D. Naik, S. Michael Crawford, Christopher Bradley, Matthew T. Seymour

Data analysis and interpretation: Ivo M. Hennig, Jay D. Naik, Sarah Brown, Alex Szubert, Julia M.B. Brown, Matthew T. Seymour

Manuscript writing: Ivo M. Hennig, Jay D. Naik, Sarah Brown, Alex Szubert, Matthew T. Seymour

Final approval of manuscript: Ivo M. Hennig, Jay D. Naik, Sarah Brown, Alex Szubert, David A. Anthoney, David P. Jackson, Alan M. Melcher, S. Michael Crawford, Christopher Bradley, Julia M.B. Brown, Matthew T. Seymour

	ACKNOWLEDGMENTS

 
We thank the participating patients, and acknowledge the valuable contributions of Jo Dent, Jonathon Joffe, David Sebag-Montefiore, Fiona Halstead, and Gwen Wagner-Adair.

	NOTES

 
Supported by Cancer Research (United Kingdom), and the National Health Service Trusts of each participating institution which include the St James's Institute of Oncology, St James's University Hospital, Leeds; Bradford Royal Infirmary, Bradford; Airedale General Hospital, Keighley; Harrogate District Hospital, Harrogate; York District Hospital, York; Huddersfield Royal Infirmary, Huddersfield; and the University of Leeds Clinical Trials Research Unit, Leeds, United Kingdom. Additional support by an unrestricted educational grant from Roche Pharmaceuticals.

J.D.N. and I.M.H. contributed equally to the writing of this article.

Presented at the European Society of Medical Oncology Conference, July 5-8, 2007, Lugano, Switzerland.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical Trials repository link available on www.JCO.org.

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Submitted December 28, 2007; accepted April 1, 2008.

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