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Luiz Eduardo Atalécio

Esta seção tem por objetivo divulgar os resumos dos mais recentes artigos publicados na literatura mundial a respeito da epidemiologia, prevenção, diagnóstico, estadiamento, tratamento e prognóstico do câncer. Caso o colega deseje receber separatas dos artigos referidos (máximo cinco), imprima nosso formulário, preencha e envie por fax.

Brain metastases as the only manifestation of an undetected primary tumor
Linh N. Nguyen, M.D., Moshe H. Maor, M.D. and Mary Jane Oswald, B.S. Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.

Background: The prognosis of patients with brain metastasis as the only manifestation of an undetected primary tumor generally is considered to be poor. Therefore, most treatment is palliative. The authors reviewed the clinical outcomes and treatment results of patients presenting with brain metastasis from an undetected primary tumor at The University of Texas M. D. Anderson Cancer Center.

Methods: Between 1977-1996, 220 patients were referred to the study department for the treatment of brain metastasis from an undetected primary tumor. The patients' records were reviewed to identify those for whom brain metastasis was the only manifestation of the primary tumor. The majority of patients were excluded from the current analysis because extracranial metastasis also were present. Thirty-nine patients qualified for this retrospective review. The level of neurosurgical excision varied, but all patients received radiotherapy. Tumor control in the brain and survival were analyzed by various tumor-related and treatment-related factors.

Results: In 31 patients, the brain metastasis were adenocarcinomas, whereas the remaining patients had tumors of various other histologies. In 12 patients, the primary tumor eventually was found, most commonly in the lung. The median survival time for all patients was 13.4 months. Overall survival rates (OS) at 1, 3, and 5 years were 56%, 19%, and 15%, respectively. Intracranial disease control was 72% at 5 years. Patients who received gross total resection (GTR) and radiotherapy had significantly better OS than patients who received radiotherapy alone. The OS of patients whose primary tumor was identified was similar to that of patients in whom the primary tumor remained occult.

Conclusions: Brain metastasis as the only manifestation of an unknown primary tumor is a distinct clinical entity. The prognosis for patients with this presentation is better than that of patients with brain metastasis in general. Although the majority of patients die of extracranial disease, a few will achieve long term survival. Treatment to the brain is effective in controlling local disease; aggressive treatment with GTR and radiotherapy is recommended.

Key words: brain; metastasis; undetected primary tumor; radiotherapy; surgery

The quality of care for treatment of early stage breast carcinoma. Is it consistent with national guidelines?
Edward Guadagnoli, Ph.D., Charles L. Shapiro, M.D., Jane C. Weeks, M.D., Jerry H. Gurwitz, M.D., Catherine Borbas, Ph.D., M.P.H. and Stephen B. Soumerai, Sc.D.

Background: In response to the importance of early stage breast carcinoma as a public health concern and to the complexity of the clinical literature devoted to treatment of the disease, the National Institutes of Health has held a series of Consensus Development Conferences on the treatment of early stage breast carcinoma. The authors assessed compliance with standards of care for women treated in two states.

Methods: The authors identified patients diagnosed at 18 randomly selected hospitals (N = 1514) in Massachusetts and at 30 hospitals (N = 1061) in Minnesota. They collected data from medical records, patients, and their surgeons to assess compliance with four indicators of quality of care: radiation therapy after breast-conserving surgery, axillary lymph node dissection, chemotherapy for premenopausal women with positive lymph nodes, and hormonal therapy for postmenopausal women with positive lymph nodes and positive estrogen receptor status.

Results: Rates of compliance for 3 of the 4 standards of care were > 80% in both states. Only the rate for hormonal therapy for postmenopausal women was low (< 64%). However, the proportion of these women who received either chemotherapy or hormonal therapy was > 90% in both states.

Conclusions: In the states studied, practice appears to be consistent with the results of national consensus conferences and clinical trials regarding the treatment of early stage breast carcinoma. For practices demonstrated to be associated definitively with better outcomes (for example, chemotherapy for premenopausal women with positive lymph nodes) or to be important with respect to prognosis (axillary lymph node dissection) high rates of compliance were observed.

Key Words: quality of care; early stage breast carcinoma; axillary lymph node dissection; radiation therapy; adjuvant therapy; health services research

A randomized trial of hybrid administration of cyclophosphamide, doxo-rubicin, and vincristine (CAV)/cisplatin and etoposide (PVP) versus se-quential administration of CAV-PVP for the treatment of patients with small cell lung carcinoma. - Results of long term follow-up
Hiroshi Ueoka, M.D., Katsuyuki Kiura, M.D., Masahiro Tabata, M.D., Haruhito Kamei, M.D., Kenichi Gemba, M.D., Katsuyoshi Sakae, M.D., Yoshio Hiraki, M.D., Shunkichi Hiraki, M.D., Yoshihiko Segawa, M.D. and Mine Harada, M.D.

Background: In an attempt to determine the efficacy of cyclophosphamide, doxorubicin, and vincristine (CAV)/cisplatin and etoposide (PVP) hybrid chemotherapy (HYB), a rapidly alternating chemotherapy, in patients with small cell lung carcinoma (SCLC), the authors conducted a randomized study to compare HYB with CAV-PVP sequential chemotherapy (SEQ).

Methods: Patients in the HYB group received the 3-drug CAV combination on Day 1 and the 2-drug PVP combination on Day 8, repeated every 4 weeks for up to 6 cycles. Patients in the SEQ group, received 3 cycles each of CAV and PVP sequentially every 4 weeks, delivered on Days 1 and 8. All responding patients with limited disease (LD) received thoracic irradiation (50 gray) after chemotherapy.

Results: Between April 1988 and October 1992, 129 patients were evaluated fully. There were no significant differences in the treatment outcome between patients in the HYB and SEQ groups in terms of the complete response rate (59% for LD patients and 21% for extensive disease [ED] patients in the HYB group vs. 45% for LD patients and 16% for ED patients in the SEQ group), or median survival time (17.9 months for LD patients and 9.7 months for ED patients in the HYB group vs. 20.6 months for LD patients and 12.2 months for ED patients in the SEQ group).

Conclusions: Hybrid CAV-PVP therapy is effective for the treatment of SCLC, but appears to be no better than sequential therapy with the same regimen.

Key Words: small cell lung carcinoma; chemotherapy; dose-intensity; drug resistance

Eating patterns and risk of colon cancer
Martha L. Slattery, Kenneth M. Boucher, Bette J.Caan, John d. Potter, and Khe-Ni Ma

Colon cancer has been associated with several nutrients and foods. The authors used data from a population-based study conduced in Northern California, Utah, and Minnesota to examine associations between dietary eating patterns and risk of developing colon cancer. Through factor analysis, detailed dietary intake data obtained from 1,993 cases (diagnosed in 1991-1994) and 2,410 controls were grouped into factors that were evaluated for relations with lifestyle characteristics and colon cancer risk. Several dietary patterns emerged. The dietary patterns with the most variation were labeled "Western," "prudent", "high fat/sugar dairy", "substituters", and "drinkers". The "Western" dietary patterns was associated with a higher body mass index and a greater intake of total energy and dietary cholesterol. The "prudent" pattern was associated with higher levels of vigorous leisure time physical activity, smaller body size, and higher intakes of dietary fiber and folate. Persons who had high scores on the "drinker" were also more likely to smoke cigarettes. The "Western" dietary pattern was associated with an increased risk of colon cancer in both men and women. The association was strongest among people diagnosed prior to age 67 years (for men, odds ratio (OR) = 1.96, 95% confidence interval (Cl) 1.22-3.15; for women, OR = 2.02, 95% Cl 1.21-3.36) and among men with distal tumors (OR = 2.25, 95% Cl 1.47-3.46).The "prudent" diet was protective, with the strongest associations being observed among people diagnosed prior to age 67 years (men: OR = 0.63, 95% Cl 0.43-0.92; women: OR = 0.58, 95% Cl 0.38-0.87); associations with this dietary pattern were also strong among persons with proximal tumors (men: OR = 0.55, 95% Cl 0.38-0.80; women: OR = 0.64, 95% Cl 0,45-0.92). Although "substituters" (people who substituted low fat dairy products for high fat dairy products, margarine for butter, poultry for red meat, and whole grains for refined grains) were at reduced risk of colon cancer, the reduction in risk was not statistically significant. These data support the hypothesis that overall dietary intake pattern is associated with colon cancer, and that the dietary pattern associated with the greatest increase in risk is the one which typifies a Western-style diet.

Key Words: colonic neoplasms; diet; eating; factor analysis; statistical; food habits; meat; vegetarianism

Evaluation of clinical efficacy of new medical treatments in advanced colorectal cancer. Results of a workshop organized by the EORTIC GITCCG
Jacques Wils, Tarek Sahmoud, Alberto Sobrero, Harry Bleiberg, Sam Ahmedzai, Jane Blazeby, Geert Blijham, Thierry Conroy, David Cunningham, Desmond Curran, Eduardo Díaz-Rubio, Michel Ducreux, Jeff Evans, Bengt Glimelius, Gillian Hutchinson, David Kerr, Gwendoline Kiebert, Hennig Köhne, Roberto Labianca, Rina Langendijk, Donato Nitti, Bernard Nordlinger, Philippe Rougier, Werner Scheithauer, Hans-Joachim Schmoll, Eric Van Cutsem, Theo Wagener, Jochen Wilke, Ann Marinus, and Patrick Therasse

During the last few years several factors have contributed to an increasing change in the medical treatment of advanced colorectal cancer. Among them are the more general acceptance of the impact of chemotherapy on quality of life and survival in first as well as in second-line treatment, the introduction of new drugs and the definition of novel endpoints which can roughly be defined as "patient benefit". For this reason the European Organization for Research and Treatment of Cancer (EORTC) Gastrointestinal Tract Cancer Cooperative Group (GITCCG) felt it was appropriate to organize a workshop with experts from different countries and national groups to discuss in depth several aspects concerning the treatment of patients with advanced colorectal cancer.

Key Words: advanced colorectal cancer; endopoints of medical treatment

Maintenance treatment with interferon alpha-2b in multiple myeloma: a prospective randomized study from PETHEMA (Program for the Study and Treatment of Hematological Malignancies, Spanish Society of Hematology)
J. Bladé, J.F. San Miguel, M.L. Escudero, M. Fontanillas, J.Besalduch, S. Gardella, J. Arias, J.García-Conde, M. Carnero, J.M. Marti, C. Rozman, J. Estapé and E. Montserrat
PETHEMA, Hematology Department, Hospital Clinic, Villarroel 170, 08036-Barcelona, Spain

The objectives of the present study were to investigate whether interferon alpha (IFN) maintenance could prolong response duration and survival in patients with multiple myeloma (MM) in objective response and to analyze the characteristics of relapse and subsequent survival. From January 1991 to November 1994, 92 patients from the Spanish Cooperative Group PETHEMA with MM in objective response after 12 courses of VCMP/VBAP chemotherapy were randomized to receive IFN maintenance vs no treatment until relapse. Prognostic factors at diagnosis were similar in both groups. IFN was administered at a starting dose of 3 mU/m2 three times per week. The IFN toxicity was moderate with granulocytopenia and fatigue being the most common adverse effects. Median duration of response from randomization until relapse was 13 months in the IFN group vs 7.7 months in the no treatment arm (p= 0.042). Median survival from randomization was 38.8 months for patients given IFN vs 32.7 months for those allocated to the no treatment arm (p = 0.12). Features at relapse were similar in patients who received IFN maintenance and in those assigned to no treatment. Finally, survival from relapse was identical in both groups. In summary, our results show a significant prolongation of response in patients maintained with IFN with no significant influence on survival. In addition, in our series features at relapse and subsequent outcome were similar in both groups.

Key Words: multiple myeloma; maintenance treatment; interferon

Weekly paclitaxel-cisplatin administration with G-CSF support in advanced breast cancer. A phase II study
Giuseppe Frasci, Pasquale Comella, Giusppe D'Aiuto, Alfredo Budillon, Deborah Barbarulo, Renato Thomas, Immacolata Capasso, Rossana Casaretti, Antonio Daponte, Francesco Caponigro, Adriano Gravina, Luigi Maiorino, Giacomo Caratení, Alfonso Gentile, and Giuseppe Comella
Division of Medical Oncology, Division of Surgical Oncology A, Laboratory of Experimental Oncology C, National Tumor Institute; Division of Medical Oncology, Cardarelli Hospital; Unit of Medical Oncology, S. Gennaro General Hospital, Naples, Italy; Bristol-Myers Squibb, Rome, Italy

Summary

Purpose: In a previous phase I study we found the MTDs of paclitaxel and cisplatin when given together weekly, with or without G-CSF support, in patients with advanced solid tumors. The present study was conducted to define the toxicity and efficacy of this regimen, when used with G-CSF support, in chemotherapy-naive or pretreated patients with advanced breast cancer, and to compare the antiproliferative activity of paclitaxel-cisplatin and paclitaxel-doxorubicin combinations on two human breast cancer cell lines. Methods: Patients with metastatic breast cancer received weekly paclitaxel (as a 3-hour IV infusion) at the dose of 85 mg/m2 (75mg/m2 in pretreated women) followed by cisplatin (40 mg/m2) for a minimum of 6 weeks. An additional 6 weekly cycles were delivered in patients showing absence of documented disease progression after the first 6 weeks. After the 12th cycle only patients who had shown a substantial tumor shrinkage received 6 further cycles. G-CSF 5 mg/kg was also given, SC on days 3 to 5 of each week, for the whole duration of chemotherapy. The combination of paclitaxel with cisplatin or doxorubicin was also tested in vitro on two breast cancer cell lines (MCF-7 and MDAMB-231). Results: Forty-three women with metastatic breast cancer entered this trial between June 1995 and January 1997. Twenty-seven patients were previously untreated for their metastatic disease (but 23 had previously received adjuvant chemotherapy). The dominant site of disease involvement was visceral in 23, bone in 13, and soft tissues in 7 patients. Seven complete and 15 partial responses were observed in unpretreated patients, while no complete and 6 partial responses were achieved in the pretreated population. The overall response rate, assessed on an 'intent to treat' basis, was 81% (26% CRs) in patients unpretreated for metastatic disease and 37% in those who had received one or more previous chemotherapy regimens. Eighteen responder patients had previously received anthracyclines either as adjuvant chemotherapy (12) or in the treatment of metastatic disease (6). At a median potential follow-up of 12 (range, 3-21) months, 14/27 unpretreated and 12/16 pretreated patients had shown disease progression. The median time to treatment failure was 13 and 7 months, respectively, in the 2 subgroups. The 1-year survival probability was 95% in unpretreated patients. The treatment showed a moderate toxicity in both subgroups of patients. Both hematological toxicity and peripheral neuropathy occurred more frequently in pretreated patients. Treatment-related deaths did not occur, and severe myelosuppression was observed only in pretreated patients with massive liver involvement. Delays in che-motherapy administration were very uncommon, especially during the first 6 treatment cycles, and the average actually delivered dose intensity exceeded 90% in unpretreated patients. The in vitro data on MCF-7 and MDA-MB-231 human breast cancer cell lines showed that exposure to the combination of cisplatin and paclitaxel produced a tumor cell killing similar to that achieved with equivalent concentrations of doxorubicin and paclitaxel. Conclusions: Weekly paclitaxel and cisplatin with G-CSF support is an active and particularly well tolerated treatment for patients with either unpretreated or pretreated metastatic breast cancer. This approach seems quite effective also in patients relapsing after anthracycline-based adjuvant chemotherapy. In view of the negligible hematological toxicity associated with this regimen, further clinical trials testing the addition of non cross-resistant drugs to this combination should be performed.

Key Words: advanced breast cancer; chemotherapy; cisplatin; paclitaxel; weekly schedule

Randomised trial of interferon a-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases
Jean Jacques Grob, Brigitte Dreno, Pauline de la Salmonière, Michèle Delaunay, Didier Cupissol, Bernard Guillot, Pierre Souteyrand, Bruno Sassolas, Jean-Pierre Cesarini, Sylvie Lionnet, Catherine Lok, Claude Chastang, Jean Jacques Bonerandi, for the French Cooperative Group on Melanoma

Background: Owing to the limited efficacy of therapy on melanoma at the stage of distant metastases, a well-tolerated adjuvant therapy is needed for patients with high-risk primary melanoma. Our hypothesis was that an adjuvant treatment with low doses of interferon a could be effective in patients with localised melanoma.

Methods: After resection of a primary cutaneous melanoma thicker than 1.5mm, patients without clinically detectable node metastases were randomly assigned to receive either 3x106 IU interferon a-2a, three-times weekly for 18 months, or no treatment. The primary endpoint was the relapse-free interval.

Findings: 499 patients were enrolled, of whom 489 were eligible. When used as part of a sequential procedure, interferon a-2a was of significant benefit for relapse-free interval (p= 0.038). A long-term analysis, after a median follow-up of 5 years, showed a significant extension of relapse-free interval (p = 0.035) and a clear trend towards an increase in overall survival (p = 0.059) in interferon a-2a-treated patients compared with controls. There were 100 relapses and 59 deaths among the 244 interferon a-2a-treated patients compared with 119 relapses and 76 deaths among the 245 controls. The estimated 3-year-relapse rates were 32% in the interferon a-2a group and 44% in controls; the 3-year death rates were 15% and 21%, respectively. Only 10% of patients experienced WHO grade 3 or 4 adverse events. Treatment was compatible with normal daily life.

Interpretation: Adjuvant therapy of high-risk melanoma with low doses of interferon a-2a for 18 months is safe and is beneficial when started before clinically detectable node metastases develop.

Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women
U. Veronesi, P. Maisonneuve, A. Costa, V. Sacchini, C. Maltoni, C. Robertson, N. Rotmensz, and P. Boyle on behalf of the Italian Tamoxifen Prevention Study

Background: Tamoxifen is a candidate chemopreventive agent in breast cancer, although the drug may be associated with the development of endometrial cancer. Therefore we did a trial in hysterectomised women of tamoxifen as a chemopreventive.

Methods: In October, 1992, we started a double-blind placebo-controlled, randomised trial of tamoxifen in women (mainly in Italy) who did not have breast cancer and who had had a hysterectomy. Women were randomised to receive tamoxifen 20 mg per day or placebo, both orally for 5 years. The original plan was to follow the intervention phase by 5 years' follow-up. In June, 1997, the trialists and the data-monitoring committee decided to end recruitment primarily because of the number of women dropping out of the study. Recruitment ended on July 11, 1997, and the study will continue as planned. The primary endpoints are the occurrence of and deaths from breast cancer. This preliminary interim analysis is based on intention-to-treat.

Findings: 5408 women were randomised; participating women have a median follow-up of 46 months for major endpoints. 41 cases of breast cancer occurred so far; there have been no deaths from breast cancer. There is no difference in breast-cancer frequency between the placebo (22 cases) and tamoxifen (19) arms. There is a statistically significant reduction of breast cancer among women receiving tamoxifen who also used hormone-replacement therapy during the trial: among 390 women on such therapy and allocated to placebo, we found eight cases of breast cancer compared with one case among 362 women allocated to tamoxifen. Compared with the placebo group, there was a significantly increased risk of vascular events and hypertriglyceridaemia among women on tamoxifen.

Interpretation: Although this preliminary analysis has low power, in this cohort of women at low-to-normal risk of breast cancer, the postulated protective effects of tamoxifen are not yet apparent. Women using hormone-replacement therapy appear to have benefited from use of tamoxifen. There were no deaths from breast cancer recorded in women in the study. It is essential to continue follow-up to quantify the long-term risks and benefits of tamoxifen therapy.

Direct comparisons of adjuvant endocrine therapy, chemotherapy, and chemoendocrine therapy for operable breast cancer patients stratified by estrogen receptor and menopausal status
Yasuo Nomura, Mitsunori Shirouzu and Takahiro Takayama Department of Breast Surgery, National Kyushu Cancer Center, Fukuoka, Japan

Key Words: breast cancer; adjuvant therapy; endocrine therapy; chemotherapy; che-moendocrine therapy; randomized trial; estrogen receptors; menopause

Summary

Based on estrogen receptor (ER) and menopausal status, operable breast cancer (UICC stage I, II, III-a) patients were randomized for adjuvant endocrine therapy, chemotherapy, and chemoendocrine therapy, and the effects on the relapse-free survival (RFS) and overall survival (OS) were compared. Tamoxifen (TAM) 20 mg/day was administered orally for 2 years after mastectomy as an adjuvant endocrine therapy in postmenopausal patients. In premenopausal patients, oophorectomy (OVEX) was performed before TAM administration. In the chemotherapy arm (CHEM), patients were given 0.06 mg/kg of body weight of mitomycin C (MMC) intravenously, followed by an oral administration of cy-clo-phos-phamide (CPA) 100 mg/day in an administration of a 3-month period and a 3-month intermission. This 6-month schedule was repeated 4 times in 2 years. The chemoendocrine arm (CHEM +TAM) was composed of TAM with MMC + CPA chemotherapy. The patients were randomized according to ER and menopausal status. ER-positive patients were randomized to three arms: OVEX ± TAM, CHEM, and CHEM + TAM. For ER-negative patients there were two arms: CHEM and CHEM + TAM. 1579 patients entered the trial between September 1978 and December 1991, with median follow-up of 8.2 years. In ER-positive, premenopausal patients, there were no significant differences in RFS or OS among OVEX + TAM, MMC + CPA, TAM + MMC + CPA arms. On the contrary, in ER-positive, postmenopausal patients, the chemoendocrine therapy showed a significantly higher RFS (p = 0.0400) and OS (p = 0.0187) as compared with TAM to chemotherapy alone. There were no significant differences in RFS or OS by addition of TAM on the chemotherapy, in both pre- and post-menopausal ER-negative patients. It was concluded that in ER-positive premenopausal breast cancer, endocrine therapy alone may be equivalent in prolonging RFS and OS to chemotherapy or chemoendocrine therapy, and that ER-positive post-menopausal breast cancer may be better controlled with the combination of TAM and chemotherapy, as compared to TAM or chemotherapy alone. The importance of stratification of operable breast cancer by ER and menopausal status, as well as the direct comparisons of different treatments, were stressed.

Epirubicin/vinorelbine as first line therapy in metastatic breast cancer
Editta Baldini, Carmelo Tibaldi, Franco Chiavacci, Marco Di Lieto, Luisa Fioretto, Annalia Giallombardo, Roberto Taviani, Paolo Ghezzi, Anna Bolognini, and Pierfranco Conte

Key Words: epirubicin/vinorelbine combination chemotherapy; metastatic breast cancer

Summary:

This study was aimed at investigating the toxicity and activity of the combination epirubicin and vinorelbine in chemotherapy-naive patients with metastatic breast cancer. Fifty-one patients with measurable or evaluable metastatic breast cancer entered the study. There regimen consisted of epirubicin 90 mg/m2 as a slow i.v. infusion on day 1, followed by vinorelbine 25 mg/m2 by 30-minute intravenous infusion on days 1 and 8; the courses were repeated every 21 days for a maximum of 8 cycles. All the patients were assessable for toxicity and 47 were evaluable for response according to the World Health Organization (WHO) criteria.

Objective responses were observed in 33 out of 47 evaluable patients (70.2%; 95% C.I. 55.1% - 82.6%) with 4 complete (8.5%) and 29 partial responses (61.7%); 11 patients had stable disease (23.4%) and 3 patients progressed while on treatment. The median time to progression was 10 months (range 1 - 21) and the median overall survival was 23 months (range 2 - 32+). Neutropenia was the most frequent toxicity: a grade 4 neutropenia (WHO) was reported in 70% of 252 courses with a median duration of 3 days (range 1-6). Seventeen episodes of febrile neutropenia were observed but only 1 patient required hospital admission. Other hematologic toxicities were negligible. One patient experienced a paralytic ileus requiring hospitalization; no peripheral neuropathy such as muscle weakness or paresthesia was observed. No treatment-related cardiotoxicity was reported. The encouraging response rate achieved with epirubicin/vinorelbine, the easily manageable toxicities of the com-bination, and its feasibility in an outpatient setting make this combination worthy of further comparative trials with standard regimens.

From the R.E.A.L. Classification to the upcoming WHO scheme: A step toward universal categorization of lymphoma entities?
S.A. Pileri, M. Milani, G. Fraternali-Orcioni and E. Sabattini Service of Pathologic Anatomy/Haematopathology Unit, Institute of Haematology S. Orsola Hospital, University of Bologna, Bologna, Italy.

Key Words: classification; Hodgkin's disease; malignant lymphoma

Revised European - American lymphoma classification: General principles

In 1991, a group of experienced European and American haematopathologists, none of whom had previously been involved in the writing of a lymphoma classification, founded the International Lymphoma Study Group (ILSG) for discussion of the problems related to the categorization of such tumours. After completion of two pilot studies, on mantle cell lymphomas [1] and Hodgkin's disease [2], the group, which in the meantime had expanded (Appendix), decided to tackle the problem of lymphoma classification and formulate a proposal for overcoming the seemingly endles conflicts between the American and European schools [3-13].

In April 1993, the first draft of a new classification was discussed, since all members felt that the limitations of the two previous schemes (the Working Formulation (WF) and the Updated Kiel Classification (UKC)) [11-13] were severe enough to render an update difficult or even impossible. With respect to the WF, its basic concept itself comprised its main limitation: in fact, it was originally intended as a transduction system among the clas-sifications in use in the 1970s [3-9]. This compromise provided for no distinction between B- and T-cell-derived neoplasms, while allowing the fragmentation of otherwise ho-mo-geneous tumours (e.g., follicle centre cell lymphomas) and, conversely, the lumping together of lymphoma types which are different in terms of histogenesis and clinical course (e.g., diffuse mixed lymphomas). Moreover, the database used for construction of the WF consisted of 1,000 patients treated by chemotherapeutic protocols in use in the 1970s, morphologically diagnosed only on H&E stained slides and grouped according to the type of growth, cell size and mere survival, without consideration of important clinical data (stage, systemic symptoms, presence of bulky disease, monoclonal gammopathy, leukaemic phase) as well as phenotypic and molecular findings.

The role of radiotherapy in the conservative treatment of rectal carcinoma The Lyon Experience
Jean-Pierre Gerard, Jacques Baulieux, Yves Francois, Jean-Paul Grandjean, Pascale Ro-mestaing, Françoise Mornex, Pascale Munoz and Louis Ayzac

The purpose of this study was to present the Lyon experience using radiotherapy alone or with surgery, with intent to cure rectal cancer and to avoid rectal amputation. Two groups of patients were treated between 1980 and 1996: Group I with radiotherapy alone with contact x-ray for T1 N0(101 patients) or with a combination of external beam radiation therapy (EBRT), contact x-ray and I92 iridium implant in inoperable T2-3 N0-1 patients (43 patients); Group II with preoperative EBRT either as a pilot study (158 patients) or in a randomized trial (210 patients). With contact x-ray alone it was possible to control T1 N0 in 90% of cases, and with the combined approach 70% of the inoperable patients were controlled. In Group II, anterior resection was performed in 60% to 70% of the patients. Local recurrence was seen in 11% of cases. Surgery is the basic treatment used for rectal cancer but radiotherapy is playing an increasing role in the conservative treatment of this cancer.

Controlled trials and chemoprevention of cancer
Olli P. Heinonen - From the Department of Public Health, University of Helsinki, Finland

Epidemiological and laboratory studies provide preliminary evidence that a compound may prevent certain types of clinical cancer. The final proof for practical application demands two controlled trials with similar, decisive results. Controlled chemoprevention trial on clinical cancer are large, time-consuming and expensive, whereas studies on cancer surrogates are smaller but less reliable. Rational trial design often lacks sufficient information about the sensitive period and the time from that point to clinically detectable cancer. The correct dose of chemopreventive agent and an expected preventive fraction of cancer are also often based on informed guesswork. Long trials call for special arrangements to guarantee the staying will of the participants and key research personal. Although large chemoprevention trials are currently being carried out without any certainty of successful outcome, the situation is not so different from the early days of chemoprevention trials for cardiovascular diseases. Cancer trials will be conducted based on the 'learning-by-doing' approach, and in the more distant future based on research designed to provide information for trial needs.

Effective treatment of advanced biliary tract carcinoma using 5-fluorouracil continuous infusion with cisplatin
M. Ducreux, P. Rougier, A. Fandi, M.-C. Clavero-Fabri, A.-L. Villing, F. Fassone, L. Fandi, J. Zarba and J.-P. Armand - Department of Medicine, Institut Gustave Roussy, Villejuif, France

Background: The combination of 5-fluorouracil (5-FU) and cisplatin has shown great activity in many different types of tumour with an in vitro synergistic effect between 5-FU and cisplatin. A phase II study of 5-FU plus cisplatin was performed in 25 previously untreated patients with inoperable locally advanced or metastatic biliary tract carcinoma.

Patients and methods: Twenty-five patients, 10 of them men and 15 women with a median age of 58, were entered into the study. The chemotherapy regimen consisted of 5-FU: 1 g/m2/day in continuous intravenous (i.v.) infusion for five consecutive days, and cisplatin: 100 mg/m2/day on day 2 in a one-hour infusion with standard hyperhydration. Twenty-two patients had metastatic tumours and three had locally advanced disease.

Results: Of the 25 patients entered into the study, 24 were evaluable for response and 25 for toxicity. Nausea and vomiting was the main toxic side effect in 19 patients. Severe, WHO grade 3-4 thrombocytopenia or neutropenia were observed in three and seven patients, respectively. There were no toxic deaths. Of 25 patients, six had partial remissions (overall response 24%, 95% confidence interval 7%-41%). For three patients, tumour reduction permitted local radiotherapy and one of these patients with initially advanced disease is still alive six years after the beginning of treatment.

Conclusions: This study, one of the largest phase II trials performed in this disease, shows interesting activity of the combination of 5-FU and cisplatin in advanced biliary tract carcinoma.

Key Words: biliary tract cancer; chemotherapy

Predictors of survival for prostate carcinoma patients treated with salvage radical prostatectomy after radiation therapy
Liang Cheng, M.D., Thomas J. Sebo, M.D. Ph.D., Jeff Slezak, B.S., Thomas M. Pisansky, M.D., Erik J. Bergstralh, M.S., Roxann M. Neumann, R.N., Kenneth A. Iczkowski, M.D., Horst Zincke, M.D. and David G. Bostwick, M.D.

Background: Salvage radical prostatectomy is a treatment option for patients with recurrent cancer following radiation therapy. This study was conducted to identify predictors of survival for patients treated with salvage radical prostatectomy.

Methods: The authors studied 86 prostate carcinoma patients who underwent salvage radical prostatectomy for locally persistent or recurrent prostate carcinoma at Mayo Clinic between 1967 and 1996. The mean interval from radiation therapy to biopsy-proven recurrence was 3.7 years (range, 6 months to 17 years). Patient age at surgery ranged from 51 to 78 years (median, 66 years). The mean follow-up after surgery was 5.8 years (range, 1.0-15.2 years). Cox proportional hazards models were used to identify clinical and pathologic factors associated with distant metastasis free survival and cancer specific survival.

Results: Actuarial distant metatasis free survival, cancer specific survival, and overall survival were 83%, 91%, and 85% at 5 years and 69%, 64%, and 54% at 10 years, respectively. In multivariate analysis, radical prostatectomy Gleason score and DNA ploidy were independent predictors of distant metastasis free survival and cancer specific survival.

Conclusions: Postirradiation Gleason score and DNA ploidy were highly predictive of the clinical outcomes of patients treated by salvage radical prostatectomy after radiation therapy.