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Background. In 1986, the European Organization for Research and Treatment of Cancer (EORTC) initiated a research program to develop an integrated, modular approach for evaluating the quality of life of patients participating in international clinical trials. Purpose: We report here the results of an international field study of the practicality, reliability, and validity of the EORTC QLQ-C30, the current core questionnaire. The QLQ-C30 incorporates nine multi-item scales: five functional scales (physical, role, cognitive, emotional, and social); three symptom scales (fatigue, pain, and nausea and vomiting); and a global health and quality-of-life scale. Several single-item symptom measures are also included. Methods: The questionnaire was administered before treatment and once during treatment to 305 patients with nonresectable lung cancer from centers in 13 countries. Clinical variables assessed included disease stage, weight loss, performance status, and treatment toxicity. Results: The average time required to complete the questionnaire was approximately 11 minutes, and most patients required no assistance. The data supported the hypothesized scale structure of the questionnaire with the exception of role functioning (work and household activities), which was also the only multi-item scale that failed to meet the minimal standards for reliability (Cronbach's alpha coefficient [is greater than or equal to].70) either before or during treatment. Validity was shown by three findings. First, while all interscale correlations were statistically significant, the correlation was moderate, indicating that the scales were assessing distinct components of the quality-of-life construct. Second, most of the functional and symptom measures discriminated clearly between patients differing in clinical status as defined by the Eastern Cooperative Oncology Group performance status scale, weight loss, and treatment toxicity. Third, there were statistically significant changes, in the expected direction, in physical and role functioning, global quality of life, fatigue, and nausea and vomiting, for patients whose performance status had improved or worsened during treatment. The reliability and validity of the questionnaire were highly consistent across the three language-cultural groups studied: patients from English-speaking countries, Northern Europe, and Southern Europe. Conclusions: These results support the EORTC QLQ-C30 as a reliable and valid measure of the quality of life of cancer patients in multicultural clinical research settings. Work is ongoing to examine the performance of the questionnaire among more heterogenous patient samples and in phase II and phase III clinical trials. [J Natl Cancer Inst 85:365-376, 1993]

Background: Previous investigators have found that compliance with quality-of-life data collection on cancer clinical trials is poor. There is general belief that collecting complete quality-of-life data is at present an unachievable goal. Purpose: We assessed the completeness of quality-of-life data collection on trials instituted by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG), since incorporation of quality-of-life outcomes into trials became mandatory for the group. Methods: Data from three NCIC CTG trials in which quality of life was a study end point were examined to determine the extent to which protocol specifications were met with respect to questionnaire completion. Two of the studies examined adjuvant therapies, and one examined anti-emetics. In two trials, the quality-of-life questionnaire of the European Organization for Research and Treatment of Cancer was used; in the other, the Breast Cancer Chemotherapy Questionnaire. Results: Patient compliance with questionnaire completion was unexpectedly high: More than 95% of the scheduled questionnaires were returned, and more than 99% of the questions were answered. Conclusions: We attribute this success to a comprehensive set of measures taken to enhance compliance on these studies. Which of these measures was most contributory requires further investigation, as does the issue of whether similar results can be obtained in other circumstances. Implications: It seems that the commonly held belief that quality-of-life data cannot be successfully collected in multicenter cancer trials is incorrect. [J Natl Cancer Inst 84:1023-1026, 1992]

Development of effective antiemetic therapy depends upon an understanding of both the antiemetic agents and the emetogenic challenges these agents are designed to address. New potential antiemetic agents should be studied in an orderly manner, proceeding from phase I to phase II open-label trials and then to randomized double-blind phase III trials comparing new agents and regimens to best standard therapy. Use of placebos in place of antiemetic therapy against highly or moderately emetogenic chemotherapy is unacceptable. Nausea and vomiting should be evaluated separately and for both the acute and delayed periods. Defining the emetogenicity of new antineoplastic agents is a challenge, since such data are often not reliably recorded during early drug development. A four-level classification system is proposed for emetogenicity of intravenous antineoplastic agents. A separate four-level classification system for emetogenicity of oral antineoplastic agents, which are often given over an extended period of time, is also proposed.

Conventional chemotherapy regimens for the treatment of advanced Kaposi’s sarcoma (KS) show limited efficacy and considerable toxicity. Liposomal anthracyclines with potential utility in KS include pegylated liposomal doxorubicin (Doxil/Caelyx [PLD]), daunorubicin citrate liposome (DaunoXome [DNX]), and nonpegylated liposomal doxorubicin (Myocet [NPLD]). Preclinical data showed that pegylated liposomes accumulate preferentially in highly vascularized KS lesions. In randomized clinical trials, PLD induced higher response rates than did the conventional combination chemotherapy regimens, bleomycin + vincristine (BV) and BV + conventional doxorubicin (ABV); DNX produced a response rate comparable to that of ABV. NPLD has not been compared with conventional chemotherapy for KS. PLD and DNX were associated with less toxicity compared with BV or ABV, including less alopecia and fewer gastrointestinal and neurologic side effects. Grade 3/4 myelosuppression was common with both PLD and DNX; stomatitis and infusion reactions occurred with PLD treatment, but hand-foot syndrome was relatively infrequent in the dose schedules used for KS. Health-related quality of life was improved in several domains in patients treated with PLD or DNX compared with ABV.

One can classify ways to establish the interpretability of quality-of-life measures as anchor based or distribution based. Anchor-based measures require an independent standard or anchor that is itself interpretable and at least moderately correlated with the instrument being explored. One can further classify anchor-based approaches into population-focused and individual-focused measures. Population-focused approaches are analogous to construct validation and rely on multiple anchors that frame an individual's response in terms of the entire population (eg, a group of patients with a score of 40 has a mortality of 20%). Anchors for population-based approaches include status on a single item, diagnosis, symptoms, disease severity, and response to treatment. Individual-focused approaches are analogous to criterion validation. These methods, which rely on a single anchor and establish a minimum important difference in change in score, require 2 steps. The first step establishes the smallest change in score that patients consider, on average, to be important (the minimum important difference). The second step estimates the proportion of patients who have achieved that minimum important difference. Anchors for the individual-focused approach include global ratings of change within patients and global ratings of differences between patients. Distribution-based methods rely on expressing an effect in terms of the underlying distribution of results. Investigators may express effects in terms of betweenperson standard deviation units, within-person standard deviation units, and the standard error of measurement. No single approach to interpretability is perfect. Use of multiple strategies is likely to enhance the interpretability of any particular instrument.

The measurement of health-related quality of life (HRQL) in adults with cancer has proceeded more quickly than has similar measurement in children, so there may be value in applying some methods used in adults to studies in children. An example is a health-transition state instrument called the Subjective Significance Questionnaire (SSQ). The SSQ asks patients to give their own estimates of the degree to which their HRQL has changed with time and, thus, provides a method for interpreting the meaningfulness of changes in scores as derived from a general questionnaire, the EORTC QLQ-C30. The development of similar health-transition instruments for children poses special challenges and requires the development of appropriate methodology. It is suggested that, with the use of cartoons and the answers of proxies, it should be feasible to assess the meaningfulness of changes in HRQL over time in young children as well as in adolescents. Int. J. Cancer Suppl. 12:132–137, 1999. ©1999 Wiley-Liss, Inc.

The use of self-report questionnaires for the assessment of health-related quality of life (HRQOL) is increasingly common in clinical research. This method of data collection may be less suitable for patient groups who suffer from cognitive impairment, however, such as patients with brain cancer. In such cases, one can consider employing the patients' significant others as proxy raters of the patients' health-related quality of life. The authors examined the response agreement between patients with brain cancer and their significant others on a health-related quality of life instrument commonly used in cancer clinical trials, the EORTC QLQ-C30, and on a brain cancer-specific questionnaire module, the QLQ-BCM.

Measuring health-related quality of life in patients with cancer has focused primarily on the development of reliable and valid instruments (questionnaires), and on the effect of chemotherapy in phase III clinical trials. From this research several important lessons have emerged, such as: (i) the need to measure multiple domains; (ii) the importance of self-rating; (iii) the reports of counter-intuitive results; (iv) the ability to quantify the effects of symptoms on health-related quality of life; and (v) the prognostic value of health-related quality of life measurement for survival. Many challenges lie ahead. Among these are the difficulties encountered by medical clinicians in choosing appropriate instruments to measure health-related quality of life, the dilemma of choosing between aggregate scores and domain scores, questions surrounding the significance of results, and whether measurement of health-related quality of life is now at a point where it can be used in routine practice outside of the clinical trials setting. Although further research is required in all of these and other areas, the future for health-related quality-of-life measurement in oncology is promising.

The purpose of this study was to examine the factors which affect the level of fatigue among patients participating in clinical trials in which this symptom had been assessed with the EORTC QLQ-C30. Data were assembled from 2390 patients in ten clinical trials in which the QLQ-C30 had been used to assess baseline and on-study quality of life. The relationship between the level of fatigue reported by the patients on the fatigue scale of this questionnaire and patient and disease characteristics was assessed in univariate and multivariate cross-sectional analyses. In addition, changes in fatigue scores were compared in a longitudinal analysis among patients on two arms of an anti-emetic trial whose emesis control was markedly different. Baseline fatigue levels differed substantially among patients taking part in the different trials. Factors associated with greater fatigue severity on univariate analysis included: female gender, presence of metastatic disease, and poorer performance status. In addition, on multivariate analyses the oldest patients were found to have less fatigue, as were patients with breast cancer, while patients with ovarian and lung cancer experienced greater fatigue. Patients on the arm of the anti-emetic trial in which emesis was better controlled showed significantly less increase in fatigue after receiving chemotherapy. The fatigue scale of the QLQ-C30 appears to provide a useful approach to assessing this important symptom. The relationships found between fatigue and patient and disease characteristics need further exploration as does the degree to which the QLQ-C30 fully captures this dimension of quality of life.

The approach of the National Cancer Institute of Canada Clinical Trials Group to measuring compliance, that is, completion rates, for health‐related quality of life questionnaires is presented. Completion rates can be measured at the institutional, patient, questionnaire and item levels for baseline, on‐treatment and off‐treatment follow‐up study periods. Time windows are defined for each expected completion time. In seven completed clinical trials, completion rates were high with more than 93 per cent of patients completing questionnaires in the specified time windows at baseline and while on‐treatment. The rate while on off‐treatment follow‐up is still acceptable at 85 per cent. The proportions of analysable questionnaires were 97·6 per cent, 82·0 per cent and 77·0 per cent respectively, at the three study periods. Item completion rates within questionnaires were high at 95·5 per cent or more. The variables most likely to influence baseline and on‐treatment questionnaire completion rates were breast cancer, ovarian cancer, metastases and study centre size. © 1998 John Wiley & Sons, Ltd.

Antibodies toP. falciparum antigens and to the EB virus antigens, VCA and EBNA, were determined soon after the end of the major rainy season in 140 Africans living in 3 villages at varying altitudes in northeastern Tanzania. Also, their peripheral blood mononuclear cells were stored in liquid nitrogen and subsequently used for HLA phenotype determination of serologically determined antigens coded by genes at theA andB loci and for cell culture with mitogens (PHA, Con-A PWM) and with allogeneic cells in the mixed leukocyte reaction. A strong correlation was found between the presence of high titres of immunofluorescent antibody to falciparum antigens and the combination of A2 with AW30 in the same individuals. Individuals having one or the other of these specificities, but not both, did not have unusually high titres (P=0.0005). Individuals having the combination A2 and BW17 also tended to have higher than average antibody titres to falciparum antigens, but the difference was not statistically significant (P=0.09). The data suggests that individuals with A2 and AW30 may haveHLA-associated genes having the function ofIr genes and that these genes interact from the trans position to affect the capacity to make antibodies to malarial antigens. Thus, these genes may confer a survival advantage for individuals exposed to malaria. In the cell culture studies there were no correlations between responses and with IFA titres toP. falciparum, except for an inverse association between responses to PWM and level of IFA titre. This suggests that the B cell response to mitogens is impaired in individuals with strong responses to malarial antigens. There was no association between any of the cell culture responses and the HLA phenotypes of the cell donors.

Measurement of quality of life (QOL) in cancer clinical trials has increased in recent years as more groups realize the importance of such endpoints. A key problem has been missing data. Some QOL data may unavoidably be missing, as for example when patients are too ill to complete forms. Other important sources are potentially avoidable and can broadly be divided into three categories: (i) methodological factors; (ii) logistic and administrative factors; (iii) patient-related factors. Logistic and administrative factors, for example, staff oversights, have proven to be most important. Since most QOL measurements require patient self-report, it is usually not possible to rectify the failure to collect baseline data or any follow-up assessments. There is strong evidence that such data are not ‘missing at random’, and cannot be ignored without introducing bias. Although several approaches to the analysis of partly missing data have been described, none is entirely satisfactory. Prevention of avoidable missing data is better than attempted cure. In July 1996, an international conference on missing QOL data in cancer clinical trials reported the experience of most major groups involved. This paper will serve as an introduction to the problem and provide an estimation of its magnitude, and approaches to its prevention and solution. © 1998 John Wiley & Sons, Ltd.

The purpose of the study was to assess the impact of postchemotherapy nausea and vomiting (PCNV) after moderately emetogenic chemotherapy on health-related quality of life (HRQOL) in patients with cancer being treated in a routine clinical practice setting. The European Organization for Research and Treatment in Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) was administered on day 2 and day 6 following moderately emetogenic chemotherapy to 119 patients with a variety of cancers. Patients kept daily diaries to record the occurrence and severity of nausea and vomiting. The QLQ-C30 questions were modified, for this study only, to assess the impact of nausea and vomiting on HRQOL in patients who experienced nausea and/or vomiting during the six days following chemotherapy. Those patients who experienced either nausea or vomiting experienced a decrease in HRQOL from prechemotherapy levels on six functioning and five symptom scales at day 2, and on four functioning and four symptom scales on day 6. Comparison of mean scores between the unmodified QLQ-C30 and the nausea and vomiting versions demonstrated that the HRQOL rating attributed to nausea and vomiting accounted for much, but not all, of the deterioration in HRQOL scores in patients who experienced these symptoms. It can be concluded that patients who experience PCNV experience a significant negative impact on their HRQOL and that this impact can be attributed in large part to their experience of nausea and vomiting. However, since not all of the deterioration is attributable to these symptoms, other reasons for some of the decrease in HRQOL must also be identified in future studies.

Peripheral blood leukocytes from normal volunteers and from patients with untreated Hodgkin's diseases have been assayed for the magnitude of their responses to pools of selected stimulating cells in a quantitative one-way mixed leukocyte reaction (MLR). Responses by leukocytes from individuals withHLA-B8 segregated above the median response regardless of whether the donors were healthy or were patients with Hodgkin's disease. These results suggest the presence of a gene (or genes) in the responding cells that has an effect on the magnitude of the MLR. This gene is in nonrandom association with the gene coding forB8 at theB region of theHLA complex. The observed linkage disequilibrium ofB8 with a gene controlling the proliferative response to alloantigens may be the basis for the increased frequency ofB8 in long-term survivors in carcinoma of the breast and Hodgkin's disease, and for the association ofB8 with several autoaggressive diseases.

When neonatally thymectomized CBA mice were implanted at 9 to 12 days of age with Millipore diffusion chambers (pore size, 0.1 µ) containing either syngeneic or allogeneic neonatal thymus, they were subsequently found to have the capacity to reject skin homografts and to form antibodies to sheep erythrocytes. In spite of displaying restored immune reactivity, thymectomized mice bearing thymus-filled diffusion chambers still had a lymphopenia and diminished numbers of small lymphocytes in their spleens, lymph nodes and Peyer's patches. Comparison of the lymphoid organs of these mice with those of the thymectomized control mice did not reveal any appreciable difference in the numbers of primary follicles or small lymphocytes. It is postulated that the thymus humoral factor induced immunological competence in lymphoid cells which had left the thymus prior to neonatal thymectomy. The paucity of circulating and tissue small lymphocytes in thymectomized animals, the immune reactivity of which was restored by thymus tissue in diffusion chambers, argues against the theory that the thymus humoral factor has a lymphocytosis-stimulating effect. There was no restoration of immune reactivity in those neonatally thymectomized mice which had been implanted with diffusion chambers containing neonatal or adult spleens, or adult lymph nodes. Thus, the competence-inducing factor is elaborated by the thymus but not by the spleen or lymph nodes. Allogeneic (C57Bl) neonatal thymus tissue, enclosed within diffusion chambers, had the capacity to restore the immune reactivity of totally thymectomized CBA mice, not only to skin homografts of a totally unrelated strain (Ak), but also to grafts isogeneic with the donor of the allogeneic thymus. Therefore, there is no strain barrier to the action of thymus humoral factor. To explain the apparent lack of full participation of thymus lymphocytes in immune reactions it is postulated that thymus lymphocytes are functionally immature in situ, and that they leave the thymus before attaining immunological competence. In the periphery, they undergo further maturation under the influence of the competence-inducing factor produced by the thymus.

Neonatally thymectomized mice were implanted intraperitoneally at 7 days of age with Millipore diffusion chambers containing either embryonic or neonatal thymus tissue. Mice which received either empty diffusion chambers or no further treatment following neonatal thymectomy served as controls. In contrast to these controls, most of the mice implanted with thymus-filled chambers gained weight satisfactorily, did not develop a wasting syndrome, and had the capacity to produce serum antibodies in response to sheep erythrocytes and to reject allogeneic skin grafts. Lymphoid follicles were present in the lymph nodes, spleen, and intestinal tract of the implanted mice but most still showed some diminution in the population of lymphocytes in both blood and tissues. Control thymectomized mice had markedly depleted lymphoid tissues and low peripheral blood lymphocyte levels. The tissue recovered after 1 to 2 months from the diffusion chambers showed only epithelial-reticular cells but no lymphoid cells. It is suggested that a humoral factor produced by the thymus epithelial-reticular complex may be responsible for endowing lymphoid cells with immunological competence.

Experiments were designed to determine whether or not precursors of antibody-producing cells are restricted in the number of antigens to which they can respond. An in vitro culture system was used, in which the successful production of hemolysin PFC was dependent on the presence of a large number of heavily irradiated spleen cells which did not themselves give rise to PFC, but which supported the production of PFC by a small number of normal spleen cells. All spleen cells were obtained from unimmunized CBA mice. The cells were mixed with either sheep or chicken erythrocytes, or both, cultured for 4 days and analyzed for hemolysin PFC. By reducing the number of unirradiated spleen cells to limiting dilution it was shown that normal spleen cell suspensions contain approximately three times as many precursors capable of responding to chicken erythrocytes as to sheep erythrocytes. In cultures containing both antigens, the number of precursors responding to one antigen was not affected by the presence of the other antigen. In addition, some cultures were positive for PFC-producing hemolysin against chicken erythrocytes, but not against sheep erythrocytes, and vice versa. This pattern of response was independent of the concentration of antigen in the cultures. Thus, the antigen-sensitive precursors for these non-cross-reacting antigens responded independently of each other, indicating that each precursor was restricted in its capacity to respond to more than one antigen prior to stimulation.

Three classes of immunologically reactive cells, differing only slightly in size from each other, are required for the production of hemolysin-forming cells in culture. The three classes of cells can be detected in the normal mouse spleen by the combined use of rosette formation, velocity sedimentation, and irradiation. One class of cells (peak sedimentation velocity, 3.2 mm per hr) forms rosettes. The capacity of these cells to participate in immune responses to foreign erythrocytes is inhibited by relatively low doses of irradiation. These cells may be the immediate precursors of hemolysin-forming cells. A second class of cells (peak sedimentation velocity, 3.6 mm per hr) facilitates the production of hemolysin-forming cells by small numbers of normal spleen cells. Their facilitative activity is resistant to a relatively large dose of radiation. They do not form rosettes. The requirement of a third class of cells was deduced from the results of mixing experiments. Neither rosette-forming cells nor spleen cells largely depleted of rosette-forming cells could give rise to hemolysin-forming cells when cultured either alone or in the presence of large numbers of heavily irradiated cells. However, when rosette-forming cells, cells depleted of rosette-forming cells, and heavily irradiated cells were mixed together, hemolysin-forming cells were produced. The peak responses were found in fractions sedimenting at 4 mm per hr. Thus, it is suggested that these fractions contain a third class of cells. This class of cells does not form rosettes, but its function is inhibited by relatively low doses of radiation.

For patients treated with low or minimally emetogenic chemotherapy there is little evidence from clinical trials supporting the choice of a given antiemetic therapy or of any treatment at all. The panel recognized the necessity of considering the introduction into clinical practice of new agents in these categories, particularly oral cytotoxic agents and targeted biological agents and also the possibility of over-treatment with antiemetics. There was consensus among panel members regarding the recommended treatment for patients receiving chemotherapy agents with low and minimal emetic risk. Patients without a history of nausea and vomiting for whom minimally emetic risk chemotherapy is prescribed should not routinely receive antiemetic prophylaxis. A single agent such as a low-dose corticosteroid is suggested for patients receiving agents of low emetic risk. If nausea and vomiting occurs during subsequent cycles of chemotherapy, prophylaxis with a single agent such as a substituted benzamide, a corticosteroid, or a phenothiazine should be administered. Only patients with persistent nausea and vomiting despite treatment with these recommended agents should receive a 5-HT3 receptor antagonist in the following cycles.

Thymectomized and intact (non-thymectomized) adult mice were heavily irradiated and given isogeneic bone marrow. In contrast to the intact mice, thymectomized mice failed to recover the capacity to produce normal numbers of plaque-forming cells after antigenic challenge. However, when cell-impermeable diffusion chambers containing thymus were implanted into thymectomized mice, these animals produced significantly larger numbers of plaque-forming cells than did control mice bearing empty diffusion chambers or chambers containing lymph node or spleen. Since the thymus does not influence the differentiation of antigen-sensitive cells into plaque-forming cells, these results indicate that the influence of the thymus is directed at the differentiation of antigen-insensitive precursors in bone marrow to antigen-sensitive cells. The capacity of thymectomized mice bearing thymus-filled diffusion chambers to produce plaque-forming cells indicates that the thymic influence is mediated by a humoral factor.

Female CBA mice that had been thymectomized soon after birth were mated with normal male T6 mice. After delivery of at least one litter, the parous females exhibited normal immune reactions to sheep erythrocytes and skin homografts. The transplacental passage of a humoral substance from the thymus glands of the developing fetuses is suggested as the mechanism responsible for the restoration of immunological responsiveness in neonatally thymectomized parous female mice.

Patient-reported outcomes (PROs) are based on direct reporting by patients without the intervention of an observer. They include the self-assessment of functional status, symptoms, and other concerns such as needs and satisfaction with care. Health-related quality of life (HRQOL) assessment is a form of PRO and often includes both functional status and symptoms. The science underlying the assessment of HRQOL in clinical practice requires an understanding of the relationships between symptoms, functional status, and HRQOL, as well as instrument selection, and analysis and interpretation of the data. A modification of the Wilson and Cleary model is proposed to show the likelihood of bidirectional relationships between symptoms, functions, and HRQOL. Instrument selection should be based on the measurement properties of the instruments and patient populations in which they will be used. Analyses of data that allow a calculation of the proportion of patients who benefit from an intervention are preferred to analyses that show only the mean change in scores from baseline. HRQOL assessment in clinical practice has been shown to lead to a better understanding of patients' concerns with improvement in counseling and referral for required services. Potentially, HRQOL assessment should also be used to monitor the progress of a patient's disease and benefit from treatment.

To propose a taxonomy of psychometrically based, health-related quality-of-life instruments related to three levels of decision-making of health care the macro, meso and micro levels. The choice of appropriate health-related quality-of-life instruments for each level of desired decision making in various clinical settings is illustrated. A secondary objective was to describe solutions for some of the difficulties inherent in the interpretation of the results of health-related quality-of-life assessment.

Trials of selective 5-hydroxytrypta-mine3 receptor antagonists have shown excellent antiemetic activity for chemotherapy containing cisplatin when compared with high-dose metoclopramide. There is little information about the efficacy of these new agents for chemotherapy other than for high-dose cisplatin. We performed a double-blind, randomized trial comparing a single dose of the 5-hydroxytryptamine3 receptor antagonist granisetron (BRL 43694A) as a single intravenous dose with dexamethasone plus prochlorperazine in 152 patients receiving their first course of moderately emetogenic chemotherapy (mainly doxorubicin-and cyclophosphamide-containing combinations). During the first 24 hours, there was a statistically significant advantage for the granisetron group in terms of the prevention of both nausea and emesis. There was no difference in the frequency of reported adverse events. We conclude that granisetron is more effective than dexamethasone plus prochlorperazine in patients who are receiving moderately emetogenic cytotoxic agents. (J Natl Cancer Inst 83: 1169–1173, 1991)

Fifty-three patients, 17 with stage IIIB and 36 with stage IV non-small-cell lung cancer, were given CODE (cisplatin, vincristine, doxorubicin, and etoposide) plus antibiotic prophylaxis and an antiemetic regimen in an intensive chemotherapy program emphasizing weekly treatment and a planned brief duration (9–12 weeks); for 45 of these patients, the CODE program also included antifungal prophylaxis and supportive corticosteroids. Of the total study population, 33 patients (62%) responded to treatment, including five (9%) with complete response. The median survival for the entire group was 42 weeks (55 weeks for those with stage IIIB and 39 weeks for those with stage IV). More than 40% were alive at 1 year. Comparison of granulocyte counts of patients receiving prednisone with those of the subgroup to whom no corticosteroids were given showed less granulocytopenia for those receiving prednisone. Use of prednisone thus allowed improved delivery of myelosup pressive drugs. CODE was halted in nine patients because of disease progression. Although more constitutional side effects are associated with weekly chemotherapy than with standard chemotheraphy, only 12 of the remaining 44 patients (27%) failed to receive at least 9 weeks of treatment. Serious toxicity was uncommon: There were no treatment-related deaths and only three episodes of neutropenia with fever. CODE is a novel treatment for non-small-cell lung cancer that this pilot study provided entirely in an outpatient setting over a 9–12 week period with an acceptable incidence of toxicity and a promising level of efficacy. Additional testing and comparison with other regimens or supportive care alone are warranted. [J Natl Cancer Inst 83:190–194, 1991]