Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2.

BACKGROUND: In the BOLERO-2 trial, everolimus (EVE), an inhibitor of mammalian target of rapamycin, demonstrated significant clinical benefit with an acceptable safety profile when administered with exemestane (EXE) in postmenopausal women with hormone receptor-positive (HR(+)) advanced breast cancer. We report on the incidence, time course, severity, and resolution of treatment-emergent adverse events (AEs) as well as incidence of dose modifications during the extended follow-up of this study. PATIENTS AND METHODS: Patients were randomized (2:1) to receive EVE 10 mg/day or placebo (PBO), with open-label EXE 25 mg/day (n = 724). The primary end point was progression-free survival. Secondary end points included overall survival, objective response rate, and safety. Safety evaluations included recording of AEs, laboratory values, dose interruptions/adjustments, and study drug discontinuations. RESULTS: The safety population comprised 720 patients (EVE + EXE, 482; PBO + EXE, 238). The median follow-up was 18 months. Class-effect toxicities, including stomatitis, pneumonitis, and hyperglycemia, were generally of mild or moderate severity and occurred relatively early after treatment initiation (except pneumonitis); incidence tapered off thereafter. EVE dose reduction and interruption (360 and 705 events, respectively) required for AE management were independent of patient age. The median duration of dose interruption was 7 days. Discontinuation of both study drugs because of AEs was higher with EVE + EXE (9%) versus PBO + EXE (3%). CONCLUSIONS: Most EVE-associated AEs occur soon after initiation of therapy, are typically of mild or moderate severity, and are generally manageable with dose reduction and interruption. Discontinuation due to toxicity was uncommon. Understanding the time course of class-effect AEs will help inform preventive and monitoring strategies as well as patient education. TRIAL REGISTRATION NUMBER: NCT00863655.

Absence of Epstein-Barr virus in esophageal squamous cell carcinoma.

It is strongly suspected that the Epstein-Barr virus (EBV) plays a role in the genesis of nasopharyngeal and gastric carcinoma. The aim of this study was to search for such a connection between esophageal squamous cell carcinoma (ESCC) and EBV. We investigated 104 surgically resected esophageal cancers using in situ hybridization (ISH) for EBV-encoded RNA (EBER). We found no EBER-positive cancer cells in any tests, although there were five samples in which EBER-positive tumor-infiltrating lymphocytes (TILs) were found. We conclude from this study that EBV is not associated with ESCC.

Esophageal carcinoma in Southern Thailand.

BACKGROUND: Southern Thailand is an area with a high frequency of esophageal carcinoma. This paper presents basic data regarding esophageal carcinoma patients from this region. METHODS: Patients with histopathological confirmed esophageal carcinoma were retrospectively reviewed. The age, sex, location of tumor and resectability were studied. RESULTS: A total of 813 cases of esophageal carcinoma were reviewed, male:female ratio was 3.54:1 (634:179). Average age in males was 64.62 years and 64.30 years in females. The peak age-incidence was 51-70 years. Squamous cell carcinoma was most commonly found in the mid thoracic portion of the esophagus with 369 cases (45.39%), 70 cases (8.61%) were found in the cervical portion of the esophagus. Adenocarcinoma cancer was found at the esophagogastric junction in 47 cases (5.78%). Only 293 cases (36.04%) were operable. Respiratory tract involvement was noted in 49 cases. CONCLUSION: The most common type of esophageal cancer in Southern Thailand is squamous cell carcinoma, as in other countries in Asia. The status of the patients, advanced age and locally advanced tumor were major factors of our low operable rate.

TP53 mutations and MDM2 gene amplification in squamous-cell carcinomas of the esophagus in south Thailand.

Squamous-cell carcinoma of the esophagus (SCCE) shows geographic variations in incidence that are thought to reflect the etiological involvement of environmental or dietary risk factors. Mutations of TP53 are frequent in SCCE, and there is evidence that both the frequency and type of these mutations may differ from one geographic area to the other. Although SCCE is relatively rare in most parts of Thailand, the province of Songkhla (south Thailand) has been described as a high-risk area for SCCE. We have analyzed 56 SCCE cases from this area for TP53 mutations by denaturing gradient gel electrophoresis (DGGE, exons 5-8) and direct DNA sequencing. The same tumors were also analyzed for MDM2 gene amplification by differential PCR. TP53 mutations were detected in 23 cases (41%). In contrast, clear amplification of MDM2 was detected in only 2 cases (4%), both of which contained wild-type TP53. Comparison with published results from other geographic areas of high SCCE incidence revealed that the spectrum of TP53 mutations in south Thailand is similar to that observed in central China (Henan Province) but clearly differs from that of SCCE from western Europe (Normandy, France; northern Italy), with more G:T transversions and fewer mutations affecting A and T base pairs. These results suggest that SCCE from south Thailand and from central China may involve similar risk factors.

Flow cytometry in squamous cell esophageal cancer and precancerous lesions.

Flow cytometry has also been used to study the nuclear DNA content (ploidy) and cell cycle kinetics of esophageal cancers. Studies of limited numbers of patients with Barrett's esophagus undergoing endoscopic surveillance suggested that aneuploidy may be a useful marker to identify subsets of patients at increased risk for malignancy. Few studies to date have evaluated premalignant tissues associated with the development of squamous-cell cancer of the esophagus. The present retrospective study comprises 80 surgical specimens of squamous-cell carcinoma of the esophagus from a high-incidence region of Thailand. All patients had surgery at the Department of Surgery, Prince of Songkla University, between March 1983 and December 1993. Sets of serial sections were cut every 0.5 cm starting from the proximal margin and down to the distal margin, and histopathology was confirmed to flow cytometric parameters (DNA content, S-phase fraction). Aneuploidy was found in 84% of squamous-cell carcinoma, 22.2% of carcinoma in situ, 28.6% of severe dysplasia, 11.0% of moderate dysplasia and 0% of mild dysplasia and normal esophageal mucosa specimens. The percentage was higher according to the level of severity or dysplasia. S-phase fraction was found to be 21.0 +/- 0.9% in squamous-cell carcinoma, 20.3 +/- 10.3% of carcinoma in situ, 20.9 +/- 5.3% of severe dysplasia, 12.9 +/- 9.7% of moderate dysplasia 7.6 +/- 0.8% of mild dysplasia and 8.9 +/- 3.2% of normal tissue. Similarly, the percentage of S-phase fraction tends to be higher according to the level of severity or dysplasia. These findings demonstrate that the aneuploidy and percentage of S-phase fraction tend to correlate with progression of esophageal premalignant tissues to invasive carcinoma. These measures may be clinically useful to identify patients at increased risk for esophageal malignancy.

Chemical components of gallstone in southern Thailand.

The gallstones from 55 patients in Southern Thailand were analyzed to disclose the chemical components using infrared grating spectrophotometry. The main components were calcium bilirubinate, calcium phosphate, calcium carbonate, choleterol and protein inproportions 52.6, 5.5, 5.5, 30.9 and 5.5 per cent of stones, respectively. These proportions are not different from those of gallstones in the northern or central regions of Thailand.

Experience with oesophageal carcinoma in Songklanagarind Hospital.

Clinical data from 175 patients with squamous cell carcinoma of the oesophagus or cardia admitted to Songklanagarind Hospital between 1982 and 1988 were analysed to evaluate the effects on survival of various tumour and treatment variables. Most tumours (greater than = 86%) were in stage III or IV. Forty-seven percent of stage-IV tumours and 99 per cent of those in stages I, II or III were resectable. One-year and 3-year survival rates of resected stage-III patients (57.3% and 27.5%) were significantly higher than those of resected stage-IV patients (33.3% and 0%). Resection conferred no benefit over radiotherapy chemotherapy or no treatment on the survival of stage-IV cases beyond one year. Combined chemotherapy/radiotherapy/resection of stage-III and stage-IV patients gave no statistically significant improvement in survival. Among resected patients, only lymph node involvement was associated with significantly lower survival (relative risk compared to no involvement = 2.3, 95% CL: 1.2, 4.6), while the fungating type of tumour was possibly associated with improved survival (relative risk compared with all other types = 0.24, 95% CL: 0.05, 1.1).