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`Answering Patients’ Needs: Oral Alternatives
`to Intravenous Therapy
`
`MARKUS BORNER,a WERNER SCHEITHAUER,b CHRIS TWELVES,c
`JEAN MAROUN,d HANSJOCHEN WILKEe
`
`aUniversity of Bern, Bern, Switzerland; bVienna University Medical School, Vienna, Austria;
`cCancer Research Campaign Department of Medical Oncology, University of Glasgow, and Beatson
`Oncology Centre, Glasgow, UK; dOttawa Regional Cancer Centre, Ottawa, Canada; eDepartment of Internal
`Medicine and Oncology/Hematology, Kliniken Essen-Mitte, Essen, Germany
`
`Key Words. Capecitabine · 5-FU · Colorectal cancer · Fluoropyrimidines · UFT · Oral
`
`ABSTRACT
`
`Metastatic colorectal cancer has traditionally been
`treated with i.v. 5-fluorouracil (5-FU), with or without
`leucovorin (LV). 5-FU is administered as either an i.v.
`bolus or a protracted infusion. Although schedules
`using the latter method offer efficacy benefits (objective
`response rate, time to disease progression), protracted
`infusion schedules are often associated with medical
`complications, inconvenience, high costs, and poor qual-
`ity of life. Issues such as quality of life and convenience
`have influenced treatment decisions, but the availability
`of oral fluoropyrimidines represents a new development
`in this domain.
`Studies have confirmed that the majority of
`patients prefer oral to i.v. chemotherapy. Question-
`naire-based studies have also demonstrated a prefer-
`ence for home-based rather than hospital-/clinic-
`based therapy. This preference was one of the driving
`forces behind the development of the oral fluoro-
`pyrimidines capecitabine (Xeloda®) and uracil plus
`
`tegafur (UFT). Oral agents offer patients a more con-
`venient treatment option that can be administered at
`home, providing patients with a greater sense of control
`over their therapy, while avoiding the medical compli-
`cations and psychological distress associated with
`venous access.
`This article highlights some of the problems associ-
`ated with i.v. therapy and reviews the available data on
`patient preference, including results of a recent, ran-
`domized, phase II study. It also provides a critical eval-
`uation of the efficacy and safety profiles of the only two
`oral fluoropyrimidines approved for prescription,
`capecitabine and UFT/LV (UFT/LV not available in
`Germany and the U.S.), compared with those of two
`infused, 5-FU-based regimens. Finally, the results of an
`interactive debate exploring the opinions of approxi-
`mately 400 oncologists on the issues of oral versus i.v.
`therapy are presented. The Oncologist 2001;6(suppl
`4):12-16
`
`INTRODUCTION
`Cancer therapy has traditionally been evaluated using
`clinical outcomes such as objective response, time to dis-
`ease progression, control of physical symptoms, and over-
`all survival. However, increasing emphasis is being placed
`on quality of life and broader issues, such as convenience or
`allowing the patient to maintain a normal lifestyle.
`Traditionally, metastatic colorectal cancer has been treated
`with i.v. 5-fluorouracil (5-FU), administered either as a
`bolus or as a continuous or protracted infusion, with or
`without leucovorin (LV). Intravenously administered
`
`chemotherapy is inconvenient for patients, adversely affect-
`ing quality of life, and can be associated with significant
`toxicities, psychological distress, financial difficulties, and
`prolonged hospital stays [1].
`Home-based treatment may reduce some of this burden.
`Treatment at home may be associated with improved qual-
`ity of life, decreased analgesic requirements, and less psy-
`chosocial morbidity than hospital-based therapy in patients
`with advanced cancer [1, 2]. The use of ambulatory pumps
`and
`indwelling catheters enables home-based
`i.v.
`chemotherapy, but these administration techniques remain
`
`Correspondence: Markus Borner, M.D., Institute of Medical Oncology, Inselspital, Berne 3010, Switzerland. Telephone: 41-
`31-632-2111; Fax: 41-31-382-1237; e-mail: markus.borner@insel.ch Received July 13, 2001; accepted for publication
`July 19, 2001. ©AlphaMed Press 1083-7159/2001/$5.00/0
`
`The Oncologist 2001;6(suppl 4):12-16 www.TheOncologist.com
`Amerigen Exhibit 1144
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`Borner, Scheithauer, Twelves et al.
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`13
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`inconvenient for patients. Insertion of central venous lines
`can be painful and occasionally leads to pneumothorax or
`hemorrhage. In the long term, they are often associated with
`medical complications such as infection, bleeding, and
`venous thrombosis [3, 4]. Oral chemotherapeutic agents,
`such as capecitabine, potentially offer a number of advan-
`tages, including greater convenience, fewer hospital/doc-
`tor’s office visits, less pain, and the avoidance of problems
`related to venous access.
`
`PATIENT PREFERENCE FOR ORAL THERAPY
`Another
`important reason for developing oral
`chemotherapeutic agents is that patients tend to prefer oral
`treatment, as it offers a sense of control over treatment and
`interferes less with their daily lives and family or social
`activities. During the past decade, questionnaire-based
`studies have been conducted to assess patient preference for
`oral versus i.v. therapy in patients with cancer. In a
`prospective study, interviewers used a structured question-
`naire to determine the preferred route of administration in
`103 patients with advanced cancer who were likely to
`undergo palliative treatment [5]. The strength of preference
`and potential factors that might influence their choice were
`also evaluated. Finally, patients were asked whether they
`would accept decreased efficacy to keep their chosen route
`of administration.
`In total, 89% of patients preferred oral therapy. Major
`reasons for this preference were convenience (57%), prob-
`lems with i.v. lines or needles (55%), and a better environ-
`ment for administration of chemotherapy (33%). The study
`also revealed that patients were not prepared to sacrifice
`efficacy in preference for oral treatment: 70% of patients
`were not willing to accept a lower response rate and 74%
`were not willing to accept a shorter duration of response.
`A second study in 53 patients with advanced breast or
`ovarian cancers examined whether the site (home versus
`hospital-based) and method of administering chemotherapy
`influenced quality of life in patients receiving palliative
`chemotherapy for advanced cancer [1]. Quality of life was
`assessed by measuring anxiety, depression, self-esteem,
`health locus of control, physical performance, and symp-
`toms using the Hospital Anxiety and Depression scale, the
`Rosenberg self-esteem scale, and the Multidimensional
`Health Locus of Control Scale. Results showed that global
`quality of life, derived using 10 psychological and physical
`variables, was significantly (p = 0.001) reduced in patients
`receiving hospital-administered chemotherapy compared
`with those treated at home.
`More recently, patient preference for oral or i.v. treat-
`ment has been studied directly in a randomized, crossover
`trial comparing an oral fluoropyrimidine regimen (uracil plus
`
`tegafur [UFT] plus LV) versus i.v. bolus 5-FU/LV (Mayo
`Clinic regimen) in patients with advanced colorectal cancer
`[6]. Patients were randomly assigned to one cycle of oral
`therapy followed by one cycle of i.v. therapy, or vice versa.
`A questionnaire was used to assess patient preference and
`reasons for their preference, before receiving any treatment
`and again after completing both cycles of chemotherapy
`(without knowledge of tumor response). Patients then chose
`the treatment they wanted to continue receiving (i.v. or oral).
`Of 31 evaluable patients, 84% preferred to continue
`with oral therapy. The order in which patients were exposed
`to therapy did not influence patient preference. Before ther-
`apy, the characteristics most frequently considered to be
`important were that treatment should not induce vomiting
`(77%), diarrhea (55%), or painful mouth ulcers (52%), and
`that the medication could be administered at home (48%).
`The risk of infection (39%) was also considered important.
`For the 84% of patients who preferred oral therapy, the
`most important treatment features recorded after treatment
`administration were that no i.v. access was required and
`that the drug could be taken at home (Table 1).
`
`COMPARISON OF ORAL VERSUS I.V. THERAPY
`Given the fact that maintenance of treatment efficacy is
`clearly very important to patients when considering the
`benefits of different routes of administration for chemother-
`apy, it is important to look critically at outcome measures
`in trials of new therapeutic approaches. The development of
`new schedules and regimens for the first-line treatment of
`metastatic colorectal cancer and also the introduction of
`new agents led to the initiation of randomized, phase III tri-
`als to evaluate these new treatment options. Many of the tri-
`als used the Mayo Clinic regimen (20 mg/m2 LV followed
`by 425 mg/m2 5-FU, both administered as an i.v. bolus on
`days 1-5 of a 28-day cycle) as the reference arm. The Mayo
`Clinic regimen is frequently used as a comparator because
`it is a well-recognized and commonly used schedule with
`proven efficacy. In addition, it was the comparator arm
`required by the U.S. Food and Drug Administration (FDA)
`in registration trials for new colorectal cancer therapies.
`The widespread use of the Mayo Clinic regimen as a
`reference treatment enables a comparison of several of the
`
`Table 1. Key reasons for preferring oral chemotherapy
`
`n of patients
`26 (%)
`
`“I preferred that it was a pill.”
`“I preferred taking the medicine at home.”
`“I had fewer mouth sores.”
`“The medication interfered less with my daily activities.”
`“I had less diarrhea.”
`
`19 (73)
`18 (69)
`12 (46)
`12 (46)
`8 (31)
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`14
`
`Oral Versus i.v. Chemotherapy
`
`newer fluoropyrimidine regimens. Four large (> 400
`patients), randomized, phase III trials were included in a
`critical evaluation, all of which used the Mayo Clinic regi-
`men as the reference arm. These trials evaluated the effi-
`cacy and tolerability of:
`
`• capecitabine 1,250 mg/m2 twice daily, days 1-14
`every 21 days [7];
`
`• UFT 100 mg/m2 in combination with LV 25-30 mg,
`both administered three times daily, days 1-28 every
`35 days [8];
`
`• 5-FU de Gramont regimen (2-hour infusion of LV
`200 mg/m2, 5-FU 400 mg/m2 bolus, 5-FU 600 mg/m2
`22-hour infusion days 1-2 repeated every 14 days [9];
`
`• 5-FU German AIO regimen (5-FU 2,600 mg/m2, 24-
`hour weekly infusion, weeks 1-6 every 7 weeks, with
`or without LV 500 mg/m2 as a 2-hour infusion [10].
`
`The patient pretreatment characteristics in the four tri-
`als were generally similar. However, a far greater propor-
`tion of patients in the capecitabine study (77%) had more
`than one metastatic site at baseline compared with the other
`studies in which this was recorded (15%-39%). Further-
`more, fewer patients in the capecitabine trial had normal
`performance status (32%) compared with patients in the
`other studies (44%-53%).
`The intervals between tumor assessments also differed
`between the studies. The longer interval between assess-
`ments in the UFT and de Gramont trials may cause time to
`disease progression to be overestimated, potentially magni-
`fying or reducing the differences between the treatment
`arms.
`None of the fluoropyrimidine regimens were signifi-
`cantly different from the Mayo Clinic regimen in terms of
`overall survival. However, clear therapeutic benefits were
`identified when other important endpoints, such as response
`rate, time to disease progression (Table 2), tolerability, con-
`
`Table 2. Time to disease progression for four fluoropyrimidine regimens
`
`venience, and medical resource utilization, were assessed.
`Oral capecitabine achieved a significantly superior response
`rate compared with the Mayo Clinic regimen (26% versus
`17%; p < 0.0002), and time to progression was at least equiv-
`alent. The hazard ratio for disease progression (capecitabine:
`5-FU/LV) was 1.0 (95% confidence interval [CI]: 0.885-
`1.123), showing that the risk of disease progression was
`equivalent in patients treated with capecitabine compared
`with those receiving the Mayo Clinic regimen. In contrast,
`UFT/LV resulted in significantly inferior time to disease pro-
`gression compared with the Mayo Clinic regimen (p = 0.01)
`with a hazard
`ratio
`for disease progression
`(5-
`FU/LV:UFT/LV) of 0.823 (95% CI: 0.708-0.958) using the
`Mayo Clinic regimen as a reference point [8]. Using UFT/LV
`as a reference point, calculation of the inverse of this ratio
`shows that the risk of disease progression when treated with
`UFT/LV is increased by 22%, as shown by the hazard ratio
`of 1.22 (UFT/LV: 5-FU/LV). A trend towards a lower
`response rate (12% versus 15%) was also apparent.
`Both the infused de Gramont and AIO regimens
`offered modest increases in time to disease progression
`(p ≤ 0.02) compared with the Mayo Clinic regimen;
`patients receiving the de Gramont 5-FU regimen also
`achieved a significantly superior response rate (33% versus
`14%, p = 0.004). However, it is important to note that a sub-
`stantial proportion of patients in the de Gramont trial were
`excluded from the efficacy analysis (21% of the intended-
`to-treat population), as they did not have measurable dis-
`ease. Therefore, the differences in time to progression and
`response rate are likely to have been less pronounced in an
`intention-to-treat analysis as was undertaken for the
`capecitabine and UFT/LV trials. The failure to demonstrate
`a significantly superior response with the AIO regimen may
`also have been because of the small number of patients with
`measurable disease.
`All four novel regimens demonstrated safety benefits,
`including significantly lower incidences of neutropenic
`fever/sepsis compared with the Mayo Clinic regimen.
`
`Capecitabine
`
`UFT/LV
`
`de Gramont
`
`EORTC AIO
`
`(+ LV)
`(– LV)
`
`Median TTP
`months
`
`4.6/4.7
`
`3.5/3.8
`
`6.3/5.0
`
`6.4/4.1
`4.4/4.1
`
`Hazard
`ratio
`
`1.00
`
`1.22
`
`?
`
`?
`?
`
`Relation to Mayo
`Clinic regimen
`
`Equivalent
`
`Inferior
`
`Superior
`
`Superior
`Equivalent
`
`p value
`
`0.95
`
`0.01
`
`0.001
`
`0.02
`0.7
`
`TTP = time to progression; EORTC = European Organization for the Research and Treatment of Cancer
`
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`Borner, Scheithauer, Twelves et al.
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`15
`
`40
`
`30
`
`20
`
`10
`
`Patients (%)
`
`0
`Capecitabine
`
`UFT/LV
`
`de
`Gramont
`
`EORTC
`AIO
`
`Mayo
`Clinic
`
`Mayo
`Clinic
`
`Mayo
`Clinic
`
`Mayo
`Clinic
`
`Figure 1. Incidence of grade 3/4 diarrhea: fluoropyrimidines
`versus the Mayo Clinic regimen.
`
`uncommon, complications at the time of insertion include
`arrhythmia, arterial puncture, and pneumothorax. Pain and
`trauma are also frequently experienced by the patient.
`Among the five regimens assessed in the four trials
`described above, the infused regimens required the highest
`number of administration visits. During a 24-week treat-
`ment period, patients receiving either of the infused 5-FU
`regimens would typically require 36 visits. The Mayo
`Clinic regimen required an estimated 30 visits during a 24-
`week period, whereas patients receiving either capecitabine
`or UFT/LV treatment would typically make five to eight
`visits for administration of treatment.
`The oral agents provide a more convenient administra-
`tion schedule than the Mayo Clinic regimen or the infused
`regimens, and home-based therapy is possible, provided
`that patients are educated to recognize side effects and
`interrupt treatment when necessary. Both of the oral regi-
`mens also included a “drug holiday” during which
`chemotherapy is not administered. In the capecitabine regi-
`men, 1 week in every 3 is drug free; 1 week in every 5 is
`drug free with UFT/LV treatment. However, with UFT/LV
`the patient has to swallow approximately twice as many
`pills as with capecitabine therapy. Furthermore, patients are
`required to fast for 6 hours per day, 1 hour before and after
`taking UFT/LV tablets three times a day, which may cause
`considerable disruption to the patient’s daily routine. By
`contrast, capecitabine is taken twice daily and administered
`within 30 minutes of a meal and should have little or no
`impact on a patient’s life style.
`
`PATIENT PREFERENCE: ORAL VERSUS
`I.V. THERAPY
`Taking into consideration the preference for oral ther-
`apy expressed by the majority of patients, the choice of oral
`versus i.v. therapy may seem straightforward. However,
`there are many other factors to be taken into consideration
`
`Capecitabine was associated with significantly (p < 0.05)
`lower incidences of stomatitis (all grades and grades 3/4),
`nausea/vomiting, diarrhea, and alopecia compared with the
`Mayo Clinic regimen. The most common adverse event
`with capecitabine was hand-foot syndrome. Capecitabine
`was associated with a significantly lower incidence of treat-
`ment-related hospitalizations than the Mayo Clinic regimen
`(12% versus 18%; p < 0.005), and only two patients
`required hospitalization for hand-foot syndrome. UFT/LV
`was associated with significantly lower incidences of stom-
`atitis (all grades and grades 3/4), nausea/vomiting, and diar-
`rhea than the Mayo Clinic regimen. However, there was a
`trend towards an increased incidence of grade 3/4 diarrhea
`(Fig. 1), which occurred in more than 20% of patients
`receiving UFT/LV. The incidence of hand-foot syndrome
`with UFT/LV was low. Hand-foot syndrome is a side effect
`typical of prolonged infusion fluoropyrimidine therapy.
`The higher incidence of hand-foot syndrome with
`capecitabine compared with UFT/LV suggests that
`capecitabine may more closely mimic infused 5-FU. As
`previously mentioned, with capecitabine this side effect is
`rarely severe, usually does not interfere with daily activi-
`ties, and usually resolves with treatment interruption with
`or without dose reduction.
`With the de Gramont regimen, there was a significantly
`lower incidence of grade 3/4 diarrhea and stomatitis com-
`pared with the Mayo Clinic regimen. However, taking all
`grades of adverse events into account, there were no signif-
`icant differences in the incidences of diarrhea, stomatitis,
`and nausea/vomiting between the de Gramont regimen and
`the Mayo Clinic regimen. With the other infused regimen,
`the German AIO schedule, grade 3/4 diarrhea was frequent,
`occurring in approximately 20% of patients. Grade 3/4 neu-
`tropenia was again less common than with the Mayo Clinic
`regimen, as described above. Toxicity data for all grades of
`diarrhea, stomatitis, and nausea/vomiting were not
`reported.
`Another important difference between both the four
`novel regimens and the Mayo Clinic regimen is the conve-
`nience of administration. Central venous access complica-
`tions, including those associated with insertion of lines and
`Port-a-Cath® systems (SIMS Deltec, Inc.; St. Paul, MN),
`were not reported for the two trials of infused regimens.
`However, infused regimens are generally associated with
`an increased number of administration visits, complications
`arising from the use of indwelling catheters, and the incon-
`venience of portable pumps. It has been reported that up to
`30% of i.v. lines require elective removal due to infec-
`tions/sepsis, thrombosis, migration or blockage, depending
`on the system used, although the complication rate appears
`lower when using Port-a-Cath systems [11]. Serious, albeit
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`16
`
`Oral Versus i.v. Chemotherapy
`
`when deciding what treatment is most appropriate for each
`patient.
`When delegates attending the meeting were asked
`which single-agent fluoropyrimidine therapy they would
`prescribe as first-line treatment for metastatic colorectal
`cancer, the most frequent response was oral fluoropyrimi-
`dine therapy (42%). Infused 5-FU/LV or i.v. bolus 5-
`FU/LV was chosen by 37% and 15% of the audience,
`respectively. Delegates were then asked which single-agent
`fluoropyrimidine therapy their patients would prefer as
`first-line treatment of metastatic colorectal cancer. In total,
`84% of the audience believed that their patients would pre-
`fer oral treatment, which is the same figure as in the direct
`patient preference study discussed above [6]. Only 8% of
`the audience thought that their patients would prefer
`infused 5-FU/LV, with 4% each choosing i.v. bolus 5-
`FU/LV and other treatments.
`This apparent contradiction between the preference of
`the patient and his or her doctor raises the question of who
`should make the choice between oral and i.v. treatment.
`When this was put to the audience, 77% felt that the physi-
`cian and the patient should decide together between oral
`and i.v. therapy, with only 16% stating that the decision
`should be made primarily by the physician. The principal
`reasons cited as potentially discouraging the physician from
`prescribing oral chemotherapy routinely were concerns
`
`REFERENCES
`
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`2 Vinciguerra V, Degnan TJ, Sciortino A et al. A comparative
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`3 Hansen RM, Ryan L, Anderson T et al. Phase III study of
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`4 Poorter RL, Lauw FN, Bemelman WA et al. Complications
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`6 Borner M, Schöffski P, de Wit R et al. A randomized
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`
`about efficacy (34%) and over-/undercompliance (24%).
`Income issues and control of side effects were also of some
`concern (19% and 14%, respectively).
`
`CONCLUSIONS
`The choice of a fluoropyrimidine regimen in patients
`with advanced colorectal cancer is no longer straightforward.
`None of the newer regimens explored here provide a signifi-
`cant survival benefit, so other factors must be taken into
`account. Patients clearly prefer oral therapy, but only if effi-
`cacy is not compromised. Although both capecitabine and
`UFT/LV have advantages over the Mayo Clinic regimen in
`terms of toxicity, patients treated with UFT/LV have a 22%
`greater risk of disease progression than patients treated with
`5-FU/LV. By contrast, capecitabine achieves superior tumor
`response rates, and at least equivalent time to progression
`and overall survival compared with standard 5-FU/LV ther-
`apy. In general, physicians and patients alike agree that treat-
`ment decisions should be made jointly. The combination of
`patient preference for oral treatment and efficacy offered by
`oral capecitabine makes this an attractive first-line treatment
`option for patients with colorectal cancer.
`
`ACKNOWLEDGMENT
`C.T. is a member of the speaker bureau for Hoffmann-
`La Roche Inc.
`
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`10 Schmoll H, Köhne C, Lorenz M et al. Weekly 24h infusion
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`11 Partridge S, Leslie M, Irvine A. Infusional 5-fluorouracil can
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