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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.

Conformal Radiotherapy: A Clinical Review
G. Read - Royal Preston Hospital, Preston, UK

The term conformal radiotherapy was coined by Shinji Takahashi. Between 1948 and 1963 he published a series of papers on the use of rotation radiography and in 1959 began to apply these principles to radiotherapy. His seminal work, 'Conformation radiotherapy: rotation techniques as applied to radiography and radiotherapy of cancer', described the use of moving geared diaphragms and tables to irradiate irregular volumes. He described three basic techniques, 'rotational body technique', 'column focus´ and 'hollow-out technique', which could be used alone or in combination. By applying these techniques to a number of sites including the uterus, rectum, oesophagus, lung, head and neck, and pituitary he was able to demonstrate improvements in local control and reduced in toxicity. However, the evolution of a practical means of delivering conformal radiotherapy had to wait for the development of microprocessor technology in the late 1980s and hardware developments such as the multileaf collimator. Further developments such as the three-dimensional (3-D) computed tomographic simulator, intensity modulated arcs and tomotherapy offer promise for the future.

Techniques for delivering conformal radiotherapy have been described previously. Other reviews have focused on the possible benefits. This review seeks to consider the clinical rationale for conformal radiotherapy and the evidence of benefit that has been observed so far. Stereotactic radiotherapy (radiosurgery) is not considered in this article. Where multiple papers have been published from a single institution, reference is given to the most recent only.

Is Chemotherapy Beneficial in the Treatment of Locoregionally Advanced Nasopharyngeal Carcinoma?
James R. Wong, M.n. - Department of Radiation Oncology, Carol G. Simon Cancer Center, Morristown Memorial Hospital/ Atlantic Health System, Morristown, New Jersey.

Nasopharyngeal carcinoma holds an impo p t place in the debate regarding whether adjuvant chemothera is beneficial in the treatment of head and neck cancers. This is because 1) nasopharyngeal carcinoma is a very chemoresponsive tumor, and there are reports of long-standing complete responses for patients with distant metastasis who are given adequate chemotherapies; 2) of all the squamous cell carcinomas of the head and neck, nasopharyngeal carcinoma has the highest incidence (3Q-40%) of distant metastasis; and 3) numerous retrospective or single-arm studies have reported excellent and promising results with the addition of chemotherapy in the treatment of nasopharyngeal carcinoma. Because the theoretic basis of neoadjuvant chemotherapy is to enhance locoregional control by tumor debulking or sensitizing the tumor to radiation and to decrease distant metastasis by treating occult micrometastasis, nasopharyngeal carcinoma appears to be the perfect head and neck malignancy for chemotherapy to display its potential, given the considerations just listed. In this issue of Cancer, Chua et al. report the preliminary results of the Asian-Oceanian Clinical Oncology Association's randomized trial comparing cisplatin and epirubicin followed by radiotherapy versus radiotherapy alone in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma. The authors reported no significant gain in relapse free and overall survival with the addition of neoadjuvant chemotherapy and concluded that they could not recommend the routine administration of neoadjuvant chemotherapy for this group of patients.

Chemotherapy in Advanced Ovarian Cancer: Four Systematic Meta-analyses of Individual Patient Data from 37 Randomized Trials
Advanced Ovarian Cancer Trialists' Group: K Aabo, M Adams, P Adnitt, DS Alberts, A. Athanazziou, V Barley, DR Bell, U Bianchi, G Bolis, MF Brady, HS Brodovsky, H Bruckner, M Buyse, R Canetta, V Chylak, CJ Cohen, N Coiombo, PF Conte, D Crowther, JH Edmonson, C Gennatas, E Gilbey, M Gore, D Guthrie, SB Kaye, AH Laing, F Landoni, RC Leonard, C. Lewis, PY Liu, C Mangioni, S Marsoni, H Meerpohl, GA Omura, MKB Parmar, J Pater, S. Pecorelli, M Presti, W Sauerbrei, DV Skarlos, RV Smalley, HJ Solomon, LA Stewart, JFG Sturgeon, MHN Tattersall, JT Wharton, WW ten Bokkel Huinink, M Tomirotti, W Torri, C. Trope, MM Turbow, JB Vermorken, MJ Webb, DW Wilbur, CJ Williams, E Wiltshaw and BY Yeap

The purpose of this systematic study was to provide an up to date and reliable quantitative summary of the relative benefits of various types of chemotherapy (non-platinum vs platinum, single-agent vs combination and carboplatin vs cisplatin) in the treatment of advanced ovarian cancer. Also, to investigate whether well-defined patient subgroups benefit more or less from cisplatin- or carboplatin-based therapy. Meta-analyses were based on updated individual patient data from all available randomized controlled trials (published and unpublished), including 37 trials, 5667 patients and 4664 deaths. The results suggest that platinum-based chemotherapy is better than non-platinum therapy, show a trend in favour of platinum combinations over single-agent platinum, and suggest that cisplatin and carboplatin are equally effective. There is no good evidence that cisplatin is more or less effective than carboplatin in any particular subgroup of patients.

Health care professionals and patients alike are becoming increasingly aware of the need to make medical decisions on the basis of up-to-date, objective and unbiased research (Chalmers and Haynes, 1994). The most reliable information results from randomized controlled trials (RCTs). Unfortunately. most RCTs, includinz those conducted in ovarian cancer, have been too small to demonstrate moderate treatment benefits with reliability, and many results have been inconclusive or contradictory. The Advanced Ovarian Cancer Trialists Group (AOCTG) recognized that the best means of synthesizing such randomized evidence is by systematic meta-analysis. In 1988. five meta-analyses of chemotherapy in advanced ovarian cancer using updated individual patient data were initiated. The first results were published in 1991 (AOCTG,1991). The AOCTG recognized the importance of updating these results especially for the comparison of carboplatin and cisplatin, in which the data were relatively immature. The comparison of platinum analogues was considered of such clinical importance that further new investigations were initiated to identify whether any particular type of women or tumour would benefit more from either cisplatin- or carboplatin-based chemotherapy.

Chemotherapy for Ovarian Cancer - a Consensus Statement on Standard Practice
M Adams, AH Calvert, J Carmichael, PI Clark, RE Colemans, HM Earls, CJ Gallagher, TS Ganesana, ME Goreg, JD Graham, PG Harper, GC Jayson, SB Kaye, JA Ledermann, RJ Osborne, TJ Perren, CJ Poole, JA Radford, GJS Rustin, ML Slevin, JF Smyth, H.Thomas and PM Wilkinson

The management of patients with ovarian cancer is a complex and evolving field. Optimal results from therapy are obtained when patients with ovarian cancer are treated by specialist multidisciplinary teams (Junior et al. 1994). The earliest states of ovarian cancer can be treated by surgery alone with excellent results. The majority of women with ovarian cancer have advanced disease at presentation and require chemotherapy as well as surgery to improve their quality of life and increase survival.

A large meta-analysis and previous consensus statements have established that standard chemotherapy should include a platinum compound ( Advanced Ovarian Cancer Trialists Group. 1991; Allen et al. 1993: National Institute of Health, 1994). Randomized trials performed before the introduction of paclitaxel show that carboplatin and cisplatin are equally effective in terms of long-term survival (Advanced Ovarian Cancer Trialists Group. 1991)

Before the introduction of paclitarel. there had been controversy surrounding, the use of platinum-based combination chemotherapy as opposed to single-agent platinum treatment. A meta-analysis of randomized trials suggested a small advantage for platinum combined with other drugs. However, early data from a recent very large randomized trial suggest no benefit for a three- drug (non-paclitaxel-containing,) platinum-based regimen over single-agent carboplatin (Advanced Ovarian Cancer Trialists Group. 1991; Torri, 1996). Increasing the amount of treatment by more frequent dosing, more cycles of treatment, intraperitoneal delivery of chemotherapy high-dose consolidation therapy are all areas of current research. As yet, no conclusive data exist to suggest that such approaches confer a survival benefit.

Surgical Management of the Neck in Squamous Cell Carcinima of the Floor of the Mounth
A. Zupi, L. Califano, G.M. Mangone, F. Longo, P. Piombino - Department of the Maxillofacial Surgery, School of Medicine and Surgery, "Frederico II" - University of Naples, Naples, Italy

Nodal Involvment in squamous cell carcinoma considerably lowers survival rate. Despite its importance, neck management has still not been adequate explored. The Authors have treatedretrospectively reviewed the records of 112 cases. Unilateral N+ were treated with a homolateral therapeutic and a controlateral prophylactic neck dissection; bilateral N+ were treated with a bilateral therapeutic neck dissection. On first observation the majority of cases (66.1%) were T1-2. N+ patients accounted for 45.5%. Among N- patients, 21.3% of occult nodal metastases were observed. The 5-year survival rate was 52.7%. With N+lesions a With N-lesions a prophylactic modified radical neck dissection is recommended in t2-4 lesions.

Screening for Prostate Cancer - More Questions than Answers
John B. W. Rietbergen and Fritz H. Schröder - From the Department of Urology, Erasmus University and Academic Hospitai Rotterdam, Rotterdam, The Netherlands - Correspondence to: Dr John B. W. Rietbergen, Department of Urology, Erasmus University and Academic Hospital Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands. Fax: 31 10 463 5315

Whether prostate cancer screening should be applied to the male population or not, remains an extensively debated issue (1, 2). Reference can be made to the favorable results of breast cancer screening and the surprisingly unfavorable results of lung-cancer screening (3). Since 1993 the American Urological Association (AUA) and the American Cancer Society (ACS) have recommended annual prostate-specific antigen (PSA) testing and rectal examinations beginning at age 50 for early prostate cancer detection and at age 40 in men belonging to identifiable risk groups (4, 5). In most European countries. particularly in Northern Europe, routine application of screening procedures for prostate cancer is not accepted for a number of reasons: There is limited knowledge about the natural history of prostate cancer diagnosed at screening and the increasing gap between lifetime incidence and mortality suggests that there is a substantial risk of over-diagnosis and subsequent over-treatment. There is no reliable information on the effectiveness of treatment from randomized trials. The benefit of prostate cancer screening, in terms of reducing prostate-cancer-specific mortality, has not yet been shown. Adami and co-workers question whether even a randomized trial of screening for prostate cancer meets the ethical requirements (6). In this article the issues that fuel the prostate cancer screening debate are reviewed.

Treatment of Follicular Lymphoma
Joseph M. Connors, MD, and Richard Klasa, MD

Follicular lymphoma is one of the most common neoplastic lymphoproliferative diseases encountered in the western world. Intensive scientific scrutiny has led to detailed understanding of the nature of the malignant cell and the specific genetic abnormalities which are frequently encountered and likely to be etiologic. Clinical research focusing on the treatment of follicular lymphoma continues to reveal new insights into the natural history of the disease. Investigations reported during the past year have focused on a number of important issues with regard to the management of patients with diseases.

Cladribine in the Treatment of Advanced Relapsed or Refracto Low and Intermediate Grade Non-Hodgkin's Lymphoma
Anil Tulpule, M.D. Gary Schiller, M.D. Laura A. Harvey-Buchanan, B.S.N. Myung Lee, R.N. Byron M. Espina, A.B., Aziz U. Khan, M.D. William Boswell, M.D. Bharat Nathwani, M.D. Alexandra M. Levine, M.D.

Background: Cladribine (2-chlorodeoxyadenosine) is a purine nucleoside analog with cytotoxic activity against both resting and proliferating cells. Clinical studies with cladribine have reported antitumor activity against various hematologic malignancies.

Methods: The authors studied responses to cladribine among patients with low and intermediate grade non-Hodgkin's lymphoma that had been refractory to or relapsed after prior chemotherapy. Cladribine was given intravenously over 2 hours at a dose of 0.14 mg/ kg daily for 5 consecutive days, repeated every 4 weeks.

Results: Twenty-eight patients (16 males, 12 females) with a median age of 58 yesrs (range, 41-75 years) were accrued. Twenty-three patients had low grade and 5 had intermediate grade lymphoma. Stage IV disease was present in 22 (79%), and 17 (61%) had systemic B- symptoms. The majority (57%) had received 2 or more prior chemotherapy regimens (median, 2; range, 1-5); 6 had had prior fludarabine therapy. Major responses were documented in 32% (9 of 28 patients), with 4 complete remissions (CR) and 5 partial remissions (PR) after a median of 4 cycles (range, 1-9). One CR occurred in one patient with intermediate grade diffuse large cell lymphoma, and three of six patients who had had prior fludarabine therapy experienced CR or PR with cladribine. Severe hematologic toxicities included reversible neutropenia, protracted thrombocytopenia, and lymphopenia. Other reported adverse effects included mild-to-moderate fatigue, nausea, and diarrhea.

Conclusions: Cladribine is an active single agent in the treatment of patients with refractory or relapsed advanced stage indolent lymphoma, with major responses in one third of patients.

Tamoxifen in the Treatment Of Breast Cancer
C. Kent Osborne, M.D.

Breast cancer is the most common cancer in women in the Western world. Because breast cancer is estrogen-dependent, reducing estrogen secretion by oophorectomy, hypophysectomy, or adrenalectomy can cause the cancer to regress. The need for these surgical procedures was reduced by the introduction of tamoxifen, which acts as an antiestrogen by inhibiting the binding of estrogen to estrogen receptors. Tamoxifen was approved by the Food and Drug Administration in 1977 for the treatment of women with advanced breast cancer and several years later for adjuvant treatment of primary breast cancer.

The compound administered to patients is transtamoxifen (as the citrate salt), because this isomer has higher affinity for estrogen receptors than the cis isomer. These receptors are nuclear transcription factors present in normal breast and other tissues and in 60 to 70 percent of breast cancers. The transtamoxifen has not only antiestrogenic but also estrogenic properties, depending on the species, tissue, and gene. Drugs such as tamoxifen are more properly referred to as selective estrogen-receptor modulators, because of their multiple activities. The molecular basis for these properties is poorly understood, but the estrogen-agonist activity of tamoxifen may explain its favorable effects on bone and serum lipid concentrations and its ability to stimulate the endometrium. Its estrogen-antagonist activity in breast tissue accounts for its ability to inhibit tumor growth.

The major metabolites of tamoxifen in humans are N-desmethyltamoxifen and trans-4-hydroxytamoxifen (Fig. 1); the affinity of the latter for estrogen receptors is equivalent to that of 17B-estradiol. The dimethylaminoethoxv side chain and the transconfiguration are crucial for the antiestrogenic activity of tamoxifen; more highly estrogenic cis metabolites and metabolites without the side chain have been found in breast tumors, but their importance is unclear. Tamoxifen is absorbed readily after oral administration. The serum half lives of tamoxifen and its major metabolites range from 7 to 14 days, permitting once-daily administration. The usual dosage is 20 mg per day. In long-term treatment, the steady-state concentrations of tamoxifen and its metabolites in serum remain constant for as long as 10 years; reduced bioavailability is not a cause of acquired resistance to the drug. Tamoxifen can be detected in serum for several weeks and in tumor tissue for several months after treatment is discontinued. As a result, for several months after tamoxifen treatment is stopped, ligand-binding assays of estrogen receptors in tumor tissue can give false negative results because of receptor occupancy by the drug. Tamoxifen undergoes extensive metabolism in the liver and is excreted predominantly in the feces.

Serum tamoxifen concentrations vary, widely from patient to patient. Treatment responses, however, do not correlate with steady-state serum concentrations of the drug, and doses greater than 20 mg daily are not more effective than this dose.

Tamoxifen increases the action of warfarin by competing with its metabolizing enzyme, cytochrome P450 3A4, a circumstance that can lead to potentially life-threatening bleeding. Therefore, patients receiving tamoxifen should be given less warfarin, and the international normalized ratio should be closely monitored. Erythromycin, cyclosporine, nifedipine, and diltiazem can inhibit tamoxifen metabolism by a similar mechanism.

Is There a Standard Adjuvant Treatment for Rectal Cancer?
K.M. Tveit B. Nordlinger and C. Penna H.J. Schmoll - Department of Oncology, Ullevaal University Hospital, 0407 Oslo, Norway

One of the major controversies in oncology today, among oncologists as well as surgeons, is adjuvant treatment for rectal cancer. The current practice differs from Europe to the U.S.A., between countries in Europe, and even between institutions within the same country. The question of whether or not to give adjuvant treatment and what regimen should be used is extremely important, as rectal cancer is one of the most frequent cancer types [1]. Thus, an improvement of 5-year survival from, for example, 50 to 60%, corresponds to approximately 100 lives saved in a small country like Norway and approximately 5,000 lives saved in the U.S.A. In addition, successful adjuvant treatment may reduce suffering from painful recurrences and the need for resource demanding palliative treatment. Establishing an optimal treatment for rectal cancer should, therefore, be a high priority in modem medicine.

I will focus on adjuvant treatment for resectable rectal cancer (Dukes' A, B and C) and will only briefly consider primarily unresectable locally advanced cases. The discussion of standard adjuvant treatment is largely influenced by the fact that so far no standard surgery has been defined. Surgeons have resected rectal cancer for cure for decades, and with large variations in results, in terms of local recurrence rate, survival and complications [2, 3]. The surgical techniques employed differ, and it is well known that the experience of individual surgeons has a major impact on treatment results [2-5]. Recently, surgeons in many countries made an effort to standardise surgery. This change in surgical approach will also have a major impact on the question of a standard adjuvant treatment. So, what is standard adjuvant treatment today and what will be the standard tomorrow? What is standard? The introduction of a standard adjuvant treatment for rectal cancer (as with other standard treatments) should, in general, be based on available documentation from at least two or three high quality independent randomised trials (or a meta-analysis). Moreover, the benefit of the treatment should be clinically significant in terms of survival, recurrence rate or quality of life, the side- effects should be tolerable and the costs acceptable. On this background, I will discuss adjuvant treatment for rectal cancer.

Issues in the treatment of Hodgkin's Disease
Jürgen Wolf, MD, Andreas Engert, MD and Volker Diehl, MD

Introduction:

The treatment of Hodgkin's disease strikingly. In early stages of disease, extended field irradiation to date has been the standard treatment resulting in excellent cure rates. Due however to the recognition of the fatal long-terms effects, especially the high rates of second solid tumors, extended field radiation therapy is now being abandoned by most study groups. Instead, mild chemotherapy for control of occult disease is combined with involved field irradiation. In intermediate state Hodgkin's disease, where combined modality treatment already is the treatment of choice, extened field irradiation is substituted by involved field irradiatin for the same reasons. In advanced stage Hodgkin's disease, eight cycles of standard polychemotherapy ( plus additional radiotherapy for large tumor masses and residual lymphomas after chemotherapy ) for decades has cured only about 50% of the patients. While until recently ail modification of the standard chemotherapy regimens could not change the poor outcome of advanced-stage patients, the development of the new dose-intensified regimens now for the first time has significantly improved their prognosis. In patients with relapse of Hodgkin's disease after polychemotherapy, long-term survival after salvage chemotherapy is low. Numerous phase II studies suggest an improvement of their poor prognosis by high-dose chemotherapy followed by antologous bone marrow transplantation or peripheral-blood stem cell tranplantation. There are still no results of prospective, randomized trials which convincingly demonstrate the benefit of this therapeutic approach, however.

Possible Mechanisms by which Alcohol May Influence the Development of Oral Cancer a Review
A. J. Wight, G. R. Ogden - Unit of Oral Medicine and Oral Surgery, Dundee Dental Hospital and School, University of Dundee, Dundee, U.K.

Although pure ethanol has never been shown to be carcinogenic in laboratory experiments, alcoholic beverages are now recognised as being important aetiological factors in the development of oral cancer. Despite this, the exact mechanism by which alcohol may exert an infiuence upon the oral mucosa has received less attention. An overview of the association of alcohol and oral cancer. both in combination with tobacco and without. is provided and consideration given to some of the pathways by which alcohol exerts its effect upon the oral mucosa.

Addition of Etoposide to CHOP Chemotherapy in Untreated Patients with High-grade Non-Hodgkin's Lymphoma
F. Celsing, S. Widell, K. Merk, P Bernell, G. Grimfors, A. Hedlund, J. Liliemark, F. Svedmyr, E. Ösby 1 & M. Björkholm - Department of Hernutology and lnfections Diseases. Karolinska Hospital: Department of Oncology, South Hospital, Stockholm: Section of Hematology, Department of Medicine, Danderyd Hospital, Danderyd: Department of General Oncology, Karolinska Hospital. Stockholm, Sweden.

Background: Second- and third-generation chemotherapy protocols for the treatment of aggressive non-Hodgkin's lymphomas (NHL) have considerable, and age-related, toxic effects. In addition, they do not seem to prolong overall survival in comparison to standard CHOP chemotherapy. In this phase II study we investigated the feasibility and efficacy of the addition of etoposide to the conventional CHOP regimen.

Patients and methods: Toxicity and clinical efficacy were determined in 132 patients with previously untreated high-grade NHL. There were 51 patients in clinical stage I and II and 81 patients in stage III and IV, with a median age of 54 years (range 17-85). Patients received standard-dose CHOP plus etoposide 100 mg/m2 i.v. on day 1 and 200 mg/m2 p.o. on days 2-3.

Results: The overall response rate was 84%, with 70% complete and 14% partial responses. The predicted three- and five-year survivals for the group as a whole were 60% and 53% Respectively, and the corresponding disease-free survivals for patients achieving complete remissions were 65% and 56%, respectively. Outcome was not different from that of CHOP- treated patients in a recently completed Nordic study performed during the same time period. Myelosuppression (WHO grade 3-4), observed in 87% of patients and infectious complications (WHO grade 3-4) in 33%, dominated the toxicity profile of this regimen. Fifty-seven of 92 complete responders (6?%) received 6-8 CHOP-E cycles with no reductions in planned dose intensity. LDH level higher than normal, extranodal sites = 2, stage III-IV at diagnosis were all indicators of a poor survival. Conclusions: We conclude that CHOP-E treatment is effective in high-grade NHL. However, mainly due to severe myelosuppression frequent schedule modifications were required and the results are not obviously superior to those of conventional CHOP.

Preliminary Report of the Asian-Oceanian Clinical 0ncology Association Randomized Trial Comparing Cisplatin and Epirubicin followed by Radiotherapy versus Radiotherapy Alone in the Treatment of Patients with Locoregionally Advanced Nasopharyngeal Carcinoma
Daniel T. T. Chua, M.B., Ch.B., Jonathan S. T. Sham, M.D., Damon Choy, M.B.B.S., Virchan Lorvidhaya, M.D., Yupa Sumitsawan, M.D., Sumitra Thongprasert, M.D., Visoot Vootiprux, M.D., Arkom Cheirsilpa, M.D., Tahir Azhar, M.D., Ary H. Reksodiputro, M.D. and the Asian-Oceanian Clinical Oncology Association Nasopharynx Cancer Study Group

Background:The aim of this trial was to compare the outcome achieved with neoadjuvant chemotherapy followed by radiotherapy to that achieved with radiotherapy alone for patients with locoregionally advanced undifferentiated or poorly differentiated nasopharyngeal carcinoma (NPC) meeting one of the following criteria: Ho's T3 disease, Ho's N2-N3 disease, or lymph node size >3 cm.

Methods: Between September 1989 and August 1993, 334 patients were enrolled in the study, with equal numbers of patients randomized to the neoadjuvant chemotherapy arm (CT arm) and the radiotherapy arm (RT arm). Neoadjuvant chemotherapy consisting of 2-3 cycles of cisplatin (60 mg/ m² on Day 1) and epirubicin (110 mg/m² on Day 1) followed by radiotherapy was given to the CT arm. For radiotherapy, a dose of 66-74 gray (Gy) (median, 71 Gy) was delivered to the primary tumor and 60-76 Gy (median, 66 Gy) to the neck. Two hundred eighty-six eligible patients completed the treatment and were evaluable for treatment response (134 in the CT arm, 152 in the RT arm). All patients were included in the survival analysis based on the intention to treat. The median follow-up was 30 months for the whole cohort and 41 months for the surviving patients.

Results: Analysis of the 334 patients based on the intention to treat showed no significant difference in relapse free survival (RFS) or overall survival (OS) between the 2 treatment arms (3-year RFS rate: 48% in the CT arm vs. 42% in the RT arm, P = 0.45; 3-year OS rate: 78% vs. 71%, P = 0.57). In an efficacy analysis based on only the 286 evaluable patients, a trend of improved RFS favoring the CT arm was observed (3-year RFS rate: 58% vs. 46%, P = 0.053), with again no significant difference in OS (3-year OS rate: 80% vs. 72%, P = 0.21). In the subgroup of 49 patients with bulky neck lymph nodes >6 cm, improved RFS (3-year RFS rate: 63% vs. 28%, P = 0.026) and OS (3-year OS rate: 73% vs. 37%, P = 0.057) were observed. favoring the CT arm.

Conclusions: This multicenter randomized study did not demonstrate any benefit with the addition of cisplatin-epirubicin neoadjuvant chemotherapy for patients with locoregionally advanced nasopharingeal carcinoma; therefore routine administration of neoadjuvant chemotherapy to this target group cannot not be recomended. Although the overall incidence of recurrence was reduced with the addition of chemotherapy in the efficacy analysis, the overall survival was not affected. A more effective chemotherapy regimen, the selection of an appropriate target group, and use of an alternative strategy for combining chemoradiotherapy shoud be explored in future trials.

Gliomas
I- Cokgor, A.H. Friedman and H.S. Friedman - Department of Medicine; Department of Surgery; and Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, U.S.A.

Central Nervous Systems (CNS) tumours are the most common solid neoplasms of child-hood and account for 20% of all mallignancies in this age group. Gliomas constitute 40-60% of all childhood primary brain tumours [1]. Low-grade astrocytomas are the most common neoplasms of childhood glial tumours [2]. Astrocytomas are seen more frequently in the supratentorial compartment, although the cerebellar hemispheres are also a common site for astrocytoma [3]. High-grade gliomas also predominantly arise in the supratentorial compartment, although brainstem gliomas are common malignancies arising in the infratentorial compartment. In this review we will discuss all histological types of paediatric gliomas including the different anatomical locations, treatment options and prognoses.

The incidence for all paediatric brain tumours ranges betwen 2.4 and 3.5 per 100 000 children [4]. Glial tumours are classified histologically as astrocytoma, anaplastic astrocytoma (AA), subependymal giant cell astrocytoma, oligodendroglioma, ependimoma, choroid plexus, mixed glioma and glioblastoma multiforme (GBM). The aethiology of the majority of the childhood brain tumours remains obscure. However, children with phakomatoses such as neurofibromatoses and tuberous sclerosis are the higher risk of deve-loping CNS tumours [2]. Approximately 35% of all children with optic pathway gliomas [5] and 70% of patients with intra-orbital glioma [6] have neurofibromatosis. Tuberous sclerosis is most commonly associated with cortical tubers and subependymal giant cell astrocytomas within the ventricular system.

A case control study showed that realatives of children with CNS tumours are more likely to develop brain tumours or malignancies of the hematopoietic-lymphocytic systems compared with the general population [7]. Maternal exposure to nitrosamine-containing foods and drugs is another risk factor that increases the development of the astrocytoma [8]. A previous history of radiotherapy predisposes a child to developing meningioma , glioma or sarcoma later in life [9]. Classic examples include patients who received scalp irradiation for tinea capitis [10] and patients with acute limphocytic leukaemia who received prophylactic radiation to the CNS [11].

The Remission Status Before and the PCR Status after High-dose therapy with Peripheral Blood Stem Cell Support are Prognostic Factors for Relapse-free Survival in Patients with Follicular Non-Hodgkm's Lymphoma
M. Moos, R. Schultz, S. Martin, A. Benner and R. Haas - Department of Internal Medicine V, Univesity of Heidelberg; Department of Biostatistics, German Cancer Research Institute, Heidelberg; and Clinical Cooperation Unit for Molecular Hematology and Oncology, German Cancer Research Institute, Heidelberg, Germany.

It was the aim of our study to examine the clinical significance of t(14;18)-positive cells in samples from 47 patients with follicular non-Hodgkin's limphoma (NHL) who underwent high-dose therapy with autologous peripheral blood stem cell ( PBSC) transplantation. At the time of PBSC mobilization, 25 patients were in first remission, while 2 patientes had a history of previous treatment failure. At the same time, 43 patients had pholymerase chain reaction (PCR)-positive cells in samples from bone marrow (BM) and/or peripheral blood (PB). Independent of the remission status, high-dose cytarabine and mitoxantrone with granulocyte colony-stimulating factor (G-CSF) support were administered for PBSC mobilization. Following high-dose conditioning therapy which consisted of cyclophosphamide (200mg/kg) and hyperfractionated total body irradiation (TBI, 14.4 Gy) or BEAM (carmustine, etoposide, cytarabyne, melphalan), 34 patients received PCR-positive and 13 patients received PCR-negative autografts. After a median-follow-up time of 20 months (range, 6-50) post-transplantation , 33 patients were in remission, while 14 patients had relapsed after a median time of 14.5 months (range. 10-42). Using the Anderson-Gill proportional hazards regression model for the analysis of relapse-free survival , we found that PCR-positive findings in samples from BM and/or PB at any given time-point after transplantation were associed with an increased estimated hazard ratio of 4.5 in comparison with a PCR-negative finding (P=0.013). On the other hand, patients incuded while they were in first remission had a smaller estimated hazard ratio of the 0.3 whem compared with patients with history of previous treatment failure (P=0.048). For the later group of patients, this translates into a significantly smaller probability of relapse-free survival in comparison to patients who were in first remission at the time of PBSC-mobilization (P=0.012). In conclusion, the remission status of patients before autografting and PCR status as assessed on the occasion of follow-up examinations are significant prognostic parameters for relapse-free survival in patients with follicular lymphoma undergoing high-dose therapy with PBSC autografting.

Subsequent Quality of Life for Children Irradiated for a Brain Tumor Before Age Four Years
Derek Jenkin, MD, Cyril Danjox, MD and Mark Greenberg, MD

Background: We wanted to evaluate survival and functional morbidity following radiation treatment of brain tumours in children less than 4 years old.

Procedure: Outcome was evaluated for 222 children who were less than 4 years old when they were irradiated at University of Toronto Centres, 1958-1995. The status of the survivors with regard to focal neurological defects, vision, and education at last follow-up was recorded. In 23 adult survivors older than 21 years at least follow-up, information was obtained with regard to higher education, ocupation, and living arrangements.

Results: The overall 10-year survival rate was 40%, not significantly different than the 45% for 776 4-16- years old with irradiated brain tumours treated at the same institutions. Forty-five percent of the survivors had no major focal neurological, visual, or hearing defects. There were no major differences in the frequencies of these criteria or ot schooling betwen 0-2-and 2-4-year-olds. Among adult survivors, older than 21 at least follow-up , 26% successfully completed high education, 31% were in full time employment, and 37% had never been employed. For medulloblastoma, the 5-year survival rate was 61% for 30 children less than 3 years old and treated from 1975-1995. This comparad favorably with recent reports of survival following primary chemotherapy with delayed or omitted radiation treatment.

Summary: Radiatio treatment or a young child with a brain tumor was associated with cure in 1 of every 3 patients. Unfortunatel, quality of life for many survivors was not good. Only one of the every 3 adults survivors was able to have a normal life-style.

This shortfall was the results of focal neurological defects which were present from the time of first treatment, and of the long-term effects of radiation treatment.

Conclusions: The search for less toxic treatment remains appropriate, but is experimental and researches must recognize that there may be a trade-off betwen morbidity and mortality.

Doxorubicin cardiotoxicity in children: Caomparison of a Consecutive Divided Daily Dose Administration Schedule With Single Dose (Rapid) Infusion Administration
Michael S. Ewer, MD, MPH, Norman Jaffe, MD, DSC, Hubert Ried, MD, Hallie A. Zietz, RN, MSN, CPNP and Robert S, Benjamin, MD

Background: Doxorubicin cardiotoxity remains a serious problem in children malignancy. The present study was undertaken to determine if the administration of consecutive divided daily doses of doxorubicin would significantly reduce the likelihood of cardiotoxicity in children compared with a single dose administration regimen.

Procedure: One hundred thirteen children ( 60 boys and 53 girls) received doxorubicin either by single dose infusion or by a consecutive divided daily dose achedule: The divided dose patients received one third of the total cycle dose over 20 minutes for 3 consecutive days.Patients treated according to a single dose schedule received the cycle dose as a 20-minute infusion. The mean doxorubicin dose was 341 mg/m². Patients were followed up to 4-180 months.

Results: Fifteen patients developed cardiac dysfunction, eight of the whom died of progressive cardiac failure. There was no significant difference in the incidence of cardiac dysfunction between the divided and single dose infusion groups. More girls than boys developed cardiac dysfunction and more girls died of progressive cardiac failure; this difference was not statistically significant. The median time to the development of cardiac failure was 2 months.

Conclusions: The divided dose regimen did not alter the incidence of cardiotoxity. Other schedule should therefore be investigated. Our data suggest that, at similar cumulative doses, girls are more likely to develop cardiac dysfunction than are boys. If the sex-related difference is proved in larger series of patients, it may be prodent to lower the recommended cumulative doses for girls.

Surgery for Gynecologic Malignancies
Cynthia Bergman, MD, and Matthew Boente, MD

Surgery continues to play a primary role in the investigation and treatment of gynecologic neoplasia. Cold-knife conization is still preferable for diagnosis and treatment of more problematic preinvasive cervical lesions. Newer reconstructive techniques can improve quality of life in exenteration patients. Efforts continue to reduce morbidity associated with vulvar surgery and groin node dissection. Accurate staging and maximum cytoreduction remain essential goals in primary surgery for ovarian cancers. The utility of secondary surgery for disease assessment or further treatment is controversial. Laparoscopy at present has a limited role in gynecologic oncology but may be useful for prophylactic oophorectomy in selected individuals.

Paclitaxel and Cisplatin as Salvage Treatment in Patients with Non-seminomatous Germ Cell Tumour Who Failed to Achieve a Complete Remission on Induction Chemotherapy
S. A. Tjulandin, D. A. Titov, V. V. Breder, N. J. Sidorova, A. J. Popov, D. Z. Kupchan and A. M. Garin - N. N. Blokhin Cancer Research Centre of the Russian Academy of Medical Sciences, Moscow, Russia

The purpose of this study was to evaluate the efficacy and toxicity of paclitaxel and cisplatin combination chemotherapy as salvage treatment in patients with non-seminomatous germ cell tumour. Sixteen patients with histologically proven germ cell tumour, measurable disease and/or elevated serum tumour markers were eligible for the protocol. All patients had previously not achieved a complete remission (CR) to platinum-based induction chemotherapy and cytoreductive surgery. The treatment consisted of paclitaxel 175-225 mg/m² as a 3-hour infusion, followed by cisplatin 100 mg/m², repeated every 3 weeks for up to four cycles. Seven patients achieved a marker-positive partial remission (PR) by the end of the cisplatin-based induction chemotherapy; the remainder had disease progression at the start of the paclitaxel plus cisplatin treatment. One (6%) CR and 3 (19%) PRs were achieved, with an overall response rate of 25% (90% confidence interval 7-43). The duration of the CR is currently 9+ months; two PRs lasted 2 months. One patient with a PR has been lost to follow-up. During a median follow-up of 8 months (range 1-11), 12 patients died from the disease progression. The median survival for the whole group was 7 months. Toxicity was moderate, with neutropenia grade 3 occurring in 29% of patients, thrombocytopenia grade 1-3 in 29%, creatinine > 130 mmol/l in 36%, peripheral neuropathy grade 1-2 in 5O%, and nausea and vomitina in 43%. Paclitaxel plus cisplatin showed modest activity, with an overall response rate of 31 % in patients with poor prognosis who had not achieved a CR on induction chemotherapy.

Chemotherapy Compared with Autologous or Allogeneic Bone Marrow Transplantation in the Management of Acute Myeloid Leukemia in First Remission
Peter A. Cassileth, M.D., David P. Harrington, Ph.D., Frederlck R. Appelbaum, M.D., Hlllard M. Lazarus, M.D., Jacob M. Rowe, M.D., Elisabeth Paietta, Ph.D., Chefiyl Willman, M.D., David D. Hurd, M.D., John M. Bennett, M.D., Karl G. Blume, M.D., David R. Head, M.D., And Peter H. Wiernik, M.D.

Background. In young adults with acute myeloid leukemia, intensive chemotherapy during the initial remission improves the (ong-term outcome, but the role of bone marrow transplantation is uncertain. We compared high-dose cytarabine with autologous or allogeneíc marrow transplantation during the first remission of acute myeloid leukemia.

Methods. Previously untreated adolescents and adults 16 to 55 years of age who had acute myeloid leukemía received standard induction chemotherapy. After complete remission had been achieved, idarubicin (two days) and cytarabine (five days) were administered. Patients with histocompatible siblings were offered allogeneic marrow transplantation, whereas the remaining patients were randomly assigned to receive a single course of high-dose cytarabine or transplantation of autologous marrow treated with perfosfamide (4-hydroperoxycycloro or transplantation of autologous marrow treated with perfosfamide (4- hydroperoxycyclophosphamide). Oral busulfan and intravenous cyclophosphamide were used as preparative regimens for both allogeneic and autologous marrow transplantation. The end points were survival from the time of complete remission and disease-free survival.

Results. In an intention-to-treat analysis, we found no significant differences in disease-free survival among patients receiving high-dose chemotherapy, those undergoing autologous bone marrow transplantation, and those undergoirig allogeneic marrow transplantation. The median follow-up was four years. Survival after complete remission was somewhat better after chemotherapy than after autologous marrow transplantation (P=0.05). There was a marginal advantage in terms of overall survival with chemotherapy as compared with allogeneic marrow transplantation (P=0.04).

Conclusions. A postinduction course of high-dose cytarabine can provide equivalent disease-free survival and somewhat better overall survival than autologous marrow transplantation in adults with acute myeloid leukemia.

lcon2: Randomised Trial of Single-Agent Carboplatin Against Three-Drug Combination of Cap (Cyclophosphamide, Doxorubicin, And Cisplatin) In Women With Ovarian Cancer

Background. A series of meta-analyses of randomised controlled trials raised the question of whether the three-drug combination of CAP (cyclophosphamide, doxorubicin, and cisplatin) was more or less efifective than optimal-dose single-agent carboplatin for women with advanced ovarian cancer.

Methods. We carried out an international, multicentre, randomised trial to compare CAP with single-agent carboplatin in women with ovarian cancer requiring chemotherapy. 1526 patients were entered from 132 centres in nine countries. Analyses were by intention to treat.

Findings. 728 patients have died (368/766 allocated CAP vs 360/760 allocated carboplatin) and the survival curves show no evidence of a difference between CAP and carboplatin (hazard ratio 1.00 [95% CI 0.86-1.16); p=0.98). The results indicate a median survival of 33 months and a 2-year survival of 60% for both groups. We found no evidence that CAP or carboplatin were more or less efiFective in different subgroups defined by age, stage, residual disease, differentiation, histology, and coordinating centre. CAP was substantially more toxic than carboplatin, causing more alopecia, leucopenia, and nausea. More thrombocytopenia occurred with carboplatin.

Interpretation. Single-agent carboplatin, with the dose calculated by the area-under-the-curve method, is a safe, effective, and appropriate standard of treatment for women with advanced ovarian cancer.

Selective Use of PET Scan in the Preoperative Staging of NSCLC
Cemal Asim Kutlu, Ugo Pastorino, Michael Maisey, Peter Goldstraw - Department of Thoracic Surgery, Royal Brompton Hospital, Clinical PET Centre, Guy's and St. Thomas Hospitals, London, UK

Positron emission tomography (PET) is a imaging technique which identifies abnormalities by utilising their metabolic properties rather than their anatomical density. In this study, we evaluated the place of PET scanning for the characterisation of additional abnormalities discovered on routine, preoperative CT evaluation of patients with proven NSCLC. A total of 21 patients underwent PET scanning using fluorodeoxyglucose (FDG). In these patients, outine CT scans had found 26 concomitant lesions which were in lung, adrenal gland, liver, kidney, spleen and pleura. FDG uptake was positive at the primary site in all patients. FDG uptake in 13 of the concomitant lesions suggested malignancy. Malignancy was confirmed at all of these foci by histology in eight (six at thoracotomy, fine needle aspiration biopsy (FNAB) and open biopsy) and by clinical and radiological follow-up for 1-15 months in five. In 13 lesions, PET suggested benign disease. Histology reported no evidence of malignancy in five and the six foci followed on clinical and radiographic follow-up for 2-16 months had no evidence of malignancy. PET was falsely negative in only one site where malignancy was proven by thoracotomy. PET failed to detect the remaining lesion which was an unassociated primary kidney tumour in a patient with Li-Fraumeni syndrome. The accuracy of PET scanning in the assessment of those additional lesions found on CT evaluation of otherwise operable NSCLC was found to be 96% with a sensitivity of 93% and specificity of 100%. These results indicate that PET is useful to characterise additional lesions found on CT scan of patients with NSCLC.

Controlled Clinical Trial of Prophylactic Cranial Irradiation for Patients with Small-Cell Lung Cancer in Complete Remission
Agnès Laplanche, Isabelle Monnet, Juan Antonio Santos-Miranda, Etienne Bardet, Cécile Le Péchoux e, Michèle Tarayre, Rodrigo Arriagada

We conducted a randomised clinical trial on 211 patients with small-cell lung cancer in complete remission (CR). The aim of this trial was evaluate the effect of prophylactic cranial irradiation (PCI) on overall survival. Eligible patients were randomly assigned to received either PCI (100 patients) or no PCI (111 Patients). Each centre was allowed to use its own PCI protocol as long as the total dose was within the range of 24-30 Gy and delivered in less than 3 weeks with fractions of 3 Gy or less. The mean follow-up is 5 years. The survival curves do not differ significantly (P=0.25) between the two groups. The 4-year overall survival rate (95% confidence internal) is 22% [15-32%] in the PCI group versus16% [10-25%] in the control group. The relative risk of death in the PCI group compared to the control group is 0.84 (95% CI = [0.62 - 1.13]). The incidence of brain metastasis is lower in the PCI group, but the difference is not statistically significant (P=0.14). The 4-year cumulative rate of brain metastasis is 44% [32-57%] in the PCI group compared to 51% [38-63%] in the control group. In conclusion, in this study, which had to be closed prematurely, no significant difference was found in terms of the incidence of brais metastases nor in survival.

Emerging Treatments for Epidemic (AIDS-related) Kaposi's Sarcoma
Megan E. McGarvey, BA, Anil Tulpule, MD, Jie Cai, MD, Tong Zheng, DDS, Rizwan Masood, PhD, Byron Espina, AB, Naveen Arora, PhD, D. Lynne Smith, PhD, and Parkash S. Gill, MD

Kaposi's sarcoma (KS) is an opportunistic tumor that develops with increase frequency (100,000-fold) after HIV infection. KS causes significant morbidity from mucocutaneus involvement and mortality from complications of visceral sites of disease such as the lungs, gastrointestinal tract, and the liver. Progressive unraveling of the KS pathogenesis has lead to the development of novel therapeutic approaches. Newest therapies are first evoluated in patients with limited tumor burden. These include: 1) inhibitors of angiogenesis such as vascular endothelial growth factor signaling inhibitor (SU 5416), and several other inhibitors of angiogenesis such as the diipeptide IM 862, TNP-470, COL-3, and Thalidomide; 2) topical and the system retinoids; 3) antiviral agents specific for Kaposi's sarcoma herpesvirus and human herpesvirus-8, or HIV; 4) pregnancy-related factors. Patients with advanced disease such as widespread mucocutaneus disease, lymphedema, and visceral disease are treated most effectively with cytotoxic agents. The most active agents include liposomal anthracyclines, paclitaxel, vinca alkaloids, and bleomycin. The combination of liposomal antrhacyclines and paclitaxel, with or without the most promising biologicals, should now be studied to further reduce the toxicity, and enhance the antitumor effects. Furthermore, identification of risk factors for KS should serve to explore prophylactic therapies.

Impact of Hospital Volume on Operative Mortality for Major Cancer Surgery
Collin B. Begg, PhD; Laura D. Cramer, ScM; Willian J. Hoskins, MD; Murray Brennan, MD

Context: Hospital that treat a relatively high volume of patients for selected surgical oncology procedures report lower surgical in-hospital mortality rates than hospitals with a law volume of the procedures, but the reports do not take into accounnt lenght of stay or adjust for case mix.

Objective: To determine whether hospital volume was inverely associeted with 30-day operative mortality, after adjusting for case mix.

Design and Setting: Retrospective cohort study using Surveillance, Epidemiology, and End results (SEER)-Medicare linked data baes in which the hipotesis was prospectively specified. Surgeons determined in advance the surgical oncology procedures for which the experience of treating a larger volume of patients was most likely to lead to the knowledge or technical expertise that might offset surgical fatalities.

Patients: All 5013 patientsin the SEER registry aged 65 years or older at cancer diagnosis who underwent pancreatectomy, esophagectomy, pneumonectomy, liver resection, or pelvic exenteration, using incident carcers of pancreas, esophagus, lung, colon, and rectum, and various genitourinary cancers diagnosed between 1984 and 1993.

Main Outcome Measure: Thirty-day mortality in relation to procedure volume, adjusted for comorbidity, patient age, and cancer stage.

Results: Higher volume was linked with lower mortality for pancreatectomy (P=.004), esophagectomy (P<.001), liver resection (P=.04), and pelvic exenteration (P= .04), but not for pneumonectomy (P=.32). The most strinking results were for esophagectomy, for which the operative mortality rose to 17.3% in low-volume hospitals, compared with 3.4% in high-volume hospitals , and for pancreatectomy, for which the corresponding rates were 12.9% vs 5.8%. Adjutments for case mix and other patients factors did not change the finding that low volume was stongly associated with excess mortality.

Conclusions: these data support the hipothesis that when complex surgical oncologic procedures are provided by surgical teams in hospitals with specialty expertise, mortality rates are lower.

Reduction in the Requirements for Mastectomy in a Randomized Trial of Neoadjuvant Chemoendocrine Therapy in Primary Breast Cancer
A. Makris, T. J. Powles, S. E. Ashley, J. Chang, T. Hickish, V. A. Tidy, A. G. Nash & H. T. Ford - Royal Marsden Hospital, Downs Road, Sutton, Surrey, UK

Background: A prospective randomised trial was undertaken to evaluate the role of neoadjuvant chemoendocrine therapy prior to surgery in primary operable breast cancer.

Patients and methods: Three hundred nine women (median age 56 years, range 27-70) with primary operable breast cancer confirmed on fine needle aspiration (FNA) cytology were recruited to this study. They were treated with a combination of mitoantrone and methotrexate (± mitomycin-C) combined with tamoxifen (2MT). Patients received eight cycles of 2 MT (four prior to surgery in the neoadjuvant group) and tamoxifen for five years with appropriate surgery and radiotherapy. The two groups were comparable for age, meno-pausal status, stage and surgical requirements.

Results; The clinical response rates to neoadjuvant therapy were as follows: 22% complete response (CR), 29% minimal residual disease (MRD), 33% partial response (PR), 15% no change (NC) and only two patients had clinical evidence of progressive disease. Surgical requirements were reduced from 31 patients (22%) of the adjuvant group having mastectomy to 14 (10%) in the neoadjuvant group (P<0.003). At a median follow-up of 48 months (range 10-70 months) there is no statistically significant difference between the two groups in terms of local relapse, metastatic relapse or overall survival. Symptomatic and haematologic acute toxicity was low and similar for adjuvant and neoadjuvant therapy.

Conclusion: This randomised trial has shown a significant reduction in the surgical requirements for mastectomy, after treatment with neoadjuvant chemoendocrine therapy, with no deterioration in local or distal relapse.

Colorectal Cancer Screening
John H. Bond, MD

Comprehensive evidence-based guidelines for screening and surveillance for colorectal cancer were published in 1997. Backed by compelling scientific data from recently completed controlled trials and case-control studies, these guidelines recommended annual fecal occult blood test screening plus periodic flexible sigmoidoscopy about every 5 years for asymptomatic, average-risk individuals over 50 years of age. Other screening studies published during the past year refine knowledge about how these screening tests detect early cancer and polyps and assess factors that influence compliance with screening recommendations. Preliminary reports suggest revolutionary new methods of screening that may become clinically feasible in the next millennium.