UZ Leuven

Prognostic importance of degree of differentiation and cyst rupture in stage I invasive epithelial ovarian carcinoma. Vergote I, De Brabanter J, Fyles A, Bertelsen K, Einhorn N, et al.Lancet 2001;357:176-82. Abstract: Background: Previous studies on prognostic factors in stage I invasive epithelial ovarian carcinoma have been too small for robust conclusions to be reached. We undertook a retrospective study in a large international database to identify the most important prognostic variables. Methods: 1545 patients with invasive epithelial ovarian cancer (International Federation of Gynaecology and Obstetrics [FIGO] stage I) were included. The records of these patients were examined and data extracted for univariate and multivariate analysis of disease-free survival in relation to various clinical and pathological variables. Findings: The multivariate analyses identified degree of differentiation as the most powerful prognostic indicator of disease-free survival (moderately vs well differentiated hazard ratio 3•13 [95% CI 1•68–5•85], poorly vs well differentiated 8•89 [4•96–15•9]), followed by rupture before surgery (2•65 [1•53–4•56]), rupture during surgery (1•64 [1•07–2•51]), FIGO 1973 stage Ib vs Ia 1•70 [1•01–2•85]) and age (per year 1•02 [1•00–1•03]). When the effects of these factors were accounted for, none of the following were of prognostic value: histological type, dense adhesions, extracapsular growth, ascites, FIGO stage 1988, and size of tumour. Interpretation: Degree of differentiation, the most powerful prognostic indicator in stage I ovarian cancer, should be used in decisions on therapy in clinical practice and in the FIGO classification of stage I ovarian cancer. Rupture should be avoided during primary surgery of malignant ovarian tumours confined to the ovaries. For the EORTC–ACTION Collaborators. Impact of Adjuvant Chemotherapy and Surgical Staging in Early-Stage Ovarian Carcinoma: European

Organisation for Research and Treatment of Cancer–Adjuvant ChemoTherapy in Ovarian Neoplasm Trial. Trimbos JB, Vergote I, Bolis G, Vermorken JB, Mangioni C, Madronal C, Franchi M, Tateo S, Zanetta G, Scarfone G, Giurgea L, Timmers P, Coens C, Pecorelli SJ Natl Ca Instit 2003;95:113-25. Abstract: Background: All randomized trials of adjuvant chemotherapy for early-stage ovarian cancer have lacked the statistical power to show a difference in the effect on survival between adjuvant chemotherapy and no adjuvant chemotherapy. They have also not taken into account the adequacy of surgical staging. We performed a prospective unblinded, randomized phase III trial to test the efficacy of adjuvant chemotherapy in patients with early-stage ovarian cancer, with emphasis on the extent of surgical staging. Methods: Between November 1990 and January 2000, 448 patients from 40 centers in nine European countries were randomly assigned to either adjuvant platinumbased chemotherapy (n = 224) or observation (n =224) following surgery. Endpoints were overall survival and recurrence-free survival, and the analysis was on an intention-to-treat basis. The Kaplan–Meier method was used to perform time-to-event analysis, and the log-rank test was used to compare differences between treatment arms. Statistical tests were two-sided. Results: After a median follow-up of 5.5 years, the difference in overall survival between the two trial arms was not statistically significant (hazard ratio [HR] = 0.69, 95% confidence interval [CI] = 0.44 to 1.08; P = .10). Recurrence-free survival, however, was statistically significantly improved in the adjuvant chemotherapy arm (HR = 0.63, 95% CI = 0.43 to 0.92; P = .02). Approximately one-third of patients (n = 151) had been optimally staged and two-thirds (n = 297) had not. Among patients in the observation arm, optimal staging was associated with a statistically significant improvement in overall and recurrencefree survival (HR = 2.31 [95% CI = 1.08 to 4.96]; P = .03 and HR = 1.82 [95% CI = 1.02 to 3.24] P = .04, respectively). No such association was observed in the chemotherapy arm. In the non-optimally staged patients, adjuvant chemotherapy was associated with statistically significant improvements in overall and recurrence-free survival (HR = 1.75 [95% CI = 1.04 to 2.95]; P = .03 and HR = 1.78 [95% CI = 1.15 to 2.77]; P = .009, respectively). In the optimally staged patients, no benefit of adjuvant chemotherapy was seen. Conclusion: Adjuvant chemotherapy was associated with statistically significantly improved recurrence-free survival in patients with early-stage ovarian cancer. The benefit of adjuvant chemotherapy appeared to be limited to patients with non-optimal staging, i.e., patients with more risk of unappreciated residual disease.

Hormone receptors do not predict the HER2/neu status in all age groups of women with an operable breast cancer. Huang HJ, Neven P, Drijkoningen M, Paridaens R, Wildiers H, Limbergen E, Berteloot P, Amant F, Vergote I and Christiaens MR. Ann Oncol 2005;16:1755-61. Abstract: Background: In breast cancer, there is an inverse relationship between HER2/neu overexpression and receptors for estrogen (ER) or progesterone (PR). Some clinical observations such as the age-related association between hormone receptors and tumour grade, which predicts HER2/neu overexpression, suggest an age-related relationship. Patients and methods: Our study population consisted of 1362 consecutive women receiving primary surgery for non-metastatic invasive breast cancer. We compared the relationship between both hormone receptors and HER2/neu overexpression in different age groups taking other tumour characteristics into account. Results: In a multivariate model, considering the overall group, a negative ER, a negative PR and a high tumour grade were predictive for HER2/neu overexpression (P <0.001). Considering 246 women aged 45 years, the only predictor for HER2/neu overexpression in this age category was a high tumour grade (P = 0.003). Considering the 1116 women aged >45 years, ER (P = 0.001), PR (P = 0.001) and tumour grade (P <0.001) were associated with HER2/neu (P <0.001). Conclusion: Our findings indicate that the association between ER, PR and HER2/neu overexpression varies with age. The hormone receptors are not an independent predictor for the HER2/neu status in young women while they are in elder patients.

Endometrial cancer. Amant F, Moerman P, Neven P, Timmerman D, Van Limbergen E, Vergote I.Lancet 2005;366:491-505. Abstract: Each year, endometrial cancer develops in about 142,000 women worldwide, and an estimated 42,000 women die from this cancer. The typical ge-incidence curve for endometrial cancer shows that most cases are diagnosed after the menopause, with the highest incidence around the seventh decade of life. The appearance of symptoms early in the course explains why most women with endometrial cancer have early-stage disease at presentation. For all stages taken together, the overall 5-year survival is around 80%. There is a substantial prognostic difference between the histological types of endometrial cancers. The most common lesions (type 1) are typically hormone sensitive and low stage and have an excellent prognosis, whereas tumours of type 2 are high grade with a tendency to recur, even in early stage. The cornerstone of treatment for endometrial cancer is surgery, which not only is important for staging purposes but also enables appropriate tailoring of adjuvant treatment modalities that benefit high-risk atients only. We review current concepts about epidemiology, pathology, pathogenesis, risk factors and prevention, diagnosis, staging, prognostic factors, treatment, and follow-up of endometrial cancer.

In utero exposure to chemotherapy: effect on cardiac and neurological outcome. Van Calsteren K, Ganame J, Lagae L, Delforge M, Berteloot P, Paridaens R, Noens L, Humblet Y, Vandermeersch B, De Muylder X, Claus P, Hanssens M, Vergote I, Mertens L, Amant F. J Clin Oncol 2006;24:e16-7 Abstract: Although recent data support the use of chemotherapy during the second or third trimester of pregnancy, the need for qualitative follow-up studies is highly recognized, since until now information has been gathered from retrospective chart review. 1 We planned a multicenter prospective study with well defined neurologic and cardiac exams of children who were in utero exposed to cytotoxic drugs. The study protocol was approved by the ethics committee and informed consent was obtained from the parents in accordance with institutional regulations. Neonatal morbidity after intrauterine exposure to cytotoxic drugs mainly appears to be related to prematurity. Whether the occurrence of a cortical malformation in a twin member whose fraternal twin is normal, was related to cytotoxic drugs remains unclear. Otherwise, we encountered no developmental problems. Children who were exposed in utero to cytotoxic drugs showed a tendency towards a thinner ventricular wall. This finding is worrisome since chemotherapy and in particular anthracyclines or their metabolites may interfere with cardiac development and because similar findings were encountered when anthracyclines were administered during childhood. However, confirmation in larger series with longer duration of follow-up is needed to support these observations additionally.

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