Deterioration of nutritional status of patients with locally advanced cervical cancer during treatment with concomitant chemoradiotherapy.

BACKGROUND: In Mexico, 80% women with cervical cancer are diagnosed at locally advanced stages and are treated with concomitant chemoradiotherapy. The treatment modality and catabolic state confer a nutritional risk. The present study aimed to thoroughly evaluate the nutritional status and change in body composition of locally advanced cervical cancer (LACC) patients throughout treatment. METHODS: An observational prospective study, carried out at the Mexican National Cancer Institute, included 55 LACC patients. Nutritional status was evaluated before, during and after treatment, using anthropometric, dietary and biochemical measurements. Body composition was analysed using computed tomography images obtained at the time of diagnosis and approximately 4 months after treatment completion. Clinical outcomes were associated with changes in body composition. RESULTS: At the time of diagnosis, no patients were clinically malnourished, although 33.3% presented sarcopenia and most were overweight; by the end of treatment, 69% became clinically malnourished and 58% were sarcopenic. Average weight loss was 7.4 kg (P = 0.001). Adequacy of energy intake was reduced to 54%, obtained predominantly from carbohydrates. By the week 9, 62.8% patients became anemic and 34.5% had low albumin levels. Body composition analysis revealed that patients lost both, muscle and adipose tissues, although 27% patients were muscle depleted by the end of treatment. Patients who lost ≥10% skeletal muscle presented a higher tumour recurrence (hazard ratio = 2.957, P = 0.006) and a tendency towards diminished overall survival (hazard ratio = 2.572, not significant). CONCLUSIONS: The nutritional status of cervical cancer patients deteriorates during treatment with concomitant chemoradiotherapy and, most importantly, muscle loss impacts the clinical outcome of patients.

Brachytherapy versus radical hysterectomy after external beam chemoradiation with gemcitabine plus cisplatin: a randomized, phase III study in IB2-IIB cervical cancer patients.

BACKGROUND: The aim of the present study was to demonstrate that radical hysterectomy (RH) leads to improved survival outcomes in FIGO stage IB2-IIB cervical cancer when compared with standard brachytherapy (BCT) after identical external beam chemoradiation (EBRT-CT). PATIENTS AND METHODS: EBRT-CT treatment consisted of six courses of cisplatin at 40 mg/m² and gemcitabine at 125 mg/m² per week concurrent with 50.4 Gy of radiation. In the BCT arm, EBRT-CT was followed by BCT to reach a point A dose of 85 Gy, whereas in the experimental arm, a type III RH with bilateral pelvic lymph node dissection and para-aortic lymph node sampling (RH) was carried out within 4-6 weeks after EBRT-CT. RESULTS: Between May 2004 and June 2009, 211 patients were enrolled (BCT, 100 and RH, 111). At a median follow-up time of 36 months (3-80), progression-free survival (PFS) and overall survival (OS) rates were similar in both the arms. PFS rates were 74.8% and 71.7% in the BCT and RH arms [HR 0.6516 (95% confidence interval (CI) 0.3504-1.2116)], P = 0.186. OS rates were 76.3% in the BCT versus 74.5% in the surgical arm [HR 0.6981 (95% CI 0.3106-1.3439)], P = 0.236. No differences were observed in the pattern of local and systemic failures. CONCLUSIONS: This study failed to demonstrate that RH after EBRT-CT is superior to standard BCT.

Late recurrence of cervical cancer: a report of 16 cases.

PURPOSE: To analyze the clinical characteristics and outcome of cervical cancer patients presenting late recurrence. MATERIALS AND METHODS: The medical records of 16 patients who were treated between 1974 and 1999 at the Institution and whose cancer recurred after a five-year disease-free interval were reviewed. RESULTS: Mean time from initial therapy to recurrence was 162.5 months (60-360 mean). Smear abnormalities, atypical genital bleeding, abdominal and lumbar pain, and respiratory findings were the most common symptoms and signs associated with late recurrence. Fourteen patients were diagnosed by physical examination. Three of the six patients with local recurrence who were re-irradiated developed a vesico-vaginal fistula. At a median follow-up time of 12.5 months (4-38 mean), 12 patients were alive and the median survival time was 30 months. CONCLUSIONS: Cervical cancer patients surviving free of disease after the fifth year post-treatment are still at risk for relapse and in most of them, the recurrence is suspected by clinical examination alone.

The second Mexican consensus on hepatocellular carcinoma. Part I: Epidemiology and diagnosis.

Hepatocellular carcinoma (HCC) is more frequently manifesting as one of the main complications of cirrhosis of the liver, its principal risk factor. There have been modifications in its incidence over the past decade, related to an epidemiologic transition in the etiology of cirrhosis, with a decrease in the prevalence of hepatitis C and an increase in nonalcoholic fatty liver disease (NAFLD) as a cause, as well as the development of HCC in the non-cirrhotic liver due to NAFLD. Genetic markers associated with the disease have been identified, and surveillance and diagnosis have improved. Regarding treatment, surgical techniques, in both resection and transplantation, have advanced and radiologic techniques, at the curative stage of the disease, have enhanced survival in those patients. And finally, there have been radical changes in the systemic approach, with much more optimistic expectations, when compared with the options available a decade ago. Therefore, the Asociación Mexicana de Hepatología decided to carry out the Second Mexican Consensus on Hepatocellular Carcinoma, which is an updated review of the available national and international evidence on the epidemiology, risk factors, surveillance, diagnosis, and treatment of the disease, to offer the Mexican physician current information on the different topics regarding hepatocellular carcinoma. In this first part of the document, the topics related to epidemiology and diagnosis are presented.

The second Mexican consensus on hepatocellular carcinoma. Part II: Treatment.

Hepatocellular carcinoma (HCC) is more frequently manifesting as one of the main complications of cirrhosis of the liver, its principal risk factor. There have been modifications in its incidence over the past decade, related to an epidemiologic transition in the etiology of cirrhosis, with a decrease in the prevalence of hepatitis C and an increase in nonalcoholic fatty liver disease (NAFLD) as a cause, as well as the development of HCC in the non-cirrhotic liver due to NAFLD. Genetic markers associated with the disease have been identified, and surveillance and diagnosis have improved. Regarding treatment, surgical techniques, in both resection and transplantation, have advanced and radiologic techniques, at the curative stage of the disease, have enhanced survival in those patients. And finally, there have been radical changes in the systemic approach, with much more optimistic expectations, when compared with the options available a decade ago. Therefore, the Asociación Mexicana de Hepatología decided to carry out the Second Mexican Consensus on Hepatocellular Carcinoma, which is an updated review of the available national and international evidence on the epidemiology, risk factors, surveillance, diagnosis, and treatment of the disease, to offer the Mexican physician current information on the different topics regarding hepatocellular carcinoma. In this second part of the document, the topics related to the treatment of HCC are presented.

Epigenetic therapy and cisplatin chemoradiation in FIGO stage IIIB cervical cancer.

INTRODUCTION: This trial aimed to evaluate the safety and efficacy of epigenetic therapy associated with cisplatin chemoradiation in FIGO Stage IIIB patients. METHODS: Hydralazine containing either 182 mg for rapid-, or 83 mg for slow acetylators and magnesium valproate were administered at 30 mg/kg tid. Both drugs were taken until intracavitary therapy was finished. Pelvic external beam radiation and low-dose rate brachytherapy were administered at a total cumulative dose to point A of at least 85 Gy. Weekly cisplatin at 40 mg/m2 was delivered for six cycles. RESULTS: Twenty-two patients were included and 18 (82%) patients completed treatment. Mean dose to point A was 84.6 + 2.2. Median number of cisplatin cycles was 5.5 (range, 1-6). Brachytherapy was delayed for technical reasons; the mean overall treatment time was 11.8 weeks. Grade 3 anemia, leucopenia, neutropenia, and thrombocytopenia were observed in 9%, 45%, 45%, and 9% of patients, respectively. CONCLUSIONS: Hydralazine and valproate are well-tolerated and safe when administered with cisplatin chemoradiation. Unfortunately, the suboptimal administration of brachytherapy for technical reasons in this study, precluded assessing the efficacy of epigenetic therapy. However, the tolerability of this regimen administered concurrent to radiation needs to be further tested.

The Mexican consensus on nonalcoholic fatty liver disease. / Consenso mexicano de la enfermedad por hígado graso no alcohólico.

Nonalcoholic fatty liver disease (NAFLD) affects nearly one third of the population worldwide. Mexico is one of the countries whose population has several risk factors for the disease and its prevalence could surpass 50%. If immediate action is not taken to counteract what is now considered a national health problem, the medium-term panorama will be very bleak. This serious situation prompted the Asociación Mexicana de Gastroenterología and the Asociación Mexicana de Hepatología to produce the Mexican Consensus on Fatty Liver Disease. It is an up-to-date and detailed review of the epidemiology, pathophysiology, clinical forms, diagnosis, and treatment of the disease, whose aim is to provide the Mexican physician with a useful tool for the prevention and management of nonalcoholic fatty liver disease.

Concurrent chemoradiation with carboplatin for elderly, diabetic and hypertensive patients with locally advanced cervical cancer.

INTRODUCTION: Chemoradiation based on cisplatin is the standard treatment of locally advanced cervical cancer, however, a subset of patients are either elderly and/or have comorbidities such as diabetes and hypertension. These conditions may compromise the administration of cisplatin. We report our Institution experience with weekly carboplatin as a radiosensitizer for the management of this subset of patients. PATIENTS AND METHODS: We reviewed the files of 59 patients with locally advanced cervical cancer who were treated with primary chemoradiation with weekly carboplatin. Response rate, toxicity and survival were analyzed. RESULTS: Mean age was 62 years (range, 36-83 years). The majority of cases were squamous cell carcinoma (88.14%), and distribution according to FIGO Stage was IB2 8.4%, IIA 13.5%, IIB 52.5%, IIIA 3.3% and IIIB 18.6%; Overall, 100% and 91% of patients completed external beam and intracavitary therapy. Seventy-nine percent received from five to six planned cycles of weekly carboplatin. Complete responses were achieved in 49 (83.05 %) patients, whereas ten patients (16.95%) had either persistent or progressive disease. The most common toxicities were grades 1 and 2 hematological and gastrointestinal. At median follow-up (20 months; range 2-48 months), 16 patients (32.65%) have relapsed. Estimated 30-month overall survival is 63%. CONCLUSIONS: Weekly carboplatin concurrent with pelvic radiation is well tolerated in patients with locally advanced carcinoma of the cervix who are older than 70 years and/or have diabetes mellitus and/or high blood pressure, however, the apparently slighty lower survival observed cautions against its routine use.

The prognostic significance of leukocytosis in cervical cancer.

Cervical cancer is a frequent tumor with established prognostic factors such as FIGO stage and hemoglobin levels among others. Despite the fact that paraneoplastic leukocytosis is relatively common in many solid tumors, only isolated cases of cervical cancer patients presenting this abnormality have been published; hence, the clinical significance of leukocytosis is unknown in this tumor type. Retrospective review on the medical records of 294 consecutive newly diagnosed and untreated locally advanced cervical cancer patients who received radiotherapy and concurrent cisplatin was conducted. Leukocytosis was defined as a persistent white blood cell count exceeding 10,800/microL, determined at least twice before commencing chemoradiation providing that patients were free of any active acute or chronic infection or any other condition known to elevate the leukocyte count. The frequency of leukocytosis and their correlation with clinicopathologic features were investigated, as well as their impact on tumor response and survival. Leukocytosis with a median value of 13,300/microL (11,100-28,800) was observed in 35 (11.9%) patients at diagnosis. Leukocytosis was statistically associated only with advanced stages. Clinical complete response was observed in 57% versus 86% of the patients with and without leukocytosis, respectively. In the univariate analysis, leukocytosis, stage, and hemoglobin levels were significant predictors of survival; however, only leukocytosis and the hemoglobin level remained significant predictors of survival in the multivariate analysis. Leukocytosis is common in cervical cancer patients and has a negative prognostic significance.

A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors.

BACKGROUND: Epigenetic aberrations lead to chemotherapy resistance; hence, their reversal by inhibitors of DNA methylation and histone deacetylases may overcome it. PATIENTS AND METHODS: Phase II, single-arm study of hydralazine and magnesium valproate added to the same schedule of chemotherapy on which patients were progressing. Schedules comprised cisplatin, carboplatin, paclitaxel, vinorelbine, gemcitabine, pemetrexed, topotecan, doxorubicin, cyclophosphamide, and anastrozole. Patients received hydralazine at 182 mg for rapid, or 83 mg for slow, acetylators, and magnesium valproate at 40 mg/kg, beginning a week before chemotherapy. Response, toxicity, DNA methylation, histone deacetylase activity, plasma valproic acid, and hydralazine levels were evaluated. RESULTS: Seventeen patients were evaluable for toxicity and 15 for response. Primary sites included cervix (3), breast (3), lung (1), testis (1), and ovarian (7) carcinomas. A clinical benefit was observed in 12 (80%) patients: four PR, and eight SD. The most significant toxicity was hematologic. Reduction in global DNA methylation, histone deacetylase activity, and promoter demethylation were observed. CONCLUSIONS: The clinical benefit noted with the epigenetic agents hydralazine and valproate in this selected patient population progressing to chemotherapy' and re-challenged with the same chemotherapy schedule after initiating hydralazine and valproate' lends support to the epigenetic-driven tumor-cell chemoresistance hypothesis (ClinicalTrials.gov Identifier: NCT00404508).

A phase II study of multimodality treatment for locally advanced cervical cancer: neoadjuvant carboplatin and paclitaxel followed by radical hysterectomy and adjuvant cisplatin chemoradiation.

BACKGROUND: Our aim was to evaluate the efficacy and safety of neoadjuvant chemotherapy followed by radical hysterectomy and adjuvant radiation concurrent with weekly cisplatin for locally advanced cervical carcinoma. PATIENTS AND METHODS: Forty-three patients staged as IB2-IIIB were treated with three 21-day courses of carboplatin (area under the time-concentration curve 6 mg.min/ml) and paclitaxel at 175 mg/m(2) by 3-h infusion both on day 1 followed by radical type III hysterectomy and adjuvant radiation concurrent with 6-weekly doses of cisplatin at 40 mg/m(2). Response rate, resectability, toxicity and survival were evaluated. RESULTS: From December 2000 to June 2001, 43 patients were recruited. All were evaluated for response and toxicity to neoadjuvant chemotherapy. A total of 129 courses were administered. Clinical responses were seen in 41 patients (95%) [95% confidence interval (CI) 89.2% to 100%] with four (9%) complete and 37 (86%) partial. Forty-one patients underwent surgery (resectability 95%); pathologically complete or near-complete responses were seen in seven (17%) and eight (20%), respectively, positive surgical margins in five (12%), and positive pelvic lymph nodes in eight (20%). Twenty-six patients were scheduled for adjuvant chemoradiation. External radiation was delivered for 42.8 days (range 33-61), with a mean dose of 49.3 Gy (range 46-56), and a median of five cisplatin courses (two to six). The mean dose of brachytherapy was 32 Gy (range 25.5-35.6). Neoadjuvant therapy was well-tolerated with neutropenia grade 3 and 4 in 12% and 3% of the courses, respectively. Toxicity to adjuvant chemoradiation was mainly hematological and gastrointestinal, mostly grades 1/2. A total of 39 patients completed all scheduled treatment. At a median follow-up of 21 months (range 3-26), the projected overall survival in the intention-to-treat analysis was 79% (95% CI 62% to 88%). CONCLUSIONS: The triple modality of neoadjuvant chemotherapy followed by radical hysterectomy and adjuvant radiation concurrent with cisplatin is a highly active treatment for locally advanced cervical carcinoma with acceptable toxicity.

Neuroendocrine marker expression in cervical carcinomas of non-small cell type.

Small-cell carcinomas of the uterine cervix are highly aggressive tumors. Up to 100% of these tumors express at least one neuroendocrine marker such as neuron-specific enolase (NSE), chromogranin A (CgA), and synaptophysin (SYN). In other tumor types such as non-small-cell carcinomas of the lung, colon, and prostate, the presence of these markers has been associated with a better prognosis in some studies, a worsened prognosis in others, or has had no prognostic effect in still other studies. However, little is known about their expression and prognostic significance in the common "non-small-cell" carcinomas of the uterine cervix. The primary tumors of 54 previously untreated patients with histologically confirmed non-small-cell carcinoma of the cervix uteri (squamous carcinoma, adenosquamous carcinoma, and adenocarcinoma) were analyzed by immunohistochemistry for expression of NSE, CgA, and SYN. The expression status was correlated to pathological characteristics and outcome. In addition, the expression of these markers was investigated in cervical carcinoma cell lines. None of the 54 tumors expressed NSE or CgA, although SYN was positive in five tumors (9%) of which four were squamous and one was adenocarcinoma. These five patients relapsed within the first 6 months of follow-up and four have died. Among eight cancer cell lines only one was positive for CgA and another one for SYN. We conclude that the neuroendocrine marker SYN is expressed in a small subset of non-small-cell carcinomas of the cervix and its expression seems to correlate with a poor outcome.