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Fluorouracil Plus Leucovorin as Effective Adjuvant Chemotherapy in Curatively Resected Stage III Colon Cancer: Results of the Trial adjCCA-01
Rainer Porschen, Andreas Bermann, Thomas Löffler, Gregor Haack, Klaus Rettig, Yvonne Anger, and Georg Strohmeyer for the Arbeitsgemeinschaft Gastrointestinale Onkologie

Purpose: Adjuvant postoperative treatment with fluorouracil (5-FU) and levamisole in curatively resected stage III colon cancer significantly reduces the risk of cancer recurrence and improves survival. Biochemical modulation of 5-FU with leucovorin has resulted in increased remission rates in metastatic colorectal cancer, thus reflecting an increased tumor-cell kill. The impact of 5-FU plus leucovorin on survival and tumor recurrence was analyzed in comparison with the effects of 5-FU plus levamisole in the prospective multicentric trial adjCCA-01.

Patients and Methods: Patients with a curatively resected Internatianal Union Against Cancer stage III colon cancer were stratified according to T, N, and G category and randamly assigned to receive one of the two adjuvant treatment schemes: 5-FU 400 mg/m2 body-surface area intravenously in the first chemotherapy course, then 450 mg/m2 x 5 days; 12 cycles, plus leucovorin 100 mg/m2 (arm A), or 5-FU plus levamisole (Moertel scheme; arm B).

Results: Six hundred eighty (96.90;0) of 702 patients enrolled onto this study were eligible. After o median follow-up time of 46.5 months, the 5-FU plus leucovorin combination significantly improved disease-free survival (P = .037) and significantly decreased overall mortality (P = .0089) in comparison with 5-FU plus levamisole. In a multivariate proportional hazards model, adjuvant chemotherapy emerged as a significant prognostic factor for survival (P = .0059) and disease-free survival (P = .03). Adjuvant treatment with 5-FU plus levamisole as well as with 5-FU plus leucovorin was generally well tolerated; only a minority of patients experienced grade 3 and 4 toxicities.

Conclusion: After a curative resection of a stage III colon cancer, adjuvant treatment with 5-FU plus leucovorin is generally well tolerated and significantly more effective than 5-FU plus levamisole in reducing tumor relapse and improving survival.

Equivalence of Three or Four Cycles of Bleomycin, Etoposide, and Cisplatin Chemotherapy and of a 3- or 5- Day Schedule in Good Prognosis Germ Cell Cancer: A Randomized Study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council
Ronald de Wit, J. Trevor Roberts, Peter M. Wilkinson, Pieter H.M. de Mulder, Graham M. Mead, Sophie D. Fossa, Pat Cook, Linda de Prijck, Sally Stenning, and Laurence Collette

Purpose: To test the equivolence of three versus four cycles of bleomycin, etoposide, and cisplatin (BEP) and of the 5-day schedule versus 3 days per cycle in goodprognosis germ cell cancer.

Patients and Methods: The study was designed as a 2 x 2 factorial trial. The aim was to rule out a S% decrease in the 2 year progression free survival (PFS) rate. The study included the assessment of patient quality of life. A cycle of BEP consisted of etofoside 500 mg/m2, administered at either 100 mg/m2 days 1 through 5 or 165 mg/m2 days 1 through 3, cisplatin 100 mg/m2, administered at either 20 mg/m2 days 1 through 5 or 50 mg/m2 days 1 and 2. Bleomycin 30 mg was administered on days 1, 8, and 15 during cycles 1 through 3. The randomization procedure fllowed some investigators to participate only in the comparison of three versus four cycles.

Results: From March 1995 until April 1998, 812 patients were randomly assigned to receive three or four cycles: of these, 681 were also randomly assigned to the S-day or the 3 day schedule. Histology, marker values, and disease extent are well balanced in the treatment arms of the two comparisons. The projected 2-year PFS is 90.4% on three cycles and 89.4% on four cycles. The difference in PFS between three and four cycles is -1.0% (80% confidence limit [CL], -3.8%, + 1.8%). Equivalence for three versus four cycles is claimed because both the upper and lower bounds of the 80% CL are less than 5%. In the 5 versus 3 day comparison, the projected 2 year PFS is 88.8% and 89.7%, respectively (difference, -0.9% (80% CL, -4.1%, +2.2%). Hence, equivalence is claimed in this comparison also. Frequencies of hematologic and non hematologic toxicities were essentially similar. Quality of life was maintained better in patients receiving three cycles; no differences were detected between 3 and 5 days of treatment.

Conclusion: We conclude that three cycles of BEP with etoposide at 500mg/m2, is sufficient therapy in goodprognosis germ cell cancer and that the administration of the chemotherapy in 3 days has no detrimental effect on the effectiveness of the BEP regimen.

Flutamide Versus Prednisone in Patients With Prostate Cancer Symptomatically Progressing After Androgen Ablative Therapy: A Phase III Study of the European Organization for Research and Treatment of Cancer Genitourinary Group
S. D. Fossa, P. H.Th. Slee, M. Brausi, S. Horenblas, R. R. Hall, J. W. Hetherington, N. Aaronson, L. de Prijck, and L. Collette

Purpose: Time to progression (TTP), overall survival, and quality of life (QL) were compared in patients with Hormone resistant prostate cancer (HRPC) treated with prednisone (5 mg orally, four times a day) or flutamide (250 mg orally, three times a day).

Patients and Methods: Symptomatic patients were randomized to receive either prednisone (101 patients) or flutamide (100 patients). Subjective response was assessed based on performance status, the use of analgesics, and the need to apply alternative palliative treatment. Prostate-specific antigen (PSA) based biochemical response (>=50% reduction of baseline PSA) was recorded. At baseline and at 6-week intervals during followup, patients completed the European Organization for Research and Treatment of Cancer Quality of Ufe Questionnaire C-30. Results: There was no difference between the groups in median TTP (prednisone, 3.4 months; flutamide, 2.3 months) or overall survival (prednisone, 10.6 months; flutamide, 11.2 months). In the prednisone group, 56% of the patients experienced a subjective response, compared with 45% in the flutamide group (P = 18). The median response duration was 4.8 months for prednisone and 4.2 months for flutamide. A biochemical response was observed in 210;0 and 23% of the prednisone and flutamide groups, respectively. Gastrointestinal toxicity was the reason for trial discontinuation in seven patients receiving flutamide and two patients receiving prednisone. The QL assessment parameters favored the use of prednisone with statistically significant differences in pain, fatigue, role functioning, appetite loss, gastrointestinal distress, and overall QL

Conclusion: In symptomatic HRPC, treatment with prednisone or flutamide leads to similar rates of np and overall survival and no difference in subjective or biochemical response. The QL results favor the use of lowcost prednisone in patients with HRPC.

Prediction of Response to Salvage Radiation Therapy in Patients With Prostrate Cancer Recurrence After Radical Prostatectomy
Angelos K. Leventis, Shahrokh F. Shariat, Michael W. Kattan, E. Brian Butler, Thomas M. Wheeler, and Kevin M. Slawin

Purpose: To identify factors predictive of local recurrence as defined by a complete response to salvage radiation therapy in patients whose disease recurs after radical prostatectomy.

Patients and Methods: Ninety-five patients with recurrence after radical prostatectomy who were evaluated by prostatic fossa biopsies, and a subset of 49 of these patients treated with radiation for control of presumed or biopsy-proven local recurrence, were studied.

Results: Biopsies were positive in 40 (42%) of the 95 biopsied patients. Multivariate analysis revealed that prebiopsy prostate-specific antigen (PSA) level, postre currence PSA doubling time, and positive digital rectal examination (DRE) of the prostatic fossa were all statistically significant predictors of a positive biopsy. For the 49 patients subsequently treated with salvage radiation therapy, the overall actuarial 3- and 5-year PSA relapse-free probabilities were 43% and 24%, respectively. Univariate analysis showed no differences in the PSA relapse-free probabilities associated with any pathologic features of the radical prostatectomy specimen, biopsy confirmation of local recurrence, or DRE of the prostatic fossa. In multivariate analysis, controlling for all other variables, preradiation PSA and postrecurrence PSA doubling time measured before radiation were the only statistically significant predictors of outcome.

Conclusions: DRE of the prostatic fossa, prebiopsy PSA, and postrecurrence PSA doubling time predict which patients will have biopsy-proven local recurrence. However, response to salvage radiation therapy is associated with postrecurrence PSA doubling time and with preradiation PSA level only. DRE of the prostatic fossa and biopsy confirmation of local recurrence are not associated with salvage radiation outcome.

Lung Cancer After Hodgkin’s Disease: A Nested Case-Control Study of the Relation to Treatment
A.j. Swerdlow, M.j. Schoemaker, R. Allerton, A. Horwich, j.A. Barber, D. Cunningham, T.A. Lister, A.Z.S. Rohatiner, G. Vaughan Hudson, M.V. Williams, and D.C. Linch

Purpose: To investigate the causes of the raised risk of lung cancer in patients who have had Hodgkin’s disease, and in particular the relationship to treatment.

Contents and Methods: A nested case-control study was conducted within a cohort of 5,519 patients with Hodgkin's disease treated in Britain during 1963 through 1993. For 88 cases of lung cancer and 176 matched control subjects, information on treatment and other risk factors was extracted from hospital case-notes, and odds ratios for lung cancer in relation to these factors were calculated.

Results: Risk of lung cancer was borderline significantly greater in patients treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy than those who did not receive this treatment (relative risk [RR] = 1.66; 95% confidence interval [CI], 0.99 to 2.82), and increased with number of cycles of MOPP (P = .07). Exclusion of lung cancers for which histologic confirmation was not available strengthened these associations (RR = 2.41; 95% CI, 1.33 to 4.51; p = .004 for any MOPP and p=.007 for trend with number of cycles of MOPP). Risks were not raised, however, after chlorambucil, inblastine, pro-carbazine, and prednisone treatment. There was evidence that the raised risk of lung cancer occurring in relation to radiotherapy was restricted to histologies other than adenocarcinoma.

Conclusion: The results suggest that MOPP chemotherapy may lead to elevated risk of lung cancer, at least in certain subgroups of patients. The role of chemotherapy in the etiology of lung cancer after Hodgkin’s disease deserves further investigation.

Chronic myeloid leukemia: current treatment options
John M. Goldman and Brian J. Druker

The choice of primary treatment for patients with chronic myeloid leukemia (CML) diagnosed In chronic phase has become exceedingly difficult. There is little doubt that allogeneic stem cell transplantation can eradicate the leukemia and that a graft-versus-Ieukemia effect makes a major contribution to this result; conversely, only a minority of patients afeeligible for transplantation, which still carries an appreciable risk for death or protracted illness. For most patients, interferon-a (IFN-a) prolongs life to some degree in comparison with hydroxyurea, but it is associated with considerable toxicity. The newly introduced tyrosine kinase inhibitor STI571 induces complete hematologic remission in almost all patients and is associated with a very high rate of cytogenetic response; its capacity to prolong life in comparison with IFN-a is not yet established. Here are reviewed some factors that predict survival after nontransplantation therapy and after allografting for CML in chronic phase. Two Icontrasting options are considered for managing the patient with newly diagnosed disease, and it can be concluded that, for now, allogeneic stem cell transplantation soon after diagnosis should continue to be offered as an option for selected patients. Further experience with the use of STl571 as a single agent or in combination with other antileukemic agents may alter the picture in the near future.

Results of a phase III study of early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine combination in inoperable brain metastasis of non-small-celllung cancer: Groupe Fran~ais de Pneumo-Cancerologie (GFPC) Protocol 95-1
G. Robinet, P. Thomas, J. L. Breton, H. Léna, S. Gouva, G. Dabouis, J. Bennouna, P. J. Souquet, P. Balmes, L. Thiberville, P. Fournel, E. QUOiX, R. Riou, P. Rebattu, M. Perol, D. Paillotin and F. Mornex on behalf of GFPC

Purpose: To determine if the timing of whole brain radiotherapy (WBRT) with respect to chemotherapy with cisplatinand vinorelbine would influence survival in patients with non-small-celllung cancer (NSCLC) and concurrent brain metastasis.

Patients and methods: One hundred seventy-six patients with brain metastasis from NSCLC were included in the study between July 1995 and October 1997. All patients received chemotherapy with cisplatin 100 mg/m² on day 1 and vinorelbine 30 mg/m² on days 1,8, 15, 22. Cycles were repeated every four weeks. Evaluation of response was performed after two, four or six cycles. After two cycles, chemotherapy was administered to the responders to a maximum of six cycles. Patients were randomised to receive WBRT 30 Gy/l0 fx/12 days and delayed corticosteroids, (arm A) for the intracranial nonresponders, or early on day 1 to 12 during the first cycle of chemotherapy (arm B).

Results: One hundred seventy-one patients were eligible: eighty-six in arm A and eighty-five in arm B; none had received prior therapy; seventy-six and seventy-three, respectively, were assessable for response. There was a 21% overall objective response rate (OR) (with 1 complete response and 17 partial responses) after two cycles of chemotherapy alone (arm A) and a 200 OR (with 17 partial responses) to chemotherapy and early WBRT (arm B). The intracranial OR was 27% and 33%, respectively (P = 0.12). The six months survival rate (46% and 40%) and the median survival duration (24 and 21 weeks, respectively) were not significantly different between the two arms (P = 0.83, log-rank test). The major toxicity was severe or life-threatening neutropenia (grade 4), which occurred in 35% of arm A patients and 36% of arm B patients. There were thirteen treatment-related deaths (six in arm A and seven in arm B). There was no difference between the arms for haematological and neuro-toxicities.

Conclusions: These results confirm the efficacy of chemotherapy in brain metastases of NSCLC and suggest that the timing (early or delayed) of WBRT did not influence survival of NSCLC with brain metastasis treated with concurrent chemotherapy.

Increased Expression of Cyclooxygenase-2 in Human Pancreatic Neoplasms and Potential for Chemoprevention by Cyclooxygenase Inhibitors
Atsushi Kokawa, M.D., Hitoshi Kondo, M.D., Ph.D.,Takuji Gotoda, M.D., Hiroyuki Ono, M.D., Daizo Saito, M.D., Saori Nakadaira, Tomoo Kosuge, M.D., Shigeaki Yoshida, M.D.

Background: Cyclooxygenase-2 (COX-2) is thought to be linked to carcinogenesis; however, very little is known about its expression in pancreatic neoplasms. The authors studied the expression of COX-2 in human pancreatic neoplasms and investigated the effect of COX inhibitors on the growth of human pancreatic carcinoma cells.

Methods: Expression of COX-2 protein was immunohistochemically examined in 42 human pancreatic duct cell carcinomas (PDCs) and in 29 intraductal papillary mucinous tumors (IPMTs adenomas, 19; carcinomas, 101) of the pancreas that were resected surgically at the National Cancer Center Hospital in Tokyo. The growth of four human pancreatic carcinoma cell lines also was evaluated in the presence of COX inhibitors.

Results: Marked COX-2 expression was observed in 57% (24 of 42) of PDCs, in 58% (11 of 19) of adenomas, and in 70% (7 of 10) of adenocarcinomas of IPMTs. However, there was no correlation between COX-2 expression and clinicopathologic indices of the patients. All four pancreatic cancer cell lines expressed COX-2 protein weakly or strongly, and the inhibitory effect of aspirin on cell growth was correlated with the expression of COX-2.

Conclusions: COX-2 was expressed in adenomas of IPMTs as well as in carcino mas and might have played a role in the development of pancreatic tumors. In this study, COX inhibitors, as nonsteroidal anti-inflammatory drugs, were shown to be possible preventive agents against pancreatic neoplasms.

Racial and Ethnic Differences in Advanced-Stage Prostate Cancer: the Prostate Cancer Outcomes Study
Richard M. Hoffman, Frank D., Gilliland, i. William Eley, Linda C., Harlan, Robert A. Stephenson, Janet L. Staliford, Peter C. Albertson, Ann S. Hamilton, W. Curtis Hunt, Arnold L. Potosky

Background: African-Americans have twice the risk of non-Hispanic whites for presenting with advanced-stage prostate cancer. To investigate the reasons for this difference, we evaluated the association between race/ethnicity and advanced-stage prostate cancer, adjusting for demographic, socioeconomic, clinical, and pathologic factors.

Methods: A population-based cohort of 3173 men diagnosed with prostate cancer between October 1, 1994, and October 31, 1995, was analyzed. Medical record abstracts and self-administered survey questionnaires were used to obtain information regarding race/ethnicity, age, marital status, insurance status, educational level, household income, employment status, comorbidity, urinary function, prostate-specific antigen level, tumor grade, and clinical stage. The odds ratio (OR) for advanced-stage prostate cancer was estimated with weighted logistic regression analysis. All p values were two-sided.

Results: Clinically advanced-stage prostate cancers were detected more frequently in African Americans (12.3%) and Hispanics (10.5%) than in non-Hispanic whites (6.3%). Socioeconomic, clinical, and pathologic factors each accounted for Iabout 15% of the increased relative risk. After adjusting for all covariates, the risk remained statistically significantly increased for African-Americans (OR = 2.26; 95% confidence I’ interval [CI] = 1.43 to 3.58) but not for Hispanics (OR = 1.23; 95% CI = 0.73 to 2.08).

Conclusion: Traditional socioeconomic, clinical, and pathologic factors accounted for the increased relative risk for presenting with advanced-stage prostate cancer in Hispanic but not in African-American men.

Group Interventions with Cancer Patients: Efficacy of Psychoeducational Versus Supportive Groups
Sarah Edelman, PhD Ashley Craig, PhD Antony D. Kidman, PhD

Cancer support groups have become increasingly available to patients over the last two decades. Although the various patient groups differ in their philosophy, membership, and aims, the majority can be categorized as predominantly “supportive” or “psychoeducational” in their approach. To date, there is little evidence regarding the relative benefits of the two types of group in improving patients’ psychological outcomes. This article presents a critical review of the evidence for the relative efficacy of the two approaches. A search of the literature using CD-ROM databases identified 15 studies of acceptable design that quantitatively evaluated psychological outcomes of one or both types of group intervention. Although some findings have been inconsistent, the majority of evidence suggests that patients who attend psychoeducational groups experience greater benefits than do those who attend purely supportive groups. Further well-designed research in this area is needed to identify specific patient cohorts that are most likely to benefit from each approach.

Exploring the Motivations of Bone Marrow Typing Donors
Jill M. Norvilitis, PhD, Tanya M. Riley, BA

This study explored the issues of personality and knowledge of bone marrow typing in 66 students who participated in a bone marrow typing drive and 47 nonparticipants. No differences in personality between the donors and nondonors were tound on measures of perceived self-competence, satisfaction with life, and overall fear of medical procedures. However, donors reported greater concern with social desirability and less fear of needles1han did nondonors who were aware of the drive. Students who were better educated about the donation procedure were more likely to donate, as were students who had previously donated blood. Nondonors were more likely to identify incorrectly the means b which marrow is typed and to believe that process is painful.

Treatment of Neoplastic Diseases of the Sacrum
George H. Raque, Jr., MD, Todd W. Vitaz, MD, and Christopher B. Shields, MD, FRCS (C) Department of Neurological Surgery, University of Louisville School of Medicine, Louisville, Kentucky

Sacral neoplasms constitute a wide range of pathological entities including primary and metastatic as well as benign and malignant conditions. Often these lesions are large at the time of initial diagnosis and surgical cure may be difficult. Nonetheless, surgery may be indicated for a wide range of reasons including tissue diagnosis, palliation of pain, preservation of neurological function, or attempts for curative resection. There are numerous surgical approaches to lesions of this area which require a complete understanding of the neural, pelvic, and bony anatomy. For this reason we utilize a multidisciplinary team approach when treating these lesions. This allows for the combination of expertise from areas such as general surgery, orthopedic surgery, and neurosurgery that optimizes the treatment of these patients. In this article we review the basic techniques of diagnosis and treatment of these lesions. This overview includes the relative anatomy, symptoms, diagnosis, imaging, operative indications, surgical approaches, and potential complications.

Extended Left Hepatectomy (Left Hepatic Trisegmentectomy) in Childhood
Richard D. Glick, Evan P. Nadler, Leslie Ho Blumgart, and Michael P. La Quaglia, New York, NY

Background/Purpose: Extended left hepatectomy, also referred to as left hepatic trisegmentectomy, in which segments II, Ill, IV, V, and VIII are excised. is rarely performed in children. Experience with 7 such resections is reported to describe the anatomy, technique, indications, and outcomes of the operation.

Methods: The medical records of all pediatric patients treated at our institution over the last 15 years who underwent extended left hepatectomy were reviewed. Demographic information as well as operative, pathological, and follow-up data were analyzed.

Results: Seven patients underwent extended left hepatectomy over this period. There were 5 boys and 2 girls ranging in age between 4 months and 9 years with a median age of 3.1 years. Follow-up ranged from 8 months to 5 years with a median of 3.5 years. Diagnoses included hepatoblastoma (HB, n = 3), focal nodular hyperplasia (FNH, n = 1 ), leiomyosarcoma (LMS, n = 1), hepatocellular carcinoma (HCC, n = 1), and metastatic neuroblastoma (NB, n = 1). All surgical margins were grossly negative. Median operative blood loss was 13 mL/kg (range, 5 to 32 mL/kg), and mean hospital stay was 9 days (range, 7 to 12 days). No major intra- or postoperative complications were encountered, and there was no perioperative mortality. The 3 HB patients, 1 FNH patient, 1 LMS patient, and 1 NB patient are without evidence of disease, whereas the 1 child with HCC died of recurrent and distant disease. The 6 surviving children have normal hepatic function.

Conclusion: Although technically challenging and rarely performed, extended resection of the left hepatic lobe is feasible in children and can yield curative results with minimal morbidity.