Oral agents such as busulfan
(Busulfex, Myleran) and hydroxyurea (Hydrea) have been available for clinical use for the last 3 decades.
Several newer agents such as capecitabine (Xeloda), eniluracil, and UFT (Orzel)
are currently being used or investigated all over the world, and the clinical
uses of these agents are likely to expand over the next few decades. This
article discusses the various issues that need to be considered in selecting
patients for administration of these agents.
The development of oral agents for clinical use presents several
challenges. Absorption of oral agents is a complex process and can involve
passive diffusion or active transport in the gastrointestinal tract. In patients
with several types of cancer, patients often develop an underlying
gastrointestinal motility disorder. These disorders may be related to (1)
surgical procedures such as colon, small bowel, and gastric resections[1-10],
(2) the result of hormonal secretions from tumors, or (3) the complications of
chemotherapy itself, (ie, diarrhea and nausea). In addition, patients with
swallowing problems, compliance problems, geriatric patients, and other special
groups of patients may have difficulty in understanding or following the
instructions for self-administration of these oral regimens.
In a study conducted by Liu et al, the preference of 103
patients with incurable cancer for intravenous vs oral chemotherapy was assessed
via questionnaire. The survey showed that 92 patients (89%) preferred oral
chemotherapy; however, a majority (70%-74%) were not willing to accept a shorter
duration or lesser response with oral therapy. Most patients (71%) wanted active
physician participation in guiding their decision to take oral vs intravenous
therapy and most patients attributed their preference for oral chemotherapy to
convenience and problems with intravenous access. Although this was a small
study, it provided some insight into the patient preference issue and added to
physician awareness of the issues surrounding oral chemotherapy development.
The effect of dose intensity is well documented in several solid
tumors in the adjuvant setting, eg breast, colon, and ovarian cancer.[12,13] It
is especially important in the treatment of Hodgkin’s disease and other
hematologic malignancies. In the seminal study by Bonadonna, women with
breast cancer who missed more than 15% of doses had a worse outcome compared to
women who received full doses of chemotherapy.
Various factors affect compliance of patients with oral
chemotherapy and compliance can have a profound effect on the delivered dose
intensity of an oral agent. These factors include socioeconomic status,
educational level, patient-physician communication, complexity of treatment
regimen, and unrecognized depression in patients.
Why Compliance Varies
In one study of 51 patients with breast cancer, compliance to
treatment with oral cyclophosphamide (Cytoxan) was measured prospectively, with
pill counting and other questionnaire methods. Noncompliance with treatment
was defined as an intake of < 90% or > 110% of the normal dose of
cyclophosphamide.[AU: OK AS EDITED?] Patients in the academic practice setting
achieved higher (67%) overall compliance than did patients in the private
practice setting (20%).
In another study, plasma levels of prednisone and
allopurinol (Zyloprim) were used to monitor the compliance with oral therapy of
patients with multiple myeloma. In this study, the compliance rates were quite
low (16% to 24%) but increased substantially (44%) after appropriate patient
education. The authors found self-reporting to be inaccurate in this trial.
Lee et al tested compliance with oral therapy in patients with
lymphoma, ovarian cancer, and lung cancer in three different trials.[17-19] In
these trials, in addition to self reporting, an "intelligent" bottle
electronically monitored patient compliance. The authors found compliance to be
in excess of 90% with good concordance of self reporting and electronic
monitoring. It was not clear, however, if the patients who participated in the
study were aware of the alternative monitoring method.
In a large, recent randomized phase II trial of capecitabine in
colon cancer patients, no major compliance problems were reported although
this subject was not explicitly addressed.
In summary, patient compliance is a complicated issue and can
depend on the population studied, methods utilized to study compliance, and
It is always relevant to obtain a detailed medication history
for the patient prior to prescribing oral chemotherapy. This is important for
retaining the bioavailability of oral medications. For instance, in the
capecitabine trial, patients were instructed to take capecitabine with water at
12 hour intervals within 30 minutes after ingestion of food. In addition,
patients were instructed to avoid simultaneous intake of antacids. Patient
education, thus, becomes vitally important. In spite of precautions, severe drug
interactions are possible.
In a Japanese trial of tegafur, 18 deaths were attributed to
simultaneous intake of the antiviral drug, sorivudine. A metabolite of
sorivudine was thought to have inhibited dihydropyrimidine dehydrogenase, the
enzyme required for metabolism of the fluoropyrimidines.
Although oral chemotherapy has been widely perceived to be
patient friendly, several issues need careful consideration before these
medications can be prescribed. The most important assessment that needs to be
made concerns patient reliability. Generally speaking, these medications should
be avoided in patients who are not likely to be able to reliably take most doses
of the oral drugs prescribed for them. Such patient populations include those
with significant oropharyngeal disability, significant gastrointestinal
problems, eg fistulae, bowel obstruction etc, and geriatric patients with
dementia, depression, etc. Efforts should also be made to avoid prescribing oral
drugs to patients who have demonstrated unreliable behavior or lack of
motivation in the past, including missing doctor visits for unexplained reasons.
Patients who have a known history of self modulating doses of other medications
in the past may also be poor candidates for oral chemotherapy.
In addition, the prescribing oncologist must ensure that
compliance is monitored by various techniques, such as interviews, pill
counting, telephone follow-ups, etc. The use of novel methods like intelligent
bottles for assessing compliance requires further validation in clinical trials.
The Education Factor
One other major factor for assuring safe and effective oral
chemotherapy is patient education. Oncology staff in the outpatient setting need
to make use of all possible opportunities to educate patients about chemotherapy
intake at home. In addition, they must be available to answer questions and
encourage patients to call before self modulating doses of therapy and taking
The era of oral chemotherapy has arrived. Several newer drugs
are likely to be approved for use soon. In addition to the opportunity for
patient friendly and effective therapy, these drugs also generate novel
challenges for the practicing oncologist. Further clinical experience at
clinical trials will help define the optimal patients for treatment with oral
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