Lorenzo Alonso

Combined oral cyclophosphamide and bevacizumab in heavily pre-treated ovarian cancer

INTRODUCTION Metronomic chemotherapy combined with bevacizumab has proved to be effective in various tumour types. The aim of this study is to review our experience in recurrent ovarian carcinomas treated with low-dose cyclophosphamide and bevacizumab. MATERIALS AND METHODS Retrospective analysis of pre-treated ovarian cancer patients, i.e., > or =2 previous chemotherapy regimens who received treatment with oral cyclophosphamide 50 mg/day and bevacizumab 10 mg/kg IV every two weeks. Patients with a performance status 0-2 were included. The endpoints were response rates, progressionfree disease and safety profile. RESULTS Nine patients with advanced, measurable ovarian cancer were included. Of these, 8 were platinum-resistant and had received prior regimens with gemcitabine (88%), topotecan (77%) and liposomal doxorubicin (66%). There was a mean of 5 previous lines of chemotherapy, range 2-7. Applying RECIST criteria, the efficacy data were as follows: objective response (OR) 44%; 4/9 (CR 2/9 and PR 2/9), SD 2/9 and DP 3/9. At 6 months, 33% of patients were progression free. Response lasted for 12.5 months in three patients treated for 12 months; a further two patients who were re-treated achieved complete response. Mean time to progression was 5.5 months (95% CI 4.5-5.5). No severe adverse effects were reported. Only one patient had to delay several cycles due to G3 haematuria. Other toxicities observed include G3 abdominal pain (1 case); G2 mucositis and G2 dyspnoea in one patient. CONCLUSIONS Combined bevacizumab and metronomic oral cyclophosphamide is a safe and effective regimen for heavily pre-treated ovarian cancer patients. Further research is needed on predictive factors to screen for those patients who will benefit from anti-angiogenic therapy.

Negative Prognostic Impact of the Coexpression of Epidermal Growth Factor Receptor and c-erbB-2 in Locally Advanced Cervical Cancer

Objective: The objective was to determine the impact of the coexpression of epidermal growth factor receptor (EGFR) and tumor marker c-erbB-2 on disease-free survival (DFS) and pelvic relapse-free survival (PRFS) in patients with locally advanced cervical cancer (LACC) receiving concurrent chemoradiotherapy. Methods: The expression of EGFR and c-erbB-2 was assessed by immunohistochemistry, which was centralized and blinded to outcome. Univariate and multivariate analyses were used to evaluate the impact of EGFR and c-erbB-2 on DFS and PRFS. Results: 170 patients with LACC were included and received concurrent chemoradiotherapy. 25 (15%) biopsies were considered EGFR and c-erbB-2 positive; 100 (59%) were either EGFR or c-erbB-2 positive, and 45 (26%) were EGFR and c-erbB-2 negative. The 3- and 5-year DFS was 39% each for EGFR- and c-erbB-2-positive patients, 54 and 49%, respectively, for EGFR- or c-erbB-2-positive patients, and 76 and 72%, respectively, for EGFR- and c-erbB-2-negative patients (p = 0.006). EGFR- and c-erbB-2-positive tumors were significantly associated with a decrease in PRFS (hazard ratio, HR, 3.99; 95% confidence interval, CI, 1.44–11.05, p = 0.007), and DFS (HR 2.9; 95% CI, 1.26–6.66, p = 0.01). Conclusion: Patients with LACC coexpressing EGFR and c-erbB-2, and treated with concurrent chemoradiotherapy, had a worse clinical prognosis with shorter DFS and PRFS.

Adjuvant anthracycline therapy as a prognostic factor in metastatic breast cancer

AbstractBackground. Prognostic factors in metastatic breast cancer continue to be identified. Previous adjuvant chemotherapy appeared to have poor prognosis in some studies but, despite this, the prior use of anthracyclines in the adjuvant setting has not been clearly established as an adverse prognostic factor once metastatic disease develops. Patients and methods. Patients (n = 1,436) with stages I–IIIa breast cancer were surgically treated with/without radiotherapy and/or systemic adjuvant treatment. Of these, 297 patients who relapsed with metastatic disease constitute the sample population of this retrospective study. Survival, as a function of time since diagnosis of metastatic disease, was assessed in relation to the following factors: age, size of the primary tumor, grade, number of positive axillary nodes, type of surgery, type of adjuvant treatment administered, time to relapse, number of metastatic sites, presence of visceral metastases and type of treatment employed at the time of relapse. Results. In multivariable analysis three factors remained significant predictors of short survival time: more than 1 site of metastases (p = 0.00003), shorter time to relapse (p = 0.003) and the previous administration of anthracyclines as adjuvant therapy (p = 0.005). Conclusions. The prior use of adjuvant anthracyclines, with other known clinical prognostic factors, confers a poorer outcome in metastatic disease, perhaps as a result of resistant clones selection or by induction of de novo resistance.

Association between VEGF expression in tumour-associated macrophages and elevated serum VEGF levels in primary colorectal cancer patients.

OBJECTIVE Angiogenesis is stimulated by angiogenic factors released by tumour cells, though other cells, such as tumour-associated macrophages (TAMs), also contribute towards increasing the angiogenic process in colorectal cancer (CRC). The aim of this study was to determine in CRC patients the contribution of vascular endothelial growth factor (VEGF) expression in TAMs and tumour cells towards circulating VEGF levels, their association with p53 expression and microvascular density (MVD), and their prognostic value. METHODS Immunohistochemical techniques were used to identify TAMs and p53 protein, and to evaluate the VEGF expression in TAMs, MVD and tumour cells in 110 primary CRC patients. Serum VEGF levels were determined using an enzyme immune assay. RESULTS There was a greater expression of VEGF in tumours with a positive p53 expression than a negative stain (p<0.01). The macrophage index was not related to tumour VEGF secretion. No significant association was observed between serum VEGF levels and VEGF tumour expression, node status, histological grade, MVD or p53 expression. However, the patients with high values of VEGF expression in TAMs showed significantly higher presurgery serum VEGF levels than those patients with low values of VEGF expression in TAMs (p=0.021). No statistical significant differences in survival were found when we compared patients with high VEGF expression in TAMs vs low or median VEGF expression in TAMs (p=0.093). Serum VEGF levels were increased 6-8 hours after tumour removal (p=0.001). CONCLUSIONS Our data suggest that in primary CRC, presurgery circulating VEGF levels are related to VEGF produced by TAMs.

Cisplatin, 5-fluorouracil, and high-dose folinic acid in patients with advanced unresectable head and neck cancer.

For patients with advanced, unresectable head and neck (HN) cancer, surgery and/or radiotherapy are the standard treatments but have poor results. A phase II trial of a continuous infusion of cisplatin, 5-FU, and high dose folinic acid (PFL) as induction chemotherapy in patients with previously untreated, locally advanced HN cancer was performed in an attempt to confirm the encouraging results reported by Dana Farber investigators using an identical regimen. Forty-five consecutive patients with unresectable HN cancer were treated every 28 days with a continuous infusion of cisplatin 25 mg/m(2)/day (days 1-5), 5-FU 800 mg/m(2)/day (days 2-6), and folinic acid 500 mg/m(2)/day (days 1-6). After three courses of chemotherapy, patients were treated with surgery and/or radiotherapy. Objective responses were observed in 26 of 38(69%) evaluable patients with 14(37%) clinical complete responses. Grade III-IV toxicity was important and consisted mainly of mucositis and neutropenia that were found in 47 and 18%, respectively , of patients after the first course. There was one toxic death. PFL is an active, toxic induction regimen for far-advanced HN cancer, yielding a response rate in the range of the widely used cisplatin and 5-FU (PF) schedule; a comparative trial is warranted before concluding that PFL is superior to the latter combination.

¿Diagnosticar mejor? Savia nueva para un árbol viejo

El diagnóstico en Medicina, palabra que proviene del griego diagnóstikós y significa «distinguir o conocer», es la pieza clave del acto médico a partir del cual pueden tomarse decisiones con el paciente. El diagnóstico y la estrategia terapéutica están ı́ntimamente relacionados y, lejos de ser un proceso estático, es un continuo dinámico donde la variable tiempo desempeña un papel fundamental para plantear el proyecto global de actuación. Sin embargo, diagnosticar no solo no es fácil en muchas ocasiones, sino que las probabilidades de errar son elevadas si tenemos en cuenta primero el elevado número de procesos para reconocer, que alcanzan una cifra superior a 10.000 según la Clasificación de Enfermedades de la Organización Mundial de la Salud, unido a la variabilidad de la biologı́a humana y a las caracterı́sticas de los procesos mentales implicados en el razonamiento clı́nico. El contacto con el mayor número de entidades patológicas facilita su detección, pero otros factores, unos externos relacionados con el lugar de práctica y otros relacionados con la base mental del razonamiento clı́nico, influyen de manera decisiva en el resultado final. El conocimiento de estos factores, la posibilidad de detección de los puntos de mejora y la medida del posible error comienzan a ser objetivo primordial del quehacer clı́nico.

Time to Diagnosis of Ewing Tumors in Children and Adolescents Is Not Associated With Metastasis or Survival

TO THE EDITOR: Ewing=s sarcoma is special in several ways, first of all because most of the patients are young children or adolescent and second because a perfect coordination between chemotherapy, surgery, and radiotherapy must be implemented to achieve the high percentage of cure that we can see presently. The experience of the French group of pediatricians at the Institute Gustav Roussy has been fundamental to setting the algorithm of treatment and the outcome in this tumor. Brasme et al summarize this experience but from a new perspective, analyzing the association between epidemiologic variables and patient characteristic, tumor variables, and survival. The conclusion is that time to diagnosis (TtD) expressed in days, and defined as the time from onset of symptoms to the date of diagnosis, is not associated with a worse outcome in terms of metastases or survival. But we believe that to assume this conclusion as a rule can be risky for several reasons: first, the study is based on a group of patients from two different clinical trials with different treatment, even a consolidation arm, and we do not know how this variable was included in the multivariable model. Also, the authors assume a nondifferential misclassification for TtD, but this is difficult to prove because they do not show, for instance, some other possible indirect measures such as the number of visits before diagnosis. In the study by Brasme et al, the only prognostic factors independently associated with characteristic of the patients are site location and older age. The authors considered that the worst prognosis for children older than 12 years could be related to a different clinical behavior, but we think that it is also worthy to consider as an explanation a cognitive bias in the clinical reasoning process of the clinicians attending these patients. A “representativeness bias” drives the doctor=s mind to a prototypical situation where bone pain is associated with growth, which results in a longer TtD, or in other words, a diagnostic delay. We want to congratulate the authors for the clear explanations, but we think that there is still room to reduce TtD of Ewing=s sarcoma and that the clinical reasoning process in pediatricians and doctors involved in treating these patients can be improved.

Variabilidad en la utilización del tratamiento conservador del cancer de marna localizado en un área geográfica

ObjetivosConocer el porcentaje de tratamiento conservador del cancer de marna en estadios I y II en un área geográfica, la variabilidad de indicación entre diferentes centros y los posibles factores relacionados.MétodosEn un estudio de corte transversal retrospectivo se recogieron un total de 225 casos de cáncer de marna en estadios iniciales y se determinó el tipo de cirugía (conservadora o mastectomía) y su relación con posibles predictores de la misma.ResultadosLa frecuencia de conservación mamaria fue del 27% para el conjunto de casos (IC del 95%, 22–34%). En el estadio I se realizó en el 49% de casos y en el estadio II en el 21%. La probabilidad de ser tratada con tratamiento conservador no pudo establecerse ni con la edad de la paciente ni con el área de residencia rural o urbana, pero si de forma significativa con el centro de tratamiento y el estadio.ConclusionesLa menor frecuencia de conservación en estadio II no se ajusta en nuestro medio a los estándares aceptados. Factores propios de cada centro o del cirujano que atiende a la paciente pueden explicar la variabilidad en la frecuencia de indicación de conservación mamaria entre ellos.AbstractObjectivesTo determine the percentage of breast conservation surgery in patients with stage I and stage II breast cancer carried out in a geographic area, the variability in treatment among different centers and the possible factors associated with the choice of this type of procedure as opposed to another.Material and methodsRetrospective transversal study of 225 patients with early-stage breast cancer. The patients were reviewed to determine the type of surgery carried out (breast conserving or mastectomy). The possibility of a relationship between the type of surgery performed and associated variables was also evaluated.ResultsThe total frequency of breast conserving treatment was 27% (95% CI, 22%–24%). This type of treatment was carried out in 49% of patients with stage I cancer and 21% of those with the stage II cancer. The probability of being treated with breast conserving surgery was not found to be related to patient age or to rural or urban residence but was significantly related to the treatment center and to tumor stage.ConclusionsThe lower frequency of breast conserving therapy in stage II is not directly related to established clinical practice guidelines. Other factors such as the treatment center or the surgeon’s preference for one type of treatment are possible explanations for the degree of variation observed in breast conserving procedures.

WEEKLY FIRST-LINE CHEMOTHERAPY OF METASTATIC BREAST CANCER WITH CYCLOPHOSPHAMIDE AND EPIRUBICIN

Forty-six patients with metastatic breast cancer who had not received previous chemotherapy for advanced disease entered a phase II trial of weekly chemotherapy with cyclophosphamide (250 mg/m2) + epirubicin (25 mg/m2) for 16 weeks. The overall response rate was 61 % (95 % confidence limits, 47-75 %), with 10 complete and 17 partial responses. Toxicity was mild and confined to nausea and vomiting and asymptomatic neutropenia (except in 2 cases). Sixty-three per cent of patients had no side effects. Weekly cyclophosphamide + epirubicin is an active and nontoxic regimen for patients with metastatic breast cancer who have had no prior anthracycline-containing adjuvant chemotherapy.