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.

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Prognostics factors in carcinoma of the penis: multivariate analysis of 145 patients treated with amputation and lymphadenectomy
Ademar Lopes, Geraldo Santiago Hidalgo, Luiz Paulo Kowalski, Humberto Torloni, Benedito Mauro Rossi, Francisco Paulo Fonseca

Purpose: The major issue in penile cancer is deciding who should or should not undergo lymph node dissection. Clinical and invasive methods are not reliable for staging. Clinical and pathological factors involved in lymph node metastases and prognosis were evaluated in 145 patients with penile carcinoma staged according to the 1978 TNM system, and treated with amputation and lymphadenectomy.

Material and Methods: Clinical factors studied were patient age, race, disease evolution time, symptoms, and clinical T and N stages. Pathological factors of the primary tumor considered were tumor thickness, histological grade, lymphatic and venous embolization, infiltration of the corpora cavernosa, corps spongiosum and urethra, mononuclear and eosinophilic infiltrates, and cell alterations suggestive of human papillomavirus. All slides were reviewed by 1 pathologist. The Cox regression hazards method for multifactorial analysis was used.

Results: Follow-up ranged from 0.7 to 453.2 months (mean 85.8, median 32.7). The 5-year disease-free and overall survival rates were 45.3 and 54.3%, respectively. Venous and lymphatic embolizations were the main factors affecting significantly the incidence of lymph node metastatasis, which were the main risks factors for recurrance and death. Pathologically proved infiltration of the corpora cavernosa, urethra and adjacente structures, which corresponded to stages T2, T3 and T4 disease, respectively, of the current TNM classification, were not significant predictors for incidence of lymph node metastasis, disease-free and overall survival or risk factors for recurrance and death.

Conclusions: Because venous and lymphatic embolizations were related to greatest risk of lymph node metastatasis, we propose their evaluation in staging and therapeutic planning of patients with infiltrative tumors of the penis.

Unreliability of modified inguinal lymphadenectomy for clinical staging of penile carcinoma
Ademar Lopes, M.D. Ph.D.¹, Benedito Mauro Rossi, M.D.¹, Francisco Paulo Fonseca, M.D.¹, Sandra Morini, M.D.²

Background: In 1988, Catalona proposed a modified bilateral inguinal lymphadenectomy for staging of lymph node metastasis from penile carcinoma. All three patients with penile carcinoma submitted to this procedures and without histologically confirmed metastases were free of disease within a mean follow-up time of 14.6 months.

Methods: In a prospective study, the autors evaluated thirteen patients staged by the TNM system submitted to modified bilateral inguinal lymphadenectomy.

Results: None of the patients had histologic metastases in the medial quadrant lymph nodes. Two of these patients developed regional lymph node metastases within 13.2 months (mean follow-up time).

Conclusions: Catalona's procedure was not reliable. We therefore recommend standard inguinaly lymphadenectomy as the minimal treatment for patients with infiltrating carcinoma of the penis.

Pharmacologic treatment of cancer pain
Michael H. Levy, M.D., Ph.D.

Pain from cancer is a major health care problem^1-3. Thirty percent of patients with cancer have pain at the time of diagnosis, and 65 to 85 percent have pain when their disease is advanced^{2, 4-6}. The impact of cancer pain is magnified by the interaction of pain and its treatments with other commom cancer sympthoms: fatigue, weakness, dyspnea, nausea, constipation, and impaired cognition^{4, 6}. Cancer pain can be effectivelly treated in 85 to 95 percent of patients with an integrated program of systemic, pharmacologic, and anticancer therapy^{7, 8}. Many of the remaining patients can be helped by the appropriate use of invasive procedures^9-11. In the final days of life, pain not controlled by therapies aimed at both comfort and function can be relieved by intentional sedation^12-14. No patient with cancer needs to live or die with unrelieved pain.

There are three basic approaches to the control of pain: modifying the source of the pain, altering the central perception of the pain, and blocking the transmission of the pain to the central nervous system¹⁵. The optimal use of these approaches in the control of cancer pain requires a thorough assessment of each patient's pain, cancer, concurrent medical problems, and psychosocial status^16-18. And individualized plan of care must be established, implemented, reassessed, and modified on a regular basis to maximize both the quality and duration of life. The pain of the vast majority of patients with cancer can be relieved through direct and nonpharmacologic alteration of patients' perception of pain^{7, 8, 17, 18}. This paper reviews the pharmacologic treatment of cancer pain in a guideline format to facilitate the translation of current knowledge into critical practice (Table 1). Readers are referred to more extensive review articles^{16, 18, 19} guidelines^{17, 20} and textbooks^{9, 10, 21, 22} to integrate pharmacologic therapy with anticancer therapies, physical and psychosocial therapies, and procedural interventions to optimize patients' comfort and theri ability to function.

Ganciclovir
Clyde S. Crumpacker, M.D.

Ganciclovir is a nucleoside analogue of guanosine, a homologue of acyclovir, and the first antiviral drug to b effective in the treatment of cytomegalovirus (CMV) disease in humans^1-4. It inhibits not only all the herpesviruses but also the transformation of normal cord-blood lymphocytes by Epstein-Barr virus^5-7. In this review, I outline ganciclovir's mechanisms of action and resistance and discuss the clinical effectiveness of intravenous and oral ganciclovir.

The RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschsprung's disease
Charis Eng, M.D., Ph.D.

Recent years have brought major advances in our understanding of the molecular genetic basis of both types of multiple endocrine neoplasia (MEN), an autosomal dominant cancer syndrome. MEN type 1 (MEN-1 [designated "MEN" 1" by the Second International MEN Workshop]) is the triad of parathyroid, pancreatic isletcell, and anterior pituitary tumor¹. Carcinoid, adrenal cortical, and lipoid tumors may also occur in MEN-1. Its susceptibility gene has been mapped but not isolated and in some kindreds polymorphic markers that flank the gene can be used for predictive DNA testing². MEN type 2 (MEN-2) is a syndrome of medullary thyroid carcinoma, pheochromocytoma, and parathyroid hyperplasia or adenoma. Mutations in the RET proto-oncogene, which codes for a tyrosine kinase receptor, have been implicated in over 90 percent of families with MEN-2³. Predictive DNA testing of at-risk family members in kindreds with MEN-2 can now be performed with great accuracy. The identification of a mutation that indicates disease susceptibility has important implications for clinical managment, including lifesaving prophylactic treatment.

Mutations in the RET proto-oncogene are also associated with some familial forms of Hirschsprung's disease^{4, 5}. In the case of MEN-2, the RET mutations are activating - that is, they enhance the function of the encoded protein - whereas in Hirschsprung's disease, the mutattion are inactivating and lead to loss of function. In rare of families Hirschsprung's disease and MEN-2 cosegregate.

Immunomodulation following chemotherapy
M. Obadina, U. Verma, M. Hawkins, A. Mazumder
Vicent T. Lombardi Cancer Research Center, Georgetown University Hospital, Washington DC, USA

In the last decade, immunomodulation has emerged as a mode of therapy capable of mediating the regression of cancerin some patients. This article reviews our experience with immunomodulation following transplant and non-transplant chemotherapy. We used interferon and cyclosporine A following conventional chemotherapy in a non-transplant setting for a B16 melanoma in a murine model. This combination generated cells with MHC unrestricted cytotoxicity. We have also used immunotherapy in the transplant setting with IL-2 activated PBSC in patients with breast cancer. Of the 28 patients treated, 20 developed GVHD and the average time to reconstitution was 12 days (comparable to a control group). This article also raises the possibility of extending immunomodulation to breast cancer patients in the non-transplant setting to induce an antitumor immune response following cytoreductive chemotherapy.

P-Glycoprotein - A marker of cancer-cell behavior
Herbert Pinedo, Giuseppe Giaccone

Resistance to a broad array of cytotoxic drugs - multidrug resistance - is thought to be a major reason chemotherapy fails to cure most cancers. Multidrug resistance has been studied intensively since the human MDR1 gene was identified almost 10 years ago¹. Increased levesl of the MDR1 product, called P-glycoprotein, are often associated in vitro with reduced intracellular concentrations of several anticancer drugs derived from plants, such as anthracyclines (e.g. doxorubicin), epipodophyllotoxins (e.g. etoposide), vinca alkaloids (e.g., vincristine), dactinomycin, and paclitaxel. When cells are grown in increasing concentrations of one of these cytotoxic drugs, populations of cells that overexpress the MDR1 gene may be selected. These cells, selected by only one drug, have cross-resistance to all the above-mentioned drugs.

No age limit for radical radiotherapy in head and neck tumours
T. Pignon¹, J. C. Horiot², W. Van den Bogaert³, M. Van Glabbeke⁴, P. Scalliet^5
1 Department of Radiotherapy-Oncology, Hôpital de la Timone, Bd J. Moulin, 13385, Marseille Cedex 5;
² Centre G. F. Leclerc, Department of Radiotherapy, 1 Rue du Pr Marion, 21304 Dijon Cedex;
³ adiotherapy Department, UH Gasthuisberg, Herestraat 49-300 Leuven;
⁴ EORTC Data Centre, Av. Mounier 83, 1200 Brussels;
⁵ Department of Radiotherapy-Oncology, Algemeen Ziekenhuis Middelheim, Lindendreef 1-2020 Antwerpen, Belgium

The elderly are often treated less agressively in an attempt to preserve their quality of the life with regards to toxicity. However, there are few data regarding the acute and late toxicity of radiotherapy (RT) in elderly patients. From February 1980 to March 1995, 1589 patients with head and neck cancers who enrolled in EORTC trials received RT and were available for analysis on RT toxicity. Patients over 65 years of age were in excess of 20%. Data regarding age and acute objective mucosal reactions were registred for 838 patients and 824 patients had toxicity > grade 1. Body-weight alteration during treatment was avaliable in 1252 patients; it increased in 153 patients and decreased in 1099 patients. Late toxicities were examined only if they ocurred before an eventual tumour failure in order to avoid confusion between effects of first-and second-line treatments. 749 patients were available for analysis of which 646 had late toxicity grade > 1. Survival and toxicity were examined in different age ranges from 50 to 75 years and over. There was no significant difference in survical between each age group. A trend test was performed to assess any correlation between age and acute occurring toxicity. There was no significant difference in acute objective mucosal reactions (P = 0.1) and in weight loss > 10% (P = 0.441). In contrast, older patients had more severe (grade 3 and 4) functional acute toxicity (P < 0.001) than younger patients. We evaluated the probability of late toxicity occurrence in relation to time with the Kaplan-Meier method and the logrank test in each age group. Eighteen percent of patients were free of late effects at 5 years, the logrank test showing no significant difference between ages (P = 0.84). In conclusion, chronological age is irrelevant for therapeutic decisions.

Letrozole (CGS 20267), a new oral aromatase inhibitor for the treatment of advanced breast cancer in postmenopausal patients
Patrick F. Trunet, Ajay S., Bhatnagar, Hilary A. Chaudri, Ulrike Hornberger

Letrozole is a new orally, active, potent and highly specific non-steroidal aromatase inhibitor. Letrozole is about 200 and 10.000 times as potent as aminoglutethimide (AG) in vitro and in vivo, respectively. Letrozole was tested in healthy men and postmenopausal women and in postmenopausal patients with advanced breast cancer (ABC). Levels of circulating estrogens decreased by more than 75 to 95% from pre-treatment levels have been observed in patients treated with daily doses of 0.1 to 5 mg letrozole. No clinically relavant changes in other hormones of the endocrine system were found. In four phase Ib/IIa trials, letrozole has shown anti-tumor activity in postmenopausal patients with ABC previously treated with hormonotherapy and/or chemotherapy. Letrozole was well tolerated. Phase IIb/III studies are on going to compare two doses of letrozole with megesterol acetate or AG in order to confirm the anti-tumor efficacy of letrozole in the treatment of ABC in postmenopausal patients who progressed/relapsed following treatment with anti-estrogens.

High-dose chemotherapy for breast cancer
William J. Gradishar, M.D., Martin S. Tallman, M.D., Jeffrey S. Abrams, M.D.

The role of high-dose chemotherapy in the management of women with breast cancer remains one of the most controversial issues in oncology. During the past decade, numerous pilot studies have shown the feasability of administering high-dose chemotherapy followed by autologous bone marrow transplantation or peripheral blood stem-cell transplantation (referred to as high-dose chemotherapy) to women with metastatic disease. However, it appears that survival improves in few treated patients. This treatment strategy is now being evaluated in the adjuvant setting in patients who are at high risk for developing recurrent disease. The National Cancer Institute has selected two randomized, adjuvant breast cancer trials for its High-Priority Clinical Trials Program. These trials are comparing conventional-dose chemotherapy with high-dose chemotherapy in patients in the early stages of the breast cancer who are at high risk for disease recurrance.

This paper focuses on the rationale for the randomized studies evaluating high-dose chemotherapy in the early stages of breast cancer and reviews the efforts to overcome physician and patient biases so that the trials can be completed.

Combined doxorubicin and paclitaxel in advanced breast cancer: Effective and cardiotoxic
J. Gehl¹, M. Boesgaard, T. Paaske², Vittrup Jensen³, P. Dombernowsky^1
1 Department of Oncology, Herlev University Hospital, Herlev;
² Department of Oncology, National University Hospital, København;
³ Department of Clinical Physiology and Nuclear Medicine, Herlev University Hospital, Herlev, Denmark

Background: Paclitaxel has shown activity in metastatic breast cancer, including anthracycline-resistant breast cancer. The efficacy, toxicity and optimal scheduling of the combination of the two drugs needs to be defined.

Patients and methods: Thirty women with advanced breast cancer who had undergone at most one prior adjuvant chemotherapy regimen, were treated at three different dose levels with doxorubicin (50, 60 and 60mg/m², respectively) every 3 weeks.

Results: The overall response rate was 83% (95% CI: 64-94), with 24% of patients achieving CR. The median response duration for complete responders was 11 months (range 4-14+) and median survival 18 months (range 3-28+). Two hundred sixty-five treatment courses were given (median 9, range 3-13) and the median cumulative dose of doxorubicin was 369 mg/m² (range 114-550). The main toxicities were neutropenia, parestesia, nausea/vomiting, alopecia, myalgia and cardiotoxicity. Fifteen patients (50%) had reductions of left ventricular ejections fraction to below normal levels and 6 of these patients (20%) developed congestive heart failure.

Conclusion: The combination of doxorubicin and paclitaxel is highly active, but is accompanied by the dose-limiting toxic effects or neutropenia, neuropathy and cardiotoxicity.

Five versus more than five years of Tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors
Bernard Fisher, James Dignman, John Bryant, Arthur DeCillis, D. Lawrence Wickerman, Norman Wolmark, Joseph Constantino, Carol Redmond, Edwin R. Fisher, David M. Bowman, Luc Deschênes, Nikolai V. Dimitrov, Richard G. Margolese, André Robidoux, Henry Shibata, Jose Terz, A. H. G. Patersoon, Merril I., Feldman, William Farrar, James Evans, H. Lavina Lickley^*

Background: In 1982, the National Surgical Adjuvant Breast and Bowel Project initiated a randomized, double blinded, placebo-controlled trial (B-14) to determine the effectiveness of adjuvant tamoxifen therapy in patients with primary operable breast cancer who had estrogen receptor-positive tumors and no axillary lymph node involvement. The findings indicated that tamoxifen therapy provided substantial benefit to patients with early stage disease. However, questions arose about how long the observed benefit would persist, about the duration of the therapy necessary to maintain maximum benefit, and about the nature and severity of adverse effects from prolonged treatment.

Purpose: We evaluated the outcome of patients in the B-14 trial through 10 years of follow-up. In addition, the effects of 5 years versus more than 5 years of tamoxifen therapy were compared.

Methods: In the trial, patients were initially assigned to receive either tamoxifen at 20mg/day (n=1404) or placebo (n=1414). Tamoxifen-treated patients who remained disease free after 5 years of therapy were then reassigned to receive either another 5 years of tamoxifen (n=322) or 5 years of placebo (n=321). After the study began, another group of patients who met the same protocol eligibility requirements as the randomly assigned patients were registered to receive tamoxifen (n=1211). Registered patients who were disease free after 5 years of treatment were also randomly assigned to another 5 year of tamoxifen (n=261) or to 5 years of placebo (n=249). To compare 5 years with more than 5 years of tamoxifwn therapy, data relating to all patients reassigned to an additional 5 years of the drug were combined. Patients who were not reassigned to either tamoxifen or placebo continued to be followed in the study. Survival, disease-free survival, and distant disease-free survival (relating to failure at distant sites) were estimated by use of the Kaplan-Meier method; differences between the treatment groups were assessed by use of the logrank test. The relative risks of failure (with 95% confidence intervals [Cis]) were determined by use of the Cox proportional hazards model. Peported P values are two-sided.

Results: Through 10 yeares of follow-up, a significant advantage in disease-free survival (69% versus 57%, P < .0001; relative risk = 0.66; 95% CI = 0.58-0.74), distant disease-free survival (76% versus 67% versus 67%, P < .0001; relative risk = 0.70; 95% CI = 0.61-0.81), and survival (80% versus 76%, P = .02; relative risk = 0.84; 95% CI = 0.71-0.99) was found for patients in the group first assigned to receive tamoxifen. The survival benefit extended to those 49 years of age or youngers and to those 50 years of age or older. Tamoxifen therapy was associated with a 37% reduction in the incidence of contralateral (opposite) breast cancer (P = .007). Through 4 years after the reassignment of tamoxifen-treated patients to either continued-therapy or placebo groups, advantages in disease-free survival (92% versus 86%, P = .003) and distant disease-free survival (96% versus 90%, P = .01) were found for those who discontinued tamoxifen treatment. Survival was 96% for those who discontinued tamoxifen compared with 94% for those who continued tamoxifen treatment (P = .08). A higher incidence of thromboembolic events was seen in tamoxifen-treated patients (through 5 years, 1,7% versus 0.4%). Except for endometrial cancer, the incidence of second cancers was not increased with tamoxifen therapy.

Conclusions and implications: The benefit from 5 years of tamoxifen therapy persists through 10 years of follow-up. No additional advantage is obtained from continuing tamoxifen therapy for more than 5 years.

Randomized trial of two versus five years of adjuvant tamoxifen for postmenopausal early stage breast cancer
Swedish Breast Cancer Cooperative Group

Background: Postsurgical treatment with tamoxifen has been shown to improve overall survival among patients with early stage breast cancer. However, the optimal duration of tamoxifen treatment remains controversial.

Purpose: A multicenter, randomized trial was initiated in Sweden in the early 1980s to compare 2 years with 5 years of adjuvant tamoxifen in the treatment of postmenopausal women younger than 75 years of age who had early stager, axillary lymph node-negative or-positive, invasive disease.

Methods: The trial was planned and organized by the Swedish Breast Cancer Group, and it involved five regional breast cancer study organizations (South Sweden, South-East Sweden, Stockholm, Uppsala-Örebro, and North Sweden). During the period from 1983 through 1991, a total of 3887 patients were entered in the trial; 3545 (91%) women remained alive and recurrence free at 2 years and could thus contribute meaningful information to the 2-year (n=1801) versus 5-year (n=1744) comparison. Primary surgery consisted of either modified radical mastectomy or breast-conserving surgery. Radiation therapy was indicated for patients with lymph node-positive disease and was generally offered to all women who were treated with breast-conserving surgery. Only 89 (2.5%) of the 3545 women who wre recurrence free for 2 years received adjuvant chemotherapy concurrently with tamoxifen. Twenty-miligram daily doses of tamoxifen were used at two centers, and 40 mg dailyl doses were used at the remaining three centers. Estrogen receptor status of the tumor was known for 2987 women (77% of the entered patients). Primary end points in the trial were event-free survival (local-regional recurrence, distant metastasis, contralateral breast cancer, or death) and overall survival. Survial curves were estimated by use of the life-table method. The Cox proportional hazards model was used to make comparisons between the 2- and 5-year treatment groups.

Results: Patients assigned to received 5 years of tamoxifen, compared with 2 years of tamoxifen, experienced statistically significant improvements in event-free survival (relative hazard = 0.82; 95% confidence interval [CI]=0.71-0.96) and overall survival (relative hazard = 0.82; 95% CI=0.69-0.99). These findings translate into an 18% relative reduction in both first events (95% CI = 4% - 29%) and mortality (95% CI = 1% = 31%) with the longer treatment. Overall survival at 10 years was estimated to be 80% among patients in the 5-year tamoxifen group who were alive and recurrence free at 2 years, compared with 74% among corresponding patients in the 2-year treatment group. The benefit associated with the longer treatment extended to women with lymph node-positive as well as lymph node-negative disease, but it appeared to be restricted to women whose tumors were classified as estrogen receptor positive.

Conclusion: Five years of adjuvant tamoxifen is more beneficial than 2 years in the treatment of postmenopausal women with estrogen receptor-positive, early stage, invasive breast cancer.

Cohort studies of fat intake and the risk of breast cancer - a pooled analysis
David J. Hunter, M.B., B.S., Donna Spiegelman, Sc.D., Hans-Olov Adami, M.D., Lawrence Beeson, M.S.P.H., Piet A. van Den Brandt, Ph.D., Aaron R. Folsom, M.D., Gary E. Fraser, M.D., R. Alexandra Goldbohm, Ph.D., Saxon Graham, Ph.D., Geoffrey R. Howe, Ph.D., Lawrence H. Kushi, Sc.D., James R. Marshall, Ph.D., Aidan McDermott, M.A., Anthony B. Miller, M.B., B.Ch., Frank E. Speizer, M.D., Alicja Wolk, Dr.Med..Sci., Shiaw-Shyuan Yaun, M.P.H., Walter Willett, M.D.

Background: Experiments in animals, international correlation comparisons, and case-control studies support an association between dietary fat intake and the incidence of breast cancer. Most cohort studies do not corroborate the association, but they have been criticized for involving small numbers of cases, homogenous fat intake, and measurements errors in estimate of fat intake.

Methods: We identified seven prospective studies in four countries that met specific criteria and analyzed the primary data in a standardized manner. Pooled estimates of the relation of fat intake to the risk of breast cancer were calculated, and data from study-specific validation studies were used to adjust the results for measurement error.

Results: Information about 4980 cases from studies including 337,819 women was available. When women in the highest quintile of energy-adjusted total fat intake were compared with women in the lowest quintile, the multivariate pooled relative risk of breast cancer was 1.05 (95 percent confidence interval, 0.94 to 1.16). Relative risks for saturated, monounsaturated, and polyunsaturated fat and for cholesterol, considered individually, were also close to unity. There was little overall association between the percentage of energy intake from fat and the risk of breast cancer, even among women whose energy intake from fat was less than 20 percent. Correcting for error in the measurement of nutrient intake did not materially alter these findings.

Conclusions: We found no evidence of a positive association between total dietary fat intake and the risk of breast cancer. There was no reduction in risk even among women energy intake from fat was less than 20 percent of total enery intake. In the context of the Western lifestyle, lowering the total intake of fat in the midlife is unlikely to reduce the risk of breast cancer substantially.

Time distribution of the recurrence risk for breast cancer patients undergoing mastectomy: further support about the concept of tumour dormancy
Romano Demichelli, Antonello Abbattista¹, Rosalba Miceli¹, Pinuccia Valagussa, Gianni Bonadonna
Division of Medical Oncology
¹ Division of Medical Statistics and Biometry, Istituto Nazionale Tumori, Milan, Italy

Keywords: breast cancer; tumor dormancy; recurrance risk; metastasis growth

Purpose: To gather information on metastatic growth from the time-distribution of the first treatment failure in breast cancer patients undergoing mastectomy alone

Methods: The risk of recurrence at a given time after surgery was studied utilizing the cause-specific hazard function. Recurrence was categorized as first treatment failure at any site, local-regional recurrence, distant metastases, and contralateral tumor. The risk distribution was assessed relative to tumor size, axillary lymph node involvement, and menopausal status.

Results: A total of 1173 patients treated between 1964 and 1980 with mastectomy alone and no adjuvant therapy were studeid. The hazard function for first failure presented an early peak at about 18 months after surgery, a second peak at about 60 months and then a tapered plateau-like tail extending up to 15 years. A similar risk pattern was detectable for both recurrence and distant metastases, while the curve of contralateral breast tumors showed a near flat plateau. The risk of early local-regional and distant recurrences was much lower for tumors less than 2 cm in diameter than for larger tumors; the risk of late recurrence was similar for small and large primaries. Node-positive patients showed peaks four to five times higher than node-negative patients. Subdividing node-positive patients into 1-3 and > 3 node-positive subsets did not substantially change the general picture of tumor recurrence. The hazard functions for premenopausal and postmenopausal patients were virtually superimposable.

Conclusions: The multipeak hazard curve suggests that the process resulting in overt clinical metastases may have discrete features. Primary tumor size could affect in different ways early and late metastases, while axillary node status should be related to the risk level, not to the risk pattern, and menopausal status does not seem significantly affect the hazard distribution. Moreover, contralateral breast tumors, occurring at constant risk throughout the time, should be considered as second primary cancers. These findings could be reasonably explained by a tumor dormancy hypothesis, which assumes that micrometastases may be in different biological steady states, most of which do not imply tumor growth. Tumor or microenvironment changes could induce metastatic growth after given mean transition times from surgery and originate a discrete pattern of the hazard function.

Adjuvant chemotherapy plus tamoxifen compared with tamoxifen alone for postmenopausal breast cancer: meta-analysis of quality-adjusted survival
Richard D. Gelber, Bernard F. Cole, Alan Goldhirsch, Carsten Rose, Bernard Fisher, C. Kent Osborne, Francesco Boccardo, Richard Gray, Nahida H. Gordon, Nils-Olof Bengtsson, Paul Sevelda

Background: Adjuvant tamoxifen for early breast cancer provides an improvement in relapse-free (RFS) and overall sirvival (OS), especially for older women. We carried out a meta-analysis to find out where the benefit of adding chemotherapy to tamoxifen outweights its costs in terms of toxic effects for postmenopausal patients.

Methods: The meta-analysis of quality-adjusted survival was based on data from 3920 patients aged 50 years or older with node-positive breast cancer randomly assigned in nine trials that compared combination chemotherapy plus tamoxifen with tamoxifen alone. The nine trials were included in the worldwide overview conducted the early breast cancers trailists' collaborative group (EBCTCG). Thje quality adjusted time without symptoms of toxicity (Q-TWIST) method was used to provide treatment comparisons incorporating differences in quality of life associated with subjective toxic effects of treatment and symptoms of disease relapse.

Findings: Within 7 years of follow-up the modest benefit of increased RFS and OS for patients who received chemotherapy just balanced the costs in terms of acute toxic side-effects. Chemotherapy-treated patients gained an average of 5.4 months of RFS and 2 months of OS (neither statiscally significant), but have to receive cytotoxic treatment for between 2 and 24 months to acheive these gains. No values of preference weights for time spent undergoing chemotherapy and time after relapse gave significantly more Q-TWIST with chemotherapy plus tamoxifen than with tamoxifen alone.

Interpretation: Within 7 years of follow-up, adjuvant chemoendocrine therapy did not provide more quality-adjusted survival time than tamoxifen alone for women aged 50 years or older with node-positive breast cancer. Better selection and administration of chemotherapy regimen, different scheduling of chemotherapy and tamoxifen, and appropriate use of patient and tumor characteristics may increase the therapeutic advantage of the combination.

Impact of adjuvant therapy on quality of life in women with node-positive operable breast cancer
Christoph H¨rny, J¨rg Bernhard, Alan S. Coates, Monica Castiglione-Gertsch, Harriet F. Peterson, Richard D. Gelber, John F. Forbes, Carl-Magnus Rudenstam, Edda Simoncini, Diana Crivellari, Aron Goldhirsch, Hans-J&oml;rg Senn, for the International Breast Cancer Study Group^*

Background: Adjuvant therapy for early breast cancer is effective but may be toxic. Our aim was to investigate the impact of the presence, timing, and duration of adjuvant chemotherapy on patients' perceptions of their quality of life (QL).

Methods: International Breast Cancer Study Group trial VI assessed adjuvant chemotherapy in 1475 premenopausal and perimenopausal patients, and trial VII assessed adjuvant tamoxifen of chemoendocrine therapy in 1212 postmenopausal patients with node-positive breast cancer. Patients were asked to complete a QL questionnaire - single item linear analogue self-assessment scales measured physical wellbeing, mood, appetite, and perceived adjustment/coping. QL was assessed in this way at the beginning of treatment, 2 months after the start of treatment, every 3 months, and at 1 and 6 months after recurrence.

Findings: Baseline QL scores decreased as the number of involved axillary nodes increased (for example, mean mood score: 66.1 for women with one positive node, 66.4 for two to four positive nodes, 61.3 for five to nine positive nodes, and 59.1 for ten or more positive nodes; p=0.008 for trends), and were lower in patients with oestrogen-receptor-negative than in patients with oestrogen-receptor-positive tumours (61.4 vs. 66.3, p=0.0009). All treatment groups showed substantial improvement in QL scores during adjuvant therapy. Patterns of QL scores reflected presence, duration, and timing of cytotoxic treatment. Longer initial cytotoxic therapy delayed improviment in QL scores. Later cytotoxic therapy had translent adverse effects. Anticipation of future therapy also affected QL scores.

Interpretation: Overall, chemotherapy had a measurable adverse effect on QL, but this effect was treatment and minor compared with patient's adaptation/coping after diagnosis and surgery. This finding should encourage patients and doctors to choose appropriate adjuvant therapy with less concern for initial toxicity.

Local control following breast-conserving surgery for invasive cancer: results of clinical trials
Monica Marrow, Jay R. Harris, Stuart J. Schnitt^*

Prospective, randomized clinical trials have demonstrated that the alternatives of mastectomy or conservative surgery plus radiation therapy provide equivalent survival for patients with invasive breast cancer. The identification of a subset of women who could undergo conservative surgery without radiotherapy would avoid the costs, inconvenience, and complications of radiotherapy and is an important research goal. Four randomized trial comparing conservative surgery alone with conservative surgery plus radiotherapy have demonstrated an average reduction in the risk of disease recurrence in the breast of 84% with the use of radiotherapy. No significant differences in survival have been observed, although the available studies lack sufficient numbers of patients to demonstrate a potential small, but clinically important, survival advantage for patients treated with radiotherapy. Subset analysis in the randomized trials and prospective studies of highly selected patients have failed to consistently identify a group of patients who do not benefit from radiation therapy. Any recurrence of breast cancer is psycologically devastating, and fewer than one half of the patients who have had disease recurrence after conservative surgery alone have undergone further breast-conserving treatment. At present, a group of patients who not require radiotherapy has not been reproducibly identified, and radiotherapy should remain a part of breast-conserving therapy for invasive carcinoma.

Neoadjuvant therapy in advanced ovarian cancer
A. Onnis, M. Marchetti, P. Padovan, L. Castellan
Gynaecologic Oncology Department, Institute of Obstetrics and Gynaecology, University of Padua (Italy)

Eighty-eight patients out of 396 were treated for advanced ovarian cancer first by some cycles of chemotherapy - neoadjuvant chemotherapy - and after by surgery.

An improvement in the quality of surgery and disease-free period was observed while survival rate did not improve, compared with the patients treated by surgery before chemotherapy.

It should be stressed that neoadjuvant chemotherapy was applied only in very advanced PS Figo stages.

The results are the same in the three studied decades: even in the last one, when cases were selected following new protocols. In our case series all patients after chemotherapy underwent surgery and not only those with partial or complete response to chemotherapy.

Preoperative value of CA 125 as a reflection of tumor grade in epithelial ovarian cancer
Igor But, M.D. Sc.¹, Borut Gorisek, M.D., Ph.D.^2
1Division of Gynaecologic Oncology and
²Department of Gynecologic and Obstetrics, Maribor Teaching Hospital, Ljubljanska 5, 2000 Maribor, Slovenia

A retrospective study of 60 patients with invasive epithelial ovarian cancer was conducted. The significance of preoperative serum CA 125 level with respect to tumor grade and tumor stage was determined. Tumor grade bears a strong influence on the preoperative CA 125 level; the correlation is high and statistically significant (r=0.74, P<0.01). The influence of FIGO stage on preoperative CA 125 level is also significant (r=0.51, P<0.01), but the results of the multivariate analysis show that the influence of tumor grade on preoparative CA 125 level is stronger (P<0.01). It is believed that tumor grade is the decisive factor dictating the level of CA 125 in a certain stage of the disease and so influences the preoperative CA 125 level. It is also believed that low preoperative antigen levels of well-differentiated ovarian carcinomas in FIGO stage I are the cause of poor sensitivity of the CA 125 test, thus limiting its applicability for screening purposes.

High frequency of BRCA1 185delAG mutation in ovarian cancer in Israel
Baruch Modan, M.D., Eva Gak, Ph.D., Revital Bar Sade-Bruchim, MSc, Galit Hirsh-Yechezkel, MSc; Livia Theodor, Ph.D., Flora Lubin, MSc, Gilad Ben-Baruch, M.D., Uzi Beller, M.D., Amiram Fishman, M.D., Ram Dgani, M.D., Joseph Menczer, M.D., Moshe Papa, M.D., Eitan Friedman, M.D., Ph.D. for the National Israel Study of Ovarian Center

Objective: To determine the role of BRCA1 185delAG mutation in ovarian carcinogenesis.

Design: Genetic testing of a subset of cases from an ongoing study of ovarian cancer and of controls.

Setting: A community-based case-control incidence study.

Subjects: Seventy-nine patients with ovarian cancer, 62 hospitalized women without cancer (controls), and 120 healthy women participating in a fragile X screening program (also controls), examined for the presence of germline BRCA1 185delAG mutation.

Main Outcome Measures: Polymerase chain reaction-amplified BRCA1 exon 2 fragments generated from patients 'and controls' blood samples, analyzed by heteroduplex gel shift assay and direct sequence analyses.

Results: The 185delAG mutation was detected in 38.9% (7/18) of ovarian cancer patients with familial history, and 13.1% (8/61) of family history-negative ovarian cancer cases. Only 1 carrier was detected among the 120 healthy controls, and none in the hospital controls. A significant difference in mutation carrier rates between family history - negative cases and control groups of 120 and 62 subjects was identified (Fisher exact test, P=.001 and P=.003, respectivelly). The median age (± SE) at disease diagnosis was lower among both familial and family history-negative mutation carriers, as compared with mutation-negative, family history-negative cases -50 (± 1.4) vs 60.5 (± 3.5) years old, respectivelly (hazard ratio, 1.68; 95% confidence interval, 0.94 - 3.01).

Conclusions: Our data are preliminary but suggest that BRCA1 185delAG germline mutation is frequent in Israeli ovarian cancer patients, irrespective of family history, and may confer an early-onset phenotype of ovarian cancer.

Intermediate-risk endometrial cancer: A management approach
Benjamin W. Corn, M.D.

In the United States, endometrial cancer remains the mos frequently diagnosed tumor of the female genital tract. The Gynecologic Oncology Group (GOC) has previously included patients disease confined to the uterus and moderately or poorly differentiated tumors that invade at least half the myometrium in protocols designed for "intermediate level of risk". Although such patients are ideally staged surgically, the role of adjuvant therapies such as postoperative pelvic irradiation remains unclear. This report offers a management approach for these women based on opportunities for enhanced local control with an acceptable level for morbidity according to suportive data from the available literature.

Hepatomegaly in neuroblastoma stage 4s: Criteria for treatment of the vulnerable neonate
Lewis L. Hsu, M.D., Audrey E. Evans, M.D., Giulio J. D'Angio, M.D.

Infants with neuroblastoma (NBL) frequently present as stage 4s overall, such patients have a good prognosis. However not all survive,and neonates with hepatomegaly are particularly at risk. We therefore reviewd our 4s experience, the objective being to identify lethal patterns of disease progression.

The specific aims of this work were (1) to develop a semiquantitative scoring system based on the severity of signs and symptoms that alone or in combination presaged a fatal outcome, and (2) to determine if early intervention could reverse life-threatening disease.

Thirty-five patients were seen over a period of 50 years. The signs and symptoms of organ distress caused by hepatomegaly occurred in the lungs, kidneys, gastrointestinal tract (GI), the inferior vena cava (IVC), and the liver. A scoring scale reflecting organ compromise was developed, the scores ranging from 0 (0 compromise) to 10 (all 5 systems showing evidence of impairment). Scores were derived for 32 of 35 patients; 13 were 4 weeks old or under (neonates) when first seen, and 19 were aged 1-12 months (infants). Neonates were more likely than infants to develop increasing symptomatology (50% versus 25%) and were more likely to die when a score of 2 or more developed. None of the 6 neonates who did so survived despite treatment, compared with three of four infants.

Early intervention is recommended: (1) for 4s neonates who develop a score of 1 and (2) for older infants with a score > 2.

Etoposide for the treatment of paediatric tumours: what is the best way to give it?
S.P. Lowis¹, D.R. Newell^2
1Bristol Royal Hospital for Sick Children, St Michael' Hill, Bristol BS2 8BJ;
²Cancer Research Unit, University of Newcastle upon Tyne, Newcastle NE2 4HH, U.K.

Etoposide is one of the most important drugs available for the treatment of paediatric malignancies. Although there is evidence of schedule dependency for etoposide therapy in adults with small-cell lung cancer, the relevance of this observation to childhood cancers is uncertains. Prolonged parenteral or oral etoposide therapy has not yet shown a clear-cut advantage over intermittent treatment, and there are still no data to show that the administration of etoposide as a short intravenous (i.v.) daily infusion for 5 days does not represent acceptable therapy for primary disease. The pharmacokinetic variability seen with etoposide argues strongly for the use of pharmacologically guided dosing, and the introduction of etoposide phosphate will simplify both parenteral etoposide administration and the future evaluation of alternative etoposide schedules. Although impact of molecular and celullar pharmacological investigations on the clinical use of etoposide has yet to be felt, the tools to perform these studies are now available and propsective trials can be designed. Such studies, performed in the setting of a pharmacologically guided trial to ensure contro over pharmacokinetic variability, should identify the best way of treating children etoposide.

Phase I trial and pharmacokinetic (PK) and pharmacodynamics (PD) study of topotecan using a five-day course in children with refractory solid tumors: A Pediatric Oncology Group Study
Davi G. Tubergen, M.D., Clinton F. Stewart, Pharm. D., Charles B. Pratt, M.D., William C. Zamboni, Pharm D., Naomi Winick, M.D., Victor M. Santana, M.D., Zo Anne Dryer, M.D., Joanne Kurtzberg, M.D., Beverly Bell, M.D., Holcombe Grier, M.D., Teresa J. Vietti, M.D.

Purpose: A phase I was conducted in chindren with refractory solid tumors to determine the maximum tolerated dose (MTD), dose-limitting toxicity (DLT), pharmacokinetics, and pharmacodynamics for topotecan administered by a 30-min infusion for 5 consecutive days.

Patients and Methods: Forty children with a variety of recurrent solid tumors, including nine patients with neuroblastoma and 10 with brain tumors, were given topotecan as a 30-min infusion for 5 consecutive days, beginning with a dose of 1.4 mg/m²/day. The dose was escalated in 20% increments after establishing that DLT was not present at the prior dose. Drug toxicity was graded using standard criteria. Dose-limiting toxicity was defined as grade 3 or 4 nonhematopoietic toxicity or grade 4 hematopoietic toxicity lasting > 7 days. Pharmacokinetic studies were performed during the first infusion course.

Results: The DLT was hematopoietic and involved both platelets and neutrophils. Grade 4 hematopoietic toxicity of brief duration was seen at all levels. Over half of the patients received red blood cell transfusion support, and 19/40 received platelet transfusions. Hospital admissions for fever and neutropenia or for documented infections occurred in 32 of 169 courses of therapy. Gastrointestinal symptoms with nausea and vomiting or diarrhea were mild to moderate in 12 of the 40 patients. Antitumor responses were seen in three patients with neuroblastoma. An additional four patients (one with neuroblastoma, two with anaplastic astrocytomas, one with Ewing) had stable disease with continued therapy for > 6 months. Using a limited sampling model, pharmacokinetics studies were performed in 36 of the 40 patients. Topotecan lactone and total clearance were similar to those reported in other pediatric populations receiving topotecan by continuous infusion. A pharmacodynamic relation between systemic exposure to topotecan lactone and myelosuppression was observed.

Conclusions: In heavitly pretreated children, the MTD for topotecan given by intermittent 30 min-infusion for 5 days is 1.4 mg/m² without GCSF and 2.0 mg//m²/day with GCSF. The dose-limiting toxicity is hematopoietic. Data from this study provide the basis for further studies of topotecan in children with cancer.

Keywords: phase I; topotecan; children; solid tumors; pharmacokinetics; pharmacodynamics 14/

Birth characteristics and risk of Wilms'tumour: a nationwide prospective study in Norway
J. M. Heuch¹, I. Heuch², G. Kvåle^3
1Section for Medical Informatics and Statistics, University of Bergen, Armauer Hansen's Building , N-5021 Bergen, Norway;
²Department of Mathematics, University of Bergen, N-5007 Bergen, Norway;
³Centre for International Health, University of Bergen, Armauer Hansen's Building, N-5021 Bergen, Norway.

Relationship between incidence of Wilms'tumour and information recorded at birth were investigated in a prospective study of the 1 489 297 children born in Norway between 1967 and 1992. A total of 119 individuals were diagnosed with Wilms'tumour in the age interval 0-14 years. A high length at birth was significantly associated with a high risk (incidence rate ratio 1.8 for length > 53 cm vs < 49 cm, 95% CI 1.0-3.2). A low Apgar score at 1 min was also associated with an increased risk (incidence rate ratio 2.2 for Apgar score < 8 vs a score > 9.95% CI 1.2-3.9). For all variables for which an association was indicated, the association seemed to be restricted mainly to children ages less than 2 years. This suggests that Wilms'tumour diagnosed early in life may differ aetiologically from that of cases diagnosed later.

Intensive chemotherapy for poor prognosis myelodysplasia (MDS) and secondary acute myeloid leukemia (sAML) following MDS of more than 6 months duration. A pilot study by the Leukemia Cooperative Group of the European Organization for Resaerch and Treatment in Cancer (EORTC-LCG)
T. de Witte¹, S. Suciu², M. Peetermans³, FP. Fenaux⁴, P. Strijckmans⁵, M. Hayat⁶, B. Jaksic⁷, D. Selleslag⁸, R. Zittoun⁹, M. Dardenne², G. Soulbu², H. Zwierzina¹⁰, P. Muus^1
1Division of Hematology, University Hospital, St. Radboud, Nijmegen, The Netherlands;
²EORTC Data Center, Brussels, Belgium;
³UniversitiesZiekenhuis Antwerpen, Edegem, Belgium
⁴Centre Hospitalier et Universitaire de Lille, Lille, France;
⁵Institut Jules Bordet, Brussels, Belgium;
⁶Institut Gustave Roussi, Villejuif, France;
⁷University Hospital Merkur, Zagreb, Croatia;
⁸St. Jan's Hospital, Brugge, Belgium;
⁹Hôpital Dieu, Paris, France;
¹⁰Medische Klinik Innsbruck, Innsbruck, Austria

We conducted a prospective, multicenter pilot study of remission induction therapy in patients with poor prognosis MDS and AML evolving from a preceding phase of MDS. Fifty evaluable patients from 15 institutions were treated with one or two remission-induction courses consisting of i.v. idarubicin 12 mg/m²/day on days 1, 2 and 3 combined with a continuous i.v. infusion of cytarabine of 200 mg/m²/day on days 1 to 7. Of the 27 complete remitters (54%), 23 received a consolidation course which was identical to the remission-induction course except for the idarubicin 12 mg/m² which was given on day 1 only. Fifteen patients received maintenance therapy consisting of six courses of cytarabine 10 mg/m², s.c. twice daily, for 14 days. Two complete remitters were allograted and five patients received an ABMT. The median survival of all 50 treated patients was 14 months. The median duration of disease-free survival was 11 months with two patients in CR more than 2 years after entering CR. Twenty-four of the27 remitters have relapsed. Four patients died during remission-induction therapy, but no patient died as a result of persisting hypoplasia. No fatal complications occurred during the consolidation and maintenance courses. Age and stage of the disease had no significant impact on CR rate nor on remission duration. The CR rate was significantly (P=0.03) higher in patients with only normal metaphases compared to patients with cytogenetic abnormalities. The DFS at 2 years was 33 vs 8%, respectively, for patients without or with cytogenetic adnormalities ((P=0.02). This study shows that patients bellow the age of 60 years with poor risk features are candidates for treatment with combination chemotherapy. A complete remission rate of more than 50% may be expected. Maintaining remission after remission-induction chemotherapy is a difficult issue. Patients not eligible for allogenic BMT may be treated with intensive post-remission chemotherapy or autologous BMT.

Keywords: myelodysplatic syndrome; secondary acute myeloid leukemia; cytogenetics; chemotherapy

A prognostic index for multiple myeloma
G. Grignani, P. G. Gobbi, R. Formisano, C. Pieresca, G. Ucci, S. Brugnatelli, A. Riccardi, E. Ascari
Medicina Interna e Oncologia Médica, Università di Pavia, IRCCS Policlinico S. Matteo, Pavia, Italy

The current prognostic systems have failed to identify multiple myeloma (MM) patients who require aggressive therapy. These stanging systems do not reliably ditinguish patients with different prognoses. These paper explores the possibility of improving the prognostic forecast in MM by considering some clinical characteristics at diagnosis together with response to first-line chemotherapy. A total of 231 patients were prospectively randomised in a multicentre trial to no therapy vs. malphalan + prednisone (MP) for stage I. MP in stage II, and MP vs. peptichemio, vincristine and prednisone for stage III. The clinical features of these groups were evaluated for prognostic variables predictive of overall survival by means of univariate and multivariate analysis. The independently significant variables were incorporated into a model that identified three groups of patients with different risks of death and different overall survival. Three variables retained statistical significance: the staging system proposed by the British Medical Research Council, a composite parameter integrating the percentage of bone marrow plasma cells with cytological features of the infiltrating elements (plasma cell vs plasmablast), and response to 6 months of first-line chemotherapy. These three variables led to proposal of a scoring system able to identify three different risk classes (with median overall survival of 52,28 and 13 months respectively) and to estimate individual patient prognosis more flexibly. The proposed risk classes, drawn from both diagnostic and therapeutic parameters, are thought to be a clinical and investigational instrument for separating MM patients into comparable groups, for selecting the best available therapy and for evaluating response with respect to the disease of each new patient.

Celullar and molecular mechanisms in chronic myeloid leukaemia: biology and treatment
M. Y. Gordon, J. M. Goldman

Chronic myeloid leukaemia (CML) is a haemopoietic stem cell disorder progresses, sooner or later, from a relatively benign chronic phase to an agressive and terminal acute phase. It is associated with the Philadelphia (Ph) chromossomal t(9:22) translocation (Nowell & Hungerford, 1960: Rowley, 1973) which results in the juxtaposition of parts of BCR and ABL genes to form a BCR-ABI, chimaeric gene. This fuston gene expresses an 8.5 kb mRNA transcript and the corresponding p210 protein with tyrosine kinease activity (Groften et al. 1984: Ben-Neriah et al. 1986). Expression of p210 is presumed to be causal in CML, but its critical function has not yet been defined.

Recent efforts in molecular biology have been directed towards understanding the complex intracellular reactions whereby BCR-ABL, might transform stem cells whilst cell biology studies have attempted to deline the major functional abnormalities that could be a consequence of BCR-ABL, gene expression. However, many questions remain to be answered before an internally consistent model for the cellular and molecular pathogenesis of CML can be constructed and new strategies for therapy can be designed. The purpose of this review is to identify important questions and to offer at least partial answers to some of them.