Clear cell carcinoma compared to serous carcinoma in early ovarian cancer: same prognosis in a large randomized trial.

BACKGROUND: An analysis was performed comparing survival of patients with clear cell carcinoma (CCC) to patients with serous adenocarcinoma (SAC) in early ovarian cancer. Furthermore, a literature search was done to clarify the clinical and histopathological features of clear cell tumors of the ovary. METHODS: Between November 1990 and March 2000, 448 patients with ovarian cancer International Federation of Gynecology and Obstetrics stages I to IIa were enrolled in the European Organisation for Research and Treatment of Cancer-Adjuvant Chemotherapy in Ovarian Neoplasm Trial, a randomized study comparing adjuvant platinum-based chemotherapy to observation after surgical treatment in patients with early ovarian cancer. RESULTS: Sixty-three patients (14.1%) with CCC were compared with 156 patients (34.8%) with serous tumors. A significant difference was found in the International Federation of Gynecology and Obstetrics stage Ic with capsule rupture, 28 (44.4%) of 63 patients with CCC and 29 (18.6%) of 156 patients with SAC (P < 0.001). Recurrences occurred in 25% of the patients, and this was similar in the CCC and SAC groups. No significant difference was found in overall survival between patients with CCC and patients with SAC in both treatment arms together. In the observation arm, the 5-year disease-free survival was 71% in the CCC group versus 61% in the SAC group, whereas in the chemotherapy arm, the 5-year disease-free survival was higher in the SAC group compared with the CCC group (78% vs 60%). Both differences were not statistically significant. CONCLUSIONS: The present study showed no worse prognosis in patients with CCC as compared with patients with serous carcinoma in early ovarian cancer.

Phase III randomised study to evaluate the role of adjuvant pelvic radiotherapy in the treatment of uterine sarcomas stages I and II: an European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group Study (protocol 55874).

The management of uterine sarcomas continues to present many difficulties. Primary surgery is the optimal treatment but the role of post-operative radiation remains uncertain. In the mid-1980s, the European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group Study proposed a trial to evaluate adjuvant radiotherapy, as previous non-randomised studies had suggested a survival advantage and improved local control when post-operative radiation was administered. The study opened in 1987 taking 13 years to accrue 224 patients. All uterine sarcoma subtypes were permitted. Patients were required to have undergone as a minimum, TAH and BSO and wahsings (166 patients) but nodal sampling was optional. There were 103 leiomyosarcomas (LMS), 91 carcinosarcomas (CS) and 28 endometrial stromal sarcomas (ESS). Patients were randomised to either observation or pelvic radiation, 51 Gy in 28 fractions over 5 weeks. Hundred and twelve were recruited to each arm. The initial analysis has shown a reduction in local relapse (14 versus 24, p=0.004) but no effect on either OS or PFS. No unexpected toxicity was seen in the radiation arm. No difference in either overall or disease-free survival was demonstrated but there is an increased local control for the CS patients receiving radiation but without any benefit for LMS. Prognostic factor analysis shows that stage, age and histological subtype were important predictors of behaviour which may explain differences between CS and LMS. CS appears to show more kinship to poorly differentiated endometrial carcinomas in behaviour. LMS did not show the same benefit from radiation. These results will help shape future management and clinical trials in uterine sarcomas.

Randomised trial of drains versus no drains following radical hysterectomy and pelvic lymph node dissection: a European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group (EORTC-GCG) study in 234 patients.

Drainage, following radical hysterectomy and pelvic lymph node dissection to prevent postoperative lymphocyst formation and surgical morbidity, is controversial. To study the clinical significance of drainage, 253 patients were registered and 234 patients were randomised into two arms. In one arm (n=117) postoperative drainage was performed, in the other arm (n=117) no drains were inserted. In both arms closure of the peritoneum of the operating field was omitted. The main exclusion criteria were blood loss of more than 3000 ml during surgery or persistent oozing at the end of the operation. Clinical and ultrasound or CT-scan evaluation was done at one and 12 months postoperatively. The median follow-up amounted to 13.3 months. No difference in the incidence of postoperative lymphocyst formation or postoperative complications was found between the two study arms. The late (12 months) incidence of symptomatic lymphocysts was 3.4% (drains: 5.9%; no drains: 0.9%). The difference showed a p-value of 0.06 in Fisher's Exact test. The operating time was related to the occurrence of postoperative lymphocyst formation. It was concluded that drains can be safely omitted following radical hysterectomy and pelvic node dissection without pelvic reperitonisation in patients without excessive bleeding during or oozing at the end of surgery.

TuBaFrost: European virtual tumor tissue banking.

TuBaFrost is a consortium responsible for the task to create a virtual European human frozen tumor tissue bank, composed of high quality frozen tumor tissue collections with corresponding accurate diagnosis stored in European cancer centers and universities, searchable on the Internet, providing rules for access and use and a code of conduct to comply with the various legal and ethical regulations in European countries. Such infrastructure would enlarge tissue availability and accessibility in large amounts of specified or even rare tumor samples. Design of an infrastructure for European residual tissue banking with the described characteristics, clear focus points emerge that can be broken down in dedicated subjects: (1) standardization and quality assurance (QA) to avoid inter-institute quality variation; (2) law and ethics enabling exchange of tissue samples possible between institutes in the different European countries, where law and ethics are characterized by a strong variability; (3) rules for access, with sufficient incentives for collectors; (4) central database application containing innovations on search and selection procedures; (5) support when needed with histology images; and (6) Internet access to search and upload, with in addition a solid website giving proper information on the procedures, intentions and activities not only to the scientific community, but also to the general public. One consortium decision, part of the incentives for collectors, had major impact on the infrastructure; custodianship over the tissues as well as the tissues stay with the collector institute. Resulting in specimens that are not given to an organization, taking decisions on participation of requests, but instead the local collected tissues stay very easy to access by the collector and allows autonomous negotiation between collector and requestor on cooperation, coauthorship in publication or compensation in costs. Thereby, improving availability of large amounts of high quality samples of a highly specified or rare tumor types and contact opportunities for cooperation with other institutes.

Virtual microscopy in virtual tumor banking.

Many systems have already been designed and successfully used for sharing histology images over large distances, without transfer of the original glass slides. Rapid evolution was seen when digital images could be transferred over the Internet. Nowadays, sophisticated virtual microscope systems can be acquired, with the capability to quickly scan large batches of glass slides at high magnification and compress and store the large images on disc, which subsequently can be consulted through the Internet. The images are stored on an image server, which can give simple, easy to transfer pictures to the user specifying a certain magnification on any position in the scan. This offers new opportunities in histology review, overcoming the necessity of the dynamic telepathology systems to have compatible software systems and microscopes and in addition, an adequate connection of sufficient bandwidth. Consulting the images now only requires an Internet connection and a computer with a high quality monitor. A system of complete pathology review supporting biorepositories is described, based on the implementation of this technique in the European Human Frozen Tumor Tissue Bank (TuBaFrost).

TuBaFrost 6: virtual microscopy in virtual tumour banking.

Many systems have already been designed and successfully used for sharing histology images over large distances, without transfer of the original glass slides. Rapid evolution was seen when digital images could be transferred over the Internet. Nowadays, sophisticated Virtual Microscope systems can be acquired, with the capability to quickly scan large batches of glass slides at high magnification and compress and store the large images on disc, which subsequently can be consulted through the Internet. The images are stored on an image server, which can give simple, easy to transfer pictures to the user specifying a certain magnification on any position in the scan. This offers new opportunities in histology review, overcoming the necessity of the dynamic telepathology systems to have compatible software systems and microscopes and in addition, an adequate connection of sufficient bandwidth. Consulting the images now only requires an Internet connection and a computer with a high quality monitor. A system of complete pathology review supporting bio-repositories is described, based on the implementation of this technique in the European Human Frozen Tumor Tissue Bank (TuBaFrost).

TuBaFrost 1: Uniting local frozen tumour banks into a European network: an overview.

TuBaFrost is the consortium responsible for the creation of a virtual European human frozen tumour tissue bank: a collection of high quality frozen residual, accurately classified tumour tissue samples, which are stored in European cancer centres and universities. This virtual tissue bank, searchable on the internet, has rules for access and use, and a code of conduct to comply with the various legal and ethical regulations in European countries. The easy accessibility and the European scale of the bank will result in the availability of a large number of samples even of rarer tumour types. Standardisation of collection, storage and quality control throughout the network is achieved minimising inter-institutional variability. A website providing access to upload, search and request samples is a key tool of the tissue bank. The search engine makes use of virtual microscopy. An overview of the development of the European virtual frozen tissue bank infrastructure is described in this paper. The various key aspects are described in more detail in a series of articles to appear in this Journal.

TuBaFrost 2: Standardising tissue collection and quality control procedures for a European virtual frozen tissue bank network.

Tumour Bank Networking presents a great challenge for oncological research as in order to carry out large-scale, multi-centre studies with minimal intrinsic bias, each tumour bank in the network must have some fundamental similarities and be using the same standardised and validated procedures. The European Human Frozen Tumour Tissue Bank (TuBaFrost) has responded to this need by the promotion of an integrated platform of tumour banks in Europe. The operational framework for TuBaFrost has drawn upon the best practice of standard workflows and operating procedures employed by members of the TuBaFrost project and key initiatives worldwide.

TuBaFrost 4: access rules and incentives for a European tumour bank.

When designing infrastructure for a networked virtual tumour bank (samples remain at the collector institutes and sample data are collected in a searchable central database), it is apparent that this can only function properly after developing an adequate set of rules for use and access. These rules must include sufficient incentives for the tissue sample collectors to remain active within the network and maintain sufficient sample levels in the local bank. These requirements resulted in a key TuBaFrost rule, stating that the custodianship of the samples remains under the authority of the local collector. As a consequence, the samples and the decision to issue the samples to a requestor are not transferred to a large organisation but instead remain with the collector, thus allowing autonomous negotiation between collector and requestor, potential co-authorship in publications or compensation for collection and processing costs. Furthermore, it realises a streamlined cost effective network, ensuring tissue visibility and accessibility thereby improving the availability of large amounts of samples of highly specific or rare tumour types as well as providing contact opportunities for collaboration between scientists with cutting edge technology and tissue collectors. With this general purpose in mind, the rules and responsibilities for collectors, requestors and central office were generated.

TuBaFrost 3: regulatory and ethical issues on the exchange of residual tissue for research across Europe.

The regulatory regimes for research with residual tissue and accompanying data differ widely between countries in the European Union (EU): from specific consent to opt-out or even no consent at all. This could greatly hamper research where the exchange of tissue and accompanying data has become the gold standard, like in TubaFrost. Instead of adhering to international guidelines, which have a democratic deficit, or an attempt for a new set of possible harmonising rules, TubaFrost chose to create a coordinating rule: if tissue may legitimately be used for a certain kind of research in the country where it was taken and under whose jurisdiction the patient falls, it may also be used for such research in the country where it is sent to in the context of a scientific program even if in that other country other regulations would apply for research with residual tissue taken from patients under their jurisdiction. This coordinating rule has a sound basis in EU law in general and will solve the problems related to diverging national regulatory regimes in the case of cross national research with residual tissue.

TuBaFrost 5: multifunctional central database application for a European tumor bank.

Developing a tissue bank database has become more than just logically arranging data in tables combined with a search engine. Current demand for high quality samples and data, and the ever-changing legal and ethical regulations mean that the application must reflect TuBaFrost rules and protocols for the collection, exchange and use of tissue. To ensure continuation and extension of the TuBaFrost European tissue bank, the custodianship of the samples, and hence the decision over whether to issue samples to requestors, remains with the local collecting centre. The database application described in this article has been developed to facilitate this open structure virtual tissue bank model serving a large group. It encompasses many key tasks, without the requirement for personnel, hence minimising operational costs. The Internet-accessible database application enables search, selection and request submission for requestors, whereas collectors can upload and edit their collection. Communication between requestor and involved collectors is started with automatically generated e-mails.

Alterations in the p53 pathway and prognosis in advanced ovarian cancer: a multi-factorial analysis of the EORTC Gynaecological Cancer group (study 55865).

PURPOSE: The study was designed to determine independent prognostic variables in suboptimally debulked advanced ovarian cancer patients entered in the randomised phase III study EORTC 55865. EXPERIMENTAL DESIGN: Retrospectively collected paraffin blocks from 169 patients with stages IIb-IV epithelial ovarian cancer, taken at primary debulking surgery, were analysed. All patients were treated with cyclophosphamide and cisplatin (CP), and followed up for a median of 10 years. Expression of p53, bcl-2, P21, Ki-67 and HER-2 status was assessed by immunohistochemistry (IHC). RESULTS: Expression of p21, a downstream effector of the p53 gene, was found to be a favourable prognostic factor for survival (HR 0.58, CI 0.36-0.94, p=0.025) in addition to FIGO stage (HR 1.54, CI 1.08-2.21, p=or<0.02). For progression free survival (PFS), both p21 (HR 0.52) and Ki-67 (HR 0.6) were significant factors. CONCLUSION: P21 overexpression is a positive prognostic factor for survival and PFS in advanced ovarian carcinoma with residual lesions of more than 1 cm.

Pollution of the Begej Canal sediment--metals, radioactivity and toxicity assessment.

The Begej Canal is one among a large number of canals in Vojvodina (Northern Province of Serbia and Montenegro). The paper describes a study of metal and radioactivity contamination of the Begej Canal sediment. It is also concerned with the evaluation of sediment acute toxicity based on standard test species Daphnia magna and simultaneously extracted metals and acid volatile sulfides. The quality of sediment was assessed according to Dutch standards, but the results were also compared with some Canadian and USEPA (United States Environmental Protection Agency) guidelines for sediment quality. The results showed severe pollution with chromium, copper, cadmium and zinc, whereby the anthropogenic origin of these contaminants was indicated. The tests of toxicity of sediment pore water to D. magna, gave no indication of the presence of substances in acutely toxic concentrations to this species. It can be speculated that, despite of high metal contents, the observed toxicity was low because of the high contents of clay and iron, as well as sulphide. Also, based on a comparison with the Danube sediment and Vojvodina soil in general, the data of the Begej sediment contamination with 238U and 137Cs. The 137Cs data were used for approximate dating of the sediment. No traces of contamination by nuclear power plants in the region were found, while the presence of technologically enhanced naturally occurring radioactive materials (TENORM) was proved. Conclusions based on different criteria for sediment quality assessment were in some cases contradictory. Study also showed that radioactivity aspects can be useful in sediment quality surveys. The obtained results will be invaluable for the future activities regarding integrated water management based on EC Water Framework Directive (2000/60/EC) in the Danube basin, and particularly in the region of crossborder water body of the Begej Canal.

Long-term efficacy of the CHVmP/BV regimen used for aggressive non-Hodgkin's lymphoma in three randomised EORTC trials.

We analysed data from 936 newly-diagnosed patients with advanced, aggressive non-Hodgkin's lymphoma (NHL) treated in three randomised European Organisation for Research and Treatment of Cancer (EORTC) trials performed between 1980 and 1999 (median follow-up of 8.7 (0.2-20.4) years). The CHOP-like regimen CHVmP/BV (cyclophosphamide, doxorubicin, teniposide and prednisone with bleomycin and vincristine at mid-interval), was compared with CHVmP (CHVmP/BV without bleomycin and vincristine), ProMACE-MOPP (methotrexate, doxorubicin, cyclophosphamide, etoposide, mechlorethamide, vincristine, procarbazine and prednisone) and CHVmp/BV with additional, autologous stem-cell transplantation, respectively. Overall, treatment with CHVmP/BV resulted in a better long-term outcome with 63% complete responses being observed and an overall survival (OS) of 59 and 43% at 5 and 10 years, respectively. Remarkably, OS after CHVmP/BV improved across the trials, even after stratifying for the International Prognostic Index (IPI). This finding could not be directly related to better salvage treatments during the last decade. Selection bias appears to be responsible: stepwise corrections for small differences in inclusion criteria eliminated the difference in OS, especially when histological subgroups were studied. This systemic review underlines the difficulties encountered in retrospective sub-set analyses and the biases that can be introduced when recent studies are compared with older ones.

Medical fellowship programme within the Gynaecological Cancer Group of the European Organisation for Research and Treatment of Cancer.

In 1962, the European Organisation for Research and Treatment of Cancer (EORTC) was founded, and in the course of the years it developed into the leading European organisation in cancer research. Currently, the EORTC is organised into (Pre-)Clinical Groups and Task Forces consisting of scientists and/or clinicians. One of these groups with a specific area of interest in cancer research is the Gynaecological Cancer Group (GCG). The EORTC offers fellowship programmes to physicians and scientists from all over the world to create a possibility to be temporarily linked to an EORTC group or a specific research project. Over the past decade, 76 research fellowships have been appointed at the EORTC Data Center. This paper shows an overview of the activities of one EORTC/GCG medical fellow.

Human tissue research: EORTC recommendations on its practical consequences.

Improvement in cancer care is possible by applying new treatment modalities, which are emerging from knowledge and discoveries coming from laboratory research. This is possible through international collaboration and the collection of tumour tissues. Creation of a European Organisation for Research and Treatment of Cancer (EORTC) Tumor Bank is a natural step in this direction, by offering tumour sample collection from patients entered in EORTC trials. The aim of such a bank is not only to improve the diagnostic review process, but also to facilitate translational research by allowing clinicians and basic scientists to enter into close collaborations. The EORTC Tissue Research Policy is developed to assure, under the EORTC legal framework, an ethical and scientific review of research projects, guarantee adequate information is given to patients, establish procedures on the use of materials, including legal aspects, and publication policies. Being part of the EU TubaFrost project, the EORTC will provide a common international platform for the use of tissues for research purposes, finding a balance between different laws and assuring scientific progress.

Cisplatin, doxorubicin and ifosfamide in carcinosarcoma of the female genital tract. A phase II study of the European Organization for Research and Treatment of Cancer Gynaecological Cancer Group (EORTC 55923).

Carcinosarcomas of the female genital tract are highly malignant tumours composed of carcinomatous and sarcomatous elements. In the past, these tumours were frequently treated as sarcomas. However, a number of arguments, including the sensitivity of these tumours to platinum-based chemotherapy, suggest that these tumours behave more like poorly differentiated carcinomas. The European Organization for Research and Treatment of Cancer (EORTC) Gynaecological Cancer Group therefore decided to perform a prospective phase II study in patients with advanced or metastatic carcinosarcoma with an approach such as that used in gynaecological carcinomas. Eligible patients could have primary or recurrent disease, but prior radiotherapy or chemotherapy was not allowed. The treatment plan recommended upfront debulking, followed by chemotherapy with cisplatin, ifosfamide and doxorubicin. Patients who could be debulked to non-measurable disease remained eligible for the study, but the response assessment was restricted to patients who had measurable disease before the start of chemotherapy. A total of 48 patients (39 primary disease, 9 recurrent disease) were registered, 41 of them being eligible. In 9 patients, all macroscopic lesions could be removed, 32 patients were left with residual disease and were assessable for response. The overall response rate was 56%: a complete response (CR) was observed in 11 (34%) patients and partial response (PR) in 7 (22%) patients. No change occurred in 5 patients and progression in 2 patients. In 7 patients, response could not be assessed. Median survival for all of the 41 eligible patients was 26 months. Severe leucopenia and thrombocytopenia were common and necessitated dose reductions or delays in 60% of patients. From a clinical point of view, the most severe non-haematological toxicity was renal dysfunction, and one patient died of this complication in the absence of disease progression. The results of this study are in-line with the hypothesis that carcinosarcomas are chemosensitive, in particular for the currently investigated regimen. The treatment also included upfront cytoreduction when feasible. Considering the observed toxicities, alternative platinum-based regimens with more favourable toxicity profiles should be explored.

Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomised study (55872) by the EORTC Gynaecological Cancer Group.

BACKGROUND: Combination chemotherapy yields better response rates which do not always lead to a survival advantage. The aim of this study was to investigate whether the reported differences in the efficacy and toxicity of monotherapy with doxorubicin (DOX) versus combination therapy with cisplatin (CDDP) in endometrial adenocarcinoma lead to significant advantage in favour of the combination. PATIENTS AND METHODS: Eligible patients had histologically-proven advanced and/or recurrent endometrial adenocarcinoma and were chemo-naïve. Treatment consisted of either DOX 60 mg/m(2) alone or CDDP 50 mg/m2 added to DOX 60 mg/m2, every 4 weeks. RESULTS: A total of 177 patients were entered and median follow-up is 7.1 years. The combination DOX-CDDP was more toxic than DOX alone. Haematological toxicity consisted mainly of white blood cell toxicity grade 3 and 4 (55% versus 30%). Non-haematological toxicity consisted mainly of grade 3 and 4 alopecia (72% versus 65%) and nausea/vomiting (36 % versus 12%). The combination DOX-CDDP provided a significantly higher response rate than single agent DOX (P <0.001). Thirty-nine patients (43%) responded on DOX-CDDP [13 complete responses (CRs) and 26 partial responses (PRs)], versus 15 patients (17%) on DOX alone (8 CR and 7 PR). The median overall survival (OS) was 9 months in the DOX-CDDP arm versus 7 months in the DOX alone arm (Wilcoxon P = 0.0654). Regression analysis showed that WHO performance status was statistically significant as a prognostic factor for survival, and stratifying for this factor, treatment effect reaches significance (hazard ratio = 1.46, 95% confidence interval 1.05-2.03, P = 0.024). CONCLUSIONS: In comparison to single agent DOX, the combination of DOX-CDDP results in higher but acceptable toxicity. The response rate produced is significantly higher, and a modest survival benefit is achieved with this combination regimen, especially in patients with a good performance status.