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.

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.

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.

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.

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.

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.

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.