Ismael Ghanem

Bevacizumab plus low-dose metronomic oral cyclophosphamide in heavily pretreated patients with recurrent ovarian cancer.

Aim: To retrospectively assess the efficacy and safety of bevacizumab plus low-dose metronomic oral cyclophosphamide in heavily pretreated patients with recurrent ovarian cancer. Patients and Methods: Patients with recurrent ovarian cancer and prior treatment with platinum- and taxane-based chemotherapy were included. Treatment consisted of bevacizumab 10 mg/kg intravenously every 2 weeks plus oral cyclophosphamide 50 mg daily until disease progression or unacceptable toxicity. Response rates (RR) were determined according to RECIST criteria and by monitoring the CA 125 serum tumor marker according to Rustin’s criteria. The endpoints were progression-free survival (PFS), RR, overall survival (OS), and safety. Results: Thirty-eight patients were treated; 79% were platinum resistant and 21% were platinum sensitive. The median number of previous treatments was 4 (range 1–8). Seventy-nine percent of patients had received more than 2 previous lines of treatment. Eighty-one percent of patients had received gemcitabine, 76% liposomal doxorubicin, and 50% topotecan. A median of 8 (range 1–70) cycles of bevacizumab were administered. The overall RR was a complete response (CR) in 3 patients (8.1%), a partial response (PR) in 12 (32.4%), and stable disease (SD) ≧6 months in 3 (8.1%). The median PFS and OS were 4.5 and 10.7 months, respectively. Thirty-nine percent of patients were progression free for at least 6 months. In an exploratory analysis there was a significant relation of prior platinum response and performance status with the risk of progression. Grade 3–4 toxicities included anemia (1), hypertension (2), hematuria (1), arterial thrombosis in the leg (1), dyspnea (1), and intestinal fistulae (1). There were no cases of gastrointestinal perforation (GIP) or treatment-related deaths. Conclusion: The combination of bevacizumab and metronomic cyclophosphamide was active and well-tolerated in heavily pretreated patients with recurrent ovarian cancer.

Prediction of Serious Complications in Patients With Seemingly Stable Febrile Neutropenia: Validation of the Clinical Index of Stable Febrile Neutropenia in a Prospective Cohort of Patients From the FINITE Study

PURPOSE To validate a prognostic score predicting major complications in patients with solid tumors and seemingly stable episodes of febrile neutropenia (FN). The definition of clinical stability implies the absence of organ dysfunction, abnormalities in vital signs, and major infections. PATIENTS AND METHODS We developed the Clinical Index of Stable Febrile Neutropenia (CISNE), with six explanatory variables associated with serious complications: Eastern Cooperative Oncology Group performance status ≥ 2 (2 points), chronic obstructive pulmonary disease (1 point), chronic cardiovascular disease (1 point), mucositis of grade ≥ 2 (National Cancer Institute Common Toxicity Criteria; 1 point), monocytes < 200 per μL (1 point), and stress-induced hyperglycemia (2 points). We integrated these factors into a score ranging from 0 to 8, which classifies patients into three prognostic classes: low (0 points), intermediate (1 to 2 points), and high risk (≥ 3 points). We present a multicenter validation of CISNE. RESULTS We prospectively recruited 1,133 patients with seemingly stable FN from 25 hospitals. Complication rates in the training and validation subsets, respectively, were 1.1% and 1.1% in low-, 6.1% and 6.2% in intermediate-, and 32.5% and 36% in high-risk patients; mortality rates within each class were 0% in low-, 1.6% and 0% in intermediate-, and 4.3% and 3.1% in high-risk patients. Areas under the receiver operating characteristic curves in the validation subset were 0.652 (95% CI, 0.598 to 0.703) for Talcott, 0.721 (95% CI, 0.669 to 0.768) for Multinational Association for Supportive Care in Cancer (MASCC), and 0.868 (95% CI, 0.827 to 0.903) for CISNE (P = .002 for comparison between CISNE and MASCC). CONCLUSION CISNE is a valid model for accurately classifying patients with cancer with seemingly stable FN episodes.

Management of pancreatic cancer in the elderly

Currently, pancreatic adenocarcinoma mainly occurs after 60 years of age, and its prognosis remains poor despite modest improvements in recent decades. The aging of the population will result in a rise in the incidence of pancreatic adenocarcinoma within the next years. Thus, the management of pancreatic cancer in the elderly population is gaining increasing relevance. Older cancer patients represent a heterogeneous group with different biological, functional and psychosocial characteristics that can modify the usual management of this disease, including pharmacokinetic and pharmacodynamic changes, polypharmacy, performance status, comorbidities and organ dysfunction. However, the biological age, not the chronological age, of the patient should be the limiting factor in determining the most appropriate treatment for these patients. Unfortunately, despite the increased incidence of this pathology in older patients, there is an underrepresentation of these patients in clinical trials, and the management of older patients is thus determined by extrapolation from the results of studies performed in younger patients. In this review, the special characteristics of the elderly, the multidisciplinary management of localized and advanced ductal adenocarcinoma of the pancreas and the most recent advances in the management of this condition will be discussed, focusing on surgery, chemotherapy, radiation and palliative care.

Role of inhibitors of mammalian target of rapamycin in the treatment of luminal breast cancer.

Approximately 75% of patients with breast cancer present hormone receptor-positive tumors. This subtype of breast cancer initially shows a high overall response rate to hormonal treatments. However, resistance eventually develops, resulting in tumor progression. The PI3K/Akt/mTOR pathway regulates several cellular functions in cancer such as cell growth, survival, and proliferation. In addition, a high activation level of the PI3K/Akt/mTOR pathway is related to resistance to conventional chemotherapy and hormone therapy. The mTOR inhibitor everolimus, in combination with hormonal treatments, has led to excellent results in progression-free survival in patients with metastatic breast cancer resistant to hormone therapies. Therefore, everolimus has entered the National Comprehensive Cancer Network (NCCN) guidelines 2012 and its combination with exemestane was approved recently by the US Food and Drug Administration and the European Medicines Agency. This is the first time that a drug will have been approved for the restoration of hormone sensitivity in breast cancer.

A nomogram for predicting complications in patients with solid tumours and seemingly stable febrile neutropenia

Background:We sought to develop and externally validate a nomogram and web-based calculator to individually predict the development of serious complications in seemingly stable adult patients with solid tumours and episodes of febrile neutropenia (FN).Patients and methods:The data from the FINITE study (n=1133) and University of Salamanca Hospital (USH) FN registry (n=296) were used to develop and validate this tool. The main eligibility criterion was the presence of apparent clinical stability, defined as events without acute organ dysfunction, abnormal vital signs, or major infections. Discriminatory ability was measured as the concordance index and stratification into risk groups.Results:The rate of infection-related complications in the FINITE and USH series was 13.4% and 18.6%, respectively. The nomogram used the following covariates: Eastern Cooperative Group (ECOG) Performance Status ⩾2, chronic obstructive pulmonary disease, chronic cardiovascular disease, mucositis of grade ⩾2 (National Cancer Institute Common Toxicity Criteria), monocytes <200/mm3, and stress-induced hyperglycaemia. The nomogram predictions appeared to be well calibrated in both data sets (Hosmer–Lemeshow test, P>0.1). The concordance index was 0.855 and 0.831 in each series. Risk group stratification revealed a significant distinction in the proportion of complications. With a ⩾116-point cutoff, the nomogram yielded the following prognostic indices in the USH registry validation series: 66% sensitivity, 83% specificity, 3.88 positive likelihood ratio, 48% positive predictive value, and 91% negative predictive value.Conclusions:We have developed and externally validated a nomogram and web calculator to predict serious complications that can potentially impact decision-making in patients with seemingly stable FN.

A nomogram for predicting serious complications in patients with solid tumors and apparently stable febrile neutropenia: Prospective data on 781 consecutive episodes from the FINITE study.

165 Background: An accurate estimate of the likelihood of serious complications in patients with otherwise apparently stable febrile neutropenia (FN) may assist in decision-making regarding individualized therapy. Our group has developed a prognostic score for predicting complications in patients with solid tumors and apparently stable episodes called CISNE (Clinical Index for Stable Febrile Neutropenia). The purpose of this study is to present a nomogram based on the previously mentioned index in a broader dataset of patients. METHODS FINITE is a prospective and multicenter study which aims to investigate prognostic factors and outcomes of FN episodes with clinical stability at first assessment, defined as events without acute organ dysfunction, vital signs abnormalities or major infections. We performed a nomogram based on the CISNE score which includes the following prognostic variables: ECOG PS≥2, chronic obstructive pulmonary disease, cardiovascular disease, mucositis NCI grade ≥2, monocytes <200/mm3 and stress-induced hyperglycemia. A calibration plot was used to analyze the accuracy of this multivariate nomogram. RESULTS From October 2012 to December 2013, 781 patients with apparently stable FN were recruited in 21 Spanish hospitals. The rate of infection-related complications and death was 15.6% (95% confidence interval [CI], 12.9-18.6%) and 1.7% (95% CI, 0.98%-3.01%). A nomogram was designed according to the CISNE score. The area under the ROC curve was 0.836 (95% CI, 0.808-0.861). The observed and predicted probabilities also matched closely. CONCLUSIONS Our group has developed a user-friendly nomogram for predicting complications in patients with apparently stable FN. This nomogram may be particularly useful to prevent premature discharges of cancer patients starting inpatient management.

Lapatinib plus trastuzumab in pretreated human epidermal growth factor receptor 2-positive metastatic breast cancer

BACKGROUND Dual human epidermal growth factor receptor 2 (HER2) blockade has been preclinically and clinically assessed in HER2-overexpressing metastatic breast cancer (mBC) with encouraging results. PATIENTS AND METHODS This is a descriptive retrospective study of trastuzumab plus lapatinib activity in patients with HER2-overexpressing mBC from two centers. The primary endpoints were to assess objective response rate (ORR) and toxicity. The secondary endpoints were to assess progression-free survival (PFS) and overall survival. RESULTS A total of 23 HER2-positive mBC patients previously treated with trastuzumab received a trastuzumab plus lapatinib based therapy. Chemotherapy (CT) was added to the dual HER2 blockade treatment in 13 patients (56%), whereas hormonotherapy (HT) was added in 8 patients (35%) and 2 patients (9%) received lapatinib plus trastuzumab without any other agent. ORR was 22% (5/23) and 39% (9/23) of patients had stable disease. PFS in the overall population was 4 months. PFS in patients with CT was 5 months, whereas PFS in patients with HT was 2 months. Grade≥3 adverse events were diarrhea (26%) and hand-and-foot syndrome (9%). CONCLUSIONS These findings suggest that dual HER2 blockade in combination with CT is feasible in pretreated HER2-positive mBC patients.

Estoicismo frente al cáncer: riesgo o protección

Detectar una actitud de afrontamiento estoica en los pacientes con cancer es importante porque puede favorecer o dificultar el tratamiento oncologico. Objetivo: En este trabajo, analizamos si en funcion de la edad, el genero, la presencia de dolor y el tiempo transcurrido desde que empezaron los sintomas hasta el diagnostico del cancer, podemos asignar a las conductas estoicas un valor positivo o negativo, como factor de proteccion o de riesgo en los pacientes. Material y Metodos: evaluamos 540 pacientes que acudieron a la consulta de Oncologia Medica para valoracion de tratamiento adyuvante tras una cirugia oncologica, entre junio del 2015 y diciembre del 2016. Los datos clinicos y demograficos se obtuvieron a traves de la entrevista medica y fueron: genero, edad, estado civil, nivel educativo, area ocupacional, localizacion del tumor, estadio y tiempo trascurrido desde la presencia de los sintomas y la consulta al medico. Se administraron en papel y presencialmente los siguientes cuestionarios: Inventario de Dolor Breve, Brief Symptom Inventory y Liverpool Stoicism Scale . Resultados: Los hombres de la muestra mostraron casi 5 veces mas probabilidad de presentar altas puntuaciones en estoicismo que las mujeres y 7 veces mas si se asocia un estado de animo decaido y edad avanzada. El estoicismo fue mayor en los pacientes de mas edad. No se ha hallado relacion entre el estoicismo y las escalas de dolor. Conclusion: Las tres caracteristicas que discriminan mejor entre los pacientes con altas y/o bajas puntuaciones en estoicismo son el genero, la edad y el estado de animo depresivo. El hecho de que el estoicismo este asociado a hombres ancianos con depresion nos hace pensar que el estoicismo debe ser considerado mas como un factor de riesgo que de proteccion. La madurez relacionada con la edad conlleva inevitablemente una mayor aceptacion de las perdidas y una propension a ocultar el dolor, o a no buscar ayuda para evitar mostrar debilidad. Ante esta situacion es importante contar con la informacion que nos proporciona la familia y reconocer la importancia del apoyo familiar sobre a estas personas que pueden ser de entrada mas vulnerables.

Analysis of response rate with ANTI PD1/PD-L1 monoclonal antibodies in advanced solid tumors: a meta-analysis of randomized clinical trials

Background Anti-PD1/PD-L1 monoclonal antibodies (mAbs) increase overall survival compared to standard of care (SOC) in different tumors. However, a proportion of patients (pts) will have progressive disease (PD) as best response. We conducted a meta-analysis to study the rates of response comparing these antibodies with SOC. Methods A search of published trials in MEDLINE and EMBASE analyzing anti-PD1/PD-L1mAbs monotherapy compared to SOC. Relative risk (RR) with 95% confidence interval (CI) of response rates between groups was estimated. Subgroup analyses for location of primary tumor, number of previous treatment lines, selected population by PD-L1 expression and type of radiological assessment were made. Results Twelve studies accounting for 6,700 pts were included (anti-PD1/PD-L1 mAbs: 3,451 pts; SOC: 3,249 pts [2,823 pts: chemotherapy, 426 pts: targeted therapy]). Adjusted response rates were (N, %): Complete Response (CR) (69/3153, 2.19%), Partial Response (PR) (596/3153, 18.90%), Stable Disease (SD) (632/2463, 25.66%) and PD (1027/2463, 41.70%); and CR (16/2955, 0.54%), PR (263/2955, 8.90%), SD (835/2269, 36.80%) and PD (834/2269, 36.76%) with anti-PD1/PD-L1 mAbs and SOC, respectively. Anti-PD1/PD-L1 mAbs improved CR rate (RR 3.48) and PR rate (RR 2.27). There were no differences in the PD rate between groups (RR 1.10). Subgroup analyses showed an improvement in clinical benefit with anti-PD1/PD-L1 mAbs for melanoma (RR 1.59; 1.37–1.84 95% CI) and those treated in the first line setting (RR 1.57; 1.27–1.95 95% CI). Conclusions Anti-PD1/PD-L1 mAbs increase overall response rate compared to SOC without an increase in PD rate. Melanoma and pts treated in first line setting seem to have greater benefit with anti-PD1/PD-L1 mAbs. Findings In this systematic meta-analysis, anti-PD1/PD-L1 mAbs were associated with a greater overall response rate. Patients with melanoma and those managed in the first line setting seem to have an additional benefit with anti-PD1/PD-L1 mAbs.

Psychometric properties of the Shared Decision-Making Questionnaire (SDM-Q-9) in oncology practice

Background/Objective: This study sought to assess the psychometric properties of the 9-item Shared Decision-Making Questionnaire (SDM-Q-9) in patients with resected, non-metastatic cancer and eligible for adjuvant chemotherapy. Method: A total of 568 patients were recruited from a multi-institutional, prospective, transversal study. Patients answered the SDM-Q-9 after visiting their medical oncologist who, in turn, completed the SDM-Q–Physician version. Reliability, factorial structures [exploratory factor analysis (EFA), confirmatory factor analysis (CFA)], and convergent validity of the SDM-Q-9 scores were explored. Results: SDM-Q-9 showed a clear factorial structure, compatible with a strong and replicable general factor and a secondary group factor, in patients with resected, non-metastatic cancer. Total sum scores derived from the general factor showed good reliability in terms of omega coefficient: .90. The association between patient and physician perception of SDM was weak and failed to reach statistical significance. Males and patients over 60 years of age displayed the greatest satisfaction with SDM. Conclusions: SDM-Q-9 can aid in evaluating SDM from the cancer patients’ perspective. SDM-Q-9 is helpful in studies examining patient perspectives of SDM and as an indicator of the degree of quality and satisfaction with health care and patient-physician relationship.