Compliance with cancer therapy by patients and physicians

SPECIAL ARTICLE

Compliance with Cancer Therapy by Patients and Physicians

CAROL LEWIS, Sc.D., M.P.H. MARTHA S. LINET, M.D., M.P.H. MARTIN D. ABELOFF, M.D.

E3alfimore, Maryland

From the Departments of Health Services Ad- ministration and Epidemiology, The Johns Hopkins University School of Hygiene and Public Health and The Johns Hopkins Oncology Center, Balti- more, Maryland. Requests for reprints should be addressed to Dr. Carol Lewis, Department of Health Services Administration, Division of Health Education, The Johns Hopkins University School of Hygiene and Public Health, 615 North Wolfe Street, Baltimore, Maryland 21205. Manuscript accepted November 10, 1982.

Although compliance with treatment regimens has been shown to be a significant problem in many areas of medicine, there are little data quantitativeiy describing the extent of the compliance probiem for cancer patients. Traditianaiiy, compliance has been understood as the degree to which a patient’s behavior coincides with the prescribed medical regimen. However, patient behavior may be only one of several factors that determine comoiiance; other important components may include physician behavior, the patient-physician relationship, and the patient’s support system, including family. in this report, we review the literature on cancer compliance in terms of the patient, the physkian, and patient-physician relationships. Subgroups of patients are identified as appropriate for compliance research, and methodoiogic considerations and research strategies are explored.

Compliance with treatment regimens is a significant problem in many areas of medicine [ 11. However, there is little quantitative information regarding the magnitude of the compliance problem for cancer patients undergoing active therapy. Health-related behavior, on the part of both patient and physician, may play a greater role in the outcome of the course of cancer treatment than has been recognized. Over the past 25 years, increasingly effective therapies for tumor have been developed, and higher proportions of patients with hematologic malig- nancies and solid tumors are cured or experience longer remissions. Yet, in spite of the increasingly effective therapies, there remain a substantial number of patients who fail to show improvement. Biologic explanations (i.e., metastatic potential and resistance of tumor to systemic antitumor therapy) are known to account for the majority of these failures. However, behavioral scientists are also beginning to seek explanations for therapeutic failure of potentially curative regimens that may be related more to variance in behavior of patients and physicians than to treatment efficacy.

In other areas, such as hypertension, failure of treatment has frequently been shown to be related to lack of compliance with the medical regimen by the patients, or to inappropriate choice of drug and dosage by physician. The failure of some cancer therapies could be due to similar behavior, which, if more clearly identified, might be altered and a more favorable outcome achieved. We recognize that there are many other alternative explanations when treatment fails, such as ineffectiveness of antineoplastic agents, differential responses in populations of a given tumor, metabolic characteristics of a given host, and genetic factors. However, this report is concerned with behavioral aspects of cancer treatment, or what may be termed compliance of patients and their physicians.

April 1983 The American Journal of Medicine Volume 74 673

COMPLIANCE WITH CANCER THERAPY-LEWIS ET AL

IS THERE A COMPLIANCE PROBLEM IN CANCER CASES?

Cancer therapists in university centers, community hospitals, and private practice have not generally recognized compliance per se to be a major problem. It is commonly assumed that patients who seek consultation from cancer specialists are highly motivated both because of fear of this group of diseases and specific, often severe, symptomatology that requires immediate help from the physician. In addition, many of the treatments prescribed by cancer specialists involve direct administration by medical personnel throughout the course of therapy (such as parenteral medications and/or radiation therapy), so compliance may not ap- pear to be a problem.

However, there is evidence that in a significant number of cases, cancer patients terminate therapeutic regimens because of non-life-threatening side effects [ 21. These side effects include direct physical toxicities of therapy (most commonly, nausea and vomiting), psychologic distress, disruption of life-style, and com- binations of these factors. Compliance with parenteral regimens or radiotherapy, as well as adherence to oral cytotoxic and hormonal regimens, may also be affected by such adverse influences. Toxicities of antitumor therapy may also influence compliance with regimens of antibiotics, analgesics, antiemetics, and other drugs (e.g., allopurinol) which are necessary for treating complications of both the cancer and the therapy.

In addition, termination of treatment and dose ad- justment often cannot be explained solely on the basis of direct toxicities of chemotherapy. The role physicians play in these modifications of treatment regimens has not been given systematic attention. It now seems ap propriate to attempt to quantitate the degree of termination, or significant alteration, of treatment regimens by both patients and physicians, particularly in areas where cure or significant prolongation of life can be achieved if protocols are carefully followed.

Traditionally, compliance has been understood as the degree to which a patient’s behavior coincides with the prescribed medical regimen [ 31. However, research increasingly suggests that patient behavior alone may not entirely define the compliance issue. For instance, a patient may follow the prescribed regimen completely, yet an optimal outcome may not be achieved, if the physician has not been prescribing a maximally effective regimen. We are suggesting that a concept of compliance that is taken to mean only the dutiful following of orders by the patient may be inadequate to describe the complex interactions that occur among the physician, the patient, and the patient’s support system, including family. For instance, in the hypertension lit-

erature, it has been well demonstrated that satisfaction with physician, complexity of regimen, accessibility to the health care system, perception of seriousness of illness, belief in efficacy of treatment, time spent with the health care provider, home visits by the health care provider, content of health education interventions, and social support all affect compliance behavior [4-71.

COMPLIANCE WITH CANCER REGIMENS: THE PATIENT

We have found few studies in the cancer literature that directly examine patients’ compliance with medication regimens. In one, Smith et al [8] evaluated prednisone compliance in children with acute leukemia and lym- phorna. The purpose of this study was to determine the reliability of an increase in the hemoglobin level, weight gain (both associated with use of prednisone), and random urinary 17ketogenic steroid determinations as a means of assessing prednisone compliance. Pred- nisone was studied because it is an oral drug that is a commonly used and effective antileukemic agent; however, many patients, particularly adolescents, complained about this drug because of its bitter taste and undesirable side effects, and it was suspected that optimal doses were not being taken, particularly by children in remission.

The 52 study subjects were heterogeneous in age (ranging from eight months to 17 years), subtype of leukemia (43 had acute lymphocytic leukemia, five had acute myelocytic leukemia, and four had non-Hodgkin’s lymphoma), remission status, and place of treatment (inpatient versus outpatient).

Both hemoglobin levels and weight changes were shown to be poor parameters for assessing compliance, probably because many of the children were also si- multaneously being treated with chemotherapeutic agents that had such side effects as anorexia, gastrointestinal toxicity, and bone marrow hypoplasia. Some or all of these side effects may have occurred often enough to block the usual increase in hemoglobin level and weight gain.

The random urine 17-ketogenic steroid assay, however, was found to be a fast, simple, and reliable method for evaluating compliance, and clearly differ- entiated those patients who were taking prednisone from those who were not. About one third of the entire group who were receiving prednisone therapy were found to be noncompliant. When patie/nts for whom prednisone was prescribed were separately analyzed by age, the investigators found a 59 percent noncompliance rate among the adolescents. The investigators concluded that these high levels of noncompliance might seriously affect survival; these data might also partly explain the recognized poorer prognosis of ad-

674 April 1983 The American Journal of Medlcine Volume 74


olescents with acute leukemia compared with that Of younger children.

Another way of measuring drug compliance is by the reports of attending hospital staff in medical charts during episodes of acute illness. In a study examining efficacy of oral, nonabsorbable antibiotics in treating infection in patients with acute leukemia, Hahn et al [9] studied 70 hospitalized patients (primarily adult) on an oral antibiotic regimen as well as on an intensive program of infection prevention. The ingestion of the antibiotics had several negative side effects: bad after- taste, frequent nausea, diarrhea, and occasional vomiting. The incidence of infection in compliant patients was compared with the incidence in patients who only partially complied with the oral antibiotic regimen. Sixty-nine percent of the patients discontinued ingestion at some point because of the side effects. In these patients, the incidence of infection and the infectious death rate were higher than in those who remained on the antibiotic regimen throughout the course of treatment. Even in this highly supervised setting, in which staff support was available, many patients traded off the medical benefits of total compliance for the reduction in the discomfort created by the drugs.

Barofsky and Sugarbaker [IO] found that 15 to 38 percent of a referred sample of medically eligible patients with soft-tissue sarcoma and osteosarcoma re- fused to participate or withdrew from clinical protocols. The purpose of the study was to determine the extent and nature of nonparticipation by patients with soft- tissue sarcoma and osteosarcoma in protocols of the National Cancer Institute. Different protocols involved randomization to amputation versus limb-sparing surgery, amputation and randomization to different drug regimens, and randomization to limited surgery plus radiation and different drug regimens.

Participants and nonparticipants underwent a standardized interview to identify causes for failure to choose to be randomly selected to participate in, or for withdrawal from, protocol treatments. For patients with soft-tissue sarcoma, nearly all nonparticipation (90 percent) occurred at the point of randomization. Re- sponses showed no socioeconomic differences between participants and nonparticipants, nor were differences found in degree of personal or family problems, work status, or social activities.

Rates of participation, particularly willingness to be randomly selected, varied with severity of the possible consequences of randomization, i.e., the chance of being randomly selected to participate in an amputation protocol or an intensive inpatient chemotherapy regimen with significant side effects. The investigators concluded that the severity of treatment influenced patients’ willingness to participate, and that patient

nonparticipation (both unwillingness to be randomly selected and withdrawal from treatment protocols) was dependent on treatment-related factors, rather than social or psychologic factors.

COMPLIANCE WITH CANCER REGIMENS: PATIENT AND PHYSICIAN

There are other studies in the literature that, although not designed to assess compliance, do comment on compliance with treatment regimens for cancer patients. Bonadonna and Valagussa [ 1 l] have reported results from their retrospective analysis of adjuvant therapy for breast cancer, which showed that only 17 percent of their patients received 85 percent or more of the prescribed dose of cyclophosphamide, methotrexate, and 5fluorouracil. Fifty percent of patients received 65 to 84 percent of the full dose, and 33 percent of the women received less than 65 percent of full-dose cyclophosphamide/methotrexate/5-fluorouracil. The reasons for dose reduction included toxicity of cyclophosphamkfe/methotrexate/5-fluorouracii (32 percent), patient refusals (8 percent), and age of patient ( 10 percent).

A review of the National Surgical Adjuvant Breast Project’s adjuvant protocols for patients with breast cancer revealed that about a third of the patients did not complete the two years of therapy on each protocol [ 121. Most of the patients who failed to complete their therapy did so because of treatment failure or toxicity; gastrointestinal toxicity was the major reason for patients being withdrawn from participation in protocol due to toxicity. The authors of the National Surgical Adjuvant Breast Project report commented on the variability of incidence of gastrointestinal toxicity from institution to institution, suggesting substantial differences in the recognition of and/or emphasis given to patients’ complaints.

A further study at the Johns Hopkins Oncology Center and its community cancer network has analyzed adherence to the planned treatment in a comparison of standard- and low-dose cyclophosphamide/methotrexate/5-fluorouracil as adjuvant therapy for breast cancer [ 13,141. Thirty-three percent of patients withdrew before completion of the two years of therapy for reasons other than relapse. It is interesting to note that termination of treatment did not occur more frequently in the group who received higher doses of cyclophosphamide/methotrexate/5-fluorouracil. Dose adjust- ments were made for the majority of patients. Although termination of treatment was due in large part to patient complaints of nausea and vomiting, other reasons for cessation of therapy included a variety of physical and psychosocial side effects and physician judgments,



which were often only vaguely described in the protocol flow sheets.

The frequent modifications of adjuvant therapy regimens for patients with breast cancer that have been made during the last decade are of considerable con- cern, since there are data, albeit controversial, that dose reductions of cyclophosphamide/methotrexate/5fIu- orouracil to reduce toxicity and improve patient ac- ceptance may compromise the cure rate [ 111. Non- compliance with potentially curative treatment regimens has also been commented upon by Laszlo and Lucas in a recent editorial in The New England Journal of Medicine [ 151. These investigators noted that ap- proximately half of their patients with disseminated testicular cancer missed appointments or delayed the prescribed course of therapy with cisplatin, vinblastine, and bleomycin because of severe nausea and vomiting.

COMPLIANCE WITH CANCER REGIMENS: THE PHYSICIAN

Herbert [ 161 carried out a study of physician behavior related to radiation schedules for treating local disease in cancer patients. He used clinical data from 46 patients with carcinoma of the oropharynx and from 458 patients with Hodgkin’s disease, all of whom were treated with radiation. The investigator found that a variety of circumstances-medical, social, and tech- nical-can cause radiation schedules actually com- pleted to differ from those originally prescribed. In an attempt to estimate the change in therapeutic effect that might be expected from small deviations, the clinical significance of nonadherence to a regimen originally developed by the radiation oncologist was assessed in terms of deviation from the initial regimen and the expected degree of local control of disease. Deviations as small as f5 percent in dose and time resulted in some clinical failures, depending upon the type of disease, prognostic factors, and level of control initially achieved by the prescribed regimen.

PATIENT-PHYSICIAN RELATIONSHIPS

Barriers to improved cancer cure rates thus include not only the current limits of scientific knowledge and the patient’s biologic responses to the regimen, but also the physician’s and the patient’s behavioral responses to the regimen. We believe that there is another important area to which little attention has been given-the kind and quality of agreement, or commitment, to the course of treatment made between physician and patient. Some recent reports have focused on such concepts as patient-physician negotiation, bargaining, and the development of a therapeutic alliance between physician and patient [ 17,181. There is also evidence that positive physician-patient relationships can increase patients’ compliance [ 19-221, although no such studies

of cancer patients have been found. One study has examined the right of patients with breast cancer to share in decision-making about medical care and the influence of the physician-patient behavior [23]. The relationship between active participation by the cancer patient in medical/surgical decision-making and sub- sequent compliance deserves critical evaluation, as does the effect on compliance of the physician’s commitment to the therapeutic regimen and willingness to support a patient both emotionally and physically during a period of adverse reactions.

CURRENT LIMITATIONS TO SUCCESSFUL OUTCOMES INVOLVE BEHAVIORAL VARIABLES

While current limitations with respect to biologic and pharmacologic variables do affect cancer treatment outcomes, we recognize that patient characteristics and behavior can also result in less than optimal outcomes. Subgroups of patients that deserve study include:

1. Patients who choose not to participate in treatment regimens; we know little about persons who ref- use treatment for whom there is evidence of cure or long-term remission.

2. Persons who receive treatment but either comply erratically with the regimen, or withdraw from participation.

3. Patients who enter treatment protocols and comply, but whose physicians do not encourage or support strict adherence to the planned treatment regimen.

4. A combination of situations described in 1, 2, and 3.

Important factors related to poor outcomes for these subgroups have not been clearly identified. Along with efforts devoted to clinical and pharmacologic research, such as in vitro assays for determining the sensitivity of the patient’s tumor to specific drugs and the mea- surement of plasma levels of cytotoxic drugs, methodologies to assess the nature and extent of behavioral problems in cancer treatment need to be developed and refined.

Characteristics of participants and nonparticipants in trials and treatment regimens require study by clinical oncologists, epidemiologists, and behavioral scientists. Since patients who withdraw from participation in clinical trials are likely to differ significantly from participants in clinical trials, the methodologic problems of following patients who withdraw need to be con- fronted. Patients who do participate in controlled trials need to be studied along epidemiologic, pharmacologic, social/psychologic, and behavioral lines. There has been a proliferation of behavioral science research involving other chronic diseases for which effective drug treatments have been developed, (e.g., hypertension, asthma); health-related behavior of both patients and providers has been shown to affect outcomes of clinical

076 April 1963 The American Journal of Medlclne Volume 74


trials. While chemotherapy treatment for cancer is not trials designed to assess the efficacy of antiemetic

entirely analogous to lifetime medication treatment for medications.

hypertension, for example, both are, in a sense, chronic diseases requiring prolonged periods of treatment and involving repeat& behavioral choices. It is possible that behavioral determinants of treatment outcomes for cancer may be similar to those of diseases that have been better studied.

FURTHER METHODOLOGIC CONSIDERATIONS

The direct and indirect measures of patient compliance mentioned here (all somewhat imprecise) have mainly been used in behavioral research involving other diseases; with rare exception, they have not yet been applied to cancer. In the limited number of behavioral research studies carried out in populations of cancer patients, interpretation of data has often been con- founded by absence of control groups or use of inadequate control groups, inadequate follow-up of participants, use of highly selected patient groups (as opposed to studies of patients with cancer who are from defined populations), deficiencies in record-keeping, and lack of information about those family and social support factors that are known to affect medical outcomes. Physician behavior, largely unexamined, needs to be analyzed in relation to training, knowledge of cancer literature, prescribing patterns, profiles of each physician’s patient populations, and the influence on practice of institutional structures and policies. Of particular relevance would be the study of any changes the physician makes in the original treatment plan protocol and what determines these changes, including the effect of patient complaints on the physician’s decision to change treatment.

METHODOLOGIES TO ASSESS COMPLIANCE

Measures of patient behavior in terms of compliance have been developed for the study of a number of diseases other than cancer. Although a frequent focus has been on medication-taking, there are other aspects of treatment regimens and compliance behavior to be considered, such as appointment-keeping, diet, reha- bilitation activities, and self-care of surgical wounds.

Compliance can sometimes be measured directly, by blood or urine levels of specific medications or metabolites. Another direct measure that has received attention is compliance in keeping scheduled clinic appointments. Appointment-keeping behavior has been studied in relation to both screening or preventive health services and to visits for treatment. It has also been analyzed in terms of patient characteristics; low socioeconomic status and educational levels, male sex, and younger age are known to be related to earlier withdrawal from treatment protocols and lower appointment-keeping rates for diseases other than cancer

[241. Because the application of direct methodologies to

assess compliance is often difficult or impossible, indirect measures have also been used, including pill counts and patient reports [25,26]. The validity of the latter has received increasing attention in the compliance literature. Early research that compared patient self-reports with pill counts and urine tests, for the purpose of assessing compliance, suggested that patients over-reported compliant behavior and under- reported noncompliant behavior [27].

However, recent work related to hypertension indi- cates fairly high correlation between patient reports of medication taken and the indirect measure of blood pressure control [28]; in addition, there appears to be consistency between patient reports about appointment-keeping behavior and confirmatory evidence from medical records [29]. A practical and inexpensive method of assessing cancer patients’ compliance may be to use self-reports, which can also be compared with some indirect measure, such as pill counts.

The cooperation of the patient as informant has probably been underutilized. There is evidence that, if given guidance and support, patients can be taught to keep accurate daily records and diaries. This is, in fact, currently being done with cancer patients in clinical

We realize that these are sensitive and difficult areas of investigation, and that most clinicians have limited time for research. However, we also believe that an important part of the education of the cancer clinician should stress the value of participation in such research, and the necessity of keeping comprehensive and de- tailed records.

The availability of adequate data with respect to compliance behavior of both cancer patients and physicians would make it possible to develop techniques to promote higher rates of compliance. Health education strategies for modifying noncompliant behavior have proven efficacious with other chronic diseases; similar strategies, employed with those subgroups of cancer patients and physicians who have poor compliance rates, can be expected to affect clinical outcomes positively.

We have mentioned some specific methodologic considerations that we believe need to be addressed

in behavioral research with cancer patients. There are also more general methodologic considerations. Be- cause of the large number of observations required to collect data about compliance, collaborative efforts, both nationally and internationally, would shorten the time required to carry out such research. Long follow-up periods are needed in order to determine treatment outcomes, as well as relevant changes in physician and patient behavior: statistically, if large numbers of pa-



tients can be pooled in collaborative studies, follow-up times can be shortened.

In addition, investigators in this area need to agree on standardized terminology and definitions, as well as to develop new terminology to describe adequately the behavioral aspects of treatment. Since investigators who carry out studies in related areas of behavioral research often represent a variety of disciplines (including oncology, psychiatry, health education, and cardiovascular disease), international research and consensus meetings would enable researchers with diverse backgrounds to discuss their work, develop new ideas, and standardize terminology and definitions.

CONCLUSION

We believe that many aspects of compliance behavior in relation to cancer treatment are poorly understood, and have received little scientific attention. We also

1.

2.

3.

4.

5.

6.

7.

6.

9.

10.

11.

12.

13.

believe that the concept of compliance ought to be broadened to include those aspects of physician behavior that may affect treatment outcomes. We have suggested some research strategies that could be used to study the behavioral components of compliance, as well as some limitations of these strategies, and have identified the need for refinement of research meth- odology in this area. Priority needs to be given to ob- taining appropriate data as quickly as possible, to determine whether specific behavior of patients and physicians negatively affects treatment efficacy. If well-designed studies, carried out in a sound methodologic fashion, show this to be the case, efforts to modify such behavior will become an important part of cancer treatment. We realize that not all would agree with our viewpoint, or the emphasis we give it, and we welcome responses of readers from both clinical and research perspectives.

REFERENCES

Haynes RB, Taylor DW, Sackett DL, eds: Compliance in health care. Baltimore: The Johns Hopkins University Press, 1979; i-22.

Meyerwitz BE, Sparks FC. Spears IK: Adjuvant chemotherapy for breast carcinoma. Psychological implications. Cancer 1979; 43: 1613-1616.

Barsky AJ, Gillum R: Diagnosis and management of patient noncompliance. JAMA 1974; 226: 1563-1567.

Podell RN: Physicians’ guide to compliance in hypertension. West Point, Pennsylvania: Merck, Sharp and Dohme, 1975.

Sackett DL, Haynes RB, Gibson ES, et al: Randomized clinical trial of strategies for improving medication compliance in primary hypertension. Lancet 1975; I: 1205- 1207.

Green LW. Levine DM. Deeds S: Clinical trials of health education for hypertensive outpatients. Prev Med 1975; 4: 417-425.

Fass MF: An experimental intervention to increase family support for patient compliance [doctoral dissertation]. Baltimore: The Johns Hopkins University School of Hygiene and Public Health, 1977.

Smith SD, Rosen D, Trueworth RC, Lowman JT: A reliable method for evaluating drug compliance in children with cancer. Cancer 1979; 43: 169-173.

Hahn D, Schimpff SC, Former CL, Smyth AC, Young VM. Wiernick PH: Infection in acute leukemia patients receiving oral nonabsorbable antibiotics. Antimicrob Agents Che- mother 1978; 13: 958-984.

19.

20.

21.

22.

23.

24.

Barofsky I, Sugarbaker PH: Determinants of patients’ nonparticipation in randomized clinical triils for the treatment of sarcomas. Cancer Clin Trials 1979: 2: 237-246.

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

25.

26.

27. Glass A, Wieand HS, Fisher B, et al: Acute toxicity during

chemotherapy for breast cancer. Cancer Treat Rep 1981; 65: 363-376: 28.

Abeloff MD, Mellits ED, Baumgardner R, et al: Prospective trial of standard vs. low dose cvtoxan, methotrexate, 5-FU (CMF) in adjuvant therapy of breast cancer-assessment of therapeutic efficacy and toxicity. Proc Am Assoc Cancer Res and Am Sot Clin Oncol 1981; 22: 440.

14.

15.

16.

17.

18.

29.

Wilcox PM, Fetting JH, Nettesheim KM, Abeloff MD: Antici- patory vomiting in women receiving cyclophosphamide, methotrexate, and 5-FU (CMF) adjuvant chemotherapy for breast carcinoma. Cancer Treat Rep 1982; 66: 1601-4.

Laszlo J, Lucas VS: Emesis as a critical problem in chemotherapy [editorial]. N Engl J Med 1981; 305: 948-949.

Herbert D: The assessment of the clinical significance of noncompliance with prescribed schedules of irradiation. J Radiat Oncol Biol Phvs 1977: 2: 763-772.

Hayes-Bautista D: Modifying the treatment: patient compliance, patient control, and medical care. Sot Sci Med 1976; 10: 233-238.

Barofsky I: Compliance, adherence and the development of the therapeutic alliance: steps in the development of self- care. Sot Sci Med 1978; 12A: 369-376.

Francis V, Korsch BM, Morris MJ: Gap in doctor-patient communication. N Engl J Med 1969; 280: 535-540.

Davis MS: Variations in patient’s compliance with doctors’ orders. J Med Educ 1966; 41: 1037-1048.

Ware JE, Snyder MK: Dimensions of patient attiiudes regarding doctors and medical care services. Med Care 1975; 13: 669-682.

Hulka BS: Patient-clinician interactions and compliance. In Ref 1: Chap 5; 63-77.

Schain WS: Patients’ rights in decision making. Cancer 1980; 46: 1035-1041.

Deeds S: Factors associated with appointment-keeping and compliance of hypertensive patients [doctoral dissertation]. Pittsburgh, Pennsylvania: University of Pittsburgh, 1977.

Gordis L: Conceptual and methodologic problems in measuring patient compliance. In Ref 1: 23-45.

Roth HP, Caron HS, Hsi BP: Estimating a patient’s cooperation with his regimen. Am J Med Sci 1971; 262: 269-273.

Gcrdis L, Markowitz M, Lilienfeld AM: The inaccuracy of using interviews to estimate patient reliability in taking medications at home. Med Care 1969; 7: 49-54.

Green LW, Levine DM, Deeds S: Clinical trials of health education for hypertensive outpatients; design and baseline data. Prev Med 1975; 4: 417-425.

Lewis C: Determinants of referral completion in a statewide hypertension screening program [doctoral dissertation]. Baltimore: The Johns Hopkins University, 1983.

678 April 1983 The American Journal of Medicine Volume 74

Documents

Compliance with cancer therapy by patients and physicians