Imatinib dose reduction in major molecular response of chronic myeloid leukemia: results from the German Chronic Myeloid Leukemia-Study IV.

Standard first-line therapy of chronic myeloid leukemia is treatment with imatinib. In the randomized German Chronic Myeloid Leukemia-Study IV, more potent BCR-ABL inhibition with 800 mg ('high-dose') imatinib accelerated achievement of a deep molecular remission. However, whether and when a de-escalation of the dose intensity under high-dose imatinib can be safely performed without increasing the risk of losing deep molecular response is unknown. To gain insights into this clinically relevant question, we analyzed the outcome of imatinib dose reductions from 800 mg to 400 mg daily in the Chronic Myeloid Leukemia-Study IV. Of the 422 patients that were randomized to the 800 mg arm, 68 reduced imatinib to 400 mg after they had achieved at least a stable major molecular response. Of these 68 patients, 61 (90%) maintained major molecular remission on imatinib at 400 mg. Five of the seven patients who lost major molecular remission on the imatinib standard dose regained major molecular remission while still on 400 mg imatinib. Only two of 68 patients had to switch to more potent kinase inhibition to regain major molecular remission. Importantly, the lengths of the intervals between imatinib high-dose treatment before and after achieving major molecular remission were associated with the probabilities of maintaining major molecular remission with the standard dose of imatinib. Taken together, the data support the view that a deep molecular remission achieved with high-dose imatinib can be safely maintained with standard dose in most patients. Study protocol registered at clinicaltrials.gov 00055874.

Impact of comorbidities on overall survival in patients with chronic myeloid leukemia: results of the randomized CML study IV.

We studied the influence of comorbidities on remission rate and overall survival (OS) in patients with chronic myeloid leukemia (CML). Participants of the CML Study IV, a randomized 5-arm trial designed to optimize imatinib therapy, were analyzed for comorbidities at diagnosis using the Charlson Comorbidity Index (CCI); 511 indexed comorbidities were reported in 1519 CML patients. Age was an additional risk factor in 863 patients. Resulting CCI scores were as follows: CCI 2, n = 589; CCI 3 or 4, n = 599; CCI 5 or 6, n = 229; and CCI ≥ 7, n = 102. No differences in cumulative incidences of accelerated phase, blast crisis, or remission rates were observed between patients in the different CCI groups. Higher CCI was significantly associated with lower OS probabilities. The 8-year OS probabilities were 93.6%, 89.4%, 77.6%, and 46.4% for patients with CCI 2, 3 to 4, 5 to 6, and ≥7, respectively. In multivariate analysis, CCI was the most powerful predictor of OS, which was still valid after removal of its age-related components. Comorbidities have no impact on treatment success but do have a negative effect on OS, indicating that survival of patients with CML is determined more by comorbidities than by CML itself. OS may therefore be inappropriate as an outcome measure for specific CML treatments. The trial was registered at www.clinicaltrials.gov as #NCT00055874.

Older patients with chronic myeloid leukemia (≥65 years) profit more from higher imatinib doses than younger patients: a subanalysis of the randomized CML-Study IV.

The impact of imatinib dose on response rates and survival in older patients with chronic myeloid leukemia in chronic phase has not been studied well. We analyzed data from the German CML-Study IV, a randomized five-arm treatment optimization study in newly diagnosed BCR-ABL-positive chronic myeloid leukemia in chronic phase. Patients randomized to imatinib 400 mg/day (IM400) or imatinib 800 mg/day (IM800) and stratified according to age (≥65 years vs. <65 years) were compared regarding dose, response, adverse events, rates of progression, and survival. The full 800 mg dose was given after a 6-week run-in period with imatinib 400 mg/day. The dose could then be reduced according to tolerability. A total of 828 patients were randomized to IM400 or IM800. Seven hundred eighty-four patients were evaluable (IM400, 382; IM800, 402). One hundred ten patients (29 %) on IM400 and 83 (21 %) on IM800 were ≥65 years. The median dose per day was lower for patients ≥65 years on IM800, with the highest median dose in the first year (466 mg/day for patients ≥65 years vs. 630 mg/day for patients <65 years). Older patients on IM800 achieved major molecular remission and deep molecular remission as fast as younger patients, in contrast to standard dose imatinib with which older patients achieved remissions much later than younger patients. Grades 3 and 4 adverse events were similar in both age groups. Five-year relative survival for older patients was comparable to that of younger patients. We suggest that the optimal dose for older patients is higher than 400 mg/day. ClinicalTrials.gov identifier: NCT00055874

Predictors of chemotherapy patients' intentions to engage in medical error prevention.

BACKGROUND: Patients can make contributions to the safety of chemotherapy administration but little is known about their motivations to participate in safety-enhancing strategies. The theory of planned behavior was applied to analyze attitudes, norms, behavioral control, and chemotherapy patients' intentions to participate in medical error prevention. METHODS: A quantitative, cross-sectional survey study among chemotherapy patients treated at the oncology/hematology department of a large regional hospital was conducted. Confirmatory factor analysis and structural equation modeling were used to investigate the relationship between patients' responses to measures of attitudes, norms, and behavioral control and their intentions. RESULTS: Four hundred seventy-nine patients completed the survey (52% response rate). Attitudes, perceived behavioral control, and subjective norms explained 62% of the variance in intentions to engage in error monitoring and reporting. Perceived behavioral control (beta = 0.476), norms relating to patients' relatives (beta = 0.343), and instrumental attitudes (beta = 0.281) were the strongest (direct) predictors of patients' intentions. Experiential attitudes had the smallest effect on intentions (beta = 0.178). Subjective norms relating to expectations attributed to oncology staff had strong direct and indirect effects on patients' intentions (total effect, 0.382). CONCLUSIONS: Patients acknowledge the benefit of error monitoring and reporting and anticipate positive outcomes of involvement, but their valuations of the process of engaging in error prevention are less positive. Behavioral control and perceptions of staff approval are central for patients. Involvement of cancer patients in safety requires oncologists to address their patients' normative and control beliefs through education and proactive approval of patient engagement.

Chemotherapy patients' perceptions of drug administration safety.

PURPOSE: To explore chemotherapy patients' experiences of drug administration safety and to investigate the relationship between perceptions of risk and harm from error, staff safety practices, and patients' engagement in error prevention strategies. PATIENTS AND METHODS: Four hundred seventy-nine chemotherapy patients treated at the oncology/hematology department of a large regional hospital in Switzerland completed a self-administered survey (53% response rate). RESULTS: Sixteen percent of patients reported having experienced an error in their care, and 11% were currently very concerned about errors. Patients perceived the risk of four detailed errors as rather low, whereas the mean rating of potential harm from error was substantial. Relative to other errors, patients seem to underestimate the harm associated with drug overdosing. Seventy-seven percent of responders agreed that patients can help to prevent errors. Although patients perceived staff as being committed to providing safe care, ratings related to patient involvement in safety were considerably lower. More than one quarter of patients disagreed that staff instructed them to watch for and report errors. Patients engaged in safety behaviors, particularly in those behaviors that are compatible with traditional patient-provider relations. Risk of error perceptions, affirmative attitudes toward patient preventability, and error experience were positively linked to safety-related behaviors, whereas higher levels of global trust in staff safety practices were inconsistently associated with lower frequency of engagement in safety strategies. CONCLUSION: Chemotherapy safety is a considerable concern for patients. Many patients are prepared to be involved in error prevention. The results highlight areas for improvement in communication and cooperation for safety between patients and providers.

Am I (un)safe here? Chemotherapy patients' perspectives towards engaging in their safety.

OBJECTIVES: To assess chemotherapy patients' perceptions of safety and their attitudes towards participating in error-prevention strategies. DESIGN: Semistructured interviews were conducted with 30 chemotherapy patients at baseline. Follow-up interviews were conducted 9 weeks later. SETTING: A community hospital in Switzerland. RESULTS: Though patients had experienced errors in their care, they were only moderately worried about safety, risk of errors and the potential for harm. At follow-up, worries about safety had increased, and patients reported a higher degree of vigilance. Participants unequivocally agreed that patients can make contributions to their safety, and many patients were prepared to get involved. Patients described engaging in their safety as a learning process and highlighted the importance of being proactive, asking questions and communicating any observations of deviations from routines. Commonly recommended error-prevention strategies were rated as highly effective. Instruction by nurses was central for patients, but the underlying reasons varied. There was no indication that patients perceive participation in safety actions as eroding trust in their providers. CONCLUSIONS: Patients are prepared to engage in their safety, but the encouragement by staff is vital. Involvement of patients with cancer in medication administration safety needs to acknowledge patients' conceptions of these activities and their varying abilities at different stages in the treatment process.

Oncology nurses' perceptions about involving patients in the prevention of chemotherapy administration errors.

PURPOSE/OBJECTIVES: To explore oncology nurses' perceptions and experiences with patient involvement in chemotherapy error prevention. DESIGN: Qualitative descriptive study. SETTING: In- and outpatient oncology units of a community hospital in Switzerland. SAMPLE: 11 actively practicing oncology nurses working in an ambulatory infusion unit or on wards. METHODS: Oncology nurses participated in two focus groups on two occasions. Participants discussed their personal experiences with patients intervening to intercept errors, attitudes toward patient involvement in error prevention, and changes in relationships with patients. A content-analysis framework was applied to the transcripts and analytical categories were generated. MAIN RESEARCH VARIABLES: Perceptions about patient involvement in error prevention. FINDINGS: Participants shared affirmative attitudes and overwhelmingly reported positive experiences with engaging patients in safety behaviors, although engaging patients was described as a challenge. Nurses intuitively chose among a set of strategies and patterns of language to engage patients and switch between participative and authoritative models of education. Patient involvement in error prevention was perceived to be compatible with trustful relationships. Efforts to get patients involved have the potential for frustration if preventable errors reach patients. Considerable differences exist among organizational barriers encountered by nurses. CONCLUSIONS: Nurses acknowledged the diverse needs of patients and deliberately used different strategies to involve patients in safety. Patient participation in safety is perceived as a complex learning process that requires cultural change. IMPLICATIONS FOR NURSING: Oncology nurses perceive patient education in safety as a core element of their professional role and are receptive to advancing their expertise in this area.

DV-ICE, intensive induction and early transplantation for adult patients with acute lymphoblastic leukemia: a phase II study.

OBJECTIVES: Eighty percent of adult patients with acute lymphoblastic leukemia (ALL) achieve a complete remission (CR) but only 30-40% are long term survivors. Best treatment strategies remain to be defined. The role of induction intensity, first remission hematopoietic stem cell transplantation (HSCT) and maintenance chemotherapy continues to be discussed. We tested a strategy of high intensity treatment of short duration followed by HSCT. PATIENTS AND METHODS: This prospective phase II study used induction with DV-ICE followed by immediate allogeneic or autologous HSCT (depending on donor availability) without additional consolidation or maintenance treatment. DV-ICE consisted of dexamethasone, vincristine, idarubicin, etoposide, and conventional dose cytosine arabinoside; HSCT was planned immediately if CR was achieved or after an additional course of intermediate high dose cytosine arabinoside and etoposide for patients with induction failure. A total of 42 consecutive patients between 17 and 67 yr of age (median 43 yr) were enrolled. Of the 42 patients, 57% were male, 76% had B-lineage ALL, 19% T-lineage ALL and two patients biphenotypic ALL. 29% were Ph+; 7% had 11q23 and 45% had a normal karyotype. CNS involvement was found in three patients. RESULTS: Thirty-three patients (79%) achieved a CR, 24 patients after induction I or II and nine patients after rescue HSCT. 31 patients received a HSCT (seven autologous and 24 allogeneic). 11 patients did not receive a HSCT because of early death in nine (treatment toxicity in five, refractory disease in four), one patient refused transplantation, one patient was not suitable. Disease-free survival (DFS) of the entire cohort was 46% (95% CI +/-16%) at 1 yr and 16% (+/-13%) at 5 yr. Overall survival (OS) was 63% (+/-15%) at 1 yr and 23% (+/-15%) at 5 yr, with a median follow-up of surviving patients of 55 (4-136) months. Neither disease subtype, cytogenetic abnormalities nor patient age or gender was significantly associated with survival. CONCLUSIONS: Intensive induction using DV-ICE followed by early transplantation without treatment beyond 4 months failed to improve outcome compared with standard treatment.

Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research.

PURPOSE: This randomized phase II trial evaluated two docetaxel-based regimens to see which would be most promising according to overall response rate (ORR) for comparison in a phase III trial with epirubicin-cisplatin-fluorouracil (ECF) as first-line advanced gastric cancer therapy. PATIENTS AND METHODS: Chemotherapy-naïve patients with measurable unresectable and/or metastatic gastric carcinoma, a performance status

Mediastinal lymph node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pN2 non-small-cell lung cancer: a multicenter phase II trial.

PURPOSE: A multicenter, phase II trial investigated the efficacy and toxicity of neoadjuvant docetaxel-cisplatin in locally advanced non-small-cell lung cancer (NSCLC) and examined prognostic factors for patients not benefiting from surgery. PATIENTS AND METHODS: Ninety patients with previously untreated, potentially operable stage IIIA (mediastinoscopically pN2) NSCLC received three cycles of docetaxel 85 mg/m2 day 1 plus cisplatin 40 mg/m2 days 1 and 2, with subsequent surgical resection. RESULTS: Administered dose-intensities were docetaxel 85 mg/m2/3 weeks (range, 53 to 96) and cisplatin 95 mg/m2/3 weeks (range, 0 to 104). The 265 cycles were well tolerated, and the overall response rate was 66% (95% confidence interval [CI], 55% to 75%). Seventy-five patients underwent tumor resection with positive resection margin and involvement of the uppermost mediastinal lymph node in 16% and 35% of patients, respectively (perioperative mortality, 3%; morbidity, 17%). Pathologic complete response occurred in 19% of patients with tumor resection. In patients with tumor resection, downstaging to N0-1 at surgery was prognostic and significantly prolonged event-free survival (EFS) and overall survival (OS; P =.0001). At median follow-up of 32 months, the median EFS and OS were 14.8 months (range, 2.4 to 53.4) and 33 months (range, 2.4 to 53.4), respectively. Local relapse occurred in 27% of patients with tumor resection, with distant metastases in 37%. Multivariate analyses identified mediastinal clearance (hazard ratio, 0.22; P =.0003) and complete resection (hazard ratio, 0.26; P =.0006) as strongly prognostic for increased survival. CONCLUSION: Neoadjuvant docetaxel-cisplatin is effective and tolerable in stage IIIA pN2 NSCLC. Resection is recommended only for patients with mediastinal downstaging after chemotherapy.

Phase II study of capecitabine and oxaliplatin in first- and second-line treatment of advanced or metastatic colorectal cancer.

PURPOSE: To determine the efficacy and tolerability of combining oxaliplatin with capecitabine in the treatment of advanced nonpretreated and pretreated colorectal cancer. PATIENTS AND METHODS: Forty-three nonpretreated patients and 26 patients who had experienced one fluoropyrimidine-containing regimen for advanced colorectal cancer were treated with oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1,250 mg/m(2) bid on days 1 to 14 every 3 weeks. Patients with good performance status (World Health Organization grade 0 to 1) were accrued onto two nonrandomized parallel arms of a phase II study. RESULTS: The objective response rate was 49% (95% confidence interval [CI], 33% to 65%) for nonpretreated and 15% (95% CI, 4% to 35%) for pretreated patients. The main toxicity of this combination was diarrhea, which occurred at grade 3 or 4 in 35% of the nonpretreated and 50% of the pretreated patients. Grade 3 or 4 sensory neuropathy, including laryngopharyngeal dysesthesia, occurred in 16% of patients on both cohorts. Capecitabine dose reductions were necessary in 26% of the nonpretreated and 45% of the pretreated patients in the second treatment cycle. The median overall survival was 17.1 months and 11.5 months, respectively. CONCLUSION: Combining capecitabine and oxaliplatin yields promising activity in advanced colorectal cancer. The main toxicity is diarrhea, which is manageable with appropriate dose reductions. On the basis of our toxicity experience, we recommend use of capecitabine in combination with oxaliplatin 130 mg/m(2) at an initial dose of 1,250 mg/m(2) bid in nonpretreated patients and at a dose of 1,000 mg/m(2) bid in pretreated patients.