Phase II randomized, double-blind, placebo-controlled study of whole-brain irradiation with concomitant chloroquine for brain metastases.

BACKGROUND AND PURPOSE: Chloroquine (CLQ), an antimalarial drug, has a lysosomotropic effect associated with increased radiationsensibility, which is mediated by the leakage of hydrolytic enzymes, increased apoptosis, autophagy and increased oxidative stress in vitro. In this phase II study, we evaluated the efficacy and safety of radiosensibilization using CLQ concomitant with 30 Gray (Gy) of whole-brain irradiation (WBI) to treat patients with brain metastases (BM) from solid tumors. METHODS: Seventy-three eligible patients were randomized. Thirty-nine patients received WBI (30 Gy in 10 fractions over 2 weeks) concomitant with 150 mg of CLQ for 4 weeks (the CLQ arm). Thirty-four patients received the same schedule of WBI concomitant with a placebo for 4 weeks (the control arm). All the patients were evaluated for quality of life (QoL) using the EORTC Quality of Life (QoL) Questionnaire (EORTC QLQ-C30) (Mexican version) before beginning radiotherapy and one month later. RESULTS: The overall response rate (ORR) was 54% for the CLQ arm and 55% for the control arm (p=0.92). The progression-free survival of brain metastases (BMPFS) rates at one year were 83.9% (95% CI 69.4-98.4) for the CLQ arm and 55.1% (95% CI 33.6-77.6) for the control arm. Treatment with CLQ was independently associated with increased BMPFS (RR 0.31,95% CI [0.1-0.9], p=0.046).The only factor that was independently associated with increased overall survival (OS) was the presence of< 4 brain metastases (RR 1.9, 95% CI [1.12-3.3], p=0.017). WBI was associated with improvements in cognitive and emotional function but also with worsened nausea in both patients groups. No differences in QoL or toxicity were found between the study arms. CONCLUSION: Treatment with CLQ plus WBI improved the control of BM (compared with the control arm) with no increase in toxicity; however, CLQ did not improve the RR or OS. A phase III clinical trial is warranted to confirm these findings.

Clinical features and prognostic factors in patients with carcinomatous meningitis secondary to breast cancer.

Prognosis in patients with carcinomatous meningitis (CM) is poor, and numerous prognostic factors for response and survival have been described, but remain controversial. In general, series are small and involve a heterogeneous type of solid neoplasms. The purpose of this study was to describe a series of patients with breast cancer-associated CM to determine the clinical features and prognostic factors associated with survival. We conducted a retrospective study on 49 patients diagnosed between January 2003 and December 2007 at the Instituto Nacional de Cancerología in Mexico City. CSF cytopathology samples were re-reviewed to confirm the diagnosis. Overall survival (OS) for patients with breast cancer with CM was 7 weeks. Factors independently associated with better OS included absence of encephalopathy at diagnosis (11 weeks versus 1 week; p = .036), low CSF protein content (15 versus 5 weeks; p = .022), and nontriple-negative receptor status in the primary breast cancer tumor (13 versus 3 weeks; p = .015). According to multivariate analysis, patients were divided into favorable and poor prognostic groups, with OS of 14 weeks and 2 weeks, respectively (p < .001). These factors can identify a subgroup of patients who are candidates for an intensive management approach.

Whole-brain irradiation with concomitant daily fixed-dose temozolomide for brain metastases treatment: a randomised phase II trial.

BACKGROUND AND PURPOSE: This randomised phase II study evaluated the use of Temozolomide (TMZ) concomitant with 30 Gray (Gy) of Whole-brain irradiation (WBI) for 2 weeks without adjuvant TMZ vs. WBI alone in patients with Brain metastases (BM) from solid tumours. MATERIALS AND METHODS: Fifty-five patients were randomised into the following groups: 28 patients received WBI (30 Gy in 10 fractions over 2 weeks) concomitant with once-daily 200 mg TMZ on Mondays, Wednesdays, and Fridays, and 300 mg TMZ on Tuesdays and Thursdays (TMZ plus WBI arm). Twenty-seven patients received the same schedule of WBI alone (control arm). RESULTS: The objective response (OR) was 78.6% for the TMZ plus WBI arm, (95% confidence interval [CI], 63.4-93.8%) and 48.1% (29.3-66.9%) for the control arm (p=0.019). Median Progression-free survival (PFS) of BM was 11.8 months (CI, 4.7-8.9 months) and 5.6 months (4.9-6.2 months) for the TMZ plus WBI and control arms, respectively, (Hazard ratio [HR], 0.24; CI, 0.09-0.65; p=0.005). Overall survival (OS) of 8.0 Months for the TMZ plus WBI arm and 8.1 months for the control arm, were not significantly different. CONCLUSION: A daily fixed dose of TMZ during WBI without adjuvant TMZ was well tolerated and significantly improved local control of BM compared with WBI alone. These findings require confirmation in a phase III trial (ClinicalTrials.gov number, NCT01015534).

Concurrent chemo-radiotherapy following neoadjuvant chemotherapy in locally advanced breast cancer.

BACKGROUND: Despite broad advances in multimodal treatment of locally advanced breast cancer (LABC), 30 to 40% of patients develop loco-regional relapse. The aim of this study was to analyze in a retrospective manner the effectiveness of concurrent chemo-radiotherapy (CCRTh) after neoadjuvant chemotherapy (NCT) in patients with LABC. METHODS: One hundred twelve patients with LABC (stage IIB-IIIB) were treated with NCT (5-fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 (FAC), or doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (AC) IV in four 21-day courses) followed by CCRTh (60 Gy breast irradiation and weekly mitomycin 5 mg/m2, 5-fluorouracil 500 mg/m2, and dexamethasone 16 mg, or cisplatin 30 mg/m2, gemcitabine 100 mg/m2 and dexamethasone 16 mg), and 6-8 weeks later, surgery and two additional courses of FAC, AC, or paclitaxel 90 mg/m2 weekly for 12 weeks, and in case of estrogen-receptor positive patients, hormonal therapy. RESULTS: Stages IIB, IIIA and -B were 21.4, 42.9, and 35.7%, respectively. Pathological complete response (pCR) in the breast was 42% (95% CI, 33.2-50.5%) and, 29.5% (95% CI, 21.4-37.5%) if including both the breast and the axillary nodes. Multivariate analysis showed that the main determinant of pCR was negative estrogen-receptor status (HR=3.8; 95% CI, 1.5-9; p=0.016). The 5-year disease-free survival (DFS) was 76.9% (95% CI, 68.2-84.7%). No relationship between pCR and DFS was found. Multivariate analysis demonstrated that the main DFS determinant was clinical stage (IIB and IIIA vs. IIIB, HR=3.1; 95% CI, 1.02-9.74; p=0.04). Only one patient had local recurrence. Five-year overall survival was 84.2% (95% CI, 75-93.2%). The toxicity profile was acceptable. CONCLUSION: This non-conventional multimodal treatment has good loco-regional control for LABC. Randomized clinical trials of preoperative CCRTh following chemotherapy, in patients with LABC are warranted.

Complications after breast cancer surgery in patients treated with concomitant preoperative chemoradiation: A case-control analysis.

BACKGROUND: Nearly 60% of breast cancer cases in Mexico are in advanced stages. At our institution, concomitant preoperative chemoradiation is being used in patients with advanced breast cancer. In the present study, we evaluated the postoperative wound complications and risk factors associated. PATIENTS AND METHODS: The study included breast cancer patients from January 2000 to December 2002 treated with concomitant preoperative chemoradiation and mastectomy. Wound complication rates were described along with a nested case-control analysis to evaluate risk factors for postoperative major wound complications. RESULTS: We evaluated 360 patients treated with preoperative chemoradiation. About 165 patients (45.8%) developed a wound complication (infection and/or flap necrosis); 60 (16.6%) patients had a surgical site infection (SSI) and 61 (16.9%), flap necrosis; 44 (12.2%) developed both complications, and 25 (6.9%) experienced late dehiscence after suture removal. Epidermolysis, seroma, and hematoma occurred in 93 (25.8%), 80 (22.2%), and 12 patients (3.3%), respectively. Case-control analysis was conducted in 335 patients. After logistic regression analysis, the sole variable found associated with SSI and/or flap necrosis was epidermolysis (OR = 8.81, 95% CI = 4.52-17.18). Although not significant and of lesser magnitude, adjusted risk estimates of overweight, age >50 years, and type of mastectomy showed the same trend. CONCLUSIONS: Postoperative wound complications were not different from those observed in non-radiated patients, but its rate was higher. Epidermolysis was associated with SSI and/or flap necrosis. Careful surgical technique should be encouraged.

Diagnóstico y tratamiento de los sarcomas de partes blandas / Soft tissue sarcomas, diagnosis and treatment

En este artículo se presentan algunos conocimientos básicos y avanzados sobre el estudio de los carcomas, así como de su biología y manejo multidisciplinario. También se presenta parte de las experiencias que hemos adquirido en el Instituto Nacional de Cancerología

Radioterapia en el tratamiento conservador de los sarcomas de los tejidos blandos / Soft tissue sarcomas radiotherapy

El presente artículo es una revisión de las aportaciones más notables de la radioterapia en el campo de la terapéutica de los sarcomas de los tejidos blandos. Se sabe que el manejo clásico de este tipo de neoplasias es quirúrgico y que, según la magnitud del procedimiento empleado, la recurrencia local varía desde un 90 por ciento para la biopsia excisional únicamente, hasta un 18 por ciento para la cirugía radical o amputación. Por otra parte, en algunas series publicadas, hasta más del 50 por ciento de enfermos sufrieron de cirugías mutilantes. La ridoterapia sola, utilizada comúnmente en forma paliativa, resulta en índices de control local del 29 al 33 por ciento. Cuando la radioterapia se emplea antes de la cirugía, brinda control local de 90 a 97 por ciento. Con la aplicación de radioterapia postoperatoria se obtiene control local de 78 a 91 por ciento, la tasa de falla local es del 18.5 por cento y la preservación funcional del miembro afectado puede ser hasta de 84.7 por ciento. La radioterapia intraoperatoria, con braquiterapia de carga diferida con Ir-192, es otra modalidad terapéutica exitosa; sobre todo en los sarcomas de alto grado, en lo que se puede obtenerse control local hasta del 90 por ciento a cinco años. El tratamiento combinado de cirugía más radioterapia en cualquiera de sus variantes constituye el avance más trascendente para el manejo de los sarcomas de los tejidos blandos durante las últimas décadas

Radioterapia en sarcoma de los tejidos blandos / Radiotherapy in soft tissue carcoma

El presente artículo es una breve revisión de las contribuciones más notables que ha hecho la radiotrapia al campo de la terapéutica de los sarcomas de los tejidos blandos. De antemano se sabe que el manejo clásico de este tipo de neoplasias es quirúrgico y que, según la amplitud del procedimiento empleado, la recurrencia local varía desde un 90 por ciento para la biopsia excisional únicamente, hasta un 18 por ciento para la cirugía radical o amputación. En algunas series se informa que más del 50 por ciento de pacientes sufrieron de cirugías mutilantes. En pacientes casi siempre inoperables, la radioterapia como tratamiento único resulta en índices de control local del 29 al 33 por ciento. Combinar radioterapia preoperatoria y cirugía brinda control local de 90 a 97 por ciento. Con la aplicación de la radioterapia después de la cirugía se logra control local de 78 a 91 por ciento; la tasa de falla local es del 18.5 por ciento; la preservación funcional del miembro afectado puede ser hasta de 84.7 por ciento. La radioterapia intraoperatoria, con braquiterapia de carga diferida con Ir-192, es otra modalidad terapéutica exitosa, sobre todo en los sarcomas de alto grado en los que se obtiene control local a cinco años hasta del 90 por ciento. El tratamiento combinado ciugía más radioterapia en cualquiera de sus variantes es el mayor avance registrado en el manejo de los sarcomas de los tejidos blandos en las últimas décadas