Responsável
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.

Evaluation of the newly updated TNM classification of head and neck carcinoma with data from 3247 patients
Heinrich Iro, M.D. and Frank Waldfahrer, M.D. - Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University, Homburg, Germany.

Background: The fifth edition of the TNM classification contains a number of changes concerning head and neck tumors. The division of Stage IV tumors into three subcategories marks a significant expansion of the stage grouping procedure.

Methods: In a retrospective study, the clinical courses of 3247 patients with carcinoma of the oral cavity, the oro- and hypopharynx, the larynx, the salivary glands, and the maxillary sinus were comparatively evaluated according to the fourth and fifth editions of the TNM classification agreed upon by the International Union Against Cancer and the American Joint Committee on Cancer. The particular aim of this study was to test the prognostic relevance of the subdivision of Stage IV, especially for mucosal carcinoma.

Results: In classifying the primary tumor, the most extensive changes were noted for supraglottic and salivary gland tumors. On the basis of the fourth edition of the TNM classification, the following recurrence free 5-year survival rates for 3033 cases of mucosal cancer were calculated: Stage I, 91.0%; Stage II, 78.6%; Stage III, 61.4%; Stage IV, 31.0%. The calculations based on the fifth edition yielded the following: Stage I, 91.0%; Stage II, 77.2%; Stage III, 61.2%; Stage IVA, 32.4%; Stage IVB, 25.3%; Stage IVC, 3.6%.

Conclusions: The adequacy of the revised stage classification in establishing a prognostic hierarchy was confirmed. However, a significant prognostic distinction between N2 metastasis (Stage IVA) and N3 metastasis (Stage IVB) could not be found.

Key words: TNM classification (fourth edition), TNM classification (fifth edition), head and neck cancer, tumor staging, International Union Against Cancer, American Joint Committee on Cancer.

Adjuvant therapy in head and neck cancer
Bhadrasain Vikram, MD

Introduction: Patients with early cancers of the head and neck can be treated by irradiation or surgery with a high expectation of cure. Unfortunately, most patients present with more advanced disease for which the results of treatment are much less satisfactory. If multimodality therapy is skill-fully applied, however, cure with a reasonable quality of life is possible if no clinical evidence exists of disease outside the head and neck region.

The principal goals of curative treatment are to render the patient grossly free of cancer, with functional and cosmetic outcomes acceptable to the patient; to prevent relapse of the cancer; and to prevent the appearance of new cancers. Surgical resection is often the most expeditious method of rendering the patient grossly free of cancer. Those for whom resection is not advisable (because of the extent of the cancer or the patient's general medical condition or because resection would result in an unacceptable deficit) usually are treated by radiation therapy. This review discusses the role of adjuvant treatment in the management of patients with locally advanced head and neck cancers.

Pleural mesothelioma: dose-response relation at low levels of asbestos exposure in a French population-based case-control study
Y. Iwatsubo, J.C. Pairon, C. Boutin, O. Ménard, N. Massin, D. Caillaud, E. Orlowski, F. Galateau-Salle, J. Bignon and P. Brochard

A hospital-based case-control study of the association between past occupational exposure to asbestos and pleural mesothelioma was carried out in five regions of France. Between 1987 and 1993, 405 cases and 387 controls were interviewed. The job histories of these subjects were evaluated by a group of experts for exposure to asbestos fibers according to probability, intensity, and frequency. A cumulative exposure index was calculated as the product of these three parameters and the duration of the exposed job, summed over the entire working life. Among men, the odds ratio increased with the probability of exposure and was 1.2 (95% confidence interval (CI) 0.8-1.9) for possible exposure and 3.6 (95% CI 2.4-5.3) for definite exposure. A dose-response relation was observed with the cumulative exposure index: The odds ratio increased from 1.2 (95% CI 0.8-1.8) for the lowest exposure category to 8.7 (95% CI 4.1-18.5) for the highest. Among women, the odds ratio for possible or definite exposure was 18.8 (95% CI 4.1-86.2). We found a clear dose-response relation between cumulative asbestos exposure and pleural mesothelioma in a population-based case-control study with retrospective assessment of exposure. A significant excess of mesothelioma was observed for levels of cumulative exposure that were probably far below the limits adopted in most industrial countries during the 1980s.
asbestos; case-control studies; mesothelioma; occupational exposure

Prognostic value of bone marrow biopsy in operable breast cancer patients at the time of initial diagnosis: Results of a 20-year median follow-up
K. Landys, S. Persson, J. Kovarík, R. Hultborn1, and E. Holmberg - Departments of Oncology and Pathology, (DOP), Sahlgrenska University Hospital, Göteborg, Sweden; Masaryk Memorial Cancer Institute, (MCI), Brno, Czech Republic

Key words: bone marrow micrometastases; breast cancer; monoclonal antibodies; prognosis

Summary

From May 1975 until May 1980, 128 operable breast cancer patients, clinical stage I-II, had a core bone marrow biopsy (BMB) from the posterior iliac crest as a part of the routine diagnostic work-up at the time of initial diagnosis. The mean age of the patients was 56 years, range 26-93. In a previous study on this material, 10 patients (7.8 per cent) were positive for tumor cells and 118 negative by conventional histopathology of BMB [1]. In 1996 we reexamined all BMB separately at two laboratories, using monoclonal antibodies against cytokeratins AE1-AE3, KL1, CAM5-2 (DOP), and DC10, BA17 (MCI). The number of extrinsic cells in the bone marrow was graded positive for micrometastases when 5 cells or suspicious when 1-4 cells per ~ 2 x 10⁶ bone marrow cells were found, using high power field magnification. Micrometastases were detected in 17 patients (13.3 per cent) and another 8 patients were classified as suspicious. The presence of micrometastases was correlated to the axillary lymph node stage and primary tumor location. Median follow-up was 20 years. All 17 micrometastatic patients relapsed and died within 6 years of disease progression with evident osseous metastases. There was one disease-free survivor of the 8 patients with suspicious BMB after 17 years of follow-up. The median overall survival was significantly shorter in tumor-cell positive patients, being 1.9 years compared to 11.7 years in the BMB negative and BMB suspicious groups (p< 0.0001). Immunohistochemical analysis of core BMB taken postoperatively may be useful in predicting the prognosis in patients with breast cancer clinical stage I-II.

The role of chemotherapy and radiation in the management of biliary cancer: a review of the literature
M. Hejna (Department of Internal Medicine I, Division of Oncology), M. Pruckmayer (Department of Nuclear Medicine, University of Vienna, A-1090 Vienna, Austria) and M. Raderer (Department of Internal Medicine I, Division of Oncology)

Carcinoma of the biliary tract is a rare tumour. To date, there is no therapeutic measure with curative potential apart from surgical intervention. Thus, patients with advanced, i.e. unresectable or metastatic disease, face a dismal prognosis. They present a difficult problem to clinicians as to whether to choose a strictly supportive approach or to expose patients to the side-effects of a potentially ineffective treatment. The objective of this article is to review briefly the clinical trials available in the current literature utilising non-surgical oncological treatment (radiotherapy and chemotherapy) either in patients with advanced, i.e. locally inoperable or metastatic cancer of the biliary tract or as an adjunct to surgery. From 65 studies identified, there seems to be no standard therapy for advanced biliary cancer. Despite anecdotal reports of symptomatic palliation and survival advantages, most studies involved only a small number of patients and were performed in a phase II approach. In addition, the benefit of adjuvant treatment remains largely unproven. No clear trend in favour of radiation therapy could be seen when the studies included a control group. In addition, the only randomised chemotherapeutic series seemed to suggest a benefit of treatment in advanced disease, but due to the small number of patients included, definitive evidence from large, randomised series concerning the benefit of non-surgical oncological intervention as compared with supportive care is still lacking. Patients with advanced biliary tract cancer should be offered the opportunity to participate in clinical trials.

Key words: biliary tract cancer; chemotherapy; radiation

Normal tissue protection in cancer therapy
Pathirissery Uma Devi
From the Department of Radiobiology, Kasturba Medical College, Manipal, India

Normal tissue tolerance is a major dose-limiting factor in radiotherapy and chemotherapy of cancer. During the past few decades several investigations have been directed toward increasing normal tissue tolerance by using chemical protectors against radiation and drug toxicity. WR-2721, the phosphorylated aminothiol, synthesized in the 1960s, has been hailed as the best chemical protector discovered so far. But its systemic toxicity after repeated administration in cancer patients during clinical trials has been a deterrent against its acceptance in routine radiotherapy, though more encouraging results have been reported with chemotherapy. The 1980s found a surge of activity in the field of chemical protection research, which has resulted in the discovery of many non-thiol protectors, particularly the biological response modifiers and antioxidants. It has also been found that protection by WR-2721 can be improved and its toxicity reduced by combination with some low potent protective chemicals. This review analyzes the major reports on chemical protectors published during the past ten years.

Tamoxifen in treatment of hepatocellular carcinoma: a randomised controlled trial
CLIP Group (Cancer of the Liver Italian Programme)

Summary

Background: Results from small randomised trials on tamoxifen in the treatment of hepatocellular carcinoma (HCC) are conflicting. We studied whether the addition of tamoxifen to best supportive care prolongs survival of patients with HCC.

Methods: Patients with any stage of HCC were eligible, irrespective of locoregional treatment. Randomisation was centralised, with a minimisation procedure accounting for centre, evidence of disease, and time from diagnosis. Patients were randomly allocated best supportive care alone or in addition to tamoxifen. Tamoxifen was given orally, 40 mg per day, from randomisation until death.

Results: 496 patients from 30 institutions were randomly allocated treatment from January, 1995, to January, 1997. Information was available for 477 patients. By Sept 15, 1997, 119 (50%) of 240 and 130 (55%) of 237 patients had died in the control and tamoxifen arms, respectively. Median survival was 16 months and 15 months (p = 0.54), respectively. No differences were found within subgroups defined by prognostic variables. Relative hazard of death for patients receiving tamoxifen was 1.07 (95% CI 0.83-1.39).

Interpretation: Our finding show that tamoxifen is not effective in prolonging survival of patients with HCC.

Comparison between four and eight cycles of intensive chemotherapy in adult acute myeloid leukemia: a randomized trial of the Finnish Leukemia Group
E. Elonen¹, A. Almqvist², A. Hänninen³, S-E Jansson¹, G. Järventie⁴, P. Koistinen⁵, E. Koivunen⁴, R. Lahtinen³, M. Lehtinen⁴, T. Nousiainen³, T-T Pelliniemi⁶, A. Rajamäki⁶, K.Remes⁶, T. Timonen⁵, J.Vilpo⁵, L. Volin¹, and T. Ruutu¹, for Finnish Leukemia Group ¹Helsinki University Central Hospital; ³Kuopio University Hospital; ⁵Oulu University Hospital; ⁴Tampere University Hospital; ⁶Turku University Central Hospital; and ²Vaasa Central Hospital, Finland.

In acute myelogenous leukemia (AML) intensive postremission treatment is needed for an optimal result. However, it is not known how long the treatment should last and how many courses are necessary. The object of this prospective study was to compare four and eight intensive chemotherapy cycles in the treatment of adult de novo AML. In a multicenter study, 248 consecutive patients, aged from 16 to 65 years, were treated with intensive induction treatment. The patients in remission after two courses were randomized to receive either two (short arm) or six (long arm) additional intensive cycles of chemotherapy. The median follow-up time of the living patients is 68 months. Of the patients, 77% achieved complete remission, and 36% of all patients survived for 5 years. Seventy-three patients were randomized to the short arm and 66 to the long arm. There was no significant difference in the relapse-free survival (median 21 months vs 17 months) or overall survival (43 months vs 39 months) between the short and long arms, respectively. Treatment-related deaths occurred in 31 patients (13%), 11 of them in first remission. More than one-third of the patients survived for 5 years. It seems probable that the first few months after diagnosis are decisive for the prognosis if the chemotherapy is intensive, and further treatment cannot markedly influence the outcome.

Key words: acute leukemia; myeloid; drug therapy; postremission therapy; treatment outcome; survival

Lung cancer from passive smoking at work
A. Judson Wells, PhD

Objectives: This study was undertaken to determine whether exposure at work to envi-ronmental tobacco smoke is associated with an increased risk of lung cancer.

Methods: Data from 14 studies providing information on lung cancer and exposure to environmental tobacco smoke at work were examined. Six quality criteria were developed for determining usable data. A meta-analysis was performed to obtain a combined risk for those data that met the quality restrictions.

Results. Five studies met the quality standards. Their combined relative risk was 1.39 (95% confidence interval [CI] = 1.15, 1.68) based on 835 lung cancer cases. In various meta-analyses prepared by tobacco industry employees or consultants, no increase in risk was found. The main reason for this difference is that the earlier analysts failed to find errors in 2 underlying studies that resulted in overweighting of the odds ratios from those studies, both of which were less than unity.

Conclusions. When appropriate cognizance is taken of the quality of data inputs, the increase in lung cancer risk from workplace exposure to environmental tobacco smoke is about the same as that from household exposure.

Five-year follow-up of a prospective randomised multi-centre trial of weekly chemotherapy (CAPOMEt) versus cyclical chemotherapy (CHOP-Mtx) in the treatment of aggressive non-Hodgkin's lymphoma
N.P. Bailey, N.S.A. Stuart, E.M. Bessell, J.A. Child, D. Norfolk, J. Fletcher, R.J. Grieve, A.V. Simmons, D.L. Barnard, A. Jack, J. Farish, J. Dunn1, C.M. Woodroffe, C. Stack and M.H. Cullen on behalf of the Central Lymphoma Group

Summary

Background: Weekly alternating regimen known as CAPOMEt is compared to standard cyclical chemotherapy (CHOP-Mtx) in aggressive non-Hodgkin's lymphoma (NHL).

Patients and methods: Three hundred and eighty-one patients with aggressive NHL were randomised to receive either cyclophosphamide, doxorubicin, vincristine, prednisone and methotrexate (CHOP-Mtx) on a cyclical basis or a weekly regimen incorporating the same drugs with the addition of etoposide (CAPOMEt).

Results: After pathological review, 281 patients were deemed eligible. At the census date of 31 March 1994, 158 patients were alive with a median follow up of 5.9 years (minimum 3.0 years). Analysis of all patients and eligible patients showed no significant treatment differences in the rates of complete remission (CR), failure free survival (FFS) or overall survival (OS) between the two arms. The actuarial median OS was 24 months for CAPOMEt compared with 31 months for CHOP-Mtx, with five-year actuarial survival rates of 37% and 43%, respectively. Myelosuppression was significantly more severe with CHOP-Mtx and neurotoxicity was much more common with CAPOMEt.

Conclusion: Weekly CAPOMEt is equally effective as standard cyclical CHOP-Mtx treatment in aggressive NHL.

Key words: CHOP-Mtx vs. CAPOMEt; non-Hodgkin's lymphoma; randomised trial

Symptoms in early head and neck cancer: An inadequate indicator
Robert W. Dolan, MD, FACS, Charles W. Vaughan, MD, FACS, and Nabil Fuleihan, MD, Boston, Massachusetts

Screening programs show promise in increasing the rate of early detection of head and neck cancers in high-risk populations. Prout et al. (Otolaryngol Head Neck Surg 1997; 116: 201-8) examined the usefulness of a large-scale screening program for head and neck cancer in an inner city population by primary care physicians. Symptom assessment was based on the American Cancer Society's "Seven Warning Signs for Cancer," (Cancer manual. 8th ed. Boston: American Cancer Society, Massachusetts Division; 1990. p. 40-64) 4 of which are relevant to the head and neck. However, these signs may be insufficient for detection of early head and neck cancer. We analyzed these and other typical symptoms to determine their role in early detection. Coincident medical problems, tobacco abuse, and alcohol abuse were also analyzed. Our findings indicate that no symptom or symptom complex is strongly correlated with early head and neck cancer for any subsite except the glottis. Symptom duration is an unreliable indicator of the duration of disease. However, patients under medical supervision are more likely to have their cancers detected early, supporting the value of surveillance by the primary care physician. The absence of definite early warning signs for most head and neck cancers suggests the need to develop essential screening criteria. Defining the population that is at high risk for head and neck cancer and subjecting it to an aggressive screening protocol is essential.

New real clinical entities
Richard I. Fisher, MDa, Maywood, Illinois; Thomas P. Miller, MDa, Thomas M. Grogan, MDb, Tucson, Arizona

Purpose
In 1994, the International Lymphoma Study Group proposed a "Revised European-American Lymphoma (REAL) Classification of Lymphoid Neoplasms." This classification system was developed because (1) new lymphoid disease entities have been recognized that are not part of the National Cancer Institute Working Formulation (WF) and (2) there was a need to develop a common classification system that could be used internatonally. The REAL classification itself had never been tested, however, to determine whether it was reproducible or defined distinct clinicopathologic entities. Therefore, in the past two years, two studies were conducted by the South-West Oncology Group (SWOG) Lymphoma Committee and the Non-Hodgkin's Lymphoma (NHL) Classification Project to validate the REAL classification.

Patients And Methods
The SWOG Lymphoma Committee reviewed the pathology and clinical course of 376 previously untreated patients with stage III or IV disease within WF categories A, B, C, D or E who received full-dose cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) in SWOG studies 7204, 7426, and 7713. No patients in this data-base had localized mucosa-associated lymphoid tissue (MALT) lymphoma. The NHL Classification Project performed a retrospective study of 1,403 consecutive patients with previously untreated NHL seen between 1988 and 1990 at nine sites around the world. Five expert hema-topathologists reached a consensus diagnosis on every case by using histologic, clinical, and immunophenotypic data, and 20% of all cases were randomly reviewed.

Results
The most common diagnosis was diffuse large B-cell lymphoma (31%), which combines the large-cell and immunoblastic WF categories (WF G/H). The next most common diagnosis was follicular lymphoma (22%; WF B, C, and D). Marginal zone B-cell (including MALT), peripheral T-cell, small B-lymphocytic, and mantle cell lymphoma each constituted between 5% and 10% of diagnoses. Primary mediastinal large B-cell, anaplastic large T/null cell, high-grade B-cell, Burkitt-like, and precursor T-lymphoblastic lymphoma made up the remaining 10 most frequent diagnoses.

Conclusions
The analyses conducted by the SWOG Lymphoma Committee and the NHL Classification Project have demonstrated that the REAL classification does define "real" clinical entities that can be diagnosed by expert hematopathologists. The understanding gained from study of "real" entities should permit hematologists/oncologists to better predict the clinical course of their patients and also to develop improved therapy.

Key words: lymphomas; REAL classification; working formulation; diffuse large B-cell lymphoma; follicular lymphoma; MALT lymphoma; mantle cell lymphoma; peripheral T-cell lymphoma

Current diagnosis and treatment of leptomeningeal metastasis
Lisa M. DeAngelis
Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

Key words: leptomeningeal metastasis; radiotherapy; chemotherapy; cancer

Summary

Meningeal metastasis occurs in 3-8% of all cancer patients, producing neurologic morbidity and a high mortality. Diagnosis is best established by the demonstration of malignant cells in the cerebrospinal fluid. However, in patients with known cancer, MR scan with gadolinium may be diagnostic when subarachnoid nodules can be demonstrated in the head or spine. Therapy usually involves radiotherapy to symptomatic sites, often followed by intrathecal chemotherapy. Intrathecal chemotherapy is best delivered by an intraventricular reservoir system but can also be delivered by repeated lumbar puncture. Methotrexate, cytarabine and thiotepa are the most common agents instilled into the subarachnoid space. Their limited efficacy can be explained by their restricted spectrum of antitumor activity. Patients with leptomeningeal metastasis from leukemia, lymphoma or breast cancer tend to respond best and this may, in part, be attributed to the relative sensitivity of these primary tumor types to the agents administered intrathecally. Systemic chemotherapy may prove a more attractive alternative to intrathecal drugs since it can penetrate into bulky disease, reach all areas of the subarachnoid space, and not be restricted by CSF bulk flow. The prognosis for patients with leptomeningeal metastasis is poor, most individuals surviving a median of only about four months. Occasional patients do have prolonged survival and improvement of their neurologic function.

First-line treatment of advanced nonsmall cell lung carcinoma with docetaxel and vinorelbine
Charalambos Kourousis, M.D., Ph.D, Nicos Androulakis, M.D., Stelios Kakolyris, M.D., Ph.D., John Souglakos, M.D., George Maltezakis, M.D., George Metaxaris, M.D., George Chalkiadakis, M.D., Ph.D., George Samonis, M.D., Ph.D., John Vlachonikolis, Ph.D. and Vassilis Georgoulias, M.D., Ph.D.

Background: Docetaxel and vinorelbine are active agents in the treatment of nonsmall cell lung carcinoma (NSCLC). The efficacy and toxicity of this combination was evaluated in a Phase II study in patients with advanced NSCLC.

Methods: Forty-six chemotherapy-naive patients (44 men and 2 women with a median age of 64 years) with NSCLC (11 with Stage IIIB and 35 with Stage IV disease) were entered into the study; the World Health Organization (WHO) performance status was 0, 1, and 2 in 32, 11, and 3 patients, respectively. Patients received vinorelbine (25 mg/m2) on Day 1 and docetaxel (100 mg/m2) on Day 2 in cycles repeated every 3 weeks. Granulocyte-colony stimulating factor was given to all patients from Day 3 to Day 10.

Results: One hundred and seventy-seven course of chemotherapy were administered. Adverse events included WHO Grade 4 neutropenia (15 patients), Grade ¾ thrombocytopenia (3 patients), Grade 3 anemia (2 patients), Grade 2 and 3 neurotoxicity (7 patients and 1 patient, respectively), and Grade 3 fatigue (2 patients). Twenty patients (43%) required hos-pitalization: 11 (24%) for neutropenic fever (2 deaths from sepsis), and 9 (20%) for nonneutropenic pulmonary infections (2 deaths from cardiopulmonary insufficiency). The median overall survival was 5 months and the 1-year survival was 24%. Four complete responses (9.8%) and 11 partial responses (26.8%) (overall response rate of 36.6%; 95% confidence interval, 21.8-51.3%) were documented in 41 evaluable patients (intent-to-treat:32.6%). Stable and progressive disease occurred in 13 patients each (31.7%). The median duration of response was 5 months and the median time to progression was 3 months (6 months for the responders).

Conclusions: This schedule of docetaxel and vinorelbine combination is effective but its relatively high incidence of complicated neutropenia precludes its general use in patients with advanced NSCLC.

Key words: docetaxel; vinorelbine; nonsmall cell lung carcinoma; chemotherapy