Real-world safety and effectiveness of maintenance niraparib for platinum-sensitive recurrent ovarian cancer: A GEICO retrospective observational study within the Spanish expanded-access programme.

AIM: To describe patient characteristics, effectiveness and safety in a real-world population treated with niraparib in the Spanish expanded-access programme. PATIENTS AND METHODS: This retrospective observational study included women with platinum-sensitive recurrent high-grade serous ovarian cancer who received maintenance niraparib within the Spanish niraparib expanded-access programme. Eligible patients had received ≥2 previous lines of platinum-containing therapy, remained platinum-sensitive after the penultimate line of platinum and had responded to the most recent platinum-containing therapy. Niraparib dosing was at the treating physician's discretion (300 mg/day fixed starting dose or individualised starting dose [ISD] according to baseline body weight and platelet count). Safety, impact of dose adjustments, patient characteristics and effectiveness were analysed using data extracted from medical records. RESULTS: Among 316 eligible patients, 80% had BRCA wild-type tumours and 66% received an ISD. Median niraparib duration was 7.8 months. The most common adverse events typically occurred within 3 months of starting niraparib. Median progression-free survival was 8.6 (95% confidence interval [CI] 7.6-10.0) months. One- and 2-year overall survival rates were 86% (95% CI 81-89%) and 65% (95% CI 59-70%), respectively. Dose interruptions, dose reductions, haematological toxicities and asthenia/fatigue were less common with ISD than fixed starting dose niraparib, but progression-free survival was similar irrespective of dosing strategy. Subsequent therapy included platinum in 71% of patients who received further treatment. CONCLUSION: Outcomes in this large real-world dataset of niraparib-treated patients are consistent with phase III trials, providing reassuring evidence of the tolerability and activity of niraparib maintenance therapy for platinum-sensitive recurrent ovarian cancer. GOV REGISTRATION: NCT04546373.

Rucaparib in recurrent ovarian cancer: real-world experience from the rucaparib early access programme in Spain - A GEICO study.

BACKGROUND: Rucaparib is a poly(ADP-ribose) polymerase inhibitor approved in Europe as maintenance therapy for recurrent platinum-sensitive (Pt-S) ovarian cancer (OC). The Rucaparib Access Programme (RAP) was designed to provide early access to rucaparib for the above-mentioned indication, as well as for patients with BRCA-mutated Pt-S or platinum-resistant (Pt-R) OC and no therapeutic alternatives. METHODS: In this observational, retrospective study we analysed the efficacy and safety of rucaparib within the RAP in Spain. Hospitals associated with the Spanish Ovarian Cancer Research Group (GEICO) recruited patients with high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer treated with rucaparib 600 mg twice daily as maintenance or treatment (Pt-S/Pt-R) in the RAP. Baseline characteristics, efficacy, and safety data were collected. RESULTS: Between July 2020 and February 2021, 51 patients treated in 22 hospitals in the RAP were included in the study. Eighteen patients with a median of 3 (range, 1-6) prior treatment lines received rucaparib as maintenance; median progression-free survival (PFS) for this group was 9.1 months (95% confidence interval [CI], 4.2-11.6 months). Among 33 patients (median 5 [range, 1-9] prior treatment lines) who received rucaparib as treatment, 7 and 26 patients had Pt-S and Pt-R disease, respectively. Median PFS was 10.6 months (95% CI, 2.5 months-not reached) in the Pt-S group and 2.2 months (95% CI, 1.1-3.2 months) in the Pt-R group. Grade ≥ 3 treatment-emergent adverse events were reported in 39% of all patients, the most common being anaemia (12% and 15% in the maintenance and treatment groups, respectively). At data cut-off, 5 patients remained on treatment. CONCLUSION: Efficacy results in these heavily pre-treated patients were similar to those from previous trials. The safety profile of rucaparib in real life was predictable and manageable.

Cutaneous adverse events in patients receiving anticancer therapy in a tertiary hospital setting: the old and the new.

BACKGROUND: Targeted therapies and immunotherapies are increasingly prescribed, but classic chemotherapy agents are still highly used in cancer treatment. Both therapies, the old and the new, are associated with cutaneous adverse events (CAEs) that can cause treatment interruptions or reduce the quality of life of patients. METHODS: An observational, cross-sectional, single-center study that included consecutive cancer patients presenting CAEs. The main objective was to describe CAEs derived from antineoplastic drugs. Secondary objectives were to determine the number and severity of CAEs and if there were differences regarding CAEs between conventional chemotherapeutics and targeted therapies. RESULTS: A total of 114 patients were included with a total number of 177 CAEs. Of the 114 patients, 64 presented a single CAE, 37 patients had two CAEs, and 13 patients presented three CAEs. The most frequent CAEs were pruritus, xerosis, palmar-plantar erythrodysesthesia (PPE), and alopecia. The majority of CAEs were mild (63.2%), followed by moderate (29.9%) and severe (6.7%) CAEs. Of the 114 patients, 103 (90.3%) received topical agents and 11 (9.7%) required systemic treatment for the management of CAEs. Prophylactic treatment for CAE was delivered to only 4/114 (3.5%) patients. No significant differences were found in the number or severity of CAEs between conventional chemotherapy and targeted therapy. CONCLUSIONS: Close collaboration between oncologists and dermatologists is essential to start preventive measures on time, enhance patient education, and avoid unnecessary dose reductions or treatment interruptions. The multidisciplinary approach can offer better management of skin toxicities.

Working towards a consensus on the oncological approach of breakthrough pain: a Delphi survey of Spanish experts.

PURPOSE: There is a lack of standards for the diagnosis, assessment and management of breakthrough cancer pain (BTcP). La Fundación ECO (the Foundation for Excellence and Quality in Oncology) commissioned a study to establish a consensus and lay the foundations for the appropriate management of BTcP in oncology patients. PATIENTS AND METHODS: A modified Delphi survey comprising two rounds was used to gather and analyze data, which was conducted over the Internet. Each statement that reached a consensus with the respondents was defined as a median consensus score (MED) of ≥7, and agreement among panelists as an interquartile range (IQR) of ≤3. RESULTS: In total, 69 medical oncologists responded, with a broad consensus that BTcP implied exacerbations of high-intensity pain, as opposed to moderate pain. Furthermore, they concurred that appropriate diagnostic equipment is needed, and that rapid-onset fentanyl formulations should be the preferred treatment for BTcP management. The panelists agreed that a lack of appropriate information and training to attend to patients, as well as limited patient visitation rights, were barriers to effective BTcP management. Regarding gaps in detected knowledge, the panelists were unsure of the measures necessary to assess the burden of the disease on the patient's quality of life and associated medication costs. Alongside this, there was a lack of awareness of the technical specifics of the different formulations of rapid-onset fentanyl. CONCLUSION: These results represent the current status of BTcP management. They may inform recommendations and provide a framework for future research.

Estudio comparativo de la supervivencia tras procedimientos videotoracoscópicos para la lobectomía del cáncer de pulmón: abordaje por puerto único frente a múltiple / Comparative study of survival following videothoracoscopic lobectomy procedures for lung cancer: single-versus multiple-port approaches

Introducción: La cirugía toracoscópica videoasistida se ha convertido en la técnica de elección para las intervenciones de cáncer de pulmón en estadio inicial en muchos centros, a pesar de que no se ha probado que la supervivencia a largo plazo sea la misma con todos los abordajes quirúrgicos. Método: Efectuamos una revisión retrospectiva de 276 lobectomías practicadas en nuestro servicio mediante cirugía videoasistida, y analizamos la edad, sexo, comorbilidades, tabaquismo, FEV1 y FCV, abordaje quirúrgico, estadios TNM y patológico, tipo histológico, quimioterapia neoadyuvante o coadyuvante y tiempo hasta la recidiva o la detección de metástasis con el objetivo de evaluar la tasa de supervivencia y la duración del periodo sin enfermedad en relación con el abordaje quirúrgico, dos/tres puertos o puerto único, de los pacientes. Resultados: Las tasas de supervivencia global al cabo de uno y cuatro años fueron del 88,1 y 67,6%, respectivamente. En el análisis bivariante se observó que las variables que se asociaban con la supervivencia eran las comorbilidades, el tipo histológico, el estadio, el abordaje quirúrgico y la necesidad de quimioterapia. Al analizar el abordaje quirúrgico de forma independiente, se observó que la tasa de supervivencia era inferior en el grupo en el que se utilizó la técnica monoportal frente al grupo en el que se utilizaron dos o tres puertos (VATS). Al estratificar a los pacientes según el estadio tumoral (estadio I) y el tamaño del tumor (T2), la supervivencia fue significativamente inferior en los pacientes tratados con el abordaje monoportal, en comparación con la VATS. En el análisis multivariante, el riesgo de muerte fue mayor con la técnica monoportal (HR = 1,78). En el análisis del tiempo transcurrido sin enfermedad se observó una tendencia hacia una mayor supervivencia favorable a la VATS con dos/tres puertos, tanto para la recidiva local (p = 0,093) como para el desarrollo de metástasis (p = 0,091). Conclusiones: Estos resultados cuestionan el uso de la técnica uniportal en las neoplasias malignas de pulmón, lo que sugiere la necesidad de efectuar ensayos clínicos que permitan identificar el papel de esta técnica en la cirugía del cáncer de pulmón

Introduction: Video-assisted thoracoscopic surgery has become the technique of choice in the early stages of lung cancer in many centers although there is no evidence that all of the surgical approaches achieve the same long-term survival. Method: We carried out a retrospective review of 276 VATS lobectomies performed in our department, analyzing age, sex, comorbidities, current smoker, FEV1 and FCV, surgical approach, TNM and pathological stage, histologic type, neoadjuvant or coadjuvant chemotherapy, relapse and metastasis time, with the main aim of evaluating the survival rate and disease-free time, especially with regard to the two/three versus single port approach. Result: The one/four year global survival rate was 88.1 and 67.6% respectively. Bivariate analysis found that the variables associated with survival are comorbidity, histological type, stage, surgical approach and need for chemotherapy. When we independently analyzed the surgical approach, we found a lower survival rate in the single-port group vs. the two/three-port group (VATS). Stratifying by tumoral stage (stage I) and by tumor size (T2) survival was significantly lower for patients with single-port group in comparison to VATS approach. In the multivariate analysis, single-port group is associated with a higher risk of death (HR = 1.78). In analyzing disease-free survival, differences were found in both cases in favor of two/three port VATS: p = .093 for local relapses and p = .091 for the development of metastasis. Conclusions: These results challenge the use of the single port technique in malignant lung pathologies, suggesting the need for clinical trials in order to identify the role this technique may have in lung cancer surgery

Comparative Study of Survival following Videothoracoscopic Lobectomy Procedures for Lung Cancer: Single- versus Multiple-port Approaches. / Estudio comparativo de la supervivencia tras procedimientos videotoracoscópicos para la lobectomía del cáncer de pulmón: abordaje por puerto único frente a múltiple.

INTRODUCTION: Video-assisted thoracoscopic surgery has become the technique of choice in the early stages of lung cancer in many centers although there is no evidence that all of the surgical approaches achieve the same long-term survival. METHOD: We carried out a retrospective review of 276 VATS lobectomies performed in our department, analyzing age, sex, comorbidities, current smoker, FEV1 and FCV, surgical approach, TNM and pathological stage, histologic type, neoadjuvant or coadjuvant chemotherapy, relapse and metastasis time, with the main aim of evaluating the survival rate and disease-free time, especially with regard to the two/three versus single port approach. RESULT: The one/four year global survival rate was 88.1 and 67.6% respectively. Bivariate analysis found that the variables associated with survival are comorbidity, histological type, stage, surgical approach and need for chemotherapy. When we independently analyzed the surgical approach, we found a lower survival rate in the single-port group vs. the two/three-port group (VATS). Stratifying by tumoral stage (stage I) and by tumor size (T2) survival was significantly lower for patients with single-port group in comparison to VATS approach. In the multivariate analysis, single-port group is associated with a higher risk of death (HR=1.78). In analyzing disease-free survival, differences were found in both cases in favor of two/three port VATS: p=.093 for local relapses and p=.091 for the development of metastasis. CONCLUSIONS: These results challenge the use of the single port technique in malignant lung pathologies, suggesting the need for clinical trials in order to identify the role this technique may have in lung cancer surgery.

Standard versus continuous administration of capecitabine in metastatic breast cancer (GEICAM/2009-05): a randomized, noninferiority phase II trial with a pharmacogenetic analysis.

BACKGROUND: The approved capecitabine regimen as monotherapy in metastatic breast cancer (MBC) is 1,250 mg/m(2) twice daily for 2 weeks on and 1 week off (Cint). Dose modifications are often required because of severe hand-foot syndrome (HFS). We tested a continuous regimen with a lower daily dose but a similar cumulative dose in an attempt to reduce the severity of adverse events (AEs) while maintaining efficacy. METHODS: We randomized 195 patients with HER-2/neu-negative MBC to capecitabine 800 mg/m(2) twice daily throughout the 21-day cycle (Ccont) or to Cint to assess noninferiority in the percentage of patients free of progression at 1 year. Secondary endpoints included efficacy and safety. Associations between polymorphisms in capecitabine metabolism-related genes and drug response were assessed. RESULTS: The percentage of patients free of progression at 1 year was 27.3% with Cint versus 25.3% with Ccont (difference of -2.0%; 95% confidence interval: -15.5% to 11.5%, exceeding the 15% deemed noninferior). Differences regarding other efficacy variables were also not found. Grade 3-4 HFS was the most frequent AE (41.1% in Cint vs. 42.3% in Ccont). Grade 3-4 neutropenia, thrombocytopenia, diarrhea, and stomatitis were more frequent with Cint. A 5' untranslated region polymorphism in the carboxylesterase 2 gene was associated with HFS. One polymorphism in cytidine deaminase and two in thymidine phosphorylase were associated with survival. CONCLUSION: Our study was unable to show noninferiority with the continuous capecitabine regimen (Ccont) compared with the approved intermittent regimen (Cint). Further investigation is required to improve HFS. Polymorphisms in several genes might contribute to interindividual differences in response to capecitabine.

Darbepoetin alfa administered once every three weeks for the treatment of anemia in elderly patients with non-myeloid tumors receiving chemotherapy.

AIMS AND BACKGROUND: The present study aims to describe the hematological response to darbepoetin alfa (DA) under daily clinical practice conditions in anemic elderly patients with non-myeloid tumors receiving chemotherapy. METHODS AND STUDY DESIGN: This was a prospective, observational, multicenter study in elderly (≥65 years) patients with non-myeloid cancer receiving DA (500 µg every 3 weeks) for chemotherapy-induced anemia (hemoglobin [Hb] level ≤11.0 g/dL). RESULTS: A total of 102 anemic patients with solid tumors and 51 with hematological malignancies were included in 28 centers in Spain. Mean age (±SD) was 73.4 (±5.8) years, and mean baseline Hb level was 10.0 (±0.8) g/dL. DA was administered for a median of 8 weeks. Of the 115 subjects with a post-baseline Hb value, the percentage of patients who achieved a hematopoietic response (Hb increase ≥2 g/dL or reaching ≥12 g/dL without transfusions in the previous 28 days) was 69.7% (95% CI 56.1% to 83.3%). Functional Assessment of Cancer Therapy-Fatigue subscale scores increased during the study (median change 1.0 [Q1 -5.0, Q3 9.0], P = 0.04). One patient (0.7%) experienced a non-serious adverse reaction (cutaneous rash). CONCLUSION: The study results suggest that DA is an effective and well-tolerated therapy for the treatment of chemotherapy-induced anemia in elderly patients.

Cisplatin plus oral vinorelbine as first-line treatment for advanced non-small-cell lung cancer: a prospective study confirming that the day-8 hemogram is unnecessary.

INTRODUCTION: Cisplatin plus oral vinorelbine, one of the standard treatments for metastatic non-small-cell lung cancer (NSCLC), is associated with a high rate of neutropenia, and a hemogram is performed on day 8. We analyzed the oncologists' opinions and the result of the hemogram on day 8 to address the question of whether this hemogram could be avoided. MATERIALS AND METHODS: Fifty-eight chemotherapy-naive, advanced NSCLC patients were included. Each received intravenous doses of 75 mg/m(2) cisplatin on day 1 plus oral vinorelbine [60 mg/m(2) in the first cycle (80 mg/m(2) in subsequent cycles) on days 1 and 8], every 3 weeks, for a maximum of six cycles. RESULTS: Out of 257 cycles analyzed, oral vinorelbine was administered on day 8 in 214 (83.2 %) and the dose was canceled in 6 cycles (2.3 %) due to hematological toxicity. On analyzing the patients to whom chemotherapy had been administered on day 8, based on medical opinion without the doctor knowing the hemogram result, we found that the cycle had been administered with a hemogram showing fewer than 1,500 × 10(6) neutrophils in only 3 of the 185 evaluable cycles [event rate of 1.6 %, with confidence interval 95 % = (0.34-4.67 %)]. CONCLUSION: The hemogram on day 8 can be avoided and oral vinorelbine administered in relative safety in patients with good performance status, when confirmed by the clinician's perception, thereby making this regimen more comfortable for the patient. This is the first prospective study to examine this issue.

Risk factors for chemotherapy-induced neutropenia occurrence in breast cancer patients: data from the INC-EU Prospective Observational European Neutropenia Study.

BACKGROUND: Chemotherapy-induced neutropenia (CIN) places patients at risk of life-threatening infections. While reduction of chemotherapy dose or delay of the subsequent treatment cycle and, consequently, reduction of relative dose intensity (RDI) may limit myelotoxicity, these actions can also impact adversely on treatment outcome and should be avoided in adjuvant settings. PATIENTS AND METHODS: Based on data from 444 breast cancer patients in the INC-EU Prospective Observational European Neutropenia Study, we have evaluated patient-specific and treatment-specific factors that impact on the incidence of grade 4 CIN (absolute neutrophil count <0.5 × 10(9)/L), either during the first or in any cycle of (neo)adjuvant chemotherapy, across a range of regimens and doses. RESULTS: Using multivariate logistic regression analysis, risk factors for grade 4 CIN were identified as older age, lower weight, higher planned dose intensity of doxorubicin, epirubicin, or docetaxel, higher number of planned cycles, vascular comorbidity, lower baseline white blood cell count, and higher baseline bilirubin. Use of colony-stimulating factor before a neutropenic event occurred, dose delays, and dose reductions were protective against grade 4 CIN. CONCLUSIONS: By identifying risk factors for grade 4 CIN, CSF prophylaxis may be appropriately targeted to prevent low RDI in patients treated with curative intent.

Cetuximab given every 2 weeks plus irinotecan is an active and safe option for previously treated patients with metastatic colorectal cancer.

BACKGROUND: We gathered data from multiple institutions on the cetuximab regimen of patients with metastatic colorectal cancer. METHODS: 126 patients from 19 centers were included from July 2006 to July 2007 in this prospective non-controlled study. Irinotecan-refractory metastatic colorectal cancer patients with Karnofsky >or=70 received cetuximab 500 mg/m(2) every 2 weeks (q2w) in combination with irinotecan 180 mg/m(2) q2w until disease progression or unacceptable toxicity. The primary endpoint was the progression-free rate at 12 weeks. RESULTS: Median age was 65 years; 65.9% male; colon/rectum 64.3/34.1%; Karnofsky status or=90% in 45.3/54.7% of the patients. The progression-free rate was 42.7 (95% CI 32.8-52.6) and 22.4% (95% CI 14.2-30.7) at 12 and 24 weeks, respectively. The main grade 3 or 4 toxicities were: diarrhea 13.5% and acne-like rash 10.3%. No grade 3 or 4 infusional or allergic reactions were reported. CONCLUSIONS: The progression-free rates confirm that cetuximab q2w in combination with irinotecan is an option, and is as active and safe as the standard weekly regimen.

Multivariate analysis of febrile neutropenia occurrence in patients with non-Hodgkin lymphoma: data from the INC-EU Prospective Observational European Neutropenia Study.

Myelosuppression, particularly febrile neutropenia (FN), are serious dose-limiting toxicities that occur frequently during the first cycle of chemotherapy. Identifying patients most at risk of developing FN might help physicians to target prophylactic treatment with colony-stimulating factor (CSF), in order to decrease the incidence, or duration, of myelosuppression and facilitate delivery of chemotherapy as planned. We present a risk model for FN occurrence in the first cycle of chemotherapy, based on a subgroup of 240 patients with non-Hodgkin lymphoma (NHL) enroled in our European prospective observational study. Eligible patients had an International Prognostic Index of 0-3, and were scheduled to receive a new myelosuppressive chemotherapy regimen with at least four cycles. Clinically relevant factors significantly associated with cycle 1 FN were older age, increasing planned cyclophosphamide dose, a history of previous chemotherapy, a history of recent infection, and low baseline albumin (<35 g/l). Prophylactic CSF use and higher weight were associated with a significant protective effect. The model had high sensitivity (81%) and specificity (80%). Our model, together with treatment guidelines, may rationalise the clinical decision of whether to support patients with CSF primary prophylaxis based on their risk factor profile. Further validation is required.

Neutropenia occurrence and predictors of reduced chemotherapy delivery: results from the INC-EU prospective observational European neutropenia study.

GOALS OF WORK: Neutropenia is a life-threatening, dose-limiting toxicity of many chemotherapy regimens. The goals of this study were to assess the incidence and risk of chemotherapy-induced neutropenia, febrile neutropenia (FN) and dose limitations in breast cancer and lymphoma patients undergoing chemotherapy in Europe. PATIENTS AND METHODS: Four hundred forty-four breast cancer and 305 lymphoma patients undergoing chemotherapy at 66 practices in five European countries participated in this prospective, observational study. Predictors of impaired chemotherapy delivery were investigated using a logistic regression model. MAIN RESULTS: In breast cancer, FN incidence was low (6%); however, grade 4 neutropenia was frequent (34%). Lymphoma patients experienced higher incidences of FN (non-Hodgkin lymphoma (NHL) 22%; Hodgkin lymphoma (HL) 15%) and grade 4 neutropenia (NHL 54%; HL 40%). For both diseases, FN and grade 4 neutropenia were associated with low relative dose intensity (RDI). Multivariate regression models indicated that first cycle FN, age > or = 65 years and Eastern Co-operative Oncology Group > 1 were associated with low RDI in breast cancer and lymphoma, while colony-stimulating factor (CSF) primary prophylaxis appeared to be protective in lymphoma only. Primary CSF prophylaxis was provided to 9% of breast cancer, 28% of NHL and 19% of HL patients. CONCLUSIONS: Neutropenia and low RDI remain serious problems in both breast cancer and lymphoma populations undergoing chemotherapy. Several risk factors which can trigger reduced chemotherapy delivery were identified. These results can support physicians in identifying patients most at risk of receiving impaired chemotherapy delivery who would benefit from suitable preventive measures.

High circulating HER2 extracellular domain levels correlate with reduced efficacy of an aromatase inhibitor in hormone receptor-positive metastatic breast cancer: a confirmatory prospective study.

BACKGROUND: In this specifically designed, prospective study, the authors addressed the predictive value of circulating levels of the extracellular domain (ECD) of HER2 in patients with metastatic breast cancer who were treated with letrozole. METHODS: Two hundred twenty-six patients with hormone receptor-positive, metastatic breast cancer received letrozole (2.5 mg daily) until they developed either disease progression or unacceptable toxicity. Efficacy was measured primarily as the time to progression (TTP) and, secondarily, as the objective response rate (ORR) and overall survival. HER2 ECD levels were determined by using a sandwich enzyme HER2/neu immunoassay before letrozole treatment was initiated. Positive HER2 ECD status was correlated with treatment efficacy. RESULTS: Forty-two patients (19%) had elevated HER2 ECD levels, which were associated with primary tumor HER2 expression (P < .001) but not with age, performance status, location, or number of metastatic sites. The median TTP was significantly shorter among patients who had elevated HER2 ECD compared with the median TTP among patients who had normal levels (4 months vs 14 months; P = .0004), and the ORR was lower in the group with elevated HER2 ECD levels (14% vs 30%; P < .036). Overall survival was significantly shorter among patients with elevated serum HER-2 ECD (P < .0005). CONCLUSIONS: Elevated HER2 ECD concentrations predicted poorer outcomes in postmenopausal women with metastatic hormone receptor-positive breast cancer who were treated with aromatase inhibitors like letrozole.

Clinical benefit with docetaxel plus fluorouracil and cisplatin compared with cisplatin and fluorouracil in a phase III trial of advanced gastric or gastroesophageal cancer adenocarcinoma: the V-325 Study Group.

PURPOSE: For patients with advanced gastric or gastroesophageal cancer (AGGEC) providing clinical benefit with improved palliation is highly desirable. However, a prospective evaluation of clinical benefit in AGGEC patients has never before been reported in a phase III setting. PATIENTS AND METHODS: In a multinational trial (V325), 445 patients were randomly assigned and treated with either docetaxel plus cisplatin and fluorouracil (DCF) or cisplatin and fluorouracil (CF). Clinical benefit was prospectively evaluated in this trial as a secondary end point. The primary measure for clinical benefit analysis was time to definitive worsening by one or more categories of Karnofsky performance status (KPS). Secondary clinical benefit end points included time to 5% definitive weight loss, time to definitive worsening of appetite by one grade, pain-free survival (defined as time to first appearance of pain), and time to first cancer pain-related opioid intake. Clinical benefit assessments were recorded at each clinic visit. RESULTS: Clinical benefit assessments were performed in more than 75% of patients throughout V325. DCF significantly prolonged time to definitive worsening of KPS compared with CF (median, 6.1 v 4.8 months; hazard ratio, 1.38; 95% CI, 1.08 to 1.76; log-rank P = .009). Although time to definitive weight loss and time to definitive worsening of appetite favored DCF, the results were not statistically significant. Pain-free survival and time to first cancer pain-related opioid intake were comparable. CONCLUSION: To our knowledge, V325 is the first phase III trial to report clinical benefit in AGGEC patients. Clinical benefit was assessed beyond protocol-specific chemotherapy. The addition of D to CF not only significantly improved clinical benefit but also improved quality of life, time to progression, and overall survival compared with CF.

Quality of life with docetaxel plus cisplatin and fluorouracil compared with cisplatin and fluorouracil from a phase III trial for advanced gastric or gastroesophageal adenocarcinoma: the V-325 Study Group.

PURPOSE: Therapy of patients with advanced gastric or gastroesophageal junction cancer should provide symptom relief and improve quality of life (QOL) because most patients are symptomatic at baseline. Using validated instruments, we prospectively assessed QOL (even after completion of protocol treatment) as one of the secondary end points of the V325 phase III trial. PATIENTS AND METHODS: Four hundred forty-five patients randomly received either docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) each on day 1 plus fluorouracil 750 mg/m(2)/d continuous infusion on days 1 to 5 every 3 weeks (DCF) or cisplatin 100 mg/m(2) on day 1 plus fluorouracil 1,000 mg/m(2)/d continuous infusion on days 1 to 5 every 4 weeks (CF). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and, where available, the EuroQOL EQ-5D questionnaire were administered every 8 weeks from baseline until progression and then every 3 months. Time to definitive deterioration of QOL parameters was analyzed. RESULTS: The proportions of patients having assessable EORTC QLQ-C30 and EQ-5D questionnaires at baseline were 86.0% and 78.7% with DCF, respectively, and 89.7% and 92.8% with CF, respectively. Time to 5% deterioration of global health status (primary end point) significantly favored DCF over CF (log-rank test, P = .01). QOL was preserved longer for patients on DCF than those on CF for all time to deterioration analyses, demonstrating the statistical superiority of DCF compared with CF. CONCLUSION: V325 represents the largest trial with the longest prospectively controlled evaluations of QOL during protocol chemotherapy and follow-up in patients with advanced gastric or gastroesophageal junction cancer. In V325, advanced gastric or gastroesophageal junction cancer patients receiving DCF not only had statistically improved overall survival and time to tumor-progression, but they also had better preservation of QOL compared with patients receiving CF.

Gemcitabine plus docetaxel as first-line chemotherapy in patients with advanced non-small cell lung cancer: a lung cancer Galician group phase II study.

BACKGROUND: Numerous phase II and III clinical trials have demonstrated a higher activity of combined gemcitabine plus docetaxel schedules against non-small cell lung cancer (NSCLC) than that of both agents in monotherapy. METHODS: This phase II study evaluated a 3-week based schedule of docetaxel 85 mg/m(2) (1-h i.v. infusion, d8) combined with gemcitabine 1,000 mg/m(2) (30-min i.v. infusion; d1,8) as first-line chemotherapy for patients with advanced NSCLC. RESULTS: Forty-one patients with non-resectable, stage IIIB/IV, and bidimensionally measurable disease were enrolled. A total of 182 chemotherapy cycles (median 6, range 1-6) was administered to 40 patients during the study; one patient did not receive chemotherapy due to a protocol deviation. Two patients were not evaluable for treatment efficacy. The overall response rate found was 44% (95% CI, 29-59%): three patients (7%) had a complete response and 15 patients (37%) had a partial response (median duration of response = 4.0 months). With a median follow-up of 8.7 months, the median time to disease progression was 4.4 months and the median overall survival was 7.3 months. The combined gemcitabine plus docetaxel chemotherapy was well tolerated except for pulmonary toxicity. The main grade 3-4 hematological toxicity was neutropenia (28% of patients, 9% of cycles). Two cases of febrile neutropenia were reported. The main grade 3-4 non-hematological toxicity was pulmonary toxicity (23% of patients, 6% of cycles). CONCLUSION: Gemcitabine 1,000 mg/m(2) on days 1 and 8 in combination with docetaxel 85 mg/m(2) on day 8 given in 3-week cycles is an active and well-tolerated first-line chemotherapeutic regimen for advanced NSCLC.

Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group.

PURPOSE: In the randomized, multinational phase II/III trial (V325) of untreated advanced gastric cancer patients, the phase II part selected docetaxel, cisplatin, and fluorouracil (DCF) over docetaxel and cisplatin for comparison against cisplatin and fluorouracil (CF; reference regimen) in the phase III part. PATIENTS AND METHODS: Advanced gastric cancer patients were randomly assigned to docetaxel 75 mg/m2 and cisplatin 75 mg/m2 (day 1) plus fluorouracil 750 mg/m2/d (days 1 to 5) every 3 weeks or cisplatin 100 mg/m2 (day 1) plus fluorouracil 1,000 mg/m2/d (days 1 to 5) every 4 weeks. The primary end point was time-to-progression (TTP). RESULTS: In 445 randomly assigned and treated patients (DCF = 221; CF = 224), TTP was longer with DCF versus CF (32% risk reduction; log-rank P < .001). Overall survival was longer with DCF versus CF (23% risk reduction; log-rank P = .02). Two-year survival rate was 18% with DCF and 9% with CF. Overall response rate was higher with DCF (chi2 P = .01). Grade 3 to 4 treatment-related adverse events occurred in 69% (DCF) v 59% (CF) of patients. Frequent grade 3 to 4 toxicities for DCF v CF were: neutropenia (82% v 57%), stomatitis (21% v 27%), diarrhea (19% v 8%), lethargy (19% v 14%). Complicated neutropenia was more frequent with DCF than CF (29% v 12%). CONCLUSION: Adding docetaxel to CF significantly improved TTP, survival, and response rate in gastric cancer patients, but resulted in some increase in toxicity. Incorporation of docetaxel, as in DCF or with other active drug(s), is a new therapy option for patients with untreated advanced gastric cancer.

Neutropenic event risk and impaired chemotherapy delivery in six European audits of breast cancer treatment.

GOALS OF WORK: The aims of this study were to assess chemotherapy treatment characteristics, neutropenic event (NE) occurrence and related risk factors in breast cancer patients in Western Europe. MATERIALS AND METHODS: Six retrospective audits of breast cancer chemotherapy were combined into a dataset of 2,860 individuals. NEs were defined as neutropenia-related hospitalisation, dose reduction > or = 15% or dose delay > or = 7 days. Summation dose intensity (SDI) was calculated to compare different types of chemotherapy regimens on a single scale. Risk factors of NE occurrence and of low relative dose intensity (RDI) < or = 85% were identified by multiple logistic regression. MAIN RESULTS: Patient populations were comparable between audits. Until 1998, cyclophosphamide, methotrexate and fluorouracil regimens were most frequently used, but thereafter, anthracycline-based regimens were most common. NEs occurred in 20% of the patients and low RDI in 16%. NE occurrence predicted low RDI and was associated with higher age, bigger body surface area, lower body mass index, regimen type, more chemotherapy cycles planned, normal to high SDI, concomitant radiotherapy and year of treatment. First cycle NE occurrence predicted NEs from cycle 2 onwards. A risk score using age, SDI, number of planned chemotherapy cycles and concomitant radiotherapy differentiated patients with increasing NE risk (9-37%). An alternative score version not using concomitant radiotherapy performed moderately less well. CONCLUSIONS: NEs occurred frequently in this combined dataset and they affected treatment delivery. Identifying patients at high NE risk enables targeted prophylaxis and may avoid dose limitations.

5-HT3 receptor antagonists for prevention of late acute-onset emesis.

OBJECTIVE: To review the currently available literature on the efficacy of the 5-HT(3) receptor antagonists in the prevention of late acute-onset chemotherapy-induced nausea and vomiting (12-24 h after cytotoxic treatment). DATA SOURCES: Primary articles were identified by PubMed search (performed in March 2004) and through secondary sources. Search terms included granisetron, ondansetron, tropisetron, dolasetron, acute, chemotherapy, nausea, and vomiting (a further search was performed for palonosetron in March 2004). STUDY SELECTION AND DATA EXTRACTION: All studies that performed regular assessments (every 2-6 h) of antiemetic control over the first 24 hours with 5-HT(3) receptor antagonists were evaluated. DATA SYNTHESIS: Current guidelines recommend the use of 5-HT(3) receptor antagonists for the control of chemotherapy-induced nausea and vomiting but do not differentiate between the available agents. However, there is variability in the pharmacokinetic and pharmacodynamic profiles of these agents, and this has implications for dosing regimen, safety, efficacy, and potential drug-drug interactions. Cytotoxic agents vary in the time profile of their emetic effect; this must be considered when choosing an appropriate 5-HT(3) receptor antagonist. The optimal agent should be simple to administer and provide safe and effective antiemetic protection over the whole 24-hour period. CONCLUSIONS: The differences between the 5-HT(3) receptor antagonists have important consequences for their dosing and efficacy in the control of late acute-onset chemotherapy-induced nausea and vomiting.