Patient Selection for Oral Chemotherapy

January 2, 2001

Oral chemotherapy has evolved with several new agents such as capecitabine, UFT, eniluracil, etc. in active clinical trials or already approved for use in the western world. Several distinct issues, apart from the usual criteria

ABSTRACT: Oral chemotherapy has evolved with several new agents such ascapecitabine, UFT, eniluracil, etc. in active clinical trials or alreadyapproved for use in the western world. Several distinct issues, apart from theusual criteria for selecting patients for intravenous chemotherapy, dictatepatient selection for these drugs. This article discusses these issues, whichinclude patient preference, selection, and compliance. [ONCOLOGY 15(Suppl2):33-35, 2001]


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 clinicaluses of these agents are likely to expand over the next few decades. Thisarticle discusses the various issues that need to be considered in selectingpatients for administration of these agents.

Oral Chemotherapy: Challenges

The development of oral agents for clinical use presents severalchallenges. Absorption of oral agents is a complex process and can involvepassive diffusion or active transport in the gastrointestinal tract. In patientswith several types of cancer, patients often develop an underlyinggastrointestinal 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 ofchemotherapy itself, (ie, diarrhea and nausea). In addition, patients withswallowing problems, compliance problems, geriatric patients, and other specialgroups of patients may have difficulty in understanding or following theinstructions for self-administration of these oral regimens.

Patient Preference

In a study conducted by Liu et al[11], the preference of 103patients with incurable cancer for intravenous vs oral chemotherapy was assessedvia questionnaire. The survey showed that 92 patients (89%) preferred oralchemotherapy; however, a majority (70%-74%) were not willing to accept a shorterduration or lesser response with oral therapy. Most patients (71%) wanted activephysician participation in guiding their decision to take oral vs intravenoustherapy and most patients attributed their preference for oral chemotherapy toconvenience and problems with intravenous access. Although this was a smallstudy, it provided some insight into the patient preference issue and added tophysician awareness of the issues surrounding oral chemotherapy development.

Patient Compliance

The effect of dose intensity is well documented in several solidtumors in the adjuvant setting, eg breast, colon, and ovarian cancer.[12,13] Itis especially important in the treatment of Hodgkin’s disease and otherhematologic malignancies.[14] In the seminal study by Bonadonna,[12] women withbreast cancer who missed more than 15% of doses had a worse outcome compared towomen who received full doses of chemotherapy.

Various factors affect compliance of patients with oralchemotherapy and compliance can have a profound effect on the delivered doseintensity of an oral agent. These factors include socioeconomic status,educational level, patient-physician communication, complexity of treatmentregimen, and unrecognized depression in patients.

Why Compliance Varies

In one study of 51 patients with breast cancer, compliance totreatment with oral cyclophosphamide (Cytoxan) was measured prospectively, withpill counting and other questionnaire methods.[15] Noncompliance with treatmentwas defined as an intake of < 90% or > 110% of the normal dose ofcyclophosphamide.[AU: OK AS EDITED?] Patients in the academic practice settingachieved higher (67%) overall compliance than did patients in the privatepractice setting (20%).

In another study[16], plasma levels of prednisone andallopurinol (Zyloprim) were used to monitor the compliance with oral therapy ofpatients with multiple myeloma. In this study, the compliance rates were quitelow (16% to 24%) but increased substantially (44%) after appropriate patienteducation. The authors found self-reporting to be inaccurate in this trial.

Lee et al tested compliance with oral therapy in patients withlymphoma, ovarian cancer, and lung cancer in three different trials.[17-19] Inthese trials, in addition to self reporting, an "intelligent" bottleelectronically monitored patient compliance. The authors found compliance to bein excess of 90% with good concordance of self reporting and electronicmonitoring. It was not clear, however, if the patients who participated in thestudy were aware of the alternative monitoring method.

In a large, recent randomized phase II trial of capecitabine incolon cancer patients,[20] no major compliance problems were reported althoughthis subject was not explicitly addressed.

In summary, patient compliance is a complicated issue and candepend on the population studied, methods utilized to study compliance, andpatient education.

Concomitant Medications

It is always relevant to obtain a detailed medication historyfor the patient prior to prescribing oral chemotherapy. This is important forretaining the bioavailability of oral medications. For instance, in thecapecitabine trial, patients were instructed to take capecitabine with water at12 hour intervals within 30 minutes after ingestion of food. In addition,patients were instructed to avoid simultaneous intake of antacids. Patienteducation, thus, becomes vitally important. In spite of precautions, severe druginteractions are possible.

In a Japanese trial of tegafur, 18 deaths were attributed tosimultaneous intake of the antiviral drug, sorivudine.[21] A metabolite ofsorivudine was thought to have inhibited dihydropyrimidine dehydrogenase, theenzyme required for metabolism of the fluoropyrimidines.

Patient Selection

Although oral chemotherapy has been widely perceived to bepatient friendly, several issues need careful consideration before thesemedications can be prescribed. The most important assessment that needs to bemade concerns patient reliability. Generally speaking, these medications shouldbe avoided in patients who are not likely to be able to reliably take most dosesof the oral drugs prescribed for them. Such patient populations include thosewith significant oropharyngeal disability, significant gastrointestinalproblems, eg fistulae, bowel obstruction etc, and geriatric patients withdementia, depression, etc. Efforts should also be made to avoid prescribing oraldrugs to patients who have demonstrated unreliable behavior or lack ofmotivation in the past, including missing doctor visits for unexplained reasons.Patients who have a known history of self modulating doses of other medicationsin the past may also be poor candidates for oral chemotherapy.

In addition, the prescribing oncologist must ensure thatcompliance is monitored by various techniques, such as interviews, pillcounting, telephone follow-ups, etc. The use of novel methods like intelligentbottles for assessing compliance requires further validation in clinical trials.

The Education Factor

One other major factor for assuring safe and effective oralchemotherapy is patient education. Oncology staff in the outpatient setting needto make use of all possible opportunities to educate patients about chemotherapyintake at home. In addition, they must be available to answer questions andencourage patients to call before self modulating doses of therapy and takingconcomitant medications.

The era of oral chemotherapy has arrived. Several newer drugsare likely to be approved for use soon. In addition to the opportunity forpatient friendly and effective therapy, these drugs also generate novelchallenges for the practicing oncologist. Further clinical experience atclinical trials will help define the optimal patients for treatment with oralchemotherapy.


1. Bradley EL III, Isaacs J, Hersh T, et al: Nutritionalconsequences of total gastrectomy. Ann Surg 182:415-429, 1975.

2. Bruno MJ, Haverkort EB, Tytgat GN, et al: Maldigestionassociated with exocrine pancreatic insufficiency: Implications ofgastrointestinal physiology and properties of enzyme preparations for acause-related and patient-tailored treatment. Am J Gastroenterol 90:1383-1393,1995.

3. Burrington JD, Hamilton JR: Steatorrhea after massive bowelresection: Effects of surgical reduction of gastric acid secretion. Surg Forum20:341-343, 1969.

4. Catchpole BN: Motor pattern of the left colon before andafter surgery for rectal cancer: Possible implications in other disorders. Gut29:624-630, 1988.

5. Irie M, Kajiyama Y, Enjoji A, et al: Changes in colonicmotility in dogs after a resection of the inferior mesenteric ganglion andplexus. Surg Today 28:626-632, 1998.

6. Kvietys PR: Intestinal physiology relevant to short-bowelsyndrome. Eur J Pediatr Surg 9:196-199, 1999.

7. Muller MW, Friess H, Beger HG, et al: Gastric emptyingfollowing pylorus-preserving Whipple and duodenum-preserving pancreatic headresection in patients with chronic pancreatitis. Am J Surg 173:257-263, 1997.

8. Neal DE, Williams NS, Barker MC, et al: The effect ofresection of the distal ileum on gastric emptying, small bowel transit, andabsorption after proctocolectomy. Br J Surg 71:666-670, 1984.

9. Schmidt T, Pfeiffer A, Hackelsberger N, et al: Effect ofintestinal resection on human small bowel motility. Gut 38:859-863, 1996.

10. Scolapio JS, Camilleri M, Fleming CR: Gastrointestinalmotility considerations in patients with short-bowel syndrome. Dig Dis15:253-262, 1997.

11. Liu G, Franssen E, Fitch MI, et al: Patient preferences fororal vs intravenous palliative chemotherapy. J Clin Oncol 15:110-115, 1996.

12. Bonadonna G, Valagussa P: Dose-response effect of adjuvantchemotherapy in breast cancer. N Engl J Med 304:10-15, 1981.

13. Levin L, Hryniuk WM: Dose intensity analysis of chemotherapyregimens in ovarian carcinoma. J Clin Oncol 5:756-767, 1987.

14. van Rijswijk RE, Haanen C, Dekker AW, et al: Dose intensityof MOPP chemotherapy and survival in Hodgkin’s disease [see comments]. J ClinOncol 7:1776-1782, 1989.

15. Lebovits AH, Strain JJ, Schleifer SJ, et al: Patientnoncompliance with self-administered chemotherapy. Cancer 65:17-22, 1990.

16. Levine AM, Richardson JL, Marks G, et al: Compliance withoral drug therapy in patients with hematologic malignancy. J Clin Oncol5:1469-1476, 1987.

17. Lee CR, Nicholson PW, Souhami RL, et al: Patient compliancewith oral chemotherapy as assessed by a novel electronic technique. J Clin Oncol10:1007-1013, 1992.

18. Lee CR, Nicholson PW, Souhami RL, et al: Patient compliancewith prolonged low-dose oral etoposide for small-cell lung cancer. Br J Cancer67:630-634, 1993.

19. Lee CR, Nicholson PW, Ledermann JA, et al: Patientcompliance with prolonged oral altretamine treatment in relapsed ovarian cancer.Eur J Gynaecol Oncol 17:99-103, 1996.

20. Van Custem E, Findlay M, Osterwalder B, et al: Capecitabine,an oral fluoropyrimidine carbamate with substantial activity in advancedcolorectal cancer: Results of a randomized trial. J Clin Oncol 18:1337-1345,2000.

21. Okuda H, Ogura K, Kato A, et al: A possible mechanism of 18patient deaths caused by interactions of sorivudine, a new antiviral drug, withoral 5-fluorouracil prodrugs. J Pharmacol Exp Ther 287:791-799, 1998.